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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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LASMIDITAN


Lasmiditan skeletal.svg

LASMIDITAN, COL-144 , LY-573144

613677-28-4 HYDROCHLORIDE
439239-90-4 (free base)

2,4,6-Trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide

2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide

CoLucid Pharmaceuticals, PHASE 3, MIGRAINE

UNII:760I9WM792

Lasmiditan succinate; UNII-W64YBJ346B; Lasmiditan succinate [USAN]; W64YBJ346B; 439239-92-6; Lasmiditan succinate (USAN)

Lasmiditan succinate.png

Molecular Formula: C42H42F6N6O8
Molecular Weight: 872.822 g/mol

Lasmiditan (COL-144) is an investigational drug for the treatment of acute migraine. It is being developed by Eli Lilly and is in phase III clinical trials. It is a first-in-class “neurally acting anti-migraine agent” ditan.

WO-2018010345,  from Solipharma and the inventor on this API. Eli Lilly , following its acquisition of CoLucid Pharmaceuticals , is developing lasmiditan, a 5-HT 1f agonist, for treating acute migraine.

WATCH THIS SPACE, SYNTHESIS COMING………..

noname01

 

SYN 2

noname01

Mechanism of action

Lasmiditan is a serotonin receptor agonist that, like the unsuccessful LY-334,370, selectively binds to the 5-HT1F receptor subtype. A number of triptans have been shown to act on this subtype as well, but only after their affinity for 5-HT1B and 5-HT1D has been made responsible for their anti-migraine activity. The lack of affinity for these receptors might result in fewer side effects related to vasoconstriction compared to triptans in susceptible patients, such as those with ischemic heart diseaseRaynaud’s phenomenon or after a myocardial infarction,[1] although a 1998 review has found such side-effects to rarely occur in patients taking triptans.[2][3]

Discovery and development

Lasmiditan was discovered by Eli Lilly and Company and was out-licensed to CoLucid Pharmaceuticals in 2006, until CoLucid was bought by Eli Lilly in 2017 to reacquire the drug.[4] The drug is protected by patents until 2031.[5]

Phase II clinical trials for dose finding purposes were completed in 2007 for an intravenous form[6] and in early 2010 for an oral form.[7]Two separate Phase III clinical trials for the oral version are currently ongoing under special protocol agreements with the US Food and Drug Administration (FDA). Eli Lilly has stated that they intend to submit a new drug application to the FDA in early 2018.[5]

As of 2017, three phase III clinical trials have been completed or are in progress. The SPARTAN trial compares placebo with 50, 100, and 200 mg of lasmiditan.[8] SAMURAI compared placebo with 100 and 200 mg doses of lasmidatin. In 2016, CoLucid announced that the trial had met its primary and secondary endpoints of patients being pain-free two hours after dosing.[5] GLADIATOR is an open-labelstudy comparing 100 and 200 mg doses of lasmidatin in patients that received the drug as part of a prior trial.[9] In August 2017 topline results from the SPARTAN trial showed that the drug induced met its primary and secondary endpoints in the trial. The primary result showed a statistically significant improvement in pain relief relative to placebo 2 hours after the first dose. The secondary result showed a statistically significantly greater percentage of patients were free of their most bothersome symptom (MBS) compared with placebo at two hours following the first dose. [10]

Novel crystalline forms of a 5-HT1F receptor agonist, particularly lasmiditan – designated as Forms 1-3 and A-D – processes for their preparation and compositions comprising them are claimed. Also claim is their use for treating anxiety, fatigue, depression, premenstrual syndrome, trauma syndrome, memory loss, dementia (including Alzheimer’s), autism, schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, epilepsy, anorexia nervosa, alcoholism, tobacco abuse, mutism and trichotillomania.

Biological Activity

Lasmiditan (also known as COL-144 and LY573144) is a high-affinity, highly selective serotonin (5-HT) 5-HT(1F) receptor agonist.

In vitro binding studies show a K(i) value of 2.21 nM at the 5-HT(1F) receptor, compared with K(i) values of 1043 nM and 1357 nM at the 5-HT(1B) and 5-HT(1D) receptors, respectively, a selectivity ratio greater than 470-fold. Lasmiditan showed higher selectivity for the 5-HT(1F) receptor relative to other 5-HT(1) receptor subtypes than the first generation 5-HT(1F) receptor agonist LY334370.

In two rodent models of migraine, oral administration of lasmiditan potently inhibited markers associated with electrical stimulation of the trigeminal ganglion (dural plasma protein extravasation, and induction of the immediate early gene c-Fos in the trigeminal nucleus caudalis).

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Image result for LASMIDITAN

Image result for LASMIDITAN

PATENT

WO 03084949

https://www.google.co.in/patents/WO2003084949A1?cl=en

8. 2,4,6-Trifluoro-N-[6-(l -methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide mono-hydrochloride salt

Figure imgf000035_0001

Combine 2-amino-6-(l-methylpiperidin-4-ylcarbonyl)pyridine (0.20 g, 0.92 mmol), 2,4,6-Trifluorobenzoyl chloride (0.357 g, 1.84 mmol), and 1 ,4-Dioxane (10 mL), and stir while heating at reflux. After 3 hr., cool the reaction mixture to ambient temperature and concentrate. Load the concentrated mixture onto an SCX column (lOg), wash with methanol, and elute with 2M ammonia in methanol. Concentrate the eluent to obtain the free base of the title compound as an oil (0.365 g (>100%)). Dissolve the oil in methanol (5 mL) and treat with ammonium chloride (0.05 g, 0.92 mmol). Concentrate the mixture and dry under vacuum to obtain the title compound. HRMS Obs. m/z 378.1435, Calc. m/z 378.1429; m.p. 255°C (dec).

Examples

21. 2,4,6-Trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide

Figure imgf000049_0001

Add triethylamine (10.67 mL, 76.70 mmol, 2.4 eq) to a solution of 2-amino-(6-(l- methylpiperidin-4-ylcarbonyl)-pyridine (7g, 31.96 mmol, 1 eq) in anhydrous THF (100 mL) under a nitrogen atmosphere. Add 2,4,6-triflubenzoylchloride (7.46g, 5 mL, 38.35 mmol, 1.20 eq) dropwise at room temperature. After 2 hrs., add additional 2,4,6- triflubenzoylchloride (0.75 mL, 0.15 eq) and triethylamine (1.32 mL, 0.3 eq) to the reaction mixture and agitate the mixture for an additional 3 hrs. Quench the reaction with distilled water (10 mL) and 30%o NaOH (15 mL). Stir the resulting biphasic system for 1 hour and then separate the phases. Extract the organic fraction by adding H2O (75 mL) and acetic acid (12 mL), followed by cyclohexane (70 mL). Wash the organic fraction with H2O (50 mL) containing acetic acid (1 mL). Combine all the aqueous fractions and washes and neutralize the mixture with 30% NaOH (15 mL). Extract with methyl-tert- butyl ether (MTBE) (3×50 mL). Combine the organic fractions and dry with MgSO4, filter, concentrate under reduce pressure, and vacuum dry at room temperature, to obtain the title compound as a light-brown solid (11.031 g, 91 % yield).

Mass spectrum, (Electrospray) m/z = 378 (M+l); Η NMR (250 MHz, Chloroform-D) ppm 1.54 (m, 2 H) 2.02 (m, 2 H) 2.13 (t, J=l 1.48 Hz, 2 H) 2.29 (s, 3 H) 2.80 (m, J=l 1.96 Hz, 1 H) 3.56 (m, 1 H) 4.26 (d, J=7.87 Hz, 1 H) 6.17 (d, J=8.50 Hz, 1 H) 6.75 (m, 2 H) 7.45 (t, J=7.87 Hz, 1 H) 7.53 (m, 1 H) 7.95 (s, 1 H); 13C-NMR: (62.90 MHz, Chloroform-D) ppm 202.78; 162.6 (dm C-F-couplings); 162.0 (m C-F-couplings); 160.1 (m C-F-couplings); 158.1 ; 150.0; 139.7; 1 19.3; 1 17.9; 1 10.2 (m C-F-couplings); 100.9 (m C-F-couplings); 55.2; 46.5; 41.9; 28.1

22. 2,4,6-Trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide mono-hydrochloride salt

Figure imgf000049_0002

Dissolve 2,4,6-trifluoro-N-[6-(l-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide – free base (5g, 23.26mmol) in isopropanol (50 mL) at room temperature and add a solution of 3.3 M diethylether/HCl (8 mL). Heat the reaction mixture under reflux for 30 minutes. Cool the reaction mixture to room temperature and agitate for 2 hrs. Filter the resulting white precipitate and rinse with isopropanol (5 mL). Dry the residual solid under reduce pressure at 40°C overnight to obtain the title compound (5.12 g, 93% yield). M.p. 223-224°C (sublimation); Η NMR (400 MHz, d6-DMSO) d ppm 1.94 (m, 2 H) 2.14 (m, J=11.15 Hz, 2 H) 2.74 (s, 3 H) 2.99 (m, J=9.19 Hz, 2 H) 3.49 (m, J=1 1.15 Hz, 2 H) 3.77 (m, 1 H) 7.41 (t, J=8.71 Hz, 2 H) 7.78 (d, J=7.43 Hz, 1 H) 8.10 (t, J=7.92 Hz, 1 H) 8.37 (d, J=6.85 Hz, 1 H) 10.50 (s, 1 H) 1 1.51 (s, 1 H); 13C-NMR: (100.61 MHz, Chloroform-D) ppm 200.7; 130.6-158.0 (m, C-F-couplings); 150.4; 150.1; 140.2; 118.5; 1 18.2; 11 1.9; 101.3 (t, C-F couplings); 52.8; 42.6; 25.2

23. 2,4,6-Trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]- benzamide hemi-succinate salt

Figure imgf000050_0001

Add succinic acid (0.25g, 2.148 mmol, 0.5eq) to a solution of 2,4,6-trifluoro-N-[6-

(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide – free base (1.62g, 4.297 mmol, leq) in acetone (16.2 mL), at room temperature. Warm the solution under reflux for 30 minutes. Cool the solution to room temperature and filter off the resulting white precipitate. Rinse the precipitate with acetone (0.2 mL) and dry under vacuum at 50°C for 16 hours to provide the title compound (1.5g, 80% yield). M.p. 198.5°C; mass spectrum (Electrospray) m/z = 495.45

The following examples are prepared by combinatorial chemistry techniques as follows:

Examples 24-54

Figure imgf000050_0002

Combine R-acid (300 μL of 0.5M solution in dimethylformamide (DMF)), HATU (57 mg, 0.15 mmol), collidine (19 μL, 0.15 mmol), 2-amino-(6-(l-methylpiperidin-4- ylcarbonyl)-pyridine and DMF (1.5 mL), and agitate for 48 hr. Dilute the reaction mixture with 10% acetic acid in methanol (0.5 L). Load the resulting reaction mixture onto a 2 g SCX column. Wash the column thoroughly with methanol and then elute with 1 M ammonia in methanol. Concentrate the eluent and further purify the product by high- throughput mass guided chromatography. This procedure is repeated in parallel for examples 24-54.

Examples 55-58

Figure imgf000051_0001

Heat R-acid chloride (300 μL of 0.5M solution in pyridine) to 55°C, add 2-amino- (6-(l-methylpiperidin-4-ylcarbonyl)-pyridine (200 μL of 0.5M solution in pyridine), and continue heating the reaction mixture for 24 hr. Concentrate the reaction mixture and then dilute with 10% Acetic acid in methanol (0.5 mL) and methanol (0.5 mL). Load the resulting reaction mixture directly onto a 2 g SCX column. Thoroughly wash the column with methanol and then elute the column with 1 M ammonia in methanol. Concentrate the eluent and then further purify the product by high- throughput mass guided chromatography. This procedure is repeated in parallel for examples 55-58.

Examples 59-71

Figure imgf000051_0002

Heat 2-amino-(6-(l-methylpiperidin-4-ylcarbonyl)-pyridine (200 μL of 0.5M solution in pyridine) to 55°C then add R-acid chloride (0.10 mmol), heat for 2 hr. Concentrate the reaction mixture and then dilute with 10% Acetic acid in methanol (0.5 mL) and methanol (0.5 mL). Load the resulting reaction mixture directly onto a 2 g SCX column. Thoroughly wash the column with methanol and then elute the column with 1 M ammonia in methanol. Concentrate the eluent and then further purify the product by high-throughput mass guided chromatography. This procedure is repeated in parallel for examples 59-71.

PATENT

WO 2018010345

Lasmiditan, also known as COL-144, LY573144, is a 5-HT 1F receptor agonist. Can be used to inhibit neuronal protein extravasation, to treat or prevent migraine in patients with diseases or conditions associated with other 5-HT 1F receptor dysfunction. The chemical name is 2,4,6-trifluoro-N- [6 – [(1 -methylpiperidin-4-yl) carbonyl] -pyridin- 2-yl] -benzamide, which has the chemical structure shown below I) shows:
Lasmiditan is a new and selective 5-HT 1F receptor agonist. It acts against migraine and other 5-HT 1F receptor related diseases by enhancing 5-HT 1F receptor activation while avoiding vasoconstrictive activity and inhibiting neuronal protein extravasation such as Migraine (including migraine, migraine headache, neurovascular headache), general pain, trigeminal neuralgia, anxiety, panic disorder, depression, post traumatic syndrome, dementia and the like.
Patent document CN100352817C reports on Lasmiditan, Lasmiditan hemisuccinate and Lasmiditan hydrochloride and the synthetic preparation thereof, and discloses the mass spectra of Lasmiditan, Lasmiditan hemisuccinate and Lasmiditan hydrochloride, 1 H-NMR, 13 C -NMR detection data and the melting points of Lasmiditan hemisuccinate and Lasmiditan hydrochloride. The inventor of the present invention has found that Lasmiditan, which is obtained according to the preparation method of Example 17 and Example 21 in CN100352817C, is a light brown oily amorphous substance, which has the defects of instability, moisture absorption and poor morphology.
Example 8 of patent document CN100352817C reports the preparation of Lasmiditan hydrochloride, which mentions Lasmiditan free base as an oily substance. The Lasmiditan hydrochloride obtained according to the preparation method of Example 8 in CN100352817 is a white amorphous substance which also has the disadvantages of unstable crystalline form, high hygroscopicity and poor topography.
The synthesis of Lasmiditan hemisuccinate intermediate, including Lasmiditan and Lasmiditan hydrochloride, is reported in Example 2 of U.S. Patent No. 8,697,876 B2. The inventor’s study found that Lasmiditan prepared according to US8697876B2 is also a pale brown oily amorphous substance and Lasmiditan hydrochloride is also a white amorphous substance.
In view of the deficiencies in the prior art, there is still a need in the art for the development of crystalline polymorphic Lasmiditan solid forms with more improved properties to meet the rigorous requirements of pharmaceutical formulations for physico-chemical properties such as morphology, stability and the like of active materials.
Preparation 1 Preparation of Lasmiditan (Prior Art)
Lasmiditan was prepared as described in Example 21 of CN100352817C by the following procedure: Triethylamine (10.67 mL, 76.70 mmol, 2.4 equiv) was added to a solution of 2-amino- (6- (1-methylpiperidine -4-yl) -carbonyl) -pyridine (7 g, 31.96 mmol, 1 eq) in dry THF (100 mL). 2,4,6-Trifluorobenzoyl chloride (7.46 g, 5 mL, 38.35 mmol, 1.20 equiv.) Was added dropwise at room temperature. After 2 hours, an additional 2,4,6-trifluorobenzoyl chloride (0.75 mL, 0.15 eq) and triethylamine (1.32 mL, 0.3 eq) were added to the reaction mixture and the mixture was stirred for a further 3 h. The reaction was quenched with distilled water (10 mL) and 30% NaOH (15 mL). The resulting two-phase system was stirred for 1 hour, then the two phases were separated. By addition of H 2 to extract the organic portion O (75mL) and acetic acid (12mL), followed by addition of cyclohexane (70mL). The organic portion was washed with water (50 mL) containing acetic acid (1 mL). All aqueous phases were combined, washed and neutralized with 30% NaOH (15 mL). Extract with methyl tert-butyl ether (MTBE) (3 x 50 mL). The organic phases were combined, dried MgS04 . 4 dried, filtered, and concentrated under reduced pressure and dried in vacuo at room temperature to give the title compound as a pale brown solid (11.031g, 91% yield).
The 1 H-NMR (CDCl 3 ) data of the product are as follows:
1 H NMR (400 MHz, CHLOROFORM-D) ppm 1.54 (m, 2H) 2.02 (m, 2H) 2.13 (t, J = 18.37 Hz, 2H) 2.29 (s, 3.56 (d, J = 12.59 Hz, 1H) 6.17 (d, J = 13.6 Hz, 1H) 6.75 (m, 2H) 7.45 (t, J = 12.59 Hz, 1H) 7.53 (m, 1H ) 7.95 (s, 1H).
The isothermal adsorption curve shown in Figure 5, in the 0% to 80% relative humidity range of 9.5% weight change.
The above characterization results show that Lasmiditan obtained by the preparation method of Example 21 according to CN100352817C is amorphous.
Preparation 2 Preparation of Lasmiditan hydrochloride (Prior Art)
The Lasmiditan hydrochloride was prepared as described in Example 8 of CN100352817C by the following procedure: A mixture of 2-amino-6- (1-methylpiperidin-4-yloxy) pyridine Trifluorobenzoyl chloride (3.57 g, 18.4 mmol) and 1,4-dioxane (100 mL) were combined and heated to reflux with heating. After 3 hours, cool the reaction mixture to room temperature, reduce pressure and concentrate. The concentrated mixture was loaded onto a SCX column (10 g), washed with methanol and eluted with 2M ammonia in methanol. The eluate was concentrated to give the title compound as an oily free base (3.65 g (> 100%)). The oil was dissolved in methanol (50 mL) and treated with ammonium chloride (0.5 g, 9.2 mmol). The mixture was concentrated and dried in vacuo to give a white amorphous.
IC characterization showed that Lasmiditan hydrochloride salt formed by Lasmiditan and hydrochloric acid in a molar ratio of 1: 1.
The XRPD pattern shown in Figure 19, no diffraction peaks, no amorphous.
The PLM pattern is shown in Figure 20 as an irregular, unpolarized solid.
The isotherm adsorption curve is shown in FIG. 21, with a weight change of 8.1% in a relative humidity range of 0% to 80%.
The above characterization results show that: Lasmiditan hydrochloride obtained by the preparation method of Example 8 with reference to CN100352817C is amorphous.
Example 1
Take 500mg of Lasmiditan of Preparation 1, add 1mL methanol solution containing 5% water to clarify, evaporate the crystals at room temperature and evaporate dry after 1 day to obtain 487mg Lasmiditan Form 1 in 95% yield.

References

  1.  “Molecule of the Month July 2010: Lasmiditan hydrochloride”Prous Science. Retrieved 2011-08-03.
  2.  Dahlöf, CG; Mathew, N (1998). “Cardiovascular safety of 5HT1B/1D agonists–is there a cause for concern?”. Cephalalgia : an international journal of headache18 (8): 539–45. doi:10.1046/j.1468-2982.1998.1808539.xPMID 9827245.
  3.  Mutschler, Ernst; Geisslinger, Gerd; Kroemer, Heyo K.; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8th ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 265. ISBN 978-3-8047-1763-3OCLC 47700647.
  4.  http://www.fiercebiotech.com/biotech/lilly-buys-migraine-biotech-colucid-for-960m-and-drug-it-out-licensed
  5.  http://adisinsight.springer.com/drugs/800028519
  6.  Clinical trial number NCT00384774 for “A Placebo-Controlled Adaptive Treatment Assignment Study of Intravenous COL-144 in the Acute Treatment of Migraine” at ClinicalTrials.gov
  7.  Clinical trial number NCT00883051 for “Dose-ranging Study of Oral COL-144 in Acute Migraine Treatment” at ClinicalTrials.gov
  8. Clinical trial number NCT02605174 for “Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the Acute Treatment of Migraine (SPARTAN)” at ClinicalTrials.gov
  9.  Clinical trial number NCT02565186 for “An Open-label, Long-term, Safety Study of Lasmiditan for the Acute Treatment of Migraine (GLADIATOR)” at ClinicalTrials.gov
  10.  https://investor.lilly.com/releasedetail.cfm?ReleaseID=1036101
Lasmiditan
Lasmiditan skeletal.svg
Clinical data
Routes of
administration
By mouthintravenous
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C19H18F3N3O2
Molar mass 377.36 g/mol
3D model (JSmol)

/////////////LASMIDITAN, phase III, LILY, COL-144 , LY-573144, CoLucid Pharmaceuticals, PHASE 3, MIGRAINE

CN1CCC(CC1)C(=O)C2=NC(=CC=C2)NC(=O)C3=C(C=C(C=C3F)F)F.CN1CCC(CC1)C(=O)C2=NC(=CC=C2)NC(=O)C3=C(C=C(C=C3F)F)F.C(CC(=O)O)C(=O)O

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ELAGOLIX


Elagolix.svgChemSpider 2D Image | Elagolix | C32H30F5N3O5Elagolix.png

ELAGOLIX

  • Molecular FormulaC32H30F5N3O5
  • Average mass631.590 Da
NBI56418, ABT 620
UNII:5B2546MB5Z
4-({(1R)-2-[5-(2-Fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]-1-phenylethyl}amino)butanoic acid
834153-87-6 FREE ACID
SODIUM SALT  832720-36-2
Acide 4-({(1R)-2-[5-(2-fluoro-3-méthoxyphényl)-3-[2-fluoro-6-(trifluorométhyl)benzyl]-4-méthyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]-1-phényléthyl}amino)butanoïque
Butanoic acid, 4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-1-phenylethyl]amino]-

GNRH antagonist, Endometriosis

Endometriosis PREREGISTERED

Phase III Uterine leiomyoma

WO2001055119A2,

Inventors Yun-Fei ZhuChen ChenFabio C. TucciZhiqiang GuoTimothy D. GrossMartin RowbottomR. Scott Struthers,
Applicant Neurocrine Biosciences, Inc.

WO 2005007165 PDT PATENT

Image result for Neurocrine Biosciences, Inc.

Inventors Zhiqiang GuoYongsheng ChenDongpei WuChen ChenWarren WadeWesley J. DwightCharles Q. HuangFabio C. Tucci
Applicant Neurocrine Biosciences, Inc.
  • Originator Icahn School of Medicine at Mount Sinai
  • Developer AbbVie; Neurocrine Biosciences
  • Class Antineoplastics; Fluorinated hydrocarbons; Pyrimidines; Small molecules
  • Mechanism of Action LHRH receptor antagonists
  • Highest Development Phases
  • Preregistration Endometriosis
  • Phase III Uterine leiomyoma
  • Discontinued Benign prostatic hyperplasia; Prostate cancer
  • Most Recent Events
  • 23 Nov 2017 AbbVie plans a phase III trial for Endometriosis (Monotherapy, Combination therapy) in USA in November 2017 (NCT03343067)
  • 01 Nov 2017 Updated efficacy and adverse events data from two phase III extension trials in Endometriosis released by AbbVie
  • 27 Oct 2017 Elagolix receives priority review status for Endometriosis in USA

 

SYN

Elagolix is a specific highly potent non-peptide, orally active antagonist of the GnRH receptor. This compound inhibits pituitary luteinizing hormone (LH) secretion directly, potentially preventing the several week delay and flare associated with peptide agonist therapy.

Image result for Neurocrine Biosciences, Inc.

In 2010, elagolix sodium was licensed to Abbott by Neurocrine Biosciences for worldwide development and commercialization for the treatment of endometriosis. In January 2013, Abbott spun-off its research-based pharmaceutical business into a newly-formed company AbbVie.

AbbVie , following its spin-out from Abbott in January 2013, under license from Neurocrine , is developing elagolix, the lead from a series of non-peptide gonadotropin-releasing hormone antagonists, for treating hormone-dependent diseases, primarily endometriosis and uterine fibroids.

Elagolix sodium is an oral gonadotropin releasing hormone (GnRH) antagonist in development at Neurocrine Biosciences and Abbvie (previously Abbott). In 2017, Abbvie submitted a New Drug Application (NDA) in the U.S. for the management of endometriosis with associated pain. The candidate is being evaluated in phase III trials for the treatment of uterine fibroids.

Elagolix (INNUSAN) (former developmental code names NBI-56418ABT-620) is a highly potent, selective, orally-active, short-duration, non-peptide antagonist of the gonadotropin-releasing hormone receptor (GnRHR) (KD = 54 pM) which is under development for clinical use by Neurocrine Biosciences and AbbVie.[2][3] As of 2017, it is in pre-registration for the treatment of endometriosis and phase III clinical trials for the treatment of uterine leiomyoma.[1][4] The drug was also under investigation for the treatment of prostate cancer and benign prostatic hyperplasia, but development for these indications was ultimately not pursued.[4] Elagolix is the first of a new class of GnRH inhibitors that have been denoted as “second-generation”, due to their non-peptide nature and oral bioavailability.[1]

Because of the relatively short elimination half-life of elagolix, the actions of gonadotropin-releasing hormone (GnRH) are not fully blocked throughout the day.[1][5] For this reason, gonadotropin and sex hormone levels are only partially suppressed, and the degree of suppression can be dose-dependently adjusted as desired.[1][5] In addition, if elagolix is discontinued, its effects are rapidly reversible.[1][5] Due to the suppression of estrogen levels by elagolix being incomplete, effects on bone mineral density are minimal, which is in contrast to first-generation GnRH inhibitors.[6][7] Moreover, the incidence and severity of menopausal side effects such as hot flashes are also reduced relative to first-generation GnRH inhibitors.[1][5]

Elagolix sodium is a non-peptide antagonist of the gonadotropin-releasing hormone receptor and chemically known as sodium;4-[[(lR)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl] -4-methyl-2,6-dioxopyrimidin- 1 -yl] -1 -phenylethyl] amino] butanoate as below.

The US patent number 7056927 B2 discloses, elagolix sodium salt as a white solid and process for its preparation in Example-1; Step-IH.

The US patent number 8765948 B2 discloses a process for preparation of amorphous elagolix sodium by spray drying method and solid dispersion of amorphous elagolix sodium with a polymer.

The US patent number 7056927 B2 discloses a process for preparation of elagolix sodium salt in Example -1 as given in below scheme -I.

Scheme -I

The US patent number 8765948 B2 describes a process for preparation of elagolix sodium in example- 1 and 4 as given below scheme-II:

(1c) (1e) (4a)

Scheme-II

Further, the US patent number 8765948 B2 discloses an alternate process for the preparation of compound of formula (le) as mentioned below scheme-Ill.

Scheme -III

PATENT

WO2001055119A2 * Jan 25, 2001 Aug 2, 2001 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

PATENT

WO 2005007165

https://encrypted.google.com/patents/WO2005007165A1?cl=en

EXAMPLE 1

3-[2(R)-{HYD OXYCARBONYLPROPYL-AMINθ} -2-PHENYLETHYL]-5-(2-FLUORO-3- METHOXYPHENYL)-l-[2-FLUORO-6-(TRIFLUOROMETHYL)BENZYL]-6-METHYL- PYRIMIDINE-2,4(lH,3H)-DIONE

Figure imgf000027_0001

Step IA: Preparation of 2-fluoro-6-(trifluoromethyl)benzylamine la To 2-fluoro-6-(trifluoromethyl)benzonitrile (45 g, 0.238 mmol) in 60 mL of TΗF was added 1 M BΗ3:TΗF slowly at 60 °C and the resulting solution was refluxed overnight. The reaction mixture was cooled to ambient temperature. Methanol (420 mL) was added slowly and stirred well. The solvents were then evaporated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4. Evaporation gave la as a yellow oil (46 g, 0.238 mmol). MS (C\) m/z 194.0 (MH+).

Step IB: Preparation of N-|2-fluoro-6-(trifluoromethyl)benzyl|urea lb To 2-fluoro-6-(trifluoromethyl)benzylamine la (51.5 g, 0.267 mmol) in a flask, urea (64 g, 1.07 mmol), HC1 (cone, 30.9 mmol, 0.374 mmol) and water (111 mL) were added. The mixture was refluxed for 6 hours. The mixture was cooled to ambient temperature, further cooled with ice and filtered to give a yellow solid. Recrystallization with 400 mL of EtOAc gave lb as a white solid (46.2 g, 0J96 mmol). MS (CI) m/z 237.0 (MH+).

Step 1C: Preparation of l-[2-fluoro-6-(trifluoromethyl)benzyl]-6- methylpyrimidine-2.4(lH.3H)-dione lc Nal (43.9 g, 293 mmol) was added to N-[2-fluoro-6- (trifluoromethyl)benzyl]urea lb (46.2 g, 19.6 mmol) in 365 mL of acetonitrile. The resulting mixture was cooled in an ice-water bath. Diketene (22.5 mL, 293 mmol) was added slowly via dropping funnel followed by addition of TMSCl (37.2 mL, 293 mmol) in the same manner. The resulting yellow suspension was allowed to warm to room temperature slowly and was stirred for 20 hours. LC-MS showed the disappearance of starting material. To the yellow mixture 525 mL of water was added and stirred overnight. After another 20 hours stirring, the precipitate was filtered via Buchnner funnel and the yellow solid was washed with water and EtOAc to give lc as a white solid (48.5 g, 16 mmol). 1H ΝMR (CDC13) δ 2.15 (s, 3Η), 5.37 (s, 2H), 5.60 (s, 1H), 7.23-7.56 (m, 3H), 9.02 (s, 1H); MS (CI) m/z 303.0 (MH+).

Step ID: Preparation of 5-bromo-l -[2-fluoro-6-(trifluoromethyl)benzyl|-6- methylpyrimidine-2.4(lH.3H)-dione Id Bromine (16.5 mL, 0.32 mmol) was added to l-[2-fluoro-6-

(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(lHJH)-dione lc (48.5 g, 0J6 mol) in 145 mL of acetic acid. The resulting mixture became clear then formed precipitate within an hour. After 2 hours stirring, the yellow solid was filtered and washed with cold EtOAc to an almost white solid. The filtrate was washed with sat. ΝaΗCO3 and dried over Na2SO4. Evaporation gave a yellow solid which was washed with EtOAC to give a light yellow solid. The two solids were combined to give 59.4 g of Id (0J56 mol) total. Η NMR (CDC13) δ 2.4 (s, 3H), 5.48 (s, 2H), 7.25-7.58 (m, 3H), 8.61 (s, 1H); MS (CI) m/z 380.9 (MH+). 5-Bromo-l-[2, 6-difluorobenzyl]-6-methylpyrimidine-2,4(lHJH)-dione ld.l was made using the same procedure.

Step IE: Preparation of 5-bromo-l -r2-fluoro-6-(trifluoromethyl)benzyll-6- methyl-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyll-pyrimidine-2.4(lHJH)-dione le To 5-bromo- 1 -[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine- 2,4(lHJH)-dione Id (15 g, 39.4 mmol) in 225 mL of TΗF were added N-t-Boc-D- phenylglycinol (11.7 g, 49.2 mmol) and triphenylphosphine (15.5 g, 59J mmol), followed by addition of di-tert-butyl azodicarboxylate (13.6 g, 59J mmol). The resulting yellow solution was stirred overnight. The volatiles were evaporated and the residue was purified by silica gel with 3:7 EtOAc Ηexane to give le as a white solid (23.6 g, 39.4 mmol). MS (CI) m/z 500.0 (MΗ+-Boc).

Step IF: Preparation of 3-[2(R)-amino-2-phenylethyll-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyll-6-methyl-pyrimidine- 2.4(lH.3H)-dione If To 5-bromo-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[2(R)- tert-butoxycarbonylamino-2-phenylethyl]-pyrimidine-2,4(lH,3H)-dione le (15 g, 25 mmol) in 30 mL/90 mL of Η2O/dioxane in a pressure tube were added 2-fluoro-3- methoxyphenylboronic acid (4.25 g, 25 mmol) and sodium carbonate (15.75 g, 150 mmol). N2 gas was bubbled through for 10 min.

Tetrakis(triphenylphosphine)palladium (2.9 g, 2.5 mmol) was added, the tube was sealed and the resulting mixture was heated with stirring at 90 °C overnight. After cooling to ambient temperature, the precipitate was removed by filtration. The volatiles were removed by evaporation and the residue was partitioned between EtOAc/sat. NaHCO3. The organic solvent was evaporated and the residue was chromatographed with 2:3 EtOAc/Hexane to give 13.4 g (20.8 mmol, 83 %) yellow solid. This yellow solid (6.9 g, 10.7 mmol) was dissolved in 20 mL/20 mL CH2C12/TFA. The resulting yellow solution was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue was partitioned between EtOAc/ sat. NaHCO3. The organic phase was dried over Na2SO4. Evaporation gave If as a yellow oil (4.3 g, 7.9 mmol, 74%). Η NMR (CDC13) δ 2.03 (s, 3H), 3.72-4.59 (m, 6H), 5.32-5.61 (m, 2H), 6.74-7.56 (m, 11H); MS (CI) m/z 546.0 (MH+). 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2,6- difluorobenzyl]-6-methyl-pyrimidine-2,4(lH,3H)-dione lf.l was made using the same procedure described in this example.

Step 1G: Preparation of 3-[2(R)- {ethoxycarbonylpropyl-amino} -2-phenylethyll-5-

(2-fluoro-3 -methoxyphenyl)- 1 -[2-fluoro-6-(trifluoromethyl)benzyl|-6-methyl- pyrimidine-2,4(lHJH)-dione lg To compound 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine- 2,4(lH,3H)-dione If (5 g, 9.4 mmol) in 100 mL of acetonitrile were added ethyl 4- bromobutyrate (4 mL, 28.2 mmol) and Ηunig’s base (1.6 mL, 9.4 mmol). After reflux at 95 °C overnight, the reaction mixture was cooled to ambient temperature and the volatiles were removed. The residue was chromatographed with 10:10: 1 EtOAc/Ηexane/Et3N to give lg as a yellow oil (3.0 g, 4.65 mmol). MS (CI) m/z 646.2 (MH+).

Step 1H: Preparation of 3-[2(R)- {hydroxycarbonylpropyl-amino} -2-phenylethyl]- 5-(2-fluoro-3-methoxyphenyl)-l- 2-fluoro-6-(trifluoromethyl)benzyl1-6-methyl- pyrimidine-2,4(lHJH)-dione 1-1 Compound 3-[2(R)- {ethoxycarbonylpropyl-amino} -2-phenylethyl]-5-(2- fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine- 2,4(lH,3H)-dione lg (2.6 g, 4.0 mmol) was dissolved in 30 mL/30 mL of TΗF/water. Solid NaOΗ (1.6 g, 40 mmol) was added and the resulting mixture was heated at 50 °C overnight. The mixture was cooled to ambient temperature and the volatiles were evaporated. Citric acid was added to the aqueous solution until pΗ = 3. Extraction with EtOAc followed by evaporation of solvent gave 1.96 g of a white gel. The gel was passed through a Dowex MSC-1 macroporous strong cation-exchange column to convert to sodium salt. Lyopholization gave white solid 1-1 as the sodium salt (1.58 g, 2.47 mmol). Η NMR (CD3OD) δ 1.69-1.77 (m, 2H), 2.09 (s, 3H), 2.09-2.19 (t, J = 7.35 Hz, 2H), 2.49-2.53 (t, J = 735 H, 2H), 3.88 (s, 3H), 4.15-4.32 (m, 3H), 5.36-5.52 (m, 2H), 6.60-7.63 (m, 1 IH); HPLC-MS (CI) m/z 632.2 (MH+), tR = 26.45, (method 5)

PATENT

WO 2017221144

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017221144&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Process for the preparation of elagolix sodium and its polymorph forms and intermediates is claimed. Represents first filing from Dr. Reddy’s Laboratories Limited and the inventors on this API.

n a seventh aspect, the present invention provides a process for preparation of compound of formula (VII)

(VII)

wherein R is alkyl such as methyl, ethyl, propyl, isopropyl and the like,

comprising;

a) reacting the compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV)

wherein t-BOC is tertiary butoxycarbonyl group; R is as described above

b) reacting the compound of formula (IV) with the compound of formula (V) to obtain the compound formula (VI), and

c) N-deprotection of the compound of formula (VI) to obtain the compound of formula

(VII)

(VI) (VII)

The reaction of compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV) is carried in the presence of triarylphosphine such as triphenyl phosphine and the like and azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate (DIAD) and the like.

The seventh aspect of the present invention is depicted below scheme-IV.

Scheme-IV

The eighth aspect of the present invention is depicted below scheme-IV.

R=alkyl

Scheme-IV

Example 11: Preparation of ethyl (R)-4-((2-hydroxy-l-phenylethyl)amino)butanoate (Ilia; R is ethyl)

R-(-)-2-phenylglycinol (10 g), DMAP (0.17 g) were added in THF (80 ml) at room temperature under nitrogen atmosphere. Triethylamine (30.48 ml) was added to the reaction mixture and stirred for five minutes. Ethyl-4-bromo butyrate (15.64 ml) was added and the reaction mixture heated to 80°C then stirred for 16 hours. Water (20 volumes) followed by ethyl acetate (200 ml) were added to separate the aqueous and organic layer. The organic layer was washed with IN HC1 (100 ml) followed by neutralize the resulting aqueous layer with saturated sodium carbonate solution then extract with ethyl acetate (100 ml) and the organic layer was dried over anhydrous sodium sulfate then evaporated below 50°C under reduced pressure to obtain the title compound. Yield: 14.50 g. Purity: 94.75% (by HPLC). ¾ NMR (400 MHz, DMSO-d6): δ 7.17-7.30 (m, 5H), 4.83 (m, 1H), 3.99 (q, 2H), 3.58 (dd, 1H, J = 8.8, 4.4 Hz), 3.88 (m, 1H ), 3.27 (m, 1H), 2.38 (m, 1H), 2.26 (m, 3H), 2.10 (s, 1H), 1.61 (m, 2H), 1.12 (t, 3H); m/z: 252 (MH )

Example 12: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)(2-hydroxy-l-phenylethyl) amino)butanoate (III; R is ethyl)

Ethyl (R)-4-((2-hydroxy-l-phenylethyl)amino)butanoate (14 g) was added to THF (140 ml) at room temperature. The reaction mixture was cooled to 0-5 °C. Triethylamine (16.9 mL) was added to the reaction mixture followed by Di-tert-butyl dicarbonate (13.37 g) was added to reaction mixture at 0-5 °C. The reaction mixture was heated to room temperature and stirred for 16 hours. Water (300 mL) and ethyl acetate (300 mL) were added and the layers were separated. The organic layer was washed with sodium chloride then died over sodium sulfate followed by evaporation at 45°C to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) withl5-20% EtOAc/Hexane to obtain the title compound as a pale yellow syrup. Yield: 9.5 g. Purity: 95.42% (by HPLC). ¾ NMR (400 MHz, CDC13): δ 7.24-7.34 (m, 5H), 5.08 (m, 1H), 4.09 (m, 4H), 3.10 (m, 2H), 3.00 (s, 1H), 2.21(m, 2H), 1.82 (m, 2H), 1.46 (s, 9H), 1.23 (t, 3H). m/z: 352.20 (MH )

Example 13: Preparation of ethyl (R)-4-((2-(5-bromo)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)(tert-butoxycarbonyl) amino)butanoate (IV; R is ethyl)

Ethyl (R)-4-((tert-butoxycarbonyl)(2-hydroxy-l -phenyl ethyl) amino)butanoate (III; R is ethyl) (1.0 g), 5-bromo-l-(2-fluoro-6-trifluoromethyl)benzyl-6-methylpyrimidine-2,4 (1H, 3H)-dione (II) (1.08 g), Triphenyl phosphine (1.49 g) were added to THF (30 mL) at room temperature under nitrogen atmosphere. DIAD (1.11 mL) was added to the reaction mixture and stirred for 16 hours at room temperature. Water (60 volume) was added to the reaction mixture followed by ethylacetate (60 mL) was added then the layers were separated. The organic layer was dried over sodium sulfate and evaporated below 50°C under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) withl5-20% EtOAc/Hexane to obtain the title compound. Yield (1.3 g). Purity: 68.87% (by HPLC); l NMR (DMSO-d6) δ 1.15-2.0 (11H), 2.43-2.48 (4H), 3.9 (2H), 4.71-4.8 (5H), 5.3 -5.4 (3H), 7.28-7.3 (8H), 8.4 (2H); m/z: 616 (M-BOC)+

Example 14: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VI; R is ethyl)

Ethyl (R)-4-((2-(5-bromo)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)(tert-butoxycarbonyl) amino)butanoate (IV; R is ethyl) (0.9 g), 2-fluoro-3-methoxy phenyl boronic acid (V) (0.214 g) and sodium carbonate (0.797 g) were added to the mixture of 1,4-dioxane (9 mL) and water (3.06 mL) at room temperature under nitrogen atmosphere. Argon gas was bubbled through for 30 minutes. Tetrakis (triphenylphosphine)palladium (0.145 g) was added to the reaction mixture at room temperature then heated to 90-95 °C and stirred for 5 hours. The reaction mixture cooled to room temperature and filtered through celite bed then the filtrate washed with ethylacetate (9 mL) and water (36 mL) was added and stirred for 30 minutes at room temperature. Ethylacetate (36 mL) was added and the separated organic layer washed with brine and dried over sodium sulfate followed by evaporation at 45°C to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) with 20-25% EtOAc/Hexane to obtain the title compound as yellow solid. Yield: 0.5 g; Purity: 75.1% (by HPLC); m/z: 660 (M-BOC)+.

Example 15: Preparation of ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VII; R is ethyl)

Ethyl(R)-4-((tert-butoxycarbonyl)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoro methyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VI; R is ethyl) (0.4 g) was added to dichloromethane (4 mL) at room temperature. The reaction mixture was cooled to 0-5 °C then trifluoroacetic acid (2 mL) was added and stirred for five hours at 0-5 °C. Saturated sodium bicarbonate solution (40 mL) was added to the reaction mixture followed by dichloromethane (40 mL) was added. The organic layer was washed with brine then dried over sodium sulfate and evaporated at 35°C to obtain the crude compound. The crude compound purified by silica gel (60/120 mesh) with 30-35% EtOAc/Hexane to obtain the title compound as yellow solid. Yield: 160 mg; Purity: 88.6% (by HPLC). ‘H NMR (400 MHz, DMSO-d6): δ 7.64 (m, 1H), 7.54 (m, 2H), 7.15-7.27 (m, 6H), 6.85 (m, 2H), 5.31 (s, 2H), 3.99 (m, 3H), 3.87 (m, 2H), 3.83 (s, 3H), 2.30-2.16 (m, 4H), 2.10 (s, 3H), 1.50 (m, 2H), 1.10 (t, 3H). m/z: 660 (MH )

PAPER

Discovery of sodium R-(+)-4-(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl-)benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-1-phenylethamino)butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor
J Med Chem 2008, 51(23): 7478

Discovery of Sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor

Department of Medicinal Chemistry, Department of Endocrinology, and Department of Preclinical Development, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130
J. Med. Chem.200851 (23), pp 7478–7485
DOI: 10.1021/jm8006454

* To whom correspondence should be addressed. Phone: 1-858-617-7600. Fax: 1-858-617-7925. E-mail: cchen@neurocrine.comsstruthers@neurocrine.com., †

Department of Medicinal Chemistry., ‡ Department of Endocrinology., § Department of Preclinical Development.

Abstract

Abstract Image

The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.

NA SALT

(R)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric Acid Sodium Salt

sodium salt as a white solid (1.58 g, 2.47 mmol, 62%). HPLC purity: 100% (220 and 254 nm). 1H NMR (CD3OD): 1.72 (m, 2H), 2.08 (s, 3H), 2.16 (t, J = 6.9 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 3.86 (s, 3H), 4.24 (m, 3H), 5.40 (d, J = 9.0 Hz, 1H), 5.46 (d, J = 9.0 Hz, 1H), 6.62 and 6.78 (m, 1H), 7.12 (m, 2H), 7.34 (m, 5H), 7.41 (m, 1H), 7.56 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H). MS: 632 (M − Na + 2H+). Anal. (C32H29F5N3O5Na·0.75H2O): C, H, N, Na.

PATENT

CN 105218389

PATENT

WO2014143669A1

“Elagolix” refers to 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2- fluoro-6 rifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-yl]-l- phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof. Elagolix is an orally active, non-peptide GnRH antagonist and is unlike other GnRH agonists and injectable (peptide) GnRH antagonists. Elagolix produces a dose dependent suppression of pituitary and ovarian hormones in women. Methods of making Elagolix and a pharmaceutically acceptable salt thereof are described in WO 2005/007165, the contents of which are herein incorporated by reference.

References

  1. Jump up to:a b c d e f g Ezzati, Mohammad; Carr, Bruce R (2015). “Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain”. Women’s Health11(1): 19–28. doi:10.2217/whe.14.68ISSN 1745-5057.
  2. Jump up^ Chen C, Wu D, Guo Z, Xie Q, Reinhart GJ, Madan A, Wen J, Chen T, Huang CQ, Chen M, Chen Y, Tucci FC, Rowbottom M, Pontillo J, Zhu YF, Wade W, Saunders J, Bozigian H, Struthers RS (2008). “Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor”. J. Med. Chem51 (23): 7478–85. doi:10.1021/jm8006454PMID 19006286.
  3. Jump up^ Thomas L. Lemke; David A. Williams (24 January 2012). Foye’s Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1411–. ISBN 978-1-60913-345-0.
  4. Jump up to:a b AdisInsight: Elagolix.
  5. Jump up to:a b c d Struthers RS, Nicholls AJ, Grundy J, Chen T, Jimenez R, Yen SS, Bozigian HP (2009). “Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix”J. Clin. Endocrinol. Metab94 (2): 545–51. doi:10.1210/jc.2008-1695PMC 2646513Freely accessiblePMID 19033369.
  6. Jump up^ Diamond MP, Carr B, Dmowski WP, Koltun W, O’Brien C, Jiang P, Burke J, Jimenez R, Garner E, Chwalisz K (2014). “Elagolix treatment for endometriosis-associated pain: results from a phase 2, randomized, double-blind, placebo-controlled study”. Reprod Sci21 (3): 363–71. doi:10.1177/1933719113497292PMID 23885105.
  7. Jump up^ Carr B, Dmowski WP, O’Brien C, Jiang P, Burke J, Jimenez R, Garner E, Chwalisz K (2014). “Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density”Reprod Sci21 (11): 1341–51. doi:10.1177/1933719114549848PMC 4212335Freely accessiblePMID 25249568.

External links

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US8084614 Apr 4, 2008 Dec 27, 2011 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8263588 Apr 4, 2008 Sep 11, 2012 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8481738 Nov 10, 2011 Jul 9, 2013 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
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US8952161 Jun 5, 2013 Feb 10, 2015 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US9034850 Nov 19, 2010 May 19, 2015 Sk Chemicals Co., Ltd. Gonadotropin releasing hormone receptor antagonist, preparation method thereof and pharmaceutical composition comprising the same
US9422310 Jan 8, 2015 Aug 23, 2016 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
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2014-06-19
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US2014288031 METHODS OF TREATING HEAVY MENSTRUAL BLEEDING
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2010-04-15
US2010061976 Method for treating or preventing osteoporosis by reducing follicle stimulating hormone to cyclic physiological levels in a mammalian subject
2009-07-27
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US9701647 Tetrazolones as a carboxylic acid bioisosteres
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US9439888 Tetrazolones as a carboxylic acid bioisosteres
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2016-09-13
US7419983 Gonadotropin-releasing hormone receptor antagonists and methods related thereto
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US7176211 Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
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US7056927 Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
2005-02-17
2006-06-06
Elagolix
Elagolix.svg
Clinical data
Synonyms NBI-56418; ABT-620
Routes of
administration
By mouth
Drug class GnRH analogueGnRH antagonistantigonadotropin
Pharmacokinetic data
Biological half-life 2.4–6.3 hours[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C32H30F5N3O5
Molar mass 631.590 g/mol
3D model (JSmol)

///////////////ELAGOLIX, NBI 56418, UNII:5B2546MB5Z, ABT 620, priority review status, PHASE 3, AbbVie, Neurocrine Biosciences, Endometriosis

CC1=C(C(=O)N(C(=O)N1CC2=C(C=CC=C2F)C(F)(F)F)CC(C3=CC=CC=C3)NCCCC(=O)O)C4=C(C(=CC=C4)OC)F

Gedatolisib, гедатолисиб , غيداتوليسيب , 吉达利塞 ,


Image result for GedatolisibImage result for Gedatolisib

Gedatolisib

Pfizer

PF-05212384; PF-5212384; PKI-587

CAS 1197160-78-3
Chemical Formula: C32H41N9O4
Molecular Weight: 615.72

1-(4-{[4-(Dimethylamino)-1-piperidinyl]carbonyl}phenyl)-3-{4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}urea
3-{4-[bis(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-1-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}urea
N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N’-[4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl]urea
гедатолисиб [Russian] [INN]
غيداتوليسيب [Arabic] [INN]
吉达利塞 [Chinese] [INN]
  • Phase III Acute myeloid leukaemia
  • Phase II Colorectal cancer; Non-small cell lung cancer
  • Phase I Breast cancer; Solid tumours
  • Discontinued Endometrial cancer

Most Recent Events

  • 22 Nov 2017Pfizer suspends patient enrolment in a phase I/II trial due to drug supply delay in Non-small cell lung cancer (Combination therapy, Inoperable/Unresectable, Metastatic disease, Late-stage disease) in USA (IV) (NCT02920450)
  • 04 Nov 2017No recent reports of development identified for phase-I development in Solid-tumours(Combination therapy, Late-stage disease, Second-line therapy or greater) in Canada (IV, Infusion)
  • 04 Nov 2017No recent reports of development identified for phase-I development in Solid-tumours(Combination therapy, Late-stage disease, Second-line therapy or greater) in Italy (IV, Infusion)

Gedatolisib, also known as PKI-587 and PF-05212384, is an agent targeting the phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. Upon intravenous administration, PI3K/mTOR kinase inhibitor PKI-587 inhibits both PI3K and mTOR kinases, which may result in apoptosis and growth inhibition of cancer cells overexpressing PI3K/mTOR. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy; mTOR, a serine/threonine kinase downstream of PI3K, may also be activated independent of PI3K.

PKI-587 is a PI3K/mTOR inhibitor, currently being developed by Pfizer. The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. PKI-587  has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously.

PATENT

WO 2009143317

WO 2010096619

WO 2012148540

WO 2014151147

PATENT

US 20170119778

PAPER

Journal of Medicinal Chemistry (2010), 53(6), 2636-2645

http://pubs.acs.org/doi/abs/10.1021/jm901830p

Bis(morpholino-1,3,5-triazine) Derivatives: Potent Adenosine 5′-Triphosphate Competitive Phosphatidylinositol-3-kinase/Mammalian Target of Rapamycin Inhibitors: Discovery of Compound 26 (PKI-587), a Highly Efficacious Dual Inhibitor

 Chemical Sciences
 Oncology
§ Drug Metabolism
Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965
J. Med. Chem.201053 (6), pp 2636–2645
DOI: 10.1021/jm901830p
Publication Date (Web): February 18, 2010
Copyright © 2010 American Chemical Society
*To whom correspondence should be addressed. Phone: (845) 602-4023. Fax (845) 602-5561. E-mail: venkata@wyeth.com or venkata699@gmail.com.

Abstract

Abstract Image

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure−activity relationships and the in vitro and in vivo activity of analogues in this series are described.

Preparation of 1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4- yl-1,3,5-triazin-2-yl)phenyl]urea (26)

MS (ESI) m/z = 616.7. HRMS: calcd for C32H41N9O4 + H+, 616.335 43; found (ESI-FTMS, [M + H]+), 616.334 24. Purity by analytical HPLC 99.3%. (Prodigy ODS3, 0.46 cm × 15 cm, 20 min gradient acetonitrile in water, trifluoroacetic acid, detector wavelengths, 215 and 254 nm.) 1H NMR (DMSO-d6) δ 1.29−1.36 (m, 6H), 2.6 (m, 4H), 2.9 (m,1H), 3.3 (m, 4H), 3.6 (m, 8H), 3.7 (m, 8H), 7.3 (d, J = 8.3 Hz, 2H), 7.51−7.57 (m, 4H), 8.3 (d, J = 8.3 Hz 2H), 8.9 (s, 1H), 9.0 (s, 1H) ppm. Anal. Calcd for C32H41N9O4: C 62.42%, H 6.71%, N 20.47%. Found: C 62.34%, H 6.67%, N 20.39%.

PAPER

Bioorganic & Medicinal Chemistry Letters (2011), 21(16), 4773-4778.

http://www.sciencedirect.com/science/article/pii/S0960894X11008468

PAPER

New and Practical Synthesis of Gedatolisib

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00298

 College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, China
 Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Hainan Normal University, 99 South Longkun Road, Haina 571158, China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00298
*Fax: +86 21 67791214. E-mail: yongjun.mao@hotmail.com.

Abstract

Abstract Image

A new, practical, and convergent synthetic route of gedatolisib, an antitumor agent, is developed on a hectogram scale which avoids the Pd coupling method. The key step is adopting 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine and 2,2′-dichlorodiethyl ether to prepare the key 4,4′-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine in 77% yield and 98.8% purity. Gedatolisib is obtained in 48.6% yield over five simple steps and 99.3% purity (HPLC). Purification methods of the intermediates and the final product involved in the route are given.

off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.46 (brs, 2H), 1.89 (brs, 2H), 2.29 (s, 6H), 2.94 (brs, 2H), 3.76 (m, 8H), 3.89 (m, 8H), 7.09 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 8.28 (s, 1H), 8.31 (d, J = 8.6 Hz, 2H), 8.48 (s, 1H). ESI-MS (m/z) 615.9 (M + H). HPLC conditions: Column: Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5 μm); Detection: 254 nm; Flow rate: 0.8 mL/min; Temperature: 30 °C; Injection load: 1 μL; Solvent: MeOH; Concentration: 0.5 mg/mL; Run time: 20 min; Mobile phase A: water; Mobile phase B: MeOH/TEA = 100:0.1; Gradient program: time (min): 20; % of mobile phase A: 10; % of mobile phase B: 90; tR = 2.598 min, purity: 99.34%

  • ZhaoX.; TanQ.ZhangZ.ZhaoY. Med. Chem. Res. 2014235188– 5196 DOI: 10.1007/s00044-014-1084-z
  • KhafizovaG.PotoskiJ. R. PCT Int. Appl. WO 2010096619, 2010.
  • VenkatesanA. M.ChenZ.DehnhardtC. M.Dos SantosO.Delos SantosE. G.ZaskA.VerheijenJ. C.KaplanJ. A.RichardD. J.Ayral-KaloustianS.MansourT. S.GopalsamyA.CurranK. J.ShiM. PCT Int. Appl. WO 2009143317, 2009.

REFERENCES

1: Gedaly R, Galuppo R, Musgrave Y, Angulo P, Hundley J, Shah M, Daily MF, Chen C, Cohen DA, Spear BT, Evers BM. PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation. J Surg Res. 2013 Nov;185(1):225-30. doi: 10.1016/j.jss.2013.05.016. Epub 2013 May 25. PubMed PMID: 23769634.

2: Gedaly R, Angulo P, Hundley J, Daily MF, Chen C, Evers BM. PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation. J Surg Res. 2012 Aug;176(2):542-8. doi: 10.1016/j.jss.2011.10.045. Epub 2011 Nov 21. PubMed PMID: 22261591.

3: Dehnhardt CM, Venkatesan AM, Chen Z, Delos-Santos E, Ayral-Kaloustian S, Brooijmans N, Yu K, Hollander I, Feldberg L, Lucas J, Mallon R. Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors. Bioorg Med Chem Lett. 2011 Aug 15;21(16):4773-8. doi: 10.1016/j.bmcl.2011.06.063. Epub 2011 Jun 21. PubMed PMID: 21763134.

4: Mallon R, Feldberg LR, Lucas J, Chaudhary I, Dehnhardt C, Santos ED, Chen Z, dos Santos O, Ayral-Kaloustian S, Venkatesan A, Hollander I. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res. 2011 May 15;17(10):3193-203. doi: 10.1158/1078-0432.CCR-10-1694. Epub 2011 Feb 15. PubMed PMID: 21325073.

5: Venkatesan AM, Chen Z, dos Santos O, Dehnhardt C, Santos ED, Ayral-Kaloustian S, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Chaudhary I, Mansour TS. PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5869-73. doi: 10.1016/j.bmcl.2010.07.104. Epub 2010 Jul 30. PubMed PMID: 20797855.

6: Venkatesan AM, Dehnhardt CM, Delos Santos E, Chen Z, Dos Santos O, Ayral-Kaloustian S, Khafizova G, Brooijmans N, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Gibbons J, Abraham RT, Chaudhary I, Mansour TS. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem. 2010 Mar 25;53(6):2636-45. doi: 10.1021/jm901830p. PubMed PMID: 20166697.

????????????PF 05212384, PF 5212384, PKI-587, PF-05212384; PF-5212384; PKI 587, gedatolisib, antitumor agent, PHASE 3, PFIZER, гедатолисиб غيداتوليسيب 吉达利塞 

O=C(NC1=CC=C(C2=NC(N3CCOCC3)=NC(N4CCOCC4)=N2)C=C1)NC5=CC=C(C(N6CCC(N(C)C)CC6)=O)C=C5

 Journal of Medicinal Chemistry (2017), 60(17), 7524-7538 PQR 309

FEVIPIPRANT


Fevipiprant.svg

Fevipiprant.png

FEVIPIPRANT

Molecular Formula: C19H17F3N2O4S
Molecular Weight: 426.41 g/mol

UNII-2PEX5N7DQ4; 2PEX5N7DQ4; NVP-QAW039; QAW039;

CAS 872365-14-5

Product patent WO2005123731A2, NOVARTIS

Image result for novartis

2-[2-methyl-1-[[4-methylsulfonyl-2-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-b]pyridin-3-yl]acetic acid

  • 2-Methyl-1-[[4-(methylsulfonyl)-2-(trifluoromethyl)phenyl]methyl]-1H-pyrrolo[2,3-b]pyridine-3-acetic acid
  • [1-(4-((Methane)sulfonyl)-2-trifluoromethylbenzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]acetic acid

Fevipiprant (INN; code name QAW039) is a drug being developed by Novartis which acts as a selective, orally available antagonistof the prostaglandin D2 receptor 2 (DP2 or CRTh2).[1][2][3]

As of 2016, it is in Phase III[4] clinical trials for the treatment of asthma.[5]

Novartis is developing fevipiprant, a prostaglandin D2 receptor (PD2/CRTh2) antagonist, as an oral capsule formulation for treating asthma and moderate to severe atopic dermatitis.

Image result for FEVIPIPRANT

Inventors Kamlesh BalaCatherine LeblancDavid Andrew SandhamKatharine Louise TurnerSimon James WatsonLyndon Nigel BrownBrian Cox
Applicant Novartis AgNovartis Pharma Gmbh

PATENT

WO2005123731

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2005123731

PATENT

CN 106188040

The invention discloses a Fevipiprant and Fevipiprant intermediate preparation method. The method is characterized in that 2-amino-3-bromopyridine and 4-mesyl-2-trifluoromethylbenzaldehyde to condensation reaction to obtain a Schiff base intermediate, then performing reduction reaction to obtain 3-bormo-N-(4-(mesyl)-2-(trifluoromethyl)phenyl)-pyridine-2-amine, subjecting the 3-bormo-N-(4-(mesyl)-2-(trifluoromethyl)phenyl)-pyridine-2-amine to ullmann ring closing reaction with methyl levulinate or ethyl levulinate, and performing saponification reaction or decarboxylic reaction to obtain Fevipiprant namely N[1-(4-((methane)sulfonyl)-2-trifluoromethylphenyl-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl] acetic acid. The Fevipiprant and Fevipiprant intermediate preparation method which is a brand new method is short in step, technically convenient in operation, easy in product purification and large-scale production, high yield can be achieved, and Fevipiprant industrial production can be realized easily.

Example 5: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0056] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40 · 9g, 0 · lmo 1) and levulinic acid A ester (13.0g, 0. lmo 1) was added 300 mL N, N- dimethylformamide, was added copper iodide (1 · 9g, 0 · 0lmo 1) and N, N- dimethylglycine (1.0g , 0.01 mol), after nitrogen substitution, the reaction temperature was raised to 120 degrees 12h, water was added 200mL of saturated sodium chloride solution was cooled and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water , was added sodium hydroxide (8g, 0.2mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give the crude product after recrystallization from ethanol in pure 34.5g, yield 81%.

[0057] · ΜΚ (300ΜΗζ, (16-0Μ50) δ: 12 · 3 (ΐ3Γ, 1Η, α) 2Η), 8.24 (s, lH, PhH), 8.11 ~ 8.12 (d, lH, PhH), 8.00 ~ 8.02 (d, lH, PyH), 7.91 ~ 7.93 (d, lH, PyH), 7.09 ~ 7.10 (d, lH, PhH), 6.46 ~ 6.48 (d, lH, PhH), 5.73 (s, 2H, NCH2) , 3.70 (s, 2H, q ^ C〇2H), 3.30 (s, 3H, CH 3).

[0058] HPLC: 99.9%.

[0059] Example 6: N [l- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0060] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – (. 40.9g, 0 lmo 1) pyridin-2-amine and acetyl malonate methyl ester (18.8g, 0. lmol) was added 300 mL N, N- dimethylformamide, was added copper iodide (1.9g, O.Olmol) and N, N- dimethylglycine (1. (^ , 0.01111〇1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 1211, 200mL saturated brine was added after cooling, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL of water, was added sodium hydroxide (8g, 0.2mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol, a crude product was obtained from ethanol crystallized to give pure 34. lg, 80% yield.

[0061] HPLC: 99.8%.

[0062] Example 7: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0063] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40 · 9g, 0 · lmo 1) and levulinic acid A ester (13. (^, 0.1111〇1) was added ^ 3,001,111, 1-dimethyl formamide, was added copper iodide (3.88,0.02111〇1) and N, N- dimethylglycine (2. (^, 0.02111〇1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 1211, 200mL saturated brine was added after cooling, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water , was added sodium hydroxide (8g, 0.2mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure 34. lg, 80% yield billion

[0064] HPLC: 99.9%.

[0065] Example 8: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0066] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40.9 8,0.1111〇1) was added 300mL N, N- two after dimethylformamide, was added copper iodide (1.9g, 0.01mol) and 2,2,6,6-tetramethyl-heptane-3,5-dione (3.6g, 0.02mo 1), purged with nitrogen , the reaction temperature was raised to 120 degrees 12h, water was added 200mL of saturated sodium chloride solution was cooled and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water was added sodium hydroxide (8g , 0.2 mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure product 30.2 g, yield 71%.

[0067] HPLC: 99.6%.

[0068] Example 9: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0069] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40.9 8,0.1111〇1) was added 1’1 ^ 3,001,111, 1 ‘| – dimethylformamide, was added copper iodide (1.98,0.011] 1〇1) and proline (1.28,0.011] 1〇1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 12h, after cooling, 200mL saturated brine, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water was added sodium hydroxide (8g, 0.2mol) was heated to 60 degrees reaction 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure product 33.2 g, 78% yield.

[0070] HPLC: 99.8%.

[0071] Example 10: N [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] pyridin – preparation of 3- yl] acetic acid (1).

[0072] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40.9 8,0.1111〇1) was added 300mL N, N- two after dimethylformamide, was added copper iodide (1.9g, 0. Olmol) and N, N- dimethylglycine (1.0g, 0.01 mo 1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 12h, cooled was added 200mL saturated brine, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL of acetic acid and 100mL of concentrated hydrochloric acid was heated to reflux for 6h, cooled to 0 ° C, was added 100mL water analysis crystal was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure product 33.2 g, 78% yield.

[0073] HPLC: 99.1%.

PATENT

WO 2017056001

Example 3b: Preparation of Compound A

Production of C8: Compound C6, (3-[2-({[4-Methanesulfonyl-2-(trifluoromethyl)-phenyl]methyl}amino)pyridin-3-yl]prop-2-yn-l-ol) (20 g, 52 mmol) was dissolved in a mixture of methyl isobutyl ketone (MIBK, 125 g), 25.3 g (156 mmol) of 1 , 1 , 1 -triethoxy ethane, and acetic acid (0.625 g, 10 mmol). The mixture was heated within 40 minutes to 140 °C under a N2 over-pressure of 1 – 4 bar. During the reaction ethanol was formed and removed from the vessel by a pressure-regulated valve. After 3.5 h a second portion of acetic acid (0.625g) was added and the mixture was heated for 3.5 h at 140 °C under a N2 over-pressure of 1 – 4 bar. The resultant product was a solution of Ethyl 2-(l- {[4-methanesulfonyl-2-(trifluoromethyl)phenyl]methyl}-2-methyl-lH-pyrrolo[2,3-¾]pyridin-3-yl)acetate and the conversion rate was measured at 98% and the yield 90%. The solution was filtered and 40 g MIBK was added. The solution was heated to IT=80 °C and cooled down within 3 h to

IT=20 °C. At an IT of 65 °C seed crystals were added. At IT 20 °C intermediate C8 was isolated and washed with 40 g MIBK and dried in the oven at IT=60°C/20mbar.

Conversion to Compound A: The intermediate C8 was concentrated under vacuum at

100 °C/200 mbar and water (6000ml). A sodium hydroxide solution (1734 g, 30%, 13 mol) was added to the mixture and heated for 4 h at 50 °C. The solution was distilled again at 100 °C/100 mbar. The phases were separated at 50 °C and the water phase was extracted with methyl isobutyl ketone (2000 ml). Again the phases were separated and the water phase was filtered at 50 °C. To the filtrate methyl isobutyl ketone (5000 ml) was added and the aqueous solution neutralized in 2 portions with hydrochloric acid (963 g, 37%, 9.8 mol) to pH 4 – 4.5. The phases were heated to 80 °C and the organic phases separated. Water (1000 ml) was added to wash the organic phase and after phase separation the organic phase was cooled down to 70 °C. Seed crystals of Compound A were added along with heptane (1000 ml). The resulting suspension was stirred for 30 minutes before cooling further down to 0 °C within 3 h. The suspension was stirred for 3 h at 0 °C and then filtered through a nutsche. The filter cake was washed first with pre-cooled HPTF/methyl isobutyl ketone (1000 g, 5: 1), then with acetone/water (1000 g, 1 :2) and finally with water (1000 g). Wet Compound A was dried in the oven at 60 °C for 8 h under vacuum to isolate 804 g of compound A. The conversion was calculated to be 99%; the yield was 79%.

Example 3 c: Alternative Preparation of Compound A

Molecular Weight: 426 41

Exact Mass: 384.08 Molecular Weight: 453.48

5 g of (3-[2-({[4-Methanesulfonyl-2-(trifluoromethyl)-phenyl]methyl}amino)pyridin-3-yl]prop-2-yn-l-ol), methyl isobutyl ketone (MIBK, 50 ml), and 1 , 1 -dimethoxy-N,N-dimethylethanamine were put together in a 200 ml reactor and stirred for 15 h at 100 °C. The mixture was acidified by addition of hydrochloric acid (15 ml) and kept stirring for 15 h at 100 °C. Then water (25 ml) was added, and the temperature was decreased to 50 °C. Caustic soda (about 15 ml) was added to set the pH around 12. Then, after phase split and a second extraction with water (10 ml), the combined aqueous phases were diluted with methyl isobutyl ketone (25 ml) and acidified at 80 °C to pH 4 with hydrochloric acid. The mixture was cooled to 70 °C, seeded and cooled to 0 °C within 2 h. After 2 h aging at 0 °C, the crystalline solid was collected by filtration, washed with methyl isobutyl ketone (10 ml) and water (10 ml), and dried under vacuum at 60 °C until constant weight. Yield 2.93 g.

PATENT

WO-2017210261

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017210261&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Novel deuterated analogs of pyrrolo[2,3-b]pyridine compounds, particularly fevipiprant and their salts and compositions and combination comprising them are claimed. Also claims is their use for treating asthma, allergic rhinitis and atopic dermatitis. Compounds are claimed to be a prostaglandin D2 receptor 2 antagonist. Represents first PCT filing from CoNCERT Pharmaceuticals and the inventor on this API.

PAPER

ACS Medicinal Chemistry Letters (2017), 8(5), 582-586

Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP2Receptor Antagonist for Treatment of Asthma

Novartis Institutes for Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom
ACS Med. Chem. Lett.20178 (5), pp 582–586
DOI: 10.1021/acsmedchemlett.7b00157
*E-mail: david.sandham@novartis.com. Tel: + 1 (617)-871-8000.

Abstract

Abstract Image

Further optimization of an initial DP2 receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.

RM  sodium methanesulfinate and 4-fluoro-2-(trifluoromethyl)benzaldehyde

Step 1:

4-(methylsulfonyl)-2-(trifluoromethyl)benzaldehyde

A suspension of sodium methanesulfinate (29.6 g, 290 mmol) and 4-fluoro-2-(trifluoromethyl)benzaldehyde (50 g, 260 mmol) in DMSO (200 ml) was heated at 90˚C overnight. The thick yellow suspension was poured onto crushed ice (ca 800 g), diluted with water and the solid reside collected by filtration, washed with water and dried in vacuo to afford 4- (methylsulfonyl)-2-(trifluoromethyl)benzaldehyde as an off-white solid (50.7 g, 77%). LRMS mass ion not detected. 1H NMR (CDCl3) 3.14 (3H s), 8.30 (1H d J=7.5), 8.36 (1H d J=7.5), 8.40 (1H s), 10.49 (1H s).

Step 2:

(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)methanol

(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)methanol as an off-white solid (50.7 g, 99%). LRMS mass ion not detected. 1H NMR (CDCl3) 3.11 (3H s), 5.02 (2H s), 8.09 (1H d J=7.5), 8.19 (1H d J=7.5), 8.25 (1H s).

STEP 3

1-(bromomethyl)-4-(methylsulfonyl)-2-(trifluoromethyl)benzene

1-(bromomethyl)-4-(methylsulfonyl)-2- (trifluoromethyl)benzene (47.1 g, 74%) as a white solid. LRMS mass ion not detected. 1H NMR (CDCl3) 3.11 (3H s), 4.67 (2H s), 7.86 (1H d J=7.5), 8.14 (1H d J=7.5), 8.25 (1H s).

STEP 4

methyl 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate

(83:17) of methyl 2-(2-methyl-1-(4-(methylsulfonyl)-2- (trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate (N-1 product) and methyl 2-(2-methyl-7-(4- (methylsulfonyl)-2-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3-b]pyridin-3-yl)acetate (N-7 product) as a white solid (22.5 g 42%). LRMS C20H19F3N2O4S requires M+ 440.4 found [MH]+ m/z 441. 1H NMR (CDCl3) 2.27 (3H s), 3.06 (3H s N-1 product), 3.11 (3H s N-7 product), 3.72 (3H s), 3.77 (2H s), 5.03 (2H s N-7 product), 5.82 (2H s N-1 product), 6.66 (1H d J=8.2), 7.16 (1H dd J=7.8, 4.8), 7.91 (1H d, J=8.3), 7.95 (1H d J=7.7), 8.12 (1H d J=7.8 N-7), 8.19 (1H d J=8.1 N-7), 8.17 (1H s N-7), 8.27 (1H d J=3.6), 8.30 (1H s).

FINAL

2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid 11 as needles, m.p. 208˚C (16.3 g, 44%). HRMS C19H18F3N2O4S requires [MH]+ 427.0939 found [MH]+ 427.093. 1H NMR (500 MHz, DMSO-d6) 2.28 (3H s), 3.28 (3H s), 3.73 (2H s), 5.76 (2H s), 6.49 (1H d J=8.3), 7.12 (1H dd J=7.7, 4.8), 7.95 (1H d J=7.8), 8.04 (1H d, J=8.3), 8.14 (1H d J=4.7), 8.26 (1H s), 12.28 (1H br s ). Elemental analysis calcd. for C19H17F3N2O4S: C, 53.52; H, 4.02; N, 6.57; S, 7.52%. Found C, 53.90 ± 0.04; H, 4.28 ± 0.06; N, 6.43 ± 0.02; S, 7.76 ± 0.09%.

PAPER

Drug Metabolism & Disposition (2017), 45(7), 817-825

Patent ID

Patent Title

Submitted Date

Granted Date

US9169251 PYRROLOPYRIDINE DERIVATIVES AND THEIR USE AS CRTH2 ANTAGONISTS
2014-06-26
2014-10-16
Patent ID

Patent Title

Submitted Date

Granted Date

US2016108123 ANTIBODY MOLECULES TO PD-L1 AND USES THEREOF
2015-10-13
2016-04-21
US8455645 Organic compounds
2010-08-19
US8470848 Organic compounds
2010-08-12
US7666878 Pyrrolopyridine Derivatives And Their Use As Crth2 Antagonists
2008-05-15
2010-02-23
US8791256 Pyrrolopyridine derivatives and their use as CRTH2 antagonists
2013-06-05
2014-07-29

References

  1. Jump up to:a b Erpenbeck VJ, Vets E, Gheyle L, Osuntokun W, Larbig M, Neelakantham S, et al. (2016). “Pharmacokinetics, Safety, and Tolerability of Fevipiprant (QAW039), a Novel CRTh2 Receptor Antagonist: Results From 2 Randomized, Phase 1, Placebo-Controlled Studies in Healthy Volunteers”Clin Pharmacol Drug Dev5 (4): 306–13. doi:10.1002/cpdd.244PMC 5071756Freely accessiblePMID 27310331.
  2. Jump up^ Sykes DA, Bradley ME, Riddy DM, Willard E, Reilly J, Miah A, Bauer C, Watson SJ, Sandham DA, Dubois G, Charlton SJ. Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy. Mol Pharmacol. 2016 May;89(5):593-605. doi: 10.1124/mol.115.101832 PMID 26916831
  3. Jump up^ Erpenbeck VJ, Popov TA, Miller D, Weinstein SF, Spector S, Magnusson B, et al. (2016). “The oral CRTh2 antagonist QAW039 (fevipiprant): A phase II study in uncontrolled allergic asthma”. Pulm Pharmacol Ther39: 54–63. doi:10.1016/j.pupt.2016.06.005PMID 27354118.
  4. Jump up^ https://clinicaltrials.gov/ct2/show/NCT02555683
  5. Jump up^ Gonem S, Berair R, Singapuri A, Hartley R, Laurencin M, Bacher G, et al. (2016). “Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial”. Lancet Respir Med4: 699–707. doi:10.1016/S2213-2600(16)30179-5
Fevipiprant
Fevipiprant.svg
Clinical data
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Bioavailability Unaffected by food[1]
Metabolism Hepatic glucuronidation
Biological half-life ~20 hours
Excretion Renal (≤30%)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C19H17F3N2O4S
Molar mass 426.41 g/mol
3D model (JSmol)

////////////////FEVIPIPRANT, QAW039, PHASE 3, asthma, UNII-2PEX5N7DQ4,2PEX5N7DQ4, NVP-QAW039, QAW039, 872365-14-5,

CC1=C(C2=C(N1CC3=C(C=C(C=C3)S(=O)(=O)C)C(F)(F)F)N=CC=C2)CC(=O)O

LL 3858, SUDOTERB


SUDOTERB.png

Figure imgf000023_0002

LL 3858, SUDOTERB

UNII-SK2537665A;

CAS 676266-31-2;

N-[2-methyl-5-phenyl-3-[[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]methyl]pyrrol-1-yl]pyridine-4-carboxamide;

N-[2-Methyl-5-phenyl-3-[[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]methyl]-1H-pyrrol-1-yl]-4-pyridinecarboxamide

Sudoterb(TM)

Molecular Formula: C29H28F3N5O
Molecular Weight: 519.572 g/mol
  • Originator Lupin
  • Class Antituberculars; Isonicotinic acids; Pyrroles
  • Mechanism of Action Undefined mechanism
  • Orphan Drug Status No
  • New Molecular Entity Yes

Highest Development Phases

  • No development reported Tuberculosis

Most Recent Events

  • 23 Jul 2015 No recent reports on development identified – Phase-II for Tuberculosis in India (unspecified route)
  • 11 Dec 2013 Lupin completes a phase II trial in Tuberculosis in India prior to December 2013 (CTRI2009-091-000741)
  • 31 Jul 2010 Lupin completes enrolment in its phase II trial for Tuberculosis in India (CTRI2009-091-000741)

img

Sudoterb HCl
CAS: 1044503-04-9 (2HCl)
Chemical Formula: C29H30Cl2F3N5O
Molecular Weight: 592.4882

Image result

Image result for sudoterb

SYNTHESIS

WO 2006109323

Tuberculosis (TB) is a contagious disease, which usually runs a protracted course, ending in death in majority of the cases, with relapse being a common feature of the disease. It is one of the most important causes of prolonged disability and chronic ill health. It is caused by the tubercle bacillus Mycobacterium tuberculosis, which is comparatively difficult to control. Drugs such as isoniazid, rifampicin, pyrazinamide, ethambutol streptomycin, para- aminosalisylic acid, ethionamide, cycloserine, capreomycin, kanamycin, thioacetazone etc. have been and are being currently used to treat TB. Amongst these, isoniazid, rifampicin, ethambutol and pyrazinamide are the first-line drugs of choice, which are administrated either as a single drug formulation or as a fixed-dose combination of two or more of the aforesaid drugs. Even though, each of the abovementioned first-line drug regimen is highly effective for treatment of TB, however, they are associated with shortcomings, such as unpleasant side- effects and relatively long course of treatment. The later one results in non-compliance of the patient to the treatment leading often to failure of the treatment and most importantly, development of drug resistance. The development of drug resistance has long constituted a principal difficulty in treating human tuberculosis. The second-line drugs, on the other hand are less effective, more expensive and more toxic.

It is estimated that in the next twenty years over one billion people would be newly infected with TB, with 35 million people succumbing to the disease (WHO Fact Sheet No. 104, Global

Alliance for TB Drug Development- Executive Summary of the Scientific Blueprint for TB

Development : http://www.who.int/inf-fs/en/factl04.hfaiil). With the emergence of HIV related

TB, the disease is assuming alarming proportions as one of the killer diseases in the world today.

A major thrust in research on antimycobacterials in the last decade has witnessed the development of new compounds for treatment of the disease, a) differing widely in structures, b) having different mode/mechanism of action, c) possessing favourable pharmacokinetic properties, d) which are safe and having low incidence of side-effects, and e) which provide a cost-effective dosage regimen.

Several new class of compounds have been synthesized and tested for activity against Mycobacterium tuberculosis, the details of chemistry and biology of which could be found in a recent review by B. N. Roy et. al. in J. Ind. Chem. Soc, April 2002, 79, 320-335 and the references cited therein.

Substituted pyrrole derivatives constitute another class of compounds, which hold promise as antimycobacterial agents. The pyrrole derivatives which have been synthesized and tested for antitubercular as well as non-tubercular activity has been disclosed by : a) D. Deidda et. al. in Antimicrob. Agents and Chemother., Nov 1998, 3035-3037. This article describes the inhibitory activity shown by one pyrrole compound, viz. BM 212 having the structure shown below, against both Mycobacterium tuberculosis including drug-resistant mycobacteria and some non-tuberculosis mycobacteria.

Figure imgf000004_0001

The MIC value (μg/ml) against the M. tuberculosis strain 103471 exhibited by BM 212 was 0.70 as against 0.25 found for isoniazid.

b) M. Biava et. al. in J. Med. Chem. Res., 1999, 19-34 have reported the synthesis of several analogues of BM 212, having the general formula (The compounds disclosed by M. Biava et. al. inJ. Med. Chem. Res., 1999, 19-34.) shown hereunder

Figure imgf000005_0001

wherein,

Figure imgf000005_0002

X is H, . CH2— (Oy-Cl ; CH2-(CH2)4-CH3

Figure imgf000005_0003
Figure imgf000005_0004

Z is H ; Y

and the in vitro antimicrobial activity of the compounds against Candida albicans, Candida sp, Cryptococcus neoforma s, Gram- positive or Gram-negative bacteria, isolates of pathogenic plant fungi, Herpes simplex virus, both HSV1 and HSN2, M. tuberculosis, M. smegmαtis, M. mαrinum and M. αvium.

However, the MIC values (μg/ml) of these compounds against the M. tuberculosis strain 103471 are found to be inferior to BM 212 and are in the range of 4-16.

M. Biava et. al. in Bioorg. & Med. Chem. Lett., 1999, 9, 2983-2988. This article describes the synthesis of pyrrole compounds of formula (: The compounds disclosed by M. Biava et. al. in Bioorg. & Med. Chem. Lett., 1999, 9, 2983-2988) shown hereunder

Figure imgf000006_0001

wherein,

X is H or Cl Y is H or Cl

R is N-methyl piperazinyl or thiomorphinyl

and their respective in vitro activity against M. tuberculosis and non-tuberculosis species of mycobacteria .

However, the MIC values (μg/ml) of these compounds against the M. tuberculosis strain 103471 are found to be inferior to BM 212 and are in the range of 2-4.

d) F. Cerreto et. al. in Eur. J. Med. Chem., 1992, 27, 701-708 have reported the synthesis of certain 3-amino-l,5-diary-2 -methyl pyrrole derivatives and their in vitro anti-fungal activity against Candida albicans and Candida sp. However, there is no report on the activity of such compounds against M. tuberculosis.

e) C. Gillet et. al. in Eur. J. Med. Chem.-Chimica Therapeutica, March- April 1976, ϋ(2), 173-181 report the synthesis of several pyrrole derivatives useful as anti-inflammatory agents and as anti-allergants.

f) R. Ragno et. al., Bioorg. & Med. Chem., 2000, 8, 1423-1432. This article reports the synthesis and biological activity of several pyrrole derivatives as well as describes a structure activity relationship between the said pyrrole compounds and antimycobacterial activity. The compounds (The compounds disclosed by R. Rango et. al., Bioorg. & Med. Chem., 2000, 8, 1423-1432)synthesized and tested by the authors is summarized hereunder

Figure imgf000007_0001

wherein,

X is COOH, COOEt, CONHNH2, CH2OH, CH(OH)C6H5, NO2

Figure imgf000007_0002

Y is H, CH3, OCH3, CH2, SO2, or a group of formula

Figure imgf000007_0003

wherein,

R is H, Cl, C2H5, or OCH3 and R1 is H, Cl, F, CH3, or NO2,

A is H or R

Z is a group of formula,

Figure imgf000007_0004

R2 is H, Cl, OH, or OCH3 and R3 is H or Cl

None of the abovementioned disclosures report or suggest the in vivo efficacy including toxicity of any of the compounds described therein against experimental tuberculosis in animal model. Moreover, the higher MIC values of the compounds reported suggest that they may not be very effective in inhibition of Mycobacterium tuberculosis.

NO PIC

Sudershan Kumar Arora

sudershan arora, Formerly: President R&D, Ranbaxy Lab Limited,

Experience

Inventors Sudershan Kumar AroraNeelima SinhaSanjay JainRam Shankar UpadhayayaGourhari JanaShankar AjayRakesh Kumar Sinha
Applicant Lupin Limited

PATENT

WO 2004026828

https://www.google.com/patents/WO2004026828A1?cl=en

PATENT

US 20050256128

PATENT

https://encrypted.google.com/patents/WO2005107809A2?cl=en

Thus the invention relates to an antimycobacterial combination comprising a therapeutically effective amount of N-(3-[[4-(3-trifluoromethylphenyl)piperazinyl]methyl]-2- methy 1-5 -phenyl- pyrrolyl)-4-pyridylcarboxamide of formula (I) or a pharmaceutically acceptable non- toxic salt thereof

Figure imgf000011_0001

and a therapeutically effective amount of one or more first line antitubercular drugs selected from the group consisting of isoniazid, rifampicin, ethambutol and pyrazinamide. Further according to the invention there is provided a process for preparation of an antimycobacterial pharmaceutical composition comprising combining a compound of formula I or a pharmaceutically acceptable salt thereof

Figure imgf000011_0002

and one or more of the first line antitubercular drugs using a dry granulation method, a wet granulation method or a direct compression method. The present invention further provides an antimycobacterial combination comprising a therapeutically effective amount of N-(3-[[4-(3-trifluoromethylphenyl)piperazinyl]methyl]-2- methyl-5-phenyl-pyrrolyl)-4-pyridylcarboxamide of formula (I) the compound of formula (I) or a pharmaceutically acceptable non-toxic salt thereof

Figure imgf000012_0001

and a therapeutically effective amount of one or more first line antitubercular drugs selected firom isoniazid, rifampicin, ethambutol and pyrazinamide for treatment of multi-drug resistant tuberculosis including latent tuberculosis. The present invention provides an antimycobacterial combination comprising a therapeutically effective amount of N-(3-[[4-(3-trifluoromethylphenyl)piperazinyl]methyl]-2- methyl-5-phenyl-pyrrolyl)-4-pyridylcarboxamide of formula (I) or a pharmaceutically acceptable non-toxic salt thereof

Figure imgf000012_0002

and a therapeutically effective amount of one or more first line antitubercular drugs selected from isoniazid, rifampicin, ethambutol and pyrazinamide for treatment and/or inhibition of one or more mycobacterial conditions/ cells including but not limited to sensitive and multi- drug resistant strains of Mycobacterium tuberculosis, Mycobacterium avium – intracellular complex, M. fortutium, M. kansasaii and other related mycobacterial species.

ynthesis of Compound of Formula (I) The compound of formula (I) and the pharmaceutically acceptable salts thereof can be synthesized by any known method including but not limited to the methods disclosed in our PCT Application No. PCT/IN02/00189 (WO 04/026828 Al), which is incorporated herein by reference. An example of the preparation of N-(3-[[4-(3-trifluoromethylphenyl) piperazinyl]methyl]-2-methyl-5-phenyl-pyrrolyl)-4-pyridylcarboxamide is as follows:

Preparation of N-(3 ~[[4-(3 -trifluoromethylphenyl)piperazinyl]methyl)] -2-methyl-5 – phenylpyrrolyl)-4-pyridylcarboxamide

Step l 1 -(4-chlorophenyl)pentane- 1 ,4-dione To a well stirred suspension of anhydrous aluminium chloride (27.0gm, 205.9mmol) in

126ml. of chlorobenzene was added oxopentanoylchloride (23.0gm, 171.6 mmol) drop-wise, over a period of 30-35 minutes at room temperature (25-30EC). The reaction mixture was stirred at the same temperature for 1 hour. After decomposition of the reaction mixture by the addition of solid ice and hydrochloric acid (10ml) the precipitated solid was filtered and the filtrate evaporated on a rotary evaporator to remove all the solvents. The residue was dissolved in ethyl acetate (400 ml), washed with water (2 x 100ml.), brine (100 ml.) and dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product so obtained was chromatographed over silica gel (100-200 mesh) using chloroform as eluent to give 8.6gm (24.07%) of the title compound.

Step 2 N-(5-methyl-2-phenylpyrrolyl)-4 pyridylcarboxamide

A mixture of 1- (chlorophenyl)pentane-l,4-dione (6.0g, 28.50 mmol, as obtained in Step-1) and isonicotinic hydrazide (4.30gm, 31.35 mmol) in benzene (6.0 ml.) was refluxed by over molecular sieves. After two hours, benzene was removed under reduced pressure and the residue dissolved in ethyl acetate, washed with water (2 x 100 ml.) and brine (1 x 50 ml.). The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product so obtained as purified by column chromatography over silica gel (100-200 mesh) using 0.2% methanol in chloroform as eluent to give 3.50gm (39.42%) of the title compound.

Step 3 N-(3 – { [4-(3-trifuoromethylphenyl)piperazinyl]methyl} -2-methyl-5 -phenylpyrrolyl)-4- pyridylcarboxamide

To a stirred solution of N-(5-methyl-2-phenylpyrrolyl)-4-pyridylcarboxamide (0.300gm, 1.083 mmol, as obtained in Step-2) in acetonitrile (5.0 ml.) was added a mixture of l-(3-trifluoromethylphenyl)piperazine hydrochloride (0.288gm, 1.083mmol), 40% formaldehyde (0.032gm, 1.083 mmol) and acetic acid (0.09 ml), drop-wise. After the completion of addition, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized with sodium hydroxide (20% aq. Soln.) and extracted with ethyl acetate (2 x 50 ml.). The combined ethyl acetate extract was washed with water (2 x 25 ml.), brine (1-χ 20 ml.), and dried over anhydrous sodium sulfate and the solvent evaporated off. TLC of the crude product indicated two spots, which were separated by column chromatography over silica gel (100-200mesh). The more polar compound a eluted out using 80% ethyl acetate- hexane mixture was obtained in 24.34 % (0.130 gm) and was identified as N-(3-{[4-(3- trifluoromethylphenyl)piperazinyl]methyl}-2-methyl-5-phenylpyrrolyl)-4- pyridylcarboxamide m.p.80-82°C, MS: m/z 520 (M+l)

1HNMR(CDC13, *): 2:13 (s, 3H,CH3), 2.60 (bs, 4H, 2xN-CH2), 3.18 (bs, 4H, 2xN-CH2), 3.41 (s, 2H, N-CH2), 6.24 (s, lH,H-4), 6.97-7.03 (4H, m, ArH), 7.22-7.29 (m, 5H,AιΗ), 7.53 (d, 2H, J=6Hz, pyridyl ring), 8.50 (bs, 1H,NH D2O exchangeable), 8.70 (d, 2H, J=6Hz, pyridyl ring).

PATENT

WO 2006109323

Compounds of Formula I are known from PCT International Patent Application WO 2004026828, and were screened for antimycobacterial activity, in various in vitro and in vivo models in mice and guinea pigs. Several compounds exhibited strong antimycobacterial activity against sensitive and MDR strains of Mycobacterium tuberculosis in the in vitro and in vivo experiments. Further the compounds of Formula I were also found to be bioavailable, less toxic and safe compared to available anti TB drugs in various animal models.

Thus compounds of Formula I are useful for the effective treatment of Mycobacterium tuberculosis infection caused by sensitive/MDR strains. PCT International Patent Application WO 2004026828 also discloses the synthesis of compounds of Formula I,

Figure imgf000004_0001

wherein,

Ri is phenyl or substituted phenyl

R2 is selected from a group consisting of i) phenyl which is unsubstituted or substituted with 1 or 2 substituents, each independently selected from Cl, F, or, ii) pyridine, or iii) naphthalene, or iv) NHCOR4 wherein R4 is aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclyl. R3 is selected from a group of formula

/~-\ /-Un

— N N-R5 and — N X

wherein R5 is phenyl which is unsubstituted or substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, Ci-C4 alkyl, Ci-C4 alkoxy, nitro, amino, haloalkyl, haloalkoxy etc.; unsubstituted or substituted benzyl; unsubstituted or substituted heteroaryl; unsubstituted or substituted heteroaroyl; unsubstituted or substituted diphenylmethyl,

n = 0-2 and X = -NCH3, CH2, S, SO, or SO2

Such that when R2 is phenyl, which is unsubstituted or substituted with 1 or 2 substituents, each independently selected from Cl, F; R5 is not Ci-C4 alkyl, or X is not -NCH3, CH2, S, SO, or SO2, when n = 1, or X is not -CH2 when n = 0 which comprises reacting the compound of Formula Il

»o-i >-CH, (H)

O O

with thionyl chloride, followed by reaction with RiH (wherein Ri is phenyl or substituted phenyl) in presence of aluminium chloride, and then condensation with R2NH2 (wherein R2 is as described above) in presence of p-toluenesulphonic acid to yield the corresponding unsubstituted pyrrole derivatives of Formula V,

Figure imgf000005_0001

which on further treatment with suitable secondary amines in the presence of formaldehyde and acetic acid afforded the desired pyrrole derivatives of Formula I,

Figure imgf000006_0001

which, on reacting with hydrochloric acid give a hydrochloride salt of compound of Formula Ia. wherein m = 1-2, Ri, R2 and R3 are the same as defined earlier. The above-mentioned methods in the prior art for the synthesis of compound of the Formula I suffer from the limitations,

1. In methods described in PCT International Patent Application WO 2004026828 for the synthesis of compounds of Formula I, positional isomers, the compound of Formula I’, are formed. The necessity of their removal through column chromatography decreases the yield of final pure product.

Figure imgf000006_0002

2. The synthesis of oxopentanoyl chloride (compound of Formula III) for the synthesis of compound of Formula I has been described in J. Org. Chem.

1960, 25, 390-392. It comprises reaction of levulinic acid with thionyl chloride at 50 0C for 1h, which results in poor yield.

3. In method described in PCT International Patent Application WO 2004026828 for the synthesis of 1-aryl-pentane-1,4-dione (compound of Formula IV), impurities are formed and purification involves column chromatography which decreases the yield of the product. 4. The synthesis of the intermediate of Formula V requires the use of benzene and high temperature conditions, which involves the formation of undesired by- products.

5. The above-mentioned methods in prior art for the synthesis of all the intermediates and final compounds of Formula I involves column chromatography for purification, which is cumbersome, tedious and not practicable on an industrial scale.

Example 1: Preparation of /V-(2-methyl-5-phenyl-3-f4-C3-trifluoromethyl-phenyl)- piperazin-1-ylmethyli-pyrrol-i-ylHsonicotinamide hydrochloride

Step (a): Preparation of 4-oxo-pentanoyl chloride

To a stirred mixture of levulinic acid (340.23 g, 2.93 mol) and Λ/./V- dimethylformamide (6.8 mL, catalytic amount) was added thionyl chloride (367.36 g, 3.087 mol, 1.05 equivalent) drop-wise at 20-30 0C in 1.5-2.0 h. After the complete addition of thionyl chloride, the reaction mixture was stirred at same temperature for 0.5 h (completion of reaction or formation of acid chloride was monitored by GC). After the completion of reaction, thionyl chloride was distilled off under reduced pressure at 20-30 0C. Traces of thionyl chloride were removed by adding benzene (136 mL) under reduced pressure at 30-35 0C and residue was dried at reduced pressure (1-2 mm) at 20-30 0C for 30-60 min to yield 370 g (93.8%) of 4-oxo-pentanoyl chloride as light orange oil. Step (b): Preparation of 1-phenyl-pentane-1,4-dione

Figure imgf000016_0001

(B) (A)

To a stirred suspension of benzene (3700 mL, 10 T w/v of acid chloride) and anhydrous aluminium chloride (440.02 g, 3.30 mol, 1.20 equivalent) was added A- oxo-pentanoyl chloride (370 g, 2.75 mol) drop-wise; the rate of addition was regulated so that the addition required 1.5-2 h and the temperature of the reaction mixture was kept at 25-35 0C. The reaction was completed in 2 h and monitored by GC. After completion of reaction, the reaction mixture was added slowly into cold (5-10 0C) 5% HCI (3700 mL) solution maintaining the temperature below 30 0C. The layers were separated; aqueous layer was extracted with ethyl acetate (1×1850 mL). The combined organic phase was washed with water (1 *1850 mL), 5% NaHCO3 solution (1×1850 mL), water (1×1850 mL), 5% NaCI solution (1×1850 mL), dried (Na2SO4), filtered and concentrated under reduced pressure at 35-40 0C, which was finally dried under reduced pressure (1-2 mm) at 35-400C to yield 185.6 g (38.3%) of 1-phenyl-pentane-1,4-dione as thick oil.

Step (c): Preparation of /V-(2-methyl-5-phenyl-pyrrol-1-yI)-isonicotinamide

A mixture of 1-(phenyl)-pentane-1,4-dione (185 g, 1.05 mol), isonicotinic hydrazide (158.4 g, 1.155 mol, 1.1 equivalent), p-toluenesulphonic acid (1.85 g, 1% w/w) and dichloromethane (1850 ml_) was heated under reflux at 40-50 0C under azeotropic distillation for 2-3 h (water was collected in dean stark apparatus). The completion of reaction was monitored by HPLC. After cooling to 25-30 0C the resulting mixture was washed with saturated NaHCO3 solution (1×925 mL), aqueous layer was back extracted with EtOAc (1×925 ml_). The combined organic layers were washed with water (1×925 mL), 5% brine solution (1×925 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to obtain the solid product, which was further dried under reduced pressure (1-2 mm) at 35-40 0C. To this, cyclohexane (925 mL) was added and stirred for 25-30 min, solid separated out was filtered washed with cyclohexane (370 mL). This process was repeated two times more with the same amount of cyclohexane and finally solid was dried under reduced pressure (1-2 mm) at 40-500C; yield 162.23 g (55.7%). White solid, mp 177-179 0C. 1H NMR (CDCI3): δ 2.10 (s, 3H), 5.98 (d, J = 3.4 Hz, 1H), 6.22 (d, J = 3.7 Hz, 1H), 7.237.28 (m, 5H), 7.50 (d, J = 5.6 Hz, 2H), 8.55 (d, J = 5.0 Hz, 2H), 9.82 (s, 1H). MS: m/z (%) 278 (100) [M+1]. Anal. Calcd for C17H15N3O (277.32): C, 73.63; H, 5.45; N, 15.15. Found: C, 73.92; H, 5.67; N, 15.29.

Step (d): Preparation of /V-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl- phenyl)-piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide

To a stirred solution of Λ/-(2-methyl-5-phenyl-pyrrol-1-yl)-isonicotinamide (160 g, 0.577 mol) in acetonitrile (1600 mil), was added drop-wise through pressure equalizing funnel a mixture of 1-(3-trifluoromethyl-phenyl)-piperazine monohydrochloride (153.75 g, 0.667 mol, 1.155 equivalent), formaldehyde (17.34 g, 0.577 mol, 1.0 equivalent) and acetic acid (480 mL) at 25-30 0C over a period of 60-90 min. The resulting reaction mixture was stirred for 14-16 h at same temperature and completion of reaction was monitored by TLC. After the completion of reaction, reaction mixture was treated with 20% aqueous NaOH solution (2600 mL). Layers were separated, EtOAc (4000 mL) was added to organic layer, washed with water (2×2000 mL), brine (2×1250 mL), dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure at 35-38 0C and then dried under reduced pressure (1-2 mm) to yield the mixture of Λ/-{5-methyl-2-phenyl-3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-pyrrol- 1-yl}-isonicotinamide (A) and Λ/-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl- phenyl)-piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide (B), yield 289 g (97.8%). The ratio of A and B was determined by reverse phase HPLC, which was found to be 19.4% and 76.7%, respectively.

Step (e): Purification of yV-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl-phenyl)- piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide i) The mixture of A and B obtained from Step (d) (279 g) was dissolved in EtOAc (1960 ml_, 7 times) by heating at 50-60 0C. To this activated charcoal (14 g) was added and stirred for 10 min at the same temperature, filtered the activated charcoal through celite bed at 50-60 0C, washed with EtOAc (560 mL). After cooled to 25-30 0C, cyclohexane (2800 mL) was added to the filtrate and stirred the reaction mixture for 14-15 h at 20-35 0C. Solid separated out was filtered, washed with cyclohexane (3500 mL) and dried under reduced pressure (1-2 mm) for 4-5 hours. Yield 151 g (52%). Ratio of A and B was found to be 1.7% and 96.6%, respectively.

ii) The mixture of A and B obtained from Step (e)(i) (151 g) was dissolved in

EtOAc (755 mL, 5 times) by heating at 50-60 0C. After cooled to 25-30 0C, cyclohexane (1510 mL) was added and stirred the reaction mixture for 14-15 h at 20-35 0C. Solid separated out was frltered, washed with cyclohexane (3000 mL) and dried under reduced pressure (1-2 mm) for 4-5 hours. Yield 140 g (92%). Ratio ofA and B was found to be 0.2% and 98.1%, respectively.

Off white solid, mp 191-193 0C. 1H NMR (CDCI3): δ 2.13 (s, 3H), 2.60 (br s, 4H), 3.13 (br s, 4H), 3.41 (s, 2H), 6.24 (s, 1H), 6.977.29 (m, 9H), 7.53 (d, J = 5.6 Hz, 2H), 8.50 (S, 1H), 8.70 (d, J = 5.6 Hz, 2H). 13C NMR (CDCI3): δ 165.93, 151.77, 150.86, 139.74, 133.02, 131.99, 131.43, 129.92, 129.01, 127.79, 127.49, 121.74, 119.09, 116.18, 115.05, 112.48, 109.51, 54.87, 52.99, 48.93, 9.77. MS: m/z (%) 520 (100) [M+U Anal. Calcd for C29H28F3N5O (519.56): C, 67.04; H, 5.43; N, 13.48. Found: C, 67.36; H, 5.71; N, 13.69.

The free base Λ/-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl-phenyl)-piperazin-1- ylmethyl]-pyrrol-1-yl}-isonicotinamide is obtained in a crystalline form having characteristic powder X-ray diffraction pattern given in Figure 1 with 2Θ values 4.85, 5.99, 6.83, 7.34, 9.15, 9.78, 10.93, 11.98, 13.17, 13.98, 14.33, 14.75, 15.73, 16.42, 17.11. 17.72, 17.95, 18.32, 19.11, 19.75, 20.32, 21.36, 22.04, 23.19, 25.17

Step (f): Preparation of /V-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl-phenyl)- piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide hydrochloride

To a stirred solution of 6% w/v HCI-EtOAc solution (821.8 mL, 1.351 mol, 7.0 equivalent) in EtOAc (2000 mL) was added a solution of Λ/-{2-methyl-5-phenyl-3- [4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide (100 g, 0.193 mol) in EtOAc (2000 mL) through dropping funnel at 15-20 0C. When the addition was completed (~60 min), the reaction mixture was stirred at 10-150C for 1 h and then nitrogen gas was passed through reaction mass for 1 h until all the excess HCI fumes were removed. Solid so obtained was filtered through suction in an inert atmosphere, washed with ethyl acetate (2×500 mL), diisopropyl ether (2×500 mL) and dried in vacuum oven under reduced pressure (1-2 mm) at 35-40 0C for 15-20 h. Yield 115 g (99%).

Yellow solid, mp 177-179 0C. 1H NMR (DMSO-d6): δ 2.21 (s, 3H), 3.11-3.42 (m, 6H), 3.93-4.23 (m, 4H), 6.62 (s, 1H), 7.09-7.51 (m, 9H), 8.19-8.21 (d, 2H, J = 4.6 Hz), 8.95-8.97 (d, 2H1 J = 4.6 Hz), 11.30 (br s, 1H), 12.86 (s, 1H). MS: m/z (%) 520 (100) [M+1]. Anal. Calcd for C29H28F3N5O.2HCI.3H2O (646.53): C, 53.87; H, 5.61; N, 10.83. Found: C, 53.67; H, 5.59; N, 10.86.

The product obtained was amorphous in nature having the characteristic X-ray powder diffraction pattern given in Figure 2.

Cited Patent Filing date Publication date Applicant Title
WO2004026828A1 * Sep 20, 2002 Apr 1, 2004 Lupin Limited Pyrrole derivatives as antimycobacterial compounds
WO2005107809A2 * Aug 27, 2004 Nov 17, 2005 Lupin Limited Antimycobacterial pharmaceutical composition comprising an antitubercular drug
US3168532 * Jun 12, 1963 Feb 2, 1965 Parke Davis & Co 1, 5-diarylpyrrole-2-propionic acid compounds
Reference
1 * BIAVA M ET AL: “SYNTHESIS AND MICROBIOLOGICAL ACTIVITIES OF PYRROLE ANALOGS OF BM 212, A POTENT ANTITUBERCULAR AGENT” MEDICINAL CHEMISTRY RESEARCH, BIRKHAEUSER, BOSTON, US, vol. 9, no. 1, 1999, pages 19-34, XP008016949 ISSN: 1054-2523
2 * BIAVA, MARIANGELA ET AL: “Antimycobacterial compounds. New pyrrole derivatives of BM212” BIOORGANIC & MEDICINAL CHEMISTRY , 12(6), 1453-1458 CODEN: BMECEP; ISSN: 0968-0896, 2004, XP002390961
3 * PARLOW J.J.: “synthesis of tetrahydonaphthaenes. part II” TETRAHEDRON, vol. 50, no. 11, 1994, pages 3297-3314, XP002391102
4 * R. RIPS , CH. DERAPPE AND N. BII-HOÏ: “1,2,5-trisubstituted pyrroles of pharmacologic interest” JOURNAL OF ORGANIC CHEMISTRY, vol. 25, 1960, pages 390-392, XP002390960 cited in the application

REFERENCES

1: Didilescu C, Craiova UM. [Present and future in the use of anti-tubercular
drugs]. Pneumologia. 2011 Oct-Dec;60(4):198-201. Romanian. PubMed PMID: 22420168.

2: Nuermberger EL, Spigelman MK, Yew WW. Current development and future prospects
in chemotherapy of tuberculosis. Respirology. 2010 Jul;15(5):764-78. doi:
10.1111/j.1440-1843.2010.01775.x. Review. PubMed PMID: 20546189; PubMed Central
PMCID: PMC4461445.

3: LL-3858. Tuberculosis (Edinb). 2008 Mar;88(2):126. doi:
10.1016/S1472-9792(08)70015-5. Review. PubMed PMID: 18486049.

4: Ginsberg AM. Drugs in development for tuberculosis. Drugs. 2010 Dec
3;70(17):2201-14. doi: 10.2165/11538170-000000000-00000. Review. PubMed PMID:
21080738.

Patent ID

Patent Title

Submitted Date

Granted Date

US2016318925 IMIDAZO [1, 2-a]PYRIDINE COMPOUNDS, SYNTHESIS THEREOF, AND METHODS OF USING SAME
2016-02-29
US9309238 IMIDAZO [1, 2-a]PYRIDINE COMPOUNDS, SYNTHESIS THEREOF, AND METHODS OF USING SAME
2010-11-05
2012-08-30
US7491721 Antimycobacterial pharmaceutical composition
2005-11-17
2009-02-17
US2009118509 PREPARATION OF [2-METHYL-5-PHENYL-3-(PIPERAZIN-1-YLMETHYL)] PYRROLE DERIVATIVES
2009-05-07

///////////////LL 3858, SUDOTERB, TB, LUPIN

CC1=C(C=C(N1NC(=O)C2=CC=NC=C2)C3=CC=CC=C3)CN4CCN(CC4)C5=CC=CC(=C5)C(F)(F)F

VOXELOTOR


Image result for VOXELOTOR

VOXELOTOR

GBT 440; GTx-011, Treatment of Sickle Cell Disease

RN: 1446321-46-5
UNII: 3ZO554A4Q8

Molecular Formula, C19-H19-N3-O3, Molecular Weight, 337.3771

Benzaldehyde, 2-hydroxy-6-((2-(1-(1-methylethyl)-1H-pyrazol-5-yl)-3-pyridinyl)methoxy)-

2-hydroxy-6-((2-(1-(propan-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

  • Originator Global Blood Therapeutics
  • Class Antianaemics; Small molecules
  • Mechanism of Action Abnormal haemoglobin modulators; Sickle haemoglobin modulators
  • Orphan Drug Status Yes – Sickle cell anaemia
  • New Molecular Entity Yes

Highest Development Phases

  • Phase III Sickle cell anaemia
  • Phase I Hypoxia; Liver disorders
  • Discontinued Idiopathic pulmonary fibrosis

Most Recent Events

  • 01 Nov 2017 Chemical structure information added
  • 28 Oct 2017 Efficacy and adverse event data from a case study under the compassionate use programme in Sickle cell anaemia released by Global Blood Therapeutics
  • 27 Oct 2017 Discontinued – Phase-II for Idiopathic pulmonary fibrosis in USA (PO)

Voxelotor, also known as GBT-440, is a hemoglobin S allosteric modulator. GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under In Vitro Conditions Mimicking Strenuous Exercise. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease.

Image result for VOXELOTORImage result for VOXELOTOR

Image result for VOXELOTOR

PATENT

WO 2013102142

Inventors Brian MetcalfChihyuan ChuangJeffrey WarringtonKumar PAULVANNANMatthew P. JacobsonLan HUABradley Morgan
Applicant Global Blood Therapeutics, Inc.Cytokinetics, Inc.The Regents Of The University Of California

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013102142

Hemoglobin (Hb) is a tetrameric protein in red blood cells that transports up to four oxygen molecules from the lungs to various tissues and organs throughout the body.

Hemoglobin binds and releases oxygen through conformational changes, and is in the tense (T) state when it is unbound to oxygen and in the relaxed (R) state when it is bound to oxygen. The equilibrium between the two conformational states is under allosteric regulation. Natural compounds such as 2,3-bisphosphoglycerate (2,3-BPG), protons, and carbon dioxide stabilize hemoglobin in its de-oxygenated T state, while oxygen stabilizes hemoglobin in its oxygenated R state. Other relaxed R states have also been found, however their role in allosteric regulation has not been fully elucidated.

Sickle cell disease is a prevalent disease particularly among those of African and Mediterranean descent. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing the T state to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels. Certain synthetic aldehydes have been found to shift the equilibrium from the polymer forming T state to the non-polymer forming R state (Nnamani et al. Chemistry & Biodiversity Vol. 5, 2008 pp. 1762-1769) by acting as allosteric modulators to stabilize the R state through formation of a Schiff base with an amino group on hemoglobin.

US 7, 160,910 discloses 2-furfuraldehydes and related compounds that are also allosteric modulators of hemoglobin. One particular compound 5-hydroxymethyl-2-furfuraldehyde (5HMF) was found to be a potent hemoglobin modulator both in vitro and in vivo. Transgenic mice producing human HbS that were treated with 5HMF were found to have significantly improved survival times when exposed to extreme hypoxia (5% oxygen). Under these hypoxic conditions, the 5HMF treated mice were also found to have reduced amounts of hypoxia-induced sickled red blood cells as compared to the non-treated mice.

A need exists for therapeutics that can shift the equilibrium between the deoxygenated and oxygenated states of Hb to treat disorders that are mediated by Hb or by abnormal Hb such as HbS. A need also exists for therapeutics to treat disorders that would benefit from having Hb in the R state with an increased affinity for oxygen. Such therapeutics would have applications ranging, for example, from sensitizing hypoxic tumor cells that are resistant to standard radiotherapy or chemotherapy due to the low levels of oxygen in the cell, to treating pulmonary and hypertensive disorders, and to promoting wound healing

Example 18. Preparation of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (Compound 43).

A mixture of 2,6-dihydroxybenzaldehyde (1.58 g, 11.47 mmol, 2 eq.) and K2CO3 (2.4 g, 17.22 mmol, 3 eq.) in DMF (150 mL) was stirred at rt for 10 min. To this mixture was added 3-(chloromethyl)-2-(1-isopropyI-1H-pyrazol-5-yl)pyridine hydrochloride (1.56 g, 5.74 mmol, leq.) at rt. The mixture was heated at 50 °C for 2 h, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (1.71 g, 88%) as a pale yellow solid.

PAPER

ACS Medicinal Chemistry Letters (2017), 8(3), 321-326.

http://pubs.acs.org/doi/full/10.1021/acsmedchemlett.6b00491

Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin

 Global Blood Therapeutics, Inc., South San Francisco, California 94080, United States
 Cytokinetics, Inc., South San Francisco, California 94080, United States
 Albert Einstein College of Medicine, Bronx, New York 10461, United States
 Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States
§ Tandem Sciences, Inc., Menlo Park, California 94025, United States
ACS Med. Chem. Lett.20178 (3), pp 321–326
DOI: 10.1021/acsmedchemlett.6b00491

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Abstract Image

We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).

Figure

cheme 1. Synthesis of 36a

aReagents and conditions: (a) MOMCl, DIEPA, DCM, 0 °C to rt 2 h, 90%; (b) nBuLi, DMF, THF, −78 to 0 °C, 94%; (c) 12 N HCl, THF, rt, 1.5 h, 81%; (d) Pd(dppf)Cl2, NaHCO3, H2O/dioxane, 100 °C, 12 h, 40%; (e) SOCl2, DCM, rt, 100%; (f) Na2CO3, DMF, 65 °C, 1.5 h, 81%; (g) 12 N HCl, THF, rt, 3 h, 96%.

GBT440 (36) (15.3 g).

HRMS calcd for C19H20N3O3 (M+H + ) 338.1499, found 338.1497; MS (ESI) m/z 338.4 [M+H]+ ;

1H NMR (400 MHz, Chloroform-d) δ 11.94 (s, 1H), 10.37 (d, J = 0.6 Hz, 1H), 8.75 (dd, J = 4.8, 1.7 Hz, 1H), 7.97 (dd, J = 7.8, 1.6 Hz, 1H), 7.63 – 7.57 (m, 1H), 7.46 – 7.33 (m, 2H), 6.57 (dt, J = 8.6, 0.7 Hz, 1H), 6.34 (d, J = 1.9 Hz, 1H), 6.27 (dt, J = 8.3, 1.0 Hz, 1H), 5.07 (s, 2H), 4.65 (hept, J = 6.6 Hz, 1H), 1.47 (d, J = 6.6 Hz, 7H);

13C NMR (101 MHz, DMSO-d6) δ 194.0, 162.9, 161.1, 149.6, 149.1, 139.1, 138.2, 138.2, 138.0, 131.6, 124.0, 111.1, 110.2, 107.4, 103.5, 67.8, 50.5, 23.1.

http://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00491/suppl_file/ml6b00491_si_001.pdf

PATENT

WO 2015031285

https://www.google.co.in/patents/WO2015031285A1?cl=en

2-Hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde is a compound having the formula:

Sickle cell disease is a disorder of the red blood cells, found particularly among those of African and Mediterranean descent. The basis for sickle cell disease is found in sickle hemoglobin (HbS), which contains a point mutation relative to the prevalent peptide sequence of hemoglobin (Hb).

[ Hemoglobin (Hb) transports oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through

conformational changes. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing HbS to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels. A need exists for therapeutics that can treat disorders that are mediated by Hb or by abnormal Hb such as HbS, such as 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde hydrochloride.

When used for treating humans, it is important that a crystalline form of a therapeutic agent, like 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, or a salt thereof, retains its polymorphic and chemical stability, solubility, and other physicochemical properties over time and among various manufactured batches of the agent. If the physicochemical properties vary with time and among batches, the administration of a therapeutically effective dose becomes problematic and may lead to toxic side effects or to ineffective therapy, particularly if a given polymorph decomposes prior to use, to a less active, inactive, or toxic compound. Therefore, it is important to choose a form of the crystalline agent that is stable, is manufactured reproducibly, and has physicochemical properties favorable for its use as a therapeutic agent.

Example ί : Synthesis of Compound 15

OH DIPEA OMOM

(8063J To s solution of 2 >ronao enzsae-i -diol (5 g, 26.45 m ol) m. DCM (50 ml) at 0 *C was added DIPEA (11.54 mL, 66.13 aan l) and MOMCi (4.42 mL. 58.19 ratnoi). The mixture was stirred at 0 °C for 1.5 h, and then warmed to room temperature. The so ntioa was dilated with DCM, washed with sat. NaH€<¾, brum dried and concentrated to give crude product, which was purified by coinran ihexane&/EtOAc~4;l) to give desired product 15.58 g (90%).

14C

Example 2: Synthesis of Compound 13 from 15

[0064] To a solution of 2-bromo-l ,3-bis(methoxymethoxy)benzene (15) (19.9g, 71.8 mmol) in THF (150 mL) at -78 °C was added BuLi (2.5 M, 31.6 mL, 79.0 mmol) dropwise. The solution was stirred at -78 °C for 25 min (resulting white cloudy mixture), then it was warmed to 0 °C and stirred for 25 min. The reaction mixture slowly turns homogenous. To the solution was added DMF at 0 °C. After 25 min, HPLC showed reaction completed. The mixture was quenched with sat. NH4C1 (150 mL), diluted with ether (300 mL). The organic layer was separated, aq layer was further extracted with ether (2X200 mL), and organic layer was combined, washed with brine, dried and concentrated to give crude product, which was triturated to give 14.6 g desired product. The filtrate was then concentrated and purified by column to give additional 0.7 g, total mass is 15.3 g.

Example 3: Synthesis of Compound 13 from resorcinol 11

1.1 R:TMEDA R:BuLi S:THF 2 h -10°C

Journal of Organic Chemistry, 74(1 1), 431 1-4317; 2009

[0065] A three-necked round-bottom flask equipped with mechanical stirrer was charged with 0.22 mol of NaH (50 % suspension in mineral oil) under nitrogen atmosphere. NaH was washed with 2 portions (100 mL) of n-hexane and then with 300 mL of dry diethyl ether; then 80 mL of anhydrous DMF was added. Then 0.09 mol of resorcinol 11, dissolved in 100 mL of diethyl ether was added dropwise and the mixture was left under stirring at rt for 30 min. Then 0.18 mol of MOMCI was slowly added. After 1 h under stirring at rt, 250 mL of water was added and the organic layer was extracted with diethyl ether. The extracts were

15A

washed with brine, dried (Na2S04), then concentrated to give the crude product that was purified by silica gel chromatography to give compound 12 (93 % yield).

15B

[0066] A three-necked round-bottom flask was charged with 110 mL of n-hexane, 0.79 mol of BuLi and 9.4 mL of tetramethylethylendiamine (TMEDA) under nitrogen atmosphere. The mixture was cooled at -10 °C and 0.079 mol of bis-phenyl ether 12 was slowly added. The resulting mixture was left under magnetic stirring at -10 °C for 2 h. Then the temperature was raised to 0 °C and 0.067 mol of DMF was added dropwise. After 1 h, aqueous HC1 was added until the pH was acidic; the mixture was then extracted with ethyl ether. The combined extracts were washed with brine, dried (Na2S04), and concentrated to give aldehyde 13

(84%).

[0067] 2,6-bis(methoxymethoxy)benzaldehyde (13): mp 58-59 °C (n-hexane) ; IR (KBr) n: 1685 (C=0) cm“1; 1H-NMR (400 MHz, CDC13) δ 3.51 (s, 6H, 2 OCH3), 5.28 (s, 4H, 2 OCH20), 6.84 (d, 2H, J = 8.40 Hz, H-3, H-5), 7.41 (t, 1H, J = 8.40 Hz, H-4), 10.55 (s, 1H, CHO); MS, m/e (relative intensity) 226 (M+, 3), 180 (4), 164 (14), 122 (2), 92 (2), 45 (100); Anal. Calc’d. for CnHi405: C,58.40; H, 6.24. Found: C, 57.98; H, 6.20.

Example 4: The Synthesis of Compound 16

13 16

81 %

[0068] To a solution of 2,6-bis(methoxymethoxy)benzaldehyde (13) (15.3 g, 67.6 mmol) in THF (105 mL) (solvent was purged with N2) was added cone. HC1 (12N, 7 mL) under N2, then it was further stirred under N2 for 1.5 h. To the solution was added brine (100 mL) and ether (150 ml). The organic layer was separated and the aqueous layer was further extracted with ether (2×200 mL). The organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (300g,

hexanes/EtOAc=85: 15) to give desired product 16 (9.9 g) as yellow liquid.

Example 5: Synthesis of Compound 17

16

[0069] To a solution of 2-hydroxy-6-(methoxymethoxy)benzaldehyde (16) (10.88 g, 59.72 mmol) in DMF (120 mL) (DMF solution was purged with N2 for 10 min) was added K2C03 (32.05 g, 231.92 mmol) and 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine hydrochloride (10) (15.78 g, 57.98 mmol). The mixture was heated at 65 °C for 1.5 h, cooled to rt, poured into ice water (800 mL). The precipitated solids were isolated by filtration, dried and concentrated to give desired product (17, 18 g).

Example 6: Synthesis of Compound (I)

[0070] To a solution of 2-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-(methoxymethoxy)benzaldehyde (17) (18 g, 47.19 mmol) in THF (135 mL, solution was purged with N2) was added cone. HCI (12N, 20 mL). The solution was stirred at rt for 3 h when HPLC showed the reaction complete. The mixture was added to a solution of NaHC03 (15 g) in water (1.2 L), and the resulting precipitate was collected by filtration, dried to give crude solid, which was further purified by column (DCM/EtOAc=60:40) to give pure product

(15.3 g).

Example 7: Synthesis of Compound I (free base) and its HCI salt form

[0071] Compound (I) free base (40g) was obtained from the coupling of the alcohol intermediate 7 and 2,6-dihydroxybenzaldedhye 9 under Mitsunobu conditions. A procedure is also provided below:

17

Example 8: Synthesis of Compound (I) by Mitsunobu coupling

[0072] Into a 2000-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of [2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-yl]methanol (7) (70 g, 322.18 mmol, 1.00 equiv) in tetrahydrofuran (1000 mL). 2,6-Dihydroxybenzaldehyde (9) (49.2 g, 356.21 mmol, 1.10 equiv) and PPh3 (101 g, 385.07 mmol, 1.20 equiv) were added to the reaction mixture. This was followed by the addition of a solution of DIAD (78.1 g, 386.23 mmol, 1.20 equiv) in tetrahydrofuran (200 ml) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 500 ml of H20. The resulting solution was extracted with 3×500 ml of dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EA:PE (1 :50-l :3) as eluent to yield the crude product. The crude product was re-crystallized from i-propanol/H20 in the ratio of 1/1.5. This resulted in 40 g (37%) of 2-hydroxy-6-([2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-yl]methoxy)benzaldehyde as a light yellow solid. The compound exhibited a melting point of 80-82 °C. MS (ES, m/z): 338.1 [M+l]. 1H NMR (300 MHz, DMSO-d6) δ 11.72(s, 1H), 10.21(s, 1H), 8.76(d, J=3.6Hz, 1H), 8.24(d, J=2.7Hz, lH),7.55(m, 3H), 6.55(m,3H) ,5.21 (s, 2H), 4.65 (m, 1H), 1.37 (d, J=5.1Hz, 6H). 1H NMR (400 MHz, CDC13) δ 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J= 4.8, 1.5 Hz, 1H), 8.00 (d, J= 7.8 Hz, 1H), 7.63 (d, J= 1.8 Hz, 1H), 7.49 – 7.34 (m, 2H), 6.59 (d, J= 8.5 Hz, 1H), 6.37 (d, J= 1.8 Hz, 1H), 6.29 (d, J= 8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J= 6.7 Hz, 1H), 1.50 (d, J= 6.6 Hz, 6H).

[0073] In another approach, multiple batches of Compound (I) free base are prepared in multi gram quantities (20g). The advantage of this route is the use of mono-protected 2,6-dihydroxybenzaldehyde (16), which effectively eliminates the possibility of bis-alkylation side product. The mono-MOM ether of 2,6-dihydroxybenzaldehyde (16) can be obtained from two starting points, bromoresorcinol (14) or resorcinol (11) [procedures described in the Journal of Organic Chemistry, 74(11), 4311-4317; 2009 ]. All steps and procedures are provided below. Due to the presence of phenolic aldehyde group, precautions (i.e., carry out all reactions under inert gas such as nitrogen) should be taken to avoid oxidation of the phenol and/or aldehyde group.

18

Preparation of compound I HC1 salt: A solution of compound I (55.79 g, 165.55 mmol) in acetonitrile (275 mL) was flushed with nitrogen for 10 min, then to this solution was added 3N aqueous HC1 (62 mL) at room temperature. The mixture was stirred for additional 10 min after the addition, most of the acetonitrile (about 200 mL) was then removed by evaporation on a rota

PATENT

WO2017096230

PATENT

WO-2017197083

Processes for the preparation of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (also referred to as voxelotor or Compound (I)) and its intermediates is claimed. Compound (I) binds to hemoglobin and increases it oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.

Disclosed herein are processes for synthesizing 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (Compound (I)) and intermediates used in such processes. Compound (I) binds to hemoglobin and increases it oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.

BACKGROUND

Compound (I) is disclosed in Example 17 of the International Publication No.

WO2013/102142. Compound (I) binds to hemoglobin and increases it oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.

In general, for a compound to be suitable as a therapeutic agent or part of a therapeutic agent, the compound synthesis must be amendable to large scale manufacturing and isolation. The large scale manufacturing and isolation should not impact the physical properties and purity of the compound nor should it negatively impact cost or efficacy of a formulated active ingredient. Accordingly, scale up of manufacturing and isolation may require significant efforts to meet these goals.

ompound (I) has been synthesized by certain methods starting with 2,6-dihydroxbenzaldehyde (compound 1) where each hydroxyl moiety is protected with an unbranched, straight-chain alkyl or alkoxyalkyl such as, for example, methyl or methoxymethyl. Following installation of the aldehyde group, various methods of deprotection of the hydroxyl group were employed to synthesize compound (1) used in the synthesis and production of Compound (I). However, the deprotection processes used lead to unwanted polymerization and decomposition reactions of compound (1) – attributed, in part, to the conditions used for

deprotection of the hydroxy groups. The undesired byproducts yield complex mixtures, lower yields of Compound (I), and require significant effort to purify Compound (I) to a degree acceptable for use as a part of a therapeutic agent, thus rendering the above processes impractical for commercial scale synthesis of Compound (I).

Provided herein are processes for the synthesis of Compound (I):

Examples

Example 1

Synthesis of 2,6-dihydroxybenzaldehyde (Compound (1))

Step 1:

Tetrahydrofuran (700 mL) was added to resorcinol (170g, 1.54 mol, leq.) under inert gas protection, followed by addition of pyridinium tosylate (3.9 g, 15.4 mmol, O.Oleq.), THF 65 mL) and the reaction mixture was cooled down to 0 – 5 °C. Within 1 – 1.5 h ethylvinyl ether (444 mL, 4.63 mol, 3.0 eq.) was added while maintaining a temperature <5°C. After the addition was complete the reaction mixture was allowed to reach room temperature within 1.5 h. The reaction was stirred overnight, cooled down to 10-15 °C, and 510 mL of ½ sat. NaHC03 was added while maintaining the reaction solution below 20 °C. The phases were separated. The organic phase was washed once with 425 mL of water and once with 425 mL 12.5% NaCl solution and evaporated and azeotroped with THF to give bis-EOE-protected resorcinol (401.2 g, 1.55 mol, 102% uncorrected) as a clear colorless to yellowish oil.

Step 2:

Bis-EOE-protected resorcinol (390 g of, actual: 398.6g = 1.53 mol, 1 eq., corrected to 100%) conversion) was added under inert gas protection to a 6 L glass vessel and THF (1170 mL) was added. The reaction mixture was cooled down to -10°C to -5°C and n-BuLi (625 mL, 2.7 M in heptane, 1.687 mol, 1.1 eq.) was added. The reaction mixture was agitated at -5°C- 0°C for 30-40 min and then DMF (153.4 mL, 1.99 mmol, 1.3 eq.) was added starting at -10°C to -5°C. The reaction mixture was stirred until complete and then quenched with lNHCl/EtOAc. It was also discovered, inter alia, that protection with the EOE groups not only resulted in less byproducts but appeared to increase the speed of the formylation reaction to provide 2,6-bis(l-ethoxyethoxy)benzaldehyde (compound (2)).

The mixture was worked up, phase separated and the aqueous washed with MTBE. After aqueous wash to remove salts the organic phase was concentrated to the neat oil to obtain the compound (2) as yellow oil (almost quantitative).

A batch preparation was performed using solvent swap and was completed faster than other known methods for synthesizing Compound (I) with better purity and yield. The deprotection sequence allowed in-situ use of compound (2).

Step 3:

To the reaction solution of Step 2 was added IN HC1 (1755 mL) while maintaining the temperature < 20°C. The pH was of the solution was adjusted to pH = 0.7 – 0.8 with 6 M HC1.

The reaction mixture was stirred for 16 h. After the reaction was complete the organic phase was separated and 1560 mL of methyl tert butyl ether was added. The organic phase was washed once with 1170 mL of IN HC1, once with 780 mL of ½ sat. NaCl solution and once with 780 mL of water and then concentrated to a volume of – 280mL. To the solution was added 780 mL of methyl tert butyl ether and concentrate again to 280 mL [temperature <45°C, vacuo]. To the slurry was added 780 mL of acetonitrile and the solution was concentrated in vacuo at T < 45°C to a final volume of – 280 mL. The slurry was heated to re-dissolve the solids. The solution was cooled slowly to RT and seeded at 60-65 °C to initiate crystallization of the product. The slurry was cooled down to -20°C to -15°C and agitated at this temperature for 1-2 h. The product was isolated by filtration and washed with DCM (pre-cooled to -20°C to -15°C) and dried under a stream of nitrogen to give 2,6-dihydroxybenzaldehyde as a yellow solid. Yield: 138.9 g (1.00 mol, 65.6%).

Example 1A

Alternate Synthesis of 2,6-dihydroxybenzaldehyde compound (1)

Step 1:

In a suitable reactor under nitrogen, tetrahydrofuran (207 L) was added to resorcinol (46 kg, 0.42 kmol, leq.) followed by addition of pyridinium tosylate (1.05 kg, 4.2 mol, O.Oleq.), and the reaction mixture was cooled down to 0 – 5 °C. Within 1 – 1.5 h ethylvinyl ether (90.4 kg, 120.5 L, 125 kmol, 3.0 eq.) was added while maintaining a temperature <5°C. After the addition was complete the reaction mixture was allowed to reach room temperature within 1.5 h. The reaction was stirred overnight, cooled down to 10-15 °C, and 138 L of aqueous 4% NaHC03 was added while maintaining the reaction solution below 20 °C. The phases were separated. The organic phase was washed once with 115 L of water and once with 125.2 kg of a 12.5% NaCl solution. The organic layer was dried by azeotropic distillation with THF to a water content value < 0.05%) (by weight) to yield bis-EOE-protected resorcinol (106.2 kg, 0.42 kmol) as a solution in THF. An advantage over previously reported protection procedures is that the bis-EOE-protected resorcinol product does not need to be isolated as a neat product. The

product-containing THF solution can be used directly in the next reaction step thus increasing throughput and reducing impurity formation.

Step 2:

Bis-EOE-protected resorcinol solution (assumption is 100% conversion) was added under inert gas protection to suitable reactor. The reaction mixture was cooled down to -10°C to -5°C and n-BuLi (117.8 kg, 25% in heptane, 1.1 eq.) was added. The reaction mixture was agitated at -5°C- 0°C for 30-40 min and then DMF (39.7 kg, 0.54 kmol, 1.3 eq.) was added at -10°C to -5°C. The reaction mixture was stirred until complete and then quenched with aqueous HC1 (1M, 488.8 kg) to give 2,6-bis(l-ethoxyethoxy)benzaldehyde. An advantage over previously reported procedures of using EOE protecting group is that the HC1 quenched solution can be used directly in the deprotection step, and 2,6-bis(l-ethoxyethoxy)benzaldehyde does not need to be isolated as a neat oil.

Step 3:

The pH of the quenched solution was adjusted to < 1 with aqueous HC1 (6M, ca 95.9 kg) and the reaction mixture stirred at ambient temperature for 16 h. After the reaction was complete the organic phase was separated and 279.7 kg of methyl tert butyl ether was added. The organic phase was washed once with aqueous IN HC1 (299 kg), once with aqueous 12.5% NaCl (205.8 kg) and once with 189 kg of water and then concentrated to a volume of ca. 69 L. To the slurry was added 164 kg of acetonitrile and the solution was concentrated in vacuo at T < 45°C to a final volume of ca. 69 L. The slurry was heated to re-dissolve the solids. The solution was seeded at 60-65 °C to initiate crystallization of the product and cooled slowly to RT over 8 hrs. The slurry was cooled down to -20 °C to -15°C and agitated at this temperature for l-2h. The product was isolated by filtration and washed with DCM (50.3 kg, pre-cooled to -20 °C to -15 °C) and dried under a stream of nitrogen to yield 2,6-dihydroxybenzaldehyde as a yellow solid. Yield: 37.8 kg (0.27 kmol, 65.4% Yield). The described telescoped approach from deprotection to crystallization increases the throughput and integrity of the product.

Example 2

Synthesis of 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine

dihydrochloride salt

Step 1:

An appropriately sized flask was purged with nitrogen and charged with (2-chloropyridin-3-yl)methanol (1.0 equiv), sodium bicarbonate (3.0 equiv), [1, l ‘-bis(diphenyl-phosphino)-ferrocene]dichloropalladium (5 mol %), l-isopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.2 equiv), and a mixture of 2-MeTHF (17.4 vol) and deionized water (5.2 vol). The resulting solution was heated to 70°C to 75°C and conversion monitored by HPLC. Once the reaction was complete, the reaction mixture was cooled to room temperature, diluted with deionized water, and the phases were separated. The organic layer was extracted with 2 N HC1 (10 vol) and the phases were separated. The aqueous phase was washed with MTBE. The pH of the aqueous phase was adjusted to 8-9 with 6 N NaOH. The product was extracted into EtOAc, treated with Darco G-60 for 30 to 60 min, dried over MgS04, filtered through Celite®, and concentrated to give (2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol as a brown oil.

Step 2:

A suitably equipped reactor was charged with (2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol hydrochloride salt (1 equivalent) and purified water. An aqueous sodium

bicarbonate solution (8% NaHC03) was added slowly to maintain the solution temperature between 17 °C to 25 °C. After addition was complete, the reaction mixture was stirred at 17 °C to 25 °C and dichloromethane was added and the organic layer was separated. DCM solution was then distilled under atmospheric conditions at approximately 40°C and the volume was reduced. DCM was added the reactor and the contents of the reactor are stirred at 20°C to 30°C until a clear solution is formed. The contents of the reactor were cooled to 0°C to 5°C and thionyl chloride was charged to the reactor slowly to maintain a temperature of < 5 °C. The reaction solution was stirred at 17 °C to 25 °C. When the reaction was complete, a solution of HC1 (g) in 1,4-dioxane (ca. 4 N, 0.8 equiv.) was charged to the reactor slowly to maintain the solution temperature between 17 °C and 25 °C. The product 3-(chloromethyl)-2-(l-isopropyl- lH-pyrazol-5-yl)pyridine dihydrochloride salt was filtered washed with dichloromethane and dried.

Example 3

Synthesis of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde

Form I

(I)

tably equipped reactor was charged with 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine dihydrochloride salt (1 equivalent), sodium iodide (0.05 equivalent), sodium bicarbonate (4 equivalent), l-methyl-2-pyrrolidinone (NMP), and 2,6-dihydroxy-benzaldehyde (1 to 1.05 equiv.). The reaction mixture was heated slowly to 40 °C to 50 °C and stirred until the reaction was complete. Water was then added and the reaction mixture was cooled and maintained at 17 °C to 25 °C. When the water addition was complete, the reaction mixture was stirred at 17 °C to 25 °C and slowly cooled to 0°C to 5°C and the resulting solids were collected by filtration. The solids were washed with a 0 °C to 5 °C 2: 1 water/NMP solution, followed by 0 °C to 5 °C water. The solids were filtered and dried to give 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde as Form I or a mixture of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde as Form I Form I and NMP solvates.

Alternative Synthesis:

A suitably equipped reactor was charged with 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine bishydrochloride salt (1 equivalent), sodium iodide (0.05 equivalent), sodium bicarbonate (3 to 4 equivalent), l-methyl-2-pyrrolidinone (7 equivalent, NMP), and 2,6-dihydoxybenzaldehyde (1.05 equivalent). The reaction mixture was heated to 40 °C to 50° C and stirred until the reaction was complete. Water (5 equivalent) was then added while maintaining the contents of the reactor at 40 °C to 460 C and the resulting clear solution seeded with 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde Form I. Additional water (5 equivalent) was added while maintaining the contents of the reactor at 40 °C to 500 C, the reactor contents cooled to 15 °C to 25 0 C, and the reactor contents stirred for at least 1 hour at 15 °C to 25 0 C. The solids were collected, washed twice with 1 :2 NMP: water and twice with water, and dried to yield 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde Form I devoid of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde as NMP solvates.

Example 4

Preparation of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)- benzaldehyde Form II

Step 1:

A suitably equipped reactor with an inert atmosphere was charged with crude 2-hydroxy- 6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (from Example 3 above) and MTBE and the contents stirred at 17°C to 25°C until dissolution was achieved. The reaction solution was passed through a 0.45 micron filter and MTBE solvent volume reduced using vacuum distillation at approximately 50 °C. The concentrated solution was heated to 55°C to 60°C to dissolve any crystallized product. When a clear solution was obtained, the solution was cooled to 50 °C to 55 °C and n-heptane was added. 2-Hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (e.g., Form II) seeds in a slurry of n-heptane were charged and the solution was stirred at 50°C to 55°C. The solution was cooled to 45 °C to 50 °C and n-heptane was added to the reactor slowly while maintaining a reaction solution temperature of 45°C to 50°C. The reaction solution are stirred at 45°C to 50°C and then slowly cooled to 17°C to 25°C. A sample was taken for FTIR analysis and the crystallization was considered complete when FTIR analysis confirmed 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)-benzaldehyde (Form II). The contents of the reactor were then cooled to 0°C to 5°C and the solids were isolated and washed with cold n-heptane and dried.

REFERENCES

1: Oksenberg D, Dufu K, Patel MP, Chuang C, Li Z, Xu Q, Silva-Garcia A, Zhou C, Hutchaleelaha A, Patskovska L, Patskovsky Y, Almo SC, Sinha U, Metcalf BW, Archer DR. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J Haematol. 2016 Oct;175(1):141-53. doi: 10.1111/bjh.14214. PubMed PMID: 27378309.

2: Dufu K, Lehrer-Graiwer J, Ramos E, Oksenberg D. GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under In Vitro Conditions Mimicking Strenuous Exercise. Hematol Rep. 2016 Sep 28;8(3):6637. PubMed PMID: 27757216; PubMed Central PMCID: PMC5062624.

3: Ferrone FA. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J Haematol. 2016 Aug;174(4):499-500. doi: 10.1111/bjh.14212. PubMed PMID: 27410726.

4: Oder E, Safo MK, Abdulmalik O, Kato GJ. New developments in anti-sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo? Br J Haematol. 2016 Oct;175(1):24-30. doi: 10.1111/bjh.14264. Review. PubMed PMID: 27605087; PubMed Central PMCID: PMC5035193.

////////////VOXELOTOR, GBT 440, GTx-011, Treatment of Sickle Cell Disease, phase 3, gbt, 1446321-46-5, orphan drug

CC(C)n1nccc1c2ncccc2COc3cccc(O)c3C=O

DISCLAIMER

“NEW DRUG APPROVALS ” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

Pracinostat


Pracinostat.svg

ChemSpider 2D Image | Pracinostat | C20H30N4O2

Pracinostat.png

2D chemical structure of 929016-96-6

Pracinostat

  • Molecular Formula C20H30N4O2
  • Average mass 358.478 Da
2-Propenamide, 3-[2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl]-N-hydroxy-, (2E)-
929016-96-6 [RN]
SB939
(2E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1,3-benzodiazol-5-yl}-N-hydroxyprop-2-enamide
N-hydroxy-1-[(4-methoxyphenyl)methyl]-1H-indole-6-carboxamide
PCI 34051,  UNII: GPO2JN4UON
929016-98-8 DI HCl salt, C20 H30 N4 O2 . 2 Cl H, 431.4
929016-96-6 (free base)
929016-97-7 (trifluoroacetate)
S*BIO (Originator)
Leukemia, acute myeloid, phase 3, helsinn
Image result for S*BIO
str1
CAS 929016-98-8 DI HCl salt, C20 H30 N4 O2 . 2 Cl H, 431.4
E)-3-[2-Butyl-1-(2-diethylaminoethyl)-1H-benzimidazol-5-yl]-N-hydroxyacrylamide Dihydrochloride Salt

Pracinostat (SB939) is an orally bioavailable, small-molecule histone deacetylase (HDAC) inhibitor based on hydroxamic acid with potential anti-tumor activity characterized by favorable physicochemical, pharmaceutical, and pharmacokinetic properties.

WO-2017192451  describes Novel polymorphic crystalline forms of pracinostat (designated as Form 3) and their hydrates, processes for their preparation and compositions and combination comprising them are claimed. Also claimed is their use for inhibiting histone deacetylase and treating cancer, such as myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), breast cancer, colon cancer, prostate cancer, pancreas cancer, leukemia, lymphoma, ovary cancer, melanoma and neuroblastoma.

See WO2014070948 ,  Helsinn , under sub-license from MEI Pharma (under license from S*Bio), is developing pracinostat, an oral HDAC inhibitor, for treating hematological tumors, including AML, MDS and myelofibrosis.

The oncolytic agent pracinostat hydrochloride is an antagonist of histone deacetylase 1 (HDAC1) and 2 (HDAC2) that was discovered by the Singapore-based company S*BIO. Helsinn obtained the exlusive development and commercialization rights in July 2016, and is conducting phase III clinical trials in combination with azacitidine in adults with newly diagnosed acute myeloid leukemia. Phase II trials are also under way for the treatment of previously untreated intermediate-2 or high risk myelodysplastic syndrome patients and for the treatment of primary or post essential thrombocythemia/polycythemia vera) in combination with ruxolitinib.In North America, S*BIO had been conducting phase II clinical trials of pracinostat hydrochloride in patients with solid tumors and for the treatment of myeloproliferative diseases and phase I clinical trials in patients with leukemia; however, recent progress reports are not available at present. The University of Queensland had been evaluating the compound in preclinical studies for malaria.

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University of Queensland

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MEI Pharma

The Canadian Cancer Society Research Institute (the research branch of the Canadian Cancer Society upon its integration with the National Cancer Institute of Canada to form the new Canadian Cancer Society) is conducting phase II clinical trials in Canada for the treatment of recurrent or metastatic prostate cancer.

Image result for Canadian Cancer Society Research Institute

Canadian Cancer Society Research Institute

In 2012, the product was licensed to MEI Pharma by S*BIO on a worldwide basis. In 2016, MEI Pharma and Helsinn entered into a licensing, development and commercialization agreement by which Helsinn obtained exclusive worldwide rights (including manufacturing and commercialization rights).

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HELSINN

In 2014, the FDA assigned an orphan drug designation to MEI Pharma for the treatment of acute myeloid leukemia. In 2016, the product received breakthrough therapy designation in the U.S. in combination with azacitidine for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are older than 75 years of age or unfit for intensive chemotherapy.

Pracinostat is an orally available, small-molecule histone deacetylase (HDAC) inhibitor with potential antineoplastic activity. Pracinostat inhibits HDACs, which may result in the accumulation of highly acetylated histones, followed by the induction of chromatin remodeling; the selective transcription of tumor suppressor genes; the tumor suppressor protein-mediated inhibition of tumor cell division; and, finally, the induction of tumor cell apoptosis. This agent may possess improved metabolic, pharmacokinetic and pharmacological properties compared to other HDAC inhibitors.

Pracinostat is a novel HDAC inhibitor with improved in vivo properties compared to other HDAC inhibitors currently in clinical trials, allowing oral dosing. Data demonstrate that Pracinostat is a potent and effective anti-tumor drug with potential as an oral therapy for a variety of human hematological and solid tumors

SYNTHESIS

Figure

Clinically tested HDAC inhibitors.

Activity

Pracinostat selectively inhibits HDAC class I,II,IV without class III and HDAC6 in class IV,[1] but has no effect on other Zn-binding enzymes, receptors, and ion channels. It accumulates in tumor cells and exerts a continuous inhibition to histone deacetylase,resulting in acetylated histones accumulation, chromatin remodeling, tumor suppressor genes transcription, and ultimately, apoptosis of tumor cells.[2]

Clinical medication

Clinical studies suggests that pracinostat has potential best pharmacokinetic properties when compared to other oral HDAC inhibitors.[3]In March 2014, pracinostat has granted Orphan Drug for acute myelocytic leukemia (AML) and for the treatment of T-cell lymphoma by the Food and Drug Administration.

Clinical Trials

CTID Title Phase Status Date
NCT03151304 A Safety and Efficacy Study of Pracinostat and Azacitidine in Patients With High Risk Myelodysplastic Syndromes 2 Recruiting
2017-10-27
NCT03151408 An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia 3 Recruiting
2017-10-17
NCT02267278 Ruxolitinib and Pracinostat Combination Therapy for Patients With Myelofibrosis (MF) 2 Active, not recruiting
2017-04-27
NCT01873703 Phase 2 Study of Pracinostat With Azacitidine in Patients With Previously Untreated Myelodysplastic Syndrome 2 Active, not recruiting
2017-04-21
NCT02118909 Evaluate the Effects of Itraconazole and Ciprofloxacin on Single-Dose PK of Pracinostat in Healthy Nonsmoking Subjects 1 Completed
2017-02-22
NCT02058784 Study to Evaluate the Food Effect of Single-dose Bioavailability of Pracinostat in Healthy Adult Subjects 1 Completed
2017-02-22
NCT01993641 Phase 2 Study Adding Pracinostat to a Hypomethylating Agent (HMA) in Patients With MDS Who Failed to Respond to Single Agent HMA 2 Completed
2017-02-22
NCT01112384 A Study of SB939 in Patients With Translocation-Associated Recurrent/Metastatic Sarcomas 2 Completed
2016-11-25
NCT01184274 A Phase I Study of SB939 in Pediatric Patients With Refractory Solid Tumours and Leukemia 1 Completed
2014-01-16
NCT01200498 Study of SB939 in Subjects With Myelofibrosis 2 Completed
2013-12-13

PATENT

WO2005028447

Inventors Dizhong ChenWeiping DengKanda SangthongpitagHong Yan SongEric T. SunNiefang YuYong Zou
Applicant S*Bio Pte Ltd

Scheme I

Figure imgf000041_0001

Scheme II

Figure imgf000042_0001Scheme III

Figure imgf000043_0001Scheme IV

Figure imgf000044_0001 Scheme V

Figure imgf000045_0001

PAPER

Discovery of (2E)-3-{2-Butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinical Profile

Chemistry Discovery, Biology Discovery, and §Pre-Clinical Development, S*BIO Pte Ltd., 1 Science Park Road, No. 05-09 The Capricorn, Singapore Science Park II, Singapore 117528, Singapore
J. Med. Chem.201154 (13), pp 4694–4720
DOI: 10.1021/jm2003552
Phone: +65-68275019. Fax: +65-68275005. E-mail: haishan_wang@sbio.com.

Abstract

Abstract Image

A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC50), liver microsomal stability (t1/2), cytochrome P450 inhibitory (3A4 IC50), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.

(E)-3-[2-Butyl-1-(2-diethylaminoethyl)-1H-benzimidazol-5-yl]-N-hydroxyacrylamide Dihydrochloride Salt (3)

The freebase of 3 was prepared according to procedure D. The hydroxamic acid moiety was identified by 1H–15N HSQC (DMSO-d6) with δN = 169.0 ppm (CONHOH). Other nitrogens in 3were identified by 1H–15N HMBC (DMSO-d6) with δN of 241.4 ppm for N3 of the benzimidazole ring, 152.3 ppm for N1, and 41.3 ppm for the diethylamino group (reference to nitromethane δN = 380.0 ppm in CDCl3). The dihydrochloride salt of 3 was prepared according to procedure D as white or off-white solid or powder in ∼60% yield from 9 in two steps. LC–MS m/z 359.2 ([M + H]+).
1H NMR (DMSO-d6) δ 11.79 (brs, 1H, NH or OH), 10.92 (very br s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 15.8 Hz, 1H), 6.65 (d, J = 15.8 Hz, 1H), 5.01 (t-like, J = 7.7 Hz, 2H), 3.48 (m, 2H), 3.30–3.19 (m, 6H), 1.87 (quintet, J = 7.8 Hz, 2H), 1.47 (sextet, J = 7.5 Hz, 2H), 1.29 (t, J = 7.2 Hz, 6H), 0.97 (t, J = 7.3 Hz, 3H);
13C NMR (DMSO-d6) δ 162.3, 156.0, 137.3 (CH), 132.8, 132.3, 132.0 (br, identified by HMBC), 124.7 (CH), 120.2 (CH), 113.1 (2 × CH), 48.2, 46.3, 39.0, 28.1, 25.0, 21.7, 13.6, 8.3.
Anal. (C20H30N4O2·2HCl·0.265H2O) C, H, N, Cl. Water content = 1.09% (Karl Fisher method). HRMS (ESI) m/z [M + H]+ calcd for C20H31N4O2, 359.2442; found, 359.2449.

PATENT

WO 2007030080

http://google.com/patents/WO2007030080A1?cl=en

 
Inventors Dizhong ChenWeiping DengKen Chi Lik LeePek Ling LyeEric T. SunHaishan WangNiefang Yu
Applicant S*Bio Pte Ltd

SEE

WO 2008108741

WO 2014070948

Patent

WO-2017192451

References

  1. Jump up^ “In vitro enzyme activity of SB939 and SAHA”. 22 Aug 2014.
  2. Jump up^ “The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML”. Blood Cancer Journaldoi:10.1038/bcj.2012.14.
  3. Jump up^ Veronica Novotny-Diermayr; et al. (March 9, 2010). “SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer”Mol Cancer Therdoi:10.1158/1535-7163.MCT-09-0689.
PATENT 
Cited Patent Filing date Publication date Applicant Title
WO2005028447A1 * Sep 21, 2004 Mar 31, 2005 S*Bio Pte Ltd Benzimidazole derivates: preparation and pharmaceutical applications
US20050137234 * Dec 14, 2004 Jun 23, 2005 Syrrx, Inc. Histone deacetylase inhibitors
Reference
1 None
2 See also references of EP1937650A1
Citing Patent Filing date Publication date Applicant Title
WO2009084544A1 * Dec 24, 2008 Jul 9, 2009 Idemitsu Kosan Co., Ltd. Nitrogen-containing heterocyclic derivative and organic electroluminescent device using the same
WO2010043953A2 * Oct 14, 2009 Apr 22, 2010 Orchid Research Laboratories Ltd. Novel bridged cyclic compounds as histone deacetylase inhibitors
WO2010043953A3 * Oct 14, 2009 Mar 24, 2011 Orchid Research Laboratories Ltd. Novel bridged cyclic compounds as histone deacetylase inhibitors
WO2017030938A1 * Aug 12, 2016 Feb 23, 2017 Incyte Corporation Heterocyclic compounds and uses thereof
DE102007037579A1 Aug 9, 2007 Feb 19, 2009 Emc Microcollections Gmbh Neue Benzimidazol-2-yl-alkylamine und ihre Anwendung als mikrobizide Wirkstoffe
US8865912 Jan 27, 2014 Oct 21, 2014 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9024029 Sep 3, 2013 May 5, 2015 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9062003 Sep 9, 2014 Jun 23, 2015 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9156797 May 15, 2015 Oct 13, 2015 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9402829 Feb 20, 2015 Aug 2, 2016 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9717713 Jun 10, 2016 Aug 1, 2017 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
Patent ID

Patent Title

Submitted Date

Granted Date

US2016158186 USE OF DIANHYDROGALACTITOL AND ANALOGS AND DERIVATIVES THEREOF TO TREAT RECURRENT MALIGNANT GLIOMA OR PROGRESSIVE SECONDARY BRAIN TUMOR
2015-04-09
2016-06-09
US2015051288 Methods and Compositions for Treatment of Autism
2014-10-10
2015-02-19
US2017128534 TREATING ROTATOR CUFF CONDITIONS
2015-07-09
Patent ID

Patent Title

Submitted Date

Granted Date

US2014235649 USE OF PHOSPHATASE INHIBITORS OR HISTONE DEACETYLASE INHIBITORS TO TREAT DISEASES CHARACTERIZED BY LOSS OF PROTEIN FUNCTION
2012-05-24
2014-08-21
US2013102595 TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
2012-10-15
2013-04-25
US9624515 System and Method of Producing Volatile Organic Compounds from Fungi
2013-02-01
2013-05-30
US2014349938 METHODS OF DIAGNOSING AND TREATING AMYOTROPHIC LATERAL SCLEROSIS
2012-06-01
2014-11-27
US2017100354 COMPOSITIONS AND METHODS FOR TREATING KABUKI SYNDROME AND RELATED DISORDERS
2015-05-29
Patent ID

Patent Title

Submitted Date

Granted Date

US9387263 RbAp48 TRANSGENIC MICE FOR DRUG DISCOVERY IN AGE-RELATED MEMORY DECLINE
2012-08-02
2014-10-02
US2014051716 COMPOUNDS AND METHODS FOR IMPROVING IMPAIRED ENDOGENOUS FIBRINOLYSIS USING HISTONE DEACETYLASE INHIBITORS
2012-03-09
2014-02-20
US2010098691 COMBINATION OF BENZIMIDAZOLE ANTI-CANCER AGENT AND A SECOND ANTI-CANCER AGENT
2010-04-22
US2016069887 BIOMARKERS FOR PROGNOSIS
2014-04-08
2016-03-10
US8937050 Methods and compositions for treatment of autism
2012-10-31
2015-01-20
Patent ID

Patent Title

Submitted Date

Granted Date

US2017049784 METHOD OF TREATING ACUTE MYELOID LEUKEMIA AND/OR ACUTE LYMPHOBLASTIC LEUKEMIA USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2015-05-01
US2017095484 METHOD OF TREATING RESISTANT NON-HODGKIN LYMPHOMA, MEDULLOBLASTOMA, AND/OR ALK+NON-SMALL CELL LUNG CANCER USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2015-05-01
US2017157141 METHOD OF TREATING LEUKEMIA USING PHARMACEUTICAL FORMULATION CONTAINING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2014-11-26
US2015258068 COMBINATION THERAPIES
2013-10-30
2015-09-17
US2015182490 METHODS FOR TREATING TYROSINE-KINASE-INHIBITOR-RESISTANT MALIGNANCIES IN PATIENTS WITH GENETIC POLYMORPHISMS OR AHI1 DYSREGULATIONS OR MUTATIONS EMPLOYING DIANHYDROGALACTITOL, DIACETYLDIANHYDROGALACTITOL, DIBROMODULCITOL, OR ANALOGS OR DERIVATIVES THEREOF
2013-06-24
2015-07-02
Patent ID

Patent Title

Submitted Date

Granted Date

US8143282 Heterocyclic Compounds
2009-02-19
2012-03-27
US2017020874 COMPOUNDS AND METHODS FOR IMPROVING IMPAIRED ENDOGENOUS FIBRINOLYSIS USING HISTONE DEACETYLASE INHIBITORS
2015-12-01
US2017231931 PRODUCTS FOR THE TREATMENT AND PREVENTION OF NEUROLOGICAL DISORDERS COURSING WITH A COGNITION DEFICIT OR IMPAIRMENT, AND OF NEURODEGENERATIVE DISEASES
2015-08-25
US2017273988 METHODS OF TREATING LYMPHOMA USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2015-08-19
US2017095436 METHODS FOR TREATING MENDELIAN DISORDERS OF THE EPIGENETIC MACHINERY
2015-05-29
Pracinostat
Pracinostat.svg
Names
IUPAC name

(E)-3-(2-Butyl-1-(2-(diethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
Other names

Pracinostat
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
Properties
C20H30N4O2
Molar mass 358.49 g·mol−1
Density 1.1±0.1 g/cm3
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

//////////////Pracinostat, PCI 34051, SB939, orphan drug designation, Leukemia, acute myeloid, phase 3, helsinn

CCCCC1=NC2=C(N1CCN(CC)CC)C=CC(=C2)C=CC(=O)NO

 

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

Peptide Drugs: RAPASTINEL рапастинел , راباستينيل , 雷帕替奈


File:Rapastinel.svg

Rapastinel.png

RAPASTINEL

  • Molecular Formula C18H31N5O6
  • Average mass 413.469 Da

L-threonyl-L-prolyl-L-prolyl-L-threoninamide

(2S)-1-[(2S)-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]-N-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]pyrrolidine-2-carboxamide

117928-94-6 [RN]
L-Threoninamide, L-threonyl-L-prolyl-L-prolyl-
рапастинел [Russian]
راباستينيل [Arabic]
雷帕替奈 [Chinese]
(S)-N-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-((S)-1-((2S,3R)-2-amino-3-hydroxybutanoyl)pyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide

UNII-6A1X56B95E; 117928-94-6; 6A1X56B95E

(S)-N-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-((S)-1-((2S,3R)-2-amino-3-hydroxybutanoyl)pyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide
[117928-94-6]
GLYX-13 trifluoroacetate
GLYX-13;GLYX13;GLYX 13;Thr-Pro-Pro-Thr-NH2
L-Threonyl-L-prolyl-L-prolyl-L-threoninamide trifluoroacetate
MFCD20527320
Thr-Pro-Pro-Thr-NH2 trifluoroacetate
TPPT-amide trifluoroacetate
UNII:6A1X56B95E

BV-102; GLYX13, GLYX-13, in phase 3 clinical trials


Originator 
Northwestern University

  • Developer Allergan; Naurex
  • Class Amides; Antidepressants; Neuropsychotherapeutics; Oligopeptides; Small molecules
  • Mechanism of Action NR2B N-Methyl-D-Aspartate receptor agonists

Highest Development Phases

  • Phase III Major depressive disorder
  • Discontinued Bipolar depression; Neuropathic pain

Most Recent Events

  • 01 Jan 2017 Allergan initiates enrolment in a phase III trial for Major depressive disorder (Adjunctive treatment) in USA (IV, Injection) (NCT03002077)
  • 21 Dec 2016 Allergan plans a phase III trial for Major depressive disorder (Adjunctive treatment) in USA (IV, Injection) (NCT03002077)
  • 01 Nov 2016 Phase-III clinical trials in Major depressive disorder (Adjunctive treatment, Prevention of relapse) in USA (IV) (NCT02951988)Image result for RAPASTINELImage result for RAPASTINEL

It is disclosed that GLYX-13 (Rapastinel) acts as NMDA receptor partial agonist, useful for treating neurodegenerative disorders such as stroke-related brain cell death, convulsive disorders, and learning and memory. See WO2015065891 , claiming peptidyl compound. Naurex , a subsidiary of Allergan is developing rapastinel (GLYX-13) (in phase3 clinical trials), a rapid-acting monoclonal antibody-derived tetrapeptide and NMDA receptor glycine site functional partial agonist as well as an amidated form of NT-13, for treating depression.

Rapastinel (INN) (former developmental code names GLYX-13BV-102) is a novel antidepressant that is under development by Allergan (previously Naurex) as an adjunctive therapy for the treatment of treatment-resistant major depressive disorder.[1][2] It is a centrally activeintravenously administered (non-orally activeamidated tetrapeptide (Thr-Pro-Pro-Thr-NH2) that acts as a selective, weak partial agonist (mixed antagonist/agonist) of an allosteric site of the glycine site of the NMDA receptor complex (Emax ≈ 25%).[1][2]The drug is a rapid-acting and long-lasting antidepressant as well as robust cognitive enhancer by virtue of its ability to both inhibit and enhance NMDA receptor-mediated signal transduction.[1][2]

On March 3, 2014, the U.S. FDA granted Fast Track designation to the development of rapastinel as an adjunctive therapy in treatment-resistant major depressive disorder.[3] As of 2015, the drug had completed phase II clinical development for this indication.[4] On January 29, 2016, Allergan (who acquired Naurex in July 2015) announced that rapastinel had received Breakthrough Therapydesignation from the U.S. FDA for adjunctive treatment of major depressive disorder.

Rapastinel belongs to a group of compounds, referred to as glyxins (hence the original developmental code name of rapastinel, GLYX-13),[5] that were derived via structural modification of B6B21, a monoclonal antibody that similarly binds to and modulates the NMDA receptor.[2][6][7] The glyxins were invented by Joseph Moskal, the co-founder of Naurex.[5] Glyxins and B6B21 do not bind to the glycine site of the NMDA receptor but rather to a different regulatory site on the NMDA receptor complex that serves to allosterically modulate the glycine site.[8] As such, rapastinel is technically an allosteric modulator of the glycine site of the NMDA receptor, and hence is more accurately described as a functional glycine site weak partial agonist.[8]

In addition to its antidepressant effects, rapastinel has been shown to enhance memory and learning in both young adult and learning-impaired, aging rat models.[9] It has been shown to increase Schaffer collateralCA1 long-term potentiation in vitro. In concert with a learning task, rapastinel has also been shown to elevate gene expression of hippocampal NR1, a subunit of the NMDA receptor, in three-month-old rats.[10] Neuroprotective effects have also been demonstrated in Mongolian Gerbils by delaying the death of CA1, CA3, and dentate gyrus pyramidal neurons under glucose and oxygen-deprived conditions.[11] Additionally, rapastinel has demonstrated antinociceptive activity, which is of particular interest, as both competitive and noncompetitive NMDA receptor antagonists are ataxic at analgesic doses, while rapastinel and other glycine subunit ligands are able to elicit analgesia at non-ataxic doses.[12]

Apimostinel (NRX-1074), an analogue of rapastinel with the same mechanism of action but dramatically improved potency, is being developed by the same company as a follow-on compound to rapastinel.

CN 104109189,

PAPER

Tetrahedron Letters (2017), 58(16), 1568-1571

http://www.sciencedirect.com/science/article/pii/S0040403917303015

Novel silaproline (Sip)-incorporated close structural mimics of potent antidepressant peptide drug rapastinel (GLYX-13)

Highlights

Structural mimics of rapastinel comprising silaproline is reported.

Sip introduction is expected to improve its pharmacokinetic profiles.

Standard peptide coupling strategy in the solution-phase is utilized for synthesis.

Abstract

Rapastinel (GLYX-13) is a C-amidated tetrapeptide drug under clinical development for adjunctive treatment of major depressive disorder (MDD). Rapastinel features two consecutive proline residues centered at the peptide sequence (Thr-Pro-Pro-Thr-NH2), which are detrimental to its biological activity. In this communication, we report the synthesis of very close structural analogues of rapastinel comprising silaproline (Sip) as proline surrogate. By virtue of its enhanced lipophilicity and metabolic stability, Sip introduction in the native rapastinel sequence is expected to improve its pharmacokinetic profiles.

Graphical abstract

This paper reports the synthesis of silaproline (Sip)-incorporated close structural mimics of potent antidepressant peptide drug rapastinel (GLYX-13).

Unlabelled figure

PATENT

CN 104109189

Depression is the most common neuropsychiatric diseases, seriously affecting people’s health. In China With accelerated pace of life, increasing the incidence of depression was significantly higher social pressure.

[0003] Drug therapy is the primary means of treatment of depression. The main treatment drugs, including tricyclic antidepressants such as imipramine, amitriptyline and the like; selective serotonin reuptake inhibitors such as fluoxetine, sertraline and the like; serotonin / norepinephrine dual uptake inhibitors such as venlafaxine, duloxetine. However, commonly used drugs slow onset, usually takes several weeks to months, and there is not efficient and toxicity obvious shortcomings.

[0004] GLYX-13 is a new antidepressant, Phase II clinical study is currently underway. It does this by regulating the brain NMDA (N_ methyl -D- aspartate) receptors play a role, and none of them have serious side effects such as ketamine and R-rated, such as hallucinations and schizophrenia and so on.GLYX-13 can play a strong, fast and sustained antidepressant effects, the onset time of less than 24 hours, and the sustainable average of 7 days. As a peptide drug, GLYX-13 was well tolerated and safe to use.

[0005] GLYX-13 is a tetrapeptide having the sequence structure Thr-Pro-Pro-Thr, which is a free N-terminal amino group, C terminal amide structure. GLYX-13 synthesis methods include traditional methods of two solid-phase peptide synthesis and liquid phase peptide synthesis, because of its short sequence, the amount of solid phase synthesis of amino acids, high cost, and difficult to achieve a lot of preparation. A small amount of liquid phase amino acids, high yield can be prepared in large quantities.

The present invention can be further described by the following examples.

Preparation of r-NH2; [0013] Example 1 Four peptide H-Thr-Pr〇-P; r〇-Th

[0014] 1.1 threonine carboxyl amidation (H-Thr-NH2)

[0015] 500ml three flask was added Boc-Thr (tBu) -0H20g (0.073mol), anhydrous tetrahydrofuran (THF) 150ml, stirring to dissolve the solid. Ice-salt bath cooled to -10 ° C~_15 ° C, was added N- methylmorpholine 8ml, then l〇ml isobutyl chloroformate, keeping the temperature not higher than -10 ° C, after the addition was complete retention low temperature reaction 10min, then adding ammonia 20ml, ice bath reaction 30min, then at room temperature the reaction 8h. The reaction was stopped, water 300ml, 200ml ethyl acetate was added to extract the precipitate, washed with water 3 times.Dried over anhydrous sodium sulfate 6h. Filtered, and then the solvent was distilled off under reduced pressure to give a white solid 16. 6g, 83% yield.

[0016] The above product was dissolved in 50ml of trifluoroacetic acid or 2N hydrochloric acid / ethyl acetate solution was reacted at room temperature lh, the solvent was distilled off to give a white solid, i.e. amidated carboxyl threonine trifluoroacetic acid / hydrochloric acid salt H- Thr-NH 2. HC1.

[0017] 1.2 Pro – Preparation of threonine dipeptide fragment H-Pr〇-Thr-NH2 of

[0018] 500ml flask was added Boc-Pr〇 three-0H20g (0. 093mol), in anhydrous tetrahydrofuran (TH F) 200ml, stirring to dissolve solids, cooled to ice-salt bath -l〇 ° C~-15 ° C, added N- methylmorpholine 11ml, then dropwise isobutyl 13ml, keeping the temperature not higher than -10 ° C, keep it cool after the addition was complete the reaction 10min. H-Thr-NH2. HC114. 5g dissolved in 50ml of tetrahydrofuran, was added N- methyl morpholine 11ml. The above solution was added to the reaction mixture, the low temperature reaction 30min, then at room temperature the reaction 8h. The reaction was stopped, water 300ml, 200ml ethyl acetate was added to extract the precipitate, washed with water 3 times. Dried over anhydrous sodium sulfate 6h. Filtered and then evaporated under reduced pressure to give a white solid 25.7g, 82% yield.

[0019] The above product was dissolved in 100ml of 2N trifluoroacetic acid or hydrochloric acid / ethyl acetate solution was reacted at room temperature lh, the solvent was distilled off to give a white solid, i.e., proline – threonine dipeptide hydrochloride salt of H-Pr〇 -Thr-NH 2. HC1.

[0020] The above product was dissolved in 100ml of pure water, sodium carbonate solution was added to adjust the PH value, the precipitated white solid was filtered and dried in vacuo to give the desired product proline – threonine dipeptide fragment H-Pr square-Thr- NH223g.

Protected threonine [0021] 1.3 – Preparation of dipeptide fragment Boc-Thr (tBu) -Pr〇-0H of

[0022] Boc-Thr (tBu) -0H20g (0 · 073mol) was dissolved in dry tetrahydrofuran (THF) 150ml, stirring to dissolve the solid.Ice-salt bath cooled to -10 G~-15 ° C, was added N- methylmorpholine 8ml, then dropwise isobutyl 10ml, maintained at a temperature no higher than -10 ° C, kept cold reaction After dropping 10min. Proline methyl ester hydrochloride

PAPER

Journal of Medicinal Chemistry (1989), 32(10), 2407-11.

Threonylprolylprolylthreoninamide (HRP-7). The synthesis of HRP-7 was begun with 3 g of p-methylbenzhydrylamine-resin containing 1.41 mmol of attachment sites. The protected tetrapeptidyl-resin (1.63 g) was subjected to HF cleavage. Radioactivity was found in the 1% acetic acid extract (77%) and in the 5% extract (24%). These solutions were combined and lyophilized. Crude peptide (309 mg, 97%) was gel filtered on Sephadex G-15 (1.1 X 100 cm). Peptide eluting between 34 and 46 mL was pooled and lyophilized to yield 294 mg (95%, overall yield 92%) of homogeneous HRP-7.

PATENT

WO 2010033757

PATENT

WO 2017136348

Process for synthesizing dipyrrolidine peptide compounds (eg GLYX-13) is claimed.

An N-methyl-D-aspartate (NMDA) receptor is a postsynaptic, ionotropic receptor that is responsive to, inter alia, the excitatory amino acids glutamate and glycine and the synthetic compound NMDA. The NMDA receptor (NMDAR) appears to controls the flow of both divalent and monovalent ions into the postsynaptic neural cell through a receptor associated channel and has drawn particular interest since it appears to be involved in a broad spectrum of CNS disorders. The NMDAR has been implicated, for example, in neurodegenerative disorders including stroke-related brain cell death, convulsive disorders, and learning and memory.

NMDAR also plays a central role in modulating normal synaptic transmission, synaptic plasticity, and excitotoxicity in the central nervous system. The NMDAR is further involved in Long-Term Potentiation (LTP), which is the persistent strengthening of neuronal connections that underlie learning and memory The NMDAR has been associated with other disorders ranging from hypoglycemia and cardiac arrest to epilepsy. In addition, there are preliminary reports indicating involvement of NMDA receptors in the chronic neurodegeneration of Huntington’s, Parkinson’s, and Alzheimer’s diseases. Activation of the NMDA receptor has been shown to be responsible for post-stroke convulsions, and, in certain models of epilepsy, activation of the NMDA receptor has been shown to be necessary for the generation of seizures. In addition, certain properties of NMDA receptors suggest that they may be involved in the information-processing in the brain that underlies consciousness itself. Further, NMDA receptors have also been implicated in certain types of spatial learning.

[0003] In view of the association of NMDAR with various disorders and diseases, NMDA-modulating small molecule agonist and antagonist compounds have been developed for therapeutic use. NMDA receptor compounds may exert dual (agonist/antagonist) effect on the NMDA receptor through the allosteric sites. These compounds are typically termed “partial agonists”. In the presence of the principal site ligand, a partial agonist will displace some of the ligand and thus decrease Ca flow through the receptor. In the absence of the principal site ligand or in the presence of a lowered level of the principal site ligand, the partial agonist acts to increase Ca++ flow through the receptor channel.

Example 2: Synthesis of GLYX-13

[00119] GLYX-13 was prepared as follows, using intermediates KSM-1 and KSM-2 produced in Example 1. The synthetic route for the same is provided in Figure 2.

Stage A – Preparation of (S)-N-((2S, 3R)-l-amino-3-hydroxy-l-oxobutan-2-yl)-l-((S)-pyrrolidine-2-carbonyl) pyrrolidine-2-carboxamide (Compound XI)

[00120] In this stage, KSM -1 was reacted with 10%Pd/C in presence of methanol to produce a compound represented by Formula XI. The reaction was optimized and performed up to 4.0 kg scale in the production plant and observed consistent quality (>80% by HPLC%PA) and yields (80% to 85%).

[00121] The reaction scheme involved in this method is as follows:

[00122] Raw materials used for this method are illustrated in Table 7 as follows:

Table 7.

[00123] In stage A, 10% Palladium on Carbon (w/w, 50% wet) was charged into the pressure reactor at ambient temperature under nitrogen atmosphere. KSM-1 was dissolved in methanol in another container and sucked into above reactor under vacuum. Hydrogen pressure was maintained at 45-60 psi at ambient temperature for over a period of 5-6 hrs. Progress of the reaction mixture was monitored by HPLC for KSM-1 content; limit is not more than 5%.

Hyflow bed was prepared with methanol (Lot-II). The reaction mass was filtered through nutsche filter under nitrogen atmosphere and bed was washed with Methanol Lot-Ill. Filtrate was transferred into the reactor and distilled completely under reduced pressure at below 50 °C (Bath temperature) to get the syrup and syrup material was unloaded into clean and dry container and samples were sent to QC for analysis.

[00124] From the above reaction(s), 1.31 kg of compound represented by Formula XI was obtained with a yield of 89.31% and with a purity of 93.63%).

Stage B – Preparation of Benzyl (2S, 3R)-l-((S)-2-((S)-2-((2S, 3R)-I-amino-3-hydroxy-I- oxobutan-2-ylcarbamoyl) pyrrolidine-! -carbonyl) pyrrolidin-1 -yl)-3-hydroxy-l -oxobutan-2- ylcarbamate (Compound XII)

[00125] In this stage the compound represented by Formula XI obtained above was reacted with KSM-2 to produce a compound represented by Formula XII. This reaction was optimized and scaled up to 3.0 kg scale in the production plant and obtained 25% to 28% yields with UPLC purity (>95%).

[00126] The reaction scheme is as follows:

[00127] Raw materials used for this method are illustrated in Table 8 as follows:

Table 8.

[00128] Stage B: ethanol was charged into the reactor at 20 to 35 °C. Compound represented by Formula XI was charged into the reactor under stirring at 20 to 35 °C and reaction mass was cooled to -5 to 0°C. EDC.HC1 was charged into the reaction mass at -5 to 0 °C and reaction mass, was maintained at -5 to 0 °C for 10-15 minutes. N-Methyl morpholine was added drop wise to the above reaction mass at -5 to 0 °C and reaction mass was maintained at -5 to 0 °C for 10-15 minutes.

[00129] KSM-2 was charged into the reactor under stirring at -5 to 0 °C and reaction mass was maintained at -5 to 0 °C for 3.00 to 4.00 hours. The temperature of the reaction mass was raised to 20 to 35 °C and was maintained at 20 to 35 °C for 12 – 15 hours under stirring. (Note:

Monitor the reaction mass by HPLC for Stage A content after 12.0 hours and thereafter every 2.0 hours. The content of stage A should not be more than 2.0%). Ethanol was distilled out completely under vacuum at below 50 °C (Hot water temperature) and reaction mass was cooled to 20 to 35 °C. Water Lot-1 was charged into the residue obtained followed by 10% DCM-Isopropyl alcohol (Mixture of Dichloromethane Lot-1 & Isopropyl alcohol Lot-1 prepared in a cleaned HDPE container) into the reaction mass at 20 – 35 °C.

[00130] Both the layers were separated and the aqueous layer was charged into the reactor. 10%) DCM-Isopropyl alcohol (Mixture of Dichloromethane Lot-2 & Isopropyl alcohol Lot-2 prepared in a cleaned HDPE container) was charged into the reaction mass at 20 to 35 °C. Both the layers were separated and the aqueous layer was charged back into the reactor. 10%> IDCM-isopropyl alcohol (Mixture of Dichloromethane Lot-3 & Isopropyl alcohol Lot-3 prepared in a cleaned HDPE container) was charged into the reaction mass at 20 to 35 °C. Both the layers were separated and the aqueous layer was charged back into the reactor. 10%> DCM-Isopropyl alcohol (Mixture of Dichloromethane Lot-4 & Isopropyl alcohol Lot-4 prepared in a cleaned HDPE container) was charged into the reaction mass at 20 to 35 °C and separated both the layers. The above organic layers were combined and potassium hydrogen sulfate solution (Prepare a solution in a HDPE container by dissolving Potassium hydrogen sulfate Lot-1 in water Lot-2) was charged into the reaction mass at 20 to 35 °C. Separated both the layers and charged back organic layer into the reactor. Potassium hydrogen sulfate solution (Prepared a solution in a HDPE container by dissolving Potassium hydrogen sulfate Lot-2 in water Lot-3) was charged into the reaction mass at 20 to 35 °C. Separated both the layers and the organic layer was dried over Sodium sulfate and distilled out the solvent completely under vacuum at below 45 °C (Hot water temperature).

[00131] The above crude was absorbed with silica gel (100-200mesh) Lot-1 in

dichloromethane. Prepared the column with silica gel (100-200 mesh) Lot-2, and washed the silica gel bed with from Dichloromethane Lot-5 and charged the adsorbed compound into the column. Eluted the column with 0-10% Methanol Lot-1 in Dichloromethane Lot-5 and analyzed fractions by HPLC. Solvent was distilled out completely under vacuum at below 45 °C (Hot water temperature). Methyl tert-butyl ether Lot-1 was charged and stirred for 30 min. The solid was filtered through the Nutsche filter and washed with Methyl tert-butyl ether Lot-2 and

samples were sent to QC for complete analysis. (Note: If product quality was found to be less than 95%, column purification should be repeated).

[00132] From the above reaction(s), 0.575 kg of compound represented by Formula XII was obtained with a yield of 17% and with a purity of 96.28%).

Stage C – Preparation of Benzyl (S)-N-((2S, 3R)-l-amino-3-hydroxy-l-oxobutan-2-yl)-l-((S)-l- ((2R, 3R)-2-amino-3-hydroxybutanoyl) pyrrolidine-2 carbonyl) pyrrolidine-2-carboxamide (GLYX-13)

[00133] In this reaction step the compound of Formula XII obtained above was reacted with 10%oPd in presence of methanol to produce GLYX-13. This reaction was optimized and performed up to 2.8 kg scale in the production plant and got 40% to 45% of yields with UPLC purity >98%.

[00134] The reaction scheme involved in this method is as follows:

i

[00135] Raw materials used for this method are illustrated in Table 9 as follows:

Table 9.

30 Nitrogen cylinder – – – – – 31 Hydrogen cylinder – – – – –

[00136] In an exemplary embodiment of stage C, 10% Palladium Carbon (50% wet) was charged into the pressure reactor at ambient temperature under nitrogen atmosphere. Compound of Formula XII was dissolved in methanol in a separate container and sucked into the reactor under vacuum. Hydrogen pressure was maintained 45-60 psi at ambient temperature over a period of 6-8 hrs. Progress of the reaction was monitored by HPLC for stage-B (compound represented by Formula XII) content (limit is not more than 2%). If HPLC does not comply continue the stirring until it complies. Prepared the hyflow bed with methanol (Lot-II) and the reaction mass was filtered through hyflow bed under nitrogen atmosphere, and the filtrate was collected into a clean HDPE container. The bed was washed with Methanol Lot-Ill and the filtrate was transferred into the Rota Flask and distilled out the solvent completely under reduced pressure at below 50°C (Bath temperature) to get the crude product. The material was unloaded into clean HDPE container under Nitrogen atmosphere.

[00137] Neutral Alumina Lot-1 was charged into the above HDPE container till uniform mixture was formed. The neutral Alumina bed was prepared with neutral alumina Lot-2 and dichloromethane Lot-1 in a glass column. The neutral Alumina Lot-3 was charged and

Dichloromethane Lot-2 into the above prepared neutral Alumina bed. The adsorbed compound was charged into the column from op.no.11. The column was eluted with Dichloromethane Lot-2 and collect 10 L fractions. The column was eluted with Dichloromethane Lot-3 and collected 10 L fractions. The column was eluted with Dichloromethane Lot-4 and Methanol Lot-4 (1%) and collected 10 L fractions. The column was eluted with Dichloromethane Lot-5 and Methanol Lot-5 (2%) and collected 10 L fractions. The column was eluted with Dichloromethane Lot-6 and Methanol Lot-6 (3%) and collected 10 L fractions. The column was eluted with

Dichloromethane Lot-7 and Methanol Lot-7 (5%). and collected 10 L fractions. The column was eluted with Dichloromethane Lot-8 and Methanol Lot-8 (8%). and collected 10 L fractions. The column was eluted with Dichloromethane Lot-9 and Methanol Lot-9 (10%) and collected 10 L fractions. Fractions were analyzed by HPLC (above 97% purity and single max impurity >0.5% fractions are pooled together)

[00138] Ensured the reactor is clean and dry. The pure fractions were transferred into the reactor.

[00139] The solvent was distilled off completely under vacuum at below 45 °C (Hot water temperature). The material was cooled to 20 to 35°C. Charged Dichloromethane Lot- 10 and Methanol Lot- 10 into the material and stirred till dissolution. Activated carbon was charged into the above mixture at 20 to 35°C and temperature was raised to 45 to 50 °C.

[00140] Prepared the Hyflow bed with Hyflow Lot-2 and Methanol Lot-11 Filtered the reaction mass through the Hy-flow bed under nitrogen atmosphere and collect the filtrate into a clean FIDPE container. Prepared solvent mixture with Dichloromethane Lot-11 and Methanol Lot- 12 in a clean FIDPE container and washed Nutsche filter with same solvent. Charged filtrate in to Rota evaporator and distilled out solvent under vacuum at below 50°C. Dry the compound in Rota evaporator for 5 to 6 hours at 50°C, send sample to QC for Methanol content (residual solvent) which should not be more than 3000 ppm. The material was cooled to 20 to 35 °C and the solid material was unloaded into clean and dry glass bottle. Samples were sent to QC for complete analysis.

[00141] From the above reaction(s), 0.92 kg of Glyx-13 was obtained with a yield of 43.5% and with a purity of 99.73%.

Patent ID

Patent Title

Submitted Date

Granted Date

US9593145 SECONDARY STRUCTURE STABILIZED NMDA RECEPTOR MODULATORS AND USES THEREOF 2015-05-14 2016-04-28
US2017049844 STABLE COMPOSITIONS OF NEUROACTIVE PEPTIDES 2015-04-27
US2017049845 METHODS OF TREATING ALZHEIMER’S DISEASE, HUNTINGTON’S DISEASE, AUTISM, OR OTHER DISORDERS 2016-04-14
US2017072005 COMBINATIONS OF NMDAR MODULATING COMPOUNDS 2015-05-06
US2016345855 METHODS OF TREATING BRAIN DISORDERS OR IDENTIFYING BIOMARKERS RELATED THERETO 2014-12-15
Patent ID

Patent Title

Submitted Date

Granted Date

US2015182582 Methods of Treating Depression and Other Related Diseases 2014-08-05 2015-07-02
US2015253305 METHODS OF IDENTIFYING COMPOUNDS FOR TREATING DEPRESSION AND OTHER RELATED DISEASES 2013-10-11 2015-09-10
US2015343013 METHODS OF TREATING NEUROPATHIC PAIN 2014-12-16 2015-12-03
US2016002292 METHODS OF TREATING DEPRESSION AND OTHER RELATED DISEASES 2015-02-06 2016-01-07
US2016244485 NMDA RECEPTOR MODULATORS AND PRODRUGS, SALTS, AND USES THEREOF 2014-10-27 2016-08-25
Patent ID

Patent Title

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Granted Date

US2013296248 Methods of Treating Depression and Other Related Diseases 2013-07-09 2013-11-07
US9101612 Secondary Structure Stabilized NMDA Receptor Modulators and Uses Thereof 2011-02-11 2013-02-28
US2012178695 METHODS OF TREATING NEUROPATHIC PAIN 2010-07-02 2012-07-12
US8951968 Methods of treating depression and other related diseases 2012-04-05 2015-02-10
US8492340 Methods of treating depression and other related diseases 2012-09-10 2013-07-23
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US8673843 NMDA receptors modulators and uses thereof 2012-06-18 2014-03-18
US2014249088 METHODS OF TREATING NEUROPATHIC PAIN 2013-09-27 2014-09-04
US9198948 Methods of Treating Depression and Other Related Diseases 2013-07-09 2013-11-21
US9149501 Methods of Treating Depression and Other Related Diseases 2013-07-09 2013-11-28
US9340576 Methods of Treating Depression and Other Related Diseases 2013-06-04 2013-10-31

See also

References

  1. Jump up to:a b c Hashimoto K, Malchow B, Falkai P, Schmitt A (August 2013). “Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders”. Eur Arch Psychiatry Clin Neurosci263 (5): 367–77. PMID 23455590doi:10.1007/s00406-013-0399-y.
  2. Jump up to:a b c d Moskal JR, Burgdorf JS, Stanton PK, Kroes RA, Disterhoft JF, Burch RM, Amin Khan M (2016). “The Development of Rapastinel (Formerly GLYX-13); a rapid acting and long lasting antidepressant”. Curr NeuropharmacolPMID 26997507.
  3. Jump up^ FDA Grants Fast Track Designation to Naurex’s Rapid-Acting Novel Antidepressant GLYX-13 http://www.prnewswire.com/news-releases/fda-grants-fast-track-designation-to-naurexs-rapid-acting-novel-antidepressant-glyx-13-248174561.html
  4. Jump up^ http://naurex.com/wp-content/uploads/2014/12/Naurex_P2b_Data_Press_Release_FINAL_Approved.pdf
  5. Jump up to:a b Burgdorf, Jeffrey; Zhang, Xiao-lei; Weiss, Craig; Matthews, Elizabeth; Disterhoft, John F.; Stanton, Patric K.; Moskal, Joseph R. (2011). “The N-methyl-d-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats”Neurobiology of Aging32 (4): 698–706. ISSN 0197-4580PMC 3035742Freely accessiblePMID 19446371doi:10.1016/j.neurobiolaging.2009.04.012.
  6. Jump up^ Haring R, Stanton PK, Scheideler MA, Moskal JR (1991). “Glycine-like modulation of N-methyl-D-aspartate receptors by a monoclonal antibody that enhances long-term potentiation”. J. Neurochem57 (1): 323–32. PMID 1828831doi:10.1111/j.1471-4159.1991.tb02131.x.
  7. Jump up^ Moskal JR, Kuo AG, Weiss C, Wood PL, O’Connor Hanson A, Kelso S, Harris RB, Disterhoft JF (2005). “GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator”. Neuropharmacology49 (7): 1077–87. PMID 16051282doi:10.1016/j.neuropharm.2005.06.006.
  8. Jump up to:a b Burch RM, Amin Khan M, Houck D, Yu W, Burgdorf J, Moskal JR (2016). “NMDA Receptor Glycine Site Modulators as Therapeutics for Depression: Rapastinel has Antidepressant Activity without Causing Psychotomimetic Side Effects”. Curr NeuropharmacolPMID 26830963.
  9. Jump up^ Burgdorf, Jeffrey; Zhang, Xiao-lei; Weiss, Craig; Matthews, Elizabeth; Disterhoft, John F.; Stanton, Patric K.; Moskal, Joseph R. (2011). “The N-methyl-d-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats”Neurobiology of Aging32 (4): 698–706. PMC 3035742Freely accessiblePMID 19446371doi:10.1016/j.neurobiolaging.2009.04.012.
  10. Jump up^ Moskal, Joseph R.; Kuo, Amy G.; Weiss, Craig; Wood, Paul L.; O’Connor Hanson, Amy; Kelso, Stephen; Harris, Robert B.; Disterhoft, John F. (2005). “GLYX-13: A monoclonal antibody-derived peptide that acts as an N-methyl-d-aspartate receptor modulator”. Neuropharmacology49 (7): 1077–87. PMID 16051282doi:10.1016/j.neuropharm.2005.06.006.
  11. Jump up^ Stanton, Patric K.; Potter, Pamela E.; Aguilar, Jennifer; Decandia, Maria; Moskal, Joseph R. (2009). “Neuroprotection by a novel NMDAR functional glycine site partial agonist, GLYX-13”. NeuroReport20 (13): 1193–7. PMID 19623090doi:10.1097/WNR.0b013e32832f5130.
  12. Jump up^ Wood, Paul L.; Mahmood, Siddique A.; Moskal, Joseph R. (2008). “Antinociceptive action of GLYX-13: An N-methyl-D-aspartate receptor glycine site partial agonist”. NeuroReport19(10): 1059–61. PMID 18580579doi:10.1097/WNR.0b013e32830435c9.

External links

rapastinel
Rapastinel.svg
GLYX-133DanFrame1.svg
Clinical data
Pregnancy
category
  • US: N (Not classified yet)
ATC code
  • none
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
Formula C18H31N5O6
Molar mass 413.47 g/mol
3D model (JSmol)

/////////////RAPASTINEL, BV-102, GLYX-13, PEPTIDE, phase 3, рапастинел , راباستينيل , 雷帕替奈

CC(C(C(=O)N1CCCC1C(=O)N2CCCC2C(=O)NC(C(C)O)C(=O)N)N)O

Rosiptor acetate


imgThumbUNII-F6X6NZ9D95.png2D chemical structure of 782487-29-0

Rosiptor acetate

CAS: 782487-29-0 (acetate)  782487-28-9 (free base)
Chemical Formula: C22H39NO4
Molecular Weight: 381.557

AQX-1125; AQX 1125; AQX1125; AQX-1125 acetate; Rosiptor acetate

PHASE 3 …..a SH2-containing inositol 5-phosphatase 1 (SHIP1) modulator for treating cancer, inflammatory disorders and immune disorders.

(1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(Aminomethyl)-7a-methyl-1- methyleneoctahydro -1H – inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol, acetate

IUPAC/Chemical Name: (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexan-1-ol acetate

  • Originator Aquinox Pharmaceuticals
  • Class Anti-inflammatories; Immunotherapies; Small molecules
  • Mechanism of Action Inositol-1,4,5-trisphosphate 5-phosphatase stimulants

Image result

Highest Development Phases

  • Phase III Interstitial cystitis
  • Phase II Allergic asthma
  • Discontinued Atopic dermatitis; Chronic obstructive pulmonary disease; Haematological disorders; Hypersensitivity; Immunological disorders; Inflammation; Irritable bowel syndrome; Pulmonary fibrosis

Most Recent Events

  • 09 Mar 2017 Phase-III clinical trials in Interstitial cystitis in United Kingdom, Poland, Latvia and Canada before March 2017 (PO) (EudraCT2016-000906-12) (NCT02858453)
  • 04 Jan 2017 Aquinox Pharmaceuticals completes a phase I trial in Healthy volunteers in United Kingdom (NCT03185195)
  • 07 Sep 2016 Phase-III clinical trials in Interstitial cystitis in Czech Republic, Hungary, Denmark (PO) (EudraCT2016-000906-12)

Rosiptor, also known as AQX-1125 is a potent and selective SHIP1 activator currently in clinical development.

AQX-1125 inhibited Akt phosphorylation in SHIP1-proficient but not in SHIP1-deficient cells, reduced cytokine production in splenocytes, inhibited the activation of mast cells and inhibited human leukocyte chemotaxis.

AQX-1125 suppresses leukocyte accumulation and inflammatory mediator release in rodent models of pulmonary inflammation and allergy. As shown in the mouse model of LPS-induced lung inflammation, the efficacy of the compound is dependent on the presence of SHIP1. Pharmacological SHIP1 activation may have clinical potential for the treatment of pulmonary inflammatory diseases.

Dysregulated activation of the PI3K pathway contributes to inflammatory/immune disorders and cancer. Efforts have been made to develop modulators of PI3K as well as downstream kinases (Workman et al., Nat. Biotechnol. 24, 794-796, 2006; Simon, Cell 125, 647-649, 2006; Hennessy et al., Nat. Rev. Drug. Discov. 4, 988-1004, 2005; Knight et al., Cell 125, 733-747, 2006; Ong et al., Blood (2007), Vol. 110, No. 6, pp 1942-1949). A number of promising new PI3K isoform specific inhibitors with minimal toxicities have recently been developed and used mouse models of inflammatory disease (Camps et al., Nat. Med. 11, 936-943, 2005; Barber et al., Nat. Med. 11, 933-935, 2005) and glioma (Fan et al., Cancer Cell 9, 341-349, 2006). However, because of the dynamic interplay between phosphatases and kinases in regulating biological processes, inositol phosphatase activators represent a complementary, alternative approach to reduce PIPlevels. Of the phosphoinositol phosphatases that degrade PIP3, SHIP1 is a particularly ideal target for development of therapeutics for treating immune and hemopoietic disorders because of its hematopietic-restricted expression (Hazen et al., Blood 113, 2924-2933, 2009; Rohrschneider et al., Genes Dev. 14, 505-520, 2000).
      Small molecule SHIP1 modulators have been disclosed, including sesquiterpene compounds such as pelorol. Pelorol is a natural product isolated from the tropical marine sponge Dactylospongia elegans (Kwak et al., J. Nat. Prod. 63, 1153-1156, 2000; Goclik et al., J. Nat. Prod. 63, 1150-1152, 2000). Other reported SHIP1 modulators include the compounds set forth in PCT Published Patent Applications Nos. WO 2003/033517, WO 2004/035601, WO 2004/092100, WO 2007/147251, WO 2007/147252, WO 2011/069118, WO 2014/143561 and WO 2014/158654 and in U.S. Pat. Nos. 7,601,874 and 7,999,010.
      One such molecule is AQX-1125, which is the acetate salt of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (AQX-1125). AQX-1125 is a compound with anti-inflammatory activity and is described in U.S. Pat. Nos. 7,601,874 and 7,999,010, the relevant disclosures of which are incorporated in full by reference in their entirety, particularly with respect to the preparation of AQX-1125, pharmaceutical compositions comprising AQX-1125 and methods of using AQX-1125.
      AQX-1125 has the molecular formula, C20H36NO2+.C2H3O2, a molecular weight of 381.5 g/mole and has the following structural formula:

AQX-1125 is useful in treating disorders and conditions that benefit from SHIP1 modulation, such as cancers, inflammatory disorders and conditions and immune disorders and conditions. AQX-1125 is also useful in the preparation of a medicament for the treatment of such disorders and conditions.

Synthetic methods for preparing AQX-1125 are disclosed in U.S. Pat. Nos. 7,601,874 and 7,999,010. There exists, therefore, a need for improved methods of preparing AQX-1125.

Inventors Jeffery R RaymondKang HanYuanlin ZhouYuehua HeBradley NorenJames Gee Ken Yee
Applicant Inflazyme Pharm LtdJeffery R RaymondKang HanYuanlin ZhouYuehua HeBradley NorenJames Gee Ken Yee

Image result for Inflazyme Pharm Ltd

PATENT

WO-2016210146 

Dysregulated activation of the PI3K pathway contributes to

inflammatory/immune disorders and cancer. Efforts have been made to develop modulators of PI3K as well as downstream kinases (Workman et al., Nat. Biotechnol 24, 794-796, 2006; Simon, Cell 125, 647-649, 2006; Hennessy et al., Nat Rev Drug Discov 4, 988-1004, 2005; Knight et al., Cell 125, 733-747, 2006; Ong et al., Blood (2007), Vol. 110, No. 6, pp 1942-1949). A number of promising new PI3K isoform specific inhibitors with minimal toxicities have recently been developed and used in mouse models of inflammatory disease (Camps et al., Nat Med 1 1 , 936-943, 2005; Barber et ai, Nat Med 1 1 , 933-935, 2005) and glioma (Fan et al., Cancer Cell 9, 341-349, 2006). However, because of the dynamic interplay between phosphatases and kinases in regulating biological processes, inositol phosphatase activators represent a complementary, alternative approach to reduce PIP3 levels. Of the phosphoinositol phosphatases that degrade PIP3i SHIP1 is a particularly ideal target for development of therapeutics for treating immune and hemopoietic disorders because of its

hematopietic-restricted expression (Hazen et al., Blood 1 13, 2924-2933, 2009;

Rohrschneider et ai, Genes Dev. 14, 505-520, 2000).

Small molecule SHIP1 modulators have been disclosed, including

sesquiterpene compounds such as pelorol. Pelorol is a natural product isolated from the tropical marine sponge Dactylospongia elegans (Kwak et al., J Nat Prod 63, 1 153-1 156, 2000; Goclik et al., J Nat Prod 63, 1150-1152, 2000). Other reported SHIP1 modulators include the compounds set forth in PCT Published Patent Applications Nos. WO 2003/033517, WO 2004/035601 , WO 2004/092100, WO 2007/147251 , WO 2007/147252, WO 2011/069118, WO 2014/143561 and WO 2014/158654 and in U.S. Patent Nos. 7,601 ,874 and 7,999,010.

While significant strides have been made in this field, there remains a need for effective small molecule SHIP1 modulators.

One such molecule is the acetate salt of (1 S,3S,4 )-4-((3aS,4 ,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1 /-/-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (referred to herein as Compound 1). Compound 1 is a compound with anti-inflammatory activity and is described in U.S. Patent Nos. 7,601 ,874 and 7,999,010, the relevant disclosures of which are incorporated in full by reference in their entirety, particularly with respect to the preparation of Compound 1 ,

pharmaceutical compositions comprising Compound 1 and methods of using

Compound 1.

Compound 1 has the molecular formula, C2oH36N02+ · C2H302, a molecular weight of 381.5 g/mole

front page image

The application is directed to crystalline forms of the acetate salt of (1S,3S,4R)-4-(3aS,4R,5S,7aS)-4-(aminomethyl)-7a- methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl) -4-methylcyclohexanol and processes for their preparation. The compound acts as a SHIP1 modulator and is thus useful in the treatment of cancer or inflammatory and immune disorders and conditions.

(EN)

PATENT

https://encrypted.google.com/patents/WO1998002450A2?cl=en

Inventors David L. BurgoyneYaping ShenJohn M. LanglandsChristine RogersJoseph H.-L. ChauEdward PiersHassan Salari
Applicant Inflazyme Pharmaceuticals Ltd.University Of British ColumbiaUniversity Of Alberta

SYNTHESIS

WO 199802450

WO 2004092100

PATENT

WO 2004092100

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2004092100

 

 

 

PATENT

US 20170204048

https://patentscope.wipo.int/search/en/detail.jsf?docId=US200947106&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Process for the synthesis of substituted indene derivative (particularly AQX-1125 ) as a SH2-containing inositol 5-phosphatase 1 (SHIP1) modulator for treating cancer, inflammatory disorders and immune disorders. Aquinox Pharmaceuticals is developing AQX-1125 (phase III clinical trial in July 2017), a SHIP1 agonist, for the treatment of inflammatory diseases. For a prior filing see WO2016210146 , claiming novel crystalline forms of rosiptor acetate. In July 2017, Seenisamy and Chetia were associated with Syngene

Synthetic Method 1

In one aspect of the invention, AQX-1125 was prepared by the method described below in Reaction Scheme 1 where Pgis an oxygen-protecting group, Pgis a carbonyl protecting group, Lgis a leaving group and X is bromo or chloro:



Reaction Scheme 1A:



Synthetic Example 77

Step 11: Preparation of AQX-1125 from Compound 16

A. To a stirred solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexan-1-ol (Compound 16, 58.0 g, 0.180 mol, 1.0 eq, from Synthetic Example 76) in methanol (174 mL, 3 V) was added acetic acid (23.5 mL, 0.4 V) dropwise at 10° C. under a nitrogen atmosphere over 20 min. The reaction mixture was stirred at room temperature for 1 h. The solution was filtered to remove undissolved particles and washed with methanol (58 mL, 1 V). The filtrate was collected and evaporated at 35° C. to half the volume (˜125 mL). MTBE (348 mL, 6 V) was slowly added to the above concentrated mixture and the reaction stirred at 10° C. for 2 h. During the MTBE addition, slow precipitation of the product was observed. The solids were filtered and washed with MTBE (116 mL, 2V) to afford (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexan-1-ol, acetic acid salt, (AQX-1125) as a white solid (50 g, yield 72.6%). 1H NMR (400 MHz, pyridine-d5): δ 5.85 (br s, 5H), 4.70 (s, 2H), 4.08 (dd, J=10.4, 2 Hz, 1H), 3.95-3.85 (m, 1H), 3.60-3.50 (m, 1H), 3.18 (d, J=14 Hz, 1H), 2.92-2.86 (m, 1H), 2.80 (d, J=13.6 Hz, 1H), 2.50-2.40 (m, 1H), 2.25-1.97 (m, 3H), 2.15 (s, 3H), 1.90-1.65 (m, 4H), 1.56-1.40 (m, 4H), 1.39-1.20 (m, 2H), 1.25 (s, 3H), 0.78 (s, 3H). LCMS: (Method A) 322.4 (M+1), Retention time: 1.95 min, HPLC (Method H): 95.5 area %, Retention time: 16.66 min.

Synthetic Example 66

Preparation of Compound 16 and AQX-1125

      A. To a solution of 7a-methyl-5-((1S,2R,5S)-2-methyl-7-oxo-6-oxabicyclo[3.2.1]octan-2-yl)-1-methyleneoctahydro-1H-indene-4-carbaldehyde oxime (Compound 68, 100 mg, 0.30 mmol, from Synthetic Example 65) in 1,4-dioxane (5 mL) in a 25 mL RB flask fitted with reflux condenser was added a solution of lithium aluminum hydride (1 M in THF, 1.51 ml, 1.50 mmol) at RT under nitrogen and the reaction mass was stirred using a magnetic stirrer at 100° C. for 24 hours. Another lot of a solution of lithium aluminum hydride (1 M in THF, 1.51 ml, 1.50 mmol) was added and the reaction was further refluxed for 24 hours. Completion of the reaction was monitored by LCMS analysis.
      B. The reaction mass was quenched by the drop-wise addition of saturated aq. sodium sulfate solution, filtered through a CELITE™ bed on glass frit funnel and concentrated by rotary evaporation to get a crude mass which was further purified by preparative HPLC to afford (1S,3S,4R)-4-((4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexan-1-ol (Compound 16, 35 mg, 36% yield) as an off-white solid. 1H-NMR (400 MHz, CD3OD): δ 4.69 (s, 2H), 3.73 (br d, J=10.0 Hz, 1H), 3.52-3.45 (m, 1H), 3.22-3.15 (m, 1H), 3.05-2.98 (m, 1H), 2.62-2.55 (m, 1H), 2.38-2.25 (m, 1H), 2.20-2.15 (m, 1H), 1.95-1.81 (m, 6H), 1.62-1.25 (m, 10H), 1.10 (s, 3H), 0.86 (s, 3H). LCMS (Method A) m/z: 322.5 (M+1), Retention time: 2.06 min, Purity: 98.9 area % (ELSD). HPLC (Method A): Retention time: 2.70 min, Purity: 99.3 area %.
      C. AQX-1125 was prepared from Compound 16 in the same manner as described above in Synthetic Example 16.

REFERENCES

1: Nickel JC, Egerdie B, Davis E, Evans R, Mackenzie L, Shrewsbury SB. A Phase II Study of the Efficacy and Safety of the Novel Oral SHIP1 Activator AQX-1125 in Subjects with Moderate to Severe Interstitial Cystitis/Bladder Pain Syndrome. J Urol. 2016 Sep;196(3):747-54. doi: 10.1016/j.juro.2016.03.003. PubMed PMID: 26968644.

2: Chuang YC, Chermansky C, Kashyap M, Tyagi P. Investigational drugs for bladder pain syndrome (BPS) / interstitial cystitis (IC). Expert Opin Investig Drugs. 2016;25(5):521-9. doi: 10.1517/13543784.2016.1162290. PubMed PMID: 26940379.

3: Leaker BR, Barnes PJ, O’Connor BJ, Ali FY, Tam P, Neville J, Mackenzie LF, MacRury T. The effects of the novel SHIP1 activator AQX-1125 on allergen-induced responses in mild-to-moderate asthma. Clin Exp Allergy. 2014 Sep;44(9):1146-53. doi: 10.1111/cea.12370. PubMed PMID: 25040039.

4: Stenton GR, Mackenzie LF, Tam P, Cross JL, Harwig C, Raymond J, Toews J, Wu J, Ogden N, MacRury T, Szabo C. Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 1. Effects on inflammatory cell activation and chemotaxis in vitro and pharmacokinetic characterization in vivo. Br J Pharmacol. 2013 Mar;168(6):1506-18. doi: 10.1111/bph.12039. PubMed PMID: 23121445; PubMed Central PMCID: PMC3596654.

5: Stenton GR, Mackenzie LF, Tam P, Cross JL, Harwig C, Raymond J, Toews J, Chernoff D, MacRury T, Szabo C. Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 2. Efficacy studies in allergic and pulmonary inflammation models in vivo. Br J Pharmacol. 2013 Mar;168(6):1519-29. doi: 10.1111/bph.12038. PubMed PMID: 23121409; PubMed Central PMCID: PMC3596655.

6: Croydon L. BioPartnering North America–Spotlight on Canada. IDrugs. 2010 Mar;13(3):159-61. PubMed PMID: 20191430.

Patent ID Patent Title Submitted Date Granted Date
US2016083387 SHIP1 MODULATORS AND METHODS RELATED THERETO 2014-02-27 2016-03-24
US2016031899 SHIP1 MODULATORS AND METHODS RELATED THERETO 2014-02-27 2016-02-04

AQX-1125

In the PI3K pathway, the key messenger molecule is phosphatidylinositiol-3,4,5-trisphosphate, or PIP3, which initiates the signaling pathway. In cells derived from bone marrow tissues (e.g. predominantly immune cells), the key enzymes that control levels of PIP3 are the PI3 kinase (PI3K), and the phosphatases, PTEN and SHIP1 (SH2-containing inositol-5’-phosphatase 1). PI3K generates PIP3, thus initiating the signaling pathway. This signaling is reduced by degradation of PIP3 by PTEN and SHIP1. PTEN is generally considered to be constantly working in the pathway, whereas SHIP1 is dormant until the cell is stimulated. In preclinical models, PTEN has been shown to suppress cancer by controlling cell proliferation, whereas SHIP1, when functioning, has been demonstrated to control inflammation by reducing cell migration and activation.

The SHIP1 Pathway – Highlighting the Role of AQX-1125

AQX-1125 is our lead product candidate and has generated positive clinical data from three completed clinical trials, including two proof-of-concept trials, one in COPD and one in allergic asthma, demonstrating a favorable safety profile and anti-inflammatory activity. Overall, more than 100 subjects have received AQX-1125. Importantly, our clinical trial results were consistent with the drug-like properties and anti-inflammatory activities demonstrated in our preclinical studies. AQX-1125 is a once daily oral capsule with many desirable drug-like properties. We are currently investigating AQX-1125 in two Phase 2 clinical trials, one in COPD and one in BPS/IC.

Based on our three completed clinical trials, we have demonstrated that AQX-1125:

  • has desirable pharmacokinetic, absorption and excretion properties that make it suitable for once daily oral administration;
  • is generally well tolerated, exhibiting mild to moderate adverse events primarily related to gastrointestinal upset that resolve without treatment or long-term effects and are reduced by taking the drug candidate with food; and
  • has anti-inflammatory properties consistent with those exhibited in preclinical studies and exhibited activity in two trials using two distinct inflammatory challenges.

AQX-1125 is an activator of SHIP1, which controls the PI3K cellular signaling pathway. If the PI3K pathway is overactive, immune cells can produce an abundance of pro-inflammatory signaling molecules and migrate to and concentrate in tissues, resulting in excessive or chronic inflammation. SHIP1 is predominantly expressed in cells derived from bone marrow tissues, which are mainly immune cells. Therefore drugs that activate SHIP1 can reduce the function and migration of immune cells and have an anti-inflammatory effect. By controlling the PI3K pathway, AQX-1125 reduces immune cell function and migration by targeting a mechanism that has evolved in nature to maintain homeostasis of the immune system.

AQX-1125 has demonstrated compelling preclinical activity in a broad range of relevant inflammatory studies including preclinical models of COPD, asthma, pulmonary fibrosis, BPS/IC and inflammatory bowel disease (IBD). In these studies we have seen a meaningful reduction in the relevant immune cells that are the cells that cause inflammation, such as neutrophils, eosinophils and macrophages, and a reduction in the symptoms of inflammation, such as pain and swelling. The activity, efficacy and potency seen with AQX-1125 in most preclinical studies compare favorably to published results with corticosteroids. In addition, AQX-1125 demonstrated compelling activity in the smoke airway inflammation and Bleomycin Fibrosis models, which are known to be steroid refractory, or in other words, do not respond to corticosteroids. We believe this broad anti-inflammatory profile is not typical amongst drugs in development and supports the therapeutic potential for AQX-1125.

In addition to demonstrating strong in vitro and in vivo activity, AQX-1125 was also selected as a lead candidate based on its many desirable drug-like properties. The drug candidate is highly water soluble and does not require complex formulation for oral administration. AQX-1125 has low plasma protein binding, is not metabolized and is excreted unmetabolized in both urine and feces. After oral or intravenous dosing, AQX-1125 reaches high concentrations in respiratory, urinary and gastrointestinal tracts, all of which have mucosal surfaces of therapeutic interest. In humans, AQX-1125 has shown pharmacokinetic properties suitable for once-a-day dosing. In addition, the absorption of the drug candidate is equivalent whether taken with or without food.

///////////rosiptor, AQX-1125, AQX 1125, AQX1125; AQX-1125 acetate, Rosiptor acetate, PHASE 3,  SH2-containing inositol 5-phosphatase 1, SHIP1,  cancer, inflammatory disorders, immune disorders, 782487-29-0, 782487-28-9, Aquinox

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CC(=O)O.C[C@@]1(CC[C@H](O)C[C@@H]1CO)[C@H]2CC[C@@]3(C)[C@@H](CCC3=C)[C@@H]2CN

Lanabecestat (formerly known as AZD3293 or LY3314814)


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Lanabecestat.svg

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Lanabecestat

  • Molecular FormulaC26H28N4O
  • Average mass412.527 Da

ChemSpider 2D Image | Lanabecestat | C26H28N4O

Dispiro[cyclohexane-1,2′-[2H]indene-1′(3′H),2”-[2H]imidazol]-4”-amine, 4-methoxy-5”-methyl-6′-[5-(1-propyn-1-yl)-3-pyridinyl]-, (1α,1′R,4β)-

(1r,1’R,4R)-4-Methoxy-5”-methyl-6′-[5-(1-propin-1-yl)-3-pyridinyl]-3’H-dispiro[cyclohexane-1,2′-indene-1′,2”-imidazol]-4”-amin
(1r,1’R,4R)-4-Methoxy-5”-methyl-6′-[5-(1-propyn-1-yl)-3-pyridinyl]-3’H-dispiro[cyclohexane-1,2′-indene-1′,2”-imidazol]-4”-amine
(lr,l’R,4R)- 4-methoxy-5″-methyl-6′-[5-(prop-l-yn-l-yl)pyridin-3-yl]-3’H- dispiro[cyclohexane-l,2′-inden-l’2′-imidazole]-4″-amine
(lr,4r)-4-Methoxy-5″-methyl-6′-(5-prop-l-yn-l-ylpyridin-3-yl)-3’H-dispiro[cyclohexane- l,2′-indene-l’,2″-imidazol]- “-amine
CAS 1383982-64-6
AZD3293
Dispiro[cyclohexane-1,2′-[1H]indene-1′(3’H),2”-[2H]imidazol]-4”-amine, 4-methoxy-5”-methyl-6′-[5-(1-propyn-1-yl)-3-pyridinyl]-, (1’R)-
Lanabecestat
LY3314814
UNII:X8SPJ492VF, AZ-12304146
Beta amyloid antagonist; Beta secretase 1 inhibitor; Beta secretase 2 inhibitor
Fast Track
  • (1α,1’R,4β)-4-Methoxy-5”-methyl-6′-[5-(1-propyn-1-yl)-3-pyridinyl]dispiro[cyclohexane-1,2′-[2H]indene-1′(3’H),2”-[2H]imidazol]-4”-amine
  • (1,4-trans,1’R)-4-methoxy-5”-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3’H-dispiro[cyclohexane-1,2′-indene-1′,2”-imidazol]-4”-amine
  • (1r,1’R,4R)-4-methoxy-5”-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3’H-dispiro[cyclohexane-1,2′-indene-1′,2”-imidazol]-4”-amine

Lanabecestat (formerly known as AZD3293 or LY3314814) is an oral beta-secretase 1 cleaving enzyme (BACE) inhibitor. A BACE inhibitor in theory would prevent the buildup of beta-amyloid and may help slow or stop the progression of Alzheimer’s disease.

In September 2014, AstraZeneca and Eli Lilly and Company announced an agreement to co-develop lanabecestat.[1] A pivotal Phase II/III clinical trial of lanabecestat started in late 2014 and is planned to recruit 2,200 patients and end in June 2019.[2] In April 2016 the company announced it would advance to phase 3 without modification.[3]

  • Originator Astex Pharmaceuticals; AstraZeneca
  • Developer AstraZeneca; Eli Lilly
  • Class Antidementias; Imidazoles; Pyridines; Small molecules; Spiro compounds
  • Mechanism of Action Amyloid precursor protein secretase inhibitors
  • Phase III Alzheimer’s disease

Most Recent Events

  • 15 Mar 2017 Eli Lilly and AstraZeneca initiates enrolment in an extension phase III trial for Alzheimer’s Disease (In adults, In the elderly) in USA (PO) (NCT02972658)
  • 25 Jan 2017 Chemical structure information added
  • 12 Jan 2017 Eli Lilly and AstraZeneca initiate enrolment in a phase I pharmacokinetics trial in Healthy volunteers in USA (PO) (NCT03019549
  • Astex Therapeutics Ltd

Image resultImage result for azd 3293

CHEMBL2152914.png

The prime neuropathological event distinguishing Alzheimer’s disease (AD) is deposition of the 40-42 residue amyloid β-peptide (Αβ) in brain parenchyma and cerebral vessels. A large body of genetic, biochemical and in vivo data support a pivotal role for Αβ in the pathological cascade that eventually leads to AD. Patients usually present early symptoms (commonly memory loss) in their sixth or seventh decades of life. The disease progresses with increasing dementia and elevated deposition of Αβ. In parallel, a hyperphosphorylated form of the microtubule-associated protein tau accumulates within neurons, leading to a plethora of deleterious effects on neuronal function. The prevailing working hypothesis regarding the temporal relationship between Αβ and tau pathologies states that Αβ deposition precedes tau aggregation in humans and animal models of the disease. Within this context, it is worth noting that the exact molecular nature of Αβ, mediating this pathological function is presently an issue under intense study. Most likely, there is a continuum of toxic species ranging from lower order Αβ oligomers to supramolecular assemblies such as Αβ fibrils. The Αβ peptide is an integral fragment of the Type I protein APP (Αβ amyloid precursor protein), a protein ubiquitously expressed in human tissues. Since soluble Αβ can be found in both plasma and cerebrospinal fluid (CSF), and in the medium from cultured cells, APP has to undergo proteolysis. There are three main cleavages of APP that are relevant to the pathobiology of AD, the so-called α-, β-, and γ-cleavages. The a-cleavage, which occurs roughly in the middle of the Αβ domain in APP is executed by the metalloproteases AD AMI 0 or AD AMI 7 (the latter also known as TACE). The β-cleavage, occurring at the N terminus of Αβ, is generated by the transmembrane aspartyl protease Beta site APP Cleaving Enzymel (BACE1). The γ-cleavage, generating the Αβ C termini and subsequent release of the peptide, is effected by a multi-subunit aspartyl protease named γ-secretase. ADAM10/17 cleavage followed by γ-secretase cleavage results in the release of the soluble p3 peptide, an N- terminally truncated Αβ fragment that fails to form amyloid deposits in humans. This proteolytic route is commonly referred to as the non-amyloidogenic pathway. Consecutive cleavages by BACE1 and γ-secretase generates the intact Αβ peptide, hence this processing scheme has been termed the amyloidogenic pathway. With this knowledge at hand, it is possible to envision two possible avenues of lowering Αβ production: stimulating non- amyloidogenic processing, or inhibit or modulate amyloidogenic processing. This application focuses on the latter strategy, inhibition or modulation of amyloidogenic processing.

Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of patients with Trisomy 21 (Down’s Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerative disorders.

Neurofibrillary tangles also occur in other neurodegenerative disorders including dementia- inducing disorders (Varghese, J., et al, Journal of Medicinal Chemistry, 2003, 46, 4625-4630). β-amyloid deposits are predominately an aggregate of AB peptide, which in turn is a product of the proteolysis of amyloid precursor protein (APP). More specifically, AB peptide results from the cleavage of APP at the C-terminus by one or more γ-secretases, and at the N- terminus by B-secretase enzyme (BACE), also known as aspartyl protease or Asp2 or Beta site APP Cleaving Enzyme (BACE), as part of the B-amyloidogenic pathway.

BACE activity is correlated directly to the generation of AB peptide from APP (Sinha, et al, Nature, 1999, 402, 537-540), and studies increasingly indicate that the inhibition of BACE inhibits the production of AB peptide (Roberds, S. L., et al, Human Molecular Genetics, 2001, 10, 1317-1324). BACE is a membrane bound type 1 protein that is

synthesized as a partially active proenzyme, and is abundantly expressed in brain tissue. It is thought to represent the major β-secretase activity, and is considered to be the rate-limiting step in the production of amyloid^-peptide (Αβ).

Drugs that reduce or block BACE activity should therefore reduce Αβ levels and levels of fragments of Αβ in the brain, or elsewhere where Αβ or fragments thereof deposit, and thus slow the formation of amyloid plaques and the progression of AD or other maladies involving deposition of Αβ or fragments thereof. BACE is therefore an important candidate for the development of drugs as a treatment and/or prophylaxis of Αβ-related pathologies such as Down’s syndrome, β-amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI (“mild cognitive impairment”), Alzheimer’s Disease, memory loss, attention deficit symptoms associated with Alzheimer’s disease, neurodegeneration associated with diseases such as Alzheimer’s disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson’s disease, progressive supranuclear palsy or cortical basal degeneration.

It would therefore be useful to inhibit the deposition of Αβ and portions thereof by inhibiting BACE through inhibitors such as the compounds provided herein.

The therapeutic potential of inhibiting the deposition of Αβ has motivated many groups to isolate and characterize secretase enzymes and to identify their potential inhibitors.

SYNTHESIS

As in WO 2013190302

PATENT

WO 2013190302

EXAMPLES

Example 1

6′-Bromospiro[cyclohexane-l,2′-indene]-l’,4(3’H)-dione

Figure imgf000016_0001

Potassium tert-butoxide (223 g, 1.99 mol) was charged to a 100 L reactor containing a stirred mixture of 6-bromo-l-indanone (8.38 kg, 39.7 mol) in THF (16.75 L) at 20-30 °C. Methyl acrylate (2.33 L, 25.8 mol) was then charged to the mixture during 15 minutes keeping the temperature between 20-30 °C. A solution of potassium tert-butoxide (89.1 g, 0.79 mol) dissolved in THF (400 mL) was added were after methyl acrylate (2.33 L, 25.8 mol) was added during 20 minutes at 20-30 °C. A third portion of potassium tert-butoxide (90 g, 0.80 mol) dissolved in THF (400 mL) was then added, followed by a third addition of methyl acrylate (2.33 L, 25.8 mol) during 20 minutes at 20-30 °C. Potassium tert-butoxide (4.86 kg, 43.3 mol) dissolved in THF (21.9 L) was charged to the reactor during 1 hour at 20-30 °C. The reaction was heated to approximately 65 °C and 23 L of solvent was distilled off. Reaction temperature was lowered to 60 °C and 50% aqueous potassium hydroxide (2.42 L, 31.7 mol) dissolved in water (51.1 L) was added to the mixture during 30 minutes at 55-60 °C were after the mixture was stirred for 6 hours at 60 °C, cooled to 20 °C during 2 hours. After stirring for 12 hours at 20 °C the solid material was filtered off, washed twice with a mixture of water (8.4 L) and THF (4.2 L) and then dried at 50 °C under vacuum to yield 6′- bromospiro[cyclohexane-l,2′-indene]-r,4(3’H)-dione (7.78 kg; 26.6 mol). 1H MR (500 MHz, DMSO-i¾) δ ppm 1.78 – 1.84 (m, 2 H), 1.95 (td, 2 H), 2.32 – 2.38 (m, 2 H), 2.51 – 2.59 (m, 2 H), 3.27 (s, 2 H), 7.60 (d, 1 H), 7.81 (m, 1 H), 7.89 (m, 1 H).

Example 2

(lr,4r)-6′-Bromo-4-methoxyspiro[cyclohexane-l,2′-inden]-l'(3’H)-one

Figure imgf000016_0002

Borane tert-butylamine complex (845 g, 9.7 mol) dissolved in DCM (3.8 L) was charged to a slurry of 6′-Bromospiro[cyclohexane-l,2′-indene]- ,4(3’H)-dione (7.7 kg, 26.3 mol) in DCM (42.4 L) at approximately 0-5 °C over approximately 25 minutes. The reaction was left with stirring at 0-5°C for 1 hour were after analysis confirmed that the conversion was >98%. A solution prepared from sodium chloride (2.77 kg), water (13.3 L) and 37% hydrochloric acid (2.61 L, 32 mol) was charged. The mixture was warmed to approximately 15 °C and the phases separated after settling into layers. The organic phase was returned to the reactor, together with methyl methanesulfonate (2.68 L, 31.6 mol) and tetrabutylammonium chloride (131 g, 0.47 mol) and the mixture was vigorously agitated at 20 °C. 50% Sodium hydroxide (12.5 L, 236 mol) was then charged to the vigorously agitated reaction mixture over approximately 1 hour and the reaction was left with vigorously agitation overnight at 20 °C. Water (19 L) was added and the aqueous phase discarded after separation. The organic layer was heated to approximately 40 °C and 33 L of solvent were distilled off. Ethanol (21 L) was charged and the distillation resumed with increasing temperature (22 L distilled off at up to 79 °C). Ethanol (13.9 L) was charged at approximately 75 °C. Water (14.6 L) was charged over 30 minutes keeping the temperature between 72-75 °C. Approximately 400 mL of the solution is withdrawn to a 500 mL polythene bottle and the sample crystallised spontaneously. The batch was cooled to 50 °C were the crystallised slurry sample was added back to the solution. The mixture was cooled to 40 °C. The mixture was cooled to 20 °C during 4 hours were after it was stirred overnight. The solid was filtered off , washed with a mixture of ethanol (6.6 L) and water (5 L) and dried at 50 °C under vacuum to yield (lr,4r)-6′-bromo-4- methoxyspiro[cyclohexane-l,2′-inden]-r(3’H)-one (5.83 kg, 18.9 mol) 1H MR (500 MHz,

DMSO-i¾) δ ppm 1.22-1.32 (m, 2 H), 1.41 – 1.48 (m, 2 H), 1.56 (td, 2 H), 1.99 – 2.07 (m, 2 H), 3.01 (s, 2 H), 3.16 – 3.23 (m, 1 H), 3.27 (s, 3 H), 7.56 (d, 1 H), 7.77 (d, 1 H), 7.86 (dd, 1

H).

Example 3

(lr,4r)-6′-Bromo-4-methoxyspiro[cyclohexane-l,2′-inden]-l'(3’H)-imine hydrochloride

Figure imgf000017_0001

(lr,4r)-6′-Bromo-4-methoxyspiro[cyclohexane-l,2′-inden]- (3’H)-one (5.82 kg; 17.7 mol) was charged to a 100 L reactor at ambient temperature followed by titanium (IV)ethoxide (7.4 L; 35.4 mol) and a solution of tert-butylsulfinamide (2.94 kg; 23.0 mol) in 2- methyltetrahydrofuran (13.7 L). The mixture was stirred and heated to 82 °C. After 30 minutes at 82 °C the temperature was increased further (up to 97 °C) and 8 L of solvent was distilled off. The reaction was cooled to 87 °C and 2- methyltetrahydrofuran (8.2 L) was added giving a reaction temperature of 82 °C. The reaction was left with stirring at 82 °C overnight. The reaction temperature was raised (to 97 °C) and 8.5 L of solvent was distilled off. The reaction was cooled down to 87 °C and 2- methyltetrahydrofuran (8.2 L) was added giving a reaction temperature of 82 °C. After 3.5 hours the reaction temperature was increased further (to 97 °C) and 8 L of solvent was distilled off. The reaction was cooled to 87 °C and 2- methyltetrahydrofuran (8.2 L) was added giving a reaction temperature of 82 °C. After 2 hours the reaction temperature was increased further (to 97 °C) and 8.2 L of solvent was distilled off. The reaction was cooled to 87 °C and 2-methyltetrahydrofuran (8.2 L) was added giving a reaction temperature of 82 °C. The reaction was stirred overnight at 82 °C. The reaction temperature was increased further (to 97 °C) and 8 L of solvent was distilled off. The reaction was cooled down to 25 °C. Dichloromethane (16.4 L) was charged. To a separate reactor water (30 L) was added and agitated vigorously and sodium sulfate (7.54 kg) was added and the resulting solution was cooled to 10 °C. Sulfuric acid (2.3 L, 42.4 mol) was added to the water solution and the temperature was adjusted to 20 °C. 6 L of the acidic water solution was withdrawn and saved for later. The organic reaction mixture was charged to the acidic water solution over 5 minutes with good agitation. The organic reaction vessel was washed with dichloromethane (16.4 L), and the dichloromethane wash solution was also added to the acidic water. The mixture was stirred for 15 minutes and then allowed to settle for 20 minutes. The lower aqueous phase was run off, and the saved 6 L of acidic wash was added followed by water (5.5 L). The mixture was stirred for 15 minutes and then allowed to settle for 20 minutes. The lower organic layer was run off to carboys and the upper water layer was discarded. The organic layer was charged back to the vessel followed by sodium sulfate (2.74 kg), and the mixture was agitated for 30 minutes. The sodium sulfate was filtered off and washed with dichloromethane (5.5 L) and the combined organic phases were charged to a clean vessel. The batch was heated for distillation (collected 31 L max temperature 57 °C). The batch was cooled to 40 °C and dichloromethane (16.4 L) was added. The batch was heated for distillation (collected 17 L max temperature 54 °C). The batch was cooled to 20 °C and dichloromethane (5.5 L) and ethanol (2.7 L) were. 2 M hydrogen chloride in diethyl ether (10.6 L; 21.2 mol) was charged to the reaction over 45 minutes keeping the temperature between 16-23 °C. The resulting slurry was stirred at 20 °C for 1 hour whereafter the solid was filtered off and washed 3 times with a 1 : 1 mixture of dichloromethane and diethyl ether (3 x 5.5 L). The solid was dried at 50 °C under vacuum to yield (lr,4r)-6′-bromo-4- methoxyspiro[cyclohexane-l,2′-inden]-l'(3’H)-imine hydrochloride (6.0 kg; 14.3 mol; assay 82% w/w by 1H MR) 1H NMR (500 MHz, DMSO-i¾) δ ppm 130 (m, 2 H), 1.70 (d, 2 H), 1.98 (m, 2 H), 2.10 (m, 2 H), 3.17 (s, 2 H), 3.23 (m, 1 H), 3.29 (s, 3 H), 7.61 (d, 1 H), 8.04 (dd, 1 H), 8.75 (d, 1 H), 12.90(br s,2H).

Example 4

(lr,4r)-6′-Bromo-4-methoxy-5″-methyl-3’H-dispiro[cyclohexane-l,2′-inden-l’2′- imidazole]-4″ (3″H)-thione

Figure imgf000019_0001

Trimethylorthoformate (4.95 L; 45.2 mol) and diisopropylethylamine (3.5 L; 20.0 mol) was charged to a reactor containing (lr,4r)-6′-bromo-4-methoxyspiro[cyclohexane-l,2′-inden]- l'(3’H)-imine hydrochloride (6.25 kg; 14.9 mol) in isopropanol (50.5 L). The reaction mixture was stirred and heated to 75 °C during 1 hour so that a clear solution was obtained. The temperature was set to 70 °C and a 2 M solution of 2-oxopropanethioamide in isopropanol (19.5 kg; 40.6 mol) was charged over 1 hour, were after the reaction was stirred overnight at 69 °C. The batch was seeded with (lr,4r)-6′-bromo-4-methoxy-5″-methyl-3’H- dispiro[cyclohexane-l,2′-inden- 2′-imidazole]-4″(3″H)-thione (3 g ; 7.6 mmol) and the temperature was lowered to 60 °C and stirred for 1 hour. The mixture was concentrated by distillation (distillation temperature approximately 60 °C; 31 L distilled off). Water (31 L) was added during 1 hour and 60 °C before the temperature was lowered to 25 °C during 90 minutes were after the mixture was stirred for 3 hours. The solid was filtered off , washed with isopropanol twice (2 x 5.2 L) and dried under vacuum at 40 °C to yield (lr,4r)-6′-bromo-4- methoxy-5″-methyl-3’H-dispiro[cyclohexane-l,2′-inden- 2′-imidazole]-4″(3″H)-thione (4.87 kg; 10.8 mol; assay of 87% w/w by 1H NMR). Example 5

(lr,l’R,4R)-6′-Bromo-4-methoxy-5″-methyl-3’H-dispiro[cyclohexane-l,2′-inden-l’2′- imidazole]-4″-amine D(+)-10-Camphorsulfonic acid salt

Figure imgf000020_0001

7 M Ammonia in methanol (32 L; 224 mol) was charged to a reactor containing (lr,4r)-6′-bromo-4-methoxy-5”-methyl-3’H-dispiro[cyclohexane-l,2′-inden- 2′-imidazole]- 4″(3″H)-thione (5.10 kg; 11.4 mol) and zinc acetate dihydrate (3.02 kg ; 13.8 mol). The reactor was sealed and the mixture was heated to 80 °C and stirred for 24 hours, were after it was cooled to 30 °C. 1-Butanol (51L) was charged and the reaction mixture was concentrated by vacuum distilling off approximately 50 L. 1-Butanol (25 L) was added and the mixture was concentrated by vacuum distilling of 27 L. The mixture was cooled to 30 °C and 1 M sodium hydroxide (30 L; 30 mol) was charged. The biphasic mixture was agitated for 15 minutes. The lower aqueous phase was separated off. Water (20 L) was charged and the mixture was agitated for 30 minutes. The lower aqueous phase was separated off. The organic phase was heated to 70 °C were after (l S)-(+)-10-camphorsulfonic acid (2.4 kg; 10.3 mol) was charged. The mixture was stirred for 1 hour at 70 °C and then ramped down to 20 °C over 3 hours. The solid was filtered off, washed with ethanol (20 L) and dried in vacuum at 50 °C to yield (lr,4r)-6′-bromo-4-methoxy-5″-methyl-3’H-dispiro[cyclohexane-l,2′-inden- 2′-imidazole]- 4″-amine (+)-10-Camphor sulfonic acid salt (3.12 kg; 5.13 mol; assay 102%w/w by 1H

MR).

Example 6

(lr,l’R,4R)- 4-methoxy-5″-methyl-6′-[5-(prop-l-yn-l-yl)pyridin-3-yl]-3’H- dispiro[cyclohexane-l,2′-inden-l’2′-imidazole]-4″-amine

Na2PdCl4 (1.4 g; 4.76 mmol) and 3-(di-tert-butylphosphonium)propane sulfonate (2.6 g; 9.69 mmol) dissolved in water (0.1 L) was charged to a vessel containing (lr,4r)-6′-bromo- 4-methoxy-5″-methyl-3’H-dispiro[cyclohexane-l,2′-inden- 2′-imidazole]-4″-amine (+)-10- camphorsulfonic acid salt (1 kg; 1.58 mol), potassium carbonate (0.763 kg; 5.52 mol) in a mixture of 1-butanol (7.7 L) and water (2.6 L). The mixture is carefully inerted with nitrogen whereafter 5-(prop-l-ynyl)pyridine-3-yl boronic acid (0.29 kg; 1.62 mol) is charged and the mixture is again carefully inerted with nitrogen. The reaction mixture is heated to 75 °C and stirred for 2 hours were after analysis showed full conversion. Temperature was adjusted to 45 °C. Stirring was stopped and the lower aqueous phase was separated off. The organic layer was washed 3 times with water (3 x 4 L). The reaction temperature was adjusted to 22 °C and Phosphonics SPM32 scavenger (0.195 kg) was charged and the mixture was agitated overnight. The scavenger was filtered off and washed with 1-butanol (1 L). The reaction is concentrated by distillation under reduced pressure to 3 L. Butyl acetate (7.7 L) is charged and the mixture is again concentrated down to 3 L by distillation under reduced pressure. Butyl acetate (4.8 L) was charged and the mixture was heated to 60 °C. The mixture was stirred for 1 hour were after it was concentrated down to approximately 4 L by distillation under reduced pressure. The temperature was set to 60 °C and heptanes (3.8 L) was added over 20 minutes. The mixture was cooled down to 20 °C over 3 hours and then left with stirring overnight. The solid was filtered off and washed twice with a 1 : 1 mixture of butyl acetate: heptane (2 x 2 L). The product was dried under vacuum at 50 °C to yield (lr, R,4R)-4-methoxy-5″-methyl-6′- [5-(prop-l-yn-l-yl)pyridin-3-yl]-3’H-dispiro[cyclohexane-l,2′-inden- 2′-imidazole]-4”- amine (0.562 kg; 1.36 mol; assay 100% w/w by 1H MR). 1H MR (500 MHz, DMSO-i¾) δ ppm 0.97 (d, 1 H), 1.12-1.30 (m, 2 H), 1.37-1.51 (m, 3 H), 1.83 (d, 2 H), 2.09 (s, 3 H), 2.17 (s, 2 H), 2.89-3.12 (m, 3 H), 3.20 (s, 3 H), 6.54 (s, 2 H), 6.83 (s, 1 H), 7.40 (d, 1 H), 7.54 (d, 1 H), 7.90(s,lH). 8.51(d,lH), 8.67(d, lH)

Example 7

Preparation of camsylate salt of (lr,l’R,4R)- 4-methoxy-5″-methyl-6′-[5-(prop-l-yn-l- yl)pyridin-3-yl]-3’H-dispiro[cyclohexane-l,2′-inden-l’2′-imidazole]-4′ ‘-amine

1.105 kg (lr, l ‘R,4R)- 4-methoxy-5″-methyl-6′-[5-(prop-l-yn-l-yl)pyridin-3-yl]-3’H- dispiro[cyclohexane-l,2′-inden- 2’-imidazole]-4″-amine was dissolved in 8.10 L 2-propanol and 475 mL water at 60 °C. Then 1.0 mole equivalent (622 gram) (l S)-(+)-10

camphorsulfonic acid was charged at 60 °C. The slurry was agitated until all (l S)-(+)-10 camphorsulfonic acid was dissolved. A second portion of 2-propanol was added (6.0 L) at 60 °C and then the contents were distilled until 4.3 L distillate was collected. Then 9.1 L Heptane was charged at 65 °C. After a delay of one hour the batch became opaque. Then an additional distillation was performed at about 75 °C and 8.2 L distillate was collected. The batch was then cooled to 20 °C over 2 hrs and held at that temperature overnight. Then the batch was filtered and washed with a mixture of 1.8 L 2-propanol and 2.7 L heptane. Finally the substance was dried at reduced pressure and 50 °C. The yield was 1.44 kg (83.6 % w/w). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.12 (1H, s), 9,70 (2H, d, J 40.2), 8.81 (1H, d, J2.1), 8.55 (1H, d, J 1.7), 8.05 (1H, dd, J2.1, 1.7), 7.77 (1H, dd, J7.8, 1.2), 7.50 (2H, m), 3.22 (3H, s), 3.19 (1H, d, J 16.1), 3.10 (1H, d, J 16.1), 3.02 (1H, m), 2.90 (1H, d, J 14.7), 2.60 (1H, m), 2.41 (1H, d, J 14.7), 2.40 (3H, s), 2.22 (1H, m), 2.10 (3H, s), 1.91 (3H, m), 1.81 (1H, m), 1.77 (1H, d, J 18.1), 1.50 (2H, m), 1.25 (6H, m), 0.98 (3H, s), 0.69 (3H, s).

Inventors Martin Hans Bohlin, Craig Robert Stewart
Applicant Astrazeneca Ab, Astrazeneca Uk Limited

str1

PATENT

WO 2012087237

Inventors Gabor Csjernyik, Sofia KARLSTRÖM, Annika Kers, Karin Kolmodin, Martin Nylöf, Liselotte ÖHBERG, Laszlo Rakos, Lars Sandberg, Fernando Sehgelmeble, Peter SÖDERMAN, Britt-Marie Swahn, Berg Stefan Von, Less «
Applicant Astrazeneca Ab

Example 20a (lr,4r)-4-Methoxy-5″-methyl-6′-(5-prop-l-yn-l-ylpyridin-3-yl)-3’H-dispiro[cyclohexane- l,2′-indene-l’,2″-imidazol]- “-amine

Figure imgf000117_0001

Method A

5-(Prop-l-ynyl)pyridin-3-ylboronic acid (Intermediate 15, 0.044 g, 0.27 mmol), (lr,4r)-6′- bromo-4-methoxy-5″-methyl-3’H-dispiro[cyclohexane-l,2′-indene- ,2″-imidazol]-4″-amine (Example 19 Method A Step 4, 0.085 g, 0.23 mmol), [l, l’-bis(diphenylphosphino)- ferrocene]palladium(II) chloride (9.29 mg, 0.01 mmol), K2C03 (2M aq., 1.355 mL, 0.68 mmol) and 2-methyl-tetrahydrofuran (0.5 mL) were mixed and heated to 100 °C using MW for 2×30 min. 2-methyl-tetrahydrofuran (5 mL) and H20 (5 mL) were added and the layers were separated. The organic layer was dried with MgS04 and then concentrated. The crude was dissolved in DCM and washed with H20. The organic phase was separated through a phase separator and dried in vacuo. The crude product was purified with preparative chromatography. The solvent was evaporated and the H20-phase was extracted with DCM. The organic phase was separated through a phase separator and dried to give the title compound (0.033 g, 36% yield), 1H MR (500 MHz, CD3CN) δ ppm 1.04 – 1.13 (m, 1 H), 1.23 – 1.35 (m, 2 H), 1.44 (td, 1 H), 1.50 – 1.58 (m, 2 H), 1.84 – 1.91 (m, 2 H), 2.07 (s, 3 H), 2.20 (s, 3 H), 3.00 (ddd, 1 H), 3.08 (d, 1 H), 3.16 (d, 1 H), 3.25 (s, 3 H), 5.25 (br. s., 2 H), 6.88 (d, 1 H), 7.39 (d, 1 H), 7.49 (dd, 1 H), 7.85 (t, 1 H), 8.48 (d, 1 H), 8.64 (d, 1 H), MS (MM-ES+APCI)+w/z 413 [M+H]+.

Separation of the isomers of (lr,4r)-4-methoxy-5″-methyl-6′-(5-prop-l-yn-l-ylpyridin-3- yl)-3’H-dispiro[cyclohexane-l,2′-indene-l’,2″-imidazol]-4″-amine

(lr,4r)-4-Methoxy-5″-methyl-6′-(5-prop-l-yn-l-ylpyridin-3-yl)-3’H-dispiro[cyclohexane-l,2′- indene-l’,2″-imidazol]-4″-amine (Example 20a, 0.144 g, 0.35 mmol) was purified using preparative chromatography (SFC Berger Multigram II, Column: Chiralcel OD-H; 20*250 mm; 5μιη, mobile phase: 30% MeOH (containing 0.1% DEA); 70% C02, Flow: 50 mL/min, total number of injections: 4). Fractions which contained the product were combined and the MeOH was evaporated to give: Isomer 1: (lr, R,4R)-4-methoxy-5”-methyl-6′-(5-prop-l-yn-l-ylpyridin-3-yl)-3’H-dispiro- [cyclohexane-l,2′-indene-l’,2″-imidazol]-4″-amine (49 mg, 34% yield) with retention time 2.5 min:

Figure imgf000118_0001

1H MR (500 MHz, CD3CN) δ ppm 1.07 – 1.17 (m, 1 H), 1.23 – 1.39 (m, 2 H), 1.47 (td, 1 H), 1.57 (ddq, 2 H), 1.86 – 1.94 (m, 2 H), 2.09 (s, 3 H), 2.23 (s, 3 H), 2.98 – 3.07 (m, 1 H), 3.11 (d, 1 H), 3.20 (d, 1 H), 3.28 (s, 3 H), 5.30 (br. s., 2 H), 6.91 (d, 1 H), 7.42 (d, 1 H), 7.52 (dd, 1 H), 7.88 (t, 1 H), 8.51 (d, 1 H), 8.67 (d, 1 H), MS (MM-ES+APCI)+ m/z 413.2 [M+H]+; and

Isomer 2: (lr,l’S,4S)-4-methoxy-5″-methyl-6′-(5-prop-l-yn-l-ylpyridin-3-yl)-3’H- dispiro[cyclohexane-l,2′-indene-l’,2″-imidazol]-4″-amine (50 mg, 35% yield) with retention time 6.6 min:

Figure imgf000118_0002

1H MR (500 MHz, CD3CN) δ ppm 1.02 – 1.13 (m, 1 H), 1.20 – 1.35 (m, 2 H), 1.44 (d, 1 H), 1.54 (ddd, 2 H), 1.84 – 1.91 (m, 2 H), 2.06 (s, 3 H), 2.20 (s, 3 H), 3.00 (tt, 1 H), 3.08 (d, 1 H), 3.16 (d, 1 H), 3.25 (s, 3 H), 5.26 (br. s., 2 H), 6.88 (d, 1 H), 7.39 (d, 1 H), 7.49 (dd, 1 H), 7.84 (t, 1 H), 8.48 (d, 1 H), 8.63 (d, 1 H), MS (MM-ES+APCI)+ m/z 413.2 [M+H]+.

Method B

A vessel was charged with (lr,4r)-6′-bromo-4-methoxy-5″-methyl-3’H-dispiro[cyclohexane-l,2′- indene-l’,2″-imidazol]-4″-amine (Example 19 Method B Step 4, 7.5 g, 19.9 mmol), 5-(prop-l- ynyl)pyridin-3-ylboronic acid (Intermediate 15, 3.37 g, 20.9 mmol), 2.0 M aq. K2C03 (29.9 mL, 59.8 mmol), and 2-methyl-tetrahydrofuran (40 mL). The vessel was purged under vacuum and the atmosphere was replaced with argon. Sodium tetrachloropalladate (II) (0.147 g, 0.50 mmol) and 3-(di-tert-butyl phosphonium) propane sulfonate (0.267 g, 1.00 mmol) were added and the contents were heated to reflux for a period of 16 h. The contents were cooled to 30 °C and the phases were separated. The aqueous phase was extracted with 2-methyl-tetrahydrofuran (2 x 10 mL), then the organics were combined, washed with brine and treated with activated charcoal (2.0 g). The mixture was filtered over diatomaceous earth, and then washed with 2-methyl- tetrahydrofuran (20 mL). The filtrate was concentrated to a volume of approximately 50 mL, then water (300 μL) was added, and the contents were stirred vigorously as seed material was added to promote crystallization. The product began to crystallize and the mixture was stirred for 2 h at r.t., then 30 min. at 0-5 °C in an ice bath before being filtered. The filter cake was washed with 10 mL cold 2-methyl-tetrahydrofuran and then dried in the vacuum oven at 45 °C to give the racemic title compound (5.2 g, 12.6 mmol, 63% yield): MS (ES+) m/z 413 [M+H]+.

(lr,l’R,4R)-4-Methoxy-5″-methyl-6′-[5-(prop-l-yn-l-yl)pyridin-3-yl]-3’H-dispiro- [cyclohexane-l,2′-indene-l’ “-imidazol]-4”-amine (isomer 1)

Figure imgf000119_0001

Method C

A solution of (lr,4r)-4-methoxy-5″-methyl-6′-(5-prop-l-yn-l-ylpyridin-3-yl)-3’H-dispiro- [cyclohexane-l,2′-indene-l’,2″-imidazol]-4″-amine (Example 20a method B, 4.85 g, 11.76 mmol) and EtOH (75 mL) was stirred at 55 °C. A solution of (+)-di-p-toluoyl-D-tartaric acid (2.271 g, 5.88 mmol) in EtOH (20 mL) was added and stirring continued. After 2 min. a precipitate began to form. The mixture was stirred for 2 h before being slowly cooled to 30 °C and then stirred for a further 16 h. The heat was removed and the mixture was stirred at r.t. for 30 min. The mixture was filtered and the filter cake washed with chilled EtOH (45 mL). The solid was dried in the vacuum oven at 45 °C for 5 h, then the material was charged to a vessel and DCM (50 mL) and 2.0 M aq. NaOH solution (20 mL) were added. The mixture was stirred at 25 °C for 15 min. The phases were separated and the aqueous layer was extracted with 10 mL DCM. The organic phase was concentrated in vacuo to a residue and 20 mL EtOH was added. The resulting solution was stirred at r.t. as water (15 mL) was slowly added to the vessel. A precipitate slowly began to form, and the resulting mixture was stirred for 10 min. before additional water (20 mL) was added. The mixture was stirred at r.t. for 1 h and then filtered. The filter cake was washed with water (15 mL) and dried in a vacuum oven at 45 °C for a period of 16 h to give the title compound (1.78 g, 36% yield): MS (ES+) m/z 413 [M+H]+. This material is equivalent to Example 20a Isomer 1 above. Method D

To a 500 mL round-bottomed flask was added (lr, R,4R)-6′-bromo-4-methoxy-5″-methyl-3’H- dispiro[cyclohexane-l,2′-inden- ,2′-imidazole]-4″-amine as the D(+)-10-camphor sulfonic acid salt (Example 19 Method B Step 5, 25.4 g, 41.7 mmol), 2 M aq. KOH (100 mL) and 2-methyl- tetrahydrofuran (150 mL). The mixture was stirred for 30 min at r.t. after which the mixture was transferred to a separatory funnel and allowed to settle. The phases were separated and the organic phase was washed with 2 M aq. K2C03 (100 mL). The organic phase was transferred to a 500 mL round-bottomed flask followed by addition of 5-(prop-l-ynyl)pyridin-3-ylboronic acid (Intermediate 15, 6.72 g, 41.74 mmol), K2C03 (2.0 M, 62.6 mL, 125.21 mmol). The mixture was degassed by means of bubbling Ar through the solution for 5 min. To the mixture was then added sodium tetrachloropalladate(II) (0.307 g, 1.04 mmol) and 3-(di-tert- butylphosphonium)propane sulfonate (0.560 g, 2.09 mmol) followed by heating the mixture at reflux (80 °C) overnight. The reaction mixture was allowed to cool down to r.t. and the phases were separated. The aqueous phase was extracted with 2-Me-THF (2×100 mL). The organics were combined, washed with brine and treated with activated charcoal. The mixture was filtered over diatomaceous earth and the filter cake was washed with 2-Me-THF (2×20 mL), and the filtrate was concentrated to give 17.7 g that was combined with 2.8 g from other runs. The material was dissolved in 2-Me-THF under warming and put on silica (-500 g). Elution with 2- Me-THF/ Et3N (100:0-97.5:2.5) gave the product. The solvent was evaporated, then co- evaporated with EtOH (absolute, 250 mL) to give (9.1 g, 53% yield). The HCl-salt was prepared to purify the product further: The product was dissolved in CH2C12 (125 mL) under gentle warming, HC1 in Et20 (-15 mL) in Et20 (100 mL) was added, followed by addition of Et20 (-300 mL) to give a precipitate that was filtered off and washed with Et20 to give the HCl-salt. CH2C12 and 2 M aq. NaOH were added and the phases separated. The organic phase was concentrated and then co-evaporated with MeOH. The formed solid was dried in a vacuum cabinet at 45 °C overnight to give the title compound (7.4 g, 43% yield): 1H MR (500 MHz, DMSO-i¾) δ ppm 0.97 (d, 1 H) 1.12 – 1.30 (m, 2 H) 1.37 – 1.51 (m, 3 H) 1.83 (d, 2 H) 2.09 (s, 3 H) 2.17 (s, 3 H) 2.89 – 3.12 (m, 3 H) 3.20 (s, 3 H) 6.54 (s, 2 H) 6.83 (s, 1 H) 7.40 (d, 1 H) 7.54 (d, 1 H) 7.90 (s, 1 H) 8.51 (d, 1 H) 8.67 (d, 1 H); HRMS-TOF (ES+) m/z 413.2338 [M+H]+ (calculated 413.2341); enantiomeric purity >99.5%; NMR Strength 97.8±0.6% (not including water).

References

  1. Jump up^ “AstraZeneca and Lilly announce alliance to develop and commercialise BACE inhibitor AZD3293 for Alzheimer’s disease”. http://www.astrazeneca.com. 16 Sep 2014. Retrieved 8 Oct 2014.
  2. Jump up^ “AstraZeneca and Lilly move Alzheimer’s drug into big trial”. December 2014.
  3. Jump up^ Lilly and AstraZeneca Alzheimer’s candidate advances; AstraZeneca earns $100M milestone. April 2016
PATENT CITATIONS
Cited Patent Filing date Publication date Applicant Title
WO2011002408A1 * Jul 2, 2010 Jan 6, 2011 Astrazeneca Ab Novel compounds for treatment of neurodegeneration associated with diseases, such as alzheimer’s disease or dementia
WO2012087237A1 * Dec 21, 2011 Jun 28, 2012 Astrazeneca Ab Compounds and their use as bace inhibitors
Reference
1 BUNN, C. W.: “Chemical Crystallography“, 1948, CLARENDON PRESS
2 GIACOVAZZO, C. ET AL.: “Fundamentals of Crystallography“, 1995, OXFORD UNIVERSITY PRESS
3 JENKINS, R.; SNYDER, R. L.: “ntroduction to X-Ray Powder Diffractometry“, 1996, JOHN WILEY & SONS
4 KLUG, H. P.; ALEXANDER, L. E.: “X-ray Diffraction Procedures“, 1974, JOHN WILEY AND SONS
5 ROBERDS, S. L. ET AL., HUMAN MOLECULAR GENETICS, vol. 10, 2001, pages 1317 – 1324
6 SINHA ET AL., NATURE, vol. 402, 1999, pages 537 – 540
7 VARGHESE, J. ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, 2003, pages 4625 – 4630
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Patent ID Patent Title Submitted Date Granted Date
US8865911 Compounds and their use as BACE inhibitors 2013-03-15 2014-10-21
US8415483 Compounds and their use as BACE inhibitors 2011-12-20 2013-04-09
US2015133471 COMPOUNDS AND THEIR USE AS BACE INHIBITORS 2014-09-15 2015-05-14
US2016184303 COMPOUNDS AND THEIR USE AS BACE INHIBITORS 2015-12-22 2016-06-30
Lanabecestat
Lanabecestat.svg
Names
Systematic IUPAC name

4-Methoxy-5′′-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2′′-imidazole]-4′′-amine
Other names

AZD3293; LY3314814
Identifiers
3D model (JSmol)
ChemSpider
Properties
C26H28N4O
Molar mass 412.54 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

CC#CC1=CC(=CN=C1)C2=CC3=C(CC4(C35N=C(C(=N5)N)C)CCC(CC4)OC)C=C2

PAPER

Figure

Structure of Eli Lilly/AstraZeneca BACE1 inhibitor AZD3292 (+)-camsylate and of the 3-propynylpyridine fragment common to several BACE1 inhibitors.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease resulting in personality and behavioral disturbances, impaired memory loss, inability to perform daily tasks, and death.(1) AD affects an estimated 47 million patients and their families worldwide,(2) and this number is expected to rise to 115 million by 2050.(3) AD is caused through the accumulation of β-amyloid proteins into plaques outside neurons in the brain.(4) It is thought that soluble forms of this protein are neurotoxic and are the main cause of deterioration seen in Alzheimer patients. The soluble protein fragments are made through the cutting of larger proteins, namely, amyloid precursor protein (APP), by two enzymes: β-site amyloid cleaving enzyme (BACE) and γ-secretase. Notably, BACE1 inhibitors have shown promise as potentially disease-modifying treatments for AD.(5) The novel, potent BACE-1 inhibitor AZD3293 (LY3314814) is a brain-permeable, orally active compound with a slow off-rate from its target enzyme, BACE1, which robustly reduced plasma, CSF, and brain Aβ40, Aβ42, and sAβPPβ concentrations in multiple nonclinical species, in elderly subjects, and patients with AD. Eli Lilly and Co. and AstraZeneca are currently studying AZD3293 in phase 3 clinical trials.

Development of a Continuous-Flow Sonogashira Cross-Coupling Protocol using Propyne Gas under Process Intensified Conditions

Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
§ AstraZeneca, Silk Road Business Park, Macclesfield SK10 2NA, United Kingdom
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00160

Abstract

Abstract Image

The development of a continuous-flow Sonogashira cross-coupling protocol using propyne gas for the synthesis of a key intermediate in the manufacturing of a β-amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, currently undergoing late stage clinical trials for a disease-modifying therapy of Alzheimer’s disease, is described. Instead of the currently used batch manufacturing process for this intermediate that utilizes TMS-propyne as reagent, we herein demonstrate the safe utilization of propyne gas, as a cheaper and more atom efficient reagent, using an intensified continuous-flow protocol under homogeneous conditions. The flow process afforded the target intermediate with a desired product selectivity of ∼91% (vs the bis adduct) after a residence time of 10 min at 160 °C. The continuous-flow process compares favorably with the batch process, which uses TMS-propyne and requires overnight processing, TBAF as an additive, and a significantly higher loading of Cu co-catalyst.

Product 3:

1H NMR (300 MHz, CDCl3) δ ppm 8.48 (d, J = 1.2 Hz, 1H), 8.44 (d, J = 1.2 Hz, 1H), 7.74 (t, J = 2.0 Hz, 1H), 2.00 (s, 3H).

13C NMR (75 MHz, CDCl3) δ ppm 150.2, 149.0, 140.7, 122.5, 119.9, 91.2, 75.2, 4.4.

Product 6: 1H NMR (300 MHz, CDCl3) δ ppm 8.47 (d, J = 1.9, 2H), 7.63 (t, J = 2.0 Hz, 1H) 2.08 (s, 6H).

Product 4 was isolated for NMR analysis using the same purification procedure as described for product 3.

1 H NMR (300 MHz, CDCl3) δ ppm 8.54 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 1.7 Hz, 1H), 7.81 (t, J = 2.0 Hz, 1H), 2.42 (t, J = 7.0 Hz, 2H), 1.65–1.40 (m, 4H), 0.95 (t, J = 7.2 Hz, 3H).

13C NMR (75 MHz, CDCl3) δ ppm 150.5, 149.2, 140.9, 122.8, 120.1, 95.9, 76.2, 30.6, 22.1, 19.3, 13.7.

str1 str2 str3 str4 str5 str6

///////////////LanabecestatLY3314814, 1383982-64-6, AZD3293, PHASE 3, AZ-12304146, Fast Track, Nootropic agent, Neuroprotectant

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