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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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WO 2018067805, NEW PATENT, SOTAGLIFLOZIN, TEVA


Image result

WO-2018067805

(WO2018067805) SOLID STATE FORMS OF SOTAGLIFLOZIN

TEVA PHARMACEUTICAL INDUSTRIES LTD.

GIAFFREDA, Stefano Luca; (IT).
MODENA, Enrico; (IT).
IANNI, Cristina; (IT).
MUTHUSAMY, Anantha Rajmohan; (IN).
KANNIAH, Sundara Lakshmi; (IN)

Stefano Luca Giaffreda at PolyCrystallineStefano Luca Giaffreda

Enrico Modena at PolyCrystallineEnrico Modena

Sundara Lakshmi KanniahSundara Lakshmi Kanniah
Novel crystalline forms of sotagliflozin (designated as Forms A and E) and their hydrate and monohydrate, processes for their preparation and compositions comprising them are claimed. Also claims are their use for treating diabetes. Sotagliflozin is known to be an inhibitor of sodium glucose transporter-1 and -2, useful for treating insulin dependent diabetes and non-insulin dependent diabetes

Sotagliflozin has the chemical name (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H- pyran-3,4,5-triol. Sotagliflozin has the following chemical structure:

[0003] Sotagliflozin is an orally available L-xyloside based molecule that apparently inhibits both sodium-glucose transporter type 1 (SGLT1) and type 2 (SGLT2). SGLT1 is primarily responsible for glucose and galactose absorption in the gastrointestinal tract, and SGLT2 is responsible for most of the glucose reabsorption performed by the kidney.

[0004] Sotagliflozin is known from WO 2008/109591. Amorphous forms and crystalline forms (i.e. Form 1 and Form 2) of Sotagliflozin are disclosed in WO2010/009197.

[0005] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Sotagliflozin, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis – “TGA”, or differential scanning calorimetry – “DSC”), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (13C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving

formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

[0007] Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms (including solvated forms) of Sotagliflozin.

EXAMPLES

Sotagliflozin Form-2 may be prepared according to WO2010/009197. Sotaglifiozin Form-2 may also be prepared according to Example 16 below.

Working examples:

Example- 1 : Preparation of Sotagliflozin (Amorphous Form)

[0080] 2 g of Sotagliflozin (Form-2) was taken in 250ml round bottom flask and applied vacuum (approx. 50 mbar) with continuous rotation of the flask. The flask was externally heated by hot air flow maintained at few centimetres from the rotating flask wall for few minutes until the compound melts at around 130°C and the melt was quenched to room temperature (25°C) with water bath. The amorphous solid (1.8 g) was scratched from the walls of the flask.

Example-2: Preparation of Sotagliflozin Form A

[0081] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of water, was left at variable temperature as follows: heating from 10°C to 50°C at the rate of 20°C/hr, held at 50°C for 3 hrs; cooling from 50°C to 10°C at the rate of 20°C/hr, held at 10°C for 3hrs; again heating from 10°C to 50°C at the rate of 10°C/hr, held at 50°C for 3hrs; again cooling from 50°C to 10°C at the rate of 10°C/hr, held at 10°Cfor 3hrs; further heating from 10°C to 50°C at the rate of 5°C/hr, held at 50°C for 3hrs; further cooling from 50°C to 10°C at the rate of 5°C/hr, held at 10°C for 3hrs; followed by raising the temperature from 10°C to 25°C at the rate of 10°C/hr, held at 25°C for 24hrs. The suspension was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form A has been confirmed by PXRD as presented in figure 1.

Example-3 : Preparation of Sotagliflozin Form B

[0082] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Toluene at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD as presented in figure 2.

Example-4: Preparation of Sotagliflozin Form B

[0083] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Heptane at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-5 : Preparation of Sotagliflozin Form B

[0084] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Mesitylene at room temperature (20-25°C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-6: Preparation of Sotagliflozin Form B

[0085] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of p-Xylene at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-7: Preparation of Sotagliflozin Form C

[0086] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Water at 50°C. The suspension was stirred for 72hrs which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form C has been confirmed by PXRD as presented in figure 3.

Example-8: Preparation of Sotagliflozin Form D

[0087] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of ethanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20 ml vial and left open to allow evaporation of the solvent (25°C/1 atm). Solid was observed after 3 days; it was collected and analyzed by PXRD. Sotagliflozin Form D has been confirmed by PXRD as presented in figure 4.

Example-9: Preparation of Sotagliflozin Form E

[0088] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of isopropyl acetate. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened in the refrigerator (4-7°C/l atm) to allow evaporation of the solvent. The crystals were observed after 9 days; it was collected and analyzed by PXRD. Sotagliflozin Form E has been confirmed by PXRD as presented in figure 5.

Example-9: Preparation of Sotagliflozin Form F

[0089] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of 2-propanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened to allow evaporation of the solvent (4-7°C/l atm). The crystals were observed after 13 days; it was collected and analyzed by PXRD. Sotagliflozin Form F has been confirmed by PXRD as presented in figure 6.

Example- 10: Preparation of Sotagliflozin Form G

[0090] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of 1 -propanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened in the refrigerator (4-7°C/l atm) to allow evaporation of the solvent. Solid was observed after 24 days; it was collected and analyzed by PXRD.

Sotagliflozin Form G has been confirmed by PXRD as presented in figure 7.

Example- 11 : Preparation of Sotagliflozin Form H

[0091] 15 mg of Sotagliflozin (Form- A) was kept in DVS (dynamic vapor sorption) instrument. The kinetic sorption measurement was performed at 25 °C in two full cycle of sorption and desorption as follows, from 40%RH to 90%RH, 90%RH to 0%RH then again from 0% to 90%RH, 90%RH to 0%RH. After completion of experiment, the powder was collected and analyzed by PXRD. Sotagliflozin Form H has been confirmed by PXRD as presented in figure 8.

Example- 12: Preparation of Sotagliflozin Form I

[0092] Procedure to prepare saturated solution: 1500 mg of Sotagliflozin were dissolved in 1ml of 2-Methoxyethanol and the solution was stirred overnight at 25°C; the solution was then filtered. Taken ΙΟΟμί from above saturated stock solution, 500μί of Diisopropylether was added drop by drop, no solid was observed left the solution overnight under stirring, added again 500μί of Diisopropylether into the entire solution. The solid was precipitated, stirred for 30min and filtered under vacuum. Sotagliflozin Form I has been confirmed by PXRD as presented in figure 9.

Example-13: Preparation of Sotagliflozin Form K

[0093] 10-20mg of Sotagliflozin (Form D) was kept for drying in a natural air convection oven (MPM instruments modelM40-VN) at 60°C for lh. Sotagliflozin Form K has been confirmed by PXRD as presented in figure 10.

Example-14: Preparation of Sotagliflozin Form E:

[0094] Sotagliflozin (2g) and ethyl acetate (6ml) were heated to reflux temperature (71-74°C). Heptane (6ml) was added at reflux, reaction mass was stirred for additional 15 minutes and then cooled to room temperature. Solid was precipitated out during cooling at about 57°C. A mixture of ethyl acetate and heptane (1 : 1 v/v, 24 ml) was added and the reaction mixture was heated to reflux temperature (71-74°C) to obtain a clear solution which was maintained for 15 minutes. Reaction mass was cooled to room temperature (25-30°C) and stirred for 3 hours. The slurry was filtered, washed with a mixture of ethyl acetate and heptane (l : lv/v, 8ml) and dried under vacuum at 50°C for 2Hrs. The obtained solid (1.8g) was analyzed by PXRD-Form E.

Example-15: Preparation of Sotagliflozin Form D:

[0095] 2g of sotagliflozin Form F was kept in glass petri-dish and exposed to 80%RH for 60hrs at room temperature. Solid was collected (2g) and analyzed for PXRD-Form D.

Example-16: Preparation of Sotagliflozin Form 2:

[0096] 50 gm of (2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(Methylthio) tetrahydro-2H-pyran-3,4,5-triyl triacetate (SOT-1) and 500ml of methanol were charged in round bottom flask, the slurry was cooled to 20°C then added sodium methoxide solution prepared in methanol (2.45gm of sodium methoxide in 50ml of methanol) at 20°C

over the period of 10 min and stirred the mass for 2hr at 20°C.The reaction completion was ensured by HPLC. Once the reaction is completed added 2.5gm Norit carbon to the reaction mass at 23°C and stirred for 30min. Filtered the reaction mass through Hyflo bed and washed with 20ml of methanol. Taken the filtrate into the flask and concentrated under vacuum at 45°C up to 3 volumes with respect to SOT-1 then cooled to 21°C over the period of 60 min, added 560ml of Water at 21°C over the period of 30min and stirred for 30min at 21 °C, the reaction mass left overnight (without stirring) and stirred for lhr. The obtained slurry was filtered under vacuum and washed with 55ml*3times of water then kept for suction at 20-30°C for 30min. The material was dried at 50-60°C for 9hrs under vacuum to obtain 35gm of Sotagliflozin. 5.7gm of Sotagliflozin (5.7gr, Sotagliflozin) and 28.5ml of Methyl ethyl ketone (28.5ml) were charged in round bottom flask, the slurry was stirred at 22-25°C for 5-10min gradually raised the temperature to 78°C then added 114 ml of n-Heptane (114ml) at 78°C over the period of 55min. Once the addition of n-heptane was completed, seeds of Form-2 (20 mg) were added, the slurry was gradually cooled down to 25-27°C over the period of 60 min. The obtained slurry was stirred for 2-3hrs at 25-27°C and the mass was kept overnight (without stirring) at 25-27°C then stirred for 3hr at 23 °C. The mass was filtered under vacuum and washed with 10ml of n-Heptane then kept for suction for 30min at 25-30°C. The material was dried at 50°C for 2hrs under vacuum to obtain Form-2 of Sotagliflozin.

Preparation of Form 2- Seeds

[0097] Sotagliflozin (2gr, amorphous) was dissolved in methyl ethyl ketone (10ml) The slurry was heated to 80°C, then n-Heptane (40ml) was added over 60mins. The hazy solution was cooled to 20-30° over 60mins and stirred for 3hr. The slurry was kept overnight at 20-30°C (without stirring). The obtained slurry was filtered under vacuum and washed with n-Heptane (10ml) . The material was dried at 50 °C for 4hrs under vacuum to obtain the 1.9gm of Sotagliflozin Form -2 as confirmed by PXRD.

///////////WO 2018067805, NEW PATENT,  SOTAGLIFLOZIN, TEVA

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Funapide, TV 45070, XEN-402, фунапид فونابيد 呋纳匹特


Image result for TV 450702D chemical structure of 1259933-16-8

ChemSpider 2D Image | Funapide | C22H14F3NO5Funapide.png

Funapide TV 45070,  XEN-402,  Funapide, (+)-

фунапид
فونابيد
呋纳匹特
  • Molecular FormulaC22H14F3NO5
  • Average mass429.345 Da

(S)-1′-[(5-Methyl-2-furyl)methyl]spiro[6H-furo[3,2-f][1,3]benzodioxole-7,3′-indoline]-2′-one

Spiro(furo(2,3-F)-1,3-benzodioxole-7(6H),3′-(3H)indol)-2′(1’H)-one, 1′-((5-(trifluoromethyl)-2-furanyl)methyl)-, (3’S)-

(3’S)-1′-((5-(Trifluoromethyl)furan-2-yl)methyl)-2H,6H-spiro(furo(2,3-F)(1,3)benzodioxole-7,3′-indol)-2′(1’H)-one

Spiro[furo[2,3-f]-1,3-benzodioxole-7(6H),3′-[3H]indol]-2′(1’H)-one, 1′-[[5-(trifluoromethyl)-2-furanyl]methyl]-, (7S)-
TV-45070
UNII-A5595LHJ2L
XEN-401-S
XEN402
(3’S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2H-6H-spiro[furo[2,3-f]-1,3-benzodioxole-7,3′-indol]-2′(1’H)-one
(7S)-1′-{[5-(Trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1’H)-one
1259933-16-8 CAS
UNII-A5595LHJ2L

Phase II clinical trials for Postherpetic neuralgia (PHN)

Treatment of Neuropathic Pain

  • Originator Xenon Pharmaceuticals
  • Developer Teva Pharmaceutical Industries; Xenon Pharmaceuticals
  • Class Benzodioxoles; Fluorobenzenes; Furans; Indoles; Non-opioid analgesics; Small molecules; Spiro compounds
  • Mechanism of Action Nav1.7-voltage-gated-sodium-channel-inhibitors; Nav1.8 voltage-gated sodium channel inhibitors
  • Orphan Drug Status Yes – Erythromelalgia

Highest Development Phases

  • Phase II Erythromelalgia; Postherpetic neuralgia
  • No development reported Dental pain; Pain
  • Discontinued Musculoskeletal pain

Most Recent Events

  • 09 May 2017 Teva Pharmaceutical Industries completes a phase IIb trial for Postherpetic neuralgia in USA (Topical) (NCT02365636)
  • 26 Sep 2016 Adverse events data from a phase II trial in Musculoskeletal pain presented at the 16th World Congress on Pain (PAN – 2016)
  • 19 Aug 2015 No recent reports of development identified – Phase-I for Pain (In volunteers) in Canada (PO)

MP 100 – 102 DEG CENT EP2538919

S ROT  ALPHA 0.99 g/100ml, dimethyl sulfoxide, 14.04, US 20110087027

Funapide (INN) (former developmental code names TV-45070 and XEN402) is a novel analgesic under development by Xenon Pharmaceuticals in partnership with Teva Pharmaceutical Industries for the treatment of a variety of chronic pain conditions, including osteoarthritisneuropathic painpostherpetic neuralgia, and erythromelalgia, as well as dental pain.[1][2][3][4] It acts as a small-moleculeNav1.7 and Nav1.8 voltage-gated sodium channel blocker.[1][2][4] Funapide is being evaluated in humans in both oral and topicalformulations, and as of July 2014, has reached phase IIb clinical trials.[1][3]

Image result for TV 45070

Sodium channels play a diverse set of roles in maintaining normal and pathological states, including the long recognized role that voltage gated sodium channels play in the generation of abnormal neuronal activity and neuropathic or pathological pain. Damage to peripheral nerves following trauma or disease can result in changes to sodium channel activity and the development of abnormal afferent activity including ectopic discharges from axotomised afferents and spontaneous activity of sensitized intact nociceptors. These changes can produce long-lasting abnormal hypersensitivity to normally innocuous stimuli, or allodynia. Examples of neuropathic pain include, but are not limited to, post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, and pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias.

There have been some advances in treating neuropathic pain symptoms by using medications, such as gabapentin, and more recently pregabalin, as short-term, first-line treatments. However, pharmacotherapy for neuropathic pain has generally had limited success with little response to commonly used pain reducing drugs, such as NSAIDS and opiates. Consequently, there is still a considerable need to explore novel treatment modalities.

There remain a limited number of potent effective sodium channel blockers with a minimum of adverse events in the clinic. There is also an unmet medical need to treat neuropathic pain and other sodium channel associated pathological states effectively and without adverse side effects. PCT Published Patent Application No. WO 2006/110917, PCT Published Patent Application No. WO 2010/045251 , PCT Published Patent Application No. WO 2010/045197, PCT Published Patent Application No. WO 2011/047174 and PCT Published Patent Application No. WO 2011/002708 discloses certain spiro-oxindole compounds. These compounds are disclosed therein as being useful for the treatment of sodium channel-mediated diseases, preferably diseases related to pain, central nervous conditions such as epilepsy, anxiety, depression and bipolar disease;

cardiovascular conditions such as arrhythmias, atrial fibrillation and ventricular fibrillation; neuromuscular conditions such as restless leg syndrome; neuroprotection against stroke, neural trauma and multiple sclerosis; and channelopathies such as erythromelalgia and familial rectal pain syndrome.

Methods of preparing these compounds and pharmaceutical compositions containing them are also disclosed in PCT Published Patent Application No. WO 2006/110917, PCT Published Patent Application No. WO 2010/045251 , PCT

Published Patent Application No. WO 2010/045197, PCT Published Patent Application No. WO 2011/047174 and PCT Published Patent Application No. WO 2011/002708.

Postherpetic neuralgia (PHN) is a rare disorder that is defined as significant pain or abnormal sensation 120 days or more after the presence of the initial rash caused by shingles. This pain persists after the healing of the associated rash. Generally, this affliction occurs in older individuals and individuals suffering from immunosuppression. There are about one million cases of shingles in the US per year, of which 10–20% will result in PHN.
Topical analgesics such as lidocaine and capsaicin are traditionally used to treat this disorder. Both lidocaine and TV-45070 have a mechanism of action that involves the inhibition of voltage-gated sodium ion channels.
TV-45070 (formerly XEN-402) was in-licensed by Teva from Xenon Pharmaceuticals and is reported to be an antagonist of the Nav1.7 sodium ion channel protein.
It is currently in Phase II clinical trials for PHN. Interestingly, the loss of function of the Nav1.7 sodium ion channel was reported to result in the inability to experience pain as a hereditary trait in certain individuals.
Primary erythromelalgia is another rare disease where alterations in Nav1.7 or mutations in the corresponding encoding gene SCN9A have been reported to result in chronic burning pain that can last for hours or even days. Thus, compounds which regulate this protein have potential therapeutic value as analgesics for chronic pain.
Image result for XENON PHARMA
PATENT
US 20100331386
WO 2011106729
US 20110087027
US 20110086899
US 20130143941
US 20130210884
WO 2013154712
 US 20150216794
WO 2016127068
WO 2016109795
CN 106518886
US 20170239183
SYNTHESIS
WO 2013154712
 CONTD…….
Synthesis
CN 106518886
PATENT
US 20100331386
Preparation of the (S)-Enantiomer of the Invention
The (S)-enantiomer of the invention and the corresponding (R)-enantiomer are prepared by the resolution of the compound of formula (I), as set forth above in the Summary of the Invention, using either chiral high pressure liquid chromatography methods or by simulated moving bed chromatography methods, as described below in the following Reaction Scheme wherein “chiral HPLC” refers to chiral high pressure liquid chromatography and “SMB” refers to simulated moving bed chromatography:
Figure US20100331386A1-20101230-C00006
The compound of formula (I) can be prepared by the methods disclosed in PCT Published Patent Application No. WO 2006/110917, by methods disclosed herein, or by methods known to one skilled in the art.
One of ordinary skill in the art would recognize variations in the above Reaction Scheme which are appropriate for the resolution of the individual enantiomers.
Alternatively, the (S)-enantiomer of formula (I-S) and the (R)-enantiomer of formula (I-R), can be synthesized from starting materials which are known or readily prepared using process analogous to those which are known.
Preferably, the (S)-enantiomer of the invention obtained by the resolution methods disclosed herein is substantially free of the (R)-enantiomer or contains only traces of the (R)-enantiomer.
The following Synthetic Examples serve to illustrate the resolution methods disclosed by the above Reaction Schemes and are not intended to limit the scope of the invention.
Synthetic Example 1Synthesis of 1-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (Compound of formula (I))
Figure US20100331386A1-20101230-C00007
To a suspension of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.0 g, 3.6 mmol), which can be prepared according to the methods disclosed in PCT Published Patent Application No. WO 2006/110917, and cesium carbonate (3.52 g, 11 mmol) in acetone (50 mL) was added 2-bromomethyl-5-trifluoromethylfuran (1.13 g, 3.9 mmol) in one portion and the reaction mixture was stirred at 55-60° C. for 16 hours. Upon cooling to ambient temperature, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography, eluting with ethyl acetate/hexane (1/9-1/1) to afford 1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1 ′H)-one, i.e., the compound of formula (I), (1.17 g, 76%) as a white solid: mp 139-141° C.;
1H NMR (300 MHz, CDCl3) δ 7.32-6.97 (m, 5H), 6.72 (d, J=3.3 Hz, 1H), 6.66 (s, 1H), 6.07 (s, 1H), 5.90-5.88 (m, 2H), 5.05, 4.86 (ABq, JAB=16.1 Hz, 2H), 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.9, 155.7, 153.5, 148.8, 142.2, 141.9, 140.8, 140.2, 139.7, 139.1, 132.1, 129.2, 124.7, 124.1, 123.7, 121.1, 120.1, 117.6, 114.5, 114.4, 110.3, 109.7, 103.0, 101.9, 93.8, 80.0, 57.8, 36.9;
MS (ES+) m/z 430.2 (M+1), 452.2 (M+23); Cal’d for C22H14F3NO5: C, 61.54%; H, 3.29%; N, 3.26%; Found: C, 61.51%; H, 3.29%; N, 3.26%.
Synthetic Example 2Resolution of Compound of Formula (I) by Chiral HPLC
The compound of formula (I) was resolved into the (S)-enantiomer of the invention and the corresponding (R)-enantiomer by chiral HPLC under the following conditions:

Column: Chiralcel® OJ-RH; 20 mm I.D.×250 mm, 5 mic; Lot: OJRH CJ-EH001 (Daicel Chemical Industries, Ltd)

Eluent: Acetonitrile/Water (60/40, v/v, isocratic)

Flow rate: 10 mL/min

Run time: 60 min

Loading: 100 mg of compound of formula (I) in 1 mL of acetonitrileTemperature: Ambient

Under the above chiral HPLC conditions, the (R)-enantiomer of the compound of formula (I), i.e., (R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]-benzodioxole-7,3′-indol]-2′(1′H)-one, was isolated as the first fraction as a white solid; ee (enantiomeric excess)>99% (analytical OJ-RH, 55% acetonitrile in water); mp 103-105° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.32-6.99 (m, 5H), 6.71 (d, J=3.4 Hz, 1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (d, J=6.2 Hz, 2H), 5.13, 5.02 (ABq, JAB=16.4 Hz, 2H), 4.82, 4.72 (ABq, JAB=9.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 177.2, 155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0, 129.1, 123.9, 120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9; MS (ES+) m/z 430.2 (M+1), [α]D−17.46° (c 0.99, DMSO).

The (S)-enantiomer of the compound of formula (I), i.e., (S)-1′-{[5-(trifluoromethypfuran-2-yl]methyl}spiro-[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was isolated as the second fraction as a white solid; ee >99% (analytical OJ-RH, 55% acetonitrile in water); mp 100-102° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.32-6.99 (m, 5H), 6.71 (d, J=3.4 Hz, 1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (d, J=6.3 Hz, 2H), 5.12, 5.02 (ABq, JAB=16.4 Hz, 2H), 4.82, 4.72 (ABq, JAB=9.4 Hz, 2H); 13C NMR (75MHz, CDCl3) δ 177.2, 155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0, 129.1, 123.9, 120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9; MS (ES+) m/z 430.2 (M+1), [α]D+14.04° (c 0.99, DMSO)

Synthetic Example 3Resolution of Compound of Formula (I) by SMB Chromatography

The compound of formula (I) was resolved into the (S)-enantiomer of the invention and the corresponding (R)-enantiomer by SMB chromatography under the following conditions:

Extract: 147.05 mL/min, Raffinate: 76.13 mL/min Eluent: 183.18 mL/min Feed: 40 mL/min Recycling: 407.88 mL/min Run Time: 0.57 min Temperature: 25° C. Pressure: 46 bar

The feed solution (25 g of compound of formula (I) in 1.0 L of mobile phase (25:75:0.1 (v:v:v) mixture of acetonitrile/methanol/trifluoroacetic acid)) was injected continuously into the SMB system (Novasep Licosep Lab Unit), which was equipped with eight identical columns in 2-2-2-2 configuration containing 110 g (per column, 9.6 cm, 4.8 cm I.D.) of ChiralPAK-AD as stationary phase. The first eluting enantiomer (the (R)-enantiomer of the compound of formula (I)) was contained in the raffinate stream and the second eluting enantiomer (the (S)-enantiomer of the compound of formula (I)) was contained in the extract stream. The characterization data of the (S)-enantiomer and the (R)-enantiomer obtained from the SMB resolution were identical to those obtained above utilizing chiral HPLC.

The compound of formula (I) was resolved into its constituent enantiomers on a Waters preparative LCMS autopurification system. The first-eluting enantiomer from the chiral column was brominated (at a site well-removed from the stereogenic centre) to give the corresponding 5′-bromo derivative, which was subsequently crystallized to generate a single crystal suitable for X-ray crystallography. The crystal structure of this brominated derivative of the first-eluting enantiomer was obtained and its absolute configuration was found to be the same as the (R)-enantiomer of the invention. Hence, the second-eluting enantiomer from the chiral column is the (S)-enantiomer of the invention. Moreover, the material obtained from the extract stream of the SMB resolution had a specific optical rotation of the same sign (positive, i.e. dextrorotatory) as that of the material obtained from the aforementioned LC resolution.

Patent

WO 2013154712

EXAMPLE 8

Synthesis of (7S)-1 ‘-{[5-(trifluoromethyl)furan-2- yllmethylJspirotfurop.S-flll .Sl enzoclioxole-y.S’-indoll-Zil ‘Wi-one

Compound of formula (ia1 )

Figure imgf000095_0001

To a cooled (0 °C) solution of (3S)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3- (hydroxymethyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1 ,3-dihydro-2H-indol-2-one prepared according to the procedure described in Example 7 (16.4 mmol) and 2- (diphenylphosphino)pyridine (5.2 g, 20 mmol) in anhydrous tetrahydrofuran (170 mL) was added di-ferf-butylazodicarboxylate (4.5 g, 20 mmol). The mixture was stirred for 2 h at 0 °C, then the reaction was diluted with ethyl acetate (170 mL), washed with 3 N hydrochloric acid (7 x 50 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol (80 mL), decolorizing charcoal (15 g) was added and the mixture was heated at reflux for 1 h. The mixture was filtered while hot through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue triturated in a mixture of diethyl ether/hexanes to afford (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro- [furo[2,3-/][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (1.30 g) as a colorless solid in 18% yield. The mother liquor from the trituration was concentrated in vacuo, trifluoroacetic acid (20 mL) was added and the mixture stirred for 3 h at ambient temperature. The mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride (100 mL), 3 N hydrochloric acid (4 x 60 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of ethyl acetate in hexanes to afford further (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro- [furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (2.6 g) as a colorless solid (37% yield, overall yield 55% over 2 steps): H NMR (300 MHz, CDCI3) £7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz, 1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1 ); ee (enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert- butyl ether).

EXAMPLE 9

Synthesis of 1-(diphenylmethyl)-1 H-indole-2,3-dione

Compound of formula (15a)

Figure imgf000096_0001

A. To a suspension of hexanes-washed sodium hydride (34.0 g, 849 mmol) in anhydrous Λ/,/V-dimethylformamide (400 mL) at 0 °C was added a solution of isatin (99.8 g, 678 mmol) in anhydrous Λ/,/V-dimethylformamide (400 mL) dropwise over 30 minutes. The reaction mixture was stirred for 1 h at 0 °C and a solution of benzhydryl bromide (185 g, 745 mmol) in anhydrous N-dimethylformamide (100 mL) was added dropwise over 5 minutes. The reaction mixture was allowed to warm to ambient temperature, stirred for 16 h and heated at 60 °C for 2 h. The mixture was cooled to 0 °C and water (500 mL) was added. The mixture was poured into water (2 L), causing a precipitate to be deposited. The solid was collected by suction filtration and washed with water (2000 mL) to afford 1-(diphenylmethyl)-1H-indole-2,3- dione (164 g) as an orange solid in 77% yield.

B. Alternatively, to a mixture of isatin (40.0 g, 272 mmol), cesium carbonate (177 g, 543 mmol) and A/./V-dimethylformamide (270 mL) at 80 °C was added dropwise a solution of benzhydryl bromide (149 g, 544 mmol) in N,N- dimethyiformamide (200 mL) over 30 minutes. The reaction mixture was heated at 80 °C for 3 h, allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The pad was rinsed with ethyl acetate (1000 mL). The filtrate was washed with saturated aqueous ammonium chloride (4 x 200 mL), 1 N

hydrochloric acid (200 mL) and brine (4 x 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to afford 1 -(diphenylmethyl)-1 H-indole-2,3-dione (59.1 g) as an orange solid in 69% yield. The mother liquor from the trituration was concentrated in vacuo and the residue triturated in diethyl ether to afford a further portion of 1-(diphenylmethyl)-1 H- indole-2,3-dione (8.2 g) in 10% yield: 1H NMR (300 MHz, CDCI3) £7.60 (d, J = 7.4 Hz, 1 H), 7.34-7.24 (m, 1 1 H), 7.05-6.97 (m, 2H), 6.48 (d, J = 8.0 Hz, 1 H); MS (ES+) m/z 313.9 (M + 1 ).

C. Alternatively, a mixture of isatin (500 g, 3.4 mol) and anhydrous N,N- dimethylformamide (3.5 L) was stirred at 15-35 °C for 0.5 h. Cesium carbonate (2.2 kg, 6.8 mol) was added and the mixture stirred at 55-60 °C for 1 h. A solution of benzhydryl bromide (1.26 kg, 5.1 mol) in anhydrous N, A/-dimethylformamide (1.5 L) was added and the resultant mixture stirred at 80-85 °C for 1 h, allowed to cool to ambient temperature and filtered. The filter cake was washed with ethyl acetate (12.5 L). To the combined filtrate and washes was added 1 N hydrochloric acid (5 L). The phases were separated and the aqueous phase was extracted with ethyl acetate (2.5 L). The combined organic extracts were washed with 1 N hydrochloric acid (2 * 2.5 L) and brine (3 χ 2.5 L) and concentrated in vacuo to a volume of approximately 750 mL. Methyl ferf-butyl ether (2 L) was added and the mixture was cooled to 5-15 °C, causing a solid to be deposited. The solid was collected by filtration, washed with methyl ferf- butyl ether (250 mL) and dried in vacuo at 50-55 °C for 16 h to afford 1- (diphenylmethyl)-1 H-indole-2,3-dione (715 g) as an orange solid in 67% yield: 1H NMR (300 MHz, CDCI3) 7.60 (d, J = 7.4 Hz, H), 7.34-7.24 (m, 1 H), 7.05-6.97 (m, 2H), 6.48 (d, J = 8.0 Hz, 1 H); MS (ES+) m/z 313.9 (M + 1 ).

EXAMPLE 10

Synthesis of 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3- dihydro-2H-indol-2-one

Compound of formula (16a1 )

Figure imgf000097_0001

A. To a solution of sesamol (33.1 g, 239 mmol) in anhydrous

tetrahydrofuran (500 mL) at 0 °C was added dropwise a 2 M solution of

isopropylmagnesium chloride in tetrahydrofuran (104 mL, 208 mmol), followed by 1 – (diphenylmethyl)-1H-indole-2,3-dione (50.0 g, 160 mmol) and tetrahydrofuran (100 mL). The reaction mixture was stirred at ambient temperature for 5 h, diluted with ethyl acetate (1500 mL), washed with saturated aqueous ammonium chloride (400 mL) and brine (2 x 400 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford 1- (diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-in

2- one (70.7 g) as a colorless solid in 98% yield: 1H NMR (300 MHz, CDCI3) <59.12 (br s, 1 H), 7.45-7.43 (m, 1 H), 7.30-7.22 (m, 10H), 7.09-7.07 (m, 2H), 6.89 (s, 1 H), 6.56- 6.55 (m, 1 H), 6.47-6.46 (m, 1 H), 6.29-6.28 (m, 1 H), 5.86 (s, 2H), 4.52 (br s, 1 H); MS (ES+) m/z 433.7 (M – 17).

B. Alternatviely, a mixture of sesamol (0.99 kg, 7.2 mol) and anhydrous tetrahydrofuran (18 L) was stirred at 15-35 °C for 0.5 h and cooled to -5-0 °C.

Isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran, 3.1 L, 6.2 mol) was added, followed by 1-(diphenylmethyl)-1 H-indole-2,3-dione (1.50 kg, 4.8 mol) and further anhydrous tetrahydrofuran (3 L). The mixture was stirred at 15-25 °C for 5 h. Ethyl acetate (45 L) and saturated aqueous ammonium chloride (15 L) were added. The mixture was stirred at 15-25 °C for 0.5 h and was allowed to settle for 0.5 h. The phases were separated and the organic phase was washed with brine (2.3 L) and concentrated in vacuo to a volume of approximately 4 L. Methyl ferf-butyl ether (9 L) was added and the mixture concentrated in vacuo to a volume of approximately 4 L. Heptane (6 L) was added and the mixture was stirred at 15-25 °C for 2 h, causing a solid to be deposited. The solid was collected by filtration, washed with methyl tert- butyl ether (0.3 L) and dried in vacuo at 50-55 °C for 7 h to afford 1-(diphenylmethyl)-3- hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (2.12 kg) as an off-white solid in 98% yield: 1H NMR (300 MHz, CDCI3) 9.12 (br s, 1 H), 7.45-7.43 (m, 1 H), 7.30-7.22 (m, 10H), 7.09-7.07 (m, 2H), 6.89 (s, 1 H), 6.56-6.55 (m, 1 H), 6.47-6.46 (m, 1 H), 6.29-6.28 (m, 1 H), 5.86 (s, 2H), 4.52 (br s, 1 H); MS (ES+) m/z 433.7 (M – 17).

EXAMPLE 1 1

Synthesis of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3- dihydro-2H-indol-2-one

Compound of formula (17a1)

Figure imgf000098_0001

A. A mixture of 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3- benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (30.0 g, 66.5 mmol), benzyl bromide (8.3 mL, 70 mmol), and potassium carbonate (18.4 g, 133 mmol) in anhydrous N,N- dimeihylformamide (100 mL) was stirred at ambient temperature for 16 h. The reaction mixture was filtered and the solid was washed with /V,A/-dimethylformamide (100 mL). The filtrate was poured into water (1000 mL) and the resulting precipitate was collected by suction filtration and washed with water to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol- 5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (32.0 g) as a beige solid in 83% yield: 1H NMR (300 MHz, CDCI3) 7.42-7.28 (m, 9H), 7.22-7.14 (m, 6H), 7.10- 6.93 (m, 3H), 6.89-6.87 (m, 2H), 6.53 (d, J = 7.6 Hz, 1 H), 6.29 (br s, 1 H), 5.88 (s, 1 H), 5.85 (s, 1 H), 4.66 (d, J = 14.2 Hz, 1 H), 4.51 (d, J = 14.1 Hz, 1 H), 3.95 (s, 1 H); MS (ES+) m/z 542.0 (M + 1), 523.9 (M – 17).

B. Alternatively, to a solution of 1-(diphenylmethyl)-3-hydroxy-3-(6- hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (2.1 kg, 4.6 mol) in anhydrous A/,A/-dimethylformamide (8.4 L) at 20-30 °C was added potassium carbonate (1.3 kg, 9.2 mol), followed by benzyl bromide (0.58 L, 4.8 mol). The mixture was stirred at 20-30 °C for 80 h and filtered. The filter cake was washed with

A/,/V-dimethylformamide (0.4 L) and the filtrate was poured into water (75 L), causing a solid to be deposited. The mixture was stirred at 15-25 °C for 7 h. The solid was collected by filtration, washed with water (2 L) and dried in vacuo at 50-60 °C for 48 h to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3- dihydro-2H-indol-2-one (2.1 1 kg) as an off-white solid in 84% yield; 1H NMR (300

MHz, CDCI3) £7.42-7.28 (m, 9H), 7.22-7.14 (m, 6H), 7.10-6.93 (m, 3H), 6.89-6.87 (m, 2H), 6.53 (d, J = 7.6 Hz, 1 H), 6.29 (br s, 1 H), 5.88 (s, 1 H), 5.85 (s, 1 H), 4.66 (d, J = 14.2 Hz, 1 H), 4.51 (d, J = 14.1 Hz, 1 H), 3.95 (s, 1 H); MS (ES+) m/z 542.0 (M + 1 ).

EXAMPLE 12

Synthesis of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1 -(diphenylmethyl)-l ,3-dihydro-2H- indol-2-one

Compound of formula (18a1 )

Figure imgf000099_0001

A. To a solution of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1- (diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (32.0 g, 57.7 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (50 mL) followed by triethylsilane (50 mL). The reaction mixture was stirred at ambient temperature for 2 h and concentrated in vacuo. The residue was dissolved in ethyi acetate (250 mL), washed with saturated aqueous ammonium chloride (3 x 100 mL) and brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol-5- yl]-1-(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (19.0 g) as a colorless solid in 61 % yield: 1H NMR (300 MHz, CDCI3) 7.31 -7.23 (m, 15H), 7.10-6.88 (m, 4H), 6.50-6.45 (m, 3H), 5.86 (s, 2H), 4.97-4.86 (m, 3H); MS (ES+) m/z 525.9 (M + 1).

B. Alternatively, to a solution of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1- (diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (2.0 kg, 3.7 mol) in

dichloromethane (7 L) at 20-30 °C was added trifluoracetic acid (2.5 L), followed by triethylsilane (3.1 L). The mixture was stirred at 15-35 °C for 4 h and concentrated in vacuo to dryness. To the residue was added ethyl acetate (16 L) and the mixture was stirred at 15-35 °C for 0.5 h, washed with saturated aqueous ammonium chloride (3 x 7 L) and brine (3 χ 7 L) and concentrated in vacuo to a volume of approximately 7 L. Methyl ferf-butyl ether (9 L) was added and the mixture concentrated in vacuo to a volume of approximately 9 L and stirred at 10-20 °C for 2.5 h, during which time a solid was deposited. The solid was collected by filtration, washed with methyl te/t-butyl ether (0.4 L) and dried in vacuo at 50-55 °C for 7 h to afford 3-[6-(benzyloxy)-1 ,3- benzodioxol-5-yl]-1-(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1 .26 kg) as an off-white solid in 65% yield: 1H NMR (300 MHz, CDCI3) £7.31 -7.23 (m, 15H), 7.10- 6.88 (m, 4H), 6.50-6.45 (m, 3H), 5.86 (s, 2H), 4.97-4.86 (m, 3H); MS (ES+) m/z 525.9 (M + 1).

EXAMPLE 13

Synthesis of (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1 –

(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one

Compound of formula (19a1 )

Figure imgf000100_0001

A. To a nitrogen-degassed mixture of 50% w/w aqueous potassium hydroxide (69.6 mL, 619 mmol), toluene (100 mL), and (9S)-1 -(anthracen-9- ylmethyl)cinchonan-1 -ium-9-ol chloride (0.50 g, 0.95 mmol) cooled in an ice/salt bath to an internal temperature of -18 °C was added a nitrogen-degassed solution of 3-[6- (benzyloxy)-l ,3-benzodioxol-5-yl]-1 -(diphenylmethyl)-l ,3-dihydro-2H-indol-2-one (10.0 g, 19.0 mmol) and benzyl chloromethyl ether (2.9 mL, 21 mmol) in

toluene/tetrahydrofuran (1 :1 v/v, 80 mL) dropwise over 1 h. The reaction mixture was stirred for 3.5 h and diluted with ethyl acetate (80 mL). The organic phase was washed with 1 N hydrochloric acid (3 x 150 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford (3S)-3-[6-(benzyloxy)-1 ,3- benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-(diphenylmethyl)-1 ,3-dihydro-2/-/-indol-2-one (12.6 g) as a colorless solid in quantitative yield: 1H NMR (300 MHz, CDCI3) 7.42 (d, 2H), 7.24-6.91 (m, 21 H), 6.69-6.67 (m, 2H), 6.46 (d, J = 7.7 Hz, 1 H), 6.15 (s, 1 H), 5.83- 5.81 (m, 2H), 4.53-4.31 (m, 3H), 4.17-4.09 (m, 3H); MS (ES+) m/z 646.0 (M + 1); ee (enantiomeric excess) 90% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert-butyl ether).

B. Alternatively, a mixture of 50% w/v aqueous potassium hydroxide (4.2 kg), toluene (12 L) and (9S)-1 -(anthracen-9-ylmethyl)cinchonan-1 -ium-9-ol chloride (0.06 kg, 0.1 mol) was degassed with dry nitrogen and cooled to -18 to -22 °C. To this mixture was added a cold (-18 to -22 °C), nitrogen-degassed solution of 3-[6-

(benzyloxy)-l ,3-benzodioxol-5-yl]-1 ~(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1.2 kg, 2.3 mol) and benzyl chloromethyl ether (0.43 kg, 2.8 mol) in toluene (10 L) and tetrahydrofuran (10 L) at -18 to 22 °C over 3 h. The mixture was stirred at -18 to -22 °C for 5 h, allowed to warm to ambient temperature and diluted with ethyl acetate (10 L). The phases were separated and the organic layer was washed with 1 N

hydrochloric acid (3 χ 8 L) and brine (2 χ 12 L) and concentrated in vacuo to dryness to afford (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1- (diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1.5 kg) as a colorless solid in quantitative yield: 1H NMR (300 MHz, CDCI3) £7.42 (d, 2H), 7.24-6.91 (m, 21 H), 6.69-6.67 (m, 2H), 6.46 (d, J = 7.7 Hz, 1 H), 6.15 (s, 1 H), 5.83-5.81 (m, 2H), 4.53-4.31 (m, 3H), 4.17- 4.09 (m, 3H); MS (ES+) m/z 646.0 (M + 1); ee (enantiomeric excess) 90% (HPLC, ChiralPak IA). EXAMPLE 14

Synthesis of (3S)-1-(diphenylmethyl)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3- (hydroxymethyl)-1 ,3-dihydro-2/-/-indol-2-one

Compound of formula (20a1)

Figure imgf000102_0001

A. A mixture of (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3- [(benzyloxy)methyl]-1 -(diphenylmethyl)-1 ,3-dihydro-2/-/-indol-2-one (8.8 g, 14 mmol), 10% w/w palladium on carbon (50% wetted powder, 3.5 g, 1.6 mmol), and acetic acid (3.9 ml_, 68 mmol) in a nitrogen-degassed mixture of ethanol/tetrahydrofuran (1 : 1 v/v, 140 mL) was stirred under hydrogen gas (1 atm) at ambient temperature for 4 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was rinsed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to afford (3S)-1-(diphenylmethyl)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3- dihydro-2H-indol-2-one as a colorless solid that was carried forward without further purification: H NMR (300 MHz, CDCI3) 9.81 (br s, 1 H), 7.35-7.24 (m, 1 1 H), 7.15- 7.01 (m, 3H), 6.62 (s, 1 H), 6.54-6.47 (m, 2H), 5.86-5.84 (m, 2H), 4.76 (d, J = 1 1.0 Hz, 1 H), 4.13-4.04 (m, 1 H), 2.02 (s, 1 H); MS (ES+) m/z 465.9 (M + 1); ee (enantiomeric excess) 93% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl ie t-butyl ether).

B. Alternatively, a glass-lined hydrogenation reactor was charged with (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1 -(diphenylmethyl)- 1 ,3-dihydro-2H-indol-2-one (0.1 kg, 0.15 mol), tetrahydrofuran (0.8 L), ethanol (0.4 L), acetic acid (0.02 L) and 20% w/w palladium (li) hydroxide on carbon (0.04 kg). The reactor was purged three times with nitrogen. The reactor was then purged three times with hydrogen and was then pressurized to 50-55 lb/in2 with hydrogen. The mixture was stirred at 20-30 °C for 5 h under a 50-55 lb/in2 atmosphere of hydrogen. The reactor was purged and the mixture was filtered. The filtrate was concentrated in vacuo to a volume of approximately 0.2 L and methyl te/t-butyl ether (0.4 L) was added. The mixture was concentrated in vacuo to a volume of approximately 0.2 L and methyl ie/t-butyl ether (0.2 L) was added, followed by heptane (0.25 L). The mixture was stirred at ambient temperature for 2 h, during which time a solid was deposited. The solid was collected by filtration, washed with heptane (0.05 L) and dried in vacuo at a temperature below 50 °C for 8 h to afford (3S)-1 -(diphenylmethyl)-3-(6-hydroxy- 1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2H-indol-2-one (0.09 kg) as a colorless solid in 95% yield: 1H NMR (300 MHz, CDCI3) 9.81 (br s, 1 H), 7.35-7.24 (m, 1 1 H), 7.15-7.01 (m, 3H), 6.62 (s, 1 H), 6.54-6.47 (m, 2H), 5.86-5.84 (m, 2H), 4.76 (d, J = 1 1.0 Hz, 1 H), 4.13-4.04 (m, 1 H), 2.02 (s, 1 H); MS (ES+) m/z 465.9 (M + 1); ee (enantiomeric excess) 91% (HPLC, ChiralPak IA).

EXAMPLE 15

Synthesis of (7S)-1′-(diphenylmethyl)spiro[furo[2,3-/][1 ,3]benzodioxole-7,3′-indol]-

2′(1 ‘tf)-one

Compound of formula (21 a1 )

Figure imgf000103_0001

A. To a cooled (0 °C) solution of (3S)-1 -(diphenylmethyl)-3-(6-hydroxy-1 ,3- benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2H-indol-2-one prepared according to the procedure described in Example 14 (13.6 mmol) and 2-

(diphenylphosphino)pyridine (4.3 g, 16 mmol) in anhydrous tetrahydrofuran (140 mL) was added di-tert-butylazodicarboxylate (3.8 g, 17 mmol). The reaction mixture was stirred at 0 °C for 3 h, diluted with ethyl acetate (140 mL), washed with 3 N

hydrochloric acid (6 * 50 mL) and brine (2 χ 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford (7S)-1 ‘-(diphenylmethyl)spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (4.55 g) as a colorless solid in a 75% yield over 2 steps: 1H NMR (300 MHz, CDCI3) 7.34-7.24 (m, 10H), 7.15-7.13 (m, 1 H), 7.04 (s, 1 H), 6.99-6.95 (m, 2H), 6.50-6.48 (m, 2H), 6.06 (s, 1 H), 5.85-5.83 (m, 2H), 4.96 (d, J = 8.9 Hz, 1 H), 4.69 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 447.9 (M + 1); ee

(enantiomeric excess) 93% (HPLC, Chiraipak IA, 2.5% acetonitrile in methyl te/f-butyl ether).

B. Alternativel, to a cooled (0-5 °C) solution of (3S)-1-(diphenylmethyl)-3- (6-hydroxy-1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2 -/-indol-2-one (1 .0 kg, 2.1 mol) and 2-(diphenylphosphino)pyridine (0.66 kg, 2.5 mol) in anhydrous tetrahydrofuran (20 L) was added over 2 h a solution of di-terf-butylazodicarboxylate (0.62 kg, 2.7 mmol) in anhydrous tetrahydrofuran (5 L). The mixture was stirred for 4 h at 0-5 °C and was allowed to warm to ambient temperature. The mixture was diluted with ethyl acetate (20 L), washed with 3 N hydrochloric acid (6 * 8 L) and brine (2 x 12 L) and concentrated in vacuo to a volume of approximately 1.5 L. Methyl rert-butyl ether (4 L) was added and the mixture concentrated in vacuo to a volume of

approximately 1.5 L. Methyl terf-butyl ether (2 L) and heptane (2 L) were added and the mixture was stirred at ambient temperature for 2 h, during which time a solid was deposited. The solid was collected by filtration, washed with heptane (0.5 L) and dried in vacuo below 50 °C for 8 h to afford (7S)-1′-(diphenylmethyl)spiro[furo[2,3- f][1 ,3]benzodioxole-7,3′-indol]-2′(1’H)-one (0.76 kg) as a colorless solid in 79% yield: 1H NMR (300 MHz, CDCI3) 7.34-7.24 (m, 10H), 7.15-7.13 (m, 1 H), 7.04 (s, 1 H), 6.99- 6.95 (m, 2H), 6.50-6.48 (m, 2H), 6.06 (s, 1 H), 5.85-5.83 (m, 2H), 4.96 (d, J = 8.9 Hz, 1 H), 4.69 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 447.9 (M + 1 ); ee (enantiomeric excess) 92% (HPLC, ChiralPak IA).

EXAMPLE 16

Synthesis of (7S)-spiro[furo[2,3-f][1 ,3]benzodioxole-7,3′-indol]-2′(1 ‘H)-one

Compound of formula (22a1)

Figure imgf000104_0001

A. To a solution of (7S)-1′-(diphenylmethyl)spiro[furo[2,3- f][1 ,3]benzodioxole-7,3′-indol]-2′(1’H)-one (4.55 g, 10.2 mmol) in trifluoroacetic acid (80 ml_) was added triethylsilane (7 ml_). The reaction mixture was heated at reflux for 2.5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford

(7S)-spiro[furo[2,3-/][1 ,3]benzodioxole-7,3,-indol]-2′(1’W)-one (2.30 g) as a colorless solid in 80% yield: 1H NMR (300 MHz, CDCI3) £8.27 (br s, 1 H), 7.31-7.26 (m, 1 H), 7.17-7.15 (m, 1 H), 7.07-7.02 (m, 1 H), 6.96-6.94 (m, 1 H), 6.53-6.52 (m, 1 H), 6.24-6.23 (m, 1 H), 5.88-5.87 (m, 2H), 4.95 (d, J = 8.6 Hz, 1 H), 4.68 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 281.9 (M + 1 ); ee (enantiomeric excess) 99% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl fert-butyl ether). B. Alternatively, a mixture of (7S)-1 ‘-(diphenylmethyl)spiro[furo[2,3- /Kl^benzodioxole^-indol^ r^-one (0.70 kg, 1.6 mol), trifluoroacetic acid (12 L) and triethylsilane (1.1 L) was heated at reflux under nitrogen atmosphere for 3 h, allowed to cool to ambient temperature and concentrated in vacuo to dryness. To the residue was added ethyl acetate (0.3 L), methyl fert-butyl ether (1 L) and heptane (3.5 L), causing a solid to be deposited. The solid was collected by filtration, taken up in dichloromethane (3 L), stirred at ambient temperature for 1 h and filtered. The filtrate was concentrated in vacuo to dryness. The residue was taken up in ethyl acetate (0.3 L), methyl ferf-butyl ether (1 L) and heptane (3.5 L), causing a solid to be deposited. The solid was collected by filtration and dried in vacuo below 50 °C for 8 h to afford (7S)-spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘ -/)-one (0.40 kg) as a colorless solid in 91 % yield: 1H NMR (300 MHz, CDCI3) 8.27 (br s, 1 H), 7.31-7.26 (m, 1 H), 7.17-7.15 (m, 1 H), 7.07-7.02 (m, 1 H), 6.96-6.94 (m, 1 H), 6.53-6.52 (m, 1 H), 6.24-6.23 (m, 1 H), 5.88-5.87 (m, 2H), 4.95 (d, J = 8.6 Hz, 1 H), 4.68 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 281.9 (M + 1); ee (enantiomeric excess) 98.6% (HPLC, ChiralPak IA).

EXAMPLE 17

Synthesis of of (7S)-1 ‘-{[5-(trifluoromethyl)furan-2- yl]methyl}spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(rH)-one

Compound of formula (Ia1)

Figure imgf000105_0001

A. To a mixture of (7S)-6H-spiro[[1 ,3]dioxolo[4,5-f]benzofuran-7,3′-indolin]- 2′-one (1.80 g, 6.41 mmol) and 2-(bromomethyl)-5-(trifluoromethyl)furan (1.47 g, 6.41 mmol) in acetone (200 mL) was added cesium carbonate (3.13 g, 9.61 mmol). The reaction mixture was heated at reflux for 2 h and filtered while hot through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to afford (7S)-1′-{[5- (trifluoromethyOfuran^-yllmethy^spiroIfurop.S- ltl .Slbenzodioxole^.S’-indol^ rH)- one (2.71 g) as a colorless solid in quantitative yield (97% purity by HPLC). The product was crystallized from a mixture of methanol and hexanes to afford (7S)-1 ‘-{[5- (trifluoromethy furan^-yllmethylJspirotfuro^.S- lfl .Slbenzodioxole^.S’-indoll^ rH)- one (1.46 g) as colorless needles in 53% yield. The mother liquor was concentrated in vacuo and subjected to a second crystallization in methanol and hexanes to afford further (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-/][1 ,3]benzodioxole- 7,3’-indol]-2′(1 ‘H)-one (0.469 g) as a colorless solid in 17% yield (total yield 70%): 1H NMR (300 MHz, CDCI3) δ 7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz, 1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1); ee (enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert-butyl ether).

B. Alternatively, to a solution of (7S)-spiro[furoI2,3-f][1 ,3]benzodioxole-7,3′- indol]-2′(1’H)-one (0.40 kg, 1.4 mol) in anhydrous N, W-dimethylformamide (5 L) was added cesium carbonate (1.2 kg, 3.4 mol), followed by 2-(bromomethyl)-5- (trifluromethyl)furan (0.24 L, 1.7 mol). The mixture was heated at 80-85 °C for 3 h, allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The pad was washed with ethyl acetate (8 L). The combined filtrate and washes were washed with water (4 L), saturated aqueous ammonium chloride (2 * 4 L) and brine (2 * 4 L) and concentrated in vacuo to dryness. The residue was purified by recrystallization from te/t-butyl methyl ether (0.4 L) and heptane (0.8 L), followed by drying of the resultant solid in vacuo at 40-50 °C for 8 h to afford (7S)-1 ‘-{[5- (trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)- one (0.37 kg) as a colorless solid in 61% yield: 1H NMR (300 MHz, CDCI3) δ 7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz,1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1 ); ee (enantiomeric excess) > 99% (HPLC, Chiralpak IA).

PATENT
CadieuxJ.-J.ChafeevM.ChowdhuryS.FuJ.JiaQ.AbelS.El-SayedE.HuthmannE.IsarnoT. Synthetic Methods For Spiro-Oxindole Compounds. U.S. Patent 8,445,696, May 21, 2013.
PATENT
SunS.FuJ.ChowdhuryS.HemeonI. W.GrimwoodM. E.MansourT. S. Asymmetric Syntheses of Spiro-Oxindole Compounds Useful As Therapeutic Agents. U.S. Patent 9,487,535, Nov 08, 2016.
PAPER
Abstract Image

TV-45070 is a small-molecule lactam containing a chiral spiro-ether that has been reported as a potential topical therapy for pain associated with the Nav1.7 sodium ion channel encoded by the gene SCN9A. A pilot-scale synthesis is presented that is highlighted by an asymmetric aldol coupling at ambient temperature, used to create a quaternary chiral center. Although only a moderate ee is obtained, the removal of the undesired isomer is achieved through preferential precipitation of a near racemic mixture from the reaction, leaving the enantiopure isomer in solution. Cyclization to form the final API uses an uncommon diphenylphosphine-based leaving group which proved successful on the neopentyl system when other traditional leaving groups failed.

The First Asymmetric Pilot-Scale Synthesis of TV-45070

Chemical Process Research and Development, Analytical Research and Development, Teva Branded Pharmaceutical Products R&D Inc., 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00237
Publication Date (Web): September 8, 2017
Copyright © 2017 American Chemical Society

*E-mail: jasclafan@yahoo.com.

(S)-1′-[(5-Methyl-2-furyl)methyl]spiro[6H-furo[3,2-f][1,3]benzodioxole-7,3′-indoline]-2′-one (1)

1H NMR (DMSO, 400 MHz) δ 7.32 (t, J = 7.7 Hz, 1H), 7.20 (m, 3H), 7.07 (t, J = 7.3 Hz, 1H), 6.77 (d, J= 3.3 Hz, 1H), 6.72 (s, 1H), 6.10 (s, 1H), 5.94 (d, J = 9.1 Hz, 1H), 5.94 (d, J = 9.1 Hz, 1H), 5.13 (d, J = 16.5 Hz, 1H), 5.02 (d, J = 16.5 Hz, 1H), 4.82 (d, J = 9.5 Hz, 1H), 4.73 (d, J = 9.5 Hz, 1H).
13C NMR (100 MHz, DMSO-d6): 176.48, 155.28, 153.02, 148.40, 141.80, 141.51, 139.54 (q, JCF = 41.9 Hz), 131.63, 128.79, 123.64, 123.29, 119.69, 118.92 (q, JCF = 266.4 Hz), 114.01 (q, JCF = 2.9 Hz) 109.86, 109.21, 102.55, 101.44, 93.31, 79.52, 57.41, 36.44.

References

  1. Jump up to:a b c Bagal, Sharan K.; Chapman, Mark L.; Marron, Brian E.; Prime, Rebecca; Ian Storer, R.; Swain, Nigel A. (2014). “Recent progress in sodium channel modulators for pain”. Bioorganic & Medicinal Chemistry Letters24 (16): 3690–9. ISSN 0960-894XPMID 25060923doi:10.1016/j.bmcl.2014.06.038.
  2. Jump up to:a b Stephen McMahon; Martin Koltzenburg; Irene Tracey; Dennis C. Turk (1 March 2013). Wall & Melzack’s Textbook of Pain: Expert Consult – Online. Elsevier Health Sciences. p. 508. ISBN 0-7020-5374-0.
  3. Jump up to:a b Xenon Pharma. “TV-45070: A Small Molecule for the Treatment of the Orphan Disease EM and Other Pain Disorders”.
  4. Jump up to:a b Xenon Pharma (2012). “Teva and Xenon Announce Teva’s World Wide License of Xenon’s Pain Drug XEN402”.

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US2016326184 SYNTHETIC METHODS FOR SPIRO-OXINDOLE COMPOUNDS 2016-01-06
US2017095449 PHARMACEUTICAL COMPOSITIONS OF SPIRO-OXINDOLE COMPOUND FOR TOPICAL ADMINISTRATION AND THEIR USE AS THERAPEUTIC AGENTS 2016-10-11
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US2015216794 METHODS OF TREATING PAIN ASSOCIATED WITH OSTEOARTHRITIS OF A JOINT WITH A TOPICAL FORMULATION OF A SPIRO-OXINDOLE COMPOUND 2015-02-05 2015-08-06
US9682033 METHODS OF TREATING POSTHERPETIC NEURALGIA WITH A TOPICAL FORMULATION OF A SPIRO-OXINDOLE COMPOUND 2016-02-05 2016-08-11
US2016166541 Methods For Identifying Analgesic Agents 2016-01-27 2016-06-16
US2017066777 ASYMMETRIC SYNTHESES FOR SPIRO-OXINDOLE COMPOUNDS USEFUL AS THERAPEUTIC AGENTS 2016-09-14
US2017073351 ENANTIOMERS OF SPIRO-OXINDOLE COMPOUNDS AND THEIR USES AS THERAPEUTIC AGENTS 2016-09-28
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US8742109 Synthetic methods for spiro-oxindole compounds 2012-09-14 2014-06-03
US8883840 Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents 2012-09-14 2014-11-11
US9260446 SYNTHETIC METHODS FOR SPIRO-OXINDOLE COMPOUNDS 2014-05-07 2014-11-13
US9278088 Methods for Identifying Analgesic Agents 2013-04-11 2013-08-15
US9480677 ENANTIOMERS OF SPIRO-OXINDOLE COMPOUNDS AND THEIR USES AS THERAPEUTIC AGENTS 2014-10-09 2015-01-22
Patent ID Patent Title Submitted Date Granted Date
US8450358 ENANTIOMERS OF SPIRO-OXINDOLE COMPOUNDS AND THEIR USES AS THERAPEUTIC AGENTS 2010-12-30
US2011086899 PHARMACEUTICAL COMPOSITIONS FOR ORAL ADMINISTRATION 2011-04-14
US8445696 SYNTHETIC METHODS FOR SPIRO-OXINDOLE COMPOUNDS 2011-04-14
US9487535 ASYMMETRIC SYNTHESES FOR SPIRO-OXINDOLE COMPOUNDS USEFUL AS THERAPEUTIC AGENTS 2013-03-11 2013-10-17
US9504671 PHARMACEUTICAL COMPOSITIONS OF SPIRO-OXINDOLE COMPOUND FOR TOPICAL ADMINISTRATION AND THEIR USE AS THERAPEUTIC AGENTS 2011-02-25 2013-06-06
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Funapide
Funapide.svg
Clinical data
Routes of
administration
By mouthtopical
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C22H14F3NO5
Molar mass 429.34547 g/mol
3D model (JSmol)
//////////TV 45070,  XEN 402, TEVA, XENON, Postherpetic neuralgia, PHN, PHASE 2, Funapide, фунапид , فونابيد , 呋纳匹特 , Orphan Drug Status
C1C2(C3=CC=CC=C3N(C2=O)CC4=CC=C(O4)C(F)(F)F)C5=CC6=C(C=C5O1)OCO6

Metopimazine


Metopimazine.svg

Metopimazine

RP-9965, EXP-999, NG-101

l-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide

CAS 14008-44-7
MF C22 H27 N3 O3 S2
MW 445.60
4-Piperidinecarboxamide, 1-[3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl]-
  • Isonipecotamide, 1-[3-[2-(methylsulfonyl)phenothiazin-10-yl]propyl]- (7CI,8CI)
  • 1-[3-[2-(Methylsulfonyl)-10H-phenothiazin-10-yl]propyl]-4-piperidinecarboxamide
  • 1-[3-[2-(Methylsulfonyl)phenothiazin-10-yl]propyl]-4-piperidinecarboxamide
  • 1-[3-[2-(Methylsulfonyl)phenothiazin-10-yl]propyl]isonipecotamide
  • 2-Methylsulfonyl-10-[3-(4-carbamoylpiperidino)propyl]phenothiazine
  • EXP 999
  • Metopimazine
  • RP 9965
  • Vogalene
  • metopimazine (gastroparesis), Neurogastrx

Sanofi (Originator)
Teva

Treatment of Nausea and Vomiting, APPROVED

Dopamine D3 receptor antagonist; Dopamine D2 receptor antagonist

Gastroprokinetic

Metopimazine (INN) is a phenothiazine antiemetic.

Metopimazine is an established antiemetic that has been approved and marketed for many years in Europe for the treatment of acute conditions. The compound does not cross the blood-brain-barrier, and is therefore free from central side effects, and is not associated with cardiovascular side effects

In May 2016, preclinical data were presented at the 2016 DDW in San Diego, CA. In rats, po NG-101 and domperidone did not penetrate the brain at therapeutically relevant concentrations, unlike metoclopramide. In dogs, the amplitude and frequency of antral contractions were increased by NG-101, whereas in rats, po metopimazine resulted in an increase in gastric emptying of solid foods. The blood-brain barrier was not readily crossed and there was no interaction with 5-HT3 or 5-HT4 receptors by NG-101 unlike metoclopramide and domperidone, respectively

Neurogastrx is investigating repurposed metopimazine (NG-101), a selective and peripherally restricted dopamine D2/D3 receptor antagonist, for the potential oral treatment of gastroparesis. By July 2014, preclinical studies were underway . SE BELOW REF

WO-2014105655: Methods for treating GI tract disorders
In May 2016, preclinical data were presented [SEE BELOW].

2016 May 24Abs 1079
NG101: A Potent and Selective Dopamine D2 Receptor Antagonist as a Potential Alternative to Metoclopramide and Domperidone for the Treatment of Gastroparesis
Digestive Disease Week
Cyril De Colle, Marieke van der Hart, Jiande Chen, Arash Rassoulpour, Pankaj J Pasricha

In July 2014, preclinical data were published. Metopimazine at 1mg/kg increased gastric motility in hound dogs. In studies in rodents, metopimazine at 3 and 10 mg/kg increased gastric emptying by 18 and 40%, respectively, compared with vehicle control

There is an increasing demand for antiemetic agents because of the most troublesome adverse effects of chemotherapy-induced nausea and emesis during cancer treatment.

However, the objective of complete prevention of emesis in all patients remains elusive. Therefore, there is a great demand for both development of (i) new antiemetic agents and (ii) new manufacturing processes for existing antiemetic agents. Metopimazine is an existing dopamine D2-receptor antagonist with potent antiemetic properties. It is chemically known as l-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide , which belongs to nitrogen- and sulfur-containing tricyclic compounds (phenothiazine class of drugs) with interesting biological and pharmacological activities.

Recently, it has been found that Metopimazine plays a key role as an alternative to Ondansetron in the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderate to high emetogenic noncisplatin-based chemotherapy.It has been used in France for many years for the prevention and treatment of nausea and vomiting under the brand name of Vogalene

In 1959, the first synthesis and manufacture process of Metopimazine  was reported by Jacob et al.The synthesis starts from the protection of 2-(Methylsulfanyl)-10H-phenothiazine..Jacob, R. M.; Robert, J. G. German Patent No. DE1092476, 1959.

Later, in 1990, Sindelar et al. reported a modified process , which starts from synthesis of 4-(2-fluorophenylthio)-3-nitrophenylmethylsulfone..Sindelar, K.; Holubek, J.; Koruna, I.; Hrubantova, M.; Protiva, M. Collect. Czech. Chem. Commun. 1990, 55, 15861601, DOI: 10.1135/cccc19901586

In 2010, Satyanarayana Reddy et al. reported a modified synthetic route which starts from either N-protection using acetyl chloride or N-alkylation using dihalopropane of 2-(methylsulfanyl)-10H-phenothiazine ..Satyanarayana Reddy, M.; Eswaraiah, S.; Satyanarayana, K. Indian Patent No. 360/CHE/2010 A, Aug 19, 2011.

Synthesis of 1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)piperidine-4- carboxamide (1)-Metopimazine: Pale yellow color solid, yield. 65% (82 g), DSC 189 °C.

str1 str2 str3

1H NMR (400 MHz, DMSO-d6, δ/ppm): 7.44 (d, 1H, arom H, J = 8.8 Hz), 7.37 (d, 2H, arom H, J = 8.0 Hz), 7.24 (t, 1H, arom H, J = 7.6 Hz), 7.16 (m, 2H, -NH2), 7.1 (d, 1H, arom H, J = 8.4 Hz), 6.99 (t, 1H, arom H, J = 7.6 Hz), 6.68 (s, 1H, arom H), 3.99 (t, 2H, -NCH2, J = 6.4 Hz), 3.23 (s, 3H, -S-CH3), 2.8-2.73 (m, 2H, -CH2-), 2.36 (t, 2H, -CH2-, J = 6.8 Hz), 2.02-1.96 (m, 1H, -CH-), 1.84-1.78 (m, 4H, 2-CH2-), 1.61-1.58 (m, 2H, -CH2-), 1.48-1.44 (m, 2H, – CH2-).

13C NMR (100 MHz, DMSO-d6, δ/ppm): 176.52, 145.41, 143.5, 140.12, 130.47, 128.03, 127.50, 127.25, 123.23, 122.16, 120.59, 116.38, 113.24, 54.82, 52.97, 44.64, 43.47, 41.7, 28.59, 23.52.

MS m/z (ESI): 446.21 (M+H)+.

SYNTHESIS

ChemSpider 2D Image | Metopimazine | C22H27N3O3S2

Image result for Metopimazine, SYNTHESIS

PATENT

IN 201641043070

IN 2013CH05689

IN 2013CH00361

IN 2010CH00360

DE 1092476/US 3130194

PAPER

A Simple and Commercially Viable Process for Improved Yields of Metopimazine, a Dopamine D2-Receptor Antagonist

Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, Fourth Phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore, Karnataka 560 105, India
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00052
*E-mail: pramodkumar@microlabs.in. Tel: 0811 0415647, ext. 245. Mobile No.: +91 9008448247., *E-mail: gmadhusudanrao@yahoo.com.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.7b00052

Abstract Image

An efficient, practical, and commercially viable manufacturing process was developed with ≥99.7% purity and 31% overall yield (including four chemical reactions and one recrystallization) for an active pharmaceutical ingredient, called Metopimazine (1), an antiemetic drug used to prevent emesis during chemotherapy. The development of two in situ, one-pot methods in the present synthetic route helped to improve the overall yield of 1 (31%) compared with earlier reports (<15%). For the first time, characterization data of API (1), intermediates, and also possible impurities are presented. The key process issues and challenges were addressed effectively and achieved successfully.

Synthesis of 1-(3-[2-(Methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide (1), Metopimazine

In ………………….. The obtained compound (1) was dried in a hot air oven at 50 °C.
Pale yellow color solid, yield. 65% (82 g),
DSC 189 °C.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 7.44 (d, 1H, arom H, J = 8.8 Hz), 7.37 (d, 2H, arom H, J = 8.0 Hz), 7.24 (t, 1H, arom H, J = 7.6 Hz), 7.16 (m, 2H, −NH2), 7.1 (d, 1H, arom H, J = 8.4 Hz), 6.99 (t, 1H, arom H, J = 7.6 Hz), 6.68 (s, 1H, arom H), 3.99 (t, 2H, −NCH2, J = 6.4 Hz), 3.23 (s, 3H, −S–CH3), 2.8–2.73 (m, 2H, −CH2−), 2.36 (t, 2H, −CH2–, J = 6.8 Hz), 2.02–1.96 (m, 1H, −CH−), 1.84–1.78 (m, 4H, 2–CH2−), 1.61–1.58 (m, 2H, −CH2−), 1.48–1.44 (m, 2H, −CH2−).
13C NMR (100 MHz, DMSO-d6, δ/ppm): 176.52, 145.41, 143.5, 140.12, 130.47, 128.03, 127.50, 127.25, 123.23, 122.16, 120.59, 116.38, 113.24, 54.82, 52.97, 44.64, 43.47, 41.7, 28.59, 23.52.
MS m/z (ESI): 446.21 (M + H)+.
 
Regulatory
  • Vogalene
  • metopimazina (Italian, Portuguese)
  • metopimazin (Danish, Swedish)
  • metopimazine (Dutch)
  • metopimatsiini (Finnish)

Regulatory List Number

  • EC No.: 237-818-4
  • EINECS No.: 237-818-4
  • Harmonized Tariff Code

    293430

REFERENCES
Metopimazine
Metopimazine.svg
Clinical data
AHFS/Drugs.com International Drug Names
ATC code
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
ECHA InfoCard 100.034.367
Chemical and physical data
Formula C22H27N3O3S2
Molar mass 445.6 g/mol
3D model (Jmol)

//////////////Metopimazine, Dopamine D2-Receptor Antagonist, 14008-44-7, sanofi, teva, RP-9965, Nausea and Vomiting, EXP-999, NG-101, metopimazine, gastroparesis, Neurogastrx

NC(=O)C1CCN(CC1)CCCN2c4ccccc4Sc3ccc(cc23)S(C)(=O)=O

TEV-37440, CEP-37440


str1
str1
TEV-37440, CEP-37440
CAS 1391712-60-9
Benzamide, 2-[[5-chloro-2-[[(6S)-6,7,8,9-tetrahydro-6-[4-(2-hydroxyethyl)-1-piperazinyl]-1-methoxy-5H-benzocyclohepten-2-yl]amino]-4-pyrimidinyl]amino]-N-methyl-
MW  C30 H38 Cl N7 O3
Molecular Weight, 580.12
2-[(5-Chloropyrimidin-4-yl)amino]-N-methyl-benzamide; 2-[4-[(6S)-1-Methoxy-2-(methylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl]piperazin-1-yl]ethanol
2-[[5-Chloro-2-[[(6S)-6,7,8,9-tetrahydro-6-[4-(2-hydroxyethyl)-1-piperazinyl]-1-methoxy-5H-benzocyclohepten-2-yl]amino]-4-pyrimidinyl]amino]-N-methylbenzamide

2-[[5-chloro-2-[[(6S)-6-[4-(2-hydroxyethyl)piperazin- 1 -yl]- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]amino]pyrimidin-4-yl]amino]-N-methyl-benzamide, and is also known as CEP-37440.

Image result

Applicants: CEPHALON, INC. [US/US]; 41 Moores Road P.O. Box 4011 Frazer, Pennsylvania 19355 (US)
Inventors: COURVOISIER, Laurent; (US).
JACOBS, Martin J.; (US).
OTT, Gregory R.; (US).
ALLWEIN, Shawn P.; (US)

Anaplastic Lymphoma Kinase (ALK) is a cell membrane-spanning receptor tyrosine kinase, which belongs to the insulin receptor subfamily. The most abundant expression of ALK occurs in the neonatal brain, suggesting a possible role for ALK in brain development (Duyster, J. et al, Oncogene, 2001, 20, 5623-5637).

ALK is also implicated in the progression of certain tumors. For example, approximately sixty percent of anaplastic large cell lymphomas (ALCL) are associated with a chromosome mutation that generates a fusion protein consisting of nucleophosmin (NPM) and the intracellular domain of ALK. (Armitage, J.O. et al., Cancer: Principle and Practice of Oncology, 6th edition, 2001, 2256-2316; Kutok J.L. & Aster J.C., J. Clin. Oncol, 2002, 20, 3691-3702). This mutant protein, NPM- ALK, possesses a constitutively active tyrosine kinase domain that is responsible for its oncogenic property through activation of downstream effectors. (Falini, B. et al, Blood, 1999, 94, 3509-3515; Morris, S.W. et al, Brit. J. Haematol, 2001, 113, 275-295; Duyster et al; Kutok & Aster). In addition, the transforming EML4-ALK fusion gene has been identified in non-small-cell lung cancer (NSCLC) patients (Soda, M., et al, Nature, 2007, 448, 561 – 566) and represents another in a list of ALK fusion proteins that are promising targets for ALK inhibitor therapy. Experimental data have demonstrated that the aberrant expression of constitutively active ALK is directly implicated in the pathogenesis of ALCL and that inhibition of ALK can markedly impair the growth of ALK+ lymphoma cells (Kuefer, Mu et al. Blood, 1997, 90, 2901-2910; Bai, R.Y. et al, Mol. Cell Biol, 1998, 18, 6951-6961; Bai, R.Y. et al, Blood, 2000, 96, 4319-4327; Ergin, M. et al, Exp. Hematol, 2001, 29, 1082-1090; Slupianek, A. et al, Cancer Res., 2001, 61, 2194-2199; Turturro, F. et al, Clin. Cancer Res., 2002, 8, 240-245). The constitutively activated chimeric ALK has also been demonstrated in about 60% of inflammatory myofibroblastic tumors (IMTs), a slow-growing sarcoma that mainly affects children and young adults. (Lawrence, B. et al., Am. J. Pathol, 2000, 157, 377-384; Duyster et al).

In addition, ALK and its putative ligand, pleiotrophin, are overexpressed in human glioblastomas (Stoica, G. et al, J. Biol. Chem., 2001, 276, 16772-16779). In mouse studies, depletion of ALK reduced glioblastoma tumor growth and prolonged animal

survival (Powers, C. et al, J. Biol. Chem., 2002, 277, 14153-14158; Mentlein, R. et al, J. Neurochem., 2002, 83, 747-753).

An ALK inhibitor would be expected to either permit durable cures when combined with current chemotherapy for ALCL, IMT, proliferative disorders,

glioblastoma and possible other solid tumors, or, as a single therapeutic agent, could be used in a maintenance role to prevent cancer recurrence in those patients. Various ALK inhibitors have been reported, such as indazoloisoquinolines (WO 2005/009389), thiazole amides and oxazole amides (WO 2005/097765), pyrrolopyrimidines (WO 2005080393), and pyrimidinediamines (WO 2005/016894).

WO 2008/051547 discloses fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors. The lead drug candidate disclosed in the ‘547 application is CEP-28122, a potent ALK inhibitor with oral efficacy against SUP-M2 and Karpas-299 ALK-dependent tumors in mouse xenograft models. CEP-28122 progressed to IND-enabling studies until its development was terminated due to the unexpected occurrence of severe lung toxicity in CEP-28122-treated monke s.

CEP-28122

Focal adhesion kinase (FAK) is an evolutionarily conserved non-receptor tyrosine kinase localized at focal adhesions, sites of cellular contact with the ECM (extra-cellular matrix) that functions as a critical transducer of signaling from integrin receptors and multiple receptor tyrosine kinases, including EGF-R, HER2, IGF-R1, PDGF-R and VEGF-R2 and TIE-2 (Parsons, JT; Slack-Davis, J; Tilghman, R; Roberts, WG. Focal adhesion kinase: targeting adhesion signaling pathways for therapeutic intervention. Clin. Cancer Res., 2008, 14, 627-632; Kyu-Ho Han, E; McGonigal, T. Role of focal adhesion kinase in human cancer – a potential target for drug discovery. Anti-cancer Agents Med. Chem., 2007, 7, 681-684). The integrin-activated FAK forms a binary complex with Src which can phosphorylate other substrates and trigger multiple signaling pathways. Given the central role of FAK binding and phosphorylation in mediating signal transduction with multiple SH2- and SH3- domain effector proteins (Mitra, SK; Hanson, DA; Schlaeper, DD. Focal adhesion kinase: in command and control of cell motility. Nature Rev. Mol.

Cell Biol, 2005, 6, 56-68), activated FAK plays a central role in mediating cell adhesion, migration, morphogenesis, proliferation and survival in normal and malignant cells (Mitra et al. 2005; McLean, GW; Carragher, NO; Avizzienyte, E; et al. The role of focal adhesion kinase in cancer – a new therapeutic opportunity. Nature Reviews Cancer, 2005, 5, 505-515; and Kyu-Ho Han and McGonigal, 2007). In tumors, FAK activation mediates anchorage-independent cell survival, one of the hallmarks of cancer cells. Moreover, FAK over expression and activation appear to be associated with an enhanced invasive and metastatic phenotype and tumor angiogenesis in these malignancies (Owens, LV; Xu, L; Craven, RJ; et al. Over expression of the focal adhesion kinase (pi 25 FAK) in invasive human tumors. Cancer Res., 1995, 55, 2752-2755; Tremblay, L; Hauck, W. Focal adhesion kinase (ppl25FAK) expression, activation and association with paxillin and p50CSK in human metastatic prostate carcinoma. Int. J. Cancer, 1996, 68, 164-171; Kornberg, IJ. Focal adhesion kinase in oral cancers. Head and Neck, 1998, 20: 634-639; Mc Clean et al 2005; Kyu-Ho Han and McGonigal, 2007) and correlated with poor prognosis and shorter metastasis-free survival.

Multiple proof-of-concept studies conducted in various solid tumors using siRNA

(Haider, J; Kamat ,AA; Landen, CN; et al. Focal adhesion kinase targeting using in vivo short interfering RNA delivery in neutral liposomes for ovarian carcinoma therapy. Clin. Cancer Res., 2006, 12, 4916-4924), dominant-negative FAK, and small molecule FAK inhibitors (Haider, J; Lin, YG; Merritt, WM; et al. Therapeutic efficacy of a novel focal adhesion kinase inhibitor, TAE226 in ovarian carcinoma. Cancer Res., 2007, 67, 10976-10983; Roberts, WG; Ung, E; Whalen, P; et al. Anti-tumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res., 2008, 68, 1935-1944; Bagi CM; Roberts GW; and Andersen CJ. Dual focal adhesion kinse/Pyk2 inhibitor has positive effects on bone tumors – implications for bone metastases. Cancer, 2008, 112, 2313-2321) have provided pre-clinical support for the therapeutic utility of FAK inhibition as an anti-tumor/anti-angiogenic strategy, particularly for androgen-independent prostate cancers, breast cancers, and HNSCCs. In preclinical models of human breast cancer (MDA-MB-231) in nude rats, administration of a small molecule FAK inhibitor (PF-562,271) inhibited primary tumor growth and intra-tibial tumor spread, and restored tumor-induced bone loss (Bagi et al, 2008). Roberts et al, (2008) showed that PF-562,271 inhibited bone metastases, prevented bone resorption, and increased osteogenesis in breast and androgen-independent prostate cancer patients with and without bone metastases, supporting an additional benefit of FAK inhibition in these specific malignancies.

In summary, there is clear genetic and biological evidence that links aberrant ALK activation and constitutive activation of FAK with the onset and progression of certain types of cancer in humans. Considerable evidence indicates that ALK- and FAK-positive tumor cells require these oncogenes to proliferate and survive, and in the case of FAK, to invade and metastasize to distant sites, while inhibition of both ALK and FAK signaling leads to tumor cell growth arrest or apoptosis, resulting in objective cytoreductive effects. Inhibition of FAK also results in attenuation of tumor motility, invasiveness, and metastatic spread, particularly in specific cancers characterized by bone metastatic dissemination and osteolytic disease. FAK activation protects tumor cells from

chemotherapy-induced apoptosis, contributing to tumor resistance; modulation of FAK activity (by siRNA or pharmacologically) potentiates efficacy of chemotherapeutic agents in vivo (e.g., doxorubicin, docetaxel and gemcitabine), suggesting the utility for rational combination therapies in specific cancers. ALK and FAK are minimally expressed in most normal tissues in the healthy adult and are activated and/or dysregulated in specific cancers during oncogenesis and/or during early stages of malignant progression.

Consequently, the on-target effects of treatment with a dual ALK and FAK inhibitor against normal cells should be minimal, creating a favorable therapeutic index.

A need exists for additional safe and effective ALK and/or FAK inhibitors for the treatment of cancer.

In 2012, the development of a new route to our lead anaplastic lymphoma kinase (ALK) inhibitor CEP-28122 (1) was disclosed.  This route utilized some unique synthetic approaches that included a selective nitration through a para-blocking group strategy, a one-pot amination-transfer hydrogenation to effect four reductions nearly simultaneously, an enzymatic resolution, and the leveraging of an in situ generated mixed mesylate hydrochloride salt to form the final active pharmaceutical ingredient (API). While this process development was occurring, efforts from Discovery identified TEV-37440 (2) as a suitable backup with many pharmaceutical advantages over the lead compound. The most notable of these advantages was the dual kinase selectivity for both ALK and focal adhesion kinase (FAK). Having this dual kinase effect made TEV-37440 an ideal candidate for drug development, targeting nonsmall-cell lung cancer (NSCLC). From a synthetic point of view, TEV-37440 contains numerous structural similarities to its lead development candidate CEP-28122 . The core ring system is again made up of three primary fragments with an identical central B-ring. While the C-ring is different, the challenging A-ring again contains chirality around a secondary amine of a similar 6–7 fused ring system. These similarities allow for many of the same strategies identified for CEP-28122 to be applied in the route development of TEV-37440. Described herein is the phase-appropriate development of the oncology development candidate TEV-37440. Highlights of this development include the use of a novel ring-expansion reaction, a selective nitration through a para-blocking group strategy, a single-pot amination–hydrogenation, a diastereomeric salt resolution, a through-process step to avoid a hazardous intermediate, and a practical formation of a trihydrochloride dihydrate salt.
Figure
ALK inhibitor CEP-28122 and ALK/FAK dual inhibitor TEV-37440.
Synthesis will be updated watch this space………..

CONTD……….
contd…………….
PATENT

The present invention rovides a compound of formula (I)

or a salt form thereof.

The compound of formula (I) has ALK and FAK inhibitory activity, and may be used to treat ALK- or FAK-mediated disorders or conditions.

The present invention further provides a pharmaceutical composition comprising at least one compound of the present invention together with at least one pharmaceutically acceptable excipient.

CEP-37440

The synthesis of 2-(5-chloro-2-{(S)-6-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-l-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino}-pyrimidin-4-ylamino)-N-methyl-benzamide can be carried out according Fig. 1, following the procedures outlined in Steps 1-8.

Stepl : 5-Methoxy-l-methylene-l,2,3,4-tetrahydro-naphthalene: To a slurry of 5- Methoxy-3,4-dihydro-2H-naphthalen-l-one (25 g, 0.14 mol) and methyltriphenylphos-phonium iodide (1.13 eq) in THF (250 mL) at RT was added potassium t-butoxide (1.6 eq) at such a rate as to maintain a temperature no higher than warm to the touch. The reaction was stirred for one hour and concentrated. The reaction was then azeotroped with three volumes of hexane to remove excess t-butanol. Fresh hexane was added the solution was let to stand overnight to effect trituration. The red-brown solid was removed by filtration and the filtratewas washed twice with water and was concentrated. Purification by

chromatography on ISCO (330g Si02 cartridge: stepwise hexane and then DCM) affords the title compound as a pale yellow oil (24 g, 99%). 1H-NMR (400 MHz, CDC13) 7.29 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.49 (s, 1H), 4.98 (s, 1H), 3.85 (s, 3H), 2.77 (t, J = 6.4 Hz, 2H), 2.53-2.50 (m, 2H), 1.93-1.87 (m, 2H).

Step 2: l-Methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one: 5-Methoxy-l-methylene-l,2,3,4-tetrahydro-naphthalene (23.8 g, 0.137 mol) in 150 mL MeOH added in one portion to freshly prepared solution of thallium(III)nitrate trihydrate (1.0 eq) in 300 mL MeOH. Stirred one minute and 400 mL chloroform added. The solution was filtered and the organics partitioned between dichloromethane and water. The organics were dried (MgS04) and concentrated. Purification by chromatography (ISCO, 330g silica cartridge; stepwise elution hexane (5 min) then 7 minute gradient to 100% dicloromethane (20 min) affords the title compound as the most polar of the products as a pale yellow oil (26g, 97%). 1H-NMR (400 MHz, CDC13) 7.16 (t, J = 7.9 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 7.5 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 2H), 3.05-3.01 (m, 2H), 2.55 (t, J = 7.0 Hz, 2H), 2.01-1.96 (m, 2H). LC/MS (ESI+) m/z = 191 (M+H)+

Step 3: l-Methoxy-2-nitro-5,7,8,9-tetrahydro-benzocyclohepten-6-one: To potassium nitrate in acetonitrile (50 mL) and trifluoroacetic anhydride (100 mL) at 0°C was added dropwise l-methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one (25 g, 0.131 mol) in 50 mL acetonitrile. The reaction was stirred for 2.5 hours while warming to RT. The reaction was concentrated without heat on a rotary evaporator. MeOHwas added and stirred briefly. Reconcentrated and worked-up by partitioning between dichloromethane and sat. sq. sodium bicarbonate solution. The organic layer was separated and dried (Mg2S04), concentrated and purified by chromatography ISCO (330g silica cartridge: gradient elution – 10 to 50% EA:HEX over 60 minutes) affording two isomers. The title compound was the later eluting (10.7 grams, 34.6% yield). 1H-NMR (400 MHz, CDC13) 7.70 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 2H), 3.13-3.09 (m, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.10-2.03 (m, 2H).

Step 4: 2-[4-(l-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-piperazin-l-yl]-ethanol: l-Methoxy-2-nitro-5,7,8,9-tetrahydro-benzocyclohepten-6-one (15.09 g, 64.15 mmol) in methylene chloride (870 ml)treated with 2-Piperazin-l-yl-ethanol (3 eq) followed by acetic acid (10 eq). The mixture was stirred at 50°C for 2 hrs and cooled to 0°C and sodium triacetoxyborohydride (4 eq) was added, then warmed to RT and stirred. After a few hours starting material was still present. Added

0.4 eq further of sodium triacetoxyborohydride, then again after 6 hours. Stirred overnight. Poured into a solution of sat. aq. Sodium bicarbonate and ice and made basic to pH 10 with IN sodium hydroxide, extracted 2X dichloromethane, dried MgS04, filtered and concentrated. This material was taken up into ethanol and HC1/

ethanol was added. The resulting precipitate was triturated for 2 hours then filtered. The solid was free-based using NaOH followed by sodium bicarbonate and extracted into dichloromethane to give the title compound (19g, 85% yield). 1H-NMR (400 MHz, CDCI3) 7.56 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 3.82 (s, 3H), 3.63-3.06 (m, 2H), 3.29-3.24 (m, 1H), 3.00-2.86 (m, 3H), 2.72-2.67 (m, 2H), 2.60-2.51 (m, 8H), 2.46-2.37 (m, 2H), 2.12-2.07 (m, 2H), 1.87-1.78 (m,lH), 1.37-1.29 (m, 1H). LC/MS (ESI+) m/z = 350 (M+H)+

Step 5 : 2-[4-(2-Amino- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-piperazin- 1 -yl]-ethanol. 2-[4-(l -Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-piperazin-l-yl]-ethanol (19.0 g, 54.4 mmol) was

split into two batches and dissolved in a total of Ethanol (232 mL). 10 % Pd/C (

1.74 g, 1.64 mmol) was divided in half and the reaction was hydrogenated for 3-4 hours at 50 psi. Each reaction mixture was filtered through celite to remove Pd. The filtrates were combined and then concentrated and the title compound isolated as a foamy solid (17.25g, 99% yield). 1H-NMR (400 MHz, CDC13) 6.76 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 7.9 Hz, 1H), 3.72 (broad s, 3H), 3.71 (s, 3H),3.64 (t, J = 5.4 Hz, 2H), 3.26-3.20 (m, 1H), 2.84- 2.72 (m, 5H), 2.62-2.56 (m, 8H), 2.42-2.35 (m, 2H), 2.40-2.37 (m, 1H), 1.81-1.74 (m, 1H), 1.70 (broad s,lH), 1.41-1.33 (m, 1H). LC/MS (ESI+) m/z = 320 (M+H)+

Step 6 : 2-[4-((S)-2-Amino- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-piperazin-l-yl] -ethanol: 34 grams of racemic 2-[4-(2 -Amino- l-methoxy-6, 7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-piperazin-l-yl]-ethanol were separated using SFC (supercritical fluid C02) chromatography using a Chiralcel OJ-H (3 x 15 cm) 808041 column with 15% methanol(0.2% DEA)/C02, 100 bar eluent at 80 mL/min flow rate monitoring the wavelength of 220 nm with an injection volume: 0.5 mL, 20 mg/mL ethanol. 16.9 grams of the (R)-enantiomer and 17 grams of the titled compound were isolated with a chemical purity >99% and an enantiomeric excess (ee) >99% (measured using a Chiralcel OJ-H analytical column). NMR and mass were equivalent to the racemic material. The absolute configurationof the first eluting isomer was unambiguously assigned as the (R)-configuration via small-molecule X-ray using anomalous dispersion of the bis-p-bromobenzyl derivative: 4-bromo-benzoic acid 2-{4-[(R)-2-(4-bromo-

benzoylamino)- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-piperazin-l -yl} -ethyl ester. Thus, the second eluting enantiomer was determined to be (S)-configuration.

Step 7: 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide: 2-Amino-N-methyl-benzamide (24.4 g, 0.16 mol) in DMF (0.5 L) was added 2,4,5-Trichloro-pyrimidine (39 g, 1.3 eq) and Potassium carbonate (1.3 eq). Stired under argon at 75 °C for 5 hrs and then at RT overnight. Poured into 1 L water and precipitate isolated by filtration and washed 1 : 1 acetonitrile: water followed by drying in air stream and under vacuum to afford the title compound as a yellow solid (38 g, 78% yield). 11.70 (s, 1H), 8.74 (d, J = 8.2 Hz, 1H), 8.24 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.16 (t, J = 8.4 Hz, 1H), 6.28 (s, 1H), 3.06 (d, J = 4.7 Hz, 3H).

Step 8 : 2-(5-Chloro-2- {(S)-6-[4-(2-hydroxy-ethyl)-piperazin-l -yl]- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino}-pyrimidin-4-ylamino)-N-methyl-benzamide: To a sealed vessel 2-[4-((S)-2-Amino-l-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-piperazin-l-yl]-ethano (2.69 g, 8.41 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (2.00 g, 6.73 mmol) were combined in 1-methoxy-2-propanol (120 mL, 1200 mmol) followed by the addition of Methanesulfonic acid (2.44 mL, 37.7 mmol). The reaction was then heated at 90°C for 18 hours.

The reaction mixture was added to a separatory funnel and diluted with sat. bicarb until a cloudy ppt formed. This was extracted with dichloromethane 3x. The organic

layer was then washed with brine, dried over MgS04, filtered and concentrated. The residue was pumped dry then chromatographed on ISCO flash column. It was injected in dichloromethane onto a normal phase column and eluted on a gradient of 0-10%

(dichloromethane: 10%NH4OH in MeOH). The desired product eluted around 9-10% and the 10% gradient was held until product eluted completely. Mixed fractions concentrated and were chromatographed on the Gilson reverse-phase HPLC gradient elution 0-40%

CH3CN. Chromatogrpahy was repeated using normal phase silica and reverse phase HPLC to effect further purification as desired. Following neutralization and concentration of all the material, the resulting solid was obtained by taking the foam up into EtOAc and concentrating to dryness several times to give the title compound (1.1 g, 28%>). 11.02 (s, 1H), 8.69 (d, J = 8.9 Hz, 1H), 8.13 (s, 1H), 8.08 (d, J = 8.4 Hz, 1Η),7.59-7.50 (m, 2H),

7.41 (s, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.21 (s, 1H), 3.74 (m, 3H), 3.66-3.63 (m, 2H), 3.29-3.23 (m, 1H), 3.06 (d, J = 4.3 Hz, 3H), 2.92-2.72 (m, 5H), 2.66-2.55 (m, 8H), 2.48-2.39 (m, 2H), 2.16-2.10 (m, 2H), 1.87-1.77 (m, 1H), 1.42-1.32 (m, 1H).LC/MS (ESI+) m/z = 580 (M+H)+

CEP-37440 amorphous HC1 salt

2-(5-Chloro-2- {6-[4-(2-hydroxy-ethyl)-piperazin- 1 -yl]- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino}-pyrimidin-4-ylamino)-N-methyl-benzamide hydrochloride: 2-(5-Chloro-2-{6-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-l-methoxy-6, 7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino}-pyrimidin-4-ylamino)-N-methyl-benzamide (4.90 g, 8.45 mmol) and 2.5 M of HC1 in ethanol (13.5 niL, 33.8 mmol) were heated until they dissolved in ethanol (164 mL). The reaction was concentrated two times from ethanol, then warmed in a small amount of ethanol until completely dissolved. This solution was allowed to cool slowly with a stirring (<100 rpm). A solid preciptate formed quickly before the solution had cooled. This mixture was allowed to stir until ambient temperature was achieved and then filtered. The solid was washed with ethanol followed by ether then directly pumped dry under high vac to give 2-(5-chloro-2-{6-[4-(2-hydroxy-ethyl)-piperazin-l -yl]- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino} -pyrimidin-4-ylamino)-N-methyl-benzamide hydrochloride (5.3 grams, quantitative yield). 1H-NMR (MeOD, 400 MHz) δ 8.55 (s, 1H), 8.17 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 6.8 Hz, 1H), 7.46 (broad s, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 4.00-3.95 (m, 4H), 3.83-3.72 (m, 5H), 3.73 (s, 3H), 3.65-3.59 (m, 2H), 3.47-3.38 (m, 5H), 2.95 (s, 3H), 2.72-2.65 (m, 1H), 2.44-2.38 (m, 1H), 2.29-2.28 (m, 1H), 2.19-2.12 (m, 1H), 1.59-1.49 (m, 1H). LC/MS (ESI+) m/z = 580 (M+H)+.

PATENT

2-[[5-chloro-2-[[(6S)-6-[4-(2-hydroxyethyl)piperazin-l-yl]-l-methoxy-6,7,8,9-tetrahydro-5Hbenzo[7]annulen-2-yl]amino]pyrimidin-4-yl]amino]-N-methyl-benzamide (CEP-37440) is an orally available dual kinase inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) and focal adhesion kinase (FAK) with antineoplastic activity. See, e.g., WO 2013/134353.

H


CEP-37440

[0003] In view of the surprising and unexpected properties observed with CEP-37440, improved methods for its preparation in high enantiomeric purity are needed.

CEP-37825 CEP-38063-tartrate salt

Scheme 2

CEP-37440

[0059] Preferred methods for asymmetrically producing an intermediate for the formation of CEP-37440 according to the disclosure are depicted in Scheme 3.

Scheme 3

4

[0060] Preferred methods for asymmetrically producing an intermediate for the formation of CEP-37440 according to the disclosure are depicted in Scheme 4.

[0061] The following examples are provided to illustrate the compositions, processes, and properties of the present disclosure. The examples are merely illustrative and are not intended to limit the disclosure to the materials, conditions, or process parameters set forth therein.

EXAMPLES

Chiral HPLC method:

CHIRALCEL AD column

eluent: heptane/isopropanol (90:10)

flow: 1.2 mL/min

detection: 220 nm and 254 nm.

Example 1

5-methoxytetralone CEP-41158

[0063] To a 12L 4-neck round bottom flask was added methoxytetralone (500 g, 2830 mmol, 1 eq) and Pti3PCH3I (1320 g, 3264 mmol, 1.15 eq) as solids via a powder funnel. THF (5 L) was added and the mixture was stirred with overhead stirring at 19 °C. tBuO (525 g, 4683, 1.65 eq) was added portion-wise over 2 hours to maintain a maximum reaction temperature of 47 °C. A THF solution of tBuOK can also be used with similar results. The funnel was washed with additional THF as needed. The resulting slurry was stirred for an additional hour at 30 °C. HPLC analysis showed < 0.5% starting material.

[0064] The reaction was transferred to a single neck flask and concentrated by roto-evaporator and solvent switched to heptanes (approximately 2.5L, removing as much THF as possible). The slurry was filtered, washing with an additional 0.5 L heptanes. The combined filtrant and wash (approximately 3 L) was washed 2 times with water (2 x 250 mL). The water layers were back extracted 1 time with 0.5 L heptanes which was combined with the other organic layers (total volume was approximately 3.5L).

[0065] To remove the residual amounts of Pl^PO, the solution can be dried and cooled (overnight in the cold room) to precipitate out the triphenylphosphine oxide. Filtration results in a clean product stream that can be concentrated to an oil. Alternatively, the initial heptane product stream may be passed through a plug of S1O2 followed by concentration to an oil.

Example 2

[0066] CEP-41 158 (Limiting Reagent, see Example 1 ) was charged to a reaction vessel followed by methyl tertiary butyl ether (MTBE) (6.3 volumes), isopropanol (3.3 volumes),

Triton X (0.1 volumes), water (6.3 volumes), and 2-iodo-5-methylbenzenesulfonic acid (0.125 eq). While holding the batch at 20-25 °C, oxone (0.65 eq) was added portion-wise over

approximately 1.5 h and then continued to stir at room temperature. HPLC was used to monitor reaction conversion. A typical reaction time was 4 h but the reaction can be stirred overnight, as well.

[0067] The reaction was quenched by the slow addition of sodium sulfite (0.5 eq) over 10 minutes. Peroxide test strips were used to confirm no peroxides remained. NaOH (5N) was then added at <30 °C to obtain a pH of 8 (typically this was approximately 2 volumes of 5N NaOH). Celite was added and the solution was filtered. The aqueous layer was removed and the organics were washed with brine before being concentrated to an oil.

[0068] Bisulfite adduct formation: The above oil was taken up in isopropanol (7 volumes) before adding water (4 volumes). To this solution was slowly added a freshly prepared aqueous sodium bisulfite solution (6.4 M, 2 eq) at ambient temperature. The resulting slurry was stirred overnight then filtered. The solids were washed with isopropanol and then dried at 40 °C in a vacuum oven with a nitrogen bleed.

Example 3

CEP -41609 CEP-41159

[0069] Unless otherwise noted all volumes and equivalents are based on the wt% corrected charge of CEP-41609. To a nitrogen purged 2.0 L jacketed reactor equipped with an anchor overhead stirrer, and a thermocouple probe was charged 1 17.8 g of CEP-41609 (84.9 wt%, 100.0 g, 0.3398 mol). 500 mL of acetonitrile (5 volumes) was then introduced and the jacket was set to 15 °C. 300 mL of deionized H2O (3 volumes) was then charged and the slurry cooled from -17 °C to 10 °C with stirring at 130 RPM. HC1 (86.4 mL, 1 1.8M, 1.019 mol, 3 equiv.) was added in one portion with the slurry at 10 °C. The mixture exothermed to 17.3 °C and the jacket was adjusted to 22 °C. The slurry cooled to 13.8 °C before being warmed back up to 20 °C in 13 minutes. The stirring was turned up to 175 RPM to improve mixing while completing a 30 minute age. The solids had dissolved after 30 minutes. At 57 minutes the stirring was stopped and the biphasic solution was allowed to settle and sit overnight (15 h).

[0070] After sitting overnight, stirring (175 RPM) was reinitiated and the jacket was set to -40 °C. It took 28 minutes for the mixture to reach -15 °C and in that time the jacket was adjusted to -20 °C. With the jacket at -20 and the reaction at -15 °C the first charge of N-chlorosuccinimide (NCS) was done (28.4 g, 0.2127 mol, 0.626 equiv.). The reaction exothermed to -1.2 °C in 1.5 minutes. 4 minutes later with the reaction cooled to -6.9 °C and the jacket still at -20 °C the second charge of NCS was done (85.0 g, 0.6367 mol, 1.874 equiv.). The reaction exothermed to 2.2 °C in 1.5 minutes. The reaction was then cooled to 0 °C in 1 minute and held at 0 ± 2 °C. Acetonitrile (ACN) (25 mL, 0.25 volumes vs wt% corrected CEP-41609) was used to rinse residual NCS off the wall of the reactor and into the reaction just after the second charge. After 2 hours at 0 ± 2 °C an IPC was taken from the organic layer and the HPLC showed undetectable levels of CEP-41608.

[0071] At 2 hours 22 minutes the work up began with the addition of MTBE (650 mL, 6.5 volumes) over 6 minutes at 0 to 1.7 °C. The mixture was stirred at 175 RPM (complete mixing achieved) for 2.5 minutes then stirring was stopped and the layers settled in 2.5 minutes. 280 mL of an aqueous layer was then cut at -1.6 °C. To the remaining 1500 mL of organic solution was charged 650 mL NaCl solution (6.5 volumes, 24 wt% NaCl; 189.2 g NaCl mixed with 599.25 g D.I. H20) over 8 minutes at -1.3 to 1.7 °C. Stirring was increased to 325 RPM to achieve complete mixing. The solution was allowed to stir for 1.5 minutes before stopping the stirring and allowing the layers settle in 3 minutes. 1000 mL of aqueous layer was cut at -0.4 °C. To the remaining 1 100 mL of organic layer was charged 650 mL NaHCC solution (6.5 volumes, 7.5 wt% NaHC03; 53 g NaHC03 mixed with 655.5 g D.I. H20) over 9 minutes at -0.3 to 2.6 °C with stirring at 325 RPM to achieve complete mixing. The solution was allowed to stir for 5 minutes and then the stirring was stopped and the layers settled in 4 minutes. 800 mL of an aqueous layer (pH = 8) was cut at 0.2 °C.

[0072] The remaining organic layer (1000 mL) was checked by HPLC (70.2 A% CEP-41 159, 17.5 A% impurity 1, 5.9 A% impurity 2, 2.9 A% impurity 3). Thejacket was set to 10 °C while a solution of Na2S204 (33.4 g @ 85 wt%, 0.1631 mol, in 326 mL DI H20) was prepared in a capped imax jar. 50 minutes after cutting the NaHCC layer the organic layer was at 8.8 °C. With thejacket at 10 °C the Na2S204 solution was added in one portion with the stirring at 250 RPM. The mixture warms to 15.4 °C and the jacket was adjusted to maintain the reaction at 15 ± 1 °C for 15 minutes. Stirring was then stopped and an HPLC was taken from the organic layer while holding the biphasic solution at 15 °C. The HPLC showed no detectable impurity 1 (76.1 A% CEP-41 159, 6.4 A% impurity 2, 3.1 A% impurity 3, 0.54 A% CEP-41608). After a total of 39 minutes contact time with Na2S204 solution the aqueous layer was cut leaving 925 mL of organic layer. This solution was held overnight with the jacket at 20 °C.

[0073] After 16 hours 1 1 minutes the organic solution was drained into a round bottom flask, rinsing with 100 mL MTBE (1 volume). The solution was then concentrated at 120 mbar

with the bath temperature at 35 °C. Once 590 mL (5.9 volumes vs. wt% corrected CEP-41609) was removed the remaining solution was diluted with 550 mL AcOH (5.5 volumes vs. wt% corrected CEP-41609). This solution was then concentrated again at 65 mbar with the bath temperature at 45 °C. Once 320 mL (3.2 volumes vs. wt% corrected CEP-41609) was removed the distillation was stopped and the remaining solution was weighted (523.39 g) and checked by HPLC and Ή NMR. HPLC showed 66.31 g (87.0% yield) of CEP-41 159 in solution, and the NMR showed 96.0 wt% AcOH (3.1 wt% ACN, 0.9 wt% MTBE; 93 wt% AcOH desired). The desired AcOH solution mass was calculated from the HPLC assay of CEP-41 159 (9 x 66.3 lg = 596.79 g) and the amount of AcOH needed to dilute to this mass was also calculated (596.79-523.39 = 73.4 g x (lmL/1.049g) = 70 mL AcOH). The AcOH solution was then transferred back to the 2 L JLR (which had been rinsed with H2O and dried with an N2 sweep and 40 °C jacket) and 70 mL of AcOH was used to rinse out the round bottom flask and dilute the solution.

[0074] After sitting at 20 °C for 2.5 hours this solution was diluted with 199 mL DI H20 (3 volumes vs. CEP-41 159) while setting the stirring at 225 RPM and the jacket at -30 °C. The resulting homogeneous solution was cooled to -10 °C in 21 minutes. The stirring was set to 324 RPM and after 1 minute at -10 °C seed (249.4 mg, Lot # 3292-1 1 1-Pl ) was added to the solution. A thick slurry formed in <2 minutes (exotherms to -8.6 °C) but the stir speed allowed for good mixing. After 29 minutes added 332 mL DI H2O (5 volumes vs. CEP-41 159) over 12 minutes at -10 to -8 °C. Held the slurry for 28 minutes at -10 °C and then filtered a sample to check the mother liquor losses. Losses looked good at 7.7 mg/g (desired <9 mg g). After 50 minutes at -10 °C with all water added the slurry was filtered. Filtration was quick, taking <1 minute. The flask and cake were washed with 265.3 mL of ambient temperature 25 vol% ACOH H2O (4 volumes vs. CEP-41 159). The resulting mother liquors and wash were assayed and found to contain 6.7% losses (4.0 mg/g CEP-41 159). The solids were held on the filter with the vacuum pulling air across them and with aluminum foil keeping light from them.

[0075] After 67 hours and the solids were then left on the filter for another 48 hours. A total of 58.08 g of white cottony solids were recovered and were checked by HPLC and Ή NMR. HPLC indicates the solids were 100 A% and 102.7 wt% while the NMR showed only trace levels of AcOH. Based on this data the solids were deemed 100% pure and the yield was 76.2%.

Example 4

CEP -41159 CEP-41160

All volumes and equivalents are based on the wt% corrected charge of CEP-41 159 unless other wise stated. Potassium nitrate (22.99 g, 0.2274 mol, 1.02 equivalents) was dissolved in trifluoroacetic acid (TFA) (125 mL, 2.5 volumes). This dissolution took ~5 minutes with vigorous stirring. CEP-41 159 (50.0 g, 0.2229 mol, 1.00 equivalents) was taken up in TFA (125 mL, 2.5 volumes) at 22 °C. This solution was cooled to -13 °C over 21 minutes and then the addition of the potassium nitrate/TFA solution was started. This solution was added in four equal portions. After each portion was added an HPLC was run on a sample of the reaction to evaluate if the reaction had progressed. The sample was diluted in ACN before it could warm up as a temperature rise would likely cause further reaction to occur. The HPLC after the first addition was completed (addition took 13 min at -13 to -6.2 °C) showed 20.9 % conversion. The batch was cooled to -13 °C and the second addition was done over 5 minutes at -13 to -1.2 °C. HPLC after the second addition showed 43.6% conversion. After the reaction was cooled back to -13 °C the third addition was started. This third addition was done over 5 minutes at -13 to -2.7 °C, and the HPLC showed 70.1% conversion. After the reaction was cooled back to -13 °C the final addition was started. This final addition was done over 3 minutes at -13 to -7.5 °C, and the HPLC showed 98.9% conversion. The reaction was held at -13 °C while sodium acetate (22.85 g, 0.2787 mol, 1.25 equivalents) was taken up in DI water (600 mL, 12.0 volumes). After 19 minutes at -14 to -13 °C the reaction was diluted with half of the sodium acetate solution over 3 minutes while allowing the reaction to warm from -14 °C to 14.5 °C. The resulting solution was warmed to 22 °C over 14 minutes and seeded with CEP-41 160 (50 mg, 0.001 x CEP-41 159). The resulting slurry was allowed to stir overnight. After 15 hours 51 minutes the second half of the sodium acetate solution was added over 12 minutes at 21.6-22.6 °C. The resulting slurry was stirred for 34 minutes and then assayed for losses. The losses were at 2.88mg/g. The slurry was then filtered 1 hour 07 minutes after final sodium acetate solution addition was done. The reaction vessel and cake were washed with Dl water (200 mL, 4.0 volumes). The mother liquors and wash were combined and assayed by HPLC to determine they contain 4.3% of the product. The solids were dried in the filter open to air with the vacuum pulling on the bottom of the filter. After 4 hours 52 minutes of drying 52.985g of CEP-41 160 was recovered. These were bright

yellow sandy solids which were 100 A% and 100.8 wt% (@ 238 nm). This is 88.3% yield of CEP-41 160.

Example 5

CEP-37825 CEP-3B063-Tartrate Salt

(A-Ring)

[0076] A glass jar was charged with CEP-37825 (17.0 g physical, 16.7 g corrected, 52.3m mol, 1.00 equiv, Johnson Matthey 4239.A.13.2), MeOH (167 mL) and H20 (40.5 g). The mixture was stirred at ambient temperature until complete dissolution occurred. The resulting solution was filtered over a sintered glass funnel into a 500 mL jacketed reactor, rinsing with MeOH (85 mL). The reactor was evacuated and filled with N2. The solution was heated to 35 °C (internal temperature). A solution of L-tartaric acid (7.85 g, 52.3 mmol, 1.00 equiv) in MeOH (84 mL) was added via addition funnel over 1 1 minutes. Additional MeOH (30 mL) was used as a rinse. The solution was seeded with a slurry of CEP-38063 L-tartrate (50.0 mg) in MeOH (2.5 mL). The vial containing the slurry was rinsed with additional MeOH (1.2 mL). A slurry gradually formed, and the mixture was aged at 33-34 °C for 90 min. The internal temperature was decreased to 29 °C and agitated for 63 min after which the mixture was cooled to 20-25 °C and stirred overnight.

[0077] After stirring overnight at ambient temperature, the mixture was filtered, rinsing with a solution of H20 (2.6 mL) in MeOH (49 mL). The mixture was dried at room temperature overnight under vacuum. Crude CEP-38063 L-tartrate (10.07 g) was obtained in 87.6% de (93.8% dr). The CEP-38063 free base content was 64.2%. The yield was 36% from CEP-37825 racemate.

[0078] Recrystallization: A 1 L OptiMax vessel was charged with two lots of crude CEP-38063 L-tartrate (18.9 g, 89.3% dr, 9.47 g, 88.6% de, 57.1 mmol total). Methanol (346 mL) and H20 (38.8 g) were added and the reactor was placed under nitrogen. The slurry was heated to 66.5 °C during which time the solids dissolved. The solution was then cooled to 55 °C and seeded with a slurry of CEP-38063 L-tartrate (106.9 mg) in MeOH (5.4 mL). The vial containing the slurry was rinsed with additional MeOH (2.6 mL). The slurry was agitated at 53- 54 °C for 82 min. It was then cooled to 48.5 °C over 60 minutes. It was agitated for 1 h, then cooled to 20 °C over 60 minutes.

[0079] After stirring overnight at ambient temperature, the mixture was filtered, rinsing with a solution of H2O (5.7 mL) in MeOH (107 mL). The mixture was dried under vacuum at room temperature overnight. CEP-38063 L-tartrate (21.4 g) was obtained in >99 A%, 99.4% de (99.7% dr) . The CEP-38063 free base content was 65.3%.

Example 6: Procedure for CEP-19036 (amidation and coupling step)

[0084] Into a 20-L jacketed glass reactor were charged isatoic anhydride (500 g, 3.06 mol,) and ethanol (2500 mL). This was followed by the controlled addition of 30 wt% methylamine in ethanol (378.5 g, 3.98 mol) further diluted with ethanol (330 mL) over 70 minutes from an addition funnel at 20±5 °C. The resulting mixture was stirred at 20±5 °C for 60 min and checked by HPLC for reaction completion (<1 A% S ). Upon completion, 13% NaCl

(prepared by dissolving 390 g of NaCl in 2610 mL of DI water) was added over 20.0 min. The resulting mixture was agitated at 20±5 °C for 10 min then allowed to settle for 10 min. The bottom aqueous layer was removed. The organic layer was washed with 26% NaCl (prepared by dissolving 792 g of NaCl in 2210 mL of DI water). The combined aqueous washes were extracted with ethyl acetate (5100 mL). The ethyl acetate extract was combined with the batch and concentrated under reduced pressure (50-80 mmHg) at 30-40 °C in a 12-L round-bottomed flask until the batch volume was approximately 1.5 L (3x the weight of isatoic anhydride). To the residue was added ethyl acetate (5100 mL), which was then concentrated under reduced pressure (50-80 mmHg), a second time, to approximately 1.5L (3 x the weight of isatoic anhydride). To the concentrated batch was added 5.0 L of acetonitrile. The resulting mixture was stirred at room temperature for 60 min, and filtered through a pad of Celite in a sintered glass funnel with fine porosity. The pad was rinsed with acetonitrile (500 mL) and the rinse was combined with the batch. The clear filtrate was transferred to a 20-L jacketed glass reactor. Hunig’s base (712.6 g) and 2,4,5-trichloropyrimidine (657.3 g) were added. The resulting solution was heated to 73±3 °C and agitated at 73±3 °C until the reaction was complete as indicated by an in-process test. The reaction mixture was then cooled to 0±5 °C over 30 min and stirred at this temperature for 1 -2 hrs. The product was collected by vacuum filtration on a sintered glass funnel. The cake was rinsed with acetonitrile (1240 mL) and pulled dry under vacuum with a nitrogen bleed until the residual water and acetonitrile content were less than 1 wt% by NMR analysis and KF titration. A total of 746.3 g (81.9% overall yield) of CEP- 19036 was obtained as a light tan solid with the following quality attributes: 99.8 A%, 98.99 wt%, 0.1 wt% NaCl, 0.1 wt% H20, 0.1 wt% acetonitrile.

Example 7

[0085] CEP-38063-tartrate salt (30.1 g of salt, Limiting Reagent) was charged to a vessel along with 10 volumes of water and 10 volumes of dichloromethane. At room temperature NaOH (10 N aqueous solution, 2 equiv) was added and stirred for 15 minutes. The bottom organic layer was removed and the aqueous layer was washed a second time with 10 volumes of dichloromethane. The combined organics were washed with brine (5 volumes) then concentrated under vacuum by distillation. To the concentrate, l-methoxy-2-propanol (12.7 volumes) was added along with CEP- 19036 (1.25 equiv) and methanesulfonic acid (2.75 eq). The resulting mixture was heated to 70 °C for approximately 48 hours then cooled to room temperature. Water (14 volumes) and dichloromethane (14 volumes) was added and stirred for 15 minutes. The bottom organic layer was cut to waste prior to adding an additional 14 volumes of dichloromethane and NaOH (ION, 3.6 equiv). The bottom organic layer was removed and the aqueous was washed with an additional 14 volumes of dichloromethane. The organic layers were combined, washed with brine and concentrated under vacuum by distillation. Isopropanol (30 volumes) and water (0.6 volumes) was added and heated to 70 °C. The resulting solution was cooled to 50 °C before adding additional water (5.8 volumes) which results in

crystallization. The slurry was then cooled to room temperature, filtered and dried at 60 °C to afford a 74% yield of product with >99% purity.

Example 8: Procedure for CEP-37440-3HCl-2H2O (salt formation)

[0086] Combined free base (145.83 g, 251.4 mmol) into a 5 L 3-neck round bottom flask equipped with overhead stirring and an addition funnel. To these solids was added nBuOH which resulted in a yellow cloudy solution (free of large solids) after stirring for 40 minutes. Precipitation occurred immediately and a slight exotherm to 23 °C was observed. The resulting slurry was heated to 85 °C over 45 minutes. Near 60 °C, the solids went into solution. Once the heating reached 80 °C, HC1 (2.5 M in 1 : 1 : 1 MeOH/EtOH/water, 307 mL, 767 mmol) was added via addition over 4 minutes and seed crystals (CEP-37440 H2A3, 1.7 g) were added. The seed held and more solids formed during a 1 h age at 85 °C. The solution was then cooled to room temperature over 1 h then further cooled to 2 °C over an additional 30 minutes. The slurry was stirred at 0-5 °C for lh then filtered, washing with 0 °C nBuOH (400 mL). Initial cake dimensions (cylinder) were 6.0 cm high with a diameter of 13.5 cm. After wash, compressed cake was 4.3 cm high. Losses to the mother liquor were approximately 0.5%. The resulting solids were dried in a vacuum oven at 60 °C for 24 h (with N2 purging after the first 16 h) to give 162 g of the desired product (98.8 HPLC purity, 88% isolated yield assuming 100 wt% starting material, 0.5% residual nBuOH by NMR, XRPD and m.p. confirmed H2A3 salt form).

Example 9: Enamine formation and hydrogenatlon

[0087] To CEP-41 160 (10 g) was added MgS04 (2.5 g, 25 wt%) and dichloromethane (8 volumes wrt CEP-41 160) at room temperature and stirred for 4 days. The resulting slurry was filtered and the filtrant was concentrated to an oil. The oil was then taken up into MTBE (70 mL, 7 volumes) which resulted in crystallization. The slurry was cooled to 0 °C and the product was filtered washing with cold MTBE. The product was dried with nitrogen under vacuum to afford 10.5 g of the product (68%). Additional MTBE crystallizations could be applied to increase purity as desired.

[0088] Prior to the reaction, the NaBArF was dried by co-evaporation with dry toluene (3 times) to remove traces of water. Trifluoroethanol was dried over molecular sieves (Union Carbide, Type 13X). In a pre-dried Schlenk, the appropriate amount of [Ir(COE)2Cl]2 precursor and RD81 was dissolved in dry DCM. After stirring the solution for 30 minutes, the NaBArF was added and stirred for an additional 30 minutes. In a separate Schlenk, the appropriate amount of substrate was dissolved in dry trifluoroethanol and stirred for 30 minutes. To a pre-dried high-pressure autoclave both the catalyst solution and substrate solution were transferred under a gentle stream of dry nitrogen. The autoclave was closed and pressurized to 50 bars of hydrogen and stirred for the desired reaction time. Then, the autoclave was vented and the reaction mixture collected. Work-up of the samples: all volatiles were removed in vacuo.

[

Example 10

I II

[0090] Preparation of hydrogenation substrate was accomplished by condensation of the ketone (1 eq.) and amide (1.1 eq. – 1.3 eq) catalyzed by TsOH (0.05 eq. to 0.1 eq.) in toluene.

[0091] To a solution of I (4.7 g, 20 mmol) in toluene (30 mL, 7 vol) was added acetamide (1.54 g, 26 mmol, 1.3 equiv) and TsOH.H20 (0.02 g, 1 mmol, 0.05 equiv.). The mixture was refluxed under N2 equipped with a Dean-Stark apparatus to remove H20. The progress of the reaction was monitored by TLC. When the reaction was completed, the mixture was cooled down. The solution was washed with H20, dried over Na2S04 and concentrated. The residue was purified by silica gel column chromatography with hexane/ethyl acetate (5/l→ 1/1, v/v) as eluent to give the desired product as a yellow solid (5.0 g, 90% yield).

Example 11

Π m

[0092] Asymetric hydrogenations were conducted using catalytic Ru(R-C3-TunePhos)(acac)2 in methanol with 0.25 eq. of H3P04 (20 mg/mL), at about 30, 50, and 70 °C using 10, 20, 35, 50, and 70 atm of H2. Reaction times were about 15 – 18 h.Conversions of >99% were achieved. Enantiomeric excesses (%) of 67% – 82% were observed.

Example 12

Π m

[0093] Asymetric hydrogenations were conducted using catalytic Ru(S-Cs-TunePhos)(acac)2 in methanol or ethanol with 0.063 eq., 0.125 eq. 0.25 eq., and 0.5 eq. of H3PO4 (20 mg/mL), at about 50, 70, and 90 °C using 20, 50, 70,and 75 atm of H2. Reaction times were about 15 – 18 h.Conversions of >99% were achieved. Enantiomeric excesses (%) of 79% – 86% were observed.

Example 13

π m

[0094] In a glove box, to a hydrogenator (with glass liner) were added the substrate (4.14 g, 15 mmol), Ru(S-C5-TunePhos)(acac)2 (13.8 mg, 0.015 mmol, TONI OOO), Η3ΡΟ» (9 mL, 20 mg/mL in CH3OH, 0.125 equiv), CH3OH (19 mL, 7 vol) and a magnetic stirring bar. The hydrogenator was sealed and taken out of the glove box. The hydrogenator was charged with hydrogen to 50 atm. and put in an oil bath. The reaction mixture was stirred under 50 atm. at 50 °C for 48 h. After hydrogen was released carefully, the reaction mixture was concentrated.

Recrystallization from CH3OH (55 mL) gave the desired product as an off-white solid (2.29 g, 55% yield).

References:

Allwein, S.P et al., Org. Process Res. Dev. 2012, 16, 148-155.

Purohit, V.C. Org. Lett. 2013, 15, 1650-1653.

WO2008/051547

PAPER

Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK)

Teva Branded Pharmaceutical Products R&D, 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States
Champions Oncology, Inc., One University Plaza, Suite 307, Hackensack, New Jersey 07601, United States
§ Thomas Jefferson University, 233 South 10th Street, 1002 BLSB, Philadelphia, Pennsylvania 19107, United States
J. Med. Chem., 2016, 59 (16), pp 7478–7496
DOI: 10.1021/acs.jmedchem.6b00487
*Telephone: 1-610-738-6861. E-mail: gregory.ott@tevapharm.com.
Abstract Image
Journal of Medicinal Chemistry (2016), 59(16), 7478-7496
Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein

(27b) 2-[[5-Chloro-2-[[(6S)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-1-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]amino]pyrimidin-4-yl]amino]-N-methylbenzamide

 27b (1.1 g, 28%) as an off-white foamy solid.
LC/MS (ESI+) m/z = 580.0 (M + H)+;
1H NMR (400 MHz, CDCl3) δ 11.02 (s, 1H), 8.69 (d, J = 8.9 Hz, 1H), 8.13 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.59–7.50 (m, 2H), 7.41 (s, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.21 (s, 1H), 3.74 (m, 3H), 3.66–3.63 (m, 2H), 3.29–3.23 (m, 1H), 3.06 (d, J = 4.3 Hz, 3H), 2.92–2.72 (m, 5H), 2.66–2.55 (m, 8H), 2.48–2.39 (m, 2H), 2.16–2.10 (m, 2H), 1.87–1.77 (m, 1H), 1.42–1.32 (m, 1H).
13C NMR (101 MHz, DMSO-d6) δ 168.9, 158.5, 155.0, 154.7, 149.0, 139.3, 137.3, 135.6, 131.4, 130.3, 127.9, 124.4, 121.8, 121.3, 120.5, 104.8, 63.1, 61.0, 60.4, 58.5, 53.8, 47.7, 38.1, 33.9, 26.4, 26.3, 25.7, 25.5.
High resolution mass spectrum m/z 580.2807 [(M + H)+ calcd for C30H39ClN7O3 580.2803]. HPLC purity: 99 A%.
PAPER

Development of a Process Route to the FAK/ALK Dual Inhibitor TEV-37440

Chemical Process Research & Development, Analytical Development, Teva Pharmaceuticals, 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00070
Abstract Image

The development of a scalable route to TEV-37440, a dual inhibitor of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK), is presented. The medicinal chemistry route used to support this target through nomination is reviewed, along with the early process chemistry route to support IND (inversigational new drug) enabling activities within CMC (Chemistry, Manufacturing, and Controls). The identification and development of an improved route that was performed in the pilot plant to supply early phase clinical supplies are discussed. Details surrounding the use of a novel ring expansion, a selective nitration through a para-blocking group strategy, a single-pot amination–hydrogenation, a diastereomeric salt resolution, a through-process step to avoid a hazardous intermediate, and a practical formation of a trihydrochloride dihydrate salt are disclosed.

str1 str2str3 str4

2-[(5-Chloropyrimidin-4-yl)amino]-N-methyl-benzamide; 2-[4-[(6S)-1-Methoxy-2-(methylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl]piperazin-1-yl]ethanol (2, Free Base)

 2 (75% yield) as the free base with >99.6 A% purity.
1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.74 (dd, J = 8.7, 4.1 Hz, 1H), 8.6 (d, J = 8.4 Hz, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 7.73 (dd, J = 7.9, 1.4 Hz, 1H), 7.54 (d, J = 8.1, 1H), 7.37 (ddd, J = 7.8, 7.8, 1.1, 1H), 7.10 (ddd, J = 7.6, 7.6, 1.0, 1H), 6.91 (d, J = 8.2 Hz, 1H), 4.35 (s, 1H), 3.59 (s, 3H), 3.49 (dd, J = 6.1, 6.1 Hz, 2H), 3.36 (br. s, 3H), 3.13–3.08 (m, 1H), 2.86–2.80 (part. ob. m, 1H), 2.80 (d, J = 4.5 Hz, 3H), 2.67–2.61 (m, 2H), 2.54–2.33 (m, 5H), 2.29–2.23 (m, 1H), 2.05–1.93 (m, 2H), 1.81–1.72 (m, 1H), 1.27–1.16 (m, 1H), 1.04 (d, J = 6.1 Hz, 2H);
13C NMR (100 MHz, DMSO-d6) δ 168.9, 158.4, 155.0, 154.6, 148.7, 139.3, 137.1, 135.5, 131.3, 130.2, 127.8, 124.4, 121.7, 121.2, 121.0, 120.5, 104.9, 63.0, 62.0, 60.9, 60.4, 58.5, 53.7, 47.6, 38.1, 33.8, 26.3, 25.4;
HRMS (ESI) calcd for C30H39ClN7O3 [M + H]+: 580.2797, found 580.2813.

2-[(5-Chloropyrimidin-4-yl)amino]-N-methyl-benzamide; 2-[4-[(6S)-1-Methoxy-2-(methylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl]piperazin-1-yl]ethanol Trihydrochloride Dihydrate Salt (2, Salt)

TEV-37440 trihydrochloride-dihydrate (2–3HCl·2H2O) with >99.6 A% purity and >99.5% ee. HPLC was used to determine ee with the following method: Chiralpak IC, 5 μm, 250 × 4.6 mm column, 25 °C, 1 mL/min, isocratic with 48% hexane/48% dichloromethane/2% ethanol/2% methanol/0.1% diethylamine, 20 min.
1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 12.20–11.60 (br. s, 1H), 9.96 (s, 1H), 9.04 (d, J = 4.5 Hz, 1H), 8.53 (s, 1H), 8.39 (d, J = 3.3 Hz, 1H), 7.88 (dd, J = 7.9, 1.1 Hz, 1H), 7.59 (d, J = 8.1, 1H), 7.47 (t, J = 8.1, 1H), 7.29 (ddd, J = 7.6, 7.6, 0.7 Hz, 1H) 7.05 (d, J = 7.6 Hz, 1H), 5.80–4.80 (br. s, 2H), 3.98–3.61 (m, 11H), 3.66 (part. ob. s, 3H), 3.42–3.14 (m, 7H), 2.81 (d, J = 4.5, 3H), 2.36–2.28 (m, 1H), 2.20–2.12 (m, 1H), 2.04–1.92 (m, 1H), 1.40–1.28 (m, 1H);
13C NMR (100 MHz, DMSO-d6) δ 168.4, 156.3, 152.8, 149.5, 144.2, 137.3, 136.2, 135.2, 131.4, 128.8, 128.2, 125.1, 124.3, 122.4, 122.2, 122.0, 105.5, 63.8, 61.8, 58.0, 55.3, 48.7, 43.1, 35.7, 29.4, 26.3, 24.7;
HRMS (ESI) calcd for C30H39ClN7O3 [M + H]+: 580.2797, found 580.2776. Heavy metals <20 ppm. Palladium <5 ppm.
References
  1. Allwein, S. P.; Roemmele, R. C.; Haley, J. J.; Mowrey, D. R.; Petrillo, D. E.; Reif, J. J.; Gingrich, D. E.;Bakale, R. P. Org. Process Res. Dev. 2012, 16, 148155, DOI: 10.1021/op200313v

  2. 2.Ott, G. R.; Cheng, M.; Learn, K. S.; Wagner, J.; Gingrich, D. E.; Lisko, J. G.; Curry, M.; Mesaros, E. F.;Ghose, A. K.; Quail, M. R.; Wan, W.; Lu, L.; Dobrzanski, P.; Albom, M. S.; Angeles, T. S.; Wells-Knecht, K.;Huang, Z.; Aimone, L. D.; Bruckheimer, E.; Anderson, N.; Friedman, J.; Fernandez, S. V.; Ator, M. A.;Ruggeri, B. A.; Dorsey, B. D. J. Med. Chem. 2016, 59, 74787496, DOI: 10.1021/acs.jmedchem.6b00487

///////////////////TEV-37440, TEV 37440, CEP-37440, CEP 37440

CNC(=O)c5ccccc5Nc1nc(ncc1Cl)Nc3ccc2C[C@H](CCCc2c3OC)N4CCN(CC4)CCO


Pridopidine.svg

Pridopidine

  • Molecular Formula C15H23NO2S
  • Average mass 281.414 Da
346688-38-8  CAS FREE FORM
882737-42-0 (hydrochloride)
1440284-30-9 HBr
4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidin
4- (3 -Methanesulfonyl-phenyl ) – 1-propyl -piperidine
ACR16
Huntexil
UNII-HD4TW8S2VK;
4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine
ACR 16
  • ASP 2314
FR 310826

Huntingtons chorea

Dopamine D2 receptor antagonist; Opioid receptor sigma agonist 1

Neurosearch INNOVATORS, In 2012, the product was acquired by Teva

In January 2017, pridopidine was reported to be in phase 3 clinical development,  pridopidine for treating or improving cognitive functions and Alzheimer’s disease.

Teva Pharmaceutical Industries, following an asset acquisition from NeuroSearch, is developing pridopidine, a fast-off dopamine D2 receptor antagonist that strengthens glutamate function, for treating HD.
The drug holds orphan drug designation in the U.S. and the E.U. for the treatment of Huntington’s disease

PRIDOPIDINE.png

About Huntington Disease

HD is a fatal neurodegenerative disease for which there is no known cure or prevention. People who suffer from HD will likely have a variety of steadily-worsening symptoms, including uncoordinated and uncontrolled movements, cognition and memory deterioration and a range of behavioral and psychological problems. HD symptoms typically start in middle age, but the disease may also manifest itself in childhood and in old age. Disease progression is characterized by a gradual decline in motor control, cognition and mental stability, and generally results in death within 15 to 25 years of clinical diagnosis. Current treatment is limited to managing the symptoms of HD, as there are no treatments that have been shown to alter the progression of HD. Studies estimate that HD affects about 13 to 15 people per 100,000 in Caucasians, and for every affected person there are approximately three to five people who may carry the mutation but are not yet ill.

Image result for Pridopidine

Pridopidine, also known as ACR16, is a dopamine stabilizer, which improves motor performance and shows neuroprotective effects in Huntington disease R6/2 mouse model. Huntington disease (HD) is a neurodegenerative disorder for which new treatments are urgently needed. Pridopidine is a new dopaminergic stabilizer, recently developed for the treatment of motor symptoms associated with HD.

Figure

Dopamine D2 ligands. Dopamine D2 receptor agonists dopamine (1) and apomorphine (2), classical antagonists haloperidol (3) and olanzapine (4), partial agonists (−)-3-(3-hydroxyphenyl)-Nn-propylpiperidine (5), bifeprunox (6), aripiprazole (7), and 3-(1-benzylpiperidin-4-yl)phenol (9a), and dopaminergic stabilizers S-(−)-OSU6162 (8) and pridopidine (12b).

Dopamine is a neurotransmitter in the brain. Since this discovery, made in the 1950s, the function of dopa-mine in the brain has been intensely explored. To date, it is well established that dopamine is essential in several aspects of brain function including motor, cognitive, sensory, emotional and autonomous (e.g. regulation of appetite, body temperature, sleep) functions. Thus, modulation of dopaminergic function may be beneficial in the treatment of a wide range of disorders affecting brain functions. In fact, both neurologic and psychiatric disorders are treated with medications based on interactions with dopamine systems and dopamine receptors in the brain.
Drugs that act, directly or indirectly, at central dopamine receptors are commonly used in the treatment of neurologic and psychiatric disorders, e.g. Parkinson’s disease and schizophrenia. Currently available dopaminer-gic pharmaceuticals have severe side effects, such as ex-trapyramidal side effects and tardive dyskinesia in dopaminergic antagonists used as antipsychotic agents, and dyskinesias and psychoses in dopaminergic agonists used as anti -Parkinson ‘ s agents. Therapeutic effects are un-satisfactory in many respects. To improve efficacy and reduce side effects of dopaminergic pharmaceuticals, novel dopamine receptor ligands with selectivity at specific dopamine receptor subtypes or regional selectivity are sought for. In this context, also partial dopamine receptor agonists, i.e. dopamine receptor ligands with some but not full intrinsic activity at dopamine receptors, are being developed to achieve an optimal degree of stimulation at dopamine receptors, avoiding excessive do-pamine receptor blockade or excessive stimulation.
Compounds belonging to the class of substituted 4- (phenyl-N-alkyl) -piperazine and substituted 4-(phenyl-N-alkyl) -piperidines have been previously reported. Among these compounds, some are inactive in the CNS, some dis-play serotonergic or mixed serotonergic/dopaminergic pharmacological profiles while some are full or partial dopamine receptor agonists or antagonists with high affinity for dopamine receptors.
A number of 4-phenylpiperazines and 4 -phenyl -piperidine derivatives are known and described, for example Costall et al . European J. Pharm. 31, 94, (1975), Mewshaw et al . Bioorg. Med. Chem. Lett., 8, 295, (1998). The reported compounds are substituted 4 -phenyl -piperazine ‘ s, most of them being 2-, 3- or 4 -OH phenyl substituted and displaying DA autoreceptor agonist properties .
Fuller R. W. et al , J. Pharmacol. Exp . Therapeut . 218, 636, (1981) disclose substituted piperazines (e.g. 1- (m-trifluoro-methylphenyl) piperazine) which reportedly act as serotonin agonists and inhibit serotonin uptake.

Fuller R. W. et al , Res. Commun. Chem. Pathol . Pharmacol. 17, 551, (1977) disclose the comparative effects on the 3 , 4-dihydroxy-phenylacetic acid and Res. Commun. Chem. Pathol. Pharmacol. 29, 201, (1980) disclose the compara-tive effects on the 5-hydroxyindole acetic acid concentration in rat brain by 1- (p-chlorophenol) -piperazine .
Boissier J. et al Chem Abstr. 61:10691c, disclose disubstituted piperazines. The compounds are reportedly adrenolytics, antihypertensives , potentiators of barbitu-rates, and depressants of the central nervous system.
A number of different substituted piperazines have been published as ligands at 5-HT1A receptors, for example Glennon R.A. et al J. Med. Chem., 31, 1968, (1988), van Steen B.J., J. Med. Chem., 36, 2751, (1993), Mokrosz, J. et al, Arch. Pharm. (Weinheim) 328, 143-148 (1995), and Dukat M.-L., J. Med. Chem., 39, 4017, (1996). Glennon R. A. discloses, in international patent applications WO93/00313 and WO 91/09594 various amines, among them substituted piperazines, as sigma receptor ligands. Clinical studies investigating the properties of sigma receptor ligands in schizophrenic patients have not generated evi-dence of antipsychotic activity, or activity in any other CNS disorder. Two of the most extensively studied selective sigma receptor antagonists, BW234U (rimcazole) and BMY14802, have both failed in clinical studies in schizophrenic patients (Borison et al , 1991, Psychopharmacol Bull 27(2): 103-106; Gewirtz et al , 1994, Neuropsycho-pharmacology 10:37-40) .
Further, WO 93/04684 and GB 2027703 also describe specific substituted piperazines useful in the treatment of CNS disorders

Pridopidine (Huntexil, formerly ACR16) is an experimental drug candidate belonging to a class of agents known as dopidines, which act as dopaminergic stabilizers in the central nervous system. These compounds may counteract the effects of excessive or insufficient dopaminergic transmission,[1][2] and are therefore under investigation for application in neurological and psychiatric disorders characterized by altered dopaminergic transmission, such as Huntington’s disease (HD).

Pridopidine is in late-stage development by Teva Pharmaceutical Industries who acquired the rights to the product from its original developer NeuroSearch in 2012. In April 2010, NeuroSearch announced results from the largest European phase 3 study in HD carried out to date (MermaiHD). The MermaiHD study examined the effects of pridopidine in patients with HD and the results showed after six months of treatment, pridopidine improved total motor symptoms, although the primary endpoint of the study was not met. Pridopidine was well tolerated and had an adverse event profile similar to placebo.[3]

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have both indicated they will not issue approval for pridopidine to be used in human patients on the basis of the MermaiHD and HART trials, and a further, positive phase 3 trial is required for approval.[4][5]

Image result for Pridopidine

Dopidines

Dopidines, a new class of pharmaceutical compounds, act as dopaminergic stabilizers, enhancing or counteracting dopaminergic effects in the central nervous system.[1][2] They have a dual mechanism of action, displaying functional antagonism of subcortical dopamine type 2 (D2) receptors, as well as strengthening of cortical glutamate and dopamine transmission.[6] Dopidines are, therefore, able to regulate both hypoactive and hyperactive functioning in areas of the brain that receive dopaminergic input (i.e. cortical and subcortical regions). This potential ability to restore the cortical–subcortical circuitry to normal suggests dopidines may have the potential to improve symptoms associated with several neurological and psychiatric disorders, including HD.

SYNTHESIS

Figure

aReagents and conditions: (a) n-butyllithium, 1-Boc-4-piperidone, THF; (b) trifluoroacetic acid, CH2Cl2, Δ; (c) triethylamine, methyl chloroformate, CH2Cl2; (d) m-CPBA, CH2Cl2; (e) Pd/C, H2, MeOH, HCl; (f) HCl, EtOH, Δ; (g) RX, K2CO3, acetonitrile, Δ.

Pharmacology

In vitro studies demonstrate pridopidine exerts its effects by functional antagonism of D2 receptors. However, pridopidine possesses a number of characteristics[1][2][6][7] that differentiate it from traditional D2 receptor antagonists (agents that block receptor responses).

  • Lower affinity for D2 receptors than traditional D2 ligands[8]
  • Preferential binding to activated D2 (D2high) receptors (i.e. dopamine-bound D2 receptors)[8]
  • Rapid dissociation (fast ‘off-rate’) from D2 receptors
  • D2 receptor antagonism that is surmountable by dopamine
  • Rapid recovery of D2-receptor-mediated responses after washout[1][2][6][7]

Pridopidine is less likely to produce extrapyramidal symptoms, such as akinesia (inability to initiate movement) and akathisia (inability to remain motionless), than dopamine antagonists (such as antipsychotics).[9] Furthermore, pridopidine displays no detectable intrinsic activity,[9][10] differentiating it from D2 receptor agonists and partial agonists (agents that stimulate receptor responses). Pridopidine, therefore, differs from D2 receptor antagonists, agonists and partial agonists.[6]

As a dopaminergic stabilizer, pridopidine can be considered to be a dual-acting agent, displaying functional antagonism of subcortical dopaminergic transmission and strengthening of cortical glutamate transmission.

Clinical development

The MermaiHD study

In 2009, NeuroSearch completed the largest European HD trial to date, the Multinational EuRopean Multicentre ACR16 study In Huntington’s Disease (MermaiHD) study.

This six-month, phase 3, randomized, double-blind, placebo-controlled trial recruited patients from Austria, Belgium, France, Germany, Italy, Portugal, Spain and the UK, and compared two different pridopidine dose regimens with placebo. Patients were randomly allocated to receive pridopidine (45 mg once daily or 45 mg twice daily) or placebo. During weeks 1–4, patients received once-daily treatment (as a morning dose). Thereafter, patients took two doses (one morning and one afternoon dose) until the end of the treatment period. The study had a target recruitment of 420 patients; recruitment was finalized in April 2009 with 437 patients enrolled.[14]

The purpose of the study was to assess the effects of pridopidine on a specific subset of HD motor symptoms defined in the modified motor score (mMS).[14] The mMS comprises 10 items relating to voluntary motor function from the Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS—TMS).[14] Other study endpoints included the UHDRS—TMS, submotor items, cognitive function, behaviour and symptoms of depression and anxiety.

After six months of treatment, patients who received pridopidine 45 mg twice daily showed significant improvements in motor function, as measured by the UHDRS-TMS, compared with placebo. For the mMS, which was the primary endpoint of the study, a strong trend in treatment effect was seen, although statistical significance was not reached. Pridopidine was also very well tolerated, had an adverse event profile similar to placebo and gave no indication of treatment-associated worsening of symptoms.[3]

The MermaiHD study – open-label extension

Patients who completed the six-month, randomized phase of the MermaiHD study could choose to enter the MermaiHD open-label extension study and receive pridopidine 45 mg twice daily for six months. In total, 357 patients were enrolled into the MermaiHD open-label extension study and of these, 305 patients completed the entire 12-month treatment period.[15]

The objective of this study was to evaluate the long-term safety and tolerability profile of pridopidine and to collect efficacy data after a 12-month treatment period to support the safety evaluation. Safety and tolerability assessments included the incidence and severity of adverse events, routine laboratory parameters, vital signs and electrocardiogram measurements.[15]

Results from the MermaiHD open-label extension study showed treatment with pridopidine for up to 12 months (up to 45 mg twice daily for the first six months; 45 mg twice daily for the last six months) was well tolerated and demonstrated a good safety profile.[3][15]

The HART study

In October 2010, NeuroSearch reported results from their three-month, phase 2b, randomized, double-blind, placebo-controlled study carried out in Canada and the USA – Huntington’s disease ACR16 Randomized Trial (HART). This study was conducted in 28 centres and enrolled a total of 227 patients, who were randomly allocated to receive pridopidine 10 mg, 22.5 mg or 45 mg twice daily) or placebo.[14][16] During weeks 1–4, patients received once-daily treatment (as a morning dose). Thereafter, patients took two treatment doses (one morning and one afternoon dose) until the end of the treatment period. Study endpoints were the same as those for the MermaiHD study.

Results from the HART study were consistent with findings from the larger MermaiHD study. After 12 weeks of treatment with pridopidine 45 mg twice daily, total motor function significantly improved, as measured by the UHDRS–TMS. The primary endpoint, improvement in the mMS, was not met.[16]

In both studies, the effects on the UHDRS–TMS and the mMS were driven by significant improvements in motor symptoms such as gait and balance, and hand movements, deemed by the authors to be “clinically relevant”. However, the magnitude of the improvements was small. Pridopdiine demonstrated a favourable tolerability and safety profile, including no observations of treatment-related disadvantages in terms of worsening of other disease signs or symptoms.[15][16]

Compassionate use programme and open-ended, open-label study

To meet requests from patients and healthcare professionals for continued treatment with pridopidine, NeuroSearch has established a compassionate use programme in Europe to ensure continued access to pridopidine for patients who have completed treatment in the MermaiHD open-label extension study. The programme is active in all of the eight European countries where the MermaiHD study was conducted.

NeuroSearch has initiated an open-ended, open-label clinical study in the USA and Canada, called the Open HART study. In this study, all patients who have completed treatment in the HART study are offered the chance to restart treatment with pridopidine until either marketing approval has been obtained in the countries in question, or the drug’s development is discontinued. The first patients were enrolled in March 2011.[3]

Regulatory agency advice

The results of the MermaiHD and HART trials were presented to the American and European regulatory agencies: the FDA in March 2011 and EMA in May, 2011. Both agencies indicated insufficient evidence had been produced to allow approval in human patients, and a further phase 3 trial would be required for approval.[4][5]

PATENT

WO 2001046145

Example 6: 4- (3 -Methanesulfonyl-phenyl ) – 1-propyl -piperidine
m.p. 200°C (HCl) MS m/z (relative intensity, 70 eV) 281 (M+, 5), 252 (bp) , 129 (20), 115 (20), 70 (25.

PAPER

Journal of Medicinal Chemistry (2010), 53(6), 2510-2520.

Synthesis and Evaluation of a Set of 4-Phenylpiperidines and 4-Phenylpiperazines as D2 Receptor Ligands and the Discovery of the Dopaminergic Stabilizer 4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine (Huntexil, Pridopidine, ACR16)

NeuroSearch Sweden AB, Arvid Wallgrens Backe 20, S-413 46 Göteborg, Sweden
J. Med. Chem., 2010, 53 (6), pp 2510–2520
DOI: 10.1021/jm901689v
*To whom correspondence should be addressed. Phone: +(46) 31 7727710. Fax: +(46) 31 7727701. E-mail: fredrik.pettersson@neurosearch.se.

Abstract

Abstract Image

Modification of the partial dopamine type 2 receptor (D2) agonist 3-(1-benzylpiperidin-4-yl)phenol (9a) generated a series of novel functional D2 antagonists with fast-off kinetic properties. A representative of this series, pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine; ACR16, 12b), bound competitively with low affinity to D2 in vitro, without displaying properties essential for interaction with D2 in the inactive state, thereby allowing receptors to rapidly regain responsiveness. In vivo, neurochemical effects of 12b were similar to those of D2 antagonists, and in a model of locomotor hyperactivity, 12b dose-dependently reduced activity. In contrast to classic D2 antagonists, 12b increased spontaneous locomotor activity in partly habituated animals. The “agonist-like” kinetic profile of 12b, combined with its lack of intrinsic activity, induces a functional state-dependent D2 antagonism that can vary with local, real-time dopamine concentration fluctuations around distinct receptor populations. These properties may contribute to its unique “dopaminergic stabilizer” characteristics, differentiating 12b from D2 antagonists and partial D2agonists.

4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine (12b)

Purification with flash chromatography using CH2Cl2/MeOH [1:1 (v/v)] as eluent afforded pure 12b (3.28 g, 79%).
MS m/z (relative intensity, 70 eV) 281 (M+, 5), 252 (bp), 129 (20), 115 (20), 70 (25).
1H NMR (300 MHz, CDCl3) δ ppm 0.96 (t, J = 7.3 Hz, 3 H), 1.53−1.64 (m, 2 H), 1.89 (dd, J = 9.6, 3.54 Hz, 4 H), 2.03−2.14 (m, 2 H), 2.31−2.41 (m, 2 H), 2.64 (ddd, J = 15.4, 5.7, 5.5 Hz, 1 H), 3.06−3.15 (m, 5 H), 7.51−7.58 (m, 2 H), 7.78−7.86 (m, 2 H).
13C NMR (75 MHz, CDCl3) δ ppm 11.98, 20.18, 33.29, 42.59, 44.43, 54.06, 60.93, 124.99, 125.74, 129.39, 132.04, 148.28.
The amine was converted to the HCl salt and recrystallized in EtOH/diethyl ether: mp 212−214 °C. Anal. (C15H24ClNO2S) C, H, N.

PATENT

WO-2017015609

Pridopidine (Huntexil®) is a unique compound developed for the treatment of patients with motor symptoms associated with Huntington’s disease. The chemical name of pridopidine is 4-(3-(Methylsulfonyl)phenyl)-l-propylpiperidine, and its Chemical Registry Number is CAS 346688-38-8 (CSED:7971505, 2016). The Chemical Registry number of pridopidine hydrochloride is 882737-42-0 (CSID:25948790 2016). Processes of synthesis of pridopidine and a pharmaceutically acceptable salt thereof are disclosed in U.S. Patent No. 7,923,459. U.S. Patent No. 6,903,120 claims pridopidine for the treatment of Parkinson’s disease, dyskinesias, dystonias, Tourette’s disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, mood and anxiety disorders, sleep disorder, autism spectrum disorder, ADHD, Huntington’s disease, age-related cognitive impairment, and disorders related to alcohol abuse and narcotic substance abuse.

US Patent Application Publication Nos. 20140378508 and 20150202302, describe methods of treatment with high doses of pridopidine and modified release formulations of pridopidine, respectively.

EXAMPLES

Example 1: Pridopidine-HCl synthesis

An initial process for synthesizing pridopidine HC1 shown in Scheme 1 and is a modification of the process disclosed in US Patent No. 7,923,459.

The synthesis of Compound 9 started with the halogen-lithium exchange of 3-bromothioanisole (3BTA) in THF employing n-hexyllithium (HexLi) in hexane as the lithium source. Li-thioanisole (3LTA) intermediate thus formed was coupled with 1 -propyl-4-piperidone (1P4P) forming a Li-Compound 9. These two reactions require low (cryogenic) temperature. The quenching of Li-Compound 9 was done in water HCl/MTBE resulting in precipitation of Compound 9-HCl salt. A cryogenic batch mode process for this step was developed and optimized. The 3BTA and THF were cooled to less than -70°C. A solution of HexLi in n-hexane (33%) was added at a temperature below -70°C and the reaction is stirred for more than 1 hour. An in-process control sample was taken and analyzed for completion of halogen exchange, l-propyl-4-piperidone (1P4P) was then added to the reaction at about -70°C letting the reaction mixture to reach -40°C and further stirred at this temperature for about 1 hour. An in-process sample was analyzed to monitor the conversion according to the acceptance criteria (Compound 9 not less than 83% purity). The reaction mixture was added to a mixture of 5N hydrochloric acid (HC1) and methyl teri-butyl ether (MTBE). The resulting precipitate was filtered and washed with MTBE to give the hydrochloric salt of Compound 9 (Compound 9-HCl) wet.

Batch mode technique for step 1 requires an expensive and high energy-consuming cryogenic system that cools the reactor with a methanol heat exchange, in which the methanol is circulated in counter current liquid nitrogen. This process also brings about additional problems originated from the workup procedure. The work-up starts when the reaction mixture is added into a mixture of MTBE and aqueous HC1. This gives three phases: (1) an organic phase that contains the organic solvents MTBE, THF and hexane along with other organic related materials such as thioanisole (TA), hexyl-bromide,

3-hexylthioanisole and other organic side reaction impurities (2) an aqueous phase containing inorganic salts (LiOH and LiBr), and (3) a solid phase which is mostly Compound 9-HCl but also remainders of 1P4P as an HC1 salt.

The isolation of Compound 9-HCl from the three phase work-up mixture is by filtration followed by MTBE washings. A major problem with this work-up is the difficulty of the filtration which resulted in a long filtration and washing operations. The time it takes to complete a centrifugation and washing cycle is by far beyond the normal duration of such a manufacturing operation. The second problem is the inevitable low and non-reproducible assay (purity of -90% on dry basis) of Compound 9-HCl due to the residues of the other two phases. It should be noted that a high assay is important in the next step in order to control the amount of reagents. The third problem is the existence of THF in the wet Compound 9-HCl salt which is responsible for the Compound 3 impurity that is discussed below.

Example 6.2: Pridopidine crude – work-up development

After the reduction, pridopidine HC1 is precipitated by adding HC1/IPA to the solution of pridopidine free base in ΓΡΑ in the process of Example 1. Prior to that, a solvent swap from toluene to ΓΡΑ is completed by 3 consecutive vacuum distillations. The amount of toluene in the ΓΡΑ solution affects the yield and it was set to be not more than 3% (IPC by GC method). The spontaneous precipitation produces fine crystals with wide PSD. In order to narrow the PSD, Example 1 accomplishes HC1/IPA addition in two cycles with cooling/warming profile.

The updated process is advantageous for crystallizing pridopidine free base over the procedure in Example 1 for two reasons.

First, it simplifies the work-up of the crude because the swap from toluene to PA is not required. The pridopidine free base is crystallized from toluene/n-heptanes system. Only one vacuum distillation of toluene is needed (compared to three in the work-up of Example 1) to remove water and to increase yield.

Second, in order to control pridopidine-HCl physical properties. Pridopidine free base is a much better starting material for the final crystallization step compared to the pridopidine HC1 salt because it is easily dissolved in ΓΡΑ which enables a mild absolute (0.2μ) filtration required in the final step of API manufacturing.

Crystallization of pridopidine free base in toluene/n-heptane system

First, crystallization of pridopidine free base in toluene/n-heptane mixture was tested in order to find the right ratio to maximize the yield. In order to obtain pridopidine free base, pridopidine-HCl in water/toluene system was basified with NaOH(aq) to pH>12. Two more water washes of the toluene phase brought the pH of the aqueous phase to <10. Addition of n-heptane into the toluene solution

resulted in pridopidine free base precipitation. Table 21 shows data from the toluene/n-heptane crystallization experiments.

Example 7: Development of the procedure for the purification of Compound 1 in pridopidine free base.

The present example describes lowering Compound 1 levels in pridopidine free base. This procedure involves dissolving pridopidine FB in 5 Vol of toluene at 20-30°C, 5 Vol of water are added and after the mixing phases are separated and the organic phase is washed three times with 5 Vol water. The toluene mixture is then distilled up to 2.5 Vol in the reactor and 4 Vol of heptane are added for crystallization. Experiment No. 2501 was completed using this procedure. Table 24 summarizes the results.

Example 8: Step 4 in Scheme 2: Pridopidine Hydrochloride process

This example discusses the step used to formulate pridopidine-HCl from pridopidine crude. The corresponding stage in Example 1 was part of the last (third) stage in which pridopidine-HCl was obtained directly from Compound 8 without isolation of pridopidine crude. In order to better control pridopidine-HCl physical properties, it is preferable to start with well-defined pridopidine free base which enables control on the exact amount of HC1 and IPA.

Pridopidine-HCl preparation – present procedure

Pridopidine-HCl was prepared according to the following procedure: Solid pridopidine crude was charged into the first reactor followed by 8 Vol of IPA (not more than (NMT) 0.8% water by KF) and the mixture is heated to Tr =40-45°C (dissolution at Tr = 25-28°C). The mixture was then filtered through a 0.2 μιη filter and transferred into the second (crystallizing) reactor. The first hot reactor was washed with 3.8 Vol of IPA. The wash was transferred through the filter to the second reactor. The temperature was raised to 65-67°C and 1.1 eq of IPA/HCl are added to the mixture (1.1 eq of HC1, from IPA/HCl 5N solution, 0.78 v/w). The addition of EPA HCl into the free base is exothermic; therefore, it was performed slowly, and the temperature maintained at Tr = 60-67°C. After the addition, the mixture was stirred for 15 min and pH is measured (pH<4). If pH adjustment is needed,

0.2 eq of HCl (from IPA/HC1 5 N solution) is optional. At the end of the addition, the mixture was stirred for 1 hour at Tr = 66°C to start sedimentation. If sedimentation does not start, seeding with 0.07% pridopidine hydrochloride crystals is optional at this temperature. Breeding of the crystals was performed by stirring for 2.5 h at Tr =64-67°C. The addition HCl line was washed with 0.4 Vol of ΓΡΑ to give~13 Vol solution. The mixture was cooled to Tr =0°C The solid is filtered and washed with cooled 4.6 Vol ΓΡΑ at LT 5°C. Drying as performed under vacuum (P< ) at 30-60°C to constant weight: Dried pridopidine-HCl was obtained as a white solid.

Purification of Compound 4 during pridopidine-HCl process

A relationship between high temperature in the reduction reaction and high levels of Compound 4 impurity have been observed. A reduction in 50°C leads to 0.25% of Compound 4. For that reason the process of Example 1 limits the reduction reaction temperature to 30±5°C since this is the final step and Compound 4 level should be not more than 0.15%. The present process has another crystallization stage by which Compound 4 can be purified.

PATENT

https://www.google.ch/patents/US20130150406

Pridopidine, i.e. 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine, is a drug substance currently in clinical development for the treatment of Huntington’s disease. The hydrochloride salt of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine and a method for its synthesis is described in WO 01/46145. In WO 2006/040155 an alternative method for the synthesis of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine is described. In WO 2008/127188 N-oxide and/or di-N-oxide derivatives of certain dopamine receptor stabilizers/modulators are reported, including the 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine-1-oxide.

1H NMR PREDICTIONS

ACTUAL VALUES

1H NMR (300 MHz, CDCl3) δ ppm 0.96 (t, J = 7.3 Hz, 3 H), 1.53−1.64 (m, 2 H), 1.89 (dd, J = 9.6, 3.54 Hz, 4 H), 2.03−2.14 (m, 2 H), 2.31−2.41 (m, 2 H), 2.64 (ddd, J = 15.4, 5.7, 5.5 Hz, 1 H), 3.06−3.15 (m, 5 H), 7.51−7.58 (m, 2 H), 7.78−7.86 (m, 2 H).
 
13C NMR (75 MHz, CDCl3) δ ppm 11.98, 20.18, 33.29, 42.59, 44.43, 54.06, 60.93, 124.99, 125.74, 129.39, 132.04, 148.28.

13C NMR PREDICTIONS

References

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REFERENCES CITED:

U.S. Patent No. 6,903,120

U.S. Patent No. 7,923,459

U.S. Publication No. US-2013-0267552-A1

CSED:25948790, http://w .chemspider.com/Chernical-Stmcture.25948790.

CSID:7971505, http://ww.chemspider.com/Chermcal-Stmcture.7971505.html

Ebenezer et al, Tetrahedron Letters 55 (2014) 5323-5326.

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US20160176821 * 18. Dez. 2015 23. Juni 2016 Teva Pharmaceuticals International Gmbh L-tartrate salt of pridopidine
USRE46117 22. Dez. 2000 23. Aug. 2016 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
WO2014205229A1 * 19. Juni 2014 24. Dez. 2014 IVAX International GmbH Use of high dose pridopidine for treating huntington’s disease
WO2015112601A1 * 21. Jan. 2015 30. Juli 2015 IVAX International GmbH Modified release formulations of pridopidine
WO2016106142A1 * 18. Dez. 2015 30. Juni 2016 Teva Pharmaceuticals International Gmbh L-tartrate salt of pridopidine
Pridopidine
Pridopidine.svg
Names
IUPAC name

4-(3-(Methylsulfonyl)phenyl)-1-propylpiperidine
Identifiers
346688-38-8 Yes
3D model (Jmol) Interactive image
ChemSpider 7971505 
KEGG D09953 
PubChem 9795739
UNII HD4TW8S2VK Yes
Properties
C15H23NO2S
Molar mass 281.41 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

/////////pridopidine, PHASE 3, TEVA, 346688-38-8, orphan drug designation, Neurosearch, ACR16, Huntexil, ASP 2314, FR 310826, UNII-HD4TW8S2VK

CCCN1CCC(CC1)c2cccc(c2)S(C)(=O)=O

OXIDE

Example 5 – Preparation Of Compound 5 (4-(3-(methylsulfonyl)phenyl)-l-propylpiperidine 1-oxide)

Pridopidine (50.0g, 178mmol, leq) was dissolved in methanol (250mL) and 33% hydrogen peroxide (20mL, 213mmol, 1.2eq). The reaction mixture was heated and kept at 40°C for 20h. The reaction mixture was then concentrated in a rotavapor to give 71g light-yellow oil. Water (400mL) was added and the suspension was extracted with isopropyl acetate (150mL) which after separation contains unreacted pridopidine while water phase contains 91% area of Compound 5 (HPLC). The product was then washed with dichloromethane (400mL) after adjusting the water phase pH to 9 by sodium hydroxide. After phase separation the water phase was washed again with dichloromethane (200mL) to give 100% area of Compound 5 in the water phase (HPLC). The product was then extracted from the water phase into butanol (lx400mL, 3x200ml) and the butanol phases were combined and concentrated in a rotavapor to give 80g yellow oil (HPLC: 100% area of Compound 5). The oil was washed with water (150mL) to remove salts and the water was extracted with butanol. The organic phases were combined and concentrated in a rotavapor to give 43g of white solid which was suspended in MTBE for lhr, filtered and dried to give 33g solid that was melted when standing on air. After high vacuum drying (2mbar, 60°C, 2.5h) 32.23g pure Compound 5 were obtained (HPLC: 99.5% area, 1H-NMR assay: 97.4%).

NMR Identity Analysis of Compound 5

Compound 5:

The following data in Tables 10 and 11 was determined using a sample of 63.06 mg Compound 5, a solvent of 1.2 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance ΙΠ 400 MHz.

Table 10: Assignment of ¾ NMRa,c

a The assignment is based on the coupling pattern of the signals, coupling constants and chemical shifts.

b Weak signal.

c Spectra is calibrated by the solvent residual peak (2.5 ppm).

Table 11: Assignment of 13C NMRa,b

a The assignment is based on the chemical shifts and 1H-13C couplings extracted from HSQC and HMBC experiments.

b Spectra is calibrated by a solvent peak (39.54 ppm)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016003919&recNum=5&docAn=US2015038349&queryString=EN_ALL:nmr%20AND%20PA:(teva%20pharmaceutical)&maxRec=677#H3

PATENT

http://www.google.bg/patents/WO2013086425A1?cl=en&hl=bg

Preparation of pridopidine HBr

In order to prepare 33 g of pridopidine HBr, 28.5 g of free base was dissolved in 150 ml 99% ethanol at room temperature. 1 .5 equivalents of hydrobromic acid 48% were added. Precipitation occurred spontaneously, and the suspension was left in refrigerator for 2.5 hours. Then the crystals were filtered, followed by washing with 99% ethanol and ether. The crystals were dried over night under vacuum at 40°C: m.p. 196°C. The results of a CHN analysis are presented in Table 2, below.

NMR 1 H NMR (DMSO-d6): 0.93 ( 3H, t), 1 .68-1 .80 ( 2H, m), 1 .99-2.10 ( 4H, m) 2.97-3.14 (5H, m), 3.24 ( 3H, s), 3.57-3.65 ( 2H, d), 7.60-7.68 (2H, m), 7.78-7.86 ( 2H, m) and 9.41 ppm (1 H, bs).

CEP 33779


img

CEP-33779, CEP33779
CAS 1257704-57-6
Chemical Formula: C24H26N6O2S
Molecular Weight: 462.57
Elemental Analysis: C, 62.32; H, 5.67; N, 18.17; O, 6.92; S, 6.93

N-(3-(4-methylpiperazin-1-yl)phenyl)-8-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

PRECLINICAL Treatment of Rheumatoid Arthritis, Agents for Colorectal Cancer Therapy Systemic Lupus Erythematosus,

Jak2 Inhibitors

Image result for teva logo

Matthew A. Curry, Bruce D. Dorsey, Benjamin J. Dugan, Diane E. Gingrich, Eugen F. Mesaros, Karen L. Milkiewicz,
Applicant Cephalon, Inc.

Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States

Image result for Cephalon, Inc.

Matt Curry

 Matthew A. Curry

Bruce Dorsey

Bruce Dorsey

Image result for Cephalon, Inc. Benjamin J. Dugan

Benjamin Dugan

Benjamin J. Dugan received a B.S. degree in Chemistry from the University of Delaware in 1993 under the tutelage of the late Dr. Cynthia McClure. He began his career at FMC Corporation in the agricultural products division. In 2006, he moved to Cephalon, Inc., acquired by Teva Pharmaceutical Industries Ltd. in 2011, and engaged in oncology research focused on small molecule, ATP competitive, kinase inhibitors culminating with the discovery of CEP-33779. He is currently a Research Scientist focused on the development of novel, bioactive small molecules for treatment of central nervous system disorders.

Cephalon Inc.
Malvern, United States

Image result for Cephalon, Inc. Diane E. Gingrich

Members of the Cephalon research team that discovered CEP-5214 and CEP-7055 include (from left) Hudkins, Thelma S. Angeles, Bruce A. Ruggeri, and Diane E. Gingrich. CEPHALON PHOTO

Eugen F. Mesaros

Cephalon Inc.
Malvern, United States
Image result for cephalon Karen L. Milkiewicz

Lupus (systemic lupus erythematosus, SLE) is a chronic autoimmune disease characterized by the presence of activated T and B cells, autoantibodies and chronic inflammation that attacks various parts of the body including the joints, skin, kidneys, CNS, cardiac tissue and blood vessels. In severe cases, antibodies are deposited in the cells (glomeruli) of the kidneys, leading to inflammation and possibly kidney failure, a condition known as lupus nephritis.

Although the cause of lupus remains unknown, manifestations of the disease have been linked to genetic polymorphisms, environmental toxins and pathogens (Morel;

Fairhurst, Wandstrat et al. 2006). In addition, gender, hormonal influences and cytokine dysregulation have been tightly linked to the development of lupus (Aringer and Smolen 2004; Smith-Bouvier, Divekar et al. 2008). Lupus affects nine times as many women as men. It may occur at any age, but appears most often in people between the ages of 10 and 50 years. African Americans and Asians are affected more often than people from other races.

There is no cure for lupus. Current treatments for lupus are aimed at controlling symptoms and are limited to toxic and immunosuppressive agents with severe side-effects such as high dose glucocorticoids and/or hydroxchloroquine. Severe disease (e.g., patients that have signs of renal involvement) require more aggressive drugs including

mycophenolate mofetil (MMF), azathioprine (AZA) and/or cyclophosphamide (CTX) (Bertsias and Boumpas 2008). CTX, AZA and MMF are very toxic and

immunosuppressive, and only 50% of treated patients enter complete remission, with relapse rates up to 30% over a 2-year period.

Memory B cells, and more important, long-lived plasma cells (LL-PCs) which differentiate from memory B cells, are key cell types involved in lupus (Neubert, Meister et al. 2008; Sanz and Lee 2010). Long-lived plasma cells synthesize and secrete large quantities of high-affinity isotype switched antibodies (Meister, Schubert et al. 2007;

Muller, Dieker et al. 2008). Circulating antinuclear antibodies (ANAs) increase the chances of antibody depositing onto self tissues, forming immune-complexes and eventually leading to tissue destruction, epitope spreading and involvement of other organ systems. LL-PCs are commonly found to be chemo- and radio-resistant, over expressing various heat shock proteins and drug pumps (Obeng, Carlson et al. 2006; Neubert, Meister et al. 2008). In addition, LL-PCs primarily reside in the bone marrow where they are protected from current lupus therapies such as cyclophosphamide and glucocorticoids.

A need exists for new treatments for lupus, including lupus nephritis. A need particularly exists for lupus treatments that can target and reduce LL-PCs.

str0

CEP-33779 is a highly selective, orally active, small-molecule inhibitor of JAK2. CEP-33779 induced regression of established colorectal tumors, reduced angiogenesis, and reduced proliferation of tumor cells. Tumor regression correlated with inhibition of STAT3 and NF-κB (RelA/p65) activation in a CEP-33779 dose-dependent manner. The ability of CEP-33779 to suppress growth of colorectal tumors by inhibiting the IL-6/JAK2/STAT3 signaling suggests a potential therapeutic utility of JAK2 inhibitors in multiple tumors types, particularly those with a strong inflammatory component.

str0

{[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine} (1)

LC/MS: (M+H+)+ = 463.2;
1H NMR (DMSO, 400 MHz) δ 9.61 (s, 1H), 8.85 (d, J = 6.8 Hz, 1H), 8.43 (d, J = 6.8 Hz, 2H), 8.06 (d, J = 6.8 Hz, 2H), 7.96 (d, J = 7.5 Hz, 1H), 7.59 (s, 1H), 7.17 (t, J = 6.8 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 8.6 Hz 1H), 6.49 (d, J = 8.0 Hz, 1H), 3.30 (s, 3H), 3.13 (m, 4H), 2.48 (m, 4H), 2.24 (s, 3H).
CEP-33779 Diglycolate Salt
1H NMR (DMSO, 400 MHz) δ 9.61 (s, 1H), 8.85 (d, J = 6.7 Hz, 1H), 8.43 (d, J = 6.7 Hz, 2H), 8.06 (d, J = 6.7 Hz, 2H), 7.97 (d, J = 7.5 Hz, 1H), 7.59 (s, 1H), 7.18 (d, J = 6.7 Hz, 1H), 7.11 (m, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 3.89 (s, 4H), 3.30 (s, 3H), 3.13 (m, 4H), 2.48 (m, 4H), 2.24 (s, 3H).
DSC: Endotherm onset at 153.0 °C; Peak at 155.8 °C.

PATENT

WO 2010141796

https://www.google.com/patents/WO2010141796A3?cl=en

Example 35 [8-(4-Methanesulfonyl-phenyl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-

1 -yl)-phenyl]-amine

Figure imgf000156_0001

35 a) l-(3-Bromo-phenyl)-4-methyl-piperazine was prepared from l-(3-bromo-phenyl)- piperazine (1.33 g, 5.52 mmol) in a manner analogous to Step 32a. The reaction product was isolated as a pale yellow oil (1.4 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.10 (dd, J=8.2, 8.2 Hz, IH), 7.04 (dd, J=2.1, 2.1 Hz, IH), 6.95 (ddd, J=I. S, 1.7, 0.7 Hz, IH), 6.83 (ddd, J=8.3, 2.4, 0.6 Hz, IH), 3.23-3.18 (m, 4H), 2.58-2.54 (m, 4H), 2.35 (s, 3H). MS = 255, 257 (MH)+. 35b) [8-(4-Methanesulfonyl-phenyl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-[3-(4-methyl- piperazin-l-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)- [l,2,4]triazolo[l,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and l-(3-bromo-phenyl)-4- methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow solid (0.072 g, 60%).

MP = 232-234 0C.

1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=I 2 Hz, IH), 8.25 (d, J=I .5 Hz, 2H), 8.08 (d, J=I .9 Hz, 2H), 7.65 (d, J=I .1 Hz, IH), 7.38 (s, IH), 7.27-7.20 (m, IH), 7.04-6.95 (m, 2H), 6.84 (s, IH), 6.60 (d, J=8.0 Hz, IH), 3.30-3.25 (m, 4H), 3.10 (s, 3H), 2.63-2.58 (m, 4H), 2.38 (s, 3H).

MS = 463 (MH)+.

PATENT

WO 2012078504

PATENT

WO 2012078574

https://google.com/patents/WO2012078574A2?cl=da

COMPOUND A is a JAK2 inhibitor with the chemical name [8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine. COMPOUND A has the following structure:

COMPOUND A

COMPOUND A was prepared in a manner analogous to the five-step method described below (see Example 35 of International Application No. PCT/US10/37363):

Step 1 : To a solution of 1-(3-bromo-phenyl)-piperazine (about 1 g) and acetic acid (about 0.4 mL) in methanol (about 25 mL) is added 37% formaldehyde in water/methanol (about 56.7:37:6.3, water:formaldehyde:methanol; about 5 mL). The mixture is stirred at room temperature for about 18 hours. The suspension is cooled to about 5°C in an ice/water bath and sodium cyanoborohydride (about 5 g) is added in small portions. The mixture is stirred and warmed to room temperature for about 18 hours. The mixture is slowly poured into saturated aqueous ammonium chloride (about 200 mL) and stirred for about 1 hour. The mixture is extracted with dichloromethane (3 x about 75 mL). The combined organic layers are dried over magnesium sulfate, filtered and evaporated. The material is placed under high vacuum for about 18 hours to yield 1-(3-bromo-phenyl)-4-methyl-piperazine as a pale yellow oil (about 1 g). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.10 (dd, J=8.2, 8.2 Hz, 1H), 7.04 (dd, J=2.1, 2.1 Hz, 1H), 6.95 (ddd, J=7.8, 1.7, 0.7 Hz, 1H), 6.83 (ddd, J=8.3, 2.4, 0.6 Hz, 1H), 3.23-3.18 (m, 4H), 2.58-2.54 (m, 4H), 2.35 (s, 3H). MS = 255, 257 (MH)+.

Step 2: To a solution of 3-bromo-pyridin-2-ylamine (about 10 g) in 1,4-dioxane (about 100 mL) is added dropwise ethoxycarbonyl isothiocyanate (about 7 mL). The mixture is stirred under an atmosphere of nitrogen for about 18 hours. The volatiles are evaporated to yield a waxy solid. The recovered material is triturated with hexane (about 250 mL). N-(3-bromo-2-pyridinyl)-N’-carboethoxy-thiourea is isolated and used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 11.46 (s, 1H), 11.43 (s, 1H), 8.49 (dd, J=4.6, 1.5 Hz, 1H), 8.18 (dd, J=8.0, 1.5 Hz, 1H), 7.33 (dd, J=8.0, 4.7 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H). MS = 215 (MH)+.

Step 3: To a stirred suspension of hydroxylamine hydrochloride (about 17 g) and Ν,Ν-diisopropylethylamine (about 26 mL) in a mixture of methanol (about 70 mL) and

ethanol (about 70 mL) is added N-(3-bromo-2-pyridinyl)-N’-carboethoxy-thiourea. The mixture is stirred for about 2 hours at room temperature then heated to about 60°C for about 18 hours. The suspension is cooled to room temperature, filtered and rinsed with methanol, water then methanol. 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine is isolated as an off-white solid (about 8 g). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.58 (d, J=6.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 6.80 (t, J=7.0 Hz, 1H), 6.25 (s, 2H). MS = 213, 215 (MH)+.

Step 4: An oven dried tube is charged with palladium acetate (about 0.2 g) and triphenylphosphine (about 0.6 g). The tube is evacuated under high vacuum and backflushed under a stream of nitrogen for about 5 minutes. A suitable solvent such as

1,4-dioxane (about 10 mL) is added and the mixture is stirred under nitrogen for a suitable time (e.g., for about 10 minutes). 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (about 0.75 g), (4-methylsulfonylphenyl)boronic acid (about 1 g), a suitable solvent, such as N,N-dimethylformamide (about 10 mL) and a suitable base, such as about 1.5 M of sodium carbonate in water (about 10 mL) are added. The mixture is stirred for about 2 minutes at room temperature under nitrogen then the tube is sealed and heated at about 80°C for about 18 hours. The mixture is transferred to a round bottom flask and the volatiles are evaporated under reduced pressure. The product is isolated in a suitable manner. For example, water (about 100 mL) may be added and the mixture stirred. The solid may then be collected by filtration, and optionally rinsed with water, air dried, triturated with ether/dichloromethane (about 4: 1; about 10 mL), filtered and rinsed with ether. 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine is isolated as a tan solid (about 0.6 g). MP = 236-239 °C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.63 (d, J=6.3 Hz, 1H), 8.38 (d, J=7.9 Hz, 2H), 8.03 (d, J=7.9 Hz, 2H), 7.84 (d, J= 7.3 Hz, 1H), 7.03 (t, J=7.0 Hz, 1H), 6.21 (br s, 2H), 3.28 (s, 3H). MS = 289 (MH)+.

Step 5: To an oven dried tube is added palladium acetate (about 10 mg) and 2,2′-bis-dicyclohexylphosphanyl-biphenyl (about 30 mg), 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (about 75 mg), 1-(3-bromo-phenyl)-4-methyl-piperazine (about 80 mg), a suitable base, such as cesium carbonate (about 270 mg) and a suitable solvent, such as 1,4-dioxane (about 5 mL). The tube is evacuated and backflushed with nitrogen three times. The tube is sealed and heated at about 80°C for about 72 hours. The mixture is cooled to room temperature and the product isolated in a suitable manner.

For example, the cooled mixture may be diluted with dichloromethane (about 10 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated. The material may then be purified, e.g., via chromatography, e.g., utilizing an ISCO automated purification apparatus (e.g., amine modified silica gel column 5%→100% ethyl acetate in hexanes). [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine (i.e., COMPOUND A) is isolated as a yellow solid (about 0.07 g). MP = 232-234 °C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=7.2 Hz, 1H), 8.25 (d, J=7.5 Hz, 2H), 8.08 (d, J=7.9 Hz, 2H), 7.65 (d, J=7.7 Hz, 1H), 7.38 (s, 1H), 7.27-7.20 (m, 1H), 7.04-6.95 (m, 2H), 6.84 (s, 1H), 6.60 (d, J=8.0 Hz, 1H), 3.30-3.25 (m, 4H), 3.10 (s, 3H), 2.63-2.58 (m, 4H), 2.38 (s, 3H). MS = 463 (MH)+.

PATENT

WO 2015089153

https://www.google.com/patents/WO2015089153A1?cl=un

This disclosure relates to a l,2,4 riazolo[l,5a]pyridine derivative, [8-(4 methanesulfonyl-phenyl)-[ 1 ,2,4]triazoio[1 ,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin- 1 -yl phenyl] -amine, re g structure:

or a pharmaceutical salt thereof, and its use in the treatment of multiple sclerosis.

Compound A is a potent, orally active, small molecule inhibitor of JA 2. See, e.g..International Application No. PCT/USlO/37363, U.S. Patent Nos. 8,501,936 and ,633,173, and U.S. Published Patent Application Nos. 2013/0267535 and 2014/0024655, each of which is incorporated by reference herein. Compound A can be prepared, for example, using methods analogous to Example 35 of International Application No.PCT/US 10/37363.

PAPER

A Selective, Orally Bioavailable 1,2,4-Triazolo[1,5-a]pyridine-Based Inhibitor of Janus Kinase 2 for Use in Anticancer Therapy: Discovery of CEP-33779

Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States
J. Med. Chem., 2012, 55 (11), pp 5243–5254
DOI: 10.1021/jm300248q
Publication Date (Web): May 10, 2012
Copyright © 2012 American Chemical Society
*Phone: 610-738-6733. Fax: 610-738-6643. E-Mail: bdugan@cephalon.com.

Abstract

Abstract Image

Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize selective JAK2 inhibitors to combat cancer while reducing the risk of immune suppression associated with JAK3 inhibition was undertaken. The structure–activity relationships and biological evaluation of a novel series of compounds based on a 1,2,4-triazolo[1,5-a]pyridine scaffold are reported. Para substitution on the aryl at the C8 position of the core was optimum for JAK2 potency (17). Substitution at the C2 nitrogen position was required for cell potency (21). Interestingly, meta substitution of C2-NH-aryl moiety provided exceptional selectivity for JAK2 over JAK3 (23). These efforts led to the discovery of CEP-33779 (29), a novel, selective, and orally bioavailable inhibitor of JAK2.

[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine (29)

 1H NMR (CDCl3) δ 8.49 (dd, J = 6.6, 1.0 Hz, 1H), 8.25 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H), 7.66 (dd, J = 7.5, 0.9 Hz, 1H), 7.39–7.36 (m, 1H), 7.23 (t, J = 8.2 Hz, 1H), 7.02 (t, J = 7.1 Hz, 1H), 6.97 (dd, J = 7.8, 1.4 Hz, 1H), 6.88 (s, 1H), 6.60 (dd, J = 8.3, 1.8 Hz, 1H), 3.30–3.25 (m, 4H), 3.10 (s, 3H), 2.63–2.58 (m, 4H), 2.38 (s, 3H).
13C NMR (CDCl3) δ 162.65, 152.28, 148.87, 141.00, 140.91, 140.05, 129.64, 129.29, 128.18, 127.85, 127.76, 124.77, 112.03, 109.40, 108.59, 104.80, 55.19, 49.02, 46.19, 44.59;
mp 208–211 °C.
High resolution mass spectrum (ESI+) m/z 463.1925 [(M + H)+calcd for C24H26N6O2S: 463.1916]. HPLC: 95 A%.

PAPER

An Improved Synthesis of the Free Base and Diglycolate Salt of CEP-33779; A Janus Kinase 2 Inhibitor

Chemical Process Research and Development, Teva Branded Pharmaceutical Products R&D Inc., 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00311
Publication Date (Web): November 30, 2016
Copyright © 2016 American Chemical Society

Abstract

Abstract Image

CEP-33779 is a triazole that has been reported to show highly selective inhibition of Janus kinase 2 (JAK2). An efficient process to form CEP-33779 will be presented that uses multiple palladium couplings to provide the drug substance in a convergent manner. The existing medicinal chemistry route was modified to avoid chromatographic purification, improve safety, and utilize palladium ligands which are available in quantities amenable to scale-up. Challenges faced during the development of the new process included optimization of conditions for Buchwald–Hartwig and Suzuki couplings, control of homocoupled impurities and removal of residual palladium. In addition, a screen of conditions to form a diglycolate salt of the parent compound are also presented.

REFERENCES

1: Dugan BJ, Gingrich DE, Mesaros EF, Milkiewicz KL, Curry MA, Zulli AL, Dobrzanski P, Serdikoff C, Jan M, Angeles TS, Albom MS, Mason JL, Aimone LD, Meyer SL, Huang Z, Wells-Knecht KJ, Ator MA, Ruggeri BA, Dorsey BD. A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of Janus kinase 2 for use in anticancer therapy: discovery of CEP-33779. J Med Chem. 2012 Jun 14;55(11):5243-54. doi: 10.1021/jm300248q. Epub 2012 May 18. PubMed PMID: 22594690.

2: Tagoe C, Putterman C. JAK2 inhibition in murine systemic lupus erythematosus. Immunotherapy. 2012 Apr;4(4):369-72. doi: 10.2217/imt.12.20. PubMed PMID: 22512630.

3: Seavey MM, Lu LD, Stump KL, Wallace NH, Hockeimer W, O’Kane TM, Ruggeri BA, Dobrzanski P. Therapeutic efficacy of CEP-33779, a novel selective JAK2 inhibitor, in a mouse model of colitis-induced colorectal cancer. Mol Cancer Ther. 2012 Apr;11(4):984-93. doi: 10.1158/1535-7163.MCT-11-0951. Epub 2012 Feb 14. PubMed PMID: 22334590.

4: Lu LD, Stump KL, Wallace NH, Dobrzanski P, Serdikoff C, Gingrich DE, Dugan BJ, Angeles TS, Albom MS, Mason JL, Ator MA, Dorsey BD, Ruggeri BA, Seavey MM. Depletion of autoreactive plasma cells and treatment of lupus nephritis in mice using CEP-33779, a novel, orally active, selective inhibitor of JAK2. J Immunol. 2011 Oct 1;187(7):3840-53. doi: 10.4049/jimmunol.1101228. Epub 2011 Aug 31. PubMed PMID: 21880982.

5: Stump KL, Lu LD, Dobrzanski P, Serdikoff C, Gingrich DE, Dugan BJ, Angeles TS, Albom MS, Ator MA, Dorsey BD, Ruggeri BA, Seavey MM. A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritis. Arthritis Res Ther. 2011 Apr 21;13(2):R68. doi: 10.1186/ar3329. PubMed PMID: 21510883; PubMed Central PMCID: PMC3132063.

/////////////CEP-33779, CEP33779, CEP 33779, 1257704-57-6, PRECLINICAL, TEVA,  Rheumatoid Arthritis, Colorectal Cancer Therapy, Systemic Lupus Erythematosus,

Jak2 Inhibitors

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Reslizumab


Reslizumab

(Cinqair®) Approved Active, FDA 2016-03-23

An interleukin-5 (IL-5) antagonist used to treat severe asthma.

CAS  241473-69-8

Research Code CDP-835; CEP-38072; CTx-55700; SCH-5570; SCH-55700; TRFK-5,

Anti-interleukin-5 monoclonal antibody – Celltech/Schering-Plough

Reslizumab was approved by the U.S. Food and Drug Administration (FDA) on March 23, 2016. It was developed and marketed as Cinqair® by Teva.

Reslizumab is an interleukin-5 antagonist, which binds to human IL-5 and prevents it from binding to the IL-5 receptor, thereby reducing eosinophilic inflammation. It is indicated for the maintenance treatment of patients with severe asthma in patients aged 18 years and older.

Cinqair® is available as injection for intravenous infusion, containing 100 mg of reslizumab in 10 mL solution in single-use vials. The recommended dose is 3 mg/kg once every four weeks.

  • Originator Celltech R&D; Schering-Plough
  • Developer Celltech R&D; Teva Pharmaceutical Industries
  • Class Antiasthmatics; Monoclonal antibodies
  • Mechanism of Action Interleukin 5 receptor antagonists
  • Orphan Drug Status Yes – Oesophagitis
  • 23 Mar 2016 Registered for Asthma in USA (IV) – First global approval
  • 04 Mar 2016 Pooled efficacy data from two phase III trials in Asthma presented at the 2016 Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI-2016)
  • 10 Dec 2015 Preregistration for Asthma in Canada (IV)

Reslizumab (trade name Cinqair) is a humanized monoclonal antibody intended for the treatment of eosinophil-meditated inflammations of the airways, skin and gastrointestinal tract.[1] The FDA approved reslizumab for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older on March 23, 2016. Cinqair is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines.[2]

Teva Announces FDA Acceptance of the Biologics License Application for Reslizumab

Investigational Biologic for the Treatment of Inadequately Controlled Asthma in Patients with Elevated Blood Eosinophils Accepted for Review

JERUSALEM–(BUSINESS WIRE)–Jun. 15, 2015– Teva Pharmaceutical Industries Ltd., (NYSE: TEVA) announced today that the U.S. Food and Drug Administration (FDA) has accepted for review the Biologics License Application (BLA) for reslizumab, the company’s investigational humanized monoclonal antibody (mAb) which targets interleukin-5 (IL-5), for the treatment of inadequately controlled asthma in adult and adolescent patients with elevated blood eosinophils, despite an inhaled corticosteroid (ICS)-based regimen.

“Despite currently available medicines, uncontrolled asthma remains a serious problem for patients, physicians and healthcare systems, highlighting the need for targeted new treatment options,” said Dr. Michael Hayden, President of Global R&D and Chief Scientific Officer at Teva Pharmaceutical Industries Ltd. “The reslizumab BLA filing acceptance represents a significant milestone for Teva as we work toward serving a specific asthma patient population that is defined by elevated blood eosinophil levels and inadequately controlled symptoms despite standard of care therapy. In clinical trials, patients treated with reslizumab showed significant reductions in the rate of asthma exacerbations and significant improvement in lung function. If approved, we believe reslizumab will serve as an important new targeted treatment option to achieve better asthma control for patients with eosinophil-mediated disease.”

The BLA for reslizumab includes data from Teva’s Phase III BREATH clinical trial program. The program consisted of four separate placebo-controlled Phase III trials involving more than 1,700 adult and adolescent asthma patients with elevated blood eosinophils, whose symptoms were inadequately controlled with inhaled corticosteroid-based therapies. Results from these studies demonstrated that reslizumab, in comparison to placebo, reduced asthma exacerbation rates by at least half and provided significant improvement in lung function and other secondary measures of asthma control when added to an existing ICS-based therapy. Common adverse events in the reslizumab treatment group were comparable to placebo and included worsening of asthma, nasopharyngitis, upper respiratory infections, sinusitis, influenza and headache. Two anaphylactic reactions were reported and resolved following medical treatment at the study site.

Results from the reslizumab BREATH program were recently presented at the American Thoracic Society 2015 Annual Meeting and the American Academy of Allergy, Asthma and Immunology 2015 Annual Meeting, in addition to being published in The Lancet Respiratory Medicine. The BLA for reslizumab has been accepted for filing by the FDA for standard review, with FDA Regulatory Action expected in March 2016.

About Reslizumab

Reslizumab is an investigational humanized monoclonal antibody which targets interleukin-5 (IL-5). IL-5 is a key cytokine involved in the maturation, recruitment, and activation of eosinophils, which are inflammatory white blood cells implicated in a number of diseases, such as asthma. Elevated levels of blood eosinophils are a risk factor for future asthma exacerbations. Reslizumab binds circulating IL-5 thereby preventing IL-5 from binding to its receptor.

About Asthma

Asthma is a chronic (long term) disease usually characterized by airway inflammation and narrowing of the airways, which can vary over time. Asthma may cause recurring periods of wheezing (a whistling sound when you breathe), chest tightness, shortness of breath and coughing that often occurs at night or early in the morning. Without appropriate treatment, asthma symptoms may become more severe and result in an asthma attack, which can lead to hospitalization and even death.

About Eosinophils

Eosinophils are a type of white blood cell that are present at elevated levels in the lungs and blood of many asthmatics. Evidence shows that eosinophils play an active role in the pathogenesis of the disease. IL-5 has been shown to play a crucial role in maturation, growth and activation of eosinophils. Increased levels of eosinophils in the sputum and blood have been shown to correlate with severity and frequency of asthma exacerbations.

About Teva

Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) is a leading global pharmaceutical company that delivers high-quality, patient-centric healthcare solutions to millions of patients every day. Headquartered in Israel, Teva is the world’s largest generic medicines producer, leveraging its portfolio of more than 1,000 molecules to produce a wide range of generic products in nearly every therapeutic area. In specialty medicines, Teva has a world-leading position in innovative treatments for disorders of the central nervous system, including pain, as well as a strong portfolio of respiratory products. Teva integrates its generics and specialty capabilities in its global research and development division to create new ways of addressing unmet patient needs by combining drug development capabilities with devices, services and technologies. Teva’s net revenues in 2014 amounted to $20.3 billion. For more information, visit www.tevapharm.com.

USFDA

The U.S. Food and Drug Administration today approved Cinqair (reslizumab) for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older. Cinqair is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines.

Asthma is a chronic disease that causes inflammation in the airways of the lungs. During an asthma attack, airways become narrow making it hard to breathe. Severe asthma attacks can lead to asthma-related hospitalizations because these attacks can be serious and even life-threatening. According to the Centers for Disease Control and Prevention, as of 2013, more than 22 million people in the U.S. have asthma, and there are more than 400,000 asthma-related hospitalizations each year.

“Health care providers and their patients with severe asthma now have another treatment option to consider when the disease is not well controlled by their current asthma therapies,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

Cinqair is administered once every four weeks via intravenous infusion by a health care professional in a clinical setting prepared to manage anaphylaxis. Cinqair is a humanized interleukin-5 antagonist monoclonal antibody produced by recombinant DNA technology in murine myeloma non-secreting 0 (NS0) cells. Cinqair reduces severe asthma attacks by reducing the levels of blood eosinophils, a type of white blood cell that contributes to the development of asthma.

The safety and efficacy of Cinqair were established in four double-blind, randomized, placebo‑controlled trials in patients with severe asthma on currently available therapies. Cinqair or a placebo was administered to patients every four weeks as an add-on asthma treatment. Compared with placebo, patients with severe asthma receiving Cinqair had fewer asthma attacks, and a longer time to the first attack. In addition, treatment with Cinqair resulted in a significant improvement in lung function, as measured by the volume of air exhaled by patients in one second.

Cinqair can cause serious side effects including allergic (hypersensitivity) reactions. These reactions can be life-threatening. The most common side effects in clinical trials for Cinqair included anaphylaxis, cancer, and muscle pain.

Cinqair is made by Teva Pharmaceuticals in Frazer, Pennsylvania.

References

Reslizumab
Monoclonal antibody
Type Whole antibody
Source Humanized (from rat)
Target IL-5
Clinical data
Trade names Cinquil
Identifiers
ATC code R03DX08 (WHO)
ChemSpider none

/////////CDP-835,  CEP-38072,  CTx-55700,  SCH-5570,  SCH-55700,  TRFK-5, Reslizumab, Cinqair®, teva, interleukin-5 (IL-5) antagonist, severe asthma, FDA 2016, Orphan Drug StatuS

WO 2016025720, New Patent, by Assia Chemicals and Teva on Ibrutinib


 

WO 2016025720, New Patent, by Assia Chemicals and Teva on Ibrutinib

 

ASSIA CHEMICAL INDUSTRIES LTD. [IL/IL]; 2 Denmark Street 49517 Petach Tikva (IL)
TEVA PHARMACEUTICALS USA, INC. [US/US]; 1090 Horsham Road P.O. Box 1090 North Wales, PA 19454 (US)

COHEN, Meital; (IL).
COHEN, Yuval; (IL).
MITTELMAN, Ariel; (IL).
MOHA-LERMAN, Elana, Ben; (IL).
TZANANI, Idit; (IL).
LEVENFELD, Leonid; (IL)

The present invention encompasses solid state forms of Ibrutinib, including forms G, J and K, and pharmaceutical compositions thereof.

Ibrutinib, l-{(3R)-3- [4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo [3,4-d] pyrimidin-l-yl] piperidin-l-yl] prop-2-en-l-one, having the following formula,

is a kinase inhibitor indicated for the treatment of patients with B-cell lymphoma.

Ibrutinib is described in US 7,514,444 and in US 8,008,309. Solid state forms, including forms A-F and amorphous form of Ibrutinib, are described in WO 2013/184572.

Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis – “TGA”, or differential scanning calorimetry – “DSC”), X-ray diffraction pattern, infrared absorption fingerprint, and solid state (13C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification, or may serve as desirable intermediate crystal forms that facilitate purification or conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of ibrutinib.

Example 1: Preparation of Crystalline Form G of Ibrutinib

[0057] Ibrutinib (0.3 gr, amorphous form) was dissolved in acetic acid (1.2 ml) and the obtained solution was stirred at room temperature overnight followed by the addition of water (2.4 ml). A gum was obtained which was turned into cloudy solution upon stirring. The obtained cloudy solution was stirred for 9 days at room temperature and the obtained precipitate was collected by suction filtration. The obtained solid was dried in an oven at 40°C under vacuum for 16h to obtain form G of Ibrutinib (0.12g), as confirmed by XRPD.

Example 2: Preparation of Crystalline Form J of Ibrutinib

Ibrutinib (5.2 g) was dissolved in Anisole (15 ml), the solution was stirred at room temperature until precipitation was occurred. The slurry was stirred over night at room temperature and the precipitate was collected by suction filtration. The cake was dried in a vacuum oven at 50°C overnight. The obtained product was analyzed by XRPD and found to be form J.

Example 3: Preparation of Crystalline Form J of Ibrutinib

Ibrutinib (10.5 g) was dissolved in Anisole (21 ml) and MTBE (32 ml), the solution was stirred at room temperature until precipitation was occurred . The slurry was heated to reflux and was gradually cooled to room temperature. After 3 hours the precipitate was collected by suction filtration. The obtained product was analyzed by XRPD and found to be form J.

Example 4: Preparation of Crystalline Form G of Ibrutinib

A I L reactor was charged with Ibrutinib (100 g), acetonitrile (417.5 ml_), water (417.5 ml_) and acetic acid (27.15 g). The mixture was heated to 90°C until dissolution; the solution was gradually cooled to 0°C, then heated to 25°C and stirred over 48 hours at 25°C. The obtained slurry was filtered and washed with water (100 ml_). The product was dried overnight in a vacuum oven at 40°C to obtain Ibrutinib form G (72.9 g), as confirmed by XRPD.

Example 5: Preparation of Crystalline Form G of Ibrutinib

A 250 mL round flask was charged with isopropanol (10 ml_) and water (120 ml_), and a solution of Ibrutinib (10 g) in Acetic acid (40 mL) was added dropwise. The mixture was stirred at 25°C for 48 hours. The obtained slurry was filtered and the wet product was slurried in water (50 mL) for 5 min and filtered again. The obtained product was dried under vacuum at room temp in the presence of a N2 atmosphere and found to be form G, as confirmed by XRPD.

Example 6: Preparation of Crystalline Form K of Ibrutinib

Ibrutinib (10 g) was dissolved in toluene (50 mL) and dimethylformamide (DMA) (30 mL) at room temperature, the solution was heated to 50 °C and water (30 mL) was added. The phases were separated and methyl tert-butyl ether (MTBE) (30 mL) was added to the organic phase. The solution was cooled in an ice bath and seeded with amorphous Ibrutinib. After further stirring at the same temperature the obtained slurry was filtered under vacuum. The obtained solid was analyzed by XRPD and found to be Form K (Figure 5).

assia chemical industries - teva tech site in ramat hovav

//////////////WO 2016025720, WO-2016025720, New Patent,  Assia Chemicals,  Teva,  Ibrutinib 

Teva’s Asthma Drug ‘Significantly’ Improves Lung Function In Phase 3 Trials



//

Teva Gets Orphan Drug Designation for Treanda


 

Teva Announces Additional Regulatory Exclusivity for TREANDA® (Bendamustine HCI) for Injection

Orphan Designation combined with pediatric extension provides regulatory exclusivity through April 2016 for indolent B-cell non-Hodgkin lymphoma indication

JERUSALEM, November 27, 2013 –(BUSINESS WIRE)–Teva Pharmaceutical Industries Ltd. (NYSE: TEVA) today announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug exclusivity for TREANDA through October 2015 for indolent B-cell non-Hodgkin lymphoma (iNHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.http://www.pharmalive.com/teva-announces-additional-regulatory-exclusivity-for-treanda

read my old post, contains synthesis

https://newdrugapprovals.wordpress.com/2013/09/19/fda-oks-tevas-injectable-treanda/

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