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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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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Vericiguat, ベルイシグアト


Vericiguat.pngImage result for vericiguatImage result for vericiguat

Vericiguat

BAY 102; BAY-1021189; MK-1242

1350653-20-1
Chemical Formula: C19H16F2N8O2

Molecular Weight: 426.3878

Vericiguat; 1350653-20-1; UNII-LV66ADM269; Methyl (4,6-diamino-2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)carbamate; BAY-1021189; LV66ADM269

Methyl (4,6-diamino-2-(5-fluoro-1-((2-fluorophenyl)methyl)-1H-pyrazolo(3,4-b)pyridin-3-yl(pyrimidin-5-yl)carbamate

methyl N-[4,6-diamino-2-[5-fluoro-1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]carbamate

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridi- n-3-yl]pyrimidin-5-yl}carbamate

  • Originator Bayer HealthCare Pharmaceuticals
  • Developer Bayer HealthCare Pharmaceuticals; Merck & Co
  • Mechanism of Action Guanylate cyclase stimulants
  • Phase III Chronic heart failure
  • Phase I Coronary artery disease
  • 28 May 2018 Phase II VITALITY HFpEF trial for Chronic heart failure in Austria, USA, Belgium, Portugal, Canada, Spain, Hungary and Greece (PO) (EudraCT2018-000298-65) (NCT03547583)
  • 17 May 2018 Phase-I clinical trials in Coronary artery disease (In adults, In the elderly) in Moldova and Germany (PO) (NCT03504982)
  • 20 Apr 2018 Bayer in collaboration with Merck Sharp & Dohme Corp. plans a phase I trial for Coronary Artery Disease in the Netherlands, Moldova and Germany (NCT03504982)

Vericiguat, also known as BAY1021189 or BAY10-21189, is a potent and orally active sGC stimulator (Soluble Guanylate Cyclase Stimulator). Direct stimulation of soluble guanylate cyclase (sGC) is emerging as a potential new approach for the treatment of renal disorders. sGC catalyzes the formation of cyclic guanosine monophosphate (cGMP), deficiency of which is implicated in the pathogenesis of chronic kidney disease (CKD).

Vericiguat, discovered at Bayer, is the first soluble guanylate cyclase (sGC) stimulator. Vericiguat is currently being studied in a Phase III clinical program for the treatment of heart failure with reduced ejection fraction (HFrEF)

ベルイシグアト
Vericiguat

C19H16F2N8O2 : 426.38
[1350653-20-1]

Vericiguat hydrochloride.png

Vericiguat hydrochloride

cas 1350658-96-6

PHASE 3 MERCK/BAYER

Chemical Names: UNII-5G76IGF54K; 5G76IGF54K; ; 1350658-96-6; Carbamic acid, N-(4,6-diamino-2-(5-fluoro-1-((2-fluorophenyl)methyl)-1H-pyrazolo(3,4-b)pyridin-3-yl)-5-pyrimidinyl)-, methyl ester, hydrochloride (1:1); Methyl (4,6-diamino-2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridin-3-yl)pyrimidin-5-yl)carbamate hydrochloride
Molecular Formula: C19H17ClF2N8O2
Molecular Weight: 462.846 g/mol

Image result for DRUG FUTURE Vericiguat

Clip

https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0036-1590758.pdf

Image result for vericiguat

Significance: Vericiguat (BAY 1021189) is an orally available soluble guanylate cyclase (sGC) stimulator that has entered phase-three trials for the once-daily treatment of chronic heart failure. Key steps in the synthesis depicted are (1) construction of the 5-fluoro-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate C by condensation of the 5-amino-1H-pyrazole-3-carboxylate A with the aldehyde B and (2) construction of the pyrimidine-4,5,6-triamine derivative H through reaction of [(E)-phenyldiazenyl]malononitrile (G) with amidine F.

Comment: Experimental details are provided for the noteworthy four-step synthesis (not shown) of the crystalline 2-fluoro-(3-morpholin-4-yl)acrylaldehyde B from commercially available 2,2,3,3- tetrafluoro-1-propanol. The synthesis of pyrazole A is described in a patent (A. Straub et al. WO 2000/006569 A1). The [(E)-phenyldiazenyl]malononitrile (G) was generated in situ by reaction of phenyldiazonium chloride with malononitrile.

M. FOLLM ANN * E T AL. (BAYER AG, WUPPERTAL , GE RMANY) Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure J. Med. Chem. 2017, 60, 5146–5161
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24. Yield 2.2 g (70%). 1 H NMR (400 MHz, DMSO-d6): δ = 8.89 (dd, J = 9.0, 2.8 Hz, 1H), 8.66 (m, 1H), 7.99 and 7.67 (2 br s, 1H), 7.32−7.40 (m, 1H), 7.19−7.26 (m, 1H), 7.10−7.19 (m, 2H), 6.22 (br s, 4H), 5.79 (s, 2H), 3.62 (br s, 3H). LC-MS (method d): tR (min) = 0.79. MS (ESI +): m/z = 427 [M + H]+
PATENT
US 8,802,847

Example 13

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridi- n-3-yl]pyrimidin-5-yl}carbamate

Method A:

4.0 g (77.0% by weight, 8.36 mmol) of the compound from Example 12 in 37.9 ml of isopropanol were heated to 35.degree. C. and then 0.84 ml (10.87 mmol) of methyl chloroformate was added dropwise. The mixture was stirred at 35.degree.-40.degree. C. for 20 h and heated to 50.degree. C., and 9.5 ml of methanol were added. Subsequently, 1.9 ml of triethylamine were added dropwise within 0.5 h and rinsed in with 1.3 ml of methanol, and the mixture was stirred at 50.degree. C. for 1 h. Thereafter, the reaction mixture was cooled to RT and stirred at RT for 1 h, and the solids were filtered off with suction, washed three times with 8 ml each time of ethanol, suction-dried and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 3.4 g of crude product. 3.0 g of the crude product were stirred in 8 ml of DMSO for 5 min, 13.0 ml of ethyl acetate and 50 mg of activated carbon were added, and the mixture was heated at reflux (84.degree. C.) for 15 min. The suspension was hot-filtered and the filter residue was washed with 1.9 ml of ethyl acetate.sup.1). 60 ml of ethyl acetate and 16 ml of ethanol were heated to 60.degree. C., and the combined filtrates were added dropwise and stirred at 60.degree. C. for 1.5 h. The suspension was cooled to RT within 25 min, stirred for a further 1.5 h, cooled further to 0.degree.-5.degree. C. and stirred for a further 1 h. The solids were filtered off with suction, washed twice with 6.4 ml each time of ethyl acetate, suction-dried and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 2.2 g (70.0% of theory) of the title compound. 1) According to the preparation process described, the di-dimethyl sulphoxide solvate is obtained at this point, and this is characterized in Tables 2 and 4 by the reflections in the x-ray diffractogram and bands in the IR spectrum.

MS (ESIpos): m/z=427 (M+H).sup.+

.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=3.62 (br s, 3H), 5.79 (s, 2H), 6.22 (br s, 4H), 7.10-7.19 (m, 2H), 7.19-7.26 (m, 1H), 7.32-7.40 (m, 1H), 7.67 and 7.99 (2 br s, 1H), 8.66 (m, 1H), 8.89 (dd, 1H) ppm.

The di-dimethyl sulphoxide solvate of the compound of the formula (I) has the advantage of much better filterability than the substance in the prior art. Furthermore, the preparation process via the di-dimethyl sulphoxide solvate of the compound of the formula (I) leads to a very high purity of the compound of the formula (I).

Method B:

4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml of isopropanol were heated to 35.degree. C. and then 1.1 ml (14.1 mmol) of methyl chloroformate were added dropwise. The mixture was stirred at 35.degree.-40.degree. C. for 16.5 h and cooled to RT, and 2.1 ml of aqueous ammonia (28%) were added. Subsequently, 4.2 ml of water were added and the mixture was stirred for 2.5 h. The solids were filtered off with suction, washed twice with 5 ml each time of water, suction-dried and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 4.4 g of crude product.

Method C:

4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml of isopropanol were heated to 35.degree. C. and then 1.1 ml (14.1 mmol) of methyl chloroformate were added dropwise. The mixture was stirred at 35.degree.-40.degree. C. for 16.5 h, and 9.5 ml of methanol were added at 50.degree. C. Subsequently, 2.42 ml of triethylamine were added dropwise within 20 min and rinsed in with 1.3 ml of methanol, and the mixture was stirred at 50.degree. C. for 1 h. Thereafter, the reaction mixture was cooled to RT and stirred at RT for 1 h, and the solids were filtered off with suction, washed three times with 8 ml each time of methanol, suction-dried and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 4.3 g of crude product.

Method D:

6.9 g of the crude product were stirred in 18.4 ml of DMSO for 5 min, 30.0 ml of ethyl acetate and 115 mg of activated carbon were added, and the mixture was heated at reflux (84.degree. C.) for 15 min. The suspension was hot-filtered and the filter residue was washed with 4.4 ml of ethyl acetate. 138 ml of ethyl acetate were heated to 50.degree. C., and the combined filtrates were added dropwise and stirred at 45-50.degree. C. for 1 h. The suspension was cooled to 0.degree.-5.degree. C. within 1.5 h and stirred for a further 1 h. The solids were filtered off with suction, washed twice with 14.8 ml each time of ethyl acetate and suction-dried for 1 h. 6.4 g of the di-dimethyl sulphoxide solvate were obtained as a moist product.sup.1).

Method E:

2.0 g of the di-dimethyl sulphoxide solvate were stirred at reflux temperature in 40 ml of ethyl acetate and 11.1 ml of ethanol for 17 h, cooled to RT and stirred for a further 1 h. The solids were filtered off with suction, washed four times with 1.4 ml each time of ethyl acetate and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 1.4 g of the title compound present in polymorph I.

Method F:

0.5 g of the di-dimethyl sulphoxide solvate were stirred at reflux temperature in 12.5 ml of solvent for 17 h, cooled to RT and stirred for a further 1 h. The solids were filtered off with suction, washed with 2 ml of solvent and suction-dried for 30 min. This gave 0.3 g of the title compound present in polymorph I.

The following solvents were used:

1.) 9 ml of ethyl acetate/3.5 ml of ethanol/0.3 ml of water

2.) 12.5 ml of isopropanol

3.) 12.5 ml of isopropanol/0.3 ml of water

4.) 12.5 ml of methanol

5.) 12.5 ml of methanol/0.3 ml of water

6.) 12.5 ml of acetonitrile

7.) 12.5 ml of acetone

8.) 12.5 ml of tetrahydrofuran,

9.) 12.5 ml of methyl tert-butyl ether

Table 1 indicates the reflections of the x-ray diffractogram. Table 3 shows the bands of the IR spectrum.

The compound (I) in crystalline polymorph I is notable for higher stability and more particularly for the fact that it is stable in the micronization process and hence no conversion and recrystallization takes place.

The compound of the formula (I) can be prepared by processes described above. This affords the compound of the formula (I) in a crystal polymorph referred to hereinafter as polymorph I. Polymorph I has a melting point of 257.degree. C. and a characteristic x-ray diffractogram featuring the reflections (2 theta) 5.9, 6.9, 16.2, 16.5, 24.1 and 24.7, and a characteristic IR spectrum featuring the band maxima (in cm.sup.-1) 1707, 1633, 1566, 1475, 1255 and 1223 (Tables 1 and 3, FIGS. 1 and 5).

Surprisingly, four further polymorphs, a monohydrate, a dihydrate, a DMF/water solvate and a di-dimethyl sulphoxide solvate, and also a triacetic acid solvate of the compound of the formula (I) were found. The compound of the formula (I) in polymorph II melts at approx. 253.degree. C.; the compound of the formula (I) in polymorph III has a melting point of approx. 127.degree. C. Polymorph IV of the compound of the formula I melts at a temperature of 246.degree. C., while polymorph V has a melting point of 234.degree. C. The monohydrate contains approx. 4.1% water, the dihydrate contains 7.8% water, the DMF/water solvate contains 13.6% dimethylformamide and 0.9% water, the di-DMSO solvate contains 26.8% dimethyl sulphoxide and the triacetic acid solvate contains 29.7% acetate. Each of the crystalline forms mentioned has a characteristic x-ray diffractogram and IR spectrum (Tables 2 and 3, FIGS. 1-4, 6-14).

TABLE 1
X-ray diffractometry for polymorphs I to V

FIGURES

FIG. 1: IR spectrum of the compound of the formula (I) in polymorphs I, II and III

FIG. 2: IR spectrum of the compound of the formula (I) in polymorphs IV, V and as the triacetic acid solvate

FIG. 3: IR spectrum of the compound of the formula (I) as the di-DMSO solvate, DMF/water solvate and monohydrate

FIG. 4: IR spectrum of the compound of the formula (I) as the dihydrate

FIG. 5: X-ray diffractogram of the compound of the formula (I) in polymorph I

FIG. 6: X-ray diffractogram of the compound of the formula (I) in polymorph II

FIG. 7: X-ray diffractogram of the compound of the formula (I) in polymorph III

FIG. 8: X-ray diffractogram of the compound of the formula (I) in polymorph IV

FIG. 9: X-ray diffractogram of the compound of the formula (I) in polymorph V

FIG. 10: X-ray diffractogram of the compound of the formula (I) as the triacetic acid solvate

FIG. 11: X-ray diffractogram of the compound of the formula (I) as the di-DMSO solvate

FIG. 12: X-ray diffractogram of the compound of the formula (I) as the DMF-water solvate

FIG. 13: X-ray diffractogram of the compound of the formula (I) as the monohydrate

FIG. 14: X-ray diffractogram of the compound of the formula (I) as the dihydrate

PATENT

Example 11A

2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine

      Variant A: Preparation Starting from Example 7A:
      In pyridine (30 ml), 378 mg (0.949 mmol) of the compound from Example 7A were introduced and then 143 mg (0.135 mmol) of palladium (10% on carbon) were added. The mixture was hydrogenated overnight at RT under standard hydrogen pressure. The suspension was then filtered through kieselguhr and the filtercake was washed with ethanol. The filtrate was concentrated and yielded 233 mg (81% purity, 51% of theory) of the desired compound, which was reacted without further purification.
      Variant B: Preparation Starting from Example 10A:
      In DMF (800 ml), 39.23 g (85.75 mmol) of the compound from Example 10A were introduced and then 4 g of palladium (10% on carbon) were added. The mixture was hydrogenated with stirring overnight under standard hydrogen pressure. The batch was filtered over kieselguhr and the filter product was washed with a little DMF and then with a little methanol, and concentrated to dryness. The residue was admixed with ethyl acetate and stirred vigorously, and the precipitate was filtered off with suction, washed with ethyl acetate and diisopropyl ether and dried under a high vacuum over Sicapent.
      Yield: 31.7 g (100% of theory)
      LC-MS (method 2): R t=0.78 min
      MS (ESIpos): m/z=369 (M+H) +

Working Examples

Example 1

Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate

      In pyridine (600 ml), 31.75 g (86.20 mmol) of the compound from Example 11A were introduced under argon and cooled to 0° C. Then a solution of 6.66 ml (86.20 mmol) of methyl chloroformate in dichloromethane (10 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h. Thereafter the reaction mixture was brought to RT, concentrated under reduced pressure and co-distilled repeatedly with toluene. The residue was stirred with water/ethanol and then filtered off on a frit, after which it was washed with ethanol and ethyl acetate. Subsequently the residue was again stirred with diethyl ether, isolated by filtration with suction and then dried under a high vacuum.
      Yield: 24.24 g (65% of theory)
      LC-MS (method 2): R t=0.79 min
      MS (ESIpos): m/z=427 (M+H) +
       1H NMR (400 MHz, DMSO-d 6): δ=3.62 (br. s, 3H), 5.79 (s, 2H), 6.22 (br. s, 4H), 7.10-7.19 (m, 2H), 7.19-7.26 (m, 1H), 7.32-7.40 (m, 1H), 7.67 and 7.99 (2 br. s, 1H), 8.66 (m, 1H), 8.89 (dd, 1H).
Patent ID

Title

Submitted Date

Granted Date

US2016324856 USE OF SGC STIMULATORS FOR THE TREATMENT OF NEUROMUSCULAR DISORDERS
2015-01-13
US2016158233 SGC STIMULATORS OR SGC ACTIVATORS AND PDE5 INHIBITORS IN COMBINATION WITH ADDITIONAL TREATMENT FOR THE THERAPY OF CYSTIC FIBROSIS
2014-07-21
2016-06-09
US2013158028 USE OF STIMULATORS AND ACTIVATORS OF SOLUBLE GUANYLATE CYCLASE FOR TREATING SICKLE-CELL ANEMIA AND CONSERVING BLOOD SUBSTITUTES
2011-06-21
2013-06-20
US9845300 PROCESS FOR PREPARING SUBSTITUTED 5-FLUORO-1H-PYRAZOLOPYRIDINES
2017-02-17
US9604948 PROCESS FOR PREPARING SUBSTITUTED 5-FLUORO-1H-PYRAZOLOPYRIDINES
2015-07-10
2016-01-14
Patent ID

Title

Submitted Date

Granted Date

US2017273977 SUBSTITUTED 5-FLUORO-1H-PYRAZOLOPYRIDINES AND THEIR USE
2016-11-10
US8921377 Substituted 5-fluoro-1H-pyrazolopyridines and their use
2013-03-27
2014-12-30
US8420656 Substituted 5-fluoro-1H-pyrazolopyridines and their use
2012-01-26
US9096592 BICYCLIC AZA HETEROCYCLES, AND USE THEREOF
2011-08-31
2014-05-29
US2014038956 Use of sGC stimulators, sGC activators, alone and combinations with PDE5 inhibitors for the treatment of systemic sclerosis (SSc).
2011-05-24
2014-02-06

////////////////Vericiguat,  BAY 102, BAY-1021189, MK-1242, ベルイシグアト , PHASE 3,  MERCK, BAYER

COC(=O)NC1=C(N=C(N=C1N)C2=NN(C3=NC=C(C=C23)F)CC4=CC=CC=C4F)N

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Larotrectinib, ларотректиниб , 拉罗替尼 ,


Image result for LarotrectinibImage result for Larotrectinib

Image result for LarotrectinibImage result for Larotrectinib

Larotrectinib

ARRY-470, LOXO-101, PF9462I9HX

Molecular Formula: C21H22F2N6O2
Molecular Weight: 428.444 g/mol
(3S)-N-{5-[(2R)-2-(2,5-Difluorphenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidincarboxamid
(S)-N-{5-[(R)-2-(2,5-Difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxypyrrolidine-1-carboxamide
10360
1223403-58-4 [RN]
UNII:PF9462I9HX
ларотректиниб [Russian] [INN]
拉罗替尼 [Chinese] [INN]
(3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide
NTRK-fusion solid tumours
TRK inhibitor
orphan drug designation in the U.S
In 2013, Array Biopharma licensed the product to Loxo Oncology for development and commercialization in the U.S. In 2016, breakthrough therapy designation was received in the U.S. for the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments. In 2017, Bayer acquired global co-development and commercialization rights from Loxo Oncology.
  • Originator Array BioPharma
  • Developer Array BioPharma; Loxo Oncology; National Cancer Institute (USA)
  • Class Antineoplastics; Pyrazoles; Pyrimidines; Pyrrolidines; Small molecules
  • Mechanism of Action Tropomyosin-related kinase antagonists
  • Orphan Drug Status Yes – Solid tumours; Soft tissue sarcoma

Highest Development Phases

  • Preregistration Solid tumours
  • Phase II Histiocytosis; Non-Hodgkin’s lymphoma
  • Phase I/II CNS cancer
  • Preclinical Precursor cell lymphoblastic leukaemia-lymphoma

Most Recent Events

  • 29 May 2018 FDA assigns PDUFA action date of 26/11/2018 for larotrectinib for Solid tumors
  • 29 May 2018 Larotrectinib receives priority review status for Solid tumors in the US
  • 29 May 2018 The US FDA accepts NDA for larotrectinib for Solid tumours for review

Image result for LarotrectinibImage result for Larotrectinib

Larotrectinib sulfate

(3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide;sulfuric acid

Larotrectinib (LOXO-101) sulfate is an oral potent and selective ATP-competitive inhibitor of tropomyosin receptor kinases (TRK).

    • Crystalline Form (I-HS) OF

SULFATE SALT REPORTED IN https://patents.google.com/patent/US20170165267

nmr  http://file.selleckchem.com/downloads/nmr/s796001-loxo-101-methanol-hnmr-selleck.pdf

Figure US20170165267A1-20170615-C00006Figure US20170165267A1-20170615-C00007

Molecular Weight 526.51
Formula C21H22F2N6O2.H2O4S
CAS No. 1223405-08-0
  1. LOXO-101 sulfate
  2. Larotrectinib sulfate
  3. LOXO-101 (sulfate)
  4. 1223405-08-0
  5. UNII-RDF76R62ID
  6. RDF76R62ID
  7. ARRY-470 sulfate
  8. LOXO-101(sulfate)
  9. Larotrectinib sulfate [USAN]
  10. PXHANKVTFWSDSG-QLOBERJESA-N
  11. HY-12866A
  12. s7960
  13. AKOS030526332
  14. CS-5314

LOXO-101 is a small molecule that was designed to block the ATP binding site of the TRK family of receptors, with 2 to 20 nM cellular potency against the TRKA, TRKB, and TRKC kinases. IC50 value: 2 – 20 nM Target: TRKA/B/C in vitro: LOXO-101 is an orally administered inhibitor of the TRK kinase and is highly selective only for the TRK family of receptors. LOXO-101 is evaluated for off-target kinase enzyme inhibition against a panel of 226 non-TRK kinases at a compound concentration of 1,000 nM and ATP concentrations near the Km for each enzyme. In the panel, LOXO-101 demonstrates greater than 50% inhibition for only one non-TRK kinase (TNK2 IC50, 576 nM). Measurement of proliferation following treatment with LOXO-101 demonstrates a dose-dependent inhibition of cell proliferation in all three cell lines. The IC50 is less than 100 nM for CUTO-3.29 and less than 10 nM for KM12 and MO-91, consistent with the known potency of this drug for the TRK kinase family. [1] LOXO-101 demonstrates potent and highly-selective inhibition of TRKA, TRKB, and TRKC over other kinase- and non-kinase targets. LOXO-101 is a potent, ATP-competitive TRK inhibitor with IC50s in low nanomolar range for inhibition of all TRK family members in binding and cellular assays, with 100x selectivity over other kinases. [2] in vivo: Athymic nude mice injected with KM12 cells are treated with LOXO-101 orally daily for 2 weeks. Dose-dependent tumor inhibition is observed, demonstrating the ability of this selective compound to inhibit tumor growth in vivo. [1]

Image result for Larotrectinib

DOI

https://doi.org/10.1038/nrd.2018.4

SYNTHESIS

WO 2010048314

Synthesis of larotrectinib

N-Boc-pyrrolidine as starting material The method involves enantioselective deprotonation, transmetalation with ZnCl2, Negishi coupling with 2-bromo-1,4-difluorobenzene,

N-arylation with 5-chloropyrazolo[1,5-a]pyrimidine, nitration, nitro reduction and condensation with CDI and 3(S)-pyrrolidinol.

PRODUCT Patent

WO 2010048314

https://patents.google.com/patent/WO2010048314A1

InventorJulia HaasSteven W. AndrewsYutong JiangGan Zhang

Original AssigneeArray Biopharma Inc.

Priority date 2008-10-22

Example 14


(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-alpyrimidin-3-yl)- 3 -hydroxypyrrolidine- 1 -carboxamide

[00423] To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difiuorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, (S)-pyrrolidin-3-ol (17 mg, 0.19 mmol) [purchased from Suven Life Sciences] was added in one portion. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 50% acetonitrile/water to yield the final product as a yellowish foamy powder (30 mg, 74% yield). MS (apci) m/z = 429.2 (M+H).

Example 14A


(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolori,5-alpyrimidin-3-yl)- 3 -hydroxypyrrolidine- 1 -carboxamide sulfate

[00424] To a solution of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl)-3 -hydroxypyrrolidine- 1 -carboxamide (4.5 mg, 0.011 mmol) in methanol (1 mL) at ambient temperature was added sulfuric acid in MeOH (105 μL, 0.011 mmol). The resulting solution was stirred for 30 minutes then concentrated to provide (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-3 -hydroxypyrrolidine- 1 -carboxamide sulfate (5.2 mg, 0.0099 mmol, 94 % yield) as a yellow solid.

PATENT

WO 2017201241 

Examples

Preparation of 10:

1)

(R,E)-N-(2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (17): Compound 16 and (R)-2-methylpropane-2-sulfinamide (1.05 eq.) were charged to a reactor outfitted with a mechanical stirrer, reflux condensor, J-Kem temperature probe under N2. DCM (3 mL/g of 14) was added (endothermic from 22 °C to about 5 °C) followed by addition of cesium carbonate (0.70 eq.) (exothermic to -50 °C). Once the addition was complete, the reaction mixture was stirred at room temperature for 3 h (slowly cools from about 40 °C). When the reaction was called complete (HPLC) the mixture was filtered through Celite. The Celite pad (0.3 wt eq) was equilibrated with DCM (1 mL/g of 16), and the reaction mixture was poured through the pad. The Celite cake was washed with DCM (2 x 1 mL/g), and the filtrate concentrated partially to leave about 0.5 to 1 mL/g DCM remaining. The orange solution was stored at room temperature (generally overnight) and used directly in the next reaction. (100% yield was assumed).

2)

(R)-N-((R)-l-(2,5-difluorophenyl)-3-(l,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (19): To a reactor equipped with overhead stirring, reflux condensor, under

nitrogen, was added magnesium turnings (2.0 eq), and THF (8 mL/g of 17). The mixture was heated to 40 °C. Dibal-H (25% wt in toluene, 0.004 eq) was added to the solution, and the suspension heated at 40 °C for 25 minutes. A solution of 2-(2-bromoethyl)-l,3-dioxane (18) (2 eq) in THF (4.6 mL/g of 17) was added dropwise to the Mg solution via addition funnel. The solution temperature was maintained < 55 °C. The reaction progress was monitored by GC. When the Grignard formation was judged complete, the solution was cooled to -30 °C, and 17 (1.0 eq, in DCM) was added dropwise via addition funnel. The temperature was kept between -30 °C and -20 °C and the reaction was monitored for completion (FIPLC). Once the reaction was called complete, the suspension (IT = -27.7 °C) was vacuum transferred to a prepared and cooled (10 °C) 10% aqueous citric acid solution (11 mL/g of 17). The mixture temperature rose to 20 °C during transfer. The milky solution was allowed to stir at ambient temperature overnight. MTBE (5.8 mL/g) was added to the mixture, and it was transferred to a separatory funnel. The layers were allowed to separate, and the lower aqueous layer was removed. The organic layer was washed with sat. NaHC03 (11 mL/g) and then sat. NaCl (5.4 mL/g). The organic layer was removed and concentrated to minimum volume via vacuum distillation. MTBE (2 mL/g) was added, and the mixture again concentrated to minimum volume. Finally MTBE was added to give 2 mL/g total MTBE (GC ratio of MTBE:THF was about 9: 1), and the MTBE mixture was heated to 50 °C until full dissolution occurred. The MTBE solution was allowed to cool to about 35 °C, and heptane was added portion -wise. The first portion (2 mL/g) is added, and the mixture allowed to stir and form a solid for 1-2 h, and then the remainder of the heptane is added (8 mL/g). The suspension was allowed to stir for >lh. The solids were collected via filtration through polypropylene filter cloth (PPFC) and washed with 10% MTBE in heptane (4 mL/g. The wet solid was placed in trays and dried in a vacuum oven at 55 °C until constant weight (3101 g, 80.5%, dense white solid, 100a% and 100wt%).

3)

(R)-2-(2,5-difluorophenyl)pyrrolidine (R)-2-hydroxysuccinate (10): To a flask containing 4: 1 TFA:water (2.5 mL/g, pre-mixed and cooled to <35 °C before adding 19) was added (R)-N-((R)-l-(2,5-difluorophenyl)-3-(l,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (19) (1 eq). The mixture temperature rose from 34 °C to 48 °C and was stirred at ambient temperature for 1 h. Additional TFA (7.5 mL/g) was added, followed by triethylsilane (3 eq) over 5 minutes. The biphasic mixture was stirred vigorously under nitrogen for 21 h until judged complete (by GC, <5% of imine). The mixture was then concentrated under vacuum until -10 kg target mass (observed 10.8 kg after concentration). The resulting concentrate was transferred to a separatory funnel and diluted with MTBE (7.5 mL/g), followed by water (7.5 mL/g). The layers were separated. The MTBE layer was back-extracted with 1M HC1 (3 mL/g). The layers were separated, and the aqueous layers were combined in a round-bottomed flask with DCM (8 mL/g). The mixture was cooled in an ice bath and 40% NaOH was charged to adjust the pH to >12 (about 0.5 mL/g; the temperature went from 24 °C to 27 °C, actual pH was 13), and the layers separated in the separatory funnel. The aqueous layer was back-extracted twice with DCM (2 x 4 mL/g). The organic layers were concentrated to an oil (<0.5 mL/g) under vacuum (rotovap) and EtOH (1 mL/g based on product) was added. The yellow solution was again concentrated to an oil (81% corrected yield, with 3% EtOH, 0.2% imine and Chiral HPLC showed 99.7%ee).

Salt formation: To a solution of (R)-2-(2,5-difluorophenyl)pyrrolidine 10 (1 eq) in EtOH (15 mL/g) was added Z)-(+)-Malic Acid (1 eq). The suspension was heated to 70 °C for 30 minutes (full dissolution had occurred before 70 °C was reached), and then allowed to cool to room temperature slowly (mixture was seeded when the temperature was < 40 °C). The slurry was stirred at room temperature overnight, then cooled to <5 °C the next morning. The suspension was stirred at <5 °C for 2h, filtered (PPFC), washed with cold EtOH (2 x 2 mL/g), and dried (50-55 °C) under vacuum to give the product as a white solid (96% based on 91% potency, product is an EtOH solvate or hemi- solvate).

Preparation of the compound of Formula I:

1)

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)-3-nitropyrazolo[l,5-a]pyrimidine (11):

Compound 5 and 10 (1.05 eq) were charged to a reactor outfitted with a mechanical stirrer, J-Kem temperature probe, under N2. EtOH and THF (4: 1, 10 mL/g of 5) were added and the mixture was cooled to 15-25 °C. Triethylamine (3.5 eq) was added and the internal temp generally rose from 17.3 – 37.8 °C. The reaction was heated to 50 – 60 °C and held at that temperature for 7 h. Once the reaction is judged complete (HPLC), water (12 mL/g of 5) is added maintaining the temperature at 50 – 60 °C. The heat is removed and the suspension was slowly cooled to 21 °C over two h. After stirring at -21 °C for 2 h, the suspension was centrifuged and the cake was washed with water (3 x 3 mL/g of 5). The solid was transferred to drying trays and placed in a vacuum oven at 50 – 55 °C to give 11.

2)

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine fumarate Pt/C hydrogenation (12 fumarate): To a Parr reactor was charged 11 (1.0 eq), 5% Pt/C ~ 50 wt% water (2 mol% Pt / Johnson Matthey B 103018-5 or Sigma Aldrich 33015-9), and MeOH (8 mL/g). The suspension was stirred under hydrogen at 25-30 psi and the temperature was maintained below 65 °C for ~8 h. When the reaction was called complete (HPLC), the reaction was cooled to 15 – 25 °C and the hydrogen atmosphere was replaced with a nitrogen atmosphere. The reaction mixture was filtered through a 2 micron bag filter and a 0.2 micron line filter in series. The filtrate from the Pt/C hydrogenation was transferred to a reactor under nitrogen with mechanical stirring and then MTBE (8 mL/g) and fumaric acid (1.01 eq) were charged. The mixture was stirred under nitrogen for 1 h and solids formed after -15 min. The mixture was cooled to -10 to -20 °C and stirred for 3 h. The suspension was filtered (PPFC), washed with MTBE (-2.5 mL/g), and the solids was dried under vacuum at 20-25 °C with a nitrogen bleed to yield an off-white solid (83% yield).

3)

Phenyl (5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)-3,3a-dihydropyrazolo[l,5-a]pyrimidin-3-yl)carbamate (13): To a 5 to 15°C solution of 12-fumarate (1.0 eq) in 2-MeTHF (15 mL/g) was added a solution of potassium carbonate (2.0 eq.) in water (5 mL/g) followed by phenyl chloroformate (1.22 eq.) (over 22 min, an exotherm from 7 °C to 11 °C occurred). The mixture was stirred for 2 h and then the reaction was called complete (HPLC). The stirring ceased and the aqueous layer was removed. The organic layer was washed with brine (5 mL/g) and concentrated to ca. 5 mL/g of 2-MeTHF under vacuum and with heating to 40 °C. To the 2-MeTHF solution was added heptanes (2.5 mL/g) followed by seeds (20 mg, 0.1 wt%). This mixture was allowed to stir at room temperature for 2 h (until a solid formed), and then the remainder of the heptanes (12.5 mL/g) was added. The mixture was stirred at ambient temperature for 2 h and then the solids were collected via filtration (PPFC), washed with 4: 1 heptanes :MeTHF (2 x 2 mL/g), and dried to give 13 (96%).

4)

(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide hydrogen sulfate: To a flask containing 13 (1.0 eq) was added a solution of (S)-pyrrolidin-3-ol (1.1 eq.) in EtOH (10 mL/g). The mixture was heated at 50 – 60 °C for 5 h, called complete (HPLC), and then cooled to 20-35 °C. Once <35°C, the reaction was polish-filtered (0.2 micron) into a clean reaction vessel and the mixture was cooled to -5 to 5 °C. Sulfuric acid (1.0 eq.) was added over 40 minutes, the temperature rose to 2 °C and the mixture was seeded. A solid formed, and the mixture was allowed to stir at -5 to 5 °C for 6.5 h. Heptanes (10 mL/g) was added, and the mixture stirred for 6.5 h. The

suspension was filtered (PPFC), washed with 1 : 1 EtOH:heptanes (2 x 2 mL/g), and dried (under vacuum at ambient temperature) to give Formula I (92.3%).

Preparation of the hydrogen sulfate salt of the compound of Formula I:

Concentrated sulfuric acid (392 mL) was added to a solution of 3031 g of (S)-N-(5- ((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide in 18322 mL EtOH to form the hydrogen sulfate salt. The solution was seeded with 2 g of (,S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide hydrogen sulfate and the solution was stirred at room temperature for at least 2 hours to form a slurry of the hydrogen sulfate salt. Heptane (20888 g) was added and the slurry was stirred at room temperature for at least 60 min. The slurry was filtered and the filter cake was washed with 1 : 1 heptane/EtOH. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius).

The dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5 :95 w/w solution of water/2-butanone (total weight 41652 g). The mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed. The slurry was filtered, and the filter cake was washed with a 5 :95 w/w solution of water/2-butanone. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius) to provide the crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide hydrogen sulfate.

PATENT

US2017165267

https://patents.google.com/patent/US20170165267

Provided herein is a novel crystalline form of the compound of Formula I:

[0000]

Figure US20170165267A1-20170615-C00001

also known as (S)—N-(5-((R)-2-(2, 5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide. In particular, the novel crystalline form comprises the hydrogen sulfate salt of the compound of Formula I in a stable polymorph form, hereinafter referred to as crystalline form (I-HS) and LOXO-101, which can be characterized, for example, by its X-ray diffraction pattern—the crystalline form (I-HS) having the formula:

[0000]

Figure US20170165267A1-20170615-C00002

In some embodiments of the above step (c), the base is an alkali metal base, such as an alkali metal carbonate, such as potassium carbonate.

Figure US20170165267A1-20170615-C00004

Preparation of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine Step A—Preparation of sodium pyrazolo[1,5-a]pyrimidin-5-olate

A solution of 1H-pyrazol-5-amine and 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (1.05 equiv.) were charged to a round bottom flask outfitted with a mechanical stirrer, a steam pot, a reflux condenser, a J-Kem temperature probe and an Nadaptor for positive Npressure control. Under mechanical stirring the solids were suspended with 4 vol. (4 mL/g) of absolute EtOH under a nitrogen atmosphere, then charged with 2.1 equivalents of NaOEt (21 wt % solution in EtOH), and followed by line-rinse with 1 vol. (1 mL/g) of absolute EtOH. The slurry was warmed to about 75° Celsius and stirred at gentle reflux until less than 1.5 area % of 1H-pyrazol-5-amine was observed by TRK1PM1 HPLC to follow the progression of the reaction using 20 μL of slurry diluted in 4 mL deionized water and 5 μL injection at 220 nm.

After 1 additional hour, the mixture was charged with 2.5 vol. (2.5 mL/g) of heptane and then refluxed at 70° Celsius for 1 hour. The slurry was then cooled to room temperature overnight. The solid was collected by filtration on a tabletop funnel and polypropylene filter cloth. The reactor was rinsed and charged atop the filter cake with 4 vol. (4 mL/g) of heptane with the cake pulled and the solids being transferred to tared drying trays and oven-dried at 45° Celsius under high vacuum until their weight was constant. Pale yellow solid sodium pyrazolo[1,5-a]-pyrimidin-5-olate was obtained in 93-96% yield (corrected) and larger than 99.5 area % observed by HPLC (1 mg/mL dilution in deionized water, TRK1PM1 at 220 nm).

Step B—Preparation of 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one

A tared round bottom flask was charged with sodium pyrazolo[1,5-a]pyrimidin-5-olate that was dissolved at 40-45° Celsius in 3.0 vol. (3.0 mL/g) of deionized water, and then concentrated under high vacuum at 65° Celsius in a water-bath on a rotary evaporator until 2.4× weight of starting material was observed (1.4 vol/1.4 mL/g deionized water content). Gas chromatography (GC) for residual EtOH (30 μL of solution dissolved in ˜1 mL MeOH) was performed showing less than 100 ppm with traces of ethyl nitrate fumes being observed below upon later addition of HNO3. In some cases, the original solution was charged with an additional 1.5 vol. (1.5 mL/g) of DI water, then concentrated under high vacuum at 65° Celsius in a water-bath on a rotary evaporator until 2.4× weight of starting material was observed (1.4 vol/1.4 mL/g DI water content). Gas chromatograph for residual EtOH (30 μL of solution dissolved in about 1 mL MeOH) was performed showing <<100 ppm of residual EtOH without observing any ethyl nitrate fumes below upon later addition of HNO3.

A round bottom vessel outfitted with a mechanical stirrer, a steam pot, a reflux condenser, a J-Kem temperature probe and an Nadaptor for positive Npressure control was charged with 3 vol. (3 mL/g, 10 equiv) of >90 wt % HNOand cooled to about 10° Celsius under a nitrogen atmosphere using external ice-water cooling bath under a nitrogen atmosphere. Using a pressure equalizing addition funnel, the HNO3solution was charged with the 1.75-1.95 volumes of a deionized water solution of sodium pyrazolo[1,5-a]pyrimidin-5-olate (1.16-1.4 mL DI water/g of sodium pyrazolo[1,5-a]pyrimidin-5-olate) at a rate to maintain 35-40° Celsius internal temperature under cooling. Two azeotropes were observed without any ethyl nitrate fumes. The azeotrope flask, the transfer line (if applicable) and the addition funnel were rinsed with 2×0.1 vol. (2×0.1 mL/g) deionized water added to the reaction mixture. Once the addition was complete, the temperature was gradually increased to about 45-50° Celsius for about 3 hours with HPLC showing >99.5 area % conversion of sodium pyrazolo[1,5-a]pyrimidin-5-olate to 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one.

Step C—Preparation of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine

3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one was charged to a round bottom flask outfitted with a mechanical stirrer, a heating mantle, a reflux condenser, a J-Kem temperature probe and an Nadaptor for positive N2pressure control. Under mechanical stirring the solids were suspended with 8 volumes (8 mL/g) of CH3CN, and then charged with 2,6-lutitine (1.05 equiv) followed by warming the slurry to about 50° Celsius. Using a pressure equalizing addition funnel, the mixture was dropwise charged with 0.33 equivalents of POCl3. This charge yielded a thick, beige slurry of a trimer that was homogenized while stirring until a semi-mobile mass was observed. An additional 1.67 equivalents of POClwas charged to the mixture while allowing the temperature to stabilize, followed by warming the reaction mixture to a gentle reflux (78° Celsius). Some puffing was observed upon warming the mixture that later subsided as the thick slurry got thinner.

The reaction mixture was allowed to reflux until complete dissolution to a dark solution and until HPLC (20 μL diluted in 5 mL of CH3CN, TRK1PM1 HPLC, 5 μL injection, 268 nm) confirmed that no more trimer (RRT 0.92) was present with less than 0.5 area % of 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one (RRT 0.79) being observed by manually removing any interfering and early eluting peaks related to lutidine from the area integration. On a 1.9 kg scale, 0 area % of the trimer, 0.25 area % of 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one, and 99.5 area % of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine was observed after 19 hours of gentle reflux using TRK1PM1 HPLC at 268 [0000]

Figure US20170165267A1-20170615-C00005

Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxysuccinate Step A—Preparation of tert-butyl(4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate

2-bromo-1,4-difluorobenzene (1.5 eq.) was dissolved in 4 volumes of THF (based on weight of tert-butyl 2-oxopyrrolidine-1-carboxylate) and cooled to about 5° Celsius. A solution of 2.0 M iPrMgCl in THF (1.4 eq.) was added over 2 hours to the mixture while maintaining a reaction temperature below 25° Celsius. The solution was allowed to cool to about 5° Celsius and stirred for 1 hour (GC analysis confirmed Grignard formation). A solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.0 eq.) in 1 volume of THF was added over about 30 min while maintaining a reaction temperature below 25° Celsius. The reaction was stirred at about 5° Celsius for 90 min (tert-butyl 2-oxopyrrolidine-1-carboxylate was confirmed to be less than 0.5 area % by HPLC). The reaction was quenched with 5 volumes of 2 M aqueous HCl while maintaining a reaction temperature below 45° Celsius. The reaction was then transferred to a separatory funnel adding 10 volumes of heptane and removing the aqueous layer. The organic layer was washed with 4 volumes of saturated aqueous NaCl followed by addition of 2×1 volume of saturated aqueous NaCl. The organic layer was solvent-switched to heptane (<1% wt THF confirmed by GC) at a distillation temperature of 35-55° Celsius and distillation pressure of 100-200 mm Hg for 2×4 volumes of heptane being added with a minimum distillation volume of about 7 volumes. The mixture was then diluted to 10 volumes with heptane while heating to about 55° Celsius yielded a denser solid with the mixture being allowed to cool to room temperature overnight. The slurry was cooled to less than 5° Celsius and filtered through polypropylene filter cloth. The wet cake was washed with 2×2 volumes of heptane. The solids were dried under vacuum at 55° Celsius until the weight was constant, yielding tert-butyl(4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate as a white solid at about 75% to 85% theoretical yield.

Step B—Preparation of 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole

tert-butyl(4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate was dissolved in 5 vol. of toluene with 2.2 eq. of 12M HCl being added observing a mild exotherm and gas evolution. The reaction was heated to 65° Celsius for 12-24 hours and monitored by HPLC. Upon completion the reaction was cooled to less than 15° Celsius with an ice/water bath. The pH was adjusted to about 14 with 3 equivalents of 2M aqueous NaOH (4.7 vol.). The reaction was stirred at room temperature for 1-2 hours. The mixture was transferred to a separatory funnel with toluene. The aqueous layer was removed and the organic layer was washed with 3 volumes of saturated aqueous NaCl. The organic layer was concentrated to an oil and redissolved in 1.5 volumes of heptane. The resulting suspension was filtered through a GF/F filter paper and concentrated to a light yellow oil of 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole with a 90% to 100% theoretical yield.

Step C—Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine

Chloro-1,5-cyclooctadiene iridium dimer (0.2 mol %) and (R)-2-(2-(diphenylphosphino)phenyl)-4-isopropyl-4,5-dihydrooxazole (0.4 mol %) were suspended in 5 volumes of MTBE (based on 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole) at room temperature. The mixture was stirred for 1 hour and most of the solids dissolved with the solution turning dark red. The catalyst formation was monitored using an HPLC/PDA detector. The reaction was cooled to less than 5° Celsius and 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole (1.0 eq.) was added using a 0.5 volumes of MTBE rinse. Diphenylsilane (1.5 eq.) was added over about 20 minutes while maintaining a reaction temperature below 10° Celsius. The reaction was stirred for 30 minutes below 10° Celsius and then allowed to warm to room temperature. The reaction was stirred overnight at room temperature. The completion of the reaction was confirmed by HPLC and then cooled to less than 5° Celsius. The reaction was quenched with 5 volumes of 2M aqueous HCl maintaining temperature below 20° Celsius. After 10 minutes the ice/water bath was removed and the reaction temperature was allowed to increase to room temperature while stirring for 2 hours. The mixture was transferred to a separatory funnel with 3 volumes of MTBE. The aqueous layer was washed with 3.5 volumes of MTBE followed by addition of 5 volumes of MTBE to the aqueous layer while adjusting the pH to about 14 by adding 0.75 volumes of aqueous 50% NaOH. The organic layer was washed with 5 volumes of aqueous saturated NaCl, then concentrated to an oil, and diluted with 3 volumes of MTBE. The solution was filtered through a polypropylene filter cloth and rinsed with 1 volume of MTBE. The filtrate was concentrated to an oil of (R)-2-(2,5-difluorophenyl)-pyrrolidine with a 95% to 100% theoretical yield and with 75-85% ee.

Step D—Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate

(R)-2-(2,5-difluorophenyl)-pyrrolidine (1.0 eq.) was transferred to a round bottom flask charged with 15 volumes (corrected for potency) of EtOH (200 prf). D-malic acid (1.05 eq.) was added and the mixture was heated to 65° Celsius. The solids all dissolved at about 64° Celsius. The solution was allowed to cool to RT. At about 55° Celsius the solution was seeded with (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate (about 50 mg, >97% ee) and stirred at room temperature overnight. The suspension was then filtered through a polypropylene filter cloth and washed with 2×1 volumes of EtOH (200 prf). The solids were dried under vacuum at 55° Celsius, yielding (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate with a 75% to 90% theoretical yield and with >96% ee.

Referring to Scheme 1, suitable bases include tertiary amine bases, such as triethylamine, and K2CO3. Suitable solvents include ethanol, heptane and tetrahydrofuran (THF). The reaction is conveniently performed at temperatures between 5° Celsius and 50° Celsius. The reaction progress was generally monitored by HPLC TRK1PM1.

Figure US20170165267A1-20170615-C00006

Figure US20170165267A1-20170615-C00007

[0247]

Compounds II (5-chloro-3-nitropyrazolo[1,5-a]pyrimidine) and III ((R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxysuccinate, 1.05 eq.) were charged to a round bottom flask outfitted with a mechanical stirrer, a J-Kem temperature probe and an Nadaptor for positive Npressure control. A solution of 4:1 EtOH:THF (10 mL/g of compound II) was added and followed by addition of triethylamine (NEt3, 3.50 eq.) via addition funnel with the temperature reaching about 40° Celsius during addition. Once the addition was complete, the reaction mixture was heated to 50° Celsius and stirred for 0.5-3 hours to yield compound IV.

To a round bottom flask equipped with a mechanical stirrer, a J-Kem temperature probe, and an Ninlet compound IV was added and followed by addition of tetrahydrofuran (10 mL/g of compound IV). The solution was cooled to less than 5° Celsius in an ice bath, and Zn (9-10 eq.) was added. 6M HCl (9-10 eq.) was then added dropwise at such a rate to keep the temperature below 30° Celsius (for 1 kg scale the addition took about 1.5 hours). Once the exotherm subsided, the reaction was allowed to warm to room temperature and was stirred for 30-60 min until compound IV was not detected by HPLC. At this time, a solution of potassium carbonate (K2CO3, 2.0 eq.) in water (5 mL/g of compound IV) was added all at once and followed by rapid dropwise addition of phenyl chloroformate (PhOCOCl, 1.2 eq.). Gas evolution (CO2) was observed during both of the above additions, and the temperature increased to about 30° Celsius after adding phenyl chloroformate. The carbamate formation was stirred at room temperature for 30-90 min. HPLC analysis immediately followed to run to ensure less than 1 area % for the amine being present and high yield of compound VI in the solution.

To the above solution amine VII ((S)-pyrrolidin-3-ol, 1.1 eq. based on theoretical yield for compound VI) and EtOH (10 mL/g of compound VI) was added. Compound VII was added before or at the same time as EtOH to avoid ethyl carbamate impurities from forming. The above EtOH solution was concentrated to a minimum volume (4-5 mL/g) using the batch concentrator under reduced pressure (THF levels should be <5% by GC), and EtOH (10 mL/g of compound VI) was back-added to give a total of 10 mL/g. The reaction was then heated at 50° Celsius for 9-19 hours or until HPLC shows that compound VI is less than 0.5 area %. The reaction was then cooled to room temperature, and sulfuric acid (H2SO4, 1.0 eq. to compound VI) was added via addition funnel to yield compound I-HS with the temperature usually exotherming at about 30° Celsius.

Example 1 Preparation of Crystalline Form (I-HS) (Method 1)

(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (0.500 g, 1.17 mmol) was dissolved in EtOH (2.5 mL) and cooled to about 5° Celsius. Concentrated sulfuric acid (0.0636 mL, 1.17 mmol) was added to the cooled solution and stirred for about 10 min, while warming to room temperature. Methyl tert-butyl ether (MTBE) (2 mL) was slowly added to the mixture, resulting in the product gumming out. EtOH (2.5 mL) was then added to the mixture and heated to about reflux until all solids were dissolved. Upon cooling to room temperature and stirring for about 1 hour, some solids formed. After cooling to about 5° Celsius, the solids were filtered and washed with MTBE. After filtration and drying at air for about 15 minutes, (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate was isolated as a solid.

Example 2 Preparation of Crystalline Form (I-HS) (Method 2)

Concentrated sulfuric acid (392 mL) was added to a solution of 3031 g of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide in 18322 mL EtOH to form the hydrogen sulfate salt. The solution was seeded with 2 g of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate and the solution was stirred at room temperature for at least 2 hours to form a slurry of the hydrogen sulfate salt. Heptane (20888 g) was added and the slurry was stirred at room temperature for at least 60 min. The slurry was filtered and the filter cake was washed with 1:1 heptane/EtOH. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius).

The dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5:95 w/w solution of water/2-butanone (total weight 41652 g). The mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed. The slurry was filtered, and the filter cake was washed with a 5:95 w/w solution of water/2-butanone. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius) to provide the crystalline form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate.

Example 3 Preparation of Amorphous Form AM(HS)

To a solution of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (9.40 g, 21.94 mmol) in MeOH (220 mL) was slowly added sulfuric acid (0.1 M in MeOH, 219.4 mL, 21.94 mmol) at ambient temperature under rapid stirring. After 30 minutes, the reaction was first concentrated by rotary evaporator to near dryness, then on high vacuum for 48 h to provide amorphous form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate (11.37 g, 21.59 mmol, 98.43% yield). LCMS (apci m/z 429.1, M+H).

PATENT

CN 107987082

PATENT

https://patents.google.com/patent/US20170281632A1/en

WO 2010/048314 discloses in Example 14A a hydrogen sulfate salt of (S)—N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide. WO 2010/048314 does not disclose the particular form of the hydrogen sulfate salt described herein when prepared according to the method of Example 14A in that document. In particular, WO 2010/048314 does not disclose crystalline form (l-HS) as described below.

(S)—N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide having the formula (I):

Figure US20170281632A1-20171005-C00001

Example 1 Preparation of Crystalline Form (I-HS) (Method 1)

(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (0.500 g, 1.17 mmol) was dissolved in EtOH (2.5 mL) and cooled to about 5° Celsius. Concentrated sulfuric acid (0.0636 mL, 1.17 mmol) was added to the cooled solution and stirred for about 10 min, while warming to room temperature. Methyl tert-butyl ether (MTBE) (2 mL) was slowly added to the mixture, resulting in the product gumming out. EtOH (2.5 mL) was then added to the mixture and heated to about reflux until all solids were dissolved. Upon cooling to room temperature and stirring for about 1 hour, some solids formed. After cooling to about 5° Celsius, the solids were filtered and washed with MTBE. After filtration and drying at air for about 15 minutes, (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidi n-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate was isolated as a solid.

Example 2 Preparation of Crystalline Form (I-HS) (Method 2)

Concentrated sulfuric acid (392 mL) was added to a solution of 3031 g of (S)—N-(5-((R)-2-(2, 5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1, 5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide in 18322 mL EtOH to form the hydrogen sulfate salt. The solution was seeded with 2 g of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate and the solution was stirred at room temperature for at least 2 hours to form a slurry of the hydrogen sulfate salt. Heptane (20888 g) was added and the slurry was stirred at room temperature for at least 60 min. The slurry was filtered and the filter cake was washed with 1:1 heptane/EtOH. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius).

The dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5:95 w/w solution of water/2-butanone (total weight 41652 g). The mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed. The slurry was filtered, and the filter cake was washed with a 5:95 w/w solution of water/2-butanone. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius) to provide the crystalline form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate.

Example 3 Preparation of Amorphous Form AM(HS)

To a solution of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (9.40 g, 21.94 mmol) in MeOH (220 mL) was slowly added sulfuric acid (0.1 M in MeOH, 219.4 mL, 21.94 mmol) at ambient temperature under rapid stirring. After 30 minutes, the reaction was first concentrated by rotary evaporator to near dryness, then on high vacuum for 48 h to provide amorphous form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate (11.37 g, 21.59 mmol, 98.43% yield). LCMS (apci m/z 429.1, M+H).

References

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US8865698 Method of treatment using substituted pyrazolo[1, 5-a]pyrimidine compounds
2013-07-16
2014-10-21
US8513263 Substituted Pyrazolo[1, 5-a]Pyrimidine Compounds as TRK Kinase Inhibitors
2011-08-11
US2017165267 CRYSTALLINE FORM OF (S)-N-(5-((R)-2-(2, 5-DIFLUOROPHENYL)-PYRROLIDIN-1-YL)-PYRAZOLO[1, 5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE HYDROGEN SULFATE
2017-01-05
US2017260589 POINT MUTATIONS IN TRK INHIBITOR-RESISTANT CANCER AND METHODS RELATING TO THE SAME
2016-10-26
US9676783 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-A] PYRIMIDINE COMPOUNDS
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US9676783 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-A] PYRIMIDINE COMPOUNDS
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US2015073036 NOVEL NTRK1 FUSION MOLECULES AND USES THEREOF
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US2017114067 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-A] PYRIMIDINE COMPOUNDS
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US2016137654 CRYSTALLINE FORM OF (S)-N-(5-((R)-2-(2, 5-DIFLUOROPHENYL)-PYRROLIDIN-1-YL)-PYRAZOLO[1, 5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE HYDROGEN SULFATE
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US2015366866 METHODS OF TREATING CHOLANGIOCARCINOMA
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US8865698 Method of treatment using substituted pyrazolo[1, 5-a]pyrimidine compounds
2013-07-16
2014-10-21
US8513263 Substituted Pyrazolo[1, 5-a]Pyrimidine Compounds as TRK Kinase Inhibitors
2011-08-11
US2017165267 CRYSTALLINE FORM OF (S)-N-(5-((R)-2-(2, 5-DIFLUOROPHENYL)-PYRROLIDIN-1-YL)-PYRAZOLO[1, 5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE HYDROGEN SULFATE
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US2017260589 POINT MUTATIONS IN TRK INHIBITOR-RESISTANT CANCER AND METHODS RELATING TO THE SAME
2016-10-26

///////////Larotrectinib, UNII:PF9462I9HX, ларотректиниб , 拉罗替尼 , ARRY-470, LOXO-101, PF9462I9HX, phase 3,  Array BioPharma, Loxo Oncology, National Cancer Institute, BAYER, orphan drug designation, breakthrough therapy designation

C1CC(N(C1)C2=NC3=C(C=NN3C=C2)NC(=O)N4CCC(C4)O)C5=C(C=CC(=C5)F)F.OS(=O)(=O)O

Copanlisib


Copanlisib.svgChemSpider 2D Image | Copanlisib | C23H28N8O4

Copanlisib, BAY 80-6946, 

  • BAY 84-1236
  • Molecular FormulaC23H28N8O4
  • Average mass480.520 Da

Cas 1032568-63-0 [RN]

1402152-26-4 MONO HCL

UNII-WI6V529FZ9

FDA Approved September 2017

2-Amino-N-{7-methoxy-8-[3-(4-morpholinyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-5-pyrimidinecarboxamide
5-Pyrimidinecarboxamide, 2-amino-N-[2,3-dihydro-7-methoxy-8-[3-(4-morpholinyl)propoxy]imidazo[1,2-c]quinazolin-5-yl]-

Copanlisib (BAY 80-6946), developed by Bayer, is a selective Class I phosphoinositide 3-kinase inhibitor[1] which has shown promise in Phase I/II clinical trials for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia.[2]

Image result for copanlisib

Copanlisib is a selective pan-Class I phosphoinositide 3-kinase (PI3K/Phosphatidylinositol-4,5-bisphosphate 3-kinase/phosphatidylinositide 3-kinase) inhibitor that was first developed by Bayer Healthcare Pharmaceuticals, Inc. The drug targets the enzyme that plays a role in regulating cell growth and survival. Copanlisib was granted accelerated approval on September 14, 2017 under the market name Aliqopa for the treatment of adult patients with relapsed follicular lymphoma and a treatment history of at least two prior systemic therapies. Follicular lymphoma is a slow-growing type of non-Hodgkin lymphoma that is caused by unregulated proliferation and growth of lymphocytes. The active ingredient in Aliquopa intravenous therapy is copanlisib dihydrochloride.

Image result for copanlisib

Copanlisib dihydrochloride.pngCopanlisib dihydrochloride; UNII-03ZI7RZ52O; 03ZI7RZ52O; 1402152-13-9; BAY 80-6946 dihydrochloride;

Image result for copanlisib

1402152-46-8 CAS  X=4, 

1919050-77-3 CAS X=1

The FDA awarded copanlisib orphan drug status for follicular lymphoma in February 2015.[3]

Phase II clinical trials are in progress for treatment of endometrial cancer,[4] diffuse large B-cell lymphoma,[5] cholangiocarcinoma,[6]and non-Hodgkin lymphoma.[7] Copanlisib in combination with R-CHOP or R-B (rituximab and bendamustine) is in a phase III trial for relapsed indolent non-Hodgkin lymphoma (NHL).[8] Two separate phase III trials are investigating the use of copanlisib in combination with rituximab for indolent NHL[9] and the other using copanlisib alone in cases of rituximab-refractory indolent NHL.[10]

Copanlisib hydrochloride, a phosphatidylinositol 3-Kinase inhibitor developed by Bayer, was first approved and launched in 2017 in the U.S. for the intravenous treatment of adults with relapsed follicular lymphoma who have received at least two prior treatments.

In 2015, orphan drug designation was assigned in the U.S. for the treatment of follicular lymphoma. In 2017, additional orphan drug designations were granted in the U.S. for the treatment of splenic, nodal and extranodal marginal zone lymphoma.

SYN

WO 2017049983

PATENTS

WO 2008070150

Inventors Martin HentemannJill WoodWilliam ScottMartin MichelsAnn-Marie CampbellAnn-Marie BullionR. Bruce RowleyAniko RedmanLess «
Applicant Bayer Schering Pharma Aktiengesellschaft

Example 13

Preparation of 2-amino-N-r7-methoxy-8-(3-morpholin-4-ylpropoxy)-2.3- dihvdroimidazori^-clquinazolin-S-vHpvrimidine-S-carboxamide.

Figure imgf000084_0001

Step 1 : Preparation of 4-hvdroxy-3-methoxy-2-nitrobenzonitrile

Figure imgf000084_0002

4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (200 g, 1.01 mol) was dissolved in THF (2.5 L) and then ammonium hydroxide (2.5 L) was added followed by iodine (464 g, 1.8 mol). The resulting mixture was allowed to stir for 2 days at which time it was concentrated under reduced pressure. The residue was acidified with HCI (2 N) and extracted into diethyl ether. The organic layer was washed with brine and dried (sodium sulfate) and concentrated under reduced pressure. The residue was washed with diethyl ether and dried under vacuum to provide the title compound (166 g, 84%): 1H NMR (DMSO-cfe) δ: 11.91 (1 H, s), 7.67 (1 H, d), 7.20 (1 H, d), 3.88 (3H, s)

Step 2: Preparation of 3-methoxy-4-(3-morpholin-4-ylpropoxy)-2-nitrobenzonitrile

Figure imgf000084_0003

To a solution of 4-hydroxy-3-methoxy-2-nitrobenzonitrile (3.9 g, 20.1 mmol) in DMF (150 mL) was added cesium carbonate (19.6 g, 60.3 mmol) and Intermediate C (5.0 g, 24.8 mmol). The reaction mixture was heated at 75 0C overnight then cooled to room temperature and filtered through a pad of silica gel and concentrated under reduced pressure. The material thus obtained was used without further purification

Step 3: Preparation of 2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile

Figure imgf000085_0001

3-Methoxy-4-(3-morpholin-4-ylpropoxy)-2-nitrobenzonitrile (7.7 g, 24.1 mmol) was suspended in acetic acid (170 ml_) and cooled to 0 °C. Water (0.4 ml_) was added, followed by iron powder (6.7 g, 120 mmol) and the resulting mixture was stirred at room temperature for 4 h at which time the reaction mixture was filtered through a pad of Celite and washed with acetic acid (400 ml_). The filtrate was concentrated under reduced pressure to 100 mL and diluted with EtOAc (200 ml.) at which time potassium carbonate was added slowly. The resulting slurry was filtered through a pad of Celite washing with EtOAc and water. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution. The organic layer was separated and passed through a pad of silica gel. The resultant solution was concentrated under reduced pressure to provide the title compound (6.5 g, 92%): 1H NMR (DMSO-Cf6) δ: 7.13 (1 H1 d), 6.38 (1 H, d), 5.63 (2H1 br s), 4.04 (2H, t), 3.65 (3H, s), 3.55 (4H1 br t), 2.41 (2H, t), 2.38 (4H1 m), 1.88 (2H1 quint.).

Step 4: Preparation of 6-(4.5-dihvdro-1 H-imidazol-2-v0-2-methoxy-3-(3-morpholin- 4-ylpropoxy)aniline

Figure imgf000085_0002

To a degassed mixture of 2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile (6.5 g, 22.2 mmol) and ethylene diamine (40 mL) was added sulfur (1.8 g, 55.4 mmol). The mixture was stirred at 100 °C for 3 h at which time water was added to the reaction mixture. The precipitate that was formed was collected and washed with water and then dried overnight under vacuum to provide the title compound (3.2 g, 43%): HPLC MS RT = 1.25 min, MH+= 335.2; 1H NMR (DMSO-Cf6) δ: 7.15 (1H, d), 6.86 (2H, br s), 6.25 (1 H, d), 4.02 (2H, t), 3.66 (3H, s), 3.57 (8H, m), 2.46 (2H, t), 2.44 (4H, m), 1.89 (2H, quint.). Step 5: Preparation of 7-methoxy-8-(3-morpholin-4-ylpropoxy)-2.3- dihvdroimidazof1.2-clquinazolin-5-amine

Figure imgf000086_0001

Cyanogen bromide (10.9 g, 102.9 mmol) was added to a mixture of 6-(4,5-dihydro-1 H- imidazol-2-yl)-2-methoxy-3-(3-morpholin-4-ylpropoxy)aniline (17.2 g, 51.4 mmol) and TEA (15.6 g, 154.3 mmol) in DCM (200 ml_) precooled to 0 0C. After 1 h the reaction mixture was concentrated under reduced pressure and the resulting residue stirred with EtOAc (300 mL) overnight at rt. The resulting slurry was filtered to generate the title compound contaminated with triethylamine hydrobromide (26.2 g, 71%): HPLC MS RT = 0.17 min, MH+= 360.2.

Step 6: Preparation of 2-amino-N-r7-methoxy-8-(3-morpholin-4-ylpropoxy)-2.3- dihvdroimidazori ^-clquinazolin-S-vnpyrimidine-δ-carboxamide.

Figure imgf000086_0002

7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (100 mg, 0.22 mol) was dissolved in DMF (5 mL), and Intermediate B (46 mg, 0.33 mmol) was added. PYBOP (173 mg, 0.33 mmol) and diisopropylethylamine (0.16 mL, 0.89 mmol) were subsequently added, and the mixture was stirred at rt overnight. EtOAc was added, and the solids were isolated by vacuum filtration to give the title compound (42.7 mg, 40%): HPLC MS RT = 1.09 min, MH+= 481.2; 1H NMR (DMSO-Cf6 + 2 drops TFA-tf) δ: 9.01 (2H, s), 8.04 (1 H, d), 7.43 (1 H, d), 4.54 (2H, m), 4.34 (2H, br t), 4.23 (2H, m), 4.04 (2H, m), 4.00 (3H, s), 3.65 (2H, br t), 3.52 (2H, m), 3.31 (2H, m), 3.18 (2H, m), 2.25 (2H, m).

PATENT

CN 105130998

TRANSLATED

Example VI:

[0053] a nitrogen atmosphere, the reaction flask was added 7-methoxy-8- (3-morpholin-4-yl-propoxy) -2,3-dihydro-imidazo [l, 2-c] quinoline tetrazol-5-amine (V) (0 • 36g, lmmol), 2- amino-5-carboxylic acid (0 • 15g, l.lmmol) and acetonitrile 25mL, condensing agent added benzotriazole-1-yl yloxy-tris (dimethylamino) phosphonium hexafluorophosphate key (0.49g, 1. lmmol) and the base catalyst 1,5_-diazabicyclo [4. 3.0] – non-5-ene (0 . 50g, 4mmol), at room temperature for 12 hours.Then heated to 50-60 ° C, the reaction was stirred for 6-8 hours, TLC the reaction was complete. The solvent was distilled off under reduced pressure, cooled to room temperature, ethyl acetate was added solid separated. Filter cake washed with cold methanol and vacuum dried to give an off-white solid Kupannixi (1) 0.278, showing a yield of 56.3% -] \ ^ 111/2: 481 [] \ 1+ buckle + 1 111 bandit ? (square) (: 13). 5 2.05 (111,211), 2.48 (111,411), 2. 56 (m, 2H), 3 72 (t, 4H), 4 02 (s, 3H),. 4. 16 (m, 7H), 5. 36 (s, 2H), 6. 84 (d, 1H), 7. 08 (d, 1H), 9. 10 (s, 2H) square

PATENT

WO 2016071435

2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide (10), (which is hereinafter referred to as„copanlisib”), is a proprietary cancer agent with a novel mechanism of action, inhibiting Class I phosphatidylinositol-3-kinases (PI3Ks). This class of kinases is an attractive target since PI3Ks play a central role in the transduction of cellular signals from surface receptors for survival and proliferation. Copanlisib exhibits a broad spectrum of activity against tumours of multiple histologic types, both in vitro and in vivo.

Copanlisib may be synthesised according to the methods given in international patent application PCT/EP2003/010377, published as WO 04/029055 A1 on April 08, 2004, (which is incorporated herein by reference in its entirety), on pp. 26 et seq.

Copanlisib is published in international patent application PCT/US2007/024985, published as WO 2008/070150 A1 on June 12, 2008, (which is incorporated herein by reference in its entirety), as the compound of Example 13 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide.

Copanlisib may be synthesized according to the methods given in WO 2008/070150, pp. 9 et seq., and on pp. 42 et seq. Biological test data for said compound of formula (I) is given in WO 2008/070150 on pp. 101 to 107.

2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimid-azo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride (1 1 ), (which is hereinafter referred to as „copanlisib dihydrochloride”) is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 1 1 , 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dinydrochloride : it may be synthesized according to the methods given in said Examples 1 and 2.

Copanlisib may exist in one or more tautomeric forms : tautomers, sometimes referred to as proton-shift tautomers, are two or more compounds that are related by the migration of a hydrogen atom accompanied by the migration of one or more single bonds and one or more adjacent double bonds.

Copanlisib may for example exist in tautomeric form (la), tautomeric form (lb), or tautomeric form (Ic), or may exist as a mixture of any of these forms, as depicted below. It is intended that all such tautomeric forms are included within the scope of the present invention.

Copanlisib may exist as a solvate : a solvate for the purpose of this invention is a complex of a solvent and copanlisib in the solid state. Exemplary solvates include, but are not limited to, complexes of copanlisib with ethanol or methanol.

Copanlisib and copanlisib dihydrochloride may exist as a hydrate. Hydrates are a specific form of solvate wherein the solvent is water, wherein said water is a structural element of the crystal lattice of copanlisib or of copanlisib dihydrochloride. It is possible for the amount of said water to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric hydrates, a hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, or penta-hydrate of copanlisib or of copanlisib dihydrochloride is possible. It is also possible for water to be present on the surface of the crystal lattice of copanlisib or of copanlisib dihydrochloride. The present invention includes all such hydrates of copanlisib or of copanlisib dihydrochloride, in particular copanlisib dihydrochloride hydrate referred to as “hydrate I”, as prepared and characterised in the experimental section herein, or as “hydrate II”, as prepared and characterised in the experimental section herein.

As mentioned supra, copanlisib is, in WO 2008/070150, described on pp. 9 et seq., and may be synthesized according to the methods given therein on pp. 42 et seq., viz. :

Reaction Scheme 1 :

(I)

In Reaction Scheme 1 , vanillin acetate can be converted to intermediate (III) via nitration conditions such as neat fuming nitric acid or nitric acid in the presence of another strong acid such as sulfuric acid. Hydrolysis of the acetate in intermediate (III) would be expected in the presence of bases such as sodium

hydroxide, lithium hydroxide, or potassium hydroxide in a protic solvent such as methanol. Protection of intermediate (IV) to generate compounds of Formula (V) could be accomplished by standard methods (Greene, T.W.; Wuts, P.G.M.; Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999). Conversion of compounds of formula (V) to those of formula (VI) can be achieved using ammonia in the presence of iodine in an aprotic solvent such as THF or dioxane. Reduction of the nitro group in formula (VI) could be accomplished using iron in acetic acid or hydrogen gas in the presence of a suitable palladium, platinum or nickel catalyst. Conversion of compounds of formula (VII) to the imidazoline of formula (VIII) is best accomplished using ethylenediamine in the presence of a catalyst such as elemental sulfur with heating. The cyclization of compounds of formula (VIII) to those of formula (IX) is accomplished using cyanogen bromide in the presence of an amine base such as triethylamine, diisopropylethylamine, or pyridine in a halogenated solvent such as DCM or dichloroethane. Removal of the protecting group in formula (IX) will be dependent on the group selected and can be accomplished by standard methods (Greene, T.W.; Wuts, P.G.M.; Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999). Alkylation of the phenol in formula (X) can be achieved using a base such as cesium carbonate, sodium hydride, or potassium t-butoxide in a polar aprotic solvent such as DMF or DMSO with introduction of a side chain bearing an appropriate leaving group such as a halide, or a sulfonate group. Lastly, amides of formula (I) can be formed using activated esters such as acid chlorides and anhydrides or alternatively formed using carboxylic acids and appropriate coupling agents such as PYBOP, DCC, or EDCI in polar aprotic solvents.

Reaction Scheme 2 :

Reaction Scheme 3

Step A9: N-[3-(dimethylamino)propyl]-N’-ethylcarbodiimide hydrochloride (“EDCI”) is used as coupling reagent. Copanlisib is isolated by simple filtration.

Step A1 1 : Easy purification of copanlisib via its dihydrochloride

(dihydrochloride is the final product)

Hence, in a first aspect, the present invention relates to a method of preparing copanlisib (10) via the following steps shown in Reaction Scheme 3, infra :

Reaction Scheme 3 : 

Example 1 : Step A1 : Preparation of 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (2)

3.94 kg of nitric acid (65 w%) were added to 5.87 kg of concentrated sulfuric acid at 0°C (nitrating acid). 1 .5 kg of vanillin acetate were dissolved in 2.9 kg of dichloromethane (vanillin acetate solution). Both solutions reacted in a micro reactor with flow rates of app. 8.0 mL/min (nitrating acid) and app. 4.0 mL/min (vanillin acetate solution) at 5°C. The reaction mixture was directly dosed into 8 kg of water at 3°C. After 3h flow rates were increased to 10 mL/min (nitrating acid) and 5.0 mL/min (vanillin acetate solution). After additional 9 h the flow reaction was completed. The layers were separated at r.t., and the aqueous phase was extracted with 2 L of dichloromethane. The combined organic phases were washed with 2 L of saturated sodium bicarbonate, and then 0.8 L of water. The dichloromethane solution was concentrated in vacuum to app. 3 L, 3.9 L of methanol were added and app. the same volume was removed by distillation again. Additional 3.9 L of methanol were added, and the solution concentrated to a volume of app. 3.5 L. This solution of 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (2) was directly used in the next step.

Example 2 : Step A2 : Preparation of 4-hydroxy -3-methoxy-2-nitrobenzaldehyde (2-nitro-vanillin) (3)

To the solution of 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (2) prepared as described in example 1 (see above) 1 .25 kg of methanol were added, followed by 2.26 kg of potassium carbonate. The mixture was stirred at 30°C for 3h. 7.3 kg of dichloromethane and 12.8 kg of aqueous hydrochloric acid (10 w%) were added at < 30°C (pH 0.5 – 1 ). The mixture was stirred for 15 min, and the layers were separated. The organic layer was filtered, and the filter cake washed with 0.5 L of dichloromethane. The aqueous layer was extracted twice with 4.1 kg of

dichloromethane. The combined organic layers were concentrated in vacuum to app. 4 L. 3.41 kg of toluene were added, and the mixture concentrated to a final volume of app. 4 L. The mixture was cooled to 0°C. After 90 min the suspension was filtered. The collected solids were washed with cold toluene and dried to give 0.95 kg (62 %).

1H-NMR (400 MHz, de-DMSO): δ =3.84 (s, 3H), 7.23 (d, 1 H), 7.73 (d, 1 H), 9.74 (s, 1 H), 1 1 .82 (brs, 1 H).

NMR spectrum also contains signals of regioisomer 6-nitrovanillin (app. 10%): δ = 3.95 (s, 3H), 7.37 (s, 1 H), 7.51 (s, 1 H), 10.16 (s, 1 H), 1 1 .1 1 (brs, 1 H).

Example 3 : Step A3 : Preparation of 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde (4) :

10 g of 3 were dissolved in 45 mL DMF at 25 °C. This solution was charged with 14 g potassium carbonate and the temperature did rise to app. 30 °C. Into this suspension 7.1 mL benzyl bromide was dosed in 15minutes at a temperature of 30 °C. The reaction mixture was stirred for 2 hours to complete the reaction. After cooling to 25 °C 125 mL water was added. The suspension was filtered, washed twice with 50 mL water and once with water / methanol (10 mL / 10 mL) and tried at 40 °C under reduced pressure. In this way 14.2 g (97% yield) of 4 were obtained as a yellowish solid.

1 H-NMR (500 MHz, d6-DMSO): 3.86 (s, 3H); 5.38 (s, 2 H); 7.45 (m, 5H); 7.62 (d, 2H); 7.91 (d, 2H); 9.81 (s, 1 H).

Example 4a : Step A4 : 2-[4-(benzyloxy)-3-methoxy-2-nitrophenyl]-4,5-dihydro-1 H-imidazole (5) : Method A

10 g of 4 were dissolved in 100 mL methanol and 2.5 g ethylenediamine were added at 20-25 °C. The reaction mixture was stirred at this temperature for one hour, cooled to 0°C and a solution of N- bromosuccinimide (8.1 g) in 60 mL

acetonitrile was added. Stirring was continued for 1 .5 h and the reaction mixture was warmed to 20 °C and stirred for another 60 minutes. The reaction was quenched with a solution of 8.6 g NaHCO3 and 2.2 g Na2SO3 in 100 mL water. After 10 minutes 230 mL water was added, the product was filtered, washed with 40 mL water and tried at 40 °C under reduced pressure. In this way 8.9 g (78% yield) of 5 was obtained as an white solid.

1 H-NMR (500 MHz, d6-DMSO): 3.31 (s, 4H); 3.83 (s, 3H); 5.29 (s, 2 H); 6.88 (s, 1 H); 7.37 (t, 1 H); 7.43 (m, 3H); 7.50 (m, 3H).

Example 4b : Step A4 : 2-[4-(benzyloxy)-3-methoxy-2-nitrophenyl]-4,5-dihydro-1 H-imidazole (5) : Method B

28.7 kg of compound 4 were dissolved in 231 kg dichloromethane at 20 °C and 8.2 kg ethylenediamine were added. After stirring for 60 minutes N-bromosuccinimide was added in 4 portions (4 x 5.8 kg) controlling that the temperature did not exceed 25°C. When the addition was completed stirring was continued for 90 minutes at 22 °C. To the reaction mixture 9 kg potassium carbonate in 39 kg water was added and the layers were separated. From the organic layer 150 kg of solvent was removed via distillation and 67 kg toluene was added. Another 50 kg solvent was removed under reduced pressure and 40 kg toluene was added. After stirring for 30 minutes at 35-45 °C the reaction was cooled to 20 °C and the product was isolated via filtration. The product was washed with toluene (19 kg), tried under reduced pressure and 26.6 kg (81 % yield) of a brown product was obtained.

Example 5 : Step A5 : 3-(benzyloxy)-6-(4,5-dihydro-1 H-imidazol-2-yl)-2-methoxyaniline (6) :

8.6 g of compound 5 were suspended in 55 mL THF and 1 .4 g of 1 %Pt/0.2% Fe/C in 4 mL water was added. The mixture was heated to 45 °C and hydrogenated at 3 bar hydrogen pressure for 30 minutes. The catalyst was

filtered off and washed two times with THF. THF was removed via distillation and 65 mL isopropanol/water 1/1 were added to the reaction mixture. The solvent remaining THF was removed via distillation and 86 mL isopropanol/water 1/1 was added. The suspension was stirred for one hour, filtered, washed twice with isopropanol/water 1/1 and dried under reduced pressure to yield 7.8g (99% yield) of an white solid.

1 H-NMR (500 MHz, d6-DMSO): 3.26 (t, 2H); 3.68 (s, 3H); 3.82 (t, 2H); 5.13 (s, 2 H); 6.35 (d, 1 H); 6.70 (s, 1 H); 6.93 (bs, 2 H); 7.17 (d, 1 H); 7.33 (t, 1 H); 7.40 (t, 2H); 7.45 (d, 2H).

Example 6a : Step A6 : 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (7) : Method A

10 g of 6 were suspended in 65 mL acetonitrile and 6.1 mL triethylamine were added. At 5-10 °C 8.4 mL bromocyanide 50% in acetonitrile were added over one hour and stirring was continued for one hour. 86 mL 2% NaOH were added and the reaction mixture was heated to 45 °C and stirred for one hour. The suspension was cool to 10 °C, filtered and washed with water/acetone 80/20. To further improve the quality of the material the wet product was stirred in 50 mL toluene at 20-25 °C. The product was filtered off, washed with toluene and dried under reduced pressure. In this way 8.8 g (81 % yield) of 7 was isolated as a white solid.

1 H-NMR (500 MHz, d6-DMSO): 3.73 (s, 3H); 3.87 (m, 4H); 5.14 (s, 2 H); 6.65 (bs, 2 H); 6.78 (d, 1 H); 7.33 (m, 1 H); 7.40 (m, 3 H); 7.46 (m, 2H).

Example 6b : Step A6 : 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (8) : Method B

20 kg of compound 6 were dissolved in 218 kg dichloromethane at 20 °C and the mixture was cooled to 5 °C. At this temperature 23.2 kg triethylamine was dosed in 15 minutes and subsequently 25.2 kg bromocyanide (3 M in

dichloromethane) was dosed in 60 minutes to the reaction mixture. After stirring for one hour at 22 °C the reaction was concentrated and 188 kg of solvent were removed under reduced pressure. Acetone (40 kg) and water (50 kg) were added and another 100 kg of solvent were removed via distillation. Acetone (40 kg) and water (150 kg) were added and stirring was continued for 30 minutes at 36°C. After cooling to 2 °C the suspension was stirred for 30 minutes, isolated, washed with 80 kg of cold water and tried under reduced pressure. With this procedure 20.7 kg (95% yield) of an off-white product was obtained.

Example 7a : Step A7 : Method A: preparation of 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol (8) :

A mixture of 2 kg of 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine, 203 g of 5% Palladium on charcoal (50% water wetted) and 31 .8 kg of Ν,Ν-dimethylformamide was stirred at 60°C under 3 bar of hydrogen for 18 h. The mixture was filtered, and the residue was washed with 7.5 kg of Ν,Ν-dimethylformamide. The filtrate (38.2 kg) was concentrated in vacuum (ap. 27 L of distillate collected and discarded). The remaining mixture was cooled from 50°C to 22°C within 1 h, during this cooling phase 14.4 kg of water were added within 30 min. The resulting suspension was stirred at 22°C for 1 h and then filtered. The collected solids were washed with water and dried in vacuum to yield 0.94 kg (65 %).

1H-NMR (400 MHz, de-DMSO): δ = 3.72 (s, 3H), 3.85 (m, 4H), 6.47 (d, 1 H), 6.59 (bs, 1 H), 7.29 (d, 1 H), 9.30 (bs, 1 H).

Example 7b : Step A7 Method B : preparation of 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol (8) :

222.8 g of trifluroacetic acid were added to a mixture of 600 g of 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine and 2850 g of DMF. 18 g of 5% Palladium on charcoal (50% water wetted) were added. The mixture

was stirred at under 3 bar of hydrogen overnight. The catalyst was removed by filtration and washed with 570 g of DMF. The filtrate was concentrated in vacuum (432 g of distillate collected and discarded). 4095 ml of 0.5 M aqueous sodium hydroxide solution was added within 2 hours. The resulting suspension was stirred overnight. The product was isolated using a centrifuge. The collected solids were washed with water. The isolated material (480.2g; containing app. 25 w% water) can be directly used in the next step (example 8b).

Example 8a : Step A8 : Method A : preparation of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (9) :

2.5 kg of potassium carbonate were added to a mixture of 1 .4 kg of 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol, 14 L of n-butanol, 1 .4 L of Ν,Ν-dimethylformamide and 1 .4 L of water. 1 .57 kg of 4-(3-chloropropyl)morpholine hydrochloride were added. The resulting suspension was heated to 90°C and stirred at this temperature for 5 h. The mixture was cooled to r.t.. At 50°C 8.4 kg of water were added. The mixture was stirred at r.t. for 15 min. After phase separation the aqueous phase was extracted with 12 L of n-butanol. The combined organic phases were concentrated in vacuum to a volume of ap. 1 1 L. 10.7 L of terf-butyl methyl ether were added at 50°C. The resulting mixture was cooled within 2 h to 0°C and stirred at this temperature for 1 h. The suspension was filtered, and the collected solids were washed with tert-butyl methyl ether and dried to give 1 .85 kg (86 %).

The isolated 1 .85 kg were combined with additional 0.85 kg of material produced according to the same process. 10.8 L of water were added and the mixture heated up to 60°C. The mixture was stirred at this temperature for 10 min, then cooled to 45°C within 30 min and then to 0°C within 1 h. The suspension was stirred at 0°C for 2 h and then filtered. The solids were washed with cold water and dried to yield 2.5 kg.

1H-NMR (400 MHz, de-DMSO): δ = 1 .88 (m, 4H), 2.36 (m, 4H), 2.44 (t, 2H), 3.57 (m, 4H), 3.70 (s, 3H), 3.88 (m, 4H), 4.04 (t, 2H), 6.63 (s, 2H), 6.69 (d, 1 H), 7.41 (d, 1 H).

HPLC: stationary phase: Kinetex C18 (150 mm, 3.0 mm ID, 2.6 μιτι particle size): mobile phase A: 0.5 ml_ trifluoro acetic acid / 1 L water; mobile phase B: 0.5 ml_ trifluoro acetic acid / L acetonitrile; UV detection at 256 nm; oven temperature: 40°C; injection volume: 2.0 μΙ_; flow 1 .0 mL/min; linear gradient in 4 steps: 0% B -> 6% B (20 min), 6 % B -> 16% B (5 min), 16% B -> 28 % B (5 min), 28 % B -> 80 % B (4 min), 4 minutes holding time at 80% B; purity: >99,5 % (Rt=1 1 .0 min), relevant potential by-products: degradation product 1 at RRT (relative retention time) of 0.60 (6.6 min) typically <0.05 %, 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol RRT 0.71 (7.8 min): typically <0.05 %, degradation product 2 RRT 1 .31 (14.4 min): typically <0.05 %, 7-methoxy-5-{[3-(morpholin-4-yl)propyl]amino}-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol RRT 1 .39 (15.3 min): typically <0.05 %, 9-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 1 .43 (15.7 min): typically <0.05 %, degradation product 3 RRT 1 .49 (16.4 min): typically <0.05 %, 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-N-[3-(morpholin-4-yl)propyl]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 1 .51 (16.7 min): typically <0.10 %, 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 2.56 (28.2 min): typically <0.05 %, 8-(benzyloxy)-7-methoxy-N-[3-(morpholin-4-yl)propyl]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 2.59 (28.5 min): typically <0.05 %.

Example 8b: : Step A8 (Method B): preparation of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (9) :

13.53 g of 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol (containing app. 26 w% of water) were suspended in 1 10 g of n-butanol. The mixture was concentrated in vacuum (13.5 g of distillate collected and discarded). 17.9 g of potassium carbonate and 1 1 .2 g of 4-(3-chloropropyl)morpholine hydrochloride were added. The resulting mixture was heated to 90°C and stirred at this temperature for 4 hours. The reaction mixture was cooled to to 50°C, and 70 g of water were added. The layers were separated. The organic layer was concentrated in vacuum (54 g of distillate collected and discard). 90 g of terf-butyl methyl ether were added at 65°C. The resulting mixture was cooled to 0°C. The mixture was filtered, and the collected solids washed with terf-butyl methyl ether and then dried in vacuum to yield 13.4 g (86%).

13.1 g of the isolated material were suspended in 65.7 g of water. The mixture was heated to 60°C. The resulting solution was slowly cooled to 0°C. The precipitated solids were isolated by filtration, washed with water and dried in vacuum to yield 12.0 g (92%).

Example 9: Step A10 : Preparation of 2-aminopyrimidine-5-carboxylic acid (9b)

1 kg of methyl 3,3-dimethoxypropanoate was dissolved in 7 L of 1 ,4-dioxane. 1 .58 kg of sodium methoxide solution (30 w% in methanol) were added. The mixture was heated to reflux, and ap. 4.9 kg of distillate were removed. The resulting suspension was cooled to r.t., and 0.5 kg of methyl formate was added. The reaction mixture was stirred overnight, then 0.71 kg of guanidine hydrochloride was added, and the reaction mixture was stirred at r.t. for 2 h. The reaction mixture was then heated to reflux, and stirred for 2 h. 13.5 L of water were added, followed by 0.72 kg of aqueous sodium hydroxide solution (45 w%). The reaction mixture was heated at reflux for additional 0.5 h, and then cooled to 50°C. 0.92 kg of aqueous hydrochloric acid (25 w%) were added until pH 6 was reached. Seeding crystals were added, and additional 0.84 kg of aqueous hydrochloric acid (25 w%) were added at 50°C until pH 2 was reached. The mixture was cooled to 20°C and stirred overnight. The suspension was filtered, the collected solids washed twice with water, then twice with methanol, yielding 0.61 kg (65%).

Four batches produced according to the above procedure were combined (total 2.42 kg). 12 L of ethanol were added, and the resulting suspension was stirred at r.t. for 2.5 h. The mixture was filtered. The collected solids were washed with ethanol and dried in vacuum to yield 2.38 kg.

To 800 g of this material 2.5 L of dichloromethane and 4 L of water were added, followed by 1375 ml_ of dicyclohexylamine. The mixture was stirred for 30 min. at r.t. and filtered. The collected solids are discarded. The phases of the filtrate are separated, and the organic phase was discarded. 345 ml_ of aqueous sodium hydroxide solution (45 w%) were added to the aqueous phase. The aqueous phase was extracted with 2.5 L of ethyl acetate. The phases were separated and the organic phase discarded. The pH value of the aqueous phase was adjusted to pH 2 using app. 500 ml_ of hydrochloric acid (37 w%). The mixture was filtered, and the collected solids were washed with water and dried, yielding 405 g.

The 405 g were combined with a second batch of comparable quality (152 g). 2 L of ethyl acetate and 6 L of water were added, followed by 480 ml_ of aqueous sodium hydroxide solution (45 w%). The mixture was stirred at r.t. for 30 min.. The phases were separated. The pH of the aqueous phase was adjusted to pH 2 with ap. 770 ml_ of aqueous hydrochloric acid (37 w%). The mixture was filtered, and the collected solids washed with water and dried to yield 535 g.

1H-NMR (400 MHz, de-DMSO): δ = 7.46 (bs, 2H); 8.66 (s, 2H), 12.72 (bs, 1 H).

Example 10 : Step A9 : preparation of copanlisib (10)

A mixture of 1250 g of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydro-imidazo[1 ,2-c]quinazolin-5-amine, 20.3 kg of N,N-dimethylformamide, 531 g of 2-aminopyrimidine-5-carboxylic acid, 425 g of Ν,Ν-dimethylaminopyridine and 1000 g of N-[3-(dimethylamino)propyl]-N’-ethylcarbodiimide hydrochloride was stirred at r.t. for 17 h. The reaction mixture was filtered. The collected solids were washed with Ν,Ν-dimethylformamide, then ethanol, and dried at 50°C to yield 1 .6 kg (96%). The isolated material was directly converted into the dihydrochloride.

Example 11 : Step A11 : preparation of copanlisib dihydrochloride (11)

To a mixture of 1 .6 kg of copanlisib and 4.8 kg of water were added 684 g of aqueous hydrochloric acid (32 w%) while maintaining the temperature between 20 to 25°C until a pH of 3 to 4 was reached. The resulting mixture was stirred for 10 min, and the pH was checked (pH 3.5). The mixture was filtered, and the filter cake was washed with 0.36 kg of water. 109 g of aqueous hydrochloric acid were added to the filtrate until the pH was 1 .8 to 2.0. The mixture was stirred for 30 min and the pH was checked (pH 1 .9). 7.6 kg of ethanol were slowly added within 5 h at 20 to 25°C, dosing was paused after 20 min for 1 h when crystallization started. After completed addition of ethanol the resulting suspension was stirred for 1 h. The suspension was filtered. The collected solids was washed with ethanol-water mixtures and finally ethanol, and then dried in vacuum to give 1 .57 kg of copansilib dihydrochloride (85 %).

1H-NMR (400 MHz, de-DMSO): δ = 2.32 (m, 2H), 3.1 1 (m, 2H), 3.29 (m, 2H),

3.47 (m, 2H), 3.84 (m, 2H), 3.96 (m, 2H), 4.01 (s, 3H), 4.19 (t, 2H), 4.37 (t, 2H),

4.48 (t, 2H), 7.40 (d, 1 H), 7.53 (bs, 2H), 8.26 (d, 1 H), 8.97 (s, 2H), 1 1 .28 (bs, 1 H), 12.75 (bs, 1 H), 13.41 (bs, 1 H).

HPLC: stationary phase: Kinetex C18 (150 mm, 3.0 mm ID, 2.6 μιτι particle size): mobile phase A: 2.0 ml_ trifluoro acetic acid / 1 L water; mobile phase B: 2.0 ml_ trifluoro acetic acid / L acetonitrile; UV detection at 254 nm switch after 1 minute to 282 nm; oven temperature: 60°C; injection volume: 2.0 μΙ_; flow 1 .7 mL/min; linear gradient after 1 minute isocratic run in 2 steps: 0% B -> 18% B (9 min), 18 % B -> 80% B (2.5 min), 2.5 minutes holding time at 80% B; purity: >99.8% (Rt=6.1 min), relevant potential by-products: 2-Aminopyrimidine-5-carboxylic acid at RRT (relative retention time) of 0.10 (0.6 min) typically <0.01 %, 4-dimethylaminopyrimidine RRT 0.26 (1 .6 min): typically <0.01 %, 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 0.40 (2.4 min): typically <0.03 %, by-product 1 RRT 0.93 (5.7 min): typically <0.05 %, by-product 6 RRT 1 .04 (6.4 min): typically <0.05 %, 2-amino- N-{3-(2-aminoethyl)-8-methoxy-7-[3-(morpholin-4-yl)propoxy]-4-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamicle RRT 1.12 (8.9 min); typically <0.10 %, 5-{[(2-aminopyrimidin-5-yl)carbonyl]amino}-7-methoxy-2,3-dihydroimidazo[ ,2-c]quinazolin-8-yl 2-aminopyrimidine-5-carboxylate RRT 1.41 (8.6 min): typically <0.01 %

Example 15 : Step A11 : further example of preparation of copanlisib dihydrochloride (11)

7.3 g of hydrochloric acid were added to a mixture of 12 g of copanlisib and 33 g of water at maximum 30°C. The resulting mixture was stirred at 25°C for 15 min, and the filtered. The filter residue was washed with 6 g of water. 1 1 .5 g of ethanol were added to the filtrate at 23°C within 1 hour. After the addition was completed the mixture was stirred for 1 hour at 23°C. Additional 59 g of ethanol were added to the mixture with 3 hours. After the addition was completed the mixture was stirred at 23°C for 1 hour. The resulting suspension was filtered. The collected crystals were washed three times with a mixture of 1 1 .9 g of ethanol and 5.0 g of water and the air dried to give 14.2 g of copanlisib dihydrochloride as hydrate I.

Purity by HPLC: > 99.8%; < 0.05% 2-amino-N-{3-(2-aminoethyl)-8-methoxy-7- [3-(morpholin-4-yl)propoxy]-4-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamide

Example 16 : Step A11 : further example of preparation of copanlisib dihydrochloride (11 )

9.1 kg of hydrochloric acid (25 w%) were added to a mixture of 14,7 kg of copanlisib and 41.9 kg of water at maximum temperature of 28°C. The resulting mixture was stirred at 23°C for 80 minutes until a clear solution was formed. The solution was transferred to a second reaction vessel, and the transfer lines rinsed with 6 kg of water, 14.1 kg of ethanol were slowly added within 70 minutes at 23°C. After the addition of ethanol was completed the mixture was stirred at 23°C for 1 hour. Additional 72.3 kg of ethanol were slowly added within 3.5 hours at 23°C, and resulting mixture stirred at this temperature for 1 hour. The suspension is filtered, and the collected solids were washed twice with 31 kg of an ethanol-water mixture (2.4: 1 (w w)). The product was dried in vacuum with a maximum jacket temperature of 40°C for 3.5 hours to yield 15.0 kg of copanlisib dihydrochloride as hydrate I.

Purity by HPLC: > 99.9 %; < 0.05% 2-amino-N-{3-(2-aminoethyl)-8-methoxy-7-[3-(morpholin-4-yl)propoxy]^-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamideLoss on drying: 14.7 w%

PATENT

WO 2017049983

Copanlisib is a novel oral phosphoinositide 3 kinase (PI3K) inhibitor developed by the German company Bayer. Existing clinical studies have shown that the drug inhibits the growth of cancer cells in patients with leukemia and lymphoma by blocking the PI3K signaling pathway. To further prove the promise of the drug, Bayer also conducted two more Phase III clinical studies in 2015: treating a rare non-Hodgkin’s lymphoma (NHL) by itself or in combination with Rituxan and using it alone The effect of Rituxan is compared. In addition, Bayer also plans to conduct a Phase II clinical trial of Copanlisib in the treatment of diffuse large B-cell lymphoma, a malignant NHL subtype. Because the drug does not yet have a standard Chinese translation, the applicant here transliterates “Kupanisi”.
The chemical name of Copanisibib (I) is 2-amino-N- [2,3-dihydro-7-methoxy- 8- [3- (4- morpholinyl) propoxy] Imidazo [1,2-c] quinazolin-5-yl] -5-pyrimidinecarboxamide of the formula:
PCT patent WO2008070150 from the original company discloses the preparation of cupanatinib and its analogs. The document altogether refers to the following five possible synthetic routes.
Synthetic Route 1:
Synthetic route two:
Synthetic route three:

Synthetic route four:
Synthetic route five:

Example 6:
In a nitrogen atmosphere, 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2,3-dihydroimidazo [1,2-c] quinazoline- (V) (0.36 g, 1 mmol), 2-aminopyrimidine-5-carboxylic acid (0.15 g, 1.1 mmol) and acetonitrile were added 25 mL of a condensing agent benzotriazol- (0.49 g, 1.1 mmol) and base catalyst 1,5-diazabicyclo [4.3.0] -non-5-ene (0.50 g, 4 mmol) were added and the mixture was stirred at room temperature for 12 hours . Then warmed to 50-60 ℃, the reaction was stirred for 6-8 hours, TLC detection reaction was completed. The solvent was evaporated under reduced pressure, cooled to room temperature, ethyl acetate was added and a solid precipitated. Filter cake washed with cold methanol, and dried in vacuo to give an off-white solid Kupannixi (I) 0.27g, yield% 56.3; the MS-EI m / Z: 481 [M + H] + , . 1 H NMR (CDCl3 3 ) 62.05 (m, 2H), 2.48 (m, 4H), 2.56 (m, 2H), 3.72 (t, 4H), 4.02 (s, 3H), 4.16 (m, , 6.84 (d, 1H), 7.08 (d, 1H), 9.10 (s, 2H).

PAPER

http://web.a.ebscohost.com/ehost/pdfviewer/pdfviewer?vid=1&sid=49a5a4d4-00a3-4f4a-8630-0277f78d630f%40sessionmgr4010

 ChemMedChem (2016), 11(14), 1517-1530.

2-Amino-N-{7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide (BAY 80-6946, 39i):

Amine 36 (80% purity; 100 mg, 0.22 mmol) was dissolved in DMF (5 mL), and acid 39i’ (46 mg, 0.33 mmol) was added. PyBOP (173 mg, 0.33 mmol) and DIPEA (0.16 mL, 0.89 mmol) were sequentially added, and the mixture was stirred at RT overnight. EtOAc was added, and the solids were isolated by vacuum filtration to give 39i (42.7 mg, 40%):

1H NMR ([D6 ]DMSO+ 2 drops [D]TFA): d=2.25 (m, 2H), 3.18 (m, 2H), 3.31 (m, 2H), 3.52 (m, 2H), 3.65 (brt, 2H), 4.00 (s, 3H), 4.04 (m, 2H), 4.23 (m, 2H), 4.34 (brt, 2H), 4.54 (m, 2H), 7.43 (d, 1H), 8.04 (d, 1H), 9.01 (s, 2H);

1H NMR of the bis-HCl salt (500 MHz, [D6 ]DMSO): d=2.30–2.37 (m, 2H), 3.11 (brs, 2H), 3.25–3.31 (m, 2H), 3.48 (d, J=12.1 Hz, 2H), 3.83–3.90 (m, 2H), 3.95–4.00 (m, 2H), 4.01 (s, 3H), 4.17–4.22 (m, 2H), 4.37 (t, J=6.0 Hz, 2H), 4.47 (t, J=9.7 Hz, 2H), 7.40 (d, J= 9.2 Hz, 1H), 7.54 (s, 2H), 8.32 (d, J=9.2 Hz, 1H), 8.96 (s, 2H), 11.46 (brs, 1H), 12.92 (brs, 1H), 13.41 (brs, 1H);

13C NMR (125 MHz, [D6 ]DMSO): d=23.09, 45.22, 46.00, 51.21, 53.38, 61.54, 63.40, 67.09, 101.18, 112.55, 118.51, 123.96, 132.88, 134.35, 148.96, 157.25, 160.56, 164.96, 176.02 ppm;

MS (ESI+) m/z: 481 [M+H]+ .

References

  1. Jump up^ “Phase II Data of Bayer’s Novel Cancer Drug Candidate Copanlisib to be Presented”. Retrieved 3 March 2015.
  2. Jump up^ Loguidice, Christina (8 December 2014). “Copanlisib Continues to Show Promise for Treating Indolent Lymphomas”. Rare Disease Report. Retrieved 3 March 2015.
  3. Jump up^ HealthCare, Bayer. “Bayer Advances Clinical Development Program for Investigational Cancer Drug Copanlisib”http://www.prnewswire.com.
  4. Jump up^ “Copanlisib in Treating Patients With Persistent or Recurrent Endometrial Cancer – Full Text View – ClinicalTrials.gov”.
  5. Jump up^ “Phase II Copanlisib in Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL) – Full Text View – ClinicalTrials.gov”.
  6. Jump up^ “Copanlisib (BAY 80-6946) in Combination With Gemcitabine and Cisplatin in Advanced Cholangiocarcinoma – Full Text View – ClinicalTrials.gov”.
  7. Jump up^ “Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin’s Lymphomas – Full Text View – ClinicalTrials.gov”.
  8. Jump up^ “Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin’s Lymphoma (iNHL) – Full Text View – ClinicalTrials.gov”.
  9. Jump up^ “Copanlisib and Rituximab in Relapsed Indolent B-cell Non-Hodgkin’s Lymphoma (iNHL) – Full Text View – ClinicalTrials.gov”.
  10. Jump up^ “Phase III Copanlisib in Rituximab-refractory iNHL – Full Text View – ClinicalTrials.gov”.
Patent ID

Patent Title

Submitted Date

Granted Date

US2016303136 COMBINATION OF PI3K-INHIBITORS
2014-11-28
US2015141420 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES FOR THE TREATMENT OF MYELOMA
2014-09-29
2015-05-21
Patent ID

Patent Title

Submitted Date

Granted Date

US2016058770 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES FOR TREATING LYMPHOMAS
2014-04-04
2016-03-03
US2015254400 GROUPING FOR CLASSIFYING GASTRIC CANCER
2013-09-18
2015-09-10
US2011251191 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES FOR THE TREATMENT OF MYELOMA
2011-10-13
US2013184270 SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINE-CONTAINING COMBINATIONS
2011-04-14
2013-07-18
US2014072529 SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINE SALTS
2012-03-29
2014-03-13
Patent ID

Patent Title

Submitted Date

Granted Date

US2014243295 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES
2012-03-29
2014-08-28
US2017056336 CO-TARGETING ANDROGEN RECEPTOR SPLICE VARIANTS AND MTOR SIGNALING PATHWAY FOR THE TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER
2016-05-09
US2015320754 COMBINATION THERAPIES
2015-04-15
2015-11-12
US2015320755 COMBINATION THERAPIES
2015-04-15
2015-11-12
US2016113932 TREATMENT OF CANCERS USING PI3 KINASE ISOFORM MODULATORS
2014-05-30
2016-04-28
Patent ID

Patent Title

Submitted Date

Granted Date

US8466283 Substituted 2, 3-dihydroimidazo[1, 2-c]quinazoline Derivatives Useful for Treating Hyper-Proliferative Disorders and Diseases Associated with Angiogenesis
2011-04-14
US9636344 SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINE SALTS
2016-01-07
2016-07-07
US2014377258 Treatment Of Cancers Using PI3 Kinase Isoform Modulators
2014-05-30
2014-12-25
US2015283142 TREATMENT OF CANCERS USING PI3 KINASE ISOFORM MODULATORS
2013-11-01
2015-10-08
US2013261113 SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINE DERIVATIVES USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS AND DISEASES ASSOCIATED WITH ANGIOGENESIS
2013-06-03
2013-10-03
Copanlisib
Copanlisib.svg
Names
IUPAC name

2-Amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide
Other names

BAY 80-6946
Identifiers
3D model (JSmol)
ChemSpider
KEGG
MeSH 2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo(1,2-c)quinazolin-4-yl)pyrimidine-5-carboxamide
UNII
Properties
C23H28N8O4
Molar mass 480.53 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////////////copanlisib, BAY 80-6946, BAYER, orphan drug status,  follicular lymphoma, FDA 2017, BAY 84-1236

COC1=C(C=CC2=C1N=C(N3C2=NCC3)NC(=O)C4=CN=C(N=C4)N)OCCCN5CCOCC5

 

DISCLAIMER

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

ODM-201


 

ODM-201.svg

ODM 201, BAY 1841788; ODM-201

N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide

CAS 1297538-32-9
Chemical Formula: C19H19ClN6O2
Exact Mass: 398.1258

SYNTHESIS SEE BELOW

Phase III Prostate cancer

  • 12 Feb 2016 Bayer plans a phase I trial in healthy volunteers in Germany (NCT02671097)
  • 01 Nov 2015 Orion Corporation completes a phase II trial in Prostate cancer (late-stage disease, second-line or greater) in USA, Czech Republic, Estonia, France, Finland and United Kingdom (NCT01429064)
  • 16 Oct 2015 Phase-III clinical trials in Prostate cancer (Second-line therapy or greater) in Australia, Belarus, Canada, South Africa, South Korea, Russia, Spain, Taiwan and Ukraine (PO)
  • Originator Orion

  • Developer Bayer HealthCare; Orion

 

  • Class Antineoplastics
  • Mechanism of Action Androgen receptor antagonists

ODM-201 (also known as BAY-1841788) is a non-steroidal antiandrogen, specifically, a full and high-affinity antagonist of the androgen receptor (AR), that is under development by Orion and Bayer HealthCare[1] for the treatment of advanced, castration-resistant prostate cancer (CRPC).[2][3]

 

Relative to enzalutamide (MDV3100 or Xtandi) and apalutamide (ARN-509), two other recent non-steroidal antiandrogens, ODM-201 shows some advantages.[3] ODM-201 appears to negligibly cross the blood-brain-barrier.[3] This is beneficial due to the reduced risk of seizures and other central side effects from off-target GABAA receptor inhibition that tends to occur in non-steroidal antiandrogens that are structurally similar to enzalutamide.[3] Moreover, in accordance with its lack of central penetration, ODM-201 does not seem to increase testosterone levels in mice or humans, unlike other non-steroidal antiandrogens.[3] Another advantage is that ODM-201 has been found to block the activity of all tested/well-known mutant ARs in prostate cancer, including the recently-identified clinically-relevant F876L mutation that produces resistance to enzalutamide and ARN-509.[3] Finally, ODM-201 shows higher affinity and inhibitory efficacy at the AR (Ki = 11 nM relative to 86 nM for enzalutamide and 93 nM for ARN-509; IC50 = 26 nM relative to 219 nM for enzalutamide and 200 nM for ARN-509) and greater potency/efficaciousness in non-clinical models of prostate cancer.[3]

ODM-201 has been studied in phase I and phase II clinical trials and has thus far been found to be effective and well-tolerated,[4] with the most commonly reported side effects including fatigue, nausea, and diarrhea.[5][6] No seizures have been observed.[6][7] As of July 2015, ODM-201 is in phase III trials for CRPC.[3]

ORM-15341 is the main active metabolite of ODM-201.[3] It, similarly, is a full antagonist of the AR, with an affinity (Ki) of 8 nM and an IC50 of 38 nM.[3]

ODM-201 is a new-generation, potent and selective androgen receptor (AR) inhibitor which is potential useful for treatment of castration-resistant prostate cancer (CRPC). ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. ODM-201 overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC

Figure 1: The structures of ODM-201 (A) and its main metabolite ORM-15341 (B).

Figure 1

Representative binding affinities of ODM-201, ORM-15341, enzalutamide, and ARN-509 measured in competition with [3H]mibolerone using wtAR isolated from rat ventral prostates (C). All data points are means of quadruplicates ±SEM. Ki values are presented in parentheses. D. Antagonism to wtAR was determined using AR-HEK293 cells treated with ODM-201, ORM-15341, enzalutamide, or ARN-509 together with 0.45 nM testosterone in steroid-depleted medium for 24 hours before luciferase activity measurements. All data points are means of triplicates ±SEM. IC50 values are presented in parentheses.

WHIPPANY, N.J., Sept. 16, 2014 /PRNewswire/ — Bayer HealthCare and Orion Corporation, a pharmaceutical company based in Espoo, Finland, have begun to enroll patients in a Phase III trial with ODM-201, an investigational oral androgen receptor inhibitor in clinical development. The study, called ARAMIS, evaluates ODM-201 in men with castration-resistant prostate cancer who have rising Prostate Specific Antigen (PSA) levels and no detectable metastases. The trial is designed to determine the effects of the treatment on metastasis-free survival (MFS).

“The field of treatment options for prostate cancer patients is evolving rapidly.  However, once prostate cancer becomes resistant to conventional anti-hormonal therapy, many patients will eventually develop metastatic disease,” said Dr. Joerg Moeller, Member of the Bayer HealthCare Executive Committee and Head of Global Development. “The initiation of a Phase III clinical trial for ODM-201 marks the starting point for a potential new treatment option for patients whose cancer has not yet spread.  This is an important milestone for Bayer in our ongoing effort to meet the unmet needs of men affected by prostate cancer.”

Earlier this year, Bayer and Orion entered into a global agreement under which the companies will jointly develop ODM-201, with Bayer contributing a major share of the costs of future development. Bayer will commercialize ODM-201 globally, and Orion has the option to co-promote ODM-201 in Europe. Orion will be responsible for the manufacturing of the product.

About the ARAMIS Study
The ARAMIS trial is a randomized, Phase III, multicenter, double-blind, placebo-controlled trial evaluating the safety and efficacy of oral ODM-201 in patients with non-metastatic CRPC who are at high risk for developing metastatic disease. About 1,500 patients are planned to be randomized in a 2:1 ratio to receive 600 mg of ODM-201 twice a day or matching placebo. Randomisation will be stratified by PSA doubling time (PSADT less than or equal to 6 months vs. > 6 months) and use of osteoclast-targeted therapy (yes vs. no).

The primary endpoint of this study is metastasis-free survival (MFS), defined as time between randomization and evidence of metastasis or death from any cause. The secondary objectives of this study are overall survival (OS), time to first symptomatic skeletal event (SSE), time to initiation of first cytotoxic chemotherapy, time to pain progression, and characterization of the safety and tolerability of ODM-201.

About ODM-201
ODM-201 is an investigational androgen receptor (AR) inhibitor that is thought to block the growth of prostate cancer cells. ODM-201 binds to the AR and inhibits receptor function by blocking its cellular function.

About Oncology at Bayer
Bayer is committed to science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now includes three oncology products and several other compounds in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

About Bayer HealthCare Pharmaceuticals Inc.
Bayer HealthCare Pharmaceuticals Inc. is the U.S.-based pharmaceuticals business of Bayer HealthCare LLC, a subsidiary of Bayer AG. Bayer HealthCare is one of the world’s leading, innovative companies in the healthcare and medical products industry, and combines the activities of the Animal Health, Consumer Care, Medical Care, and Pharmaceuticals divisions. As a specialty pharmaceutical company, Bayer HealthCare provides products for General Medicine, Hematology, Neurology, Oncology and Women’s Healthcare. The company’s aim is to discover and manufacture products that will improve human health worldwide by diagnosing, preventing and treating diseases.

Bayer® and the Bayer Cross® are registered trademarks of Bayer.

SYNTHESIS

str1

PATENT

US 2015203479

http://www.google.com/patents/WO2011051540A1?cl=en

 

PATENT

WO 2012143599

http://www.google.com/patents/US20140094474?cl=de

 

References

 

Fenner A. Prostate cancer: ODM-201 tablets complete phase I. Nat Rev Urol. 2015 Dec;12(12):654. doi: 10.1038/nrurol.2015.268. Epub 2015 Nov 3. PubMed PMID: 26526759.

2: Massard C, Penttinen HM, Vjaters E, Bono P, Lietuvietis V, Tammela TL, Vuorela A, Nykänen P, Pohjanjousi P, Snapir A, Fizazi K. Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study. Eur Urol. 2015 Oct 10. pii: S0302-2838(15)00964-1. doi: 10.1016/j.eururo.2015.09.046. [Epub ahead of print] PubMed PMID: 26463318.

3: Fizazi K, Albiges L, Loriot Y, Massard C. ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer. Expert Rev Anticancer Ther. 2015;15(9):1007-17. doi: 10.1586/14737140.2015.1081566. PubMed PMID: 26313416; PubMed Central PMCID: PMC4673554.

4: Bambury RM, Rathkopf DE. Novel and next-generation androgen receptor-directed therapies for prostate cancer: Beyond abiraterone and enzalutamide. Urol Oncol. 2015 Jul 7. pii: S1078-1439(15)00269-0. doi: 10.1016/j.urolonc.2015.05.025. [Epub ahead of print] Review. PubMed PMID: 26162486.

5: Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 2015 Jul 3;5:12007. doi: 10.1038/srep12007. PubMed PMID: 26137992; PubMed Central PMCID: PMC4490394.

6: Thibault C, Massard C. [New therapies in metastatic castration resistant prostate cancer]. Bull Cancer. 2015 Jun;102(6):501-8. doi: 10.1016/j.bulcan.2015.04.016. Epub 2015 May 26. Review. French. PubMed PMID: 26022286.

7: Bjartell A. Re: activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial. Eur Urol. 2015 Feb;67(2):348-9. doi: 10.1016/j.eururo.2014.11.019. PubMed PMID: 25760250.

8: De Maeseneer DJ, Van Praet C, Lumen N, Rottey S. Battling resistance mechanisms in antihormonal prostate cancer treatment: Novel agents and combinations. Urol Oncol. 2015 Jul;33(7):310-21. doi: 10.1016/j.urolonc.2015.01.008. Epub 2015 Feb 21. Review. PubMed PMID: 25708954.

9: Boegemann M, Schrader AJ, Krabbe LM, Herrmann E. Present, Emerging and Possible Future Biomarkers in Castration Resistant Prostate Cancer (CRPC). Curr Cancer Drug Targets. 2015;15(3):243-55. PubMed PMID: 25654638.

10: ODM-201 is safe and active in metastatic castration-resistant prostate cancer. Cancer Discov. 2014 Sep;4(9):OF10. doi: 10.1158/2159-8290.CD-RW2014-150. Epub 2014 Jul 9. PubMed PMID: 25185192.

11: Fizazi K, Massard C, Bono P, Jones R, Kataja V, James N, Garcia JA, Protheroe A, Tammela TL, Elliott T, Mattila L, Aspegren J, Vuorela A, Langmuir P, Mustonen M; ARADES study group. Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial. Lancet Oncol. 2014 Aug;15(9):975-85. doi: 10.1016/S1470-2045(14)70240-2. Epub 2014 Jun 25. PubMed PMID: 24974051.

12: Agarwal N, Di Lorenzo G, Sonpavde G, Bellmunt J. New agents for prostate cancer. Ann Oncol. 2014 Sep;25(9):1700-9. doi: 10.1093/annonc/mdu038. Epub 2014 Mar 20. Review. PubMed PMID: 24658665.

13: Pinto Á. Beyond abiraterone: new hormonal therapies for metastatic castration-resistant prostate cancer. Cancer Biol Ther. 2014 Feb;15(2):149-55. doi: 10.4161/cbt.26724. Epub 2013 Nov 1. Review. PubMed PMID: 24100689; PubMed Central PMCID: PMC3928129.

14: Yin L, Hu Q, Hartmann RW. Recent progress in pharmaceutical therapies for castration-resistant prostate cancer. Int J Mol Sci. 2013 Jul 4;14(7):13958-78. doi: 10.3390/ijms140713958. Review. PubMed PMID: 23880851; PubMed Central PMCID: PMC3742227.

15: Leibowitz-Amit R, Joshua AM. Targeting the androgen receptor in the management of castration-resistant prostate cancer: rationale, progress, and future directions. Curr Oncol. 2012 Dec;19(Suppl 3):S22-31. doi: 10.3747/co.19.1281. PubMed PMID: 23355790; PubMed Central PMCID: PMC3553559.

 

ODM-201
ODM-201.svg
Systematic (IUPAC) name
N((R)-1-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide[1]
Identifiers
ChemSpider 38772320
Chemical data
Formula C19H19ClN6O2
Molar mass 398.85 g·mol−1

/////

O=C(C1=NNC(C(O)C)=C1)N[C@@H](C)CN2N=C(C3=CC=C(C#N)C(Cl)=C3)C=C2

Finerenone, BAY 94-8862


Finerenone

Finerenone; UNII-DE2O63YV8R; BAY 94-8862; DE2O63YV8R; 1050477-31-0

C21H22N4O3
MW 378.42438 g/mol

(4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carbox-amide

Bayer Corp

Bayer Healthcare Ag,

Mineralocorticoid receptor antagonist

phase III in January 2016, for treating diabetic kidney disease and chronic heart failure in patients with worsening chronic cardiac insufficiency

Used as mineralocorticoid receptor antagonist for treating heart failure and diabetic nephropathy.

 

SYNTHESIS

 

 

str1

Finerenone (INN, USAN) (developmental code name BAY-94-8862) is a non-steroidal antimineralocorticoid that is in phase IIIclinical trials for the treatment of chronic heart failure as of October 2015. It has less relative affinity to other steroid hormone receptors than currently available antimineralocorticoids such as eplerenone and spironolactone, which should result in fewer adverse effects like gynaecomastia, impotence, and low sex drive.[1][2]

Pharmacology

Finerenone blocks mineralocorticoid receptors, which makes it a potassium-sparing diuretic.

This table compares inhibitory (blocking) concentrations (IC50, unit: nM) of three antimineralocorticoids. Mineralocorticoid receptor inhibition is responsible for the desired action of the drugs, whereas inhibition of the other receptors potentially leads to side effects. Lower values mean stronger inhibition.[1]

Spironolactone Eplerenone Finerenone
Mineralocorticoid receptor 24 990 18
Glucocorticoid receptor 2400 22,000 >10,000
Androgen receptor 77 21,200 >10,000
Progesterone receptor 740 31,200 >10,000

The above-listed drugs have insignificant affinity for the estrogen receptor.

Chemistry

Unlike currently marketed antimineralocorticoids, finerenone is not a steroid but a dihydropyridine derivative.

Research

The drug is also being investigated in early trials for the treatment of diabetic nephropathy.[3]

 PAPER

Discovery of BAY 94-8862: A Nonsteroidal Antagonist of the Mineralocorticoid Receptor for the Treatment of Cardiorenal Diseases

  1. Dr. Lars Bärfacker1,*,
  2. Dr. Alexander Kuhl1,
  3. Prof. Dr. Alexander Hillisch1,
  4. Dr. Rolf Grosser1,
  5. Dr. Santiago Figueroa-Pérez1,
  6. Dr. Heike Heckroth1,
  7. Adam Nitsche1,
  8. Dr. Jens-Kerim Ergüden1,
  9. Dr. Heike Gielen-Haertwig1,
  10. Dr. Karl-Heinz Schlemmer2,
  11. Prof. Dr. Joachim Mittendorf1,
  12. Dr. Holger Paulsen1,
  13. Dr. Johannes Platzek3 and
  14. Dr. Peter Kolkhof4

Article first published online: 12 JUL 2012

DOI: 10.1002/cmdc.201200081

ChemMedChem

ChemMedChem

Volume 7, Issue 8, pages 1385–1403, August 2012

Abstract

Aldosterone is a hormone that exerts manifold deleterious effects on the kidneys, blood vessels, and heart which can lead to pathophysiological consequences. Inhibition of the mineralocorticoid receptor (MR) is a proven therapeutic concept for the management of associated diseases. Use of the currently marketed MR antagonists spironolactone and eplerenone is restricted, however, due to a lack of selectivity in spironolactone and the lower potency and efficacy of eplerenone. Several pharmaceutical companies have implemented programs to identify drugs that overcome the known liabilities of steroidal MR antagonists. Herein we disclose an extended SAR exploration starting from cyano-1,4-dihydropyridines that were identified by high-throughput screening. Our efforts led to the identification of a dihydronaphthyridine, BAY 94-8862, which is a potent, selective, and orally available nonsteroidal MR antagonist currently under investigation in a clinical phase II trial.

str1

 

 

str1

 

PATENT

WO2008104306,

http://www.google.co.in/patents/WO2008104306A2?cl=en

Bayer Healthcare Ag,

Lars Baerfacker, BELOW

 

Peter Kolkhof, BELOW

 

Karl-Heinz Schlemmer, Rolf Grosser, Adam Nitsche,Martina Klein, Klaus Muenter, Barbara Albrecht-Kuepper, Elke Hartmann,

 

 

EXAMPLES

Example 1

4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2-methyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxamide

Figure imgf000066_0001

100 mg (ca. 0:24 mmol) of the compound from Example 23A are initially charged in 3 ml DMF. Is 2.94 mg Then (0.024 mmol) of 4-N, N-dimethylaminopyridine and 340 ul of ammonia (28 wt .-% – solution in water, 2:41 mmol) and 3 h at 100 0 C temperature. After cooling, the crude product is purified directly by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 → 95: 5). There are 32 mg (37% d. Th.) The title connection receive.

LC-MS (Method 3): R, = 1:57 min; MS (EIPOS): m / z = 365 [M + H] +

1 H-NMR (300 MHz, DMSOd6): δ = 1:07 (t, 3H), 2.13 (s, 3H), 3.83 (s, 3H), 4:04 (m, 2H), 5:36 (s, IH), 6:42 (d, IH), 6.66 (br. s, 2H), 7.18 (d, IH), 7.29 (dd, IH), 7:38 (d, IH), 7.67 (d, IH), 8.80 (s, IH).

Example 2

4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,7-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxamide

Figure imgf000067_0001

640 mg (1.69 mmol) of the compound from Example 27A are initially charged in 30 ml of ethyl acetate, 342 mg (2.11 mmol) l, r-carbonyldiimidazole and then stirred overnight at room temperature. A TLC check (silica gel; mobile phase: cyclohexane / ethyl acetate 1: 1 or dichloromethane / methanol 9: 1) shows complete conversion. The volatile components are removed on a rotary evaporator and the residue taken up in 20 ml DMF. Subsequently, 2.36 ml of ammonia (28 wt .-% – solution in water, 16.87 mmol) was added and the reaction mixture for 8 hours at 50 0 C temperature. The solvent is distilled off under reduced pressure and the residue purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 -> 95: 5). This gives 368 mg (58% d. Th.) Of the title compound.

LC-MS (method 7): R t = 1.91 min; MS (EIPOS): m / z = 379 [M + H] +

1 H-NMR (300 MHz, DMSO-d 6): δ = 1:05 (t, 3H), 2.13 (s, 3H), 2.19 (s, 3H), 3.84 (s, 3H), 4:02 (q, 2H) , 5:32 (s, IH), 6.25 (s, IH), 6.62 (br. s, 2H), 7.16 (d, IH), 7.28 (dd, IH), 7:37 (d, IH), 8.71 (s, IH ).

Example 3

e ‘f 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,7-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carbox- amide [(-) – enantiomer and (+) – enantiomer \

Figure imgf000068_0001

The racemate of Example 2 can be separated on a preparative scale by chiral HPLC into its enantiomers [column: Chiralpak IA, 250 mm x 20 mm; Eluent: methyl tert-butyl ether / methanol 85: 15 (v / v); Flow: 15 ml / min; Temperature: 30 0 C; UV detection: 220 Dm].

(-) – Enantiomer:

HPLC: R, = 5.28 min, ee> 98% [column: Chiralpak IA, 250 mm x 4.6 mm; Eluent: methyl tert-butyl ether / methanol 80:20 (v / v); Flow: 1 ml / min; Temperature: 25 0 C; UV detection: 220 nm];

specific optical rotation (chloroform, nm 589, 19.8 ° C, c = 0.50500 g / 100 ml): -239.3 °.

A single crystal X-ray structural analysis revealed a ^ -configuration at C * for this enantiomer – atom.

(+) – Enantiomer:

HPLC: R = 4:50 min, ee> 99% [column: Chiralpak IA, 250 mm x 4.6 mm; Eluent: methyl tert-butyl ether / methanol 80:20 (v / v); Flow: 1 ml / min; Temperature: 25 ° C; UV detection: 220 nm];

specific optical rotation (chloroform, nm 589, 20 0 C, c = 0.51000 g / 100 ml): + 222.7 °.

Example 4

4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxamide

Figure imgf000069_0001

1:46 g (3.84 mmol) of the compound from Example 3oA are introduced into 50 ml of ethyl acetate, 777 mg (4.79 mmol) l, r-carbonyldiimidazole and then stirred overnight at room temperature. A TLC check (silica gel; eluent: ethyl acetate) shows complete conversion. The volatile components are removed on a rotary evaporator and the residue taken up in 20 ml DMF.Then 10.74 ml of ammonia (28 wt% solution in water, 76.8 mmol) was added and the reaction mixture heated for 30 minutes at 100 0 C. The solvent is distilled off under reduced pressure and the residue purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 -> 95: 5). After concentrating the product fractions, the residue in 40 ml of dichloromethane / methanol (1: 1 v / v) and treated with 100 ml of ethyl acetate. The solvent is concentrated to a volume of about 20 ml, whereupon the product crystallized. The precipitate is filtered off and washed with a little diethyl ether.After drying at 40 0 C in a vacuum oven obtained 1:40 g (96%. Th.) The title connection.

LC-MS (Method 3): R, = 1.64 min; MS (EIPOS): m / z = 379 [M + H] +

1 H-NMR (300 MHz, DMSOd6): δ = 1:05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H) , 5:37 (s, IH), 6.60-6.84 (m, 2H), 7.14 (d, IH), 7.28 (dd, IH), 7:37 (d, IH), 7:55 (s, IH), 7.69 (s, IH ).

Example 5

e “M- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carbox- amide [(-) – enantiomer and (+ ) enantiomer]

Figure imgf000070_0001

The racemate of Example 4 can be separated on a preparative scale by chiral HPLC into its enantiomers [column: 680 mm x 40 mm; Silica gel phase based on the chiral selector poly (N-methacryloyl-D-leucine dicyclopropylmethylamide; eluent: ethyl acetate; temperature: 24 ° C; flow: 80 ml / min; UV detection: 260 nm].

(-) – Enantiomer:

HPLC: R = 2:48 min, ee = 99.6% [column: 250 mm x 4.6 mm; Silica gel phase based on the chiral selector poly (N-methacryloyl-D-leucine dicyclopropylmethylamide; eluent: ethyl acetate; temperature: 24 ° C; flow: 2 ml / min; UV detection: 260 nm];

specific optical rotation (chloroform, nm 589, 19.7 ° C, c = 0.38600 g / 100 ml): -148.8 °.

A single crystal X-ray structure analysis showed this enantiomer S configuration at C * – atom.

(+) – Enantiomer:

HPLC: R = 4:04 min, ee = 99.3% [column: 250 mm x 4.6 mm; Silica gel phase based on the chiral selector poly (N-methacryloyl-D-leucine dicyclopropylmethylamide; eluent: ethyl acetate; temperature: 24 ° C; flow: 2 ml / min; UV detection: 260 nm];

specific optical rotation (chloroform, nm 589, 19.8 ° C, c = 0.36300 g / 100 ml): + 153.0 °.

PATENT

WO 2016016287

The present invention relates to a novel and improved process for preparing 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1, 4-dihydro- 1, 6-naphthyridine-3-carbox- amide of formula (I)

as well as the preparation and use of crystalline modification I of (4S) – 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1, 4-dihydro- 1, 6-naphthyridine-3- carbox-amide of formula (I).

The compound of formula (I) acts as a non-steroidal mineralocorticoid receptor antagonist and can be used as agents for the prophylaxis and / or treatment of cardiovascular and renal diseases such as heart failure and diabetic nephropathy.

The compound of formula (I) and their preparation process are described in WO 2008/104306 and ChemMedChem 2012 7, described in 1385, in both publications a detailed discussion of research synthesis is disclosed. A disadvantage of the synthesis described there is the fact that this synthesis is not suitable for another large-scale process, since many steps in very high dilution, at very high reagent surpluses and thus run on a relatively low overall yield. Furthermore, many chromatographic cleanings are necessary, which are usually very expensive and require a high consumption of solvents, are costly and which should therefore be avoided if possible.Some stages can not be realized due to safety and procedural difficulties.

There is therefore a need for an industrially viable synthesis, reproducible in high overall yield, low production costs and high purity provides the compound of formula (I) and complies with all regulatory requirements in order to supply the clinical trials on drug and for subsequent regulatory submission to be used.

With the present invention a very efficient synthesis has been found, which allows to meet the above requirements.

In the publication ChemMedChem 2012 7, in which the research synthesis of the compound of formula (I) disclosed in 1385, the compound of formula (I), starting from vanillin prepared in 10 steps with an overall yield of 3.76% of theory , The compound of formula (I) was obtained by evaporation of the chromatography fractions as an amorphous solid, a defined process Kristalhsations- the stage for polymorphism-setting has not been described.

The following Scheme 1 shows the known process for preparing the compound of formula (I).

(II) (HI) (IV)

(V) (VI)

(XIII) (I)

Scheme 1: synthesis research of the compound of formula (I)

There are used 3 chromatographic purifications, and a chiral chromatography step to separate the enantiomers of the racemate of formula (XIII). The steps run partially in very high dilution and using very large amounts of reagent.

Thus, in particular the sequence of the preparation of the nitrile aldehyde intermediate (VI), which occupies a central role in the synthesis of atom not economically acceptable.

Furthermore, not to apply this process to an industrial scale, since [=> (IV) (III)] and excesses of acrylic acid tert-butyl ester are used for a very expensive reagents such as trifluoromethanesulfonic anhydride. When upscaling the Heck reaction (IV) => (V) formed in the boiler, a plastic similar residue resulting from the polymerization of acrylic acid tert.butyl ester used in excess. This is not acceptable in the technical implementation, there is a risk that there may be a Rührerbruch and it would lead to strong to remove residues in the agitators.

The subsequent cleavage of the double bond with sodium and the highly toxic osmium tetroxide is to be avoided since there is a delay of reaction and thereby caused to a strongly exothermic and connected with that comes a runaway under the test conditions described.

Scheme 2 illustrates the new process of the invention that the compound of formula (I) in 9 levels in 27.7% d. Th. Total yield without a chromatographic

Purification of intermediates supplies.

Scheme 2: According to the Invention for preparing the compound of formula (I).

Examples

example 1

Methyl 4-bromo-2-methoxybenzoate (XV)

3.06 kg (22.12 mol) potassium carbonate are placed in 1 acetone 3.6 and heated to reflux. To this suspension is metered in 1.2 kg of 4-bromo-2-hydroxybenzoic acid (5.53 mol) suspended in 7.8 1 of acetone and rinsed with 0.6 1 acetone. The mixture is heated for one hour under reflux (vigorous evolution of gas!). is boiled for 2.65 kg (21.01 mol) Dimethylsufat over 4 hours then metered. 2.5 hours then is stirred under reflux. The solvent is distilled off to a large extent (up to the stirrability) and returns to 12 1 toluene, then the remaining acetone is distilled off at 110 ° C. There are about 3 1 distillate distilled, these are supplemented by the addition of a further 3 1 toluene to approach. Allow to cool to 20 ° C and are 10.8 1 water were added and agitated vigorously. The organic phase is separated and the aqueous phase extracted again with 6.1 1 of toluene. The combined organic phases are washed with 3 1 of saturated sodium chloride solution, and the toluene phase is concentrated to about 4 first A quantitative analysis by evaporating a subset results converted a yield 1.306 kg (96.4% of theory). The solution is used directly in the next stage.

HPLC method A: RT about 11.9 min.

MS (EIPOS): m / z = 245 [M + H] +

H NMR (400 MHz, CD 2 C1 2 ): δ = 3.84 (s, 3H), 3.90 (s, 3H), 7:12 to 7:20 (m, 2H), 7.62 (d, 1H).

example 2

4-bromo-2-methoxybenzaldehyde (XVI)

It puts 1.936 kg (6.22 mol) 65% Red- Al solution in toluene with 1.25 1 of toluene at -5 ° C before. To this solution was dosed 0.66 kg (6.59 mol) of 1-methylpiperazine and rinsed with 150 ml of toluene, the temperature keeps you here from -7 to -5 ° C.. It is allowed for 30 minutes at 0 ° C. for. This solution is then dosed to a solution of 1.261 kg (5.147 mol) of methyl 4-bromo-2-methoxybenzoate (XV), dissolved in 4 1 of toluene, the temperature is maintained at – 8-0 ° C. Rinse twice with 0.7 1 of toluene and stirred for 1.5 hours at 0 ° C to. For working up, dosed to a 0 ° C cold aqueous sulfuric acid (12.5 1 water + 1.4 kg of conc. Sulfuric acid). The temperature should rise to a maximum of 10 ° C (slow dosage). The pH is, if necessary, by addition of further sulfuric acid to a pH of the first The organic phase is separated and extracted the aqueous phase with 7.6 1 of toluene. The combined organic phases are washed with 5.1 1 of water and then substantially concentrated and the residue taken up with 10 1 DMF. The mixture is concentrated again to about 5 1 volume. A quantitative analysis by evaporating a subset results converted a yield 1.041 kg (94.1% of theory). The solution is used directly in the next stage.

HPLC method A: RT approximately 12.1 min.

MS (EIPOS): m / z = 162 [M + H] +

X H-NMR (CDCl, 400MHz): δ = 3.93 (3H, s), 7.17 (2H, m), 7.68 (1H, d), 10:40 (1H, s)

example 3

4-formyl-3-methoxybenzonitrile (VI)

719 g (3.34 mol) of 4-bromo-2-methoxybenzaldehyde (XVI) as a solution in 4.5 1 of DMF with 313 g (0.74 mol) of potassium hexacyanoferrate (K4 [Fe (CN) 6]) and 354 g submitted (3.34 mol) of sodium carbonate and a further 1.2 1 of DMF and 3.8 g (0.017 mol) of palladium acetate. It is stirred for 3 hours at 120 ° C. Allow to cool to 20 ° C and are 5.7 1 water to approach. It is extracted with 17 1 ethyl acetate, and the aqueous phase is washed again with 17 1 of ethyl acetate to. The organic phases are combined and substantially concentrated with 5 1 of isopropanol was added and concentrated to about 2 1st The mixture is heated to boiling and dripping 2 1 of water.Allow to cool to 50 ° C and are again added 2 1 water. It is cooled to 3 ° C and stirred for one hour at this temperature. The product is filtered and washed with water (2 times 1.2 1) washed. It is dried at 40 ° C under vacuum.

Yield: 469 g (87% of theory.) Of a beige solid.

HPLC method A: RT about 8.3 min.

MS (EIPOS): m / z = 162 [M + H] +

1H-NMR (300 MHz, DMSO-d6): δ = 3.98 (s, 3H), 7:53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10:37 (s, 1H).

example 4

2-cyanoethyl 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5-oxo-l, 4,5,6-tett ^

din-3-carboxylate (X)

option A

1.035 kg (6.422 mol) of 4-formyl-3-methoxybenzonitrile (VI), 1.246 kg (8.028 mol) of 2-Cyanefhyl 3-oxobutanoate, 54.6 g (0.642 mol) of piperidine and 38.5 g (0.642 mol) of glacial acetic acid are heated under reflux on a water in 10 1 dichloromethane 6.5 hours. Allow to cool to room temperature and the organic phase was washed 2 times with 5 1 water. Subsequently, the dichloromethane phase is concentrated under atmospheric pressure and the still stirrable residue with 15.47 kg of 2-butanol and 0.717 kg (5.78 mol) of 4-amino-5-methylpyridone added. The residual dichloromethane is distilled off until an internal temperature of 98 ° C is reached. Then, 20 hours, heated under reflux. It is cooled to 0 ° C, can be 4 hours at this temperature is stirred and filtered off the product. It is dried at 40 ° C under vacuum to the carrier gas.

Yield: 2.049 kg (87.6% of theory based on 4-amino-5-methylpyridone, since this component is used in deficiency) of a slightly yellowish colored solid.

HPLC method A: RT about 9.7 min.

MS (EIPOS): m / z = 405 [M + H] +

Ή-NMR (300 MHz, DMSO-d 6 ): δ = 2:03 (s, 3H), 2:35 (s, 3H), 2.80 (m, 2H), 3.74 (s, 3H), 4:04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H), 7.23 (dd, 1H), 7:28 to 7:33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H) ,

variant B

1.344 kg (8.34 mol) of 4-formyl-3-methoxy-benzonitrile (VI), 71 g (0.834 mol) piperidine and 50.1 g (0.834 mol) of glacial acetic acid are introduced into 6 1 of isopropanol at 30 ° C within 3 hours, a solution of 1.747 kg (11.26 mol) of 2-cyanoethyl 3-oxobutanoate metered in 670 ml of isopropanol. Stirring an hour after at 30 ° C. It is cooled to 0-3 ° C and stirred at 0.5 hours. the product is filtered off and washed 2 times with 450 ml of cold isopropanol to. For yield determination is under vacuum at 50 ° C. (2.413 kg, 97% of theory..); but it is usually due to the high yield continued to work directly with the isopropanol-moist product. For this, the product is taken up with 29 1 of isopropanol and 1.277 kg (7.92

mol) of 4-amino-5-methylpyridone added, followed by 24 internal temperature under about 1.4 bar overpressure in the closed vessel is heated at 100 ° C h. It is cooled by a ramp within 5 h at 0 ° C. stirred for 3 hours at 0 ° C. It is filtered off and washed with 2.1 1 of cold isopropanol. It is dried under vacuum at 60 ° C.

Yield: 2.819 kg (88% of theory based on 4-amino-5-methylpyridone, since this component is used in deficiency) of a slightly yellowish colored solid.

HPLC method A: RT about 9.7 min.

MS (EIPOS): m / z = 405 [M + H] +

Ή-NMR (300 MHz, DMSO-d 6 ): δ = 2:03 (s, 3H), 2:35 (s, 3H), 2.80 (m, 2H), 3.74 (s, 3H), 4:04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H), 7.23 (dd, 1H), 7:28 to 7:33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H) ,

example 5

2- cyanoethyl-4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxylate (XI)

2.142 kg (5.3 mol) of 2-cyanoethyl 4- (4-cyano-2-methoxyphenyl) -2,8-dimefhyl-5-oxo-l, 4,5,6-tetrahydro-l, 6-naphthyridin-3 carboxylate (X) and 4.70 kg (29 mol) of triethyl orthoacetate are dissolved in 12.15 1 of dimethylacetamide and 157.5 grams of concentrated sulfuric acid was added. The mixture is heated for 1.5 hours at 115 ° C and then cooled to 50 ° C. At 50 ° C are added dropwise to 30 minutes 12.15 1 water. After complete addition the Titelbelbindung (XI) is treated with 10 g seeded and further added dropwise to 12.15 1 of water over 30 minutes at 50 ° C. It is cooled to 0 ° C (ramp, 2 hours) and stirred for 2 hours at 0 ° C to. The product is filtered, washed 2 times each with 7.7 1 of water and dried in vacuo at 50 ° C.

Yield: 2114.2 g (92.2% of theory) of a slightly yellowish colored solid.

HPLC Method B: RT 10,2 min.

MS (EIPOS): m / z = 433 [M + H] +

X H-NMR (300 MHz, DMSO-d 6 ): δ = 1.11 (t, 3H), 2.16 (s, 3H), 2:42 (s, 3H), 2.78 (m, 2H), 3.77 (s, 3H) , 4:01 to 4:13 (m, 4H), 5:37 (s, 1H), 7.25 (d, 1H), 7:28 to 7:33 (m, 2H), 7.60 (s, 1H), 8:35 (s, 1H).

Alternatively, the reaction in NMP (l-methyl-2-pyrrolidone) may be carried out

2- cyanoethyl-4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxylate (XI)

2.142 kg (5.3 mol) of 2-cyanoethyl 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5-oxo-l, 4,5,6-tetrahydro-l, 6-naphthyridin-3 carboxylate (X) and 2.35 kg (14.5 mol) of triethyl orthoacetate are in 3.21 kg NMP (l-methyl-2-pyrrolidone) and dissolved 157.5 g of concentrated sulfuric acid was added. The mixture is heated for 1.5 hours at 115 ° C and then cooled to 50 ° C. At 50 ° C are added dropwise to 30 minutes 2.2 1 water. After complete addition the Titelbelbindung (XI) is treated with 10 g seeded and dropped further 4.4 1 of water over 30 minutes at 50 ° C. It is cooled to 0 ° C (ramp, 2 hours) and stirred for 2 hours at 0 ° C to. The product is filtered off, washed 2 times each with 4 1 of water and dried under vacuum at 50 ° C.

Yield: 2180.7 g (95.1% of theory) of a slightly yellowish colored solid.

HPLC Method B: RT 10,2 min.

example 6

4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1, 4-dihydro- 1, 6-naphthyridine-3-carboxylic acid IXM

2.00 kg (4.624 mol) of 2-cyanoethyl 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxylate (XI ) are dissolved in a mixture of 12 1 THF and 6 1 of water and cooled to 0 ° C. To this solution, a sodium hydroxide solution is added in drops within 15 minutes at 0 ° C (prepared from 0.82 kg 45% aqueous. NaOH (9.248 mol) and 4.23 1 of water and stirred for 1.5 hours at 0 ° C to . The mixture is extracted 2 times with each 4.8 1 methyl tert-butyl and once with 4.8 1 of ethyl acetate. The aqueous solution is at 0 ° C with dilute hydrochloric acid (prepared from 0.371 kg 37% HCl and 1.51 1 water ) adjusted to pH 7. the mixture is allowed to warm to 20 ° C and adding an aqueous solution of 2.05 kg of ammonium chloride in 5.54 1 water. the mixture is stirred 1 hour at 20 ° C, the product filtered and 2 times with each each 1.5 1 water and washed once with 4 1 acetonitrile. It is dried at 40 ° C under vacuum to the carrier gas.

Yield: 1736.9 g (99% of theory..) Of an almost colorless powder (very slight yellow tinge).

HPLC Method C: RT: about 6.8 min.

MS (EIPOS): m / z = 380 [M + H]

X H-NMR (300 MHz, DMSO-d 6 ): δ = 1.14 (t, 3H), 2.14 (s, 3H), 2:37 (s, 3H), 3.73 (s, 3H), 4:04 (m, 2H) , 5:33 (s, 1H), 7.26 (m, 2H), 7:32 (s, 1H), 7:57 (s, 1H), 8.16 (s, 1H), 11:43 (br. s, 1H).

Alternative workup with toluene for extraction:

4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxylic-isäure (XII)

2.00 kg (4.624 mol) of 2-cyanoethyl 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxylate (XI ) are dissolved in a mixture of 12 1 THF and 6 1 of water and cooled to 0 ° C. To this solution, a sodium hydroxide solution is added in drops within 15 minutes at 0 ° C (prepared from 0.82 kg 45% aqueous. NaOH (9.248 mol) and 4.23 1 of water and stirred for 1.5 hours at 0 ° C to . Add 5 L of toluene and 381.3 g Natiumacetat added and stirred vigorously. Allow to settle the phases and the organic phase is separated. the aqueous phase is adjusted with 10% hydrochloric acid to pH 6.9 (at about pH 9.5 is inoculated with 10 g of the title compound of). After completion of the precipitation of the product for one hour at 0 ° C is stirred and then filtered and washed twice with 4 1 of water and twice with 153 ml of toluene. the mixture is dried at 40 ° C under vacuum to carrier gas (nitrogen, 200 mbar. yield:.. 1719.5 g (98% of theory) of an almost colorless powder (very slight yellow tinge).

HPLC Method C: RT: about 6.8 min).

example 7

4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1, 4-dihydro- 1, 6-naphthyridine-3-carboxamide

1.60 kg (4.22 mol) of 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxylic-isäure ( XII) and 958 g (5.91 mol) of 1,1-carbodiimidazole be presented in 8 1 of THF and at 20 ° C 51 g (0.417 mol) of DMAP was added. Stirring for one hour at 20 ° C (gas evolution!) And then heated 2.5 hours 50 ° C. are added to this solution 2.973 kg (18.42 mol) of hexamethyldisilazane and boil for 22 hours under reflux. Man admits further 1.8 1 THF and cooled to 5 ° C. A mixture is prepared from 1.17 1 of THF and 835 g of water is metered in over 3 hours, so that the temperature is between 5 and 20 ° C remains. Then boiled for one hour under reflux, then cooled via a ramp (3 hours) at 0 ° C. and stirred for one hour at this temperature. The product is filtered off and washed 2 times with 2.4 1 THF and twice with 3.2 1 water. It is dried under vacuum at 70 ° C under a carrier gas.

Yield: 1.501 kg (. 94% of theory) of an almost colorless powder (very slight yellow tinge).

HPLC Method B: RT about 6.7 min.

MS (EIPOS): m / z = 379 [M + H]

Ή-NMR (300 MHz, DMSO-d 6 ): δ = 1:05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H ), 5:37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7:37 (d, 1H), 7:55 (s, 1H), 7.69 (s, 1H).

example 8

(4S) – 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy

carbox-amide (I) as a solution in acetonitrile / Methariol 40:60

Enantiomeric separation on a SMB unit

As a feed solution a solution corresponding to a concentration is used consisting of 50 g racemic 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridin-3 -carbox-amide (XIII) dissolved in 1 liter of a mixture of methanol / acetonitrile 60:40.

There is a SMB unit on a stationary phase: 20 chromatographed μιη Chiralpak AS-V. The pressure is 30 bar, as the eluent a mixture of methanol / acetonitrile 60:40 is used.

9.00 kg of 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carbox-amide (XII) are dissolved in 180 1 a mixture dissolved consisting of methanol / acetonitrile 60:40 and chromatographed by SMB. After concentrating the product-containing fractions, 69.68 liters of a 6.2% solution (corresponding to 4.32 kg (4S) – 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl- 1, 4-dihydro- 1, 6-naphthyridine-3-carbox-amide (I) as a solution in acetonitrile / methanol 40:60).

Yield: 4.32 kg (48% of theory.) Dissolved in 69.68 liters of acetonitrile / methanol 40:60 as a colorless fraction.

Enantiomeric purity:> 98.5% ee (HPLC, method D)

A sample is concentrated in vacuum to give: MS (EIPOS): m / z = 379 [M + H] +

Ή-NMR (300 MHz, DMSO-d 6 ): δ = 1:05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H ), 5:37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7:37 (d, 1H), 7:55 (s, 1H), 7.69 (s, 1H).

example 9

(4S) – 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carbox-amide (I)

Crystallization and Polymorphism setting

64.52 liters of a 6.2% solution of Example 8 in a mixture Acetonitiril / methanol 40:60 (equal 4.00 kg of compound 1) (1.2 .mu.m) via a filter cartridge and then concentrated at 250 mbar applicable so that the solution is still stirrable. It added 48 1 of ethanol denatured with toluene and distilled again at 250 mbar to stirrability from (Umdestillation on ethanol). They gave an additional 48 1 of ethanol denatured with toluene and then distilled at atmospheric pressure to a total volume of about 14 1 from (jacket temperature 98 ° C). The mixture was cooled via a ramp (4 hours) to 0 ° C, stirred for 2 hours at 0 ° C and filtered by the product from. It was washed twice with 4 1 of cold ethanol and then dried in vacuo at 50 ° C.

Yield: 3.64 kg (91% of theory.) Of a colorless, crystalline powder

Enantiomeric purity: “99% ee (HPLC method D); Retention times / RRT: (4S) – 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carbox-amide (1) ca. 11 min. RRT: 1.00; (4R) – 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carbox-amide (I) is about 9 min ,RRT: 0.82

Purity:> 99.8% (HPLC method B) RT: about 6.7 min.

Content: 99.9% (against an external standard)

specific rotation (chloroform, 589 nm, 19.7 ° C, c = 0.38600 g / 100 ml): – 148.8 °.

MS (EIPOS): m / z = 379 [M + H] +

Ή-NMR (300 MHz, DMSO-d 6 ): δ = 1:05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H ), 5:37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7:37 (d, 1H), 7:55 (s, 1H), 7.69 (s, 1H).

Melting point: 252 ° C (compound of formula (I) in crystalline form of modification I)

Physico-chemical characterization of compound of formula (I) in crystalline form of modification I

Compound of formula (I) melts in crystalline form of modification I at 252 ° C, ΔΗ = 95 -113 Jg 1 (heating rate 20 K min 1 , Figure 1).

A depression of the melting point was observed as a function of the heating rate.

The melting point decreases at a lower heating rate (eg 2 K min “1 ) because decomposition occurs. There were no other phase transitions. A mass loss of about 0.1% was observed up to a temperature of 175 ° C.

References

  1.  Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel Herbst 2015 (German)
  2.  Pitt, B; Anker, S. D.; Böhm, M; Gheorghiade, M; Køber, L; Krum, H; Maggioni, A. P.; Ponikowski, P; Voors, A. A.; Zannad, F; Nowack, C; Kim, S. Y.; Pieper, A; Kimmeskamp-Kirschbaum, N; Filippatos, G (2015). “Rationale and design of MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF): A randomized study of finerenone vs. Eplerenone in patients who have worsening chronic heart failure with diabetes and/or chronic kidney disease”. European Journal of Heart Failure 17 (2): 224–32.doi:10.1002/ejhf.218. PMID 25678098.
  3.  Bakris, G. L.; Agarwal, R; Chan, J. C.; Cooper, M. E.; Gansevoort, R. T.; Haller, H; Remuzzi, G; Rossing, P; Schmieder, R. E.; Nowack, C; Kolkhof, P; Joseph, A; Pieper, A; Kimmeskamp-Kirschbaum, N; Ruilope, L. M.; Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy (ARTS-DN) Study Group (2015). “Effect of Finerenone on Albuminuria in Patients with Diabetic Nephropathy: A Randomized Clinical Trial”. JAMA 314 (9): 884–94. doi:10.1001/jama.2015.10081. PMID 26325557.
Finerenone.svg
Systematic (IUPAC) name
(4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide
Clinical data
Legal status
  • Investigational
Routes of
administration
Oral
Identifiers
CAS Number 1050477-31-0
ATC code None
PubChem CID 60150535
ChemSpider 28669387
UNII DE2O63YV8R
KEGG D10633
ChEMBL CHEMBL2181927
Synonyms BAY 94-8862
Chemical data
Formula C21H22N4O3
Molar mass 378.42 g/mol

 

SEE………http://apisynthesisint.blogspot.in/2016/02/finerenone-bay-94-8862.html

////Finerenone , BAYER, PHASE 3, BAY 94-8862

CCOC1=NC=C(C2=C1C(C(=C(N2)C)C(=O)N)C3=C(C=C(C=C3)C#N)OC)C

Bayer receives Canadian approval for Nexavar to treat differentiated thyroid cancer


Sorafenib3Dan.gif

 

SORAFENIB

SYNTHESIS https://newdrugapprovals.org/2014/06/26/bayer-healthcare-has-obtained-approval-from-the-japanese-ministry-of-health-labour-and-welfare-mhlw-for-its-nexavar-sorafenib-for-treatment-of-patients-with-unresectable-differentiated-thyroid-ca/

 

 

Bayer receives Canadian approval for Nexavar to treat differentiated thyroid cancer

Health Canada has approved Bayer’s Nexavar (sorafenib tablets) for treatment of patients with locally advanced or metastatic, progressive, differentiated (papillary/follicular/Hurthle cell) thyroid carcinoma, refractory to radioactive iodine.

Nexavar’s approval in Canada is supported by a positive outcome from the Phase III DECISION (‘stuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine refractory thyrOid caNcer’) trial.

http://www.pharmaceutical-technology.com/news/newsbayer-receives-canadian-approval-nexavar-treat-differentiated-thyroid-cancer-4313077?WT.mc_id=DN_News

 

 

 

FOOTBALL BRAZIL 2014

 

 

BAYER 2013 AND BEYOND


http://www.bayer.com/

Bayer

With 11 treatments in Phase I trials, 8 in Phase II, and 13 in Phase III, Bayer has a strong pipeline.

By far the most interest currently, given that the latest reports came out October 21st, is riociguat (BAY 63-2521),

Skeletal formula of riociguat

which has had good news from its ongoing Phase III clinical trials of the treatment for pulmonary arterial hypertension, also known as PAH. PAH is a progressive condition that overburdens the heart.

Trials indicate subjects had improved heart function and could better tolerate physical exercise. Patients on riociguat improved their walking distance by 36 meters on average, while those on placebo showed no improvement.

Professor Hossein Ardeschir Ghofrani of University Hospital Giessen, the principal investigator, was quite pleased with the results and explained the value of the measurement. “The six-minute walk distance test is a well-validated clinical measure in patients with PAH, and therefore, the results of the PATENT-1 trial are encouraging. . .These data from the PATENT study suggest that riociguat may be a potential treatment option both for patients who have never been treated for PAH as well as for those who have received prior treatment.”

ghofrani_hossein.jpg

Hossein A. Ghofrani
Associate Professor of Internal Medicine,
MD (University of Giessen) 1995 Research interests: pulmonary hypertension, ischaemia-reperfusion, experimental therapeutics, clinical trials

http://www.uni-giessen.de/cms/fbz/fb11/forschung/graduierte/mbml/faculty

Although Bayer put forth no sales estimate for the treatment, analysts predicted 2017 sales from riociguat of $480 million

Drag and drop me

BAYER PIPELINE AS ON OCT 25 2013

phase 1

Project Indication
CDK-Inhibitor (BAY 1000394) Cancer
Mesothelin-ADC (BAY 94-9343) Cancer
PSMA Bi TE Antibody (BAY 2010112) Cancer
PI3K-Inhibitor (BAY 1082439) Cancer
FGFR2 Antibody (BAY 1179470) Cancer
HIF-PH (BAY 85-3934) Anemia
Partial Adenosine A1 Agonist(BAY 1067197) Heart Failure
Vasopressin Receptor Antagonist(BAY 86-8050) Heart Failure
sGC Stimulator (BAY 1021189) Heart Failure
S-PRAnt (BAY 1002670) Symptomatic uterine fibroids
BAY 1026153 Endometriosis

phase2

Project Indication
PI3K-Inhibitor (BAY 80-6946) Cancer
Regorafenib Cancer
Refametinib (MEK-Inhibitor) Cancer
Radium-223-Dichloride Cancer
Sorafenib Additional Indications
MR-Antagonist (BAY 94-8862) Congestive Heart Failure (CHF)
MR-Antagonist (BAY 94-8862) Diabetic Nephopathy
Riociguat (sGC Stimulator) Pulmonary Hypertension
Neutrophil Elastase Inhibitor(BAY 85-8501) Bronchiectasis

phase 3

Project Indication
Sorafenib Breast Cancer
Sorafenib Adjuvant HCC
Sorafenib Adjuvant RCC
Regorafenib HCC 2nd line
Rivaroxaban Major Adverse Cardiac Events
Rivaroxaban CHF and CAD
peg rFVIII(BAY 94-9027) Hemophilia
Aflibercept Myopic choroidal neovascularization (mCNV)
Aflibercept Diabetic Macular Edema (DME)
LCS 16 Contraception
Vaginorm Vulvovaginal atrophy (VVA)
Sodium Deoxycholate Submental fat removal
Cipro DPI Lung infection
Tedizolid Skin and Lung Infections
Amikacin Inhale Gram-negative pneumonia

Information for Download from bayer

Sorafenib tosylate

https://newdrugapprovals.wordpress.com/2013/07/16/nexavar-sorafenib/

TEDIZOLID PHOSPHATE

https://newdrugapprovals.wordpress.com/2013/10/24/cubist-pharmaceuticals-inc-announced-that-it-has-submitted-a-nda-to-the-u-s-fda-for-approval-of-its-investigational-antibiotic-tedizolid-phosphate-tr-701/

 

Bayer Accelerates Clinical Development of Promising New Drug Candidates

Five new molecular entities projected to enter Phase III by 2015 / Addressing unmet medical needs in the areas of oncology, cardiology, and women’s health / Initiation of further studies with recently launched products planned to add new treatment options

Leverkusen, October 8, 2013 – Following the recent commercial introduction of five new drugs to address the medical needs of patients with various diseases, Bayer is now accelerating the development of further five promising drug candidates which are currently undergoing phase I and II clinical studies. The company today announced that it plans to progress these five new highly innovative drug candidates in the areas of oncology, cardiology, and women’s health into phase III clinical studies by 2015.

“Our Pharma research and development has done a tremendous job of bringing five new products to the market offering physicians and patients new treatment alternatives for serious diseases”, said Bayer CEO Dr. Marijn Dekkers. “Following our mission statement ‘Science For A Better Life’, the five chosen further drug candidates all have the potential to impact the way diseases are treated for the benefit of patients.”

Bayer CEO Dr. Marijn Dekkers
“Our research and development activities are strongly focused on areas where treatment options are not available today or where true breakthrough innovations are missing”, said Prof. Andreas Busch, member of the Bayer HealthCare Executive Committee and Head of Global Drug Discovery at Bayer HealthCare. “Our drug development pipeline holds a number of promising candidates which we want to bring to patients who need them urgently”, said Kemal Malik, member of the Bayer HealthCare Executive Committee, Chief Medical Officer and Head of Pharmaceutical Development at Bayer HealthCare. “Furthermore we are continuing to expand the range of indications for all our recently launched products Xarelto, Stivarga, Xofigo, Riociguat as well as Eylea and further refine the profile of these drugs in specific patient populations.”

Cl 223Ra Cl

Xofigo

https://newdrugapprovals.wordpress.com/2013/09/21/xofigo-injection-recommended-for-approval-in-eu/

The five mid-stage candidates have been selected for accelerated development based on positive “proof-of-concept” data from early clinical studies. Three of them are development compounds in the area of cardiology or the cardio-renal syndrome: Finerenone (BAY 94-8862) is a next generation oral, non-steroidal Mineralocorticoid Receptor antagonist which blocks the deleterious effects of aldosterone. Currently available steroidal MR antagonists have proven to be effective in reducing cardiovascular mortality in patients with heart failure but have significant side effects that limit their utilization. Finerenone is currently in clinical Phase IIb development for the treatment of worsening chronic heart failure, as well as diabetic nephropathy.

Finerenone (BAY 94-8862)

https://newdrugapprovals.wordpress.com/2013/10/09/finerenone-bay-94-8862-bayers-next-generation-oral-non-steroidal-mineralocorticoid-receptor-antagonist-which-blocks-the-deleterious-effects-of-aldosterone/

The second drug candidate in the area of cardiology is an oral soluble guanylate cyclase (sGC) stimulator (BAY 1021189). The start of a Phase IIb study in patients with worsening chronic heart failure is expected later this year.

For the cardio-renal syndrome, a Phase IIb program with the investigational new drug Molidustat (BAY 85-3934) is under initiation in patients with anemia associated with chronic kidney disease and/or end-stage renal disease. Molidustat is a novel inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) which stimulates erythropoietin (EPO) production and the formation of red blood cells. Phase I data have shown that inhibition of HIF-PH by Molidustat results in an increase in endogenous production of EPO.

Molidustat (BAY 85-3934) 

https://newdrugapprovals.wordpress.com/2013/10/09/molidustat-bay-85-3934-bayers-drug-under-initiation-in-patients-with-anemia-associated-with-chronic-kidney-disease-andor-end-stage-renal-disease/

In oncology, Copanlisib (BAY 80-6946), a novel, oral phosphatidylinositol-3 kinases (PI3K) inhibitor, was selected for accelerated development. Copanlisib demonstrated a broad anti-tumor spectrum in preclinical tumor models and promising early clinical signals in a Phase I study in patients with follicular lymphoma. A Phase II study in patients with Non-Hodgkin’s lymphoma is currently ongoing.

Bayer has also made good progress in the development of new treatment options for patients with gynecological diseases: sPRM (BAY 1002670) is a novel oral progesterone receptor modulator that holds the promises of long-term treatment of patients with symptomatic uterine fibroids. Based on promising early clinical data the initiation of a Phase III study is planned for mid-2014.

Initiation of further studies with recently launched products
Bayer has successfully launched five new pharmaceutical products, namely Xarelto™, Stivarga™, Xofigo™, Eylea™, and Riociguat, which has very recently been approved in Canada under the trade name Adempas™.

https://newdrugapprovals.wordpress.com/2013/05/27/xarelto-approved-for-secondary-prevention-in-acute-coronary-syndrome-patients-in-europe/

File:Regorafenib.svg

Regorafenib, stivarga

https://newdrugapprovals.wordpress.com/2013/08/31/bayers-stivarga-regorafenib-tablets-approved-in-europe/

Bayer’s Eylea (aflibercept),

https://newdrugapprovals.wordpress.com/2013/06/01/lucentis-rival-one-step-away-from-nhs-approval/

Xarelto has been approved globally for five indications across seven distinct areas of use, allowing doctors to treat patients in a greater variety of venous and arterial thromboembolic conditions than any other novel oral anticoagulant. The company continues to study the use of Xarelto for the treatment of further cardiovascular diseases. Ongoing clinical Phase III studies include COMPASS and COMMANDER-HF. The COMPASS study will assess the potential use of Xarelto in combination with aspirin, or as a single treatment to prevent major adverse cardiac events (MACE) in nearly 20,000 patients with atherosclerosis related to coronary or peripheral artery disease. The COMMANDER-HF study will evaluate the potential added benefit of Xarelto in combination with single or dual-antiplatelet therapy to help reduce the risk of death, heart attack and stroke in approximately 5,000 patients with chronic heart failure and coronary artery disease, following hospitalization for exacerbation of their heart failure.
In order to answer medically relevant questions for specific patient populations Bayer has initiated a range of additional Xarelto studies in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention with stent placement (PIONEER-AF-PCI), cardioversion (X-VERT) or an AF ablation procedure (VENTURE-AF).
As an extension to the Xarelto clinical trial programme, a number of real-world studies are designed to observe and further evaluate Xarelto in everyday clinical practice. These include the XAMOS study of more than 17,000 orthopaedic surgery patients, which confirmed the clinical value of oral, once-daily Xarelto in routine clinical practice in adults following orthopaedic surgery of the hip or knee. XANTUS is designed to collate data on real-world protection with Xarelto in over 6,000 adult patients in Europe with non-valvular AF at risk of stroke while XANAP is designed to collate data on real-world protection with Xarelto in over 5,000 adult patients in Europe and Asia with non-valvular AF at risk of stroke. XALIA will generate information from over 4,800 patients treated for an acute DVT with either Xarelto or standard of care.

In the area of oncology, Stivarga has been approved in 42 countries for use against metastatic colorectal cancer that is refractory to standard therapies, and additionally for gastrointestinal stromal tumor (GIST) in the US and Japan. Bayer is now planning to assess Stivarga in earlier stages of colorectal cancer as well as other cancer types. A Phase III trial in patients with colorectal cancer after resection of liver metastases is currently under initiation. Based on early clinical data Bayer has also initiated a Phase III study in liver cancer in patients who have progressed on sorafenib treatment.

Furthermore, the anti-cancer drug Xofigo (radium 223 dichloride) is a first-in-class alpha-pharmaceutical which is designed for use in prostate cancer patients with ‘bone metastases’ (secondary cancers in the bone) to treat the cancer in the bone and to help extend their lives. Xofigo is approved in the US for the treatment of patients with advanced castrate-resistant prostate cancer with symptomatic bone metastases. In addition, the European CHMP recently gave a positive opinion for radium 223 dichloride for the same use. The decision of the European Commission on the approval is expected in the fourth quarter of 2013.
Based on the excellent Phase III results for Xofigo in patients with castration resistant prostate cancer and symptomatic bone metastases Bayer is looking to expand the use of Xofigo to earlier stages of the disease, and plans to initiate a Phase III study in combination with the novel anti-hormonal agent abiraterone. In addition, early stage signal-generating studies in other cancer forms where bone metastases are important causes of morbidity and mortality are planned.

In the area of pulmonary hypertension Adempas (Riociguat) is the first member of a novel class of compounds – so-called ‘soluble guanylate cyclase (sGC) stimulators’ – being investigated as a new and specific approach to treating different types of pulmonary hypertension (PH). Adempas has the potential to overcome a number of limitations of currently approved treatments for pulmonary arterial hypertension (PAH) and addresses the unmet medical need in patients with chronic thromboembolic pulmonary hypertension (CTEPH). It was approved for the treatment of CTEPH in Canada in September 2013, making it the world’s first drug approved in this deadly disease.
Riociguat has already shown promise as a potential treatment option beyond these two PH indications. An early clinical study was conducted in PH-ILD (interstitial lung disease), a disease characterized by lung tissue scarring (fibrosis) or lung inflammation which can lead to pulmonary hypertension, and, based on positive data, the decision was taken to initiate Phase IIb studies in PH-IIP (idiopathic pulmonary fibrosis), a subgroup of PH-ILD. Moreover, scientific evidence was demonstrated in preclinical models that the activity may even go beyond vascular relaxation. To prove the hypothesis Bayer is initiating clinical studies in the indication of systemic sclerosis (SSc), an orphan chronic autoimmune disease of the connective tissue affecting several organs and associated with high morbidity and mortality. If successful, Riociguat has the potential to become the first approved treatment for this devastating disease.

In the area of ophthalmology, Eylea (aflibercept solution for injection) is already approved in Europe and several additional countries for the treatment of neovascular (wet) age-related macular degeneration and for macular edema following central retinal vein occlusion. In September, Bayer HealthCare and Regeneron Pharmaceuticals presented data of the two phase III clinical trials VIVID-DME and VISTA-DME of VEGF Trap-Eye for the treatment of diabetic macular edema (DME) at the annual meeting of the Retina Society in Los Angeles and at the EURetina Congress in Hamburg, Germany. Both trials achieved the primary endpoint of significantly greater improvements in best-corrected visual acuity from baseline compared to laser photocoagulation at 52 weeks. Bayer plans to submit an application for marketing approval for the treatment of DME in Europe in 2013.

About Bayer HealthCare 
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 54,900 employees (Dec 31, 2012) and is represented in more than 100 countries. More information at www.healthcare.bayer.com.

ALIROCUMAB


ALIROCUMAB

SAR236553 (REGN727)

http://www.ama-assn.org/resources/doc/usan/alirocumab.pdf

Immunoglobulin G1, anti-(human neural apoptosis-regulated proteinase 1) (human REGN727 heavy chain), disulfide with human REGN727 κ-chain, dimer

Immunoglobulin G1, anti-(human proprotein convertase subtilisin/kexin type 9
(EC=3.4.21.-, neural apoptosis-regulated convertase 1, proprotein convertase 9,
subtilisin/kexin-like protease PC9)); human monoclonal REGN727 des-448-
lysine(CH3-K107)-1 heavy chain (221-220′)-disulfide with human monoclonal
REGN727  light chain dimer (227-227”:230-230”)-bisdisulfide

Clinical Trials for Compound

Number of clinical trials registered at clinicaltrials.gov 30

Biological Sequence

Description Sequence
Alirocumab heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTFNNYAMNWVRQAPGKGLDWVSTISGSGGTTNY ADSVKGRFIISRDSSKHTLYLQMNSLRAEDTAVYYCAKDSNWGNFDLWGRGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPG
Alirocumab light chain DIVMTQSPDSLAVSLGERATINCKSSQSVLYRSNNRNFLGWYQQKPGQPPNLLIYWASTR ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTTPYTFGQGTKLEIKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

1245916-14-6 CAS

C6472H9996N1736O2032S42

Alirocumab is a human monoclonal antibody designed for the treatment of hypercholesterolemia.[1]

This drug was discovered by Regeneron Pharmaceuticals and is being co-developed by Regeron and Sanofi.

When the results from Phase II trials of Sanofi and Regeneron’s proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor alirocumab were presented in March, they stunned even the company representatives working on the trials. “I’m still amazed by the reduction in low-density lipoprotein cholesterol (LDL-C) that we saw with our drug,” says Bill Sasiela, vice president of cardiovascular and metabolic research at Regeneron. The monoclonal antibody (mAb) reduced LDL-C levels by up to 73% in three mid-stage trials, irrespective of baseline LDL-C levels or background treatment, offering hope for millions of patients who can’t hit the recommended cholesterol targets with statins — the standard therapies for lowering LDL-C levels in patients with cardiovascular disease. Spurred on by these results, Sanofi and Regeneron geared up into Phase III trials of the first-in-class alirocumab (also known as REGN727 and SAR236553) over the summer, and initiated the latest and largest trial — an 18,000-patient outcomes study

It is a Proprotein convertase subtilisin/kexin type 9, (also known as PCSK9) inhibitor . Phase III trials showed a 47% reduction in LDL-C. There was a high rate of adverse events with 69% experiencing side effects (most common problem was infection).

About PCSK9 PCSK9 is known to be a determinant of circulating LDL levels, as it binds to LDL receptors resulting in their degradation so that fewer are available on liver cells to remove excess LDL-cholesterol from the blood. Moreover, traditional LDL-lowering therapies such as statins actually stimulate the production of PCSK9, which limits their own ability to lower LDL-cholesterol. Blocking the PCSK9 pathway is therefore a potentially novel mechanism for lowering LDL-cholesterol.

Alirocumab is an investigational, fully-human monoclonal antibody that targets and blocks PCSK9. It is administered via subcutaneous injection. By inhibiting PCSK9, a determinant of circulating LDL-C levels in the blood, alirocumab has been shown in pre-clinical studies to increase the number of LDL receptors on hepatocytes, thereby lowering LDL-C.

The investigational agent described above is currently under clinical development and its safety and efficacy have not been fully evaluated by any regulatory authority

References

  1.  Statement On A Nonproprietary Name Adopted By The USAN Council – AlirocumabAmerican Medical Association.

PARIS and TARRYTOWN, N.Y., Oct. 16, 2013 /PRNewswire via COMTEX/ — Sanofi and Regeneron Pharmaceuticals, Inc. REGN -1.73% today announced that the Phase 3 ODYSSEY MONO trial with alirocumab, an investigational monoclonal antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), met its primary efficacy endpoint. The mean low-density lipoprotein-cholesterol (LDL-C, or “bad” cholesterol) reduction from baseline to week 24, the primary efficacy endpoint of the study, was significantly greater in patients randomized to alirocumab, as compared to patients randomized to ezetimibe (47.2% vs. 15.6%, p<0.0001). In the trial, which employed a dose increase (up-titration) for patients who did not achieve an LDL-C level of 70 milligrams/deciliter (mg/dL), the majority of patients remained on the initial low dose of alirocumab of 75 milligrams (mg).  read at

http://www.marketwatch.com/story/sanofi-and-regeneron-report-positive-top-line-results-with-alirocumab-from-first-phase-3-study-of-a-pcsk9-inhibitor-for-ldl-cholesterol-reduction-2013-10-16?reflink=MW_news_stmp

Pipeline of selected PCSK9 inhibitors

Drug name Companies Modality Clinical phase
Alirocumab (also known as REGN727 and SAR236553) Regeneron/Sanofi Monoclonal antibody III
AMG145 Amgen Monoclonal antibody II
LGT209 Novartis Monoclonal antibody II
RG7652 Roche/Genentech Monoclonal antibody II
RN316 Pfizer Monoclonal antibody II
BMS-962476 Bristol-Myers Squibb Adnectin I
ALN-PCS Alnylam RNA interference I
ISIS-405879/BMS-844421 Isis/Bristol-Myers Squibb Antisense Discontinued
PCSK9, proprotein convertase subtilisin kexin 9.

BAYER- sPRM (BAY 1002670) Vilaprisan is a novel oral progesterone receptor modulator that holds the promises of long-term treatment of patients with symptomatic uterine fibroids


WP_000066.jpg

http://www.who.int/medicines/publications/druginformation/issues/Proposed-List_109.pdf   str is available in this link

20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-
(methanesulfonyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one
progesterone receptor antagonist

BAY 1002670, vilaprisan

1262108-14-4

C27H29F5O4S544.574

http://www.who.int/medicines/publications/druginformation/issues/Proposed-List_109.pdf   str is available in this link

Bayer has also made good progress in the development of new treatment options for patients with gynecological diseases: sPRM (BAY 1002670) is a novel oral progesterone receptor modulator that holds the promises of long-term treatment of patients with symptomatic uterine fibroids. Based on promising early clinical data the initiation of a Phase III study is planned for mid-2014.

selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone receptor. A characteristic that distinguishes such substances from receptor full agonists (such as progesterone) and full antagonists (such as mifepristone) is that their action differs in different tissues (agonist in some while antagonist in others). This mixed agonist/antagonist profile of action leads to selective stimulation or inhibition progesterone-like action in different tissues and furthermore raises the possibility of dissociation of desirable therapeutic effects from undesirable side effects in synthetic progesterone receptor drug candidates

 

 

 

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Molidustat (BAY 85-3934), Bayer’s drug under initiation in patients with anemia associated with chronic kidney disease and/or end-stage renal disease.


Molidustat

UNII-9JH486CZ13, cas no 1154028-82-6, MW: 314.3076

2-(6-morpholin-4-ylpyrimidin-4-yl)-4-(triazol-1-yl)-1H-pyrazol-3-one

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

For the cardio-renal syndrome, a Phase IIb program with the investigational new drug Molidustat (BAY 85-3934) is under initiation in patients with anemia associated with chronic kidney disease and/or end-stage renal disease. Molidustat is a novel inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) which stimulates erythropoietin (EPO) production and the formation of red blood cells. Phase I data have shown that inhibition of HIF-PH by Molidustat results in an increase in endogenous production of EPO.

About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 54,900 employees (Dec 31, 2012) and is represented in more than 100 countries. More information at www.healthcare.bayer.com.

molidustat

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molidusat sodium

Sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-olate

Molidustat sodium is an orally-available hypoxia-inducible factor prolyl hydroxylase inhibitor in phase I clinical trials at Bayer for the treatment of patients suffering from renal anemia due to chronic kidney disease.

US2010305085

WO 2008067871

WO 2012065967

WO 2013167552

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2-Heteroaryl-4-aryl-1,2-dihydropyrazolones having a bactericidal and/or fungicidal action are disclosed in EP 165 448 and EP 212 281. The use of 2-heteroaryl-4-aryl-1,2-dihydropyrazolones as lipoxygenase inhibitors for treatment of respiratory tract, cardiovascular and inflammatory diseases is claimed in EP 183 159. 2,4-Diphenyl-1,2-dihydropyrazolones having a herbicidal activity are described in DE 2 651 008.

The preparation and pharmacological properties of certain 2-pyridyl-1,2-dihydropyrazolones are reported in Helv. Chim. Acta 49 (1), 272-280 (1966). WO 96/12706, WO 00/51989 and WO 03/074550 claim compounds having a dihydropyrazolone partial structure for treatment of various diseases, and hydroxy- or alkoxy-substituted bipyrazoles for treatment of neuropsychiatric diseases are disclosed in WO 2006/101903.

Heteroaryl-substituted pyrazole derivatives for treatment of pain and various CNS diseases are furthermore described in WO 03/051833 and WO 2004/089303. WO 2006/114213 has meanwhile disclosed 2,4-dipyridyl-1,2-dihydropyrazolones as inhibitors of HIF prolyl 4-hydroxylases.

The x-ray crystal structure of the compound 3-methyl-1-(pyridin-2-yl)-4-(1-pyridin-2-yl-3-methyl-1H-pyrazol-5-yl)-2H-3-pyrazolin-5 (114)-one (other name: 5,5′-dimethyl-2,2′-di-pyridin-2-yl-1′,2′-dihydro-2H,3′H-3,4′-bipyrazol-3′-one) is reported inActa Crystallogr., Section E: Structure Reports Oμline E57 (11), o1126-o1127 (2001) [Chem. Abstr. 2001:796190].

The synthesis of certain 3′,5-dimethyl-2-phenyl-1′-(1,3-thiazol-2-yl)-1′H,2H-3,4′-bipyrazol-5′-ol derivatives is described inIndian J. Heterocyclic Chem. 3 (1), 5-8 (1993) [Chem. Abstr. 1994:323362].

The preparation and tautomerism of individual 4-(pyrazol-5-yl)-pyrazolin-5-one derivatives is reported in J. Heterocyclic Chem. 27 (4), 865-870 (1990) [Chem. Abstr. 1991:428557]. A therapeutic use has not hitherto been described for the compounds mentioned in these publications. The compound 2-tert-butyl-1′-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]-3′,5-dimethyl-1′H,2H-3,4′-bipyrazol-5′-ol is listed as a test example in WO 2007/008541.

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https://www.google.co.in/patents/US20100305085

 

Example 3A 3-(Dimethylamino)-2-(1H-1,2,3-triazol-1-yl)acrylic acid ethyl ester

 

Figure US20100305085A1-20101202-C00024

 

The preparation of the starting compound is carried out analogously to 2A starting from 1.00 g (6.45 mmol) 2-(1H-1,2,3-triazol-1-yl)acetic acid ethyl ester.

Yield: 1.4 g (100% of th.)

1H-NMR (400 MHz, DMSO-d6): δ=8.10 (d, 1H), 7.78 (d, 1H), 7.65 (s, 1H), 4.03 (q, 2H), 3.06 (br. s, 3H), 2.10 (br. s, 3H), 1.12 (t, 3H).

LC-MS (Method 5): Rt=1.40 min; MS (ESIpos): m/z=211 [M+H]+.

 

 

Example 16A 4-(6-Hydrazinopyrimidin-4-yl)morpholine

 

Figure US20100305085A1-20101202-C00043

 

Stage a): 4-(6-Chloropyrimidin-4-yl)morpholine

 

Figure US20100305085A1-20101202-C00044

 

45.0 g (302.1 mmol) 4,6-dichloropyrimidine are initially introduced into 450 ml water. 26.3 g (302.1 mmol) morpholine are added and the mixture is stirred at 90° C. for 16 h. Thereafter, it is cooled to 0° C. and the precipitate formed is filtered off. The precipitate is washed once with 50 ml water and dried in air.

Yield: 51.0 g (85% of th.)

LC-MS (Method 4): Rt=1.09 min; MS (ESIpos): m/z=200 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.35 (s, 1H), 6.95 (s, 1H), 3.62 (s, 8H).

Stage b) 4-(6-Hydrazinopyrimidin-4-yl)morpholine

 

Figure US20100305085A1-20101202-C00045

 

53.0 g (2.7 mmol) 4-(6-chloropyrimidin-4-yl)morpholine are initially introduced into 260 ml ethanol. 132.9 g (2.7 mol) hydrazine hydrate are added and the mixture is stirred under reflux for 16 h. Thereafter, it is cooled to RT and approx. half of the solvent is removed by distillation. The mixture is cooled to 0° C. and the solid formed is filtered off. It is rinsed with cold ethanol and the solid is dried first in air and then in vacuo.

Yield: 35.0 g (68% of th.)

LC-MS (Method 1): Rt=0.17 min; MS (ESIpos): m/z=196 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=7.94 (s, 1H), 7.70 (s, 1H), 5.91 (s, 1H), 4.15 (s, 2H), 3.66-3.60 (m, 4H), 3.45-3.37 (m, 4H).

 

 

 

Example 71 2-(6-Morpholin-4-ylpyrimidin-4-yl)-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one

Figure US20100305085A1-20101202-C00156

1.9 g (8.8 mmol) of the compound from Example 3A and 1.9 g (9.7 mmol) of the compound from Example 16A are initially introduced into 25 ml ethyl acetate and 504 mg (4.4 mmol) TFA are added at RT. The mixture is stirred under reflux for 16 h, then cooled to 5° C. and subsequently stirred for a further 2 h. The solid formed is filtered off, washed with ethyl acetate and dried first in air and thereafter under a high vacuum. 1.7 g of product are obtained.

The mother liquor is combined with the wash solution and the solvent is removed. According to LC-MS, the residue (2.4 g) still contains the intermediate 3-[2-(6-morpholin-4-ylpyrimidin-4-yl)hydrazino]-2-(1H-1,2,3-triazol-1-yl)prop-2-enoic acid ethyl ester (intermediate stage of the cyclization), which is used directly for the preparation of Example 72 (see there).

Yield: 1.7 g (61% of th.)

LC-MS (Method 9): Rt=0.90 min; MS (ESIpos): m/z=315 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.42 (s, 1H), 8.38 (s, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 7.70 (s, 1H), 3.71-3.65 (m, 4H), 3.57-3.51 (m, 4H).

 

hydrochloride

Example 72 2-(6-Morpholin-4-ylpyrimidin-4-yl)-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one hydrochloride

 

Figure US20100305085A1-20101202-C00157

 

Batch 1: 7.5 ml of a 4 N solution of hydrogen chloride in dioxane are added to 1.7 g (5.4 mmol) of the compound from Example 71. The mixture is stirred at RT, 5 ml dioxane are added and the mixture is stirred at RT for 16 h. The solid is filtered off and washed with 5 ml dioxane. The mixture is dried under a high vacuum for 16 h, 10 ml methanol are then added and the mixture is stirred at RT for 1 h. The solid is filtered off, washed with 4 ml methanol and dried under a high vacuum. 1.6 g of the title compound are obtained.

Batch 2: A further amount of the title compound is obtained as follows: The residue (2.4 g) obtained from the mother liquor during the synthesis of Example Compound 71, which contains the open-ring intermediate state of the cyclization, 3-[2-(6-morpholin-4-ylpyrimidin-4-yl)hydrazino]-2-(1H-1,2,3-triazol-1-yl)prop-2-enoic acid ethyl ester, is dissolved in 12 ml ethanol and 1.5 ml 30% strength sodium methylate solution in methanol are added at RT, while stirring. The mixture is subsequently stirred at RT for 45 min, then adjusted to pH 5 with 2 N hydrochloric acid and subsequently stirred at RT for a further 16 h. The mixture is cooled to 10° C. and the solid is filtered off and washed with 3.5 ml dioxane. The mixture is dried under a high vacuum for 16 h, 5 ml methanol are then added and the mixture is subsequently stirred at RT for 1 h. The solid is filtered off, washed with 2 ml methanol and dried under a high vacuum to give a further 997 mg of the title compound in this way.

Yield: together 2.6 g (83% of th.)

LC-MS (Method 6): Rt=0.89 min; MS (ESIpos): m/z=315 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.54 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 7.88 (s, 1H), 7.42 (s, 1H), 3.71 (s, 8H).

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