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The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes

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somatostatin receptor antagonist

C27 H23 F N8 O

494.5229

3(R)-[4-(4-Fluorophenyl)-1H-imidazol-2-yl]-1(R)-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(1-methyl-1H-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
3(R)-[4-(4-Fluorophenyl)-1H-imidazol-2-yl]-1(R)-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(1-methyl-1H-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-beta-carboline

1H-Pyrido[3,4-b]indole, 3-[5-(4-fluorophenyl)-1H-imidazol-2-yl]-2,3,4,9-tetrahydro-1-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(1-methyl-1H-pyrazol-4-yl)-, (1R,3R)-

3-((1R,3R)-3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(1-methyl-1H-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-5-methyl-1,2,4-oxadiazole

Merck & Co. (Originator)

Somatostatin srif1C (sst3) Antagonists

The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes 
(ACS Medicinal Chemistry Letters) Thursday May 10th 2012
Author(s): Shuwen HeZhixiong YeQuang TruongShrenik ShahWu DuLiangqin GuoPeter H. DobbelaarZhong LaiJian Liu,Tianying JianHongbo QiRaman K. BakshiQingmei HongJames DellureficioAlexander PasternakZhe FengReynalda deJesusLihu YangMikhail ReibarkhScott A. BradleyMark A. HolmesRichard G. BallRebecca T. RuckMark A. Huffman,Frederick WongKoppara SamuelVijay B. ReddyStan MitelmanSharon X. TongGary G. ChicchiKwei-Lan TsaoDorina TruscaMargaret WuQing ShaoMaria E. TrujilloGeorge J. EiermannCai LiBei B. ZhangAndrew D. HowardYun-Ping Zhou,Ravi P. NargundWilliam K. Hagmann,
DOI:10.1021/ml300063m
GO TO: [Article]

 

http://pubs.acs.org/doi/suppl/10.1021/ml300063m/suppl_file/ml300063m_si_001.pdf

 

 

The fast eluting diastereomer(52 mg, 10%) was 3-((1R,3R)-3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(1-methyl-1H-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-5-methyl-1,2,4-oxadiazole(8, MK-4256).[α]D= +24.2, c=10 mg/mL in MeOH. LC-MS: m/z 495.3 (M+ H)+.

1HNMR (500 MHz, CD3OD)δ
7.74 (m, 2H), 7.65 (s, 1H), 7.52 (m, 2H), 7.37 (m,2H), 7.13
9(m, 3H), 7.04 (t, 1H), 4.47 (dd, 1H), 3.87 (s, 3H),3.24 (dd, 1H), 3.16 (dd, 1H), 2.63 (s,
3H).
13C NMR (150.8 MHz, CD3OD)
δ
178.0, 173.0, 162.0, 150.2, 139.7, 138.1, 137.1,
132.4, 130.6, 126.5, 126.4, 124.4, 122.0, 119.0, 11
8.2, 115.2, 112.4, 111.3, 109.1, 55.5,
50.2, 37.8, 27.9, 11.1. (Note: two carbons have coinciding chemical shift of 130.6 ppm).
Accurate Mass C27H23FN8O [M+H] measured 495.2068, calculated 495.2052.
Thesloweluting diastereomer (40 mg, 8%) was 3-((1S,3R)-3-(4-(4-fluorophenyl)-1H-imidazol-2-
yl)-1-(1-methyl-1H-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-5-methyl-1,2,4-oxadiazole (9). LC-MS: m/z 495.3 (M + H)+.1
H NMR (500 MHz,CD3OD):
δ
7.73 (m, 2H), 7.54 (d, 1H), 7.48 (s, 1H), 7.43 (s,
1H), 7.40 (d, 1H), 7.36 ( brs,
1H), 7.13 (m, 3H), 7.06 (t, 1H), 4.40 (dd, 1H), 3.8
4 (s, 3H), 3.26 (dd, 1H), 3.16 (dd, 1H),
2.63 (s, 3H).

……………………………….

Route Development and Multikilogram GMP Delivery of a Somatostatin Receptor Antagonist

By:Ruck, RT (Ruck, Rebecca T.)[ 1 ] ; Huffman, MA (Huffman, Mark A.)[ 1 ] ; Stewart, GW (Stewart, Gavin W.)[ 2 ] ; Cleator, E (Cleator, Ed)[ 2 ] ; Kandur, WV (Kandur, Wynne V.)[ 1 ] ; Kim, MM (Kim, Mary M.)[ 1 ] ; Zhao, DL (Zhao, Dalian)[ 1 ]

ORGANIC PROCESS RESEARCH & DEVELOPMENT

Volume:16Issue:8Pages:1329-1337

DOI:10.1021/op300128c

Author Information

Reprint Address: Ruck, RT (reprint author)

Merck & Co Inc, Dept Proc Chem, Merck Res Labs, Rahway, NJ 07065 USA.

 Addresses:

[ 1 ] Merck & Co Inc, Dept Proc Chem, Merck Res Labs, Rahway, NJ 07065 USA
[ 2 ] Merck Sharp & Dohme Res Labs, Dept Proc Chem, Hoddesdon EN11 9BU, Herts, England

http://pubs.acs.org/doi/abs/10.1021/op300128c

http://pubs.acs.org/doi/suppl/10.1021/op300128c/suppl_file/op300128c_si_001.pdf

Abstract Image

Route development and demonstration on multikilogram scale for the first GMP delivery of MK-4256 are described. Key aspects of the convergent route include a regioselective green iodination, one-pot oxadiazole synthesis, and an efficient ketone Pictet–Spengler reaction with diastereomeric upgrade via crystallization to afford 6 kg of API. A recycle procedure augmented the yield of desired diastereomer in the Pictet–Spengler reaction from a mixture of diastereomers heavily enriched in the undesired diastereomer.

Residual metals were <10 ppm. Chiral method: Chiralcel OD-H, 250 mm × 4.6 mm, 40 °C, 1 mL/min, 260 nm, 30 min run time, 20% (1:1 IPA/MeOH) in heptane +0.1% TEA isocratic: rt (1): 7.61 min, rt (enantiomer-1): 14.45 min. By HPLC assay, final product was 99.60 LCAP 1, 0.17 LCAP 22, 0.24 LCAP enantiomer-22, enantiomer-1 was undetectable.

……………………………….

http://www.google.com/patents/WO2009011836A1?cl=en

WO 2009011836

Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are either commercially available or made by known procedures in the literature or as illustrated. The present invention further provides processes for the preparation of compounds of structural formula I as defined above, hi some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for the purpose of illustration only and are not to be construed as limitations on the disclosed invention. All temperatures are degrees Celsius unless otherwise noted. The assignment of stereochemistry at the stereogenic carbon center indicated by an ** in Structure G of Scheme 3 from the Pictet-Spengler cyclization reaction to elaborate the β-carboline nucleus was determined using the aid of nuclear Overhauser effect (NOE) NMR spectroscopy. For a thorough discussion of the theory and application of NOE NMR spectroscopy, reference is made to Ernst, R.R.; Bodenhausen, B.; Wokaun, A., “Principles of Nuclear Magnetic Resonances in One or Two Dimensions”, Oxford University Press, 1992; Neuhaus, D.; Williamson, M. P., “The Nuclear Overhauser Effect in Structural and Conformational Analysis, 2nd Edition”, in “Methods in Stereochemical Analysis”, Marchand, A. P. (series editor), John A. Wiley and Sons, New York 2000.

SCHEME l

 

In Scheme 1 , substituted indoles A are treated with dimethylamine and paraformaldehyde in a Mannich reaction to form 3-(dimethylamino)methyl-indole B. Reaction of B with nitro ester C affords the 3-(indol-3-yl)-2-nitro-propionic acid, ethyl ester D which is reduced to tryptophan derivative E. Acylation of the amine in E and hydrolysis of the ester F affords the appropriately protected tryptophan derivative G. Separation of the isomers of F or G by chiral column chromatography yields the individual enantiomers.

SCHEME 2

In Scheme 2, substituted indole A is reacted with L-serine in the presence of acetic anhydride and acetic acid to form tryptophan B. Hydrolysis of the amide followed by amine protection affords the desired substituted tryptophan intermediate D.

SCHEME 3

 

In Scheme 3, substituted tryptophan derivative A is reacted with α-bromo-ketone B to afford ester C. Reaction with ammonium acetate effects cyclization to form substituted imidazole D. Removal of the N-Boc protecting group with acid yields indole imidazole E which is reacted with aldehydes or ketones F in a Pictet-Spengler cyclization to afford the desired product G.

EXAMPLE 21

 

(3i?Vr4-(4-Fluorophenvn-lH-imidazol-2-yll-l-r5-methyl-1.2.4-oxadiazol-3-vn-l-π-methyl-lH- pyrazol-4-yl)-23,4,9-tetrahydro-lH-β-carboline

(IR)-I -[4-(4-Fluorophenyl)- 1 H-imidazol-2-yl] -2-( 1 H-indol-3 -yl) ethanamine hydrochloride (370 mg, 1.037 mmol) [prepared by treatment of tert-butyl (lR)-2-(l H-indol-3 -yl)- l-(4-(4-fluorophenyl)-l H-imidazol-2-yl)- 1-ethylcarbamate with hydrochloric acid] was treated with pyridine (4 mL) followed by reaction with l-methyl-pyrazol-4-yl 5-methyl-l,2,4-triazol-3-yl ketone (Intermediate 22) (219 mg, 1.141 mmol). The reaction was heated under N2 (oil bath 7O0C) for 48 h followed by additional heating (oil bath 850C) for 3 d. The reaction mixture was concentrated and azeotroped with toluene. The residue was purified with preparative TLC eluting with 10% MeOH in CH2Cl2 to give (3i?)-[4-(4-fluorophenyl)-lH-imidazol-2-yl]-l-(5- methyl-1 ,2,4-oxadiazol-3-yl)-l-(l-methyl-pyrazol-4-yl)-2,3,4,9-tetrahydro-lH-β-carboline as a mixture of diastereoisomers which were separated by chiral ΗPLC. The isomers were characterized by an analytical chiral AD column eluting with 20% IPA in heptane. (3i?)-[4-(4- Fluorophenyl)- 1 H-imidazol-2-yl] – 1 -(5 -methyl- 1 ,2,4-oxadiazol-3 -yl)-( 1 R)-( 1 -methyl-pyrazol-4- yl)-2,3,4,9-tetrahydro-lH-β-carboline (faster eluting isomer: retention time 18.13 min): 1H NMR (500 MHz, MeOH-(I4): δ 7.74 (m, 2H), 7.65 (s, IH), 7.52 (m, 2H), 7.37 (m, 2H), 7.13 (m, 3H), 7.04 (s, IH), 4.47 (dd, IH), 3.87 (s, 3H), 3.24 (dd, IH), 3.16 (dd, IH), 2.63 (s, 3H). LC-MS: m/z 495.3 (M + H)+ (2.56 min).

(3i?)-[4-(4-Fluorophenyl)-lH-imidazol-2-yl]-l-(5-methyl-l,2,4-oxadiazol-3-yl)-(lS)-(l-methyl- pyrazol-4-yl)-2,3,4,9-tetrahydro-l//-β-carboline (slower eluting isomer: retention time 24.62 min): 1H NMR (500 MHz, MeOH-Cl4): δ 7.73 (m, 2H), 7.54 (d, IH), 7.48 (s, IH), 7.43 (s, IH),

7.40 (d, IH), 7.36 ( brs, IH), 7.13 (m, 3H), 7.06 (t, IH), 4.40 (dd, IH), 3.84 (s, 3H), 3.26 (dd, IH), 3.16 (dd, IH), 2.63 (s, 3H). LC-MS: m/z 495.3 (M + H)+ (2.61 min).

The relative stereochemistry of the two diastereoisomers was determined by nuclear Overhauser effect (nθe) NMR spectroscopy. The slower eluting diastereisoomer afforded an nOe signal between the C-3 and C-5 hydrogens on the C-I pyrazole and the C-3 hydrogen on the β-carboline and the faster eluting product did not. Therefore, the diastereoisomer that eluted first from the preparative chiral HPLC purification was assigned as the c/s-isomer (imidazole and pyrazole are cis) and the slower eluting isomer as the trørøs-isomer.

…………………..

Dobbelaar, P. H.; Du, W.; Guo, L.; Hagmann, W. K.; He, S.; Jian, T.; Liu, J.; Nargund, R. P.; Pasternak, A.; Shah, S. K.; Truong, Q. T.; Ye, Z.; Dellureficio, J.; Bakshi, R.WO/2009/011836 A1, 2009.

Drugs Fut 2012, 37(5): 379

The discovery of MK-4256, a potent SSTR3 antagonist as a potential treatment of type 2 diabetes
ACS Med Chem Lett 2012, 3(6): 484

Route development and multikilogram GMP delivery of a somatostatin receptor antagonist
Org Process Res Dev 2012, 16(8): 1329

Addressing cardiovascular issues of SSTR3 antagonists in K-4256 structural class
247th ACS Natl Meet (March 16-20, Dallas) 2014, Abst MEDI 213

Discovery of MK-4256, a subtype selective SSTR antagonist as a potential treatment of type-2 diabetes
243rd ACS Natl Meet (March 25-29, San Diego) 2012, Abst MEDI 186

………………………………

US6586445 * Jun 8, 1999 Jul 1, 2003 Société de Conseils de Recherches et d’Applications Scientifiques, S.A.S. Racemic mixtures of 1,2,3,4-tetra hydro-1-(4-methoxyphenyl)-3 -(4-phenyl-1H-imidazol-2-yl)-9H- pyrido(3,4-b)indole, which bind to somatostatin receptors and block sodium channel modulators; antidiabetic, antiinflammatory agents; diarrhea
US6864253 * Oct 1, 2002 Mar 8, 2005 Orth-Mcneil Pharmaceutical, Inc. Heterocyclic amines such as 1-(3,4-methylenedioxyphenyl)-2-(5 -(3,4-dimethoxyphenyl)pyrimidin-2-yl)- 2,3,4,9-tetrahydro-1H-beta-carboline, used as enzyme inhibitors for prophylaxix of sexual disorders
US6933303 * Oct 18, 2002 Aug 23, 2005 Transtech Pharma, Inc. Antidiabetic agents

 

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DR ANTHONY CRASTO

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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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