Maintaining That (Green) Glow
Mutation of a glutamic acid in the active site of green fluorescent protein (GFP) stabilizes its fluorescent output
http://www.chemistryviews.org/details/ezine/6193791/Maintaining_That_Green_Glow.html
Mutation of a glutamic acid in the active site of green fluorescent protein (GFP) stabilizes its fluorescent output
http://www.chemistryviews.org/details/ezine/6193791/Maintaining_That_Green_Glow.html
Smart delivery systems for the release of entrapped guests in a controlled manner
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 He, Zhixiong Ye, Quang Truong, Shrenik Shah, Wu Du, Liangqin Guo, Peter H. Dobbelaar, Zhong Lai, Jian Liu,Tianying Jian, Hongbo Qi, Raman K. Bakshi, Qingmei Hong, James Dellureficio, Alexander Pasternak, Zhe Feng, Reynalda deJesus, Lihu Yang, Mikhail Reibarkh, Scott A. Bradley, Mark A. Holmes, Richard G. Ball, Rebecca T. Ruck, Mark A. Huffman,Frederick Wong, Koppara Samuel, Vijay B. Reddy, Stan Mitelman, Sharon X. Tong, Gary G. Chicchi, Kwei-Lan Tsao, Dorina Trusca, Margaret Wu, Qing Shao, Maria E. Trujillo, George J. Eiermann, Cai Li, Bei B. Zhang, Andrew D. Howard, Yun-Ping Zhou,Ravi P. Nargund, William 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)+.
……………………………….
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
Reprint Address: Ruck, RT (reprint author)
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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
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 |
WO2010083136A1 * | Jan 12, 2010 | Jul 22, 2010 | Merck Sharp & Dohme Corp. | Oxadiazole beta carboline derivatives as antidiabetic compounds |
WO2011012661A1 | Jul 28, 2010 | Feb 3, 2011 | Novartis Ag | Pyridine and pyrazine derivatives as protein kinase modulators |
WO2011028455A1 | Aug 23, 2010 | Mar 10, 2011 | Merck Sharp & Dohme Corp. | Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
WO2011088025A1 | Jan 11, 2011 | Jul 21, 2011 | Merck Sharp & Dohme Corp. | Oxadiazole beta carboline derivatives as antidiabetic compounds |
WO2012101062A1 | Jan 20, 2012 | Aug 2, 2012 | Novartis Ag | Substituted bi-heteroaryl compounds as cdk9 inhibitors and their uses |
WO2012164071A1 | Jun 1, 2012 | Dec 6, 2012 | Intervet International B.V. | Imidazole derivatives |
WO2013068328A1 | Nov 6, 2012 | May 16, 2013 | Intervet International B.V. | Bicyclo [2.2.2] octan-1-ylcarboxylic acid compounds as dgat-1 inhibitors |
WO2013068439A1 | Nov 8, 2012 | May 16, 2013 | Intervet International B.V. | 4-amino-5-oxo-7,8-dihydropyrimido[5, 4 -f] [1, 4] oxazepine compounds as dgat1 inhibitors |
EP2676959A1 | Nov 11, 2009 | Dec 25, 2013 | Merck Sharp & Dohme Corporation | Combination drugs comprising aminotetrahydropyrans as Dipeptidyl Peptidase-IV Inhibitors for the Treatment or Prevention of Diabetes |
EP2676960A1 | Nov 11, 2009 | Dec 25, 2013 | Merck Sharp & Dohme Corp. | Combination drugs comprising aminotetrahydropyrans as Dipeptidyl Peptidase-IV Inhibitors for the Treatment or Prevention of Diabetes |
EP2676961A1 | Nov 11, 2009 | Dec 25, 2013 | Merck Sharp & Dohme Corporation | Combination drugs comprising aminotetrahydropyrans as Dipeptidyl Peptidase-IV Inhibitors for the Treatment or Prevention of Diabetes |
US20120264777 * | Jan 11, 2011 | Oct 18, 2012 | Merck Sharp & Dohme Corp. | Oxadiazole beta carboline derivatives as antidiabetic compounds |
Biphenyl urea is a novel tool to pharmacologically control the cardiac activity
http://www.chemistryviews.org/details/news/6210781/A_Funny_Control_of_Heartbeats.html
DOTA and its derivatives may be very suitable ligands for scandium radioisotopes for therapy
http://www.chemistryviews.org/details/ezine/6245141/A_Step_Toward_Scandium_Radiopharmaceuticals.html
Chemical Reviews DOI: 10.1021/cr400372p
Exploiting Intrinsic Nanoparticle Toxicity: The Pros and Cons of Nanoparticle-Induced Autophagy in Biomedical Research (Fri, 13 Jun 2014)
>> read more………http://pubs.acs.org/doi/abs/10.1021/cr400372p
http://www.google.com/patents/EP2524917A1?cl=en
(R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile AS TFA SALT
………………………………………………………………………….
………………………………………
SEE POLYMORPHS
CN 102863440
http://www.google.com/patents/CN102863440A?cl=en
Dipeptidyl peptidase-IV (DPP-IV) inhibitors are a new generation of oral treatment of type 2 diabetes by enhancing the role of incretin activity, a non-insulin therapy. With conventional medicine for treating diabetes compared, DPP-IV inhibitors have not weight gain and edema and other adverse reactions. [0003] The compound shown in formula ⑴ (R) -2 – [[7 – (3 – amino-piperidine-I-yl) -3,5 – dimethyl-2 – oxo-2 ,3 – dihydro- -IH-imidazo [4,5-b] pyridin-I-yl] methyl] benzonitrile (referred to as the specification of compound A, in the patent application CN201010291056. 9 already described) is a DPP-IV inhibitor compounds , the DPP-IV has a strong inhibitory effect and high selectivity.
V
[0004] formula ⑴
[0005] In the crystalline drug development research is very important, compound crystal form, will result in its stability, solubility and other properties are different. Therefore, the inventors of the compound or its salt polymorph A lot of research carried out, whereby it was confirmed, and the invention of the compound A crystalline salt.
3, Invention
[0006] The object of the present invention is to solve the above problems and to provide better stability, better maneuverability, good bioavailability and solubility of the compound A or a salt thereof and method for preparing the crystalline form.
[0007] The present invention provides formula (I), the compound A dihydrochloride salt polymorph I: using Cu-K α radiation, to angle 2 Θ (°) represents an X-ray powder diffraction at 8. 7 ± 0. 2 °, 19.4 ± 0.2 °, 23. 5 ± 0. 2 °, 27. 2 ± 0. 2 ° at a characteristic peaks.
Butterfly NC N
[0008] formula ⑴
[0009] A compound of the dihydrochloride salt polymorph I, with Cu-Ka radiation, to angle 2 Θ (°) represents an X-ray powder diffraction peaks in addition to the features described above, it also at 12. 5 ± 0. 2 °, 22. 5 ± 0. 2 °, 25. 5 ± 0.2 ° at a characteristic peaks.
[0010] A compound of the dihydrochloride salt polymorph I, with Cu-κα exposed to radiation angle 2 Θ (°) represents an X-ray powder diffraction peaks in addition to the features described above, it also at 11.7 ± 0.2 °, 14.6 ± 0.2 °,
26. O ± 0.2 ° at a characteristic peak.
[0011] The present invention also provides the compound A dihydrochloride Preparation of polymorph I.
[0012] Compound A was dissolved in an organic solvent, and temperature, was added dropwise a stoichiometric ratio of hydrochloric acid, after the addition was complete stirring, filtered and dried to give the dihydrochloride salt of Compound A crystalline form I.
……………………………………………….
http://www.google.com/patents/EP2524917A1?cl=en
0r
WO 2011085643
(1)2,4-dichloro-6-methyl-3-nitropyridine
(2) (R)-1-(2-chloro-3-nitro-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate
(3) (R)-1-(2-methylamino-3-nitro-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate
(4) (R)-1-(2-methylamino-3-amino-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate
(5)(R)-1-(3,5-dimethyl-2-oxo-2,3-dihydro-1
H
(6)(R)-1-[1-(2-cyanobenzyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1
H
(7)(R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dibydro-1-imidazo [4,5-b]pyridin-1-yl]methyl]benzonitrile trifluoroacetate
…………………….
PAPER
We report our discovery of a novel series of potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors. Starting from a lead identified by scaffold-hopping approach, our discovery and development efforts were focused on exploring structure–activity relationships, optimizing pharmacokinetic profile, improving in vitro and in vivo efficacy, and evaluating safety profile. The selected candidate, Imigliptin, is now undergoing clinical trial.
Discovery of Imigliptin, a Novel Selective DPP-4 Inhibitor for the Treatment of Type 2 Diabetes
http://pubs.acs.org/doi/abs/10.1021/ml5001905
synthesis………http://pubs.acs.org/doi/suppl/10.1021/ml5001905/suppl_file/ml5001905_si_001.pdf
data for LEAD compd 1
mono-TFA solvate (160mg, 71%).
2013-10-18 16:31:08 Copyfrom: Sihuan Pharmaceutical Holdings Group Ltd.
Sitagliptin (sitagliptin) is the first one listed on the DPP-IV inhibitor, in 2006 after the listing quickly became a blockbuster for Merck. July 31, 2009, FDA has approved AstraZeneca and Bristol-Myers Squibb developed saxagliptin (saxagliptin) listed. Takeda (Taketa)’s SYR-322 activity and selectivity are superior to sitagliptin and saxagliptin, is currently in pre-registration. In addition, there are three stages of drug is in phase III: Bo Mingge Yan Gehan’s BI-1356 (Iinagliptin), Pfizer’s PF-734200 (gosogliptin), phenomix company PHX 1149 (dutogliptin) [0007]
In phase II drug has nine, in phase I of seven.
[0008] However, the limited varieties of drugs, can not meet the clinical needs, the urgent need to develop more of the DPP-IV inhibitor drugs to meet the clinical medication.
Example 17 (R)-2-ΓΓ7-(3 ~ amino-piperidin-yl) -3, 5_ dimethyl _2_ oxo, 3_ dihydro-IH-blind half and P “4,5 Pyridine-b1-i-a] benzonitrile Jiamou 1 (Compound 17) The system of the
[0451]
[0452] (1) 2,4 – dichloro-6 – methyl-nitropyridine _3_
[0453]
[0454] A mixture of 6 – methyl-3 – nitropyridine 2,4 – diol (1. Lg, IOmmol) dissolved in IOmL POCl3, heated to 95 ° C, stirred for 1.5 hours, rotating to excess POCl3 , ice water was added carefully IOOmL, extracted with ethyl acetate (80mLX3), the combined organic phases washed with saturated brine, dried over anhydrous Na2SO4, rotary done 1. 773g yellow powder, yield 85.7%.
[0455] (2) (R)-I-(2 – chloro-nitro _6_ _3_ _4_ picoline) piperidin-_3_ t-butyl carbamate
[0456]
[0457] Specific operation in Reference Example 1 (1), cast _ 2,4 dichloro-6 – methyl-_3_ nitropyridine 0. 96g (4. 64mmol), R-tert-butyl piperidin-_3_ yl – carbamate 0. 933g (4. 66mmol), to give the product 1. Ig, yield 63.9%.
[0458] (3) (R)-I-(2 – methylamino-nitro _6_ _3_ _4_ picoline) piperidin-_3_ t-butyl carbamate
[0459]
[0460] Specific operation in Reference Example 1 (2), cast (R) -1 – (2 – chloro-nitro _6_ picoline _3_ _4_ yl)-piperidin-3 – tert-butyl imino ester 1. Ig (2. 97mmol), 27% methylamine alcohol solution 5mL, to give the product 1. Og, yield 92.1%.
[0461] (4) (R)-I-(2 – methyl amino -3 – diamino-6 – methylpyridine _4_ yl) piperidin-_3_ t-butyl carbamate
[0462]
[0463] Specific operation in Reference Example 1 (3), cast (R)-l_ (2 – methylamino-methyl-4 _3_ nitro _6_ – yl) piperidin-3 – tert- butyl carbamate 1.0g (2. 74mmol), 10% Pd-C 0. lg, to give the product 0. 873g, 95% yield.
[0464] (5) (R)-I-(3,5 – dimethyl-2 – oxo-2 ,3 – dihydro-IH-imidazo [4,5 _b] pyridin _7_ yl)
Piperidin-3 – t-butyl carbamate
[0465]
[0466] Specific operation in Reference Example 1 (4), cast ((R)-l_ (2 – methylamino-4 _3_ methyl amino _6_ – yl) piperidin-3 – yl t-butyl carbamate 873mg (2. 60mmol), triphosgene 849mg (2. 86mmol), triethylamine 1. 39mL (10. 4mmol), to give the product 0. 813g, yield 86.5% 0
[0467] (6) (R)-l-[l_ (2 – cyano-benzyl) -3,5 _ dimethyl-2 – oxo-2 ,3 – dihydro-IH-imidazo [4, 5 -b] pyridin-7 – yl] piperidin-3 – t-butyl carbamate
[0468]
[0469] Specific operation in Reference Example 1 (5), cast (R)-I-(3,5 – dimethyl-2 – oxo-2 ,3 – dihydro-IH-imidazo [4, 5-b] pyridin-7 – yl) piperidin-3 – t-butyl carbamate 813mg (2. 25mmol), 2_ (bromomethyl) benzonitrile 441mg (2. 25mmol), potassium carbonate 621mg (4. 50mmol), to give the product 0. 757g, yield 70.5%.
[0470] (7) (R) -2 – [[7 – (3 – amino-piperidin-1 – yl) -3,5 – dimethyl-2 – oxo-2 ,3 – dihydro-IH- imidazo [4,5-b] pyridin-1 – yl] methyl] benzonitrile
[0471]
[0472] Specific operation in Reference Example 1 (6), cast (R)-l-[l_ (2 – cyano-benzyl) -3,5-dimethyl-2-_ – oxo – two H-IH-imidazo [4,5-b] pyridin-7 – yl] piperidin-3 – t-butyl carbamate 750mg (l. 57mmol), trifluoroacetic acid 8. 5mL, 0 to give the product . 680g, yield 88.3%.
[0473] MF = C21H24N6O MW: 376 * 45 MS (M + H): 377. 2
[0474] 1H-NMR (D2OdOOMHz): δ 1. 32 (1Η, m), 1. 54 (1H, m), 1. 90 (1H, m), 2. 32 (3H, s), 2. 48 (1H, m), 2. 80-2. 60 (m, 2H), 2. 90 (2H, m), 3. 04 (1H, m), 3. 27 (3H, s), 5. 25 ( 1H, d), 5. 39 (1H, d), 6. 76 (1H, s), 6. 93 (1H, d), 7. 29 (1H, d), 7. 42 (1H, t), 7. 64 (1H, d) ·
WO2004050658A1 * | Dec 3, 2003 | Jun 17, 2004 | Boehringer Ingelheim Pharma | Novel substituted imidazo-pyridinones and imidazo-pyridazeiones, the production and use thereof as medicaments |
WO2009099594A1 * | Feb 2, 2009 | Aug 13, 2009 | Luke W Ashcraft | Certain chemical entities, compositions and methods |
WO2011085643A1 * | Jan 17, 2011 | Jul 21, 2011 | Kbp Biomedical Co., Ltd. | Fused pyridine derivatives |
CN101228164A * | May 11, 2006 | Jul 23, 2008 | 布里斯托尔-迈尔斯·斯奎布公司 | Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods |
SYNTHESIS…………..http://pubs.acs.org/doi/suppl/10.1021/ml500025p/suppl_file/ml500025p_si_001.pdf
A new study reveals the key role a protein plays in chronic obstructive pulmonary disease (COPD) and provides a potential lead for treating the incurable lung disease (Sci. Transl. Med. 2014, DOI: 10.1126/scitranslmed.3008074).
Stephen L. Nishimura, a professor in the pathology department at the University of California, San Francisco, and colleagues have engineered a monoclonal antibody that prevents the activation of a destructive protein in COPD mouse models and have explored in detail how the antibody binds to its target.
AZD 6564
SYNTHESIS SUPP INFO…..http://pubs.acs.org/doi/suppl/10.1021/ml400526d/suppl_file/ml400526d_si_001.pdf
NMR PG 16/32 AS ABOVE
R1 = NEOPENTYL R2=H
5-[(2R,4S)-2-(2,2-Dimethylpropyl)piperidin-4-yl]-1,2-oxazol-3(2H)-one
5-((2R,4S)-2-Neopentylpiperidin-4-yl)isoxazol-3(2H)-one
238.326
C13 H22 N2 O2
Antifibrinolytics
AstraZeneca (Innovator)
SYNTHESIS SUPP INFO…..http://pubs.acs.org/doi/suppl/10.1021/ml400526d/suppl_file/ml400526d_si_001.pdf
NMR PG 16 0F 32
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Discovery of the fibrinolysis inhibitor AZD6564, acting via interference of a protein – Protein interaction
ACS Med Chem Lett 2014, 5(5): 538
http://pubs.acs.org/doi/abs/10.1021/ml400526d
A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein–protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC50 of 0.44 μM, no detectable activity against GABAa, and with DMPK properties leading to a predicted dose of 340 mg twice a day oral dosing in humans.
SUPP INFO…..http://pubs.acs.org/doi/suppl/10.1021/ml400526d/suppl_file/ml400526d_si_001.pdf
Step 9: 5,((2R,4S),2,Neopentylpiperidin,4,yl)isoxazol,3(2H),one
O
L C^O”
METHOD B
O
METHOD C
METHOD D
RIB(OR)2
X = Cl, Br
METHOD E
METHOD F
METHOD G
R1 = 1-methyl-1 H-tetrazol-5-yl and 2-methyl-2H-tetrazol-5-yl
Scheme B. Formation of 5-isoxazol-3-ones
°Y I ‘relative
°Y J ‘relative
………………….
http://www.google.com/patents/EP2417131A1?cl=en
Example 14
5-((2R,4S)-2-Neopentylpiperidin-4-yl)isoxazol-3(2H)-one
Step 1 : Cis-methyl 2-neopentyl-4-(3-oxo-23-dihvdroisoxazol-5-yl)piperidine-l-carboxylate The compound was prepared as described in Example 1, Step 2 starting from cis-methyl 4-(3- ethoxy-3-oxopropanoyl)-2-neopentylpiperidine-l -carboxylate (2.68 g, 8.19 mmol) which resulted in cis-methyl 2-neopentyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-l- carboxylate (1.60 g, 66 %) : IH NMR (400 MHz, cdcl3) δ 0.89 (s, 9H), 1.18 (dd, IH), 1.45 (dd, IH), 1.80 – 1.92 (m, 2H), 1.97 – 2.17 (m, 2H), 2.94 – 3.02 (m, IH), 3.11 – 3.23 (m, IH), 3.71 (s, 3H), 3.88 – 3.99 (m, IH), 4.22 – 4.32 (m, IH), 5.72 (s, IH); m/z (MH+) 297.
Step 2: (2R,4S)-Methyl 2-neopentyl-4-(3-oxo-2,3-dihvdroisoxazol-5-yl)piperidine-l- carboxylate
Following the procedure described in Example 1, Step 3, racemic cis-methyl 2-neopentyl-4- (3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-l -carboxylate (1.60 g, 5.4 mmol) was subjected to chiral separation using Chiralcel IC mobile phase heptane/IP A/FA 60/40/0.1 which resulted in (2R,4S)-methyl 2-neopentyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-l-carboxylate (0.8 g, 2.7 mmol).
Step 3: 5-((2R,4S)-2-Neopentylpiperidin-4-yl)isoxazol-3(2H)-one
5 Starting from (2R,4S)-methyl 2-neopentyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-l- carboxylate (0.8 g, 2.7 mmol) and following the procedure described in Example 1, Step 4 the title compound was obtained (0.44 g, 69 %): 1H NMR (600 MHz, DMSO-d6) δ 0.89 (s, 9H), 1.18 (m, 2H), 1.50 (m, 2H), 1.82-1.90 (m, 2H), 2.70-2.85 (m, 3H), 3.08 (m, IH), 5.71 (s, IH). [α]20 D +43.8 (MeOH/H2O 1:1, c = 1); HRMS calculated for [C13H23N2O2]+: 239.1759; found: 10 239.1753.
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