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

http://www.chemistryviews.org/details/news/6301211/Enzymatic_Logic_Gates.html

Enzymatic Logic Gates

Smart delivery systems for the release of entrapped guests in a controlled manner

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

Uncategorized Comments Off

Jun 252014

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)+.

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)

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):

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

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, 2^nd 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.

Highlights from the American College of Cardiology 2012 Annual Meeting. March 24-27, 2012 – Chicago, Illinois, USA

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

A Funny Control of Heartbeats

Uncategorized Comments Off

Jun 252014

A Funny Control of Heartbeats

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

A Step Toward Scandium Radiopharmaceuticals

Uncategorized Comments Off

Jun 252014

A Step Toward Scandium Radiopharmaceuticals

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

Exploiting Intrinsic Nanoparticle Toxicity: The Pros and Cons of Nanoparticle-Induced Autophagy in Biomedical Research

Uncategorized Comments Off

Jun 242014

TOC Graphic

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

Karen Peynshaert †‡, Bella B. Manshian §, Freya Joris †‡, Kevin Braeckmans †‡, Stefaan C. De Smedt *†

, Jo Demeester †, and Stefaan J. Soenen *†§

†Lab of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, ‡Centre for Nano- and Biophotonics, and

Ghent Research Group on Nanomedicine, Ghent University, B9000 Ghent,Belgium

§ Biomedical MRI Unit/MoSAIC, Department of Imaging and Pathology, Faculty of Medicine, Catholic University of Leuven, B3000 Leuven, Belgium

Chem. Rev., Article ASAP

DOI: 10.1021/cr400372p

1. Introduction
2. Nanomedicine
- 2.1. Soft Nanomaterials
- 2.2. Hard Nanomaterials
3. Nanotoxicology and the Role of Autophagy
- 3.1. Key Focus Points and Challenges in the Field of Nanotoxicology
- 3.2. Process of Autophagy
- 3.3. Autophagy and Cell Death
- 3.4. How to Study Autophagy
- 3.5. Chemical Modulation of Autophagy
4. Nanomaterial-Induced Autophagy
- 4.1. Modulation of autophagy by soft particles
  - 4.1.1. Modulation of Autophagy by Liposomes
  - 4.1.2. Modulation of Autophagy by Polymeric NPs
- 4.2. Modulation of Autophagy by Hard Nanoparticles
  - 4.2.1. Gold Nanoparticles
  - 4.2.2. Iron Oxide Nanoparticles
  - 4.2.3. Quantum Dots
  - 4.2.4. Zinc Oxide Nanoparticles
  - 4.2.5. Carbon-Based Nanomaterials
  - 4.2.6. Other Hard Nanomaterials
  - 4.2.7. Physiological Effects of Nanoparticle-Mediated Autophagy Modulation
- 4.3. Influence of Nanoparticle Characteristics on Autophagy Deregulation
- 4.4. Mechanisms of Autophagy Induction by Nanomaterials
5. Dangers of Autophagy Modulation
- 5.1. Autophagy in Neurodegenerative Diseases
- 5.2. Autophagy and Cancer
6. Possibilities of Nanomaterial-Induced Autophagy
- 6.1. Selective Destruction of Cancer Cells
  - 6.1.1. Selective Autophagy in Cancer Cells
  - 6.1.2. Cancer-Specific Induction of Autophagy by Nanomaterials
  - 6.1.3. Potential of Nanoparticles in Anticancer Therapy
- 6.2. Autophagy-Mediated Synergistic Effect of Nanoparticles and Chemotherapeutics
- 6.3. Enhanced Tumor Antigen Presentation through Nanoparticle-Mediated Autophagy
- 6.4. Autophagy Induction as a Self-Protection Process against Nanotoxicity
- 6.5. Potential of Nanoparticles for Neuropathological Therapy
7. Conclusions and Outlook

Discovery of Imigliptin, a Novel Selective DPP-4 Inhibitor for the Treatment of Type 2 Diabetes

Uncategorized Comments Off

Jun 242014

compd 27 as above IN http://pubs.acs.org/doi/abs/10.1021/ml5001905

Imigliptin

CAS OF FREE BASE 1314944-07-4
C₂₁ H₂₄ N₆ O
Benzonitrile, 2-[[7-[(3R)-3-amino-1-piperidinyl]-2,3-dihydro-3,5-dimethyl-2-oxo-1H-imidazo[4,5-b]pyridin-1-yl]methyl]-

黄振华

Sihuan Pharmaceutical

Kbp Biosciences Co., Ltd., 山东轩竹医药科技有限公司

Imigliptin dihydrochloride is an orally-available dipeptidyl peptidase IV (CD26; DPP-IV; DP-IV) inhibitor in phase I clinical trials at Sihuan Pharmaceutical for the treatment of type 2 diabetes.

………………………………………………………………

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

1314944-08-5 CAS
C₂₁ H₂₄ N₆ O . C₂ H F₃ O₂
Benzonitrile, 2-[[7-[(3R)-3-amino-1-piperidinyl]-2,3-dihydro-3,5-dimethyl-2-oxo-1H-imidazo[4,5-b]pyridin-1-yl]methyl]-, 2,2,2-trifluoroacetate (1:1)

………………………………………………………………………….

LEAD compd 1 as above ……….cas ………1314943-88-8

C₁₉ H₁₉ N₅ O₂
Benzonitrile, 2-[[7-[(3R)-3-amino-1-piperidinyl]-2-oxooxazolo[5,4-b]pyridin-1(2H)-yl]methyl]-

………………………………………

SEE POLYMORPHS

EP2730575A1, WO2013007167A1

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.

[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

WO 2011085643

Diabetes mellitus is a systemic chronic metabolic disease caused by a blood glucose level higher than normal level due to loss of blood glucose control. It is basically classified into four categories, including: type I (insulin-dependent) and type II (non-insulin-dependent), the other type and gestational diabetes. Type I and type II diabetes are primary diabetes, which are the two most common forms caused by the interaction of genetic and environmental factors. The cause of diabetes is very complicated, but in the final analysis, is due to absolute or relative insulin deficiency, or insulin resistance. It is characterized by the metabolic disorder of carbohydrate, protein, fat, electrolytes and water caused by absolute or relative insulin deficiency and the reduced sensitivity of target cells to insulin.
In recent years, because of the improvement of living level, changes in the diet structure, the increasingly intense pace of life and lifestyle of less exercise and many other factors, the global incidence of diabetes is rapidly increasing, so that diabetes has become the third chronic disease which has a serious threat to human health next to tumor and cardiovascular diseases. Presently, the number of the patients suffering from diabetes has exceeded 120 million in the world, and the number in our country is the second largest in the world. According to statistics, up to 40 million people have been diagnosed as diabetes in China, and the number of the patients is increasing at a rate of 1 million per year. Among them, patients having type I and type II diabetes accounted for 10% and 90% respectively. Diabetes has become the increasingly concerned public health issue.
The main drugs currently used for the treatment of type I diabetes are insulin preparations and their substitutes; for the treatment of type II diabetes, the main drugs are oral hypoglycemic agents, generally divided into sulfonylureas, biguanides, traditional Chinese medicine preparations, other hypoglycemic agents, and auxiliary medication. Although these drugs have good effects, they can not maintain long-term efficacy in reducing the high blood glucose, and can not effectively alleviate the condition against the cause of diabetes. Many of the anti-diabetic drugs can well control the blood glucose at the beginning, but their efficacy can not be maintained when the treatment using such drugs are continuously used. It is one of the main reasons why combination therapies or drugs in different classes are used. However, the existing anti-diabetic drugs is lack of long-term efficacy mainly because their mechanism of action is to increase the sensitivity of target tissues to insulin action or improve insulin-producing activity of pancreas, but these drugs have no targeted effect to the reduced function of the pancreatic β cell, which is the fundamental cause of diabetes.
Dipeptidyl peptidase-IV (DPP-IV) is widely present in the body, and is a cell surface protein involved in a variety of biological functions. It can degrade many active enzymes in vivo, such as glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), neuropeptide, substance P, and chemokines and the like. The deficiency of GLP-1 and GIP is the main cause resulting in type II diabetes (i.e., non-insulin-dependent diabetes). DPP-IV inhibitor is a new generation of anti-diabetic drug. It protects the activity of GLP-1, GIP and the like, stimulates the secretion of insulin, lowers blood glucose level by inhibiting the activity of DPP-IV, and does not cause hypoglycemia, weight gain, edema and other side effects. Its effect for lowering blood glucose level stops when a normal blood glucose level has been reached, and hypoglycemia will not occur. It can be used for a long term, and can repair the function of β-cells.
Sitagliptin is the first marketed DPP-IV inhibitor. It rapidly became a “blockbuster” drug after marketed in 2006 by Merck. The FDA approved the saxagliptin developed by AstraZeneca and Bristol-Myers Squibb on July 31, 2009. SYR-322 developed by Takeda has an activity and selectivity better than that of sitagliptin and saxagliptin, and is currently in the phase of pre-registration. In addition, there are three drugs in clinical phase III: BI-1356 (linagliptin) developed by Boehringer Ingelheim, PF-734200 (gosogliptin) developed by Pfizer Inc, and PHX1149 (dutogliptin) developed by Phenomix Inc. Nine drugs are in the clinical phase II, and seven drugs are in clinical phase I.
However, the limited varieties of drugs can not satisfy the clinical requirements. Accordingly, there is an urgent need for development of many DPP-IV inhibitor drugs to satisfy the clinical use.

Example 17 The preparation of (R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1

(1)2,4-dichloro-6-methyl-3-nitropyridine

6-methyl-3-nitropyridin-2,4-diol (1.7 g, 10 mmol) was dissolved in 10 mL POCl₃, heated to 95°C, and stirred for 1.5 h. The excess POCl₃ was removed through centrifugation. 100 mL ice water was carefully added. The reaction solution was extracted with ethyl acetate (80 mL×3). The organic phase was combined, washed with saturated brine, dried with anhydrous Na₂SO₄ and spinned to dryness to afford 1.773 g yellow powder with a yield of 85.7 %.

(2) (R)-1-(2-chloro-3-nitro-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate

[0216]

The specific operation referred to the step (1) described in Example 1 for details. 0.96 g 2,4-dichloro-6-methyl-3-nitropyridin (4.64 mmol), and 0.933 g R-tert-butylpiperidin-3-yl-carbamate (4.66 mmol) were charged to afford 1.1 g titled product with a yield of 63.9 %.

(3) (R)-1-(2-methylamino-3-nitro-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate

The specific operation referred to the step (2) described in Example 1 for details, 1.1 g (R)-1-(2-chloro-3-nitro-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate (2.97 mmol), and 5 mL 27 % solution of methylamine in alcohol were charged to afford 1.0 g titled product with a yield of 92.1 %.

(4) (R)-1-(2-methylamino-3-amino-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate

The specific operation referred to the step (3) described in Example 1 for details. 1.0 g (R)-1-(2-methylamino-3-nitro-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate (2.74 mmol), and 0.1 g 10% Pd-C were charged to afford 0.873 g titled product with a yield of 95 %.

(5)(R)-1-(3,5-dimethyl-2-oxo-2,3-dihydro-1

The specific operation referred to the step (4) described in Example 1 for details. 873 mg (R)-1-(2-methytamino-3-amino-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate (2.60 mmol), 849 mg triphosgene (2.86 mmol), and 1.39 mL triethylamine (10.4 mmol) were charged to afford 0.813 g titled product with a yield of 86.5 %.

(6)(R)-1-[1-(2-cyanobenzyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1

The specific operation referred to the step (5) described in Example 1 for details.813 mg (R)-1-(3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)piperidin-3-yl tert-butyl carbamate (2.25 mmol), 441 mg 2-(bromomethyl)benzonitrile (2.25 mmol), and 621 mg potassium carbonate (4.50 mmol) were charged to afford 0.757 g titled product with a yield of 70.5%.

(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

The specific operation referred to the step (6) described in Example 1 for details. 750 mg (R)-1-[1-(2-cyanobenzyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin -7-yl]piperidin-3-yl tert-butyl carbamate (1.57 mmol), and 8.5 mL trifluoroacetic acid were charged to afford 0.680 g titled product with a yield of 88.3%.
Molecular formula: C₂₁H₂₄N₆O Molecular weight: 376.45 Mass spectrum (M+H): 377.2
¹H-NMR(D₂O, 400 MHz): δ 7.64 (d, 1H), 7.42 (t, 1H), 7.29 (d, 1H), 6.93(d, 1H), 6.76(s, 1H), 5.39(d, 1H), 5.25(d, 1H), 3.27(s, 3H), 3.04(m, 1H), 2.90(m, 2H), 2.80-2.60 (m, 2H), 2.48 (m, 1H), 2.32 (s, 3H), 1.90 (m, 1H), 1.54 (m, 1H), 1.32 (m, 1H).

…………………….

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

Chutian Shu †, Hu Ge ‡, Michael Song †, Jyun-hong Chen †, Huimin Zhou †, Qu Qi †, Feng Wang †, Xifeng Ma †, Xiaolei Yang †, Genyan Zhang †, Yanwei Ding †, Dapeng Zhou †, Peng Peng †, Cheng-kon Shih †‡, Jun Xu ‡, and Frank Wu *†‡

^† Department of Project Management, Medicinal Chemistry, Process, Pharmacology, Drug Metabolism and Pharmacokenetics, Toxicology, XuanZhu Pharma, 2518 Tianchen Street, Jinan, Shandong, The People’s Republic of China

^‡ School of Pharmaceutical Sciences & Institute of Human Virology, Sun Yat-Sen University, 132 East Circle Road at University City, Guangzhou, The People’s Republic of China

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/ml5001905

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%).

1H NMR (d-DMSO + D2O, 600 MHz):

8.01 (d, 1 H), 7.89 (d, 1 H), 7.69 (t, 1 H),

7.53 (t, 1 H), 7.40 (d, 1 H), 7.13 (d, 1 H),

5.41 (d, 1 H), 5.30 (d, 1 H), 3.25 (d, 1 H), 3.05

(m, 1 H), 2.93 (d, 1 H), 2.77 (m, 1 H),

2.65 (m, 1H), 1.95 (m, 1 H), 1.66 (m, 1 H),

1.46-1.26 (m, 2 H).

Molecular Formula C19H19N5O2:(M+H) 350.2

compd 27

mono-TFA solvate (680 mg, 88%).1H NMR (D2O, 400 MHz):δ7.64 (d, 1 H), 7.42 (t, 1 H), 7.29 (d, 1 H), 6.93(d, 1 H),

6.76 (s, 1 H), 5.39 (d, 1 H), 5.25 (d, 1 H), 3.27(s, 3 H), 3.04 (m, 1 H), 2.90 (m, 2 H),

2.80-2.60 (m, 2 H), 2.48 (m, 1 H), 2.32 (s, 3 H), 1.90 (m, 1 H), 1.54 (m, 1 H), 1.32 (m,1 H).

Molecular Formula C21H24N6O: (M+H) 377.2.

……………………………………………………………………………………….

http://www.sihuanpharm.com/index.php?a=show&m=Article&id=403&l=en

Start of the first 4 volunteers in Imigliptin Dihydrochloride Phase I clinical trial

2013-10-18 16:31:08 Copyfrom: Sihuan Pharmaceutical Holdings Group Ltd.

Sihuan R&D clinical research centre (based in Beijing) announced that four healthy volunteers (human subjects) were administrated Imigliptin Dihydrochloride at first dosage of 5mg this morning around 8:00 am on 18 Oct 2013, and they all are in good conditions without any observed adverse effects so far.This is the first category 1.1 innovative drug independently developed by Sihuan Group which has now officially entered into clinical trials; that is from laboratory research into human studies. The preclinical studies of Imigliptin Dihydrochloride, a novel DPP-4 inhibitor treating type II diabetes, demonstrate excellent in vitro and in vivo activities and selectivities. In animal studies, it can protect pancreatic β–cells in long-term treatment. Pharmacokinetic studies of Imigliptin Dihydrochloride show attractive profile of good oral bioavailability, fast absorption and onset, and longer half-life compatible with the once daily dosing. We anticipate the above mentioned preclinical profiles be confirmed in our ongoing clinical trials.

………………………..

http://www.google.com/patents/CN102127072A?cl=en

CN102127070A, CN102127071A,CN102741251A, EP2524917A1, US8680089,US20120289497, WO2011085643A1,WO2011085643A8,

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

Total Synthesis and Biological Studies of TMC-205 and Analogues as Anticancer Agents and Activators of SV40 Promoter

Uncategorized Comments Off

Jun 242014

TMC 205

6-[3-Methyl-1(E),3-butadienyl]-1H-indole-3-carboxylic acid

C14 H13 N O2

227.2585

Mitsubishi Tanabe Pharma (Innovator) now in biological testing

TMC-205 is a natural fungal metabolite with antiproliferative activity against cancer cell lines. The light- and air-sensitivity prevented in-depth exploitation of this novel indole derivative. Herein, we report the first synthesis of TMC-205. On the basis of its reactivity with reactive oxygen species, we developed air-stable analogues of TMC-205. These analogues are 2–8-fold more cytotoxic than TMC-205 against HCT-116 colon cancer cell line. Importantly, at noncytotoxic dose levels, these analogues activated the transcription of luciferase reporter gene driven by simian virus 40 promoter (SV40). Further, these small molecules also inhibit firefly luciferase, presumably by direct interaction.

Total Synthesis and Biological Studies of TMC-205 and Analogues as Anticancer Agents and Activators of SV40 Promoter

Yang Gao , Sami Osman , and Kazunori Koide *

Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/ml500025p

http://pubs.acs.org/doi/abs/10.1021/ml500025p

SYNTHESIS…………..http://pubs.acs.org/doi/suppl/10.1021/ml500025p/suppl_file/ml500025p_si_001.pdf

Synthesisof TMC-205 (1):MeOH (1.5 mL) and aqueous

NaOH (4 M, 2.5 mL) were added to a 25-mL oven-driedround-

bottomed flask containing6(20 mg, 0.080 mmol) un-der an open atmosphere at 23°C

. The resulting solution was

covered from light and stirred in an 80°Coil bath for 2.25 h. The solution was then cooled to 23°C

, and steps

subsequent to cooling were performed in a dark environment. The solution was washed with CH2Cl2

(1 mL), and

then the aqueous layer was acidified with KHSO4

(3 M, 10 mL). The aqueous layerwas ex

tracted with EtOAc(10 mL×3). The combined organic layers were dried over Na2SO4

, filtered, and concentrated under reduced

pressure using a rotary evaporator (T

water bath= 30°C) to afford 16 mg of TMC-205 (1)

as a pale yellow solid

(88% yield, >

95% purity).

Data for TMC-205 (1):

Rf= 0.24 (40% EtOAc in hexanes);

IR (film):νmax

= 3432 (broad, O-H), 2920,2851,1644 (C=O), 1528, 1451, 1349 cm-1;

1H NMR (500 MHz, 293K, CD3OD):δ

= 7.99 (d,J= 8.3 Hz, 1H, 4-H), 7.92 (s, 1H, 2-H), 7.48 (br s,1H, 7-H), 7.35 (dd,J= 8.3, 1.5 Hz, 1H, 5-H), 6.94 (d,J= 16 Hz, 1H, 10-H),

6.67 (d,J= 16 Hz, 1H, 9-H), 5.10 (br s, 1H, 12-H), 5.03 (br s, 1H, 12-H), 1.98 (s, 3H, 13-H);

13C NMR

(75MHz, 293 K, CD3OD):δ= 169.0, 143.7, 139.0, 134.0, 133.8, 131.3, 130.7, 127.3, 122.1, 121.3, 116.7, 111.1,

109.9, 18.8;

HRMS (EI+) calcd for C14H13NO2

[M+] 227.0946, found 227.0936.

see

TMC-205, a new transcriptional up-regulator of SV40 promoter produced by an undentified fungus. Fermentation, isolation, physico-chemical properties, structure determination and biological activities
J Antibiot 2001, 54(8): 628

http://www.ncbi.nlm.nih.gov/pubmed/11592499?dopt=Abstract

A new transcriptional up-regulator designated TMC-205 was discovered from the fermentation broth of an unidentified fungal strain TC 1630 by using an SV40 promoter-luciferase reporter assay. Based on spectroscopic analyses, its structure was determined to be (E)-6-(3-methyl-1,3-butadienyl)- H-indole-3-carboxylic acid. Expression of the luciferase activity was activated ca. 2-, 4-, and 6-fold by 1, 10, and 100 microM TMC-205, respectively. TMC-205 activated the transcriptional activity in a manner dependent on the presence of the enhancer element of SV40 in its promoter region.

Shedding Light On Lung Disease Immunochemistry: Engineered antibody reduces inflammation in mice with lung condition

Uncategorized Comments Off

Jun 242014

A deadly protein is thwarted by the binding of an engineered antibody (gray) to integrin ανβ8 (binding site in red) in this computer model.

Credit: Sci. Transl. Med.

http://cen.acs.org/articles/92/i25/Shedding-Light-Lung-Disease.html

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).

[+]Enlarge

A deadly protein is thwarted by the binding of an engineered antibody (gray) to integrin ανβ8 (binding site in red) in this computer model.

Credit: Sci. Transl. Med.

09225-notw3-antibodycxd_17033436-350

A deadly protein is thwarted by the binding of an engineered antibody (gray) to integrin ανβ8 (binding site in red) in this computer model.

Credit: Sci. Transl. Med.

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 in preclinical for Antifibrinolytics

Uncategorized Comments Off

Jun 232014

Abstract Image

AZD 6564

ACS Med. Chem. Lett., 2014, 5 (5), pp 538–543

DOI: 10.1021/ml400526d

SYNTHESIS SUPP INFO…..http://pubs.acs.org/doi/suppl/10.1021/ml400526d/suppl_file/ml400526d_si_001.pdf

NMR PG 16/32 AS ABOVE

Figure imgf000012_0002 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

……………………..

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

Abstract Image

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

Starting from (2R,4S),methyl 2,neopentyl,4,(3,oxo,2,3,dihydroisoxazol,5,

yl)piperidine,1,

carboxylate (0.8 g, 2.7 mmol) and following the procedure described in 15, Step8

the title

compound was obtained (0.44 g, 69 %):

1H NMR (600 MHz, DMSO,d6) δ 0.92 (s, 9H), 1.11 –1.34 (m, 3H), 1.35 – 1.46 (m, 1H), 1.79 – 1.98 (m, 2H), 2.65 – 2.93 (m, 3H),

3.03 – 3.14 (m,1H), 5.74 (s, 1H);13C NMR (101 MHz, CH4,d4) δ 177.39, 174.72, 95.42, 54.83, 49.32, 45.50,

37.13, 34.75, 31.19, 30.07, 28.06;

[α]20D+43.8 (MeOH/H2O 1:1, c = 1); HRMS calculated for[C13H23N2O2]+: 239.1759; found: 239.1753

………………………
http://www.google.com/patents/EP2417131A1?cl=en

Compounds of formula I- V may be prepared by the following route:Scheme A. Preparation of intermediatesMETHOD A

L C^O”

METHOD B

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.

—