1,5-BENZODIAZEPINE DERIVATIVES AS CCK-A RECEPTOR AGONISTS

Title:

1,5-BENZODIAZEPINE DERIVATIVES AS CCK-A RECEPTOR AGONISTS

Document Type and Number:

WIPO Patent Application WO/2000/068209

Kind Code:

A2

Abstract:

An enantiomerically enriched compound of Formula (I) is disclosed, processes for its preparation, pharmaceutical compositions containing it and the use therefore, for the treatment of CCK-A mediated diseases or conditions, such as obesity.

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Inventors:

COLCLOUGH DAVID (GB)
HODGSON ANNE (GB)
SZEWCZYK JERZY RYSZARD (US)

Application Number:

PCT/EP2000/003982

Publication Date:

November 16, 2000

Filing Date:

May 04, 2000

Export Citation:

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Assignee:

GLAXO GROUP LTD (GB)
COLCLOUGH DAVID (GB)
HODGSON ANNE (GB)
SZEWCZYK JERZY RYSZARD (US)

International Classes:

A61K31/551; A61P1/16; A61P3/04; A61P3/10; A61P43/00; C07D243/12; (IPC1-7): C07D243/00

Foreign References:

US5646140A

1997-07-08

Other References:

GAVIN C. HIRST ET AL.: "Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity (II): optimization of the C3 amino substituent " JOURNAL OF MEDICINAL CHEMISTRY., vol. 39, no. 26, - 1996 pages 5236-5245, XP002150743 AMERICAN CHEMICAL SOCIETY. WASHINGTON., US ISSN: 0022-2623
BRISTOL, J. A.: "Annual reports in medicinal chemistry" 1990 , ACADEMIC PRESS, INC. , SAN DIEGO, XP002150744 page 323 -page 331

Attorney, Agent or Firm:

Learoyd, Stephanie A. (GlaxoSmithKline Corporate Intellectual Property Two New Horizons Court Brentford Middlesex TW8 9EP, GB)

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Claims:

What is Claimed is :

1.	Enantiomerically enriched 3 {3 [1 (Isopropylphenylcarbamoylmethyl)2,4 dioxo5phenyl2,3,4,5tetrahydro1 Hbenzo [b] [1,4] diazepine3yl]ureido} benzoic acid, or a pharmaceutically acceptable salt or solvate thereof. <BR> <BR> <P>2.

2.	The enantiomerically enriched compound of Claim 1 wherein the (+) enantiomer, or a pharmaceutically acceptable salt or solvate thereof, is at least 90% of said compound.

3.	The enantiomerically enriched compound of Claim 1 or claim 2, wherein the (+) enantiomer, or a pharmaceutically acceptable salt or solvate thereof, is at least 99% of said compound.

4.	A pharmaceutical composition comprising the enantiomerically enriched compound as claimed in any of the claims 1 to 3 in admixture with one or more pharmaceutically acceptable carriers and or excipients.

5.	A method for treating a CCKA mediated disease or condition comprising administration of an effective amount of compound as claimed in any of claims 1 to 3.

6.	A method for treating a CCKA mediated disease or condition comprising administration of the pharmaceutical composition as claimed in Claim 4.

7.	The method as claimed in claim 5 or claim 6, wherein said disease or condition is obesity, gallbladder stasis, or diabetes.

8.	The method as claimed in claim 5 or claim 6, wherein said disease or condition is obesity.

9.	The use of a compound as claimed in any of claims 1 to 3 in the manufacture of a medicament for the treatment of a CCKA mediated disease or condition.

10.

A process for the preparation of a compound as claimed in claim 1 which comprises: (a) solution of racemic 3 [3 [1 (isopropylphenylcarbamoylmethyl) 4,5tetrahydro1 Hbenzo [b] [1,4] diazepine3 yl] benzoic acid by chiral hpic; (b) reaction of the appropriate enantiomer of the amine of formula (II). With the isocyanate of formula (III), imidazolide of formula (IV) or optionally substituted phenyl carbamate of formula (V) followed by removal of the carboxy protecting group R.

11.

A process as claimed in claim 10 wherein the required compound of claim 1 is prepared via the racemic amine (II) which has been prepared by concomitant reduction and hydrogenolysis of the oxime (VI), wherein R2 is an optionally substituted benzyl group. 12 A process as claimed in claim 11 wherein the oxime (VI) is prepared from the ortho phenylene diamine (VII) and an activated derivative of the diacid (VIII), wherein R2 is an optionally substituted benzyl group.

Description:

INTERNATIONAL SEARCH REPORT Internr al Application No PCT/EP 00/03982 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category ° Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A BRISTOL, J. A.:"Annual reports in 1 medicinal chemistry" 1990, ACADEMIC PRESS, INC., SAN DIEGO, XP002150744 page 323-page 331 1 INTERNATIONAL SEARCH REPORT Interna 1l Application No .. armatlon on patent family members PCT/EP 00/03982 Patent document Publication Patent family Publication cited in search report date member (s) date US 5646140 A 08-07-1997 AU 688316 B 12-03-1998 AU 6567594 A 08-11-1994 EP 0694040 A 31-01-1996 FI 954852 A 12-10-1995 JP 8508743 T 17-09-1996 NO 954091 A 13-12-1995 SK 125495 A 05-06-1996 US 5585376 A 17-12-1996 AP 462 A 19-02-1996 AP 512 A 29-07-1996 AU 681139 B 21-08-1997 AU 6567694 A 08-11-1994 CA 2158972 A 27-10-1994 CA 2158973 A 27-10-1994 CN 1120845 A 17-04-1996 CN 1120843 A 17-04-1996 CZ 9502675 A 17-04-1996 CZ 9502676 A 17-04-1996 WO 9424151 A 27-10-1994 WO 9424149 A 27-10-1994 EP 0694039 A 31-01-1996 FI 954853 A 12-10-1995 HU 74091 A 28-11-1996 HU 74102 A 28-11-1996 IL 109316 A 12-03-1999 JP 8508744 T 17-09-1996 NO 954090 A 13-12-1995 NZ 265271 A 24-06-1997 NZ 265272 A 27-07-1997 PL 311083 A 05-02-1996 PL 311084 A 05-02-1996 RU 2135486 C 27-08-1999 SK 125395 A 05-06-1996 ZA 9402570 A 11-11-1994 ZA 9402571 A 11-11-1994

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