Cyanopyrrolidides, process for their preparation and their use as medicaments Number:7,094,800 from the United States Patent and Trademark Office (PTO) owispatent The invention relates to compounds of the formula I ##STR00001## in which the radicals have the meanings stated in the text, their stereoisomeric forms, and their physiologically tolerated salts, physiologically functional derivatives and process for their preparation.The compounds are suitable for the treatment of disorders of metabolism, such as type 2 diabetes.<H Cyanopyrrolidides, medicaments, Cyanopyrrolidid, 7094800.html, Patent, pto, 7094800

Title: Cyanopyrrolidides, process for their preparation and their use as medicaments

Abstract: The invention relates to compounds of the formula I ##STR00001## in which the radicals have the meanings stated in the text, their stereoisomeric forms, and their physiologically tolerated salts, physiologically functional derivatives and process for their preparation.The compounds are suitable for the treatment of disorders of metabolism, such as type 2 diabetes.

Patent Number: 7,094,800 Issued on 08/22/2006 to Schoenafinger, et al.

Inventors: Schoenafinger; Karl (Alzenau, DE), Wagner; Holger (Schwalbach/Ts., DE), Jaehne; Gerhard (Frankfurt, DE), Gaul; Holger (Runkel, DE), Buning; Christian (Bonn, DE), Tschank; Georg (Essenheim, DE), Werner; Ulrich (Miehlen, DE)
Assignee: Sanofi-Aventis Deutschland GmbH (Frankfurt, DE)

Appl. No.: 10/898,752

Filed: July 26, 2004

Foreign Application Priority Data


Jul 25, 2003 [DE]			103 33 935
Apr 21, 2004 [DE]			10 2004 019 276

Current U.S. Class: 514/413 ; 514/323; 514/339; 546/200; 546/276.7; 548/466; 548/467; 548/512

Current International Class: A61K 31/40 (20060101); A61K 31/4439 (20060101); C07D 209/02 (20060101); C07D 401/02 (20060101)

Field of Search: 548/512,466 514/413 546/267.7,200

References Cited [Referenced By]

U.S. Patent Documents


6221633	April 2001	Ertl et al.
6221897	April 2001	Frick et al.
6245744	June 2001	Frick et al.
6342512	January 2002	Kirsch et al.
6380357	April 2002	Hermeling et al.
6624185	September 2003	Glombik et al.
6884812	April 2005	Glombik et al.

Foreign Patent Documents


10142734	Mar., 2003	DE
0485219	May., 1992	EP
0462884	Jun., 1993	EP
WO 91/11457	Aug., 1991	WO
WO 97/26265	Jul., 1997	WO
WO 97/41097	Nov., 1997	WO
WO 99/03861	Jan., 1999	WO
WO 99/15525	Apr., 1999	WO
WO 99/31507	Jun., 1999	WO
WO 00/34331	Jun., 2000	WO
WO 00/34332	Jun., 2000	WO
WO 00/40569	Jul., 2000	WO
WO 00/63208	Oct., 2000	WO
WO 00/64876	Nov., 2000	WO
WO 00/64888	Nov., 2000	WO
WO 00/66585	Nov., 2000	WO
WO 00/71549	Nov., 2000	WO
WO 00/78312	Dec., 2000	WO
WO 01/04156	Jan., 2001	WO
WO 01/09111	Feb., 2001	WO
WO 01/83451	Nov., 2001	WO
WO 01/85695	Nov., 2001	WO
WO 01/91752	Dec., 2001	WO

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Aicher, et al., Substituted Tetrahydroprrolo[2,1-b]Oxazol-5(6H)-Ones and Tetrahydropyrrolo[2,1-b]Thiazol-5(6H)-Ones as Hypoglycemic Agents1, J. Med. Chem. (1998) vol. 41, pp. 4556-4566. cited by other .
Asakawa, A., et al., Cocaine-Amphetamine-Regulated Transcript Infuences Energy Metabolism, Anxiety and Gastric Emptying in Mice, Hormone and Metabolic Research, 2001, vol. 33(9), pp. 554-558. cited by other .
Lee Daniel W et al., Leptin agonists as a potential approach to the treatment of obestiy, Drugs of the Future, 2001, vol. 26(9), pp. 673-881. cited by other .
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Salvador Javier et al., Perspectives in the therapeutic use of leptin, Expert Opinion Pharmacotherapy 2001, 2(10), 1615-1622. cited by other .
Tyle, Praveen, Iontophoretic Devices for Drug Delivery, Phamaceutical Research, vol. 3, No. 6, 1986 pp. 318-326. cited by other .
Zunft, H. et al., Carob Pulp Preparation for Treatment of Hypercholesterolemia, Advances in Therapy, 2001, vol. 18(5), pp. 230-236. cited by other.

Primary Examiner: Solola; Taofiq
Assistant Examiner: Freistein; Andrew B.
Attorney, Agent or Firm: Kurys; Barbara E.

Claims

The invention claimed is:

1. A compound of the formula I, ##STR00036## wherein R1 is H, (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, COR3, COOR3, CONR3R4 or CN, wherein said (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl and heterocyclyl radicals are optionally substituted one or more times by F, Cl, Br, I, CN, NO.sub.2, SH, SF.sub.5, OH, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, OR3, OP(O)(OR3).sub.2, NR3R4, NR3CONR3R4, COR3, OCOR3, OCOOR3, COOR3, CONR3R4, OCONR3R4, (C.sub.1 C.sub.6)-alkylene-OR3, (C.sub.1 C.sub.6)-alkylene-NR3R4, (C.sub.1 C.sub.6)-alkylene-NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O).sub.2R3, alkylene-S(O).sub.2NR3R4, (C.sub.1 C.sub.6)-alkylene-COR3, (C.sub.1 C.sub.6)-alkylene-COOR3, (C.sub.1 C.sub.6)-alkylene-CONR3R4, SR3, SOR3, SO.sub.2R3, SO.sub.2NR3R4, NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-(C.sub.3 C.sub.10)-cycloalkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, (C.sub.1 C.sub.6)-alkylene-heterocyclyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl or heterocyclyl; R2 is H, (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, COR3, COOR3, CONR3R4 or CN, wherein said (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl and heterocyclyl radicals are optionally substituted one or more times by F, Cl, Br, I, CN, NO.sub.2, SH, SF.sub.5, OH, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, OR3, OP(O)(OR3).sub.2, NR3R4, NR3CONR3R4, COR3, OCOR3, OCOOR3, COOR3, CONR3R4, OCONR3R4, (C.sub.1 C.sub.6)-alkylene-OR3, (C.sub.1 C.sub.6)-alkylene-NR3R4, (C.sub.1 C.sub.6)-alkylene-NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O).sub.2R3, alkylene-S(O).sub.2NR3R4, (C.sub.1 C.sub.6)-alkylene-COR3, (C.sub.1 C.sub.6)-alkylene-COOR3, (C.sub.1 C.sub.6)-alkylene-CONR3R4, SR3, SOR3, SO.sub.2R3, SO.sub.2NR3R4, NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-(C.sub.3 C.sub.10)-cycloalkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, (C.sub.1 C.sub.6)-alkylene-heterocyclyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl or heterocyclyl; R3, R4 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, (C.sub.1 C.sub.6)-alkylene-CONR5R6, CONR5R6, (C.sub.1 C.sub.6)-alkylene-COOR5, COOR5, COR5, (C.sub.1 C.sub.6)-alkylene-COR5, (C.sub.1 C.sub.6)-alkylene-OR5, (C.sub.1 C.sub.6)-alkylene-NR5R6, (C.sub.1 C.sub.6)-alkylene-SR5, (C.sub.1 C.sub.6)-alkylene-S(O)R5, (C.sub.1 C.sub.6)-alkylene-S(O).sub.2R5, S(O)R5, S(O).sub.2R5, (C.sub.1 C.sub.4)-alkylene-(C.sub.6 C.sub.10)-aryl or (C.sub.1 C.sub.4)-alkylene-heterocyclyl; R5, R6 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, --(C.sub.6 C.sub.10)-aryl, heterocyclyl or (C.sub.1 C.sub.6)-alkylene-heterocyclyl; and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein R1 is H; R2 is H, (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, COR3, COOR3, CONR3R4 or CN, wherein said (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl and heterocyclyl radicals are optionally substituted one or more times by F, Cl, Br, I, CN, NO.sub.2, SH, SF.sub.5, OH, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, OR3, OP(O)(OR3).sub.2, NR3R4, NR3CONR3R4, COR3, OCOR3, OCOOR3, COOR3, CONR3R4, OCONR3R4, (C.sub.1 C.sub.6)-alkylene-OR3, (C.sub.1 C.sub.6)-alkylene-NR3R4, (C.sub.1 C.sub.6)-alkylene-NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O).sub.2R3, alkylene-S(O).sub.2NR3R4, (C.sub.1 C.sub.6)-alkylene-COR3, (C.sub.1 C.sub.6)-alkylene-COOR3, (C.sub.1 C.sub.6)-alkylene-CONR3R4, SR3, SOR3, SO.sub.2R3, SO.sub.2NR3R4, NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-(C.sub.3 C.sub.10)-cycloalkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, (C.sub.1 C.sub.6)-alkylene-heterocyclyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl or heterocyclyl; R3, R4 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, (C.sub.1 C.sub.6)-alkylene-CONR5R6, CONR5R6, (C.sub.1 C.sub.6)-alkylene-COOR5, COOR5, COR5, (C.sub.1 C.sub.6)-alkylene-COR5, (C.sub.1 C.sub.6)-alkylene-OR5, (C.sub.1 C.sub.6)-alkylene-NR5R6, (C.sub.1 C.sub.6)-alkylene-SR5, (C.sub.1 C.sub.6)-alkylene-S(O)R5, (C.sub.1 C.sub.6)-alkylene-S(O).sub.2R5, S(O)R5, S(O).sub.2R5, (C.sub.1 C.sub.4)-alkylene-(C.sub.6 C.sub.10)-aryl or (C.sub.1 C.sub.4)-alkylene-heterocyclyl; R5, R6 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, --(C.sub.6 C.sub.10)-aryl, heterocyclyl or (C.sub.1 C.sub.6)-alkylene-heterocyclyl; and pharmaceutically acceptable salts thereof.

3. The compound of claim 2 wherein: R1 is H; R2 is (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, COR3, COOR3, CONR3R4 or CN, wherein said (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl and heterocyclyl radicals are optionally substituted one or more times by F, Cl, Br, I, CN, NO.sub.2, SH, SF.sub.5, OH, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, OR3, OP(O)(OR3).sub.2, NR3R4, NR3CONR3R4, COR3, OCOR3, OCOOR3, COOR3, CONR3R4, OCONR3R4, (C.sub.1 C.sub.6)-alkylene-OR3, (C.sub.1 C.sub.6)-alkylene-NR3R4, (C.sub.1 C.sub.6)-alkylene-NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O).sub.2R3, alkylene-S(O).sub.2NR3R4, (C.sub.1 C.sub.6)-alkylene-COR3, (C.sub.1 C.sub.6)-alkylene-COOR3, (C.sub.1 C.sub.6)-alkylene-CONR3R4, SR3, SOR3, SO.sub.2R3, SO.sub.2NR3R4, NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-(C.sub.3 C.sub.10)-Cycloalkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, (C.sub.1 C.sub.6)-alkylene-heterocyclyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl or heterocyclyl; R3, R4 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, (C.sub.1 C.sub.6)-alkylene-CONR5R6, CONR5R6, (C.sub.1 C.sub.6)-alkylene-COOR5, COOR5, COR5, (C.sub.1 C.sub.6)-alkylene-COR5, (C.sub.1 C.sub.6)-alkylene-OR5, (C.sub.1 C.sub.6)-alkylene-NR5R6, (C.sub.1 C.sub.6)-alkylene-SR5, (C.sub.1 C.sub.6)-alkylene-S(O)R5, (C.sub.1 C.sub.6)-alkylene-S(O).sub.2R5, S(O)R5, S(O).sub.2R5, (C.sub.1 C.sub.4)-alkylene-(C.sub.6 C.sub.10)-aryl or (C.sub.1 C.sub.4)-alkylene-heterocyclyl; R5, R6 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, --(C.sub.6 C.sub.10)-aryl, heterocyclyl or (C.sub.1 C.sub.6)-alkylene-heterocyclyl; and pharmaceutically acceptable salts thereof.

4. The compound of claim 3 wherein: R1 is H; R2 is (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl, a pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, thiomorpholino or homopiperazino radical, wherein said (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl, a pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, thiomorpholino and homopiperazino radicals are optionally substituted one or more times by F, Cl, Br, CN, SF.sub.5, OH, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.2 C.sub.6)-alkenyl, OR3, NR3R4, NR3CONR3R4, COR3, OCOR3, CO.sub.2R3, CONR3R4, OCONR3R4, (C.sub.1 C.sub.6)-alkylene-OR3, (C.sub.1 C.sub.6)-alkylene-NR3R4, (C.sub.1 C.sub.6)-alkylene-NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O).sub.2R3, alkylene-S(O).sub.2NR3R4, (C.sub.1 C.sub.6)-alkylene-COR3, (C.sub.1 C.sub.6)-alkylene-CO.sub.2R3, (C.sub.1 C.sub.6)-alkylene-CONR3R4, SR3, SOR3, SO.sub.2R3, SO.sub.2NR3R4, NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-(C.sub.3 C.sub.10)-cycloalkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, (C.sub.1 C.sub.6)-alkylene-heterocyclyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl or heterocyclyl, wherein said (C.sub.6 C.sub.10)-aryl is optionally substituted one or more times by F, Cl, Br, I, CN, OH, --CF.sub.3, (C.sub.1 C.sub.6)-alkyl, OR3, NR3R4, COR3, CO2R3 or CONR3R4, and wherein said heterocyclyl is optionally substituted one or more times by F, Cl, Br, CN, NO.sub.2, OH, --CF.sub.3, (C.sub.1 C.sub.6)-alkyl, OR3, NR3R4, COR3, CO2R3 or CONR3R4; R3, R4 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, (C.sub.1 C.sub.6)-alkylene-CONR5R6, (C.sub.1 C.sub.6)-alkylene-COOR5, (C.sub.1 C.sub.6)-alkylene-COR5, (C.sub.1 C.sub.6)-alkylene-OR5, (C.sub.1 C.sub.6)-alkylene-NR5R6, (C.sub.1 C.sub.6)-alkylene-SR5, (C.sub.1 C.sub.6)-alkylene-S(O)R5, (C.sub.1 C.sub.6)-alkylene-S(O).sub.2R5, (C.sub.1 C.sub.4)-alkylene-(C.sub.6 C.sub.10)-aryl or (C.sub.1 C.sub.4)-alkylene-heterocyclyl; R5, R6 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, --(C.sub.6 C.sub.10)-aryl, heterocyclyl or (C.sub.1 C.sub.6)-alkylene-(C.sub.3 C.sub.10)-heterocyclyl; and pharmaceutically acceptable salts thereof.

5. The compound of claim 4 wherein: R1 is H; R2 is (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, phenyl, (C.sub.1 C.sub.6)-alkylene-phenyl, a pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, thiomorpholino or homopiperazino radical; and pharmaceutically acceptable salts thereof.

6. A pharmaceutical composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6 further comprising at least one other active ingredient.

8. A method of reducing blood sugar comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

9. A method of treating type 2 diabetes comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

10. A method of treating insulin resistance comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

Description

The invention relates to substituted cyanopyrrolidides and to their physiologically tolerated salts.

Compounds of similar structure and their use in a screening have already been described in the prior art (WO 99/31507).

The invention was based on the object of providing compounds which display a therapeutically utilizable blood glucose-lowering effect and are suitable in particular for the treatment of diabetes.

The invention therefore relates to compounds of the formula I,

##STR00002## wherein R1 is H, (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, COR3, COOR3, CONR3R4, CN, wherein said (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl and heterocyclyl radicals are optionally substituted one or more times by F, Cl, Br, I, CN, NO.sub.2, SH, SF.sub.5, OH, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, OR3, OP(O)(OR3).sub.2, NR3R4, NR3CONR3R4, COR3, OCOR3, OCOOR3, COOR3, CONR3R4, OCONR3R4, (C.sub.1 C.sub.6)-alkylene-OR3, (C.sub.1 C.sub.6)-alkylene-NR3R4, (C.sub.1 C.sub.6)-alkylene-NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O).sub.2R3, alkylene-S(O).sub.2NR3R4, (C.sub.1 C.sub.6)-alkylene-COR3, (C.sub.1 C.sub.6)-alkylene-COOR3, (C.sub.1 C.sub.6)-alkylene-CONR3R4, SR3, SOR3, SO.sub.2R3, SO.sub.2NR3R4, NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-(C.sub.3 C.sub.10)-cycloalkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, (C.sub.1 C.sub.6)-alkylene-heterocyclyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl or heterocyclyl; R2 is H, (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, COR3, COOR3, CONR3R4 or CN, wherein said (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl and heterocyclyl radicals are optionally substituted one or more times by F, Cl, Br, I, CN, NO.sub.2, SH, SF.sub.5, OH, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, OR3, OP(O)(OR3).sub.2, NR3R4, NR3CONR3R4, COR3, OCOR3, OCOOR3, COOR3, CONR3R4, OCONR3R4, (C.sub.1 C.sub.6)-alkylene-OR3, (C.sub.1 C.sub.6)-alkylene-NR3R4, (C.sub.1 C.sub.6)-alkylene-NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O).sub.2R3, alkylene-S(O).sub.2NR3R4, (C.sub.1 C.sub.6)-alkylene-COR3, (C.sub.1 C.sub.6)-alkylene-COOR3, (C.sub.1 C.sub.6)-alkylene-CONR3R4, SR3, SOR3, SO.sub.2R3, SO.sub.2NR3R4, NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-(C.sub.3 C.sub.10)-cycloalkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, (C.sub.1 C.sub.6)-alkylene-heterocyclyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl or heterocyclyl; R3, R4 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, (C.sub.1 C.sub.6)-alkylene-CONR5R6, CONR5R6, (C.sub.1 C.sub.6)-alkylene-COOR5, COOR5, COR5, (C.sub.1 C.sub.6)-alkylene-COR5, (C.sub.1 C.sub.6)-alkylene-OR5, (C.sub.1 C.sub.6)-alkylene-NR5R6, (C.sub.1 C.sub.6)-alkylene-SR5, (C.sub.1 C.sub.6)-alkylene-S(O)R5, (C.sub.1 C.sub.6)-alkylene-S(O).sub.2R5, S(O)R5, S(O).sub.2R5, (C.sub.1 C.sub.4)-alkylene-(C.sub.6 C.sub.10)-aryl, or (C.sub.1 C.sub.4)-alkylene-heterocyclyl; R5, R6 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, --(C.sub.6 C.sub.10)-aryl, heterocyclyl or (C.sub.1 C.sub.6)-alkylene-heterocyclyl; and pharmaceutically acceptable salts thereof.

Preference is given to compounds of the formula I in which one or more radicals mean R1 is H; R2 is H, (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, COR3, COOR3, CONR3R4 or CN, wherein said (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl and heterocyclyl radicals are optionally substituted one or more times by F, Cl, Br, I, CN, NO.sub.2, SH, SF.sub.5, OH, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, OR3, OP(O)(OR3).sub.2, NR3R4, NR3CONR3R4, COR3, OCOR3, OCOOR3, COOR3, CONR3R4, OCONR3R4, (C.sub.1 C.sub.6)-alkylene-OR3, (C.sub.1 C.sub.6)-alkylene-NR3R4, (C.sub.1 C.sub.6)-alkylene-NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O).sub.2R3, alkylene-S(O).sub.2NR3R4, (C.sub.1 C.sub.6)-alkylene-COR3, (C.sub.1 C.sub.6)-alkylene-COOR3, (C.sub.1 C.sub.6)-alkylene-CONR3R4, SR3, SOR3, SO.sub.2R3, SO.sub.2NR3R4, NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-(C.sub.3 C.sub.10)-cycloalkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, (C.sub.1 C.sub.6)-alkylene-heterocyclyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl or heterocyclyl; R3, R4 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, (C.sub.1 C.sub.6)-alkylene-CONR5R6, CONR5R6, (C.sub.1 C.sub.6)-alkylene-COOR5, COOR5, COR5, (C.sub.1 C.sub.6)-alkylene-COR5, (C.sub.1 C.sub.6)-alkylene-OR5, (C.sub.1 C.sub.6)-alkylene-NR5R6, (C.sub.1 C.sub.6)-alkylene-SR5, (C.sub.1 C.sub.6)-alkylene-S(O)R5, (C.sub.1 C.sub.6)-alkylene-S(O).sub.2R5, S(O)R5, S(O).sub.2R5, (C.sub.1 C.sub.4)-alkylene-(C.sub.6 C.sub.10)-aryl, or (C.sub.1 C.sub.4)-alkylene-heterocyclyl, R5, R6 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, --(C.sub.6 C.sub.10)-aryl, heterocyclyl or (C.sub.1 C.sub.6)-alkylene-heterocyclyl; and pharmaceutically acceptable salts thereof.

Preference is further given to compounds of the formula I in which one or more radicals mean R1 is H; R2 is (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, COR3, COOR3, CONR3R4, CN, wherein said (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl and heterocyclyl radicals are optionally substituted one or more times by F, Cl, Br, I, CN, NO.sub.2, SH, SF.sub.5, OH, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, OR3, OP(O)(OR3).sub.2, NR3R4, NR3CONR3R4, COR3, OCOR3, OCOOR3, COOR3, CONR3R4, OCONR3R4, (C.sub.1 C.sub.6)-alkylene-OR3, (C.sub.1 C.sub.6)-alkylene-NR3R4, (C.sub.1 C.sub.6)-alkylene-NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O).sub.2R3, alkylene-S(O).sub.2NR3R4, (C.sub.1 C.sub.6)-alkylene-COR3, (C.sub.1 C.sub.6)-alkylene-COOR3, (C.sub.1 C.sub.6)-alkylene-CONR3R4, SR3, SOR3, SO.sub.2R3, SO.sub.2NR3R4, NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-(C.sub.3 C.sub.10)-Cycloalkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, (C.sub.1 C.sub.6)-alkylene-heterocyclyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl or heterocyclyl; R3, R4 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, (C.sub.1 C.sub.6)-alkylene-CONR5R6, CONR5R6, (C.sub.1 C.sub.6)-alkylene-COOR5, COOR5, COR5, (C.sub.1 C.sub.6)-alkylene-COR5, (C.sub.1 C.sub.6)-alkylene-OR5, (C.sub.1 C.sub.6)-alkylene-NR5R6, (C.sub.1 C.sub.6)-alkylene-SR5, (C.sub.1 C.sub.6)-alkylene-S(O)R5, (C.sub.1 C.sub.6)-alkylene-S(O).sub.2R5, S(O)R5, S(O).sub.2R5, (C.sub.1 C.sub.4)-alkylene-(C.sub.6 C.sub.10)-aryl, or (C.sub.1 C.sub.4)-alkylene-heterocyclyl; R5, R6 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, --(C.sub.6 C.sub.10)-aryl, heterocyclyl or (C.sub.1 C.sub.6)-alkylene-heterocyclyl; and pharmaceutically acceptable salts thereof.

Preference is further given to compounds of the formula I in which one or more radicals mean R1 is H; R2 is (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl, a pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, thiomorpholino or homopiperazino radical; where said (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, (C.sub.6 C.sub.10)-aryl, a pyrrolidino, piperidino, hexamethyleneimtino, morpholino, piperazino, thiomorpholino and homopiperazino radicals are optionally substituted one or more times by F, Cl, Br, CN, SF.sub.5, OH, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.2 C.sub.6)-alkenyl, OR3, NR3R4, NR3CONR3R4, COR3, OCOR3, CO.sub.2R3, CONR3R4, OCONR3R4, (C.sub.1 C.sub.6)-alkylene-OR3, (C.sub.1 C.sub.6)-alkylene-NR3R4, (C.sub.1 C.sub.6)-alkylene-NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O).sub.2R3, alkylene-S(O).sub.2NR3R4, (C.sub.1 C.sub.6)-alkylene-COR3, (C.sub.1 C.sub.6)-alkylene-CO.sub.2R3, (C.sub.1 C.sub.6)-alkylene-CONR3R4, SR3, SOR3, SO.sub.2R3, SO.sub.2NR3R4, NR3SO.sub.2R4, (C.sub.1 C.sub.6)-alkylene-(C.sub.3 C.sub.10)-cycloalkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, (C.sub.1 C.sub.6)-alkylene-heterocyclyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl, or heterocyclyl, wherein said (C.sub.6 C.sub.10)-aryl is optionally substituted one or more times by F, Cl, Br, I, CN, OH, --CF.sub.3, (C.sub.1 C.sub.6)-alkyl, OR3, NR3R4, COR3, C02R3 or CONR3R4, and wherein said heterocyclyl is optionally substituted one or more times by F, Cl, Br, CN, NO.sub.2, OH, --CF.sub.3, (C.sub.1 C.sub.6)-alkyl, OR3, NR3R4, COR3, CO2R3 or CONR3R4; R3, R4 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, --CF.sub.3, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.6 C.sub.10)-aryl, heterocyclyl, (C.sub.1 C.sub.6)-alkylene-CONR5R6, (C.sub.1 C.sub.6)-alkylene-COOR5, (C.sub.1 C.sub.6)-alkylene-COR5, (C.sub.1 C.sub.6)-alkylene-OR5, (C.sub.1 C.sub.6)-alkylene-NR5R6, (C.sub.1 C.sub.6)-alkylene-SR5, (C.sub.1 C.sub.6)-alkylene-S(O)R5, (C.sub.1 C.sub.6)-alkylene-S(O).sub.2R5, (C.sub.1 C.sub.4)-alkylene-(C.sub.6 C.sub.10)-aryl or (C.sub.1 C.sub.4)-alkylene-heterocyclyl; R5, R6 are each, independently of one another, H, (C.sub.1 C.sub.6)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, (C.sub.1 C.sub.6)-alkylene-(C.sub.6 C.sub.10)-aryl, --(C.sub.6 C.sub.10)-aryl, heterocyclyl or (C.sub.1 C6)-alkylene-(C.sub.3 C.sub.10)-heterocyclyl; and pharmaceutically acceptable salts thereof.

Preference is further given to compounds of the formula I in which one or more radicals mean R1 is H; R2 is (C.sub.1 C.sub.10)-alkyl, (C.sub.3 C.sub.10)-cycloalkyl, phenyl, (C.sub.1 C.sub.6)-alkylene-phenyl, a pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, thiomorpholino or homopiperazino radical; and pharmaceutically acceptable salts thereof.

The invention relates to compounds of the formula I in the form of all their stereoisomeric forms such as racemates, racemic and enantiomeric mixtures and pure enantiomers and diastereomers.

Compounds of the formula I,

##STR00003## which have the indicated diastereomic form Ia are particularly preferred.

The invention relates to compounds of the formula I in the form of all their stereoisomeric forms such as racemates, racemic and enantiomeric mixtures and pure enantiomers and diastereomers.

If radicals or substituents may occur more than once in the compounds of formula I, they may all, independently of one another, have the stated meaning and be identical or different.

Pharmaceutically acceptable salts are, because their solubility in water is greater than that of the initial or basic compounds, particularly suitable for medical applications. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.

The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester, which on administration to a mammal such as, for example, a human is able to form (directly or indirectly) a compound of the formula I or an active metabolite thereof.

Physiologically functional derivatives include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57 61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not.

The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention.

All references to "compound(s) of formula I" hereinafter refer to compound(s) of the formula I as described above, and their salts, solvates and physiologically functional derivatives as described herein.

An alkyl radical means a straight-chain or branched hydrocarbon chain having one or more carbons, such as, for example, methyl, ethyl, propyl, butyl, hexyl, isopropyl, isobutyl, neopentyl, tert-butyl, hexyl.

The alkyl radicals may be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH, COO(C.sub.1 C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1 C.sub.6)alkyl, CON[(C.sub.1 C.sub.6)alkyl].sub.2, cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, aryl, heterocyclyl, O--(C.sub.1 C.sub.6)-alkyl, O--COO--(C.sub.1 C.sub.6)-alkyl, O--CO--(C.sub.1 C.sub.6)-alkyl, O--CO--(C.sub.1 C.sub.6)-aryl, O--CO--(C.sub.1 C.sub.6)-heterocyclyl, PO.sub.3H.sub.2, P(O)(O alkyl)2, (C.sub.1 C.sub.6)-alkylene-P(O)(O alkyl)2, O--P(O)(OH).sub.2, O--P(O)(O alkyl)2, SO.sub.3H, SO.sub.2--NH.sub.2, SO.sub.2NH(C.sub.1 C.sub.6)-alkyl, SO.sub.2N[(C.sub.1 C.sub.6)-alkyl].sub.2, S--(C.sub.1 C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl, S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1 C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--(C.sub.1 C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl, SO.sub.2--(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--NH(CH.sub.2).sub.n-aryl, SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--N[((C.sub.1 C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl], SO.sub.2--N[((C.sub.1 C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl], SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl)).sub.2, where n can be 0 6, and the aryl or heterocyclyl radical may be substituted up to three times by F, Cl, Br, OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, NH.sub.2; C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1 C.sub.6)-alkyl, N((C.sub.1 C.sub.6)-alkyl).sub.2, NH(C.sub.1 C.sub.7)-acyl, NH--CO--(C.sub.1 C.sub.6)-alkyl, NH--COO--(C.sub.1 C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl, NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1 C.sub.6)-alkyl, NH--CO--NH-aryl, NH--CO--NH-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--(C.sub.1 C.sub.6)-alkyl, N[(C.sub.1 C.sub.6)-alkyl]-COO--(C.sub.1 C.sub.6)-alkyl, N[(C.sub.1 C.sub.6)-alkyl]-CO-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-COO-aryl, N[(C.sub.1 C.sub.6)-alkyl]-COO-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO-NH-(C.sub.1 C.sub.6)-alkyl), N[(C.sub.1 C.sub.6)-alkyl]-CO--NH-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO--NH-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N(C.sub.1 C.sub.6)-alkyl).sub.2, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl)-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N(C.sub.1 C.sub.6)-alkyl)-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N(aryl).sub.2, N[(C.sub.1 C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2, N(aryl)-CO--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-CO--(C.sub.1 C.sub.6)-alkyl, N(aryl)-COO--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-COO--(C.sub.1 C.sub.6)-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-CO--NH--(C.sub.1 C.sub.6)-alkyl, N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl, N(aryl)-CO--N((C.sub.1 C.sub.6)-alkyl).sub.2, N(heterocyclyl)-CO--N((C.sub.1 C.sub.6)-alkyl).sub.2, N(aryl)-CO--N((C.sub.1 C.sub.6)-alkyl)-aryl, N(heterocyclyl)-CO--N((C.sub.1 C.sub.6)-alkyl)-aryl, N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, aryl, O--(CH.sub.2).sub.n-aryl, O--(CH.sub.2).sub.n-heterocyclyl, where n may be 0 6, where the aryl or heterocyclyl radical may be substituted one to 3 times by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, NH.sub.2, NH(C.sub.1 C.sub.6)-alkyl, N((C.sub.1 C.sub.6)-alkyl).sub.2, SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1 C.sub.6)-alkyl, CONH.sub.2.

An alkenyl radical means a straight-chain or branched hydrocarbon chain having two or more carbons and one or more double bonds, such as, for example, vinyl, allyl, pentenyl. The alkenyl radicals may be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH, COO(C.sub.1 C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1 C.sub.6)alkyl, CON[(C.sub.1 C.sub.6)alkyl].sub.2, cycloalkyl, (C.sub.1 C.sub.1)-alkyl, (C.sub.2 C.sub.6)-alkynyl, aryl, heterocyclyl, O--(C.sub.1 C.sub.6)-alkyl O--CO--(C.sub.1 C.sub.6)-alkyl, O--CO--(C.sub.1 C.sub.6)-aryl, O--CO--(C.sub.1 C.sub.6)-heterocyclyl; PO.sub.3H.sub.2, P(O)(O alkyl)2, (C1 C6)-alkylene-P(O)(O alkyl)2, O--P(O)(OH).sub.2, O--P(O)(O alkyl)2, SO.sub.3H, SO.sub.2--NH.sub.2, SO.sub.2NH(C.sub.1 C.sub.6)-alkyl, SO.sub.2N[(C.sub.1 C.sub.6)-alkyl].sub.2, S--(C.sub.1 C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl, S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1 C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--(C.sub.1 C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl, SO.sub.2--(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--NH(CH.sub.2).sub.n-aryl, SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--N((C.sub.1 C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl, SO.sub.2--N((C.sub.1 C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be 0 6 and the aryl radical or the heterocyclic radical may be substituted up to twice by F, Cl, Br, OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, NH.sub.2; C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1 C.sub.6)-alkyl, N((C.sub.1 C.sub.6)-alkyl).sub.2, NH(C.sub.1 C.sub.7)-acyl, NH--CO--(C.sub.1 C.sub.6)-alkyl, NH--COO--(C.sub.1 C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl, NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1 C.sub.6)-alkyl, NH--CO--NH-aryl, NH--CO--NH--heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--(C.sub.1 C.sub.6)-alkyl, N[(C.sub.1 C.sub.6)-alkyl]-COO--(C.sub.1 C.sub.6)-alkyl, N[(C.sub.1 C.sub.6)-alkyl]-CO-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-COO-aryl, N[(C.sub.1 C.sub.6)-alkyl]-COO-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--NH--(C.sub.1 C.sub.6)-alkyl), N[(C.sub.1 C.sub.6)-alkyl]-CO--NH-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO--NH-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N--((C.sub.1 C.sub.6)-alkyl).sub.2, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl)-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl)-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N(aryl).sub.2, N[(C.sub.1 C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2, N(aryl)-CO--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-CO--(C.sub.1 C.sub.6)-alkyl, N(aryl)-COO--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-COO--(C.sub.1 C.sub.6)-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1 C.sub.6)-alkyl), N(heterocyclyl)-CO--NH--(C.sub.1 C.sub.6)-alkyl), N(aryl)-CO--NH-aryl, N(heterocylyl)-CO--NH-aryl, N(aryl)-CO--N((C.sub.1 C.sub.6)-alkyl).sub.2, N(heterocyclyl)-CO--N--((C.sub.1 C.sub.6)-alkyl).sub.2, N(aryl)-CO--N[(C.sub.1 C.sub.6)-alkyl]-aryl, N(heterocyclyl)-CO--N[(C.sub.1 C.sub.6)-alkyl]-aryl, N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N-(aryl).sub.2, aryl, O--(CH.sub.2).sub.n-aryl, O--(CH.sub.2).sub.n-heterocyclyl, where n may be 0 6, where the aryl or heterocyclyl radical may be substituted one to 3 times by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, NH.sub.2, NH(C.sub.1 C.sub.6)-alkyl, N((C.sub.1 C.sub.6)-alkyl).sub.2, SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1 C.sub.6)-alkyl, CONH.sub.2.

An alkynyl radical means a straight-chain or branched hydrocarbon chain having two or more carbons and one or more triple bonds, such as, for example, ethynyl, propynyl, hexynyl.

The alkynyl radicals may be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH, COO(C.sub.1 C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1 C.sub.6)alkyl, CON[(C.sub.1 C.sub.6)alkyl].sub.2, cycloalkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl O--CO--(C.sub.1 C.sub.6)-alkyl, O--CO--(C.sub.1 C.sub.6)-Aryl, O--CO--(C.sub.1 C.sub.6)-heterocyclyl; PO.sub.3H.sub.2, P(O)(O alkyl)2, (C1 C6)-alkylene-P(O)(O alkyl)2, O--P(O)(OH).sub.2, O--P(O)(O alkyl)2, SO.sub.3H, SO.sub.2--NH.sub.2, SO.sub.2NH(C.sub.1 C.sub.6)-alkyl, SO.sub.2N[(C.sub.1 C.sub.6)-alkyl].sub.2, S--(C.sub.1 C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl, S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1 C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--(C.sub.1 C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl, SO.sub.2--(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--NH(CH.sub.2).sub.n-aryl, SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--N((C.sub.1 C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl, SO.sub.2--N((C.sub.1 C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be 0 6 and the aryl radical or the heterocyclyl radical may be substituted up to twice by F, Cl, Br, OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, NH.sub.2; C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1 C.sub.6)-alkyl, N((C.sub.1 C.sub.6)-alkyl).sub.2, NH(C.sub.1 C.sub.7)-acyl, NH--CO--(C.sub.1 C.sub.6)-alkyl, NH--COO--(C.sub.1 C.sub.6)-alkyl, NH--CO--aryl, NH--CO-heterocyclyl, NH--COO-aryl, NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1 C.sub.6)-alkyl, NH--CO--NH-aryl, NH--CO--NH-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--(C.sub.1 C.sub.6)-alkyl, N[(C.sub.1 C.sub.6)-alkyl]-COO--(C.sub.1 C.sub.6)-alkyl, N[(C.sub.1 C.sub.6)-alkyl]-CO-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-COO-aryl, N[(C.sub.1 C.sub.6)-alkyl]-COO-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--NH--(C.sub.1 C.sub.6)-alkyl), N[(C.sub.1 C.sub.6)-alkyl]-CO--NH-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO--NH-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl).sub.2, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl)-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl)-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N(aryl).sub.2, N[(C.sub.1 C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2, N(aryl)-CO--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-CO--(C.sub.1 C.sub.6)-alkyl, N(aryl)-COO--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-COO--(C.sub.1 C.sub.6)-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-CO--NH--(C.sub.1 C.sub.6)-alkyl, N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl, N(aryl)-CO--N((C.sub.1 C.sub.6)-alkyl).sub.2, N(heterocyclyl)-CO--N((C.sub.1 C.sub.6)-alkyl).sub.2, N(aryl)-CO--N[(C.sub.1 C.sub.6)-alkyl]-aryl, N(heterocyclyl)-CO--N[(C.sub.1 C.sub.6)-alkyl]-aryl, N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, aryl, O--(CH.sub.2).sub.n-aryl, O--(CH.sub.2).sub.n-heterocyclyl where n may be 0 6, where the aryl or heterocyclyl radical may be substituted one to 3 times by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, NH.sub.2, NH(C.sub.1 C.sub.6)-alkyl, N((C.sub.1 C.sub.6)-alkyl).sub.2, SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1 C.sub.6)-alkyl, CONH.sub.2.

An aryl radical means a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralon-, indanyl- or indan-1-on-yl radical.

The aryl radicals may be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF.sub.3, NO.sub.2, SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1 C.sub.6)-alkyl, CONH.sub.2, CONH(C.sub.1 C.sub.6)alkyl, CON[(C.sub.1 C.sub.6)alkyl].sub.2, cycloalkyl, (C.sub.1 C.sub.10)-alkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl O--(C.sub.1 C.sub.6)-alkyl O--CO--(C.sub.1 C.sub.6)-alkyl, O--CO--(C.sub.1 C.sub.6)-aryl, O--CO--(C.sub.1 C.sub.6)-heterocyclyl; PO.sub.3H.sub.2, P(O)(O alkyl)2, (C1 C6)-alkylene-P(O)(O alkyl)2, O--P(O)(OH).sub.2, O--P(O)(O alkyl)2, SO.sub.3H, SO.sub.2--NH.sub.2, SO.sub.2NH(C.sub.1 C.sub.6)-alkyl, SO.sub.2N[(C.sub.1 C.sub.6)-alkyl].sub.2, S--(C.sub.1 C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl, S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1 C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--(C.sub.1 C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl, SO.sub.2--(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--NH(CH.sub.2).sub.n-aryl, SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--N((C.sub.1 C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl, SO.sub.2--N((C.sub.1 C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be 0 6 and the aryl radical or the heterocyclic radical may be substituted up to twice by F, Cl, Br, OH, CF.sub.3, NO.sub.2, SF.sub.5, CN, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, NH.sub.2; C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1 C.sub.6)-alkyl, N((C.sub.1 C.sub.6)-alkyl).sub.2, NH(C.sub.1 C.sub.7)-acyl, NH--CO--(C.sub.1 C.sub.6)-alkyl, NH--COO--(C.sub.1 C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl, NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1 C.sub.6)-alkyl, NH--CO--NH-aryl, NH--CO--NH-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--(C.sub.1 C.sub.6)-alkyl, N[(C.sub.1 C.sub.6)-alkyl]-COO--(C.sub.1 C.sub.6)-alkyl, N[(C.sub.1 C.sub.6)-alkyl]-CO-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-COO-aryl, N[(C.sub.1 C.sub.6)-alkyl]-COO-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--NH--(C.sub.1 C.sub.6)-alkyl), N[(C.sub.1 C.sub.6)-alkyl]-CO--NH-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO--NH-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl).sub.2, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl)-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl)-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N(aryl).sub.2, N[(C.sub.1 C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2, N(aryl)-CO--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-CO--(C.sub.1 C.sub.6)-alkyl, N(aryl)-COO--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-COO--(C.sub.1 C.sub.6)-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-CO--NH--(C.sub.1 C.sub.6)-alkyl, N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl, N(aryl)-CO--N((C.sub.1 C.sub.6)-alkyl).sub.2, N(heterocyclyl)-CO--N((C.sub.1 C.sub.6)-alkyl).sub.2, N(aryl)-CO--N[(C.sub.1 C.sub.6)-alkyl]-aryl, N(heterocyclyl)-CO--N[(C.sub.1 C.sub.6)-alkyl]-aryl, N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, aryl, O--(CH.sub.2).sub.n-aryl, O--(CH.sub.2).sub.n-heterocyclyl, where n may be 0 6, where the aryl or heterocyclyl radical may be substituted one to 3 times by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, NH.sub.2, NH(C.sub.1 C.sub.6)-alkyl, N((C.sub.1 C.sub.6)-alkyl).sub.2, SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1 C.sub.6)-alkyl, CONH.sub.2.

A cycloalkyl radical means a ring system which comprises one or more rings and which is unsaturated or partially unsaturated (with one or two double bonds), and which is composed exclusively of carbon atoms, for example, cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.

The cycloalkyl radicals radicals may be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH, COO(C.sub.1 C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1 C.sub.6)alkyl, CON[(C.sub.1 C.sub.6)alkyl].sub.2, cycloalkyl, (C.sub.1 C.sub.10)-alkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl O--(C.sub.1 C.sub.6)-alkyl O--CO--(C.sub.1 C.sub.6)-alkyl, O--CO--(C.sub.1 C.sub.6)-Aryl, O--CO--(C.sub.1 C.sub.6)-heterocyclyl; PO.sub.3H.sub.2, P(O)(O alkyl)2, (C1 C6)-alkylene-P(O)(O alkyl)2, O--P(O)(OH).sub.2, O--P(O)(O alkyl)2, SO.sub.3H, SO.sub.2--NH.sub.2, SO.sub.2NH(C.sub.1 C.sub.6)-alkyl, SO.sub.2N[(C.sub.1 C.sub.6)-alkyl].sub.2, S--(C.sub.1 C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl, S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1 C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--(C.sub.1 C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl, SO.sub.2--(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--NH(CH.sub.2).sub.n-aryl, SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--N((C.sub.1 C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl, SO.sub.2--N((C.sub.1 C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be 0 6 and the aryl radical or the heterocyclyl radical may be substituted up to twice by F, Cl, Br, OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, NH.sub.2; C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1 C.sub.6)-alkyl, N((C.sub.1 C.sub.6)-alkyl).sub.2, NH(C.sub.1 C.sub.7)-acyl, NH--CO--(C.sub.1 C.sub.6)-alkyl, NH--COO--(C.sub.1 C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl, NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1 C.sub.6)-alkyl), NH--CO--NH-aryl, NH--CO--NH-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--(C.sub.1 C.sub.6)-alkyl, N[(C.sub.1 C.sub.6)-alkyl]-COO--(C.sub.1 C.sub.6)-alkyl, N[(C.sub.1 C.sub.6)-alkyl]-CO-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-COO-aryl, N[(C.sub.1 C.sub.6)-alkyl]-COO-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--NH--(C.sub.1 C.sub.6)-alkyl), N[(C.sub.1 C.sub.6)-alkyl]-CO--NH-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO--NH-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl).sub.2, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl)-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl)-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N(aryl).sub.2, N[(C.sub.1 C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2, N(aryl)-CO--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-CO--(C.sub.1 C.sub.6)-alkyl, N(aryl)-COO--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-COO--(C.sub.1 C.sub.6)-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-CO--NH--(C.sub.1 C.sub.6)-alkyl, N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl, N(aryl)-CO--N((C.sub.1 C.sub.6)-alkyl).sub.2, N(heterocyclyl)-CO--N((C.sub.1 C.sub.6)-alkyl).sub.2, N(aryl)-CO--N[(C.sub.1 C.sub.6)-alkyl]-aryl, N(heterocyclyl)-CO--N[(C.sub.1 C.sub.6)-alkyl]-aryl, N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, aryl, O--(CH.sub.2).sub.n-aryl, O--(CH.sub.2).sub.n-heterocyclyl, where n may be 0 6, where the aryl or heterocyclyl radical may be substituted one to 3 times by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, NH.sub.2, NH(C.sub.1 C.sub.6)-alkyl, N((C.sub.1 C.sub.6)-alkyl).sub.2, SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1 C.sub.6)-alkyl, CONH.sub.2.

Heterocycle or heterocyclic radical means rings or ring systems which, apart from carbon, also comprise heteroatoms such as, for example, nitrogen, oxygen or sulfur. Ring systems in which the heterocycle or heterocyclic radical is fused to benzene nuclei are also included in this definition.

Suitable heterocyclyl rings or "heterocyclic radicals" are acridinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazoles, pyridoimidazoles, pyridothiazoles, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl, aziridinyl, azetininyl, azepanyl, azocanyl and xanthenyl.

Pyridyl stands both for 2-, 3- and 4-pyridyl. Thienyl stands both for 2- and 3-thienyl. Furyl stands both for 2- and 3-furyl.

Also included are the corresponding N-oxides of these compounds, that is to say, for example, 1-oxy-2-, 3- or 4-pyridyl.

Also included are derivatives of these heterocycles which are benzo-fused one or more times.

The heterocyclic rings or heterocyclic radicals may be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH, COO(C.sub.1 C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1 C.sub.6)alkyl, CON[(C.sub.1 C.sub.6)alkyl].sub.2, cycloalkyl, (C.sub.1 C.sub.10)-alkyl, (C.sub.2 C.sub.6)-alkenyl, (C.sub.2 C.sub.6)-alkynyl, O--(C.sub.1 C.sub.6)-alkyl O--CO--(C.sub.1 C.sub.6)-alkyl, O--CO--(C.sub.1 C.sub.6)-aryl, O--CO--(C.sub.1 C.sub.6)-heterocyclyl; PO.sub.3H.sub.2, P(O)(O alkyl)2, (C1 C6)-alkylene-P(O)(O alkyl)2, O--P(O)(OH).sub.2, O--P(O)(O alkyl)2, SO.sub.3H, SO.sub.2--NH.sub.2, SO.sub.2NH(C.sub.1 C.sub.6)-alkyl, SO.sub.2N[(C.sub.1 C.sub.6)-alkyl].sub.2, S--(C.sub.1 C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl, S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1 C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--(C.sub.1 C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl, SO.sub.2--(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--NH(CH.sub.2).sub.n-aryl, SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--N(C.sub.1 C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl, SO.sub.2--N(C.sub.1 C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl, SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, , SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2, where n can be 0 6, and the acyl radical or heterocylic radical may be substituted up to twice by F, Cl, Br, OH, CF.sub.3, SF5, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, NH.sub.2; C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1 C.sub.6)-alkyl, N((C.sub.1 C.sub.6)-alkyl).sub.2, NH(C.sub.1 C.sub.7)-acyl, NH--CO--(C.sub.1 C.sub.6)-alkyl, NH--COO--(C.sub.1 C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl, NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1 C.sub.6)-alkyl, NH--CO--NH-aryl, NH--CO--NH-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--(C.sub.1 C.sub.6)-alkyl, N[(C.sub.1 C.sub.6)-alkyl]-COO--(C.sub.1 C.sub.6)-alkyl, N[(C.sub.1 C.sub.6)-alkyl]-CO-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-COO-aryl, N[(C.sub.1 C.sub.6)-alkyl]-COO-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--NH--(C.sub.1 C.sub.6)-alkyl), N[(C.sub.1 C.sub.6)-alkyl]-CO--NH-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO--NH-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N--((C.sub.1 C.sub.6)-alkyl).sub.2, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl)-aryl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N((C.sub.1 C.sub.6)-alkyl)-heterocyclyl, N[(C.sub.1 C.sub.6)-alkyl]-CO--N-(aryl).sub.2, N[(C.sub.1 C.sub.6)-alkyl]-CO--N-(heterocyclyl).sub.2, N(aryl)-CO--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-CO--(C.sub.1 C.sub.6)-alkyl, N(aryl)-COO--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-COO--(C.sub.1 C.sub.6)-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1 C.sub.6)-alkyl, N(heterocyclyl)-CO--NH--(C.sub.1 C.sub.6)-alkyl, N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl, N(aryl)-CO--N-((C.sub.1 C.sub.6)-alkyl).sub.2, N(heterocyclyl)-CO--N--((C.sub.1 C.sub.6)-alkyl).sub.2, N(aryl)-CO--N[(C.sub.1 C.sub.6)-alkyl]-aryl, N(heterocyclyl)-CO--N[(C.sub.1 C.sub.6)-alkyl]-aryl, N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, aryl, O--(CH.sub.2).sub.n-aryl, O--(CH.sub.2).sub.n-heterocyclyl, where n may be 0 6, where the aryl or heterocyclyl radical may be substituted one to 3 times by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3, SF5, O--(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, NH.sub.2, NH(C.sub.1 C.sub.6)-alkyl, N((C.sub.1 C.sub.6)-alkyl).sub.2, SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1 C.sub.6)-alkyl, CONH.sub.2.

As used herein:

"Patient" means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.

"Treat" or "treating" means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.

"Therapeutically effective amount" means a quantity of the compound which is effective in treating the named disorder or condition.

"Pharmaceutically acceptable carrier" is a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration.

The compounds of the formula 1 can be prepared by methods known per se. Thus, the tert-butyl ester 3 can be obtained starting from commercially available S-pyroglutamic acid 2 by protection (e.g. with tert-butyl acetate and acid). Compound 4 is obtained therefrom by Boc protection (see also J. Chem. Soc., Perkin Trans 1 1996, 507 514). Reaction with suitable reducing agents (e.g. lithium triethylborohydride) affords the aminal 5. Olefination with triethyl phosphonoacetate under basic conditions (e.g. NaH) results in the pyrrolidine 6 (Tetrahedron 2000, 4289 4298). This building block can then be converted by reduction (e.g. with lithium borohydride) and oxidation (e.g. Swern Oxidation J. Org. Chem. 1976, 41, 957) into the aldehyde 7 (R=H). An alternative to this is to obtain the ketones 7 (R.noteq.H) by reaction to give the Weinreb amide (e.g. with N,O-dimethylhydroxylamine hydrochloride in the presence of trimethylaluminum) and subsequent addition of suitable organometallic reagents (Met=Li, MgX, where X=Cl, Br, I). Subsequent Strecker synthesis (e.g. with benzylamine and trimethylsilyl cyanide) then affords the nitriles 8. The nitrile group is converted into the amide (e.g. with potassium carbonate in a mixture of dimethyl sulfoxide, water and hydrogen peroxide), producing the compounds 9. Hydrolysis (e.g. with sodium hydroxide solution in ethanol) then affords the dicarboxylic acids 10. Hydrogenation (e.g. with hydrogen in the presence of palladium on activated carbon) affords the amino dicarboxylic acids 11. These are then provided with a suitable protective group on the nitrogen (e.g. Pg=benzyloxycarbonyl (Z) by reaction with N-(benzyloxycarbonyloxy)succinimide in the presence of potassium carbonate), resulting in the derivatives 12. The carboxyl groups are esterified to give the compounds 13 (e.g. with trimethylsilyldiazomethane) and then the Boc group is cleaved by reaction with a suitable acid (e.g. trifluoroacetic acid) to give the compounds 14. Cyclization under basic conditions (e.g. diisopropylethylamine in methanol) then affords the bicycles 15. The protective group Pg in 15 is then cleaved (e.g. by hydrogenation with hydrogen in the presence of palladium on activated carbon for Pg=Z) and the amino group is Boc-protected (e.g. with Boc anhydride), resulting in the compounds 16. Reaction thereof with ammonia results in the amides 17 and 18, which can be separated from one another by chromatography. Reaction of 17 with activating reagents (e.g. cyanuric chloride) subsequently affords the nitrites 19, from which the amines 20 are produced by elimination of the Boc group (e.g. with trifluoroacetic acid). Reductive amination of the amino group by conventional processes results in the compounds 21.

##STR00004## ##STR00005##

The amount of a compound of formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in th