AU2004261366A1

AU2004261366A1 - Novel cyano thiazolides, methods for the production thereof, and use thereof as a medicament

Info

Publication number: AU2004261366A1
Application number: AU2004261366A
Authority: AU
Inventors: Christian Buning; Holger Gaul; Gerhard Jaehne; Karl Schoenafinger; Georg Tschank; Holger Wagner; Ulrich Werner
Original assignee: Sanofi Aventis Deutschland GmbH
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 2003-07-25
Filing date: 2004-07-14
Publication date: 2005-02-10
Also published as: IL173203A0; JP2006528602A; CA2533672A1; DE10333935A1; ATE534650T1; EP1651653A1; PE20050255A1; EP1651653B1; TW200524944A; MXPA06000635A; JP4711959B2; BRPI0412920A; WO2005012312A1

Abstract

The invention relates to compounds of formula (I), wherein the radicals have the meanings indicated in the text, the stereoisomeric forms thereof, the physiologically acceptable salts thereof, and methods for the production thereof. The inventive compounds are suitable for the treatment of metabolic diseases such as type 2 diabetes.

Description

IN THE MATTER OF an Australian Application corresponding to PCT Application PCT/EP2004/007767 RWS Group Ltd, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England, hereby solemnly and sincerely declares that, to the best of its knowledge and belief, the following document, prepared by one of its translators competent in the art and conversant with the English and German languages, is a true and correct translation of the PCT Application filed under No. PCT/EP2004/007767. Date: 14 November 2005 S. ANTHONY Director For and on behalf of RWS Group Ltd WO 2005/012312 PCT/EP2004/007767 Novel cyanothiazolides, methods for the production thereof and use thereof as a medicament 5 The invention relates to substituted cyanothiazolides and to their physiologically tolerated salts. Compounds of similar structure and their use in a screening have already been described in 10 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. 15 The invention therefore relates to compounds of the formula I, R1 R2 x NN HN 0 CN 20 in which the meanings are RI H, (Ci-Clo)-alkyl, (C 3 -Cio)-cycloalkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl,

(C

6 -Cla)-aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be substituted one or more times by F, 25 Cl, Br, I, CN, NO 2 , OH, -CF 3 , (CI-C 6 )-alkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6

)

alkynyl, OR3, NR3R4, COR3, C0 2 R3, CONR3R4, (CI-C 6 )-alkylene-OR3,

(C

1

-C

6 )-alkylene-NR3R4, (CI-C 6 )-alkylene-SR3, alkylene-SOR3, alkylene S0 2 R3, (CI-C 6 )-alkylene-COR3, (CI-C 6 )-alkylene-COOR3, (C 1

-C

6

)

alkylene-CONR3R4, (CI-C 6 )-alkylene-O-P(O)(OR3) 2 , SR3, SOR3, 30 SO 2 NR3R4, S0 2 R3, (C 1 -C6)-alkylene-(C3-Cio)-cycloalkyl, (Ci-C 6 )-alkylene-

(C

6 -Cl)-aryl, (CI-C 6 )-alkylene-heterocyclyl, (C 3 -Cio)-cycloalkyl, (C 6 -CIo) aryl, which may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , (Ci-C 6 )-alkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, OR3, NR3R4, COR3, C0 2 R3, CONR3R4, or heterocyclyl which may be substituted one or 5 more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , (CI-C 6 )-alkyl, OR3, NR3R4, COR3, C0 2 R3, CONR3R4; R2 H, (Ci-Cio)-alkyl, (C 3 -Clo)-cycloalkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl,

(C

6 -Cio)-aryl, heterocyclyl, COR3, COOR3, CONR3R4, CN, where the 10 alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , SH, SF 5 , OH, (CI

C

6 )-alkyl, -CF 3 , (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, OR3, OP(O)(OR3) 2 , NR3R4, NR3CONR3R4, COR3, OCOR3, OCOOR3, COOR3, CONR3R4, OCONR3R4, (Ci-C 6 )-alkylene-OR3, (Ci-C 6 )-alkylene-NR3R4, (C 1

-C

6

)

15 alkylene-NR3SO 2 R4, (C 1

-C

6 )-alkylene-SR3, alkylene-S(O)R3, alkylene

S(O)

2 R3, alkylene-S(O) 2 NR3R4, (C-C 6 )-alkylene-COR3, (Ci-C 6 )-alkylene COOR3, (CI-CO)-alkylene-CONR3R4, SR3, SOR3, S0 2 R3, SO 2 NR3R4, NR3SO 2 R4, (Ci-C 6 )-alkylene-(C 3 -Cio)-cycloalkyl, (CI-C 6 )-alkylene-(C 6 Clo)-aryl, (CI-C 6 )-alkylene-heterocyclyl, (C 3 -Cio)-cycloalkyl, (C 6 -Cio)-aryl 20 or heterocyclyl; R3, R4 independently of one another H, (CI-C 6 )-alkyl, -CF 3 , (C 3 -Cio)-cycloalkyl,

(C

6 -Cio)-aryl, heterocyclyl, (Ci-C 6 )-alkylene-CONR5R6, CONR5R6, (C 1 C 6 )-alkylene-COOR5, COOR5, COR5, (CI-C 6 )-alkylene-COR5, (CI-C 6

)

25 alkylene-OR5, (Ci-C 6 )-alkylene-NR5R6, (CI-C 6 )-alkylene-SR5, (C 1

-C

6

)

alkylene-S(O)R5, (C 1

-C

6 )-alkylene-S(O) 2 R5, S(O)R5, S(O) 2 R5, (C 1

-C

4

)

alkylene-(C 6 -Cio)-aryl or (Ci-C 4 )-alkylene-heterocyclyl; R5, R6 independently of one another H, (Ci-C 6 )-alkyl, (Ci-C 6 )-alkylene-(C 6 -Cio) 30 aryl, -(C 6 -Cio)-aryl, heterocyclyl, (Ci-C 6 )-alkylene-heterocyclyl; X S, SO, S02; -1 and the physiologically tolerated salts thereof. Preference is given to compounds of the formula I in which one or more radicals mean 5 Ri H, (CI-Cio)-alkyl, (C 3 -Cio)-cycloalkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl,

(C

6 -Cio)-aryl, where the alkyl, cycloalkyl, alkenyl, alkynyl and aryl radicals may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , (Ci-C 6 )-alkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, OR3, NR3R4, COR3,

CO

2 R3, CONR3R4, (C 1

-C

6 )-alkylene-OR3, (CI-C 6 )-alkylene-NR3R4, (Ci 10 C 6 )-alkylene-SR3, alkylene-SOR3, alkylene-S0 2 R3, (CI-C 6 )-alkylene COR3, (Ci-C 6 )-alkylene-CO 2 R3, (C 1

-C

6 )-alkylene-CONR3R4, (C 1

-C

6

)

alkylene-O-P(O)(OR3) 2 , SR3, SOR3, SO 2 NR3R4, S0 2 R3, (C-C 6 )-alkylene

(C

3 -Cio)-cycloalkyl, (Ci-C 6 )-alkylene-(C 6 -Cio)-aryl, (CI-C 6 )-alkylene heterocyclyl, (C 3 -Cio)-cycloalkyl or (C 6 -Cio)-aryl which may be substituted 15 one or more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , (Ci-C 6 )-alkyl, (C 2 C 6 )-alkenyl, (C 2

-C

6 )-alkynyl, OR3, NR3R4, COR3, C0 2 R3, CONR3R4; R2 H, (CI-Cio)-alkyl, (C 3 -Clo)-cycloalkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl,

(C

6 -Cio)-aryl, heterocyclyl, COR3, C02R3, CONR3R4, CN, where the 20 alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , SH, SF 5 , OH, (C 1 C 6 )-alkyl, -CF 3 , (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, OR3, OP(O)(OR3) 2 , NR3R4, NR3CONR3R4, COR3, OCOR3, C0 2 R3, CONR3R4, OCONR3R4, (C 1

-C

6 )-alkylene-OR3, (1-C 6 )-alkylene-NR3R4, (C 1

-C

6

)

25 alkylene-NR3SO 2 R4, (CI-C 6 )-alkylene-SR3, alkylene-SOR3, alkylene S0 2 R3, alkylene-SO 2 NR3R4, (C 1

-C

6 )-alkylene-COR3, (C 1

-C

6 )-alkylene C0 2 R3, (CI-C 6 )-alkylene-CONR3R4, SR3, SOR3, S0 2 R3, SO 2 NR3R4, NR3SO 2 R4, (Ci-C 6 )-alkylene-(C 3 -Cio)-cycloalkyl, (CI-C 6 )-alkylene-(C 6 CIo)-aryl, (C1-C 6 )-alkylene-heterocyclyl, (C 3 -Cio)-cycloalkyl, (C 6 -CIo)-aryl 30 which may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, CF 3 , (Ci-C 6 )-alkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, OR3, NR3R4, COR3, C0 2 R3, CONR3R4, or heterocyclyl which may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , (Ci-C 6 )-alkyl, OR3, NR3R4, COR3, C0 2 R3, CONR3R4; 4 R3, R4 independently of one another H, (Ci-C 6 )-alkyl, -CF 3 , (C 3 -Cio)-cycloalkyl,

(C

6 -Cio)-aryl, heterocyclyl, (Ci-C)-alkylene-CONR5R6, (Ci-C 6 )-alkylene C0 2 R5, (C1-C 6 )-alkylene-COR5, (C 1

-C

6 )-alkylene-OR5, (Ci-C 6 )-alkylene NR5R6, (C1-C 6 )-alkylene-SR5, (CI-C 6 )-alkylene-SOR5, (Ci-C 6 )-alkylene 5 S0 2 R5, (CI-C 4 )-alkylene-(C 6 -Cio)-aryl or (CI-C 4 )-alkylene-heterocyclyl; R5, R6 independently of one another H, (Ci-C 6 )-alkyl, (C 3 -Cio)-cycloalkyl, (Ci-C 6

)

alkylene-(C 6 -Cio)-aryl, -(C 6 -Cio)-aryl, heterocyclyl, (Ci-C 6 )-alkylene-(C 3 Cio)-heterocyclyl; 10 X S; and the physiologically tolerated salts thereof. 15 Preference is further given to compounds of the formula I in which one or more radicals mean R1 H; 20 R2 H, (CI-Cio)-alkyl, (C 3 -Cio)-cycloalkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl,

(C

6 -Cio)-aryl, heterocyclyl, COR3, C0 2 R3, CONR3R4, CN, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , SH, SF 5 , OH, (C 1 C)-alkyl, -CF 3 , (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, OR3, OP(O)(OR3)2, 25 NR3R4, NR3CONR3R4, COR3, OCOR3, C0 2 R3, CONR3R4, OCONR3R4, (Ci-C 6 )-alkylene-OR3, (CI-C 6 )-alkylene-NR3R4, (CI-C 6

)

alkylene-NR3SO 2 R4, (C -C 6 )-alkylene-SR3, alkylene-SOR3, alkylene S0 2 R3, alkylene-S(0) 2 NR3R4, (Ci-C 6 )-alkylene-COR3, (Ci-C 6 )-alkylene C0 2 R3, (Ci-C 6 )-alkylene-CONR3R4, SR3, SOR3, S0 2 R3, SO 2 NR3R4, 30 NR3SO 2 R4, (CI-C 6 )-alkylene-(C 3 -Cio)-cycloalkyl, (Ci-C 6 )-alkylene-(C 6 Cio)-aryl, (Ci-C 6 )-alkylene-heterocyclyl, (C 3 -Cio)-cycloalkyl, (C 6 -CIo)-aryl which may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH,

-CF

3 , (Ci-C 6 )-alkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, OR3, NR3R4, COR3, C0 2 R3, CONR3R4, or heterocyclyl, which may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , (Ci-C 6 )-alkyl, OR3, NR3R4, COR3, C0 2 R3, CONR3R4; R3, R4 independently of one another H, (CI-C 6 )-alkyl, -CF 3 , (C 3 -Cio)-cycloalkyl,

(C

6 -Cio)-aryl, heterocyclyl, (C 1

-C

6 )-alkylene-CONR5R6, (CI-C6)-alkylene 5 C0 2 R5, (Ci-C 6 )-alkylene-COR5, (CI-C6)-alkylene-OR5, -C 6 )-alkylene NR5R6, (Ci-C 6 )-alkylene-SR5, (C 1

-C

6 )-alkylene-SOR5, (C 1

-C

6 )-alkylene S0 2 R5, (CI-C 4 )-alkylene-(C 6 -Cio)-aryl or (Ci-C 4 )-alkylene-heterocyclyl; R5, R6 independently of one another H, (C 1

-C

6 )-alkyl, (C 3 -Cio)-cycloalkyl, (C 1

-C

6

)

10 alkylene-(C 6 -Cio)-aryl, -(C 6 -Cio)-aryl, heterocyclyl, (CI-C 6 )-alkylene-(C 3 Co)-heterocyclyl; X S; 15 and the physiologically tolerated salts thereof. Preference is further given to compounds of the formula I in which one or more radicals mean 20 RI H; R2 H, (CI-C 1 )-alkyl, (C 3 -Cio)-cycloalkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl,

(C

6 -Cio)-aryl, a pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, thiomorpholino or homopiperazino radical; where the alkyl, 25 cycloalkyl, alkenyl, alkynyl, pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, thiomorpholino, homopiperazino and aryl radicals may be substituted one or more times by F, Cl, Br, CN, SF 5 , OH, (C 1

-C

6

)

alkyl, -CF 3 , (C 2

-C

6 )-alkenyl, OR3, NR3R4, NR3CONR3R4, COR3, OCOR3, C0 2 R3, CONR3R4, OCONR3R4, (C 1

-C

6 )-alkylene-OR3, (CI-C 6

)

30 alkylene-NR3R4, (CI-C 6 )-alkylene-NR3SO 2 R4, (CI-C 6 )-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O) 2 R3, alkylene-S(O) 2 NR3R4, (Ci-C 6

)

alkylene-COR3, (CI-C 6 )-alkylene-CO 2 R3, (CI-C 6 )-alkylene-CONR3R4, SR3, SOR3, S0 2 R3, SO 2 NR3R4, NR3SO 2 R4, (CI-C 6 )-alkylene-(C 3 -Cio) cycloalkyl, (C 1

-C

6 )-alkylene-(C 6 -CIO)-aryl, (CI-C 6 )-alkylene-heterocyclyl, U

(C

3

-C

1 o)-cycloalkyl, (C 6

-C

1 o)-aryl which may be substituted one or more times by F, Cl, Br, I, CN, OH, -CF 3 , (CI-C 6 )-alkyl, OR3, NR3R4, COR3, CO2R3, CONR3R4, or heterocyclyl which may be substituted one or more times by F, Cl, Br, CN, NO 2 , OH, -CF 3 , (Ci-C 6 )-alkyl, OR3, NR3R4, COR3, 5 CO2R3, CONR3R4; R3, R4 independently of one another H, (Ci-C 6 )-alkyl, -CF 3 , (C 3 -Clo)-cycloalkyl,

(C

6 -Cio)-aryl, heterocyclyl, (CI-C 6 )-alkylene-CONR5R6, (Ci-C 6 )-alkylene COOR5, (CI-C 6 )-alkylene-COR5, (CI-C 6 )-alkylene-OR5, (Ci-C 6 )-alkylene 10 NR5R6, (Cl-C 6 )-alkylene-SR5, (CI-C 6 )-alkylene-S(O)R5, (CI-C 6 )-alkylene S(0) 2 R5, (CI-C 4 )-alkylene-(C 6 -Cio)-aryl or (CI-C 4 )-alkylene-heterocyclyl; R5, R6 independently of one another H, (CI-C 6 )-alkyl, (C 3 -Cio)-cycloalkyl, (C 1

-C

6

)

alkylene-(C 6 -Cio)-aryl, -(C 6 -Cio)-aryl, heterocyclyl, (CI-C 6 )-alkylene-(C 3 15 Cio)-heterocyclyl; X S; and the physiologically tolerated salts thereof. 20 Preference is further given to compounds of the formula I in which one or more radicals mean RI H; 25 R2 (Ci-Cio)-alkyl, (C 3 -Cio)-cycloalkyl, phenyl, (CI-C6)-alkylene-phenyl, a pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, thiomorpholino or homopiperazino radical; 30 X S; and the physiologically tolerated 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, 5 R2 R1-N' N H 0 CN Ia which have the indicated diastereomic form Ia are particularly preferred. 10 If radicals or substituents may occur more than once in the compounds of the formula I, they may all, independently of one another, have the stated meaning and be identical or different. 15 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 20 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 25 salts), salts of 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 5 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, 10 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 15 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 20 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, neopentyl, 25 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 3 , NO 2 , N 3 , CN, COOH, COO(Ci-C 6 )alkyl, CONH 2 , CONH(CI

C

6 )alkyl, CON[(C 1

-C

6 )alkyl] 2 , cycloalkyl, (C 2 -C)-alkenyl, (C 2

-C

6 )-alkynyl, aryl, heterocyclyl, 0-(CI-C 6 )-alkyl, O-COO-(CI-C)-alkyl, O-CO-(Ci-C)-alkyl, O-CO-(C 1

-C

6

)

30 aryl, O-CO-(Ci-C 6 )-heterocyclyl; P0 3

H

2 , P(O)(Oalkyl) 2 , (CI-C 6 )-alkylene-P(O)(Oalkyl) 2 ,

O-P(O)(OH)

2 ,O-P(O)(Oalkyl) 2 , SO 3 H, S0 2 -NH2, SO 2 NH(Ci-C 6 )-alkyl, SO 2

N[(CI-C

6

)

alkyl] 2 , S-(Ci-C)-alkyl, S-(CH 2 )n-aryl, S-(CH 2 )n-heterocyclyl, SO-(Ci-C 6 )-alkyl, SO

(CH

2 )n-aryl, SO-(CH 2 )n-heterocyclyl, S0 2 -(Ci-C 6 )-alkyl, SO 2

-(CH

2 )n-aryl, SO 2

-(CH

2 )nheterocyclyl, SO 2

-NH(CH

2 )n-aryl, SO 2

-NH(CH

2 )n-heterocyclyl, S0 2 -N [((CI-C 6

)

alkyl)(CH 2 )n-aryl], S0 2

-N[((C

1

-C

6 )-alkyl)(CH 2 )n-heterocyclyl], SO 2

-N((CH

2 )n-aryl) 2 , SO 2 N((CH 2 )n-(heterocyclyl)) 2 , where n can be 0-6, and the aryl radical or heterocyclyl radical may be substituted up to three times by F, Cl, Br, OH, CF 3 , SF 5 , NO 2 , CN, OCF 3 , 0-(C 1 5 C 6 )-alkyl, (C 1

-C

6 )-alkyl, NI- 2 ;

C(NH)(NH

2 ), NH 2 , NH-(C 1

-C

6 )-alkyl, N((C 1

-C

6 )-alkyl) 2 , NH(Ci-C 7 )-acyl, NH-CO-(C 1 C 6 )-alkyl, NH-COO-(C 1

-C

6 )-alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, NH-COO-heterocyclyl, NH-CO-NH-(CI-C 6 )-alkyl, NH-CO-NH-aryl, NH-CO-NH heterocyclyl, N[(Ci-C 6 )-alkyl] -CO-(C 1

-C

6 )-alkyl, N[(Ci-C 6 )-alkyl] -COO-(C 1 -C)-alkyl, 10 N[(C 1

-C

6 )-alkyl]-CO-aryl, N[(CI-C 6 )-alkyl] -CO-heterocyclyl, N[(Ci-C 6 )-alkyl]-COO-aryl, N[(Ci-C 6 )-alkyl]-COO-heterocyclyl, N[(C 1

-C

6 )-alkyl]-CO-NH-(Ci-C 6 )-alkyl), N[(CI-C 6

)

alkyl]-CO-NH-aryl, N[(C 1

-C

6 )-alkyl] -CO-NH-heterocyclyl, N[(C 1

-C

6 )-alkyl]-CO-N((C 1 C 6 )-alkyl) 2 , N[(CI-C 6 )-alkyl]-CO-N((C 1

-C

6 )-alkyl)-aryl, N[(CI-C 6 )-alkyl]-CO-N((CI-C 6

)

alkyl)-heterocyclyl, N[(Ci-C 6 )-alkyl]-CO-N-(aryl) 2 , N[(C 1

-C

6 )-alkyl]-CO-N 15 (heterocyclyl) 2 , N(aryl)-CO-(C 1

-C

6 )-alkyl, N(heterocyclyl)-CO-(C 1

-C

6 )-alkyl, N(aryl)

COO-(C

1

-C

6 )-alkyl, N(heterocyclyl)-COO-(C 1

-C

6 )-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO-NH

(C

1

-C

6 )-alkyl, N(heterocyclyl)-CO-NH-(C 1

-C

6 )-alkyl, N(aryl)-CO-NH-aryl, N(heterocyclyl)-CO-NH-aryl, N(aryl)-CO-N((C 1

-C

6 )-alkyl) 2 , N(heterocyclyl)-CO-N((Ci 20 C 6 )-alkyl) 2 , N(aryl)-CO-N[(C 1

-C

6 )-alkyl]-aryl, N(heterocyclyl)-CO-N[(CI-C 6 )-alkyl]-aryl, N(aryl)-CO-N-(aryl) 2 , N(heterocyclyl)-CO-N-(aryl) 2 , aryl, O-(CH 2 )n-aryl, 0-(CH 2 )n heterocyclyl, where n may be 0-6, where the aryl radical or heterocyclyl radical may be substituted one to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , 0-(Ci-C 6 )-alkyl, (CI C)-alkyl, NH 2 , NH(Ci-C 6 )-alkyl, N((CI-C 6 )-alkyl) 2 , SF 5 , S0 2

-CH

3 , COOH, COO-(C 1

-C

6

)

25 alkyl, CONH 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 30 example: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO(Ci-C 6 )alkyl, CONH 2 , CONH(C 1 C 6 )alkyl, CON[(C 1

-C

6 )alkyl] 2 , cycloalkyl, (Ci-Cio)-alkyl, (C 2

-C

6 )-alkynyl, aryl, heterocyclyl, 0-(CI-C 6 )-alkyl, O-CO-(C 1

-C

6 )-alkyl, O-CO-(CI-C)-aryl, O-CO-(Ci-C 6

)

heterocyclyl,; P0 3

H

2 , P(O)(Oalkyl) 2 , (C-C 6 )-alkylene-P(O)(Oalkyl) 2 , O-P(O)(OH) 2 , O-P(O)(Oalkyl) 2 ,

SO

3 H, S0 2

-NH

2 , SO 2

NH(C

1

-C

6 )-alkyl, SO 2

N[(CI-C

6 )-alkyl] 2 , S-(CI-C 6 )-alkyl, S-(CH 2 )n aryl, S-(CH 2 )n-heterocyclyl, SO-(C-C 6 )-alkyl, SO-(CH 2 )n-aryl, SO-(CH 2 )n-heterocyclyl, 5 S0 2

-(C-C

6 )-alkyl, SO 2

-(CH

2 )n-aryl, SO 2

-(CH

2 )n-heterocyclyl , SO 2

-NH(CH

2 )n-aryl, S02

NH(CH

2 )n-heterocyclyl, S0 2

-N((C-C

6 )-alkyl)(CH 2 )n-aryl, S0 2 -N((C -C 6 )-alkyl)(CH 2 )n heterocyclyl, SO 2

-N((CH

2 )n-aryl) 2 , SO2-N((CH 2 )n-(heterocyclyl) 2 where n may be 0 - 6 and the aryl radical or heterocyclyl radical may be substituted up to twice by F, Cl, Br, OH,

CF

3 , SF 5 , NO 2 , CN, OCF 3 , O-(CrC 6 )-alkyl, (CI-C 6 )-alkyl, NH 2 ; 10 C(NH)(NH 2 ), NH 2 , NH-(Cr-C 6 )-alkyl, N((C-C 6 )-alkyl) 2 , NH(Cr-C 7 )-acyl, NH-CO-(C

C

6 )-alkyl, NH-COO-(C-C 6 )-alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, NH-COO-heterocyclyl, NH-CO-NH-(C-C 6 )-alkyl), NH-CO-NH-aryl, NH-CO-NH heterocyclyl, N[(CI-C 6 )-alkyl]-CO-(C-C 6 )-alkyl, N[(C -C 6 )-alkyl]-COO-(Cr-C 6 )-alkyl, N[(C -C 6 )-alkyl]-CO-aryl, N[(C-C6)-alkyl]-CO-heterocyclyl,

N[(C-C

6 )-alkyl]-COO-aryl, 15 N[(C-C 6 )-alkyl]-COO-heterocyclyl, N[(C -C 6 )-alkyl]-CO-NH-(C-C 6 )-alkyl), N[(C-C 6

)

alkyl]-CO-NH-aryl, N[(C-C 6 )-alkyl]-CO-NH-heterocyclyl, N[(Cr-C 6 )-alkyl]-CO-N((Cr C)-alkyl) 2 , N[(C-C 6 )-alkyl]-CO-N((C -C 6 )-alkyl)-aryl, N[(C-C 6 )-alkyl]-CO-N((C-C 6

)

alkyl)-heterocyclyl, N[(C-C 6 )-alkyl]-CO-N(aryl) 2 , N[(C-C6)-alkyl]-CO-N(heterocyclyl) 2 , N(aryl)-CO-(Cr-C 6 )-alkyl, N(heterocyclyl)-CO-(C-C 6 )-alkyl, N(aryl)-COO-(C-C 6 )-alkyl, 20 N(heterocyclyl)-COO-(C-C 6 )-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl) COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO-NH-(C-C 6 )-alkyl, N(heterocyclyl) CO-NH-(C -C 6 )-alkyl, N(aryl)-CO-NH-aryl, N(heterocyclyl)-CO-NH-aryl, N(aryl)-CO

N((C-C

6 )-alkyl) 2 , N(heterocyclyl)-CO-N((C-C 6 )-alkyl) 2 , N(aryl)-CO-N[(C-C 6 )-alkyl] aryl, N(heterocyclyl)-CO-N[(C-C 6 )-alkyl]-aryl, N(aryl)-CO-N(aryl) 2 , N(heterocyclyl) 25 CO-N(aryl) 2 , aryl, O-(CH 2 )n-aryl, 0-(CH 2 )n-heterocyclyl, where n may be 0 - 6, where the aryl radical or heterocyclyl radical may be substituted one to 3 times by F, Cl, Br, I, OH,

CF

3 , NO 2 , CN, OCF 3 , 0-(C-C 6 )-alkyl, (CI-C 6 )-alkyl, NH 2 , NH(CI-C 6 )-alkyl, N((C-C 6

)

alkyl) 2 , SF 5 , S0 2

-CH

3 , COOH, COO-(CI-C 6 )-alkyl, CONH 2 . 30 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.

I I The alkynyl radicals may be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO(CI-C 6 )alkyl, CONH 2 , CONH(C 1 C 6 )alkyl, CON[(Ci-C 6 )alkyl] 2 , cycloalkyl, (C 2

-C

6 )-alkenyl, (Ci-C 1 o)-alkyl, 0-(Ci-C 6 )-alkyl O-CO-(Ci-C 6 )-alkyl, O-CO-(C 1 -C6)-aryl, O-CO-(CI-C 6 )-heterocyclyl; 5 P0 3

H

2 , P(O)(Oalkyl)2, (C 1

-C

6 )-alkylene-P(O)(Oalkyl) 2 , O-P(O)(OH) 2 , O-P(O)(Oalkyl) 2 ,

SO

3 H, S0 2

-NH

2 , SO 2 NH(Ci-C 6 )-alkyl, SO 2

N[(C

1

-C

6 )-alkyl] 2 , S-(CI-C 6 )-alkyl, S-(CH 2 )n aryl, S-(CH 2 )n-heterocyclyl, SO-(Ci-C 6 )-alkyl, SO-(CH 2 )n-aryl, SO-(CH 2 )n-heterocyclyl, S0 2

-(CI-C

6 )-alkyl, SO 2

-(CH

2 )n-aryl, SO 2

-(CH

2 )n-heterocyclyl, SO 2

-NH(CH

2 )n-aryl, SO 2 NH(CH 2 )n-heterocyclyl, S0 2

-N((C

1

-C

6 )-alkyl)(CH 2 )n-aryl, S0 2 -N((Ci-C 6 )-alkyl)(CH 2 )n 10 heterocyclyl, SO 2

-N((CH

2 )n-aryl) 2 , SO 2

-N((CH

2 )n-(heterocyclyl) 2 where n may be 0 - 6 and the aryl radical or heterocyclyl radical may be substituted up to twice by F, Cl, Br, OH,

CF

3 , SFs, NO 2 , CN, OCF 3 , 0-(CI-C 6 )-alkyl, (CI-C 6 )-alkyl, NH 2 ;

C(NH)(NH

2 ), NH 2 , NH-(C 1

-C

6 )-alkyl, N((Ci-C 6 )-alkyl) 2 , NH(CI-C 7 )-acyl, NH-CO-(Ci

C

6 )-alkyl, NH-COO-(CI-C 6 )-alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NIH-COO-aryl, 15 NH-COO-heterocyclyl, NH-CO-NH-(CI-C 6 )-alkyl), NH-CO-NH-aryl, NH-CO-NH heterocyclyl, N[(C 1

-C

6 )-alkyl]-CO-(Ci-C 6 )-alkyl, N[(Ci-C 6 )-alkyl]-COO-(Ci-C 6 )-alkyl,

N[(C-C

6 )-alkyl]-CO-aryl, N[(Ci-C 6 )-alkyl]-CO-heterocyclyl, N[(C 1

-C

6 )-alkyl]-COO-aryl, N[(Ci-C 6 )-alkyl]-COO-heterocyclyl, N[(Ci-C 6 )-alkyl]-CO-NH-(CI-C 6 )-alkyl), N[(CI-C 6

)

alkyl]-CO-NH-aryl, N[(Ci-C 6 )-alkyl]-CO-NH-heterocyclyl, N[(Ci-C 6 )-alkyl]-CO-N((Ci 20 C 6 )-alkyl) 2 , N[(C 1

-C

6 )-alkyl]-CO-N((C 1

-C

6 )-alkyl)-aryl, N[(CI-C 6 )-alkyl]-CO-N((CI-C 6

)

alkyl)-heterocyclyl, N[(Ci-C 6 )-alkyl]-CO-N(aryl) 2 , N[(Ci-C 6 )-alkyl]-CO-N(heterocyclyl) 2 , N(aryl)-CO-(C 1

-C

6 )-alkyl, N(heterocyclyl)-CO-(C 1

-C

6 )-alkyl, N(aryl)-COO-(C 1

-C

6 )-alkyl, N(heterocyclyl)-COO-(Ci-C 6 )-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl) COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO-NH-(Ci-C 6 )-alkyl, N(heterocyclyl) 25 CO-NH-(Ci-C 6 )-alkyl, N(aryl)-CO-NH-aryl, N(heterocyclyl)-CO-NH-aryl, N(aryl)-CO

N((CI-C

6 )-alkyl) 2 , N(heterocyclyl)-CO-N((C 1

-C

6 )-alkyl) 2 , N(aryl)-CO-N[(Ci-C 6 )-alkyl] aryl, N(heterocyclyl)-CO-N[(C 1

-C

6 )-alkyl]-aryl, N(aryl)-CO-N(aryl) 2 , N(heterocyclyl) CO-N(aryl) 2 , aryl, 0-(CH 2 )n-aryl, 0-(CH 2 )n-heterocyclyl, where n may be 0 - 6, where the aryl radical or heterocyclyl radical may be substituted one to 3 times by F, Cl, Br, I, OH, 30 CF 3 , NO 2 , CN, OCF 3 , 0-(Ci-C 6 )-alkyl, (CI-C 6 )-alkyl, NH 2 , NH(Ci-C 6 )-alkyl, N((CI-C 6

)

alkyl) 2 , SF 5 , S0 2

-CH

3 , COOH, COO-(CI-C 6 )-alkyl, CONH2. An aryl radical means a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta tetralon-, indanyl- or indan-1-on-yl radical.

12 The aryl radicals may be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF 3 , NO 2 , SF 5 , N 3 , CN, COOH, COO(Ci-C 6 )alkyl, CONH 2 ,

CONH(CI-C

6 )alkyl, CON[(Ci-C 6 )alkyl] 2 , cycloalkyl, (CI-Cio)-alkyl, (C 2

-C

6 )-alkenyl, (C 2 C 6 )-alkynyl, 0 -(Ci-C 6 )-alkyl, O-CO-(CI-C 6 )-alkyl, O-CO-(Ci-C 6 )-aryl, O-CO-(CI-C 6

)

5 heterocyclyl; P0 3

H

2 , P(O)(Oalkyl) 2 , (CI-C 6 )-alkylene-P(O)(Oalkyl) 2 , O-P(O)(OH) 2 , O-P(O)(Oalkyl) 2 ,

SO

3 H, S0 2

-NH

2 , SO 2 NH(Ci-C 6 )-alkyl, SO 2 N[(Ci-C 6 )-alkyl] 2 , S-(CI-C 6 )-alkyl, S-(CH 2 )n aryl, S-(CH 2 )n-heterocyclyl, SO-(CI-C 6 )-alkyl, SO-(CH 2 )n-aryl, SO-(CH 2 )n-heterocyclyl, S0 2

-(CI-C

6 )-alkyl, SO 2

-(CH

2 )n-aryl, SO 2

-(CH

2 )n-heterocyclyl , SO 2

-NH(CH

2 ).-aryl, SO 2 10 NH(CH 2 )n-heterocyclyl, SO 2 -N((Cl-C 6 )-alkyl)(CH 2 )n-aryl, S0 2 -N((Ci-C 6 )-alkyl)(CH 2 )n heterocyclyl, SO 2

-N((CH

2 )n-aryl) 2 , SO 2

-N((CH

CF

3 , NO 2 , SF 5 , CN, OCF 3 , O-(C1-C 6 )-alkyl, (Ci-C 6 )-alkyl, NH 2 ;

C(NH)(NH

2 ), NH 2 , NH-(CI-C 6 )-alkyl, N((CI-C 6 )-alkyl) 2 , NH(CI-C 7 )-acyl, NH-CO-(CI 15 C 6 )-alkyl, NH-COO-(CI-C 6 )-alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, NH-COO-heterocyclyl, NH-CO-NH-(CI-C 6 )-alkyl), NH-CO-NH-aryl, NH-CO-NH heterocyclyl, N[(C 1

-C

6 )-alkyl]-CO-(CI-C 6 )-alkyl, N[(CI-C 6 )-alkyl]-COO-(C I-C 6 )-alkyl,

N[(CI-C

6 )-alkyl]-CO-aryl, N[(CI-C 6 )-alkyl]-CO-heterocyclyl, N[(CI-C 6 )-alkyl]-COO-aryl,

N[(CI-C

6 )-alkyl]-COO-heterocyclyl, N[(CI-C 6 )-alkyl]-CO-NH-(Ci-C 6 )-alkyl), N[(CI-C 6

)

20 alkyl]-CO-NH-aryl, N[(Ci-C 6 )-alkyl]-CO-NH-heterocyclyl, N[(CI-C 6 )-alkyl]-CO-N((Ci

C

6 )-alkyl) 2 , N[(CI-C 6 )-alkyl]-CO-N((Ci-C 6 )-alkyl)-aryl, N[(CI-C 6 )-alkyl]-CO-N((CI-C 6

)

alkyl)-heterocyclyl, N[(CI-C 6 )-alkyl]-CO-N(aryl) 2 , N[(CI-C 6 )-alkyl]-CO-N(heterocyclyl) 2 , N(aryl)-CO-(CI-C 6 )-alkyl, N(heterocyclyl)-CO-(Ci-C 6 )-alkyl, N(aryl)-COO-(Ci-C 6 )-alkyl, N(heterocyclyl)-COO-(Ci-C 6 )-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl) 25 COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO-NH-(C 1

-C

6 )-alkyl, N(heterocyclyl) CO-NIH-(Ci-C 6 )-alkyl, N(aryl)-CO-NH-aryl, N(heterocyclyl)-CO-NH-aryl, N(aryl)-CO N((Ci-C 6 )-alkyl) 2 , N(heterocyclyl)-CO-N((Ci-C 6 )-alkyl) 2 , N(aryl)-CO-N[(Ci-C 6 )-alkyl] aryl, N(heterocyclyl)-CO-N[(Ci-C 6 )-alkyl]-aryl, N(aryl)-CO-N(aryl) 2 , N(heterocyclyl) CO-N(aryl) 2 , aryl, 0-(CH 2 )n-aryl, 0-(CH 2 )n-heterocyclyl, where n may be 0 - 6, where the 30 aryl radical or heterocyclyl radical may be substituted one to 3 times by F, Cl, Br, I, OH,

CF

3 , NO 2 , CN, OCF 3 , 0-(Ci-C 6 )-alkyl, (Ci-C 6 )-alkyl, NH 2 , NH(Ci-C 6 )-alkyl, N((CI-C 6

)

alkyl) 2 , SF 5 , S0 2

-CH

3 , COOH, COO-(Ci-C 6 )-alkyl, CONH 2

.

13 A cycloalkyl radical means a ring system which comprises one or more rings and which is saturated 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. 5 The cycloalkyl radicals may be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO(Ci-C 6 )alkyl, CONH 2 ,

CONH(C

1

-C

6 )alkyl, CON[(Ci-C 6 )alkyl]2, cycloalkyl, (Ci-Clo)-alkyl, (C 2

-C

6 )-alkenyl, (C 2 C 6 )-alkynyl, 0-(Ci-C 6 )-alkyl, O-CO-(Ci-C 6 )-alkyl, O-CO-(CI-C 6 )-aryl, O-CO-(CI-C 6

)

heterocyclyl; 10 P0 3

H

SO

3 H, S0 2

-NH

2 , SO 2

NH(CI-C

6 )-alkyl, SO 2

N[(CI-C

-(CI-C

6 )-alkyl, SO 2

-(CH

2 )n-aryl, SO 2

-(CH

2 )n-heterocyclyl, SO 2

-NH(CH

2 )n-aryl, SO 2 NH(CH 2 )n-heterocyclyl, S0 2

-N((CI-C

6 )-alkyl)(CH 2 )n-aryl, S0 2

-N((CI-C

6 )-alkyl)(CH 2 )n 15 heterocyclyl, SO 2

-N((CH

2 )n-aryl) 2 , SO 2

-N((CH

CF

3 , SF 5 , NO 2 , CN, OCF 3 , O-(C 1 -C)-alkyl, (C1-C 6 )-alkyl, NH42;

C(NH)(NH

2 ), NH 2 , NH-(Ci-C 6 )-alkyl, N((CI-C 6 )-akyl) 2 , NH(Ci-C 7 )-acyl, NH-CO-(Ci

C

6 )-alkyl, NH-COO-(CI-C 6 )-alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, 20 NH-COO-heterocyclyl, NH-CO-NH-(CI-C 6 )-alkyl), NH-CO-NH-aryl, NH-CO-NH heterocyclyl, N[(Ci-C 6 )-alkyl]-CO-(CI-C 6 )-alkyl, N[(CI-C 6 )-alkyl]-COO-(Ci-C 6 )-alkyl, N[(Ci-C 6 )-alkyl]-CO-aryl, N[(CI-C 6 )-alkyl]-CO-heterocyclyl, N[(CI-C 6 )-alkyl]-COO-aryl, N[(Ci-C 6 )-alkyl]-COO-heterocyclyl, N[(CI-C 6 )-alkyl]-CO-NH-(Ci-C 6 )-alkyl), N[(C 1

-C

6

)

alkyl]-CO-NH-aryl, N[(Ci-C 6 )-alkyl]-CO-NH-heterocyclyl, N[(Ci-C 6 )-alkyl]-CO-N((Cl 25 C 6 )-alkyl) 2 , N[(C 1

-C

6 )-alkyl]-CO-N((CI-C 6 )-alkyl)-aryl, N[(C-C 6 )-alkyl]-CO-N((Ci-C 6

)

alkyl)-heterocyclyl, N[(Ci-C 6 )-alkyl]-CO-N(aryl) 2 , N[(CI-C 6 )-alkyl]-CO-N(heterocyclyl) 2 , N(aryl)-CO-(Ci-C 6 )-alkyl, N(heterocyclyl)-CO-(Ci-C 6 )-alkyl, N(aryl)-COO-(Ci-C 6 )-alkyl, N(heterocyclyl)-COO-(C 1

-C

6 )-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl) COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO-NH-(C 1

-C

6 )-alkyl, N(heterocyclyl) 30 CO-NH-(CI-C 6 )-alkyl, N(aryl)-CO-NH-aryl, N(heterocyclyl)-CO-NH-aryl, N(aryl)-CO N((Ci-C 6 )-alkyl) 2 , N(heterocyclyl)-CO-N((CI-C 6 )-alkyl) 2 , N(aryl)-CO-N[(C-C 6 )-alkyl] aryl, N(heterocyclyl)-CO-N[(CI-C 6 )-alkyl]-aryl, N(aryl)-CO-N(aryl) 2 , N(heterocyclyl) CO-N(aryl) 2 , aryl, 0-(CH 2 )n-aryl, O-(CH 2 )n-heterocyclyl, where n may be 0 - 6, where the 14 aryl radical or heterocyclyl radical may be substituted one to 3 times by F, Cl, Br, I, OH,

CF

3 , NO 2 , CN, OCF 3 , 0-(CI-C 6 )-alkyl, (Ci-C)-alkyl, NH 2 , NH(Ci-C 6 )-alkyl, N((CI-C 6

)

alkyl) 2 , SF 5 , SO 2

-CH

3 , COOH, COO-(CI-C 6 )-alkyl, CONH 2 . 5 Heterocyclyl 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. 10 Suitable heterocyclyl radicals 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] 15 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, 20 pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazoles, pyridoimidazoles, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 25 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 30 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.

Li Also included are derivatives of these heterocycles which are benzo-fused one or more times. 5 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 3 , NO 2 , N 3 , CN, COOH, COO(CI

C

6 )alkyl, CONH 2 , CONH(CI-C 6 )alkyl, CON[(C 1

-C

6 )alkyl] 2 , cycloalkyl, (CI-C 1 o)-alkyl,

(C

2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, 0-(CI-C 6 )-alkyl, O-CO-(Ci-C 6 )-alkyl, O-CO-(CI-C 6

)

aryl, O-CO-(C 1

-C

6 )-heterocyclyl; 10 PO 3

H

2 , P(O)(Oalkyl) 2 , (Ci -C6)-alkylene-P(O)(Oalkyl) 2 , O-P(O)(OH) 2 , O-P(O)(Oalkyl) 2 ,

SO

3 H, S0 2

-NH

2 , SO 2 NH(Ci-C 6 )-alkyl, SO 2 N[(Ci-C 6 )-alkyl] 2 , S-(CI-C 6 )-alkyl, S-(CH 2 )n aryl, S-(CH 2 )n-heterocyclyl, SO-(CI-C 6 )-alkyl, SO-(CH2)n-aryl, SO-(CH2)n-heterocyclyl, S0 2 -(Ci-C 6 )-alkyl, SO 2

-(CH

2 )n-aryl, SO2-(CH 2 )n-heterocyclyl , SO 2

-NH(CH

2 )n-aryl, SO 2 NH(CH 2 )n-heterocyclyl, S0 2 -N(Cj-C 6 )-alkyl)(CH 2 )n-aryl, S0 2 -N(Ci-C 6 )-alkyl)(CH 2 )n 15 heterocyclyl, SO 2

-N((CH

2 )n-aryl) 2 , SO 2 -N((CH2)n-(heterocyclyl) 2 where n can be 0 - 6, and the aryl radical or heterocyclyl radical may be substituted up to twice by F, Cl, Br, OH,

CF

3 , SF 5 , NO 2 , CN, OCF 3 , O-(Ci-C 6 )-alkyl, (C 1

-C

6 )-alkyl, NH 2 ;

C(NH)(NH

2 ), NH 2 , NH-(CI-C 6 )-alkyl, N((CI-C 6 )-alkyl) 2 , NH(Ci-C 7 )-acyl, NH-CO-(Ci

C

6 )-alkyl, NH-COO-(Ci-C 6 )-alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, 20 NH-COO-heterocyclyl, NH-CO-NH-(CI-C 6 )-alkyl), NH-CO-NIH-aryl, NH-CO-NH heterocyclyl, N[(CI-C 6 )-alkyl]-CO-(Ci-C 6 )-alkyl, N[(CI-C 6 )-alkyl]-COO-(Ci-C 6 )-alkyl, N[(Ci-C 6 )-alkyl]-CO-aryl, N[(CI-C6)-alkyl]-CO-heterocyclyl,

N[(CI-C

6 )-alkyl]-COO-aryl,

N[(CI-C

6 )-alkyl]-COO-heterocyclyl,

N[(CI-C

6 )-alkyl]-CO-NH-(C 1

-C

6 )-alkyl), N[(Ci-C 6

)

alkyl]-CO-NH-aryl, N[(CI-C6)-alkyl]-CO-NH-heterocyclyl,

N[(CI-C

6 )-alkyl]-CO-N((C 1 25 C 6 )-alkyl) 2 , N[(Ci-C 6 )-alkyl]-CO-N((Ci-C 6 )-alkyl)-aryl, N[(Ci-C 6 )-alkyl]-CO-N((C 1

-C

6

)

alkyl)-heterocyclyl, N[(CI-C 6 )-alkyl]-CO--N(aryl) 2 , N[(CI-C6)-alkyl]-CO-N(heterocyclyl) 2 , N(aryl)-CO-(CI-C 6 )-alkyl, N(heterocyclyl)-CO-(C 1

-C

6 )-alkyl, N(aryl)-COO-(C 1

-C

6 )-alkyl, N(heterocyclyl)-COO-(CI-C 6 )-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl) COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO-NH-(C 1

-C

6 )-alkyl, N(heterocyclyl) 30 CO-NH-(Ci-C 6 )-alkyl, N(aryl)-CO-NH-aryl, N(heterocyclyl)-CO-NH-aryl, N(aryl)-CO

N((CI-C

6 )-alkyl) 2 , N(heterocyclyl)-CO-N((C 1

-C

6 )-alkyl) 2 , N(aryl)-CO-N[(CI-C 6 )-alkyl] aryl, N(heterocyclyl)-CO-N[(Ci-C6)-alkyl]-aryl, N(aryl)-CO-N(aryl) 2 , N(heterocyclyl) CO-N(aryl) 2 , aryl, 0-(CH 2 )n-aryl, 0-(CH 2 )n-heterocyclyl, where n may be 0 - 6, where the 16 aryl radical or heterocyclyl radical may be substituted one to 3 times by F, Cl, Br, I, OH,

CF

3 , NO 2 , CN, OCF 3 , SF 5 , 0-(CI-C 6 )-alkyl, (Ci-C 6 )-alkyl, NH 2 , NH(C 1

-C

6 )-alkyl, N((C C 6 )-alkyl) 2 , SF 5 , S0 2

-CH

3 , COOH, COO-(Ci-C 6 )-alkyl, CONH 2 . 5 The compounds of the formula 1 can be prepared by methods known per se. Thus, it is possible starting from commercially available D-allylglycine 2 by protection of the amino group with usual protective groups such as Boc to 3, oxidation of the allyl group with ozone or osmium tetroxide/sodium periodate to the cyclic aldehyde derivative 4, reaction with cysteine derivatives such as, for example, the methyl ester to 5, cyclization with usual, 10 acid activating, reagents such as DCC or chloromethylpyridinium iodide, ammonolysis of the resulting bicyclic thiazolidine ester 6 with methanolic ammonia solution, conversion of the resulting amide 7 into the nitrile 8 and derivatization of the amine by usual methods such as alkylation with alkyl halides or reductive alkylation with aldehydes or ketones to the nitriles 9. On the other hand, it is possible by using L-allylglycine as commercially 15 available starting compound to prepare stereoisomeric forms of the derivatives 8 and 9. The diastereoisomeric mixtures 5 which are obtained on cyclization with cysteine derivatives by usual methods can be fractionated into the individual diastereomers by known methods such as, for example, by column chromatography or by recrystallization from a suitable solvent. The stereoisomeric forms can, however, also be separated and 20 purified by usual methods at a later stage of the synthesis.

1/ o 0 0 ' O Os4/NaO4 Boc2O N OsO4/NalO4 N N O 2 4 3 L-Cys-Ome.HCI NaHCO3 N., chloromethylpy- O N., S O N ridinium iodide N 0 0 0 0 0 o 0 0 6 5 NH3/MeOH H H S 1.cyanuric chloride/DMF N" N-. 2. CF3COOH N O- N- O o 0 N 8 8 N H RCHO/NaBH4 S N'. 9 N A further method for preparing the compounds of the invention of the formula 1 consists of a conversion, known per se, of commercially available acids 10, in which R2 cannot be 5 hydrogen, into the oxazolidones 11 by the action of pivalaldehyde and allyl chloroformate. It is then possible to prepare from 11 by reaction with strong bases such as, for example, potassium bistrimethylsilylamide and alkylation with allyl bromide, with subsequent removal of the protective groups and ring opening under suitable conditions, the amino acids 12 (Heterocycles 34 (5), 1992 903-906) from which the aldehydes 15 are obtainable, 10 after introduction of N-protective groups such as, for example, the BOC group to give 13 and esterification to give 14 for example with diazomethane or trimethylsilyldiazomethane, by oxidation with osmium tetroxide and sodium periodate. It is possible by heating these aldehydes with L-cysteine in pyridine to obtain the bicyclic derivatives 16 and, from them, by known methods by esterification the substances 17, and by ammonolysis the amides 18.

Is Conversion of the amide 18 into a nitrile 19 with, for example, trifluoroacetic anhydride or cyanuric chloride and elimination of the protective group by known processes leads to the substances 20 of the invention, which can be isolated where appropriate as salts or free bases. 5 R 2 o0 R2R N O O N O N' o 0 0 0 10 12 R2 O \ O R2 0 N" N"' 0 N' 0\ 0 00 13 14 15 HH R2 H S 2 H SR2 s O N N" N 0 4 j P4 N\ o 0 N 4~ 0 0~ ~ 00 16 1~7 18 H H R2 S RV S N N""' N I" 19 20 A further possibility for producing compounds of the general formula 1 consists in converting the commercially available compound 21 by deprotonation with a strong base (e.g. potassium hexamethyldisilazide (KHMDS)) and alkylation with an allyl derivative 10 (e.g. allyl bromide) into the compound 22 (Synlett 1992, 249-251). This is followed by deprotonation again with a strong base (e.g. sodium hexamethyldisilazide (NaHMDS) in the presence of 15-crown-5) and then reaction with an alkylating agent R2X (X = leaving group, e.g. Cl, Br, I, mesyl, tosyl, triflate) to give the compound 23. Cleavage with alkali metals (e.g. sodium) in liquid ammonia affords compound 24. Oxidation with osmium 15 tetroxide/sodium periodate or ozone then results in the cyclic aldehyde derivative 25. This is followed by reaction with L-cysteine derivatives (e.g. L-cysteine methyl ester 19 hydrochloride) in the presence of a base (e.g. triethylamine or Hinig's base), resulting in a thiazolidine intermediate which cyclizes in the presence of an acid activating reagent such as, for example, a carbodiimide (e.g. N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride) to give the two diastereomeric thiazolidides 26 and 27. After separation of 5 the diastereomers using suitable methods, such as by recrystallization or chromatographic methods, compound 26 is converted with ammonia into the amide 28. Reaction to give the nitrile 29 by usual methods (e.g. trifluoroacetic anhydride and triethylamine, or cyanuric chloride) and elimination of the Boc group under acidic conditions (e.g. trifluoroacetic acid in the presence of thioanisole) affords the compound 30 which can then be converted as 10 mentioned above into the substances 31. Diastereomers of these compounds can be prepared correspondingly starting from other enantiomers of the starting compound 21, or by further reaction of the diastereomers 27 to give the stereoisomeric derivatives analogous to formula 30 and 31. Ph 0 0 base, base. R2X Ph N Ph N x boc boc 15 21 22 Ph 0 0 Na, NH3/THF OsO4, Na 04 R2 OH Ph~'N "2R BocHN _a boc BocHN CO 2 H 23 24 25 a) L-CysOMe, NEt3 H R H b) EDC R2, S BocHN N + BocHN' N 0 CO2Me 0 CO 2 Me 26 27 H H NH3 R2 TFAA, NEt3 R2 26 ' BocHN"' N BocHN N 0 CONH 2 0 CN 28 29 Lu TFA, H H thioanisole R2 S R2 S HN , N1 N H 0 CN 0 CN 30 31 A further method for preparing the substances of the invention of the formula 1 begins starting from the commercially available ester 32. Deprotonation of 32 with suitable bases 5 such as NaHMDS and alkylation with allyl bromide affords 33, which can be converted by hydrolysis for example with sodium hydroxide solution and by oxidation for example with ozone or osmium teroxide/sodium periodate into the cyclic aldehyde derivative 34. Condensation with L-cysteine methyl ester hydrochloride to give the thiazolidine and subsequent cyclization with acid activating agents such as, for example, 2-chloro-1 10 methylpyridinium iodide in the presence of triethylamine affords the tricyclic thiazolidide 35, which can be isolated in addition to other diastereomers of this constitution by usual separation processes such as column chromatography. The amide 36 is then obtained with ammonia in a known manner and is converted with trifluoroacetic anhydride in the presence of suitable bases such as triethylamine into the nitrile 37. Elimination of the 15 protective groups with acidic reagents such as trifluoroacetic acid then affords the compound 38 which, after conversion into the protective aldehyde 39 (pg = protective group), can be converted by reductive amination (Nu = residue of a secondary amine) into 40 and further as mentioned above into the substances of the formula 41. N NaHMDS O 1) NaOH

CO

2 Me allyl bromide N boc / CO 2 Me 2) 03, Me2S 32 boc 20 33 O 1) L-Cys-OMe*HCI H OH N"" S NH3 N 2) NEt3, b N bo O c' O boc 35N C0 0 3 F35 C 2M O H O H N-- S TFAA, NEt3 . S boc O N* bocO N 36 CONH2 37 CN 36 37 HO H H TFA H H2N S 1.Sg-X N HN" N o 2. Oxid. H N ON 38 39 CN 5 Nu HNu ..... H red.Amin. R1 HN' R - N' p N H N P9 N N 40 CN 41 CN A further possibility for preparing compounds of the formula 41 consists of initially producing compound 42 as shown below by metallic reduction from 23 (R2 = CH 2 -OBn). 10 Double protection of hydroxy group and carboxylic acid with tert-butyl-dimethylsilyl chloride (TBSCl) and imidazole, and subsequent hydrolysis of the silyl ester affords compound 43. The cyclic aldehyde derivative 44 is obtained by reaction with osmium tetroxide and sodium periodate. Condensation with cysteine derivatives (e.g. L-cysteine methyl ester hydrochloride) and subsequent cyclization with acid activating agents such as, 15 for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) results in the diastereomeric bicycles 45 and 46. These can be separated by usual methods, for example by chromatography. Elimination of the silyl group from 45 by usual methods (e.g. tetrabutylammonium fluoride in THF) affords 47. Oxidation of the alcohol function by known processes (e.g. Dess-Martin-periodinane) and reductive amination (Nu = residue of 20 a primary or secondary amine) then produces the compounds 48. The amide is prepared 44 therefrom with ammonia and is converted with acid activating reagents (e.g. trifluoroacetic anhydride in the presence of triethylamine) into the nitrile 49. Elimination of the Boc protective group with acidic reagents (e.g. trifluoroacetic acid) then affords the compounds 41. 5 Na, NH3/THF H 1) TBSCI, imidazole N N R2 BocHN CO2H 2) K2C03, MeOH 0 42 R2 = -CH2-O-Bn TBS' OsO4, NaIO4 TBSO 1) L-CysOMe y rOH 2) EDC, NEt3 BocHN

CO

2 H 43 44 TBSO TBSO BocHN J /N + BocHN N co 2 Me Co 2 Me 45 46 HO TBAF ' }.HN >L 1) oxid. Boc BocN Ny 2) red amin. BocHN~~ 47C0 2 Me 0 8CO 2 Me 47 Nu Nu 1) NH3,. TA. s 2)TFAA BocHN N H2N N 0 0 CN CN 10 49 41 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 15 use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg and 50 mg) per day and per kilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of 10 ng to 100 ng per kilogram and per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from I ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the 5 active ingredient. Thus, ampoules for injections may contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, capsules or tablets, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. For the therapy of the abovementioned conditions, the compounds of formula I may be used as the compound itself, but they are preferably in the form of a 10 pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other 15 pharmaceutically active substances may likewise be present, including other compounds of formula I. The pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients. 20 Pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case. Coated 25 formulations and coated slow-release formulations also belong within the framework of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate. 30 Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, cachets, suckable tablets or tablets, each of which contain a defined amount of the compound of formula I; as powders or granules, as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into 5 contact. The compositions are generally produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets can be produced by tableting the compound in 10 free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one or more surface-active/dispersing agent(s) in a suitable machine. Molded tablets can be produced by molding the compound, which is in powder form and is moistened with an inert liquid diluent, in a suitable machine. 15 Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic. 20 Pharmaceutical compositions suitable for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations can preferably be produced by mixing the 25 compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound. Pharmaceutical compositions suitable for rectal administration are preferably in the form 30 of single-dose suppositories. These can be produced by mixing a compound of the formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.

Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 5 to 15% by weight of the composition, for example from 0.5 to 2%. Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active 10 ingredient in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. A particular possibility is for the active ingredient to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 318 (1986). 15 The compound(s) of formula (I) may also be administered in combination with other active ingredients. Further active ingredients suitable for combination products are: all antidiabetics mentioned in the Rote Liste 2003, chapter 12. They may be combined with 20 the compounds of the formula I of the invention in particular for a synergistic improvement of the effect. Administration of the active ingredient combination may take place either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation. Most of the active ingredients listed below are disclosed in the 25 USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001. Antidiabetics include insulin and insulin derivatives such as, for example, Lantus* (see www.lantus.com) or HMR 1964, fast-acting insulins (see US 6,221,633), GLP-1 derivatives such as, for example, those disclosed in WO 97/26265, WO 99/03861, WO 30 01/04156, WO 00/34331, WO 00/34332, WO 91/11457 and US 6,380,357 and orally effective hypoglycemic active ingredients. The orally effective hypoglycemic active ingredients include, preferably, sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase LU inhibitors, glucagon antagonists, GLP-l agonists, potassium channel openers such as, for example, those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds which 5 alter lipid metabolism, such as antihyperlipidemic active ingredients and antilipidemic active ingredients, compounds which reduce food intake, PPAR and PXR agonists and active ingredients which act on the ATP-dependent potassium channel of the beta cells. In one embodiment of the invention, the compounds of the formula I are administered in 10 combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin. In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor such as, for example, ezetimibe, 15 tiqueside, pamaqueside or compounds as described in WO 02/50027 or WO 04/007455. In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570. 20 In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR alpha agonist, such as, for example, GW 9578, GW 7647. In one embodiment of the invention, the compounds of the formula I are administered in 25 combination with a mixed PPAR alpha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT/US 00/11833, PCT/US 00/11490, DE 10142734.4. In one embodiment of the invention, the compounds of the formula I are administered in 30 combination with a fibrate such as, for example, fenofibrate, clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor such as, for example, implitapide, BMS-201038, R 103757. 5 In one embodiment of the invention, the compounds of the formula I are administered in combination with bile acid absorption inhibitor (see, for example, US 6,245,744 or US 6,221,897), such as, for example, HMR 1741. In one embodiment of the invention, the compounds of the formula I are administered in 10 combination with a CETP inhibitor, such as, for example, JTT-705. In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine, colesevelam. 15 In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer (see US 6,342,512), such as, for example, HMR1171,HMR1586. 20 In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, such as, for example, avasimibe. In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant, such as, for example, OPC-14117. 25 In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, such as, for example, NO-1886. In one embodiment of the invention, the compounds of the formula I are administered in 30 combination with an ATP-citrate lyase inhibitor, such as, for example, SB-204990. In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor, such as, for example, BMS-188494.

LO In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist, such as, for example, CI-1027 or nicotinic acid. 5 In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, such as, for example, orlistat. In one embodiment of the invention, the compounds of the formula I are administered in 10 combination with insulin. In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride. In one embodiment, the compounds of the formula I are administered in combination with a biguanide, such as, for example, metformin. 15 In one further embodiment, the compounds of the formula I are administered in combination with a meglitinide, such as, for example, repaglinide. In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione, such as, for example, troglitazone, ciglitazone, pioglitazone, 20 rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy] phenyl]methyl]-2,4-thiazolidinedione. In one embodiment, the compounds of the formula I are administered in combination with an a-glucosidase inhibitor, such as, for example, miglitol or acarbose. 25 In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide. In one embodiment, the compounds of the formula I are administered in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea 30 and metformin, with a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.

In a further embodiment, the compounds of the formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.: Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists, (e.g. naphthalene-l 5 sulfonic acid {4-[(4-aminoquinazolin-2-ylamino)methyl]- cyclohexylmethyl} amide hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino-1,2,3,4 tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7 hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-amide; (WO 01/91752)), orexin antagonists (e.g. 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl 10 urea hydrochloride (SB-334867-A)), cannabinoid 1 receptor antagonists (e.g. rimonabant or compounds as described in WO 02/28346), H3 agonists (3-cyclohexyl-1-(4,4-dimethyl 1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6-trimethylphenyl)-9H 1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585)), CRF BP antagonists (e.g. 15 urocortin), urocortin agonists, P3 agonists (e.g. 1-(4-chloro-3 methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl- 1 H-indol-6-yloxy)ethylamino] -ethanol hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g. {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2 ylcarbamoyl]-5,7-dimethylindol-1 -yl} acetic acid trifluoroacetic acid salt (WO 99/15525)), 20 serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed sertoninergic and noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g. 1-(3-ethylbenzofuran-7 yl)piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (e.g. human growth hormone), growth hormone-releasing compounds (6 benzyloxy- 1 -(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro- 1 H-isoquinoline-2 25 carboxylic acid tertiary butyl ester (WO 01/85695)), TRH agonists (see, for example, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881), DA agonists (bromocriptine, Doprexin), lipase/amylase 30 inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR-p agonists.

iU In one embodiment of the invention, the other active ingredient is leptin; see, for example, "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622. 5 In one embodiment, the other active ingredient is dexamphetamine or amphetamine. In one embodiment, the other active ingredient is a blood pressure reducing agent, such as, for example, an ACE inhibitor. In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine. In another embodiment, the other active ingredient is sibutramine. 10 In one embodiment, the other active ingredient is orlistat. In one embodiment, the other active ingredient is mazindol or phentermine. In one embodiment, the other active ingredient is rimonabant. 15 In one embodiment, the compounds of the formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob/Caromax* (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6.) Caromax is a carob containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, 20 Industriepark H6chst, 65926 Frankfurt/Main)). Combination with Caromax* is possible in one preparation or by separate administration of compounds of the formula I and Caromax*. Caromax* can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars. 25 It will be appreciated that every suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is regarded as falling within the protection conferred by the present invention.

CH

3

CH

3 0 N O 1CH 3 OH HN N 0 NH

CH

3

H

3 C CH3 J CH 3 N

CH

3 OPC-14117 0

OH

3 JTT-705 C Br Cl OH B0 SB-204990 HO N OCH 3 IN O 0 CH 3 NO-1886 0 OH

H

3 C OH

CH

3

H

3 C 0 CH 3 O C1-1027 O H3C CH 3 BMS-188494 CH3 N 0

OH

3 OH - NN 0c 0 0 G1262570 N 0 NN 110 H JTT-501 The theoretical examples listed in Table I below serve to R1 R2 X N r H N 0 CN illustrate the invention. They can be prepared in analogy to the exemplary embodiments. 5 Formula I Table I RI R2 X a H Me S b H i-Pr S c H Me SO d H Me SO 2 e H c- hexyl S f Me H S g i-Pr H S h i-Pr H SO I i-Pr Me S j S- adamantyl H S k 1- hydroxyadamant-3-yl H S 1Ph H S m 2-pyridyl H S 'n -(CH 2

)

2 -NH-2-pyridyl H S o 1,1- dimethyl-2-phenyl H S p H S qT 0 H S. r Me -CH 2

-CH(CH

2

)

2 S s Et K~iS t -CH 2

-CH

2 -OH I -0H 2

-CH(CH

3

)

2 S u -CH2-CH2-OCH3 S v -CH 2

-CH

2 ,-N(C.H3) 2

-CH

2

-CH(CH

3

)

2 S y .- CH2-CH(.CH 3

)

2

-CH

2

-CH(CH

3

)

2 S aa c-pentyl CH 2

-CH

2

-CH

3 S ba H CH 2

-CH=C(CH

3

)

3 S ca H

CH

3 S -da H CH 2

-CH

3 S ea H CH 2 0H S fa H CH 2

-O-CH

3 S ga H CH 2

-O-CH

2

-CH

3 S ha H CH 2

-S-CH

3 S Ia H CH 2

-CH

2 -N(Cli,-CH 3

)

2 S ja H CH 2

-C(CH

3

)

3 S la H

C(CH

3

)

3 S ma H CH(CH 3 )(Ph) S naH CH,--S-Ph S oa H CH 2 -O-(Cj 4 -4-CI) S pa H CH 2

-CH

2

-CH(CH

3

)

2 S qa H CH2-N(CH 3

)

2 ra H CH 2

-N(CH

2

-CH

3

)

2 S sa H S ta H S ua H S va H S wa H OH xa H OH S ya H Os S za H S ab H S bb H NH 2 S cb H r2XKNH2. S _N db H S H eb H S fb H N fb H NH -so gb H S hb H rHS ib HN ~ s jb H IS k.H F S lb HS mnb H S nb H S ob H (S pb H SF5 si qb H FS sb H FS FI

F

tb H S ub H S S vb H S wb H N S xb H S 0 yb H CI S zb H S AN ac H S 0 HO bc H No S cc H S Nko 0 cd H -CH 2

-CH(CH

3

)

2 SO ce H NH SO cf H SO cg H -CH 2

-CH(CH

3

)

2 S02 The compounds of the formula I are notable for beneficial effects on lipid and carbohydrate metabolism, in particular they lower the blood glucose level and are suitable for the treatment of type 2 diabetes, of insulin resistance, of dyslipidemias and of metabolic 5 syndrome/syndrome X. The compounds are also suitable for the prophylaxis and treatment of arteriosclerotic manifestations. The compounds can be employed alone or in combination with other blood glucose-lowering active ingredients. The compounds act as DPP-IV inhibitors and are also suitable for the treatment of disorders of wellbeing and other psychiatric indications such as, for example, depressions, anxiety states, anxiety neuroses, schizophrenia and for the treatment of disorders associated with the circadian rhythm, for weight reduction in mammals, for the treatment of immunological disorders, and for the treatment of drug abuse. They are also suitable for the treatment of cancer, arthritis, osteoarthritis, osteoporosis, 5 sleep disorders, sleep apnea, female and male sexual disorders, inflammations, acne, pigmentation of the skin, disorders of steroid metabolism, skin diseases, psoriasis, mycoses, neurodegenerative diseases, multiple sclerosis and Alzheimer's disease. The activity of the compounds was assayed as follows: 10 Measurement of the DPP-IV activity: Material: DPP-IV from porcine kidney (Sigma, Munich) 15 H-Ala-Pro-AFC (Bachem, Weil am Rhein) Assay conditions: DPP-IV (1 mU/ml, final concentration) 20 H-Ala-Pro-AFC (15pM, final concentration) in Tris/HCI (40 mM, pH 7.4), total volume 0.2 ml The reaction was carried out at room temperature for various times (typically 10 min) and 25 stopped at the end of the reaction by adding 20pl of ZnCl 2 (1M). The H-Ala-Pro-AFC conversion was determined fluorimetrically by measuring the emission at 535nm after excitation at 405nm. When inhibitors were added, the added buffer volume was adapted so that a total volume of 200pl was maintained for the assay mixture. IC50 values for inhibitors were determined by varying the inhibitor concentrations with the 30 stated substrate concentration of 15 pM. Ki and Km values were found by appropriate variation of substrate concentration and inhibitor concentration as described (Dixon, M. and Webb, E.C.(1979) Enzymes , third edition, pp. 47-206, Academic Press). The values -0 for Kin, IC50 and Ki were calculated using a commercially available software package (Leatherbarrow, R.J. (1992) GraFit Version 3.0, Erithacus Software Ltd. Staines, U.K.). The measurements yielded the following values: Exemplary embodiment No. IC-50 Remarks 1) 48 nM Trifluoroacetic acid salt 2) 47 nM Trifluoroacetic acid salt 6) 2 pM Trifluoroacetic acid salt 7) 18 nM Trifluoroacetic acid salt 8) 400 nM Trifluoroacetic acid salt 9) 110 riM Trifluoroacetic acid salt 10) 300 riM Bistrifluoroacetic acid salt 11) 500 nM Bistrifluoroacetic acid salt Exemplary embodiments 1 to 11 were prepared as follows: 1) (3R,6R,7aS)-6-Amino-6-benzyl-5-oxohexahydropyrrolo[2,1-b]thiazole-3 carbonitrile trifluoroacetate 5 / \ F

H

2 N N HO O 0 CN l a) Allyl (2S,4S)-4-benzyl-2-tert-butyl-5-oxooxazolidine-3-carboxylate 10 A mixture consisting of 5 g of (S)-phenylalanine and 30.5 ml of 1 molar sodium hydroxide solution is stirred at RT for I h and then evaporated to dryness in vacuo at 60*C. Addition of 50 ml of toluene is followed by renewed evaporation to dryness at 40*C, and the residue is suspended in 100 ml of n-pentane, mixed with 7.7 ml of trimethylacetaldehyde and stirred under reflux in an oil bath with a water trap for 15 h. 15 The volatile constituents were removed in vacuo at 40*C, and the residue is mixed with 40 ml of toluene each time and evaporated to dryness in vacuo. The residue is then suspended in 100 ml of methylene chloride and stirred in an ice bath, and 3.53 ml of allyl chloroformate are added. The mixture was stirred without renewing the ice bath while gradually reaching room temperature for 4 days. The product mixture was 20 partitioned between 100 ml of methylene chloride and 75 ml of saturated brine, the insoluble solid was removed by filtration with suction, and the organic phase was washed 3 times with saturated sodium bicarbonate solution (30 ml each time) and then once more with saturated brine, dried over sodium sulfate and concentrated in vacuo. The oily residue was purified by column chromatography (silica gel, mobile phase: 25 heptane.ethyl acetate = 45:5). Yield: 3.4 g; m.p.: oil; M+H: 274 lb) Allyl (2S,4S)-4-allyl-4-benzyl-2-tert-butyl-5-oxooxazolidine-3-carboxylate 3.16 g of allyl (2S,4S)-4-benzyl-2-tert-butyl-5-oxooxazolidine-3-carboxylate in 20 ml of tetrahydrofuran are cooled in a dry ice bath to -65*C under argon, and 20.9 ml of a 5 0.5 molar solution of potassium bistrimethylsilylamide in toluene are added dropwise, and the mixture is stirred at this temperature for 30 minutes. Then 0.861 ml of allyl bromide are added dropwise, and the mixture is stirred while gradually warming to room temperature. After being left to stand overnight, 15 ml of saturated ammonium chloride solution were added, and the product was extracted with ethyl acetate. 10 Washing of the ethyl acetate solution with saturated brine was followed by evaporation in vacuo and purification of the product by column chromatography (silica gel, mobile phase: ethyl acetate:heptane = 5:45). Yield: 2.0 g; m.p.: oil; M+H: 358 15 1c) (S)-2-Amino-2-benzylpent-4-enecarboxylic acid A mixture of 2 g of allyl (2S,4S)-4-allyl-4-benzyl-2-tert-butyl-5-oxooxazolidine-3 carboxylate, 60 ml of tetrahydrofuran, 4.88 ml of morpholine and 300 mg of tetrakis triphenylphosphinepalladium is stirred at room temperature for 20 minutes and then 20 concentrated in vacuo. The residue is stirred in a mixture of 6 ml of glacial acetic acid and 20 ml of water for 30 minutes. After the volatile constituents have been stripped off in vacuo at 40*C, the product is purified by column chromatography (silica gel, mobile phase: methylene chloride : methanol = 9:1). Yield: 680 mg m.p.: 221.2*C M+H: 206 25 ld) (S)-2-Benzyl-2-tert-butoxycarbonylaminopent-4-enecarboxylic acid 2.2 ml of IN sodium hydroxide solution are added to a solution of 450 mg of (S)-2 amino-2-benzylpent-4-enecarboxylic acid in 8 ml of dioxane and 6 ml of water, and 30 then 1.6 g of di-tert-butyl dicarbonate and 350 mg of potassium carbonate are added to the mixture, which is stirred at 40'C for 7 hours. The dioxane is then stripped off in vacuo at room temperature, and the aqueous phase is adjusted to pH = 3-4 with 10% strength citric acid and extracted with ethyl acetate (10 ml). The organic phase is dried over sodium sulfate and concentrated, and the oily residue is used unpurified for the further reactions. Yield: 490 mg m.p.: oil M+H: 306 5 1 e) Methyl (S)-2-benzyl-2-tert-butoxycarbonylaminopent-4-enecarboxylate A total of 5 ml of a 2 molar solution of trimethylsilyldiazomethane in hexane is added in portions to a solution of 490 mg of (S)-2-benzyl-2-tert-butoxycarbonylaminopent-4 enecarboxylic acid in 8 ml of methanol while stirring at room temperature. After the 10 reaction is complete, the excess trimethylsilyldiazomethane is destroyed by dropwise addition of glacial acetic acid, and the volatile constituents are stripped off in a rotary evaporator at 40*C. The residue is purified on a column (silica gel, mobile phase: methylene chloride : methanol = 95:5). Yield: 410 mg m.p.: oil M+H: 320 15 1f) Methyl (R)-2-benzyl-2-tert-butoxycarbonylamino-4-oxobutyrate 1.1 ml of a 2.5% strength solution of osmium tetroxide in tert-butanol and then, in portions, 686 mg of sodium periodate are added to a solution of 410 mg of methyl (S) 20 2-benzyl-2-tert-butoxycarbonylaminopent-4-enecarboxylate in 15 ml of tetrahydrofuran and 5 ml of water under nitrogen, and the mixture is stirred at room temperature overnight. The volatile constituents are removed in vacuo, and the residue is taken up in 26 ml of iN sodium bicarbonate solution, and the product is extracted with diethyl ether. Drying and concentration result in an oil. 25 Yield: 400 mg m.p.: oil M+H: 322 lg) (3R,6R,7aS)-6-Benzyl-6-tert-butoxycarbonylamino-5-oxohexahydropyrrolo[2,1 b]thiazole-3-carboxylic acid 30 A mixture consisting of 400 mg of methyl (R)-2-benzyl-2-tert-butoxycarbonylamino-4 oxobutyrate, 5 ml of pyridine and 166 mg of L-cysteine is heated under reflux for 4 hours. After concentration in vacuo at 50'C, the product is purified by column chromatography (silica gel, mobile phase: methylene chloride : methanol : glacial acetic acid = 90:10:1). Yield: 375 mg m.p.: oil M+H: 393 5 1h) Methyl (3R,6R,7aS)-6-benzyl-6-tert-butoxycarbonylamino-5-oxohexahydro pyrrolo[2,1 -b]thiazole-3-carboxylate A total of 1.5 ml of a 2 molar solution of trimethylsilyldiazomethane in hexane is added in portions to a solution of 250 mg of (3R,6R,7aS)-6-benzyl-6-tert 10 butoxycarbonylamino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carboxylic acid in 8 ml of methanol while stirring at room temperature. After the reaction is complete, the excess trimethylsilyldiazomethane is destroyed by dropwise addition of glacial acetic acid, and the volatile constituents are stripped off in a rotary evaporator at 40 0 C. The residue is purified on a column (silica gel, mobile phase: ethyl acetate : n-heptane = 1 15 1.5). Yield: 250 mg m.p. oil M+H: 407 li) (3R,6R,7aS)-6-Benzyl-6-tert-butoxycarbonylamino-5-oxohexahydropyrrolo[2,1 b]thiazole-3-carboxanide 20 A mixture of 170 mg of methyl (3R,6R,7aS)-6-benzyl-6-tert-butoxycarbonylamino-5 oxohexahydropyrrolo[2,1-b]thiazole-3-carboxylate and 10 ml of a 7N NH 3 solution in methanol is left to stand at room temperature overnight. The volatile constituents are stripped off in vacuo, and the residue is stirred with tert-butyl methyl ether, and the 25 solid is filtered off with suction and dried in vacuo at 40*C. Yield: 130 mg m.p.: 76.5 0 C M+H: 392 lj) tert-Butyl (3R,6R,7aS)-(6-benzyl-3-cyano-5-oxohexahydropyrrolo[2,1-b]thiazol-6 yl)-carbamate 30 100 mg of (3R,6R,7aS)-6-benzyl-6-tert-butoxycarbonylamino-5-oxohexahydro pyrrolo[2,1-b]thiazole-3-carboxamide are dissolved in 3 ml of dimethylformamide and reacted with 28.25 mg of cyanuric chloride at room temperature. After 2 hours, the 43 volatile constituents are stripped off in vacuo at 40*C, and the residue is purified on a column (silica gel, mobile phase: diisopropyl ether: methylene chloride = 100 : 10). Yield: 50 mg m.p.: oil M+H: 374 5 1k) (3R,6R,7aS)-6-Amino-6-benzyl-5-oxohexahydropyrrolo[2,1-b]thiazole-3 carbonitrile trifluoroacetate A mixture consisting of 50 mg of tert-butyl (3R,6R,7aS)-(6-benzyl-3-cyano-5-oxo hexahydropyrrolo[2,1-b]thiazol-6-yl)-carbamate, 0.1 ml of thioanisole and 1 ml of 10 trifluoroacetic acid is stirred in an ice bath for 15 minutes. After room temperature was reached, the mixture was concentrated in vacuo at 40*C, and the residue was stirred with diisopropyl ether and the solid product was filtered off with suction. Yield: 35 mg m.p.: 209*C M+H: 274 15 2) (3R,6R,7aS)-6-Amino-5-oxohexahydropyrrolo[2,1-bjthiazole-3-carbonitrile trifluoroacetate H F H

.

S F F F

H

2 N' N HO 0 0 CN 20 2a) tert-Butyl (R)-(5-hydroxy-2-oxotetrahydrofuran-3-yl)-carbamate A total of 13.4 g of sodium periodate is added in portions to a mixture consisting of 5.3 g of (R)-N-BOC-allyl-glycine, 80 ml of tetrahydrofuran, 300 ml of water and 16 ml of a 2.5% strength solution of osmium tetroxide in tert-butanol. After stirring at room 25 temperature overnight, the precipitate is filtered off with suction, and the filtrate is concentrated in vacuo. The residue is taken up in 500 ml of IN sodium bicarbonate solution and extracted with 2 portions of 250 ml of diethyl ether. The aqueous phase was adjusted to pH = 2 with 2N hydrochloric acid and again extracted with ether. The combined organic phases were dried over sodium sulfate and evaporated to dryness in 30 vacuo at room temperature. The residue was stirred with n-heptane, the solid portion of 44 product was filtered off with suction, and the filtrate was concentrated, resulting in a somewhat impure oily product. Yield: 1.58 g m.p: 112.4*C M+H: 218 Yield: 1.2 g m.p.: oil M+H: 218 5 2b) Methyl (2RS, 4R)-2-((R)-2-tert-butoxycarbonylamino-2-carboxyethyl) thiazolidine-4-carboxylate A mixture of 2.7 g of tert-butyl (R)-(5-hydroxy-2-oxotetrahydrofuran-3-yl)-carbamate, 10 46 ml of ethanol and 46 ml of water is adjusted to pH = 5 with sodium bicarbonate and, after addition of 2.2 g of L-cysteine methyl ester hydrochloride, stirred at room temperature for 3 hours. The volatile solvents were stripped off in vacuo at 40*C, the aqueous phase has a pH of about 7 and is extracted with ethyl acetate, and this organic phase is discarded. The remaining aqueous solution is adjusted to pH = 5 by adding 15 glacial acetic acid and the product is extracted with 2 portions each of 20 ml of ethyl acetate. The organic phase is dried over sodium sulfate and concentrated in vacuo. Yield: 1.2 g m.p.: resin M+H: 335 A further 2.4 g of impure product can be obtained from the aqueous phase by concentration and stirring with methylene chloride. 20 2c) Methyl (3R,6R,7aS)-6-tert-butoxycarbonylamino-5-oxohexahydropyrrolo[2,1 b]thiazole-3-carboxylate and 2d) Methyl (3R, 6R, 7aR)-6-tert-butoxycarbonylamino-5-oxohexahydropyrrolo[2,1 b]thiazole-3-carboxylate 25 A mixture consisting of 3.6 g of methyl (2RS, 4R)-2-((2R)-2-tert butoxycarbonylamino-2-carboxyethyl)-thiazolidine-4-carboxylate, 62 ml of methylene chloride, 3.3 g of 2-chloromethylpyridinium iodide and 3.6 ml of triethylamine is left to stand at room temperature for 2 days. This mixture is washed with 50 ml of iN citric 30 acid solution and then 30 ml of IN sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. Two products are obtained from the oily residue by column chromatography (silica gel, mobile phase: ethyl acetate : n-heptane = 1 : 1). (3R,6R,7aS) isomer, nonpolar compound 2c: Yield: 1080 mg m.p.: resin M+H: 317 (3R,6R,7aR) isomer, polar compound 2d: Yield: 820 mg m.p.: resin M+H: 317 5 2e) tert-Butyl (3R,6R,7aS)-(3-carbamoyl-5-oxohexahydropyrrolo[2,1-b]thiazol-6-yl) carbamate 850 mg of methyl (3R,6R,8S)-6-tert-butoxycarbonylamino-5-oxohexahydro pyrrolo[2,1-b]thiazole-3-carboxylate (2c) were dissolved in 30 ml of 7 N NH 3 solution 10 in methanol and left to stand at room temperature overnight. After concentration in vacuo at 40*C, the product was purified by stirring in tert-butyl methyl ether and filtration with suction, and dried in vacuo. Yield: 250 mg m.p.: 189.4*C M+H: 302 15 2f) tert-Butyl (3R,6R,7aR)-(3-carbamoyl-5-oxohexahydropyrrolo[2,1-b]thiazol-6-yl) carbamate was obtained in analogy to the synthesis of 2e) starting from 540 mg of methyl (3R,6R,8R)-6-tert-butoxycarbonylamino-5-oxohexahydropyrrolo[2,1-b]thiazole-3 20 carboxylate (2d). Yield: 250 mg m.p.: resin M+H: 317 2g) tert-Butyl (3R,6R,7aS)-(3-cyano-5-oxohexahydropyrrolo[2,1-b]thiazol-6-yl) carbamate 25 A solution of 538 mg of tert-butyl (3R,6R,7aS)-(3-carbamoyl-5-oxohexahydro pyrrolo[2,1-b]thiazol-6-yl)-carbamate in 35 ml of tetrahydrofuran was cooled in an ice bath and, after addition of 0.75 ml of triethylamine and 0.37 ml of trifluoroacetic anhydride, stirred at room temperature overnight. The volatile constituents were 30 stripped off in vacuo at 30'C, and the oily residue was purified by column chromatography (silica gel, mobile phase: ethyl acetate : n-heptane = 1 : 1). Yield: 320 mg m.p.: 191.2*C M+H: 284 46 2h) tert-Butyl (3R, 6R, 7aR)-(3-cyano-5-oxohexahydropyrrolo[2,1-b]thiazol-6-yl) carbamate was obtained in analogy to the synthesis of 2g), starting from 238 mg of tert-butyl 5 (3R,6R,7aR)-(3-carbamoyl-5-oxohexahydropyrrolo[2,1 -b]thiazol-6-yl)-carbamate. Yield: 130 mg m.p.: oil M+H: 284 2i) (3R,6R,7aS)-( 6-Amino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carbonitrile trifluoroacetate 10 A solution of 300 mg of tert-butyl (3R,6R,7aS)-(3-cyano-5-oxohexahydropyrrolo[2,1 b]thiazol-6-yl)-carbamate in 10 ml of methylene chloride is cooled in an ice bath, 1.5 ml of trifluoroacetic acid are added, and the mixture is stirred while gradually reaching room temperature for 2 hours. The volatile constituents were removed in 15 vacuo at 40*C, and the residue was stirred with diisopropyl ether and the solid was filtered off with suction. Yield: 280 mg m.p.: 180.3*C M+H: 184 20 3) (3R, 6R, 7aR)-( 6-Amino-5-oxohexahydropyrrolo[2,1-bJthiazole-3-carbonitrile trifluoroacetate H F H S F±F

H

2 N N HO 0 0 CN 25 was obtained in analogy to the synthesis of 2i) starting from 130 mg of tert-butyl (3R, 6R, 7aR)-(3-cyano-5-oxohexahydropyrrolo[2,1-b]thiazol-6-yl)-carbamate. Yield: 105 mg m.p.: 173.5*C M+H: 184 4/ 4) (3R,6R,7aS)-5-Oxo-6-(3-phenylpropylamino)-hexahydropyrrolo[2,1-bithiazole 3-carbonitrile H H S N" N 0 CN 5 30 mg of (3R,6R,7aS)-( 6-amino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carbonitrile trifluoroacetate, 0.0132 ml of 3-phenylpropionaldehyde and 0.115 ml of glacial acetic acid were heated in 1.5 ml of methylene chloride at 40"C for 20 minutes. The mixture was then cooled to room temperature, 8.3 mg of sodium acetate, 0.5 ml of 10 dimethoxyethane and 27.8 mg of sodium triacetoxyborohydride were added, and the mixture was stirred at RT overnight. After concentration of the mixture, the residue was purified by column chromatography (silica gel, mobile phase: ethyl acetate : n heptane = 8:1). Yield: 13 mg m.p.: oil M+H: 302 15 5) (3R,6R,7aS)-6-Benzylamino-5-oxohexahydropyrrolo[2,1-bthiazole-3 carbonitrile trifluoroacetate 20 20 mg of (3R,6R,7aS)-6-amino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carbonitrile trifluoroacetate were dissolved in 1 ml of 1,2-dichloroethane. 2 pl of acetic acid, 7 pl of benzaldehyde and 29 mg of sodium triacetoxyborohydride were successively added. The mixture was heated at 45*C for 2 h. The solvent was then removed in vacuo. The residue was purified by preparative HPLC (Merck RP18, acetonitrile/water (0.5% 25 trifluoroacetic acid), linear gradient (0->80% acetonitrile)). Yield: 5 mg of (3R,6R,(S)-6-benzylamino-5-oxohexahydropyrrolo[2,1-b]thiazole-3 carbonitrile trifluoroacetate MS: 274 (M+H) 46 6) (3R,6R,7aS)-6-Cyclopentylamino-5-oxohexahydropyrrolo[2,1-bjthiazole-3 carbonitrile trifluoroacetate 20 mg of (3R,6R,7aS)-6-amino-5-oxohexahydropyrrolo[2, 1 -b]thiazole-3-carbonitrile 5 trifluoroacetate were dissolved in 1 ml of 1,2-dichloroethane. 2 pl of acetic acid, 6 pd of cyclopentanone and 29 mg of sodium triacetoxyborohydride were successively added. The mixture was heated at 45*C for 2 h. The solvent was then removed in vacuo. The residue was purified by preparative HPLC (Merck RP18, acetonitrile/water (0.5% trifluoroacetic acid), linear gradient (0->80% acetonitrile)). 10 Yield: 15 mg of 6-cyclopentylamino-5-oxohexahydropyrrolo[2,1-b]thiazole-3 carbonitrile trifluoroacetate MS: 252 (M+H) 15 7) (3R,6R,7aS)-6-Amino-6-isobutyl-5-oxohexahydropyrrolo[2,1-bIthiazole-3 carbonitrile trifluoroacetate H F H2N N FtF 0 CNHO 0 20 7a) tert-Butyl (3S,5S,6R)-3-allyl-2-oxo-5,6-diphenylmorpholine-4-carboxylate 10 g of tert-butyl (5S,6R)-2-oxo-5,6-diphenylmorpholine-4-carboxylate were dissolved in 200 ml of THF and cooled to -78*C. 63 ml of a 0.5 M solution of KHMDS in toluene were added dropwise and, after stirring for 10 min, 3.7 ml of allyl bromide 25 were added dropwise. The mixture was allowed to warm from -78'C to -20*C over the course of 3 h, and the reaction was then stopped by adding 300 ml of a saturated ammonium chloride solution. 200 ml of ethyl acetate were added, and the phases were separated. The aqueous phase was extracted 3 times with 100 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO 4 . The solvents were 30 removed in vacuo and the residue was stirred with diisopropyl ether.

49 Yield: 7.3 g of tert-butyl (3S,5S,6R)-3-allyl-2-oxo-5,6-diphenylmorpholine-4 carboxylate MS: 338 (M+H-tBu) 5 7b) tert-Butyl (3R,5S,6R)-3-allyl-3-isobutyl-2-oxo-5,6-diphenylmorpholine-4 carboxylate 1 g of tert-butyl (3R,5S,6R)-3-allyl-2-oxo-5,6-diphenylmorpholine-4-carboxylate was dissolved in 20 ml of THF. 3 ml of 15-crown-5 were added, and the mixture was 10 cooled to -78 0 C. Then 1.4 ml of a 2 M solution of NaHMDS in THF were added dropwise. The mixture was stirred for 10 min and then 300 pl of isobutyl iodide were added dropwise. The temperature was allowed to rise to 0*C over the course of 6 h, and then the reaction was stopped by adding 50 ml of saturated ammonium chloride solution. The aqueous phase was extracted 3 times with 50 ml of ethyl acetate each 15 time, and the combined organic phases were dried with MgSO 4 . The solvents were removed in vacuo and the residue was chromatographed on silica gel with heptane/ethyl acetate 10:1. Yield: 620 mg of tert-butyl (3R,5S,6R)-3-allyl-3-isobutyl-2-oxo-5,6-diphenyl morpholine-4-carboxylate 20 MS: 394 (M+H-tBu) 7c) (R)-2-tert-Butoxycarbonylamino-2-isobutylpent-4-enoic acid 60 ml of ammonia were condensed at -78*C. Then 624 mg of sodium were added in 2 25 portions at an interval of 10 min. The mixture was stirred for 20 min. At -60*C, a solution of tert-butyl (3R,5S,6R)-3-allyl-3-isobutyl-2-oxo-5,6-diphenylmorpholine-4 carboxylate 1.22 g and 1.6 ml of ethanol in 20 ml of THF was added dropwise thereto. The mixture was stirred at -45'C for 1.5 h, and the reaction was stopped by adding solid ammonium chloride until the blue color disappeared. The ammonia is then 30 allowed to evaporate off, and 50 ml of water are added to the residue. The THF is removed in vacuo. The aqueous is adjusted to pH 2 with 1 N HCl and extracted 3 times with 60 ml of ethyl acetate each time. The combined organic phases are dried with 50 MgSO 4 . The solvents are removed in vacuo and the residue is purified by chromatography on silica gel. Yield: 508 mg of (R)- 2 -tert-butoxycarbonylamino-2-isobutylpent-4-enoic acid MS: 172 (M+H-Boc) 5 7d) Methyl (3R,6R,7aS)-6-tert-butoxycarbonylamino-6-isobutyl-5-oxohexahydro pyrrolo[2, I -b]thiazole-3-carboxylate and 7e) Methyl (3R,6R,7aR)-6-tert-butoxycarbonylamino-6-isobutyl-5-oxohexahydro 10 pyrrolo[2, 1 -b]thiazole-3-carboxylate 500 mg of (R)-2-tert-butoxycarbonylamino-2-isobutylpent-4-enoic acid were dissolved in 20 ml of THF and 5 ml of water. A solution of 24 mg of osmium tetroxide in 2 ml of THF was added dropwise thereto and, after stirring for 5 min, 985 mg of sodium 15 periodate were added. The mixture was stirred for 3 h and then filtered through kieselguhr. The filter cake was washed twice with 10 ml of THF each time. The THF was removed in vacuo, and the residue was partitioned between 60 ml of ethyl acetate and 30 ml of water. The pH was adjusted to 2 with 1 N HCI solution. The phases were separated and the aqueous phase was extracted twice with 20 ml of ethyl acetate each 20 time. The combined organic phases were dried with MgSO 4 and the solvents were removed in vacuo. The residue was chromatographed on silica gel with 5% methanol in dichloromethane. This resulted in 410 mg of the cyclic aldehyde derivative which were dissolved in 10 ml of dichloromethane. While stirring, 230 sl of triethylamine and 258 mg of L-cysteine methyl ester hydrochloride were added. The mixture was stirred 25 at room temperature for 2.5 h and then 317 mg of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride were added. After stirring at room temperature for 14 hours, the reaction was diluted with 80 ml of dichloromethane and washed twice with 80 ml of water each time. The organic phase was dried with MgSO 4 and the solvents were removed in vacuo. The diastereomeric compounds methyl (3R,6R,7aS)-6-tert 30 butoxycarbonylamino-6-isobutyl-5-oxohexahydropyrrolo[2, 1-b]thiazole-3-carboxylate and methyl 3R,6R,7R-6-tert-butoxycarbonylamino-6-isobutyl-5 oxohexahydropyrrolo[2,1-b]thiazole-3-carboxylate were separated by chromatography on silica gel.

51 Yield: 75 mg of 7d) methyl (3R,6R,7aS)-6-tert-butoxycarbonylamino-6-isobutyl-5 oxohexahydropyrrolo[2, I -b]thiazole-3-carboxylate MS: 373 (M+H) and 5 304 mg of 7e) methyl (3R,6R,7aR)-6-tert-butoxycarbonylamino-6-isobutyl-5-oxo hexahydropyrrolo[2,1-b]thiazole-3-carboxylate MS: 373 (M+H) 7f) (3R,6R,7aS)-6-tert-Butoxycarbonylamino-6-isobutyl-5-oxohexahydropyrrolo[2,1 10 b]thiazole-3-carboxamide 71 mg of methyl (3R,6R,7aS)-6-tert-butoxycarbonylamino-6-isobutyl-5-oxo hexahydropyrrolo[2,1-b]thiazole-3-carboxylate were dissolved in 10 ml of ammonia saturated methanol and cooled to 0*C. The mixture was allowed slowly to reach room 15 temperature and was stirred for 14 h. The solvents were removed in vacuo. The crude product was employed without further purification in the next reaction. MS: 302 (M+H-tBu) 7g) tert-Butyl (3R,6R,7aS)-(3-cyano-6-isobutyl-5-oxohexahydropyrrolo[2,1-b]thiazole 20 6-yl)-carbamate The crude product from 2e was dissolved in 5 ml of THF. 63 pl of triethylamine and 29 i of trifluoroacetic anhydride were added thereto. The mixture was stirred at room temperature for 3 h and then partitioned between 60 ml of water and 60 ml of ethyl 25 acetate. The aqueous phase was extracted twice with 50 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO 4 . The solvents were removed in vacuo and the residue was purified by chromatography on silica gel. Yield: 57 mg of tert-butyl (3R,6R,7aS)-(3-cyano-6-isobutyl-5-oxohexahydro pyrrolo[2,1 -b]thiazol-6-yl)-carbamate 30 MS: 284 (M+H-tBu) 7h) (3R,6R,7aS)-6-Amino-6-isobutyl-5-oxohexahydropyrrolo[2,1-blthiazole-3 carbonitrile trifluoroacetate 52 53 mg of tert-butyl (3R,6R,7aS)-(3-cyano-6-isobutyl-5-oxohexahydropyrrolo[2,1 b]thiazol-6-yl)-carbamate were reacted with 3 ml of trifluoroacetic acid and 600 tl of thioanisole at 0*C for 30 min. The solvents were then removed in vacuo, and the 5 residue was stirred in diethyl ether, filtered off with suction and dried. Yield: 39 mg of (3R,6R,7aS)-6-amino-6-isobutyl-5-oxohexahydropyrrolo[2,1 b]thiazole-3-carbonitrile trifluoroacetate MS: 240 (M+H) 10 7i) (3R,6R,7aR)-6-Amino-6-isobutyl-5-oxohexahydropyrrolo[2,1-b]thiazole-3 carbonitrile trifluoroacetate H ES F N N F t F o

CONH

2 O O was obtained in analogy to Examples 7f), 7g) and 7h) starting from the diastereomer 15 7e). MS: 240 (M+H) 8) (3R,6S,7aS)-6-Amino-6-hydroxymethyl-5-oxohexahydropyrrolo[2,1-bJthiazole 20 3-carbonitrile trifluoroacetate H H-O S F

H

2 NF- F 0 CNHO 25 8a) 3-tert-Butyl 4-methyl 4-allyl-2,2-dimethyloxazolidine-3,4-dicarboxylate 10 g of 3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate were dissolved in 270 ml of THF. After cooling to -78*C, 100 ml of a 0.5 M solution of KHMDS in toluene were added dropwise. After stirring at -78*C for 30 min, 5.4 ml of allyl bromide were added dropwise. The mixture was allowed slowly to reach room 5 temperature and was stirred for 14 h. The reaction was then stopped by adding 400 ml of saturated ammonium chloride solution. The THF was removed in vacuo and the aqueous phase was extracted 3 times with 150 ml of ethyl acetate each time. The combined organic phases were washed once with 300 ml of saturated sodium chloride solution and dried with MgSO 4 . The solvents were removed in vacuo and the residue 10 was chromatographed on silica gel. Yield: 5.58 g of 3-tert-butyl 4-methyl 4-allyl-2,2-dimethyloxazolidine-3,4 dicarboxylate MS: 322 (M+Na) 15 8b) tert-Butyl 8-hydroxy-2,2-dimethyl-6-oxo-3,7-dioxa-1-azaspiro[4.4]nonane-1 carboxylate N OH N boc 0 20 1.7 g of 3-tert-butyl 4-methyl 4-allyl-2,2-dimethyloxazolidine-3,4-dicarboxylate were dissolved in 20 ml of methanol and 8 ml of 1 N NaOH were added. The mixture was heated at 60*C for 3 h, allowed to cool, and the methanol was removed in vacuo. The pH of the aqueous phase was adjusted to 2 with 1 N HCl, and it was extracted 3 times 25 with 50 ml of dichloromethane each time. The combined organic phases were dried with MgSO 4 , and the solvent was removed in vacuo. The residue was taken up in 80 ml of dichloromethane and 10 ml of methanol. The solution was cooled to -78'C, and ozone was passed through until it assumed a pale blue color. Argon was then passed through until the blue color had completely disappeared. 3 ml of dimethyl sulfide were 30 added, and the mixture was allowed to reach room temperature overnight. The solvents 54 were then removed in vacuo. The crude product obtained in this way was employed directly in the next reaction. 8c) Acetonide of (3R,6S,7aS)-6-(tert-butyloxycarbonylamino)-6-hydroxymethyl-5 5 oxohexahydropyrrolo[2,1 -b)thiazole-3-carboxamide OH H S N bocO N 0

CONH

2 The crude product from 8b was dissolved in 40 ml of ethanol. The solution was cooled to 0*C and, under argon, 500 mg of sodium bicarbonate in 5 ml of water, and 1 g of L 10 cysteine methyl ester hydrochloride were added. The pH of the solution was adjusted to 6.5 with 1% sodium bicarbonate solution in water. The mixture was allowed slowly to reach room temperature and was stirred for 14 h. The volume was then reduced to about one half in vacuo. The pH was adjusted to 6 with 1 N HCl, and the aqueous phase was extracted with 70 ml of ethyl acetate. This procedure was repeated three 15 times. The combined organic phases were dried with MgSO 4 . The solvents were then removed in vacuo. The residue was taken up in 400 ml of 1,2-dichloroethane, and 1.7 g of 2-chloro-1-methylpyridinium iodide and 1.9 ml of triethylamine were added. The mixture was heated at 50*C for 4 h. It is then washed once with 150 ml of 1 N HCl and 150 ml of saturated sodium bicarbonate solution. The organic phase is dried with 20 MgSO 4 . The solvents are removed in vacuo, and the residue is taken up in 60 ml of ammonia-saturated methanol. The mixture was stirred for 18 h, the solvents were removed in vacuo, and the residue was. chromatographed on silica gel. Yield: 230 mg of the compound of the above formula MS: 316 (M+H-tBu) 25 8d) Acetonide of (3R,6S,7aS)-6-(tert-butyloxycarbonylamino)-6-hydroxymethyl-5 oxohexahydropyrrolo[2,1-b)thiazole-3-carbonitrile 55 0- H N boc 0 N 200 mg of the compound 8c were dissolved in 5 ml of THF. 188 pl of triethylamine and 114 pil of trifluoroacetic anhydride were successively added. The mixture was then 5 stirred at room temperature for 6 h. The solution was partitioned between 60 ml of saturated sodium bicarbonate solution and 60 ml of ethyl acetate. The aqueous phase was extracted twice with 30 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO 4 . The solvents were removed in vacuo and the residue was purified by chromatography on silica gel. 10 Yield: 90 mg of the acetonide of the above formula MS: 240 8e) (3R,6S,7aS)-6-Amino-6-hydroxymethyl-5-oxohexahydropyrrolo[2, 1 -b]thiazole-3 carbonitrile trifluoroacetate 15 5 mg of the compound 8d were dissolved in 2 ml of dichloromethane and cooled to 0*C. 300 pl of TFA were added, and the mixture was stirred at 0*C for 4 h. The solvents were then removed in vacuo, and the residue was stirred with diethyl ether. Yield: 5 mg 20 MS: 214 (M+H) 9) (3R,6S,7aS)-6-Amino-5-oxo-6-piperidin-1-ylmethyl)-hexahydropyrrolo[2,1 b]thiazole-3-carbonitrile bistrifluoroacetate 25 F C N H S F- F H ot S F ±FF

H

2 0 F-FFH O 0

CONH

2 HO 0 56 9a) tert-Butyl (3S,5S,6R)-3-allyl-3-benzyloxymethyl-2-oxo-5,6-diphenylmorpholine-4 carboxylate 5.7 g of tert-butyl 3S,5 S,6R-3-allyl-2-oxo-5,6-diphenylmorpholine-4-carboxylate were 5 dissolved in 150 ml of THF. 8.6 ml of 15-crown-5 were added and the mixture was cooled to -78*C. Then 8 ml of a 2 M solution of NaHMDS in THF were added dropwise. The mixture was stirred for 10 min and then 6.7 ml of benzyloxymethyl chloride were added dropwise. The mixture was allowed to warm to 0*C over the course of 6 h, and then the reaction was stopped by adding 200 ml of saturated 10 ammonium chloride solution. The aqueous phase was extracted 3 times with 150 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO 4 . The solvents were removed in vacuo, and the residue was chromatographed on silica gel with heptane/ethyl acetate 10:1. Yield: 620 mg of tert-butyl (3S,5S,6R)-3-allyl-3-benzyloxymethyl-2-oxo-5,6-diphenyl 15 morpholine-4-carboxylate MS: 458 (M+H-tBu) 9b) (S)-2-tert-Butoxycarbonylamino-2-hydroxymethylpent-4-enoic acid 20 450 ml of ammonia were condensed at -78*C. 4.4 g of sodium were added in 4 portions at an interval of 10 min each time, and the mixture was stirred for 20 min. At -60*C, a solution of 9.8 g of tert-butyl (3S,5S,6R)-3-allyl-3-benzyloxymethyl-2-oxo 5,6-diphenylmorpholine-4-carboxylate and 11.2 ml of ethanol in 150 ml of THF was added dropwise thereto. The mixture was stirred at -45'C for 1.5 h, and the reaction 25 was stopped by adding solid ammonium chloride until the blue color disappeared. The ammonia was then allowed to evaporate off, and 400 ml of water were added to the residue. The THF was removed in vacuo. The aqueous was adjusted to pH 2 with I N HCl and extracted 3 times with 200 ml of ethyl acetate each time. The combined organic phases were dried with MgSO 4 . The solvents were removed in vacuo and the 30 residue was purified by chromatography on silica gel. Yield: 2.6 g of (S)-2-tert-butoxycarbonylamino-2-hydroxymethylpent-4-enoic acid MS: 146 (M+H-Boc) 57 9c) (S)-2-tert-Butoxycarbonylamino-2-(tert-butyldimethylsilanyloxymethyl)-pent-4 enoic acid 1.3 g of (S)-2-tert-butoxycarbonylamino-2-hydroxymethylpent-4-enoic acid were 5 dissolved in 10 ml of dimethylformamide. 1.44 g of imidazole and 1.7 g of tert-butyl dimethylsilyl chloride were added thereto. The mixture was stirred at room temperature for 14 h and then partitioned between 150 ml of water and 200 ml of diethyl ether. The aqueous phase was extracted twice with 100 ml of diethyl ether each time, and the combined organic phases were dried with MgS04. The solvents were removed in vacuo 10 and the residue was taken up in 20 ml of THF and 60 ml of methanol. 11 ml of a 1 M potassium carbonate solution were added, and the mixture was stirred at room temperature for 2 h. Then 150 ml of a saturated sodium chloride solution were added, and the pH of the solution was adjusted to 2 with 1 M HCL solution. The aqueous phase was extracted 3 times with 100 ml of ethyl acetate each time, and the combined 15 organic phases were dried with MgSO 4 . The solvents were removed in vacuo, and the crude product was employed without further purification in the next reaction. Yield: 1.8 g of (S)-2-tert-butoxycarbonylamino-2-(tert-butyldimethyl silanyloxymethyl)-pent-4-enoic acid MS: 260 (M+H-Boc) 20 9d) Methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-6-(tert-butyldimethyl silanyloxymethyl)-5-oxohexahydropyrrolo[2, 1 -b]thiazole-3-carboxylate and 9e) Methyl (3R,6S,7aR)-6-tert-butoxycarbonylamino-6-(tert-butyldimethyl 25 silanyloxymethyl)-5-oxohexahydropyrrolo[2, 1 -b]thiazole-3-carboxylate 3.7 g of (S)-2-tert-butoxycarbonylamino-2-(tert-butyldimethylsilanyloxymethyl)-pent 4-enoic acid were dissolved in 1220 ml of THF and 30 ml of water. 131 mg of osmium tetroxide were added, and the mixture was stirred for 5 min. Then 5.5 g of sodium 30 periodate were added. The mixture was stirred at room temperature for 2 h and then filtered through kieselguhr. The filter cake was washed twice with 30 ml of THF each time. The THF was then removed in vacuo, and the residue was partitioned between 150 ml of diethyl ether and 100 ml of saturated sodium bicarbonate solution. The 58 aqueous phase was adjusted to pH 1 with 1 N HCl and extracted 3 times with 100 ml of ethyl acetate each time. The combined organic phases were dried with MgSO 4 . The solvents were removed in vacuo, and the residue was taken up in 40 ml of ethanol. The mixture was cooled to -20*C and, under argon, 864 mg of sodium bicarbonate 5 dissolved in 40 ml of water were added. Then 1.77 g of L-cysteine methyl ester hydrochloride were added, and the pH of the solution was adjusted to 6.5 with 1% strength sodium bicarbonate solution. The mixture was stirred at room temperature for 14 h. The solution was then concentrated in vacuo to half the volume. The pH was adjusted to 6 with 1 N HCl, and the solution was extracted with 100 ml of ethyl acetate. 10 Adjustment of the pH to 6 and extraction with ethyl acetate was repeated 3 times. The combined organic phases were dried with MgSO 4 . The solvents were removed in vacuo, and the residue was taken up in 200 ml of THF. 3.2 ml of triethylamine and 2.9 g of 1-(3-dimethylaininopropyl)-3-ethylcarbodiimide hydrochloride were added. The mixture was then stirred at room temperature for 1 h and at 50*C for 3 h. The solvent 15 was removed in vacuo, and the residue was partitioned between 100 ml of 1 N HCl and 100 ml of ethyl acetate. The aqueous phase was extracted twice with 50 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO 4 . The solvents were removed in vacuo, and the residue was purified by chromatography on silica gel. 20 Yield: 340 mg of 9d) methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-6-(tert-butyl dimethylsilanyloxyrnethyl)-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carboxylate MS: 405 (M+H-tBu) and 1.1 g of 9e) methyl (3R,6S,7aR)-6-tert-butoxycarbonylamino-6-(tert-butyldimethyl 25 silanyloxymethyl)-5-oxohexahydropyrrolo[2, 1 -b]thiazole-3-carboxylate MS: 405 (M+H-tBu) 9f) Methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-6-hydroxymethyl-5-oxo hexahydropyrrolo[2, 1 -b]thiazole-3-carboxylate 30 337 mg of methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-6-(tert-butyldimethyl silanyloxymethyl)-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carboxylate were dissolved in 10 ml of THF and cooled to 0*C. A 1 M solution of tetrabutylammonium fluoride 59 was added dropwise, and the mixture was allowed to reach room temperature within 2 h. It was then partitioned between 120 ml of saturated ammonium chloride solution and 120 ml of ethyl acetate. The aqueous phase was extracted twice with 40 ml of ethyl acetate each time. The combined organic phases were washed once with 80 ml of 5 saturated sodium chloride solution and dried with MgSO 4 . The solvents were removed in vacuo, and the residue was purified by chromatography on silica gel. Yield: 180 mg of methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-6-hydroxymethyl-5 oxohexahydropyrrolo[2, 1 -b]thiazole-3-carboxylate MS: 291 (M+H-tBu) 10 9g) Methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-piperidin-1-ylmethyl) hexahydropyrrolo[2, 1 -b]thiazole-3-carboxylate 170 mg of methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-6-hydroxymethyl-5-oxo 15 hexahydropyrrolo[2,1-b]thiazole-3-carboxylate were dissolved in 5 ml of dichloromethane. 400 pl of pyridine and 230 mg of Dess-Martin-periodinane were added. The mixture was then stirred at room temperature for 2 h. The solution was partitioned between 20 ml of 0.5 M HCl and 20 ml of dichloromethane. The aqueous phase was extracted twice with 10 ml of dichloromethane each time, and the combined 20 organic phases were dried with MgSO 4 . The solvent was removed in vacuo, and the residue was taken up in 5 ml of 1,2-dichloroethane. 49 pl of piperidine, 15 pl of acetic acid and 209 mg of sodium triacetoxyborohydride were successively added. The mixture was then stirred at room temperature for 14 h. The solution was partitioned between 30 ml of saturated sodium bicarbonate solution and 20 ml of dichloromethane. 25 The aqueous phase was extracted twice with 10 ml of dichloromethane each time, and the combined organic phases were dried with MgSO 4 . The solvents were removed in vacuo and the residue was chromatographed on silica gel. Yield: 30 mg of methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-piperidin-1 ylmethyl)-hexahydropyrrolo[2,1-b]thiazole-3-carboxylate 30 MS: 414 (M+H) 9h) (3R,6S,7aS)-6-Amino-5-oxo-6-(piperidin-1-ylmethyl)-hexahydropyrrolo[2,1 b]thiazole-3-carbonitrile bistrifluoroacetate 60 30 mg of methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-(piperidin- 1-yl methyl)-hexahydropyrrolo[2,1-b]thiazole-3-carboxylate were dissolved at 0*C in 30 ml of ammonia-saturated methanol. The solution was allowed to reach room temperature over the course of 4 h, and then the solvents were removed in vacuo. The residue was 5 taken up in 5 ml of THF, and 40 pl of triethylamine and 20 pl of trifluoroacetic anhydride were successively added. The mixture was stirred at room temperature for 2 h and then a further 40 pl of triethylamine and 20 pl of trifluoroacetic anhydride were added. Stirring for 2 h was followed by partition between 60 ml of 0.5 M HCl and 60 ml of ethyl acetate. The aqueous phase was extracted twice with 20 ml of ethyl 10 acetate each time, and the combined organic phases were washed once with 30 ml of saturated sodium bicarbonate solution. After drying with MgSO 4 , the solvents were removed in vacuo. The residue was taken up in a mixture of I ml of trifluoroacetic acid and 200 pl of thioanisole and stirred at room temperature for 20 min. The trifluoroacetic acid was then removed in vacuo, and the residue was chromatographed 15 on silica gel with dichloromethane/methanol/acetic acid/water 100:10:1:1. Yield: 31 mg of (3R,6S,7aS)-6-amino-5-oxo-6-piperidin-1-ylmethylhexahydro pyrrolo[2,1-b]thiazole-3-carbonitrile bistrifluoroacetate. MS: 281 (M+H) 20 9i) (3R,6S,7aR)-6-Amino-5-oxo-6-(piperidin-1-ylmethyl)-hexahydropyrrolo[2,1 b]thiazole-3-carbonitrile bistrifluoroacetate F O H FF F HO FO

H

2 N N 0 CONH 2 HO 0 25 was prepared analogously to Examples 9f), 9g) and 9h) starting from the diastereomer 9e). MS: 281 (M+H) 61 10) (3R,6S,7aS)-6-Amino-5-oxo-6-(piperidin-4-yl)-hexahydropyrrolo[2,1 bjthiazole-3-carbonitrile bistrifluoroacetate F H F---F H N HO 0 ,, F H2N N F- F 0 CN HO 0 5 10a) 2-Tnmethylsilanylethyl 4-hydroxypiperidine-1-carboxylate 6.9 g of 4-hydroxypiperidine were dissolved in 150 ml of THF. 19.4 g of 2 (trimethylsilyl)ethyl 4-nitrophenyl carbonate and 11.9 ml of N,N-diisopropylethyl 10 amine were successively added thereto. The mixture was stirred at room temperature for 1 h and then the solvent was removed in vacuo. The residue was taken up in 400 ml of ethyl acetate and washed once with 200 ml of 0.5 N HCl and twice with 200 ml of 1 N NaOH each time. The organic phase was dried with MgSO 4 , the solvent was removed in vacuo, and the residue was purified by chromatography on silica gel. 15 Yield: 15.4 g of 2-trimethylsilanylethyl 4-hydroxypiperidine-1-carboxylate MS: 218 (M+H-C2H4) 10b) 2-Trimethylsilanylethyl 4-iodopiperidine-1-carboxylate 20 12.5 g of 2-trimethylsilanylethyl 4-hydroxypiperidine-1-carboxylate were dissolved in 136 ml of dichloromethane and 264 ml of tetrachloromethane. The solution was cooled to 0*C and then 16 g of triphenylphosphine, 4.2 g of imidazole and 15.8 g of iodine were successively added. The mixture was slowly allowed to reach room temperature and was stirred for 14 h. Then 300 ml of a saturated sodium thiosulfate solution were 25 added to the solution. The mixture was stirred until it was colorless. The aqueous phase was then extracted twice with 200 ml of dichloromethane each time. The combined organic phases were washed once with 200 ml of a saturated sodium thiosulfate solution and once with 200 ml of a saturated sodium chloride solution. After drying 62 with MgSO 4 , the solvents were removed in vacuo, and the residue was purified by chromatography on silica gel. Yield: 8 g of 2-trimethylsilanylethyl 4-iodopiperidine-1-carboxylate MS: 328 (M+H-C2H4) 5 10c) tert-Butyl (3R,5R,6S)-2-oxo-5,6-diphenyl-3-[1-(2-trimethylsilanyl ethoxycarbonyl)-piperidin-4-yl]morpholine-4-carboxylate 4 g of tert-butyl (5S,6R)-2-oxo-5,6-diphenylmorpholine-4-carboxylate were dissolved 10 in 50 ml of THF. 9 ml of 15-crown-5 were added, and the mixture was cooled to -78*C. Then 6.8 ml of a 2 M solution of NaHMDS in THF were added dropwise. The mixture was stirred for 10 min and then 8 g of 2-trimethylsilanylethyl 4-iodopiperidine-1 carboxylate were added dropwise. The mixture was allowed to warm to 0*C over the course of 6 h, and then the reaction was stopped by adding 200 ml of saturated 15 ammonium chloride solution. The aqueous phase was extracted 3 times with 150 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO 4 . The solvents were removed in vacuo, and the residue was chromatographed on silica gel. Yield: 1.82 g of tert-butyl (3R,5R,6S)-2-oxo-5,6-diphenyl-3-[1-(2-trimethylsilanyl ethoxycarbonyl)piperidin-4-yl]morpholine-4-carboxylate 20 MS: 497 (M+H-C2H4-tBu) 10d) tert-Butyl (3S,5R,6S)-3-allyl-2-oxo-5,6-diphenyl-3-[1-(2-trimethylsilanyl ethoxycarbonyl)piperidin-4-yl]morpholine-4-carboxylate 25 1.8 g of tert-butyl (3R,5R,6S)-2-oxo-5,6-diphenyl-3-[1-(2-trimethylsilanyl ethoxycarbonyl)piperidin-4-yl]morpholine-4-carboxylate were dissolved in 20 ml of THF. 2.5 ml of 15-crown-5 were added, and the mixture was cooled to -78*C. Then 1.9 ml of a 2 M solution of NaHMDS in THF were added dropwise. The mixture was stirred for 10 min and then 805 pl of allyl bromide were added dropwise. The mixture 30 was allowed to warm to 0*C over the course of 6 h, and then the reaction was stopped by adding 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted 3 times with 100 ml of ethyl acetate each time, and the combined organic 63 phases were dried with MgSO 4 . The solvents were removed in vacuo, and the residue was chromatographed on silica gel. Yield: 916 mg of tert-butyl (3S,5R,6S)-3-allyl-2-oxo-5,6-diphenyl-3-[1-(2 trimethylsilanylethoxycarbonyl)piperidin-4-yl]morpholine-4-carboxylate 5 MS: 593 (M+H-C2H4) 1 Oe) 2-Trimethylsilanylethyl 4-((S)- 1 -tert-butoxycarbonylamino- 1 -methoxycarbonyl but-3-enyl)piperidine-1-carboxylate 10 50 ml of ammonia were condensed at -78*C. 340 mg of sodium were added in 2 portions at an interval of 10 min in each case and the mixture was stirred for 20 min. At -60'C, a solution of 916 mg of tert-butyl (3S,5R,6S)-3-allyl-2-oxo-5,6-diphenyl-3-[1 (2-trimethylsilanylethoxycarbonyl)piperidin-4-yl]morpholine-4-carboxylate and 866 pl of ethanol in 50 ml of THF was added dropwise. The mixture was stirred at -45*C for 15 1.5 h, and the reaction was stopped by adding solid ammonium chloride until the blue color disappeared. The ammonia was then allowed to evaporate off, and 150 ml of water were added to the residue. The THF was removed in vacuo. The aqueous solution was adjusted to pH 2 with 1 N HCl and extracted 3 times with 100 ml of ethyl acetate each time. The combined organic phases were dried with MgSO 4 . The solvents 20 were removed in vacuo, and the residue was filtered through silica gel with 4% methanol in dichloromethane. The product obtained in this way was taken up in 5 ml of methanol and cooled to 0*C. 0.5 ml of a 2 N solution of trimethylsilyldiazomethane in hexane was added thereto 5 times at intervals of 1.5 hours each. 2 ml of acetic acid were then added dropwise, and the mixture was stirred at room temperature for 1 h. 25 The solvents were removed in vacuo and the residue was chromatographed on silica gel. Yield: 233 mg of 2-trimethylsilanylethyl 4-((S)- 1 -tert-butoxycarbonylamino- 1 methoxycarbonylbut-3-enyl)piperidine-1-carboxylate MS: 373 (M+H-C2H4-tBu) 30 1 Of) (3R,6S,7aS)-6-tert-Butoxycarbonylamino-5-oxo-6-[1-(2-trimethylsilanyl ethoxycarbonyl)piperidin-4-yl]hexahydropyrrolo[2,1-b]thiazole-3-carboxylic acid 64 230 mg of 2-trimethylsilanylethyl 4-((S)- 1 -tert-butoxycarbonylamino- 1 methoxycarbonylbut-3-enyl)piperidine-1-carboxylate were dissolved in 25 ml of THF and 5 ml of water. Under argon, 157 /l of a 4% strength solution of osmium tetroxide in water and 269 mg of sodium periodate were added. The mixture was stirred at room 5 temperature for 2 h and then filtered through kieselguhr. The filter cake was washed twice with 10 ml of THF each time. The THF was removed in vacuo, and the residue was partitioned between 20 ml of ethyl acetate and 10 ml of a saturated sodium chloride solution. The aqueous phase was extracted twice with 10 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO 4 . The solvents 10 were removed in vacuo, and the residue was taken up in 15 ml of pyridine. 61 mg of L cysteine were added, and the mixture was heated at 1 00*C for 24 h. The pyridine was then removed in vacuo, and the residue was chromatographed on silica gel. Yield: 230 mg of (3R,6S,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2 trimethylsilanylethoxycarbonyl)piperidin-4-yl]hexahydropyrrolo[2, 1-b]thiazole-3 15 carboxylic acid MS: 446 (M+H-C2H4-tBu) 10g) Methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2-trimethylsilanyl ethoxycarbonyl)piperidin-4-yl]hexahydropyrrolo[2, 1 -b]thiazole-3-carboxylate 20 223 mg of (3R,6S,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2-trimethylsilanyl ethoxycarbonyl)piperidin-4-yl]hexahydropyrrolo[2,1-b]thiazole-3-carboxylic acid were dissolved in 10 ml of methanol and 10 ml of diethyl ether and cooled to 0*C. 400 41 portions of a 1 N solution of trimethylsilyldiazomethane in hexane were added 25 dropwise twice at an interval of 1.5 h. The mixture was stirred for 2 h and then 1 ml of acetic acid was added dropwise. After 1 h, the solvents were removed in vacuo and the residue was purified by chromatogrpahy on silica gel. Yield: 153 mg of methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2 trimethylsilanylethoxycarbonyl)piperidin-4-yl]hexahydropyrrolo[2, 1 -b]thiazole-3 30 carboxylate MS: 460 (M+H-C2H4-tBu) 65 10h) 2-Trimethylsilanylethyl 4-((3R,6S,7aS)-6-tert-butoxycarbonylamino-3-cyano-5 oxohexahydropyrrolo[2,1-b]thiazol-6-yl)piperidine-1-carboxylate 153 mg of methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2 5 trimethylsilanylethoxycarbonyl)piperidin-4-yl]hexahydropyrrolo[2,1-b]thiazole-3 carboxylate were dissolved at 0*C in 30 ml of ammonia-saturated methanol. The mixture was allowed to reach room temperature over the course of 4 h, and then the solvents were removed in vacuo. The residue was taken up in 5 ml of THF, and 100 pl of triethylamine and 60 jl of trifluoroacetic anhydride were successively added. The 10 mixture was stirred at room temperature for 2 h. It was then partitioned between 60 ml of 0.5 M HCl and 60 ml of ethyl acetate. The aqueous phase was extracted twice with 20 ml of ethyl acetate each time, and the combined organic phases were washed once with 30 ml of saturated sodium bicarbonate solution. After drying with MgSO 4 , the solvents were removed in vacuo. The residue was chromatographed on silica gel. 15 Yield: 108 mg of 2-trimethylsilanylethyl 4-((3R,6S,7aS)-6-tert-butoxycarbonylamino 3-cyano-5-oxohexahydropyrrolo[2,1-b]thiazol-6-yl)piperidine-1-carboxylate MS: 427 (M+H-C2H4-tBu) 10i) (3R,6S,7aS)-6-Amino-5-oxo-6-piperidin-4-ylhexahydropyrrolo[2,1-b]thiazole-3 20 carbonitrile bistrifluoroacetate 12 mg of 2-trimethylsilanylethyl 4-((3R,6S,7aS)-6-tert-butoxycarbonylamino-3-cyano 5-oxohexahydropyrrolo[2,1-b]thiazol-6-yl)piperidine-1-carboxylate were stirred in a mixture of 1 ml of trifluoroacetic acid and 200 pLl of thioanisole at 0*C for 40 min. The 25 trifluoroacetic acid was removed in vacuo, and the residue was partitioned between 6 ml of water and 10 ml of ethyl acetate. The aqueous phase was washed 3 times with 5 ml of ethyl acetate each time. The water was then removed in vacuo, and the residue was stirred with diethyl ether. Yield: 7 mg of (3R,6S,7aS)-6-amino-5-oxo-6-piperidin-4-ylhexahydropyrrolo[2,1 30 b]thiazole-3-carbonitrile bistrifluoroacetate MS: 267 (M+H) 66 11) (3R,6R,7aS)-6-Amino-5-oxo-6-(piperidin-4-ylmethyl)hexahydro pyrrolo[2,1-b]thiazole-3-carbonitrile bistrifluoroacetate F F HO 0 S F H2N N Fy F 0 CN 5 HO 0 11 a) 2-Trimethylsilanylethyl 4-hydroxymethylpiperidine-1-carboxylate 10.5 g of 4-piperidinylmethanol were dissolved in 170 ml of THF. 25.8 g of 2 10 (trimethylsilyl)ethyl 4-nitrophenyl carbonate and 15.9 ml of N,N-diisopropylethyl amine were successively added thereto. The mixture was stirred at room temperature for 1 h and then the solvent was removed in vacuo. The residue was taken up in 400 ml of ethyl acetate and washed once with 300 ml of 0.5 N HC and twice with 250 ml of 1 N NaOH each time. The organic phase was dried with MgSO 4 , the solvent was 15 removed in vacuo, and the residue was purified by chromatography on silica gel. Yield: 19.9 g of 2-trimethylsilanylethyl 4-hydroxymethylpiperidine- 1 -carboxylate MS: 232 (M+H-C2H4) 11 b) 2-Trimethylsilanylethyl 4-bromomethylpiperidine- 1 -carboxylate 20 19.9 g of 2-trimethylsilanylethyl 4-hydroxymethylpiperidine- 1 -carboxylate were dissolved in 600 ml of THF. After cooling to 0*C, 50.7 g of tetrabromomethane were added. Then 42.1 g of triphenylphosphine were added in 4 portions at intervals each of 20 min. The mixture was allowed to reach room temperature and was stirred for 14 h. 25 The solvent was then removed in vacuo, and the residue was chromatographed on silica gel. Yield: 22.2 g of 2-trimethylsilanylethyl 4-bromomethylpiperidine- 1 -carboxylate MS: 294 (M+H-C2H4) 67 11 c) tert-Butyl (3S,5S,6R)-3-allyl-2-oxo-5,6-diphenyl-3-[1-(2-trimethylsilanyl ethoxycarbonyl)piperidin-4-ylmethyl]morpholine-4-carboxylate 4.9 g of tert-butyl (3S,5S,6R)-3-allyl-2-oxo-5,6-diphenylmorpholine-4-carboxylate were 5 dissolved in 100 ml of THF. 14.9 ml of 15-crown-5 were added, and the mixture was cooled to -78*C. Then 6.8 ml of a 2 M solution of NaHMDS in THF were added dropwise. The mixture was stirred for 10 min and then 8 g of 2-trimethylsilanylethyl 4-bromomethyl piperidine-1-carboxylate were added dropwise. The mixture was allowed to warm to 0*C over the course of 6 h, and the reaction was then stopped by adding 500 ml of saturated 10 ammonium chloride solution. The aqueous phase was extracted 3 times with 400 ml of ethyl acetate each time, and the combined organic phases were dried with MgS04. The solvents were removed in vacuo, and the residue was chromatographed on silica gel. Yield: 2.76 g of tert-butyl (3S,5S,6R)-3-allyl-2-oxo-5,6-diphenyl-3-[1-(2-trimethylsilanyl ethoxycarbonyl)-(piperidin-4-ylmethyl)]morpholine-4-carboxylate 15 MS: 551 (M+H-C2H4) 11d) 2-Trimethylsilanylethyl (S)-4-(2-tert-butoxycarbonylamino-2-carboxypent-4-en-yl) piperidine-1-carboxylate 20 110 ml of ammonia were condensed at -78*C. 1 g of sodium was added in 3 portions at intervals each of 10 min, and the mixture was stirred for 20 min. Then, at - 60*C, a solution of 2.76 g of tert-butyl (3S,5S,6R)-3-allyl-2-oxo-5,6-diphenyl-3-[1-(2 trimethylsilanylethoxycarbonyl)piperidin-4-ylmethyl]morpholine-4-carboxylate 25 and 2.6 ml of ethanol in 50 ml of THF was added dropwise. The mixture was stirred at -45*C for 1.5 h and the reaction was stopped by adding solid ammonium chloride until the blue color disappeared. The ammonia was then allowed to evaporate off, and 300 ml of water were added to the residue. The THF was removed in vacuo. The aqueous solution was adjusted to pH 2 with 1 N HCl and extracted 3 times with 200 ml of ethyl acetate each 30 time. The combined organic phases were dried with MgSO 4 . The solvents were removed in vacuo, and the residue was chromatographed on silica gel. Yield: 1.3 g of 2-trimethylsilanylethyl (S)-4-(-2-tert-butoxycarbonylamino-2-carboxypent 4-enyl)piperidine-1-carboxylate 68 MS: 373 (M+H-C2H4-tBu) 1le) 2-Trimethylsilanylethyl (S)- 4

-(

2 -tert-butoxycarbonylamino-2-methoxycarbonylpent 4-enyl)piperidine- I -carboxylate 5 1.1 g of 2-trimethylsilanylethyl (S)-(2-tert-butoxycarbonylamino-2-methoxycarbonyl pent-4-enyl)piperidine-l-carboxylate were dissolved in 33 ml of methanol and cooled to 0*C. 2.3 ml of a 2 N solution of trimethylsilyldiazomethane in hexane were added dropwise. The mixture was allowed to reach room temperature in the course of 3 h, and then a further 2.3 ml of the trimethylsilyldiazomethane solution were added dropwise. The 10 mixture was stirred for 1 h and then the reaction was stopped by adding 1 ml of acetic acid. After stirring for 30 min, the solvents are removed in vacuo and the residue was chromatographed on silica gel. Yield: 755 mg of 2-trimethylsilanylethyl (S)-(2-tert-butoxycarbonylamino-2 methoxycarbonylpent-4-enyl)piperidine-1 -carboxylate 15 MS: 387 (M+H-C2H4-tBu) 11 f) 2-Trimethylsilanylethyl (R)-4-(2-tert-butoxycarbonylamino-2-methoxycarbonyl-4 oxobutyl)piperidine-1-carboxylate 20 750 mg of 2-trimethylsilanylethyl (S)-4-(2-tert-butoxycarbonylamino-2-methoxycarbonyl pent-4-enyl)piperidine-I-carboxylate were dissolved in 30 ml of THF. 852 mg of sodium periodate and 10 ml of water were added. The mixture was then stirred at room temperature for 3 h and filtered through kieselguhr. The filter cake was washed twice with 10 ml of THF each time. The THF was removed in vacuo, and the residue was partitioned 25 between 30 ml of water and 30 ml of ethyl acetate. The pH of the aqueous phase was adjusted to 2 with 1 N HCl solution. The phases were separated and the aqueous phase was extracted twice with 20 ml of ethyl acetate each time. The combined organic phases were dried with MgSO 4 . The solvents were removed in vacuo and the residue was chromatographed on silica gel. 30 Yield: 530 mg of 2-trimethylsilanylethyl (R)-4-(2-tert-butoxycarbonylamino-2 methoxycarbonyl-4-oxobutyl)piperidine- 1 -carboxylate MS: 389 (M+H-C2H4-tBu) 69 11 g) (3R,6R,7aS)-6-tert-Butoxycarbonylamino-5-oxo-6-[1-(2-trimethylsilanyl ethoxycarbonyl)piperidin-4-ylmethyl]hexahydropyrrolo[2, 1 -b]thiazole-3-carboxylic acid 5 520 mg of 2-trimethylsilanylethyl (R)-4-(2-tert-butoxycarbonylamino-2 methoxycarbonyl-4-oxobutyl)piperidine-1-carboxylate were dissolved in 25 ml of pyridine. 134 mg of L-cysteine were added, and the mixture was heated at 1 00*C for 36 h. The pyridine was then removed in vacuo, and the residue was partitioned between 50 ml of ethyl acetate and 50 ml of 0.5 N HCl. The aqueous phase was extracted twice 10 with 20 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO 4 . The solvents were removed in vacuo, and the residue was chromatographed on silica gel. Yield: 500 mg of (3R,6R,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2 trimethylsilanylethoxycarbonyl)piperidin-4-ylmethyl]hexahydropyrrolo[2,1-b]thiazole 15 3-carboxylic acid MS. 460 (M+H-C2H4-tBu) 11 h) Methyl (3R,6R,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2-trimethylsilanyl ethoxycarbonyl)piperidin-4-ylmethyl]hexahydropyrrolo[2, 1 -b]thiazole-3-carboxylate 20 497 mg of (3R,6R,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2-trimethylsilanyl ethoxycarbonyl)piperidin-4-ylmethyl]hexahydropyrrolo[2,1 -b]thiazole-3-carboxylic acid were dissolved in 8 ml of methanol and 8 ml of diethyl ether and cooled to 0*C. 914 pL of a 1 N solution of trimethylsilyldiazomethane in hexane were added dropwise. 25 The mixture was stirred for I h and then 1 ml of acetic acid was added dropwise. After 1 h, the solvents were removed in vacuo, and the residue was purified by chromatography on silica gel. Yield: 345 mg of methyl (3R,6R,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2 trimethylsilanylethoxycarbonyl)piperidin-4-ylmethyl]hexahydropyrrolo[2,1-b]thiazole 30 3-carboxylate MS: 474 (M+H-C2H4-tBu) 70 1 li) 2-Trimethylsilanylethyl 4-((3R,6R,7aS)-6-tert-butoxycarbonylamino-3-carbamoyl 5-oxohexahydropyrrolo[2,1-b]thiazol-6-ylmethyl)piperidine-1-carboxylate 340 mg of methyl (3R,6R,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2 5 trimethylsilanylethoxycarbonyl)piperidin-4-ylmethyl]hexahydropyrrolo[2,1 -b]thiazole 3-carboxylate were dissolved at 0*C in 35 ml of an ammonia-saturated methanol solution. The mixture was allowed to reach room temperature in the course of 4 h, and then the solvents were removed in vacuo. The residue was employed without further purification in the next reaction. 10 Yield: 300 mg of 2-trimethylsilanylethyl 4-((3R,6R,7aS)-6-tert-butoxycarbonylamino 3-carbamoyl-5-oxohexahydropyrrolo[2,1-b]thiazol-6-ylmethyl)piperidine-1 carboxylate MS: 300 (M+H-C2H4-tBu) 15 1 lj) 2-Trimethylsilanylethyl 4-((3R,6R,7aS)-6-tert-butoxycarbonylamino-3-cyano-5 oxohexahydropyrrolo[2,1-b]thiazol-6-ylmethyl)piperidine-1-carboxylate 295 mg of 2-trimethylsilanylethyl 4-((3R,6R,7aS)-6-tert-butoxycarbonylamino-3 carbamoyl-5-oxohexahydropyrrolo[2,1-b]thiazol-6-ylmethyl)piperidine-1-carboxylate 20 were dissolved in 20 ml of THF. 166 pl of triethylamine and 91 I of trifluoroacetic anhydride were successively added dropwise. The mixture was stirred for 1 h and then the same amounts of triethylamine and trifluoroacetic anhydride were again added. After stirring for a further hour, the mixture was partitioned between 150 ml of ethyl acetate and 150 ml of water. The organic phase was dried with MgSO 4 . The solvent 25 was removed in vacuo and the residue was chromatographed on silica gel. Yield: 254 mg of 2-trimethylsilanylethyl 4-((3R,6R,7aS)-6-tert-butoxycarbonylamino 3-cyano-5-oxohexahydropyrrolo[2,1-b]thiazol-6-ylmethyl)piperidine-1-carboxylate MS: 441 (M+H-C2H4-tBu) 30 11 h) (3R,6R,7aS)-6-Amino-5-oxo-6-piperidin-4-ylmethylhexahydropyrrolo[2,1 b]thiazole-3-carbonitrile bistrifluoroacetate 71 14 mg of 2-trimethylsilanylethyl 4-((3R,6R,7aS)-6-tert-butoxycarbonylamino-3-cyano 5-oxohexahydropyrrolo[2,1-b]thiazol-6-ylmethyl)piperidine-1-carboxylate were stirred in a mixture of 1 ml of trifluoroacetic acid and 200 pl of thioanisole at 0*C for 40 min. The trifluoroacetic acid was removed in vacuo, and the residue was stirred with diethyl 5 ether. Yield: 10 mg of (3R,6R,7aS)-6-amino-5-oxo-6-piperidin-4-ylmethylhexahydro pyrrolo[2,1-b]thiazole-3-carbonitrile bistrifluoroacetate MS: 281 (M+H)

Claims

1. A compound of the formula I, R1 R2 x N HN 5 0 CN formula I in which the meanings are 10 RI H, (Ci-Cio)-alkyl, (C 3 -Cio)-cycloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 6 -Cio)-aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, OR3, NR3R4, COR3, C02R3, CONR3R4, (CI-C 6 )-alkylene-OR3, (C 1 -C 6 ) 15 alkylene-NR3R4, (CI-C 6 )-alkylene-SR3, alkylene-SOR3, alkylene-S0 2 R3, (CI-C 6 )-alkylene-COR3, (CI-C 6 )-alkylene-COOR3, (CI-C 6 )-alkylene CONR3R4, (Ci-C 6 )-alkylene-O-P(O)(OR3) 2 , SR3, SOR3, SO 2 NR3R4, S0 2 R3, (CI-C 6 )-alkylene-(C 3 -Clo)-cycloalkyl, (Ci-C 6 )-alkylene-(C 6 -Cio) aryl, (C1-C 6 )-alkylene-heterocyclyl, (C 3 -Cio)-cycloalkyl, (C 6 -Cio)-aryl 20 which may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, CF 3 , (CI-C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, OR3, NR3R4, COR3, C0 2 R3, CONR3R4, or heterocyclyl which may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , (Ci-C 6 )-alkyl, OR3, NR3R4, COR3, CO 2 R3, CONR3R4; 25 R2 H, (Ci-Cio)-alkyl, (C 3 -Cio)-cycloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 6 -Cio)-aryl, heterocyclyl, COR3, COOR3, CONR3R4, CN, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , SH, SFs, OH, (CI 30 C)-alkyl, -CF 3 , (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, OR3, OP(O)(OR3) 2 , 73 NR3R4, NR3CONR3R4, COR3, OCOR3, OCOOR3, COOR3, CONR3R4, OCONR3R4, (Ci-C 6 )-alkylene-OR3, (C1-C)-alkylene-NR3R4, (Ci-C 6 ) alkylene-NR3S0 2 R4, (Ci-C 6 )-alkylene-SR3, alkylene-S(O)R3, alkylene S(O) 2 R3, alkylene-S(0) 2 NR3R4, (CI-C 6 )-alkylene-COR3, (Ci-C 6 )-alkylene 5 COOR3, (CI-CW)-alkylene-CONR3R4, SR3, SOR3, S0 2 R3, SO 2 NR3R4, NR3S0 2 R4, (Ci-C 6 )-alkylene-(C 3 -Cio)-cycloalkyl, (Ci-C 6 )-alkylene-(C 6 CIo)-aryl, (CI-C6)-alkylene-heterocyclyl, (C 3 -Cio)-cycloalkyl, (C 6 -Cio)-aryl or heterocyclyl; 10 R3, R4 independently of one another H, (Ci-C 6 )-alkyl, -CF 3 , (C 3 -Cio)-cycloalkyl, (C 6 -Cio)-aryl, heterocyclyl, (CI-C 6 )-alkylene-CONR5R6, CONR5R6, (C C 6 )-alkylene-COOR5, COOR5, COR5, (CI-C 6 )-alkylene-COR5, (CI-C 6 ) alkylene-OR5, (CI-C 6 )-alkylene-NR5R6, (Ci-C 6 )-alkylene-SR5, (C 1 -C 6 ) alkylene-S(O)R5, (CI-C 6 )-alkylene-S(0) 2 R5, S(O)R5, S(O) 2 R5, (C 1 -C 4 ) 15 alkylene-(C 6 -Cio)-aryl or (Ci-C 4 )-alkylene-heterocyclyl; R5, R6 independently of one another H, (Ci-C 6 )-alkyl, (CI-C 6 )-alkylene-(C 6 -CIO) aryl, -(C 6 -Clo)-aryl, heterocyclyl, (CI-C 6 )-alkylene-heterocyclyl; 20 X S, SO, S02; and the physiologically tolerated salts thereof.

2. A compound of the formula I as claimed in claim 1, characterized in that the 25 meanings therein are RI H, (CI-Cio)-alkyl, (C 3 -Cio)-cycloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 6 -Cio)-aryl, where the alkyl, cycloalkyl, alkenyl, alkynyl and aryl radicals may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , 30 (Ci-C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, OR3, NR3R4, COR3, C0 2 R3, CONR3R4, (C 1 -C 6 )-alkylene-OR3, (CI-C)-alkylene-NR3R4, (C C 6 )-alkylene-SR3, alkylene-SOR3, alkylene-S0 2 R3, (Ci-C 6 )-alkylene COR3, (CI-C)-alkylene-CO 2 R3, (C 1 -C 6 )-alkylene-CONR3R4, (Cl-C6) alkylene-O-P(O)(OR3) 2 , SR3, SOR3, SO 2 NR3R4, S0 2 R3, (CI-C 6 )-alkylene- 74 (C 3 -Cio)-cycloalkyl, (C-C 6 )-alkylene-(C 6 -CIo)-aryl, (C-C 6 )-alkylene heterocyclyl, (C 3 -Cio)-cycloalkyl or (C 6 -Cio)-aryl which may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , (C-C 6 )-alkyl, (C 2 C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, OR3, NR3R4, COR3, C0 2 R3, CONR3R4; 5 R2 H, (C-Co)-alkyl, (C 3 -Cio)-cycloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 6 -Cio)-aryl, heterocyclyl, COR3, CO2R3, CONR3R4, CN, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , SH, SF 5 , OH, (CI 10 C 6 )-alkyl, -CF 3 , (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, OR3, OP(O)(OR3) 2 , NR3R4, NR3CONR3R4, COR3, OCOR3, C0 2 R3, CONR3R4, OCONR3R4, (C-C 6 )-alkylene-OR3, (C-C 6 )-alkylene-NR3R4, (C-C 6 ) alkylene-NR3SO 2 R4, (CI-C 6 )-alkylene-SR3, alkylene-SOR3, alkylene S0 2 R3, alkylene-SO 2 NR3R4, (CI-C 6 )-alkylene-COR3, (CI-C 6 )-alkylene 15 C0 2 R3, (Ci-C 6 )-alkylene-CONR3R4, SR3, SOR3, S0 2 R3, SO 2 NR3R4, NR3S0 2 R4, (C-C 6 )-alkylene-(C 3 -Cio)-cycloalkyl, (C-C 6 )-alkylene-(C 6 Cio)-aryl, (C-C 6 )-alkylene-heterocyclyl, (C 3 -CIo)-cycloalkyl, (C 6 -CIo)-aryl, which may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , (C-C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, OR3, NR3R4, COR3, 20 C0 2 R3, CONR3R4, or heterocyclyl which may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , (C-C 6 )-alkyl, OR3, NR3R4, COR3, C0 2 R3, CONR3R4; R3, R4 independently of one another H, (CI-C 6 )-alkyl, -CF 3 , (C 3 -Cio)-cycloalkyl, 25 (C 6 -Cio)-aryl, heterocyclyl, (C-C 6 )-alkylene-CONR5R6, (C-C 6 )-alkylene CO 2 R5, (CI-C 6 )-alkylene-COR5, (C-C 6 )-alkylene-OR5, (CI-C 6 )-alkylene NR5R6, (C 1 -C 6 )-alkylene-SR5, (C 1 -C 6 )-alkylene-SOR5, (Ci-C 6 )-alkylene S0 2 R5, (C-C 4 )-alkylene-(C 6 -Cio)-aryl or (CI-C 4 )-alkylene-heterocyclyl; 30 R5, R6 independently of one another H, (C-C 6 )-alkyl, (C 3 -Cio)-cycloalkyl, (C 1 C 6 )-alkylene-(C 6 -CIo)-aryl, -(C 6 -Co)-aryl, heterocyclyl, (C-C 6 )-alkylene (C 3 -Cio)-heterocyclyl; X S; 75 and the physiologically tolerated salts thereof.

3. A compound of the formula I as claimed in claim 1 or 2, characterized in that the 5 meanings therein are R1 H; R2 H, (CI-Cio)-alkyl, (C 3 -Cio)-cycloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, 10 (C 6 -Cio)-aryl, heterocyclyl, COR3, C0 2 R3, CONR3R4, CN, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , SH, SF 5 , OH, (C C 6 )-alkyl, -CF 3 , (C 2 -C 6 )-alkenyl, (C2-C 6 )-alkynyl, OR3, OP(O)(OR3)2, NR3R4, NR3CONR3R4, COR3, OCOR3, CO 2 R3, CONR3R4, 15 OCONR3R4, (CI-C 6 )-alkylene-OR3, (Ci-C 6 )-alkylene-NR3R4, (C 1 -C 6 ) alkylene-NR3SO 2 R4, (CI-C 6 )-alkylene-SR3, alkylene-SOR3, alkylene S0 2 R3, alkylene-S(0) 2 NR3R4, (Ci-C 6 )-alkylene-COR3, (Ci-C 6 )-alkylene C0 2 R3, (Ci-C 6 )-alkylene-CONR3R4, SR3, SOR3, S0 2 R3, SO 2 NR3R4, NR3S0 2 R4, (Ci-C 6 )-alkylene-(C 3 -Cio)-cycloalkyl, (CI-C 6 )-alkylene-(C 6 20 Cio)-aryl, (Ci-C 6 )-alkylene-heterocyclyl, (C 3 -Cio)-cycloalkyl, (C 6 -CIo)-aryl which may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , (CI-C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, OR3, NR3R4, COR3, C0 2 R3, CONR3R4, or heterocyclyl which may be substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, -CF 3 , (Ci-C 6 )-alkyl, OR3, NR3R4, 25 COR3, C0 2 R3, CONR3R4; R3, R4 independently of one another H, (Ci-C 6 )-alkyl, -CF 3 , (C 3 -Cio)-cycloalkyl, (C 6 -Cio)-aryl, heterocyclyl, (CI-C 6 )-alkylene-CONR5R6, (Ci-C 6 )-alkylene C0 2 R5, (Ci-C 6 )-alkylene-COR5, (Ci-C 6 )-alkylene-OR5, (CI-C 6 )-alkylene 30 NR5R6, (C 1 -C 6 )-alkylene-SR5, (CI-C 6 )-alkylene-SOR5, (Ci-C 6 )-alkylene S0 2 R5, (Ci-C 4 )-alkylene-(C 6 -Cio)-aryl or (CI-C 4 )-alkylene-heterocyclyl; 76 R5, R6 independently of one another H, (CI-C 6 )-alkyl, (C 3 -Cio)-cycloalkyl, (CI-C 6 ) alkylene-(C 6 -Cio)-aryl, -(C 6 -Cio)-aryl, heterocyclyl, (Ci-C 6 )-alkylene-(C 3 Cio)-heterocyclyl; 5 X S; and the physiologically tolerated salts thereof.

4. A compound of the formula I as claimed in one or more of claims 1 to 3, 10 characterized in that the meanings therein are RI H; R2 H, (Ci-Clo)-alkyl, (C 3 -Cio)-cycloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, 15 (C6-Cio)-aryl, a pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, thiomorpholino or homopiperazino radical; where the alkyl, cycloalkyl, alkenyl, alkynyl, pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, thiomorpholino, homopiperazino and aryl radicals may be substituted one or more times by F, Cl, Br, CN, SF 5 , OH, (C 1 -C 6 ) 20 alkyl, -CF 3 , (C 2 -C 6 )-alkenyl, OR3, NR3R4, NR3CONR3R4, COR3, OCOR3, C0 2 R3, CONR3R4, OCONR3R4, (C-CO)-alkylene-OR3, (C 1 -C 6 ) alkylene-NR3R4, (CI-C 6 )-alkylene-NR3SO 2 R4, (Ci-C 6 )-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O) 2 R3, alkylene-S(O) 2 NR3R4, (C 1 -C 6 ) alkylene-COR3, (Ci-C)-alkylene-CO 2 R3, (CI-C 6 )-alkylene-CONR3R4, 25 SR3, SOR3, S0 2 R3, SO 2 NR3R4, NR3SO 2 R4, (Ci-C 6 )-alkylene-(C 3 -CIo) cycloalkyl, (CI-C 6 )-alkylene-(C 6 -Cio)-aryl, (CI-C 6 )-alkylene-heterocyclyl, (C 3 -Cio)-cycloalkyl, (C 6 -Clo)-aryl which may be substituted one or more times by F, Cl, Br, I, CN, OH, -CF 3 , (CI-C)-alkyl, OR3, NR3R4, COR3, C02R3, CONR3R4, or heterocyclyl which may be substituted one or more 30 times by F, Cl, Br, CN, NO 2 , OH, -CF 3 , (Ci-C 6 )-alkyl, OR3, NR3R4, COR3, CO2R3, CONR3R4; R3, R4 independently of one another H, (Ci-C 6 )-alkyl, -CF 3 , (C 3 -Clo)-cycloalkyl, (C 6 -Cio)-aryl, heterocyclyl, (Ci-C 6 )-alkylene-CONR5R6, (CI-C 6 )-alkylene- 77 COOR5, (CI-C 6 )-alkylene-COR5, (CI-C 6 )-alkylene-OR5, (CI-C 6 )-alkylene NR5R6, (C1-C 6 )-alkylene-SR5, (CI-C 6 )-alkylene-S(O)R5, (CI-C 6 )-alkylene S(O) 2 R5, (C1-C 4 )-alkylene-(C 6 -CIo)-aryl or (CI-C 4 )-alkylene-heterocyclyl; 5 R5, R6 independently of one another H, (C-C 6 )-alkyl, (C 3 -Cio)-cycloalkyl, (Ci-C 6 ) alkylene-(C 6 -Cio)-aryl, -(C 6 -Cio)-aryl, heterocyclyl, (Cl-C6)-alkylene-(C 3 Cio)-heterocyclyl; X S; 10 and the physiologically tolerated salts thereof.

5. A compound of the formula I as claimed in one or more of claims 1 to 4, characterized in that the meanings therein are 15 RI H; R2 (Ci-Cio)-alkyl, (C 3 -Cio)-cycloalkyl, phenyl, (Ci-C 6 )-alkylene-phenyl, a pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, 20 thiomorpholino or homopiperazino radical; X S; and the physiologically tolerated salts thereof. 25

6. A medicament comprising one or more of the compounds as claimed in one or more of claims 1 to 5.

7. A medicament comprising one or more of the compounds as claimed in one or 30 more of claims 1 to 5 and at least one other active ingredient.

8. The medicament as claimed in claim 6, characterized in that it comprises as other active ingredient one or more antidiabetics, hypoglycemic active ingredients, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha 78 agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas, 5 biguanides, meglitinides, thiazolidinediones, ax-glucosidase inhibitors, active ingredients which act on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, cannabinoid 1 receptor antagonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, P3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, 10 mixed sertoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, cannabinoid 1 receptor antagonists, RXR modulators or TR-p agonists or amphetamines. 15

9. The use of the compounds as claimed in one or more of claims 1 to 5 for producing a medicament for reducing blood glucose.

10. The use of the compounds as claimed in one or more of claims 1 to 5 for producing 20 a medicament for the treatment of type 2 diabetes.

11. The use of the compounds as claimed in one or more of claims 1 to 5 for producing a medicament for the treatment of disturbances of lipid and carbohydrate metabolism. 25

12. The use of the compounds as claimed in one or more of claims 1 to 5 for producing a medicament for the treatment of arteriosclerotic manifestations.

13. The use of the compounds as claimed in one or more of claims 1 to 5 for producing a medicament for the treatment of insulin resistance. 30

14. A process for producing a medicament comprising one or more of the compounds as claimed in one or more of claims 1 to 5, characterized in that the active ingredient is 79 mixed with a pharmaceutically suitable carrier and this mixture is converted into a form suitable for administration.