AU2003281027A1 - Urea-substituted and urethane-substituted acylureas, methods for the production thereof and their use as medicaments - Google Patents

Abstract

The invention relates to urea-substituted and urethane-substituted acylureas, to physiologically compatible salts thereof and to their physiologically functional derivatives. The invention thus relates to compounds of formula (I), wherein the radicals have the cited meanings. The invention also relates to the physiologically compatible salts of these compounds and to methods for the production thereof. The inventive compounds are suited for use, for example, as antidiabetics.

Description

IN THE MATTER OF an Australian Application corresponding to PCT Application PCT/EP2003/006934 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/EP2003/006934. Date: 21 October 2004 C. E. SITCH Deputy Managing Director - UK Translation Division For and on behalf of RWS Group Ltd (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International publication date (10) International publication number 22 January 2004 (22.01.2004) PCT WO 2004/007437 Al 1) International patent classification 7 : C07C 275/54, (DE). VON ROEDERN, Erich; Lindenstrasse 40, C07D 239/96, A61K 31/17, A 61P 3/10 65795 Hattersheim (DE). SCHOENAFINGER, Karl; Holunderweg 8, 63755 Alzenau (DE). 1) International application number: PCT/EP2003/006934 (81) Designated states (national): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, 2) International filing date: 30 June 2003 (30.06.2003) CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, Fl, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, 5) Language of filing: German KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, 6) Language of publication: German OM, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, UZ, VC, VN, YU, 0) Data relating to the priority: ZA, ZM, ZW. 10231 371.7 11 July 2002 (11.07.2002) DE (84) Designated states (regional): ARIPO Patent (GH, 1) Applicant: AVENTIS PHARMA DEUTSCHLAND GMBH GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, [DE/DE]; Briiningstrasse 50, 65929 Frankfurt am Main (DE). ZW), Eurasian Patent (AM, AZ, BY, KG, KZ, MD, RU, TI, TM), European Patent (AT. BE, BG. CH, 2) Inventors: DEFOSSA, Elisabeth; Scheidgraben 10, 65510 CY, CZ, DE, DK, EE, ES, Fl, FR, GB, GR, HU, IE, Idstein (DE). KADEREIT, Dieter; Johann Strauss-Strasse 18a, IT, LU, MC, NL, PT, RO, SE, SI, SK, TR), OAPI 65779 Kelkheim (DE). KLABUNDE, Thomas; Liederbacher Patent (BF, BJ. CF, CG, Cl, CM, GA, GN, GQ. GW, Str. 1, 65929 Frankfurt (DE). BURGER, Hans-Joerg; 8 ML, MR, NE, SN, TD, TG). Lawndale Avenue, Morristown, NJ 07960 (US). HERLING, Andreas; Am Walberstiick 5, 65520 Bad Camberg (DE). Published: WENDT, Karl-Ulrich; Wolfsgangstrasse 21, 60433 Frankfurt - With the International Search Report. [continued on next page] As printed () :UREA-SUBSTITUZ AND URETHANE-SUBSTITUTED ACYLUREAS, tenTtODS FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICAMENTS (54) Beveichnung: 14ARNSTOFF- UND UR1LTHAN-SUBs-ITrRTE ACYLH1ARNSTOFFE., VERFAHREN ZLT DEREN HER STELLCNY UND DEREN VERWENDUNEE AlS ARENEIMSI, ,, R6 R5 R7 R IO R 9 yN R O ML MR, NE SN DT) RI R2 R3 R R11 R12 S(57) Abstract: The invention relates to urea-substituted and urethane-substituted acylureas, to physiologically compatible salts Othereof and to their physiologically functional derivatives. The invention thus relates to compounds of formula (1), wherein the radi cals have the Cited meanings. The invention also relates to the physiologically compatible salts of these compounds and to methods for the production thereof. The inventive compounds are suited for use, for example, as antidiabetics. (57) ZusaiUnenfasUTng: Die Erfindung betifft H-astoff- und Urethan-substituierte Acyhamstoffe sowie deren physiologisch Svertregliche Saize und physiologisch funktionellen DerivAte. Die Erfindung betrifft daher Verbindungen de FOrmel (), worN die Reste dir anirenenn Bedcutungen hahen. sowle dertm pitysiologiscb vertr l_,ichen Salt.,c und \'ertalhren zru deren [lerstellung. Die Verbindunen cignen sich 13. als AntidiabetiLSa.

WO 2004/007437 Al or an explanation of the two-letter codes and the other 5breviations, reference is made to the explanations Guidance Notes on Codes and Abbreviations') at the ginning of each regular edition of the PCT Gazette WO 2004/007437 PCT/EP2003/006934 Description Urea-substituted and urethane-substituted acylureas, methods for the production 5 thereof and their use The invention relates to urea- and urethane-substituted acylureas and to their physiologically tolerated salts and physiologically functional derivatives. 10 EP 0 221 847 describes compounds of similar structure for controlling pests. The invention was based on the object of providing compounds with which prevention and treatment of type 2 diabetes is possible. The compounds are intended for this purpose to bring about a marked reduction in the blood glucose level. 15 The invention therefore relates to compounds of the formula I R6 R5 R7 N R8 R10 R9 X Y N N RI R2 R3 R4 R11 R12 20 in which W, X, Y are, independently of one another, 0 or S; R9, R10, R1 1, R12 are, independently of one another, H, F, Cl, Br, OH, CF 3 , 25 NO 2 , CN, OCF 3 , O-(C-C)-alkyl, 0-(C 2

-C

6 )-alkenyl, 0-(C 2

-C

6 )-alkynyl,

O-SO

2

-(C-C

4 )-alkyl, O-SO 2 -phenyl, where the phenyl ring may be substituted up to twice by F, Cl, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR1 3 or CON(R1 4)(R1 5), or S-( 1 C0)-alkyl, S-(C 2

-C

6 )-alkenyl, 2

S-(C

2

-C

6 )-alkynyl, SO-(CrC 6 )-alkyl, S0 2 -(CrC 6 )-alkyl, S0 2

-NH

2 , (Cr C6) alkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, (C 3

-C

7 )-cycloalkyl, (C3-C7) cycloalkyl-(C-C 4 )-alkylene, (Co-C 6 )-alkylene-COOR13, CON(R14)(R15), (Co-C 6 )-alkylene-N(R14)(R15), NH-COR13, NH-CO-phenyl, NH-SO 2 -5 phenyl or phenyl, where the phenyl ring may be substituted up to twice by F, CI, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R14)(R1 5); R13 is H, (C1-C)-alkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, (C 3

-C

7 )-cycloalkyl or

(C

3

-C

7 )-cycloalkyl-(C-C 4 )-alkylene; 10 R1, R2 are, independently of one another, H, (CrC 6 )-alkyl, where alkyl may be substituted by OH, 0-(C-C 4 )-alkyl or N(R14)(R15), or O-(CrC 6 )-alkyl, 0-(C 2

-C

6 )-alkenyl, 0-(C 2

-C

6 )-alkynyl, CO-(C-C 6 )-alkyl, CO-(C2-C6) alkenyl, CO-(C 2

-C

6 )-alkynyl, COOR13 or (Co-C 6 )-alkylene-COOR13; 15 R3, R4, R5, R6 are, independently of one another, H, F, CI, Br, OH, CF 3 ,

NO

2 , CN, OCF 3 , (CrC 6 )-alkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, 0-(C-C 1 o)-alkyl, 0-(C 2

-C

1 o)-alkenyl, 0-(C 2

-C

1 o)-alkynyl, S-(C-C 6 )-alkyl,

S-(C

2

-C

6 )-alkenyl, S-(C 2

-C

6 )-alkynyl, (C 3

-C

7 )-cycloalkyl, (C 3

-C

7

)

20 cycloalkyl-(C-C 4 )-alkyl, where alkyl, alkenyl, alkynyl and cycloalkyl may be substituted more than once by F, Cl, Br, SO-phenyl, S0 2 -phenyl, where the phenyl ring may be substituted by F, Cl, Br or R13, or OR13, COOR13, CON(R14)(R1 5), N(R14))(R15) or CO-heteroalkyl, or are O-SO-(C-C)-alkyl, O-SO 2

-(C-C

6 )-alkyl, O-SO 2

-(C-C

1 o)-aryl, 25 O-(C 6

-C

1 o)-aryl, where aryl may be substituted up to twice by F, Cl, CN, OR13, R13, CF 3 or OCF 3 , or are SO-(CrC 6 )-alkyl, S0 2

-(C-C

6 )-alkyl, S0 2

-(C

6 -C1o)-aryl, where the phenyl ring may be substituted up to twice by F, Cl, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R1 4)(R1 5), or are S0 2 -N(R14)(R1 5), COOR13, CO-heteroalkyl, N(R14)(R15) or 30 heteroalkyl; R14, R15 are, independently of one another, H, (CrC 6 )-alkyl, where alkyl may be substituted by N(R1 3)2, or are (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, (C 3

-C

7

)

cycloalkyl, (C 3 -Cr)-cycloalkyl-(C-C 4 )-alkylene, CO-(C-C 6 )-alkyl, COO- 3 (CrC 6 )-alkyl, COO-(C-C 6 )-alkylene-OCO-(C-C 6 )-alkyl, CO-phenyl, COO-phenyl, COO-(CrC 6 )-alkenyl-phenyl, OH, O-(CrC 6 )-alkyl, O-(CrC 6 )-alkenyl-phenyl or NH 2 ; 5 or the radicals R14 and R15 form with the nitrogen atom to which they are bonded a 3-7-membered, saturated heterocyclic ring which may comprise up to 2 further heteroatoms from the group of N, 0 or S, where the heterocyclic ring may be substituted up to three times by F, CI, Br, OH, oxo, N(R16)(R17) or (C-C 4 )-alkyl; 10 R16, R17 are, independently of one another, H, (CrC 6 )-alkyl, where alkyl may be substituted by N(R13)2, or are (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, (C3-C7) cycloalkyl, (C 3

-C

7 )-cycloalkyl-(Cr-C 4 )-alkylene, CO-(C-C 6 )-alkyl, COO (CrC 6 )-alkyl, COO-(C-C 6 )-alkylene-OCO-(C-C 6 )-alkyl, CO-phenyl, 15 COO-phenyl, COO-(CrC 6 )-alkenyl-phenyl, OH, O-(C-C 6 )-alkyl, O-(CrC 6 )-alkenyl-phenyl or NH 2 ; heteroalkyl is a 3-7-membered, saturated or up to triunsaturated heterocyclic ring which may comprise up to 4 heteroatoms which correspond to N, 0 or S, 20 where the heterocyclic ring may be substituted at all sensible positions up to three times by F, Cl, Br, CN, oxo, (Cr-C 4 )-alkyl, (Co-C 4 )-alkylene COOR13, CON(R1 4)(R1 5), OR13, N(R14)(R15) or phenyl, where phenyl may be substituted by COOR1 3; 25 R7 is H, (C-C 6 )-alkyl, where alkyl may be substituted by OR13 or N(R1 4)(R1 5), or is O-(C-C 6 )-alkyl, CO-(C-C 6 )-alkyl or (Co-C 6 )-alkylene COOR13; R8 is N(R18)(R19) or OR20; 30 or R8 and R4 together form the group -NH-CO-; R18, R19 are, independently of one another, H, (C-C1o)-alkyl, (C 2 -C1o)-alkenyl, (C2-Clo)-alkynyl, (C 3 -Cr)-cycloalkyl, (C 3 -C7)-cycloalkyl-(C-C 6 )-alkyl,

(C

6 -C1o)-aryl, (C 6 -C1o)-aryl-(C-C 4 )-alkyl, (C 6 -C1o)-aryl-(C 2

-C

4 )-alkenyl, 4 (C6-C1o)-aryl-(C 2

-C

4 )-alkynyl, heteroaryl, heteroaryl-(C-C 4 )-alkyl, heteroaryl-(C 2

-C

4 )-alkenyl, heteroaryl-(C 2

-C

4 )-alkynyl, where alkyl, alkenyl, alkynyl and cycloalkyl may be substituted more than once by F, Cl, CN, OR13, R13, CF 3 , OCF 3 , (C6-Clo)-aryl, NH-C(=NR14) 5 N(R14)(R15), N(R14)(R15), C(=NR14)-N(R14)(R15), COOR13 or CON(R14)(R1 5), and where aryl may be substituted more than once by F, Cl, CN, 0-(C-C 6 )-alkyl, O-(C 2

-C

6 )-alkenyl, (0C)-alkyl, (C2-C6) alkenyl, CO-(C0)-alkyl, CO-(C 2

-C

6 )-alkenyl, where alkyl and alkenyl may be substituted more than once by F, Cl, CH 3 , OCH 3 or CN, or 10 NH-C(=NR14)-N(R14)(R15), N(R14)(R15), C(=NR14)-N(R14)(R15), COOR13, CON(R14)(R15), 0-phenyl, phenyl or pyridyl; COOR13, CON-(R14)(R15), CO-heteroalkyl, CO-(C 6 -C1o)-aryl or

SO

2

-(C

6

-C

1 o)-aryl, where aryl may be substituted up to twice by F, Cl, CN, OH, (PC)-alkyl, 0-(Cr 1

C

6 )-alkyl, CF 3 , OCF 3 , COOR13 or 15 CON(R14)(R15); or the radicals R1 8 and R1 9 form with the nitrogen atom to which they are bonded a 3-7-membered, saturated heterocyclic ring which may comprise up to 2 further heteroatoms from the group of N, 0 or S, where the heterocyclic 20 ring may be substituted up to three times by F, C, Br, OH, oxo, N(R16)(R17) or (C 1

C

4 )-alkyl; R20 is (Cr-C 10 )-alkyl, (C2-C1o)-alkenyl, (C2-C1o)-alkynyl, (C 3

-C

7 )-cycloalkyl, (C3-C 7 )-cycloalkyl-(Cl-C)-alkyl, (C6-C1o)-aryl, (C 6

-C

1 o)-aryl-(C-C4)-alkyl, 25 (C 6 -C1o)-aryl-(C 2 -C4)-alkenyl or (C 6

-C

1 o)-aryl-(C 2 -C4)-alkynyl, where aryl may be substituted more than once by F, C, CN, O-(CrC 6 )-alkyl, 0-(C 2

-C

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

-C

6 )-alkenyl, CO-(OiC)-alkyl, CO

(C

2

-C

6 )-alkenyl, where alkyl and alkenyl may be substituted more than once by F, CI, CH 3 , OCH 3 or CN, or NH-C(=NR1 4)-N(R14)(R1 5), 30 N(R14)(R15), C(=NR14)-N(R14)(R15), COOR13, CON(R14)(R15), 0-phenyl, phenyl or pyridyl, where phenyl may be substituted by F, Cl, CN or (CriC 6 )-alkyl; and their physiologically tolerated salts, 5 excluding compounds of the formula I in which the radicals R6, R7, X and R8 have the following meanings at the same time: 5 R6 H, Cl, CF 3 , CH 3 ; R7 H; X 0; 10 Y O, S; R8 substituted or unsubstituted NH-phenyl. 15 Preference is given to compounds of the formula la, R5 R6 R4 RIO R9 N N N R8 H H R3 R11 R12 la in which one or more radicals has or have the following meanings: 20 R9 F, C, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O-(OiC)-alkyl, 0-(C 2

-C

6 )-alkenyl, 0-(C 2

-C

6 )-alkynyl, 0-SO 2

-(C

1

-C

4 )-alkyl, O-SO 2 -phenyl, where the phenyl ring may be substituted up to twice by F, C, Br, CN, OR13, R13, CF 3 ,

OCF

3 , COOR13 or CON(R14)(R15), or S-(CriC 6 )-alkyl, S-(C 2

-C

6

)

25 alkenyl, S-(C 2 -Ce)-alkynyl, SO-(OiC)-alkyl, S0 2 -(CriC 6 )-alkyl, S0 2

-NH

2 , (O-C)-alkyl, (C 2

-C

6 )-alkenyl, (C2-C6)-alkynyl, (C 3

-C

7 )-cycloalkyl, (C3-C7) cycloalkyl-(Cr-C 4 )-alkylene, (Co-C 6 )-alkylene-COOR13, CON(R14)(R15), 6 (Co-C 6 )-alkylene-N(R14)(R15), NH-COR113, NH-CO-phenyl, NH-SO 2 phenyl or phenyl, where the phenyl ring may be substituted up to twice by F, CI, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R14)(R1 5); 5 R10, R11, R12 independently of one another H, F, Cl, Br, OH, CF 3 , NO 2 , CN,

OCF

3 , O-(OC)-alkyl, 0-(C 2

-C

6 )-alkenyl, 0-(C 2

-C

6 )-alkynyl, 0-SO2 (Cr 1

C

4 )-alkyl, O-SO 2 -phenyl, where the phenyl ring may be substituted up to twice by F, CI, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R1 4)(R1 5), or S-(O-C)-alkyl, S-(C 2

-C

6 )-alkenyl, S-(C 2

-C

6 )-alkynyl, 10 SO-(Cr-0)-alkyl, S0 2 -(OiC)-alkyl, SO 2

-NH

2 , (CrO0)-alkyl, (C 2

-C

6

)

alkenyl, (C 2

-C

6 )-alkynyl, (C 3 -Cr)-cycloalkyl, (C 3

-C

7 )-cycloalkyl-(C-C4) alkylene, (Co-C 6 )-alkylene-COOR13, CON(R14)(R15), (Co-C 6 )-alkylene N(R14)(R15), NH-COR13, NH-CO-phenyl, NH-S0 2 -phenyl or phenyl, where the phenyl ring may be substituted up to twice by F, C, Br, CN, 15 OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R1 4)(R1 5); R13 H, (C-C)-alkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, (C 3 -Cz)-cycloalkyl or

(C

3

-C

7 )-cycloalkyl-(C-C 4 )-alkylene; 20 R3, R4, R5 independently of one another H, F, C, Br, OH, CF 3 , NO 2 , CN,

OCF

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

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, 0-(CIC 1 o)-alkyl, 0-(C 2 -C1o)-alkenyl, 0-(C2-C1o)-alkynyl, S-(CrC 6 )-alkyl, S-(C 2 -Cs) alkenyl, S-(C 2 -C)-alkynyl, (C 3

-C

7 )-cycloalkyl, (C 3

-C

7 )-cycloalkyl-(CC- 4

)

alkyl, where alkyl, alkenyl, alkynyl and cycloalkyl may be substituted 25 more than once by F, C, Br, SO-phenyl, S0 2 -phenyl, where the phenyl ring may be substituted by F, Cl, Br or R13, or OR13, COOR13, CON(R1 4)(R1 5), N(R14))(R15) or CO-heteroalkyl, or O-SO-(Cr-C6) alkyl, O-SO2-(C-C 6 )-alkyl, O-SO2-(CO-C1o)-aryl, 0-(C6-C1o)-aryl, where aryl may be substituted up to twice by F, CI, CN, OR13, R13, CF 3 or 30 OCF 3 , or SO-(CriC 6 )-alkyl, S0 2 -(OiC)-alkyl, S0 2

-(C

6 -C1o)-aryl, where the phenyl ring may be substituted up to twice by F, CI, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R1 4)(R1 5), or S0 2 -N(R14)(R1 5), COOR13, CO-heteroalkyl, N(R14)(R15) or heteroalkyl; 7 R6 F, CI, Br, OH, CF 3 , NO 2 , CN, OCF 3 , (C-C)-alkyl, (C 2

-C

6 )-alkenyl,

(C

2

-C

6 )-alkynyl, 0-(l-Co)-alkyl, 0-(C 2 -C1o)-alkenyl, 0-(C 2

-C

1 o)-alkynyl, S-(-C)-alkyl, S-(C 2

-C

6 )-alkenyl, S-(C 2

-C

6 )-alkynyl, (C 3

-C

7 )-cycloalkyl,

(C

3 -C)-cycloalkyl-(Cr-C 4 )-alkyl, where alkyl, alkenyl, alkynyl and 5 cycloalkyl may be substituted more than once by F, CI, Br, SO-phenyl, S0 2 -phenyl, where the phenyl ring may be substituted by F, CI, Br or R13, or OR13, COOR13, CON(R1 4)(R1 5), N(R14))(R15) or CO-hetero alkyl, or O-SO-(CrC 6 )-alkyl, O-SO2-(O1-C 6 )-alkyl, O-SO 2

-(C

6

-C

1 o)-aryl, 0-(C 6

-C

1 o)-aryl, where aryl may be substituted up to twice by F, CI, CN, 10 OR13, R13, CF 3 or OCF 3 , or SO-(CriC 6 )-alkyl, S0 2

-(C-C

6 )-alkyl, S02 (C6-Clo)-aryl, where the phenyl ring may be substituted up to twice by F, Cl, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R1 4)(R1 5), or S0 2 -N(R1 4)(R1 5), COOR1 3, CO-heteroalkyl, N(R1 4)(R1 5) or heteroalkyl; 15 R14, R15 independently of one another H, (C-C 6 )-alkyl, where alkyl may be substituted by N(R13)2, or (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, (C3-C7) cycloalkyl, (C 3

-C

7 )-cycloalkyl-(CrC 4 )-alkylene, CO-(Cr 1

C

6 )-alkyl, COO (OC)-alkyl, COO-(C-C 6 )-alkylene-OCO-(C-C 6 )-alkyl, CO-phenyl, 20 COO-phenyl, COO-(CriC 6 )-alkenyl-phenyl, OH, 0-(C-C 6 )-alkyl, O-(Cr- 6 )-alkenyl-phenyl or NH 2 ; or the radicals R14 and R15 form with the nitrogen atom to which they are bonded a 3-7-membered, saturated heterocyclic ring which may comprise up to 2 25 further heteroatoms from the group of N, 0 or S, where the heterocyclic ring may be substituted up to three times by F, C, Br, OH, oxo, N(R16)(R17) or (CriC 4 )-alkyl; R16, R17 independently of one another H, (C 1

C

6 )-alkyl, where alkyl may be 30 substituted by N(R13)2, or (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, (C3-C7) cycloalkyl, (C 3

-C

7 )-cycloalkyl-(Cr-C 4 )-alkylene, CO-(Cl C 6 )-alkyl, COO

(C-C

6 )-alkyl, COO-(Cr 1

C

6 )-alkylene-OCO-(Cr-C 6 )-alkyl, CO-phenyl, COO-phenyl, COO-(Cr C 6 )-alkenyl-phenyl, OH, 0-(Oi-C 6 )-alkyl, O-(PC)-alkenyl-phenyl or NH 2

;

8 heteroalkyl a 3-7-membered, saturated or up to triunsaturated heterocyclic ring which may comprise up to 4 heteroatoms which correspond to N, 0 or S, where the heterocyclic ring may be substituted at all sensible positions 5 up to three times by F, Cl, Br, CN, oxo, (C1-C 4 )-alkyl, (Co-C 4 )-alkylene COOR13, CON(R1 4)(R1 5), OR13 or N(R14)(R15) or phenyl, where phenyl may be substituted by COOR13; R8 N(R18)(R19) or 0R20; 10 or R8 and R4 together form the group -NH-CO-; R18, R19 independently of one another H, (C1-C1o)-alkyl, (C 2

-C

1 o)-alkenyl, (C2-Clo)-alkynyl, (C3-C 7 )-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C 6 )-alkyl, (C6-Clo)-aryl, (C6-C1o)-aryl-(C1-C4)-alkyl, (C 6 -C1o)-aryl-(C 2

-C

4 )-alkenyl, 15 (C 6 -CIo)-aryl-(C 2

-C

4 )-alkynyl, heteroaryl, heteroaryl-(C 2

-C

4 )-alkyl, heteroaryl-(C 2 -C4)-alkenyl, heteroaryl-(C 2

-C

4 )-alkynyl, where alkyl, alkenyl, alkynyl and cycloalkyl may be substituted more than once by F, Cl, CN, OR13, R13, CF 3 , OCF 3 , (C 6

-C

1 o)-aryl, NH-C(=NR14) N(R1 4)(R1 5), N(R1 4)(R1 5), C(=NR1 4)-N(R1 4)(R1 5), COOR1 3 or 20 CON(R1 4)(R1 5), and where aryl may be substituted more than once by F, Cl, CN, O-(C1-Ce)-alkyl, 0-(C 2

-C

6 )-alkenyl, (C1-C 6 )-alkyl, (C 2

-C

6

)

alkenyl, CO-(C1-C 6 )-alkyl, CO-(C 2

-C

6 )-alkenyl, where alkyl and alkenyl may be substituted more than once by F, Cl, CH 3 , OCH 3 or CN, or NH-C(=NR14)-N(R14)(R15), N(R14)(R15), C(=NR14)-N(R14)(R15), 25 COOR13, CON(R14)(R15), O-phenyl, phenyl or pyridyl; COOR13, CON-(R14)(R15), CO-heteroalkyl, CO-(C6-Clo)-aryl or S0 2

-(C

6 -C1o)-aryl, where aryl may be substituted up to twice by F, Cl, CN, OH, (C1-C 6 )-alkyl, 0-(C1-C 6 )-alkyl, CF 3 , OCF 3 , COOR13 or CON(R14)(R15); 30 or the radicals R1 8 and R1 9 form together with the nitrogen atom to which they are bonded a 3-7-membered, saturated heterocyclic ring which may comprise up to 2 further heteroatoms from the group of N, 0 or S, where the heterocyclic ring may be substituted up to three times by F, Cl, Br, 9 OH, oxo, N(R16)(R17) or (Cr-C4)-alkyl; R20 (C1-C1o)-alkyl, (C 2 -C1o)-alkenyl, (C2-Clo)-alkynyl, (C 3

-C

7 )-cycloalkyl,

(C

3 -C7)-cycloalkyl-(C1-C 6 )-alkyl, (C 6 -C1o)-aryl, (C 6

-C

1 O)-aryl-(C1-C 4 )-alkyl, 5 (C 6

-C

1 o)-aryl-(C 2

-C

4 )-alkenyl or (C 6

-C

1 o)-aryl-(C 2

-C

4 )-alkynyl, where aryl may be substituted more than once by F, Cl, CN, 0-(C1-C 6 )-alkyl, 0-(C 2

-C

6 )-alkenyl, (C1-C 6 )-alkyl, (C 2

-C

6 )-alkenyl, CO-(C1-C 6 )-alkyl,

CO-(C

2

-C

6 )-alkenyl, where alkyl and alkenyl may be substituted more than once by F, CI, CH 3 , OCH 3 or CN, or NH-C(=NR1 4)-N(R14)(R1 5), 10 N(R14)(R15), C(=NR14)-N(R14)(R15), COOR13, CON(R14)(R15), 0-phenyl, phenyl or pyridyl, where phenyl may be substituted by F, Cl, CN or (C 1 -C)-alkyl; and their physiologically tolerated salts, 15 excluding compounds of the formula la in which the radicals R6 and R8 have at the same time the following meanings: R6 H, CI, CF 3 , CH 3 ; 20 R8 substituted or unsubstituted NH-phenyl. Particular preference is given to compounds of the formula la in which one or more radical(s) has or have the following meaning: 25 R9, R10, R1 1 independently of one another F, Cl; R12 H; 30 R13 H, (C 1

-C

6 )-alkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, (C 3

-C

7 )-cycloalkyl or

(C

3

-C

7 )-cycloalkyl-(Cr-C 4 )-alkylene; R3, R4, R5 independently of one another H, COOR13; 10 R6 F, Cl, CF 3 , OCF 3 , (CrC 6 )-alkyl, (C 2

-C

6 )-alkenyl, (C 2

-C

6 )-alkynyl, 0 (C1-C1o)-alkyl, 0-(C 2 -C1o)-alkenyl, 0-(C 2 -C1o)-alkynyl, (C 3

-C

7 )-cycloalkyl,

(C

3

-C

7 )-cycloalkyl-(C-C 4 )-alkyl, N(R14)(R15) or heteroalkyl, where alkyl, alkenyl, alkynyl and cycloalkyl may be more than once by F, COOR13, 5 CON(R14)(R15), N(R14)(R15); R14, R15 independently of one another H, (C-C 6 )-alkyl, where alkyl may be substituted by N(R13)2; 1o heteroalkyl a 3-7-membered, saturated or up to triunsaturated heterocyclic ring which may comprise up to 4 heteroatoms which correspond to N, 0 or S, where the heterocyclic ring may be substituted at all sensible positions up to three times by F, Cl, Br, CN, oxo, (C-C 4 )-alkyl, (Co-C 4 )-alkylene COOR13, CON(R1 4)(R1 5), OR13 or N(R14)(R15) or phenyl, where 15 phenyl may be substituted by COOR13; R8 N(R18)(R19) or OR20; or R8 and R4 together form the group -NH-CO-; 2o R18, R19 independently of one another H, (C-C1o)-alkyl, (C 2 -C1o)-alkenyl, (C2-Clo)-alkynyl, (C 3 -Cr)-cycloalkyl, (C 3 -Cr)-cycloalkyl-(C-C 6 )-alkyl,

(C

6

-C

1 o)-aryl, (C 6 -C1O)-aryl-(C-C 4 )-alkyl, (C 6

-C

1 o)-aryl-(C 2

-C

4 )-alkenyl,

(C

6 -C1o)-aryl-(C 2

-C

4 )-alkynyl, heteroaryl, heteroaryl-(C 2

-C

4 )-alkyl, heteroaryl-(C 2

-C

4 )-alkenyl, heteroaryl-(C 2

-C

4 )-alkynyl, where alkyl, 25 alkenyl, alkynyl and cycloalkyl may be substituted more than once by F, Cl, CN, OR13, R13, CF 3 , OCF 3 , (C 6 -C1o)-aryl, NH-C(=NR14) N(R14)(R15), N(R14)(R15), C(=NR14)-N(R14)(R15), COOR13 or CON(R1 4)(R1 5), and where aryl may be substituted more than once by F, Cl, CN, 0-(C-C 6 )-alkyl, 0-(C 2

-C

6 )-alkenyl, (CrC 6 )-alkyl, (C 2

-C

6

)

30 alkenyl, CO-(C-C 6 )-alkyl, CO-(C 2

-C

6 )-alkenyl, where alkyl and alkenyl may be substituted more than once by F, Cl, CH 3 , OCH 3 or CN, or NH-C(=NR14)-N(R14)(R15), N(R14)(R15), C(=NR14)-N(R14)(R15), COOR13, CON(R14)(R1 5), 0-phenyl, phenyl or pyridyl; COOR13, CON-(R14)(R15), CO-heteroalkyl, CO-(C 6 -C1o)-aryl or 11 S0 2

-(C

6 -C1o)-aryl, where aryl may be substituted up to twice by F, CI, CN, OH, (C-C)-alkyl, O-(OC0)-alkyl, CF 3 , OCF 3 , COOR13 or CON(R14)(R15); 5 or the radicals R1 8 and R1 9 form together with the nitrogen atom to which they are bonded a 3-7-membered, saturated heterocyclic ring which may comprise up to 2 further heteroatoms from the group of N, 0 or S, where the heterocyclic ring may be substituted up to three times by F, CI, Br, OH, oxo, N(R16)(R17) or (CriC 4 )-alkyl; 10 R20 (CO-C1o)-alkyl, (C 2

-C

1 o)-alkenyl, (C2-C1o)-alkynyl, (C 3

-C

7 )-cycloalkyl, (C3-C 7 )-cycloalkyl-(C-C 6 )-alkyl, (C 6

-C

1 o)-aryl, (C6-C1o)-aryl-(Cr-C 4 )-alkyl,

(C

6

-C

1 o)-aryl-(C 2

-C

4 )-alkenyl or (C 6

-C

1 o)-aryl-(C 2

-C

4 )-alkynyl, where aryl may be substituted more than once by F, C, CN, 0-(Cr 1

C

6 )-alkyl, 15 0-(C 2

-C

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

-C

6 )-alkenyl, CO-(Cr 1

C

6 )-alkyl,

CO-(C

2

-C

6 )-alkenyl, where alkyl and alkenyl may be substituted more than once by F, Cl, CH 3 , OCH 3 or CN, or NH-C(=NR1 4)-N(R14)(R1 5), N(R14)(RI15), C(=NR14)-N(R14)(R15), COOR13, CON(R14)(R15), 0-phenyl, phenyl or pyridyl, where phenyl may be substituted by F, C, 20 CN or (OC)-alkyl; and their physiologically tolerated salts, excluding compounds of the formula la in which the radicals R6 and R8 have at the 25 same time the following meanings: R6 H, C, CF 3 , CH 3 ; R8 substituted or unsubstituted NH-phenyl. 30 R9, R10, R11 independently of one another F or Cl; R12 H; 12 R13 independently of one another H or (C 1 -C)-alkyl; R1, R2 H; 5 R3, R4, R5 independently of one another H, COOR1 3; R6 CI, OCF 3 , COOR13, N(R14)(R15), (C 2

-C

6 )-alkenyl, 0-(C 1

-C

10 )-alkyl, where alkyl, alkenyl may be substituted more than once by F, COOR13 or CON(R14)(R1 5); 10 R14, R15 (C 1 -C)-alkyl, where alkyl may be substituted by N(R1 3)2; or the radicals R14 and R15 form with the nitrogen atom to which they are bonded a 5-membered, saturated heterocyclic ring; 15 R8 N(R18)(R19) or 0R20; R18, R19 independently of one another H, (C 1

-C

1 o)-alkyl, (C 2 -C1o)-alkenyl, where alkyl may be substituted by COOR13, N(R1 3)2 or phenyl, or (C3-C7) 20 cycloalkyl or (C 6 -C1o)-aryl, where aryl may be substituted more than once by F, Cl, CN, (C1-C)-alkyl, O-(C1-C)-alkyl, CO-(C 1 -C)-alkyl, where alkyl may be substituted more than once by F, or O-phenyl, phenyl, pyridyl or COOR13; 25 R20 (C1-C1o)-alkyl, (C 2 -C1o)-alkenyl, (C 2 -C1o)-alkynyl or phenyl, where phenyl may be substituted by Cl or (C1-C 6 )-alkyl; and their physiologically tolerated salts. 30 The alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 R12, R13, R14, R15, R16, R17, R18, R19 or R20 may be both straight-chain and branched.

13 If radicals or substituents may occur more than once in the compounds of the formula 1, such as, for example, COOR13, they may all, independently of one another, have the stated meanings and be identical or different. 5 The invention relates to compounds of the formula I in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof. Pharmaceutically acceptable salts are, because their solubility in water is greater 10 than that of the initial or basic compounds, particularly suitable for medical applications. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and of organic acids such as, for 15 example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), and salts of 20 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 25 intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications. The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for 30 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.

14 Physiologically functional derivatives include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not. 5 The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention. 10 All references to "compound(s) of formula I" hereinafter refer to compound(s) of the formula I as described above, and their salts, solvates and physiologically functional derivatives as described herein. 15 The compound(s) of formula (1) may also be administered in combination with further active ingredients. 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, 20 the intended 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 25 minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the 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, 30 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 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 15 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 pharmaceutically active substances may likewise be present, including other compounds of formula 1. 5 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. Pharmaceutical compositions of the invention are those suitable for oral, rectal, 10 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 formulations and coated slow-release formulations also belong 15 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. 20 Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, wafers, 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 25 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 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 30 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 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 16 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. Pharmaceutical compositions which are suitable for peroral (sublingual) 5 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. 10 Pharmaceutical compositions suitable for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula 1, 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 15 preferably be produced by mixing the 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 20 form 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 25 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 to 15% by weight of the composition, for example from 0.5 to 2%. 30 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 ingredient in an aqueous solution which is buffered where appropriate, 17 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 5 (1986). Further active ingredients suitable for combination products are: all antidiabetics mentioned in the Rote Liste 2001, chapter 12. They may be combined with the compounds of the formula I of the invention in particular for a 10 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 USP Dictionary of USAN and 15 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 98/08871 of Novo Nordisk A/S, and orally effective hypoglycemic active ingredients. 20 The orally effective hypoglycemic active ingredients include, preferably, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 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 25 stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds which 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. 30 In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMG-CoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.

18 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, tiqueside, pamaqueside. 5 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. In one embodiment of the invention, the compounds of the formula I are administered 10 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 combination with a mixed PPAR alpha/gamma agonist, such as, for example, 15 GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT/USOO/11833, PCT/USO0/1 1490, DE10142734.4. In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate such as, for example, fenofibrate, clofibrate, bezafibrate. 20 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-1 03757. 25 In one embodiment of the invention, the compounds of the formula I are administered in combination with a 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 30 in 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.

19 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. 5 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 o in combination with an antioxidant, such as, for example, OPC-14117. 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. .5 In one embodiment of the invention, the compounds of the formula I are administered in 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, 2o BMS-1 88494. 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, Cl-1027 or nicotinic acid. 25 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 30 in 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.

20 In one embodiment, the compounds of the formula I are administered in combination with a biguanide, such as, for example, metformin. In one further embodiment, the compounds of the formula I are administered in 5 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, 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] i0 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. 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 15 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 and metformin, with a sulfonylurea and acarbose, repaglinide and 20 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 25 influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al. in: Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g. naphthalene-1-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 30 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-ylurea hydrochloride (SB-334867-A)), H3 agonists (3-cyclohexyl 1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-y)propan-1 -one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6-tri- 21 methylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists, P3 agonists (e.g. 1-(4-chloro-3 methanesulfonylmethylpheny)-2-[2-(2,3-dimethyl-1 H-indol-6-yloxy)ethylamino] ethanol hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) 5 agonists, CCK-A agonists (e.g. {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexyl ethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed serotoninergic 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 o 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-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.; s 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 inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR-P agonists. 2o 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. 25 In one embodiment, the other active ingredient is dexamphetamine or amphetamine. In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine. In another embodiment, the other active ingredient is sibutramine. In one embodiment, the other active ingredient is orlistat. In one embodiment, the other active ingredient is mazindol or phentermine. 30 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.) 22 Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, 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 5 administered in the form of food products such as, for example, in bakery products or muesli bars. 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 [0 more other pharmacologically active substances is regarded as falling within the protection conferred by the present invention.

23

CH

3 CHa0W O N C H 3 OH HN O NH

CH

3

H

3 C

CH

3 S C

CH

3

CH

3 OPC-14117

CH

3 JTT-705 Cl Br, C OH O SB-204990 HO N O CH 3 II ~O NCH 3 N NO-1886 0 OH HC OH

CH

3 O CI-1027 HO, //IiC O O OH 3

H

3 O H 3

O

0

H

3 BMS-1 88494 O( OH 3 0 0 N 0 0 GI 262570 0 N N 0 T H JTT-501 24 The examples detailed below serve to illustrate the invention, but without restricting it.

0 0 o 0 0 0 0 0 0 0Lfl r U) W) V) U) o-: 0 0 (0 0 o=K) 0 0 0 Ix /I 0 6o (6 tin (6 DC (0 (60c (6 CD~ L)M 0 0 0 0 ( C N I (NJC CNI CNI (N 0 cmE N C4N N 04 CI C-4 U) LL L L IL L LL LL Li.. LL O;L6) L6 L L6 A u6 L6 L6) L6 E cu 500 0 00 w ( NJ C C (N CN I CN C14 CD) n T C4 w~ w~U a( Cu I-w - e _- - ezz-1 l 0 0 0 0 0 0 0 0 0 u) m C, 0 0/V o 0 0 04 Z Z LL zZI Z I 0 00 0 0 0 0 0 0 CN ND 04 CN C4 04 CD ND 04 ___ 4 4 4 4 4 .4J lr =i Q IQ IQ lr Li IQ I C CD CD CD CD C C CD NNN V) N N N 0 o 0 0 0 0 0 IQ o o 000 0 0O CD CD C CD) CD C C) D D D C) CD CJCNJ (NI (NJ (N (NI ( N N N N N Nm N CD CD CD CD CD CD CD CD T-CM mIV W 04 0 04 04 04 0C0 (.) 0 U v C., C)c)Ce r Y C.)(Y cr) LN C.) C) C)C ) ) 0 0 0 0 0- 0 0 0 0 0 C' C' C' C' C' C' C' C' C' C' LQ LQ LQ LQ LQ LAi LA LA LA LA IIT I IT IT ITITI co - cc CD Co U 4 m-U IV WL CM e q CM V) V m 0 0 0 0 0 0 0 0 0 z 0 0 0 0 0 U. U. 0 =Z z =z =z = Z 0 0 0 0 0 0C0 0 0 0 0 0 0 0 CD CD CD CD CD CD CD ITI (a I cI m I T CV Cl l l 4I LL XL 0 Z~ Z CY) ce) CY) c~r) e) CY) CY) cr) ce) C) () a., 0. 0. C)a C) 0 0 0 0 00 0 C09C (6 (6 (6 (0 (0 (0 (0 (0 to L6 L6 L6 6A L6 LA LA L6 L6 qqI 't I4 1 IIr 14 I C. C,4 C4 N C4 4 .Cj 04 (N (Ni (i (Ni C-4 04 N LLLL UL LL LL LL LL LL If If :1 If l IfI (N (N4 C4 (N (N (N (N 04 04 C', co a, C,) le :3 "V U)e q ew 0 0 0 0 0 0 0 0 00 00 0- 0 ~ 0 0 0 0 C.6 (6 C-4 N IT IT C)) C' CD CD CD (0 CD (0 CD (0 LO 1.O W) LO LO w) LO e) oN -h 0 0 0 0 0 0 0 0 0 0 0 0 0 o 0 0 0 0 0 /l 0/ /I /I /I /I l L6 L6 L6 L6 L6 LA LA N N (1N N co (N to (No( (D (o 0 0 0 0 0 0 0 0 0 C. , 0 U.. C) Ne CV .. Y)() -l) CV Y N 0 0 0 0 0 0 0 0 0 0I 0I 01 01 0l 0I 01 0I 0I co (o to (0 (D (0 (D co (0 I6 I6 I6 LI 6 I6 I 6 3I TZ 3 II C14 C) U) U) U) U) U) U) U) CM I1 Ci I~ N CI Il C-4 * 4 I I 4 I Li. LI.L LLc Lq. U.. Lq. Lq. U fC 0) CD0 m4 9) 0 0 0 0 0 0 0 00 0 0 00 C= C) 0f C) U (V) L e 0 0 0 0 0 0 0 oI 01 0I 0I 0I 01 01 / c m a: m m (0 C D C D C D C D C D C D l*f I oo Go o 0 0 0 0 0 0 0 0 0 LL LL 04 0 0 - 0 I 0 Izx zz xz mxz x z z 0Y 0Y 0Y 0e 0Y 0r 0f 0f 0Y 0 0 0 0 0 0 0 0 0 (D (D (D (D co (0 CD CD C L6 L6 6A L6 L6 L6 L6 L6 L6 z z z z z z 3 I ~ ~ 3 IS LiLL LL U. ILLLQ CWA le LfA co1.G a DT oo co 0o coc o )a 0 0 0 0 0 0 0 0 0 0 0 0 0 0 cl) C.) UC) 0 U ~) N VN CI 4 mz -- 0-) 00 -0 0 0 0 mzOzO= ' 0 00' 00 C~ )C) C) C) C) C) C) C)CY) CY) CY) CO) mY 0 0 0 0~ C N N 00 00 00 0 00 0 0 CD CD CD CD CD CD CD CD CD CD CD CD CD CD *qL Iq Li IQ I Iq Iq l Ir Li i Ili m In D (D m a, a, Q I I CD CD C T0 T0 10 10 %0 10 -X~~~~- _X- le X _ 0 0 0 0 0 0 0 0 0 0 0 C')CI 0 C) 0C 0 0 00 0 z0 CY)) C C') C C') CY)C')) C C' () ce' ) CC') (C') 0 0 0 0 0 0 0 0 0 00 C CD C (0 C C C C C CD CD 101 IT0 01 10 01 0 1 C5 C5 5 C III I I I I I I I I II- Io m C) cm m I CD CD CD CD %- T % % o0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 i 0 3: 0 z In If VI I) C4 C i Nq Sn m (l) I I m m 3 30 1 m C) I. 000 (.) 0-)C o z 0o z 0o z 10 z z Iz z Iz Iz z Iz Ne Nf (1)(~ LL L LL oooo -Z -Z -Z I 9 0 0 00 00 (D (0 (0 (0 (0 (0 l(0 (0 (0 I(0 111 I6 LI I6 1 161 1 1 1166 6 6 L6 L6 M 3: 1: M: M m m: a: m m (0 (0 (0 LO (0 (0 (0 (0 A0 A0 ( 0 X111 3I M M M1mm11MM1M111: tL 00 a) 40 T- C4 U-) to to r U-) 0 I C4 Sq cm C4 04 I4 C4 V + CL E 0 ClCu ClCu CC. 0 0 (6 E :3 CL CD -o CCi 0 An E a) C44 40 The compounds of the formula I are distinguished by beneficial effects on glucose metabolism; in particular they lower the blood glucose level and are suitable for the treatment of type 2 diabetes. The compounds can therefore be employed alone or in combination with other blood glucose-lowering active ingredients (antidiabetics). 5 The compounds of the formula I are further suitable for the treatment of late complications of diabetes such as, for example, nephropathy, retinopathy, neuropathy and myocardial infarction, myocardial infarction, peripheral arterial occlusive diseases, thromboses, arteriosclerosis, syndrome X, obesity, inflammations, immune diseases, autoimmune diseases such as, for example, AIDS, 10 asthma, osteoporosis, cancer, psoriasis, Alzheimer's, schizophrenia and infectious diseases. The activity of the compounds was assayed as follows: 15 Glycogen phosphorylase a activity assay The effect of compounds on the activity of the active form of glycogen phosphorylase (GPa) was measured in the reverse direction by following the synthesis of glycogen 20 from glucose 1-phosphate by determining the liberation of inorganic phosphate. All the reactions were carried out as duplicate determinations in microtiter plates with 96 wells (Half Area Plates, Costar No 3696), measuring the change in absorption owing to the formation of the reaction product at the wavelength specified hereinafter in a Multiskan Ascent Elisa Reader (Lab Systems, Finland). In order to measure the 25 GPa enzymic activity in the reverse direction, the general method of Engers et al. (Engers HD, Shechosky S, Madsen NB, Can J Biochem 1970 Jul;48(7):746-754) was used to measure the conversion of glucose 1-phosphate into glycogen and inorganic phosphate, with the following modifications: human glycogen phosphorylase a (for example with 0.76 mg of protein/ml (Aventis Pharma Deutschland GmbH), dissolved 30 in buffer solution E (25 mM p-glycerophosphate, pH 7.0, 1 mM EDTA and 1 mM dithiotreitol) was diluted with buffer T (50 mM Hepes, pH 7.0, 100 mM KCI, 2.5 mM EDTA, 2.5 mM MgC1 2 -6H 2 0) and addition of 5 mg/ml glycogen to a concentration of 10 pg of protein/ml. Test substances were prepared as 10 mM solution in DMSO and diluted to 50 pM with buffer solution T. To 10 pl of this solution were added 10 pl of 41 37.5 mM glucose, dissolved in buffer solution T, and 5 mg/ml glycogen, plus 10 pl of a solution of human glycogen phosphorylase a (10 pg of protein/ml) and 20 pl of glucose 1-phosphate, 2.5 mM. The baseline glycogen phosphorylase a activity in the absence of test substance was determined by adding 10 pl of buffer solution T (0.1% 5 DMSO). The mixture was incubated at room temperature for 40 minutes, and the liberated inorganic phosphate was measured by the general method of Drueckes et al. (Drueckes P, Schinzel R, Palm D, Anal Biochem 1995 Sep 1;230(1):173-177) with the following modifications: 50 pl of a stop solution of 7.3 mM ammonium molybdate, 10.9 mM zinc acetate, 3.6% ascorbic acid, 0.9% SDS are added to 50 pl of the 10 enzyme mixture. After incubation at 45 0 C for 60 minutes, the absorption at 820 nm was measured. To determine the background absorption, in a separate mixture the stop solution was added immediately after addition of the glucose 1-phosphate solution. This test was carried out with a concentration of 10 pM of the test substance in order to determine the particular inhibition of glycogen phosphorylase a in vitro by 15 the test substance. Table 2: Biological activity Ex. % inhibition Ex. % inhibition at10pM at10pM 2 96 91 99 3 53 92 78 4 89 104 66 7 100 108 52 13 103 110 73 14 70 113 83 21 75 114 48 26 61 121 99 42 55 125 74 44 40 127 102 65 60 130 28 76 73 132 97 90 89 42 It is evident from the table that the compounds of the formula I inhibit the activity of glycogen phosphorylase a and thus are very suitable for lowering the blood glucose level. They are therefore particularly suitable for the prevention and treatment of type 2 diabetes. 5 The preparation of some examples is described in detail below, and the other compounds of the formula I were obtained analogously: Experimental part: 10 Example 1: 1 -{3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-4-methoxyphenyl}-3-methylurea a) 2-Chloro-4,5-difluorobenzoyl isocyanate 15 2-Chloro-4,5-difluorobenzamide was dissolved in dichloromethane, mixed with 1.5 eq. of oxalyl chloride and heated to reflux for 16 hours. The reaction mixture was concentrated under high vacuum and employed in stage b without further purification. 20 b) 1-(2-Chloro-4,5-difluorobenzoyl)-3-(2-methoxy-5-nitrophenyl)urea 4.0 g (23.8 mmol) of 2-methoxy-5-nitroaniline were dissolved in 10 ml of N-methyl-2 pyrrolidinone, and 5.2 g (23.8 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate were added. Slight warming occurred. After 15 minutes at room temperature, diethyl ether 25 was added, and the resulting precipitate was filtered off with suction. 6.6 g (79%) of the desired product were obtained. c) 1-(5-Amino-2-methoxyphenyl)-3-(2-chloro-4,5-difluorobenzoyl)urea 30 5.8 g (25.9 mmol) of tin dichloride hydrate were added to 2.0 g (5.2 mmol) of 1-(2-chloro-4,5-difluorobenzoyl)-3-(2-methoxy-5-nitrophenyl)urea in 20 ml of ethyl acetate/methanol mixture at 700C. After 1 hour, 30 ml of N-methyl-2-pyrrolidinone were added, and the mixture was stirred for a further 2 hours. After cooling, the reaction mixture was made basic and the resulting precipitate was filtered off with 43 suction. The phases were separated. The organic phase was then washed three times with water, dried and concentrated under high vacuum. 1.2 g (67%) of the desired product were obtained. 5 d) 1-{3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-4-methoxyphenyl}-3-methylurea 600 mg (1.7 mmol) of 1-(5-amino-2-methoxyphenyl)-3-(2-chloro-4,5-difluoro benzoyl)urea were dissolved in 5 ml of acetonitrile, and 69 mg (1.7 mmol) of methyl 10 isocyanate were added. After stirring at room temperature for one hour, the resulting precipitate was filtered off with suction. 638 mg (91 %) of the desired product were obtained. Example 3: 15 3-[3-(2-Chloro-4-fluorobenzoyl)ureido]-4-methoxycarbonylaminobenzoic acid a) 2-Chloro-4-fluorobenzoyl isocyanate 1.64 g (6 mmol) of 2-chloro-4-fluorobenzamide were dissolved in 3 ml of 20 dichloromethane and, at 00C and under a nitrogen atmosphere, 0.8 ml (9.3 mmol) of oxalyl chloride was added, and the mixture was heated to reflux for 9 hours. The reaction mixture was concentrated under high vacuum and afforded 1.17 g (5.8 mmol) of the desired product, which was employed as solution in dichloromethane (1 mmol in 1.7 ml of solution) in stage b. 25 b) 4-Amino-3-[3-(2-chloro-4-fluorobenzoyl)ureido]benzoic acid 150 mg (1 mmol) of 3,4-diaminobenzoic acid were dissolved in 2 ml of N-methyl-2 pyrrolidinone and, at 0CC, 1 ml (1.2 mmol) of the 2-chloro-4-fluorobenzoyl 30 isocyanate/dichloromethane solution prepared in stage a was added. The resulting precipitate was filtered off with suction. The crude mixture (500 mg) was purified by column chromatography (dichloromethane/methanol = 98/2 to 93/7). 80 mg (25%) of the desired product were obtained.

44 c) 3-[3-(2-Chloro-4-fluorobenzoyl)ureido]-4-methoxycarbonylaminobenzoic acid 28 mg (0.08 mmol) of 4-amino-3-[3-(2-chloro-4-fluorobenzoyl)ureido]benzoic acid were dissolved in 0.5 ml of N-methyl-2-pyrrolidinone and stirred with 0.02 ml 5 (0.24 mmol) of pyridine and 0.007 ml of methyl chloroformate at room temperature for 4 hours. Water and acetic acid were added, and the resulting precipitate was filtered off with suction. 18 mg (55%) of the desired product were obtained. Melting point: decomposition >4000C 10 Example 54: Methyl 3-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-[3-(2-trifluoromethylphenyl) ureido]phenyl}acrylate a) Methyl 3-{2-[3-(2-chloro-4,5-difluorobenzoyl)u reido]-4-nitrophenyl}acrylate 15 4.5 g (20.3 mmol) of methyl 3-(2-amino-4-nitrophenyl)acrylate were stirred with 4.41 g (20.3 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate (Example 1 a) in 50 ml acetonitrile at 500C for one hour. The reaction mixture was then concentrated, the residue was stirred with diethyl ether, and the resulting solid was filtered off with 20 suction. 8.5 g (95%) of the desired product were obtained. b) Methyl 3-{4-amino-2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]phenyl}acrylate 8.5 g (19.3 mmol) of methyl 3-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-nitro 25 phenyl}acrylate were suspended in 60 ml of a mixture of glacial acetic acid and concentrated hydrochloric acid (10:1) and heated to 700C. Then 8.85 g (135.3 mmol) of zinc powder were added. After 30 minutes, the mixture was cooled, the solid was filtered off with suction, and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with a 10% strength sodium bicarbonate solution. The 30 organic phase was dried and concentrated. 7.9 g (100%) of the desired product were obtained. c) Methyl 3-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-[3-(2-trifluoromethyl phenyl)ureido]phenyl}acrylate 45 100 mg (0.24 mmol) of methyl 3-{4-amino-2-[3-(2-chloro-4,5-difluorobenzoyl) ureido]phenyl}acrylate were dissolved in 1 ml of acetonitrile and mixed with 2-trifluoromethylphenyl isocyanate and shaken at 600C for 14 hours. The resulting 5 precipitate was filtered off with suction, and 16 mg (11%) of the desired product were obtained. Example 110: Methyl (E)-3-[2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-(4-chloro 10 phenoxycarbonylamino)phenyl]acrylate 100 mg (0.24 mmol) of methyl 3-{4-amino-2-[3-(2-chloro-4,5-difluorobenzoyl) ureido]phenyl}acrylate (example 54 b) were reacted in 2 ml of dimethylformamide with potassium carbonate and 4-chlorophenyl chloroformate. The precipitate resulting 15 after 4 hours was filtered off with suction. Preparative HPLC (column: Waters XterraTMMS C18, 5 pm, 30x100 mm, mobile phases: A: H 2 0 + 0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A / 10% B to 17.5 minutes 10% A/ 90% B) resulted in 12 mg (9%) of the desired product. 20 Example 132: 1-(2-Chloro-4,5-difluorobenzoyl)-3-(6-methoxy-2,4-dioxo-1,2,3,4-tetrahydro quinazolin-7-yl)urea a) N-(4-Methoxy-2-methylphenyl)acetamide 25 41.1 g (0.3 mol) of 4-methoxy-2-methylphenylamine and 37 g (0.5 mol) of dimethyl ethylamine were dissolved in 50 ml of tetrahydrofuran, and 35.7 g (0.35 mol) of acetic anhydride were added while stirring. The solution heated to boiling during this. It was stirred at room temperature for 1 hour and cooled to 00C. The resulting precipitate 30 was filtered off with suction and washed several times with a little cold tetrahydrofuran and dried. 40 g (75%) of colorless crystals of the desired product were obtained. b) N-(4-Methoxy-2-methyl-5-nitrophenyl)acetamide 46 34 g (0.19 mol) of N-(4-methoxy-2-methylphenyl)acetamide were added in small portions to a mixture of 40 ml of glacial acetic acid and 70 ml of fuming nitric acid at -10 to -15*C. These portions were such that the temperature did not rise above 5 -10*C. The reaction mixture was then poured onto ice. The resulting precipitate was filtered off with suction and washed with water, ethanol and diethyl ether. 22.5 g (53%) of the desired product were obtained. c) 2-Acetylamino-5-methoxy-4-nitrobenzoic acid 10 11.2 g (50 mmol) of N-(4-methoxy-2-methyl-5-nitrophenyl)acetamide and 8.5 g (62.5 mmol) of anhydrous magnesium sulfate were suspended in 500 ml of water and heated to 850C. Over the course of 30 minutes, a solution of 21.8 g (138 mmol) of potassium permanganate in 250 ml of water was added dropwise. The reaction 15 mixture was stirred at 850C for 3 hours and then filtered hot to remove manganese dioxide. The latter was extracted by boiling three times with 100 ml of water each time. The combined aqueous phases were again filtered hot and concentrated to about 150 ml in vacuo. The residue was acidified to pH 1-2 with concentrated hydrochloric acid and cooled to 00C. The resulting product was filtered off with 20 suction, washed with water and diethyl ether, dried and reacted without further purification in the next stage. d) 2-Amino-5-methoxy-4-nitrobenzoic acid 25 7.5 g of 2-acetylamino-5-methoxy-4-nitrobenzoic acid (crude mixture from stage c) were heated to reflux in 50 ml of water and 20 ml of concentrated hydrochloric acid for 3 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane/isopropanol = 9/1). 3.1 g (50%) of the desired product were obtained. 30 e) 6-Methoxy-7-nitro-1 H-benzo[d][1,3]oxazine-2,4-dione 2.0 g (9.4 mmol) of 2-amino-5-methoxy-4-nitrobenzoic acid were dissolved in 20 ml of chloroform and 10 ml of tetrahydrofuran, and 20 ml of 20% strength phosgene 47 solution (1.8 M in toluene) were added. After 3 hours under reflux, a further 10 ml of phosgene solution were added at 600C, and the mixture was stirred at 60*C for a further 12 hours. The phosgene was distilled off and the residue was concentrated in vacuo after addition of toluene several times. 2.2 g (100%) of the desired product 5 were obtained. f) 2-Amino-5-methoxy-4-nitrobenzamide 476 mg (2 mmol) of 6-methoxy-7-nitro-1 H-benzo[d][1,3]oxazine-2,4-dione and 1.5 g 10 (20 mmol) of ammonium acetate were dissolved in 20 ml of acetic acid and heated at 1050C for 3 hours. The reaction mixture was then poured into ice-water and slowly brought to pH 7 with solid sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated in vacuo. The crude product was triturated with diethyl ether, and the 15 resulting precipitate was filtered off with suction. 285 mg (68%) of the desired product were obtained. g) 6-Methoxy-7-nitro-1 H-quinazoline-2,4-dione 20 108 mg (0.5 mmol) of 2-amino-5-methoxy-4-nitrobenzamide were dissolved in 5 ml of tetrahydrofuran and 5 ml of chloroform, and oxalyl chloride (solution in toluene) was added. The mixture was stirred at 600C for 5 hours and then concentrated in vacuo. Addition of toluene was followed by renewed concentration. 120 mg (100%) of the desired product were obtained. 25 h) 7-Amino-6-methoxy-1 H-quinazoline-2,4-dione 120 mg (0.5 mmol) of 6-methoxy-7-nitro-1 H-quinazoline-2,4-dione were taken up in a mixture of 5 ml of tetrahydrofuran, 5 ml of methanol and 5 ml of acetic acid and 30 hydrogenated with palladium catalysis at room temperature for 3 hours. The reaction solution was heated to dissolve precipitated product and was filtered hot to remove the catalyst. The filtrate was concentrated and, after addition of toluene, again concentrated. 100 mg (100%) of the desired product were obtained.

48 i) 1-(2-Chloro-4,5-difluorobenzoyl)-3-(6-methoxy-2,4-dioxo-1,2,3,4-tetrahydro quinazolin-7-yl)urea 100 mg (0.53 mmol) of 7-amino-6-methoxy-1 H-quinazoline-2,4-dione were 5 suspended in 20 ml of acetonitrile and 2 ml of N-methyl-2-pyrrolidinone, and 200 mg (0.97 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate (example 1 a) were added. The reaction mixture was heated to boiling and then quenched with methanol and concentrated in vacuo. The residue was stirred with acetonitrile, and the resulting precipitate was filtered off. 64 mg (30%) of the desired product were obtained.

Claims (13)

1. A compound of the formula 1, R6 R5 R 7 N R8 RIO R9 X NAN w R1 R2 R3 R4 R11 R12 in which W, X, Y are, independently of one another, 0 or S; 10 R9, R10, R11, R12 are, independently of one another, H, F, CI, Br, OH, CF 3 , NO

2 , CN, OCF 3 , 0-(0 1 -C 6 )-alkyl, 0-(C 2 -C 6 )-alkenyl, 0-(C 2 -C 6 )-alkynyl, O-S0 2 -(C 1 -C 4 )-alkyl, O-SO 2 -phenyl, where the phenyl ring may be substituted up to twice by F, Cl, Br, CN, OR13, R13, CF 3 , OCF 3 , 15 COOR13 or CON(R14)(R1 5), or S-(CriC 6 )-alkyl, S-(C 2 -C 6 )-alkenyl, S-(C 2 -C 6 )-alkynyl, SO-(CriC 6 )-alkyl, S0 2 -(C-C 6 )-alkyl, S0 2 -NH 2 , (Cr C6) alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -Cr)-cycloalkyl, (C3-C7) cycloalkyl-(C-C 4 )-alkylene, (Co-C 6 )-alkylene-COOR13, CON(R14)(R15), (Co-C 6 )-alkylene-N(R14)(R15), NH-COR13, NH-CO-phenyl, NH-SO 2 20 phenyl or phenyl, where the phenyl ring may be substituted up to twice by F, Cl, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R1 4)(R1 5); R13 is H, (C-C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl or (C 3 -C)-cycloalkyl-(Cr-C 4 )-alkylene; 25 R1, R2 are, independently of one another, H, (Cr-C 6 )-alkyl, where alkyl may be substituted by OH, 0-(C-C4)-alkyl or N(R1 4)(R1 5), or O-(Cl-C 6 )-alkyl, 0-(C 2 -C 6 )-alkenyl, 0-(C 2 -C 6 )-alkynyl, CO-(Cr C 6 )-alkyl, CO-(C2-C6)- 50 alkenyl, CO-(C 2 -C 6 )-alkynyl, COOR13 or (Co-C)-alkylene-COOR13; R3, R4, R5, R6 are, independently of one another, H, F, CI, Br, OH, CF 3 , NO 2 , CN, OCF 3 , (Cr-0)-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, 5 0-(Cr-C10)-alkyl, 0-(C2-C10)-alkenyl, 0-(C2-C10)-alkynyl, S-(Cr-C6)-alkyl, S-(C 2 -C 6 )-alkenyl, S-(C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 ) cycloalkyl-(Cr-C 4 )-alkyl, where alkyl, alkenyl, alkynyl and cycloalkyl may be substituted more than once by F, CI, Br, SO-phenyl, SO 2 -phenyl, where the phenyl ring may be substituted by F, Cl, Br or R13, or OR13, 10 COOR13, CON(R14)(R1 5), N(R14))(R15) or CO-heteroalkyl, or are O-SO-(CrC 6 )-alkyl, O-SO 2 -(C-C 6 )-alkyl, O-SO2-(C 6 -Clo)-aryl, 0-(C 6 -C 1 o)-aryl, where aryl may be substituted up to twice by F, Cl, CN, OR13, R13, CF 3 or OCF 3 , or are SO-(Cr-0)-alkyl, S0 2 -(O,-C 6 )-alkyl, SO 2 -(C 6 -C 10 )-aryl, where the phenyl ring may be substituted up to twice 15 by F, Cl, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R1 4)(R1 5), or are S0 2 -N(R1 4)(R1 5), COOR13, CO-heteroalkyl, N(R14)(R15) or heteroalkyl; R14, R15 are, independently of one another, H, (OC)-alkyl, where alkyl may be 20 substituted by N(R1 3)2, or are (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C3-C7) cycloalkyl, (C 3 -C 7 )-cycloalkyl-(Cr-C 4 )-alkylene, CO-(CI-C 6 )-alkyl, COO (Cr C 6 )-alkyl, COO-(C-C 6 )-alkylene-OCO-(C-C)-alkyl, CO-phenyl, COO-phenyl, COO-(CriC 6 )-alkenyl-phenyl, OH, O-(P-C)-alkyl, 0-(CriC 6 )-alkenyl-phenyl or NH 2 ; 25 or the radicals R14 and R15 form with the nitrogen atom to which they are bonded a

3-7-membered, saturated heterocyclic ring which may comprise up to 2 further heteroatoms from the group of N, 0 or S, where the heterocyclic ring may be substituted up to three times by F, C, Br, OH, oxo, 30 N(R16)(R17) or (Cr 1 C 4 )-alkyl; R16, R17 are, independently of one another, H, (Ce-0)-alkyl, where alkyl may be substituted by N(R13)2, or are (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C3-C7) cycloalkyl, (C 3 -C 7 )-cycloalkyl-(Cr-C 4 )-alkylene, CO-(C-C)-alkyl, COO- 51 (CrO0)-alkyl, COO-(C-C 6 )-alkylene-OCO-(0 1 -C 6 )-alkyl, CO-phenyl, COO-phenyl, COO-(CrC 6 )-alkenyl-phenyl, OH, O-(CrO0)-alkyl, 0-(C-C 6 )-alkenyl-phenyl or NH 2 ; 5 heteroalkyl is a 3-7-membered, saturated or up to triunsaturated heterocyclic ring which may comprise up to 4 heteroatoms which correspond to N, 0 or S, where the heterocyclic ring may be substituted at all sensible positions up to three times by F, Cl, Br, CN, oxo, (C-C 4 )-alkyl, (Co-C 4 )-alkylene COOR13, CON(R14)(R1 5), OR13, N(R14)(R15) or phenyl, where 10 phenyl may be substituted by COOR1 3; R7 is H, (CrC 6 )-alkyl, where alkyl may be substituted by OR13 or N(R14)(R15), or is O-(0 1 -C 6 )-alkyl, CO-(0 1 -C 6 )-alkyl or (Co-C 6 )-alkylene COOR1 3; 15 R8 is N(R18)(R19) or OR20; or R8 and R4 together form the group -NH-CO-; R18, R19 are, independently of one another, H, (C-C1o)-alkyl, (C 2 -C1o)-alkenyl, 20 (C2-Clo)-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C-C 6 )-alkyl, (C 6 -C1o)-aryl, (C6-C1o)-aryl-(C-C 4 )-alkyl, (C 6 -C1o)-aryl-(C 2 -C 4 )-alkenyl, (C 6 -C 1 0 )-aryl-(C 2 -C 4 )-alkynyl, heteroaryl, heteroaryl-(C 2 -C 4 )-alkyl, heteroaryl-(C 2 -C 4 )-alkenyl, heteroaryl-(C 2 -C 4 )-alkynyl, where alkyl, alkenyl, alkynyl and cycloalkyl may be substituted more than once by F, 25 Cl, CN, OR13, R13, CF 3 , OCF 3 , (C 6 -C 1 o)-aryl, NH-C(=NR14) N(R14)(R15), N(R14)(R15), C(=NR14)-N(R14)(R15), COOR13 or CON(R14)(R1 5), and where aryl may be substituted more than once by F, Cl, CN, 0-(C-C 6 )-alkyl, 0-(C 2 -C 6 )-alkenyl, (CriC 6 )-alkyl, (C2-C6) alkenyl, CO-(C-C 6 )-alkyl, CO-(C 2 -Ce)-alkenyl, where alkyl and alkenyl 30 may be substituted more than once by F, Cl, CH 3 , OCH 3 or CN, or NH-C(=NR14)-N(R14)(R15), N(R14)(R15), C(=NR14)-N(R14)(R15), COOR13, CON(R14)(R15), 0-phenyl, phenyl or pyridyl; COOR13, CON-(R14)(R15), CO-heteroalkyl, CO-(C 6 -C1o)-aryl or SO 2 -(C 6 -C 1 o)-aryl, where aryl may be substituted up to twice by F, Cl, 52 CN, OH, (PC)-alkyl, O-(-C)-alkyl, CF 3 , OCF 3 , COOR13 or CON(R14)(R15); or the radicals R1 8 and R1 9 form with the nitrogen atom to which they are bonded a 5 3-7-membered, saturated heterocyclic ring which may comprise up to 2 further heteroatoms from the group of N, 0 or S, where the heterocyclic ring may be substituted up to three times by F, Cl, Br, OH, oxo, N(R16)(R17) or (C-C 4 )-alkyl; 10 R20 is (C-C1o)-alkyl, (C 2 -C1o)-alkenyl, (C2-Clo)-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C-C 6 )-alkyl, (C6-Clo)-aryl, (C 6 -C1o)-aryl-(Cr-C 4 )-alkyl, (C 6 -C 1 o)-aryl-(C 2 -C 4 )-alkenyl or (C 6 -C 1 o)-aryl-(C 2 -C 4 )-alkynyl, where aryl may be substituted more than once by F, Cl, CN, O-(CriC 6 )-alkyl, 0 (C 2 -C6)-alkenyl, (C O 0)-alkyl, (C 2 -Cs)-alkenyl, CO-(Cr-0)-alkyl, CO 15 (C 2 -C 6 )-alkenyl, where alkyl and alkenyl may be substituted more than once by F, Cl, CH 3 , OCH 3 or CN, or NH-C(=NR14)-N(R14)(R15), N(R14)(R15), C(=NR14)-N(R14)(R15), COOR13, CON(R14)(R15), 0-phenyl, phenyl or pyridyl, where phenyl may be substituted by F, Cl, CN or (C 1 -C 6 )-alkyl; 20 and its physiologically tolerated salts, excluding compounds of the formula I in which the radicals R6, R7, X and R8 have the following meanings at the same time: 25 R6 H, Cl, CF 3 , CH 3 ; R7 H; 30 X 0; Y O, S; R8 substituted or unsubstituted NH-phenyl. 53 2. A compound of the formula I as claimed in claim 1, wherein the compounds therein have the structure la R5 R6 R4 RIO RHO N N N R8 H H R3 R11 R12 . la 5 in which one or more radicals has or have the following meanings: R9 F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O-(PiC)-alkyl, 0-(C 2 -C 6 )-alkenyl, 10 0-(C 2 -C 6 )-alkynyl, O-SO 2 -(C-C 4 )-alkyl, O-SO 2 -phenyl, where the phenyl ring may be substituted up to twice by F, Cl, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R14)(R1 5), or S-(CrC 6 )-alkyl, S-(C 2 -C 6 )-alkenyl, S-(C 2 -C 6 )-alkynyl, SO-(Cr 1 C 6 )-alkyl, S0 2 -(0-C)-alkyl, S0 2 -NH 2 , (CrC6) alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C3-C7) 15 cycloalkyl-(CrC 4 )-alkylene, (Co-C 6 )-alkylene-COOR13, CON(R14)(R15), (Co-C)-alkylene-N(R14)(R15), NH-COR13, NH-CO-phenyl, NH-SO 2 phenyl or phenyl, where the phenyl ring may be substituted up to twice by F, C, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R14)(R1 5); 20 R10, R11, R12 independently of one another H, F, C, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O-(O-C)-alkyl, 0-(C 2 -C 6 )-alkenyl, 0-(C 2 -C 6 )-alkynyl, 0-SO 2 (CriC 4 )-alkyl, O-SO 2 -phenyl, where the phenyl ring may be substituted up to twice by F, Cl, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R14)(R1 5), or S-(CriC 6 )-alkyl, S-(C 2 -C 6 )-alkenyl, S-(C 2 -C 6 )-alkynyl, 25 SO-(0 1 C)-alkyl, S0 2 -(OiC)-alkyl, S0 2 -NH 2 , (O-C)-alkyl, (C2-C6) alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -Cr)-cycloalkyl-(C-C4) alkylene, (Co-C6)-alkylene-COOR13, CON(R14)(R15), (Co-C 6 )-alkylene- 54 N(R1 4)(R1 5), NH-COR13, NH-CO-phenyl, NH-S0 2 -phenyl or phenyl, where the phenyl ring may be substituted up to twice by F, Cl, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R14)(R1 5); 5 R13 H, (OC)-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl or (C 3 -C 7 )-cycloalkyl-(C-C 4 )-alkylene; R3, R4, R5 independently of one another H, F, CI, Br, OH, CF 3 , NO 2 , CN, OCF 3 , (CrC 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, 0-(C-C1o)-alkyl, 10 0-(C2-C1o)-alkenyl, 0-(C2-C1o)-alkynyl, S-(C 1 -C 6 )-alkyl, S-(C 2 -C 6 ) alkenyl, S-(C 2 -C 6 )-alkynyl, (C3-C7)-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(Cr-C 4 ) alkyl, where alkyl, alkenyl, alkynyl and cycloalkyl may be substituted more than once by F, C, Br, SO-phenyl, S0 2 -phenyl, where the phenyl ring may be substituted by F, C, Br or R13, or OR13, COOR13, 15 CON(R14)(R1 5), N(R14))(R15) or CO-heteroalkyl, or O-SO-(C 1 -C 6 ) alkyl, O-SO2-(Cl-C 6 )-alkyl, O-SO2-(C6-Clo)-aryl, 0-(C 6 -C1o)-aryl, where aryl may be substituted up to twice by F, C, CN, OR13, R13, CF 3 or OCF 3 , or SO-(CrC 6 )-alkyl, S02-(C-C 6 )-alkyl, SO2-(CO6-Co)-aryl, where the phenyl ring may be substituted up to twice by F, C, Br, CN, OR13, 20 R13, CF 3 , OCF 3 , COOR13 or CON(R14)(R1 5), or S0 2 -N(R1 4)(R1 5), COOR13, CO-heteroalkyl, N(R14)(R15) or heteroalkyl; R6 F, C, Br, OH, CF 3 , NO 2 , CN, OCF 3 , (Cr 1 C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, 0-(Cr-C 1 o)-alkyl, 0-(C2-C1o)-alkenyl, 0-(C2-C1o)-alkynyl, 25 S-(CrC 6 )-alkyl, S-(C 2 -C 6 )-alkenyl, S-(C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C7)-cycloalkyl-(CrC 4 )-alkyl, where alkyl, alkenyl, alkynyl and cycloalkyl may be substituted more than once by F, C, Br, SO-phenyl, S0 2 -phenyl, where the phenyl ring may be substituted by F, C, Br or R13, or OR13, COOR13, CON(R14)(R15), N(R14))(R15) or CO 30 heteroalkyl, or O-SO-(CriC 6 )-alkyl, O-SO 2 -(Cr-C 6 )-alkyl, O-SO2-(C6-C1O) aryl, 0-(C 6 -C 10 )-aryl, where aryl may be substituted up to twice by F, C, CN, OR13, R13, CF 3 or OCF 3 , or SO-(CriC 6 )-alkyl, S02-(CiC 6 )-alkyl, S02-(C6-Clo)-aryl, where the phenyl ring may be substituted up to twice by F, C, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R1 4)(R1 5), 55 or S0 2 -N(R14)(R1 5), COOR13, CO-heteroalkyl, N(R14)(R15) or heteroalkyl; R14, R15 independently of one another H, (Cr-0)-alkyl, where alkyl may be 5 substituted by N(R1 3)2, or (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C3-C7) cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C-C 4 )-alkylene, CO-(CrO0)-alkyl, COO (C 1 -C 6 )-alkyl, COO-(Cl C 6 )-alkylene-OCO-(C-C 6 )-alkyl, CO-phenyl, COO-phenyl, COO-(CrC 6 )-alkenyl-phenyl, OH, 0-(C-C 6 )-alkyl, O-(CrC 6 )-alkenyl-phenyl or NH 2 ; 10 or the radicals R14 and R15 form with the nitrogen atom to which they are bonded a 3-7-membered, saturated heterocyclic ring which may comprise up to 2 further heteroatoms from the group of N, 0 or S, where the heterocyclic ring may be substituted up to three times by F, Cl, Br, OH, oxo, 15 N(R16)(R17) or (C-C 4 )-alkyl; R16, R17 independently of one another H, (CrC 6 )-alkyl, where alkyl may be substituted by N(R1 3)2, or (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C3-C7) cycloalkyl, (C3-C 7 )-cycloalkyl-(Cl-C 4 )-alkylene, CO-(CrC 6 )-alkyl, COO 20(C-C)-alkyl, COO-(C-C 6 )-alkylene-OCO-(0 1 -C 6 )-alkyl, CO-phenyl, COO-phenyl, COO-(C-C 6 )-alkenyl-phenyl, OH, 0-(C-C 6 )-alkyl, O-(CrC 6 )-alkenyl-phenyl or NH 2 ; heteroalkyl a 3-7-membered, saturated or up to triunsaturated heterocyclic ring 25 which may comprise up to 4 heteroatoms which correspond to N, 0 or S, where the heterocyclic ring may be substituted at all sensible positions up to three times by F, Cl, Br, CN, oxo, (Cr-C4)-alkyl, (Co-C 4 )-alkylene COOR13, CON(R14)(R1 5), OR13 or N(R14)(R15) or phenyl, where phenyl may be substituted by COOR13; 30 R8 N(R18)(R19) or OR20; or R8 and R4 together form the group -NH-CO-; R18, R19 independently of one another H, (C 1 -C1o)-alkyl, (C 2 -C1o)-alkenyl, 56 (C 2 -C 1 o)-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C1-C 6 )-alkyl, (C 6 -C1o)-aryl, (C 6 -C 1 o)-aryl-(Cr-C 4 )-alkyl, (C 6 -C1o)-aryl-(C 2 -C 4 )-alkenyl, (C 6 -C1o)-aryl-(C 2 -C 4 )-alkynyl, heteroaryl, heteroaryl-(C1-C 4 )-alkyl, heteroaryl-(C 2 -C 4 )-alkenyl, heteroaryl-(C 2 -C 4 )-alkynyl, where alkyl, 5 alkenyl, alkynyl and cycloalkyl may be substituted more than once by F, CI, CN, OR13, R13, CF 3 , OCF 3 , (C6-C1o)-aryl, NH-C(=NR14) N(R1 4)(R1 5), N(R1 4)(R1 5), C(=NR1 4)-N(R1 4)(R1 5), COOR1 3 or CON(R14)(R1 5), and where aryl may be substituted more than once by F, CI, CN, 0-(C-C 6 )-alkyl, 0-(C 2 -C 6 )-alkenyl, (C-C 6 )-alkyl, (C 2 -C 6 ) 10 alkenyl, CO-(C1-C 6 )-alkyl, CO-(C 2 -C 6 )-alkenyl, where alkyl and alkenyl may be substituted more than once by F, CI, CH 3 , OCH 3 or CN, or NH-C(=NR14)-N(R14)(R15), N(R14)(R15), C(=NR14)-N(Rl4)(Rl5), COOR13, CON(R14)(R1 5), 0-phenyl, phenyl or pyridyl; COOR13, CON-(R14)(R15), CO-heteroalkyl, CO-(C 6 -C1o)-aryl or 15 S0 2 -(C 6 -C1o)-aryl, where aryl may be substituted up to twice by F, C, CN, OH, (OC)-alkyl, 0-(CriC 6 )-alkyl, CF 3 , OCF 3 , COOR13 or CON(R14)(R15); or the radicals R1 8 and R1 9 form together with the nitrogen atom to which they are 20 bonded a 3-7-membered, saturated heterocyclic ring which may comprise up to 2 further heteroatoms from the group of N, 0 or S, where the heterocyclic ring may be substituted up to three times by F, CI, Br, OH, oxo, N(R16)(R17) or (Cr 1 C 4 )-alkyl; 25 R20 (C-C1o)-alkyl, (C2-Clo)-alkenyl, (C2-C1o)-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(Cr-C 6 )-alkyl, (C 6 -C1o)-aryl, (C 6 -C1o)-aryl-(Cr-C 4 )-alkyl, (C6-C1o)-aryl-(C 2 -C 4 )-alkenyl or (C 6 -C 1 o)-aryl-(C 2 -C 4 )-alkynyl, where aryl may be substituted more than once by F, CI, CN, 0-(C-C 6 )-alkyl, 0-(C 2 -C 6 )-alkenyl, (C-C 6 )-alkyl, (C 2 -C 6 )-alkenyl, CO-(CriC 6 )-alkyl, 30 CO-(C 2 -C 6 )-alkenyl, where alkyl and alkenyl may be substituted more than once by F, CI, CH 3 , OCH 3 or CN, or NH-C(=NR14)-N(R14)(R1 5), N(R1 4)(R1 5), C(=NR1 4)-N(R1 4)(R1 5), COOR1 3, CON(R1 4)(RI 5), 0-phenyl, phenyl or pyridyl, where phenyl may be substituted by F, C, CN or (Cr-C 6 )-alkyl; 57 and its physiologically tolerated salts, excluding compounds of the formula I in which the radicals R6 and R8 have at the 5 same time the following meanings: R6 H, Cl, CF 3 , CH 3 ; R8 substituted or unsubstituted NH-phenyl. 10 3. A compound of the formula la as claimed in claim 2, where the meanings are R9, R10, R11 independently of one another F, Cl; 15 R12 H; R13 H, (C1-C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl or (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkylene; 2o R3, R4, R5 independently of one another H, COOR13; R6 F, CI, CF 3 , OCF 3 , (C 1 -C)-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, 0-(C1-C1o)-alkyl, 0-(C 2 -C 1 o)-alkenyl, 0-(C2-C1o)-alkynyl, (C3-C7) cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl, N(R1 4)(R1 5) or heteroalkyl, 25 where alkyl, alkenyl, alkynyl and cycloalkyl may be more than once by F, COOR13, CON(R14)(R15), N(R14)(R15); R14, R15 independently of one another H, (C1-C)-alkyl, where alkyl may be substituted by N(R13)2; 30 heteroalkyl a 3-7-membered, saturated or up to triunsaturated heterocyclic ring which may comprise up to 4 heteroatoms which correspond to N, 0 or S, where the heterocyclic ring may be substituted at all sensible positions up to three times by F, Cl, Br, CN, oxo, (C-C 4 )-alkyl, (Co-C 4 )-alkylene- 58 COOR13, CON(R1 4)(R1 5), OR13 or N(R14)(R15) or phenyl, where phenyl may be substituted by COOR13; R8 N(R18)(R19) or OR20; 5 or R8 and R4 together form the group -NH-CO-; R18, R19 independently of one another H, (C1-C 10 )-alkyl, (C 2 -C1o)-alkenyl, (C 2 -C 1 o)-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C7)-cycloalkyl-(Cr-C 6 )-alkyl, (C 6 -C1o)-aryl, (C6-C1o)-aryl-(C-C 4 )-alkyl, (C6-C1o)-aryl-(C 2 -C 4 )-alkenyl, 10 (C6-C1o)-aryl-(C 2 -C 4 )-alkynyl, heteroaryl, heteroaryl-(C 2 -C 4 )-alkyl, heteroaryl-(C 2 -C 4 )-alkenyl, heteroaryl-(C 2 -C 4 )-alkynyl, where alkyl, alkenyl, alkynyl and cycloalkyl may be substituted more than once by F, CI, CN, OR13, R13, CF 3 , OCF 3 , (C6-Clo)-aryl, NH-C(=NR14) N(R1 4)(R1 5), N(R1 4)(R1 5), C(=NR1 4)-N(R1 4)(R1 5), COOR1 3 or 15 CON(R1 4)(R1 5), and where aryl may be substituted more than once by F, CI, CN, O-(CC 6 )-alkyl, 0-(C 2 -C 6 )-alkenyl, (Cl-C 6 )-alkyl, (C2-C6) alkenyl, CO-(C-C 6 )-alkyl, CO-(C 2 -C 6 )-alkenyl, where alkyl and alkenyl may be substituted more than once by F, CI, CH 3 , OCH 3 or CN, or NH-C(=NR14)-N(R14)(R15), N(R14)(R15), C(=NR14)-N(R14)(R15), 20 COOR13, CON(R14)(R1 5), 0-phenyl, phenyl or pyridyl; COOR13, CON-(R14)(R15), CO-heteroalkyl, CO-(C 6 -C1o)-aryl or S0 2 -(C 6 -C 1 o)-aryl, where aryl may be substituted up to twice by F, CI, CN, OH, (Cr 1 C 6 )-alkyl, O-(CriC 6 )-alkyl, CF 3 , OCF 3 , COOR13 or CON(R14)(R15); 25 or the radicals R1 8 and R1 9 form together with the nitrogen atom to which they are bonded a 3-7-membered, saturated heterocyclic ring which may comprise up to 2 further heteroatoms from the group of N, 0 or S, where the heterocyclic ring may be substituted up to three times by F, Cl, Br, 30 OH, oxo, N(R16)(R17) or (CriC 4 )-alkyl; R20 (C-C1o)-alkyl, (C 2 -C 1 o)-alkenyl, (C 2 -C 1 o)-alkynyl, (C 3 -C 7 )-cycloalkyl, (C3-C7) cycloalkyl-(Cr-C 6 )-alkyl, (C6-C1o)-aryl, (C 6 -C 10 )-aryl-(CC 4 )-alkyl, (C6-Clo)-aryl (C 2 -C 4 )-alkenyl or (C6-C1o)-aryl-(C 2 -C 4 )-alkynyl, where aryl may be substituted more 59 than once by F, Cl, CN, O-(PC)-alkyl, 0-(C 2 -C 6 )-alkenyl, (OC)-alkyl, (C2-C6) alkenyl, CO-(OC)-alkyl, CO-(C 2 -C 6 )-alkenyl, where alkyl and alkenyl may be substituted more than once by F, Cl, CH 3 , OCH 3 or CN, or NH-C(=NR14) N(R14)(R15), N(R14)(R15), C(=NR14)-N(R14)(R15), COOR13, CON(R14)(R15), 5 0-phenyl, phenyl or pyridyl, where phenyl may be substituted by F, Cl, CN or (CrC6) alkyl; and their physiologically tolerated salts, 10 excluding compounds of the formula la in which the radicals R6 and R8 have at the same time the following meanings: R6 H, C, CF 3 , CH 3 ; 15 R8 substituted or unsubstituted NH-phenyl.

4. A compound of the formula la as claimed in claim 2 or 3, where the meanings are 20 R9, R10, R1 1 independently of one another F or Cl; R12 H; R13 independently of one another H or (OC)-alkyl; 25 R1, R2 H; R3, R4, R5 independently of one another H, COOR1 3; 30 R6 C, OCF 3 , COOR13, N(R14)(R15), (C 2 -C 6 )-alkenyl, 0-(Cr-C1o)-alkyl, where alkyl, alkenyl may be substituted more than once by F, COOR13 or CON(R14)(R1 5); R14, R15 (CriC 6 )-alkyl, where alkyl may be substituted by N(R13)2; 60 or the radicals R14 and R15 form with the nitrogen atom to which they are bonded a

5-membered, saturated heterocyclic ring; 5 R8 N(R1 8)(R1 9) or OR20; R18, R19 independently of one another H, (C1-C1o)-alkyl, (C 2 -C 1 o)-alkenyl, where alkyl may be substituted by COOR13, N(R1 3)2 or phenyl, or (C 3 -C 7 ) cycloalkyl or (Ce-C 1 o)-aryl, where aryl may be substituted more than 10 once by F, Cl, CN, (C 1 -C 6 )-alkyl, 0-(C1-C 6 )-alkyl, CO-(C1-C 6 )-alkyl, where alkyl may be substituted more than once by F, or O-phenyl, phenyl, pyridyl or COOR13; R20 (C 1 -C 1 o)-alkyl, (C 2 -C1o)-alkenyl, (C 2 -C 1 o)-alkynyl or phenyl, where phenyl 15 may be substituted by Cl or (C 1 -C 6 )-alkyl; and its physiologically tolerated salts. 5. A medicament comprising one or more of the compounds as claimed in one or 20 more of claims 1 to 4.

6. A medicament comprising one or more of the compounds as claimed in one or more of claims 1 to 4 and at least one other active ingredient. 25

7. A medicament as claimed in claim 6, wherein the other active ingredient comprises one or more antidiabetics, hypoglycemic active ingredients, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor 30 inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, a-glucosidase inhibitors, active ingredients which act on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 61 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, p3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed sertoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth 5 hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-p agonists or amphetamines.

8. The use of the compounds as claimed in one or more of claims 1 to 5 for 10 producing a medicament for reducing blood glucose.

9. The use of the compounds as claimed in one or more of claims 1 to 4 for producing a medicament for the treatment of type 2 diabetes. 15

10. The use of the compounds as claimed in one or more of claims 1 to 4 for producing a medicament for the treatment of disturbances of lipid and carbohydrate metabolism.

11. The use of the compounds as claimed in one or more of claims 1 to 4 for 20 producing a medicament for the treatment of arteriosclerotic manifestations.

12. The use of the compounds as claimed in one or more of claims 1 to 4 for producing a medicament for the treatment of insulin resistance. 25

13. A process for producing a medicament comprising one or more of the compounds as claimed in one or more of claims 1 to 4, which comprises mixing the active ingredient with a pharmaceutically suitable carrier and converting this mixture into a form suitable for administration.