U.S. patent application number 11/759510 was filed with the patent office on 2008-02-21 for use of substituted cyclopropane acid derivatives for producing drugs for use in the treatment of metabolic syndrome.
This patent application is currently assigned to SANOFI-AVENTIS DEUTSCHLAND GMBH. Invention is credited to Harm Brummerhop, Hubert Heuer, Dieter Kadereit, Siegfried Stengelin.
Application Number | 20080045590 11/759510 |
Document ID | / |
Family ID | 35945136 |
Filed Date | 2008-02-21 |
United States Patent
Application |
20080045590 |
Kind Code |
A1 |
Kadereit; Dieter ; et
al. |
February 21, 2008 |
USE OF SUBSTITUTED CYCLOPROPANE ACID DERIVATIVES FOR PRODUCING
DRUGS FOR USE IN THE TREATMENT OF METABOLIC SYNDROME
Abstract
Disclosed is the use of certain substituted cyclopropane acid
derivatives of Formula 1 as defined herein and of their
physiologically tolerated salts for treating metabolic syndrome and
related disorders.
Inventors: |
Kadereit; Dieter;
(Offenbach, DE) ; Stengelin; Siegfried; (Eppstein,
DE) ; Heuer; Hubert; (Schwabenheim, DE) ;
Brummerhop; Harm; (Frankfurt, DE) |
Correspondence
Address: |
Irving Newman;sanofi-aventis U.S. LLC
U.S. Patent Operations
Route #202-206 / P.O. Box 6800
Bridgewater
NJ
08807-0800
US
|
Assignee: |
SANOFI-AVENTIS DEUTSCHLAND
GMBH
Bruningstrasse 50
Frankfurt
DE
65929
|
Family ID: |
35945136 |
Appl. No.: |
11/759510 |
Filed: |
June 7, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
PCT/EP05/12763 |
Nov 30, 2005 |
|
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11759510 |
Jun 7, 2007 |
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Current U.S.
Class: |
514/531 |
Current CPC
Class: |
A61P 9/12 20180101; A61P
19/02 20180101; A61P 11/00 20180101; A61P 3/10 20180101; A61P 5/50
20180101; A61P 29/00 20180101; A61P 1/04 20180101; A61P 35/00
20180101; A61P 3/00 20180101; A61P 17/02 20180101; A61P 9/10
20180101; A61P 25/16 20180101; A61P 17/00 20180101; A61P 25/28
20180101; A61P 3/04 20180101; A61P 9/00 20180101; A61K 31/215
20130101; A61P 7/02 20180101; A61P 9/06 20180101; A61P 3/06
20180101; A61P 43/00 20180101; A61P 19/06 20180101 |
Class at
Publication: |
514/531 |
International
Class: |
A61K 31/225 20060101
A61K031/225; A61P 3/00 20060101 A61P003/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 14, 2004 |
DE |
102004060041.4 |
Aug 19, 2005 |
DE |
102005039245.8 |
Claims
1. A method for the treatment of metabolic syndrome in a mammal,
which comprises administering to said mammal a therapeutically
effective amount of a compound of formula I, ##STR26## in which R1
is selected from H, as well as from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl, and
heterocyclyl, where the alkyl, alkenyl, alkynyl, aryl and
heterocyclyl radicals may be substituted one or more times by a
substituent selected from F, Cl, Br, I, CF.sub.3, NO.sub.2,
N.sub.3, CN, COOH, COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
cycloalkyl, (C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl), SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclic radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(Aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.; R2 is selected from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl,
(C.sub.3-C.sub.7)-cycloalkyl, and heterocycle, where the alkyl,
alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl radicals may be
substituted one or more times by a substituent selected from F, Cl,
Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclyl radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(Aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2; and R3, R4, R5, and R6 are, independently of one
another, selected from H, F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, (C.sub.1-C.sub.6)-alkyl, and O--(C.sub.1-C.sub.6)-alkyl;
or a physiologically tolerated salt thereof.
2. The method of claim 1, wherein R1 is H, or
(C.sub.1-C.sub.20)-alkyl; R2 is selected from
(C.sub.1-C.sub.20)-alkyl, (C.sub.2-C.sub.20)-alkenyl,
(C.sub.2-C.sub.20)-alkynyl, aryl, (C.sub.3-C.sub.7)-cycloalkyl, and
heterocycle, where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl
and heterocyclyl radicals may be substituted one or more times by a
substituent selected from F, Cl, Br, I, CF.sub.3, NO.sub.2,
N.sub.3, CN, COOH, COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)alkyl, CON[(C.sub.1-C.sub.6)alkyl].sub.2,
cycloalkyl, (C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl,
O--CO--(C.sub.1-C.sub.6)-heterocyclyl, PO.sub.3H.sub.2,
P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclic radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2; and R3, R4, R5, and R6 are, independently of one
another, selected from H, F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, (C.sub.1-C.sub.6)-alkyl, and
O--(C.sub.1-C.sub.6)-alkyl.
3. The method of claim 1, wherein R1 is H; R2 is selected from
(C.sub.1-C.sub.20)-alkyl, (C.sub.2-C.sub.20)-alkenyl,
(C.sub.2-C.sub.20)-alkynyl, and (C.sub.3-C.sub.7)-cycloalkyl, where
the alkyl, alkenyl, alkynyl and cycloalkyl radicals may be
substituted one or more times by a substituent selected from F, Cl,
Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
O--CO--(C.sub.1-C.sub.6)-alkyl, and O--CO--(C.sub.1-C.sub.6)-aryl,
as well as from NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--COO--(C.sub.1-C.sub.6)-alkyl,
NH--CO-aryl, NH--COO-aryl, NH--CO--NH--(C.sub.1-C.sub.6)-alkyl),
NH--CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl N(aryl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, aryl, and O--(CH.sub.2).sub.n-aryl; and
R3, R4, R5, and R6 are, independently of one another, selected from
H, F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
(C.sub.1-C.sub.6)-alkyl, and O--(C.sub.1-C.sub.6)-alkyl.
4. The method of claim 1, wherein R1 is H; R2 is selected from
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.10)-alkenyl,
(C.sub.2-C.sub.10)-alkynyl, where the alkyl, alkenyl and alkynyl
radicals may be substituted one or more times by F, Cl, Br,
CF.sub.3, NO.sub.2, CN, COOH, COO(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.10)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-alkyl, and
O--CO--(C.sub.1-C.sub.6)-aryl; and R3, R4, R5, and R6 are,
independently of one another, selected from H, F, and
(C.sub.1-C.sub.4)-alkyl.
5. A method for reducing plasma lipids in a mammal, which comprises
administering to said mammal a therapeutically effective amount of
a compound of formula I, ##STR27## in which R1 is selected from H,
as well as from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl, and
heterocyclyl, where the alkyl, alkenyl, alkynyl, aryl and
heterocyclyl radicals may be substituted one or more times by a
substituent selected from F, Cl, Br, I, CF.sub.3, NO.sub.2,
N.sub.3, CN, COOH, COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
cycloalkyl, (C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclic radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(Aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.; R2 is selected from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl,
(C.sub.3-C.sub.7)-cycloalkyl, and heterocycle, where the alkyl,
alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl radicals may be
substituted one or more times by a substituent selected from F, Cl,
Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclyl radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(Aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2; and R3, R4, R5, and R6 are, independently of one
another, selected from H, F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, (C.sub.1-C.sub.6)-alkyl, and O--(C.sub.1-C.sub.6)-alkyl;
or a physiologically tolerated salt thereof.
6. A method for reducing plasma free fatty acids (FFA) in a mammal,
which comprises administering to said mammal a therapeutically
effective amount of a compound of formula I, ##STR28## in which R1
is selected from H, as well as from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl, and
heterocyclyl, where the alkyl, alkenyl, alkynyl, aryl and
heterocyclyl radicals may be substituted one or more times by a
substituent selected from F, Cl, Br, I, CF.sub.3, NO.sub.2,
N.sub.3, CN, COOH, COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
cycloalkyl, (C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclic radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(Aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.; R2 is selected from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl,
(C.sub.3-C.sub.7)-cycloalkyl, and heterocycle, where the alkyl,
alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl radicals may be
substituted one or more times by a substituent selected from F, Cl,
Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclyl radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(Aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2; and R3, R4, R5, and R6 are, independently of one
another, selected from H, F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, (C.sub.1-C.sub.6)-alkyl, and O--(C.sub.1-C.sub.6)-alkyl;
or a physiologically tolerated salt thereof.
7. A method for reducing plasma glycerol in a mammal, which
comprises administering to said mammal a therapeutically effective
amount of a compound of formula I, ##STR29## in which R1 is
selected from H, as well as from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl, and
heterocyclyl, where the alkyl, alkenyl, alkynyl, aryl and
heterocyclyl radicals may be substituted one or more times by a
substituent selected from F, Cl, Br, I, CF.sub.3, NO.sub.2,
N.sub.3, CN, COOH, COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
cycloalkyl, (C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclic radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(Aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO-NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.; R2 is selected from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl,
(C.sub.3-C.sub.7)-cycloalkyl, and heterocycle, where the alkyl,
alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl radicals may be
substituted one or more times by a substituent selected from F, Cl,
Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclyl radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(Aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2; and R3, R4, R5, and R6 are, independently of one
another, selected from H, F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, (C.sub.1-C.sub.6)-alkyl, and O--(C.sub.1-C.sub.6)-alkyl;
or a physiologically tolerated salt thereof.
8. A method for reducing plasma triglycerides in a mammal, which
comprises administering to said mammal a therapeutically effective
amount of a compound of formula I, ##STR30## in which R1 is
selected from H, as well as from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl, and
heterocyclyl, where the alkyl, alkenyl, alkynyl, aryl and
heterocyclyl radicals may be substituted one or more times by a
substituent selected from F, Cl, Br, I, CF.sub.3, NO.sub.2,
N.sub.3, CN, COOH, COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
cycloalkyl, (C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclic radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(Aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.; R2 is selected from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl,
(C.sub.3-C.sub.7)-cycloalkyl, and heterocycle, where the alkyl,
alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl radicals may be
substituted one or more times by a substituent selected from F, Cl,
Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclyl radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(Aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2; and R3, R4, R5, and R6 are, independently of one
another, selected from H, F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, (C.sub.1-C.sub.6)-alkyl, and O--(C.sub.1-C.sub.6)-alkyl;
or a physiologically tolerated salt thereof.
9. A method for the prophylaxis of type 2 diabetes in a mammal,
which comprises administering to said mammal a therapeutically
effective amount of a compound of formula I, ##STR31## in which R1
is selected from H, as well as from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl, and
heterocyclyl, where the alkyl, alkenyl, alkynyl, aryl and
heterocyclyl radicals may be substituted one or more times by a
substituent selected from F, Cl, Br, I, CF.sub.3, NO.sub.2,
N.sub.3, CN, COOH, COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
cycloalkyl, (C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl), SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclic radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(Aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.; R2 is selected from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl,
(C.sub.3-C.sub.7)-cycloalkyl, and heterocycle, where the alkyl,
alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl radicals may be
substituted one or more times by a substituent selected from F, Cl,
Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclyl radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(Aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2; and R3, R4, R5, and R6 are, independently of one
another, selected from H, F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, (C.sub.1-C.sub.6)-alkyl, and O--(C.sub.1-C.sub.6)-alkyl;
or a physiologically tolerated salt thereof.
10. A method for the treatment of diabetic dyslipidemia in a
mammal, which comprises administering to said mammal a
therapeutically effective amount of a compound of formula I,
##STR32## in which R1 is selected from H, as well as from
(C.sub.1-C.sub.20)-alkyl, (C.sub.2-C.sub.20)-alkenyl,
(C.sub.2-C.sub.20)-alkynyl, aryl, and heterocyclyl, where the
alkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be
substituted one or more times by a substituent selected from F, Cl,
Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
cycloalkyl, (C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl), SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclic radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(Aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.; R2 is selected from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl,
(C.sub.3-C.sub.7)-cycloalkyl, and heterocycle, where the alkyl,
alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl radicals may be
substituted one or more times by a substituent selected from F, Cl,
Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclyl radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from C(NH)(NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocyclyl,
NH--COO-aryl, NH--COO-heterocyclyl,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl), NH--CO--NH-aryl,
NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(Aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2; and R3, R4, R5, and R6 are, independently of one
another, selected from H, F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, (C.sub.1-C.sub.6)-alkyl, and O--(C.sub.1-C.sub.6)-alkyl;
or a physiologically tolerated salt thereof.
Description
FIELD OF THE INVENTION
[0001] The invention relates to the use of certain substituted
cyclopropane acid derivatives and of their physiologically
tolerated salts for treating metabolic syndrome and related
disorders.
BACKGROUND OF THE INVENTION
[0002] WO2002/066469 describes substituted cyclopropane acid
derivatives as dopamine receptor ligands.
[0003] This invention is based on pursuit of the object of
providing compounds which can be used for the treatment of the
metabolic syndrome and which display, in particular, a
therapeutically useful lipid-lowering effect. It was further
intended, preferably, that they be suitable for the treatment of
diabetic dyslipidemia. It was further intended, preferably, that a
reduction in the free fatty acids (FFA), of glycerol and of
triglycerides in the plasma be achieved.
SUMMARY OF THE INVENTION
[0004] The present invention relates to the use of compounds of the
formula I ##STR1## in which:
[0005] R1 is selected from H, as well as from
(C.sub.1-C.sub.20)-alkyl, (C.sub.2-C.sub.20)-alkenyl,
(C.sub.2-C.sub.20)-alkynyl, aryl, and heterocyclyl, where the
alkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be
substituted one or more times by a substituent selected from F, Cl,
Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
cycloalkyl, (C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2-(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl ,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be 0
-6, and the aryl radical or heterocyclic radical may be substituted
up to twice by a substituent selected from F, Cl, Br, OH, CF.sub.3,
SF.sub.5, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl, and NH.sub.2; as well as from
[0006] C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--COO--(C.sub.1-C.sub.6)-alkyl,
NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl,
NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1-C.sub.6)-alkyl),
NH--CO--NH-aryl, NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(Aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.;
[0007] R2 is selected from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl,
(C.sub.3-C.sub.7)-cycloalkyl, and heterocycle, where the alkyl,
alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl radicals may be
substituted one or more times by a substituent selected from F, Cl,
Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as from
PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclyl radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from
[0008] C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--COO--(C.sub.1-C.sub.6)-alkyl,
NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl,
NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1-C.sub.6)-alkyl),
NH--CO--NH-aryl, NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(Aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, Aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2;
[0009] R3, R4, R5, and R6 are, independently of one another,
selected from H, F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, (C.sub.1-C.sub.6)-alkyl, and
O--(C.sub.1-C.sub.6)-alkyl;
[0010] and the physiologically tolerated salts thereof for the
treatment of metabolic syndrome.
[0011] Preference is given to the use of the compounds of the
formula I in which:
[0012] R1 is H, or (C.sub.1-C.sub.20)-alkyl;
[0013] R2 is selected from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, aryl,
(C.sub.3-C.sub.7)-cycloalkyl, and heterocycle, where the alkyl,
alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl radicals may be
substituted one or more times by a substituent selected from F, Cl,
Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl,
O--CO--(C.sub.1-C.sub.6)-heterocyclyl,
[0014] PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclic radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as from
[0015] C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--COO--(C.sub.1-C.sub.6)-alkyl,
NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl,
NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1-C.sub.6)-alkyl),
NH--CO--NH-aryl, NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2;
[0016] R3, R4, R5, and R6 are, independently of one another,
selected from H, F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, (C.sub.1-C.sub.6)-alkyl, and
O--(C.sub.1-C.sub.6)-alkyl;
[0017] and the physiologically tolerated salts thereof.
DETAILED DESCRIPTION
[0018] Particular preference is given to the use of the compounds
of the formula I in which:
[0019] R1 is H;
[0020] R2 is selected from (C.sub.1-C.sub.20)-alkyl,
(C.sub.2-C.sub.20)-alkenyl, (C.sub.2-C.sub.20)-alkynyl, and
(C.sub.3-C.sub.7)-cycloalkyl, where the alkyl, alkenyl, alkynyl and
cycloalkyl radicals may be substituted one or more times by a
substituent selected from F, Cl, Br, I, CF.sub.3, NO.sub.2,
N.sub.3, CN, COOH, COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)alkyl, CON[(C.sub.1-C.sub.6)alkyl].sub.2,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.10)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-alkyl, and
O--CO--(C.sub.1-C.sub.6)-aryl, as well as from
[0021] NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--COO--(C.sub.1-C.sub.6)-alkyl,
NH--CO-aryl, NH--COO-aryl, NH--CO--NH--(C.sub.1-C.sub.6)-alkyl),
NH--CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl N(aryl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, aryl, and O--(CH.sub.2).sub.n-aryl;
[0022] R3, R4, R5, and R6 are, independently of one another,
selected from H, F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, (C.sub.1-C.sub.6)-alkyl, and
O--(C.sub.1-C.sub.6)-alkyl;
[0023] and the physiologically tolerated salts thereof.
[0024] Very particular preference is given to the use of the
compounds of the formula I in which:
[0025] R1 is H;
[0026] R2 is selected from (C.sub.1-C.sub.10)-alkyl,
(C.sub.2-C.sub.10)-alkenyl, (C.sub.2-C.sub.10)-alkynyl, where the
alkyl, alkenyl and alkynyl radicals may be substituted one or more
times by F, Cl, Br, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
O--CO--(C.sub.1-C.sub.6)-alkyl, and
O--CO--(C.sub.1-C.sub.6)-aryl;
[0027] R3, R4, R5, and R6 are, independently of one another,
selected from H, F, and (C.sub.1-C.sub.4)-alkyl;
[0028] and the physiologically tolerated salts thereof.
[0029] The invention includes the use of the compounds of the
formula I in the form of their racemates, racemic mixtures and pure
enantiomers, and to their diastereomers and mixtures thereof.
[0030] If radicals or substituents may occur more than once in the
compounds of the formula I, then they may all independently of one
another have the stated meanings and be identical or different.
[0031] As used herein, `alkyl radical` means a straight-chain or
branched hydrocarbon chain having one or more carbon atoms, such
as, for example, methyl, ethyl, propyl, butyl, hexyl, isopropyl,
isobutyl, neopentyl, tert-butyl, and hexyl. The alkyl radicals may
be substituted one or more times by suitable substituent groups
such as, for example, F, Cl, Br, I, CF.sub.3, NO.sub.2, N.sub.3,
CN, COOH, COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)alkyl, CON[(C.sub.1-C.sub.6)alkyl].sub.2,
cycloalkyl, (C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
aryl, heterocyclyl, O--(C.sub.1-C.sub.6)-alkyl,
O--COO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-alkyl,
O--CO--(C.sub.1-C.sub.6)-aryl,
O--CO--(C.sub.1-C.sub.6)-heterocyclyl, PO.sub.3H.sub.2,
P(O)(O-alkyl)2, (C1-C6)-alkylene-P(O)(O-alkyl)2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl)2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N[((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl],
SO.sub.2--N[((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl],
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl)).sub.2, where n may be
0-6 and the aryl or heterocyclyl radical may be substituted up to
three times by a substituent selected from F, Cl, Br, OH, CF.sub.3,
SF.sub.5, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl, and NH.sub.2; as well as from
[0032] C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--COO--(C.sub.1-C.sub.6)-alkyl,
NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl,
NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1-C.sub.6)-alkyl),
NH--CO--NH-aryl, NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.
[0033] `Alkenyl radical` means a straight-chain or branched
hydrocarbon chain having two or more carbon atoms and one or more
double bonds, such as, for example, vinyl, allyl, and pentenyl. The
alkenyl radicals may be substituted one or more times by suitable
groups such as, for example, F, Cl, Br, I, CF.sub.3, NO.sub.2,
N.sub.3, CN, COOH, COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)alkyl, CON[(C.sub.1-C.sub.6)alkyl].sub.2,
cycloalkyl, (C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkynyl,
aryl, heterocyclyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; PO.sub.3H.sub.2,
P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclyl radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2; as
well as from
[0034] C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--COO--(C.sub.1-C.sub.6)-alkyl,
NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl,
NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1-C.sub.6)-alkyl),
NH--CO--NH-aryl, NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.
[0035] `Alkynyl radical` means a straight-chain or branched-chain
hydrocarbon having two or more carbon atoms and one or more triple
bonds, such as, for example, ethynyl, propynyl, hexynyl. The
alkynyl radicals may be substituted one or more times by suitable
groups such as, for example, F, Cl, Br, I, CF.sub.3, NO.sub.2,
N.sub.3, CN, COOH, COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)alkyl, CON[(C.sub.1-C.sub.6)alkyl].sub.2,
cycloalkyl, (C.sub.2-C.sub.6)-alkenyl, (C.sub.1-C.sub.10)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl O--CO--(C.sub.1-C.sub.6)-alkyl,
O--CO--(C.sub.1-C.sub.6)-aryl,
O--CO--(C.sub.1-C.sub.6)-heterocyclyl;
[0036] PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclic radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as
[0037] C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--COO--(C.sub.1-C.sub.6)-alkyl,
NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl,
NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1-C.sub.6)-alkyl),
NH--CO--NH-aryl, NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.
[0038] `Aryl radical` means a phenyl, naphthyl, biphenyl,
tetrahydronaphthyl, alpha- or beta-tetralon-, indanyl or
indan-1-onyl radical. The aryl radicals may be substituted one or
more times by suitable groups such as, for example, F, Cl, Br, I,
CF.sub.3, NO.sub.2, SF.sub.5, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl,
O--CO--(C.sub.1-C.sub.6)-heterocyclyl,
[0039] PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclic radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, NO.sub.2, SF.sub.5, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as
[0040] C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--COO--(C.sub.1-C.sub.6)-alkyl,
NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl,
NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1-C.sub.6)-alkyl),
NH--CO--NH-aryl, NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.
[0041] `Cycloalkyl radical` means a ring system which comprises one
or more rings and which is in saturated or partially unsaturated
(having one or two double bonds) form, which is composed
exclusively of carbon atoms, such as, for example, cyclopropyl,
cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl. The cycloalkyl
radicals may be substituted one or more times by suitable groups
such as, for example, F, Cl, Br, I, CF.sub.3, NO.sub.2, N.sub.3,
CN, COOH, COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)alkyl, CON[(C.sub.1-C.sub.6)alkyl].sub.2,
cycloalkyl, (C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as
[0042] PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2, and
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclic radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as
[0043] C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--COO--(C.sub.1-C.sub.6)-alkyl,
NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl,
NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1-C.sub.6)-alkyl),
NH--CO--NH-aryl, NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, aryl,
O--(CH.sub.2).sub.n-aryl, and O--(CH.sub.2).sub.n-heterocyclyl,
where n may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.
[0044] `Heterocycle`, `heterocyclyl` or `heterocyclic radical`
means rings and ring systems which, apart from carbon, also
comprise heteroatoms such as, for example, nitrogen, oxygen or
sulfur. This definition also includes ring systems in which the
heterocycle or the heterocyclic radical is fused to one or more
benzene nuclei.
[0045] Suitable heterocyclyl or "heterocyclic radicals" are
acridinyl, benzimidazolyl, benzofuryl, benzothienyl,
benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,
benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,
quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]-tetrahydrofuran, furyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl,
indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl
(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl,
pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pyridooxazoles, pyridoimidazoles, pyridothiazol, pyridinyl,
pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,
pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,
1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl, aziridinyl,
azetininyl, azepanyl, azocanyl and xanthenyl.
[0046] `Pyridyl` stands for 2-, 3- and 4-pyridyl. `Thienyl` stands
both for 2- and 3-thienyl.
[0047] `Furyl` stands both for 2- and 3-furyl.
[0048] Also included are the corresponding N-oxides of these
compounds, i.e. for example 1-oxy-2-, 3- or 4-pyridyl.
[0049] Also included are derivatives of these heterocycles which
are benzo-fused one or more times.
[0050] The heterocyclic rings or heterocyclic radicals may be
substituted one or more times by suitable groups such as, for
example, F, Cl, Br, I, CF.sub.3, NO.sub.2, N.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl
O--CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-aryl, and
O--CO--(C.sub.1-C.sub.6)-heterocyclyl; as well as
[0051] PO.sub.3H.sub.2, P(O)(O-alkyl).sub.2,
(C.sub.1-C.sub.6)-alkylene-P(O)(O-alkyl).sub.2, O--P(O)(OH).sub.2,
O--P(O)(O-alkyl).sub.2, SO.sub.3H, SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-aryl,
S--(CH.sub.2).sub.n-heterocyclyl, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N(C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N(C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocyclyl,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2,
SO.sub.2--N((CH.sub.2).sub.n-(heterocyclyl).sub.2 where n may be
0-6, and the aryl radical or heterocyclic radical may be
substituted up to twice by a substituent selected from F, Cl, Br,
OH, CF.sub.3, SF.sub.5, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, and NH.sub.2;
as well as C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--COO--(C.sub.1-C.sub.6)-alkyl,
NH--CO-aryl, NH--CO-heterocyclyl, NH--COO-aryl,
NH--COO-heterocyclyl, NH--CO--NH--(C.sub.1-C.sub.6)-alkyl),
NH--CO--NH-aryl, NH--CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-COO-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH--(C.sub.1-C.sub.6)-alkyl),
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--NH-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-aryl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N((C.sub.1-C.sub.6)-alkyl)-heterocyclyl,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(aryl).sub.2,
N[(C.sub.1-C.sub.6)-alkyl]-CO--N(heterocyclyl).sub.2,
N(aryl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-COO--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-COO--(C.sub.1-C.sub.6)-alkyl, N(aryl)-CO-aryl,
N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl,
N(heterocyclyl)-COO-aryl, N(aryl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(heterocyclyl)-CO--NH--(C.sub.1-C.sub.6)-alkyl,
N(aryl)-CO--NH-aryl, N(heterocyclyl)-CO--NH-aryl,
N(aryl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(heterocyclyl)-CO--N((C.sub.1-C.sub.6)-alkyl).sub.2,
N(aryl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(heterocyclyl)-CO--N[(C.sub.1-C.sub.6)-alkyl]-aryl,
N(aryl)-CO--N(aryl).sub.2, N(heterocyclyl)-CO--N(aryl).sub.2, aryl,
O--(CH.sub.2).sub.n-aryl, O--(CH.sub.2).sub.n-heterocyclyl, where n
may be 0-6, where the aryl or heterocyclyl radical may be
substituted one to 3 times by a substituent selected from F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3, SF.sub.5,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SF.sub.5, SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
and CONH.sub.2.
[0052] 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 formula I are salts of inorganic acids such as
hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric,
sulfonic and sulfuric acids, 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, tartaric and trifluoroacetic acids, as well as
L-ascorbic acid, salicylic acid, 1,2-benzisothiazol-3(2H)-one and
6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide. The chlorine salt
is particularly preferably used for medical purposes. Suitable
pharmaceutically acceptable basic salts are ammonium salts, alkali
metal salts (such as sodium and potassium salts) and alkaline earth
metal salts (such as magnesium and calcium salts).
[0053] Salts with a pharmaceutically unacceptable anion likewise
belong within the framework of the invention as useful
intermediates for preparing or purifying pharmaceutically
acceptable salts and/or for use in nontherapeutic, for example in
vitro, applications.
[0054] The compounds of the formula I may also exist in various
polymorphous forms, for example, as amorphous and crystalline
polymorphous forms. All polymorphous forms of the compounds of the
formula I belong within the framework of the invention and comprise
a further aspect of the invention.
[0055] All references to "compound(s) of formula (I)" hereinafter
refer to compound(s) of the formula (I) as described above, and
their salts and solvates as described herein.
[0056] The compound(s) of the formula (I) may also be administered
in combination with a further active ingredient.
[0057] The amount of a compound of formula (I) necessary to achieve
the desired biological effect depends on a number of factors, e.g.,
the specific compound chosen, 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 to 50 mg) per day per kilogram of body weight, e.g. 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 per minute. Suitable
infusion solutions for these purposes may comprise, for example,
from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter.
Single doses may comprise, for example, from 1 mg to 10 g of the
active ingredient. Thus, ampoules for injections may comprise, 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 comprise, for example, from 1.0 to 1000 mg, typically
from 10 to 600 mg. In the case of pharmaceutically acceptable
salts, the aforementioned weight data refer to the weight of the
benzothiazepine ion derived from the salt. For the prophylaxis or
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 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
comprise from 0.05% to 95% by weight of the active ingredient.
Further pharmaceutically active substances may likewise be present,
including further 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.
[0058] Pharmaceutical compositions of the invention are those
suitable for oral, rectal, topical, peroral (for example
sublingual) and parenteral (e.g. 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
within the framework of the invention. Preference is given to acid-
and gastric juice-resistant formulations. Suitable gastric
juice-resistant coatings include cellulose acetate phthalate,
polyvinal acetate phthalate, hydroxypropylmethylcellulose phthalate
and anionic polymers of methacrylic acid and methyl
methacrylate.
[0059] 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 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 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. 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.
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 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.
[0060] Pharmaceutical compositions suitable for rectal
administration are preferably in the form of single-dose
suppositories. These can be produced by mixing a compound of
formula (I) with one or more conventional solid carriers, for
example, cocoa butter, and shaping the resulting mixture.
[0061] 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 to 15% by weight of the
composition, for example, from 0.5 to 2%.
[0062] 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, 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).
[0063] Further active ingredients suitable for combination products
are all antidiabetics mentioned in the Rote Liste 2004, chapter 12.
They may be combined with 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 USP Dictionary of USAN and International
Drug Names, US Pharmacopeia, Rockville 2001. Antidiabetics include
insulin and insulin derivatives such as, for example, Lantus.RTM.
(see www.lantus.com) or HMR 1964, fast-acting insulins (see U.S.
Pat. No. 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.
[0064] The orally effective hypoglycemic active ingredients
include, preferably, sulfonylureas, biguanidines, 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 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. In one
embodiment of the invention, the compounds of the formula I are
administered in combination with an HMGCoA reductase inhibitor such
as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,
cerivastatin, rosuvastatin.
[0065] 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, or with a compound as described in PCT/EP 2004/00269,
PCT/EP 2003/05815, PCT/EP 2003/05814, PCT/EP 2003/05816, EP
0114531, U.S. Pat. No. 6,498,156.
[0066] 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.
[0067] 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.
[0068] 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, GW 1536, AVE 8042, AVE
8134, AVE 0847, or as described in PCT/US 2000/11833, PCT/US
2000/11490, WO 03/020269.
[0069] 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. 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.
[0070] 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, U.S. Pat. No. 6,245,744 or
U.S. Pat. No. 6,221,897), such as, for example, HMR 1741.
[0071] In one embodiment of the invention, the compounds of the
formula I are administered in combination with a CETP inhibitor,
such as, for example, JTT-705.
[0072] 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.
[0073] In one embodiment of the invention, the compounds of the
formula I are administered in combination with an LDL receptor
inducer (see U.S. Pat. No. 6,342,512), such as, for example,
HMR1171, HMR1586.
[0074] 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.
[0075] 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.
[0076] 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.
[0077] 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.
[0078] 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.
[0079] 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.
[0080] 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.
[0081] In one embodiment of the invention, the compounds of the
formula I are administered in combination with insulin.
[0082] 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.
[0083] In one embodiment, the compounds of the formula I are
administered in combination with a biguanide, such as, for example,
metformin.
[0084] In one further embodiment, the compounds of the formula I
are administered in combination with a meglitinide, such as, for
example, repaglinide.
[0085] 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]-phenyl]methyl]--
2,4-thiazolidinedione.
[0086] In one embodiment, the compounds of the formula I are
administered in combination with an .alpha.-glucosidase inhibitor,
such as, for example, miglitol or acarbose.
[0087] In one embodiment, the compounds of the formula I are
administered in combination with an adenosine A1 agonist such as,
for example, those described in EP 0912520 or PCT/EP06749.
[0088] 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.
[0089] 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
metformin, insulin and a sulfonylurea, insulin and metformin,
insulin and troglitazone, insulin and lovastatin, etc.
[0090] 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-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-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-
l)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]dipropyla-
mine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin
agonists, .beta.3 agonists (e.g.
1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6--
yloxy)-ethylamino]ethanol hydrochloride (WO 01/83451)), CB1
(cannabinoid receptor 1) receptor antagonists (e.g. rimonabant or
the active ingredients mentioned in WO 02/28346, MSH
(melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g.
{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcar-
bamoyl]-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 agonists, galanin antagonists, growth hormone
(e.g. human growth hormone), growth hormone-releasing compounds
(6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquino-
line-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.; 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-.beta. agonists.
[0091] 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.
[0092] In one embodiment, the other active ingredient is
dexamphtamine or amphetamine.
[0093] In one embodiment, the other active ingredient is
fenfluramine or dexfenfluramine.
[0094] In another embodiment, the other active ingredient is
sibutramine.
[0095] In one embodiment, the other active ingredient is
orlistat.
[0096] In one embodiment, the other active ingredient is mazindol
or phentermine.
[0097] In a further embodiment, the other active ingredient is
rimonabant.
[0098] 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.RTM.
(Zunft H J; et al., Carob pulp preparation for treatment of
hypercholesterolemia, ADVANCES IN THERAPY (September-October 2001),
18(5), 230-6.) Caromax is a carob-containing product from
Nutrinova, Nutrition Specialties & Food Ingredients GmbH,
Industriepark Hochst, 65926 Frankfurt/Main)). Combination with
Caromax.RTM. is possible in one preparation or by separate
administration of compounds of the formula I and Caromax.RTM..
Caromax.RTM. can in this connection also be administered in the
form of food products such as, for example, in bakery products or
muesli bars.
[0099] 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. ##STR2##
##STR3##
[0100] The examples detailed below serve to illustrate the
invention but without restricting it, however. TABLE-US-00001
Example Formula Name Salt 1 ##STR4## 1R-Methoxycarbonyl-2R-
hydroxycarbonyl- cyclopropane Diethylmethylamine 2 ##STR5##
1R-Methoxycarbonyl-2R- hydroxycarbonyl- cyclopropane Quinidine 3
##STR6## 1R-Methoxycarbonyl-2R- hydroxycarbonyl- cyclopropane 4
##STR7## Dimethyl cis-1,2- cyclopropanedicarboxylate 5 ##STR8##
Dimethyl trans-1,2- cyclopropanedicarboxylate 6 ##STR9## Dimethyl
1-methyl-trans- cyclopropane-1,2- dicarboxylate 7 ##STR10##
1RS-Methoxycarbonyl- 2RS-hydroxycarbonyl- cyclopropane 8 ##STR11##
Diethyl trans-1,2- cyclopropanedicarboxylate 9 ##STR12##
1RS-Methoxycarbonyl- 2RS-hydroxycarbonyl-3,3- dimethyl-cyclopropane
10 ##STR13## 1RS-Ethoxycarbonyl-2RS- hydroxycarbonyl- cyclopropane
11 ##STR14## 1RS-Propoxycarbonyl- 2RS-hydroxycarbonyl- cyclopropane
12 ##STR15## 1RS-Butoxycarbonyl-2RS- hydroxycarbonyl- cyclopropane
13 ##STR16## 1RS-Pentoxycarbonyl-2RS- hydroxycarbonyl- cyclopropane
14 ##STR17## 1RS-iso-Propoxycarbonyl- 2RS-hydroxycarbonyl-
cyclopropane 15 ##STR18## 1RS- Cyclohexylmethyloxycarbonyl-
2RS-hydroxycarbonyl- cyclopropane 16 ##STR19##
1RS-isobutoxycarbonyl- 2RS-hydroxycarbonyl- cyclopropane 17
##STR20## 1RS-allyloxycarbonyl-2RS- hydroxycarbonyl- cyclopropane
18 ##STR21## 1RS- Propargyloxycarbonyl- 2RS-hydroxycarbonyl-
cyclopropane 19 ##STR22## 1RS-Butinyloxycarbonyl-
2RS-hydroxycarbonyl- cyclopropane 20 ##STR23##
1RS-tertButoxycarbonyl- 2RS-hydroxycarbonyl-3,3-
dimethyl-cyclopropane 21 ##STR24## Diethyl 3,3-dimethyl-trans- 1,2-
cyclopropanedicarboxylate
[0101] The compounds of the formula I are suitable for the
treatment of the metabolic syndrome (see Datamonitor November 2002,
chapter 2, pages 19-32), for prediabetes treatment and for the
prophylaxis of type 2 diabetes. They are particularly suitable for
the treatment of diabetic dyslipidemia. Diabetic dyslipidemia is
manifested by an elevation of plasma triglycerides, a reduction in
HDL cholesterol and frequently in elevated LDL levels. Owing to the
increased occurrence of small, dense LDL cholesterol particles of
high atherogenic potency, diabetic dyslipidemia is a serious
cardiovascular risk factor.
[0102] These compounds are further suitable for the treatment
and/or prevention of 1.
[0103] disorders of fatty acid metabolism and glucose utilization
disorders,
[0104] disorders in which insulin resistance is involved,
[0105] hyperglycemia,
[0106] improvement in insulin resistance,
[0107] improvement in glucose tolerance,
[0108] protection of the pancreatic .beta. cells
[0109] prevention of macro- and microvascular disorders
[0110] dyslipidemias and their sequelae such as, for example,
atherosclerosis, coronary heart disease, cerebrovascular disorders
etc.
[0111] obesity (excess weight), including abdominal obesity
[0112] thromboses, hypercoagulable and prothrombotic stages
(arterial and venous)
[0113] high blood pressure
[0114] heart failure such as, for example, (but not restricted
thereto), following myocardial infarction, hypertensive heart
disease or cardiomyopathy
[0115] 2. further disorders or conditions in which for example
inflammatory reactions or cell differentiation are involved: [0116]
atherosclerosis such as, for example (but not restricted thereto),
coronary sclerosis including angina pectoris or myocardial
infarction, stroke [0117] vascular restenosis or reocclusion [0118]
chronic inflammatory bowel diseases such as, for example, Crohn's
disease and ulcerative colitis [0119] pancreatitis [0120] other
inflammatory conditions [0121] retinopathy [0122] adipose cell
tumors [0123] adipose cell carcinomas such as, for example,
liposarcomas [0124] solid tumors and neoplasms such as, for example
(but not restricted thereto), carcinomas of the gastrointestinal
tract, of the liver, of the biliary tract and of the pancreas,
endocrine tumors, carcinomas of the lung, of the kidney and the
urinary tract, of the genital tract, prostate carcinomas etc.
[0125] acute and chronic myeloproliferative disorders and lymphomas
[0126] angiogenesis [0127] neurodegenerative disorders [0128]
Alzheimer's disease [0129] multiple sclerosis [0130] Parkinson's
disease [0131] erythemato-squamous dermatoses such as, for example,
psoriasis [0132] acne vulgaris [0133] other skin disorders and
dermatological conditions modulated by PPAR [0134] eczemas and
neurodermatitis [0135] dermatitis such as, for example, seborrheic
dermatitis or photodermatitis [0136] keratitis and keratoses such
as, for example, seborrheic keratoses, senile keratoses, actinic
keratosis, photo-induced keratoses or keratosis follicularis [0137]
keloids and keloid prophylaxis [0138] warts, including condylomata
or condylomata acuminata [0139] human papilloma viral (HPV)
infections such as, for example, venereal warts, viral warts such
as, for example, molluscum contagiosum, leukoplakia [0140] papular
dermatoses such as, for example, lichen planus [0141] skin cancer
such as, for example, basal-cell carcinomas, melanomas or cutaneous
T-cell lymphomas [0142] localized benign epidermal tumors such as,
for example, keratoderma, epidermal naevi [0143] chilblains [0144]
high blood pressure [0145] syndrome X [0146] polycystic ovary
syndrome (PCOS) [0147] asthma [0148] osteoarthritis [0149] lupus
erythematosus (LE) or inflammatory rheumatic disorders such as, for
example, rheumatoid arthritis [0150] vasculitis [0151] wasting
(cachexia) [0152] gout [0153] ischemia/reperfusion syndrome [0154]
acute respiratory distress syndrome (ARDS)
[0155] The compounds of the formula I can be formulated for example
in the following preparations:
EXAMPLE A
[0156] Soft gelatin capsules containing 100 mg of active ingredient
per capsule: TABLE-US-00002 per capsule active ingredient 100 mg
triclyceride mixture fractionated from coconut fat 400 mg capsule
contents 500 mg
EXAMPLE B
[0157] Emulsion containing 60 mg of active ingredient per 5 ml:
TABLE-US-00003 per 100 ml of emulsion active ingredient 1.2 g
neutral oil q.s. sodium carboxymethylcellulose 0.6 g
polyoxyethylene stearate q.s. glycerol, pure 0.2 to 2.0 g flavoring
q.s. water (deionized or distilled) ad 100 ml
EXAMPLE C
[0158] Rectal drug form containing 40 mg of active ingredient per
suppository: TABLE-US-00004 per suppository active ingredient 40 mg
suppository base ad 2 g
EXAMPLE D
[0159] Tablets containing 40 mg of active ingredient per tablet:
TABLE-US-00005 per tablet lactose 600 mg corn starch 300 mg soluble
starch 20 mg magnesium stearate 40 mg 1000 mg
EXAMPLE E
[0160] Coated tablets containing 50 mg of active ingredient per
coated tablets: TABLE-US-00006 per coated tablet active ingredient
50 mg corn starch 100 mg lactose 60 mg sec. calcium phosphate 30 mg
soluble starch 5 mg magnesium stearate 10 mg colloidal silica 5 mg
260 mg
EXAMPLE F
[0161] The following formulations are suitable for producing the
contents of hard gelatin capsules: TABLE-US-00007 a) active
ingredient 100 mg corn starch 300 mg 400 mg b) active ingredient
140 mg lactose 180 mg corn starch 180 mg 500 mg
EXAMPLE G
[0162] Drops can be produced using the following formulation (100
mg of active ingredient in 1 ml=20 drops): TABLE-US-00008 active
ingredient 10 g methyl benzoate 0.07 g ethyl benzoate 0.03 g
ethanol, 96% 5 ml demineralized water ad 100 ml
[0163] The activity of the compounds of the formula I was tested as
follows:
[0164] Biological Test Model:
[0165] The effect was tested on the whole animal (mouse, rat,
hamster or dog), after a fasting period (e.g. of about 16 hours the
substance is administered (e.g. p.o., iv., i.p., s.c.) and, with or
without additional stimulation of endogenous lipolysis (e.g. by a
bolus injection of 2 mg/kg i.p. isoprenaline), the effect of the
test substance on lipolysis was determined on the basis of the
liberated free fatty acids (FFA), glycerol and triglycerides by
obtaining a blood sample (e.g. by retroorbital blood sampling) e.g.
15 min, 30, 60, 120 etc minutes after p.o. administration, and
analyzing by standard methods of clinical chemistry (e.g. L.
Thomas: Labor und Diagnose, 2nd edition, Medizinische
Verlagsgesellschaft, Marburg/L. 1984; ISBN 3-921320-10-9)). The
inhibition of lipolysis by the inhibitors is analyzed by comparing
with the rate of lipolysis in correspondingly treated control
animals.
[0166] The product of Example 5 was administered in doses of from
0.3 to 30 mg/kg po, whereby the lipolysis was distinctly reduced,
as it was possible to show from the reduction in free fatty acids
(FFA), glycerol and triglycerides. TABLE-US-00009 Time Control n =
15 3 mg/kg n = 6 FFA 0 0.47 0.47 15 0.60 0.17 30 0.62 0.13 60 0.62
0.11 120 0.69 0.25 Glycerol 0 89 87 15 98 39 30 94 33 60 96 28 120
130 57 Triglyceride Time Control n = 14 3 mg/kg n = 6 0 0.36 0.45
15 0.40 0.45 30 0.38 0.26 60 0.37 0.15 120 0.37 0.13 "n" stands for
the number of animals. Wistar rats were tested.
[0167] The activity of the compounds of the formula I was also
tested in the following assays: in vitro functional assays with
recombinant cells; function-testing assays were carried out by
means of the FLIPR technique ("Fluorescence Imaging Plate Reader",
Molecular Devices Corp.). For this purpose, agonist-induced changes
in the intracellular concentration of Ca.sup.2+ in recombinant
HEK293 cells which express both the GPCR HM74A (niacin receptor)
and the hybrid G-protein G.quadrature.6qi4myr (see, for example, DE
patent application 10033353) were determined.
[0168] For the investigations, cells were seeded into 96-well
microtiter plates (60 000 cells/well) and allowed to grow over
night. The medium was removed and the cells were incubated in
buffer which contained the fluorescent dye Fluo-4. After this
loading with dye, the cells were washed, test substance was added,
and changes in the intracellular Ca.sup.2+ concentration were
measured in the FLIPR apparatus. Results have been shown as
percentage change relative to the control (0%: no test substance
added; 100%: 1 .mu.M reference agonist niacin added), used to
calculate dose/activity plots and EC50 values determined.
TABLE-US-00010 TABLE 2 Biological activity Example No. EC50 (HM74a)
.mu.M 1 0.07 2 0.13 3 0.19 4 >30 5 >30 6 >30 7 0.63 8
>30 9 >30 10 1.48 11 2.16 12 0.67 13 1.61 14 >30 15 >30
16 >30 17 2.83 18 1.51 19 1.63 20 >30 21 >30
[0169] The compounds of examples 1, 4, 5, 6, 8 and 21 were
purchased from chemicals suppliers such as Fluka.RTM., Aldrich.RTM.
or Acros.RTM.. The compounds of examples 2 and 3 are disclosed in
WO 2002/066469.
Synthesis of
(1RS)-pentoxycarbonyl-(2RS)-hydroxycarbonylcyclopropane (example
13):
[0170] ##STR25##
[0171] 250 mg (1.58 mmol) of dimethyl
trans-cyclopropane-1,2-dicarboxylate are dissolved in 5 ml of
1-pentanol, and 0.36 ml of a 5 molar aqueous NaOH solution is
added. The reaction mixture is stirred at 25.degree. C. for 5 days.
Subsequently, 50 ml of water are added and the reaction mixture is
extracted twice with 30 ml of ethyl acetate each time. The organic
phase is discarded, and the aqueous phase is adjusted to pH=2 with
2 molar hydrochloric acid and extracted 3 times with ethyl acetate.
The combined organic phase is dried over MgSO.sub.4 and
concentrated in a rotary evaporator.
[0172] 220 mg (1.10 mmol) of
1RS-pentoxycarbonyl-2RS-hydroxycarbonylcyclopropane are obtained as
a colorless oil.
[0173] Examples 7, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19 and 20
were synthesized in analogy to this general procedure starting from
the appropriate dimethyl ester or diethyl ester.
* * * * *
References