# US 7,612,104 B2 · Bicyclic aryl-sulfonic acid [1,3,4]-thiadiazol-2-yl-amides, processes for their preparation, pharmaceutical compositions and methods for their use

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- Number: US 7,612,104 B2
- Document ID: US7612104B2
- Status: Granted
- Kind: B2
- Application number: 12/062,759
- Filed: 2008-04-04
- Published: 2008-11-27
- Granted: 2009-11-03
- Earliest claimed: 2005-10-06
- Assignees: Sanofi-Aventis
- Inventors: Karl Schoenafinger; Stefanie Keil; Matthias Urmann; Hans Matter; Maike Glien; Wolfgang Wendler
- Web page: https://patentgrep.com/patent/US7612104B2

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/12: Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- A61P 11/06: Antiasthmatics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07D 285/135: Nitrogen atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention comprises bicyclic aryl-sulfonic acid [1,3,4]-thiadiazol-2-yl-amides, their functional derivatives thereof as well as their physiologically acceptable salts and pharmaceutical compositions thereof that exhibit peroxisome proliferator activated receptor (PPAR) PPARdelta and PPARgamma agonist activity. The structure of the compounds of the invention are defined by Formula I below, wherein the various substituents are defined herein, including their physiologically acceptable salts. Processes for the compounds preparation are also disclosed. The compounds are suitable for the treatment of fatty acid metabolism and glucose utilization disorders, disorders relating to insulin resistance are involved as well as demyelinating and other neurodegenerative disorders of the central and peripheral nervous system.

## Claims

### Claim 1

A compound of formula I:
wherein
R1 is selected from the group consisting of (C1-C6)alkyl, (C0-C6)alkylene (C3-C6) cycloalkyl, (C0-C6)alkylene-O—(C1-C6)alkyl, (C0-C6)alkylene-O—(C3-C6) cycloalkyl, (C0-C6)alkylene-(C6-C14)aryl and (C0-C6) alkylene-(C5-C15) heteroaryl, wherein the alkyl, alkylene, aryl, heteroaryl and cycloalkyl can be unsubstituted or mono, di- or trisubstituted by F, Cl, Br, OCF3, CN, CO—(C1-C6) alkyl, COO(C1-C6)alkyl, CON((C0-C6)alkylene-H)((C0-C6)alkylene-H), or S(O)m (C1-C6)alkyl;
R2, R3, R4 and R5 are independently selected from the group consisting of H, halogen, (C1-C6)alkyl, (C0-C4)alkylene-O—(C0-C4)alkylene-H, CN, COO(C1-C6)alkyl, CON((C0-C6)alkylene-H)((C0-C6)alkylene-H) and S(O)m(C1-C6)alkyl, wherein the alkyl and alkylene are unsubstituted or mono, di- or trisubstituted by F;
A is (C6-C14)aryl;
n is 1, 2, or 3;
m and z are 0, 1, or 2; and
R6, R7 and R8 are independently selected from the group consisting of H, (C1-C6)alkyl, CN, CO—(C1-C6)alkyl, COO—(C1-C6)alkyl, CON((C0-C6)alkylene-H((C0-C6) alkylene-H), S(O)m(C1-C6)alkyl, N((C0-C6)alkylene-H)((C0-C6)alkylene-H), N((C0-C6)alkylene-H)—CO—(C1-C6)alkyl, N((C0-C6)alkylene-H)—CO—(C1-C6) alkyl, halogen, (C0-C6)alkylene-O—(C0-C6)alkylene-H, (C0-C6)alkylene-O—(C6-C14) aryl, SCF3, S(O)2CF3 and NO2, wherein the alkyl, aryl and alkylene are unsubstituted or mono, di- or trisubstituted by F and the aryl can be unsubstituted or monosubstituted by CF3;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein
R1 is selected from the group consisting of (C1-C6)alkyl, (C0-C6)alkylene-(C3-C6) cycloalkyl, (C0-C6)alkylene-O—(C1-C6)alkyl, (C0-C6)alkylene-O—(C3-C6) cycloalkyl and (C0-C6)alkylene-(C6-C14)aryl, wherein the alkyl, alkylene, aryl, and cycloalkyl can be unsubstituted or mono, di- or trisubstituted by F, Cl, or Br;
R2, R3, R4, R5 are independently selected from the group consisting of H, halogen, (C1-C6) alkyl, and (C0-C4)alkylene-O—(C0-C4)alkylene-H, wherein the alkyl and alkylene are unsubstituted or mono, di- or trisubstituted by F;
n is 1, or 2;
z is 1, or 2; and
R6, R7 and R8 are independently selected from the group consisting of H, (C1-C6)alkyl, CN, halogen, (C0-C6)alkylene-O—(C0-C6)alkylene-H, (C0-C6)alkylene-(C6-C14) aryl, (C0-C6)alkylene-O—(C6-C14)aryl, SCF3, and S(O)2CF3, wherein the alkyl, aryl and alkylene are unsubstituted or mono, di- or trisubstituted by F and the aryl can be unsubstituted or monosubstituted by CF3;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein
R1 is selected from the group consisting of (C1-C6)alkyl, (C0-C6)alkylene (C3-C6) cycloalkyl and (C0-C6)alkylene-(C6-C14)aryl, wherein the alkyl, alkylene, aryl, and cycloalkyl can be unsubstituted or mono, di- or trisubstituted by F;
R2, R3, R4 and R5 are independently selected from the group consisting of H, halogen, (C1-C6)alkyl and (C0-C4)alkylene-O—(C0-C4)alkylene-H, wherein the alkyl and alkylene are unsubstituted or mono, di- or trisubstituted by F;
A is phenyl;
n is 1;
z is 1;
R6 is F, Cl, Br, or O(C1-C4)-alkyl, and is in the ortho position;
R7 is F, Cl, Br, CH3 or CF3, and is in the para position; and
R8 is H;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound according to claim 1 wherein
R1 is selected from the group consisting of (C1-C4)alkyl, (C0-C2)alkylene (C3-C6) cycloalkyl and (C0-C2)alkylene-(C6-C10)aryl, wherein the alkyl, aryl, and cycloalkyl can be unsubstituted or mono, di- or trisubstituted by F;
R2 is selected from the group consisting of H, halogen, (C1-C6)alkyl and O—(C0-C4) alkylene-H, wherein the alkyl and alkylene are unsubstituted or mono, di- or trisubstituted by F;
R3 is H;
R4 is H;
R5 is H, or (C1-C4)alkyl;
A is (C6)aryl;
n is 1, or 2;
z is 1;
R6 is selected from the group consisting of (C1-C4)alkyl, halogen, (C0-C2)alkylene-O—(C0-C6)alkylene-H and (C0-C2)alkylene-(C6-C10)aryl, wherein the alkyl, aryl and alkylene are unsubstituted or mono, di- or trisubstituted by F and the aryl can be unsubstituted or monosubstituted by CF3;
R7 is selected from the group consisting of H, (C1-C4)alkyl and halogen, wherein the alkyl is unsubstituted or mono, di- or trisubstituted by F; and
R8 is H or F;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein
R1 is selected from the group consisting of (C1-C4)alkyl, (C3-C6)cycloalkyl, and phenyl, wherein the alkyl can be unsubstituted or mono, di- or tri substituted by F;
R2 is selected from the group consisting of H, F, Cl and O—(C1-C4)alkylene-H, wherein the alkylene is unsubstituted or mono, di- or trisubstituted by F;
R3 is H;
R4 is H;
R5 is H or (C1-C4)alkyl;
A is phenyl;
n is 1, or 2;
z is 1;
R6 is selected from the group consisting of (C1-C4)alkyl, F, Cl, O—(C0-C6)alkylene-H, and phenyl, wherein the phenyl can be unsubstituted or monosubstituted by CF3;
R7 is selected from the group consisting of H, (C1-C4)alkyl, and Cl, wherein the alkyl is unsubstituted or mono, di- or trisubstituted by F; and
R8 is H or F;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound according to claim 1 wherein
R1 is selected from the group consisting of ethyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl and trifluoromethyl;
R2, R3, R4 and R5 are selected from the group consisting of H, F, Cl, CH3 and OCH3;
A is phenyl;
n is 1;
z is 1;
R6 is Cl, Br, or O(C1-C2)-alkyl and is in the ortho position;
R7 is Cl, Br or CF3 and is in the ortho position; and
R8 is H;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein
R1 is isopropyl;
R2, R3, R4 and R5 are H;
A is phenyl;
n is 1;
z is 1;
R6 is O(C1-C2)-alkyl, and is in ortho position;
R7 is Cl or CF3 and is in the para position; and
R8 is H;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein
R1 is trifluoromethyl;
R2, R3, R4 and R5 are H;
A is phenyl;
n is 1;
z is 1;
R6 is O-ethyl, and is in ortho position;
R7 is Cl or CF3 and is in the para position; and
R8 is H;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein
R1 is cyclohexyl;
R2, R3, R4, R5 are H;
A is phenyl;
n is 1;
z is 1;
R6 is O-ethyl and in ortho position;
R7 is Cl or CF3, and is in the para-position; and
R8 is H;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein
R1 is phenyl;
R2, R3, R4 and R5 are H;
A is phenyl;
n is 1;
z is 1;
R6 is O-ethyl, and is in ortho position;
R7 is Cl or CF3, and is in para position; and
R8 is H;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein
R1 is cyclopropyl;
R2, R3, R4, R5 are H;
A is phenyl;
N is 1;
z is 1;
R6 is O-ethyl and in the ortho-position;
R7 is Cl or CF3 and in the para-position;
R8 is H;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising at least one compound according to claim 1, or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.

### Claim 13 (depends on 12)

The pharmaceutical composition according to claim 12, further comprising at least one additional active pharmaceutical compound, wherein the additional active pharmaceutical compound is effective in the treatment of metabolic disturbance or a physiological disorder associated therewith.

### Claim 14 (depends on 13)

The pharmaceutical composition according to claim 13 wherein said additional active pharmaceutical compound is an anti-diabetic compound effective in the treatment of diabetes.

### Claim 15 (depends on 13)

The pharmaceutical composition according to claim 13 wherein said additional active pharmaceutical compound is a lipid modulator compound.

### Claim 16 (depends on 13)

The pharmaceutical composition according to claim 13 wherein said active pharmaceutical compound is a compound effective in the treatment of metabolic syndrome or a physical manifestation thereof.

### Claim 17 (depends on 1)

A process for preparing a pharmaceutical comprising at least one compound according to claim 1, or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof, in combination with a pharmaceutically acceptable salt thereof, with the pharmaceutically acceptable carrier or excipient, and bringing this mixture into a form suitable for administration.