# US 8,541,410 B2 · Sulfur substituted sulfonylaminocarboxylic acid N-arylamides, their preparation, their use and pharmaceutical preparations comprising them

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- Number: US 8,541,410 B2
- Document ID: US8541410B2
- Status: Granted
- Kind: B2
- Application number: 13/345,223
- Filed: 2012-01-06
- Published: 2012-05-03
- Granted: 2013-09-24
- Earliest claimed: 1998-07-08
- Assignees: Sanofi-Aventis Deutschland GmbH
- Applicants: Ursula Schindler; Karl Schönafinger; Hartmut Strobel
- Inventors: Ursula Schindler; Karl Schönafinger; Hartmut Strobel
- Web page: https://patentgrep.com/patent/US8541410B2

## CPC

- C07C 311/21: having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 15/10: for impotence
- A61P 25/00: Drugs for disorders of the nervous system
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 311/46: Y being a hydrogen or a carbon atom
- C07C 311/51: Y being a hydrogen or a carbon atom
- C07C 311/58: having nitrogen atoms of the sulfonylurea groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C 317/40: Y being a hydrogen or a carbon atom
- C07C 323/42: Y being a carbon atom of a six-membered aromatic ring
- C07C 323/52: the carbon skeleton being acyclic and saturated
- C07C 323/60: with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
- C07C 331/12: having sulfur atoms of thiocyanate groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07D 207/12: Oxygen or sulfur atoms
- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 207/20: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 207/48: Sulfur atoms
- C07D 209/10: with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 211/46: having a hydrogen atom as the second substituent in position 4
- C07D 211/54: Sulfur atoms
- C07D 211/62: attached in position 4
- C07D 211/96: Sulfur atom
- C07D 213/71: to which a second hetero atom is attached
- C07D 213/78: Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 213/80: in position 3
- C07D 213/82: in position 3
- C07D 215/36: Sulfur atoms (C07D215/24 takes precedence)
- C07D 221/20: Spiro-condensed ring systems
- C07D 231/18: One oxygen or sulfur atom
- C07D 231/38: Nitrogen atoms (nitro radicals C07D231/16)
- C07D 231/42: Benzene-sulfonamido pyrazoles
- C07D 233/84: Sulfur atoms
- C07D 235/18: with aryl radicals directly attached in position 2
- C07D 239/06: having one double bond between ring members or between a ring member and a non-ring member
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 243/08: not condensed with other rings
- C07D 261/10: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 261/16: Benzene-sulfonamido isoxazoles
- C07D 265/30: not condensed with other rings
- C07D 277/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 277/36: Sulfur atoms
- C07D 277/46: by carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D 277/52: to sulfur atoms, e.g. sulfonamides
- C07D 277/54: Nitrogen and either oxygen or sulfur atoms
- C07D 277/64: with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D 279/12: not condensed with other rings
- C07D 295/26: Sulfur atoms
- C07D 333/34: Sulfur atoms
- C07D 333/38: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 333/40: Thiophene-2-carboxylic acid
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 491/10: Spiro-condensed systems
- C07C 2601/02: with a three-membered ring
- C07C 2601/14: The ring being saturated
- C07C 2602/04: One of the condensed rings being a six-membered aromatic ring
- C07C 2602/08: the other ring being five-membered, e.g. indane
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to compounds of the formula I wherein A1, A2, R1, R2, R3, X and n are as defined in the claims, which are valuable pharmaceutically active compounds for the therapy and prophylaxis of diseases, for example of cardiovascular diseases such as hypertension, angina pectoris, cardiac insufficiency, thromboses or atherosclerosis. The compounds of the formula I are capable of modulating the body's production of cyclic guanosine monophosphate (cGMP) and are generally suitable for the therapy and prophylaxis of diseases which are associated with a disturbed cGMP balance. The invention furthermore relates to processes for preparing compounds of the formula I, to their use for the therapy and prophylaxis of the abovementioned diseases and for preparing pharmaceuticals for this purpose, and to pharmaceutical preparations which comprise compounds of the formula I.

## Claims

### Claim 1

A compound, a stereoisomeric form thereof, or a physiologically acceptable salt thereof, of the formula XII:
wherein:
A1 is phenylene which is unsubstituted or substituted by one or more identical or different substituents chosen from halogen, (C1-C4)-alkyl, CF3, —O—(C1-C4)-alkyl, and —CN;
A2 is a benzene ring;
R1 is NR5R6;
R3 is one or more identical or different residues chosen from hydrogen, halogen, CF3, —O—(C1-C4)-alkyl, —CN, and (C1-C4)-alkyl;
R5 and R6 together with the nitrogen atom to which they are bonded form a 5-membered or 6-membered saturated heterocycle, wherein said heterocycle optionally further comprises an additional ring heteroatom chosen from nitrogen, oxygen, and sulfur, and said heterocycle is unsubstituted or substituted by one or more identical or different residues chosen from (C1-C3)-alkyl, hydroxy-(C1C3)-alkyl-, aryl, carbamoyl, hydroxy, and oxo;
aryl is phenyl or 5-membered or 6-membered heteroaryl comprising one or more identical or different ring heteroatoms chosen from nitrogen, oxygen, and sulfur, and is unsubstituted or substituted by one or more identical or different substituents chosen from halogen, (C1-C4)-alkyl, CF3, NO2, —O—(C1-C4)-alkyl, —NH—CO—(C1-C4)-alkyl, and —CN;
n is 2; and
X is oxygen.

### Claim 2 (depends on 1)

The compound of the formula XII, according to claim 1, wherein:
A1 is an unsubstituted divalent phenylene residue;
R3 is one or more identical or different residues chosen from hydrogen, halogen, —O—(C1-C4)-alkyl, and (C1-C4)-alkyl;
R5 and R6 together with the nitrogen atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocycle optionally further comprises an additional ring heteroatom chosen from nitrogen, oxygen, and sulfur, and said heterocycle is unsubstituted or substituted by one or more identical or different residues chosen from (C1-C3)-alkyl, aryl, oxo, and carbamoyl; and
aryl is phenyl or 5-membered or 6-membered heteroaryl comprising one or more identical or different ring heteroatoms chosen from nitrogen, oxygen, and sulfur, and is unsubstituted or substituted by one or more identical or different substituents chosen from halogen, (C1-C4)-alkyl, CF3, —O—(C1-C4)-alkyl.

### Claim 3 (depends on 1)

The compound of he formula XII, according to claim 1, wherein:
A 1 is an unsubstituted divalent 1,4-phenylene residue;
A2, together with the residues R3, is a benzene ring which is substituted with one or two identical or different substituents chosen from chlorine and methoxy; and
R5 and R6 together with the nitrogen atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocycle optionally further comprises an additional ring heteroatom chosen from oxygen and sulfur, and said heterocycle is unsubstituted or substituted by one or two methyl residues.

### Claim 4

A compound, a stereoisomeric form thereof, or a physiologically acceptable salt thereof, of the formula XIII:
wherein:
A1 is phenylene which is unsubstituted or substituted by one or more identical or different substituents chosen from halogen, (C1-C4)-alkyl, CF3, —O—(C1-C4)-alkyl, and —CN;
A2 is a benzene ring;
R1 is NR5R6;
R3 is one or more identical or different residues chosen from hydrogen, halogen, CF3, —O—(C1-C4)-alkyl, —CN, and (C1-C4)-alkyl;
R5 and R6 together with the nitrogen atom to which they are bonded form a 5-membered or 6-membered saturated heterocycle, wherein said heterocycle optionally further comprises an additional ring heteroatom chosen from nitrogen, oxygen, and sulfur, and said heterocycle is unsubstituted or substituted by one or more identical or different residues chosen from (C1-C3)-alkyl, hydroxy-(C1-C3)-alkyl-, aryl, carbamoyl, hydroxy, and oxo;
aryl is phenyl or 5-membered or 6-membered heteroaryl comprising one or more identical or different ring heteroatoms chosen from nitrogen, oxygen, and sulfur, and is unsubstituted or substituted by one or more identical or different substituents chosen from halogen, (C1-C4)-alkyl, CF3, NO2, —O—(C1-C4) alkyl —NH—CO—(C1-C4)-alkyl, and —CN;
n is 2; and
X is oxygen;

### Claim 5 (depends on 4)

The compound of the formula XIII ccording to claim 4, wherein:
A1 is an unsubstituted divalent phenylene residue;
R3 is one or more identical or different residues chosen from hydrogen, halogen, —O—(C1-C4)-alkyl, and (C1-C4)-alkyl;
R5 and R6 together with the nitrogen atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocycle optionally further comprises an additional ring heteroatom chosen from nitrogen, oxygen, and sulfur, and said heterocycle is unsubstituted or substituted by one or more identical or different residues chosen from (C1-C3)-alkyl, aryl, oxo, and carbamoyl; and
aryl is phenyl or 5-membered or 6-membered heteroaryl comprising one or more identical or different ring heteroatoms chosen from nitrogen, oxygen, and sulfur, and is unsubstituted or substituted by one or more identical or different substituents chosen from halogen, (C1-C4)-alkyl, CF3, —O—(C1-C4)-alkyl.

### Claim 6 (depends on 4)

The compound of the formula XIII, according to claim 4, wherein:
A1 is an unsubstituted divalent 1,4-phenylene residue;
A2, together with the residues R3, is a benzene ring which is substituted with one or two identical or different substituents chosen from chlorine and methoxy; and
R5 and R6 together with the nitrogen atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocycle optionally further comprises an additional ring heteroatom chosen from oxygen and sulfur, and said heterocycle is unsubstituted or substituted by one or two methyl residues.