# US 7,186,752 B2 · Derivatives of N-(iminomethyl)amines, their preparation, their use as medicaments and the pharmaceutical compositions containing them

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- Number: US 7,186,752 B2
- Document ID: US7186752B2
- Status: Granted
- Kind: B2
- Application number: 11/114,803
- Filed: 2005-04-26
- Published: 2005-09-08
- Granted: 2007-03-06
- Earliest claimed: 1998-09-23
- Assignees: Scras
- Inventors: Dennis Bigg; Pierre-Etienne Chabrier de Lassauniere; Serge Auvin; Jeremiah Harnett; Gérard Ulibarri
- Web page: https://patentgrep.com/patent/US7186752B2

## CPC

- 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
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- 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 9/10: 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/16: Anti-Parkinson drugs
- 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 25/32: Alcohol-abuse
- A61P 25/36: Opioid-abuse
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 27/12: for cataracts
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 39/06: Free radical scavengers or antioxidants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

N-(imino)amines and their preparation and their use as NO synthase inhibitors and selective or non-selective traps for a reactive oxygen species.

## Claims

### Claim 1

A compound of the formula
wherein
Φ is phenylene with 1 to 2 substituents selected from the group consisting of hydrogen, halogen, —OH, and alkyl or alkoxy of 1 to 6 carbon atoms;
A is
W is a bond;
R1, R2, R3, R4, R5 are individually selected from the group consisting of hydrogen, halogen, —OH, alkyl or alkoxy of 1 to 6 carbon atoms, cyano, nitro and —NR6R7;
R6 and R7 are individually selected from the group consisting of hydrogen, —OH, alkyl or alkoxy of 1 to 6 carbon atoms, and —COR8,
R8 is selected from the group consisting of hydrogen, —OH, alkyl or alkoxy of 1 to 6 carbon atoms, and —NR9R10,
R9 and R10 are individually selected from the group consisting of hydrogen, —OH or alkyl of 1 to 6 carbon atoms,
B is selected from the group consisting of —CH2—NO2; alkyl of 1 to 6 carbon atoms; —NR13R14; and unsubstituted or substituted carbocyclic aryl or heterocyclic aryl carbocyclic or heterocyclic aryl of 5 to 6 ring members containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen, the aryl substituents being selected from the group consisting of alkyl alkenyl and alkoxy of up to 6 carbon atoms,
R13 and R14 are individually selected from the group consisting hydrogen, alkyl of 1 to 6 carbon atoms, cyano, nitro radical, or together with the nitrogen form a non aromatic heterocycle of 5 to 6 ring members, selected from the group consisting of —CH2—, —NH—, —O—or —S—;
X is selected from the group consisting of a bond, —(CH2)k—NR16—, —O—, —S—, —CO—, —NR16—CO—, —CO—NR16—, —O—CO—, —CO—O—, —NR16—CO—O—, —NR16—CO—NR17—,
k representing 0 or 1;
Y is selected from the group consisting of a bond, —(CH2)m—, —(CH2)m—O—(CH2)n—, —(CH2)m—S—(CH2)n—, —(CH2)m—NR18—(CH2)n—, —(CH2)m—NR18—CO—(CH2)n—, —(CH2)m—CO—NR18—(CH2)n—, —(CH2)m-Q-(CH2)n—,
Q is selected from the group consisting of piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine radicals,
m and n are individually integers from 0 to 6;
R16, R17 and R18 are individually hydrogen or akyl of 1 to 6 carbon atoms;
and a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1 wherein A is
R1, R2, R3, R4, R5 are individually selected from the group consisting of hydrogen, —OH and alkyl and alkoxy of 1 to 6 carbon atoms,
R11 is hydrogen or alkyl of 1 to 6 carbon atoms;
B is a substituted or unsubstituted carbocyclic aryl or heterocyclic aryl of 5 to 6 ring members containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen, the aryl substituents being selected from the group consisting of alkyl, alkenyl and alkoxy of up to 6 carbon atoms;
W is a bond
X is selected from the group consisting of a bond, —(CH2)k—NR16—, —O—, —S—, —CO—, —NR16—CO—, —CO—NR16—, —O—CO—, —CO—O—, —NR16—CO—O—, —NR16—CO—NR17—;
k representing 0 or 1;
Y is selected from the group consisting of a bond, —(CH2)m—, —(CH2)m—O—(CH2)n—, —(CH2)m—S—(CH2)n—, —(CH2)m—NR18—(CH2)n—, —(CH2)m—NR18—CO—(CH2)n—, —(CH2)m—CO—NR18—(CH2)n—, —(CH2)m-Q-(CH2)n—;
Q is selected from the group consisting of piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine,
m and n are integers from 0 to 6.

### Claim 3 (depends on 1)

The compound of claim 1 wherein B as heterocyclic aryl is selected from the group consisting of thiophene, furan, pyrrole and thiazole.

### Claim 4 (depends on 1)

The compound of claim 1 wherein A is
R1, R2, R3, R4 and R5 are individually selected from the group consisting of hydrogen, —OH and alkyl and alkoxy of 1 to 6 carbon atoms,
R11 is hydrogen or methyl;
B is selected from the group consisting of unsusbstituted or substituted phenyl, thiophene, furan, pyrrole and thiazole, the substituents being at least one member of the group consisting of alkyl alkenyl and alkoxy of 1 to 6 carbon atoms;
W is a bond;
X is selected from the group consisting of a bond, —(CH2)k—NR16—, —O—, —S—, —CO—, —NR16—CO—, —CO—NR16—, —O—CO—, —CO—O—, —NR16—CO—O—, —NR16CO—NR17—,
k representing 0 or 1;
Y is selected from the group consisting of a bond, —(CH2)m—, —CH2)m—O—(CH2)n —, —(CH2)m—S—(CH2)n—, —(CH2)m—NR18—(CH2)n—, —(CH2)m—NR18—CO—(CH2)n—, —(CH2)m—CO—NR18—(CH2)n—, —(CH2)m-Q-(CH2)n—,
Q is selected from the group consisting of piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4oxypiperidine or 4-aminopiperidine,
m and n being integers comprised from 0 to 6.

### Claim 5 (depends on 1)

A compound of claim 1 which is 4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(4-phenoxyphenyl)butanamide or
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-4-(4-hydroxyphénoxy)benzamide.

### Claim 6 (depends on 5)

A compound of claim 5 in the form of its hydrochloride salt.

### Claim 7 (depends on 1)

A composition for inhibiting NO synthase and/or lipidic peroxidation comprising an effective amount of a compound of claim 1 and an inert pharmaceutical carrier.