Amidine derivatives, their preparation and application as medicines and pharmaceutical compositions containing same

• US 6,653,312 B1
• Filed: 03/16/2001
• Issued: 11/25/2003
• Est. Priority Date: 09/23/1998
• Status: Expired due to Fees

• Current Assignee: Ipsen Pharma Sas (Ipsen Sa)
• Original Assignee: Societe de Conseils de Recherches et d'Applications Scientifiques
• Inventors: Ulibarri, Gérard, Harnett, Jeremiah, Auvin, Serge, Pons, Dominique, Chabrier de Lassauniere, Pierre-Etienne
• Primary Examiner(s): LIU, HONG
• Application Number:
  US09/787,467
• Time in Patent Office: 984 Days
• Field of Search: 544/295, 544/269, 544/272, 514/252.19, 514/314, 514/414, 514/263.23, 514/263.34, 514/326, 514/336, 514/357, 546/177, 546/231, 546/332, 548/467
• US Class Current: 514/252.19
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: 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
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07C 217/84 : the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 333/36 : Nitrogen atoms
• CPC Class Codes: 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
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 473/08 : with methyl radicals in positions 1 and 3, e.g. theophylline

Abstract

Amidine compounds of the formula

wherein the substituents are defined as in the application useful as NO-synthase enzyme inhibitors.

Claims

1. A compound of the formula

wherein A is

T is —

CH₂—

, k is 1, R₃₁ is selected from the group consisting of alkyl of 1 to 6 carbon atoms and one of the aralkyl, diaralkyl, bis-aralkyl, amino alkyl, alkylaminoalkyl, dialkylaminoalkyl and heterocycloalkyl radicals wherein the alkyl radicals each have 1 to 6 carbon atoms and the saturated or unsaturated heterocycle has 3 to 7 ring members and has at least one nitrogen with a hydrogen or alkyl substituent, X is selected from the group consisting of a bond, —

(CH₂)_m—

, —

(CH₂)_m—

CO—

, —

O—

(CH₂)_m—

, —

S—

(CH₂)_m—

, —

NR₃₆—

(CH₂)_m—

, —

CO—

NR₃₆—

, —

O—

(CH₂)_m—

CO—

, —

S—

(CH₂)_m—

CO—

, —

NR₃₆—

(CH₂)_m—

CO—

, —

(CH₂)_m—

C(OH)(CH₃)—

CO—

, —

CH═

CH— and

—

CH═

N—

, Y is selected from the group consisting of a bond, —

(CH₂)_n— and

—

(CH₂)_r—

Q—

(CH₂)_s—

, Q is selected from the group consisting of piperazine, homopiperazine, 2-methyl-piperazinc, 2,5-dimethyl-piperazine, 1,2,3,6-tetrahydro-pyridine, pyrrolidine, azetidine, thiazolidine and a saturated carbon ring of 3 to 7 carbon atoms , Φ

is selected from the group consisting of a bond, —

(CH₂)_p—

O—

(CH₂)_q—

, —

(CH₂)_p—

S—

(CH₂)_q—

, —

(CH₂)_p—

NR₃₇—

(CH₂)_q—

, —

(CH₂)_p—

CO—

NR₃₇—

(CH₂)_q— and

—

CO—

(CH₂)_p—

NR₃₇—

(CH₂)_q—

, B is selected from the group consisting of alkyl of 1 to 6 carbon atoms, unsubstituted or substituted carbocyclic and heterocyclic aryl of 5 to 6 ring members with 1 to 4 heteroatoms selected from the group consisting of nitrogen and sulfur and

 

the substituents being

at least one member of the group consisting of alkyl, alkenyl and alkoxy of up to 6 carbon atoms, R₃₄ and R₃₅ are individually hydrogen or alkyl of 1 to 6 carbon atoms 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— and

—

S—

, m, n, p, q, r and s are individually integers from 0 to 6, R₃₆ and R₃₇ are individually selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and —

CO—

R₃₈, R₃₈ is alkyl or alkoxy of 1 to 6 carbon atoms, R₃₉ is hydrogen or alkyl of 1 to 6 carbon atoms or its non-toxic, pharmaceutically acceptable salts.

2. A compound of claim 1 wherein B is selected from the group consisting of thiophene, furon, pyrrole and thiazole.

3. A compound of claim 1 wherein B is thiophene.

4. A composition of claim 1 wherein R₃₁ is selected from the group consisting of methyl, benzyl and naphthylmethyl.

5. A compound of claim 1 selected from the group consisting of:

3-[(3-{[amino(2-thienyl)methylidene amino)-benzyl)amino]-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)propanamide;

3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(1-benzyl-2,3-dihydro-1H-indol-5-propanamide;

3-(3-{[amino(2-thienyl)methylidene]amino}benzyl)amino]-N-[1-(1-naphthylmethyl)-2,3-dihydro-1H-indol-5-yl]propanamide;

4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-{1-[3-dimethylamino)propyl]-2,3-dihydro-1H-indol-5-yl}butanamide;

3-[(5-amino(2-thienyl)methylidene]amino}-2-methoxybenzyl)amino]-N-[1-(1-naphthylmethyl)-2,3-dihydro-1H-indol-5-yl]propanamide;

or its non-toxic, pharmaceutically acceptable salts.

6. A composition to inhibit NO synthase and/or lipidic peroxidation comprising an inhibitorily effective amount of a compound of claim 1 and an inert carrier.

7. A method of inhibiting NO synthase in warm-blooded animals comprising administering to said warm-blooded animals an amount of a compound of claim 1 sufficient to inhibit NO synthase.

8. A method of inhibiting lipidic peroxidation in warm-blooded animals comprising administering to said warm-blooded animals an amount of a compound of claim 1 sufficient to inhibit lipidic peroxidation.

9. A method of inhibiting NO synthase and lipidic peroxidation in warm-blooded animals comprising administering to said warm-blooded animals an amount of a compound of claim 1 sufficient to inhibit NO synthase and lipidic peroxidation.