3-(amino-or aminoalkyl) pyridinone derivatives and their use for the treatment of HIV related diseases

• US 6,683,079 B2
• Filed: 07/15/2002
• Issued: 01/27/2004
• Est. Priority Date: 04/27/1998
• Status: Expired due to Fees

• Current Assignee: Centre National De La Recherche Scientifique, Insitut Curie
• Original Assignee: Centre National De La Recherche Scientifique, Insitut Curie
• Inventors: Dolle, Valerie, Grierson, David, Nguyen, Chi Hung, Bisagni, Emile, Monneret, Claude, Aubertin, Anne-Marie
• Primary Examiner(s): DESAI, RITA J
• Application Number:
  US10/194,240
• Publication Number:
  US 20030125340A1
• Time in Patent Office: 561 Days
• Field of Search: 546/194, 544/124, 544/128, 514/233.5, 514/235.5, 514/312, 514/314
• US Class Current: 514/233.5
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07D 213/73 Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

3-(amino- or aminoalkyl) pyridinone derivatives having the formula (1)

wherein Q, X, Y, and R³-R⁶ are as defined, which derivatives are useful for the treatment of HIV related diseases.

Claims

1. A method of treatment of an HIV infection comprising administration of an effective amount of a compound having the formula (1)

wherein:

Q represents —

NR₁R₂ or —

R₀NR₁R₂ wherein;

R₀ represents C_1-5 alkanediyl;

R₁ and R₂ are taken together and form a bivalent radical —

R₁-R₂—

wherein —

R₁-R₂—

represents —

(CH₂)₂—

O—

(CH₂)₂—

, —

(CH₂)₂—

NR₇—

(CH₂)₂, —

(CH₂)₂—

CH(NHR₇)—

(CH₂)₂—

or —

(CH₂)_n wherein R₇ represents hydrogen or C_1-4alkyl and n represents 2, 3, 4, 5 or 6;

R₃ represents phenyl or substituted phenyl;

R₄ and R₅ each independently represent hydrogen, C_1-6alkyl, C_3-6alkenyl, C_1-4 alkoxy, C_1-4 alkyloxy C_1-4 alkyl, amino, mono- or di (C_1-4alkyl) amino, formyl, C_1-4alkylcarbonyl carboxyl, C_1-4alkyloxycarbonyl, or C_1-4alkyl aminocarbonyl;

wherein C_1-6alkyl and C_3-6alkenyl may be substituted with one, two or three substituents selected from hydroxy, C_1-4alkyloxy, C_1-4alkyl thio, aryloxy, arylthio, amino, mono- or di(_C1-4alkyl)amino and aryl;

or R₄ and R₅ taken together form a bivalent radical or formula —

R₄-R₅—

wherein —

R₄-R₅—

represents —

CH═

CH—

CH═

CH—

or —

(CH₂)_t, wherein t represents 3 or 4;

R₆ represents hydrogen, hydroxy, C_1-4alkyloxy, C_1-6alkyl, C_3-6alkenyl, aryl, C_1-4alkyl, amino, mono- or di(C_1-4alkyl)amino or alkylaryl;

Y represents O or S;

X represents a radical of formula;

2. The method according to claim 1 wherein X represents —

CH₂— and

R₃ represents a phenyl group substituted with two methyl groups.

3. A process of making compounds having the formula (1)

wherein:

Q represents '"'"'NR₁R₂ or —

R₀NR₁R₂ wherein;

R₀ represents C_1-5 alkanediyl;

R₁ and R₂ are taken together and form a bivalent radical —

R₁—

R₂—

wherein —

R₁—

R₂—

represents —

(CH₂)₂—

O—

(CH₂)₂—

, —

(CH₂)₂—

NR₇—

(CH₂)₂, —

(CH₂)₂—

CH(NHR₇)—

(CH₂)₂—

or —

(CH₂)_n wherein R₇ represents hydrogen or C_1-4alkyl and n represents 2, 3, 4, 5 or 6;

R₃ represents phenyl or substituted phenyl;

R₄ and R₅ each independently represent hydrogen, C_1-6alkyl, C_3-6alkenyl, C_1-4 alkoxy, C_1-4 alkyloxy C_1-4 alkyl, amino, mono- or di (C_1-4alkyl) amino, formyl, C_1-4alkylcarbonyl carboxyl, C_1-4alkyloxycarbonyl, or C_1-4alkyl aminocarbonyl;

wherein C_1-6alkyl and C_3-6alkenyl may be substituted with one, two or three substituents selected from hydroxy, C_1-4alkyloxy, C_1-4alkyl thio, aryloxy, arylthio, amino, mono- or di(C_1-4alkyl)amino and aryl;

or R₄ and R₅ taken together form a bivalent radical or formula —

R₄-R₅—

wherein —

R₄-R₅—

represents —

CH═

CH—

CH═

CH—

or —

(CH₂)_t, wherein t represents 3 or 4;

R₆ represents hydrogen;

Y represents O;

X represents —

CH₂—

;

or

a N-oxide, a stereochemically isomeric form or a pharmaceutically acceptable addition salt thereof,

comprising the following steps;

a) reacting a pyridine, substituted in position 2 with an alkoxy group and in position 3 with an amidoalkyl group, with a C₁-C₆ alkyllithium, resulting in a lithiated derivative of the said pyridine;

b) transforming said lithiated derivative into an organocopper reagent by reacting it with a complex formed by Cu I and dimethyl sulphide;

c) obtaining a protected pyridinone by reacting the organocopper reagent with optionally substituted benzyl halide;

d) hydrolysing said protected pyridinone and obtaining a deprotected pyridinone; and

e) substituting the amine-3 group of said deprotected pyridinone and obtaining the desired pyridinone compound.

4. A process of making compounds having the formula (1)

wherein:

Q represents —

NR₁R₂ or —

R₀NR₁R₂ wherein;

R₀ represents C_1-5 alkanediyl;

R₁ and R₂ are taken together and form a bivalent radical —

R₁-R₂—

wherein —

R₁-R₂—

represents —

(CH₂)₂—

O—

(CH₂)₂—

, —

(CH₂)₂—

NR₇—

(CH₂)₂, —

(CH₂)₂—

CH(NHR₇)—

(CH₂)₂—

or —

(CH₂)_n wherein R₇ represents hydrogen or C_1-4alkyl and n represents 2, 3, 4, 5 or 6;

R₃ represents phenyl or substituted phenyl;

R₄ and R₅ each independently represent hydrogen, C_1-6alkyl, C_3-6alkenyl, C_1-4 alkoxy, C_1-4 alkyloxy C_1-4 alkyl, amino, mono- or di (C_1-4alkyl) amino, formyl, C_1-4alkylcarbonyl carboxyl, C_1-4alkyloxycarbonyl, or C_1-4alkyl aminocarbonyl;

wherein C_1-6alkyl and C_3-6alkenyl may be substituted with one, two or three substituents selected from hydroxy, C_1-4alkyloxy, C_1-4alkyl thio, aryloxy, arylthio, amino, mono- or di(C_1-4alkyl)amino and aryl;

or R₄ and R₅ taken together form a bivalent radical or formula —

R₄-R₅—

wherein —

R₄-R₅—

represents —

CH═

CH—

CH═

CH—

or —

(CH₂)_t, wherein t represents 3 or 4;

R₆ represents hydrogen;

Y represents O;

X represents —

C(═

O);

or

a N-oxide, a stereochemically isomeric form or a pharmaceutically acceptable addition salt thereof,

comprising the following steps;

a) reacting a pyridine, substituted in position 2 with an alkoxy group and in position 3 with an amidoalkyl group, with a C₁-C₆ alkyllithium, resulting in a lithiated derivative of said pyridine;

b) reacting the lithiated derivative with an optionally substituted benzaldehyde, resulting in a substituted pyridinone;

c) oxidizing said substituted pyridinone, resulting in a protected pyridinone; and

d) deprotecting said protected pyridinone by hydrolysis, resulting in the desired pyridinone compound.