HIV inhibiting pyrimidines derivatives

• US 7,125,879 B2
• Filed: 08/09/2002
• Issued: 10/24/2006
• Est. Priority Date: 08/13/2001
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Palandjian, Patrice, Lewi, Paulus Joannes, Guillemont, Jérôme Emile Georges, Heeres, Jan, Koymans, Lucien Maria Henricus, Van Aken, Koen Jeanne Alfons, Vinkers, Hendrik Maarten, Daeyaert, Frederik Frans Desiré, de Jonge, Marc René
• Primary Examiner(s): Rao, Deepak
• Assistant Examiner(s): Johnsen, Jason H.
• Application Number:
  US10/485,636
• Publication Number:
  US 20040198739A1
• Time in Patent Office: 1,537 Days
• Field of Search: 514/256, 514/247, 544/297
• US Class Current: 514/256
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 255/42 the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
• CPC Class Codes: C07C 257/12 having carbon atoms of amidino groups bound to hydrogen atoms
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

This invention concerns HIV replication inhibitors of formula (I) the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, wherein the ring containing −a¹=a²−a³=a⁴—and −b¹=b²−b³=b⁴represents pheynl, pyridyl, pyrimidinyl, pirazinyl, pyridazinyl; n is 0 to 5; m is 1 to 4; R¹ is hydrogen; aryl; formyl; C_1-6alkylcarbonyl; C^1-6alkyl; C_1-6alkyloxycarbonyl, substituted C_1-6alkyl, C_1-6alkylcarbonyl; R² is hydroxy, halo, optionally substituted C_1-6alkyl, C_3-7cycloalkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6alkynyl, C_1-6alkyloxy, C_1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C_1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)_pR⁶, —NH—S(═O)_pR⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH?2?, —NHC(═O)R⁶, —C(═NH)R⁶ or a 5-membered hetrocycl; X₁ is —NR⁵—, —NH—NH—, —N═N—, —O—, —C(═O)—, C_1-4alkanediyl, —CHOH—, —S—, —S(═O)_p—, —X₂—C_1-4alkanediyl- or —C_1-4alkanediyl-X₂—; R³ is NHR¹³, NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵; —CH═N—NH—C(═O)—R¹⁶; substituted C_1-6alkyl; optionally substituted C_1-6alkyloxyC_1-6alkyl; substituted C_2-6alkenyl; substituted C_2-6alkynyl; substituted C_2-6alkylenyl; C_1-6alkyl substituted with hydroxy and a second substituent; —C(═N—O—R⁸)—C_1-4alkyl; R⁷; or —X₃—R⁷; R⁴ is halo, hydroxy, C_1-6alkyl, C_3-7cycloalkyl, C_1-6alkyloxy, cyano, nitro, polyhaloC_1-6alkyl, polyhaloC_1-6alkyloxy, aminocarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylcarbonyl, formyl, amino, mono- or di(C_1-4alkyl) amino; their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them

Claims

1. A compound 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, an N-oxide, an addition salt, a quaternary amine or a stereochemically isomeric form thereof, said compound having the following structure:

5. A compound as claimed in claim 1, wherein the compound is an addition salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.

6. A compound as claimed in claim 1, wherein the compound is an addition salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (E).

7. A compound as claimed in claim 5, wherein the addition salt is the hydrochloride salt.

8. A compound as claimed in claim 6, wherein the additional salt is the hydrochloride salt.

9. A compound as claimed in claim 1, wherein the compound is an N-oxide of 4-[[4-[[4-(2cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.

10. A compound as claimed in claim 1, wherein the compound is an N-oxide of 4-[[4-[[4-(2cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (E).

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to any of claims 1, 2, 3, 10, 8.

12. A process for preparing a pharmaceutical composition, comprising mixing a therapeutically effective amount of a compound as claimed in any one of claims 1,2,3,10,8 with a pharmaceutically acceptable carrier.

13. A method of treating subjects suffering from HIV (Human Immunodeficiency Virus) infection comprising administering to the subject an effective amount of a compound according to any one of claims 1,2,3,10,8.

14. A pharmaceutical composition as claimed in claim 11, wherein the pharmaceutical composition is a tablet.

15. A pharmaceutical composition as claimed in claim 11, wherein the effective amount is between 1 to 1000 mg of active ingredient per unit dosage form.

16. A pharmaceutical composition as claimed in claim 11, wherein the effective amount is between 5 and 200 mg of active ingredient per unit dosage form.

17. A tablet as claimed in claim 14, wherein the effective amount is between 1 to 1000 mg of active ingredient.

18. A tablet asclaimed in claim 14, wherein the effective amount is between 5 to 200 mg of active ingredient.

19. A method of treating subjects suffering from HIV-1 (Human Immunodeficiency Virus) infection that have acquired resistance to art-known non-nucleoside reverse transcriptase inhibitors comprising administering to the subject an effective amount of a compound according to any of claims 1, 2, 3, 10, 8.

2. A compound 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, said compound having the following structure:

3. A compound having the following structure:

4. A compound having the following structure: