Hiv inhibiting pyrimidines derivatives

• US 20040198739A1
• Filed: 02/03/2004
• Published: 10/07/2004
• 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, Heeres, Jan, Janssen, Paul Adriaan Jan, Guillemont, Jerome Emile Georges, Koymans, Lucien Maria Henricus, Van Aken, Koen Jeanne Alfons, Vinkers, Hendrik Maarten, Daeyaert, Frederik Frans Desire, de Jonge, Marc Rene
• Granted Patent: US 7,125,879 B2
• Time in Patent Office: Days
• US Class Current: 514/252.02
• 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=b⁴- represents 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 of formula

2. A compound according to claim 1 wherein R³ is C_1-6alkyl substituted with at least one substituent selected from cyano, aminocarbonyl, NR⁹R¹⁰ and R⁷;

C_1-6alkyl substituted with at least one substituent selected from cyano, aminocarbonyl, NR⁹R¹⁰, and R⁷ and wherein 2 hydrogen atoms bound at the same carbon atom are replaced by C_1-4alkanediyl;

C_1-6alkyl substituted with hydroxy and a second substituent selected from cyano, aminocarbonyl, NR⁹R¹⁰, and R⁷;

C_1-6alkyloxyC_1-6alkyl substituted with at least one substituent selected from cyano, aminocarbonyl, NR⁹R¹⁰, and R⁷;

C_2-6alkenyl substituted with at least one substituent selected from cyano, aminocarbonyl, NR⁹R¹⁰, and R⁷;

C_2-6alkynyl substituted with at least one substituent selected from cyano, aminocarbonyl, NR⁹R¹⁰, and R⁷;

—

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, or mono- or di(C_1-4alkyl)amino;

R⁷ is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, mono or di(C_1-6alkyl)aminoC_1-6alkyl, C_1-6alkylcarbonyl, C_3-7cycloalkyl, C_1-6alkyloxy, C_1-6alkyloxycarbonyl, C_1-6alkylthio, cyano, nitro, polyhaloC_1-6alkyl, polyhaloC_1-6alkyloxy, aminocarbonyl, R^7a, —

X₃—

R^7a and R^7a—

C_1-4alkyl;

R^7ais a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, mono or di(C_1-6alkyl)aminoC_1-6alkyl, C_1-6alkylcarbonyl, C_3-7cycloalkyl, C_1-6alkyloxy, C_1-6alkyloxycarbonyl, C_1-6alkylthio, cyano, nitro, polyhaloC_1-6alkyl, polyhaloC_1-6alkyloxy, and aminocarbonyl;

R⁹ and R¹⁰ each independently are one of hydrogen;

hydroxy;

C_1-6alkyl;

C_1-6alkyloxy;

C_1-6alkylcarbonyl;

C_1-6alkyloxycarbonyl;

amino;

mono- or di(C_1-6alkyl)amino;

mono- or di(C_1-6alkyl)aminocarbonyl, and R⁷ wherein each of the aforementioned C_1-6alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, carboxyl, C_1-6alkyloxycarbonyl, cyano, amino, imino, mono- or di(C_1-4alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —

S(═

O)_pR⁶, —

NH—

S(═

O)_pR⁶, —

C(═

O)R⁶, —

NHC(═

O)H, —

C(═

O)NHNH₂, —

NHC(═

O)R⁶,—

C(═

NH)R⁶, and R⁷.

3. A compound according to claim 1 having the formula

4. A compound according to claim 1 having the formula

5. A compound according to claim 1 having the formula

6. A compound according to claim 3 wherein R^2′

is cyano, aminocarbonyl, or C_1-6alkyl substituted with cyano or aminocarbonyl.

8. A method for the prevention or the treatment of HIV (Human Immunodeficiency Virus) infection, said method comprising administering an effective amount of a compound as claimed in claim 1.

9. A method for the prevention or the treatment of a drug resistant HIV infection, comprising administering an effective amount of a compound as claimed in claim 1.

10. A pharmaceutical composition comprising as an active ingredient a compound as claimed in claim 1.

11. A process for preparing a pharmaceutical composition according to claim 10, comprising mixing a therapeutically effective amount of a compound as claimed in claim 1 with a pharmaceutically acceptable carrier.

12. A process for preparing a compound as claimed in claim 1, comprising:

a) reacting an intermediate of formula (II) with an intermediate of formula (III)

with W₁ being a suitable leaving group, and R¹, R², R³, R⁴, X₁, m, n, -a¹ =a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1;

b) reacting an intermediate of formula (IV) with an intermediate of formula (V) in the presence of a suitable catalyst, a suitable salt and a suitable solvent

with W₂ being a suitable leaving group, and R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1 and R^7′

representing a monocyclic, bicyclic or tricyclic aromatic ring system and R^a representing a boronate or a tri(C_1-4alkyl)stannane;

c) reacting an intermediate of formula (IV) with an intermediate of formula (VI)

with W₂ being a suitable leaving group, and R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1 and R^7″

representing a monocyclic, bicyclic or tricyclic saturated ring system;

d) reacting an intermediate of formula (VII) with a suitable cyanide salt in the presence of a suitable solvent

with W₃ being a suitable leaving group, and R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1;

e) reacting an intermediate of formula (VII) with an intermediate of formula (VIII) optionally in the presence of a suitable salt and a suitable solvent

with W₃ being a suitable leaving group, and R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and b¹=b²-b³=b⁴- as defined in claim 1 and Q representing R ⁷;

NR⁹R¹⁰ or C_1-6alkyloxy optionally substituted with CN, R⁷ or NR⁹R¹⁰;

f) reacting an intermediate of formula (IX) with an intermediate of formula (X) in the presence of a suitable solvent

with R¹, R², R⁴, R⁸, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1;

g) reacting an intermediate of formula (XI) with a Wittig or Homer-Emmons reagens of formula (XII) representing a suitable precursor of a phosphorus ylide in the presence of a suitable salt and a suitable solvent

with R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1, R^c representing hydrogen or C_1-4alkyl, R^c′

representing hydrogen, C_1-4alkyl or R⁷, provided that CR^c′

═

CR^c is limited to C_2-6alkenyl, and R^b representing (Phenyl)₃P⁺—

Cl⁻

or (CH₃CH₂—

O)₂P(═

O)—

;

h) reacting an intermediate of formula (XI) with an intermediate of formula (XIII) in the presence of a suitable solvent

with R¹, R², R⁴, R⁷, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1, R^c representing hydrogen or C_1-4alkyl, R^c″

representing NR⁹R¹⁰, —

C(═

O)—

NR⁹R¹⁰, —

C(═

O)—

C_1-6alkyl or R⁷;

i) reacting an intermediate of formula (XI-b) with 2-butenedlintrile in the presence of tributylphosphine and a suitable solvent

with R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1;

j) reacting an intermediate of formula (XI-b) with propanedintrile in the presence of a suitable base and a suitable solvent

k) reacting an intermediate of formula (XI-b) with CH₃—

CN in the presence of a suitable proton abstracting agent, a suitable substrate for the proton abstracting agent and in the presence of a suitable solvent

with R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1;

l) reacting an intermediate of formula (XI) with a Wittig or Homer-Emmons reagens of formula (XII′

) representing a suitable precursor of a phosphorus ylide in the presence of nBuLi and a suitable solvent

with R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1, R^c representing hydrogen or C_1-4alkyl, R^c′

representing hydrogen, C_1-4alkyl or R⁷, provided that CR^c″

═

CR^c is limited to C_2-6alkenyl, and R^b representing (Phenyl)₃P⁺—

Cl⁻

or (CH₃CH₂—

O)₂P(═

O)—

;

m) reacting an intermediate of formula (XI-a) with an intermediate of formula (XIII′

) in the presence of a suitable Homer-Emmons reagent, nBuLi, 1,1,1-trimethyl-N-(trimethylsilyl)-silanamine, and a suitable solvent

with R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1, R^c representing hydrogen or C_1-4alkyl, R^c″

representing CN, NR⁹R¹⁰, —

C(═

O)—

NR⁹R¹⁰, —

C(═

O)—

C_1-6alkyl or R⁷;

n) reacting an intermediate of formula (XVIII) with CBr₄ in the presence of a suitable catalyst salt, a suitable base and a suitable solvent

reacting an intermediate of formula (XIV) with Cl₂C═

S in the presence of a suitable solvent

R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1;

p) reacting an intermediate of formula (XV) with an intermediate of formula (XVI) in the presence of a suitable solvent

with R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1;

q) reacting an intermediate of formula (XXIX) with an intermediate of formula (XXX) in the presence of hydroxybenzotriazole and ethyldimethylaminopropyl carbodiimide, a suitable solvent and optionally in the presence of a suitable base

with R¹, R², R⁴, R⁹, R¹⁰,X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1 and C_2-6alkenyl'"'"' representing C_2-6alkenyl optionally substituted with cyano;

r) reacting an intermediate of formula (XXXI) with an intermediate of formula (XXXII-1) or (XXXII-2) in the presence of hydroxybenzotriazole, ethyldimethylaminopropyl carbodiimide and a suitable solvent, and optionally in the presence of a suitable base

with R¹, R², R⁴, R¹³, R¹⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1;

s) reacting an intermediate of formula (XI-b) with an intermediate of formula (XXXIII) in the presence of a suitable solvent

with R¹, R², R⁴, R¹⁶, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1;

t) reductive methylation of an intermediate of formula (XXXIV) with formaldehyde in the presence of a suitable catalyst, a suitable reductive agent and a suitable solvent

with R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1;

u) reacting an intermediate of formula (XXXIV) with 2,5-dimnethoxytetrahydrofuran in the presence of a suitable acid

with R¹, R², R⁴ , X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b²-b³=b⁴- as defined in claim 1;

and

v) reacting an intermediate of formula (XXXV) with an intermediate of formula (XXXVI) in the presence of nBuLi and a suitable solvent

with R¹, R², R⁴, R⁷, X₁, m, n, -a¹=a²-a³=a⁴- and -b¹=b ²-b³=b⁴- as defined in claim 1.

13. A product containing (a) a compound according to claim 1, and (b) another antiretroviral compound, as a combined preparation.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound according to claim 1, and (b) another antiretroviral compound.

20. A method according to claim 12, further comprising converting the compounds of formula (I) into each other following art-known transformations.

21. A method according to claim 12, further comprising converting the compounds of formula (I) into a therapeutically active non-toxic acid addition salt by treatment with an acid.

22. A method according to claim 12, further comprising converting the compounds of formula (I) into a therapeutically active non-toxic acid addition salt and converting said salt into a free base by treatment with an alkali.

23. A method according to claim 12, further comprising preparing a stereochemically isomeric form, an N-oxide form, or a quaternary amine thereof.

24. A pharmaceutical composition according to claim 10, further comprising a pharmaceutically acceptable carrier.

7. (canceled)

15. A compound of formula

16. A compound of formula

17. A compound of formula

18. A compound of formula

19. A compound of formula