Broadspectrum 2-(substituted-amino)-benzoxazole sulfonamide hiv protease inhibitors

• US 20040132791A1
• Filed: 10/07/2003
• Published: 07/08/2004
• Est. Priority Date: 04/09/2001
• Status: Active Grant

• Current Assignee: Tibotec Pharmaceuticals Limited (Johnson & Johnson)
• Original Assignee: Tibotec Pharmaceuticals Limited (Johnson & Johnson)
• Inventors: Verschueren, Wim Gaston Berchem, Vendeville, Sandrine Marie Helene, De Kock, Herman Augustinus, Tahri, Abdellah, Surleraux, Dominique Louis Nestor Ghislain, Erra Sola, Montserrat, De Bethune, Marie-Pierre T.M.M.G.
• Granted Patent: US 7,244,752 B2
• Time in Patent Office: Days
• US Class Current: 514/375
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 263/58 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 493/04 Ortho-condensed systems

Abstract

The present invention concerns the compounds having the formula

N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein R₁ and R₈ each are H, optionally substituted C_1-6alkyl, C_2-6alkenyl, C_3-7cycloalkyl, aryl, Het¹, Het²; R₁ may also be a radical of formula (R_11aR_11b)NC(R_10aR_10b)CR₉—; t is 0, 1 or 2; R₂ is H br C_1-6alkyl; L is —C(═O)—, —O—C(═O)—, —NR₈—C(═O)—, —C_1-6alkanediyl-C(═O)—, —NR₈—C_1-6alkanediyl-C(═O)—, —S(═O)₂—, —O—S(═O)₂—, —NR₈—S(═O)₂; R₃ is C_1-6alkyl, aryl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-4alkyl, or arylC_1-4alkyl; R₄ is H, C_1-4alkylOC(═O), carboxyl, aminoC(═O), mono- or di(C_1-4alkyl)aminoC(═O), C_3-7cycloalkyl, C_2-6alkenyl, C_2-6alkynyl or optionally substituted C_1-6alkyl; A is C_1-6alkanediyl, —C(═O)—, —C(═S)—, —S(═O)₂—, C_1-6alkanediyl-C(═O)—, C_1-6alkanediyl-C(═S)—or C_1-6alkanediyl-S(═O)₂—; R₅ is H, OH, C_1-6alkyl, Het¹C_1-6alkyl, Het²C_1-6alkyl, optionally substituted aminoC_1-6alkyl; R₆ is C_1-6alkylO, Het¹, Het¹O, Het², Het²O, aryl, arylO, C_1-6alkyloxycarbonylamino or amino; and in case -A- is other than C_1-6alkanediyl then R₆ may also be C_1-6alkyl, Het¹C_1-4alkyl, Het¹OC_1-4alkyl, Het²C_1-4alkyl, Het²OC_1-4alkyl, arylC_1-4alkyl, arylOC_1-4alkyl or aminoC_1-4alkyl; whereby each of the amino groups in the definition of R₆ may optionally be substituted; -A-R₆ is hydroxyC_1-6alkyl; R₅ and -A-R₆ taken together with the nitrogen atom to which they are attached may also form Het¹ or Het². It further relates to their use as broadspectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. It also concerns combinations thereof with another anti-retroviral agent, and to their use in assays as reference compounds or as reagents.

Claims

1. A compound having the formula

2. A compound according to claim 1, wherein:

R₉, R_10a and R_10b are, each independently, hydrogen, C_1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C_1-4alkyl)aminocarbonyl, C_3-7cycloalkyl, C_2-6alkenyl, C_2-6alkynyl or C_1-4alkyl optionally substituted with aryl, Het¹, Het², C_3-7cycloalkyl, C_1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C_1-4alkyl)aminocarbonyl, aminosulfonyl, C_1-4alkylS(O)_t, hydroxy, cyano, halogen or amino optionally mono- or disubstituted where the substituents are selected from C_1-4alkyl, aryl, arylC_1-4alkyl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-4alkyl, Het¹, Het², Het¹C_1-4alkyl and Het²C_1-4alkyl;

whereby R₉, R_10a and the carbon atoms to which they are attached may also form a C_3-7cycloalkyl radical;

R_11a is hydrogen, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, aryl, aminocarbonyl optionally mono- or disubstituted, aminoC_1-4alkylcarbonyloxy optionally mono- or disubstituted, C_1-4alkyloxycarbonyl, aryloxycarbonyl, Het¹oxycarbonyl, Het²oxycarbonyl, aryloxycarbonylC_1-4alkyl, arylC_1-4alkyloxycarbonyl, C_1-4alkylcarbonyl, C_3-7cycloalkylcarbonyl, C_3-7cycloalkylC_1-4alkyloxycarbonyl, C_3-7cycloalkylcarbonyloxy, carboxylC_1-4alkylcarbonyloxy, C_1-4alkylcarbonyloxy, arylC_1-4alkylcarbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy, Het¹carbonyl, Het¹carbonyloxy, Het¹C_1-4alkyloxycarbonyl, Het²carbonyloxy, Het²C_1-4alkylcarbonyloxy, Het²C_1-4alkyloxycarbonyloxy or C_1-4alkyl optionally substituted with aryl, aryloxy, Het² or hydroxy;

wherein the substituents on the amino groups are each independently selected from C_1-4alkyl, aryl, arylC_1-4alkyl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-4alkyl, Het¹, Het², Het¹C_1-4alkyl and Het²C_1-4alkyl;

R_11b is hydrogen, C_3-7cycloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, Het¹, Het² or C_1-4alkyl optionally substituted with halogen, hydroxy, C_1-4alkylS(═

O)_t, aryl, C_3-7cycloalkyl, Het¹, Het², amino optionally mono- or disubstituted where the substituents are selected from C_1-4alkyl, aryl, arylC_1-4alkyl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-4alkyl, Het¹, Het², Het¹C_1-4alkyl and Het²C_1-4alkyl;

whereby R_11b may be linked to the remainder of the molecule via a sulfonyl group;

t is zero, 1 or 2;

L is —

C(═

O)—

, —

O—

C(═

O)—

, —

NR₈—

C(═

O)—

, —

O—

C_1-6alkanediyl-C(═

O)—

, —

NR₈—

C_1-6alkanediyl-C(═

O)—

, —

S(═

O)₂—

, —

O—

S(═

O)₂—

, —

NR₈—

S(═

O)₂ whereby either the C(═

O) group or the S(═

O)₂ group is attached to the NR₂ moiety;

R₄ is hydrogen, C_1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C_1-4alkyl)aminocarbonyl, C_3-7cycloalkyl, C_2-6alkenyl, C_2-6alkynyl, or C_1-6alkyl optionally substituted with one or more substituents selected from aryl, Het¹, Het², C_3-7cycloalkyl, C_1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C_1-4alkyl)aminocarbonyl, aminosulfonyl, C_1-4alkylS(═

O)_t, hydroxy, cyano, halogen and amino optionally mono- or disubstituted where the substituents are selected from C_1-4alkyl, aryl, arylC_1-4alkyl, C_3-7cycloalkyl, C_3-7cycloalkyl-C_1-4alkyl, Het¹, Het², Het¹C_1-4alkyl and Het²C_1-4alkyl;

R₆ is C_1-6alkyloxy, Het¹, Het¹oxy, Het², Het²oxy, aryl, aryloxy or amino; and

in case -A- is other than C_1-6alkanediyl then R may also be C_1-6alkyl, Het¹C_1-4alkyl, Het¹oxyC_1-4alkyl, Het²C_1-4alkyl, Het²oxyC_1-4alkyl, arylC_1-4alkyl, aryloxyC_1-4alkyl or aminoC_1-6alkyl;

whereby each of the amino groups in the definition of R₆ may optionally be substituted with one or more substituents selected from C_1-4alkyl, C_1-4alkylcarbonyl, C_1-4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het¹, Het², arylC_1-4alkyl, Het¹C_1-4alkyl or Het²C_1-4alkyl.

3. A compound according to any of claim 1 to 2 wherein

R₁ is hydrogen, C_1-6alkyl, C_2-6alkenyl arylC_1-6alkyl, C_3-7cycloalkyl, C_3-7cycloalkyl-C_1-6alkyl, aryl, Het¹, Het¹C_1-6alkyl, Het² or Het²C_1-6alkyl;

wherein Het¹ is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring members, which contains one or more heteroatom ring members each independently selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms.

4. A compound according to any of claims 1 to 3 wherein L is —

O—

C_1-6alkanediyl-C(═

O)—

.

5. A compound according to any one of claims 1 to 4 wherein

A is C_1-6alkanediyl, —

C(═

O)—

or C_1-6alkanediyl-C(═

O)—

;

whereby the point of attachment to the nitrogen atom is the C_1-6alkanediyl group in those moieties containing said group;

R₅ is hydrogen, C_1-6alkyl, Het¹C_1-6alkyl, Het²C_1-6alkyl, aminoC_1-6alkyl whereby the amino group may optionally be mono- or di-substituted with C_1-4alkyl; and

in case -A- is —

C(═

O)-then R₆ is C_1-6alkyloxy, Het¹, Het¹oxy or Het²oxy, aryl, Het¹C_1-4alkyl, Het¹oxyC_1-4alkyl, Het²C_1-4alkyl, Het²oxyC_1-4alkyl, arylC_1-4alkyl, aryloxyC_1-4alkyl or aminoC_1-4alkyl; and

in case -A- is C_1-6alkanediyl then R₆ is amino, C_1-6alkyloxy, Het¹, Het¹oxy or Het²oxy; and

in case -A- is C_1-6alkanediyl-C(═

O)-then R₆ is C_1-6alkyloxy, Het¹, Het¹oxy or Het²oxy, aryl, C_1-6alkyl, Het¹C_1-4alkyl, Het¹oxyC_1-4alkyl, Het²C_1-4alkyl, Het²oxyC_1-4alkyl, arylC_1-4alkyl, aryloxyC_1-4alkyl or aminoC_1-4alkyl;

whereby each of the amino groups in the definition of R₆ may optionally be substituted with one or more substituents selected from C_1-4alkyl, C_1-4alkylcarbonyl, C_1-4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het¹, Het², arylC_1-4alkyl, Het¹C_1-4alkyl or Het²C_1-4alkyl; and

R₅ and -A-R₆ taken together with the nitrogen atom to which they are attached may also form Het¹ whereby Het¹ is substituted by at least an oxo group.

6. A compound according to any of claims 1 to 3, wherein

R₁ is Het² or Het²C_1-6alkyl;

wherein said Het² is an aromatic heterocycle having at least one heteroatom each independently selected from nitrogen, oxygen and sulfur; and

L is —

C(═

O)—

, —

O—

C(═

O)—

or —

O—

C_1-6alkyl-C(═

O)—

.

7. A compound according to any of claims 1 to 3, wherein

R₁ is Het² or Het²C_1-6alkyl;

wherein said Het² is an aromatic heterocycle having at least two heteroatom each independently selected from nitrogen, oxygen and sulfur; and

L is —

C(═

O)—

, —

O—

C(═

O)—

or —

O—

C_1-6alkyl-C(═

O)—

.

8. A compound according to any of claims 1 to 4, wherein

A is C_1-6alkanediyl or —

C(═

O)—

;

R₅ is hydrogen or methyl; and

R₆ is C_1-6alkyloxy, Het¹, Het², amino or amino C_1-6alkyl;

whereby each amino optionally may be mono- or disubstituted where the substituents are each independently selected from C_1-4alkyl, aryl, arylC_1-4alkyl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-4alkyl, Het¹, Het², Het¹C_1-4alkyl and Het²C_1-4alkyl.

9. A compound according to any of claims 1 to 3, wherein

R₁ is Het² or Het²C_1-6alkyl;

wherein said Het² is an aromatic heterocycle having at least one heteroatom each independently selected from nitrogen, oxygen and sulfur;

L is —

C(═

O)—

, —

O—

C(═

O)—

or —

O—

C_1-6alkyl-C(═

O)—

;

A is C_1-6alkanediyl or —

C(═

O)—

;

R₅ is hydrogen or methyl; and

R₆ is C_1-6alkyloxy, Het¹, Het², amino or amino C_1-6alkyl;

whereby each amino optionally may be mono- or disubstituted, where the substituents are each independently selected from C_1-4alkyl, aryl, arylC_1-4alkyl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-4alkyl, Het¹, Het², Het¹C_1-4alkyl and Het²C_1-4alkyl.

10. A compound according to any of claims 1 to 3, wherein,

R₁ is 2-thiazolylmethyl-;

and L is —

O—

C(═

O)—

.

11. A compound according to any of claims 1 to 3, wherein

R₅ is hydrogen;

A is —

C(═

O)—

; and

R₆ is Het²;

wherein said Het² contains 5 or 6 ring members and one heteroatom selected from nitrogen, oxygen or sulfur.

12. A compound according to any of claims 1 to 3, wherein

R₁ is Het¹, having 8 ring members and two heteroatoms each independently selected from nitrogen, oxygen or sulfur;

L is —

O—

C(═

O)—

;

R₅ is hydrogen or methyl;

A is —

C(═

O)—

or C_1-6alkanediyl; and

R₆ is optionally mono- or disubstituted aminoC_1-4alkyl, Het¹, Het²;

wherein said Het² contains 5 or 6 ring members and one heteroatom selected from nitrogen, oxygen or sulfur;

wherein the amino substituents are each independently selected from C_1-4alkyl, aryl, arylC_1-4alkyl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-4alkyl, Het¹, Het², Het¹C_1-4alkyl and Het²C_1-4alkyl.

13. A compound as claimed in any one of claim 1 to 12 in a prodrug form.

14. A compound as claimed in any one of claim 1 to 12 in a pharmaceutically tolerable salt form.

15. A pharmaceutical composition, comprising an effective amount of at least one compound as claimed in any one of claims 1 to 14, and a pharmaceutically tolerable excipient.

16. A compound as claimed in any one of claims 1 to 14 for use as a medicine.

17. A method of inhibiting a protease of a retrovirus in a mammal infected with said retrovirus, comprising a protease inhibiting amount of a compound according to any one of claims 1 to 14 to said mammal in need thereof.

18. A method of treating or combating infection or disease associated with retrovirus infection in a mammal, comprising administering an effective amount of at least one compound according to any one of claims 1 to 14 to said mammal.

19. The methods of claim 17 or 18, wherein said mammal is a human.

20. A method of inhibiting retroviral replication, comprising contacting a retrovirus with an effective amount of at least one compound according to any one of claims 1 to 14.

21. The method of claim 17 or 18 or 19, wherein the retrovirus is a human immunodeficiency virus (HIV).

22. The method as claimed in claim 21, wherein the HIV virus is a multi-drug resistant strain.

23. A compound as claimed in any one of claims 1 to 14 for use as a medecine.

24. The use of a compound as claimed in any one of claims 1 to 14 in the manufacture of a medicament for treating or combating infection or disease associated with retrovirus infection in a mammal.

25. The use of a compound as claimed in any one of claims 1 to 14 in the manufacture of a medicament for inhibiting a protease of a retrovirus in a mammal infected with said retrovirus.

26. The use of a compound as claimed in any one of claims 1 to 14 in the manufacture of a medicament for inhibiting retroviral replication.

27. The use of a compound as claimed in any one of claims 24 to 26 wherein the retrovirus is a human immunodeficiency virus (HIV).

28. The use of a compound as claimed in any one of claims 24 to 26 wherein the retrovirus is a multi-drug resistant strain.