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

• US 7,595,334 B2
• Filed: 01/23/2007
• Issued: 09/29/2009
• Est. Priority Date: 04/09/2001
• Status: Expired due to Fees

• Current Assignee: Tibotec Pharmaceuticals (Johnson & Johnson)
• Original Assignee: Tibotec Pharmaceuticals (Johnson & Johnson)
• Inventors: Erra Sola, Montserrat, Verschueren, Wim Gaston, Vendeville, Sandrine Marie Helene, De Kock, Herman Augustinus, Tahri, Abdellah, De Bethune, Marie-Pierre T. M. M. G., Surleraux, Dominique Louis Nestor Ghislain
• Primary Examiner(s): Shameem; Golam M
• Application Number:
  US11/626,183
• Publication Number:
  US 20070135447A1
• Time in Patent Office: 980 Days
• Field of Search: 548/146, 548/203, 548/215, 546/268.1, 546/269.7, 514/336, 514/339, 514/365, 514/374, 514/377
• US Class Current: 514/374
• 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 or C_1-6alkyl; 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; 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 method of inhibiting a protease of a retrovirus in a mammal infected with said retrovirus, said method comprising administering a protease inhibiting amount of a compound having the formula

2. The method of claim 1, wherein said mammal is a human.

3. The method as claimed in claim 1, wherein the HIV virus is a multi-drug resistant strain.

7. The method of 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;

wherein 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;

wherein 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—

, —

NR—

S(═

O)₂ wherein 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_3-7cycloalkylC_1-4alkyl, Het¹, Het², Het¹C_1-4alkyl and Het²C_1-4alkyl; and

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

in case -A- is other than C_1-6alkanediyl then R₆ 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;

wherein 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, Het¹ C_1-4alkyl and Het²C_1-4alkyl.

8. The method of claim 1, wherein:

R₁ is hydrogen, C_1-6alkyl, C_2-6alkenyl, arylC_1-6alkyl, C_3-7cycloalkyl, C_3-7cycloalkylC_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 and sulfur and which is optionally substituted on one or more carbon atoms.

9. The method of claim 1, wherein:

L is —

O—

C_1-6alkanediyl-C(═

O)—

.

10. The method of claim 1, wherein:

A is C_1-6alkanediyl, —

C(═

O)—

or C_1-6alkanediyl-C(═

O)—

;

wherein 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 wherein the amino group may optionally be mono- or di-substituted with C_1-4alkyl; and

in case -A- is —

C(═

O)—

then R_1-6 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;

wherein 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 and Het²C_1-4alkyl; and

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

11. The method of claim 1, 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)—

.

12. The method of claim 1, 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)—

.

13. The method of claim 1, 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;

wherein 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.

14. The method of claim 1, 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;

wherein 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.

15. The method of claim 1, wherein:

R₁ is 2-thiazolylmethyl-; and

L is —

O—

C(═

O)—

.

16. The method of claim 1, 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 and sulfur.

17. The method of claim 1, wherein:

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

4. A method of inhibiting a protease of a retrovirus in a mammal infected with said retrovirus, said method comprising administering a protease inhibiting amount of a compound selected from the group consisting of compounds of the following formula:

5. The method of claim 4, wherein said mammal is a human.

6. The method as claimed in claim 5, wherein the HIV virus is a multi-drug resistant strain.