S-TRIAZOLYL ALPHA-MERCAPTO ACETANILIDES AS INHIBITORS OF HIV REVERSE TRANSCRIPTASE
A series of S-triazolyl α-mercaptoacetanilides having general structure (1) are provided, where Q is CO 2 H, CONR 2 , SO 3 H, or SO 2 NR 2 . The compounds inhibit several variants of the reverse transcriptase of HIV, and are useful in the treatment of HIV infections.
1 . A compound of formula A
wherein:
Q is selected from the group consisting of CO 2 H or a salt thereof, CONR′R″, SO 3 H or a salt thereof, and SO 2 NR′R″;
P is selected from the group consisting of (a), (b), (c) and (d)
R 1 is selected from the group consisting of Cl, Br, I, CH 3 , CF 3 , CHF 2 , and CH 2 F;
R 3 is H or CH 3 ;
R′ and R″ are independently selected from the group consisting of H, lower alkyl, and lower alkyl substituted with one or more OR, CO 2 R, NHR, NR 2 , or CF 3 groups wherein R is H or lower alkyl, or R′ and R″ together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring;
R 0 is selected from the group consisting of Cl, Br, CF 3 and methyl;
R P is selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, cyclopropylmethyl, and C 3 -C 6 cycloalkyl;
R 4 , R 5 and R 6 are independently selected from the group consisting of H, F, Cl, Br, CH 3 , CF 3 , CFH 2 , CF 2 H, isopropyl, cyclopropyl, OCH 3 , OH, OCF 3 , NH 2 and NHCH 3 ;
U and U′ are independently selected from N and CH;
R 7 is selected from the group consisting of Cl, Br, I, CH 3 , CF 3 , OCH 3 , isopropyl, cyclopropyl, tert-butyl, and cyclobutyl; and
R 8 , R 9 , R 10 and R 11 are independently H or CH 3 ;
with the provisos that, when Q is SO 2 NH 2 ,
R 1 is not methyl unless R P is halogen, cyclopropylmethyl or C 3 -C 6 cycloalkyl, and R 7 is methyl only if R 6 is methyl.
2 . The compound of claim 1 , wherein none of R 4 , R 5 , and R 6 are OH, NH 2 or NHCH 3 .
3 . The compound of claim 1 , wherein P is not substituted phenyl and at least one of R 4 , R 5 , and R 6 is other than H or CH 3 .
4 . The compound of claim 1 , wherein P is a substituted phenyl and R 6 is not methyl.
5 . The compound of claim 2 , wherein P is not substituted phenyl and at least one of R 4 , R 5 , and R 6 is other than H or CH 3 .
6 . The compound of claim 3 , wherein P is not substituted phenyl and at least one of R 4 , R 5 , and R 6 is other than H or CH 3 .
7 . The compound of claim 2 , wherein P is a substituted naphthyl and R 1 is selected from the group consisting of Br, CF 3 , CFH 2 , and CF 2 H.
8 . The compound of claim 7 , wherein each of R 4 , R 5 , and R 6 is H.
9 . The compound of claim 7 , wherein R P is cyclopropyl.
10 . The compound of claim 7 , wherein R 1 is Br and R 0 is Cl.
11 . The compound of claim 2 , wherein P is a substituted quinoline or isoquinoline and R 1 is selected from the group consisting of Br, CF 3 , CFH 2 , and CF 2 H.
12 . The compound of claim 11 , wherein each of R 4 , R 5 , and R 6 is H.
13 . The compound of claim 11 , wherein R P is cyclopropyl.
14 . The compound of claim 11 , wherein R 1 is Br and R 0 is Cl.
15 . The compound of any one of claims 3 , 7 , and 11 , wherein Q is SO 2 NH 2 .
16 . The compound of any of claim 2 , 4 , 9 or 11 wherein Q is CO 2 H.
17 . The compound of claim 16 , wherein the salt is Na + , K + , Ca ++ , Mg ++ , or DABCO salt.
18 . A pharmaceutical composition comprising a compound of any of claims 1 - 17 in combination with one or more pharmaceutically acceptable carriers.
19 . A compound having a structure according to any one of Formula A
wherein R 1 is C 1-3 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —Cl, —Br, —NH 2 , or hydrogen;
R 2 is an aryl or heteroaryl moiety containing a cycloalkyl or heterocyclic group which can be further substituted with alkyl, cycloalkyl, aryl or heteroaryl moieties, Q is a C 3-5 cycloalkyl, W is S, O, or an optionally substituted amine;
X and Y are independently CH and N, and Z is, CH 2 , NH, NR, O, or S, where R is optionally substituted N-alkyl, N-acyl, or N-alkyl-acyl;
R 3 is C 1-3 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —Cl, —Br; and
R 4 is COOH, —COR′ or —S(O) 2 R′, wherein R′ is —NH 2 or —NH(alkyl).
20 . The compound of claim 20 wherein R 2 is 4-Q-naphth-1-yl or 4-Q-phen-1-yl.
21 . The compound of claim 20 , wherein R′ is NH 2 and R 4 is other than COOH.
22 . The compound of claim 21 , wherein Q is cyclopropyl.
23 . The compound of claim 21 , wherein W is S.
24 . The compound of claim 22 , wherein W is S.
25 . The compound of claim 24 , wherein R 1 is other than hydrogen.
26 . The compound of claim 25 , wherein R 1 is Br, R 2 is naphthyl, and R 3 is methyl or Cl.
27 . The compound of claim 26 , which is 2-[5-bromo-4-(4-cyclopropyl-naphthalen-1-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-chloro-4-sulfamoyl-phenyl)-acetamide or 2-[5-bromo-4-(4-cyclopropyl-naphthalen-1-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-chloro-4-carbamoyl-phenyl)-acetamide.
28 . The compound of claim 26 , which is 2-[5-bromo-4-(4-cyclopropyl-naphthalen-1-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-sulfamoyl-phenyl)-acetamide or 2-[5-bromo-4-(4-cyclopropyl-naphthalen-1-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-carbamoyl-phenyl)-acetamide.
29 . A compound of Formula A
wherein R 1 is C 1-3 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —Cl, —Br, —NH 2 , or hydrogen;
R 2 is an 4-Q-naphth-1-yl or 4-Q-phen-1-yl-, Q is C 2-5 alkyl, W is S, O or an optionally substituted amine;
R 3 is C 1-3 alkyl, —CF 3 , —CHF 2 , —CH 2 F, —Cl, —Br; and
wherein R 4 is COOH, —COR′ or —S(O) 2 R′, wherein R′ is —NH 2 or —NH(alkyl).
30 . The compound of claim 30 , where W is S.
31 . The compound of claim 30 , wherein R′ is NH 2 and R 4 is other than COOH.
32 . The compound of claim 30 , wherein R 1 is other than H.
33 . The compound of claim 32 , wherein Q is ethyl.
34 . The compound of claim 33 , wherein R 3 is chloro or methyl.
35 . The compound of claim 34 , which is 2-[5-bromo-4-(4-ethyl-naphthalen-1-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-chloro-4-sulfamoyl-phenyl)-acetamide or 2-[5-bromo-4-(4-ethyl-naphthalen-1-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-chloro-4-carbamoyl-phenyl)-acetamide.
36 . A compound of formula
wherein:
P is selected from the group consisting of (a), (b), (c) and (d):
R 1 is selected from the group consisting of Cl, Br, I, CH 3 , CF 3 , CHF 2 , and CH 2 F;
R 2 , and R 2′ are independently selected from the group consisting of H, optionally substituted C 1-5 acyl, 1-(C 2-4 acyloxy)C 1-4 alkoxycarbonyl, and an acyl group derived from an α-amino acid;
R 3 is H or CH 3 ;
R 0 is selected from the group consisting of Cl, Br, CF 3 and methyl;
R P is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropylmethyl, and C 3-6 cycloalkyl;
R 4 , R 5 and R 6 are independently selected from the group consisting of H, F, Cl, Br, CH 3 , CF 3 ;
CFH 2 , CF 2 H, isopropyl, cyclopropyl, OCH 3 , OH, OCF 3 , NH 2 and NHCH 3 ;
U and U′ are independently selected from N and CH;
R 7 is selected from the group consisting of Cl, Br, I, CH 3 , CF 3 , OCH 3 , isopropyl, cyclopropyl, tert-butyl, cyclobutyl, and methyl; and
R 8 , R 9 , R 10 and R 11 are independently H or CH 3 ;
with the provisos that, when R 2 and R 2′ are H,
R 1 is not methyl unless R P is cyclopropyl, and
R 7 is methyl only if R 6 is methyl.
37 . The compound of claim 36 , wherein none of R 4 , R 5 , and R 6 are OH, NH 2 or NHCH 3 .
38 . The compound of claim 36 , wherein P is not substituted phenyl and at least one of R 4 , R 5 , and R 6 is other than H or CH 3 .
39 . The compound of claim 36 , wherein P is a substituted phenyl and R 6 is not methyl.
40 . The compound of claim 37 , wherein P is not substituted phenyl and at least one of R 4 , R 5 , and R 6 is other than H or CH 3 .
41 . The compound of claim 38 , wherein P is not substituted phenyl and at least one of R 4 , R 5 , and R 6 is other than H or CH 3 .
42 . The compound of claim 37 , wherein Ar is a substituted naphthyl and R 1 is selected from the group consisting of Br, CF 3 , CFH 2 , and CF 2 H.
43 . The compound of claim 42 , wherein each of R 4 , R 5 , and R 6 is H.
44 . The compound of claim 42 , wherein R P is cyclopropyl.
45 . The compound of claim 42 , wherein R 1 is Br and R 0 is Cl.
46 . The compound of claim 37 , wherein P is a substituted quinoline or isoquinoline and R 1 is selected from the group consisting of Br, CF 3 , CFH 2 , and CF 2 H.
47 . The compound of claim 46 , wherein each of R 4 , R 5 , and R 6 is H.
48 . The compound of claim 46 , wherein R P is cyclopropyl.
49 . The compound of claim 46 , wherein R 1 is Br and R 0 is Cl.
50 . The compound of claim 38 , wherein R 2 is acetyl or 2-acetyl-propoxycarbonyl.
51 . The compound of claim 37 , wherein R 2 is acetyl or 1-acetoxyethoxycarbonyl.
52 . The compound of claim 46 , wherein R 2 is acetyl or 1-acetoxyethoxycarbonyl.
53 . The compound of any one of claims 50 , 51 and 52 , wherein R 2′ is H.
54 . The compound of any one of claims 38 , 42 , and 46 , wherein R 2 and R 2′ are both H.