US 5,491,149 AGranted

Dihydroxypropylamine containing retroviral protease inhibitors

AssigneeThe Du Pont Merck Pharmaceutical Company

InventorPrabhakar K. Jadhav

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Abstract

This invention relates to substituted dihydroxypropylamines, a process to prepare intermediates useful for the synthesis of these compounds, compositions comprising such compounds, and a method of treating retroviral infection.

Claims42

Dependent claims

A compound of the formula (I):

or a pharmaceutically acceptable salt, chiral, diastereomeric or racemic form thereof wherein:
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.12 ;
C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.12 ;
C.sub.3 -C.sub.8 alkynyl substituted with 0-3 R.sup.12 ;
C.sub.3 -C.sub.8 cycloalkyl substituted with 0-3 R.sup.12 ;
C.sub.6 -C.sub.10 bicycloalkyl substituted with 0-3 R.sup.12 ;
aryl substituted with 0-3 R.sup.13 ;
a C.sub.6 -C.sub.14 carbocyclic ring substituted with 0-3 R.sup.13 ;
a heterocyclic ring substituted with 0-2 R.sup.13, composed of 5 to 10 atoms including from 1 to 3 nitrogen, oxygen or sulfur atoms, with the remaining atoms being carbon;
additionally, R.sup.7 and R.sup.8 may join together to form a saturated or unsaturated C.sub.5 -C.sub.14 carbocyclic ring substituted with 0-3 R.sup.12, or a heterocyclic ring substituted with 0-2 R.sup.13, said heterocyclic ring being composed of 5 to 10 atoms including 1 to 3 nitrogen, oxygen, or sulfur atom with the remaining atoms being carbon;
R.sup.2A, R.sup.3A, R.sup.4A, R.sup.9A, and R.sup.10A are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.4 alkyl substituted with halogen or C.sub.1 -C.sub.2 alkoxy;
benzyl substituted with halogen or C.sub.1 -C.sub.2 alkoxy;
R.sup.5 and R.sup.6 are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.6 alkoxycarbonyl;
C.sub.1 -C.sub.6 alkylcarbonyl;
benzoyl;
phenoxycarbonyl;
or
phenylaminocarbonyl;
wherein said alkyl groups are substituted with 0-3 R.sup.12, and said aryl groups are substituted with 0-3 R.sup.13 ;
or a hydrolyzable group that, when administered to a mammalian subject, is metabolically cleaved to form the diol in which R.sup.5 and R.sup.6 are hydrogen;
R.sup.12 is selected from one or more of the following:
keto, halogen, cyano, --NR.sup.14 R.sup.15, --CO.sub.2 R.sup.14, --OC(.dbd.O)R.sup.15, --OR.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl, --S(O).sub.m R.sup.14, --NHC(.dbd.NH)NHR.sup.14, --C(.dbd.NH)NHR.sup.14, --C(.dbd.O)NR.sup.14 R.sup.15, --NR.sup.15 C(.dbd.O)R.sup.15, --NR.sup.15 C(.dbd.O)OR.sup.15, --OC(.dbd.O)NR.sup.14 R.sup.15, --NR.sup.14 C(.dbd.O)NR.sup.14 R.sup.15, --NR.sup.15 SO.sub.2 NR.sup.14 R.sup.15, --NR.sup.15 SO.sub.2 R.sup.14, --SO.sub.2 NR.sup.14 R.sup.15, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl;
a C.sub.5 -C.sub.14 carbocyclic ring substituted with 0-3 R.sup.13 ;
aryl substituted with 0-3 R.sup.13 ;
or a heterocyclic ring substituted with 0-2 R.sup.13, said heterocyclic ring being composed of 5 to 10 atoms including 1 to 3 nitrogen, oxygen, or sulfur atom with the remaining atoms being carbon;
R.sup.13, when a substituent on carbon, is selected from one to 3 of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C.sub.7 -C.sub.10 arylalkyl, alkoxy, --NR.sup.14 R.sup.15, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --S(O).sub.m R.sup.14, --SO.sub.2 NR.sup.14 R.sup.15, --NHSO.sub.2 R.sup.15 ;
or R.sup.13 may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being substituted on the aliphatic carbons with from 1 to 3 halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, or NR.sup.14 R.sup.15 ;
or, when R.sup.13 is attached to a saturated carbon atom it may be carbonyl or thiocarbonyl;
and R.sup.13, when a substituent on nitrogen, is independently selected from the following:
phenyl, benzyl, phenethyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, --NR.sup.14 R.sup.15, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl;
R.sup.14 is H, phenyl, benzyl or C.sub.1 -C.sub.6 alkyl;
R.sup.15 is H or C.sub.1 -C.sub.4 alkyl;
or R.sup.14 and R.sup.15 can join to form (CH.sub.2).sub.4, (CH.sub.2).sub.5, (CH.sub.2 CH.sub.2 N(R.sup.16)CH.sub.2 CH.sub.2), or (CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2);
R.sup.16 i s H or CH.sub.3 ;
a is a double or single bond;
m is 0, 1 or 2;
n and n.sup.1 are independently 0 or 1;
o is 0, 1, 2 or 3;
W and W.sup.1 are independently selected from the following:
--NR.sup.16 C(.dbd.Q)NR.sup.16 --;
--C(.dbd.Q)NR.sup.16 --;
--C(.dbd.Q)O--;
--NR.sup.16 C(.dbd.Q)O--;
--OC(.dbd.Q)NR.sup.16 --;
--NR.sup.16 C(.dbd.Q)--;
--C(.dbd.Q)--;
--C(.dbd.Q)CH.sub.2 --;
--NR.sup.16 SO.sub.2 NR.sup.16 -- --NR.sup.16 SO.sub.2 --;
--SO.sub.2 NR.sup.16 -- --SO.sub.2 --;
--QCH.sub.2 --;
--Q--;
--(CH.sub.2).sub.p NR.sup.16 --;
--CH.sub.2 CH.sub.2 --;
--CH.dbd.CH--;
--CH(OH)CH(OH)--;
--CH(OH)CH.sub.2 --;
--CH.sub.2 CH(OH)--;
--CH(OH)--;
--NH--NH--;
--C(.dbd.O)NH--NH--;
--C(Cl).dbd.N--;
--C(--OR.sup.16).dbd.N--;
--C(--NR.sup.16 R.sup.17).dbd.N--;
--OP(.dbd.O)(Q.sup.1 R.sup.16)O--;
--P(.dbd.O)(Q.sup.1 R.sup.16)O--;
--SO.sub.2 NHC(.dbd.O)NH--;
or a direct bond;
X and X.sup.1 are independently selected from the following:
--C(.dbd.Q)NR.sup.16 --;
--C(.dbd.Q)O--;
--C(.dbd.Q)--;
--CH.sub.2 C(.dbd.Q)--;
--CH.sub.2 C(.dbd.Q)CH.sub.2 --;
--C(.dbd.Q)CH.sub.2 --;
--SO.sub.2 NR.sup.16 --;
--SO.sub.2 --;
--CH.sub.2 QCH.sub.2 --;
--CH.sub.2 Q--;
--CH.sub.2 NR.sup.16 --;
--CH.sub.2 CH.sub.2 --;
--CH.dbd.CH--;
--CH(OH)CH(OH)--;
--CH(OH)CH.sub.2 --;
--CH.sub.2 CH(OH)--;
--CH(OH)--;
--C(.dbd.Q)NH--NH--;
--C(--OR.sup.16).dbd.N--;
--C(--NR.sup.16 R.sup.17).dbd.N--;
--C(L).dbd.N--;
Y and Y.sup.1 are independently selected from the following:
--C(.dbd.Q)NR.sup.16 --;
--(CH.sub.2).sub.p C(.dbd.Q)NR.sup.16 --;
--SO.sub.2 NR.sup.16 --;
--CH.sub.2 NR.sup.16 --;
--C(L).dbd.N--;
--C(--OR.sup.16).dbd.N--;
--C(--NR.sup.16 R.sup.17).dbd.N--;
--NR12C(.dbd.O)NR.sup.16 --;
--(CH.sub.2).sub.p NR12C(.dbd.O)NR.sup.16 --;
--OC(.dbd.O)NR.sup.16 --;
--(CH.sub.2).sub.p OC(.dbd.O)NR.sup.16 --;
R.sup.17 is H, benzyl or C.sub.1 -C.sub.4 alkyl;
R.sup.18 is H or C.sub.1 -C.sub.4 alkyl;
L is Cl or Br;
p is 1 or 2;
Q is selected from oxygen or sulfur;
and
Q.sup.1 is selected from oxygen, sulfur, NR.sup.14 or a direct bond.

112 more elements

Dependencies are inferred from the claim text.

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