US 5,811,422 AGranted

Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors

AssigneeThe DuPont Merck Pharmaceutical Company

InventorsPatrick Yuk-Sun Lam, Prabhakar Kondaji Jadhav, Charles Joseph Eyermann, Carl Nicholas Hodge, George Vincent De Lucca, James David Rodgers

Life of this patent

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Abstract

This invention relates to substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors, to pharmaceutical compositions comprising such compounds, and to methods of using these compounds for treating viral infection. A representative compound of the invention is the compound of formula: ##STR1## wherein R.sup.22 and R.sup.23 are allyl.

Claims21

Dependent claims

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I):

##STR112## or a pharmaceutically acceptable salt form thereof wherein:
R.sup.4 and R.sup.7 are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.11 ;
C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.11 ;
C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.11 ;
a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-3 R.sup.11 or 0-3 R.sup.12 ;
a heterocyclic ring selected independently from indolyl, furanyl, pyridyl, thienyl, pyrrolyl, benzob!thienyl, pyrazolyl, thiazolyl, benzofuranyl, tetrahydroisoquinolinyl, benzotriazolyl, benzimidazolyl, or imidazolyl, said heterocyclic ring system being substituted with 0-2 R.sup.12 ;
--CO.sub.2 R.sup.13 ;
R.sup.4A and R.sup.7A are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.4 alkyl substituted with 0-6 halogen or 0-3 C.sub.1 -C.sub.2 alkoxy;
benzyl substituted with 0-6 halogen or 0-3 C.sub.1 -C.sub.2 alkoxy;
--CO.sub.2 R.sup.13 ;
R.sup.4 and R.sup.4A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R.sup.12 ;
R.sup.7 and R.sup.7A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R.sup.12 ;
n is 1;
R.sup.5 is selected from H;
halogen;
--N(R.sup.20).sub.2, --SR.sup.20, --OR.sup.20, --N.sub.3 or C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
R.sup.6 is independently selected from:
hydrogen, halogen, --N(R.sup.20).sub.2, --SR.sup.20, --OR.sup.21, --N.sub.3 or C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
R.sup.5 and R.sup.6 can alternatively join to form an epoxide or aziridine ring;
--OCH.sub.2 SCH.sub.2 O--;
--OC(.dbd.O)O--;
--OCH.sub.2 O--;
--OC(.dbd.S)O--;
--OC(.dbd.O)C(.dbd.O)O--;
--OC(CH.sub.3).sub.2 O--;
--OC((CH.sub.2).sub.3 NH.sub.2)(CH.sub.3)O--;
--OC(OCH.sub.3)(CH.sub.2 CH.sub.2 CH.sub.3)O--;
--OS(.dbd.O)O--;
--NHC(.dbd.O)NH--;
--OC(.dbd.O)NH--;
--NHC(.dbd.O)O--;
--NHCH.sub.2 O--;
--OCH.sub.2 NH--;
--NHC(.dbd.S)O--;
--OS(.dbd.O)NH--;
--NHC(.dbd.O)C(.dbd.O)O--;
--OC(.dbd.O)C(.dbd.O)NH--;
--NHC(.dbd.O)C(.dbd.O)NH--;
--NHC(CH.sub.3).sub.2 O--;
or --OC(CH.sub.3).sub.2 NH--;
R.sup.5a is selected from hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, --N(R.sup.20).sub.2, --SR.sup.20, or --OR.sup.20 ;
R.sup.6a is selected from:
hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, --N(R.sup.20).sub.2, --SR.sup.20 or --OR.sup.21 ;
R.sup.5 and R.sup.5a can alternatively join to form .dbd.O, .dbd.S, or a ketal ring;
R.sup.6 and R.sup.6a can alternatively join to form .dbd.O, .dbd.S, or a ketal ring;
R.sup.20 and R.sup.21 are independently selected from:
hydrogen;
C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11 ;
C.sub.1 -C.sub.6 alkylcarbonyl substituted with 0-3 R.sup.11 ;
C.sub.1 -C.sub.6 alkoxycarbonyl substituted with 0-3 R.sup.11 ;
C.sub.1 -C.sub.6 alkylaminocarbonyl substituted with 0-3 R.sup.11 ;
benzoyl substituted with 0-3 R.sup.12 ;
phenoxycarbonyl substituted with 0-3 R.sup.12 ;
phenylaminocarbonyl substituted with 0-3 R.sup.12 ;
or
phosphate ester;
R.sup.11 is selected from one or more of the following:
H, keto, halogen, cyano, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, --CO.sub.2 R.sup.13, --OC(.dbd.O)R.sup.13, --OR.sup.13, --S(O).sub.m R.sup.13, --NHC(.dbd.NH)NHR.sup.13, --C(.dbd.NH)NHR.sup.13, --C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 C(.dbd.O)R.sup.13, .dbd.NOR.sup.14, --NR.sup.14 C(.dbd.O)OR.sup.14, --OC(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.13 C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, --OP(O)(OR.sup.13).sub.2, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.13 R.sup.14, 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, pyridylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --OCH.sub.2 CO.sub.2 H, 2-(1-morpholino)ethoxy, azido, or --C(R.sup.14).dbd.N(OR.sup.14);
- 3amino acids linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus;
C.sub.3 -C.sub.10 cycloalkyl substituted with 0-2 R.sup.12 ;
C.sub.1 -C.sub.4 alkyl substitued with 0-2 R.sup.12
aryl(C.sub.1 -C.sub.3 alkyl)-, substituted with 0-2 R.sup.12 ;
C.sub.2 -C.sub.6 alkoxyalkyl-, substituted with 0-2 R.sup.12 ;
C.sub.1 -C.sub.4 alkylcarbonyloxy substituted with 0-2 R.sup.12,
C.sub.6 -C.sub.10 arylcarbonyloxy substituted with 0-2 R.sup.12,
a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12 ;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R.sup.12 ;
R.sup.11A is selected from one or more of the following:
H, keto, halogen, cyano, --CH.sub.2 N(R.sup.13A)R(.sup.14A), --N(R.sup.13A)R(.sup.14A), --CO.sub.2 H, --OC(.dbd.O)(C.sub.1 -C.sub.3 alkyl), --OH, C.sub.2 -C.sub.6 alkoxyalkyl, --C(.dbd.O)NH.sub.2, --OC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NH.sub.2, --SO.sub.2 NH.sub.2, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --NH.sub.2, 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, --OCH.sub.2 CO.sub.2 H, 2-(1-morpholino)ethoxy, azido, aryl(C.sub.1 -C.sub.3 alkyl), a C.sub.5 -C.sub.14 carbocyclic residue;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system substituted with 0-3 R.sup.12A.
R.sup.12, when a substituent on carbon, is selected from one or more 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, C.sub.1 -C.sub.4 alkoxy, --CO.sub.2 H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OR.sup.13, C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkylene optionally substituted with --Si(CH.sub.3).sub.3, 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.13, --SO.sub.2 NR.sup.13 R.sup.14, --NHSO.sub.2 R.sup.14, --OCH.sub.2 CO.sub.2 R.sup.13, 2-(1-morpholino)ethoxy, --C(R.sup.14).dbd.N(OR.sup.14);
or
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
or R.sup.12 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 optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, or
--NR.sup.13 R.sup.14 ;
or, when R.sup.12 is attached to a saturated carbon atom, it may be .dbd.O or .dbd.S;
or when R.sup.12 is attached to sulfur it may be .dbd.O;
R.sup.12, when a substituent on nitrogen, is selected from one or more of 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, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --CO.sub.2 H, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, --C(R.sup.14).dbd.N(OR.sup.14);
R.sup.12A, when a substituent on carbon, is selected from one or more 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, C.sub.1 -C.sub.4 alkoxy, --CO.sub.2 H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OR.sup.13, C.sub.1 -C.sub.4 alkyl substituted with --NH.sub.2, --NH.sub.2, --NHMe, C.sub.2 -C.sub.6 alkoxyalkyl optionally substituted with --Si(CH.sub.3).sub.3, 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 Me, --SO.sub.2 NH.sub.2, --NHSO.sub.2 Me, --OCH.sub.2 CO.sub.2 R.sup.13, 2-(1-morpholino)ethoxy, --C(.dbd.NOH)NH.sub.2 ;
or
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
or R.sup.12A 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 optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, or
--NH.sub.2 ;
or, when R.sup.12A is attached to a saturated carbon atom, it may be .dbd.O or .dbd.S;
or when R.sup.12 is attached to sulfur it may be .dbd.O;
R.sup.12A, when a substituent on nitrogen, is selected from one or more of 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, --CH.sub.2 NH.sub.2, --NH.sub.2, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --CO.sub.2 H, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, --C(.dbd.NOH)NH.sub.2 ;
R.sup.13 is selected from:
H;
phenyl substituted with 0-3 R.sup.11A ;
benzyl substituted with 0-3 R.sup.11A ;
C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11A ;
C.sub.2 -C.sub.4 alkenyl substituted with 0-3 R.sup.11A ;
C.sub.1 -C.sub.6 alkylcarbonyl substituted with 0-3 R.sup.11A ;
C.sub.1 -C.sub.6 alkoxycarbonyl substituted with 0-3 R.sup.11A ;
C.sub.1 -C.sub.6 alkylaminocarbonyl substituted with 0-3 R.sup.11A ;
and
C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11A ;
R.sup.14 is hydrogen, hydroxy, C.sub.1 -C.sub.6 alkyl substituted with 0-3 groups selected from OH, C.sub.1 -C.sub.4 alkoxy, halogen, NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.6 alkenyl, phenyl, and benzyl;
R.sup.13 and R.sup.14 can alternatively join to form --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2 --, or --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --;
R.sup.13A and R.sup.14A are independently selected from:
H, C.sub.1 -C.sub.6 alkyl;
R.sup.13A and R.sup.14A can alternatively join to form --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2 --, or --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --;
R.sup.15 is H or CH.sub.3 ;
m is 0, 1 or 2;
W is selected from:
--N(R.sup.22)C(.dbd.Z)N(R.sup.23)--;
--N(R.sup.22)S(.dbd.Z')N(R.sup.23)--;
--N(R.sup.22)S(.dbd.Z').sub.2 N(R.sup.23)--;
and
--N(R.sup.22)P(.dbd.O)(R.sup.24a)N(R.sup.23)--;
wherein:
Z is O, S, NR.sup.24 ;
Z' is O or NR.sup.24 ;
R.sup.22 and R.sup.23 are independently selected from the following:
hydrogen;
--OR.sup.22a ;
--N(R.sup.22a)(R.sup.22b);
C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.31 ;
C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.31 ;
C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.31 ;
a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-5 R.sup.31 or 0-5 R.sup.32 ;
a heterocyclic ring system selected independently from pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, tetrazoyl, triazinyl, pyrazinyl, pyridazinyl, oxazolidinyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R.sup.32 ;
R.sup.22a and R.sup.22b are independently selected from the following:
hydrogen;
C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.31 ;
C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.31 ;
C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.31 ;
a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-5 R.sup.31 or 0-5 R.sup.32 ;
a heterocyclic ring system selected independently from pyridinyl, furanyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl, said heterocyclic ring system being substituted with 0-2 R.sup.32 ;
R.sup.24 is selected from:
hydrogen;
hydroxy;
amino;
C.sub.1 -C.sub.4 alkyl;
C.sub.1 -C.sub.4 alkoxy;
mono- or di-(C.sub.1 -C.sub.6 alkyl)amino;
cyano;
nitro;
benzyloxy;
--NHSO.sub.2 aryl, aryl being optionally substituted with (C.sub.1 -C.sub.6)alkyl;
R.sup.24a is selected from:
hydroxy;
amino;
C.sub.1 -C.sub.4 alkyl;
C.sub.1 -C.sub.4 alkoxy;
mono- or di-(C.sub.1 -C.sub.6 alkyl)amino;
cyano;
nitro;
benzyloxy;
or phenoxy;
alternatively, R.sup.22 can join with R.sup.4 or R.sup.4A to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R.sup.12, said heterocyclic ring selected from pyrrolidine, morpholine, thiomorpholine, piperidine, or piperazine;
or
alternatively, R.sup.23 can join with R.sup.7 or R.sup.7A to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R.sup.12, said heterocyclic ring selected from pyrrolidine, morpholine, thiomorpholine, piperidine, or piperazine;
or
alternatively, R.sup.22 or R.sup.23, can join with R.sup.5 or R.sup.6 to form a 0- to 7-membered bridge to form a carbocyclic or heterocyclic ring, said bridge being substituted with 0-2 R.sup.12 and said heterocyclic ring being selected from pyrrolidine, morpholine, thiomorpholine, piperidine, or piperazine;
alternatively R.sup.23 can join with R.sup.7A to form a direct bond;
alternatively R.sup.22 can join with R.sup.4A to form a direct bond;
R.sup.31 is selected from one or more of the following:
keto, halogen, cyano, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, --CO.sub.2 R.sup.13, --C(.dbd.O)R.sup.11, --OC(.dbd.O)R.sup.13, --OR.sup.13, C.sub.2 -C.sub.6 alkoxyalkyl, --S(O).sub.m R.sup.13, --NHC(.dbd.NH)NHR.sup.13, --C(.dbd.NH)NHR.sup.13, --C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 C(.dbd.O)R.sup.13, .dbd.NOR.sup.14, --NR.sup.14 C(.dbd.O)OR.sup.14, --OC(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.13 C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.13 C(.dbd.S)NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.13 R.sup.14, 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, --OCH.sub.2 CO.sub.2 R.sup.13, 2-(1-morpholino)ethoxy, azido, --C(R.sup.14).dbd.N(OR.sup.14);
or
- 3amino acids, linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus;
a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-5 R.sup.32 ;
or
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R.sup.32 ;
R.sup.32, when a substituent on carbon, is selected from one or more of the following:
phenethyl, phenoxy, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C.sub.7 -C.sub.10 arylalkyl, hydrazide, oxime, boronic acid, C.sub.2 -C.sub.6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 alkylcarbonyloxy, --NHSO.sub.2 R.sup.14, benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO.sub.2 R.sup.13, hydroxamic acid, --CONR.sup.13 NR.sup.13 R.sup.14, cyano, sulfonamide, --CHO, C.sub.3 -C.sub.6 cycloalkoxy, --NR.sup.13 R.sup.14, --C(R.sup.14).dbd.N(OR.sup.14), --NO.sub.2, --OR.sup.13, --NR.sup.40 R.sup.41, --SO.sub.m R.sup.13, --SO.sub.m NR.sup.13 R.sup.14, --C(.dbd.O)NR.sup.13 R.sup.14, --OC(.dbd.O)NR.sup.13 R.sup.14, --C(.dbd.O)R.sup.11, --OC(.dbd.O)R.sup.11, --OCO.sub.2 R.sup.13, phenyl, --C(.dbd.O)NR.sup.13 -(C.sub.1 -C.sub.4 alkyl)--NR.sup.13 R.sup.14, --C(.dbd.O)NR.sup.40 R.sup.41, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.2 -C.sub.4 haloalkenyl, C.sub.1 -C.sub.4 haloalkynyl, or
--C(.dbd.O)NR.sup.13 C(R.sup.11).sub.2 NR.sup.13 R.sup.14 ;
--C(.dbd.O)NR.sup.13 C(R.sup.11).sub.2 NR.sup.13 CO.sub.2 R.sup.13 ;
--C(.dbd.O)NR.sup.13 --(C.sub.1 -C.sub.4 alkyl)--NR.sup.13 CO.sub.2 R.sup.13 ;
--C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)--R.sup.11 ;
or
--C(.dbd.O)C(R.sup.11).sub.2 NR.sup.13 R.sup.14 ;
--C(.dbd.O)C(R.sup.11).sub.2 NR.sup.13 CO.sub.2 R.sup.13 ;
--C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--NR.sup.13 R.sup.14 ;
--C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--NR.sup.13 CO.sub.2 R.sup.13 ;
or
C.sub.1 -C.sub.4 alkoxy substituted with 0-4 groups selected from:
R.sup.11, C.sub.3 -C.sub.6 cycloalkyl, --CO.sub.2 R.sup.13, --C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14 or OH;
C.sub.1 -C.sub.4 alkyl substituted with 0-4 groups selected from:
R.sup.11, .dbd.NR.sup.14, .dbd.NNR.sup.13 C(.dbd.O)NR.sup.13 R.sup.14, .dbd.NNR.sup.13 C(.dbd.O)OR.sup.13, or --NR.sup.13 R.sup.14 ;
C.sub.2 -C.sub.4 alkenyl substituted with 0-4 R.sup.11 ;
C.sub.2 -C.sub.4 alkynyl substituted with 0-4 R.sup.11 ;
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted with 0-2 R.sup.12 ;
or R.sup.32 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 optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, or
--NR.sup.13 R.sup.14 ;
or, when R.sup.32 is attached to a saturated carbon, it may be .dbd.O, .dbd.S, .dbd.NOH;
or when R.sup.32 attached to sulfur it may be .dbd.O.
R.sup.32, when a substituent on nitrogen, is selected from one or more of 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, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --CO.sub.2 H, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, --C(R.sup.14).dbd.N(OR.sup.14);
R.sup.40 is selected from:
H, C.sub.1 -C.sub.3 alkyl;
R.sup.41 is selected from:
--C(.dbd.O)NR.sup.13 R.sup.14 ;
--C(.dbd.O)NR.sup.13 NR.sup.13 R.sup.14 ;
--C(.dbd.O)C(R.sup.11).sub.2 NR.sup.13 R.sup.14 ;
--C(.dbd.O)C(R.sup.11).sub.2 NR.sup.13 NR.sup.13 R.sup.14 ;
--C(.dbd.O)C(R.sup.11).sub.2 NR.sup.13 CO.sub.2 R.sup.13 ;
--C(.dbd.O)H;
--C(.dbd.O)R.sup.11 ;
--C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--NR.sup.13 R.sup.14 ;
--C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--NR.sup.13 CO.sub.2 R.sup.13 ;
- 3amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus;
wherein said aryl group is phenyl or naphthyl;
provided that:
R.sup.4, R.sup.4A, R.sup.7 and R.sup.7A are not all hydrogen;
when R.sup.4, R.sup.4A are hydrogen, then R.sup.22 is not hydrogen.

212 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/770,546Filed 22 Nov 1996 · division
Priority: 11 Oct 1991
Granted: 22 Sep 1998
Term ends: Not estimatedThe source records don’t support an estimate.

Classification41 codes

C07D 239/10
With hetero atoms directly attached in position 2: oxygen or sulfur atoms
A61P 31/12
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antivirals
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07C 49/723
Containing hydroxy groups: polycyclic

Family

Serial776,491Parent of this continuation-in-part · filed 11 Oct 1991
Serial883,944Parent of this continuation-in-part · filed 15 May 1992
Serial953,272Parent of this continuation-in-part · filed 30 Sep 1992
Serial23,439Parent of this continuation-in-part · filed 26 Feb 1993
Serial47,330Parent of this continuation-in-part · filed 15 Apr 1993
Serial197,630Parent of this division · filed 16 Feb 1994
US 5,610,294 AParent of this division
US 5,811,422 AThis patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

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Abstract

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I):

##STR112## or a pharmaceutically acceptable salt form thereof wherein:
R.sup.4 and R.sup.7 are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.11 ;
C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.11 ;
C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.11 ;
a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-3 R.sup.11 or 0-3 R.sup.12 ;
a heterocyclic ring selected independently from indolyl, furanyl, pyridyl, thienyl, pyrrolyl, benzob!thienyl, pyrazolyl, thiazolyl, benzofuranyl, tetrahydroisoquinolinyl, benzotriazolyl, benzimidazolyl, or imidazolyl, said heterocyclic ring system being substituted with 0-2 R.sup.12 ;
--CO.sub.2 R.sup.13 ;
R.sup.4A and R.sup.7A are independently selected from the following groups:
hydrogen;
C.sub.1 -C.sub.4 alkyl substituted with 0-6 halogen or 0-3 C.sub.1 -C.sub.2 alkoxy;
benzyl substituted with 0-6 halogen or 0-3 C.sub.1 -C.sub.2 alkoxy;
--CO.sub.2 R.sup.13 ;
R.sup.4 and R.sup.4A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R.sup.12 ;
R.sup.7 and R.sup.7A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R.sup.12 ;
n is 1;
R.sup.5 is selected from H;
halogen;
--N(R.sup.20).sub.2, --SR.sup.20, --OR.sup.20, --N.sub.3 or C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
R.sup.6 is independently selected from:
hydrogen, halogen, --N(R.sup.20).sub.2, --SR.sup.20, --OR.sup.21, --N.sub.3 or C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
R.sup.5 and R.sup.6 can alternatively join to form an epoxide or aziridine ring;
--OCH.sub.2 SCH.sub.2 O--;
--OC(.dbd.O)O--;
--OCH.sub.2 O--;
--OC(.dbd.S)O--;
--OC(.dbd.O)C(.dbd.O)O--;
--OC(CH.sub.3).sub.2 O--;
--OC((CH.sub.2).sub.3 NH.sub.2)(CH.sub.3)O--;
--OC(OCH.sub.3)(CH.sub.2 CH.sub.2 CH.sub.3)O--;
--OS(.dbd.O)O--;
--NHC(.dbd.O)NH--;
--OC(.dbd.O)NH--;
--NHC(.dbd.O)O--;
--NHCH.sub.2 O--;
--OCH.sub.2 NH--;
--NHC(.dbd.S)O--;
--OS(.dbd.O)NH--;
--NHC(.dbd.O)C(.dbd.O)O--;
--OC(.dbd.O)C(.dbd.O)NH--;
--NHC(.dbd.O)C(.dbd.O)NH--;
--NHC(CH.sub.3).sub.2 O--;
or --OC(CH.sub.3).sub.2 NH--;
R.sup.5a is selected from hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, --N(R.sup.20).sub.2, --SR.sup.20, or --OR.sup.20 ;
R.sup.6a is selected from:
hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, --N(R.sup.20).sub.2, --SR.sup.20 or --OR.sup.21 ;
R.sup.5 and R.sup.5a can alternatively join to form .dbd.O, .dbd.S, or a ketal ring;
R.sup.6 and R.sup.6a can alternatively join to form .dbd.O, .dbd.S, or a ketal ring;
R.sup.20 and R.sup.21 are independently selected from:
hydrogen;
C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11 ;
C.sub.1 -C.sub.6 alkylcarbonyl substituted with 0-3 R.sup.11 ;
C.sub.1 -C.sub.6 alkoxycarbonyl substituted with 0-3 R.sup.11 ;
C.sub.1 -C.sub.6 alkylaminocarbonyl substituted with 0-3 R.sup.11 ;
benzoyl substituted with 0-3 R.sup.12 ;
phenoxycarbonyl substituted with 0-3 R.sup.12 ;
phenylaminocarbonyl substituted with 0-3 R.sup.12 ;
or
phosphate ester;
R.sup.11 is selected from one or more of the following:
H, keto, halogen, cyano, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, --CO.sub.2 R.sup.13, --OC(.dbd.O)R.sup.13, --OR.sup.13, --S(O).sub.m R.sup.13, --NHC(.dbd.NH)NHR.sup.13, --C(.dbd.NH)NHR.sup.13, --C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 C(.dbd.O)R.sup.13, .dbd.NOR.sup.14, --NR.sup.14 C(.dbd.O)OR.sup.14, --OC(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.13 C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, --OP(O)(OR.sup.13).sub.2, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.13 R.sup.14, 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, pyridylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --OCH.sub.2 CO.sub.2 H, 2-(1-morpholino)ethoxy, azido, or --C(R.sup.14).dbd.N(OR.sup.14);
- 3amino acids linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus;
C.sub.3 -C.sub.10 cycloalkyl substituted with 0-2 R.sup.12 ;
C.sub.1 -C.sub.4 alkyl substitued with 0-2 R.sup.12
aryl(C.sub.1 -C.sub.3 alkyl)-, substituted with 0-2 R.sup.12 ;
C.sub.2 -C.sub.6 alkoxyalkyl-, substituted with 0-2 R.sup.12 ;
C.sub.1 -C.sub.4 alkylcarbonyloxy substituted with 0-2 R.sup.12,
C.sub.6 -C.sub.10 arylcarbonyloxy substituted with 0-2 R.sup.12,
a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12 ;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R.sup.12 ;
R.sup.11A is selected from one or more of the following:
H, keto, halogen, cyano, --CH.sub.2 N(R.sup.13A)R(.sup.14A), --N(R.sup.13A)R(.sup.14A), --CO.sub.2 H, --OC(.dbd.O)(C.sub.1 -C.sub.3 alkyl), --OH, C.sub.2 -C.sub.6 alkoxyalkyl, --C(.dbd.O)NH.sub.2, --OC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NH.sub.2, --SO.sub.2 NH.sub.2, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --NH.sub.2, 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, --OCH.sub.2 CO.sub.2 H, 2-(1-morpholino)ethoxy, azido, aryl(C.sub.1 -C.sub.3 alkyl), a C.sub.5 -C.sub.14 carbocyclic residue;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system substituted with 0-3 R.sup.12A.
R.sup.12, when a substituent on carbon, is selected from one or more 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, C.sub.1 -C.sub.4 alkoxy, --CO.sub.2 H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OR.sup.13, C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkylene optionally substituted with --Si(CH.sub.3).sub.3, 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.13, --SO.sub.2 NR.sup.13 R.sup.14, --NHSO.sub.2 R.sup.14, --OCH.sub.2 CO.sub.2 R.sup.13, 2-(1-morpholino)ethoxy, --C(R.sup.14).dbd.N(OR.sup.14);
or
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
or R.sup.12 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 optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, or
--NR.sup.13 R.sup.14 ;
or, when R.sup.12 is attached to a saturated carbon atom, it may be .dbd.O or .dbd.S;
or when R.sup.12 is attached to sulfur it may be .dbd.O;
R.sup.12, when a substituent on nitrogen, is selected from one or more of 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, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --CO.sub.2 H, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, --C(R.sup.14).dbd.N(OR.sup.14);
R.sup.12A, when a substituent on carbon, is selected from one or more 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, C.sub.1 -C.sub.4 alkoxy, --CO.sub.2 H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OR.sup.13, C.sub.1 -C.sub.4 alkyl substituted with --NH.sub.2, --NH.sub.2, --NHMe, C.sub.2 -C.sub.6 alkoxyalkyl optionally substituted with --Si(CH.sub.3).sub.3, 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 Me, --SO.sub.2 NH.sub.2, --NHSO.sub.2 Me, --OCH.sub.2 CO.sub.2 R.sup.13, 2-(1-morpholino)ethoxy, --C(.dbd.NOH)NH.sub.2 ;
or
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
or R.sup.12A 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 optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, or
--NH.sub.2 ;
or, when R.sup.12A is attached to a saturated carbon atom, it may be .dbd.O or .dbd.S;
or when R.sup.12 is attached to sulfur it may be .dbd.O;
R.sup.12A, when a substituent on nitrogen, is selected from one or more of 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, --CH.sub.2 NH.sub.2, --NH.sub.2, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --CO.sub.2 H, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, --C(.dbd.NOH)NH.sub.2 ;
R.sup.13 is selected from:
H;
phenyl substituted with 0-3 R.sup.11A ;
benzyl substituted with 0-3 R.sup.11A ;
C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11A ;
C.sub.2 -C.sub.4 alkenyl substituted with 0-3 R.sup.11A ;
C.sub.1 -C.sub.6 alkylcarbonyl substituted with 0-3 R.sup.11A ;
C.sub.1 -C.sub.6 alkoxycarbonyl substituted with 0-3 R.sup.11A ;
C.sub.1 -C.sub.6 alkylaminocarbonyl substituted with 0-3 R.sup.11A ;
and
C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11A ;
R.sup.14 is hydrogen, hydroxy, C.sub.1 -C.sub.6 alkyl substituted with 0-3 groups selected from OH, C.sub.1 -C.sub.4 alkoxy, halogen, NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.6 alkenyl, phenyl, and benzyl;
R.sup.13 and R.sup.14 can alternatively join to form --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2 --, or --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --;
R.sup.13A and R.sup.14A are independently selected from:
H, C.sub.1 -C.sub.6 alkyl;
R.sup.13A and R.sup.14A can alternatively join to form --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2 --, or --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --;
R.sup.15 is H or CH.sub.3 ;
m is 0, 1 or 2;
W is selected from:
--N(R.sup.22)C(.dbd.Z)N(R.sup.23)--;
--N(R.sup.22)S(.dbd.Z')N(R.sup.23)--;
--N(R.sup.22)S(.dbd.Z').sub.2 N(R.sup.23)--;
and
--N(R.sup.22)P(.dbd.O)(R.sup.24a)N(R.sup.23)--;
wherein:
Z is O, S, NR.sup.24 ;
Z' is O or NR.sup.24 ;
R.sup.22 and R.sup.23 are independently selected from the following:
hydrogen;
--OR.sup.22a ;
--N(R.sup.22a)(R.sup.22b);
C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.31 ;
C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.31 ;
C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.31 ;
a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-5 R.sup.31 or 0-5 R.sup.32 ;
a heterocyclic ring system selected independently from pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, tetrazoyl, triazinyl, pyrazinyl, pyridazinyl, oxazolidinyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R.sup.32 ;
R.sup.22a and R.sup.22b are independently selected from the following:
hydrogen;
C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.31 ;
C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.31 ;
C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.31 ;
a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-5 R.sup.31 or 0-5 R.sup.32 ;
a heterocyclic ring system selected independently from pyridinyl, furanyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl, said heterocyclic ring system being substituted with 0-2 R.sup.32 ;
R.sup.24 is selected from:
hydrogen;
hydroxy;
amino;
C.sub.1 -C.sub.4 alkyl;
C.sub.1 -C.sub.4 alkoxy;
mono- or di-(C.sub.1 -C.sub.6 alkyl)amino;
cyano;
nitro;
benzyloxy;
--NHSO.sub.2 aryl, aryl being optionally substituted with (C.sub.1 -C.sub.6)alkyl;
R.sup.24a is selected from:
hydroxy;
amino;
C.sub.1 -C.sub.4 alkyl;
C.sub.1 -C.sub.4 alkoxy;
mono- or di-(C.sub.1 -C.sub.6 alkyl)amino;
cyano;
nitro;
benzyloxy;
or phenoxy;
alternatively, R.sup.22 can join with R.sup.4 or R.sup.4A to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R.sup.12, said heterocyclic ring selected from pyrrolidine, morpholine, thiomorpholine, piperidine, or piperazine;
or
alternatively, R.sup.23 can join with R.sup.7 or R.sup.7A to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R.sup.12, said heterocyclic ring selected from pyrrolidine, morpholine, thiomorpholine, piperidine, or piperazine;
or
alternatively, R.sup.22 or R.sup.23, can join with R.sup.5 or R.sup.6 to form a 0- to 7-membered bridge to form a carbocyclic or heterocyclic ring, said bridge being substituted with 0-2 R.sup.12 and said heterocyclic ring being selected from pyrrolidine, morpholine, thiomorpholine, piperidine, or piperazine;
alternatively R.sup.23 can join with R.sup.7A to form a direct bond;
alternatively R.sup.22 can join with R.sup.4A to form a direct bond;
R.sup.31 is selected from one or more of the following:
keto, halogen, cyano, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, --CO.sub.2 R.sup.13, --C(.dbd.O)R.sup.11, --OC(.dbd.O)R.sup.13, --OR.sup.13, C.sub.2 -C.sub.6 alkoxyalkyl, --S(O).sub.m R.sup.13, --NHC(.dbd.NH)NHR.sup.13, --C(.dbd.NH)NHR.sup.13, --C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.14 C(.dbd.O)R.sup.13, .dbd.NOR.sup.14, --NR.sup.14 C(.dbd.O)OR.sup.14, --OC(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.13 C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.13 C(.dbd.S)NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.13 R.sup.14, 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, --OCH.sub.2 CO.sub.2 R.sup.13, 2-(1-morpholino)ethoxy, azido, --C(R.sup.14).dbd.N(OR.sup.14);
or
- 3amino acids, linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus;
a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-5 R.sup.32 ;
or
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R.sup.32 ;
R.sup.32, when a substituent on carbon, is selected from one or more of the following:
phenethyl, phenoxy, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C.sub.7 -C.sub.10 arylalkyl, hydrazide, oxime, boronic acid, C.sub.2 -C.sub.6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 alkylcarbonyloxy, --NHSO.sub.2 R.sup.14, benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO.sub.2 R.sup.13, hydroxamic acid, --CONR.sup.13 NR.sup.13 R.sup.14, cyano, sulfonamide, --CHO, C.sub.3 -C.sub.6 cycloalkoxy, --NR.sup.13 R.sup.14, --C(R.sup.14).dbd.N(OR.sup.14), --NO.sub.2, --OR.sup.13, --NR.sup.40 R.sup.41, --SO.sub.m R.sup.13, --SO.sub.m NR.sup.13 R.sup.14, --C(.dbd.O)NR.sup.13 R.sup.14, --OC(.dbd.O)NR.sup.13 R.sup.14, --C(.dbd.O)R.sup.11, --OC(.dbd.O)R.sup.11, --OCO.sub.2 R.sup.13, phenyl, --C(.dbd.O)NR.sup.13 -(C.sub.1 -C.sub.4 alkyl)--NR.sup.13 R.sup.14, --C(.dbd.O)NR.sup.40 R.sup.41, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.2 -C.sub.4 haloalkenyl, C.sub.1 -C.sub.4 haloalkynyl, or
--C(.dbd.O)NR.sup.13 C(R.sup.11).sub.2 NR.sup.13 R.sup.14 ;
--C(.dbd.O)NR.sup.13 C(R.sup.11).sub.2 NR.sup.13 CO.sub.2 R.sup.13 ;
--C(.dbd.O)NR.sup.13 --(C.sub.1 -C.sub.4 alkyl)--NR.sup.13 CO.sub.2 R.sup.13 ;
--C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)--R.sup.11 ;
or
--C(.dbd.O)C(R.sup.11).sub.2 NR.sup.13 R.sup.14 ;
--C(.dbd.O)C(R.sup.11).sub.2 NR.sup.13 CO.sub.2 R.sup.13 ;
--C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--NR.sup.13 R.sup.14 ;
--C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--NR.sup.13 CO.sub.2 R.sup.13 ;
or
C.sub.1 -C.sub.4 alkoxy substituted with 0-4 groups selected from:
R.sup.11, C.sub.3 -C.sub.6 cycloalkyl, --CO.sub.2 R.sup.13, --C(.dbd.O)NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14 or OH;
C.sub.1 -C.sub.4 alkyl substituted with 0-4 groups selected from:
R.sup.11, .dbd.NR.sup.14, .dbd.NNR.sup.13 C(.dbd.O)NR.sup.13 R.sup.14, .dbd.NNR.sup.13 C(.dbd.O)OR.sup.13, or --NR.sup.13 R.sup.14 ;
C.sub.2 -C.sub.4 alkenyl substituted with 0-4 R.sup.11 ;
C.sub.2 -C.sub.4 alkynyl substituted with 0-4 R.sup.11 ;
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted with 0-2 R.sup.12 ;
or R.sup.32 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 optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, or
--NR.sup.13 R.sup.14 ;
or, when R.sup.32 is attached to a saturated carbon, it may be .dbd.O, .dbd.S, .dbd.NOH;
or when R.sup.32 attached to sulfur it may be .dbd.O.
R.sup.32, when a substituent on nitrogen, is selected from one or more of 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, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --CO.sub.2 H, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, --C(R.sup.14).dbd.N(OR.sup.14);
R.sup.40 is selected from:
H, C.sub.1 -C.sub.3 alkyl;
R.sup.41 is selected from:
--C(.dbd.O)NR.sup.13 R.sup.14 ;
--C(.dbd.O)NR.sup.13 NR.sup.13 R.sup.14 ;
--C(.dbd.O)C(R.sup.11).sub.2 NR.sup.13 R.sup.14 ;
--C(.dbd.O)C(R.sup.11).sub.2 NR.sup.13 NR.sup.13 R.sup.14 ;
--C(.dbd.O)C(R.sup.11).sub.2 NR.sup.13 CO.sub.2 R.sup.13 ;
--C(.dbd.O)H;
--C(.dbd.O)R.sup.11 ;
--C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--NR.sup.13 R.sup.14 ;
--C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--NR.sup.13 CO.sub.2 R.sup.13 ;
- 3amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus;
wherein said aryl group is phenyl or naphthyl;
provided that:
R.sup.4, R.sup.4A, R.sup.7 and R.sup.7A are not all hydrogen;
when R.sup.4, R.sup.4A are hydrogen, then R.sup.22 is not hydrogen.

212 more elements

Facts

Application

08/770,546Filed 22 Nov 1996 · division

Priority

11 Oct 1991

Granted

22 Sep 1998

Term ends

Not estimatedThe source records don’t support an estimate.

Classification41 codes

C07D 239/10
With hetero atoms directly attached in position 2: oxygen or sulfur atoms
A61P 31/12
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antivirals
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07C 49/723
Containing hydroxy groups: polycyclic

Family

Serial776,491Parent of this continuation-in-part · filed 11 Oct 1991

Serial883,944Parent of this continuation-in-part · filed 15 May 1992

Serial953,272Parent of this continuation-in-part · filed 30 Sep 1992

Serial23,439Parent of this continuation-in-part · filed 26 Feb 1993

Serial47,330Parent of this continuation-in-part · filed 15 Apr 1993

Serial197,630Parent of this division · filed 16 Feb 1994

US 5,610,294 AParent of this division

US 5,811,422 AThis patent

From the US filing history. Foreign family members aren’t listed.