Back to results
US 5,506,355 AGranted
Method for preparing cyclic sulfamides and their use for the synthesis of HIV protease inhibitors
AssigneeThe Du Pont Merck Pharmaceutical Company
InventorsPrabhakar K. Jadhav, Wayne F. Daneker, Francis J. Woerner
Life of this patent
Estimating the term…
Abstract
The present invention discloses processes for the preparation of substituted cyclic sulfamides which are useful as intermediates for the synthesis of cyclic sulfamide human immunodeficiency virus (HIV) protease inhibitors. Such substituted cyclic sulfamide intermediates contain a cyclic acetal-protected diol.
Claims25
A process for the preparation of compounds of formula (III) ##STR21## 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 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 0-2 R.sup.12 ;
- --OR.sup.13 ;
- --SR.sup.13 ;
- 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 C.sub.1 -C.sub.2 alkoxy;
- benzyl substituted with C.sub.1 -C.sub.2 alkoxy;
- --OR.sup.13 ;
- --SR.sup.13 ;
- 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 ;
- R.sup.1 and R.sup.2 are independently H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.14 arylalkyl, C.sub.3 -C.sub.7 cycloalkyl, or, alternately, R.sup.1 and R.sup.2 can be taken together with the carbon to which they are attached to form a 3-7 membered saturated carbocyclic ring system;
- R.sup.11 is selected from one or more of the following:
- H, keto, 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, 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.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, 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 (O-protected), methylenedioxy, ethylenedioxy, 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, or --C(R.sup.14).dbd.N(OR.sup.14);
- - 3amino acids linked together via amide bonds, and said amino acid being linked to R.sup.4 or R.sup.7 via the amine or carboxylate terminus;
- --(C.sub.1 -C.sub.3 alkyl)aryl 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, cyano, --CH.sub.2 NH.sub.2, --NH.sub.2, --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 (O-protected), methylenedioxy, ethylenedioxy, 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;
- R.sup.12 when a substituent on carbon, is selected from one or more of the following:
- phenyl, benzyl, phenethyl, phenoxy, benzyloxy, O-protected 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 alkoxyalkyl, C.sub.1 -C.sub.4 hydroxyalkyl (O-protected), methylenedioxy, ethylenedioxy, 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 H, 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 C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, O-protected 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;
- R.sup.12 when a substituent on nitrogen, is selected from one or more of the following:
- phenyl, benzyl, phenethyl, O-protected hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl (O-protected), 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 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.13 is selected from:
- 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 ;
- C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11A ;
- an amine protecting group when R.sup.13 is bonded to N;
- a hydroxy protecting group when R.sup.13 is bonded to O;
- R.sup.14 is selected from:
- CF.sub.3 ;
- C.sub.1 -C.sub.6 alkyl substituted with 0-3 groups selected from --O--SEM, C.sub.1 -C.sub.4 alkoxy, --NHCO.sub.2 Bu.sup.t, --N(C.sub.1 -C.sub.4 alkyl)--CO.sub.2 Bu.sup.t ;
- C.sub.1 -C.sub.6 alkoxy;
- --NH--CO.sub.2 Bu.sup.t ;
- C.sub.2 -C.sub.6 alkenyl;
- benzyl;
- an amine protecting group when R.sup.14 is bonded to N;
- a hydroxy protecting group when R.sup.14 is bonded to O;
- 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.15 is H or CH.sub.3 ;
- m is 0, 1 or 2;
- R.sup.22 and R.sup.23 are independently selected from the following:
- 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 R.sup.32 ;
- 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 ;
- --OR.sup.22a ;
- --N(R.sup.22a) (R.sup.22b);
- 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 R.sup.32 ;
- 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.31 is selected from one or more of the following:
- ketal, acetal, cyano, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, --CO.sub.2 Bu.sup.t, --C(.dbd.O)R.sup.11, --C (OR.sup.22a).sub.2 --R.sup.11, --OR.sup.13, C.sub.2 -C.sub.6 alkoxyalkyl, --S(O).sub.m R.sup.13, --N(SEM)C(.dbd.NSEM)N(SEM)R.sup.13, --C(.dbd.NSEM)N(SEM)R.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, 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, SEM protected oxime, SEM protected 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 SEM protected hydroxyalkyl, methylenedioxy, ethylenedioxy, 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, and said amino acid being linked to R.sup.22 or R.sup.23 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, BOC protected hydrazide, benzyl protected oxime, C.sub.2 -C.sub.6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 alkylcarbonyloxy, --NHSO.sub.2 R.sup.14, benzyloxy, 2-(1-morpholino) ethoxy, --CO.sub.2 Bu.sup.t, --CONR.sup.13 NR.sup.13 R.sup.14, cyano, boronic acid, 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, 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, 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 NR.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 NR.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 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;
- 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 C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, benzyloxy, or --NR.sup.13 R.sup.14 ;
- or, when R.sup.32 is attached to a saturated carbon atom, it may be .dbd.O, .dbd.NObenzyl or .dbd.S;
- R.sup.32 when a substituent on nitrogen, is selected from one or more of the following:
- phenyl, benzyl, phenethyl, O-protected hydroxy, C.sub.1 -C.sub.14 hydroxyalkyl (O-protected), 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 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:
- 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.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.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;
- with the proviso that:
- R.sup.4, R.sup.4A, R.sup.7 and R.sup.7A are not all hydrogen;
- said process comprising the steps of:
- (1) contacting a compound of formula (I) or (IA) (IB):
- ##STR22## wherein R.sup.22, R.sup.23, R.sup.4, R.sup.4A, R.sup.7, R.sup.7A, R.sup.1, and R.sup.2 are defined above, in a suitable solvent with a hindered amine base and a --S(.dbd.O).sub.2 -- precursor to obtain a compound of the formula (II) or (IIA) or (IIB);
- ##STR23## (2) contacting the compound of formula (II) or (IIA) or (IIB) of step (1) above, with a suitable base and an alkylating agent of formula R.sup.22 --Y or R.sup.23 --Y, where Y is a suitable leaving group, to obtain a compound of formula (III).
123 more elements
A process for the preparation of compounds of formula (IV):
- ##STR25## 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 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 0-2 R.sup.12 ;
- --OR.sup.13 ;
- --SR.sup.13 ;
- CO.sub.2 .sup.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 C.sub.1 -C.sub.2 alkoxy;
- benzyl substituted with C.sub.1 -C.sub.2 alkoxy;
- --OR.sup.13 ;
- --SR.sup.13 ;
- 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 ;
- R.sup.1 and R.sup.2 are independently H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.14 arylalkyl, C.sub.3 -C.sub.7 cycloalkyl, or, alternately, R.sup.1 and R.sup.2 can be taken together with the carbon to which they are attached to form a 3-7 membered saturated carbocyclic ring system;
- R.sup.11 is selected from one or more of the following:
- H, keto, cyano, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, --CO.sub.2 .sup.R.sup.13, --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.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, 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 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, or --C(R.sup.14).dbd.N(OR.sup.14);
- - 3amino acids linked together via amide bonds, and said amino acid being linked to R.sup.4 or R.sup.7 via the amine or carboxylate terminus;
- --(C.sub.1 -C.sub.3 alkyl)aryl 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, cyano, --CH.sub.2 NH.sub.2, --NH.sub.2, --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 (O-protected), methylenedioxy, ethylenedioxy, 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;
- R.sup.12 when a substituent on carbon, is selected from one or more of the following:
- phenyl, benzyl, phenethyl, phenoxy, benzyloxy, O-protected 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 alkoxyalkyl, C.sub.1 -C.sub.4 hydroxyalkyl (O-protected), methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 alkoxy, 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 H, 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 C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, O-protected 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;
- R.sup.12 when a substituent on nitrogen, is selected from one or more of the following:
- phenyl, benzyl, phenethyl, O-protected hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl (O-protected), 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 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.13 is selected from:
- 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 ;
- C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11A ;
- an amine protecting group when R.sup.13 is bonded to N;
- a hydroxy protecting group when R.sup.13 is bonded to O;
- R.sup.14 is selected from:
- CF.sub.3 ;
- C.sub.1 -C.sub.6 alkyl substituted with 0-3 groups selected from --O--SEM, C.sub.1 -C.sub.4 alkoxy, --NHCO.sub.2 Bu.sup.t, --N(C.sub.1 -C.sub.4 alkyl)--CO.sub.2 Bu.sup.t ;
- C.sub.1 -C.sub.6 alkoxy;
- --NH--CO.sub.2 Bu.sup.t ;
- C.sub.2 -C.sub.6 alkenyl;
- benzyl;
- an amine protecting group when R.sup.14 is bonded to a hydroxy protecting group when R.sup.14 is bonded to O;
- 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.15 is H or CH.sub.3 ;
- m is 0, 1 or 2;
- R.sup.22 and R.sup.23 are independently selected from the following:
- 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 R.sup.32 ;
- 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 ;
- --OR.sup.22 a;
- --N(R.sup.22a)(R.sup.22b);
- 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 R.sup.32 ;
- 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.31 is selected from one or more of the following:
- ketal, acetal, cyano, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, --CO.sub.2 Bu.sup.t, --C(.dbd.O)R.sup.11, --C(OR.sup.22a).sub.2 --R.sup.11, --OR.sup.13, C.sub.2 -C.sub.6 alkoxyalkyl, --S(O).sub.m R.sup.13, --N(SEM)C(.dbd.NSEM)N(SEM)R.sup.13, --C(.dbd.NSEM)N(SEM)R.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, 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, SEM protected oxime, SEM protected 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 protected hydroxyalkyl(O-protected), methylenedioxy, ethylenedioxy, 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
- 1-3 amino acids, linked together via amide bonds, and said amino acid being linked to R.sup.22 or R.sup.23 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, BOC protected hydrazide, benzyl protected oxime, C.sub.2 -C.sub.6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 alkylcarbonyloxy, --NHSO.sub.2 R.sup.14, benzyloxy, 2-(1-morpholino)ethoxy, --CO.sub.2 Bu.sup.t, --CONR.sup.13 NR.sup.13 R.sup.14, cyano, boronic acid, 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, 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, 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 NR.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 NR.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 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;
- 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 C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, benzyloxy, or --NR.sup.13 R.sup.14 ;
- or, when R.sup.32 is attached to a saturated carbon atom, it may be .dbd.O, .dbd.NObenzyl or .dbd.S;
- R.sup.32 when a substituent on nitrogen, is selected from one or more of the following:
- phenyl, benzyl, phenethyl, O-protected hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl (O-protected), 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 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:
- 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.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.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;
- with the proviso that:
- R.sup.4, R.sup.4A, R.sup.7 and R.sup.7A are not all hydrogen;
- said process comprising the steps of:
- (1) contacting a compound of formula (IC):
- ##STR26## wherein R.sup.22, R.sup.23, R.sup.4, R.sup.4A, R.sup.7, R.sup.7A, R.sup.1, and R.sup.2 are defined above, in a solution with a hindered amine base and a --S(.dbd.O).sub.2 -- precursor to obtain a compound of the formula (III):
- ##STR27## (2) treatment of the compound of formula (III) of step (1) above under conditions effective to remove the cyclic acetal protecting group, to obtain a compound of formula (IV).
123 more elements
Dependencies are inferred from the claim text.