Claims
- 1. A process for the preparation of a compound of formula: ##STR37## comprising the steps of: (a) coupling an amino tripeptide of formula: ##STR38## wherein z is a carboxylic acid protecting group and Y is an amine protecting group, with a carboxylic acid derivative of formula: ##STR39## wherein G is an amine protecting group, to produce a protected linear peptide of formula: ##STR40## (b) removing the Z and G protecting groups of the product of Step (a) in one step to produce a deprotected linear peptide of formula: ##STR41## (c) cyclizing the deprotected linear peptide of Step (b) to produce a cyclic peptide of formula: ##STR42## (d) removing the Y group and R.sup.25 of the product of Step (c) to produce an amine of formula (I):
- wherein:
- w is 0 or 1;
- R.sup.1 is ##STR43## wherein p and p' are 0 or 1;
- R.sup.19 is a C.sub.6 -C.sub.14 saturated, partially saturated, or aromatic carbocyclic ring system or heterocyclic ring system composed of at least 1-3 heteroatoms selected from the group consisting of N, O, and S; all these ring systems may be optionally substituted with 0-2 R.sup.7 ;
- R.sup.17 and R.sup.16 are independently selected form the group consisting of:
- hydrogen;
- C.sub.1 -C.sub.4 alkyl, optionally substituted with halogen;
- C.sub.1 -C.sub.2 alkoxy; and
- benzyl;
- R.sup.15 and R.sup.18 are independently selected form the group consisting of;
- hydrogen, C.sub.1-4 alkoxy
- C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.8,
- C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.8,
- C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.8,
- C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.8,
- C.sub.6 -C.sub.10 bicycloalkyl substituted with 0-2 R.sup.8,
- benzyl.
- aryl substituted with 0-2 R.sup.13,
- phenyl--C.sub.2-4 alkyl and
- a heterocylic ring system composed of 5-10 atoms including 1-3 nitrogen, oxygen, or sulfur heteroatoms, optionally substituted with 0-2 R.sup.13 ;
- R.sup.15 and R.sup.11 can alternatively join to form a 5-8 membered carbocyclic ring substituted with 0-2 R.sup.13, when R.sup.17 is H;
- R.sup.7 is independently selected at each occurrence from the group consisting of:
- H, C.sub.1-8 alkyl, Dhenyl, benzyl, phenethyl, phenoxy, benzyloxy,halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.5 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 R.sup.20, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OC(.dbd.O)R.sup.20, --C(.dbd.O)R.sup.20, --OC(--O)OR.sup.20, --OR.sup.20, --CH.sub.2 OR.sup.20, and C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.20 R.sup.21 ;
- R.sup.8 is independently selected at each occurrence from the group consisting of:
- .dbd.0. F, C.sub.1, Br, I, --CF.sub.3, --CN, --CO2R.sup.20, --C(.dbd.O)NR.sup.20 R.sup.21, --CH.sub.2 OR.sup.20, --OC(.dbd.O)R.sup.20, --CH.sub.2 NR.sup.20 R.sup.21, and --NR.sup.20 R.sup.21 ;
- R.sup.13 is independently selected at each occurrence from the group consisting of:
- phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.5 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C7-C.sub.10 arylalkyl, C.sub.1 -C.sub.4 alkoxy, --CO.sub.2 R.sup.20, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OC(.dbd.O)R.sup.20, --C(.dbd.O)R.sup.20, --OC(.dbd.O)OR.sup.20, --OR.sup.20, --CH.sub.2 OR.sup.20, and C.sub.1 -C.sub.4 alkyl (substituted with --NR.sup.20 R.sup.21);
- R.sup.20 is independently:
- H, C.sub.1 -C.sub.7 alkyl, aryl, --(C.sub.1 -C.sub.6 alkyl)aryl, or C.sub.3 -C.sub.6 alkoxyalkyl;
- R.sup.21 is independently:
- H, C.sub.1 -C.sub.4 alkyl, or benzyl;
- R.sup.11 is H or C.sub.1 -C.sub.8 alkyl;
- R.sup.12 is H or C.sub.1 -C.sub.8 alkyl;
- R.sup.2 is H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C.sub.1 -C.sub.6 cycloalkylethyl, phenyl, phenylmethyl, CH.sub.2 OH, CH.sub.2 SH, CH.sub.2 OCH.sub.3, CH.sub.2 SCH.sub.3, CH.sub.2 CH.sub.2 SCH.sub.3, (CH.sub.2).sub.s NH.sub.2, (CH.sub.2).sub.s NHC(.dbd.NH) (NH.sub.2), or (CH.sub.2).sub.s NHR.sup.21, wherein s=3-5;
- R.sup.12 and R.sup.2 can be taken together to form--(CH.sub.2)t--, wherein t=2-4, or --CH.sub.2 SC(CH.sub.3).sub.2 --;
- R.sup.3 is H or C.sub.1 -C.sub.8 alkyl;
- A is selected from the group consisting of:
- -C.sub.1 -C.sub.7 alkyl-, ##STR44## and provided that w=0, --(CH.sub.2).sub.m --O--(C.sub.1-4 alkyl)--NH--(C.sub.1-6 alkyl), wherein m=1,2,
- --(CH.sub.2).sub.m O--(C.sub.1 -C.sub.4 alkyl)--, wherein m=1,2, and
- --(CH.sub.2).sub.m S--(C.sub.1 -C.sub.4 alkyl)--, wherein m=1,2,
- R.sup.3 and A may also be taken together to form ##STR45## wherein n=0-1 and provided that w=0; R.sup.9 is, H or C.sub.1 -C.sub.8 alkyl;
- R.sup.5 is, H C.sub.1 -C.sub.8 alkyl; and
- R.sup.25 is t-butyl or benzyl wherein the phenyl ring is substituted with 0-5 C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups, or 1-2 halogen atoms.
- 2. The process of claim 1 wherein:
- R.sup.19 is: ##STR46## R.sup.15 and R.sup.18 are independently selected from H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, phenyl-(C.sub.2 -C.sub.4)alkyl, or C.sub.1 -C.sub.4 alkoxy;
- R.sup.17 and R.sup.16 are independently H or C.sub.1 -C.sub.4 alkyl;
- R.sup.7 is H, C.sub.1 -C.sub.8 alkyl, phenyl, halogen, or C.sub.1 -C.sub.4 alkoxy;
- R.sup.11 is H or C.sub.1 -C.sub.3 alkyl;
- R.sup.12 is H or CH.sub.3 ;
- A is:
- C.sub.1 -C.sub.7 alkyl, ##STR47## and provided that w=0, or --(CH.sub.2).sub.m --O--(C.sub.1 -C.sub.4 alkyl)--NH--(C.sub.1 -C.sub.6 alkyl), wherein m=1-2,
- R.sup.3 and A may be taken together to form ##STR48## wherein n=0-1 and provided that w=0; R.sup.9 is H or C.sub.1 -C.sub.3 alkyl;
- R.sup.5 is H or C.sub.1 -C.sub.3 alkyl.
- 3. The process of claim 2 wherein:
- Z=benzyl;
- Y=tosyl;
- G=CBz;
- R.sup.5, R.sup.9, R.sup.16, R.sup.17 and R.sup.18 are H;
- R.sup.11, R.sup.12, and R.sup.14 are H or CH.sub.3 ;
- R.sup.15 is H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, or phenyl-(C.sub.2 -C.sub.4)alkyl; and
- R.sup.3 is H or C.sub.1 -C.sub.3 alkyl.
- 4. The process of claim 1 wherein:
- w is 1;
- p is 0;
- R.sup.19 is ##STR49## R.sup.5, R.sup.9, R.sup.17, R.sup.15, R.sup.11, R.sup.12, R.sup.14 are H; R.sup.2 is C.sub.2 H.sub.5 ;
- R.sup.3 is CH.sub.3 ; and
- A is --(CH.sub.2).sub.3 --.
- 5. A process for the preparation of a compound of ##STR50## comprising cyclizing a compound of formula: ##STR51## wherein: w is 0 or 1;
- R.sup.1 is ##STR52## wherein: p and p' are 0 or 1;
- R.sup.19 is a C.sub.6 -C.sub.14 saturated, partially saturated, or aromatic carbocyclic ring system or heterocyclic ring system composed of at least 1-3 heteroatoms selected from N, O, S; all these ring systems may be optionally substituted with 0-2 R.sup.7 ;
- R.sup.17 and R.sup.16 are independently:
- hydrogen;
- C.sub.1 -C.sub.4 alkyl, optionally substituted with halogen;
- C.sub.1 -C.sub.2 alkoxy; or
- benzyl;
- R.sup.15 and R.sup.18 are independently;
- hydrogen,
- C.sub.1-4 alkoxy
- C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.8,
- C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.8,
- C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.8,
- C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.8,
- C.sub.6 -C.sub.10 bicycloalkyl substituted with 0-2 R.sup.8,
- benzyl,
- aryl substituted with 0-2 R.sup.13,
- phenyl--C.sub.2-4 alkyl or
- a heterocylic ring system composed of 5-10 atoms including 1-3 nitrogen, oxygen, or sulfur heteroatoms, optionally substituted with 0-2 R.sup.13 ;
- R.sup.15 and R.sup.17 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R.sup.13 ;
- R.sup.18 and R.sup.16 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R.sup.13 ;
- R.sup.15 and R.sup.11 can alternatively join to form a 5-8 membered carbocyclic ring substituted with 0-2 R.sup.13, when R.sup.17 is H;
- R.sup.7 is independently;
- H, C.sub.1-8 alkyl, phenyl, benzyl, phenethyl, phenoxy, benzyloxy,halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.5 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 R.sup.20, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OC(.dbd.O)R.sup.20, --C(.dbd.O)R.sup.20, --OC(--O)OR.sup.20, --OR.sup.20, --CH.sub.2 OR.sup.20, or C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.20 R.sup.21 ;
- R.sup.8 is independently;
- .dbd.O, F, Cl, Br, I, --CF.sub.3, --CN, --CO.sub.2 R.sup.20, --C(.dbd.O)NR.sup.20 OR.sup.21, --CH.sub.2 OR.sup.20, --OC(.dbd.O)R.sup.20, --CH.sub.2 NR.sup.20 R.sup.21, or --NR.sup.20 R.sup.21 ;
- R.sup.13 is independently;
- phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.5 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 R.sup.20, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OC(.dbd.O)R.sup.20, --C(.dbd.O)R.sup.20, --OC(.dbd.O)OR.sup.20, --OR.sup.20, --CH.sub.2 OR.sup.20, or C.sub.1 -C.sub.4 alkyl (substituted with --NR.sup.20 R.sup.21);
- R.sup.20 is independently;
- H, C.sub.1 -C.sub.7 alkyl, aryl, --(C.sub.1 -C.sub.6 alkyl)aryl, or C.sub.3 -C.sub.6 alkoxyalkyl;
- R.sup.21 is independently;
- H, C.sub.1 -C.sub.4 alkyl, or benzyl;
- R.sup.11 is H, or C.sub.1 -C.sub.8 alkyl;
- R.sup.12 is H, or C.sub.1 -C.sub.8 alkyl;
- R.sup.2 is H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C.sub.1 -C.sub.6 cycloalkylethyl, phenyl, phenylmethyl, CH.sub.2 OH, CH.sub.2 SH, CH.sub.2 OCH.sub.3, CH.sub.2 SCH.sub.3, CH.sub.2 CH.sub.2 SCH.sub.3, (CH.sub.2)sNH2, (CH.sub.2).sub.s NHC(.dbd.NH)(NH.sub.2), or (CH.sub.2).sub.s NHR.sup.21, wherein s=3-5;
- R.sup.12 and R.sup.2 can be taken together to form --(CH.sub.2).sub.t --, wherein t=2-4, or --CH.sub.2 SC(CH.sub.3).sub.2 --;
- R.sup.3 is H or C.sub.1 -C.sub.8 alkyl;
- A is:
- --C.sub.1 -C.sub.7 alkyl--, ##STR53## and provided that w=0, R.sup.3 and A may be taken together to form ##STR54## wherein n=0-1 and provided that w=0; R.sup.9 is H, or C.sub.1 -C.sub.8 alkyl;
- R.sup.5 is H, or C.sub.1 -C.sub.8 alkyl; and
- R.sup.25 is t-butyl or benzyl wherein the phenyl ring is substituted with 0-5 C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups, or 1-2 halogen atoms.
- 6. The process of claim 5 wherein:
- R.sup.19 is: ##STR55## R.sup.15 and R.sup.18 are independently H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, phenyl-(C.sub.2 -C.sub.4)alkyl, or C.sub.1 -C.sub.4 alkoxy;
- R.sup.17 and R.sup.16 are independently H or C.sub.1 -C.sub.4 alkyl;
- R.sup.7 is H, C.sub.1 -C.sub.8 alkyl, phenyl, halogen, or C.sub.1 -C.sub.4 alkoxy;
- R.sup.11 is H or C.sub.1 -C.sub.3 alkyl;
- R.sup.12 is H or CH.sub.3 ;
- A is:
- --C.sub.1 -C.sub.7 alkyl--, ##STR56## wherein v is 0-3 and provided that w=0, R.sup.3 and A may be taken together to form ##STR57## wherein n=0-1 and provided that w=0; R.sup.9 is H or C.sub.1 -C.sub.3 alkyl; and
- R.sup.5 is H or C.sub.1 -C.sub.3 alkyl.
- 7. The process of claim 6 wherein:
- R.sup.5, R.sup.9, R.sup.16, R.sup.17 and R.sup.18 are H;
- R.sup.11, R.sup.12, and R.sup.14 are H or CH.sub.3 ;
- R.sup.15 is H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, or phenyl-(C.sub.2 -C.sub.4)alkyl; and
- R.sup.3 is H or C.sub.1 -C.sub.3 alkyl.
- 8. The process of claim 7 wherein:
- w is 1;
- p is 0;
- R.sup.19 is ##STR58## R.sup.5, R.sup.9, R.sup.17, R.sup.15, R.sup.11, R.sup.12, R.sup.14 are H; R.sup.2 is C.sub.2 H.sub.5 ;
- R.sup.3 is CH.sub.3 ; and
- A is --(CH.sub.2).sub.3 --.
- 9. The compounds of formula: ##STR59## wherein: w=0 or 1;
- Y is H or tosyl;
- Z is H or benzyl;
- G is H or CBZ;
- R.sup.1 is ##STR60## wherein p and p' are 0 or 1;
- R.sup.19 is a C.sub.6 -C14 saturated, partially saturated, or aromatic carbocyclic ring system; all these ring systems are substituted with 0-2 R.sup.7 ;
- R.sup.17 and R.sup.16 are independently:
- hydrogen;
- C.sub.1 -C.sub.4 alkyl, optionally substituted with halogen;
- C.sub.1 -C.sub.2 alkoxy; or
- benzyl;
- R.sup.15 and R.sup.18 are independently;
- hydrogen,
- C.sub.1-4 alkoxy
- C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.8,
- C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.8,
- C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.8,
- C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.8,
- C.sub.6 -C.sub.10 bicycloalkyl substituted with 0-2 R.sup.8,
- benzyl,
- aryl substituted with 0-2 R.sup.13,
- phenyl-C.sub.2-4 alkyl or
- a heterocylic ring system composed of 5-10 atoms including 1-3 nitrogen, oxygen, or sulfur heteroatoms, optionally substituted with 0-2 R.sup.13 ;
- R.sup.15 and R.sup.17 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R.sup.13 ;
- R.sup.18 and R.sup.16 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R.sup.13 ;
- R.sup.15 and R.sup.11 can alternatively join to form a 5-8 membered carbocyclic ring substituted with 0-2 R.sup.13, when R.sup.17 is H;
- R.sup.7 is independently;
- H, C.sub.1-8 alkyl, phenyl, benzyl, phenethyl, phenoxy, benzyloxy,halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.5 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 R.sup.20, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OC(.dbd.O)R.sup.20, --C(.dbd.O)R.sup.20, --OC(--O)OR.sup.20, --OR.sup.20, --CH.sub.2 OR.sup.20, or C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.20 R.sup.21 ;
- R.sup.8 is independently;
- .dbd.O , F, Cl, Br, I, --CF.sub.3, --CN, --CO.sub.2 R.sup.20, --C(.dbd.O)NR.sup.20 R.sup.21, --CH.sub.2 OR.sup.20, --OC(.dbd.O)R.sup.20, --CH.sub.2 NR.sup.20 R.sup.21, or --NR.sup.20 R.sup.21 ;
- R.sup.13 is independently;
- phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.5 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 R.sup.20, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OC(.dbd.O)R.sup.20, --C(.dbd.O)R.sup.20, --C(.dbd.O)OR.sup.20, --OR.sup.20, --CH.sub.2 OR.sup.20, or C.sub.1 -C.sub.4 alkyl (substituted with --NR.sup.20 R.sup.21);
- R.sup.20 is independently;
- H, C.sub.1 -C.sub.7 alkyl, aryl, --(C.sub.1 -C.sub.6 alkyl)aryl, or C.sub.3 -C.sub.6 alkoxyalkyl;
- R.sup.21 is independently;
- H, C.sub.1 -C.sub.4 alkyl, or benzyl;
- R.sup.11 is H or C.sub.1 -C.sub.8 alkyl;
- R.sup.12 is H or C.sub.1 -C.sub.8 alkyl;
- R.sup.2 is H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C.sub.1 -C.sub.6 cycloalkylethyl, phenyl, phenylmethyl, CH.sub.2 OH, CH.sub.2 SH, CH.sub.2 OCH.sub.3, CH.sub.2 SCH.sub.3, CH.sub.2 CH.sub.2 SCH.sub.3, (CH.sub.2).sub.s NH.sub.2, (CH.sub.2).sub.s NHC(.dbd.NH)(NH.sub.2), or (CH.sub.2).sub.s NHR.sup.21, wherein s=3-5;
- R.sup.12 and R.sup.2 can be taken together to form --(CH.sub.2).sub.t --, wherein t=2-4, or --CH.sub.2 SC(CH.sub.3).sub.2 --;
- R.sup.3 is H or C.sub.1 -C.sub.8 alkyl;
- A is:
- --C.sub.1 -C.sub.7 alkyl--, ##STR61## and provided that w=0, --(CH.sub.2).sub.m O--(C.sub.1 -C.sub.4 alkyl)--, wherein m=1,2, or
- --(CH.sub.2).sub.m S--(C.sub.1 -C.sub.4 alkyl)--, wherein m=1,2,
- R.sup.3 and A may also be taken together to form ##STR62## wherein n=0-1 and w=0; R.sup.9 is H or C.sub.1 -C.sub.8 alkyl;
- R.sup.5 is H or C.sub.1 -C.sub.8 alkyl; and
- R.sup.25 is t-butyl or benzyl wherein the phenyl ring is substituted with 0-5 C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups, or 1-2 halogen atoms.
- 10. The compounds of claim 9 wherein:
- Y is H or tosyl;
- Z is H or benzyl;
- G is H or CBZ;
- R.sup.19 is: ##STR63## R.sup.15 and R.sup.18 are independently H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, phenyl-(C.sub.2 -C.sub.4)alkyl, or C.sub.1 -C.sub.4 alkoxy;
- R.sup.17 and R.sup.16 are independently H or C.sub.1 -C.sub.4 alkyl;
- R.sup.7 is H, C.sub.1 -C.sub.8 alkyl, phenyl, halogen, or C.sub.1 -C.sub.4 alkoxy;
- R.sup.11 is H or C.sub.1 -C.sub.3 alkyl;
- R.sup.12 is H or CH.sub.3 ;
- A is:
- --C.sub.1 -C.sub.7 alkyl--, ##STR64## wherein v is 0-3 and provided that w=0, R.sup.3 and A may be taken together to form ##STR65## 10 wherein n 0-1 and provided that w=0; R.sup.9 is H or C.sub.1 -C.sub.3 alkyl; and
- R.sup.5 is H or C.sub.1 -C.sub.3 alkyl.
- 11. The compounds of claim 10 wherein:
- R.sup.5, R.sup.9, R.sup.16, R.sup.17 and R.sup.18 are H;
- R.sup.11, R.sup.12, and R.sup.14 are H or CH.sub.3 ;
- R.sup.15 is H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, or phenyl-(C.sub.2 -C.sub.4)alkyl; and
- R.sup.3 is H or C.sub.1 -C.sub.3 alkyl.
- 12. The compounds of claim 11 wherein:
- w is 1;
- p is 0;
- R.sup.19 is ##STR66## R.sup.5, R.sup.9, R.sup.17, R.sup.15,R.sup.11, R.sup.12, R.sup.14 are H; R.sup.2 is C.sub.2 H.sub.5 ;
- R.sup.3 is CH.sub.3 ; and
- A is --(CH.sub.2).sub.3 --.
- 13. A process for the preparation of a compound of formula: ##STR67## comprising reacting a compound of Formula: ##STR68## with (a) trifluoracetic acid, (b) triflic acid and (c) anisole, wherein: w is 0 or 1;
- R.sup.1 is ##STR69## wherein p and p' are 0 or 1'
- R.sup.19 is a C.sub.6 -C.sub.14 saturated, partially saturated, or aromatic carbocyclic ring system or heterocyclic ring system composed of at least 1-3 heteroatoms selected from N, O, S; all these ring systems may be optionally substituted with 0-2 R.sup.7 ;
- R.sup.17 and R.sup.16 are independently:
- hydrogen;
- C.sub.1 -C.sub.4 alkyl, optionally substituted with halogen;
- C.sub.1 -C.sub.2 alkoxy; or
- benzyl;
- R.sup.15 and R.sup.18 are independently;
- hydrogen,
- C.sub.1-4 alkoxy
- C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.8,
- C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.8,
- C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.8,
- C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.8,
- C.sub.6 -C.sub.10 bicycloalkyl substituted with 0-2 R.sup.8,
- benzyl.
- aryl substituted with 0-2 R.sup.13, phenyl-C.sub.2-4 alkyl or
- a heterocylic ring system composed of 5-10 atoms including 1-3 nitrogen, oxygen, or sulfur heteroatoms, optionally substituted with 0-2 R.sup.13 ;
- R.sup.15 and R.sup.11 can alternatively join to form a 5-8 membered carbocyclic ring substituted with 0-2 R.sup.13, when R.sup.17 is H;
- R.sup.7 is independently:
- H, C.sub.1 -8 alkvl. phenyl, benzyl, phenethyl, phenoxy, benzyloxy,halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.5 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 R.sup.20, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OC(.dbd.O)R.sup.20, --C(.dbd.O)R.sup.20, --OC(--O)OR.sup.20, --OR.sup.20, --CH.sub.2 OR.sup.20, or C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.20 R.sup.21 ;
- R.sup.8 is independently:
- .dbd.O, F, Cl, Br, I, --CF.sub.3, --CN, --CO.sub.2 R.sup.20, --C(.dbd.O)NR.sup.20 R.sup.21, --CH.sub.2 OR.sup.20, --OC(.dbd.O)R.sup.20, --CH.sub.2 NR.sup.20 R.sup.21, or --NR.sup.20 R.sup.21 ;
- R.sup.13 is independently;
- phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.5 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 R.sup.20, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OC((.dbd.O)R.sup.20, --C(.dbd.O)R.sup.20, --OC(.dbd.O)OR.sup.20, --OR.sup.20, --CH.sub.2 OR.sup.20, or C.sub.1 -C.sub.4 alkyl (substituted with --NR.sup.20 R.sup.21);
- R.sup.20 is independently:
- H, C.sub.1 -C.sub.7 alkyl, aryl, --(C.sub.1 -C.sub.6 alkyl)aryl, or C.sub.3 -C.sub.6 alkoxyalkyl;
- R.sup.21 is independently:
- H, C.sub.1 -C.sub.4 alkyl, or benzyl;
- R.sup.11 is H or C.sub.1 -C.sub.8 alkyl;
- R.sup.12 is H or C.sub.1 -C.sub.8 alkyl;
- R.sup.2 is H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C.sub.1 -C.sub.6 cycloalkylethyl, phenyl, phenylmethyl, CH.sub.2 OH, CH.sub.2 SH, CH.sub.2 OCH.sub.3, CH.sub.2 SCH.sub.3, CH.sub.2 CH.sub.2 SCH.sub.3, CH.sub.s NH.sub.2, (CH.sub.2).sub.s NHC(.dbd.NH)(NH.sub.2), (CH.sub.2).sub.s NHR.sup.21, wherein s=3-5;
- R.sup.12 and R.sup.2 can be taken together to form --(CH.sub.2).sub.t --, wherein t=2-4, or --CH.sub.2 SC(CH.sub.3).sub.2 --;
- R.sup.3 is H or C.sub.1 -C.sub.8 alkyl;
- A is:
- -C.sub.1 -C.sub.7 alkyl-, ##STR70## and provided that w=0, --(CH.sub.2).sub.m --O--(C.sub.1-4 alkyl)--Nh--(C.sub.1-6 alkyl), wherein m=1.2
- --(CH.sub.2).sub.m O--(C.sub.1 -C.sub.4 alkyl)--, wherein m=1,2, or
- --(CH.sub.2).sub.m S--(C.sub.1 -C.sub.4 alkyl)--, wherein m=1,2,
- R.sup.3 and A may also be taken together to form ##STR71## wherein n=0-1 and provided that w=0; R.sup.9 is H or C.sub.1 -C.sub.8 alkyl;
- R.sup.5 is H or C.sub.1 -C.sub.8 alkyl; and
- R.sup.25 is t-butyl or benzyl wherein the phenyl ring is substituted with 0-5 C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups, or 1-2 halogen atoms.
- 14. The process of claim 13 wherein:
- R.sup.19 is: ##STR72## R.sup.15 and R.sup.18 are independently H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, phenyl-(C.sub.2 -C.sub.4)alkyl, or C.sub.1 -C.sub.4 alkoxy;
- R.sup.17 and R.sup.16 are independently H or C.sub.1 -C.sub.4 alkyl;
- R.sup.7 is H, C.sub.1 -C.sub.8 alkyl, phenyl, halogen, or C.sub.1 -C.sub.4 alkoxy;
- R.sup.11 is H or C.sub.1 -C.sub.3 alkyl;
- R.sup.12 is H or CH.sub.3 ;
- A is selected from the group:
- C.sub.1 -C.sub.7 alkyl, ##STR73## 10 and provided that w=0, or --(CH.sub.2).sub.m --O--(C.sub.1 -C.sub.4 alkyl)--NH--(C.sub.1 -C.sub.6 alkyl), wherein m=1-2,
- R.sup.3 and A may be taken together to form ##STR74## 10 wherein n=0-1 and provided that w=0; R.sup.9 is H or C.sub.1 -C.sub.3 alkyl; and
- R.sup.5 is H or C.sub.1 -C.sub.3 alkyl.
- 15. The process of claim 14 wherein:
- R.sup.5, R.sup.9, R.sup.16, R.sup.17 and R.sup.18 are H;
- R.sup.11, R.sup.12, and R.sup.14 are H or CH.sub.3 ;
- R.sup.15 is H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, or phenyl-(C.sub.2 -C.sub.4)alkyl; and
- R.sup.3 is H or C.sub.1 -C.sub.3 alkyl.
- 16. The process of claim 15 wherein:
- w is 1;
- p is 0;
- R.sup.19 is ##STR75## R.sup.5, R.sup.9, R.sup.17, R.sup.15,R.sup.11, R.sup.12, R.sup.14 are H;
- R.sup.2 is C.sub.2 H.sub.5 ;
- R.sup.3 is CH.sub.3 ; and
- A is --(CH.sub.2).sub.3 --.
- 17. The process of claims any of 13-16 wherein trifluoroacetic acid, triflic acid, and anisole are added sequentially.
- 18. The process of claims any of 13-16 wherein trifluoroacetic acid is ommitted.
- 19. The compounds of formula: ##STR76## wherein: w=0 or 1;
- Y is H or tosyl;
- Z is H or benzyl;
- G is H or CBZ; ##STR77## R.sup.1 is wherein
- p and p' are 0 or 1;
- R.sup.19 is a heterocyclic ring system composed of at least 1-3 heteroatoms selected from N, O, S; all these ring systems are substituted with 0-2 R.sup.7 ;
- R.sup.17 and R.sup.16 are independently:
- hydrogen;
- C.sub.1 -C.sub.4 alkyl, optionally substituted with halogen;
- C.sub.1 -C.sub.2 alkoxy; or
- benzyl;
- R.sup.15 and R.sup.18 are independently;
- hydrogen,
- C.sub.1-4 alkoxy
- C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.8,
- C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.8,
- C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.8,
- C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.8,
- C.sub.6 -C.sub.10 bicycloalkyl substituted with 0-2 R.sup.8,
- benzyl,
- aryl substituted with 0-2 R.sup.13,
- phenyl--C.sub.2-4 alkyl
- a heterocylic ring system composed of 5-10 atoms including 1-3 nitrogen, oxygen, or sulfur heteroatoms, optionally substituted with 0-2 R.sup.13 ;
- R.sup.15 and R.sup.17 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R.sup.13 ;
- R.sup.18 and R.sup.16 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R.sup.13 ;
- R.sup.15 and R.sup.11 can alternatively join to form a 5-8 membered carbocyclic ring substituted with 0-2 R.sup.13, when R.sup.17 is H;
- R.sup.7 is independently;
- H, C.sub.1-8 alkyl, phenyl, benzyl, phenethyl, phenoxy, benzyloxy,halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.5 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C7-C.sub.10 arylalkyl, C.sub.1 -C.sub.4 alkoxy, --CO.sub.2 R.sup.20, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OC (.dbd.O)R.sup.20, --C(.dbd.O)R.sup.20, --OC(--O)OR.sup.20, --OR.sup.20, --CH.sub.2 OR.sup.20, or C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.20 OR.sup.21 ;
- R.sup.8 is independently;
- .dbd.O, F, Cl, Br, I, --CF.sub.3, --CN, --CO.sub.2 R.sup.20, --C(.dbd.O)NR.sup.20 R.sup.21, --CH.sub.2 OR.sup.20, --OC(.dbd.O)R.sup.20, --CH.sub.2 NR.sup.20 R.sup.21, or --NR.sup.20 R.sup.21 ;
- R.sup.13 is independently;
- phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.5 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 R.sup.20, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --OC(.dbd.O)R.sup.20, --C(.dbd.O)R.sup.20, --OC(.dbd.O)OR.sup.20, --OR.sup.20, --CH.sub.2 OR.sup.20, or C.sub.1 -C.sub.4 alkyl (substituted with --NR.sup.20 R.sup.21);
- R.sup.20 is independently;
- H, C.sub.1 -C.sub.7 alkyl, aryl, --(C.sub.1 -C.sub.6 alkyl)aryl, or C.sub.3 -C.sub.6 alkoxyalkyl;
- R.sup.21 is independently;
- H, C.sub.1 -C.sub.4 alkyl, or benzyl;
- R.sup.11 is H or C.sub.1 -C.sub.8 alkyl;
- R.sup.12 is H or C.sub.1 -C.sub.8 alkyl;
- R.sup.2 is H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C.sub.1 -C.sub.6 cycloalkylethyl, phenyl, phenylmethyl, CH.sub.2 OH, CH.sub.2 SH, CH.sub.2 OCH.sub.3, CH.sub.2 SCH.sub.3, CH.sub.2 CH.sub.2 SCH.sub.3, or (CH.sub.2)sNH2, (CH.sub.2).sub.s NHC(.dbd.NH)(NH2), (CH.sub.2).sub.s NHR.sup.21, wherein s=3-5;
- R.sup.12 and R.sup.2 can be taken together to form --(CH.sub.2).sub.t --, wherein t=2-4, or --CH.sub.2 SC(CH.sub.3).sub.2 --;
- R.sup.3 is H or C.sub.1 -C.sub.8 alkyl;
- A is selected from the group:
- -C.sub.1 -C.sub.7 alkyl-, ##STR78## and provided that w=0, --(CH.sub.2).sub.m O--(C.sub.1 -C.sub.4 alkyl)--, wherein m=1,2, or
- --(CH.sub.2).sub.m S--(C.sub.1 -C.sub.4 alkyl)--, wherein m=1,2,
- R.sup.3 and A may also be taken together to form ##STR79## wherein n=0-1 and w=0; R.sup.9 is H, C.sub.1 -C.sub.8 alkyl;
- R.sup.5 is H, C.sub.1 -C.sub.8 alkyl; and
- R.sup.25 is t-butyl or benzyl wherein the phenyl ring is substituted with 0-5 C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups, or 1-2 halogen atoms.
Parent Case Info
This is a continuation of application Ser. No. 08/038,434, filed Mar. 29, 1993 now abandoned.
US Referenced Citations (3)
Number |
Name |
Date |
Kind |
5192746 |
Lobl et al. |
Mar 1993 |
|
5322931 |
Hubbs et al. |
Jun 1994 |
|
5384309 |
Barker et al. |
Jan 1995 |
|
Foreign Referenced Citations (10)
Number |
Date |
Country |
0192135 |
Aug 1986 |
EPX |
0422937 |
Apr 1991 |
EPX |
0425212 |
May 1991 |
EPX |
0444898 |
Sep 1991 |
EPX |
0406428 |
Jan 1992 |
EPX |
289543 |
May 1991 |
DDX |
103252 |
Feb 1993 |
ILX |
WO9207870 |
May 1992 |
WOX |
WO 9307170 |
Apr 1993 |
WOX |
WO9415958 |
Jul 1994 |
WOX |
Non-Patent Literature Citations (2)
Entry |
Miller, A.E. and Bischoff, J.J., "Facile Conversion of Amino Acids to Guanidino Acids", Journal of Synthetic Organic Chemistry, 1986 No. 9, 777-779. |
Eberhard Schroder and Klaus Lubke, "The Synthesis of Cyclis peptides", The Peptides, 1965, vol. I, 271-272. |
Continuations (1)
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Number |
Date |
Country |
Parent |
38434 |
Mar 1993 |
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