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US 5,849,866 AGranted
Peptidase inhibitors
AssigneeMerrell Pharmaceuticals Inc.
InventorsH. Michael Kolb, Joseph P. Burkhart, Michel J. Jung, Fritz E. Gerhart, deceased, Eugene L. Giroux, Bernhard Neises, Daniel G. Schirlin
Life of this patent
Estimating the term…
Abstract
This invention relates to analogs of peptidase substrates in which the amide group containing the scissile amide bond of the substrate peptide has been replaced by an activated electrophilic ketone moiety. These analogs of the peptidase substrates provide specific enzyme inhibitors for a variety of proteases, the inhibition of which will have useful physiological consequences in a variety of disease states.
Claims27
A compound useful for inhibiting plasmin of the formula ##STR64## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X is X.sub.1 or X.sub.2,
- wherein
- X.sub.1 is --CF.sub.3, --CF.sub.2 H, --CO.sub.2 R.sub.3 or --CONHR.sub.3,
- X.sub.2 is ##STR65## R.sub.1 is -P.sub.2 -P.sub.3 -P.sub.g with P.sub.2 being selected from Group F, P.sub.3 is selected from Groups B or F, and P.sub.g is an optional Group K amino protecting group,
- R.sub.2 is a side chain of an amino acid selected from Groups A and J
- R.sub.3 is hydrogen, C.sub.1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl,
- R.sub.4 is the side chain of an .alpha.-amino acid,
- R.sub.5 is an .alpha.-amino acid or a peptide having up to 3 .alpha.-amino acids sequenced in their P.sub.2 ' to P.sub.4 ' positions, or is deleted,
- Y is --NHR.sub.3 or OR.sub.3
- wherein the said .alpha.-amino acid and peptide moieties are selected from Groups A, B, C, D, E, F, G and J, and K is a terminal amino protecting group, members of these groups being
- Group
- A:
- Lys and Arg
- B:
- Glu, Asp
- C:
- Ser, Thr, Gln, Asn, Cys, His
- D:
- Pro, Ind
- E:
- Ala, Leu, Ile, Val, n-Val, Met, n-Leu and N-methyl derivatives
- F:
- Phe, Tyr, Trp, Nal (1), and N-methyl derivatives
- G:
- Gly, Sar
- J:
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)NHC(.dbd.NH)--NH.sub.2 (J-1),
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)C(.dbd.NH)--NH.sub.2 (J-2),
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 NHC(.dbd.NH)--NH.sub.2 (J-3), and
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 C(.dbd.NH)--NH.sub.2 (J-4) with .PHI. representing phenyl,
- K:
- Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoxy (CBZ), Tosyl(Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesulphonyl (AdSO.sub.2), 1-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CBZ) and such other terminal amino protecting groups which are functionally equivalent thereto.
29 more elements
A compound useful for inhibiting C.sub.1 -esterase of the formula ##STR66## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X generically is X.sub.1 or X.sub.2
- wherein
- X.sub.1 is --CF.sub.3, --CF.sub.2 H, --CO.sub.2 R.sub.3 or --CONHR.sub.3,
- X.sub.2 is ##STR67## R.sub.2 is a side chain of an amino acid selected from Groups A and J, R.sub.1 generically is -P.sub.2 -P.sub.g with P.sub.2 being selected from Groups E, G, D, C, F, A and B, and P.sub.g is selected from Group K,
- R.sub.4 is a side chain of an amino acid selected from Group E,
- R.sub.5 is selected from Group E and Y is NH.sub.2,
- R.sub.3 is hydrogen, C.sub.1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl,
- Y is --NHR.sub.3 or OR.sub.3,
- wherein Groups A, B, C, D, E, F, G, J and K are as follows:
- Group
- A:
- Lys and Arg
- B:
- Glu, Asp
- C:
- Ser, Thr, Gln, Asn, Cys, His
- D:
- Pro, Ind
- E:
- Ala, Leu, Ile, Val, n-Val, Met, n-Leu and N-methyl derivatives
- F:
- Phe, Tyr, Trp, Nal (1), and N-methyl derivatives
- G:
- Gly, Sar
- J:
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)NHC(.dbd.NH)--NH.sub.2 (J-1),
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)C(.dbd.NH)--NH.sub.2 (J-2),
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 NHC(.dbd.NH)--NH.sub.2 (J-3), and
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 C(.dbd.NH)--NH.sub.2 (J-4) with .PHI. representing phenyl,
- K:
- Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoxy (CBZ), Tosyl(Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesulphonyl (AdSO.sub.2), 1-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CBZ) and such other terminal amino protecting groups which are functionally equivalent thereto.
28 more elements
A compound useful for inhibiting C.sub.3 -convertase of the formula ##STR68## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X is X.sub.1 or X.sub.2,
- wherein
- X.sub.1 is --CF.sub.3, --CF.sub.2 H, --CO.sub.2 R.sub.3 or --CONHR.sub.3,
- X.sub.2 is ##STR69## R.sub.4 is a side chain of an amino acid selected from Group E, R.sub.5 Y is OR.sub.3,
- R.sub.2 is a side chain of an amino acid selected from Groups A or J,
- R.sub.1 is -P.sub.2 -P.sub.3 -P.sub.g with P.sub.2 being selected from Groups E or F, P.sub.3 is selected from Groups E or F, and P.sub.4 is selected from Group K
- R.sub.3 is hydrogen, C.sub.1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl,
- wherein Groups A, E, F, J and K are as follows:
- Group
- A:
- Lys and Arg
- E:
- Ala, Leu, Ile, Val, n-Val, Met, n-Leu and N-methyl derivatives
- F:
- Phe, Tyr, Trp, Nal (1), and N-methyl derivatives
- J:
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)NHC(.dbd.NH)--NH.sub.2 (J-1),
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)C(.dbd.NH)--NH.sub.2 (J-2),
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 NHC(.dbd.NH)--NH.sub.2 (J-3), and
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 C(.dbd.NH)--NH.sub.2 (J-4) with .PHI. representing phenyl,
- K:
- Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoxy (CBZ), Tosyl(Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesulphonyl (AdSO.sub.2), 1-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CBZ) and such other terminal amino protecting groups which are functionally equivalent thereto.
19 more elements
A compound useful for inhibiting Urokinase of the formula ##STR70## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X is X.sub.1 or X.sub.2,
- wherein
- X is --CF.sub.3, --CF.sub.2 H, --CO.sub.2 R.sub.3 or --CONHR.sub.3,
- X.sub.2 is ##STR71## R.sub.4 is a side chain of an amino acid of Group E, R.sub.5 is Group E, and
- Y is NH.sub.2,
- R.sub.1 is -P.sub.2 -P.sub.3 with P.sub.2 being selected from Groups E and G, and P.sub.3 is selected from Group B,
- R.sub.2 is a side chain of an amino acid selected from Groups A and J,
- R.sub.3 is hydrogen, C.sub.1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl,
- wherein Groups A, B, E, G and J are as follows:
- Group
- A:
- Lys and Arg
- B:
- Glu, Asp
- E:
- Ala, Leu, Ile, Val, n-Val, Met, n-Leu and N-methyl derivatives
- G:
- Gly, Sar
- J:
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)NHC(.dbd.NH)--NH.sub.2 (J-1),
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)C(.dbd.NH)--NH.sub.2 (J-2),
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 NHC(.dbd.NH)--NH.sub.2 (J-3), and
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 C(.dbd.NH)--NH.sub.2 (J-4) with .PHI. representing phenyl.
20 more elements
A compound useful for inhibiting a plasminogen activator of the formula ##STR72## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X is X.sub.1 or X.sub.2,
- wherein
- X.sub.1 is --CF.sub.3, --CF.sub.2 H, --CO.sub.2 R.sub.3 or --CONHR.sub.3,
- X.sub.2 is ##STR73## R.sub.4 is a side chain of an amino acid of Group E, R.sub.5 is Group E,
- Y is NH.sub.2
- R.sub.1 generically is -P.sub.2 -P.sub.3 -P.sub.g wherein P.sub.2 is Gly, P.sub.3 is selected from Group B, and P.sub.g is an optional Group K protecting group, and
- R.sub.2 is a side chain of an amino acid selected from Groups A and J,
- R.sub.3 is hydrogen, C.sub.1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl,
- wherein Groups A, B, E, J and K are as follows:
- Group
- A:
- Lys and Arg
- B:
- Glu, Asp
- E:
- Ala, Leu, Ile, Val, n-Val, Met, n-Leu and N-methyl derivatives
- J:
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)NHC(.dbd.NH)--NH.sub.2 (J-1),
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)C(.dbd.NH)--NH (J-2),
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 NHC(.dbd.NH)--NH.sub.2 (J-3), and
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 C(.dbd.NH)--NH.sub.2 (J-4) with .PHI. representing phenyl,
- K:
- Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoxy (CBZ), Tosyl (Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesulphonyl (AdSO.sub.2), 1-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CBZ) and such other terminal amino protecting groups which are functionally equivalent thereto.
20 more elements
A compound useful for inhibiting acrosin of the formula ##STR74## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X is X.sub.1 or X.sub.2,
- wherein
- X.sub.1 is --CF.sub.3, --CF.sub.2 H, --CO.sub.2 R.sub.3 or --CONHR.sub.3,
- X.sub.2 is ##STR75## R.sub.4 is a side chain of an amino acid of Group E, R.sub.5 is Group E, or is deleted and Y is NH.sub.2,
- R.sub.1 is -P.sub.2 -P.sub.3 -P.sub.g with P.sub.2 being selected from Group E, P.sub.3 is selected from Group E, P.sub.g is an optional Group K protecting group,
- R.sub.2 is a side chain of an amino acid selected from Groups A and J,
- R.sub.3 is hydrogen, C.sub.1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl,
- wherein Groups A, E, J and K are as follows:
- Group
- A:
- Lys and Arg
- E:
- Ala, Leu, Ile, Val, n-Val, Met, n-Leu and N-methyl derivatives
- J:
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)NHC(.dbd.NH)--NH.sub.2 (J-1),
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)C(.dbd.NH)--NH.sub.2 (J-2),
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 NHC(.dbd.NH)--NH.sub.2 (J-3), and
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 C(.dbd.NH)--NH.sub.2 (J-4) with .PHI. representing phenyl,
- K:
- Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoxy (CBZ), Tosyl(Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesulphonyl (AdSO.sub.2), 1-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CBZ) and such other terminal amino protecting groups which are functionally equivalent thereto.
17 more elements
A compound useful for inhibiting cathepsin B of the formula ##STR76## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X is X.sub.1 or X.sub.2
- wherein
- X.sub.1 is --CF.sub.3, --CF.sub.2 H, --CO.sub.2 R.sub.3 or --CONHR.sub.3,
- X.sub.2 is ##STR77## R.sub.4 is a side chain of an amino acid selected from Group E, R.sub.5 is selected from Groups G, E or F and Y is OH,
- R.sub.1 is (a)-P.sub.2 -P.sub.g or (b)-P.sub.2 -P.sub.3 -P.sub.g wherein for
- (a) P.sub.2 is selected from Groups E and F and P.sub.g is selected from Group K, and
- (b) P.sub.2 is selected from Groups E and F, -P.sub.3 being selected from Groups E and F, and P.sub.g is selected from Group K,
- R.sub.2 is a side chain of an amino acid selected from Group A, J or ThrCOCH.sub.2 .PHI.,
- R.sub.3 is hydrogen, C.sub.1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl,
- wherein Groups A, E, F, G, J and K are as follows:
- Group
- A:
- Lys and Arg
- E:
- Ala, Leu, Ile, Val, n-Val, Met, n-Leu and N-methyl derivatives
- F:
- Phe, Tyr, Trp, Nal (1), and N-methyl derivatives
- G:
- Gly, Sar
- J:
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)NHC(.dbd.NH)--NH.sub.2 (J-1),
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)C(.dbd.NH)--NH.sub.2 (J-2),
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 NHC(.dbd.NH)--NH.sub.2 (J-3), and
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 C(.dbd.NH)--NH.sub.2 (J-4) with .PHI. representing phenyl,
- K:
- Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoxy (CBZ), Tosyl(Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesulphonyl (AdSO.sub.2), 1-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CBZ) and such other terminal amino protecting groups which are functionally equivalent thereto.
23 more elements
A compound useful as inhibitors of renin of the formula ##STR78## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X is X.sub.1 or X.sub.2
- wherein
- X.sub.1 is --CF.sub.3, --CF.sub.2 H, --CO.sub.2 R.sub.3 or --CONHR.sub.3,
- X.sub.2 is ##STR79## R.sub.4 is a side chain of an amino acid selected from Groups E, F or G, R.sub.5 is -P.sub.2 '-P.sub.3 '-P.sub.4 ', P.sub.2 ' being from Groups E, F or is deleted, with P.sub.3 ' being selected from Groups E or F or is deleted with P.sub.4 ' being selected from Groups E, C or F or is deleted and Y is OH or NH.sub.2,
- R.sub.2 is a side chain of an amino acid selected from Groups E or F or is cyclohexylmethylene,
- R.sub.1 generically is -P.sub.2 -P.sub.3 -P.sub.4 -P.sub.5 -P.sub.g wherein P.sub.2 is selected from Groups E, C or F, P.sub.3 is selected from Groups E or F, P.sub.4 is selected from Groups E, D, F or is deleted, P.sub.5 is selected from Groups E, C, F or is deleted, and P.sub.g is selected from Group K
- R.sub.3 is hydrogen, C.sub.1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl,
- wherein Groups C, D, E, F, G and K are as follows:
- Group
- C:
- Ser, Thr, Gln, Asn, Cys, His
- D:
- Pro, Ind
- E:
- Ala, Leu, Ile, Val, n-Val, Met, n-Leu and N-methyl derivatives
- F:
- Phe, Tyr, Trp, Nal (1), and N-methyl derivatives
- G:
- Gly, Sar
- K:
- Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoxy (CBZ), Tosyl(Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesulphonyl (AdSO.sub.2), 1-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CBZ) and such other terminal amino protecting groups which are functionally equivalent thereto.
18 more elements
A compound useful for inhibiting pepsin of the formula ##STR80## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X is X.sub.1 or X.sub.2
- wherein
- X.sub.1 is --CF.sub.3, --CF.sub.2 H, --CO.sub.2 R.sub.3 or --CONHR.sub.3,
- X.sub.2 is ##STR81## R.sub.4 is a side chain of an amino acid selected from the Groups E, G and F,
- R.sub.5 is selected from Groups E and F and Y is --NHCH.sub.2 CH(CH.sub.3).sub.2 or --NHCH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2,
- R.sub.1 is -P.sub.2 -P.sub.3 -P.sub.g with P.sub.2 being selected from Groups E or F, P.sub.3 is selected from Groups E or F or is deleted and P.sub.g is selected from Group K, and
- R.sub.2 is a side chain of an amino acid selected from Groups E and F
- R.sub.3 is hydrogen, C.sub.1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl,
- wherein Groups E, F, G and K are as follows:
- Group
- E:
- Ala, Leu, Ile, Val, n-Val, Met, n-Leu and N-methyl derivatives
- F:
- Phe, Tyr, Trp, Nal (1), and N-methyl derivatives
- G:
- Gly, Sar
- K:
- Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoxy (CBZ), Tosyl(Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesulphonyl (AdSO.sub.2), 1-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CBZ) and such other terminal amino protecting groups which are functionally equivalent thereto.
15 more elements
A compound useful for inhibiting cathepsin D of the formula ##STR82## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X is X.sub.1 or X.sub.2
- wherein
- X.sub.1 is --CF.sub.3, --CF.sub.2 H, --CO.sub.2 R.sub.3 or --CONHR.sub.3,
- X.sub.2 is ##STR83## R.sub.4 is a side chain of an amino acid selected from Groups E and F, R.sub.5 is selected from Groups E and F,
- Y is --NH(CH.sub.2).sub.2 CH(CH.sub.3).sub.2 or --NHCH.sub.2 CH(CH.sub.3).sub.2,
- R.sub.1 generically is -P.sub.2 -P.sub.3 -P.sub.g with P.sub.2 being selected from Groups E and F, P.sub.3 is selected from Groups E and F, and P.sub.g is selected from Group K, and
- R.sub.2 is a side chain of an amino acid selected from Groups E and F
- R.sub.3 is hydrogen, C.sub.1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl,
- wherein Groups E, F, and K are as follows:
- Group
- E:
- Ala, Leu, Ile, Val, n-Val, Met, n-Leu and N-methyl derivatives
- F:
- Phe, Tyr, Trp, Nal (1), and N-methyl derivatives
- K:
- Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoxy (CBZ), Tosyl(Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesulphonyl (AdSO.sub.2), 1-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CBZ) and such other terminal amino protecting groups which are functionally equivalent thereto.
13 more elements
A compound useful as an ACE inhibitor of the formula ##STR84## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X is X.sub.2
- wherein
- X.sub.2 is ##STR85## R.sub.4 is a side chain of an amino acid selected from Groups E or G, R.sub.5 is selected from Groups A, B, C, D, E, F and G,
- R.sub.1 is selected from Group K, and
- R.sub.2 is a side chain of an amino acid selected from Group E, F and G,
- Y is --NHR.sub.3 or OR.sub.3,
- R.sub.3 is hydrogen, C.sub.1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl,
- wherein Groups A, B, C, D, E, F, G and K are as follows:
- Group
- A:
- Lys and Arg
- B:
- Glu, Asp
- C:
- Ser, Thr, Gln, Asn, Cys, His
- D:
- Pro, Ind
- E:
- Ala, Leu, Ile, Val, n-Val Met, n-Leu and N-methyl derivatives
- F:
- Phe, Tyr, Trp, Nal (1), and N-methyl derivatives
- G:
- Gly, Sar
- K:
- Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoxy (CBZ), Tosyl(Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesuiphonyl (AdSO.sub.2), 1-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CBZ) and such other terminal amino protecting groups which are functionally equivalent thereto.
22 more elements
A compound useful for inhibiting enkephalinase of the formula ##STR86## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X is X.sub.2
- wherein
- X.sub.2 is ##STR87## R.sub.4 is a side chain from an amino acid selected from Group E or F, R.sub.5 is selected from Groups E or F or zero with the proviso that when R.sub.5 zero, Y is NH.sub.2, and
- Y is NH.sub.2 or OH,
- R.sub.1 is -P.sub.2 -P.sub.3, with P.sub.2 being Gly and P.sub.3 being selected from Group F or is deleted, and
- R.sub.2 is the side chain of Gly
- wherein Groups E and F are as follows:
- Group
- E:
- Ala, Leu, Ile, Val, n-Val, Met, n-Leu and N-methyl derivatives
- F:
- Phe, Tyr, Trp, Nal (1), and N-methyl derivatives.
9 more elements
A compound useful as an inhibitors of pseudomonas elastase of the formula ##STR88## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X is X.sub.2
- wherein
- X.sub.2 is ##STR89## R.sub.4 is a side chain of an amino acid selected from Groups E and F, R.sub.5 is selected from Groups E and G, and
- Y is NH.sub.2,
- R.sub.1 is -P.sub.2 -P.sub.g with P.sub.2 being selected from Group E, P.sub.g is selected from Group K,
- R.sub.2 is a side chain of an amino acid selected from Groups E and G
- wherein Groups E, F, G and K are as follows:
- Group
- E:
- Ala, Leu, Ile, Val, n-Val, Met, n-Leu and N-methyl derivatives
- F:
- Phe, Tyr, Trp, Nal (1), and N-methyl derivatives
- G:
- Gly, Sar
- K:
- Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoxy (CBZ), Tosyl(Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesulphonyl (AdSO.sub.2), 1-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CBZ) and such other terminal amino protecting groups which are functionally equivalent thereto.
13 more elements
A compound useful for inhibiting leucine aminopeptidase of the formula ##STR90## the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein
- X is X.sub.1 or X.sub.2
- wherein
- X.sub.1 is --CF.sub.3, --CF.sub.2 H, --CO.sub.2 R.sub.3 or --CONHR.sub.3,
- X.sub.2 is ##STR91## R.sub.4 is a side chain of an amino acid selected from any Group except K, R.sub.5 is any group except K, and
- Y is NH.sub.2,
- R.sub.1 is hydrogen or K,
- R.sub.2 is a side chain of an amino acid selected from Groups A, B, E, F and J
- R.sub.3 is hydrogen, C.sub.1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl,
- wherein Groups A, B, C, D, E, F, G, J and K are as follows:
- Group
- A:
- Lys and Arg
- B:
- Glu, Asp
- C:
- Ser, Thr, Gln, Asn, Cys, His
- D:
- Pro, Ind
- E:
- Ala, Leu, Ile, Val, n-Val, Met, n-Leu and N-methyl derivatives
- F:
- Phe, Tyr, Trp, Nal (1), and N-methyl derivatives
- G:
- Gly, Sar
- J:
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)NHC(.dbd.NH)--NH.sub.2 (J-1),
- --NHCH(--C.dbd.O)--CH.sub.2 .PHI.(.rho.-)C(.dbd.NH)--NH.sub.2 (J-2),
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 NHC(.dbd.NH)--NH.sub.2 (J-3), and
- --NHCH(--C.dbd.O)--.PHI.CH.sub.2 C(.dbd.NH)--NH.sub.2 (J-4) with .PHI. representing phenyl,
- K:
- Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoxy (CBZ), Tosyl(Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesulphonyl (AdSO.sub.2), 1-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CBZ) and such other terminal amino protecting groups which are functionally equivalent thereto.
28 more elements
Dependencies are inferred from the claim text.