Patent EP0195212A2 successfully refreshed from Google Patents.
EP0195212A2
Expired / Lapsed
EP
⏱️ 0.0 years remaining
Novel peptidase inhibitors
Assignee: Aventis Pharmaceuticals Inc
•
Filing: 1986-02-04
•
Granted: —
•
Expires: 2006-02-04
Abstract
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of peptidase substrates in which the amide group containing the scissile amide bond of the substrate peptide has been replaced by an activated electrophilic ketone moiety.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.
Inventors
- 👤 Michael Kolb
- 👤 Joseph P. Burkhart
- 👤 Michel J. Jung
- 👤 Fritz E. Gerhart
- 👤 Eugene L. Giroux
- 👤 Daniel G. Schirlin
- 👤 Bernhard Neises
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-09 00:41
CPC Classifications
C; C07; C07K; C07K5/00; C07K5/02; C07K5/0227; A; A61; A61P; A61P13/00; A61P13/02; A61P15/00; A61P17/00; A61P29/00; A61P31/00; A61P31/04; A61P35/00; A61P43/00; A61P7/00; A61P7/02; A61P7/06; A61P9/00; A61P9/12; C07C; C07C271/00; C07C271/06; C07C271/08; C07C271/10; C07C271/22; C07C279/00; C07C279/18; C07D; C07D207/00; C07D207/02; C07D207/04; C07D207/10; C07D207/16; C07D209/00; C07D209/02; C07D209/04; C07D209/30; C07D209/42; C07K5/0202; C07K5/0205; C07K5/0207; C07K5/04; C07K5/06; C07K5/06008; C07K5/06017; C07K5/06026; C07K5/06191; C07K5/08; C07K5/0802; C07K5/0804; C07K5/0806; C07K5/0821; C07K5/0823; C07K5/0827; A61K; A61K38/00; Y; Y02; Y02A; Y02A50/00; Y02A50/30; Y02P; Y02P20/00; Y02P20/50; Y02P20/55
Claims Analysis
Total Claims: 57
Claim 1
Independent Claim
265 words
An activated electrophilic ketone-bearing peptidase inhibitor of the formula the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein R l may be hydrogen, an amino protecting group selected from Group K, an α-amino acid or a peptide comprised of a number of a-amino acid building blocks, each of said α-amino acid or peptide optionally bearing an amino protecting group selected from Group K, R 2 is the R group side chain of an a-amino acid building block, X is X 1 or X 2 wherein X 1 is -CF 3 , -CF 2 H, C0 2 R 3 or -CONHR 3 , X 2 is R 3 is hydrogen, C 1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl, R 4 is the R group side chain of an a-amino acid building block, R 5 is and-amino acid or peptide building block, or deleted Y is -NHR 3 or -OR 3 , said a-amino building blocks being selected from Groups A, B, C, D, E, F, G, K and J, members of these Groups being Group A; Lys and Arg, B: Glu and A sp, C: Ser, Thr, Gln, Asn, Cys and His, D: Pro, Ind E: Ala, Leu, Ile, Val, n-Val, Met and n-Leu, and their N-methyl derivatives, F: Phe, Tyr and Trp, Nal(l) and their N-methyl derivatives, G: Gly, Sar with Ø representing phenyl K: Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoyl (CBz), Tosyl (Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesulphonyl (AdS0 2 ), l-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CB)and.such other terminal amino protecting groups which are functionally equivalent thereto.
Claim 2
Dependent Claim
265 words
An activated electrophilic ketone-bearing peptidase inhibitor of the formula the hydrates thereof, and the pharmaceutically acceptable salts thereof wherein R l may be hydrogen, an amino protecting group selected from Group K, an α-amino acid or a peptide comprised of a number of a-amino acid building blocks, each of said α-amino acid or peptide optionally bearing an amino protecting group selected from Group K, R 2 is the R group side chain of an a-amino acid building block, X is X 1 or X 2 wherein X 1 is -CF 3 , -CF 2 H, C0 2 R 3 or -CONHR 3 , X 2 is R 3 is hydrogen, C 1-4 straight or branched alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl, R 4 is the R group side chain of an a-amino acid building block, R 5 is and-amino acid or peptide building block, or deleted Y is -NHR 3 or -OR 3 , said a-amino building blocks being selected from Groups A, B, C, D, E, F, G, K and J, members of these Groups being Group A; Lys and Arg, B: Glu and A sp, C: Ser, Thr, Gln, Asn, Cys and His, D: Pro, Ind E: Ala, Leu, Ile, Val, n-Val, Met and n-Leu, and their N-methyl derivatives, F: Phe, Tyr and Trp, Nal(l) and their N-methyl derivatives, G: Gly, Sar with Ø representing phenyl K: Acetyl (Ac), Succinyl (Suc), Benzoyl (Bz), t-Butyloxycarbonyl (Boc), Carbobenzoyl (CBz), Tosyl (Ts), Dansyl (DNS), Isovaleryl (Iva), Methoxysuccinyl (MeOSuc), 1-Adamantanesulphonyl (AdS0 2 ), l-Adamantaneacetyl (AcAc), 2-Carboxybenzoyl (2-CB)and.such other terminal amino protecting groups which are functionally equivalent thereto.
Claim 3
Dependent Claim
121 words
A compound of claim 1 useful for inhibiting human leukocyte elastase wherein R 1 is - P2P3 P 4 P 5 wherein P 2 is selected from Groups D, E or F, P 3 is selected from Groups D or E, P 4 is selected from Group E or is zero, R 5 is selected from Group K, R 2 is the R group side chain of an α-amino acid of Groups E and G, X is either X 1 or X2 wherein R 4 is the R group side chain of an a-amino acid of Groups E and G, R 5 is a building block having its a-amino acids selected from Groups E and G, and - Y is NH2.
Claim 4
Dependent Claim
13 words
A compound of claim 2 having the formula MeOSuc-Ala-Ile-Pro-Val[CF 2 -AlalAlaNH 2 .
Claim 5
Dependent Claim
100 words
A compound of claim 1 useful for inhibiting Cathepsin G wherein X 1 , X 2 , R 3 , R 4 , R 5 and Y are as defined in claim 2, R 1 is P 2 P 3 P 4 P 5 wherein P 2 is selected from Groups D, E, G or K, P 3 is selected from Groups E or G or is deleted, P 4 is selected from Groups E or G or is deleted, P 5 is selected from Group K, R 2 is the R group side chain of Groups E and F.
Claim 6
Dependent Claim
11 words
A compound of claim 4 having the formula Suc-Ala-Ala-Pro-Phe-CF 3 .
Claim 7
Dependent Claim
147 words
A compound of claim 1 useful for inhibiting thrombin with X 1 , X 2 , R 3 being as defined in claim 1, R 2 is an R group side chain of Groups A and J, R 4 is an R group side chain of Group C or G, R 5 has its a-amino acids selected from Groups E, D or is zero, R 1 is (a) -P 2 P 3 , (b) -P 2 or (c) -P 2 P 3 P 4 wherein (a) P 2 is selected from Groups E and F, P 3 is selected from Group F, each P 3 in its D configuration, (b) P 2 is selected from Group K, (c) P 2 is selected from Group E, P 3 is selected from Groups G or E, and P 4 is selected from Groups G or E or is zero.
Claim 8
Dependent Claim
11 words
A compound of claim 6 having the formula D-Phe-Pro-Arg-CF 3 .
Claim 9
Dependent Claim
107 words
A compound of claim 1 useful for inhibiting chymotrypsin wherein X 1 , X 2 , R 3 , R 4 , R 5 and Y are as defined in claim 2, R 1 is -P 2 P 3 P 4 P 5 , P 2 is selected from Groups D, E, G or H, P 3 is selected from Groups E or G or is zero, P 4 is selected from Groups E or G or is zero, P 5 is selected from Group K or is zero when P 2 is H. R 2 is an R group side chain of Groups E or F.
Claim 10
Dependent Claim
18 words
A compound of claim 8 selected from the group Bz-Phe-CF 3 , BzPhe-COOH, BzPheCOOMe, BzTyrCF 3 , Bz-Tyr-COOMe.
Claim 11
Dependent Claim
37 words
A compound of claim 1 useful for inhibiting trypsin wherein X 1 , X 2 , R 3 , Y, R 2 , R 4 , R 5 and R l are as defined in claim 1.
Claim 12
Dependent Claim
17 words
A compound of claim 10 having the formula Bz-Arg-COOH, Bz-Arg-C0 2 CH 3 , Bz-Arg-CF 3 .
Claim 13
Dependent Claim
61 words
A compound of claim 1 useful for inhibiting plasmin wherein X is X 1 , Rl is -P 2 P 3 P 4 wherein P 2 is selected from Group F, P 3 is selected from Groups B or F, and P 4 is selected from Group K. R 2 is the R group side chain of Groups A or J.
Claim 14
Dependent Claim
15 words
A compound of claim 12 selected from the group DNS-Glu-Phe-Lys-COOH, DNS-Glu-Phe-Lys-CF 3 , or DNS-Glu-Phe-Lys-COOMe.
Claim 15
Dependent Claim
88 words
A compound of claim 1 useful for inhibiting C l - esterase with X 1 , X 2 , R 5 and R 3 as defined in claim 1, Y is NH 2 , R l is -P 2 P 3 wherein P 2 is selected from Groups E, G, D, C, F, A or B, and P 3 is selected from Group K, R 2 is the R group side chain of Groups A and J, R 4 is the R group side chain of Group E.
Claim 16
Dependent Claim
19 words
A compound of claim 14 selected from the group consisting of CBZ-Ala-Arg-CF 3 , C BZ -Ala-Arg-COOH and CBZ-Ala-Arg-COOMe.
Claim 17
Dependent Claim
91 words
A compound of claim 1 useful for inhibiting C 3 - convertase with X 1 , X 2 and R 3 being as defined in claim 1, Y is OR3, R l is -P 2 P 3 P 4 with P 2 being selected from Groups E or F, P 3 is selected from Groups E or F, P 4 is selected from Group K, R 2 is the R group side chain selected from Groups A or J, R 4 is selected from Group E, and R 5 is zero.
Claim 18
Dependent Claim
24 words
A compound of claim 16 selected from the group consisting of Bz-Leu-Ala-Arg-CF 2 COOCH 2 0, Bz-Leu-Ala-Arg⁅CF 2 -Ala⁆OCH 2 Ø, Bz-Leu-Ala-Arg-COOCH 2 0.
Claim 19
Dependent Claim
76 words
A compound of claim 1 useful for inhibiting Urokinase wherein X l and X 2 are as defined in claim 1, Y is NH 2 , R l is -P 2 P 3 wherein P 2 is selected for Groups E and G, P 3 is selected from Group B, R 2 is the R group side chain selected from Groups A and J, and each of R 4 and R5 is selected from Group E.
Claim 20
Dependent Claim
22 words
A compound of claim 18 selected from the group consisting of Glu-Gly-Arg-CF 2 H, Glu-Gly-Arg-CF 3 , Glu-Gly-Arg-COOH and Glu-Gly-Arg-CONH 2 .
Claim 21
Dependent Claim
89 words
A compound of claim 1 useful for inhibiting plasminogen activator with X 1 and X 2 being as defined in claim 1, Y is NH 2 , R 1 is -P 2 P 3 P 4 wherein P 2 is Gly, P 3 is selected from Group B, and P 4 is selected from Group K, R 2 is the R group side chain selected from Groups A and J, R 4 is the R group side chain selected from Group E, R 5 is selected from Group E.
Claim 22
Dependent Claim
16 words
A compound of claim 20 selected from the group consisting of DNS-Glu-Gly-Arg-COOMe, DNS-Glu-Gly-Arg-CF 3 , DNS-Glu-Gly-Arg-COOH.
Claim 23
Dependent Claim
90 words
A compound of claim 1 useful for inhibiting acrosin wherein X l and X2 are as defined in claim 1, Y is NH 2 , R 4 is an R group side chain selected from Group E, R 5 is selected from Group E, R 1 is -P 2 P 3 P 4 wherein P 2 is selected from Group E, P 3 is selected from Group E, and P 4 is selected from Group K, R 2 is an R group side chain selected from Groups A and J.
Claim 24
Dependent Claim
18 words
A compound of claim 22 selected from the group consisting of Boc-Leu-Leu-Arg-CF 2H , Boc-Leu-Leu-Arg-CF 3 and Boc-Leu-Leu-Arg-COOH.
Claim 25
Dependent Claim
64 words
A compound of claim 1 useful for inhibiting B-lactamase wherein X is X l , as defined in claim 1 with the proviso that the P 1 carbonyl moiety may also exist in its reduced form, R 1 is P 2 which is selected from Group K or is R 2 is an R group side chain selected from Groups E, G and C.
Claim 26
Dependent Claim
40 words
A compound of claim 24 selected from the group consisting of ØCH 2 CONHCH 2 COCF 3 , ØCH 2 CONH 2 CHOHCF3, ØCH 2 CONHCH 2 COCOOH, 0CH 2 CONHCH 2 COCOOMe, ØCH 2 CONHCH 2 CHOHCOOH and OCH2CONHCH2CHOHCOOMe.
Claim 27
Dependent Claim
78 words
A compound of claim 1 useful for inhibiting D- A la-D-Ala carboxypeptidase wherein X 1 , X 2 and R 3 are as defined in claim 1, Y is OH or OR 3 R 5 is deleted, R 4 is D-Ala, R 2 is the R group side chain of D-Ala and R 1 is -P 2 P 3 wherein P 2 is selected from Groups E, C and (Nα,ε)-di-AcLys, and P 3 is selected from Group K.
Claim 28
Dependent Claim
16 words
A compound of claim 26 selected from the group Ala⁅CF 2 -D-Ala⁆OH and Ala⁅CF 2 -D-Ala⁆OMe.
Claim 29
Dependent Claim
127 words
A compound of claim 1 useful for inhibiting cathepsin B wherein X l , X2 , R 3 are as defined in claim 1, Y is OH, R 5 is selected from Groups E, F or G, R 4 is the R group side chain selected from Group E, R l is (a) -P 2 P 3 or (b) -P 2 P 3 P 4 wherein (a) P 2 is selected from Groups E and F, P 3 is selected from Group K, (b) P 2 is selected from Groups E and F, P 3 is selected from Groups E and F, and P 4 is selected from Group K, R 2 is the R group side chain selected from Groups A, J or Thr-CH 2 0.
Claim 30
Dependent Claim
20 words
A compound of claim 28 selected from the group consisting of Ac-Leu-Leu-Arg⁅CF 2 -Leu⁆Gly-OH, CBZ-Phe-Arg⁅CF 2 -Leu⁆Gly-OH and CBZ-Phe- -LeufGly-OH.
Claim 31
Dependent Claim
169 words
A compound of claim 1 useful as inhibitor of renin wherein X 1 , X 2 and R3 are as defined in claim 1, Y is OH wherein R 4 is the R group side chain selected from Groups E, P or G, R 5 is P 2 P 3 P 4 wherein P 2 is selected from Groups E, F or is deleted, P 3 is selected from Groups E, F or is deleted, P4 is selected from Groups E, C, F or is deleted, R 2 is the R group side chain selected from Groups E or F, or is cyclohexylmethyl, Rl is -P 2 P 3 P 4 P 5 P 6 wherein P 2 is selected from Groups E, C or F, P 3 is selected from Groups E or F, P 4 is selected from Groups E, D or F or is deleted, P 5 is selected from Groups E, C or F or is deleted, and P 6 is selected from Group K.
Claim 32
Dependent Claim
14 words
A compound of claim 30 selected from the group consisting of MeOSuc-His-Pro-Phe-His-⁅CF 2 -Val⁆Ile-His-OH,
Claim 35
Dependent Claim
112 words
A compound of claim 1 useful for inhibiting pepsin wherein X 1 , X2 and R 3 being as defined in claim 1 wherein R 4 is an R group side chain selected from Groups E, G or F, R 5 is selected from Groups E or F and Y is NHCH 2 C H2 CH(CH 3 ) 2 or -NHCH 2 CH(CH3)2, R 2 is an R group side chain selected from Groups E or F, R l is -P 2 P 3 P 4 wherein P 2 is selected from Groups E or F, P 3 is selected from Groups E or F, P 4 is selected from Group K.
Claim 36
Dependent Claim
25 words
A compound of claim 32 selected from the group consisting of Iva-Val-Val-Leu-CF 2 and Iva-Val-Val-Leu⁅CH 2 -Gly⁆AlaNRCH 2 CH 2 CH(CH 3 ) 2 .
Claim 37
Dependent Claim
112 words
A compound of claim 1 useful for inhibiting cathepsin D wherein X l , X 2 and R 3 are as defined in claim 1, Y is -NH(CH 2 ) 2 CH(CH 3 ) 2 or -NHCH 2 CH(CH3)2, R 4 is an R group side chain selected from Groups E or F, R 5 is selected from Groups E or F, R 2 is an R group side chain selected from Groups E or F, R l is -P 2 P 3 P 4 wherein P 2 is selected from Groups E or F, P 3 is selected from Groups E or F, and P 4 is selected from Group K.
Claim 38
Dependent Claim
15 words
A compound of claim 34 selected from the group consisting of CBZ-Val-Val-Phe-CF2H, CBZ-Val-Val-Phe-CF 3 ,
Claim 41
Dependent Claim
72 words
A compound of claim 1 useful as an ACE inhibitor wherein X is X 2 wherein R 4 is an R group side chain selected from Groups E or G , R 5 is selected from Groups A, B, C, D, E, F and G and Y is OH, R 2 is an R group side chain selected from Groups E, F or G, and R l is selected from Group K.
Claim 42
Dependent Claim
11 words
A compound of claim 36 having the formula Bz-Phe[CF 2 -GlylPro-OH.
Claim 43
Dependent Claim
94 words
A compound of claim 1 useful for inhibiting enkephalinase wherein X is X 2 wherein R 4 is an R group side chain selected from Group E or F, R 5 is selected from Groups E or F or is zero with the proviso that when R 5 is zero, Y is -NH 2 and when it is not zero, Y is -NH 2 or OH, R 2 is Gly, and R 1 is -P 2 P 3 wherein P 2 is Gly, and P 3 is selected from Group F or is zero.
Claim 44
Dependent Claim
14 words
A compound of claim 38 selected from the group consisting of Tyr-Gly-Gly-[CF 2 -Phe]-Met-OH,
Claim 45
Dependent Claim
86 words
A compound of claim 1 useful as inhibitor of pseudomonas elastase wherein X is X 2 , wherein R 4 is an R group side chain selected from Groups E or F, R 5 is selected from Groups E or G and Y is NH 2 , R 2 is an R group side chain selected from Groups E and G, and R 1 is -P 2 P 3 , wherein P 2 is selected from Group E and P 3 is selected from Group K.
Claim 46
Dependent Claim
13 words
A compound of claim 40 having the formula MeOSuc-Ala-Ala[CF 2 -IlelAla-NH 2 .
Claim 47
Dependent Claim
68 words
A compound of claim 1 useful for inhibiting leucine aminopeptidase wherein X l , X 2 and R 3 are as defined in claim 1, R 4 is an R group selected from any Group except H and R 5 is selected from any Group except H, Y is NH 2 , R l is hydrogen, R 2 is an R group selected from Groups E or F.
Claim 48
Dependent Claim
23 words
A compound of claim 42 selected from the group consisting of Leu-CF 3 , L euCOOH, Leu[CF 2 -AlalAlaNH 2 , and LeuCOOMe.
Claim 49
Dependent Claim
50 words
A compound of claim 1 useful as an inhibitor of kallikreins wherein X is X 1 , R 2 is Arg, R 1 is a peptide P 2 P 3 with P 2 being selected from Groups F and E, P 3 being selected from Groups C, E or F.
Claim 50
Dependent Claim
11 words
A compound of claim 44 selected from the group consisting of
Claim 51
Dependent Claim
54 words
The process for producing compounds of the formula . and the hydrate thereof which comprises effecting a Swern oxidation on a compound of the formula wherein X 1 is CF 2 H or CF 3 , and R 1 and R 2 are as defined in claim 1, and optionally removing any protecting group.
Claim 52
Dependent Claim
56 words
The process for preparing compounds of the formulae and the hydrates thereof which comprises effecting a Swern oxidation on compounds of the formulae wherein R 3 is as defined in claim 1, R3 is R 3 except H, and R 1 and R 2 are as defined in claim 1, and optionally removing any protecting group.
Claim 53
Dependent Claim
35 words
A process for preparing a compound of the formula which comprises treating a compound of the formula with a base, whrein R 1 , R 2 and R 3 are as defined in claim 47.
Claim 54
Dependent Claim
47 words
A process for preparing a compound of the formula which comprises coupling R 3 NH 2 to a compound of formula according to standard coupling procedures wherein R 1 , R 2 and R 3 are as defined in claim 47, and optionally removing any protecting group.
Claim 55
Dependent Claim
49 words
A process for preparing a compound of the formula which comprises coupling R 5 Y to a compound of the formula according to standard peptide chemistry procedures, and optionally removing any protecting groups, wherein R l , R 2 , R 5 Y are as defined in claim 1.
Claim 56
Dependent Claim
43 words
A process for preparing a compound of the formula which comprises effecting a Swern oxidation on a compound of the formula and optionally removing any protecting group, wherein R 1 , R 2 and R 5 Y are as defined in claim 1.
Claim 57
Dependent Claim
27 words
The process for preparing a compound of the formula which comprises effecting a Swern oxidation on a compound of the formula and optionally removing any protecting groups.
Claim 58
Dependent Claim
27 words
The process for preparing a compound of the formula which comprises effecting a Swern oxidation on a compound of the formula and optionally removing any protecting groups.
Claim 59
Dependent Claim
54 words
A process for preparing a compound of the formula which comprises effecting a Swern oxidation on a compound of the formula and optionally removing any protecting group wherein R 2 , R 4 , R 5 Y are as defined in claim 1, and R 6 is phenyl, benzyl or other equivalently functioning group.
Claim 60
Dependent Claim
46 words
A process for preparing a compound of the formula which comprises coupling R 5 Y with a compound of the formula and optionally removing any protecting group, wherein R 2 , R 4 , R 5 Y and R 6 are as defined in claim 53.
Claim 61
Dependent Claim
64 words
A process for preparing a compound of the formula which comprises oxidizing a compound of the formula according to Swern oxidation conditions or with pyridinium dichromate, and optionally removing any protecting group wherein R 1 and R 2 are as defined in claim 1 and R' 5 Y is as defined for R 5 Y except that R 5 optionally contains a protecting group.
References Cited (Backward Citations)
No citation records indexed.
USPTO Annuity & Maintenance Windows
Maintenance schedule is calculated for granted US utility patents.