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1. (WO1991005763) DIPEPTIDE-ANALOG-BASED METALLOENDOPEPTIDASE INHIBITORS AND METHODS OF USING SAME
Latest bibliographic data on file with the International Bureau

Pub. No.: WO/1991/005763 International Application No.: PCT/US1990/005902
Publication Date: 02.05.1991 International Filing Date: 15.10.1990
Chapter 2 Demand Filed: 10.05.1991
IPC:
A61K 38/00 (2006.01) ,C07C 255/41 (2006.01) ,C07K 5/06 (2006.01) ,C07K 5/062 (2006.01) ,C07K 5/065 (2006.01) ,C07K 5/078 (2006.01)
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
38
Medicinal preparations containing peptides
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
C
ACYCLIC OR CARBOCYCLIC COMPOUNDS
255
Carboxylic acid nitriles
01
having cyano groups bound to acyclic carbon atoms
32
having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
41
the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
K
PEPTIDES
5
Peptides having up to four amino acids in a fully defined sequence; Derivatives thereof
04
containing only normal peptide links
06
Dipeptides
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
K
PEPTIDES
5
Peptides having up to four amino acids in a fully defined sequence; Derivatives thereof
04
containing only normal peptide links
06
Dipeptides
062
the side chain of the first amino acid being acyclic, e.g. Gly, Ala
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
K
PEPTIDES
5
Peptides having up to four amino acids in a fully defined sequence; Derivatives thereof
04
containing only normal peptide links
06
Dipeptides
065
the side chain of the first amino acid containing carbocyclic rings, e.g. Phe, Tyr
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
K
PEPTIDES
5
Peptides having up to four amino acids in a fully defined sequence; Derivatives thereof
04
containing only normal peptide links
06
Dipeptides
078
the first amino acid being heterocyclic, e.g. Pro, His, Trp
Applicants:
THE SALK INSTITUTE BIOTECHNOLOGY/INDUSTRIAL ASSOCIATES, INC. [US/US]; 10280 North Torrey Pines Road La Jolla, CA 92037, US (AllExceptUS)
KAISER, Bonnie, Lu +ef [US/US]; US (UsOnly)
GHOSH, Soumitra, Shankar [IN/US]; US (UsOnly)
Inventors:
GHOSH, Soumitra, Shankar; US
KAISER, Emil, Thomas +di; null
Agent:
WATT, Phillip, H. ; Fitch, Even, Tabin & Flannery Room 900 135 South LaSalle Street Chicago, IL 60603 , US
Priority Data:
421,10813.10.1989US
Title (EN) DIPEPTIDE-ANALOG-BASED METALLOENDOPEPTIDASE INHIBITORS AND METHODS OF USING SAME
(FR) INHIBITEURS DE METALLOENDOPEPTIDASE A BASE D'ANALOGUES DIPEPTIDIQUES ET LEURS MODES D'EMPLOI
Abstract:
(EN) Inhibitors of the Zn+2-metalloendopeptidases, enkephalinase, angiotensin-converting enzyme, and collagenase are provided. The enkephalinase inhibitors of the invention are useful as analgesics or antihypertensives. The angiotensin-converting enzyme inhibitors of the invention are useful as antihypertensives. The collagenase inhibitors of the invention are useful in treating diseases, such as corneal ulceration, periodontal disease, and arthritis, which involve undesirable activity of bacterial or mammalian collagenases. The inhibitors of the invention are peptide or peptide-ester derivatives of the dipeptide analogs of the formula X1-(CR3R4)z-(CR5R6)x-CHR9-CO2H wherein X1- is a functional group, such as (N=C) (CH2) (C=0)-, from which a Zn+2 metalloendopeptidase, at its active site, is capable of abstracting a proton to yield and activated functional group capable of forming a stable, covalent bond with a residue in the active site; z is 0 or 1, wherein, when z is 0, the group -(CR3R4)z-(CR5R6)x- is not in the compound and the group X1-is bonded directly to the group -(CHR9)-; x is 0 if z is 0 or is 0 or 1 if z is 1, wherein, when x is 0 and z is 1, the group -(CR5R6)x- is not in the compound and the group -(CR3R4)- is bonded directly to the group -(CHR9)-; R2, R3, R4, R5, and R6 are independently hydrogen or alkyl of 1 to 3 carbon atoms; and R9 is benzyl, alkyl of 1 to 5 carbon atoms, or hydrogen. Among the dipeptide analogs derivatized with peptides or peptide esters in accordance with the invention is 2-benzyl-5-cyano-4-oxopentanoic acid, which the invention provides substantially free of its 3- benzyl regioisomer.
(FR) Inhibiteurs de Zn+2-métalloendopeptidases d'enképhalinase, d'enzyme de conversion d'angiotensine, et de collagénase. Les inhibiteurs d'enképhalinase de l'invention sont utiles comme analgésiques ou anti-hypertenseurs. Les inhibiteurs d'enzyme de conversion d'angiotensine de l'invention sont utiles en tant qu'anti-hypertenseurs. Les inhibiteurs de collagénase de l'invention sont utiles dans le traitement de maladies, telles que l'ulcération de la cornée, la paradontolyse, et l'arthrite, lesquelles impliquent une activité indésirable de collagénases bactériennes ou mammifères. Les inhibiteurs de l'invention sont des dérivés peptidiques ou d'esters peptidiques d'analogues dipeptidiques de la formule X1-(CR3R4)z-(CR5R6)x-CHR9CO2H, dans laquelle X1- représente un groupe fonctionnel, tel que (N|||C) (CH2) (C=O)-, duquel une Zn+2 métalloendopeptidase, au niveau de son site actif, est capable de soustraire un proton afin de produire un groupe fonctionnel activé capable de former une liaison covalente stable avec un résidu se trouvant dans le site actif; z représente 0 ou 1, dans laquelle, lorsque z représente 0, le groupe -(CR3R4)z- (CR5R6)x- ne représente pas le composé et le groupe X1- est lié directement au groupe -(CHR9)-; x représente 0 si z représente 0, ou il représente 0 ou 1 si z représente 1, dans laquelle, lorsque x représente 0 et z représente 1, le groupe -(CR5R6)x- ne représente pas le composé et le groupe -(CR3R4)- est lié directement au groupe -(CHR9)-; R3, R4, R5 et R6 représentent indépendamment hydrogène ou alkyle contenant 1 à 3 atomes de carbone; et R9 représente benzyl, alkyl contenant 1 à 5 atomes de carbone, ou hydrogène. Parmi les analogues dipeptidique transformés par dérivation à l'aide de peptides ou d'esters peptidiques selon l'invention, se trouve l'acide 2-benzyl-5-cyano-4-oxopentanoïque, que l'invention produit exempt de son régioisomère de 3-benzyl.
Designated States: CA, JP, NO, US
European Patent Office (AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LU, NL, SE)
Publication Language: English (EN)
Filing Language: English (EN)