Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-06-24
2001-06-26
Allen, Marianne P. (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S009100, C514S017400, C530S317000
Reexamination Certificate
active
06251861
ABSTRACT:
This application is based on application No. 167507/1996 filed in Japan, the content of which is incorporated hereinto by reference.
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition for prophylaxis or treatment of cerebral infarction which comprises a compound having a specific chemical structure and anti-endothelin activity.
BACKGROUND ART
Endothelin (ET) is a vasoconstrictor peptide composed of 21 amino acid residues, which was first isolated from a culture supernatant of porcine aortic endothelial cells and characterized (Yanagizawa et al., Nature, 332, 411-415, 1988). Subsequent research suggested that endothelin occurs in at least 3 isoforms (ET-1, ET-2 and ET-3), and two endothelin receptors, ET
A
(being concerned with only action of vasoconstriction) and ET
B
(being concerned with mainly action of vasodilation), have been identified.
Since the discovery of endothelin, searches for anti-endothelin compounds have been energetically undertaken to develop therapeutic drugs for diseases pathologically associated with endothelin. Results of such exploratory endeavors have been reported in EP-A-552,489, EP-A-528,312, EP-A-499,266, WO 91/13089, EP-A-436,189, EP-A-457,195, EP-A-510,526, WO 92/12991, EP-A-496,452, EP-A-526,708, EP-A-460,679, WO 92/20706, among other reports. The compounds described in the above reports are suggested to be effective as anti-hypertensive agents, therapeutic drugs for cardiovascular/cerebrovascular diseases (such as myocardial infarction), therapeutic drugs for diseases of the kidney, antiasthmatic agents, antiinflammatory agents, and/or antiarthritic agents but there is no specific description about their application as a therapeutic or prophylactic drug for cerebral infarction. On the other hand, EP-A-655,463 describes that a compound which exhibits excellent antagonistic action against endothelin B receptors is useful for diseases caused by endothelin, such as hypertension, cerebral infarction, etc.
In view of the above state of the art, the inventors of the present invention investigated agents of use for the clinically beneficial prevention or treatment of cerebral infarction and firstly found surprisingly that anti-endothelin compounds having specific chemical structure are effective for the purpose, based on concrete data. They accordingly have perfected the present invention.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition for the prophylaxis and/or therapeutic efficacy of cerebral infarction which comprises a compound having a specific chemical structure and anti-endothelin activity.
DETAILED EXPLANATION OF THE INVENTION
The present invention relates to:
(1) a pharmaceutical composition for the prophylaxis or treatment of cerebral infarction which comprises a compound having anti-endothelin activity;
(2) the pharmaceutical composition according to (1) wherein the anti-endothelin activity is endothelin receptor antagonistic activity;
(3) the pharmaceutical composition according to (1) wherein the compound having anti-endothelin activity is a peptide compound;
(4) the pharmaceutical composition according to (1) wherein the compound having anti-endothelin activity is a cyclic hexapeptide of the formula:
wherein X and Y each represents an &agr;-amino acid residue having D-, L- or DL-form; A represents a D-acidic &agr;-amino acid residue; B represents a D- or L-neutral-&agr;-amino acid residue; C represents a L-&agr;-amino acid residue; E represents a D-&agr;-amino acid residue having an aromatic ring group, or an ester thereof, or a salt thereof;
(5) the pharmaceutical composition according to (3) wherein the cyclic hexapeptide is a compound of the formula
Cyclo[-D-Asp-Asp(R1)-Asp-D-Thg(2)-Leu-D-Trp-]
wherein Asp(R1) is an aspartic acid &bgr;-4-phenylpiperazine amide residue and Thg(2) is a 2-thienylglycine residue or a salt thereof; and so forth.
The anti-endothelin compound that can be used in the present invention is any peptide compound that can be administered as an anti-endothelin drug and is capable of accomplishing the object of the invention.
Among the preferred examples of such anti-endothelin compound are peptides of the formula [I] and their salts. Such salts are pharmaceutically acceptable salts such as salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.
Among preferred salts with inorganic bases are salts with alkali metals such as sodium, potassium, etc., salts with alkaline earth metals such as calcium, magnesium, etc., aluminum salts, and ammonium salts.
Among preferred salts with organic acids are salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, and N,N′-dibenzylethylenediamine.
Among preferred salts with inorganic acids are salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid.
Among preferred salts with organic acids are salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
Among preferred salts with basic amino acids are salts with arginine, lysine, and ornithine.
Among preferred salts with acidic amino acids are salts with aspartic acid and glutamic acid.
Referring to the formula [I], the precursor amino acid for the &agr;-amino acid residue for X and Y can be any &agr;-amino acid, thus including alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, 2-aminomalonic acid, 2-aminoadipic acid, glycine, histidine, isoleucine, leucine, lysine, ornithine, 2,4-diaminobutyric acid, methionine, phenylalanine, proline, 4-hydroxyproline, thioproline, azetidine-2-carboxylic acid, pipecolic acid (piperidine-2-carboxylic acid), indoline-2-carboxylic acid, tetrahydroisoquinoline-3-carboxylic acid, serine, thereonine, tryptophan, 5-methyltryptophan, tyrosine, valine, alloisoleucine, norvaline, norleucine, tert-leucine, &ggr;-methylleucine, phenylglycine, 2-aminobutyric acid, cysteic acid, homocysteic acid, 1-naphthylalanine, 2-naphthylalanine, 2-thienylglycine, 3-thienylglycine, 3-benzothienylalanine, 4-biphenylalanine, pentamethylphenylalanine, 1-aminocyclopropane-1-carboxylic acid, 1-aminocyclobutane-1-carboxylic acid, 1-aminocyclopentane-1-carboxylic acid, 1-aminocyclohexane-1-carboxylic acid, and 1-aminocycloheptane-1-carboxylic acid.
Where such &agr;-amino acids have functional groups such as hydroxy, thiol, amino, imino, carboxy, etc., such functional groups may be substituted by suitable substituent groups.
The substituted hydroxy, for instance, includes C
1-6
alkanoyloxy (e.g. formyloxy, acetoxy, propionyloxy, etc.), C
4-9
alicycle-carbonyloxy (e.g. cyclopentanecarbonyloxy, cyclohexanecarbonyloxy, etc.), C
7-15
arylcarbonyloxy (e.g. benzoyloxy, 4-methylbenzoyloxy, etc.), C
8-16
aralkylcarbonyloxy (e.g. phenylacetoxy, 2-phenylpropionyloxy, 3-phenylpropionyloxy, diphenylacetoxy, etc.), aromatic heterocycle-alkylcarbonyloxy (e.g. indol-2-ylacetoxy, indol-3-ylacetoxy, etc.), C
1-6
alkoxy (e.g. methoxy, ethoxy, n-propoxy, tert-butoxy, etc.), C
3-8
cycloalkoxy (e.g. cyclopentyloxy, cyclohexyloxy, etc.), C
6-12
aryloxy (e.g. phenyloxy, 4-methylphenyloxy, etc.), and C
7-15
aralkyloxy (e.g. benzyloxy, phenethyloxy, diphenylmethoxy, etc.), among others. The &agr;-amino acid containing such a substituted hydroxy group includes but is not limited to O-acetylserine, O-acetylthreonine, 4-acetoxyproline, O-benzoylserine, O-benzoylthreonine, 4-benzoyloxyproline, O-phenylacetylserine, O-phenylacetylthreonine, 4-phenylacetoxyproline, O-ethylserine, O-ethylthreonine, 4-ethoxyproline, O-cyclohexylserine, O-cyclohexylthreonine, 4-cyclohexyloxyproline, O-phenylserine, O-phenylthreonine, 4-phenoxyproline, O-benzylserine, O-benzylthreonine, 4-benzyloxyproline, O-diphenylmethylserine, O-diphenylmethylthreonine, and 4-diphen
Imamoto Tetsuji
Nagisa Yasutaka
Allen Marianne P.
Conlin David G.
Dike Bronstein Roberts & Cushman
Intellectual Property Group of Edwards & Angell, LLP
Takeda Chemical Industries Ltd.
LandOfFree
Treatment of cerebral infarction using cyclic hexapeptides does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Treatment of cerebral infarction using cyclic hexapeptides, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Treatment of cerebral infarction using cyclic hexapeptides will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2541722