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WO1992001468A1 - Inhibiteur d'enzyme de conversion d'endoserine ou remede contre les contractions vasculaires - Google Patents

Inhibiteur d'enzyme de conversion d'endoserine ou remede contre les contractions vasculaires Download PDF

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Publication number
WO1992001468A1
WO1992001468A1 PCT/JP1991/000808 JP9100808W WO9201468A1 WO 1992001468 A1 WO1992001468 A1 WO 1992001468A1 JP 9100808 W JP9100808 W JP 9100808W WO 9201468 A1 WO9201468 A1 WO 9201468A1
Authority
WO
WIPO (PCT)
Prior art keywords
residue
hydroxyl group
general formula
alkyl
represent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1991/000808
Other languages
English (en)
Japanese (ja)
Inventor
Shiro Morimoto
Yasuo Matsumura
Takeshi Uchida
Hideaki Kido
Hiroshi Shinyama
Masahiro Watanabe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Tanabe Pharma Corp
GC Biopharma Corp
Original Assignee
Green Cross Corp Japan
Green Cross Corp Korea
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Green Cross Corp Japan, Green Cross Corp Korea filed Critical Green Cross Corp Japan
Publication of WO1992001468A1 publication Critical patent/WO1992001468A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure

Definitions

  • the present invention relates to an endoselin converting enzyme inhibitor or a therapeutic agent for vasospasm comprising a compound having a specific structure described below as an active ingredient.
  • Endoselin (hereinafter referred to as “ET”) is a peptide isolated from a culture supernatant of vascular endothelial cells and is known to contribute to vasoconstriction.
  • ⁇ ⁇ There are three types of ⁇ ⁇ in humans, ⁇ ⁇ — I, ⁇ ⁇ — II, and ⁇ ⁇ — ⁇ [, and their existence has been confirmed in the central nervous system. It is also considered to be.
  • the process of conversion from the precursor to the active form, ⁇ , by the ⁇ -converting enzyme is important for the expression of vasoconstriction activity, bronchoconstriction, and the like.
  • the —-converting enzyme causes the ET-I precursor (in pigs to consist of 39 amino acids and in humans to consist of 38 amino acids).
  • the amide bond between the ribotophan (21) and the valin (22) is cleaved to generate 1 ⁇ -I consisting of 21 amino acids.
  • ⁇ has a very weak vasoconstrictive activity in the form of a precursor, it has a strong vasoconstrictive activity when converted into ⁇ ⁇ ⁇ by the action of ⁇ ⁇ converting enzyme. Therefore, drugs having a ⁇ ⁇ converting enzyme inhibitory effect are of interest for their effects on the circulatory system.
  • the compound represented by the following general formula (I) (hereinafter referred to as “compound (I) J”) and a salt thereof have a metalloproteinase activity and can be used as an anti-inflammatory agent and as an anti-inflammatory agent.
  • Compound (I) J a metalloproteinase activity
  • the compound is useful as a protective agent against infection
  • the compound has a vasospasm inhibitory effect.
  • Vasospasm refers to the transient tonic contraction of blood vessels, especially of the arteries, causing severe dysfunction of the governing organs due to the disruption of blood circulation. Common sites include coronary arteries, brain or limb arteries, etc.
  • Vasospasm occurs in the brain, for example, due to cerebral hemorrhage, subarachnoid hemorrhage, cerebral thrombosis, etc.In coronary arteries, it occurs due to luminal damage, arteriosclerosis, etc., resulting in cerebral ischemia, cerebral infarction, myocardial ischemia It induces blood, myocardial infarction and angina. In peripheral blood vessels, Reino's disease and intermittent claudication occur. When it occurs in the gastrointestinal arteries, it causes ischemic colitis.
  • nitroglycerin, nicorandil and the like have been used as therapeutic agents for vasospasm.
  • dihydroxypyridine-based compounds are thought to be useful in treating vasospasm, and some are being used clinically, but none of them are sufficiently satisfactory.
  • An object of the present invention is to provide an ET converting enzyme inhibitor that is effective for treating and preventing hypertension, bronchial asthma, peripheral circulatory disorders, ischemia of the brain, heart, ⁇ , and vasospasm.
  • Another object of the present invention is to provide a therapeutic agent for vasospasm that does not rely on the inhibition of ET converting enzyme.
  • a and A 2 are each an amino acid residue
  • X is a hydroxyl group or a monosaccharide residue
  • R is a hydroxyl group, an alkyl, an alkoxy, an aryl or a compound of the general formula
  • R 2 and R 3 each represent a hydrogen atom or an alkyl
  • an ET-converting enzyme inhibitor or a therapeutic agent for vasospasm comprising an effective amount of the compound represented by or a salt thereof and a pharmaceutically acceptable carrier.
  • amino acids include glycine, alanine, valiline, leucine, soleucine, serine, threonine, cystine, cystine, methionine, aspartic acid, glutamic acid, and lysine.
  • Examples thereof include arginine, phenylalanine, tyrosine, triflate, histidine, and proline.
  • a leucine residue is particularly preferred, and a tri- 2 residue is preferably a tributane residue.
  • Examples of the monosaccharide of the monosaccharide residue include glucose, fructos, galactose, mannose, rhamnose, and arabinose, and rhamnose is particularly preferred.
  • Alkyl may be either linear or cyclic, and examples of linear alkyl include those having 1 to carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, S-butyl, t-butyl, etc. Chain 4 Or branched alkyl, and methyl and ethyl are particularly preferred.
  • Examples of the cyclic alkyl include those having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptane.
  • alkoxy examples include alkoxy having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, and t-butoxy, with methoxy and ethoxy being particularly preferred.
  • Preferable examples of the group represented by are, for example, an amino group, an N-methylamino group, an N-ethylamino group, an N, N-dimethylamino group, an N-methyl-N-ethylamino group , N, N-Jetylamino group and the like.
  • the compound of the general formula (I) wherein R, is a hydroxyl group can be prepared by a conventional method using an inorganic acid or base (for example, sodium hydroxide, sodium hydroxide, calcium hydroxide, lithium hydroxide, lithium hydroxide, magnesium hydroxide, water).
  • an inorganic acid or base for example, sodium hydroxide, sodium hydroxide, calcium hydroxide, lithium hydroxide, lithium hydroxide, magnesium hydroxide, water.
  • organic acids or bases eg, triethylamine, dicyclohexylamine, N-methylmorpholine, pyridine, acetic acid, succinic acid
  • amino acids lysine, histidine, orditin, arginine, etc.
  • Particularly preferred examples of the compound (I) according to the present invention include a lysine residue, A 2 a tritophane residue, X a rhamnose residue, R, is phosphoramidone represented by a hydroxyl group.
  • the compound (I), which is an active ingredient of the present invention is a substantially known compound.
  • the above-mentioned phosphoramidone is described in Japanese Patent Publication No. 54-2277, which describes the compound itself and a method for producing the same.
  • Other compounds (I) and salts thereof are produced in a similar manner.
  • the ET converting enzyme inhibitor or the therapeutic agent for vasospasm of the present invention may be a compound (I) or Z and a salt thereof or a carrier (eg, physiological saline, distilled water for injection, glucose injection, etc.), an excipient, and the like.
  • Agents eg, lactose, crystalline cellulose, magnesium metasilicate aluminate, partially alpha starch, hydrous silicon dioxide, hydroxypropyl starch, etc.
  • disintegrants eg, carboxymethylcellulose, croscarmellose sodium type A
  • Lubricants eg, magnesium stearate, talc, hydrogenated oil, etc.
  • dissolution promoters eg, polyoxyl stearate 40, polysorbate 80, sodium lauryl sulfate, etc.
  • Tablets injections, capsules, powders, granules, etc. Is Zaika.
  • the dose and the number of doses of the compound (I) of the present invention and its salt may vary depending on the age, sex, weight, symptoms, administration form, etc. of the patient, but are generally from 0.01 to 10 per adult.
  • the dose is about 0,000 mg, which is administered about 1 to 4 times a day.
  • Examples of the administration route include oral, intravenous, subcutaneous, rectal, transdermal and the like.
  • the drug containing the compound (I) or a salt thereof as an active ingredient of the present invention has an ET converting enzyme inhibitory action.
  • the ET converting enzyme inhibitors of the present invention include humans, as well as humans, pests, pests, It is effective in preventing or treating hypertension, bronchial asthma, peripheral circulatory disorders, ischemia and vasospasm in the brain, heart, kidney, etc. in mammals such as dogs, rats and mice.
  • compound (I) also has a function of producing and suppressing vasospasm (including those not inhibiting ET converting enzyme), and is useful as a therapeutic agent for vasospasm in humans and other mammals. .
  • drugs containing compound (I) or its salt include cerebral vasospasm (cerebral vasospasm after cerebral hemorrhage or subarachnoid hemorrhage) or coronary vasospasm (occurs when stenosis is reopened by laser ablation or the like) Seizures due to spasm, especially those that are intractable and are ineffective against glycerol in the mouth, including postoperative coronary spasm, angina pectoris induced by coronary spasm, and coronary spasm angina ) And other vasospasm.
  • cerebral vasospasm Cerebral vasospasm after cerebral hemorrhage or subarachnoid hemorrhage
  • coronary vasospasm occurs when stenosis is reopened by laser ablation or the like
  • Seizures due to spasm especially those that are intractable and are ineffective against glycerol in the mouth, including postoperative coronar
  • a male SD rat (body weight: 300-330 g) was fixed on a heated operating table under anesthesia with thiobutaparbital sodium (100 mg / kg body weight, intraperitoneal administration), and then into the rectum. Body temperature was maintained at 37-38. After tracheotomy, a catheter was inserted into the right posterior artery for blood pressure measurement. A catheter was inserted into the right posterior vein for drug administration. Rats were given intravenous pentolinium (5 mgZkg body weight) to block ganglia. 20 Grade of ET-I precursor or ET-I after equilibration period of 0-25 minutes Increased doses were administered intravenously (each dose was given in a fixed volume of 1 Zkg body weight).
  • Intravenous administration of ET-I showed a hypotensive effect and then a hypertensive effect in a dose-dependent manner.
  • Administration of fosphoramidone at 0.25 mg / kg body weight Z min had no effect on this effect.
  • the dose-dependent curve for the pressor effect of ET-I was not affected by phosphoramidone. The results are shown in Table 2.
  • a polyethylene catheter was inserted into the vertebral artery under anesthesia with Chobutabarbi Yuichi Lunatum. After the brain blood vessels were taken by X-ray, and 1 0 _ 4 M a Fosuhora Mi Don in the cerebrospinal fluid Intraosseous administration was performed so that 30 minutes later, 5 mi of arterial blood was administered into the cisterna magna. Two days later, cerebral blood vessels were photographed with X-rays, and fosphoramidone and arterial blood were intravesically administered in the same manner. Seven days later, cerebral blood vessels were radiographed, and fosphoramidone and arterial blood were intravesically administered in the same manner.
  • cerebrovascular contraction was 76.9% and 54.8% on days 2 and 7, respectively, compared to before administration.
  • cerebral blood vessels tended to contract at 78.7% on the second day, but on the seventh day, cerebral blood vessels became 79.4% and the physiological saline solution was administered.
  • Cerebral vasoconstriction tended to remit compared to the group.
  • the tendency of cerebral vasoconstriction to remit was not observed as in foshoramidon.
  • Cerebral blood vessels in the fosphoramidone-administered group on day 7 of administration were significantly thicker than in the control group.
  • the upper values show the values when the cerebral blood vessel diameter before administration of the drug was 100.
  • the lower value shows the measured value (wake) of the basilar artery.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Inhibiteur d'enzyme de conversion d'endosérine, agent de contraction vasculaire ou remède contre les contractions vasculaires renfermant un composé représenté par la formule générale (I), ou son sel comme matière active. Dans cette formule A1 et A2 représentent chacun un reste d'acide aminé, X représente un reste hydroxy ou un reste monosaccharide, et R1 représente hydroxy, alkyle, alcoxy, allyle ou -NR2R3 dans lequel R2 et R3 représentent chacun hydrogène ou alkyle. Une préparation pharmaceutique contenant le composé (I) ou son sel comme ingrédient actif a une activité d'inhibition d'une enzyme transformant une endosérine ou de régulation des contractions vasculaires. Cet inhibiteur est donc efficace pour prévenir ou soigner l'hypertension, l'asthme bronchique, les troubles de la circulation périphérique, le spasme cérébrovasculaire (se produisant après une hémorragie cérébrale, une hémorragie sous-arachnoïde, etc.), une contraction coronaire (y compris une attaque provoquée par une contraction se produisant lorsqu'un endroit reserré est réouvert par exemple, par une chirurgie au laser, plus particulièrement lorsqu'il est difficilement soignable et pour lequel même le nitroglycérol est inefficace, c'est-à-dire lorsqu'il s'agit d'une attaque provoquée par une contraction coronaire post-opératoire et d'une angine de poitrine induite par une contraction coronaire) et d'autres contractions vasculaires des mammifères comprenant l'homme, le porc, le bétail, le cheval, le chien, le rat et la souris.
PCT/JP1991/000808 1990-07-25 1991-06-15 Inhibiteur d'enzyme de conversion d'endoserine ou remede contre les contractions vasculaires Ceased WO1992001468A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP19736890 1990-07-25
JP2/197368 1990-07-25
JP41741190 1990-12-29
JP2/417411 1990-12-29

Publications (1)

Publication Number Publication Date
WO1992001468A1 true WO1992001468A1 (fr) 1992-02-06

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Application Number Title Priority Date Filing Date
PCT/JP1991/000808 Ceased WO1992001468A1 (fr) 1990-07-25 1991-06-15 Inhibiteur d'enzyme de conversion d'endoserine ou remede contre les contractions vasculaires

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5608078A (en) * 1993-03-30 1997-03-04 Merrell Pharmaceuticals Inc. Phosphonomethyldipeptides and process for preparation thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2207351A (en) * 1987-06-08 1989-02-01 Squibb & Sons Inc Inhibitors of neutral endopeptidase
EP0331105A2 (fr) * 1988-03-03 1989-09-06 E.R. Squibb & Sons, Inc. Hydroxy phosphonates-1,2 et leurs dérivés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2207351A (en) * 1987-06-08 1989-02-01 Squibb & Sons Inc Inhibitors of neutral endopeptidase
EP0331105A2 (fr) * 1988-03-03 1989-09-06 E.R. Squibb & Sons, Inc. Hydroxy phosphonates-1,2 et leurs dérivés

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5608078A (en) * 1993-03-30 1997-03-04 Merrell Pharmaceuticals Inc. Phosphonomethyldipeptides and process for preparation thereof

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