WO1992001468A1

WO1992001468A1 - Endoserine converting enzyme inhibitor or vascular twitch remedy

Info

Publication number: WO1992001468A1
Application number: PCT/JP1991/000808
Authority: WO
Inventors: Shiro Morimoto; Yasuo Matsumura; Takeshi Uchida; Hideaki Kido; Hiroshi Shinyama; Masahiro Watanabe
Original assignee: The Green Cross Corporation
Priority date: 1990-07-25
Filing date: 1991-06-15
Publication date: 1992-02-06

Abstract

An endoserine converting enzyme inhibitor, a vascular twitching agent or a vascular twitch remedy containing a compound represented by general formula (I) or its salt as the active ingredient, wherein A1 and A2 represent each amino acid residue, X represents hydroxy or monosaccharide residue, and R1 represents hydroxy, alkyl, alkoxy, allyl or -NR2R3 wherein R2 and R3 represent each hydrogen or alkyl. A pharmaceutical preparation containing the compound (I) or its salt as the active ingredient has an activity of inhibiting an endoserine converting enzyme or controlling vascular twitch. Therefore, it is effective in preventing or treating hypertension, bronchial asthma, peripheral circulatory disturbance, cerebrovascular spasm (occurring after cerebral hemorrhage, subarachnoid hemorrhage, etc.), coronary twitch (including attack caused by twitch occurring when a constricted site is reopened by, for example, laser cautery, especially one which is difficultly curable and for which even nitroglycerol is inefficacious, that is, attack caused by postoperational coronary twitch and angina pectoris induced by coronary twitch) and other vascular twitches of mammals including man, pig, cattle, horse, dog, rat and mouse.

Description

Specification

Endoselin converting enzyme inhibitor or vasospasm treatment

"Technical field"

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.

`` Conventional technology J

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 Ε Τ in humans, Ε Τ— I, Ε Τ— II, and Π Τ— Π [, and their existence has been confirmed in the central nervous system. It is also considered to be. In addition, the process of conversion from the precursor to the active form, Τ, by the Τ-converting enzyme is important for the expression of vasoconstriction activity, bronchoconstriction, and the like.

For example, in the case of Ε Τ-I, 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 Τ-I consisting of 21 amino acids. Although 血管 has a very weak vasoconstrictive activity in the form of a precursor, it has a strong vasoconstrictive activity when converted into により by the action of Τ Τ converting enzyme. Therefore, drugs having a Τ Ε converting enzyme inhibitory effect are of interest for their effects on the circulatory system.

By the way, 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.対 Against bacterial infections Although it is known that the compound is useful as a protective agent against infection, it has not been known that 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.

Conventionally, nitroglycerin, nicorandil and the like have been used as therapeutic agents for vasospasm. On the other hand, dihydroxypyridine-based compounds are thought to be useful in treating vasospasm, and some are being used clinically, but none of them are sufficiently satisfactory.

"Disclosure of the invention"

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, 肾, 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.

That is, the present invention

General formula

Wherein A and A ₂ are each an amino acid residue, X is a hydroxyl group or a monosaccharide residue, and R is a hydroxyl group, an alkyl, an alkoxy, an aryl or a compound of the general formula

One _{_{N (R 2) (R 3}} )

(Wherein, R ₂ and R ₃ each represent a hydrogen atom or an alkyl).

Or 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.

In this specification, each symbol means the following.

Amino acids The remaining 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. Of these, 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.

Examples of the alkoxy 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. .

General formula

One _{_{N (R 2) (R 3}} )

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). Zinc oxide, hydrochloric acid, hydrogen bromide, phosphoric acid, sulfuric acid, etc.), organic acids or bases (eg, triethylamine, dicyclohexylamine, N-methylmorpholine, pyridine, acetic acid, succinic acid) , Maleic acid, fumaric acid, lingoic acid, tartaric acid, methanesulfonic acid, etc.), and amino acids (lysine, histidine, orditin, arginine, etc.) to form salts be able to.

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. For example, 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.), and others 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. For this reason, 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. In addition, 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. . In particular, 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. Hereinafter, Experimental Examples and Examples will be given in order to explain the present invention in more detail, but the present invention is not limited thereto.

Experimental Example 1 Blood pressure elevation test

〔Method〕

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). After the effect of the previous administration was settled, the next administration was performed. For administration of fosphoramidon, intravenous infusion was started 30 minutes before the first administration of ET-I precursor or ET-I. In addition, a group to which physiological saline was administered was provided as a control group (results were expressed by mean soil standard error).

[Result]

Normal mean blood pressure was 71 ± 2 mmHg (n = 20). The continuous administration of the ET-I precursor showed a dose-dependent and long-lasting pressor effect. At 0.5 and 1 nmolZkg body weight doses, mean blood pressure increased by 21 ± 3 and 46 ± 4 mmHg, respectively. The temporary hypotensive effect observed with ET-I administration was not observed with ET-I presymptomatic administration. Administration of fosphoramidon at 0.05 mg / kg body weight Z dose had no effect on the pressor action induced by the ET-I precursor. However, intravenous administration of fosphoramidon at 0.25 mgZkg body weight // min clearly suppressed the pressor action of ET-I precursor. Even at the highest dose, mean blood pressure increased only slightly by 8 ± 5 Hg compared to the standard value (71 soil 2 thigh Hg). The administration of the physiological saline alone did not affect blood pressure. The results are shown in Table 1. Table 1

Phosphoramidon 0.2 5 m Zkg

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.

Table 2

Experimental Example 2 Preventive effect of phosphoramidone on delayed cerebral vasospasm in dogs

〔Method〕

Using male and female dogs, 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.

As a control, the same volume of physiological saline as that of phosphoramidone was administered to the large tank. A similar experiment was performed using dicalcidipine, a calcium antagonist.

Using 6 cases of the compound of the present invention (phosphoramidone), 5 cases of physiological saline (control group), and 2 cases of dicardipine, the effect was judged by the diameter of the cerebral blood vessel diameter before and on the 2nd and 7th days before administration. went.

[Result]

In the saline-administered group, cerebrovascular contraction was 76.9% and 54.8% on days 2 and 7, respectively, compared to before administration. On the other hand, in the fosphoramidone group, 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. However, in the group treated with dicardipine, 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.

C ¾sn)

From the above results, it is considered that administration of fosphoramidon into the cisterna magna is effective for cerebral vasospasm, especially for late cerebral vasospasm. Table 3 Changes in cerebral blood vessel diameter

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.

Experimental example 3 Acute toxicity test

When a male SD rat (body weight: 300-330 g, 3 animals) was intravenously administered with fosphoramidon dissolved in physiological saline, it was administered at 500 mg / kg body weight. No deaths were observed at any dose.

(Formulation example)

Formulation Example 1 Tablet

(1) Phosphoramidon 5.0 mg

(2) Fine granules for direct hitting 2α209 (Fuji Kagaku) 46.6 m

(3) Microcrystalline cellulose 24, 0 mg

(4) Carboxymethyl cellulose 4.0 mg

(5) Magnesium stearate 0.4 mg The mixed powder was tableted to give a tablet of 80 mg per tablet.

Formulation Example 2 Injection (Intravenous injection)

(1) Fosholamidon 50 mg (2) Glucose 100 mg

(3) Physiological saline 1 Ο τη After filtering the above mixture with a membrane filter, sterilization filtration was performed again, and the filtrate was aseptically dispensed into vials one by one and filled with nitrogen gas. Thereafter, the solution was sealed to give an intravenous injection.

Formulation Example 3 Capsule

(1) Fosholamidon 50 g

(2) Lactose 9 3 5 g

(3) Magnesium stearate 15 g The above components were uniformly mixed, and the mixed powder was filled into hard gelatin capsules at a dose of 200 mg.

Although the present invention has been adequately and fully described in the foregoing specification and the examples contained therein, they can be changed or modified without departing from the spirit and scope of the invention.

Claims

The scope of the claims

1. General formula

[Wherein, A and A ₂ each represent an amino acid residue, X represents a hydroxyl group or a monosaccharide residue, and R, represents a hydroxyl group, alkyl, alkoxy, aryl, or a general formula.

-N (R ₂ ) (R ₃ )

(Wherein, R ₂ and R ₃ each represent a hydrogen atom or an alkyl).

An endoselin converting enzyme inhibitor comprising an effective amount of the compound represented by or a salt thereof and a pharmaceutically acceptable carrier.

2. In formula A, but leucine residue, A ₂ Gat Ributofa down residue, X is rhamnose residues, R, but E down Doseri down converting enzyme inhibitor according to claim 1, wherein a hydroxyl group.

3. General formula

Wherein, and A ₂ are each an amino acid residue, X is a hydroxyl group or a monosaccharide residue, and R, is a hydroxyl group, alkyl, alkoxy, aryl or a compound of the general formula

-N (R ₂ ) (R ₃ )

(Wherein R ₂ and R ₃ are each a hydrogen atom or an alkyl Represents a group represented by

A therapeutic agent for vasospasm, comprising an effective amount of the compound represented by or a salt thereof and a pharmaceutically acceptable carrier.

4. A, but leucine residue in the formula, A ₂ Gat Ributofa down residue, X is rhamnose residues, R, but vasospasm therapeutic agents in the range 3 according claims is a hydroxyl group.

5. General formula

0

II

X- PA ₁ -A ₂ -R _] (I)

I

OH

[Wherein, A and A ₂ each represent an amino acid residue, X represents a hydroxyl group or a monosaccharide residue, and represents a hydroxyl group, an alkyl, an alkoxy, an aryl or a general formula.

-N (R ₂ ) (R ₃ )

(Wherein, R ₂ and R ₃ each represent a hydrogen atom or an alkyl).

A method for treating a disease caused by an endoselin converting enzyme, which comprises administering an effective amount of a compound represented by the formula (I) or a salt thereof.

6. —In the general formula, A is a leucine residue, A _{2 is a} tritophane residue, X is a rhamnose residue, and R is a hydroxyl group.

5. A method for treating a disease caused by the endoselin converting enzyme according to 5.

7. —General formula

One N (R ₂ ) (R ₃ )

(Wherein, R ₂ and R ₃ each represent a hydrogen atom or an alkyl).

A method for treating vasospasm, which comprises administering an effective amount of a compound represented by the formula (I) or a salt thereof.

8. The method for treating vasospasm according to claim 7, wherein, in the general formula, A! Is a leucine residue, A _{2 is a} tritophan residue, X is a rhamnose residue, and R 1 is a hydroxyl group.

9. General formula

[Wherein, and A ₂ are amino acid residues, X is a hydroxyl group or a monosaccharide residue, and R] is a hydroxyl group, alkyl, alkody, aryl, or a general formula.

One N (R ₂ ) (R ₃ )

(Wherein, R ₂ and R ₃ each represent a hydrogen atom or an alkyl).

Or a salt thereof.

1 0. - in general formula, A, but leucine residue, A ₂ Gat Ributo fan residue, X is rhamnose residues, but using in the range 9 according claims is a hydroxyl group.

1 1. General formula for the manufacture of an agent for treating vasospasm

0

II

X- PA, -A ₂ -R, (I)

I

0 H

[Wherein, and A ₂ are each an amino acid residue, X is a hydroxyl group or a monosaccharide residue, and R, is a hydroxyl group, alkyl, alkoxy, aryl or a general formula.

-N (R ₂ ) (R ₃ )

(Wherein, R ₂ and R ₃ each represent a hydrogen atom or an alkyl).

Or a salt thereof.

1 2. In the general formula, A, but the mouth leucine residue, A ₂ Gat Ributo fan residue, X is rhamnose residues, R, but using in the range 1 1 wherein according a hydroxyl group.