JPH01157919A - Control treatment agent of hemicrania - Google Patents

Abstract

PURPOSE: To prepare a therapeutic agent, comprising an inhibitor of angiotensin- converting enzymes and, as necessary, a calcium channel blocker and capable of effectively reducing the frequency and severity of migraine during a therapeutic period by systemically administering a therapeutically effective amount thereof for a long period. CONSTITUTION: This inhibiting therapeutic agent for migraine comprises (A) an inhibitor of angiotensin-converting enzymes, e.g. a phosphonate-substituted amino acid or imino acid, a substituted proline derivative, a carboxyalkyl dipeptide derivative, a phosphinylalkanoyl proline derivative or a phosphonamidate derivative and, as necessary, (B) a calcium channel blocker, e.g. diltiazem or 4-phenyl-1,4-dihydropyridine. The dose thereof is preferably within the range of about 0.1-25 mg/kg ingredient A for oral administration when using the ingredient A alone or within the range of about 0.1-25mg/kg ingredient B when using the ingredient A together with the ingredient B and within the range of about 0.01-1 mg/kg ingredient A for parenteral administration when using the ingredient A alone or within the range of about 0.01-2 mg/kg ingredient B when using the ingredient A together with the ingredient B.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a migraine suppressive therapeutic agent, more specifically, an angiotensin-converting enzyme inhibitor (for example, captopril, zofenopril, fosinopril, or enalapril) alone or in combination with a calcium duct blocker (cal) as a medicinal ingredient.
cium channel blocker) (eg diltiazem or nifedipine) for suppressing the symptoms of migraine or treating migraine in mammals.

Structure and Effects of the Invention The present invention provides angiotensin converting enzyme inhibitor [hereinafter referred to as A
CE inhibitors] and optionally calcium tube blockers, which can be administered systemically in therapeutically effective amounts over long periods of time, such as orally or parenterally. Administration can effectively reduce the frequency and/or severity of migraine headaches during the treatment period.

When an ACE inhibitor and a calcium duct blocker are used in combination, the weight ratio of the former to the latter is about 0.1:1 to 10:1;
Preferably, the ratio may be selected within the range of about 0.4:1 to 2.5:1.

Examples of ACE inhibitors that can be used in the present invention include the substituted proline derivatives disclosed in Ondetsutei et al. [-L-proline is preferred), U, S, carboxyalkyl dipeptide derivatives disclosed in Patent No. 4374829 (among them enalapril, i.e. N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline) ) are included.

Other suitable ACE inhibitors include, for example, U.

Phosphonate-substituted amino acids or imino acids or their salts (among others (
S) -1-(6-amino-2-[[hydroxy-(4
-phenylbutyl)phosphinyl]oxy]-1-oxohexyl)-L-proline is preferred) 1, U, S,
Phosphinylalkanoylproline derivatives disclosed in Patent No. 4168267 (fosinopril is preferred among them)
, tLs, mercaptoacyl derivatives of substituted prolines (of which zofenopril is preferred) disclosed in Patent No. 4316906, U, S, phosphinylalkanoylproline derivatives disclosed in Patent No. 4337201, and U, S, Patent No. 4432971 Examples include phosphonamidate derivatives disclosed in No.

Furthermore, other ACE inhibitors used in the present invention include:
Beecham's BRL36 disclosed in European Patent Nos. 80822 and 60668
378, CA, 102 Near 2588v and Jap,
J, Pharmacol, 40:373 (
Chugai's MC-838, U, disclosed in [1986]; Ciba Geigy's CG, disclosed in Patent No. 2103614.
514824, i.e. 3-([1-ethoxycarbonyl-3-phenyl-(Is)-propylcoamino)-2
,3,4,5-tetrahydro-2-oxo-1-(3S
)-benzazepine-1-acetic acid HCt salt and U,
S, CG51661 disclosed in Patent No. 4473575
7, i.e. 3 (S)-[[(Is)-5-amino-1-carboxypentyl]amino)-2,3,4,5
-Tetrahydro-2-oxo-IH-1-benzazepine-1-ethanoic acid, Eur, Therap, Res
, 39:671 (1986) and 40:5
43 (1986), European Patent No. 79-022 and Curr, Ther, Res, 40 Near 4 (1986).
Ramipril (Hoechst) disclosed in 6), Arzne
imittelforschung 35 : 1
254 (1985) (Hoechst), J. Cardiovasc, Pharma
col, 9: 39 (1987), Cilazapril (Hoffman-La-Roche), FEBS Le.
No. 31- disclosed in TT, 165:201 (1984)
2201 (Hoffman-La-Roche), Curr, T.
herap, Res, 37:342 (1985
) and Dinopril (Merck & Co.) disclosed in European Patent Application No. 12-401, U.S. Patent No. 43850
Intrapril (delapril) disclosed in No. 51, Cl1
n, Exp, Pharmacol.

Physiol=10:131 (1983), lentiapril (Santensha's Fenthiapril), J
.

Cardiovasc, Pharmacol, 5
: 643, 655 (1983), Intrapril (Schering Co.), Acta, Pharmac.
ol, Toxicol, 59 (Appendix 5): 17
3 (1986) Spirapril (Schiering)
, Eur, J., Cl1n, Pharmacol,
31:519 (1987).
Quinapril (Warner-Lambert) and Ph
armacologist 26: 243, 2
66 (1984) (Warner-Lambert), namely C3S-(2[R(')R(town)]3R(town)-2-[:2-C(1-(ethoxycarbonyl)-) 3-phenylpropyl]ami/)-1-oxopropyl)-1,2,3,4-tetrahydro-6゜7
-Simethoxy 3-yne quinolin carboxylic acid HCl salt, J. Med, Chem. 26:394 (198
3] includes WY-44221 (WY-S Co., Ltd.) disclosed.

Calcium tube blockers (also referred to as calcium antagonists) that may be used in the present invention include U.

S, disclosed in Patent No. 3562257, 3-(acetyloxy)-5-(2-(dimethylamino)ethyl-2
,3-dihydro-2-(4-methoxyphenyl)-1,
Examples include diltiazem having the chemical name of 5-benzothiazepin-4(5H)-one and the following structural formula.

CH2CH2N (CH3) 2 A calcium antagonist of 4-phenyl-1,4-dihydropyridine can also be used, which has the following structural formula [wherein R and R2 are the same or different, lower alkyl or lower alkoxy (lower alkyl ), and the number of carbon atoms of lower alkyl and lower alkoxy is 1 to 4.] Regarding the above-mentioned compound [Ca and its production method,
U, S, Patent No. 3644627.3485847.34
88359.3574843.3799934.393
2645 and 4154839.

The dihydropyridine calcium antagonist to be incorporated into the inhibitory therapeutic agent of the present invention is nifedipine disclosed in U.S. Patent Nos. 3644627 and 3485847, namely R,
is CH3, R2 is CH3, and No2 is present at the 2nd position,
Compound (C) of formula: is preferred.

Other preferred calcium antagonists of 4-phenyl-1,4-dihydropyridine include U.S. Patent No. 3488
359 and 3574843, i.e. R1 is -(CH2)2oC3H7, R2 is -(C
H2) 20C3H7, a compound in which NO2 is present at the 3rd position [Ca, U, S, Patent Nos. 3799934 and 3932
Nimodipine disclosed in No. 645, i.e., R□ is -(CH
2) 20CH3, R2 is -CH(CH3)2, N02
is present in the 3rd position [C], U, S, Patent No. 379
9934 and 3932645, i.e., Ro is -CH2CH3 and R2 is -CH3
, a compound [C] in which NO2 is present at the 3rd position, and U,
S, Patent Nos. 3799934.3932645 and 41
Nisoldipine disclosed in No. 54839, namely R-
Examples include a compound (C) in which CH3 and R2 are -CH2CH(CH3)2 and NO2 is present at the 2-position. Verapamil can also be used.

To carry out treatment using the inhibitory therapeutic agent of the present invention, the above-mentioned A
The CE inhibitor alone or in combination with a calcium duct blocker may be administered to mammals (e.g. monkeys, dogs, cats, rats and humans) in conventional systemic dosage forms such as tablets, capsules, etc. It may be administered as an elixir or an injectable solution. Such dosage forms may also contain the necessary carrier materials, excipients, lubricants, buffers, antimicrobials, bulking agents (e.g. mannitol), antioxidants (e.g. ascorbic acid or sodium bisulfite), etc. Although oral dosage forms are preferred, parenteral dosage forms such as intramuscular, intraperitoneal or intravenous injection may also achieve satisfactory therapeutic effects.

The dosage should be carefully adjusted according to the age, weight and condition of the patient as well as the route of administration, dosage form, lifestyle habits and desired therapeutic result.

That is, in oral administration, when an ACE inhibitor is used alone, the oi is ~100~/9, preferably about 0.
．． In a dosage range of 1 to 25 Mg/Ni, and when used in combination with a calcium duct blocker, about 0.01 to 10011197 kQ of the calcium duct blocker.

Satisfactory therapeutic results are obtained by preferably using a dosage range of about 0.1 to 2511197 kQ and administering the ACE inhibitor and calcium duct blocker in the same oral dosage form or in separate oral dosage forms administered simultaneously. It will be done.

In preferred oral dosage forms such as tablets or capsules, this is about 0.1-5001q for the ACE inhibitor alone.
, preferably about 125 to 200 M9, more preferably about 25 to 150 M9, and when combined with a calcium tube blocker, about 1 to 350 M9, preferably about 2 to 2
00, more preferably about 30 to 15,031% of calcium duct blocker.

On the other hand, for parenteral administration, the ACE inhibitor alone is typically 0.005 to 10 MfllkQ, preferably about 0.0
When used in a dosage range of 1 to IIIg/19, and in combination with a calcium duct blocker, the calcium duct blocker is about 0.005 to 2 ottv/cti, preferably about 0.
．． It may be used in a dosage range of 0.01 to 2.0 to 9.0%.

The inhibitory therapeutic agent of the present invention can be administered in the above-mentioned dosage form once a day or in divided doses of 2 to 4 times a day. It is prudent to begin administering a low dose combination of an ACE inhibitor and a calcium duct blocker to a patient and gradually increase the dose.

Tablets can be manufactured in various sizes, for example from 50 to 700 kg in total weight, and the tablets contain one or both of the above-mentioned medicinal ingredients, with the remainder being a physiologically active ingredient according to normal pharmaceutical practice. An acceptable carrier or other material is present. Of course, these tablets can be scored to provide discrete amounts. Similar to tablets, gelatin capsules can be manufactured.

Liquid formulations can also be prepared by dissolving or suspending one or both of the above medicinal ingredients in a conventional liquid vehicle acceptable for pharmaceutical administration to a desired dosage of 1 to 4 scoops. can.

Such dosage forms can be administered to patients on a daily basis by administering them 1 to 4 times a day.

Alternatively, to more finely tune the dosing schedule, the two active pharmaceutical ingredients may be administered simultaneously in separate dosage units or at carefully coordinated times. The simultaneous presence of the two medicinal ingredients produces the same result, as blood levels are increased and maintained by a controlled schedule of administration. Each active pharmaceutical ingredient can be formulated separately in separate unit dosage forms by methods similar to those described above.

Combinations of ACE inhibitors and calcium duct blockers are particularly useful in tablets or capsules for oral administration;
preferable.

To prepare the inhibitory therapeutic agent of the present invention, the above-mentioned amount of the medicinal ingredient is added in accordance with pharmaceutical practice in a physiologically acceptable vehicle,
They are combined with carriers, excipients, binders, preservatives, stabilizers, flavoring agents, and the like to form individual dosage units.

The adhesion aids incorporated into the tablets include, for example, binders such as gum tragacanth, gum acacia, cornstarch or gelatin, excipients such as dicalcium phosphate or cellulose, disintegrants such as cornstarch, potato starch, alginic acid, stearic acid or Lubricants such as its magnesium salts, sweetening agents such as sucrose, lactose or saccharin, and flavoring agents such as orange, peppermint, wintergreen or cherry oils. When the dosage unit form is a capsule, it may contain, in addition to the additive ingredients enumerated above, a liquid carrier such as a fatty oil. Various other materials may also be used as coatings or to otherwise modify the exterior surfaces of the unit dosage form. For example, tablets or capsules may be coated with shellac, sugar or both. Elixir syrups contain the active compound, a carrier such as water or alcohol, glycerol as a solubilizer, sucrose as a sweetening agent, preservatives such as methylparaben or propylparaben, a coloring agent, and a flavoring such as cherry or orange. You can.

Many of the medicinal ingredients used in this invention form commonly known pharmaceutically acceptable salts, such as alkali metal salts, other conventional basic salts, or acid addition salts. Accordingly, reference to base materials is intended to include those salts that are known to be substantially equivalent.

These combination preparations are administered chronically, ie, for as long as possible if signs of migraine remain or migraine symptoms persist. Such specific release form dosage forms may be used on a biweekly, weekly, or monthly basis at the dosages described above.

A period of administration of at least 2 weeks, preferably 4 to 6 weeks, is required to obtain minimal efficacy.

The following examples are preferred embodiments of the invention.

Example 1 A captopril formulation suitable for oral administration in the suppression of migraine symptoms or treatment of migraine is described below.

Component 1-C(2S)-3-mercapto-2-methylpropionyl]-L-proline (captopril)
・・・25g cornstarch ・・・・・・・・・
50g gelatin ・・・・・・・・・
7.5g Avicel (microcrystalline cellulose) 25I Magnesium stearate 2
．． From 5g of the above ingredients, 25μ of 1-((2S)
1000 tablets containing -3-mercapto-2-methylpropionyl]-L-proline are manufactured. That is, captopril and corn starch are mixed with an aqueous solution of gelatin, the mixture is dried and ground into a fine powder. Avicel and then magnesium stearate are mixed while being crushed. Then, it is compressed into tablets using a tablet molding machine.
1000 tablets each containing 25 ml of medicinal ingredient are formed and used for the above therapeutic applications.

Example 2 In Example 1, instead of captopril, 50 g of 1
-(3-mercapto-2-D-methylpropanoyl)-
501s9no1- (
3-1 le fy boudo 2-D-if) I/propanoyl)
- forming 1000 tablets containing L-proline;
Used for the same therapeutic applications as in Example 1.

Example 3 Ingredient Captopril ・・・・・・・・・10
0g carbamazepine...4...500
p-lactose song...100j
! Avicel...4...150g cornstarch...50
．． 9 Magnesium stearate ・・・・・・・・・
5g of the above ingredients, each containing 100μ of captopril and 500μ of carbamazepine
Manufacture tablets. That is, captopril, carbamazepine, lactose and Avicel are mixed and then blended with cornstarch. Add magnesium stearate. The dried mixture was compressed into tablets using a tablet machine to form 100 tablets each containing 600 μg of medicinal ingredient.
0 tablets (1205 ■) are formed. An aqueous solution of methylcellulose (Methocel E 15 ) (containing yellow #6 containing lake as a coloring agent) was added to these tablets.
Apply. The resulting tablets are used for the same therapeutic applications as in Example 1.

Example 4 Two-piece #1 gelatin capsules each containing 25,114 Da of captopril and 100 Da of carbamazepine are filled with the following ingredient mixture.

Ingredients Captopril ・・・・・・・・・ 2
5 Magnesium stearate ・・・・・・・・・
7■USP Lactose ・・・・・・
...1931s9 The resulting capsules are used for the same therapeutic applications as in Example 1.

Implementation-5 An injection solution used for the treatment or symptom suppression of migraine (trigeminal neuralgia) is manufactured according to the following procedure.

Captopril ・・・・・・・・・50
0# Methylparaben ・・・・・・・・・
5 ~ Propylparahen ・・・・・・
... 1jl17 Sodium chloride ・
・・・・・・・・・ 25g water for injection (sufficient amount) 51 Add the above captopril, preservative and sodium chloride to 34
of water for injection and adjust the volume to 54 liters. The solution is filtered through a sterile filter and aseptically filled into sterile vials, which are then closed with sterile rubber stoppers. Each vial is 5mQ
injection solution with a liquid concentration of 100η of medicinal ingredients/m
It was ff1. Such an injection solution is used for the above-mentioned therapeutic purposes.

Example 6 In Example 1, N-(1-
Tablets for use in migraine treatment or headache suppression are produced in the same manner, except that ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (enalapril) is used.

Example 7 In Example 5, N-(1-
An injection solution for migraine treatment or migraine suppression is produced in the same manner, except that ethoxycarbonyl-3-phenylpropyl)-L-alanyl-proline (enalapril) is used.

Example 8 A formulation of zofenopril suitable for oral administration in suppressing migraine symptoms or treating migraine is described below.

Ingredients (1(S), 4(S))-1-[3-(benzoylthio)-2-methyl-1-oxopropyl-4-(phenylthio)-L-proline (zofenopril)
・・・・・・・・・100y cornstarch ・・・・・・・・・50g gelatin ・・・・・・・・・7.5y Avicel (microcrystalline cellulose)・
・・・・・・・・・ 25g Magnesium stearate ・・・・・・・・・ 2
．． 1000 tablets each containing 10011 g of zofenopril are manufactured from 5 g of the above ingredients. That is, zofenopril and cornstarch are mixed with an aqueous solution of gelatin, the mixture is dried and ground into a fine powder. Avicel and then magnesium stearate are mixed while being crushed. It is then compressed in a tablet machine to form 1000 tablets, each containing 100 ml of medicinal ingredient, which are used for the above-mentioned therapeutic applications.

Example 9 In Example 8, 100 instead of zofenopril,
1000 tablets containing 100 mg of fosinopril each are formed and used for the same therapeutic application as Example 8.

Example 10 Ingredient Fosinopril ・・・・・・・・・20
0g carbamazepine ・・・・・・・・・
200g lactose ・・・・・・
...100.9 Avisel...
・・・・・・150g cornstarch
・・・・・・・・・ 50g Magnesium Stearate ・・・・・・・・・ 5g from above bones, 200ml each of Fosinopril and 200III! 7
1000 tablets containing carbamazepine are manufactured. That is, fosinopril, carbamazepine, lactose and Avicel are mixed and then blended with cornstarch. Add magnesium stearate.

The dried mixture is compressed in a tablet machine to form 1000 tablets (705q) each containing 40014g of active ingredient. Methylce/L in these tablets
/Apply an aqueous solution of Rho x (Methocel E 15) containing yellow #6 containing lake as colorant. The resulting tablets are used for the treatment of migraines or for the suppression of headaches.

Example 11 In Example II, 1-(
N-(Hydroxy(4-phenylbutyl)phosphinyl)-L-alanyl-L-7'loline disodium salt (
Tablets for use in migraine treatment or migraine suppression are produced in the same manner, except that the method described in U.S., Patent No. 4,432,971 is used.

Example 12 In Example 5, 1-(N
-C hydroxy(4-phenylbutyl)phosphinyl]
-L-alanyl)-L-proline disodium salt (U
, S, manufactured according to the description in Patent No. 4432971), an injection solution for use in treating migraine or suppressing headaches is manufactured in the same manner.

Example 13 A captopril-diltiazem formulation suitable for oral administration in the suppression of migraine symptoms or treatment of migraine is described below.

Component 1-((2S)-3-mercapto-2-methylpropionyl]-L-proline (captopril)...
...100g diltiazem ...1
00g cornstarch... River...
51' Gelatin ・・・・・・・・・
・ 7.5g Avicel (microcrystalline cellulose) 25g Magnesium stearate 2
．． 1-4 (2S
]-3-Mercapto-2-methylpropionyl)-L-
1000 tablets containing proline and 10011 g of diltiazem are manufactured. That is, captopril, diltiazem and corn starch are mixed with an aqueous solution of gelatin, the mixture is dried and ground into a fine powder.

Avicel and then magnesium stearate are mixed while being crushed. It is then compressed in a tablet machine to form 1000 tablets, each containing 200q of medicinal ingredient, which are used for the above-mentioned therapeutic applications. 9 Example 14 In Example 13, ioog was used instead of captopril.
1-(3-mercapto-2-D-methylpropanoyl)-L-proline of 1001q, respectively.
(3-Mercapto-2-D-methylpropanoyl)-L
- 1 containing proline and 100 μ diltiazem
000 tablets are formed and used for the same therapeutic application as Example 13.

Example 15 Ingredient Captopril 20
0,9' Nianidipine ・・・・・・・・・
...200. p-lactose...
...100g Avicel
・・・・・・・・・150g cornstarch
50 g Magnesium Stearate 5 g From the above bones, 1000 tablets are prepared, each containing 200 μ of captopril and 200 mg of nifedipine. That is, cabtopril, nifedipine, lactose and Avicel are mixed and then blended with cornstarch.

Add magnesium stearate. The dried mixture is compressed in a tablet machine to form 1000 tablets (505 Jl17) each containing 200 ml of active ingredient. These tablets contain methylcellulose (Meth
ocel E 15 ) (containing yellow #6 containing lake as a coloring agent) is applied. The resulting tablets are used for the prevention or treatment of migraine.

Example 16 Two-piece #1 gelatin capsules each containing 250 q of enalapril and 150 q of nitrendipine are filled with the following ingredient mixture.

Ingredient Enalapril ・・・・・・・・・25
011g Nitrendipine ・・・・・・・・・
・・150Mgg Magnesium Stearate ・・・
・・・・・・ 7 Da USP Lactose
...... Capsules containing 193 Mg,
Used to prevent or treat migraine.

Example 17 An injection solution for use in the treatment or prevention of migraine is produced by the following procedure.

Captopril ・・・・・・・・・50
0q Diltiazem・・・・・・・・・
・30011Ig Methylparaben...
・・・・・・ 5,9 propylparaben,
・・・・・・・・・ 1g sodium chloride
25.9 Water for injection (sufficient amount) 51 Captopril, diltiazem, preservative and chloride) Dissolve IJum in 34 Water for injection, Adjust the capacity to 54.

The solution is filtered through a sterile filter and aseptically filled into sterile vials, which are then closed with sterile rubber stoppers. Each vial contained 5 mQ of injection solution, and the solution concentration was 100 Mg active ingredient/mQ.

Example 18 In Example 13, N-(1
-c)-t'zcarbonyl-3-phenylpropyl)-
Using L-alanyl-L-proline (enalapril),
Other than using nifedipine instead of diltiazem,
Tablets for use in migraine prevention or treatment are produced in the same manner.

Example 19 A tablet for use in the treatment or prevention of migraine is produced in the same manner as in Example 13, except that zofenopril is used instead of captopril and nisoldipine is used instead of diltiazem.

Example 20 A tablet for use in the treatment or prevention of migraine is produced in the same manner as in Example 13, except that fosinopril is used instead of captopril.

Example 21 A tablet for use in the treatment or prevention of migraine is produced in the same manner as in Example 13, except that alacepril is used instead of captopril.

Example 22 In Example 13, (S) instead of captopril
-1-(6-amino-2-[[hydroxy(4-phenylbutyl]phosphinyl]oxy]-1-oxohexyl)-L-proline (or dinopril) was used to treat migraine in the same manner. Patent Applicant E.R. Squibb & Sons, Inc.

Claims (1)

[Scope of Claims] 1. A drug for suppressing or treating migraine or symptoms thereof in mammals, comprising an angiotensin-converting enzyme inhibitor and, if necessary, a calcium duct blocker. Suppressive therapeutic agents. 2. The angiotensin converting enzyme inhibitor according to claim 1, wherein the angiotensin converting enzyme inhibitor is a phosphonate-substituted amino acid or imino acid or a salt thereof, a substituted proline derivative, a carboxyalkyl dipeptide derivative, a phosphinylalkanoylproline derivative, or a phosphonamidate derivative. Suppressive therapeutic agents. 3. The inhibitory therapeutic agent according to claim 1, which comprises an angiotensin converting enzyme inhibitor and, if necessary, a calcium tract blocker, mixed with a pharmaceutically acceptable carrier. 4. The inhibitory therapeutic agent according to claim 1, wherein the angiotensin converting enzyme inhibitor is a substituted proline derivative. 5. The inhibitory therapeutic agent according to claim 1, wherein the angiotensin converting enzyme inhibitor is a carboxyalkyl dipeptide derivative. 6. The inhibitory therapeutic agent according to claim 1, wherein the angiotensin converting enzyme inhibitor is a phosphinylalkanoylproline derivative, a phosphonamidate derivative, a phosphonate-substituted amino acid or imino acid, or a salt thereof. 7. The inhibitory therapeutic agent according to claim 1, wherein the angiotensin converting enzyme inhibitor is captopril. 8. The inhibitory therapeutic agent according to claim 1, wherein the angiotensin converting enzyme inhibitor is enalapril. 9. Angiotensin converting enzyme inhibitor is 1-[N-[
Hydroxy(4-phenylbutyl)phosphinyl]-2
-Alanyl]-L-proline or its disodium salt, the inhibitory therapeutic agent according to claim 1. 10. The inhibitory therapeutic agent according to claim 1, which comprises an angiotensin converting enzyme inhibitor and a calcium tube blocker. 11. The calcium duct blocker is diltiazem or 4-
Claim 1 which is phenyl-1,4-dihydropyridine
The inhibitory therapeutic agent according to item 0. 12. The inhibitory therapeutic agent according to claim 11, wherein the 12,4-phenyl-1,4-dihydropyridine is nifedipine. 13. The inhibitory therapeutic agent according to claim 10, wherein the weight ratio of the angiotensin converting enzyme inhibitor to the calcium tube blocker is about 0.1:1 to 10:1.