JPH0240385A - Condensed ring dihydropyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [Ar is (substituted) phenyl or group shown by formula II; X is R<3>N< (R3 is H, lower alkyl or aralkyl) or O: R<1> is H, Iower alkyl, cycloalkyl, OH or lower alkoxycarbonyl; R<2> is nitroxy-substituted alkyl, nitroxy-substituted cycloalkyl or group shown by formula III (R<4> is aralkyl heteroaralkyl; m is 1-3] or an acid addition salt thereof. EXAMPLE:6-Methyl-4-(3-nitrophenyl)-4,7-dihydropyrazolo[3,4-b]pyridine- 5-carboxylic acid 3-nitroxypropyl ester. USE:An antihypertensive and a calcium antagonist. PREPARATION:A 5-amino pyrazole or isoxazole derivative shown by formula IV is reacted with a 2-benzylideneacetoacetic ester derivative shown by formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel fused dihydropyridine derivative useful as a medicine exhibiting antihypertensive and calcium antagonistic effects.

The present inventors synthesized ring-fused dihydropyridine derivatives for the purpose of developing cardiovascular drugs, conducted pharmacological tests on the derivatives, and investigated the structure-activity relationship. It was discovered that the compound exhibits pharmacological activities such as calcium antagonistic action, antihypertensive action, vasodilatory action, hyperlipidemia improving action, and lipid peroxide formation inhibiting action, and has low toxicity.

The present invention was completed after recognizing that the present invention is useful as a medicine for treating circulatory system diseases such as angina pectoris.

Composition of the invention The present invention is.

This invention relates to a fused ring dihydropyridine derivative represented by the general formula or an acid addition salt thereof.

In the above formula, Ar is a nitro group, a halogen lower alkyl group, a halogen lower alkoxy group, a cyano group, or a phenyl group which may have one or two halogen atoms, a hydrogen atom, or a lower alkyl group as a substituent. group, cycloalkyl group.

The hydroxyl group represents a lower alkoxycarbonyl group, and R2
is an alkyl group substituted with a nitroxy group.

Nine cycloalkyl groups substituted with nitroxy groups.

It represents a heteroaralkyl group, and 5m represents an integer of 1 to 3. ) or a cinnamyl group.

In the general formula (1), Ar preferably represents a substituent such as a nitro group, trifluoromethyl, a halogenoalkyl group having 1 to 2 carbon atoms such as 2,2゜2-trifluoroethyl, difluoromethoxy, or trifluoromethoxy. fluoromethoxy,
2. Halogenoalkoxy group having 1 to 2 carbon atoms such as 2-difluoroethoxy, cyano group or 1 or 2
Halogen R3 such as fluorine, chlorine, bromine, and iodine represents a hydrogen atom, a lower alkyl group, or an aral group.

Indicates a kill group. )Ma7? + indicates an oxygen atom, R1 is
and Indicates an aralkyl group.

] or indicates an oxygen atom.

R1 is a hydrogen atom, methyl, ethyl, n-glovir, inglovir, n-butyl, isobutyl.

□□□-butyl, tert-butyl, n-pentyl,
Straight chain or branched alkyl group having 1 to 6 carbon atoms such as n-hexyl; 3 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
to 6 cycloalkyl groups; the hydroxyl groups are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl;

Indicates an alkoxycarbonyl group having 2 to 4 carbon atoms such as isopropoxycarbonyl.

R2 is nitroxy-substituted methyl, ethyl, n-
propyl, isopropyl, n-butyl, isophthyl, n
- Straight-chain or branched alkyl groups having 1 to 10 carbon atoms such as pentyl, n-hexyl, n--, pudel, n-octyl, decyl; substituted with a nitroxy group and then cyclopropyl, cyclobutyl , cyclopentyl.

Syndyl having 3 to 6 carbon atoms such as cyclohexyl,
an aralkyl group such as phenethyl, 3-phenylpropylbenzhydryl or λ3- or 4-pyridylmethyl;4. or 6-pyrimidinylmethyl, furfuryl, 2- or 3-thenyl, 2.4- or 6-thiazolylmethyl, 2.4- or 5-oxasilylmethyl, 2.41- or 5-imidazolylmethyl,
2-penzothiazolylnot'thyl, 2-benzoxasilylmethyl, 2-benzimidazolylmethyl m is 1 to 3
indicates an integer. ] or a cinnamyl group.

In addition, in the above-mentioned substituents, "Riryl group.

The aromatic ring of "aralkyl group and heteroaralkyl group" is
Alkyl groups having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy,
Alkoxy groups having 1 to 3 carbon atoms such as n-propoxy and inpropoxy, fluorine, chlorine, and bromine. It may be substituted with a halogen atom such as iodine.

Particularly suitable compounds in the general formula (1) include:
Ar is a 2- or 3-nitrophenyl group.

2-tL<U3-trifluoromethylphenyl group or t is 2,3-dichlorophenyl group and a! 5. X is an imino group, a benzylimino group, or an oxygen atom, R1 is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an inglovir group, an n-butyl group, a 5ee-butyl group, tart
- an alkyl group having 1 to 4 carbon atoms such as a butyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group,
a 7-chloroalkyl group having 3 to 6 carbon atoms such as a cyclohexyl group; a hydroxyl group or a methoxycarbonyl group; an alkoxycarbonyl group having 2 to 9 carbon atoms such as an ethoxycarbonyl group;

R2 is a 2-nitroxyethyl group, 3-nitroxypropyl group, 2-nitroxyglobyl group, 4-nitroxybutyl group, 5-nitroxybe/thyl group, 6-nitroxyhexyl group, 2,3-dinitroxy Propyl group, alkyl group having 2 to B carbon atoms substituted with nitroxy group such as 1,3-dinitroxyisopropyl group, 2-nitroxycyclopentyl group, 2-nitroxycyclohexyl group, 4-
Substituted with a nitroxy group, such as nitroxycyclohexyl group, and the next cycloalkyl group having 5 or more carbon atoms, 1-
Mention may be made of compounds which are benzyl-3-piperidyl groups or cinnamyl groups.

The compound having the general formula (1) can be converted into a pharmacologically acceptable acid addition salt if necessary, and examples of such salts include hydrochloride, hydrobromide, and hydroiodide. Acid addition salts of mineral acids such as sulfate, acid addition salts of sulfonic acids such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleic acid Salt, fumarate.

Examples include acid addition salts of organic acids such as tartrates and citrates.

It is a compound having the above general formula (1).

Optical isomers based on the asymmetric carbon atom in the alcohol residue forming the 4-position of the condensed dihydropyridine ring or the Iti-1-ste/l/bond, or geometric (cis, trans) isomers depending on the type of alcohol 31i. However, the present invention includes these isomers or mixtures thereof.

The compounds having the general formula (1) obtained by the present invention are exemplified below.

For example, it can be produced by the reaction shown below.

That is, a 5-amino-pyrazole or inoxazole derivative having the general formula and a 2-benzylideneacetoacetate derivative having the general formula are produced by a known method [for example, JP-A-59-118786]. be able to. (&A in the above formula
r, R1, R2 and X have the same meanings as described above. 9 To carry out this process, compound (II) is mixed with preferably equimolar amounts of compound (f), such as methanol, ethanol, isopropyl alcohol.

tert-butyl alcohol, dioxane, dimethylformamide, dimethyl sulfoxide, acetonium) IJ
The reaction is carried out at room temperature in the presence or absence of an organic vehicle such as alcohol, a solvent such as water, or a mixed vehicle thereof, or under heating and normal pressure or increased pressure. Usually in the presence of the above organic vehicle.

It is carried out at normal pressure and at a temperature near the boiling point of the catalyst used.

The reaction time varies depending on K such as the reaction temperature, but is from several hours to several days.

After the completion of the reaction, the target compound (1) is obtained by treating the reaction mixture according to a conventional method, and if necessary, the 5-amino compound is purified using a conventional purification method such as recrystallization method or column chromatography. The pyrazole derivative 1-na) has the general formula R1-Co-01(2-ON
3-ketonitrile of formula R5-NHNH2(I
from hydrazine represented by ll') [for example, -The Chemistry of Hete-
rocyclic Compounds' vol,X
X, 4j-43 pages, W1187 and Wile
y Publisher, New York, 196
4 years], 5-aminoisoxazole derivatives (Ilb,
) can be prepared by known methods from β-ketonitrile (t) and hydroxylamine hydrochloride [for example, "Roda's C
hemistry of 0arbon Compoun
ds” vol, IV-a, 2ni Ed, 244 pages,
S, aof'fe7 and M, F, Ansell
, F! 1sev1er, NewYork, 1888].

In addition, a compound (jD is 1, for example, an aldehyde represented by the formula Ar-CHO and an acetoacetate represented by the general formula CH300CH2000R2) by a known method [for example,
0+Jones “The Kn08’17
elnagel C! ondensation'
□rg, React1ons, Volume 15,
204-(1967)] by dehydration condensation.

The acetoacetate used herein is a diketene and has the formula R
From the alcohol represented by 20H, known methods (for example A
, B., Boese, Jr., industrial an.
a Kngineering Chemistry,
32, p. 16, 1940).

Among the alcohols represented by R20H.

Those having a nitroxy group in the molecule can be prepared using the known method 4, for example, the sacell method of reacting a halogenated alcohol with silver nitrate [
A,y,F'ellis et al,,J,A,O,.
S.

Volume 75, page 407B (1953)] or 1.2-
Method of ring-opening epoxide with nitrogen peroxide or nitric acid [A
,M.,Pujo et al., ,Bull,Soc.
Chim, France 1955, p. 974; P.
L, N1chols Jr, et al.

J, A, C, S, Vol. 75, p. 4255 (1953)].

M;2'(, is produced by reacting among the alcohols represented by R20H. (In the above formula, Ar
, R1, R2, R5, R4, m and X have the same meanings as described above, and Y represents a ].logen atom such as chlorine, bromine, iodine, etc. ] (W (VD) Effects of the Invention The ring-fused dihydropyridine derivative of the present invention having the general formula (1) exhibits significant medicinal efficacy in the following pharmacological tests aimed at antihypertensive action.

Antihypertensive effect The antihypertensive effect was tested by orally administering the sample to spontaneously hypertensive rats (hereinafter referred to as SHR).

A 15-week-old male SHR was anesthetized with sodium bendoparbital (50 nQ/'4 intraperitoneal administration).
θl(8 and Jones method [, T, R1Week8 an
d J, A.

Jones, Proc, Soc, Exptl, Bill
, Mea, , vol. 104, pp. 64B-648 (110
polyethylene cannula 1 in the abdominal aorta according to
The other end of the cannula was brought out of the body and fixed to the neck. One week after the surgery, when the animal has recovered from the shock of the surgery, the other end of the animal's cannula is connected to a blood pressure measuring device, and the blood pressure and heart rate are directly measured without anesthesia or restraint. It was measured. The blood pressure measuring device uses the Laffan et al. method (
P, J, Laffan, A, P+3t8r80n, 8.
W.

Hltch and O, Jeunelot,
(4rd1ovasc uarRe8.

6, pp. 319-324 (1972)] was used.

The test drug was suspended in 0.3% carboxymethyl cellulose and administered orally. The blood pressure and heart rate of the control subjects were observed for 1 hour before administration of the sample, and administration was performed when they became stable. After administering the sample, blood pressure and heart rate were adjusted to 15%.
Measure and compare every minute over 24 hours.

Results 1 For example, the compound of Example 5 exhibited a slower and significantly more sustained hypotensive action than nifedipine or nicardipine.

Compound of Test Drug Example 5: Therefore, the compound having the general formula (1) is useful as a therapeutic agent for circulatory system diseases such as angina pectoris, myocardial infarction, arrhythmia, arteriosclerosis, and cerebrovascular disorders. Examples of dosage forms include tablets, capsules, granules, powders,
Examples include oral administration using syrup, etc., parenteral administration via subcutaneous injection, intravenous injection, and equivalent doses.

These various preparations are prepared according to conventional methods using crude drugs, excipients, binders, disintegrants, and lubricants depending on the purpose.

The formulation can be formulated using adjuvants commonly used in the field of formulation technology, such as flavoring agents, solubilizing agents, and suspending agents. The dosage varies depending on symptoms, age, body weight, etc., administration method, and number of administrations, but is usually about 3η to 30,011 Ig per day for adults, and can be administered once or in divided doses.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 4.7-Sihydropyrazolo[:3,4-b:l pyridine f1.47 (IH, s, N and) + 7.1~
8.1 5 (8H, m.

Ester 5-aminopyrazole 0.50 f (0,006 mol),! -2-(3-nitrobenzylidene)acetoacetic acid 5
The mixture was heated to reflux for an hour. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (toluene:ethyl acetate = 3:1).
) to obtain the desired product as yellowish-white crystals. Recrystallized from toluene/ethyl acetate.

Yield 1.54y ([13%) mp134 S-136
°C engineering R spectrum (KBr) νff1aX 6111:
3200.

312o(>NH), 190()O=O)1g20.
1275880 (, -ON○2) MS spectrum cut m/e: 403 (M+riNM
R spectrum (cDaA!3) δ: 1O(2H, qul
n.

J=5Hz, -CH2]H20H2-), Z5
Q (3H, 8, -OHM,).

4, 15 (2H, t, J = 5Hz, -Co-OH
2-), 4.32 (2H.

Original purple analysis easy. Calculated value (%i) as 17H17N5°7
0.5G, 62; H, 4°25; N, 17.36 Actual value (@C, 5α84; H, 4,39; N, 1″7.3
1 React in the same manner as in Example 1 to obtain the compounds shown in Table 3.

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, Ar is a nitro group, a halogeno lower alkyl group, a halogeno lower alkoxy group, a cyano group, or one or two halogen atoms as a substituent. There are phenyl groups that may have ▲ mathematical formulas, chemical formulas, tables, etc. ▼
represents a group, and X represents a formula ▲ mathematical formula, chemical formula, table, etc. ▼ group (in the formula, R^3 represents a hydrogen atom, lower alkyl group, or aralkyl group) or an oxygen atom, and R^1 represents hydrogen atom,
Indicates a lower alkyl group, cycloalkyl group, hydroxyl group, or lower alkoxycarbonyl group, R^2 is an alkyl group substituted with a nitroxy group, a cycloalkyl group substituted with a nitroxy group, formula ▲ Numerical formula, chemical formula, table, etc. ▼
group (wherein R^4 represents an aralkyl group or a heteroaralkyl group, m represents an integer of 1 to 3) or a cinnamyl group. ] or an acid addition salt thereof.