JPS595183A - 1,4-dihydropyrimidine derivative, manufacture and medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel optically active or racemic forms of 1,4-dihydropyridine derivatives, processes for their production and pharmaceutical compositions.

European Patent No. 150 discloses a wide range of 1,4-dihydropyridine derivatives. UK Patent Application No. 20
No. 37766A discloses a number of other examples of the above derivatives.

The inventors have discovered that a special group of hitherto unknown optically active or racemic forms of 1,4-dihydropyridine derivatives, which are neither specifically disclosed nor suggested herein, exhibit particularly interesting pharmacological behavior. I discovered that it shows.

This invention relates to compounds of formula CI)C, where k□ and R2 are one methyl and the other inpropyl, n-butyl, isobutyl, cyclopentyl, or impropoxyethyl, R3 is hydrogen, or optionally substituted (C , -6) meaning alkyl), and when R3 is hydrogen, it is an optically active form;
When 3 is other than hydrogen, compounds which are in racemic or optically active form, and acid addition salts thereof (hereinafter referred to as compounds of the present invention) are provided.

The compound of formula CI) has two different carboxylic acid ester groups C0 in the 4-position of the 1,4-dihydropyridine ring in the molecule.
It has chiral carbon atoms based on the presence of OR and C00R2. When (Cero)alkyl is substituted, it is preferably substituted with hydroxy, acetoxy, methoxy, ethynyl, dimethylamino, or morpholino. Preferred compounds are K□ and 艮. One is methyl and the other is Hull.

1-N-alkylating a compound represented by (wherein k□ and 2 are the above-mentioned meanings), or 3 (wherein □ and R3 are the above-mentioned meanings, and R4 is a leaving group). ) Group 4 in the optical isomer of the compound represented by 0k
2 (R2 is as defined above), formula CI
) is basic, the present invention provides a method for producing the compound of the present invention, which comprises recovering the compound as it is or in the form of an acid addition salt.

The 1-N-alkylation product of step a) is prepared by adding a suitable alkylating agent, such as an alkyl halide, preferably a base,
For example, it can be produced according to conventional methods by using it in the presence of sodium hydroxide. If the alkyl group is substituted and the substituent group reacts with the halogen functionality, it is preferred to protect it and remove it after alkylation.

The 1-N-alkylation product can be recovered by conventional methods. If the 1-N-alkyl group contains a salt-forming group such as a dimethylamino group or a morpholino group, the 1-N-alkylated product can be prepared as an acid addition salt, e.g. with an organic acid such as fumaric acid. It can be obtained as a salt or as a salt with an inorganic acid such as a hydrohalic acid, for example HQ.

The starting compounds in step a) are known or can be produced from known compounds by methods known per se. In addition, the raw material compound in step a) can be produced in the same manner as in step b) if it is optically active.

The product of step b) can also be used, for example in formula (TI)
It can be prepared according to conventional methods by using starting compounds in which 4 is a leaving group, for example Ofr or an azolide group. Suitable azolide groups include imidazolide groups. In particular, an azolide group such as It is known that it can be easily exchanged with other groups.

Other suitable azolide groups are, for example, 1,2,3-1-riazolide, 1,2,4-1-riazolide, penzotriazolido, benzimidazolide and tetrazolide groups.

The product of step b) also has formula (n) in which R4 is a group O
R5, and p-5 is a chiral hydrocarbon residue containing substantially no epimer form and containing one or more electron-withdrawing groups, or a hydrocarbon residue containing an amine group. can be manufactured according to conventional methods.

Preferred electron-withdrawing groups include phenyl, methoxy or quaternized amine groups.

A preferred amine group is di(CI-4)alkyl amine 7 group. A preferred quaternized amine 7 group is tri(C1-4
) is an alkylamino group. Preferred groups R5 are 2-
(R) -CH30-2-Phenylethyl group or an ethyl group substituted with an electron-withdrawing group or an amino group at the β position, such as a trimethylammonioethyl or dimethylaminoethyl group.

Since the carboxylic acid ester group -C-0-R5 has an electron-withdrawing group or an amino group, it can be reacted with, for example, alcohol λ2011, preferably under basic conditions. In formula (n), R4=0)1 and other compounds also,
A similar reaction can be performed. The final raw hydrochloride can be isolated and purified by methods known per se, if desired and possible in the form of acid addition.

In the optically active compound (II) of step b), R4 is an azolide group or a chiral hydrocarbon residue containing one or more electron-withdrawing groups without substantially containing an epimer form of R4. ) is preferable.

A typical starting compound (n) has two optically active forms (II
b, 1.1) and (Ilb, 1.2) can be produced by the methods shown in Reaction Schemes 1 and 2 below, which show how they can be obtained by chromatographic separation or selective crystallization, respectively. .

Whereas the optically active compound (Ilb, 1.1) of the reaction formula (1) is prepared directly by chromatographic separation of the corresponding diastereoinmer-ester mixture, the optically active compound (Ilb, 1.3) is obtained from a diastereomeric mixture (nb, 1.2) whose components are separated by selective crystallization.

When carried out on an industrial scale, crystallization is a preferred means of resolution over chromatography.

After separation, compounds (nb, 1.1) and (TIb, 1.2
) to obtain the final compound of formula (I).

Both the chiral ester group of compound (11, b, 1.1) and the protonated dimethylaminoethyl ester group of compound (ilb.12) can be converted into an ester group OR2, but in reaction formula The preferred manufacturing method is the direct method.

Although in principle it is possible to prepare the final compound CI) by direct transesterification starting from compound (IIb, 1.2) or more preferably from compound (Xi), a more preferred method is to prepare (compound (XI) ) A strong electron-withdrawing group is created by quaternization (compound (X11)), and the second
The purpose is to enable the salt crystallization and purification of

Similar to compound (Ilb, 1.2), compounds of type (Xl+) can also be transesterified directly to compounds of formula CI). However, by hydrolyzing the ester group, either directly or via the 3-azolido compound (IIb, 1.3),
The 3-carboxylic acid compound (compound (XIIT)) can be converted into the final compound CI), and the reaction can be carried out according to conventional methods to form the formula (XIIT) in good yield and in extremely pure state. can be obtained.

EXAMPLES This invention will be explained below with reference to examples, and at the same time, methods for producing the intermediate compounds shown in reaction formulas (1) and (2) will also be explained.

Example 1 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-1,
2,6-Trimethyl-3-pyridinecarboxylic acid isopropyl ester [(I) Racemic compound production step a)] 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro- 5-methoxycarbonyl-2,
1.5 g of solid powdered potassium hydroxide and 0.84 ml of methyl iodide are added to a solution of 2.5 g of 6-dimethyl-3-pyridinecarboxylic acid isopropyl ester and 40 ml of dimethyl sulfoxide under a nitrogen atmosphere. The mixture is stirred at room temperature. The 1.5 hour rewarmed mixture is poured into ice water and extracted with methylene chloride. The methylene chloride solution is dried over magnesium sulfate and concentrated under reduced pressure.

The title compound was purified by silica gel chromatography using methylene chloride as eluent and chromatography using ether.
Crystallizes from petroleum ether mixture. mp125℃ Example 2 (-) -(S) and (+)-(-R) -4-(2
,1,3-benzoxadiazol-4-yl)-1,
4-dihydro-5-methoxycarbonyl-1,2,6-
) Dimethyl-3-pyridinecarboxylic acid isopropyl ester [(■), enantiomer] a) (+) , -(R) and (-) -(S)-4
-(2,1,,3-penzoxadiazol-4-yl) -11,4-dihydro-5-impropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (2
-(R)-methoxy2-phenylethyl) ester C
(+) (nb, 1.1) and (-) (Tub,
1.1) 1) 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-(I
II-imidazol-1-ylcarbonyl)-2,6-
Dimethyl-3-pyridinecarboxylic acid inpropyl ester (4111) 10.5! i' and ('')-2-meth-4-cy2-7ethylethanol [W, Karms et al.
A solution of 35.09 (manufactured by Hemitsche Berichte Vol. 108, p. 79 (1975)) is heated at 120° C. for 7 hours.

Excess optically active alcohol was heated at 80-110°C under high vacuum.
Distill it away. The residue is dissolved in methylene chloride, the solution is washed with cold 2N hydrochloric acid, dried and concentrated to dryness under reduced pressure.

2) 2-acetyl-3-(2,L3-benzoxadiazol-4-yl)-2-propenoic acid isopropyl ester (■) c (Z) or (E) or (Z) CF,
) Isomer mixture) 3.5P and 3-aminocrotonic acid (2-(R)-methoxy-2-phenylethyl) ester (■) A solution of 3.0i17 in dioxane 100- was heated to reflux temperature for 20 hours. Heat and concentrate to dryness under reduced pressure.

The diastereomeric mixture obtained in 1) or 2) is separated by chromatography on silica gel under 5 atmospheres using hexane-ether (1,5:1) as eluent.

The first eluting compound is crystallized from ethyl acetate-hexane. +np 89°C, [α-120=g46 2° (ethanol).

The second eluting compound is crystallized from ethanol/hexane or methanol/water. mp 127℃, [α
]20-+77° (ethanol).

46 b) (+) -(S) -4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5
-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester C(Ia), enantiomer, reaction step b)] (-) -(S)-4-(2,1,3-benzoxadi azol-4-yl)-1,4-dihydro-5-impropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (2,-(R)-methoxy-2-phenylethyl ester C (nb, 1. 1) (-) 15.3
The sample was placed in a solution of 0.32% sodium and 100% methanol and heated to reflux temperature for 50 hours in a nitrogen atmosphere.

Reduce the volume of the solution by 50% under reduced pressure to 100 m7 of ice water! Add. The mixture is extracted with methylene chloride. The methylene chloride solution is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel under low pressure (flash). Hexane-ether (1:4) is used as eluent. The temperature of the pure (+)-(45)-enantiomer [(Ia)(10)] crystallized from ether-hexane is 142°C.

[α]x76-+9.9° (ethanol, c = 1.
597di) [α] Otsu 0-+6.7° (ethanol, C
=1.5g/city) c) (-) -(S) -4-(2
,1,3-benzoxadiazol-4-yl)-1,
4-dihydro-5-methoxycarbonyl-1,2,6-
1-dimethoxy-3-pyridinecarboxylic acid isopropyl ester [(1), anti-carboxylic acid, reaction step a)) (+)-(45)-(2,1,3-benzoxadiazol-4-yl)- To a solution of 0.7 to 7 of 1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid impropyl ester and 10 of dimethyl sulfoxide, 0.439 of powdered potassium hydroxide is added. After adding 0.23 ml of methyl iodide, the mixture is stirred for 1 hour under nitrogen. The mixture is then poured into ice water and extracted with methylene chloride. The methylene chloride solution is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography under low pressure (flash). Methylene chloride ether (49:1) is used as eluent. The title compound is crystallized from ranithyl hexane. mP92℃. [α3
20-3° (ethanol, C=0.67g46/dJ!,), [α]20 knee 250 [chloroform, C; 1°460 P/d)).

d)(-)-(R)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid Isopropyl ester C (Ia), tetrapod,
Reaction step b)] This compound is the enantiomer (+)-(4 techniques) of a)
Produced from the same method as described in b). mp140℃
[Crystallized from ether hexane]. [α heat beam 6= −
10, to (ethanol, C=1.67F/d]], [
α] total −6.7° (ethanol, C = 1.67 g/d
i).

e) (+)-(艮)-4-(2,1,3-Benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-1,2,6-drimethyl-3-pyridine Carboxylic acid isopropyl ester C(I), enantiomer,
Reaction step a)) This compound is the enantiomer (-)-(4R) of d)
It is produced from the body in the same manner as described in C). mp93℃(
crystallized from ether hexane).

d), [α]20-+23° (chloroform, C-1
゜46 1g/d)).

a) The imidazolide CII+) used in l) is m
4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (IV) with a p of 166°C It is prepared by reacting 1,1-carbonyldiimidazole with a slight excess of 1,1-carbonyldiimidazole in dioxane at 50°C.

ay) is +11p213°C with 4-(2,1,3
-penzoxadiazol-4-yl)-1,4-dihydro-5-impropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (2-cyanoethyl) ester (V) in water-1,2- Dimethoxyethane (2:1)
It is produced by hydrolysis using 3 mol of NaOH at room temperature.

Ester (V) has a mp of 125°C and is an aminocrotonic acid (2-cyanoethyl) ester (VT) all 2-acetyl-3-(2,1,3-benzoxadiazole-
4-yl)-2-propenoic acid isopropyl ester (■
) in dioxane.

The ester (VI) has a mp of 88°C and is obtained by reacting the corresponding acetoacetic acid (2-cyanoethyl) ester with ammonia cassette in benzene.

The ester (■) is obtained by condensation of 2,1,3-benzoxadiazole-4-aldehyde and the corresponding acetoacetic ester in boiling benzene in the presence of a catalytic amount of piperidine and acetic acid.

The ester (V[l) crystallizes as a mixture and mP7
It can be separated into the E isomer at 5°C and the Z isomer at mpss°C.

Example 3 (+)-(S)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-medoxycarbonyl-2,6-dimethyl-3-pyridine Carboxylic acid inpropyl ester CI) [lI (■), reaction step b) ) a) 4-(2,1,,3-benzoxadiazole-
a, 1°4-(2,1,3 -benzoxadiazol-4-yl)-1,4-dihydro-5-(1)L-imidazole-
1-ylcarbonyl)-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester (1111) 5.
0 i7 and 2-dimethylamine ethanol 24.5
ml is heated to boiling temperature in 20 rnl of dioxane for 5 hours. The mixture is extracted with ice water and ethyl acetate. The organic layer is dried over magnesium sulfate, concentrated to dryness under reduced pressure, and the residue is purified by silica gel chromatography. Methylene chloride ether C4:1) is used as eluent. The hydrochloride salt of the product is crystallized from ethanol-ether. mP 150℃.

2-acetyl-3-(2,1,3-benzoxadiazol-4-yl)-2-propenoic acid isopropyl ester (■) (ZE isomer mixture) 182°6 g and 3-
Aminocrotonic acid (2-dimethylaminoethyl) ester 114.7! i' is heated to boiling temperature in a 11 J bottle of dioxane for 16 hours.

The mixture is concentrated to dryness under reduced pressure. The 1-1 residue is converted to the hydrochloride salt and crystallized from ethanol-ether.

b) (-)-(S)-4-(2,1,3-penzoxadiazol-4-yl)-1,4-dihydro-5-impropoxycarbonyl-2,6-simethyl-3-pyridine Carboxylic acid (2-dimethylaminoethyl) ester (
Edited) a) Title compound (IX) 52.6!17 and (-)
-Z0.0-p-toluoyl-(L)-tartaric acid49.
62 was dissolved in 200 ml of heat-improper tool and allowed to stand. Di0.0-p-toluoyl-(L)-tartrate (
X) is generated. Cool to room temperature, separate the formed crystals, and recrystallize from impropanol.
The o2p-1-luoyl (L)-tartrate salt is dried in a high vacuum oven at 90°C. mp146℃. [σ product 0--12
2° (ethanol nope (=1g/dJ2), [α]20
=-156° (ethanol, (=146!7/d i). Add dilute sodium hydroxide to the salt and extract with ether to convert to the title compound (XI). Oily substance 0. [α].-1 45° (ethanol, C=IJ/d)
), [α] Buy. -158° (Ethanonope c-ILi
/d)).

C)(-)-(S)-4-(2,1,3-penzoxadiazol-4-yl)-1,4-dihydro-5-impropoxycarbonyl-2,6-simethyl-3-pyridine Carboxylic acid [2-trimethylammonioethyl) ester (Xll) b) Title compound (Kari) 12.4F was dissolved in methanol 120
- dissolves in After adding 2.34 ml of methyl iodide,
The solution is left at room temperature for 15 hours. The resulting crystals are separated and recrystallized from methanol/ether. mP222℃
. [α] 20 = -75° (Equation 9/-le, c = 19/d
)), [α]20--99° (ethanol, C=lF/d)).

d) (+)-(S)-4-("2,1..3-benzoxadiazol-4-yl)-1,4-dihydro-5-
Impropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (xm) 15 g of iodomethylate (XIl) of C) was mixed with 150 g of dioxane and 300 ml of 2'N aqueous sodium hydroxide solution.
Dissolve in Z and leave at room temperature for 16 hours. While stirring and cooling, the solution is acidified by adding concentrated hydrochloric acid dropwise. After stirring for 30 minutes in a water bath, the formed crystals were separated, washed with ice water, and placed in a high vacuum at 80°C with C=1! i'/di
.

e) C)-(S)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-(
1F(-imidazol-l-ylcarbonyl)-2,6
-Simethyl-3-pyridinecarboxylic acid isopropyl ester (IIb, 1.3) 8.6 g of the acid (Xl[) obtained in d), 975 g of 1,1-carbonyldiimidazole and 190 m7 of dioxane
! The mixture is stirred for 2 hours at a bath temperature of 50°C. The solution is concentrated to dryness under reduced pressure and the residue is purified by chromatography on silica gel under slight pressure using methylene chloride/ethanol (L9:1) as eluent. The product is crystallized from methylene chloride ether. mp 182℃. [α]. -15
0° (ethanol, c=lP/d)), [α]20--
71046 (ethanol, C=ly-/d)).

f>(+)-(s)-4-c2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl Imidazolide (IIb, 1.3) obtained with ester CI) e) 5 i7 and methanol 50r
The solution of nl is heated at reflux temperature for 16 hours and concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica gel under slight pressure using hexane ether (3) as eluent. The product is crystallized from ether hexane. mp141℃. [α] Total = +8° (ethanol, c = 1 g-/d, #), [α] 20-+120 (
Ethanol, C46 = 1'7/(1,/liter.

The following compound is produced in the same manner as in Example 1.

The starting compounds are known or can be produced from known compounds by methods known per se.

and ether removal by HC2) i) by reaction of the compound of Example 8 with acetic anhydride;
Alkylation with x-(CH2) 2-O-CH3 5
) B'r-(, R2-CmiCH alkylation 6
) Alkylation with Cno(CH2)2-N(CH3)2 8) Alkylation of the compound of Example 3f by the method of Example 12 9) Alkylation of the compound of Example 2d by the method of Example 12 This invention The compound has pharmacological activity and is therefore useful as a medicine.

The compounds of this invention exhibit typical calcium antagonist action. They are particularly effective against smooth muscle, as shown by their vasodilatory and hypotensive activity in standard tests.
Shows muscle relaxing effect. For example, an anesthetized cat experiment using tracer microspheres (R. Hopp et al., Ba5ic et al.
Res, Cardiol, Vol. 75 (1980), pp. 747-756 and Vol. 76 (1981), No. 63.
0-6: 38 pages, k.

Hopp et al., J., Cardiovasc., Phar+n.
acol, Vol. 4 (1982), pp. 352-362), the 1-N-alkyl compound of formula (1) is administered by intravenous administration of about 5 to about 200 μl'i/9 Coronary artery dilatation was observed with intravenous administration of A9 or intravenous administration of A9 at about 5 to about 50 μg of the compound with R3=H or about 10 to about 200 μg/7 of the 1-N-alkyl compound.
A decrease in blood pressure was observed with intravenous administration of 7 and intravenous administration of approximately 5 to 50 μg of R3-'H compound/9.

In addition, intentionally spontaneously hypertensive rats [Gerold and Tsuchirki, Alzunaimitzterhorschung, Vol. 18 (1)
968), p. 1285], subcutaneous administration of about 0.1 to about 50 mg/KSI of the 1-N-alkyl compound and about 0.1 to about 10 mP of the 3-H compound.
A decrease in blood pressure was also observed with subcutaneous administration of /Kli'. The title compound of Example 2C produced a 36% reduction in blood pressure in cats at an intravenous dose of 9 to 0.7 m97.

The compounds of this invention are therefore useful for treating coronary artery insufficiency, such as angina pectoris, cerebrovascular insufficiency, such as cerebrovascular accidents such as stroke, and cerebrovascular spasm, peripheral circulation disorders, such as intermittent claudication in the extremities, and It is useful as a calcium channel blocker for the prevention and treatment of attacks such as acute abdominal pain, asthma such as exercise asthma, and hypertension.

In the above applications, the dosage will, of course, vary depending on the compound used, the method of administration and the treatment intended. However, in general, a daily dose of about 50 μg to about 50 mg of the 1-N-alkyl compound or about 50 μg to about 10''+9 of the R3-H compound per 2 body weight of the animal is preferably administered per day.
or as four divided doses or with a sustained release formulation.1. Satisfactory results are obtained when administered with In larger animals, the total daily dose is 1-N-alkyl compound 5
mt; 1 to about 400rn9, R3=H(7) compound 5"ig to about 200rn9, dosage forms suitable for oral administration are l-h-alkyl compound 1.mt;
25 mW to about 200 mW, 1.25 mg to about 100 mW of R-3-H, mixed with a solid or liquid pharmaceutical carrier or diluent. 1
An example of a daily dosage is from about 5 m9 to about 200 mfl of the compound of Example 2C, preferably from about IO to about 50 mfl.

The compounds of this invention can be administered similarly to known standard compounds such as verapamil or diltiazem. The appropriate dosage of a particular compound will vary depending on a number of factors, such as relative activities.

For example, one of the preferred compounds of this invention, the title compound of Example 2C, has been shown to be approximately 5 to about 30 μ7/Ky, especially 15
While effective at an intravenous dose of μ7/7,
About 300 to about 1 for verapamil and diltiazem
It was found that 9,000 μg/intravenous administration was required. Therefore, it is clear that doses equivalent to or lower than this invented dose may be administered.

Preferred compounds are the title compounds of Examples 2b and 2C.

The 1-N-alkylated compound in formula (1), particularly the compound of Example 2C, has the advantage that when administered intravenously, the onset of action is slower and the duration is longer than when administered intraduodenumally.

These compounds exhibit approximately the same activity upon subcutaneous or intravenous administration.

The slow onset and long duration of action, combined with the lack of side effects, make these compounds safer than other 1,4-dihydropyridines for intravenous administration.

Compounds of S-configuration, such as the compounds of Examples 2b and 2C, exhibit better pharmacological properties in terms of their activity than the corresponding R-configuration compounds and racemates.

The compounds of this invention can be administered in free form or, where possible and appropriate, as pharmaceutically acceptable acid addition salts.

Such salts exhibit activity on the same order of magnitude as the free form;
It can be easily produced by conventional methods.

The invention also provides pharmaceutical compositions comprising the compound in free form or, where possible and appropriate, in pharmaceutically acceptable salt form, and a pharmaceutical carrier or diluent.

Such compositions can be in the form of solutions or tablets, for example.

Patent applicant Sand Akchengesellschaft on behalf of
Continued from page 1 Priority claim 06/15/1982 ■Switzerland (CH)
■3693/82 Procedural amendment (salmon) 1 Indication of case Visit, ζ, (A', 23, Relationship with the case of the person making the amendment Patent applicant's address Basel, Switzerland (no street address indicated) Name Sand・Date of Akchengesellschaft 4 Agent 5 amendment order: Contents of spontaneous 7 amendment: In the title of the invention column, “1,4-dihydropyrimidine derivative, manufacturing method and pharmaceutical composition thereof” was replaced with “1,4 -Dihydro-pyridine derivatives, their production methods and pharmaceutical compositions.''

that's all

Claims (1)

[Scope of claims] and R3 means the meaning below, R4 means a leaving group) 4 is the group in the optical isomer of the compound shown by 0k
2 (R2 has the meaning below), and the formula CI
) is basic, the compound of formula (wherein k□ and R2 are methyl and the other isopropyl, n-butyl, isophthyl, cyclopentyl) is recovered as is or in the form of an acid addition salt. , or impropoxyethyl, R3 is hydrogen, or optionally substituted (C
□-6) meaning alkyl), and when R3 is hydrogen, it is an optically active form;
A compound which is in racemic form or optically active form when 3 is other than hydrogen, and a method for producing an acid addition salt thereof. (2) The compound of formula (II) is an azolide or a group Okg
(R5' means a chiral hydrocarbon residue substantially free of its epimeric form and containing one or more electron-withdrawing groups) as defined in step b); A method according to claim 1. (3) The method according to claim 2, wherein in the compound of formula (n), R4 is OR5' and R1 is methyl or isopropyl. (4) Formula CI) substantially as described in any of the Examples
A method for producing a compound or an acid addition salt thereof. (5) A compound of formula (I) and its acid addition salt produced by the method described in claim 1. (6) Compounds of formula CI) as described in claim 1 and acid addition salts thereof. (7) The compound according to claim $6, wherein one of k□ and ni2 is methyl and the other is isopropyl. (8) The compound according to claim 7, wherein R3 is (C□-6)alkyl. (9) The compound according to claim 7, wherein R3 is methyl. (10) The compound according to claim 7, wherein R3 is hydrogen. (121( -) -(S) -4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-
5-Methoxycarbonyl-1,2,6-t+)lf-3-pyridinecarboxylic acid isopropyl ester. +13) (10) -(-5) -4-(2,1,3
-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-1,2,6-drimethyl-3-pyridinecarboxylic acid isopropyl ester. (14) (+) −(S) −4−(2,1,3−
benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-simethyl-3-
Pyridine carboxylic acid isopropyl ester. +15) (-) -(R) -4-(2,1,3-
benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-simethyl-3-
Pyridine carboxylic acid isopropyl ester. +16+ 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-1,2,6-1-tumethyl-3-pyridinecarbo7mn-methyl ester. (1η 4-(2,1,3-benzoxadiazole-
4-yl)-1,4-dihydro-5-methoxycarbonyl-1,2,6-drimethyl-3-pyridinecarboxylic acid isophthyl ester. +18+ 4-(2,1,3-Benzoxacyasol-4-yl)-1,4-dihydro-5-methoxycarbonyl-1,2,6-dolimethyl-3-pyridinecarbonyl cyclopentyl ester. +19] 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-1,2,6-drimethyl-3-pyridinecarboxylic acid 2-inpropoxyethyl ester . +201 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-1-(2-hydroxyethyl)-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid Isopropyl ester. +2111-(2-acetoxyethyl)-4-(2゜1.3-benzoxadiazol-4-yl)-1゜4
-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid inpropyl ester. +221 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-1-(2-methoxyethyl)-2,6-dimethyl-3-pyridinecarboxylic acid Isopropyl ester. f23] 4-(2,1,3-benzoxadiazol-4-yl)-1,4 dihydro-5-methoxycarbonyl-2,6-dimethyl-1-(2-propynyl)
-3-Pyridinecarboxylic acid inpropyl ester. 041 4-(2,1,3-penzoxadiazol-4-yl)-1-(2-dimethylamineethyl)-1
, 4-dihydro-5-methoxycarbonyl-2°6-dimethyl-3-pyridinecarboxylic acid isoflobil ester and its acid addition salt. +251 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-1-1:2-(4-morpholinyl)ethylcou 3- Pyridine carboxylic acid isopropyl ester and its acid addition salts. t'lol C+) -(S) -4-(2,1,3
-benzoxadiazol-4-yl)-1-(2-dimethylaminoethyl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester and its acid addition salt. □□□ (-) -(R) -4-(2,1,3-benzoxadiazol-4-yl)-1-(2-dimethylaminoethyl)-1,4-dihydro-5-methoxycarbonyl -2,6-dimethyl-3-pyridinecarboxylic acid isoflovir ester and its acid addition salt. (2) of formula (II) described in claim 1
91 -Pyridinecarboxylic acid (2-(R)-methoxy-2-phenylethyl) ester of formula (11) as defined in claim 3. (311(+) -(R) -4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-
5-Impropoxycarbonyl-2,6-cymethyl-3
-pyridinecarbonm (2-(R)-methoxy-2-
phenylethyl) ester. (Support) + 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-(I H-imidazol-1-ylcarbonyl)-2,6-dimethyl-3- Pyridine carboxylic acid isopropyl ester. Total (-) -(S) -4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-
(IH-imidazol-1-ylcarbonyl)-2,6
-Simethyl-3-pyridinecarboxylic acid isopropyl ester. +34+ (+) -(I-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-(l H-imidazol-l-ylcarbonyl)
-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester. (351) A compound according to any one of claims 5 to 27, which is used as a medicine. (3G) A compound used in the treatment of coronary artery insufficiency, cerebrovascular insufficiency, peripheral circulation disorder, hypertension, or asthma. A compound according to any one of claims 5 to 27. A pharmaceutical composition comprising a compound according to any one of claims 5 to 27 and a pharmaceutical carrier or diluent. 68) Coronary artery insufficiency, cerebrovascular insufficiency, peripheral circulatory disorder, which consists of administering the compound according to any one of claims 5 to 27 to a subject in need of treatment. , how to treat high blood pressure or asthma.