JPH08143546A - N-substituted-idoindole-1,3-dione derivative - Google Patents

Abstract

PURPOSE: To obtain a new N-substituted isoindole-1,3-dione derivative, having excellent inhibiting actions on blood platelet agglutination, useful as an inhibitor of the blond agglutination and expected of use as a preventing and treating agent for diseases caused by the blood platelet agglutination, especially thrombosis such as cardiac or cerebral infarction. CONSTITUTION: This compound of formula I [A and Rare each a lower alkyl; Q is a heterocyclic group, carboxyl, a substituted phenyl, a cyclic amino, a di-substituted lower alkyl or a cycloalkyl; (n) is 0-4], e.g. N-(2-pyridyl)methyl-4,6- dimethyl-5-ethoxycarbonyl-1H-isoindole-1,3-dione. The compound of formula I is obtained by reacting a compound of formula II with a compound of the formula H2 N-(CH2 )n -Q in or without an inert solvent such as dry DMF at 50-200 deg.C, especially 100-150 deg.C temperature, as necessary, in the coexistence of a desiccant such as molecular sieve.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel N-substituted-isoindole which has a platelet aggregation inhibitory effect and is useful as a drug having the effect of preventing or treating thrombotic diseases.
The present invention relates to a 1,3-dione derivative.

[0002]

2. Description of the Related Art 1H-isoindole-1,3-dione derivatives described in JP-A-56-115773 as having a lower alkyl group at the 4- and 6-positions and a lower alkoxycarbonyl group at the 5-position. However, the substituents on the ring nitrogen are limited to the trans-4-carboxycyclohexylmethyl group.

[0003]

[Problems to be Solved by the Invention] Today, ischemic heart disease,
The causes of death in cardiovascular diseases such as cerebrovascular disease, arteriosclerosis, and hypertension account for a large proportion, and the number of deaths is increasing. Among these circulatory system disorders, thrombosis is a disease in which a blood clot is formed in a blood vessel called a blood clot, or a blood vessel is blocked by a detached blood clot called a blockage, which impairs normal blood flow. Various organs such as cardiopulmonary system, causing functional disorders such as tissues, and thrombus generated due to various causes promote arteriosclerosis as wall pressure thrombus, or when thrombus flowing out into bloodstream becomes embolus, It causes circulatory disorders, and arteriosclerosis and circulatory disorders are considered to be the cause of stroke and myocardial infarction attack. Conventionally, as a compound having an inhibitory effect on platelet aggregation, indomethacin, a non-steroidal anti-inflammatory agent such as aspirin, a pyrazole derivative such as sulfinpyrazone, a pyrimidopyrimidine derivative such as dipyridamole, an adenosine derivative, papaverine and the like are known. However, at present, there is a demand for the development of a drug having a better pharmacological effect and safety.

[0004]

The present invention has the following general formula (I):

Embedded image (In the formula, A and R represent a lower alkyl group, n represents an integer of 0 to 4, and Q represents a heterocyclic group, a carboxyl group, a substituted phenyl group, a cyclic amino group, a disubstituted lower alkyl or a cycloalkyl group.) The present invention relates to a novel N-substituted-isoindole-1,3-dione derivative represented by More specifically, the N-substituted-isoindole-1,3-dione derivative of the present invention is a 1H-isoindole-1,3-dione derivative (alias:
(Phthalimide derivative) having a lower alkyl group at the 4- and 6-positions and a lower alkoxycarbonyl group at the 5-position. The lower alkyl groups of A and R are methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso
It means an alkyl group having 1 to 4 carbon atoms such as -butyl and tert-butyl. Among them, the lower alkyl groups represented by A are preferably the same lower alkyl groups as each other. n represents an integer of 0 to 4 and represents the connected state of nitrogen and Q on the isoindolone ring. The heterocyclic group represented by Q is unsubstituted or substituted pyrrolyl, furyl,
Thienyl, imidazolyl, oxazolyl, thiazolyl,
It means a 5- or 6-membered heterocyclic group such as pyridyl or pyrimidinyl. The substituted phenyl group of Q means a phenyl group having 1 to 3 substituents. The substituents on the heterocyclic group and the phenyl group are methyl, ethyl, n-propyl, is
o-propyl, n-butyl, iso-butyl, tert
A lower alkyl group having 1 to 4 carbon atoms such as butyl or a lower alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, etc. To do.
The cyclic amino group of Q means a 5- or 6-membered cyclic amino group such as pyrrolidino, piperidino, morpholino, piperazino and the like. The di-substituted lower alkylamino group for Q means a dimethylamino group, a diethylamino group and a dipropylamino group. The cycloalkyl group means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. When the compound represented by the general formula (I) is used as a medicine, a tablet, as it is or together with a known excipient,
As a suitable dosage form such as capsules, powders, fine granules, suppositories, injections, creams, aerosols and the like, it can be stably administered generally systemically or locally, orally or parenterally. The dose is appropriately determined according to the symptoms, age, sex, etc. of the subject to be administered, but when orally administered to an adult usually, the compound (I) or a salt thereof is administered in a single dose of 10 to 10 times.
It is preferable to administer about 500 mg about once to several times a day.

Next, a method for producing the compound of the present invention will be described. The compound of the present invention can be obtained by the methods described below, but the scope of the present invention is not limited thereto.

Embedded image A compound represented by the general formula (II) (provided that A and R have the same meaning as described above) and an amine compound represented by the general formula (III) (provided that Q has the same meaning as described above); At 50 to 200 ° C. without solvent or in an inert solvent such as dry benzene, dry toluene, dry xylene, and dry DMF.
The object compound (I) is obtained by heating at (preferably 100 to 150 ° C.) for 1 to 15 hours (preferably 2 to 5 hours). If necessary, a Dean Stark water separator is used, or a drying agent such as a molecular sieve is allowed to coexist in the reaction solution to increase the reaction efficiency.

[0006]

The compound of the present invention exhibits a platelet aggregation inhibitory activity equivalent to or remarkable as aspirin, and is expected to be applied as a preventive or therapeutic drug for thrombotic diseases.

[0007]

EXAMPLES The present invention will be described in more detail below with reference to Examples.
Reveal Of course, the invention is not limited to these examples only.
It is not something to be done. Example 1 3,5-Dimethyl-4-ethoxycarbonyl anhydrous phthalate
1 g of acid and 0.6 g of 2-picolylamine were added to anhydrous DMF5.
It was dissolved in ml and heated with stirring at about 130 ° C. for 3 hours. reaction
After completion of the reaction, add the reaction solution gradually to about 30 ml of ice water and add acetic acid.
It was extracted twice with 20 ml of chill. The extract is magnesium sulfate
Silica gel chromatography
Purify with (eluent; ethyl acetate) to obtain crude crystals. vinegar
Recrystallized with a mixed solvent of ethyl acid and isopropyl ether
1.1 g of N- (2-pyridyl) methyl-4,6-di
Methyl-5-ethoxycarbonyl-1H-isoindole
Le-1,3-dione was obtained. Melting point 126-129 ° C MS 92,293 (base), 309,338 (M⁺) Elemental analysis value (C₁₉H₁₈N 2 O Calculated value C: 67.45 H: 5.36 N: 8.28 Measured value C: 67.60 H: 5.39 N: 8.27 The following compounds were synthesized according to the method of Example 1.

Example 2 N- (2-thiazolyl) -4,6-dimethyl-5-eth
Xycarbonyl-1H-isoindole-1,3-dio
Melting point 138-139 ° C MS 285,301 (base), 330 (M⁺) Elemental analysis value (C₁₆H₁₄N 2 O Calculated value C: 58.17 H: 4.27 N: 8.48 Actual value C: 58.29 H: 4.05 N: 8.70

Example 3 N- (2-furylmethyl) -4,6-dimethyl-5-ethoxycarbonyl-1H-isoindole-1,3-dione Melting point 84-85 ° C MS 282 (base), 327 (M ⁺⁾ elemental analysis (C ₁₈ as H ₁₇ NO5) calculated C: 66.05 H: 5.23 N: 4.28 Found C: 66.21 H: 5.25 N: 4.28

Example 4 N- (3-carboxypropyl) -4,6-dimethyl-
5-ethoxycarbonyl-1H-isoindole-1,
3-dione melting point 138-141 ° C MS 274 (base), 333 (M⁺) Elemental analysis value (C₁₇H₁₉NO 6) Calculated value C: 61.25 H: 5.75 N: 4.20 Actual value C: 61.27 H: 5.88 N: 4.09

Example 5 N-[(3,4-dimethoxyphenyl) ethyl] -4,
6-dimethyl-5-ethoxycarbonyl-1H-isoi
Ndole-1,3-dione Melting point 95-96 ° C MS 366 (base), 411 (M⁺) Elemental analysis value (C_{twenty three}H_{twenty five}NO 6) Calculated value C: 67.14 H: 6.12 N: 3.40 Actual value C: 67.23 H: 6.08 N: 3.41

Example 6 N- (3,4,5-trimethoxyphenyl) -4,6-
Dimethyl-5-ethoxycarbonyl-1H-isoindo
1,3-dione Melting point 182-185 ° C MS 384 (base), 413 (M⁺) Elemental analysis value (C_{twenty two}H_{twenty three}NO 7) Calculated value C: 63.92 H: 5.61 N: 3.39 Actual value C: 64.01 H: 5.73 N: 3.25

Example 7 N- (5-methyl-2-pyridyl) -4,6-dimethyl
-5-Ethoxycarbonyl-1H-isoindole-
1,3-dione Melting point 148-149 ° C MS 309 (base), 338 (M⁺) Elemental analysis value (C₁₉H₁₈N 2 O 4) Calculated value C: 67.45 H: 5.36 N: 8.28 Measured value C: 67.44 H: 5.33 N: 8.29

Example 8 N- (3-Morifolinopropyl) -4,6-dimethyl-
5-ethoxycarbonyl-1H-isoindole-1,
3-dione melting point 105-106 ° C MS 345 (base), 374 (M⁺) Elemental analysis value (C₂₀H₂₆N 2 O 5) Calculated value C: 64.16 H: 7.00 N: 7.48 Measured value C: 64.27 H: 7.08 N: 7.53

Example 9 N- (2-piperidinoethyl) -4,6-dimethyl-5
-Ethoxycarbonyl-1H-isoindole-1,3
-Dione melting point oil MS 329 (base), 358 (M⁺) Elemental analysis value (C₂₀H₂₆N 2 O 4) Calculated value C: 67.02 H: 7.31 N: 7.82 Actual value C: 67.11 H: 7.62 N: 7.99

Example 10 N- (2-diethylaminoethyl) -4,6-dimethyl
-5-Ethoxycarbonyl-1H-isoindole-
1,3-dione Melting point Oil MS 317 (base), 346 (M⁺) Elemental analysis value (C₁₉H₂₆N 2 O 4) Calculated value C: 65.88 H: 7.56 N: 8.09 Actual value C: 65.93 H: 7.28 N: 7.79

Example 11 N-Cyclopropylmethyl-4,6-dimethyl-5-d
Toxycarbonyl-1H-isoindole-1,3-di
On melting point Oil MS 256 (base), 301 (M⁺) Elemental analysis value (C₁₇H₁₉NO Calculated value C: 67.76 H: 6.36 N: 4.65 Actual value C: 68.01 H: 6.29 N: 4.42

Test Example 1 Platelet aggregation inhibitory activity test Using a syringe containing 3.8% sodium citrate (1 volume), 9 volumes of blood are collected from the rabbit carotid artery. The blood was centrifuged and platelet-rich plasma (PRP: 5 × 10 ⁵
Cells / μl). 250 μl of the PRP was placed in a cuvette, heated for 2 minutes in a constant temperature bath of 37 ° C., 20 μl of a solution of the compound of the present invention to be tested [7 × 10 ⁻³ M ethanol solution diluted with tris buffer isotonic saline solution] was added and incubated for 3 minutes. After that, an arachidonic acid solution or a collagen solution, which is an aggregation inducer, is added to induce platelet aggregation (Bor).
n) nephelometry [eg Journal of Physiology; J. Physiol. , 168 , 178, (196
8). The method described above]. Arachidonic acid (100
μM) and collagen (20 μg / ml) to 50% inhibitory concentration against platelet aggregation induced by aspirin as a comparative example. Incidentally, the 50% inhibitory concentration in the table means that, when the aggregating ability of platelets without introducing the present name compound is taken as 100%, it was necessary to suppress the aggregating ability of the platelets by 50% by introducing the compound of the present invention. It means the derivative concentration.

[Table 1]

[0019]

As a result of the test, the compound of the present invention was confirmed to have a prominent platelet aggregation inhibitory activity and is useful as a platelet aggregation inhibitor. Further, diseases caused by platelet aggregation, particularly myocardial infarction, is expected to be used as a prophylactic or therapeutic agent for thrombosis associated with platelet aggregation such as cerebral infarction, and is extremely useful in the pharmaceutical industry as an antithrombotic agent. .

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Claims (3)

[Claims] 1. A compound of the general formula (I) (In the formula, A and R represent a lower alkyl group, n represents an integer of 0 to 4, Q represents a heterocyclic group, a carboxyl group, a substituted phenyl group, a cyclic amino group, a disubstituted lower alkyl group and a cycloalkyl group. N-substituted-isoindole-1,3-dione derivative represented by). 2. An antithrombotic agent containing the compound according to claim 1 as an active ingredient. 3. A platelet aggregation inhibitor containing the compound according to claim 1 as an active ingredient.