JPH04211666A - 4-phenylphthalazine derivative - Google Patents

Abstract

PURPOSE:To obtain a new 4-phthalazine derivative, having powerful inhibitory action on blood platelet agglutination and further direct action on contraction of cardiac infarction lesions even by oral administration as a preventive and therapeutic agent for cerebral angiopathy, ischemic cardiopathy and circulation disorder. CONSTITUTION:A compound, e.g. D-1-alpha-methylbenzylamino-4-phenylphthalazine expressed by formula I [R<1> is 1-5C alkyl or 1-5C hydroxyalkyl; R<2> is H or 1-5C alkyl or R<1> and R<2> mutually link to form 2-6C alkylene which may have 0; R<3> to R<5> are H, halogen, 1-4C alkyl or 1-4C alkoxy; the adjacent R<3> and R<4> or R<5> may mutually form 0(CH2)pO (p is 1, 2 or 3) or further R<5> is CF3 or OH; l and m are 1 or 2; m is 1, 2 or 3], its optical antipode or pharmaceutically permissible acid addition salt. The aforementioned compound is obtained by reacting a compound expressed by formula V with a compound expressed by formula VI and useful as a preventive and therapeutic agent for cerebral thrombosis, cerebral embolism, cardiac infarction, peripheral circulation disorder, etc.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention has a platelet aggregation inhibiting effect, and is therefore used as a preventive treatment for cerebrovascular disorders such as cerebral thrombosis and cerebral emboli, ischemic heart diseases such as myocardial infarction, and circulatory disorders such as peripheral circulatory disorders. Useful aminophthalazine derivatives, more particularly 1-α-substituted benzylamino-4-
The present invention relates to phenyl phthalazine derivatives or pharmaceutically acceptable acid addition salts thereof.

0002

[Prior Art] Circulatory disorders such as myocardial infarction, ischemic heart diseases such as angina, cerebrovascular disorders such as cerebral thrombosis and cerebral embolism, and peripheral circulatory disorders are often caused by the formation of blood clots within blood vessels. is caused by blockage. Platelet aggregation, which occurs at the initial stage of thrombus formation, is an important factor in this.

Conventionally, various 4-phenylphthalazine derivatives have been known as compounds having the effect of inhibiting platelet aggregation. For example, JP-A-56-5365
Publication No. 9, Publication No. 56-53660 and Publication No. 57-4
No. 897 discloses a 1-anilino-4-phenyl phthalazine derivative, and JP-A-60-218377 and JP-A No. 60-243074 disclose the following two compounds, which have strong in vitro properties. It is disclosed that it has a platelet aggregation inhibitory effect.

[Case 2]

[Chemical formula 3]

[0004] However, these compounds show almost no effect when administered orally, and their platelet aggregation inhibiting effects in actual in vivo systems cannot be said to be sufficient. On the other hand, British Patent No. 1303016, Journal of Medicinal Chemistry (J.Med.Chem.
．． ), 12, 555 (1969), etc. (IV)
1-Amino-4-phenylphthalazine derivatives of the formula are disclosed.

##STR00004## However, the structures of the specifically disclosed compounds are limited, and only anti-inflammatory and anti-rheumatic actions have been described regarding their pharmacological actions.

[0005]

[Means for Solving the Problems] The present inventors have discovered that among 4-phenylphthalazine derivatives, they have an excellent platelet aggregation inhibitory effect even in vivo, and furthermore, they have been found to have an excellent platelet aggregation inhibiting effect in the in vivo system, and furthermore, they have been found to As a result of searching for compounds that also have the effect of directly suppressing the harmful changes in , we have completed the present invention.

That is, the gist of the present invention is the following formula (I):

[Formula, R1 represents an alkyl group having 1 to 5 carbon atoms or a hydroxyalkyl group having 1 to 5 carbon atoms, R2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or R1 and R2's are linked together to form an alkylene group having 2 to 6 carbon atoms which may have an oxygen atom. R3 and R
4 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or -O-(C
H2) p-O- (p represents an integer of 1 to 3), R5 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, trifluoromethyl R representing or adjacent to a group or a hydroxyl group
5 to form -O-(CH2)p-O-. l and m each independently represent 1 or 2, and n is 1 to
Represents an integer of 3. 4-phenyl phthalazine derivatives represented by the following formulas, their optical antipodes, or pharmaceutically acceptable acid addition salts thereof.

The present invention will be explained in detail below. The compound of the present invention is represented by the above general formula (I). In the formula, R is a methyl group, an ethyl group, an n-propyl group, an i-propyl group,
n-butyl group, i-butyl group, sec-butyl group, te
rt-butyl group, n-pentyl group, neopentyl group, 1
-C1-C5 alkyl group such as ethylpropyl group or hydroxymethyl group, 2-hydroxyethyl group, 1-
Hydroxyethyl group, 3-hydroxypropyl group, 1-
Methyl-2-hydroxyethyl group, 4-hydroxybutyl group, 1,1-dimethyl-2-hydroxyethyl group, 2
-Represents a hydroxyalkyl group having 1 to 5 carbon atoms such as methyl-3-hydroxypropyl group, 5-hydroxypentyl group, 2,2-dimethyl-3-hydroxypropyl group, and R2 is a hydrogen atom or a methyl group or an ethyl group. , n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, neopentyl group, 1-ethylpropyl group, etc. having 1 to 1 carbon atoms 5 alkyl group, or R1 and R2 are connected to each other to form an ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, -CH
An alkylene group having 2 to 6 carbon atoms which may have an oxygen atom such as 2OCH2- and -CH2CH2OCH2CH2- is formed. R3 and R4 are each independently a hydrogen atom; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom; a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a tert-butyl group, etc. an alkyl group having 1 to 4 carbon atoms; or a methoxy group, an ethoxy group,
Represents an alkoxy group having 1 to 4 carbon atoms such as n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, R5 is hydrogen atom; halogen atom such as fluorine atom, chlorine atom, bromine atom; Methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, tert-
Alkyl group having 1 to 4 carbon atoms such as butyl group; methoxy group, ethoxy group, n-propoxy group, i-propoxy group,
An alkoxy group having 1 to 4 carbon atoms such as n-butoxy group and i-butoxy group; represents a trifluoromethyl group or a hydroxyl group. Furthermore, R3, R4, or R5 may form a methylenedioxy group, an ethylenedioxy group, or a trimethylenedioxy group with adjacent R3, R4, or R5 comrades. l and m each independently represent 1 or 2, and n represents an integer of 1 to 3.

In the present invention, 1) R1 has 1 to 1 carbon atoms;
5 alkyl group or a hydroxyalkyl group having 1 to 3 carbon atoms, R2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or R1 and R2 are connected to each other to form an alkylene group having 4 to 6 carbon atoms. 2) a compound forming R
3 and R4 each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms; and/or 3) R5 is a hydrogen atom, a halogen atom, a compound having a carbon number of 1 to 4; 1 to 4 alkyl groups,
Represents an alkoxy group or trifluoromethyl group having 1 to 4 carbon atoms, or -O-(CH2)p with adjacent R5 comrades
Compounds that form -O- are preferred.

Furthermore, in the present invention, 4) R1 represents an alkyl group having 1 to 5 carbon atoms, R2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or R1 and R2
5) R3 and R4 are each independently a hydrogen atom, a fluorine atom, a chlorine atom, an alkyl group having 1 to 3 carbon atoms, or a C 1 to 3 alkyl group. A compound representing an alkoxy group of 3,
and/or 6) R5 is preferably a compound representing a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. Particularly preferably l,
A compound where m and n are 1.

Specific examples of the compounds of the present invention are shown in Table I below (Tables 1 to 9), which include not only individual isomers but also mixtures thereof. Table-I

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9] Note) The position numbers attached to the structural formula are added for convenience to indicate the positions of substituents, and do not necessarily correspond to the official position numbers of the compound.

Next, the method for producing the compound of the present invention will be explained. The compound of the present invention can be produced by any suitable method, including the following synthetic method.

[Formula 6] (wherein, R1, R2, R3, R4, R5, l, m, and n have the same meanings as above)

This production method consists of reacting the starting material (V) with the compound (VI) in the presence or absence of a solvent and in the presence or absence of a basic catalyst. Starting material (V) is Pharmaceutical Journal, 86 576 (1966)
It can be synthesized according to the method described in .

The reaction temperature is usually 0 to 250°C, preferably 20 to 200°C, and the reaction time is 10 minutes to 24 hours. When using a solvent, ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform and methylene chloride, aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, dimethylformamide, dimethylacetamide, N- Amides such as methylpyrrolidone or dimethyl sulfoxide are used in a weight ratio of 0.1 to 100 relative to compound (V). When using a catalyst, an organic base such as triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, or NaHCO3, Na2C
The molar ratio of an inorganic base such as O3, K2CO3, NaOH, KOH, etc. to compound (V) is usually 0.5 to 5, preferably 1 to 3. The amount of compound (VI) to be used is usually 0.5 to 30, preferably 1 to 10 in molar ratio to compound (V).

After the reaction is completed, if necessary, the solvent is distilled off,
After pouring into a large excess of water or directly dissolving in a solvent such as dichloromethane, it is neutralized with an aqueous alkaline solution and purified by a conventional method such as recrystallization or chromatography.

The salts of the compound represented by formula (I) are preferably physiologically acceptable salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc. salts of inorganic acids, or methanesulfonates, p-
Toluene sulfonate, benzene sulfonate, camphor sulfonate, acetate, benzoate, malate,
Examples include salts of organic acids such as lactate, glycolate, glucuronate, maleate, fumarate, oxalate, ascorbate, citrate, salicylate, nicotinate, tartrate and the like. Since the compound of formula (I) and its salts may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds of the present invention.

When the compound of the present invention is clinically applied as a circulation improving agent, when used orally, it is recommended to
It is preferable to administer 1 to 100 mg once to 3 times a day, and in the case of intravenous injection, 0.01 to 10 mg per dose for adults.
It is preferable to administer 2 to 5 times a day, and in the case of rectal administration, it is preferable to administer 1 to 100 mg at a time, 1 to 3 times a day. Further, it is more preferable that the above dosage is adjusted as appropriate depending on the age, pathological condition, and symptoms.

[0017] For formulation, compound (I) or one or more pharmaceutically acceptable salts thereof are mixed with commonly used pharmaceutical carriers, excipients, and other additives. The carrier may be solid or liquid; examples of solid carriers include lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, acacia, stearic acid, magnesium stearate, lecithin, and sodium chloride. can be mentioned.

Examples of liquid carriers include syrup, glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, water, and the like.

Pharmaceutical formulations can take a variety of dosage forms, including tablets, powders, granules, hard gelatin capsules, suppositories, or troches when solid carriers are used. The amount of solid carrier can vary widely, but
Preferably it is about 1 mg to about 1 g.

When a liquid carrier is used, it can be a syrup, emulsion, soft gelatin capsule, sterile injectable solution such as an ampoule, or an aqueous or non-aqueous suspension.

[0021] The present invention will be explained in more detail with reference to examples below, but the present invention is not limited to the following examples.

[0022]

[Example] Example 1 Synthesis of D-1-α-methylbenzylamino-4-phenylphthalazine (D form of compound No. 1 in Table I) N
- After adding 5.0 g of 1-chloro-4-phenylphthalazine (compound V) and 5.0 g of D-α-methylbenzylamine to 5 ml of methylpyrrolidone, the mixture was
The mixture was heated and stirred at 40°C for 3 hours. After the reaction is completed, cool and
After adding 20 ml of % NaOH aqueous solution, the mixture was extracted with chloroform. The organic layer was dried over MgSO4, concentrated, purified using silica gel column chromatography (eluent: ethyl acetate-n-hexane-chloroform), and recrystallized from ethyl acetate-n-hexane to give D-1- as colorless crystals. α-methylbenzylamino-4-phenylphthalazine 3.31g
I got it. Melting point: 184-185.5°C.

Examples 2 to 38 The compounds shown in Table II below (Tables 10 to 11) were synthesized in the same manner as in Example 1.

Example 39 Synthesis of 1-α,α-dimethylbenzylamino-4-phenylphthalazine (Compound No. 119 in Table I) N
- After adding 1.5 g of 1-chloro-4-phenylphthalazine and 2.1 g of α,α-dimethylbenzylamine to 4 ml of methylpyrrolidone, the mixture was heated and stirred at 160° C. for 6 hours. After the reaction is completed, cool and add 5% NaOH aqueous solution 2.
After adding 0 ml, extraction was performed with chloroform. The organic layer was dried over MgSO4, concentrated, purified by silica gel column chromatography, and recrystallized from chloroform-ether to give 0.79 g of 1-α,α-dimethylbenzylamino-4-phenylphthalazine as colorless crystals. Obtained. Melting point 234-235°C.

Examples 40 to 42 The compounds shown in Table II below were synthesized in the same manner as in Example 39. Table-II

[Table 10]

[Table 11]

Test Example 1 In vitro platelet aggregation inhibitory effect Rat arterial blood was centrifuged to produce platelet-rich plasma (Platelet-rich plasma).
let rich plasma) and 250 μl of it.
After adding 5 μl of the drug solution and incubating for 2 minutes, collagen (Hormon-
Chemie) was added to 3 μg, and the change in platelet aggregation was
Channel platelet aggregometer (Sienco DP247E
Observations and records were made for 10 minutes using a mold). The platelet aggregation inhibition rate was calculated using the following formula. Inhibition rate = (Tc - Ts) / Tc x 100 Tc: Aggregation degree when only solvent is added Ts: Aggregation degree when drug solution is added The inhibition rate at each molar concentration of the compound is shown in Table II
I (Tables 12 to 15).

Test Example 2 Ex Vivo Platelet Aggregation Inhibition Effect (Oral) Male Wistar weighing approximately 250 g
-Eight ST rats were used per group. 4ml/kg of a suspension of each compound in 1% tragacanth aqueous solution
was orally administered, and 1 hour later, blood was collected from the common carotid artery using a cannula. Blood was diluted with 3.8% sodium citrate (1
/10 volumes), stirred by inversion, and centrifuged at 200 x g for 15 minutes. The supernatant was used as platelet-rich plasma (PRP), and the residue was further centrifuged at 2000 x g for 15 minutes. The supernatant was separated and used as platelet-poor plasma (PPP), which was used to measure platelet aggregation ability. To measure platelet aggregation ability, a two-channel platelet aggregometer (Sienco DP) was used.
247E) on a two-pen recorder. Collagen (Hormon-Chemie) at a concentration of 7 to 10 μg/ml was used as the aggregation inducing agent. The inhibition rate of platelet aggregation was calculated using the following formula. Inhibition rate = (A-B)/A x 100 (%) A: Aggregation rate of the group administered with 1% tragacanth solution alone (control group) B: Aggregation rate of the group administered with compound-containing tragacanth solution The results are shown in Table-
It is shown in III.

Table III

[Table 12]

[Table 13]

[Table 14]

[Table 15]

Test Example 3 Effect on myocardial infarction induced by ligation of the rat left coronary artery One group of 8 SD male rats weighing 200 to 250 g were used. The patient was fixed in the dorsal position under light ether anesthesia, and according to the method of Selye et al., a vertical incision of approximately 1.5 cm was made along the left sternal line, the chest was opened, the pericardium was broken, the heart was exposed, and the left main coronary artery was opened from its origin. After ligating with black braided silk suture (Hama Medical Industries, 4-O) at ~2 mm, the heart was returned to its original position and the chest was immediately closed. After compressing the chest on both sides, expelling the air in the chest cavity, and restarting breathing exercises, an electrocardiograph (Nihon Kohden,
ST elevation in induction II was confirmed using ECG-6601). 24 hours after ligation, blood was collected from the abdominal vena cava, the heart was sacrificed by exsanguination, and the central transverse circular section (approximately 2 mm) was dissolved in 0.09 M phosphate buffer (pH 8.6).
%TTC(tryphenyl tetrazoliu)
The mixture was incubated in 20 ml of m chloride (Wako Pure Chemical Industries) at 37° C. for 20 minutes in the dark. Thereafter, the sections were photographed under a stereomicroscope and color slides were created. Project the slide on the wall and examine the cut plane and the infarcted area (TT
C, non-stained area) and non-infarcted area (TTC-stained area) were traced, and the area of the infarcted area in the total cross-sectional area was calculated. The drug was suspended in a 1% aqueous tragacanth solution and orally administered 60 minutes before coronary artery ligation. The suppression rate of myocardial infarction was calculated using the following formula. Suppression rate = (A-B) / A × 100 (%) A: Infarction rate of the group administered with 1% tragacanth solution alone (control group) B: Infarction rate of the group administered with drug-containing tragacanth solution The results are shown in Table-I
V (Table 16). Table-IV

[Table 16]

[0030]

EFFECTS OF THE INVENTION The compounds of the present invention have a strong effect of inhibiting platelet aggregation not only in vitro but also when administered orally, and therefore are useful as preventive and therapeutic agents for various circulatory disorders. Furthermore, with regard to ischemic heart disease, it is considered to be particularly useful because it also has the effect of directly reducing myocardial infarction focus, not based on the platelet aggregation inhibitory effect.

Claims (1)

[Claims] Claim 1: Formula (I): [Formula, R1 represents an alkyl group having 1 to 5 carbon atoms or a hydroxyalkyl group having 1 to 5 carbon atoms, and R2 represents a hydrogen atom or a hydroxyalkyl group having 1 to 5 carbon atoms] -5 alkyl group, or R1 and R2 are linked to each other to form an alkylene group having 2 to 6 carbon atoms which may have an oxygen atom. R3 and R
4 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or -O-(C
H2) p-O- (p represents an integer of 1 to 3), R5 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, trifluoromethyl R representing or adjacent to a group or a hydroxyl group
5 to form -O-(CH2)p-O-. l and m each independently represent 1 or 2, and n is 1 to
Represents an integer of 3. ] A 4-phenylphthalazine derivative, its optical antipode, or a pharmaceutically acceptable acid addition salt thereof.