JPH03284669A - 4-phenylphthlazine derivative - 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] [Industrial Application Fields] The present invention has a platelet aggregation inhibiting effect, thereby preventing cerebrovascular disorders such as cerebral thrombosis and cerebral emboli, ischemic heart diseases such as myocardial infarction, and peripheral circulatory disorders. Aminophthalazine derivatives useful as preventive and therapeutic agents for circulatory disorders, more specifically 1
-(3-hydroxy 2,2-dimethylpropylamino)
-4-Phenylphthalazine derivatives or pharmaceutically acceptable acid addition salts thereof.

[Prior art and problems to be solved by the invention] In many cases, circulatory disorders such as myocardial infarction, ischemic heart diseases such as angina pectoris, cerebrovascular disorders such as cerebral thrombosis and cerebral embolism, and peripheral circulatory disorders It is caused when a blood clot forms inside the blood vessel and blocks it. 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 suppressing such platelet aggregation. for example! Kaikai 5e, -53659 publication,
No. 56-53660 and No. 57-4897 disclose 1-anilino-4-phenylphthalazine derivatives,
Also, JP-A No. 60-218377 and JP-A No. 60-2
Publication No. 43074 discloses the following two compounds, which are disclosed to have a strong platelet aggregation inhibiting effect in vitro.

Le of Medicinal Chemistry (J, Me
d.

Chem, ), Sat. 2,555 (1969), etc. below (
IV) 1-amino-4-phenylphthalazine derivatives of the formula are disclosed.

CI(.

CB, C)] 9 However, these compounds showed almost no effect when administered orally, and their platelet aggregation inhibitory effects in actual in vivo systems were not sufficient.

On the other hand, British Patent No. 1303016, Jharna However,
The structures of the specifically disclosed compounds are limited, and their pharmacological effects are only described as anti-inflammatory and anti-rheumatic.

[Means for Solving the Problems] The present inventors have discovered that among 4-phenylphthalazine derivatives,
As a result of searching for a compound that has an excellent platelet aggregation inhibitory effect in vivo and also has the effect of directly suppressing detrimental changes at the lesion site such as myocardial infarction lesion reduction, we found that 4-phenylphthalazine was found. The present inventors have discovered that a compound in which the first position of the skeleton is substituted with a specific α-hydroxyalkyl amine 7 group satisfies these requirements, and has completed the present invention.

That is, the gist of the present invention is the following formula (1) [wherein R1 is a hydrogen atom, a halogen atom, and a carbon number of 1 to 4]
represents an alkyl group or an alkyl group having 1 to 4 carbon atoms, R2 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and m and n each independently represent 1 or 2] It consists of 4-phenylphthalazine derivatives and pharmaceutically acceptable salts thereof.

In the following detailed explanation of the present invention, the compound of the present invention is
It is expressed by formula (1). In the formula, R1 is 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, n
- Straight chain or branched alkyl group having 1 to 4 carbon atoms such as butyl group, tert-butyl group: or methoxy group, ethquine group, n-propoxy group, i-propoquine group, n-butoxy group, 1-butoxy group R' represents a straight chain or branched alkoxy group having 1 to 4 carbon atoms, such as a hydrogen atom or a methyl group, ethyl group, n-propyl group, 1-propyl group, n-butyl group, tert-butyl group. etc. carbon number 1-4
represents a straight-chain or branched alkyl group, m and n
each independently represents 1 or 2.

In the present invention, compounds in which R1 represents a hydrogen atom, a chlorine atom, a methyl group, or an Etquin group, and R2 represents a hydrogen atom or a methyl group are preferred.

Table 1 below shows specific examples of the compounds of the present invention.

Table 1* CH3 This is provided for convenience and does not necessarily correspond to the official position number of the compound of the present invention.

Next, a method for producing the compound of the present invention will be explained.

Compound (I) of the present invention can be produced by any suitable method, and can be easily synthesized, for example, by the method shown below.

C1,.

(In the formula, R1, R2, m, and n have the same meanings as above.) The production method involves starting the starting material (V) in the presence of a solvent or without a solvent, in the presence of a base catalyst or in the absence of a catalyst. 3-
It consists of reacting with hydroquine-2,2-dimethylpropylamine.

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 dimethylanilindo, etc. as compound (V)
The weight ratio is 0.1 to 100.

When using a catalyst, an organic base such as triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, or NaHCO3, Na, Co
8. The molar ratio of an inorganic base such as K, Co5, Na0HSKOH to compound (V) is usually 05 to 5, preferably 1.
~3 uses.

The amount of 3-hydroxy-22-dimethylpropylamine used is usually 0.5 to 30 molar ratio to compound (V).
, preferably 1 to 1o.

After the reaction is complete, if necessary, the solvent is distilled off and the solution is poured into a large excess of water, or dissolved directly in a solvent such as dichloromethane, neutralized with an aqueous alkaline solution, and then subjected to conventional methods such as recrystallization or chromatography. refine.

The salts of the compound represented by formula (1) are preferably physiologically acceptable salts, such as inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate. or methanesulfone Wm, p-toluenesulfonate, benzenesulfonate, camphorsulfonate, acetate, benzoate, malate, lactate, glyfurate, glucuronate, maleic acid L Salts of organic acids such as fumarates, oxalates, ascorbates, citrates, salicylates, nicotinates, tartrates and the like can be mentioned. Since the compound of formula (1) and its salt 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, 1 to 100 doses per dose for adults.
It is preferable to administer x9 1 to 3 times a day, and in the case of intravenous injection, the dose for adults is 0゜0]~10廣9 once per day for 2~3 times a day.
It is preferable to administer 5 times, and in the case of rectal administration, it is preferable to administer 1 to 100 r9 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.

For formulation, compound (1) 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, crystalline cellulose, cornstarch, talc, agar, pectin, acacia, stearic acid, magnesium stearate, lentin, 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 support can vary widely, but is preferably from about 1+H to about 1 g.

If a liquid carrier is used, it can be a sterile injectable solution such as a 70 knob, emulsion, soft gelatin capsule, or even an ampoule or an aqueous or non-aqueous suspension.

The pharmaceutical preparation containing the compound of the present invention thus obtained is
It has an excellent platelet aggregation inhibitory effect and also has a myocardial infarction lesion reduction effect that is not based on the platelet aggregation inhibitory effect. Therefore, it can be a useful therapeutic agent for circulatory disorders.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded.

Example 1 l-(3-hydroxy7-2.2-dimethylbrobylamino)-4-phenylphthalazine (compound No. in Table 1,
Synthesis of 1) After adding 4.2 g of 1-chloro-4 phenyl phthalazine (compound III) and 7.09 g of 3-hydroxy-2,2-dimethylpropylamine to 4MQ of N-methylpyrrolidone, the mixture was heated to 140 ~ The mixture was heated and stirred at 150°C for 5 hours. After the reaction is completed, cool and add 5% Na○1-1 aqueous solution 20x.
Q was added and allowed to cool, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 1-(3-hydroxy-2,2-dimethylflobylamino)-4-phenylphthalazine as colorless crystals.3. I got 29. Melting point: 202°C6 Examples 2 to 10 The compounds shown in Table 2 below were synthesized in the same manner as in Example 1.

Table 2 Hs Test Example 1 In vitro platelet aggregation inhibitory effect
Arterial blood is centrifuged to obtain platelet-rich plasma (P1atel).
et rich plasma) and its 250μρ
After adding 5 μC of drug solution to the platelet and incubating for 2 minutes, collagen (TJ ormo) was added as a platelet aggregation inducer.
n-Chemie) 3μ9, and changes in platelet aggregation were measured using a 2-channel platelet aggregometer (S1enco DP2).
47E model) for 10 minutes.

The platelet aggregation inhibition rate was calculated using the following formula.

Te Aggregation degree Ts when only solvent is added Aggregation degree when drug solution is added The inhibition rate at each molar concentration of the compound is shown in Tables 3 and 4.

Test Example 2 Exνivo platelet aggregation inhibitory effect (oral)
Male Wistar weighing approximately 2,509 lbs.
Eight ST rats were used per group. A solution of fi4d/ky in which each compound was suspended in a 1% tragacanth aqueous solution was administered intravenously [7], and 1 hour later, blood was collected from the common carotid artery using a cannula. Blood was diluted with 38% sodium citrate (1
After stirring by inverting on the hips, centrifugation was performed for 15 minutes at 200XII, the supernatant was used as platelet-rich plasma (PRP), and the residue was further centrifuged at 2000X9 for 15 minutes. Platelet poor plasma (PPP)
and used to measure platelet aggregation ability. The platelet aggregation ability was measured using a 2-channel platelet aggregometer (Model DP247E, S1enco) and recorded on a 2-ben type recorder.

As the aggregation inducing agent, Kolaken (Hormon-Chemie) with a concentration of 7 to 0 μy/uQ was used.

The inhibition rate of platelet aggregation was calculated using the following formula.

A. Aggregation rate B of the group administered with 1% tragacanth solution alone (control group) The results are shown in Tables 3 and 4.

Test Example 3 Effect on myocardial infarction induced by ligation of the left coronary artery in rats Groups of SI) male rats weighing 200-2509
I used two. Fixed in the dorsal position under light ether anesthesia.
According to their method, a vertical incision of approximately 15 cm was made along the left sternal line, the heart was opened, the 8 membranes were broken, and the heart was exposed. After ligating the heart (Medical Jl. 1, 10), the heart was returned to its original position and the eyelids were immediately closed. Both sides of the chest were compressed,
After expelling the air in the thoracic cavity and resuming breathing movements, an electrocardiograph (Nihon Kohden F') was applied.

CG-6601), H-induced octopus was confirmed. 24 hours after ligation, blood was collected from the abdominal vena cava. 1% TTC (tryphenyl tetrazo
liumchloride, Wako Pure Chemical Industries) 20J17!
The ink was heated for 20 minutes at 37°C in the dark.

Thereafter, the sections were photographed under a stereomicroscope and color slides were created. The slide was projected onto the wall, and the cut surface, infarcted area (TTC1-unstained area), and non-infarcted area (TTC-stained area) were traced, and 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.

A: The infarction rate B of the group administered with 1% tragacanth solution alone (control group) and the infarction rate of the group administered with drug-containing tragacanth solution are shown in Table 5.

[Effects of the Invention] The compounds of the present invention have the effect of strongly 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] 1. The following formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a hydrogen atom, a halogen atom, or a carbon number of 1 to
4 alkyl group or an alkoxy group having 1 to 4 carbon atoms, R^2 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, m and n each independently represent 1 or 2] 4-phenylphthalazine derivatives and pharmaceutically acceptable salts thereof.