JPH03106873A - 1-pyridylphthalazine derivative and inhibitor of blood platelet agglutination containing same derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [pyridyl substitution position is any position of 2-, 3- and 4-positions; R1 is H or methoxy; Y is phenyl shown by formula II (R3 is lower or middle alkyl, halogen, phenyl which may be replaced with cyano or pyrimidinyl; R3 is H, lower alkyl or bonded into R2-N-R3 to form piperidino or morpholino) or group shown by formula -X-R2 (X is O or S)]. EXAMPLE:1-Anilino-4-(3-pyridyl)phthalazine. USE:An inhibitor of blood platelet agglutination having more excellent activity than aspirin and useful for preventing and remedying cerebral thrombosis, cerebral infarct, peripheral arterial atresia, etc. PREPARATION:A 1-pyridyl-4-chlorophthalazine derivative shown by formula III is reacted with an amine, alcohol, phenol, mercaptan or thiophenol in a solvent such as methylene chloride in the presence of a base (e.g. sodium carbonate) at 50-200 deg.C to give a compound shown by formula I.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to l-pyridyl phthalazine derivatives and their pharmacologically acceptable salts having excellent platelet aggregation properties and platelet aggregation containing the same. It concerns inhibitors. [Prior Art] l-Alkylamino-4-phenyl phthalazine has been disclosed as an anti-inflammatory agent in British Patent No. 1303061, and in JP-A No. 6
0-218377 as a circulation improving agent.
Furthermore, 1-anilino-4-phenylphthalazine derivatives are disclosed as platelet aggregation suppressants in JP-A-56-53659, JP-A-56-53660 and JP-A-57-48972. However, there is no suggestion whatsoever regarding phthalazine derivatives having a pyridyl group and their platelet aggregation inhibiting effects.

[Problem to be solved by the invention] In recent years, as the aging society progresses, the increase in serious diseases such as thrombosis has come into focus, and it is particularly important to prevent or treat these diseases using antiplatelet agents. Attempts to do so are attracting attention. Various drugs are used as antiplatelet agents depending on their mechanism of action, but only a few drugs have actually been used clinically, and they are not always satisfactory. The present inventors have conducted extensive research with the aim of obtaining a compound that is highly safe and exhibits excellent medicinal efficacy as a prophylactic or therapeutic agent for various thromboses. As a result, we have found excellent compounds that achieve the intended purpose among l-pyridyl phthalazine derivatives and their pharmacologically acceptable salts, and have completed the present invention. [Means for Solving the Problem] The present invention is based on the following general formula (1) (wherein, the substitution position of the pyridyl group is any of the 2-, 31- and 41-positions, and R' is hydrogen Y represents an atom or a methoxy group.Y represents the following formula (II) [R2 represents a low or intermediate alkyl group that may be linear or branched, or a halogen atom, or a phenyl group or a substituent that may be substituted with a cyano group. represents a pyrimidinyl group that may have R3
represents a hydrogen atom and a lower alkyl group, or R” −
Together with NR3, biveridino group, biperazino group,
[indicates that it may form a morpholino group or an imidazolyl group], or 1- represented by the following formula (I [[X represents oxygen or sulfur, and R2 has the same meaning as above]) This invention relates to a platelet aggregation inhibitor characterized by containing a pyridyl phthalazine derivative, a pharmacologically acceptable salt thereof, or a compound thereof as an effective component. In formula (1), R1 represents a hydrogen atom or a methoxy group, the substitution position of the pyridyl group is any position of the 2,3-1 and 4-1 positions, and R2 is specifically a methyl group, Ethyl group, probyl group, isoprobyl group, n~
butyl group, isobutyl group, sec-butyl group, ter
t-butyl group, neobentyl group, isobentyl group, 1-
Ethylbubutyl group, n-pebutyl group, 3-morpholinobyl group, phenyl L 3-chlorophenyl group, 4-chlorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2. Regarding 4-difluorophenyl group, 4-cyanophenyl group, 4-methylpyrimidin-2-yl group, R3, specific examples include hydrogen atom, methyl group, ethyl group, proyl group, butyl group, pentyl group, Examples of R''N together with R3 include a biperidino group, a piperazino group, a morpholino group, or an imidazolyl group, and X can represent oxygen or sulfur.

The compound of the present invention is a novel compound that has not been described in any literature, and is useful as a platelet aggregation inhibitor. Next, a method for producing the compound of the present invention will be explained.

The compound of the present invention can be synthesized by the method shown in [Reaction Formula 1] below.

(Left below) [Reaction formula-1] (In the formula, Rl and Y have the same meanings as above.) That is, the compound (1) of the present invention can be optionally added to the 1-pyridyl-4-chlorophthalazine derivative [■]. It can be produced by reacting an amine or any alcohol, phenol, mercaptan, or thiophenol. Examples of the solvent used in this reaction include benzene,
Aromatic hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran, dioxane, ethylene glycol diethyl ether and ethylene glycol dimethyl ether, ketones such as acetone and methyl ethyl ketone,
Alkyl halides such as methylene chloride and chloroform, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine, and methanol,
Ethanol, t-butyl alcohol, etc. can be used. The reaction temperature was 50°C to 200'C, and the reaction time was 50°C.
It can be carried out for 1 minute to 24 hours, but it is preferably carried out at 60 to 150°C for 15 minutes to 10 hours. Compounds (EV) used in this reaction, amines, alcohols, phenols, and mercabutane! The ratio of thiophenols used is usually 2 to 5 times the molar amount of the latter to the former. In this reaction, inorganic bases such as sodium carbonate and potassium carbonate, tertiary adamanes such as triethylamine and N,N-jethylaniline, and bases such as sodium hydride can be used. Additionally, excess amounts of amines, alcohols, phenols, mercabutanes, and thiophenols may be used. The starting material compound (IV) of [Reaction formula-1] can be easily synthesized by reacting 4-pyridyl-1(IH) phthalazinone with phosphorus oxychloride.

The platelet aggregation inhibitor of the present invention is effective to some extent on the compound represented by the general formula (1). When the compound (1) of the present invention is used as a pharmaceutical, it can be administered either orally or parenterally. The dosage of compound (1) varies depending on the patient's age, weight, disease severity, etc., but the usual dosage is 5 to 2000 mg per day.
Preferably it is 100 to 500 mg. Furthermore, the compound (1) of the present invention can also be used in the form of a mixture with excipients suitable for oral or parenteral administration. Such excipients include, for example, lactose, satjM, kaolin, crystalline cellulose, corn starch, magnesium stearate, glucose, talc, sodium chloride,
Examples include lecithin, gelatin, peptin, and vegetable oil. In addition, various dosage forms, for example, solid preparations such as tablets, granules, powders, capsules, and pills, can be taken, and stabilizers, wetting agents are added. It may also contain auxiliary agents such as emulsifiers. Furthermore, when administered parenterally, it can be used as an injection. Next, the present invention will be explained with reference to Examples.

[Example 1] 1-chloro-4-(3-pyridyl)phthalazine (20.
0 g) and aniline (23.0 g) were heated and stirred at 100'C for 30 minutes. The solidified reaction solution was dissolved in methylene chloride, and washed successively with a dilute aqueous sodium carbonate solution and water. The organic layer was diluted with Na. S.O. After drying, the solvent was distilled off and the residue was recrystallized from ethanol to obtain 1-anilino-4-(3-bilidyl)phthalazine (19.3 g).

Melting point 204-206℃ TR I/IIIX (Nujol) cm-'
:3360(NH). Mass m/z: 298 (M
”).' +1-NMII (DASO-d!) δ(
+)1111) :7.08(H,t,J=7.3
Hz, 7: Phosphorus-1 {L7.39 (H, t, J=7
．． 9Hz 7: Phosphorus-H) 7.59-7.64 (
ill, dd, J=7.8, 4.8HZ, Virizon-8
) 7.86-8.14 (6H, a+) 8.69-8.77 (2H, m) 8.88-8.89 (IH, d, J = 1.9Hz, Virigi: z-H), 9.35 (IH, s, NH) Elemental analysis (C + wll + Jn) Theoretical value (z): C, 76.49; H, 4.73; N,
18.77. Actual value C%> :C, 76.20;}1
, 4.74; N, 19.05. [Example 2] -Chloro-4-(3-bilidyl)phthalazine (3.0
g) and 2,2-dimethylbrobyluane (4.2
g) was heated and stirred at 100°C for 3.5 hours. The amine was distilled off under reduced pressure, and the residue was dissolved in methylene chloride. The organic layer was washed sequentially with water, dilute NaOH aqueous solution, and water, and then diluted with NazSO
Dry in a. The solid obtained by distilling off the solvent was recrystallized from a mixture of ethanol and isobrobyl ether to obtain l-(2,2-dimethylbrobylamino)-4-
(3-pyridyl)phthalazine (1.4 g) was obtained. Melting point 225-227°C IR νmaw (Nujol). cm-': 326
0 (NH). Mass ts/z: 292(M')
．． }1-NMI? (DMSO-d4) δ (pp
Seagull>: 1.01 (9tl,s,C}I!X3), 3.6
0(2H.d, J=6.OHZ, CI{zc(CH3)
i) 7.40 (IH, t, J=6.0Hz, NH)7
．． 55-7.65 (LH, at pyridine-■), 7.7
5 8.10(411,*) 8.50(IH.d,J=8.O}Iz,'Cnze)-
1{) ,8.75(LH,d,J=7.5Hz,
Viridin-■). 8.82 (18, d, J=2Hz,
Birign-11), elemental analysis cps}It. N4 Theoretical value (X): C, 73.94; H, 6.90; N,
19. 16. Actual value (χ): C. 74.16;H.
4. l6;N. 19.11. [Examples 3 to 22] According to the method of Example 1 or Example 2, Examples 3 to 22
The compound was synthesized. The structural formulas and melting points of the obtained compounds are listed in Table 1. Table 1 Note) The Py item indicates the bonding position of pyridine. 1) P
h- represents a phenyl group, and 4-Cl-Ph- represents a 4-chlorophenyl group. 2) 24-F-Ph- means 2,4-difluorophenyl group. 3) L-Et-Pr- means l-ethylbrobyl group. 4) 3-Mo-Pr- means 3-morpholinobrovir group. 5) diMeo-Ph-Pi- means N-(2,5-dimethoxyphenyl)piperazinyl group. [Execution N23] l-chloro-4-(2-pyridyl)phthalazine (5.6
g) and n-butylbutane (2.2 g) as κ
Ethanol (150 g) in the presence of zcOs (3.5 g)
ml) and heated under reflux for 18 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in methylene chloride, washed with water,
Dry with NazSOa. The residue obtained by distilling off the solvent was recrystallized from isobrobyl ether to obtain 1-butylthio-4-(2-pyridyl)phthalazine (3.0 g). Melting point 63-64°C Mass wIiz: 295(M”).'H-NM
R(DMSO-di) δ(pp-): 0.95 (31
, t. J=7.3Hz. cHi), 1.43-1.5
8 (2H, m, CICHs). 1.74-1.86 (2
11, m, CLLCII. Clh), 3.49 (21+
, t, J=7.3Hz, SCjilCH3) ,
7.61-7.64 (IH, m, benzene-}1)
, 8.01-8.20 (5H, ++). 8.60-8.64 (IH, (Pyridun-■) 8.81
-8.84 (LH, m, viridine-H). elemental analysis
C+J+JhS Theoretical value (χ): C, 69.11; I{, 5.80; N,
14.22. Actual value (χ): C, 69.06; H, 5.
74;N, 14.24. [Example 24] According to the method of Example 23, 1-(4-chlorophenoxy)-4-(3-pyridyl)fuclazine (melting point 166-1
[Example 25] Sodium hydroxide (1.4 g) was dissolved in ethanol (80 °C).
ml>, 2-mercapto-4-methylpyrimidine hydrochloride (2.8 g) was added. After stirring at room temperature for a while, 1-chloro-4-(3-bilidyl)phthalazine (4.0 g) was added, and the mixture was heated under reflux for 3.5 hours. The reaction solution was concentrated to dryness, and the residue was dissolved in methylene chloride, washed with water, and then dried. The solvent was distilled off and the residue was recrystallized from ethanol to give 1-(4-methylpyrimidin-2-ylthio)-4-(3-pyridyl)phthalazine (4.0 g).
Obtained. Melting point 175-177°C Mass mHz: 331(M”).'l{-NM
R([lMSO-d.) δ (ppm): 2.3
7 (3Ls, CL) 7.17-7.19 (IH, d.J=5.1Hz, Virigi:/-H), 7.67-7.73 (18, td, J=
4.9, 0.7Hz, pyridine-H), 8.08-8.
09 (3H4, pyridine-■, phthalacin-H), 8.
25-8.36 (38, m, pyrimidine-H phthalazine-■), 8.84-8.86 (IH dd, J=1
．． 6, 4.9Hz, Viridine-H), 9.01 (IH.
d, J=0.7Hz, pyridine-H) elemental analysis C+a
H+3NsS Theoretical value (X): C, 65.23; H, 3.95; N
, 21.13. Actual value (X): C, 64.96HH,
3.84;N. 21. OO. [Example 26] Ethanol (100 ml) was added with sodium hydroxide (2.
After adding 4 g of sodium hydroxide and dissolving the sodium hydroxide, l-
Chloro-4-(2-biridyl)phthalazine (6.0 g
) and heated under reflux for 3 hours. After evaporating the solvent, the residue was dissolved in methylene chloride, washed with water, and dried. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from ethanol to obtain 1-ethoxy-4-(2-bilidyl)phthalazine (2.4 g). Melting point 129°C Mass s/z: 251 (M”) .IH-N
MR (DMSO-d.) δ (ppm): 1.53
(3H. t, J=7.0Hz, Clls), 4.73
(2H, q, J=7.OH2, CHz). 7.56-7
．． 62 (LH, m, phthalazine-H), 7.98-8.
07 (4H4, pyridine-■, phthalazine-■). 8.
26-8.29 (38, *, pyridin-1 {) 8.57
-8.61 (IH.m.Viridin-H), 8.79-
8.81 (ILa+, viridi:l-1{). elemental analysis
C+sH+JbO Theoretical value (χ): C, 70.56; H, 5.13; N, 1
6.46. Actual value ($): C+ 70.88; H, 5
．． 37;N, 16.76. As a reference example, the method of preparing (IV), which is a raw material compound for the compound of the present invention, will be described below. [Reference example 1] Acetonitrile (150a+1) d4 (3!
:”J Jill) -1 (2H)7 Taraji/n (19.0
g), N,N-diethylaniline (18.0 g)
and phosphorus oxychloride (19.0 g) were added, and the mixture was heated under reflux for 6 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in methylene chloride and neutralized with saturated aqueous NaHCO3 solution. After washing the organic layer with water, it was dried with NazSOa. By recrystallizing the obtained residue from ethanol, 1-chloro-4-(3-biridyl)phthalazine (14.6 g)
I got it. Melting point 175-177°C Mass ts/z: 241(M”).'H
-NMR (DMSO-d!) δ (ppm): 7.
66-7.71 (ill, Tsuru. Pyridine-H), 8.0
3-8.06 (1}1, d, J = 7.9 Hz, Phthalazine-11), 8.14-8.25 (38, 1,) 8.42-8.45 (IH, d. J = 7.9) Iz, phthalacin-H) +8.82-8.85 (IH, dd,
J=4.9, 1.6Hz, P1lshin-H), 8.93
-8.94 (18, d.J=1.5Hz, Viridine-H
), elemental analysis C+J*N3CI 0.1HgO theoretical value (X): C, 64.12; 1, 3.39; N. 17.
25. Actual value (X): C, 64.09; }1, 3.4
2;N, 16.99. (Reference Example 2) In the same manner as Reference Example 1, 4-(2-pyridyl)-1
1-chloro-4-(2-pyridyl)phthalazine (5.6 g) was synthesized from (2H) phthalazinone (9.3 g). Melting point 152-154°C Mass m/z: 241(M”).'H-N?I
Il (DMSO-d!) δ (ppm): 7.64
-7.70(1l(4,Viridine-H)l8.11-
8.22 (4B, s.) 8.39-8.42 (I
II. Seagull, lid 5':/n-H), 8.65-8.68
(11{,m,viridin-II), 8.84-8.87
(IH4, pyridine=H). Elemental analysis C+JsNsC
I Theory {i(X) :C, 64.60; H, 3.34; N
．． 17.57. Actual value (X):C. 64.63;H
, 3.26;N. 17.24. [Reference Example 3] In the same manner as Reference Example 1, 4-(4-pyridyl)1 (2
H) From phthalazinone (10.9 g), 1-chloro-
4-(4-pyridyl)phthalazine (4.6 g) was combined. Melting point 195-198°C Mass I1/2: 241(M”).1{-NM
R(DMSO-dh) δ(+)l)I1):7.
76-7.78 (2H, d, J=5.9Hz, Virigi:
/-H), 8.01-8.04 (IH, d.J=8.2
Hz, phthalazine-1{), 8.13-8.27 (21
1, Ko, Futarajishi = H), 8.41-8.45 (IH
, d, J=8.5Hz, butalazine-H), 8.85-
8.87 (IH, d, pyridine-H). Elemental content tfr
C+2HJ*Cl 0.15LO theoretical value (X): C
, 63.89; H. 3.42;N, 17.19. Actual value (X): C, 64.09; H, 3.39; N. 1
6.89. [Formulation example as a platelet aggregation inhibitor] [Formulation example 1] Active substance 50mg Lactose 200mg Crystalline cellulose 40mg Magnesium stearate 5Ilg The above mixture was mixed in a conventional manner and the tablets containing 50 kg of crude drug were obtained by beating. Ta.

(!! Formulation example 2) Active substance 50vag lactose
90g corn lees 50mg talc
30mg magnesium stearate 1
0+sg The above mixture is granulated according to a conventional method to obtain granules.

(Formulation Example 3) Active substance 10s+g Solubilizing agent (used as desired) Appropriate amount of sodium chloride (used as desired) Appropriate amount of distilled water for injection It
! The above ingredients are mixed according to a conventional method, filled into ampoules and sterilized to prepare ampoules for injection.

[Pharmacological experiment]

(1) Platelet aggregation inhibitory effect The platelet aggregation inhibitory effect of the compound of the present invention was determined by the Born method (G
J. Born, Nature, 927-929. (1
962) ). Specifically, citrated blood was collected from a Japanese white male rabbit, and centrifuged to collect plasma with a high platelet count of 4 (PRP) and serum vi. ?
Blood with low a grade H (PPP) was obtained. Then test compound 1. dissolved in dimethyl sulfoxide (DMSO) was added.
5 μl was added to 270 μl of PRP, and after incubation at 37°C for 1 minute, arachidonic acid (AA) was added to induce aggregation. Platelet aggregation was measured with NKK hematotracer at 50% imprint concentration (IC,) of the test compound.

μM) was determined from the concentration inhibition rate curve. Note that aspirin was used as a control drug. The results of representative examples are shown in Table 2.

Table 2 (2) Effect on arachidonic acid (u)-induced pulmonary thrombosis death model Method of Silver et al. (Science, 1fJiL)
1085 (1974)). That is, AA (1.6s+g/kg) dissolved in 0.1M sodium carbonate was administered to Japanese white male rabbits that had been fasted for 24 hours.
was administered into the ear vein to induce pulmonary thrombosis caused by platelet aggregation. The test compound was administered at 100 mg 1 hour before administration.
/kg was administered orally. The effectiveness was determined based on the mortality rate 5 hours after AA administration.

The results are shown in Table 3.

(3) Effect on arachidonic acid (AA)-induced mouse thrombocytopenia model using the method of Griffatt et al. (Griffatt et al., 3', J
, Pharmacol. Yu L697, (1981)
) was used as a reference. Specifically, AA (15 mg/kg) dissolved in 0.1 M sodium carbonate was administered intravenously to ady male mice that had been fasted for 16 hours. After 15 seconds, IOXEDTA was administered by cardiac puncture without anesthesia.
・2Na 10! 0.1 for the syringe containing jl! d Blood is collected and the number of platelets is measured using an automatic platelet counter (Toa Medical Electronics,
PL-110). The test compound was orally administered at 100 mg/kg 1 hour before AA administration. The effect is IOOX the activity of aspirin (300mg/kg, p.o.)
It was shown as The results are shown in Table 4. [Toxicity test] (1) Mouse acute toxicity test example no. Test compounds 1.5 and 6.8 were each suspended in a 0.5% carboxymethylcellulose aqueous solution,
The drug was orally administered to ddy male mice (5 mice per group), and symptoms were observed for 7 days after administration.

As a result, for each compound, 1000mg/
No deaths were observed in patients administered 1 kg. [Effects of the Invention] The compound of the present invention has extremely low toxicity in toxicity experiments using mice, and its pharmacological action is stronger than aspirin in producing platelet aggregation in vitro, and it can be used as an antithrombotic drug. For example, it exhibits excellent effects in the prevention and treatment of cerebral thrombosis, cerebral infarction, peripheral arteriovenous occlusion, etc.

Claims (2)

[Claims] (1) General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, the substitution position of the pyridyl group indicates any position at the 2-, 3-, or 4-position, and R^1 represents a hydrogen atom or a methoxy group, Y is the following formula [II] ▲ Numerical formula, chemical formula, table, etc. ▼ [II] Represents a halogen atom, a phenyl group that may be substituted with a cyano group, or a pyrimidinyl group that may have a substituent, R^3 represents a hydrogen atom and a lower alkyl group, or R^2-N-R^3 Indicates that they can be taken together to form a piperidino group, piperazino group, morpholino group or imidazolyl group], or the following formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [III] [X is oxygen or 1-pyridylphthalazine derivatives and pharmacologically acceptable salts thereof. (2) A platelet aggregation inhibitor containing the compound of general formula [I] according to claim 1 as an active ingredient.