TREA

4-phenylphthalazine derivatives which inhibit platelet aggregation

Follow

Information

  • Patent Grant
  • 5089494
  • Patent Number
    5,089,494
  • Date Filed
    Wednesday, March 27, 1991
    33 years ago
  • Date Issued
    Tuesday, February 18, 1992
    32 years ago
Information
Abstract
4-Phenylphthalazine derivatives having platelet aggregation inhibitory activity of the formula: ##STR1## wherein R.sup.1 is an alkyl or hydroxyalkyl group of 1-5 carbon atoms; R.sup.2 is a hydrogen atom or an alkyl group of 1-5 carbon atoms; or R.sup.1 and R.sup.2, when taken together, may represent an alkylene group of 2-6 carbon atoms, said group optionally containing one or more oxygen atoms; R.sup.3 and R.sup.4 are independently a hydrogen or halogen atom, an alkyl or alkoxy group of 1-4 carbon atoms, or when two of R.sup.3 are adjacently positioned, (R.sup.3)l may represent a --O--(CH.sub.2).sub.p --O-- group and/or when two of R.sup.4 are adjacently positioned, (R.sup.4).sub.m may represent a --O--(CH.sub.2).sub.p --O-- group; R.sup.5 is a hydrogen or halogen atom, an alkyl or alkoxy group of 1-4 carbon atoms, a trifluoromethyl group or a hydroxy group, or when two of R.sup.5 are adjacently positioned, (R.sup.5).sub.n may represent a --O--(CH.sub.2).sub.p --O-- group; p is an integer of 1-3; l and m are independently an integer of 1-2; and n is an integer of 1-3, and optical isomers and pharmaceutically acceptable acid addition salts thereof.
Description

The present invention relates to aminophthalazine derivatives having platelet aggregation inhibitory activity and thus being useful as prophylactic or therapeutic agents for cerebrovascular diseases such as cerebral thrombosis, cerebral embolus or the like, ischemic heart diseases such as cardiac infarction or the like, and circulatory disorders such as peripheral circular disease. More particularly, this invention is directed to 1-.alpha.-substitutedbenzylamino-4-phenylphthalazine derivatives or their pharmaceutically acceptable acid addition salts.
Ischemic heart diseases such as cardiac infarction, angina pectoris or the like, cerebrovascular diseases such as cerebral thrombosis, cerebral embolus or the like and circulatory disorders such as peripheral circulatory disease are often attributable to generation of intravascular thrombosis which blocks the vessel. This phenomenon is mainly based on the platelet aggregation which takes place at the preliminary stage of thrombosis formation.
Many 4-phenylphthalazine derivatives have heretofore been known as having platelet aggregation-inhibitory activity. For example, Japanese Patent Publication (Kokai) Nos. 53659/1981, 53660/1981 and 4897/1982 disclose 1-anilino-4-phenylphthalazine derivatives, and Japanese Patent Publication (Kokai) Nos. 218377/1985 and 243074/1985 disclose that the following two compounds show potent platelet aggregation-inhibitory activity in vitro. ##STR2##
However, some of these known compounds hardly show the activity when orally administrated, and others have only insufficient platelet aggregation-inhibitory activity in vivo.
On the other hand, 1-amino-4-phenylphthalazine derivatives of the following formula (IV) are disclosed in British Patent No. 1,303,061, J. Med. Chem., 12, 555 (1969) and the like. ##STR3##
However, only a few compounds are specifically disclosed in the above literatures, and as for the pharmacological activity, only antiinflammatory activity and antirheumatic activity are described therein.
As the result of investigations on the 4-phenylphthalazine derivatives to find out compounds having excellent platelet aggregation inhibitory activity in vivo and also having an activity directly inhibiting the undesirable affecting change in the affected region such as shrinkage of cardiac infarction nest or the like, the present inventors have discovered that the 4-phenylphthalazines having special .alpha.-substitutedbenzylamino group at the 1-position suffice the above requirements.
Accordingly, the present invention provides 4-phenylphthalazine derivatives of the following formula (I): ##STR4## wherein R.sup.1 is an alkyl or hydroxyalkyl group of 1-5 carbon atoms; R.sup.2 is a hydrogen atom or an alkyl group of 1-5 carbon atoms; or R.sup.1 and R.sup.2, when taken together, may represent an alkylene group of 2-6 carbon atoms, said group optionally containing one or more oxygen atoms; R.sup.3 and R.sup.4 are independently a hydrogen or halogen atom, an alkyl or alkoxy group of 1-4 carbon atoms, or when two of R.sup.3 are adjacently positioned, (R.sup.3).sub.l may represent a -O-(CH.sub.2).sub.p -O- group and/or when two of R.sup.4 are adjacently positioned, (R.sup.4).sub.m may represent a -O-(CH.sub.2).sub.p -O- group; R.sup.5 is a hydrogen or halogen atom, an alkyl or alkoxy group of 1-4 carbon atoms, a trifluoromethyl group or a hydroxy group, or when two of R.sup.5 are adjacently positioned, (R.sup.5).sub.n may represent a -O-(CH.sub.2).sub.p -O- group; p is an integer of 1-3; l and m are independently an integer of 1-2; and n is an integer of 1-3, and optical isomers and pharmaceutically acceptable acid addition salts thereof. The present invention will be explained below in detail.
In the compounds of the present invention represented by the general formula (I), R.sup.1 is an alkyl group of 1 to 5 carbon atoms such as methyl group, 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, or 1-ethylpropyl group or a hydroxyalkyl group of 1-5 carbon atoms such as 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-methyl-3-hydroxypropyl group, 5-hydroxylpentyl group, or 2,2-dimethyl-3-hydroxypropyl group. R.sup.2 is a hydrogen atom or an alkyl group of 1-5 carbon atoms such as methyl group, 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, or 1-ethylpropyl group. However, R.sup.1 and R.sup.2 may combine together and represent an alkylene group of 2-6 carbon atoms optionally containing one or more oxygen atoms, such as ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, -CH.sub.2 OCH.sub.2 -group, -CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 - group, and the like. R.sup.3 and R.sup.4 are independently hydrogen atom; halogen atom such as fluorine atom, chlorine atom, bromine atom or the like; alkyl group of 1 to 4 carbon atoms such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, tert-butyl group or the like; or alkoxy group of 1 to 4 carbon atoms such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group or the like. R.sup.5 is hydrogen atom; halogen atom such as fluorine atom, chlorine atom, bromine atom or the like; alkyl group of 1 to 4 carbon atoms such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, tert-butyl group or the like; or alkoxy group of 1 to 4 carbon atoms such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group or the like; trifluoromethyl group or hydroxy group. However, two of R.sup.3, R.sup.4 or R.sup.5, when adjacently positioned, may form methylenedioxy group, ethylenedioxy group or trimethylenedioxy group. Finally, l and m are independently an integer of 1 or 2, and n is an integer of 1 to 3.
Preferred compounds of the present invention are those of the formula (I) wherein:
(i) R.sup.1 is an alkyl group of 1-5 carbon atoms or a hydroxyalkyl of 1-3 carbon atoms; R.sup.2 is a hydrogen atom or an alkyl group of 1-5 carbon atoms; or R.sup.1 and R.sup.3, taken together, represent an alkylene group of 4-6 carbon atoms;
(ii) R.sup.3 and R.sup.4 are independently a hydrogen or halogen atom, or an alkyl or alkoxy group of 1-4 carbon atoms; and/or
(iii) R.sup.5 is a hydrogen or halogen atom, an alkyl or alkoxy group of 1-4 carbon atoms, or a trifluoromethyl group; or two of R.sup.5 adjacently positioned represent -O-(CH.sub.2).sub.p -O- group.
More preferred compounds (I) of the present invention are those wherein:
(iv) R.sup.1 is an alkyl group of 1-5 carbon atoms, R.sup.2 is a hydrogen atom or an alkyl group of 1-5 carbon atoms, or R.sup.1 and R.sup.2, taken together, represent an alkylene group of 4-6 carbon atoms;
(v) R.sup.3 and R.sup.4 are independently a hydrogen, fluorine, or chlorine atom, or an alkyl or alkoxy group of 1-3carbon atoms; and/or
(vi) R.sup.5 is a hydrogen or halogen atom, or an alkyl or alkoxyl group of 1-4 carbon atoms.
Most preferred compounds (I) are those in which l, m, and n are 1.
The following Table 1 shows illustrative examples of the compounds in the present invention, but their respective isomers as well as their mixture are included in the present invention.
TABLE 1__________________________________________________________________________ ##STR5##Compound No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5__________________________________________________________________________ 1 CH.sub.3 H H H H 2 CH.sub.2 CH.sub.3 H H H H 3 CH.sub.2 CH.sub.2 CH.sub.3 H H H H 4 CH(CH.sub.3).sub.2 H H H H 5 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H H H H 6 CH.sub.2 CH(CH.sub.3)CH.sub.3 H H H H 7 CH.sub.2 (CH.sub.3)CH.sub.2 CH.sub.3 H H H H 8t-C.sub.4 H.sub.9 H H H H 9 CH.sub.2 (CH.sub.2).sub.3 CH.sub.3 H H H H10 CH.sub.2 C(CH.sub.3).sub.3 H H H H11 CH(CH.sub.2 CH.sub.3).sub.2 H H H H12 CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.3 H H H H13 CH.sub.3 H 4-CH.sub.3 H H14 CH.sub.2 CH.sub.3 H 4-CH.sub.3 H H15t-C.sub.4 H.sub.9 H 4-CH.sub.3 H H16 CH.sub.3 H 4-CH.sub.2 CH.sub.3 H H17 CH.sub.3 H 4-CH.sub.2 CH.sub.2 CH.sub.3 H H18 CH.sub.3 H 4-CH(CH.sub.3).sub.2 H H19 CH.sub.3 H 4-C.sub.4 H.sub.9 H H20 CH.sub.3 H 3-CH.sub.3 H H21 CH.sub.3 H 2-CH.sub.3 H H22 CH.sub.3 H 3,4-diCH.sub.3 H H23 CH.sub.3 H 4-OCH.sub.3 H H24 CH.sub.2 CH.sub.3 H 4-OCH.sub.3 H H25t-C.sub. 4 H.sub.9 H 4-OCH.sub.3 H H26 CH.sub.3 H 4-OCH.sub.2 CH.sub.3 H H27 CH.sub.3 H 4-OCH.sub.2 CH.sub.2 CH.sub.3 H H28 CH.sub.3 H 4-OCH(CH.sub.3).sub.2 H H29 CH.sub.3 H 4-OC.sub.4 H.sub.9 H H30 CH.sub.3 H 3-OCH.sub.3 H H31 CH.sub.3 H 2-OCH.sub.3 H H32 CH.sub.3 H 3,4-diOCH.sub.3 H H33 CH.sub.3 H ##STR6## H H34 CH.sub.3 H 4-Cl H H35 CH.sub.2 CH.sub.3 H 4-Cl H H36t-C.sub.4 H.sub.9 H 4-Cl H H37 CH.sub.3 H 3-Cl H H38 CH.sub.3 H 2-Cl H H39 CH.sub.3 H 3,4-diCl H H40 CH.sub.3 H 4-F H H41 CH.sub.2 CH.sub.3 H 4-F H H42t-C.sub.4 H.sub.9 H 4-F H H43 CH.sub.3 H 4-Br H H44 CH.sub.3 H H 6,7-diCH.sub.3 H45 CH.sub.2 CH.sub. 3 H H 6,7-diCH.sub.3 H46t-C.sub.4 H.sub.9 H H 6,7-diCH.sub.3 H47 CH.sub.3 H H 6,7-diOCH.sub.3 H48 CH.sub.2 CH.sub.3 H H 6,7-diOCH.sub.3 H49t-C.sub.4 H.sub.9 H H H 6,7-diOCH.sub.3 H50 CH.sub.3 H H ##STR7## H51 CH.sub.2 CH.sub.3 H H ##STR8## H52t-C.sub.4 H.sub.9 H H ##STR9## H53 CH.sub.3 H H 6,7-diCl H54 CH.sub.2 CH.sub.3 H H 6,7-diCl H55t-C.sub.4 H.sub.9 H H 6,7-diCl H56 CH.sub.3 H H H 4-CH.sub.357 CH.sub.3 H H H 3-CH.sub.358 CH.sub.3 H H H 2-CH.sub.359 CH.sub.3 H H H 4-CH.sub.2 CH.sub.360 CH.sub.3 H H H 4-CH.sub.2 CH.sub.2 CH.sub.361 CH.sub.3 H H H 4-CH(CH.sub.3).sub.262 CH.sub.3 H H H 4-C.sub.4 H.sub.963 CH.sub.3 H H H 3,4-diCH.sub.364 CH.sub.3 H H H 3,5-diCH.sub.365 CH.sub.3 H H H 2,4-diCH.sub.366 CH.sub.3 H H H 2,4,6-triCH.sub.367 CH.sub.2 CH.sub.3 H H H 4-CH.sub.368t-C.sub.4 H.sub.9 H H H 4-CH.sub.369 CH.sub.3 H H H 4-OCH.sub.370 CH.sub.2 CH.sub.3 H H H 4-OCH.sub.371t-C.sub.4 H.sub.9 H H H 4-OCH.sub.372 CH.sub.3 H H H 3-OCH.sub.373 CH.sub.3 H H H 2-OCH.sub.374 CH.sub.3 H H H 4-OCH.sub.2 CH.sub.375 CH.sub.3 H H H 4-OCH.sub.2 CH.sub.2 CH.sub.376 CH.sub.3 H H H 4-OCH(CH.sub.3).sub.277 CH.sub.3 H H H 4-OC.sub.4 H.sub.978 CH.sub.3 H H H 3,4-diOCH.sub.379 CH.sub.3 H H H ##STR10##80 CH.sub.3 H H H 4-Cl81 CH.sub.3 H H H 3-Cl82 CH.sub.3 H H H 2-Cl83 CH.sub.2 CH.sub.3 H H H 4-Cl84t-C.sub.4 H.sub.9 H H H 4-Cl85 CH.sub.3 H H H 4-F86 CH.sub.3 H H H 3-F87 CH.sub.3 H H H 2-F88 CH.sub.2 CH.sub.3 H H H 4-F89t-C.sub.4 H.sub.9 H H H 4-F90 CH.sub.3 H H H 4-Br91 CH.sub.3 H H H 4-CF.sub.392 CH.sub.3 H H H 3-CF.sub.393 CH.sub.3 H H H 2-CF.sub.394 CH.sub.2 CH.sub.3 H H H 4-CF.sub.395t-C.sub.4 H.sub.9 H H H 4-CF.sub.396 CH.sub.3 H H H 4-OH97 CH.sub.3 H H H 3-OH98 CH.sub.3 H H H 3,4-diOH99 CH.sub.3 H H H 3-CH.sub.3, 4-Cl100 CH.sub.3 H 4-CH.sub.3 H 4-CH.sub.3101 CH.sub.2 CH.sub.3 H 4-CH.sub.3 H 4-CH.sub.3102 CH.sub.3 H 4-CH.sub.3 H 3-CH.sub.3103 CH.sub. 3 H 4-CH.sub.3 H 4-Cl104 CH.sub.3 H 4-CH.sub.3 H 3-Cl105 CH.sub.2 CH.sub.3 H 4-CH.sub.3 H 3-Cl106 CH.sub.3 H 4-Cl H 4-CH.sub.3107 CH.sub.2 CH.sub.3 H 4-Cl H 4-CH.sub.3108 CH.sub.3 H 4-Cl H 3-CH.sub.3109 CH.sub.3 H 4-Cl H 4-Cl110 CH.sub.3 H 4-F H 4-CH.sub.3111 CH.sub.2 CH.sub.3 H 4-F H 4-CH.sub.3112 CH.sub.3 H H 6,7-diCH.sub.3 4-CH.sub.3113 CH.sub.3 H H 6,7-diCH.sub.3 3-CH.sub.3114 CH.sub.3 H H 6,7-diCH.sub.3 4-Cl115 CH.sub.2 CH.sub.3 H H 6,7-diCH.sub.3 3-Cl116 CH.sub.3 H 4-Cl 6,7-diCH.sub.3 4-CH.sub.3117 CH.sub.3 H 4-Cl 6,7-diCH.sub.3 3-Cl118 CH.sub.2 OH H H H H119 CH.sub.3 CH.sub.3 H H H120 CH.sub.2 CH.sub.3 CH.sub.3 H H H121 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H H H122 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.3 H H H123 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H H H124 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.3 H H H125 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.3 H H H126 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H H H127 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.3 H H H128 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H H H129 ##STR11## CH.sub.3 H H H130 ##STR12## CH.sub.2 CH.sub.3 H H H131t-C.sub.4 H.sub.9 CH.sub.3 H H H132t-C.sub.4 H.sub.9 CH.sub.2 CH.sub.3 H H H133 CH.sub.2C(CH.sub.3).sub.3 CH.sub.3 H H H134 CH.sub.2C(CH.sub.3).sub.3 CH.sub.2 CH.sub.3 H H H135 (CH.sub.2).sub.4 H H H136 (CH.sub.2).sub.5 H H H137 (CH.sub.2).sub.6 H H H138 CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 H H H139 CH.sub.3 CH.sub.3 4-CH.sub.3 H H140 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 4-CH.sub.3 H H141 (CH.sub.2).sub.5 4-CH.sub.3 H H142 CH.sub.3 CH.sub.3 4-CH.sub.2 CH.sub.3 H H143 CH.sub.3 CH.sub.3 4-CH.sub.2 CH.sub.2 CH.sub.3 H H144 CH.sub.3 CH.sub.3 ##STR13## H H145 CH.sub. 3 CH.sub.3 3-CH.sub.3 H H146 CH.sub.3 CH.sub.3 2-CH.sub.3 H H147 CH.sub.3 CH.sub.3 4-OCH.sub.3 H H148 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 4-OCH.sub.3 H H149 (CH.sub.2).sub.5 4-OCH.sub.3 H H150 CH.sub.3 CH.sub.3 4-OCH.sub.2 CH.sub.3 H H151 CH.sub.3 CH.sub.3 4-OCH.sub.2 CH.sub.2 CH.sub.3 H H152 CH.sub.3 CH.sub.3 ##STR14## H H153 CH.sub.3 CH.sub.3 3-OCH.sub.3 H H154 CH.sub.3 CH.sub.3 2-OCH.sub.3 H H155 CH.sub.3 CH.sub.3 4-Cl H H156 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 4-Cl H H157 (CH.sub.2).sub.5 4-Cl H H158 CH.sub.3 CH.sub.3 3-Cl H H159 CH.sub.3 CH.sub.3 2-Cl H H160 CH.sub.3 CH.sub.3 4-F H H161 CH.sub.3 CH.sub.3 4-Br H H162 CH.sub.3 CH.sub.3 H 6,7-diCH.sub.3 H163 CH.sub.3 CH.sub.3 H 6,7-diOCH.sub.3 H164 CH.sub.3 CH.sub.3 H ##STR15## H165 CH.sub.3 CH.sub.3 H 6,7-diCl H166 CH.sub.3 CH.sub.3 H H 4-CH.sub.3167 CH.sub.3 CH.sub.3 H H 3-CH.sub.3168 CH.sub.3 CH.sub.3 H H 2-CH.sub.3169 CH.sub.3 CH.sub.3 H H 4-CH.sub.2 CH.sub.3170 CH.sub.3 CH.sub.3 H H 4-CH.sub.2 CH.sub.2 CH.sub.3171 CH.sub.3 CH.sub.3 H H ##STR16##172 CH.sub.3 CH.sub.3 H H 4-OCH.sub.3173 CH.sub.3 CH.sub.3 H H 3-OCH.sub.3174 CH.sub.3 CH.sub.3 H H 2-OCH.sub.3175 CH.sub.3 CH.sub.3 H H 4-OCH.sub.2 CH.sub.3176 CH.sub.3 CH.sub.3 H H 4-OCH.sub.2 CH.sub.2 CH.sub.3177 CH.sub.3 CH.sub.3 H H ##STR17##178 CH.sub.3 CH.sub.3 H H 3,4-diOCH.sub.3179 CH.sub.3 CH.sub.3 H H ##STR18##180 CH.sub.3 CH.sub.3 H H 4-Cl181 CH.sub.3 CH.sub.3 H H 3-Cl182 CH.sub.3 CH.sub.3 H H 2-Cl183 CH.sub.3 CH.sub.3 H H 4-F184 CH.sub.3 CH.sub.3 H H 3-F185 CH.sub.3 CH.sub.3 H H 2-F186 CH.sub.3 CH.sub.3 H H 4-CF.sub.3187 CH.sub.3 CH.sub.3 H H 3-CF.sub.3188 CH.sub.3 CH.sub. 3 H H 2-CF.sub.3189 CH.sub.3 CH.sub.3 H H 4-OH190 CH.sub.3 CH.sub.3 H H 3-OH191 CH.sub.3 CH.sub.3 H H 2-OH__________________________________________________________________________ Note: Position numbers of substituents are given for showing the position of th substituents on relevant benzene ring, and are not necessarily consistent with the formal position number of the compound.
Production of the compounds of the present invention will be explained below. The compounds of the present invention can be prepared by any one of conventional methods. For example, the following synthetic process is illustrated. ##STR19## (wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, l , m and n have the same significance as defined above)
The above process consists of reacting the starting material (V) with the compound (VI) in the presence or absence of a base catalyst with or without a solvent.
The starting material (V) can be synthesized according to the process as described in Yakugaku Zasshi, 86 576 (1966).
The reaction is generally carried out at temperature from 0.degree. to 250.degree. C., preferably from 20.degree. to 200.degree. C. over a period of 10 minutes to 24 hours. Examples of the solvents, when used, are ethers such as tetrahydrofuran, dioxane or the like, halogenohydrocarbons such as chloroform, methylene chloride or the like, aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or the like, amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone or the like, or dimethyl sulfoxide. The amount of the solvent may range from 0.1 to 100 parts by weight with respect to the compound (V). Examples of the catalysts, when used, are organic bases such as triethylamine, diisopropylamine, N,N-dimethylaniline, pyridine or the like or inorganic bases such as sodium hydride, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or the like. The amount of the catalyst to be used may range between 0.5 and 5 mol, preferably 1 and 3 mol with respect to the compound (V). Appropriate amount of the compound (VI) to be used in the reaction is generally 0.5 to 30 mol, preferably 1 to 10 mol, with respect to the compound (V).
After completion of the reaction, and after removal of the solvent if necessary, the reaction mixture may be poured into an excessive amount of water or dissolved in a solvent such as dichloromethane or the like. Then it may be neutralized with an aqueous alkali solution and the product may be purified in a conventional manner such as recrystallization or chromatography.
Physiologically acceptable salts of the compounds (I) are preferable as their salts. For example, there are exemplified an inorganic acid salt such as hydrochloride, hydroiodide, sulfate, phosphate or the like, and an organic acid salt such as methanesulfonate, p-toluenesulfonate, benzenesulfonate, camphor sulfonate, acetate, benzoate, malate, lactate, glycolate, glucuronate, maleate, fumarate, succinate, ascorbate, citrate, salicylate, nicotinate, tartarate or the like. Since the compounds (I) and their salts may exists in the form of hydrate or solvated product, these hydrate and solvated product may be included in the compounds of the present invention.
When the compound of the present invention is applied clinically as a circulatory improving agent, appropriate single dosage for adult is 1 to 100 mg for oral administration, and it is given 1 to 3 times per day. For intravenous administration, 0.01 to 10 mg is an appropriate single dosage and it is given 2 to 5 times per day for adult. For rectal administration, 1 to 100 mg is preferred single dosage and it is applied 1 to 3 times per day for adult. Preferably, said dosage may be appropriately increased or reduced, depending upon age, pathology and symptoms of particular patient.
Pharmaceutical formulation can be prepared by admixing at least one of the compounds (I) or pharmaceutically acceptable salts thereof with customarily usable pharmaceutical carriers, lubricants and other additives. The carrier may be solid or liquid. The solid carrier illustratively includes lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, acasia, stearic acid, magnesium stearate, lecithin, sodium chloride and the like.
The liquid carrier illustratively includes syrup, glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, water and the like.
The pharmaceutical formulation may take various types. When the solid carrier is used, tablets, powders, granules, hard gelatin capsules, suppositories, or troches may be formulated. Appropriate amount of the solid carrier may vary broadly, but it is preferably about 1 mg to about 1 g per single dosage.
Syrups, emulsions, soft gelatin capsules, sterilized injections, or aqueous or non-aqueous suspensions may be prepared using liquid carrier.
The following detailed examples are presented by way of illustration of certain specific embodiments of the invention.





EXAMPLE 1
Preparation of D-1-.alpha.-methylbenzylamino-4-phenylphthalazine (D-form of Compound No. 1 in Table 1)
To 5 ml of N-methylpyrrolidone were added 5.0 g of 1-chloro-4-phenylphthalazine (Compound V) and 5.0 g of D-.alpha.-methylbenzylamine, and the resultant mixture was stirred with heating at 130.degree. to 140.degree. C. for 3 hours. After finishing the reaction, the mixture was cooled, mixed with 20 ml of 5% aqueous sodium hydroxide and extracted with chloroform. The organic layer was separated and dried over magnesium sulfate, concentrated and purified on a silica gel column (eluent: ethyl acetate-n-hexane-chloroform). The product was recrystallized from ethyl acetate-n-hexane to give 3.31 g of D-1-.alpha.-methylbenzylamino-4-phenylphthalazine as colorless crystals. M.P. 184.degree. to 185.5.degree. C.
EXAMPLE 2 to 38
The compounds listed in the following Table 2 were prepared in the same manner as in Example 1.
TABLE 2__________________________________________________________________________ ##STR20##Example Compound No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 M.P. (.degree.C.)__________________________________________________________________________ 2 1 (L) CH.sub.3 H H H H 185 to 186.5 3 1 (DL) CH.sub.3 H H H H 196.5 to 197.5 4 2 (DL) CH.sub.2 CH.sub.3 H H H H 164.5 to 165 5 4 (DL) CH(CH.sub.3).sub.2 H H H H 188 to 189 6 5 (DL)n-C.sub.4 H.sub.9 H H H H 129 to 131 7 8 (DL)t-C.sub.4 H.sub. 9 H H H H 237 to 237.5 8 34 (DL) CH.sub.3 H 4-Cl H H 213.5 to 214 9 81 (DL) CH.sub.3 H H H 3-Cl 184 to 184.510 3 (DL) CH.sub.2 CH.sub.2 CH.sub.3 H H H H 154 to 15511 13 (D) CH.sub.3 H 4-CH.sub.3 H H 136 to 13912 20 (D) CH.sub.3 H 3-CH.sub.3 H H 132 to 13513 21 (D) CH.sub.3 H 2-CH.sub.3 H H 182 to 18314 23 (D) CH.sub.3 H 4-OCH.sub.3 H H 195 to 19715 30 (D) CH.sub.3 H 3-OCH.sub.3 H H 155 to 15616 31 (D) CH.sub.3 H 2-OCH.sub.3 H H 123 to 12617 37 (D) CH.sub.3 H 3-Cl H H 165 to 17218 40 (D) CH.sub.3 H 4-F H H 180.5 to 181.519 44 (D) CH.sub.3 H H 6,7-diCH.sub.3 H 176 to 17920 53 (D) CH.sub.3 H H 6,7-diCl H 233 to 23621 56 (DL) CH.sub.3 H H H 4-CH.sub.3 190.5 to 191.522 57 (DL) CH.sub.3 H H H 3-CH.sub.3 150 to 151.523 58 (DL) CH.sub.3 H H H 2-CH.sub.3 214 to 21524 59 (DL) CH.sub.3 H H H 4-CH.sub.2 CH.sub.3 156 to 15925 69 (DL) CH.sub.3 H H H 4-OCH.sub.3 156.5 to 15826 72 (DL) CH.sub.3 H H H 3-OCH.sub.3 197 to 19827 73 (DL) CH.sub.3 H H H 2-OCH.sub.3 181 to 182.528 78 (DL) CH.sub.3 H H H 3,4-diOCH.sub.3 184 to 18529 79 (DL) CH.sub.3 H H H ##STR21## 135 to 13730 80 (DL) CH.sub.3 H H H 4-Cl 145 to 146.531 82 (DL) CH.sub.3 H H H 2-Cl 241 to 24532 85 (DL) CH.sub.3 H H H 4-F 152 to 152.533 86 (DL) CH.sub.3 H H H 3-F 180 to 18334 87 (DL) CH.sub.3 H H H 2-F 227 to 22935 91 (DL) CH.sub.3 H H H 4-CF.sub.3 215 to 21736 92 (DL) CH.sub.3 H H H 3-CF.sub.3 180 to 18137 118 (D) CH.sub.2 OH H H H H 209 to 21038 118 (L) CH.sub.2 OH H H H H 207 to 210__________________________________________________________________________
EXAMPLE 39
Preparation of 1-.alpha.,.alpha.-dimethylbenzylamino-4-phenylphthalazine (Compound No. 119 in Table 1)
To 4 ml of N-methylpyrrolidone were added 1.5 g of 1-chloro-4-phenylphthalazine and 2.1 g of .alpha.,.alpha.-dimethylbenzylamine, and the mixture was heated at 160.degree. C. for 6 hours with stirring. After completion of the reaction, the reaction mixture was cooled, and extracted with chloroform with addition of 5% NaOH aqueous solution. The organic layer was separated, dried over MgSO.sub.4, concentrated, and purified by silica gel chromatography. The resultant product was recrystallized using chloroform and ether to obtain 1-.alpha.,.alpha.-dimethylbenzylamino-4-phenylphthalazine as colorless crystals. M.P. 234.degree.-235.degree. C.
EXAMPLES 40-42
The compounds listed in the following Table 3 were prepared in the same manner as in Example 39.
TABLE 3______________________________________ Com-Ex- poundample No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 M.P. (.degree.C.)______________________________________40 136 --(CH.sub.2).sub.5 -- H H H 219 to 22141 166 --CH.sub.3 --CH.sub.3 H H 4-CH.sub.3 221 to 22442 167 --CH.sub.3 --CH.sub.3 H H 3-CH.sub.3 201 to 203______________________________________
Experiment 1
Platelet aggregation-inhibitory activity in vitro
Rat arterial blood was centrifuged to obtain platelet rich plasma. To 250 .mu.l of said platelet rich plasma was added 5 .mu.l of a solution of the test compound, and the mixture was incubated for 2 minutes, mixed with 3 .mu.l of collagen (Hormon-Chemie) as a platelet aggregation-inducer, and the change of platelet aggregation was observed and recorded for 10 minutes with 2 channels aggregometer (Sienco DP 247E).
Platelet aggregation inhibitory ratio was calculated by the following formula: ##EQU1## Tc: Aggregation degree where only a solvent was added. Ts: Aggregation degree where a solution of the test compound was added.
Table 4 shows the inhibitory ratio of the compounds tested at each of the mol concentrations indicated.
Experiment 2
Platelet aggregation inhibitory activity ex vivo (by oral administration)
A group of 8 male Wistar ST rats each weighing about 250 grams were used. To the test animal was orally administered 4 ml/kg of a solution made by suspending a test compound in 1% aqueous tragacanth solution, and one hour later blood was collected from common carotid artery with a cannula. The blood was put in a plastic test tube in which 3.8% aqueous sodium citrate (1/10 volume) had been charged, and the mixture was stirred by overturning the tube, centrifuged by 200.times.g for 15 minutes, and the supernatant was recovered as platelet rich plasma (PRP). The residue was further centrifuged by 200033 g for 15 minutes and the supernatant was recovered as poor platelet plasma (PPP). The plasma samples were used for assaying the platelet aggregating ability. For assaying platelet aggregating ability, 2 channels aggregometer (Sienco DP 247E) was used, and the data were recorded on two pens recorder.
As an aggregation inducer, 7 to 10 .mu.g/ml of collagen (Hormon-Chemie) was used.
Platelet Aggregation-inhibitory ratio was calculated by the following formula: ##EQU2## A: Aggregating ratio of the group (control) in which only 1% aqueous tragacanth solution was administered.
B: Aggregating ratio of the group in which a solution of the test compound in tragacanth solution was administered.
Table 4 shows the test results.
TABLE 4 ##STR22## in vitro ex vivo Example Compound No. Inhibitory ratio (%) Inhibitory ratio (%) (p.o.) No. in Table 1 R.sup.1 R.sup.2 (R.sup.3).sub. l (R.sup.4).sub.m (R.sup.5).sub.n 10.sup.-7 M 3 .times. 10.sup.-7 M 10.sup.-6 M 10 mg/kg 3 mg/kg 1 mg/kg 1 1 (D) CH.sub.3 H H H H 100 100 88.5 80.2 65.5 3 1 (DL) CH.sub.3 H H H H 72.2 84.0 79.8 76.2 4 2 (DL) C.sub.2 H.sub.5 H H H H 100 96.4 94.5 52.3 37.8 5 4 (DL) CH(CH.sub.3).sub.2 H H H H 49.3 96.6 6 5 (DL) C.sub.4 H.sub.9 H H H H 20.6 98.4 7 8 (DL) C.sub.4 H.sub.9 (t) H H H H 100 100 69.9 35.1 22.0 8 34 (DL) CH.sub.3 H 4-Cl H H 100 9 81 (DL) CH.sub.3 H H H 3-Cl 40.7 98.3 72.5 10 3 (DL) C.sub.3 H.sub.7 H H H H 65.9 96.8 11 13 (D) CH.sub.3 H 4-CH.sub.3 H H 48.0 88.2 12 20 (D) CH.sub.3 H 3-CH.sub.3 H H 94.3 13 21 (D) CH.sub.3 H 2-CH.sub.3 H H 95.1 14 23 (D) CH.sub.3 H 4-OCH.sub.3 H H 16.7 76.8 15 30 (D) CH.sub.3 H 3-OCH.sub.3 H H 4.8 92.9 16 31 (D) CH.sub.3 H 2-OCH.sub.3 H H 93.0 17 37 (D) CH.sub.3 H 3-Cl H H 91.9 18 40 (D) CH.sub.3 H 4-F H H 14.2 93.4 19 44 (D) CH.sub.3 H H 6,7-diCH.sub.3 H 20.0 66.3 20 53 (D) CH.sub.3 H H 6,7-diCl H 6.9 52.5 21 56 (DL) CH.sub.3 H H H 4-CH.sub.3 92.9 22 57 (DL) CH.sub.3 H H H 3-CH.sub.3 90.3 61.8 23 58 (DL) CH.sub.3 H H H 2-CH.sub.3 89.9 24 59 (DL) CH.sub.3 H H H 4-C.sub.2 H.sub.5 56.5 25 69 (DL) CH.sub. 3 H H H 4-OCH.sub.3 21.0 74.7 26 72 (DL) CH.sub.3 H H H 3-OCH.sub.3 14.9 94.8 27 73 (DL) CH.sub.3 H H H 2-OCH.sub.3 93.3 28 78 (DL) CH.sub.3 H H H 3,4-diOCH.sub.3 6.2 93.6 29 79 (DL) CH.sub.3 H H H ##STR23## 6.3 95.3 30 80 (DL) CH.sub.3 H H H 4-Cl 26.3 93.3 31 82 (DL) CH.sub.3 H H H 2-Cl 58.5 65.5 32 85 (DL) CH.sub.3 H H H 4-F 10.2 94.1 33 86 (DL) CH.sub.3 H H H 3-F 100 100 40.5 34 87 (DL) CH.sub.3 H H H 2-F 52.4 35 91 (DL) CH.sub.3 H H H 4-CF.sub.3 22.5 36 92 (DL) CH.sub.3 H H H 3-CF.sub.3 1.5 89.5 37 118 (D) CH.sub.2 OH H H H H 6.0 49.1 38 118 (L) CH.sub.2 OH H H H H 30.2 94.4 39 119 CH.sub.3 CH.sub.3 H H H 93.0 40 136 (CH.sub.2).sub.5 H H H 94.7 41 166 CH.sub.3 CH.sub.3 H H 4 -CH.sub.3 100 100 42 167 CH.sub.3 CH.sub.3 H H 3-CH.sub.3 100 100 Control 1 ##STR24## 11.0 52.1 13.5 Control 2 ##STR25## 0 Control 3 ##STR26## 12.6 40.7 Control 4 ##STR27## 7.1
Experiment 3
Activity of the compounds (I) to rat left coronary artery ligation-induced cardiac infarction
A group of 8 male SD rats weighing 200 to 250 g were used. The rats were fixed at the dosal position under light ether paralysis, subjected to longitudinal incission in about 1.5 cm along the sternal left line to make thoractonomy under breaking the heart sac and exposing the heart. After ligating the left main coronary artery at 1 to 2 mm from the origin with black blade silk suture (Hama Ika Kogyo, 4-0), the heart was returned at the original position and the breast was closed immediately. The bilateral breast was pressed to exclude the air in the thoracic cavity to resume respiration. Electrocardiography (Nippon Koden, ECG-6601) showed ST elevation of II induction. Twenty-four hours after ligation, the blood was collected from the ventral vena cava, and the rat was killed by complete bleeding. The heart was taken out, and the cross circular slice (about 2 mm) at the central part of the heart was incubated at 37.degree. C. in the dark for 20 minutes in 20 ml of 1% solution of TTC (tryphenyl tetrazolium chloride, Wako Junyaku) in 0.09 M phosphate buffer (pH 8.6). The slice was photographed under a stereoscopic microscope, and the colored slides were prepared therefrom. The slides were projected on the wall, and the sections, the infarction parts (TTC non-dyed part) and non-infarction parts (TTC dyed part), were traced. So, the area of the infarction part in the total section area was calculated. A solution made by suspending the test compound in 1% aqueous tragacanth solution was orally administered 60 minutes prior to the coronary artery ligation. ##EQU3## A: Infarction ratio where only 1% tragacanth solution was administered for control.
B: Infarction ratio where the tragacanth solution containing the test compound was administered.
Table 5 shows the test results.
TABLE 5______________________________________Compound No.in Cardiac infarction inhibitory ratioTable 1 Dosage (mg/kg) %______________________________________1 (D) 2 81.11 (D) 10 76.6Aspirin* 100 10.7Ticlopidine* 30 10.1______________________________________ *Commercially available platelet aggregation inhibitor
Since the compounds of the present invention inhibit remarkably platelet aggregation not only in vitro but in vivo by oral administration, these compounds are useful as a prophylactic or therapeutic agent for various circulatory disorders.
Further, these compounds can reduce the cardiac infarction nest by direct action without being based on platelet aggregation inhibitory activity. Accordingly, the compounds are highly useful for treating ischemic heart diseases.
Claims
  • 1. 4-Phenylphthalazine compound of the formula: ##STR28## wherein R.sup.1 is an alkyl or hydroxyalkyl group of 1-5 carbon atoms; R.sup.2 is a hydrogen atom or an alkyl group of 1-5 carbon atoms; or R.sup.1 and R.sup.2, when taken together, may represent an alkylene group of 2-6 carbon atoms; R.sup.3 and R.sup.4 are independently a hydrogen or halogen atom, an alkyl or alkoxy group of 1-4 carbon atoms, or when two of R.sup.3 are adjacently positioned, (R.sup.3).sub.l may represent a -O-(CH.sub.2).sub.p -O- group and/or when two of R.sup.4 are adjacently positioned, (R.sup.4).sub.m may represent a -O-(CH2).sub.p -O- group; R.sup.5 is a hydrogen or halogen atom, an alkyl or alkoxy group of 1-4 carbon atoms, a trifluoromethyl group or a hydroxy group, or when two of R.sup.5 are adjacently positioned, (R.sup.5).sub.n may represent a -O-(CH.sub.2).sub.p -O- group; p is an integer of 1-3; l and m are independently an integer of 1-2; and n is an integer of 1-3, and optical isomers and pharmaceutically acceptable acid addition salts thereof.
  • 2. The compounds according to claim 1 wherein R.sup.3 and R.sup.4 are independently a hydrogen or halogen atom, or an alkyl or alkoxy group of 1-4 carbon atoms.
  • 3. The compounds according to claim 2 wherein R.sup.3 and R.sup.4 are independently a hydrogen, fluorine, or chlorine atom, or an alkyl or alkoxy group of 1-3 carbon atoms.
  • 4. The compounds according to claim 3 wherein l and m are an integer of 1.
  • 5. The compounds according to claim 4 wherein R.sup.3 and R.sup.4 are independently a hydrogen or chlorine atom, or an alkyl group of 1-3 carbon atoms.
  • 6. The compounds according to claim 5 wherein R.sup.3 is a hydrogen or chlorine atom or an alkyl group of 1-3 carbon atoms; and R.sup.4 is a hydrogen atom.
  • 7. The compounds according to claim 6 wherein R.sup.1 is an alkyl group of 1-5 carbon atoms or a hydroxyalkyl group of 1-3 carbon atoms; R.sup.2 is a hydrogen atom or an alkyl group of 1-5 carbon atoms; or R.sup.1 and R.sup.2, taken together, represent an alkylene group of 4-6 carbon atoms.
  • 8. The compounds according to claim 7 wherein R.sup.1 is an alkyl group of 1-5 carbon atoms; R.sup.2 is a hydrogen atom or an alkyl group of 1-5 carbon atoms; or R.sup.1 and R.sup.2, taken together, represent an alkylene group of 4-6 carbon atoms.
  • 9. The compounds according to claim 8 wherein R.sup.5 is a hydrogen or halogen atom, an alkyl or alkoxy group of 1-4 carbon atoms, or a trifluoromethyl group; or when two of R.sup.5 are adjacently positioned, (R.sup.5).sub.n may represent a -O-(CH.sub.2).sub.p -O- group.
  • 10. The compounds according to claim 9 wherein R.sup.5 is a hydrogen or halogen atom, or an alkyl or alkoxy group of 1-4 carbon atoms.
  • 11. The compounds according to claim 10 wherein n is an integer of 1.
  • 12. A pharmaceutical composition which comprises one of the compounds according to claim 1 together with a pharmaceutically acceptable carrier therefor.
  • 13. A pharmaceutical composition according to claim 12 which is useful as a platelet aggregation inhibitory agent containing an effective platelet aggregation inhibitory amount of the compound(s) of claim 1.
Priority Claims (1)
Number Date Country Kind
2-85447 Mar 1990 JPX
Foreign Referenced Citations (4)
Number Date Country
0159652 Oct 1985 EPX
2021195 Nov 1970 DEX
1303061 Jan 1973 GBX
2063249 Jun 1981 GBX
Non-Patent Literature Citations (5)
Entry
Patent Abstracts of Japan, vol. 5, No. 114 (C-64) (786) 23 Jul. 1981, of JP-A-56 53659 (Mitsubishi Yuki Yakuhin K.K.) 13 May 1981, [cat. D].
Patent Abstracts of Japan, vol. 5, No. 114 (-64) (786) 23 Jul. 1981, of JP-A-56 53660 (Mitsubishi Yuka Yakuhin K.K.) 13 May 1981, [cat. D].
Patent Abstracts of Japan, vol. 10, No. 112 (-342) (2169) 25 Apr. 1986, of JP-A-60 243074 (Mitsubishi Yuka Yakuhin K.K.) 03 December 1985, [cat. D].
Chemical Abstracts, vol. 71, (Aug. 1969) Columbus, Ohio, USA H. H. Holava, Jr., et al.: "1-Substituted 4-aryl-[or 4-aralkyl-]phthalazines", ref. No. 22093A.
Holava, J Med. Chem. 12, 555 (1969).