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GB2063249A - 4-Phenylphthalazine derivatives - Google Patents

4-Phenylphthalazine derivatives Download PDF

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Publication number
GB2063249A
GB2063249A GB8030906A GB8030906A GB2063249A GB 2063249 A GB2063249 A GB 2063249A GB 8030906 A GB8030906 A GB 8030906A GB 8030906 A GB8030906 A GB 8030906A GB 2063249 A GB2063249 A GB 2063249A
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phenylphthalazine
group
carbon atoms
phthalazine
zero
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Mitsubishi Yuka Pharmaceutical Co Ltd
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Mitsubishi Yuka Pharmaceutical Co Ltd
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Priority claimed from JP13043479A external-priority patent/JPS5653660A/en
Priority claimed from JP12464480A external-priority patent/JPS5748972A/en
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Publication of GB2063249A publication Critical patent/GB2063249A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/34—Phthalazines with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heat Sensitive Colour Forming Recording (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

4-phenylphthalazine derivatives of formula (I), and represented by pharmaceutically acceptable salts thereof have potent inhibitory activities against platelet aggregation <IMAGE> wherein X is NH or O; R<1>, R<2> and R<3> are each alkyl, alkoxy, halogen, alkoxycarbonyl, carboxyl. alkylcarbonyl group, hydroxyl, trifluoromethyl, and R<1> can also be cyano, l, m and n are each 0, 1, 2 or 3 (provided that l = 1 to 3 and m = n = zero when X is 0, and the case where l = m = n = zero is excluded when X is NH).

Description

SPECIFICATION 4-phenylphthalazine derivatives This invention relates to a 4-phenylphthalazine derivative represented by the following formula [I] or a pharmaceutically acceptable salt thereof:
wherein X stands for NH or O; R' an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a halogen atom, an alkoxycarbonyl group having 2 to 6 total carbon atoms, a carboxyl group, a cyano group, an alkylcarbonyl group having 2 to 4 total carbon atoms, a hydroxyl group or a trifluoromethyl group;R2 and R3, which may be identical or different (may also be the same as or different from R1), each represent an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a halogen atom, an alkoxycarbonyl group having 2 to 6 total carbon atoms, a carboxyl group, an alkylcarbonyl group having 2 to 4 total carbon atoms, a hydroxyl group or a trifluoromethyl group; and each of I, m and n is an integer of zero to 3 (provided that 1=1 to 3 and m=n=zero when X is 0, and the case where l=m=n=zero is excluded when X is NH), each plural number of R', R2 and R3 being identical or different when the integers I, m and n are two or more, and also to. a process for producing the same.
As 4-phenylphthalazine derivatives analogous to those of the present invention, there have heretofore been known 1 -anilino-4-phenylphthalazine (Ber., 38, 3923 (1905)], 1 -phenoxy-4- phenylphthalazine [Journal of Pharmacology, 88, 83 (1968], l-[2-(2-methylallyl)-phenoxy]-4- phenylphthalazine, 1 -(2-allylphenoxy)-4-phenylphthalazine [Chem. Pharm. Bull., 24, 1581-1595 (1976)]. These compounds are disclosed merely as intermediates and there is nothing done about uses thereof.The compounds I -[2-(2-methylallyl)phenoxyj-4-phenylphthalazine and 1 -(2-allylphenoxy)-4- phenylphthalazine are iiable to undergo ring-closure reaction or other undesirable reactions due to the presence of double bonds in the substituents, whereby structural changes are caused.
On the other hand, studies have been made about 1 -alkylamino-4-phenylphthalazine derivatives, 1-alkoxy-4-phenylphthalazine derivative [J. Med.Chem. '2,555(1969)] and 1-(piperazine-1-yl)-4phenylphthalazine derivative (Japanese Patent Publication 39944/1973) for their uses as antiinflammatory agents. However, there is no description about 1-anilino derivatives and 1 -phenoxy derivatives.
The present inventors have successfully synthesized the novel compounds represented by the above formula [I] which have not been described in literatures. They have further progressed their studies to find out that these compunds have potent inhibitory activity against platelet aggregation.
Thus, the compounds of the present invention are considered to be applicable for prevention or therapy of the diseases induced by increased platelet aggregation ability such as cerebral thrombosis, cerebral infarction, myocardial infarction and arteriosclerotic diseases. It is therefore the primary object of the present invention to provide a novel compound represented by the formula 111 having a potent inhibitory activity against platelet aggregation.
The compound according to the present invention is represented by the following formula [I]:
wherein all the symbols have the same meanings as defined above.
In the above formula [I], the alkyl group as represented by R', R2 and R3 may be exemplified by methyl, ethyl, propyl, iso-propyl, n-butyl, t-butyl and amyl. Typical examples of the alkoxy group are methoxy, ethoxy, propoxy, butoxy and amyloxy. As a halogen atom, there may be mentioned fluorine, chlorine, bromine and iodine. The alkoxycarbonyl group may include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, amyloxycarbonyl, etc. As the alkylcarbonyl group there may be used acetyl, propionyl, butylyl or others.
In the compounds of the present invention, R' may preferably be an alkyl group, an alkoxy group, a halogen atom or a trifluoromethyl group. On the other hand, R2 may preferably be an alkyl group, an alkoxy group or a halogen atom, while R3 an alkyl group.
In the above formula [I], each of the integers represented by I, m and n may be variable from zero to 3. But there are some restrictions depending on the species of X. When X represents 0 (an oxygen atom), both m and n are required to be zero, while I may be variable from 1 to 3. On the other hand, when X represents NH group, the case where all of the integers are zero is excluded; in other words, there is at least one substituent on the aromatic nuclei. Thus, when X is NH, there are so many possible combinations in number of the substituents on the aromatic nuclei. Among them, the following four combinations are found to be particularly preferred: (1) I=1 to 3, m=n=zero; (2) 1=1 to 2, m=1 to 2, n=zero; (3) 1=1 to 2, m=zero, n=1 to 2; and (4)- I=m=zero, n=1 to 2.
Also, when X is 0, I is preferred to be 1 or 2, while m=n=O.
The compound represented by the formula [I] can also form a pharmaceutically acceptable salt through the reaction of the basic nitrogen thereof with an acid. For example, there may be mentioned salts with mineral acids such as hydrogen chloride, sulfuric acid, hydrobrobromic acid, phosphoric acid, etc. or methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, acetic acid, glycolic acid, glucuronic acid, maleic acid, oxalic acid, ascorbic acid, citric acid, salicylic acid, and so on.
In the following, there are enumerated concrete examples of the compounds represented by the formula [I].
Compound No. Name of Compound (1) 1 -(4-Methylanilino)-4-phenylphthalazine (2) 1 (3-Methylanilino)-4-phenylphthalazine (3) 1-(2-Methylanilino)-4-phenylphthalazine (4) 1 -(4-Ethylanilino)-4-phenylphthalazine (5) 1-(2-Ethylanilino)-4-phenylphthalazine (6) 1 -(4-n-Butylani lino)-4-phenylphthalazine (7) 1-(3-n-Butylanilino)-4-phenylphthalazine (8) 1-(4-t-Butylanilino)-4-phenylphthalazine (9) 1-(4-Methoxyanilino)-4-phenylphthalazine (10) 1 -(3-Methoxyanilino)-4-phenylphthalazine (11) 1 -(3-Propoxyanilino)-4-phenylphthalazine (12) 1 -(4-n-Butoxyanilino)-4-phenylphthalazine (13) 1 -(4-Fluoroanilino)-4-phenylphthalazine (14) 1 -(3-Fluoroanilino)-4-phenylphthalazine (15) 1 -(2-Fluoroanilino)-4-phenylphthalazine (16) 1 -(4-Chloroanilino)-4-phenylphthalazine (17) 1 -(3-Chloroanilino)-4-phenylphthalazine (18) 1 -(2-Chloroanilino)-4-phenylphthalazine (19) 1 -(4-Bromoanilino)-4-phenylphthalazine (20) 1-(3-Bromoanilino)-4-phenylphthalazine (21) 1 -4-lodoanilino)-4-phenylphthalazine (22) 1-(3-lodoanilino)-4-phenylphthalazine (23) 1 -(4-Ethoxycarbonylanilino)-4-phenylphthalazine (24) 1-(4-Carboxylanilino)-4-phenylphthalazine (25) 1 -(4-Cyanoanilino)-4-phenylphthalazine (26) 1-(4-Acetylanilino)-4-phenylphthalazine (27) 1 -(4-Tdfluoromethylanilino)-4-phenylphthalazine (28) 1 -(3-Trifluoromethylanilino)-4-phenylphthalazine (29) 1-(2-Trifluoromethylanilino)-4-phenylphthalazine (30) 1 -(3-Hydroxylanilino)-4-phenylphthalazine Compound No. Name of Compound (31) 1 -(2,3-Dimethylanilino)-4-phenylphthalazine (32) 1-(2,4-Dimethylanilino)-4-phenylphthalazine (33) 1-(2,50Dimethylanilino)-4-phenylphthalazine (34) 1-(3,4-Dimethylanilino)-4-phenylphthalazine (35) 1-(2,5-Diethylanilino)-4-phenylphthalazine (36) 1-(2,5-Dipropylanilino)-4-phenylphthalazine (37) 1 -(2,5-Dimethoxyanilino)-4-phenylphthalazine (38) 1-(3,4-Dimethoxyanilino)-4-phenylphthalazine (39) 1-(2,5-Dichloroanilino)-4-phenylphthalazine (40) 1 -(3,4-Dichloroanilino)-4-phenylphthalazine (41) 1-(2,5-Difluoroanilino)-4-phenylphthalazine (42) 1 -(3-Chloro-4-methylanilino)-4phenylphthalazine (43) 1-(2-Methyl-3-chloroanilino)-4-phenylphthalazine (44) 1-(2-Methyl-4-chloroanilino)-4-phenylphthalazine (45) 1 -(3-Methyl-4-chlorani lino)-4-phenylphthalazine (46) 1 -(3-Fluoro-4-methylanilino)-4-phenylphthalazine (47) 1-(2-lVlethoxy-5-methylanilino)-4-phenylphthalazine (48) 1 -(5-Chloro-2-methoxyanilino)-4-phenylphthalazine (49) 1-(2-Methyl-5-trifluoromethylanilino)-4-phenylphthalazine (50) 1-(2-Methoxy-5-trifluoromethylanilino)-4-phenylphthalazine (51) 1 -(2,4,6-Trimethylanilino)-4-phenylphthalazine (52) 1-(3,4,5-Trimethoxyanilino)-4-phenylphthalazine (53) 1 -Anilino-4-(4-methyl phenyl)phthalazine (54) 1-(4-Methylanilino)-4-(4-methylphenyl)phthalazine (55) 1 -(4-Butylanilino)-4-(4-methylphenyl)phthalazine (56) 1-(2,5-Dimethylanilino)-4-(4-methylphenyl)phthalazine (57) 1 -(3-Methoxyanilino)-4-(4-methylphenyl)phthalazine (58) 1 -(4-Butoxya nilino)-4-(4-methylphenyl)phthalazine (59) 1 -(2,5-Dimethoxyanilino)-4-(4-methylphenyl)phthalazine (60) 1-(3-Chloroaniiino)-4-(4-methylphenyl)phthalazine (61) 1-(3-Bromoanilino)-4-(4-methylphenyl)phthalazine (62) 1 -(3-Fluoroanilino)-4-(4-methylphenyl)phthalazine (63) 4-(4-Methylphenyl)-1 -(3-trifluoromethylaniliono)phthalazine (64) 1 -(5-Chloro-2-methoxyanilino)-4-(4-methyl phenyl)phthalazine (65) 1-(3-Chloro-4-methylanilino)-4-(4-methylphenyl)phthalazine (66) 1 -(4-Ethoxywarbonylani lino)-4-(4-methylphenyl)phthalazine (67) 1-Anilino-4-(4-butylphenyl) phthanlazine (68) 4-(4-Butylphenyl)-1-(2,5-dimethylanilino)phthalazine (69) 4-(4-Butylphenyl)-1 -(2,5-dimethoxyanilino)phthalazine (70) 4-(4-Butylphenyl)-1 -(3-chloroanilino)phthalazine (71) 4-(4-Butylphenyl)- 1 -(3-t?ifluornmethylanilino)phthalazine (72) 4-(4-Butylphenyl)-1 -(5-chloro-2-methoxyanilino)phthalazine (73) 1 -Anilino-4-(2,4-dimethylphenyl)phthalazine (74) 1 -Anilino-4-(4-methoxyphenyl)phthalazine (75) 1 -(4-Butylanilino)-4-(4-methoxyphenyl)phthalazine t76) 1 -(2,5-Dimethylanilino)-4-(4-methoxyphenyl)phthalazine (77) 1-(2,5-Dimethoxyanilino)-4-(4-methoxyphenyl) phehalazine (78) 1-(3-Chloroanilino)-4-(4-methoxyphenyl)phthalazine (79) 4-(4-Methoxyphenyl)- 1 -(3-trifl uoromethylanilino)phthalazine (8) 1 -(5-Chloro-2-methoxyanilino)-4-(4-methoxyphenyl)phthalazine (81) 1 -(4-ethoxywarbonylanilino)-4-(4-methoxyphenyl)phthalazine (82) 1 -Anilino-4-(4-butoxyphenyl)phthalazine (83) 4-(4-Butoxyphenyl)-1 -(2,5-dimethylanilino)phthalazine (84) 4-(4-Butoxyphenyl)-1 -(2,5-dimethoxyanilino)phthalazine (85) 4-(4-Butoxyphenyl)-1 -(3-chloroanilino)phthalazine (86) 4-(4-Butoxyphenyl)-1-(3-trifluoromethylanilino)phthalazine (87) 4-(4-Butoxyphenyl)- 1 -(5-chloro-2-methoxyanilino)phthalazine (88) 1 -Anilino-4-(2,4-dimethoxyphenyl)phthalazine (89) 1 -(2,5-Dimethylanilino)-4-(2,4-dimethoxyphenyl)phthalazine (90) 1-(2,5-Dimethoxyanilino)-4-(2,4-dimethoxyphenyl)phthalazine (91) 1 -(3-Chloroanilino)-4-(2,4-dimethoxyphenyl)phthalazine (92) 4-(2,4-Dimethoxyphenyl)-1 -(3-trifluoromethylanilino)-phthalazine (93) 1 -(5-Chloro-2-methoxyanilino)-4-(2,4-dimethoxyphenyl)-phthalazine (94) 1 -Anilino-4-(4-chlorophenyl)phthalazine (95) 4-(4-Chlorophenyl)- 1 -(2,5-dimethylanilino)phthalazine (96) 4-(4-Chlorophenyl)- 1 -(2,5-dimethoxyanilino)phthalazine (97) 1-(3-Chloroanilino)-4-(4-chlorophenyl)-phthalazine (98) 4-(4-Chlorophenyl)- 1 -(3-trifluoromethylanilino)phthalazine (99) 1 -(5-Chloro-2-methoxyanilino)-4-(4-chlorophenyl)phthalazine (100) 1 -Anilino-4-(4-bromophenyl)phthalazine (101) 1 -Anilino-4-(4-fluorophenyl)phthalazine (102) 1 -(2,5-Dimethylanilino)-4-(4-fluorophenyl)phthalazine (103) 1 -(2,5-Dimethoxyanilino)-4-(4-fluorophenyi)phthalazine (104) 1 -(3-Chloroanilino)-4-(4-fluorophenyl)phthalazine (105) 4-(4-Fluorophenyl)- 1 -(3-trifl uoromethylani lino)phthalazine (106) 1 -(5-Chloro-2-methoxyanilino}-4-(4-fluorophenyl)phthalazine (107) 1 -Anilino-4-(4-ethoxycarbonylphenyl)phthalazine (108) 1 -(2,5-Dimethylanilino)-4-(4-ethoxycarbonylphenyl)phthalazine (109) 1 -(2,5-Dimethoxyanilino)-4-(4-ethoxycarbonylphenyl)phthalazine (110) 1 -(3-Chloroanilino)-4-(4-ethoxycarbonylphenyl)phthalazine (111) 4-(4-Ethoxycarbonylphenyl)-1 -(3-trifluoromethylanilino)phthalazine (112) 1 -(5-Chloro-2-methoxyanilino)-4-(4-ethoxycarbonylphenyl)phthalazine (113) 1 -Anilino-6-methyl-4-phenylphthalazine (114) 1-Anilino-7-methyl-4-phenylhthalazine (115) 1 -(2,5-Dimethylanilino)-6-methyl-4-phenylphthalazine (116) 1-(2,5-Dmethylanilino)-7-methyl-4-phenylphthalazine (117) 1-(2,5-Dimethylanilino)-6-methyl-4-phenylphthalazine (118) 1 -(2,5-Dimethoxyanilino)-7-methyl-4-phenylphthalazine (119) 1 -(3-Chloroanilino)-6-methyl-4-phenylphthalazine (120) 1 -(3-Chloroanilino)-7-methyl-4-phenylphthalazine (121) 6-Methyl-4-phenyl-1 -(3-trifluoromethylanilino)phthalazine (122) 7-Methyl-4-phenyl- 1 -(3-trifluoromethylanilino)phthalazine (123) 1 -(5-Chloro-2-methoxyanilino)-6-methyl-4-phenylphthalazine (124) 1 -(5-Chloro-2-methoxyanilino)-7-methyl-4-phenylphthalazine (125) 1-Anilino-6,7-dimethyl-4-phenylphthalazine (126) 1-(4-Butylanilino)-6,7-dimethyl-4-phenylphthalazine (127) 1-(2,5-Dimethylanilino)-6,7-dimethyl-4-phenylphthalazine (128) 1-(2,5-Dimethoxyanilino)-6,7-dimethyl-4-phenylphthalazine (129) - 1 -(4-Butoxyanilino)-6,7-dimethyl-4-phenylphthalazine (130) 1 -(3-Chloroanilino)-6,7-dimethyl-4-phenylphthalazine (131) 6,7-Dimethyl-4-phenyl-1 -(3-trifluoromethylanilino)phthalazine (132) 1 -(5-Chloro-2-methoxyanilino)-6,7-dimethyl-4-phenylphthalazine (133) 1 -(3-Chloro-4-methylanilino)-6,7-dimethyl-4-phenylphthalazine (134) 6,7-Dimethyl- 1 -(4-ethoxycarbonylanilino)-4-phenylphthalazine (135) 1 -Anilino-5,8-dimethyl-4-phenylphthalazine (136) 1 -(3-Chloroanilino)-5,8-dimethyl-4-phenylphthalazine (137) 1 -Anilino-6,7-dibutyl-4-phenylphthalazine (138) 1 -Anilino-6,7-dimethoxy-4-phenylphthalazine (139) 6,7-Dimethoxy- 1 -(2,5-dimethylanilino)-4-phenylphthalazine (140) 6,7-Dimethoxy- 1 -(2,5-dimethoxyanilino)-4-phenylphthalazine (141) 1-(3-Chloroanilino)-6,7-dimethoxy-4-phenylphthalazine (142) 6,7-Dimethoxy-4-phenyl-1 -(3-trifluoromethylanilino)phthalazine (143) 1 -(5-Chlorn-2-methoxyanilino)-6,7-dimethoxy-4-phenylphthalazine (144) 1 -(4-Butylanilino)-6,7-dimethoxy-4-phenylphthalazine (145) 1 -(4-Butoxyanilino)-6,7-dimethoxy-4-phenylphthalazine (146) 1 -Anilino-5,8-dimethoxy-4-phenylphthalazine (147) 1 -Anilino-6,7-dibutoxy-4-phenylphthalazine (148) 1 -Anilino-6,7-dichloro-4-phenylphthalazine (149) 6,7-Dichloro-1 -(2,5-dimethylanilino)-4-phenylphthalazine (150) 6,7-Dichloro-1-(2,5-dimethoxyanillno)-4-phenylphthalazine (151) 1 -(3-Chloroanilino)-6,7-dichloro-4-phenylphthalazine (152) 6,7-Dichloro-4-phenyl- 1 -(3-trifluoromethylanilino)phthalazine (153) 1 -(4-Chloro-2-methoxyanilino)-6,7-dichloro-4-phenylphthalazine (154) 1 -Anilino-5,8-dichloro-4-phenylphthalazine (155) 1 -Anilino-6-ethoxycarbonyl-4-phenylphthalazine (156) 1 -Anilino-6,7-dimethyl-4-(4-methylphenyl)phthalazine (157) 1 -(4-Butylanilino)-6,7-dimethyl-4-(4-methylphenyl)phthalazine (158) 6,7-Dimethyl-1 -(2,5-dimethylanilino)-4-(4-methylphenyl)phthalazine (159) 6,7-Dimethyl- 1 -(3-methoxyanilino)-4-(4-methylphenyl)phthalazine (160) 1 -(2,5-Dimethoxyanilino)-6,7-dimethyl-4-(4-methylphenyl)-phthalazine (161) 1-(3-Chloroanilino)-6,7-dimethyl-4-(4-methylphenyl) phthalazine (162) 6,7-dimethyl-4-(methylphenyl)-1-(3-trifluoromethylanilino) phthanlazine (163) 1 -(4-Chloro-2-methoxyanilino)-6,7-dimethyl-4-(4-methylphenyl)phthalazine (164) 6,7-Dimethyl-1-(4-ethoxycarbonylanilino-4(4-methylphenyl) phthalaze (165) 1 -Anilino-4-(4-butylphenyl)-6,7-dimethylphthalazine (166) 1-Anilino-6,7-dimethyl-4-(4-methoxyphenyl0 phthalazine (167) 6,7-Dimethyl-1 -(2,5-dimethylanilino)-4-(4-methoxyphenyl)phthalazine (168) 1-(2,5-Dimethoxyanilino)-6,7-dimethyl-4-(4-methoxyphenyl) phthalazine (169) 1-(3-Chloroanilino)-6,7-dimethyl-4-(4-methoxyphenyl)phthalazine (170) 6,7-Dimethyl-4-(4-methoxyphenyl)-1 -(3-trifluoromethylanilino)phthalazine (171) 1 -(5-Chloro-2-methoxyanilino)-6,7-dimethyl-4-(4-methoxyphenyl)phthalazine (172) 1 -Anilino-4-(4-butoxyphenyl)-6,7-dimethylphthalazine (173) 1 -Anilino-4-(2,4-dimethoxyphenyl)-6,7-dimethylphthalazine (174) 1 -Anilino-4-(4-chlorophenyl)-6,7-dimethylphthalazine (175) 1-(3-Chloroanilino)-4-(4-chlorophenyl)-6,7-dimethylphthalazine (176) 1 -(3-Chloro-4-methylanilino)-4-(4-chlorophenyl)-6,7-dimethylphthalazine (177) 1-Anilino-6,7-dimethyl-4-(4-fluorophenyl)phthalazine (178) 1 -Anilino-6,7-dimethyl-4-(4-ethoxycarbonylphenyl)phthalazine (179) 1-Anilino-6,7-dimethoxy-5 (4-methylphenyl) phthalazine (180) 6,7-Dimethoxy- 1 -(2 ,5-dimethylanilino)-4-(4-methylphenyl)phthalazine (181) 6,7-Dimethoxy- 1 -(2,5-dimethoxyanilino)-4-(4-methylphenyl)phthalazine (182) 1 -(3-Chloroanilino)-6,7-dimethoxy-4-(4-methylphenyl)phthalazine (183) 1-Anilino-4-(4-butylphenyl)-6,7-dimethoxyphthalazine (184) 1 -Anilino-6,7-dimethoxy-4-(4-methoxyphenyl)phthalazine (185) 1 -Anilino-6,7-dimethoxy-4-(2,4-dimethoxyphenyl)phthalazine (186) 1 -Aniiino-4-(4-chlorophenyl)-6,7-dimethoxyphthalazine (187) 1-Aniiino-6,7-dimethoxy-4-(4-fluorophenyl)phthalazine (188) 1 -Anilino-6,7-dimethoxy-4-(4-ethoxycarbonylphenyl) phthalazine (189) 1 -Anilino-6,7-dichloro-4-(4-methylphenyl)phthalazine (190) 1-Anilino-4-(4-butylphenyl)-6,7-dichlorophthalazine (191) 1-Anilino-6,7-dichloro-4-(4-methoxyphenyl) phthalazine (192) 1 -Anilino-4-(4-butoxyphenyl)-6,7-dichlorophthalazine (193) 1 -Anilino-6,7-dichloro-4-(2,4-dimethoxyphenyl)phthalazine (194) 1 Anilino-4-(4-chlorophenyl)-6,7-dichlorophthalazine (195) 1 -Anilino-6,7-dichloro-4-(4-fluorophenyl)phthalazine (196) 1-Anilino-6,7-dichloro-4-(4-ethoxycarbonylphenyl)phthalazine (197) 1 -Anilino-4-(4-carboxyphenyl)phthalazine (198) 4-(4-Carboxyphenyl)- 1 -(2,5-dimethylanilino)phthalazine (199) 4-(4-Carboxyphenyl)- 1 -(2,5-dimethoxyanilino)phthalazine (200) 4-(4-Carboxyphenyl)- 1 -(3chloroanilino)phthalazine (201) 4-(4-Carboxyphenyl)- 1 -(3-trifl uoromethylanilino)phthalazine (202) 4-(4-Carboxyphenyl)- 1 -(5-chloro-2-methoxyanilino)phthalazine (203) 1-Anilino-4-(4-hydroxyphenyl) phthalazine (204) 1-(2,5-Dimethylanilino)-4-(4-hydroxyphenyl)phthalazine (205) 1-(2,5-Dimethylanilino)-4-(4-hydroxyphenyl)phthalazine (206) 1-(3-Chloroanilino)-4-(4-hydroxyphenyl)phthalazine (207) 4-(4-Hydroxyphenyl)-1 -(3-trifl uoromethylanilino)phthalazine (208) 1 -(5-Chlora-2-methoxyanilino)-4-(4-carboxyphenyl)phthalazine (209) 1-(4-Acetylanilino)-4-(4-methylphenyl)phthalazine (210) 1 -(4-Acetylanilino)-6,7-dimethyl-4-phenylphthalazine (211) 1 (4-Methylphenoxy)-4-phenylphthalazine (212) 1-(3-Methylphenoxy)-4-;;henylphthalazine (213) 1 -(2-Methylphenoxy)-4-phenylphthalazine (214) 1 -(4-Ethylphenoxy)-4-phenylphthalazine (215) 1 -(2-Ethylphenoxy)-4-phenylphthalazine (216) 1 -(4-n-Butylphenoxy)-4-phenylphthalazine (217) 1 -(3-Butylphenoxy)-4-phenylphthalazine (218) 1 -(4-t-Butylphenoxy)-4-phenylphthalazine (219) 1 -(4-Methoxyphenoxy)-4-phenylphthalazine (220) 1-(3-Methoxyphenoxy)-4-;;henylphthalazine (221) 1 -(3-Propoxyphenoxy)-4-phenylphthalazine (222) 1-(3-Butoxyphenoxy)-4-phenylphthalazine (223) 1 -(4-Fluorophenoxy)-4-phenylphthalazine (224) 1-(3-Fluorophenoxy)-4-phenylphthalazine (225) 1 -(4-Chlorophenoxy)-4-phenylphthalazine (226) 1 (3-Chlorophenoxy)-4-phenylphthalazine (227) 1 -(2-Chlorophenoxy)-4-phenylphthalazine (228) 1 -(4-Bromophenoxy)-4-phenylphthalazine (229) 1 -(3-Bromophenoxy)-4-phenylphthalazine (230) 1-(3-lodophenoxy)-4-phenylphthalazine (231) 1 -(4-Ethoxycarbonylphenoxy)-4-phenylphthalazine (232) 1 -(4-Carboxyphenoxy)-4-phenylphthalazine (233) 1 -(4-Cyanophenoxy)-4-phenylphthalazine (234) 1-(4-Acetylphenoxy)-4-;;henylphthalazine (235) 1 -(4-Trifl uoromethylphenoxy)-4-phenylphthalazine (236) 1 -(3-Trifluoromethylphenoxy)-4-phenylphthalazine (237) 1 -(3-Hydroxyphenoxy)-4-phenylphthalazine (238) 1-(2,3-pimethylphenoxy)-4-phenylphthalazine (239) 1 -(2,5-Dimethylphenoxy)-4-phenylphthalazine (240) 1 -(2,5-Diethylphenoxy)-4-phenylphthalazine (241) 1 -(2,5-Dipropylphenoxy)-4-phenylphthalazine (242) 1 -(2,5-Dimethoxyphenoxy)-4-phenylphthalazine (243) 1 -(3,4-Dimethoxyphenoxy)-4-phenylphthalazine (244) 1 -(2,5-Dichlorophenoxy)-4-phenylphthalazine (245) 1-(2,6-Dichlorophenoxy)-4-phenylphthalazine (246) 1 -(2,5-Difluorophenoxy)-4-phenylphthalazine (247) 1 -(3-Chloro-4-methylphenoxy)-4-phenylphthalazine (248) 1 -(3-Methyl-4-chlorophenoxy)-4-phenylphthalazine (249) 1 -(3-Fluoro-4-methylphenoxy)-4-phenyl phthalazine (250) 1 -(2-Methoxy-4-chlorophenoxy)-4-phenylphthalazine (251) 1 -(2-Methoxy-5-methylphenoxy)-4-phenylphthalazinee (252) 1-(2-Methyl-4-trifluoromethylphenoxy)-4-phenylphthalazine (253) 1 -(2,4,6-Trimethylphenoxy)-4-phenylphthalazine Process for preparation of the compound (I) The compound represented by the formula [I] can be prepared according to any suitable process, which is not particularly limited.Preferably, however, the compound (I) can be synthesized by the following reaction route:
In the above formulae, X' represents -NH2 or OH; Y a halogen atom (e.g., chlorine, bromine or iodine), a group of the formula: S(0)pR4 (p=0--2, R4 is a C15 alkyl, phenyl or a substituted phenyl) or a group of the formula: -OR5 (R5 is a C15 alkyk, phenyl or a substituted phenyl); and all of the other symbols have the same meanings as defined above.
According to this process, the starting compound represented by the formula (II), namely 1 -chloro4-phenylphthalazine or its derivative, is allowed to react with a benzene derivative represented by the formula (III), in either the presence or absence of a solvent, preferably in the presence of a catalyst, to prepare a 4-phenylphthalazine derivative represented by the formula [I].
The starting materials, i.e., 1 -choloro-4-phenylphthalazine [II] or derivatives thereof were synthesized according to the method as described in Journal of Pharmacology 86, 576 (1966) or the methods similar thereto.
As the benzene derivative [III] to be reacted with the compound (II) as mentioned above, there may be employed suitable substituted anilines or substituted phenols.
The reaction temperature may be in the range from -20 to 2500C., preferably from -10 to 1 800C. The reaction time may be from 5 minutes to 24 hours, preferably from 10 minutes to 10 hours.
When a catalyst is to be employed, there may be used an organic base such as ammonia, triethylamine, piperidine or pyridine, or an inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or sodium amide may be added at a molar ratio relative to the compound (II) in the range from 0.5 to 5, preferably from 1 to 3. Alternatively, it is also possible to use a metal such as copper, magnesium, cadmium, sodium or potassium, at a molar ratio relative to the compound (II) in the range from 0.001 to 2, preferably from 0.01 to 1.5.
When a solvent is to be employed, there may be used a solvent selected from ethers such as ethyl ether, tetrahydrofuran, and dioxane; halogenated alkanes such as chloroform, methylene chloride, etc.; alcohols such as methanol, ethanol, etc.; aromatic hydrocarbons such as benzene, toluene, xyrene, etc.) amides such as defnethylformamide, dimethylacetamide, etc.; and dimethylsulfoxide; and so on.
The compound (Ill) may be used in an amount of 0.5 to 30 moles, preferably 1 to 2V moles, per mole of the compound (II).
After completion of the reaction, the reaction mixture may be poured into a large excess of water or dissolved as such in a solvent such as chloroform to be neutralized therein. If desired, the precipitated orystals may be collected by filtration after concentration, or alternatively the product may be extracted with a suitable solvent such as chloroform when there is no precipitation, followed by recrystallization or chromatography according to conventional procedures.
The present invention is further illustrated by the following Examples, by which the present invention is not limited.
EXAMPLE 1 Synthesis of I-(4-methylanilino)-4-phenylphthalazine (Compound No. Il To 2.41 g of 1 -chloro-4-phenylphthalazine, there were added 5.35 g of p-toluidine and 70 mg of copper powders. The mixture was then subjected to stirring under heating for one hour while maintaining the reaction temperature at 100 C. After the reaction mixture was left to cool, a large excess of chloroform was added thereto. The resultant insolubles were filtered off and the filtrate was washed with a 5% aqueous sodium hydroxide and then with water. The organic layer was dried and concentrated, and the residue was recrystallized from ethanol to give 910 mg (yield: 29%) of pale yellow crystals.
m.p.: 185-1860C.
I.R.: cm-l, 1510 cm-l, 1410 cm-l M.S;: 310(M±1) EXAMPLES 2-30 The compounds as shown in Table 1 were synthesized according to the methods similar to Example 1.
TABLE 1
Compound Example No. m.p./"C I R/cm ' M.S.
2 (2) 202@ 203 3270, 1575, 1520 310 (M#1) 141D, 790 3 (3) 188 3200. 1500, 1400 311 (M+) 1200, 755 296 4 (4) 206 w 207 2990, 1625, 1520 324 (M - 1) 1420, 780 5 (6) 189 # 190 2860, 1620, 1520 353 (M+) 1420, 780 310 6 (9) 206 # 207.5 2950, 1640, 1510 327 (M+) 1420, 1240, 785 312 7 (10) 196 3000, 1610, 1500 326 (M#1 ) 1400; 1155, 780 8 (12) 168.5 # 169 2950, 1620, 1505 369(M+) 1410, 1240, 790 312 9 (13) 206 # 207 3050, 1620, 1620 314 (M#1) 1410, 1220, 780 10 (14) 239 # 240 3280, 1620, 1520 314 (M#1) 1400, 1140, 790 11 (16) 193 # 194 1620, 1580, 1500 330 } (M+) 1400, 820, 770 332 12 (17) 191 # 194 1600, 1510, 1420 330 1390, 770 332 13 (18) 170 # 171.5 3440, 1500, 1520 330 # (M+) 1400, 1040, 760 332 14 (19) 219 # 222 3000, 1625 1510 376 1400, 820, 780 374 (M#1) 15 (23) 236 # 237.5 3000, 1720, 1615 369 1520, 1410, 1280 368 (M+) 16 (25) 240 # 242.5 3360, 2210, 1610 321 (M#1) 1510, 1410, 790 17 (26) 247 # 248.5 3400, 1680, 1600 338 (M#1) 1520, 1400, 1280 18 (28) 174 # 175.5 3040, 1630, 1520 364 (M#1) 1410, 1340, 1100 TABLE 1 (Continued)
Compound Example No. m.p./ C # R/cm M.S.
19 (31) 240 # 242 3200, 1520, 1415 325 (M+) 790, 770 310 20 (32) 206.5 # 207.5 3400, 1500, 1400 325 (M+) 810, 780 310 21 (33) 202 # 203.5 3200, 1500, 1400 325 (M+) 810, 780 310 22 (34) 204 # 204.5 3200, 1510, 1420 324 (M#1) 790, 770 23 (37) 215 # 216 3440, 1610, 1520 357 (M+) 1430, 790 326 24 (43) 217 1590, 1510, 1410 347 # (M+) 780, 700 345 25 (44) 232 # 232.5 3400, 1490, 1400 347 820, 780, 700 346 # (M+) 26 (42) 171 # 172 3000, 1610, 1500 346 1400, 775, 700 344 # (M#1) 27 (47) 129 # 132 3450, 1530, 1430 341 (M+) 1230, 790, 710 310 28 (48) 74.575 1600, 1500, 1420 364 1220, 790, 780 362 #(M@@) 29 (51) 200 # 202.5 3200,1500,1400 339 (M+) 780, 700 30 (24) 250 < 3360, 1680, 1600 340 (M+1) 1520, 1410, 780 EXAMPLE 31 Synthesis of 1 -(2-methylphenoxy)-4-phenylphthalazine (Compound No. 213) To 1.20 g of 1 -chloro-4-phenylphthalazine, there were added 5.40 9 of o-cresol and 360 mg of potassium hydroxide. The resultant mixture was subjected to stirring under heating for 2 hours, while maintaining the reaction temperature at 100 C.After the reaction mixture was poured into 12 ml of an aqueous solution having 3.6 g of potassium hydroxide dissolved therein, the crystals precipitated were recovered by filtration. The crude crystals were dissolved in chloroform, washed with water, dried and concentrated. Thea residue was recrystallized from ethanol-n-hexane to give 725 mg (yield : 46%) of white crystals.
136.5 - 137.5 CV.
1490 cm-1, 1385cm-1, 1230 cm-1, 1190 cm-1, 790 cm-1, 750 cm-1.
M.S.: 312 (M+) EXAMPLES 32-44 According to procedures similar to that as described in Example 31, there were synthesized the compounds as shown in Table 2.
TABLE 2
Compound Example No. m.p./ C # R/cm M.S.
32 (212) 148150. 1490, 1390, 1250 312 (M+) 1165, 800, 770 295 33 (214) 171.5 # 172 1510, 1385, 1210 326 (M+) 850, 770, 700 311 34 (218) 211 -212.5 2970, 1500, 1390 354 (M+) 1230, 790 339 35 (219) 163 ~164 1510, i390, 1205 328 (M+) 1030, 850, 700 121 36 (227) 171 # 172 1550, 1480, 1380 331 + 1230, 790, 780 297 37 (228) 179 # 180 1490, 1380, 1220 3761(M+) 1010, 790 378 38 (234) 139 # 141.5 1700, 1600, 1380 340 1220, 850, 800 325 # (M+) 39 (236) 119 - 121 1450, 1385, 1330 366 (M+) 1170, 1120, 900 365 40 (28) 149 # 149.5 1596, 1380, 1220 332 # (M+) 890, 795, 700 334 41 (239) 153 - 155 @ 1570, 1385, 1250 326 (M+) 1120, 770 309 42 (248) 155.5156 1480,1390, 1240 346 I(M+) 1170, 1050, 790 348 43 (244) 175.5 # 176.5 1580, 1470, 1365 365 (M# 1) 1220, 1090, 770 331 44 (245) 210 # 210.5 1450, 1380, 1360 366 (M+) 1240, 770 331 EXAMPLE 45 Synthesis of 1-(3-chloroanilino)-4-(4-methylphenyl) phthalazine (Compound No. 60) To 172 mg of 1 -chloro-4-(4-methylphenyl)phthalazine, there was added 319 mg of mchloroaniline, and the resultant mixture was heated at 1 000C with stirring for one hour. After the reaction mixture was left to cool to room temperature, a large excess of chloroform was added thereto, followed by washing with a 5% aqueous sodium hydroxide and then with water. The organic layer was dried and subjected to concentration. The residue was recrystallized from ethanol to give 145 mg (yield: 62%) of pale yellow crystals.
m.p. : 211.5 - 212. C.
#.R. : 595 cm-1, 1510 cm-1, 1475 cm-1, 1405 cm-1, 770 cm-1.
M.S.: 345 (M+), 343 (M+), 344.
EXAMPLES 46-109 The compounds as shown in Table 3, having the following formula:
were prepared according to the procedures similarly as described in Example 45. TABLE 3
Compound Example No. R R R m.p./ C I.R./cm-1 MS 46 (63) 3-CF3 4-CH3 H 179-180 3240, 1595, 1510 379 (M+) 1400, 1330, 1160 378 47 (56) 2-CH2, 5-CH3 4-CH3 H 184-185 3200, 1610, 1490 339 (M+) 2-OCH3, 1405, 1020 324 48 (59) 5-OCH3 4-CH3 H 192.5-193 3425, 1800, 1510 371 (M+) 2-COH2 1420, 1200, 1035 340 49 (85) 4-Cl 4-CH3 H 197-197.5 3430, 1595, 1510 377 (M+) 1420, 1240, 1010 375 (M+) 50 (78) 3-Cl 4-OCH3 H 227-228 1600, 1460, 1400 363 (M+) 1250, 770 361 (M+) 360 51 (78) 3-CF3 4-OCH3 H 228-229 3230, 1610, 1515 396 (M+) 1405, 1335, 1250 394 52 (76) 2-CH3, 5-CH 4-OCH3 H 179-180 1610, 1490, 1400 355 (M+) 2-OCH3, 1250, 1175 340 53 (77) 5-OCH3 4-OCH3 H 185-186 3435, 1610, 1515 387 (M+) 1250, 1020 358 54 (80) 2-OCH2, 4-Cl 4-OCH3 H 206-207 3435, 1600, 1515 393 (M+) 1420, 1250, 1020 391 (M+) 55 (97) 3-Cl 4-Cl H 222-223 1600, 1480, 1410 367 (M+) 1080, 780 366 (M+) 364 TABLE 3 (Continued)
Example Compound R1 R2 R3 m.p./ C I.R./CM-1 MS No.
56 (96) 3-CF3 4-Cl H 180-181 3270, 1605, 1450 401 (M+) 1415, 1340, 1120 399 (M+) 396 57 (95) 2-CH3, 5-CH 4-Cl H 196-197 1590, 1500, 1410 361 (M+) 1090, 935 369 (M+) 344 58 (96) 2-OCH3, 4-Cl H 190-192 3440, 1600, 1510 399 (M+) 5-OCH3 1430, 1220, 1045 391 (M+) 380 59 (99) 2-OCH3, 4-Cl H 200-201 3420, 1600, 1410 397 (M+) 4-Cl 1420, 1250 395 (M+) 384 60 (70) 3-Cl 4-C3H9 H 193-194 2920, 1600, 1410 389 (M+) 900, 770 387 (M+) 388 61 (71) 3-CF3 4-C4H9 H 164-167 2920, 1610, 1410 421 (M+) 1330, 1170, 1120 420 62 (88) 2-CH3 5-CH3 4-C4H9 H 169.5-171 2920, 1610, 1490 381 (M+) 1400, 805, 775 366 63 (89) 2-OCH3, 4-C4H9 H 169.5-160 2920, 1510, 1520 413 (M+) 5-OCH3 1430, 1205, 785 382 64 (72) 2-OCH3, 5-Cl 4-C4H9 H 173.6-174.5 3440, 2920, 1595 419 (M+) 1510, 1420, 1250 417 (M+) 398 TABLE 3 (Continued)
Example Compound R1 R2 R3 m.p./ C I.R./CM-1 MS No.
65 (85) 3-Cl 4-OC4H9 H 184.5-185.5 2950, 1600, 1616 405 (M+) 1420, 1260, 770 403 (M+) 402 66 (86) 3-CF3 4-OC4H9 H 183-184 2950, 1610, 1510 437 (M+) 1400, 1330, 1110 436 67 (88) 2-CH3, 5-CH3 4-OC4H9 H 156.5-158 2950,1610, 1510 397 (M+) 1400, 1250 382 68 (84) 2-OCH3, 4-OC4H9 H 163-163.5 3440, 2950, 1605 429 (M+) 5-OCH3 1505,1240 398 69 (87) 2-OCH3, 4-OC4H9 H 181.5-182.5 3420, 2950, 1600 435 (M+) 5-Cl 1510, 1410, 1260 433 (M+) 402 70 (104) 3-Cl 4-F H 228.5-229.5 1600, 1515, 1420 351 (M+) 1220, 1150, 775 349 348 71 (105) 3-CF3 4-F H 205-206.5 1610, 1620, 1420 383 (M+) 1335, 1120, 800 382 72 (102) 2-CH3 4-F H 188.5-189.5 1600, 1500, 1415 343 (M+) 5-CH3 1225, 328 73 (103) 2-OCH3 4-F H 176-177 3445, 1600, 1510 375 (M+) 5-OCH3 1430, 1210, 1020 344 74 (105) 2-OCH3 4-F H 216-217 3445, 1600, 1515 381 (M+) 5-Cl 1430, 1240, 1015 379 (M+) 348 TABLE 3 (Continued)
Example Compound R1 R2 R3 m.p./ C I.R./CM-1 MS No.
75 (91) 3-Cl 2-OCH3 H 200-201.5 1600, 1486 1400 393 (M+) 4-OCH3 1215, 1180, 775 391 (M+) 76 (92) 3-CF3, 2-OCH3 H 213-214 1620, 1500, 1400 425 (M+) 4-OCH3 1340, 1215, 1110 394 77 (89) 2-CH3 2-OCH3 H 220-221.5 1615, 1505, 1410 385 (M+) 5-CH3 4-OCH3 1215, 1160, 1040 370 78 (90) 2-OCH3 2-OCH3 H 177-177.5 3440, 1615, 1515 417 (M+) 5-OCH3 4-OCH3 1210, 1030 388 79 (93) 2-OCH3, 2-OCH3 H 203.5-205 3450, 1600, 1510 392 (M-1) 5-Cl 4-OCH3 1420, 1210, 1030 390 (M-1) 80 (110) 3-Cl 4-COOEt H 173-174 1710, 1590, 1500 405 (M+) 1410, 1270, 770 403 (M+) 402 81 (111) 3-CF3 4-COOEt H 215.5-216.5 1710, 1625, 1495 437 (M+) 1400, 1330, 1270 438 82 (108) 2-CH3, 4-COOEt H 201-5-202.5 3300, 1710, 1460 397 (M+) 5-CH3 1400, 1270, 1100 382 83 (109) 2-OCH3 4-COOEt H 198-199.5 3440, 1725, 1600 429 (M+) 5-OCH3 1560, 1270, 1090 398 84 (112) 2-OCH3, 4-COOEt H 208-207.5 3435, 1725, 1600 435 (M+) 5-Cl 1510, 1420, 1270 433 (M+) 402 TABLE 3 (Continued)
Example Compound R1 R2 R3 m.p./ C I.R./CM-1 MS No.
85 (119) 3-Cl 6 -CH3 221-223 1590, 1475, 1400 347 (M+) (120) H 7 -CH3 # mix. 1260, 770 345 (M+) 344 86 (121) 3-CF, 6 -CH3 221-222.5 1600, 1440, 1400 379 (M+) (122) H 7 -CH3 # mix. 1330, 1150, 1110 378 87 (115) 2-CH3, 6 -CH3 164-168 1620, 1500, 1410 339 (M+) (116) 5-CH3 H 7 -CH3 # mix. 800 324 88 (117) 2-OCH3, 6 -CH3 192-193 3430, 1600, 1520 371 (M+) (118) 5-COH3 H 7 -CH3 # mix. 1450, 1210, 1210 340 89 (123) 2-OCH3, 6 -CH3 146-147.5 3430, 1600, 1510 377 (M+) (124) 5-Cl H 7 -CH3 # mix. 1420, 1240, 1210 375 (M+) 344 90 (125) H H 6-CH3, 7-CH3 238-239 1605, 1500, 1410 326 (M+) 750 324 91 (130) 3-Cl H 6-CH3, 243.5-244.5 1606, 1500, 1400 361 (M+) 7-CH3 775, 765 359 (M+) 358 92 (131) 3-CF3 H 6-CH3, 255-258 1615, 1670, 1445 393 (M+) 7-CH3 1420, 1330, 1170 392 93 (127) 2-CH3, H 6-CH3, 153.5-156 1600, 1575, 1440 353 (M+) 5-CH3 7-CH3 810, 770 338 94 (128) 2-OCH3, H 6-CH3, 232-233 3450, 1610, 1520 385 (M+) 5-COH3 7-CH3 1400, 1220, 1010 354 TABLE 3 (Continued)
Example Compound R1 R2 R3 m.p./ C I.R./CM-1 MS No.
95 (132) 2-OCH3, H 6-CH3, 237-238 3450, 1600, 1520 391 (M+) 5-Cl 7-CH3 1425, 1250, 1020 389 (M+) 358 96 (138) H H 6-OCH3, 205.5-207 1620, 1500, 1410 367 (M+) 7-COH3 1220, 1100, 750 358 97 (141) 3-Cl H 6-OCH3, 199.5-204 1620, 1600, 1520 393 (M+) 7-OCH3 1410, 1220, 775 391 390 98 (142) 3-CF3 H 6-OCH3, 223-228 1610, 1510, 1400 425 (M+) 7-OCH3 1330, 1155, 1115 424 99 (139) 2-CH3, H 6-OCH3, 192-193.5 1610. 1510, 1410, 385 (M+) 5-CH3 7-OCH3 1250, 1210 370 100 (140) 2-OCH3, H 6-OCH3, 158-158 3440, 1610, 1510 417 (M+) 5-OCH3, 7-OCH3 1410 1215, 1080 386 101 (143) 2-OCH3, H 6-OCH3, 211.5-213 3440, 1610, 1590 423 (M+) 5-Cl 7-OCH3 1510, 1410, 1240 421 (M+) 390 102 (144) 4-C4H5 H 6-OCH3, 167.5-189 2920, 1615, 1495 413 (M+) 7-OCH3 1405, 1240, 1090 412 103 (145) 4-OC4H5 H 6-OCH3, 183.5-186 2940, 1615, 1500 429 (M+) 7-OCH3 1405, 1220, 825 372 104 (151) 3-Cl H 6-OCH3, 248-250 1600, 1480, 1405 403 (M+) 7-OCH3 1090, 890, 760 402 (M+) 401 (M+) 400 TABLE 3 (Continued)
Example Compound R1 R2 R3 m.p./ C I.R./CM-1 MS No.
105 (152) 3-CF, H 6-Cl, 243-244.5 1610, 1515, 1450 435 (M+) 7-Cl 1415, 1335, 1110 434 (M+) 433 (M+) 432 106 (149) 2-CH2, H 6-Cl, 204-205.5 1606, 1560, 1498 396 (M+) 5-CH, 7-Cl 1400, 1560, 393 (M+) 107 (150) 2-OCH3, H 6-Cl, 199.5-201 3435, 1610, 1560 427 (M+) 5-OCH3, 7-Cl 1400, 1210, 425 (M+) 394 108 (153) 2-OCH2, H 6-Cl, 201-202 3435, 1600, 1550, 431 (M+) 5-Cl 7-Cl 1500, 1420, 1250 429 (M+) 400 109 (202) 2-OCH3, 4-COOH H 274-275.5 3440, 1690, 1600, 405 (M+) 5-Cl 1510, 1420, 1240 374 Pharmacological tests: Artery blood of a rabbit was subjected to centrifugation to obtain platelet rich plasma. To an aliquot of 250 ,ul of the plasma, there was added 5 jul of each pharmaceutical solution. After incubation for two minutes, platelet aggregation was induced by adding 3 iug of collagen to the mixture. The change in platelet aggregationn was monitored and recorded by means of an aggregometer for 10 minutes.
The platelet aggregation inhibitory percentage was calculated by the following formula: Texts Inhibitory percentage= - x 100 Tc wherein Tc is the degree of aggregation when only a solvent is added and Ts is that when a pharmaceutical solution is added.
Table 4 shows inhibitory percentages at indicated mole concentrations for each compound. As apparently seen from the results, among these compounds, the anilinophthalazine derivatives are generally found to have more potent activity than the phenoxyphthalazine derivatives.
TABLE 4
Mole concentration Compound Example No. 3 x 10'' 10 1 (1) 56.5 33.9 2 (2) 80.6 66.1 3 (3) 100 60.9 4 (4) 100 100 5 (6) 100 100 6 (9) 76.6 39.1 7 (10) 100 100 8 (12) 100 100 9 -(13) 100 100 10 (14) 100 100 11 (16) 100 38.8 12 (17) 100 100 13 (18) 100 100 14- (19) 100 100 15 (23) 65.5 50.9 16 (25) 13.6 17 (26) 100 21.1 18 (28) 100 100 19 (31) 82.5 24.6 20 (32) 100 45.3 21 (33) 100 100 22 (34) 100 100 23 (37) 100 100 24 (43) 100 100 25 (44) 85.5 56.5 26 (42) 100 100 27 (47) 100 100 28 (48) 100 100 TABLE 4 (Continued)
Mole concentration Compound Example No. 3 x 10 6 10 29 (51) 100 100 30 (24) 13A - 31 (213) 100 100 32 (212) 100 51.3 33 (214) 100 30.4 34 (218) 6.38 9.6 35 (21 9) 100 100 36 (227) 73A 23.8 37 (228) 100 28.9 38 (234) 104 39 (236) 100 100 40 (226) 100 100 41 (239) 100 100 42 (248) 100 25.5 43 (244) 68A 26.3 44 (245) 84.1 15.9 45 (60) 100 100 46 (63) 100 100 47 (56) 100 7.6 48 (59) 100 100 49 (64) 100 100 50 (78) 100 100 51 (79) 100 100 52- (76) 33.6 11.8 53 (77) 100 100 54 (80) 100 100 55 (97) 100 100 56 (98) 100 100 TABLE 4 (Continued)
Mole concentration Compound Example No. 3 x 10-6 10' 57 (95) 58.7 15.1 58 (96) 100 59 (99) 100 100 60 (70) 28.0 23.4 61 (71) 100 26,2 62 (68) 55.8 63 (69) 100 100 64 (72) 100 54.9 65 (85) 30.5 18.3 66 (86) 482 25.9 67 (83) 27.9 68 (84) 100 100 69 (87) 61 2 35.8 70 (1 04) 100 66.7 71 (105) 100 74.1 72 (1 02) 100 69.8 73 (1 03) 100 91.9 74 (1 06) 84.4 50.0 75 (91) 92.6 10.6 76 (92) 29.7 77 (89) 100 84.9 78 (90) 30.5 11.9 79 (93) 17.7 80 (110) 12.0 81 (111) 48.2 36,6 82 (1 08) 30.5 4.3 83 (1 09) 100 100 84 (112) 100 100 TABLE 4 (Continued)
Mole concentration Compound Example No. 10-5 3 x10-6 1o-6 85 #(119) 100 100 (120) 86 #(121) 93.1 34.5 (122) 87 #(115) 100 100 (116) 88 #(117) 100 100 (118) 89 # (123) 100 100 90 (125) 100 91 (1 30) 100 92 (131) 100 93 (127) 100 23.1 94 (128) 100 95 (132) 100 96 (138) 9.1 97 (141) 10.7 98 (142) 46.3 103 (145) 8.9 104 (151) 13.3 105 (152) 100 152 107 (150) 15.8 108 (153) 27.6 Safety Each of the compounds according to the present invention was found to be veryk low in toxicity, namely not less than 5000 mg/kg in terms of LD50 as measured by oral administration for mouse.

Claims (16)

1. A 4-phenylphthalazine derivative represented by the following formula or a pharmaceutically acceptable salt thereof:
wherein X stands for NH or O; R' an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a halogen atom, an alkoxycarbonyl group having 2 to 6 total carbon atoms, a carboxyl group, a cyano group, an alkylcarbonyl group having 2 to 4 total carbon atoms, a hydroxyl group or a trifluoromethyl group;R2 and R3, which may be identical or different (may also be the same as or different from R'), each represent an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a halogen atom, an alkoxycarbonyl group having 2 to 6 total carbon atoms, a carboxyl group, an alkylcarbonyl group having 2 to 4 total carbon atoms, a hydroxyl group or a trifluoropmethyl group; and each of l, m and n is an integer ofzero to 3 (provided that 1=1 to 3 and m=n=zero when X is 0, and the case where l=m=n=zero is excluded when X is NH), each plural number of R', R2 and R3 being identical or different when the integers I, m and n are two or more,
2. A 4-phenylphthalazine derivative according to Claim 1, wherein X is NH.
3. A 4-phenylphthalazine derivative according to Claim 2, wherein 1, m and n are one combination selected from the following combinations (1) to (4): (1) I=1 to 3, m=n=zero; (2)1=1 to 2, m=1 to 2, n=zero; (3)1=1 to 2, m=zero, n=1 to 2; and (4) I=m=zero, n=1 to 2.
4. A 4-phenylphthalazine derivative according to Claim 3, wherein 1=1 to 3 and m=n=zero.
5. A 4-phenylphthalazine derivative according to Claim 3, wherein 1=1 to 2, m=1 to 2 and n=zero.
6. A 4-phenylphthalazine derivative according to Claim 3, wherein 1=1 to 2, m=zero and n=1 to 2.
7. A 4-phenylphthalazine derivative according to Claim 3, wherein l=m=zero and n=1.
8. A 4-phenylphthalazine derivative according to Claim 1, wherein X is O.
9. A 4-phenylphthalazine derivative according to Claim 8, wherein 1=1 to 3 and m=n=zero.
10. A 4-phenylphthalazine derivative according to Claim 9, wherein 1=1 to 2.
1 A 4-phenylphthalazine derivative according to Claim 1, wherein R1 is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a halogen atom or a trifluormethyl group.
12. A 4-phenylphthalazine derivative according to Claim 1, wherein R2 is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms or a halogen atom.
13. A 4-phenylphthalazine derivative according to Claim 1, wherein R3 is an alkyl group.
14. A process for preparing a 4-phenylphthalazine derivative represented by the following formula:
wherein X stands for NH or O; R1 an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a halogen atom, an alkoxycarbonyl group having 2 to 6 total carbon atoms, a carboxyl group, a cyano group, an alkylcarbonyl group having 2 to 4 total carbon atoms, a hydroxyl group or a trifluoromethyl group; R2 and R3, which may be identical or different (may also be the same as or different from R'), each represent an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a halogen atom, an alkoxycarbonyl group having 2 to 6 total carbon atoms, a carboxyl group, an alkylcarbonyl group having 2 to 4 total carbon atoms, a hydroxyl group or a trifluoromethyl group; and each of I, m and n is an integer of zero to 3 (provided that 1=1 to 3 and m=n=zero when X is 0, and the case where l=m=n=zero is excluded when X is NH), each plural number of R', R2 and R3 being identical or different when the integers I, m and n are two or more, which comprises allowing a compound of the formula:
Y represents a halogen atom, a group of the formula : - S(O)p - R4, in which p = o-2, R4 is a C1-5 alkyl, phenyl or a substituted phenyl or a group of the formula : - OR5, in which R5 is a C1-5 alkyl, phenyl or a substituted phenyl; R2, R3, m and n have the same meanings as defined above, to react with a compound of the formula:
wherein X' represents -NH2 of OH, and R1 and I have the same meanings as defined above.
15. A process as claimed in Claim 14 and substantially as hereinbefore described with reference to Examples 1 to 109.
16. 4-phenylphthalazine derivatives when prepared by a process as claimed in Claim 14 or 15.
GB8030906A 1979-10-09 1980-09-25 4-Phenylphthalazine derivatives Withdrawn GB2063249A (en)

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Cited By (46)

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Publication number Priority date Publication date Assignee Title
EP0449203A1 (en) * 1990-03-30 1991-10-02 Mitsubishi Chemical Corporation 4-Phenylphthalazine derivatives
US5324727A (en) * 1991-09-26 1994-06-28 Mitsubishi Chem Ind 3,6-disubstituted pyridazine derivatives
US5696159A (en) * 1994-08-03 1997-12-09 Cell Pathways, Inc. Lactone compounds for treating patients with precancerous lesions
EP0825187A1 (en) * 1996-08-22 1998-02-25 Takeda Chemical Industries, Ltd. Condensed pyridazinyl guanidines, their production and use
US5776962A (en) * 1994-08-03 1998-07-07 Cell Pathways, Inc. Lactone compounds for treating patient with precancerous lesions
WO1998046574A1 (en) * 1997-04-16 1998-10-22 Smithkline Beecham Plc Pyridazine and phthalazine derivatives, process of their preparation and their use as anticonvulsants
US5852035A (en) * 1997-12-12 1998-12-22 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to substituted N- arylmethyl and heterocyclmethyl-1H-pyrazolo (3,4-B) quinolin-4-amines
US5874440A (en) * 1995-06-07 1999-02-23 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with phenyl pyrimidinone derivatives
US5942520A (en) * 1998-01-27 1999-08-24 Cell Pathways, Inc. Method for inhibiting neoplastic cells by exposure to substituted N-cycloalkylmethyl-1-H-pyrazolo (3,4-B) quinolone-4 amines
US5990117A (en) * 1998-04-15 1999-11-23 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to quinazoline derivatives
US6020379A (en) * 1999-02-19 2000-02-01 Cell Pathways, Inc. Position 7 substituted indenyl-3-acetic acid derivatives and amides thereof for the treatment of neoplasia
US6034099A (en) * 1998-11-24 2000-03-07 Cell Pathways, Inc. Method for inhibiting neoplastic lesions by administering 4-(arylmethylene)- 2, 3- dihydro-pyrazol-3-ones
US6046199A (en) * 1998-01-14 2000-04-04 Cell Pathways, Inc. Method of inhibiting neoplastic cells with tetracyclic pyrido[3,4-B]indole derivatives
US6046216A (en) * 1995-06-07 2000-04-04 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with phenyl pyridinone derivatives
US6046206A (en) * 1995-06-07 2000-04-04 Cell Pathways, Inc. Method of treating a patient having a precancerous lesions with amide quinazoline derivatives
US6060477A (en) * 1995-06-07 2000-05-09 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with phenyl cycloamino pyrimidinone derivatives
US6077842A (en) * 1998-11-24 2000-06-20 Cell Pathways, Inc. Method of inhibiting neoplastic cells with pyrazolopyridylpyridazinone derivatives
US6114530A (en) * 1996-12-18 2000-09-05 Neurogen Corporation Isoquinolinamine and phthalazinamine derivatives: corticotropin-releasing factor receptor CRF1 specific ligands
US6124303A (en) * 1998-09-11 2000-09-26 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 9-substituted 2-(2-N-aloxyphenyl) purin-6-ones
US6130053A (en) * 1999-08-03 2000-10-10 Cell Pathways, Inc. Method for selecting compounds for inhibition of neoplastic lesions
US6133271A (en) * 1998-11-19 2000-10-17 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure thienopyrimidine derivatives
US6156528A (en) * 1997-05-30 2000-12-05 Cell Pathways, Inc Methods for using a phosphodiesterase in pharmaceutical screening to identify compounds for treatment of neoplasia
US6177471B1 (en) 1999-01-29 2001-01-23 Cell Pathways, Inc. Method for treating patients with acne by administering a CGMP-specific PDE inhibitor
US6180629B1 (en) 1998-08-14 2001-01-30 Cell Pathways, Inc. [4,5]-Fused-1,3-disubstituted-1,2-diazine-6-one derivatives with nitrogen containing substitutents in position one for the treatment of neoplasia
US6187779B1 (en) 1998-11-20 2001-02-13 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 2,8-disubstituted quinazoline derivatives
US6200771B1 (en) 1998-10-15 2001-03-13 Cell Pathways, Inc. Method of using a novel phosphodiesterase in pharmaceutical screeing to identify compounds for treatment of neoplasia
US6200980B1 (en) 1995-06-07 2001-03-13 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with phenyl purinone derivatives
US6232312B1 (en) 1995-06-07 2001-05-15 Cell Pathways, Inc. Method for treating patient having precancerous lesions with a combination of pyrimidopyrimidine derivatives and esters and amides of substituted indenyl acetic acides
US6262059B1 (en) 1995-06-07 2001-07-17 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with quinazoline derivatives
US6268372B1 (en) 1998-09-11 2001-07-31 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 2,9-disubstituted purin-6-ones
US6329370B1 (en) * 1998-07-21 2001-12-11 Zambon Group S.P.A. Phthalazine derivatives phosphodiesterase 4 inhibitors
US6369092B1 (en) 1998-11-23 2002-04-09 Cell Pathways, Inc. Method for treating neoplasia by exposure to substituted benzimidazole derivatives
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US6555547B1 (en) 2000-02-28 2003-04-29 Cell Pathways, Inc. Method for treating a patient with neoplasia by treatment with a vinca alkaloid derivative
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US7115647B2 (en) 1998-01-14 2006-10-03 Osi Pharmaceuticals, Inc. Method of inhibiting neoplastic cells with indole derivatives
US7208516B2 (en) 2002-03-20 2007-04-24 Celgene Corporation Methods of the treatment of psoriatic arthritis using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US7276529B2 (en) 2002-03-20 2007-10-02 Celgene Corporation Methods of the treatment or prevention of exercise-induced asthma using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US7893101B2 (en) 2002-03-20 2011-02-22 Celgene Corporation Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof
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WO2022216971A1 (en) * 2021-04-07 2022-10-13 Ventus Therapeutics U.S., Inc. Pyridazine compounds for inhibiting nlrp3
US11618751B1 (en) 2022-03-25 2023-04-04 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives

Families Citing this family (17)

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Publication number Priority date Publication date Assignee Title
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EP3884935B1 (en) 2013-08-09 2023-06-14 Ardelyx, Inc. Compounds and methods for inhibiting phosphate transport
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Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1303061A (en) * 1969-05-03 1973-01-17

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US5324727A (en) * 1991-09-26 1994-06-28 Mitsubishi Chem Ind 3,6-disubstituted pyridazine derivatives
US5462941A (en) * 1991-09-26 1995-10-31 Mitsubishi Chemical Corporation 3,6-disubstituted pyradazine derivatives
US5696159A (en) * 1994-08-03 1997-12-09 Cell Pathways, Inc. Lactone compounds for treating patients with precancerous lesions
US5776962A (en) * 1994-08-03 1998-07-07 Cell Pathways, Inc. Lactone compounds for treating patient with precancerous lesions
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US6492360B1 (en) 1998-07-21 2002-12-10 Zambon Group S.P.A. Phthalazine derivatives phosphodiesterase 4 inhibitors
AU765457B2 (en) * 1998-07-21 2003-09-18 Zambon Group S.P.A. Phthalazine derivatives phosphodiesterase 4 inhibitors
US6329370B1 (en) * 1998-07-21 2001-12-11 Zambon Group S.P.A. Phthalazine derivatives phosphodiesterase 4 inhibitors
US6180629B1 (en) 1998-08-14 2001-01-30 Cell Pathways, Inc. [4,5]-Fused-1,3-disubstituted-1,2-diazine-6-one derivatives with nitrogen containing substitutents in position one for the treatment of neoplasia
US6440981B1 (en) 1998-09-11 2002-08-27 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 2,9-disubstituted purin-6-ones
US6124303A (en) * 1998-09-11 2000-09-26 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 9-substituted 2-(2-N-aloxyphenyl) purin-6-ones
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US6200771B1 (en) 1998-10-15 2001-03-13 Cell Pathways, Inc. Method of using a novel phosphodiesterase in pharmaceutical screeing to identify compounds for treatment of neoplasia
US6133271A (en) * 1998-11-19 2000-10-17 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure thienopyrimidine derivatives
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US6034099A (en) * 1998-11-24 2000-03-07 Cell Pathways, Inc. Method for inhibiting neoplastic lesions by administering 4-(arylmethylene)- 2, 3- dihydro-pyrazol-3-ones
US6077842A (en) * 1998-11-24 2000-06-20 Cell Pathways, Inc. Method of inhibiting neoplastic cells with pyrazolopyridylpyridazinone derivatives
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US6020379A (en) * 1999-02-19 2000-02-01 Cell Pathways, Inc. Position 7 substituted indenyl-3-acetic acid derivatives and amides thereof for the treatment of neoplasia
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US9018243B2 (en) 2002-03-20 2015-04-28 Celgene Corporation Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof
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US7427638B2 (en) 2002-03-20 2008-09-23 Celgene Corporation (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione:, and methods of synthesis and compositions thereof
US7507759B2 (en) 2002-03-20 2009-03-24 Celgene Corporation Methods of using(+)-2-[1-(3-ethoxy-4methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3,-dione
US7659303B2 (en) 2002-03-20 2010-02-09 Celgene Corporation Methods of using (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- acetylaminoisoindoline-1,3-dione
US6962940B2 (en) 2002-03-20 2005-11-08 Celgene Corporation (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
US7893101B2 (en) 2002-03-20 2011-02-22 Celgene Corporation Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof
US8093283B2 (en) 2002-03-20 2012-01-10 Celgene Corporation Solid forms comprising (+)-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisinoline-1,3-dione, compositions thereof, and uses thereof
US11260046B2 (en) 2002-03-20 2022-03-01 Amgen Inc. (+)-2-[1-(3-Ethoxy-4- methoxyphenyl)-2-methylsulfonylethyl]- 4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
US8455536B2 (en) 2002-03-20 2013-06-04 Celgene Corporation Methods of using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline 1,3-dione
US11040024B2 (en) 2002-03-20 2021-06-22 Amgen Inc. Methods of using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US8629173B2 (en) 2002-03-20 2014-01-14 Celgene Corporation Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof
US8802717B2 (en) 2002-03-20 2014-08-12 Celgene Corporation Methods of treating arthritic conditions using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline 1,3-dione
US7208516B2 (en) 2002-03-20 2007-04-24 Celgene Corporation Methods of the treatment of psoriatic arthritis using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US9283207B2 (en) 2002-03-20 2016-03-15 Celgene Corporation Methods of using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US9433606B2 (en) 2002-03-20 2016-09-06 Celgene Corporation Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof
US9724330B2 (en) 2002-03-20 2017-08-08 Celgene Corporation Methods of using (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US10092542B2 (en) 2002-03-20 2018-10-09 Celgene Corporation Methods of using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US10610516B2 (en) 2002-03-20 2020-04-07 Amgen Inc. Methods of using (+)- 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1, 3-dione
US20130165440A1 (en) * 2010-09-14 2013-06-27 Exelixis, Inc. JAK1 Inhibitors
WO2012037132A1 (en) * 2010-09-14 2012-03-22 Exelixis, Inc. Phtalazine derivatives as jak1 inhibitors
US10300042B2 (en) 2014-06-23 2019-05-28 Celgene Corporation Apremilast for the treatment of a liver disease or a liver function abnormality
WO2022216971A1 (en) * 2021-04-07 2022-10-13 Ventus Therapeutics U.S., Inc. Pyridazine compounds for inhibiting nlrp3
EP4331668A3 (en) * 2021-04-07 2024-06-05 Ventus Therapeutics U.S., Inc. Compounds for inhibiting nlrp3 and uses thereof
US11618751B1 (en) 2022-03-25 2023-04-04 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
US12168657B2 (en) 2022-03-25 2024-12-17 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
US12195460B2 (en) 2022-03-25 2025-01-14 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors

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IT1148727B (en) 1986-12-03
IT8025206A0 (en) 1980-10-08

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