Mitsubishi Chemical Industries Limited

Other

Mitsubishi Kasei Corporation

Mitsubishi Chemical Corporation

Shosuke Okamoto

Yoshikuni Tamao

Ryoji Kikumoto

Shinji Tonomura

Kazuo Ohkubo

Akiko Hijikata

Tohru Tezuka

Yasuhiro Morinaka

Ryoichi Ando

Chizuko Takahashi

Akihiro Tobe

Norimichi Iwase

Naoko Ando

Hirokazu Masuda

Toshiji Kanayama

Masahiro Ohshima

Kumi Yamada

Toshiro Sasaki

Akira Maruyama

Hiroto Hara

Toshiro Sakaki

Koichi Sugawara

Akiko Okunomiya

Misao Okitsu

Shigeo Sugiyama

Masanori Osakabe

Hyogi Kikumoto

Kazdo Ohkubo

A novel ketone derivative (I) which possesses a potent inhibitory activity against thiol protease such as papain, cathepsin B, cathepsin H, cathepsin L, calpain or the like with excellent properties regarding oral absorbance, tissue transference and cell membrane permeability, and are clinically useful in the treatment of various diseases such as muscular dystrophy, amyotrophy. Also provided are a process for producing the compound (I) and a pharmaceutical composition containing the same.

Ketone derivatives

A prolineamide derivative represented by the formula (I): ##STR1## or a salt or hydrate thereof or a pharmaceutically acceptable salt thereof, which has a protease inhibition activity and is useful as an active ingredient of pharmaceutical compositions is provided.

Prolineamide derivatives

A method is provided for treating a disease caused by smooth muscle cell hyperplasia. According to this method, there is administered to a patient suffering from said disease a therapeutically or prophylactically effective amount of an aminopyridazine derivative or a salt thereof represented by the formula: ##STR1##

Medicament for therapeutic and prophylactic treatment of diseases caused

A 3,6-disubstituted pyridazine derivative having excellent platelet agglutination inhibitory effects. It is useful for a preventive medicine or a therapeutic medicine for a cerebrovascular disorder such as cerebral thrombosis and cerebral embolism, an ischemic heart disease such as myocardial infarction, and a circulation disorder such as peripheral circulation disorder. A pharmaceutical composition containing a compound of the present invention as an effective ingredient and a process for preparing the same are also disclosed. The compound has the formula (I) ##STR1## wherein A represents an alkyl group having 3 to 6 carbon atoms; a cycloalkyl group having 5 to 7 carbon atoms; a phenyl group, a thienyl group, a furyl group, a thiazolyl group, a phenoxy group, a phenylalkyl group having 7 to 9 carbon atoms, a phenylthio group, a 5-6 membered saturated heterocyclic group containing one or more nitrogen atoms, a pyridyl group or an imidazolyl group each of which may have at least one substituent selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms and a halogen atom; B represents (a) --NH--D wherein D represents ##STR2## (4) --CH.sup.3 R.sup.4 ; or (5) an alkyl group having 3 to 8 carbon atoms; or ##STR3## and the ring C represents a benzene ring.

3,6-disubstituted pyradazine derivatives

Aminoketone derivatives according to the present invention strongly inhibit thiol protease such as calpain, papain, cathepsin B, cathepsin H, cathepsin L or the like and have excellent properties concerning absorbance on oral administration, tissue distribution and cell membrane permeability. The aminoketone derivatives cart thus be used as therapeutic agents for treating muscular dystrophy, cataract, cardiac infarction, stroke, Alzheimer's disease, amyotrophy, osteoporosis and hypercalcemia and so on. It may also be used as therapeutic agents for preventing metastasis of cancer. In addition, the present derivatives are also applicable as intermediates for the preparation of ketone derivatives, which have inhibitory activity against thiol protease.

Aminoketone derivatives

Alpha-aminoketone derivatives of the present invention strongly inhibit thiol protease such as papain, cathepsin B, cathepsin H, cathepsin L and calpain or the like and have excellent properties in absorbance on oral administration, tissue distribution and cell membrane permeability. The alpha-aminoketone derivatives can thus be used as therapeutic agents for treating muscular dystrophy, amyotrophy, cardiac infarction, stroke, Alzheimer's disease, disturbance of consciousness or dyskinesia caused upon brain trauma, multiple sclerosis, peripheral nervous neuropathy, cataract, inflammation, allergosis, fulminant hepatitis, osteoporosis, hypercalcemia, breast carcinoma, prostatic carcinoma or prostatomegaly. They may also be used as therapeutic agents for suppressing growth of cancer cells, preventing metastasis of cancer or suppressing aggregation of plaques.

.alpha.-aminoketone derivatives

A novel cyclopropenone derivative (I) which possesses a potent inhibitory activity against thiol protease such as papain, cathepsin B, cathepsin H, cathepsin L, calpain or the like with excellent properties regarding oral absorbance, tissue transference and cell membrane permeability, and are clinically useful in the treatment of various diseases such as muscular dystrophy, amyotrophy. Also provided are a process for producing the compound (I) and a pharmaceutical composition containing the same.

Cyclopropenone derivatives

Disclosed herein is a fibrinolysis-enhancing agent comprising, as an effective ingredient, an N.sup.2 -arylsulfonyl-L-arginine amide represented by the general formula (I): ##STR1## wherein R.sup.1 is a group of the formula: ##STR2## where R.sup.3 is an alkyl group having 3 to 5 carbon atoms or an alkoxyalkyl group having 2 to 4 carbon atoms and R.sup.4 is an alkyl group having 1 to 3 carbon atoms; and R.sup.2 is a group of the formula: ##STR3## where R.sup.5 and R.sup.6 are independently hydrogen atom, methyl group or methoxy group provided that they cannot be hydrogen atoms simultaneously, and R.sup.7 is an alkyl group having 1 to 3 carbon atoms; or a salt thereof. The agent is used in combination with a plasminogen activator.

Fibrinolysis-enhancing agents

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.

4-phenylphthalazine derivatives which inhibit platelet aggregation

A method of suppressing vasoconstriction in a warm-blooded animal which comprises administering to said warm-blooded animal an effective amount of a serotonin antagonist compound of the formula (I): ##STR1## wherein: R.sup.1 is hydrogen, halo, C.sub.1 -C.sub.5 alkoxy or C.sub.2 -C.sub.6 dialkyl amino;

Serotonin antagonist

Novel arginine derivatives represented by the general formula ##STR1## wherein R.sup.1 stands for a naphthalenesulfonyl, a naphthalenecarbonyl, a 1,2,3,4-tetrahydronaphthalenesulfonyl, a 1,2,3,4-tetrahydronaphthalenecarbonyl, a dioxa b-6,7-naphthalenesulfonyl, a dioxa b-6,7-naphthalenecarbonyl, a 1,2,3,4-tetrahydro-8-quinolinesulfonyl, a 1,2,3,4-tetrahydro-8-quinolinecarbonyl, a dibenzofuransulfonyl, a dibenzofurancarbonyl, a fluorenesulfonyl, a fluorenecarbonyl, a dibenzothiophenesulfonyl or a dibenzothiophene, and R.sup.2 stands for a piperidino or a piperazino are disclosed. These arginine derivatives and their pharmaceutically acceptable salts have trypsin-inhibiting activity and useful as a pancreatitis remedy.

Arginine derivatives and pharmaceutically acceptable acid addition salts

N.sup.2 -dansyl-L-arginine esters and amides having the formula ##STR1## or the acid addition salts thereof with a pharmaceutically acceptable acid, wherein R is selected from the group consisting of (1) alkoxy, alkenyloxy, alkynyloxy, and cycloalkoxy, respectively, containing not more than 10 carbon atoms, aralkyl of not more than 15 carbon atoms, tetrahydrofurfuryloxy, and alkoxy of not more than 10 carbon atoms substituted with an alkoxy group of not more than 10 carbon atoms, halogen or nitro; (2) ##STR2## wherein R.sub.1 and R.sub.2 are members selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkenyl, and alkyl, wherein said member has no more than 10 carbon atoms, and wherein said alkyl may be substituted with a member selected from the group consisting of alkoxy, alkoxycarbonyl, arylcarbamoyl, acyl, acyloxy, N,N-polymethylenecarbamoyl, respectively, containing not more than 10 carbon atoms, and carboxyl; and (2) ##STR3## wherein Z is a divalent group containing up to 10 carbon atoms, which consists of more than one group selected from the group consisting of methylene --CH.sub.2, monosubstituted methylene ##STR4## wherein R.sub.3 is selected from the group consisting of alkyl, acyl, alkoxy, and alkoxycarbonyl, respectively, containing not more than 10 carbon atoms, and carbamoyl, and disubstituted methylene ##STR5## wherein R.sub.4 R.sub.5 are alkyl groups of not more than 10 carbon atoms, and which may further contain at least one member selected from the group consisting of oxy--O--, thio --S--, cycloalkylene of not more than 10 carbon atoms, imino ##STR6## alkyl substituted imino ##STR7## wherein R.sub.6 is an alkyl group of not more than 10 carbon atoms, acyl substituted imino ##STR8## wherein R.sub.7 is an alkyl group of not more than 10 carbon atoms, phenylene ##STR9## and carbonyl ##STR10## which completes the ring together with the said methylene, mono-substituted methylene or disubstituted methylene.

N.sup.2 -dansyl-L-arginine derivatives, and the pharmaceutically

N.sup.2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.

Growing community of inventors

Machida, Japan

Yoshikuni Tamao