Ono Pharmaceutical Co., Ltd.

Ono Pharmaceuticals Co., Ltd.

Hisao Nakai

Yoshinobu Arai

Hiroshi Terashima

Masanori Kawamura

Masayasu Kurono

Tsumoru Miyamoto

Yoshifumi Kagamiishi

Koumei Kamiyasu

Shingo Yamamoto

Shingo Nakatani

Takashi Muryobayashi

Shigeru Sakuyama

Katsuya Kishikawa

Tomomi Hirosaki

Nobuyuki Hamanaka

Yoshikazu Takaoka

Hiroshi Ochiai

Susumu Yamamoto

Hiroshi Kido

Mikio Ogawa

Akira Ohhata

Takeshi Chiba

It is intended to provide a compound represented by the formula (I): 

Nitrogen-containing heterocyclic compound and pharmaceutical application thereof

Tri-heterocyclic compound of formula (I) wherein each of W, X and Y is carbon or nitrogen; each of U and Z is CR, NR, nitrogen, oxygen, sulfur etc.; A ring is carbocyclic ring, heterocyclic ring; Ris alkyl, alkenyl, alkynyl, NRR, ORetc.; Ris carbocyclic ring, heterocyclic ring;and a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical comprising them as an active ingredient. A compound of formula (I) is useful, in order to possess corticotropin releasing factor receptor antagonistic activity, for the prevention and/or treatment of depression, anxiety, eating disorder, posttraumatic stress disorder, peptic ulcer, irritable bowl syndrome, Alzheimer's disease, drug addiction or alcohol dependence syndrome etc.

Tri-heterocyclic compounds and a pharmaceutical comprising them as an active ingredient

The present invention relates to a compound that has p38 MAP kinase inhibitory activity useful as drug medicine, represented by the general formula (I):  The compound of the general formula (I) has a p38 MAP kinase inhibitory activity and is useful for the prevention and/or treatment of diseases in which an abnormal production of cytokine, such as inflammatory cytokine or chemokine, or an over-reaction thereto would be instrumental in the cause and aggravation of pathologic condition thereof, namely, cytokine-mediated diseases, for example, inflammatory diseases, respiratory diseases, circulatory diseases, central nervous diseases, etc.

Nitrogenous heterocyclic compound and pharmaceutical use thereof

Piperidine derivatives represented by formula (I) or nontoxic salts thereof (wherein symbols are defined in the description):  Since the compound represented by formula (I) has a PDE4 inhibitory activity, it is useful for preventing and/or treating inflammatory diseases, diabetic diseases, allergic diseases, autoimmune diseases, osteoporosis, bone fracture, obesity, depression, Parkinson's disease, dementia, ischemia-reperfusion injury, leukemia and the like.

Piperidine derivatives and agent comprising the derivative as active ingredient

A nitrogen-containing bicyclic compound of formula (I) or a pharmaceutically acceptable salt thereof (wherein the symbols have the same meanings as described in the specification).  The compound of formula (I) has an inhibitory activity against PDE7 and it is useful for the prevention and/or treatment of various diseases, i.e. autoimmune diseases (ulcerative colitis, Crohn's disease, rheumatism, psoriasis, multiple sclerosis, collagenosis, etc.), inflammatory diseases (obstructive pulmonary disease, sepsis, pancreatitis, sarcoidosis, nephritis, hepatitis, enteritis, etc.), allergic diseases (asthma, allergic rhinitis, allergic conjunctivitis, seasonal conjunctivitis, atopic dermatitis, etc.), rejection of organ transplants, serious graft versus host disease (GVHD), diabetic disease, osteoporosis, bone fracture, restenosis, atherosclerosis, obesity, ischemic reperfusion injury, depression, Parkinson's disease, dementia, leukemia, etc.

Nitrogen-containing bicyclic compounds and drugs containing the same as the active ingredient

Tri-heterocyclic compound of formula (I)wherein each of W, X and Y is carbon or nitrogen; each of U and Z is CR, NR, nitrogen, oxygen, sulfur etc.; A ring is carbocyclic ring, heterocyclic ring; Ris alkyl, alkenyl, alkynyl, NRR, ORetc.; Ris carbocyclic ring, heterocyclic ring;and a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical comprising them as an active ingredient. A compound of formula (I) is useful, in order to possess corticotropin releasing factor receptor antagonistic activity, for the prevention and/or treatment of depression, anxiety, eating disorder, posttraumatic stress disorder, peptic ulcer, irritable bowl syndrome, Alzheimer's disease, drug addiction or alcohol dependence syndrome etc.

Tricyclic and heterocyclic derivative compounds and drugs containing these compounds as the active ingredient

Leukotriene B4 antagonist compounds and method for treatment

A tryptase inhibitor comprising as an active ingredient at least one member selected from among guanidinoaliphatic acid derivatives of the formula (I), guanidinobenzoic acid derivatives of the formula (II), guanidinophenol derivatives of the formula (III), amidinophenol derivatives of the formula (IV), and novel guanidinophenol derivatives of the formula (V) (in the formulae, Gu is guanidino).

Tryptase inhibitor and novel guanidino derivatives

Novel amidinophenol derivatives of formula (IB)

Amidinophenol derivatives of the formula (I): ##STR1## wherein R.sup.1 and R.sup.2 are (i) H, (ii) C1-4 alkoxy, (iv) C2-5 acyl, (v) halogen, (vi) NO.sub.2, (vii) benzoyl, (viii) COOR.sup.4 (in which R.sup.4 is C1-3 alkyl); A is bond, C1-4 alkylene, --C(R.sup.5).dbd.C(R.sup.6)--(in which R.sup.5 and R.sup.6 are H or C1-4 alkyl; R.sup.3 is (i) CON(R.sup.7)(R.sup.8), (ii) CON(R.sup.9)--CH(R.sup.7)(R.sup.8) or (iii) ##STR2## in which R.sup.7 and R.sup.8 are (1) H,(2) phenyl, (3) C7-10 phenylalkyl, (4) phenyl or C7-10 phenylalkyl substituted by 1 or 2 C1-4 alkyl, halogen or R.sup.11 --COOR.sup.12 (in which R.sup.11 is bond, C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene; R.sup.12 is H, C1-4 alkyl, C7-10 phenylalkyl, phenyl, allyl, propargyl), (5) C1-10 alkyl, (6) C2-10 alkenyl having 1 to 3 double bonds, (7) C2-10 alkynyl having 1 or 2 triple bonds, (8) R.sup.11a --COXR.sup.12 (in which R.sup.11a is (a) bond, (b) C1-8 alkylene, (c) C2-8 alkylene in which 1 or 2 carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, (d) C2-8 alkenylene, (e) C4-8 alkenylene in which 1 or 2 carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, (f) C2-8 alkynylene, (g) C4-8 alkynylene in which 1 or 2 carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene; X is --O-- or --NH--), (9) C1-4 alkyl substituted by a 7-14 membered, bi- or tri-cyclic hetero ring containing one N atom, (10) C3-7 cycloalkyl); R.sup.9 is (1) H, (2) C1-8 alkyl, (3) C7-10 phenylalkyl, (4) C2-10 alkenyl having 1 to 3 double bonds, (5) C2-10 alkynyl having 1 or 2 triple bonds, (6) R.sup.11 --COOR.sup.12, (7) C3-7 cycloalkyl; ##STR3## is 4-7 membered, mono-cyclic hetero ring containing 1 or 2 N atom; R.sup.10 is H, C7-10 phenylalkyl or COOR.sup.13 (in which R.sup.13 is H, C1-4 alkyl or C7-10 phenylalkyl)); with the proviso that (i) both R.sup.7 and R.sup.8 do not represent hydrogen at the same time, and (ii) when at least one group in R.sup.7, R.sup.8 and R.sup.9 represents the group containing t-butyl ester, the other groups do not represent the group containing carboxy; or an acid-addition salt thereof, have inhibitory activities on PLA.sub.2 and on various proteases such as trypsin, plasmin, thrombin, kallikrein, especially trypsin, and are useful for the prevention and/or the treatment of various inflammatory diseases, allergic diseases, disseminated intravascular coagulation, pancreatitis, severity in pancreatitis and multiple organ failure.

Amidinophenol derivatives

Amidinophenol derivatives of the formula (I) ##STR1## wherein the various symbols are as defined herein; which have inhibitory activities on PLA.sub.2 and on various proteases such as trypsin, plasmin, thrombin, kallikrein, especially trypsin, and are useful for the prevention and/or the treatment of various inflammatory diseases, allergic diseases, disseminated intravascular coagulation, pancreatitis, severity in pancreatitis and multiple organ failure.

Disclosed are amidinophenol derivatives of the formula (I) and acid-addition salts thereof (in which R.sup.1 and R.sup.2 are alkyl, alkoxy, acyl, halogen, nitro, benzoyl, COOR.sub.4 ; A is bond, alkylene, group of the formula (II); R.sup.3 is group of the formula (III), (IV)) ##STR1## Compounds of the formula (I) have inhibitory activities on phospholipase A.sub.2 and proteases (especially trypsin), and are useful for the prevention and/or the treatment of inflammatory diseases, allergic diseases, disseminated intravascular coagulation, pancreatitis, severity in pancreatitis and multiple organ failure.

Amidinophenol derivatives of the formula (I): ##STR1## wherein R.sup.1 and R.sup.2 are (i) H, (ii) C1-4 alkyl, (iii) C1-4 alkoxy, (iv) C2-5 acyl, (v) halogen, (vi) NO.sub.2, (vii) benzoyl, (viii) COOR.sup.4 (in which R.sup.4 is C1-3 alkyl); A is bond, C1-4 alkylene, --C(R.sup.5).dbd.C(R.sup.6)-- (in which R.sup.5 and R.sup.6 are H or C1-4 alkyl; R.sup.3 is (i) CON(R.sup.7)(R.sup.8), (ii) CON(R.sup.9)--CH(R.sup.7)(R.sup.8) or (iii) ##STR2## in which ##STR3## is 4-7 membered, mono-cyclic hetero ring containing 1 or 2 N atom; R.sup.10 is H, C7-10 phenylalkyl or COOR.sup.13 (in which R.sup.13 is H, C1-4 alkyl or C7-10 phenylalkyl)); with the proviso that (i) both R.sup.7 and R.sup.8 do not represent hydrogen at the same time, and (ii) when at least one group in R.sup.7, R.sup.8 and R.sup.9 represents the group containing t-butyl ester, the other groups do not represent tile group containing carboxy; or an acid-addition salt thereof, have inhibitory activities on PLA.sub.2 and on various proteases such as trypsin, plasmin, thrombin, kallikrein, especially trypsin, and are useful for the prevention and/or the treatment of various inflammatory diseases, allergic diseases, disseminated intravascular coagulation, pancreatitis, severity in pancreatitis and multiple organ failure.

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Mishima-gun, Japan

Hisao Nakai