Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-09-13
2002-07-02
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C558S083000, C558S390000, C564S015000, C564S016000, C564S184000, C514S119000, C514S255030, C514S331000, C514S357000, C514S396000, C514S438000, C514S459000, C514S617000, C544S377000, C544S393000, C546S234000, C546S337000, C549S060000, C549S076000, C549S414000
Reexamination Certificate
active
06413947
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an anilide derivative or a salt thereof having antagonistic activity on MCP-1 (monocyte chemoattractant protein-1) receptor, production method and use thereof.
BACKGROUND ART
MCP-1 is known to be a monocyte chemotactic factor relating to inflammatory diseases, and belongs to CC chemokine sub-family. MCP-1 is found to express not only from monocyte but also from cardiac muscle cell, blood vessel endothelial cell, fibroblast, chondrocyte, smooth muscle cell, mesangial cell, aveolar cell, T lymphocyte, macrophage, etc. in various pathosis (specifically, angiostenosis, arteriosclerosis, rheumatic arthritis, diabetic microangiopathy, granulomatous inflammation (tuberculosis, sarcoidosis, etc.), solid cancer, diastolic cardiomyopathy (chronic heart failure, etc.), glomerulonephritis, etc.), and MCP-1 deeply relate to crisis and progression these pathosis. Therefore, MCP-1 receptor antagonists are used as a medicament for the treatment and prophylaxis of these pathosis.
So far, there have been only a little reports on low molecule compounds having antagonistic activity on MCP-1 receptor. For example, it is disclosed that aryloxy-propanolamine derivatives being active as &bgr;-blocker show weak inhibitory activity on MCP-1 binding to its receptor in JP-A-25756/1995 and that phenylethanolamine derivatives having sympathetic activity and sympatholytic activity show weak inhibitory activity on MCP-1 binding to its receptor in JP-A-25757/1995.
On the other hand, phosphonic acid derivatives having osteogenesis activity is disclosed in JP-A-73476/1996 but there is no description on MCP-1 receptor antagonistic activity.
The present invention is to provide a new anilide derivative or a salt thereof having antagonistic activity on MCP-1 receptor and therapeutic and prophylactic effect on cardiac infarction, myocarditis, cardiomyopathy, chronic heart failure, restenosis after angioplasty, disorder after reperfusion in lung and heart, inflammatory diseases (e.g. arteriosclerosis, arteriosclerosis after heart transplantation, (chronic) rheumatic arthritis, nephritis, etc.), rejection after organ transplantation, fibroid lung, renal insufficiency, diabetic diseases (e.g. diabetes, diabetic nephropathy, diabetic complication, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, etc.), tumor (e.g. bladder cancer, breast carcinoma, cervical carcinoma, chronic lymphocytic leukemia, chronic myelocytic leukemia, colon carcinoma, multiple myeloma, malignant myeloma, prostatic cancer, lung cancer, stomach cancer, Hodgkin's disease, etc.) infectious diseases (e.g. tuberculosis, invasive staphylococcia, etc.), etc.; production method and use thereof.
DISCLOSURE OF INVENTION
The present inventors diligently made extensive studies on compounds having MCP-1 receptor antagonistic activity and, as a result, they found that an anilide derivative of the following formula (I) or a salt thereof [hereinafter, referred to as Compound (I)] unexpectedly possesses potent MCP-1 receptor antagonistic activity and clinically desirable pharmaceutical effect. Based on the finding, the present invention was accomplished.
More specifically, the present invention relates to
(1) a compound of the formula:
wherein R
1
is an optionally substituted 5- to 6-membered ring, W is a divalent group of the formula:
wherein the ring A is an optionally substituted 5- to 6-membered aromatic ring, X is an optionally substituted carbon atom, an optionally substituted nitrogen atom, sulfur atom or oxygen atom, the ring B is an optionally substituted 5- to 7-membered ring, Z is a chemical bond or a divalent group, R
2
is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium, (3) a group binding through a sulfur atom or (4) a group of the formula:
wherein k is 0 or 1, and when k is 0, a phosphorus atom may form a phosphonium; and R
5
and R
6
are independently an optionally substituted hydrocarbon group or an optionally substituted amino group, and R
5
and R
6
may bind to each other to form a cyclic group together with the adjacent phosphorus atom, or a salt thereof;
(2) a compound of the above (1) wherein R
1
is benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine piperazine, morpholine, thiomorpholine or tetrahydropyran, each of which may be substituted;
(3) a compound of the above (1), wherein R
1
is an optionally substituted benzene;
(4) a compound of the above (1), wherein the ring A is furan, thiophene, pyrrole, pyridine or benzene, each of which may be substituted;
(5) a compound of the above (1), wherein the ring A is an optionally substituted benzene;
(6) a compound of the above (1), wherein W is a group of the formula:
wherein each symbol is as defined in the above (1);
(7) a compound of the above (1), wherein W is a group of the formula:
wherein each symbol is as defined in the above (1);
(8) a compound of the above (7), wherein the ring B is a 5- to 7-membered ring group of the formula:
wherein Y is —Y′—(CH
2
)
m
—(Y′ is —S—, —O—, —NH— or —CH
2
—, and m is an integer of 0-2), —CH═CH— or —N═CH—), which may have a substituent at any possible position;
(9) a compound of the above (8), wherein Y is —Y′—(CH
2
)
2
—(Y′ is —S—, —O—, —NH— or —CH
2
—);
(10) a compound of the above (8), wherein Y is —(CH
2
)
2
—, —(CH
2
)
3
— or —O—(CH
2
)
2
—;
(11) a compound of the above (10), wherein the ring A is an optionally substituted benzene;
(12) a compound of the above (1), wherein Z is an optionally substituted C
1-3
alkylene:
(13) a compound of the above (1), wherein Z is a divalent group of the formula: —Z′—(CH
2
)
n
—(Z′ is —CH(OH)—, —C(O)— or —CH
2
—, and n is an integer of 0-2) in which an optional methylene group may be substituted;
(14) a compound of the above (1), wherein Z is methylene;
(15) a compound of the above (1), wherein Z is substituted at para position of the benzene ring;
(16) a compound of the above (1), wherein R
2
is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium, or (3) a group of the formula:
wherein R
5
and R
6
are independently an optionally substituted hydrocarbon group, and R
5
and R
6
may bind to each other to form a cyclic group together with the adjacent phosphorus atom;
(17) a compound of the formula:
wherein X
−
is an anion;
(18) a compound of the above (17), wherein X is a halogen atom;
(19) a compound selected from the class consisting of N-methyl-N-[4-[[[2—(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]-piperidinium iodide, N-methyl-N-[4-[[[7—(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl]carbonyl]amino]benzyl]piperidinium iodide, N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]-phenyl]-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxmide, N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]-phenyl]-7—(4-morpholinophenyl)-2,3-dihydro-1-benzoxepine-4-carboxmide, 7—(4-ethoxyphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzoxepine-4-carboxmide, N,N-dimethyl-N-[4-[[[2—(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]-N-(tetrahydropyran-4-yl)ammonium iodide and N-methyl-N-[4-[[[7—(4-methylphenyl)-3,4-dihydronaphthalen-2-yl]carbonyl]amino]benzyl]piperidinium iodide,
or a salt thereof;
(20) a method for producing a c
Aramaki Yoshio
Honda Susumu
Kitayoshi Takahito
Oda Tsuneo
Shiraishi Mitsuru
Powers Fiona T.
Takeda Chemical Industries Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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