The present invention relates to a novel amine derivative having an excellent inhibiting effect for the production and/or secretion of amyloid-xcex2 protein and production thereof.
Alzheimer""s disease is a neurodegenerative disease, which is characterized by the degeneration and loss of neuronal cells accompanied by the formation of senile plaques and neurofibrillary tangles. Senile plaques that are the most characteristic in Alzheimer""s disease consist of essentially amyloid-xcex2 protein (hereinafter, sometimes, abbreviated to Axcex2) [see Biochem. Biophys. Res. Commun., 122, 1311 (1984)] and other intracerebral components. It is known that Axcex2 is composed of 40 or 42 amino acids (hereinafter abbreviated to Axcex21-40 and Axcex21-42, respectively) and is toxic to neurons and induces neurofibrillary changes.
Some patients with familial Alzheimer""s disease are known to have APP (Amyloid Precursor Protein) gene mutation, and it is well known that the cells transfected with such mutated gene produce and secrete an increased amount of Axcex2 [for example, see Nature, 360, 672 (1992); Science, 259, 514 (1993); Science, 264, 1336 (1994), etc.].
Based on this information, medicines which inhibit the production and/or secretion of Axcex2 are useful for preventing and/or treating diseases caused by Axcex2 (e.g., Alzheimer""s disease, Down""s syndrome, etc).
In particular, for patients who are highly susceptible to the diseases, hereditarily, such as patients with familial Alzheimer""s disease, etc., medicines which inhibit production and/or secretion of Axcex2 are especially useful for the prevention of such diseases.
On the other hand, the secreted form of APP is reported to have a neurotrophic factor like property (Neuron, 10, 243-254,1993). Example of neurotrophic factor like properties are given as, 1) survival and preserving effect to the neuronal cell; 2) stimulating the synapse formation; 3) protection of neuronal cell death; and 4) long term potentiation in hippocampus. By the above-mentioned properties, drugs which stimulate the secretion of the secreted form of APP are also useful in preventing and treating 1) neurodegenerative diseases (e.g., Alzheimer""s disease, Down""s syndrome, senile dementia, Parkinson""s disease, Creutzfeldt-Jacob disease, amyotrophic sclerosis on lateral fasciculus, diabetic neuropathy, Huntington""s disease, multiple sclerosis, etc.), 2) neurological disorders involved in cerebrovascular disorders (e.g., cerebral infarction, encephalorrhagia, etc.), a head injury or an injury of spinal cord, and so forth.
EP-A-652009 discloses peptide derivatives which are protease inhibitors exhibiting an Axcex2 production inhibiting effect in in vitro experiments using cell lines.
JP-A-2-91052 discloses a cholinesterase inhibitor comprising a substituted amine of the formula: 
wherein R1 and R2 are independently hydrogen atom or a hydrocarbon group which may be substituted, or they form, together with the adjacent nitrogen atom, a fused heterocyclic group; R3 and R4 are such that, when R3 is hydrogen atom, or a hydrocarbon group or an acyl group each or which may have substituent(s), R4 is hydrogen atom, or R3 and R4 are bound to each other to form xe2x80x94(CH2)mxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94 (CH2)mxe2x80x94 or xe2x80x94(CH2)m+1xe2x80x94 (wherein m is 0, 1 or 2); A is xe2x80x94(CH2)1xe2x80x94(wherein 1 is 0, 1 or 2) or xe2x80x94CHxe2x95x90CHxe2x80x94; X is one or more substituents and n is an integer of 4 to 7, or a salt thereof.
JP-A-2-73069 discloses a thiazole derivative having monoamine oxidase inhibitory activity.
WO98/38156 discloses a compound having a fused ring skeleton of a benzene ring and a 4- to 8-membered ring and having an inhibitory activity for the production and/or secretion of amyloid-xcex2 protein.
JP-A-5-239005 discloses Nxe2x80x94(2-aminoethyl)benzamides useful for the treatment of senile dementia. However, this does not disclose an inhibitory activity of production and/or secretion of amyloid-xcex2 protein.
WO95/17183 discloses a compound having a phospholipase A2 inhibitory activity and utility for treating senile dementia, etc. However, this does not disclose an inhibitory activity for the production and/or secretion of amyloid-xcex2 protein.
WO98/06691 discloses amine derivatives having an inhibitory activity of aggregation and/or accumulation of amyloid-xcex2 protein and useful for preventing and treating Alzheimer""s disease. However, this does not disclose an inhibitory activity for the production and/or secretion of amyloid-xcex2 protein.
WO91/19697 discloses pyridine derivatives having angiotensin II antagonistic activity.
JP-A-3-142277 discloses amine compounds to be used for recording materials.
WO93/23040 discloses 17-ether and thioether of 4-azasteroid having 5xcex1-reductase inhibitory activity.
It is desired to develop a compound which is different from the above known compounds in its chemical structure and which has an excellent inhibitory activity for the Axcex2 production and/or secretion and is therefore satisfactorily used in medicines.
The present inventors have studied various compounds having an inhibitory activity for the Axcex2 production and/or secretion and, as a result, have found that a compound of the formula: 
wherein Ar represents an aromatic group which may be substituted; X and Y are the same or different and each is a bivalent group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94CONR8xe2x80x94, SO2NR8 and xe2x80x94COOxe2x80x94 (wherein R8 is hydrogen atom, a hydrocarbon group which may be substituted or acyl), or a bivalent C1-6 aliphatic hydrocarbon group which may contain one or two above bivalent groups; R1 and R2 are hydrogen atom or C1-6 alkyl which may be substituted, or R1 and R2 may form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring which may be substituted; and ring A is a monocyclic aromatic ring which may be further substituted, or a salt thereof has an unexpected excellent inhibitory activity for the production and/or secretion of amyloid-xcex2 protein. On the basis of this finding, the present inventors have further studied and completed the present invention.
That is, the present invention provides:
1. An amyloid-xcex2 protein production and/or secretion inhibitor which comprises a compound of the formula: 
wherein Ar is an aromatic group which may be substituted; X and Y are the same or different and each is a bivalent group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94CONR8xe2x80x94, SO2NR8 and xe2x80x94COOxe2x80x94 (wherein R8 is hydrogen atom, a hydrocarbon group which may be substituted or acyl), or a bivalent C1-6 aliphatic hydrocarbon group which may contain one or two above bivalent groups; R1 and R2 are hydrogen atom or C1-6 alkyl which may be substituted, or R1 and R2 may form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring which may be substituted; and ring A is a monocyclic aromatic ring which may be further substituted, or a salt thereof;
2. The inhibitor according to the above 1, wherein Ar is:
(1) a monovalent monocyclic aromatic group formed by removing any one of hydrogen atoms from a benzene ring or a 5- or 6-membered aromatic heterocyclic ring having, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom,
(2) an aromatic ring assembly group formed by removing any one of hydrogen atoms from an aromatic ring assembly of 2 or 3 rings of [1] C6-14 monocyclic or bi- or tricyclic aromatic hydrocarbon aromatic ring or [2] 5- to 14-membered aromatic heterocyclic ring having, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, or rings formed by the aromatic heterocyclic ring fused together with 1 or 2 benzene rings, said rings being bound to each other directly through a single bond, and the number of the bonds which bind the rings directly being smaller than the number of the rings by 1, or
(3) a monovalent fused aromatic group formed by removing any one of hydrogen atoms from [1] C9-14 bi- or tricyclic aromatic hydrocarbon or [2] a 9- to 14-membered fused polycyclic aromatic ring having, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom,
which may be substituted with 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) C1-6 alkyl which may be halogenated, (vi) C6-10 aryloxy-C1-6 alkyl, (vii) C1-6 alkyl-C6-10 aryl-C2-6 alkenyl, (viii) C3-6 cycloalkyl which may be halogenated, (ix) C7-16 aralkyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) halogen atom, (b) C1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) C1-6 alkyl which may be halogenated, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, (x) C1-6 alkoxy which may be halogenated, (xi) C1-6 alkylthio which may be halogenated, (xii) hydroxy, (xiii) C6-10 aryloxy which may be substituted with 1 to 5 substituents selected from the group consisting of (a) halogen atom, (b) C1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) C1-6 alkyl which may be halogenated, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, (xiv) C6-10 aryl-C7-16 aralkyloxy, (xv) amino, (xvi) mono-C1-6 alkylamino, (xvii) di-C1-6 alkylamino, (xviii) 5- to 7-membered saturated cyclic amino which may be substituted with 1 to 3 substituents selected from the group consisting of [1] C6-14 aryl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [2] C7-9 aralkyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [3] 5 to 10 membered aromatic heterocyclic group having, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [4] C6-14 aryl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C1-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [2] C6-10 aryl-carbonyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C16 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [5] C1-6 alkyl-carbonyl which may be halogenated, and [6] C1-6 alkyl-sulfonyl, (xix) acyl represented by the formula: xe2x80x94COxe2x80x94R3, xe2x80x94COxe2x80x94OR3, xe2x80x94COxe2x80x94NR3R4, xe2x80x94CSxe2x80x94NHR3, xe2x80x94SO2xe2x80x94R3a or xe2x80x94SOxe2x80x94R3a [wherein R3 is hydrogen atom, or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, a fused ring of C3-6 cycloalkyl and a benzene ring, C6-14 aryl, C7-19 aralkyl or 5- to 14-membered heterocyclic group having, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which may be substituted with 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) C1-6 alkyl which may be halogenated, (vi) C3-6 cycloalkyl which may be halogenated, (vii) C1-6 alkoxy which may be halogenated, (viii) C1-6 alkylthio which may be halogenated, (ix) hydroxy, (x) amino, (xi) mono-C1-6 alkylamino, (xii) di-C1-6 alkylamino, (xiii) 5- to 7-membered saturated cyclic amino which may be substituted with 1 to 3 substituents selected from the group consisting of [1] C6-14 aryl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated, (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [2] C7-19 aralkyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [3] 5 to 10 membered aromatic heterocyclic group having, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [4] C6-14 aryl-carbonyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [5] C1-6 alkyl-carbonyl which may be halogenated, and [6] C1-6 alkyl-sulfonyl, (xiv) formyl, (xv) carboxy, (xvi) carbamoyl, (xvii) C1-6 alkyl-carbonyl which may be halogenated, (xviii) C1-6 alkoxy-carbonyl, (xix) C6-10 aryl-carbonyl, (xx) C6-10 aryloxy-carbonyl, (xxi) C7-16 aralkyloxy-carbonyl, (xxii) mono-C1-6 alkyl-carbamoyl, (xxiii) di-C1-6 alkylcarbamoyl, (xxiv) C6-10 arylcarbamoyl, (xxv) C1-6 alkylsulfonyl which may be halogenated, (xxvi) C6-10 arylsulfonyl, (xxvii) formnylamino, (xxviii) C1-6 alkyl-carboxamido which may be halogenated, (xxix) C6-10 aryl-carboxamido, (xxx) C1-6 alkoxy-carboxamido, (xxxi) C1-6 alkylsulfonylamino, (xxxii) C1-6 alkyl-carbonyloxy, (xxxiii) C6-10 aryl-carbonyloxy, (xxxiv) C1-6 alkoxy-carbonyloxy, (xxxv) mono-C1-6 alkyl-carbamoyloxy, (xxxvi) di-C1-6 alkyl-carbamoyloxy, (xxxvii) C6-10 aryl-carbamoyloxy, (xxxviii) nicotinoyloxy and (xxxix) C6-10 aryloxy, R3a is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, a fused ring of C3-6 cycloalkyl and a benzene ring, C6-14 aryl, C7-19 aralkyl or 5- to 14-membered heterocyclic group having, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which may be substituted with 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) C1-6 alkyl which may be halogenated, (vi) C3-6 cycloalkyl which may be halogenated, (vii) C1-6 alkoxy which may be halogenated, (viii) C1-6 alkylthio which may be halogenated, (ix) hydroxy, (x) amino, (xi) mono-C1-6 alkylamino, (xii) di-C1-6 alkylamino, (xiii) 5- to 7-membered saturated cyclic amino which may be substituted with 1 to 3 substituents selected from the group consisting of [1] C6-14 aryl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated, (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [2] C7-19 aralkyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [3] 5 to 10 membered aromatic heterocyclic group having, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [4] C6-14 aryl-carbonyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [5] C1-6 alkyl-carbonyl which may be halogenated, and [6] C1-6 alkyl-sulfonyl, (xiv) formyl, (xv) carboxy, (xvi) carbamoyl, (xvii) C1-6 alkyl-carbonyl which may be halogenated, (xviii) C1-6 alkoxy-carbonyl, (xix) C6-10 aryl-carbonyl, (xx) C6-10 aryloxy-carbonyl, (xxi) C7-16 aralkyloxy-carbonyl, (xxii) mono-C1-6 alkyl-carbamoyl, (xxiii) di-C1-6 alkyl-carbamoyl, (xxiv) C6-10 arylcarbamoyl, (xxv) C1-6 alkylsulfonyl which may be halogenated, (xxvi) C6-10 arylsulfonyl, (xxvii) formnylamino, (xxviii) C1-6 alkyl-carboxamido which may be halogenated, (xxix) C6-10 aryl-carboxamido, (xxx) C1-6 alkoxy-carboxamido, (xxxi) C1-6 alkylsulfonylamino, (xxxii) C1-6 alkyl-carbonyloxy, (xxxiii) C6-10 aryl-carbonyloxy, (xxxiv). C1-6 alkoxy-carbonyloxy, (xxxv) mono-C1-6 alkyl-carbamoyloxy, (xxxvi) di-C1-6 alkyl-carbamoyloxy, (xxxvii) C6-10 aryl-carbamoyloxy, (xxxviii) nicotinoyloxy and (xxxix) C6-10 aryloxy, R4 is hydrogen atom or C1-6 alkyl, or R3 and R4 may form, together with the adjacent nitrogen atom, 5- to 7-membered nitrogen-containing heterocyclic ring having, in addition to carbon atom, at least one nitrogen atom, which may further have 1 to 3 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom], (xx) acylamino represented by the formula: xe2x80x94NR5xe2x80x94COR6, xe2x80x94NR5xe2x80x94COOR6a, xe2x80x94NR5xe2x80x94SO2RR6a or xe2x80x94NR5 xe2x80x94CONR6aR6b [wherein R5 is hydrogen atom or C1-6 alkyl, R6 is as defined above R3, R6a is as defined above R3a, R6b is as defined above R4] and (xxi) acyloxy represented by the formula: xe2x80x94Oxe2x80x94COR7, xe2x80x94Oxe2x80x94COOR7 or xe2x80x94Oxe2x80x94CONHR7 [wherein R7 is as defined above R3],
X and Y are the same and different and each is a bivalent group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94SO2NR8xe2x80x94 and xe2x80x94COOxe2x80x94 [wherein R8 is (1) hydrogen atom, (2) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, a fused ring of C3-6 cycloalkyl and a benzene ring, C3-6 aryl or C7-19 aralkyl, which may be substituted with 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) C1-6 alkyl which may be halogenated, (vi) C3-6 cycloalkyl which may be halogenated, (vii) C1-6 alkoxy which may be halogenated, (viii) C1-6 alkylthio which may be halogenated (ix) hydroxy, (x) amino, (xiii) [1] C6-14 aryl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated, (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [2] C7-19 aralkyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [3] 5 to 10 membered aromatic heterocyclic group having, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [4] C6-14 aryl-carbonyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [5] C1-6 alkyl-carbonyl which may be halogenated, and [6] C1-6 alkyl-sulfonyl, (xiv) formyl, (xv) carboxy, (xvi) carbamoyl, (xvii) C1-6 alkyl-carbonyl which may be halogenated, (xviii) C1-6 alkoxy-carbonyl, (xix) C6-10 aryl-carbonyl, (xx) C6-10 aryloxy-carbonyl, (xxi) C7-16 aralkyloxy-carbonyl, (xxii) mono-C1-6 alkyl-carbamoyl, (xxiii) di-C1-6 alkyl-carbamoyl, (xxiv) C6-10 arylcarbamoyl, (xxv) C1-6 alkylsulfonyl which may be halogenated, (xxvi) C6-10 arylsulfonyl, (xxvii) formnylamino, (xxviii) C1-6 alkyl-carboxamido which may be halogenated, (xxix) C6-10 aryl-carboxamido, (xxx) C1-6 alkoxy-carboxamido, (xxxi) C1-6 alkylsulfonylamino, (xxxii) C1-6 alkyl-carbonyloxy, (xxxiii) C6-10 aryl-carbonyloxy, (xxxiv) C1-6 alkoxy-carbonyloxy, (xxxv) mono-C1-6 alkyl-carbamoyloxy, (xxxvi) di-C1-6 alkyl-carbamoyloxy, (xxxvii) C6-10 aryl-carbamoyloxy, (xxxviii) nicotinoyloxy and (xxxix) C6-10 aryloxy, (3) acyl represented by the formula: xe2x80x94COxe2x80x94R3, xe2x80x94COxe2x80x94OR3, xe2x80x94COxe2x80x94NR3R4, xe2x80x94CSxe2x80x94NHR3, xe2x80x94SO2xe2x80x94R3a or xe2x80x94SOxe2x80x94R3a [wherein R3 is hydrogen atom, or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, a fused ring of C3-6 cycloalkyl and a benzene ring, C6-14 aryl, C7-19 aralkyl or 5- to 14-membered heterocyclic group having, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which may be substituted with 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) C1-6 alkyl which may be halogenated, (vi) C3-6 cycloalkyl which may be halogenated, (vii) C1-6 alkoxy which may be halogenated, (viii) C1-6 alkylthio which may be halogenated, (ix) hydroxy, (x) amino, (xi) mono-C1-6 alkylamino, (xii) di-C1-6 alkylamino, (xiii) 5- to 7-membered saturated cyclic amino which may be substituted with 1 to 3 substituents selected from the group consisting of [1] C6-14 aryl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated, (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [2] C7-19 aralkyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [3] 5 to 10 membered aromatic heterocyclic group having, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [4] C6-14 aryl-carbonyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [5] C1-6 alkyl-carbonyl which may be halogenated, and [6] C1-6 alkyl-sulfonyl, (xiv) formyl, (xv) carboxy, (xvi) carbamoyl, (xvii) C1-6 alkyl-carbonyl which may be halogenated, (xviii) C1-6 alkoxy-carbonyl, (xix) C6-10 aryl-carbonyl, (xx) C6-10 aryloxy-carbonyl, (xxi) C7-16 aralkyloxy-carbonyl, (xxii) mono-C1-6 alkyl-carbamoyl, (xxiii) di-C1-6 alkyl-carbamoyl, (xxiv) C6-10 arylcarbamoyl, (xxv) C1-6 alkylsulfonyl which may be halogenated, (xxvi) C6-10 arylsulfonyl, (xxvii) formnylamino, (xxviii) C1-6 alkyl-carboxamido which may be halogenated, (xxix) C6-10 aryl-carboxamido, (xxx) C1-6 alkoxy-carboxamido, (xxxi) C1-6 alkylsulfonylamino, (xxxii) C1-6 alkyl-carbonyloxy, (xxxiii) C6-10 aryl-carbonyloxy, (xxxiv) C1-6 alkoxy-carbonyloxy, (xxxv) mono-C1-6 alkyl-carbamoyloxy, (xxxvi) di-C1-6 alkyl-carbamoyloxy, (xxxvii) C6-10 aryl-carbamoyloxy, (xxxviii) nicotinoyloxy and (xxxix) C6-10 aryloxy, R3a is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, a fused ring of C3-6 cycloalkyl and a benzene ring, C6-14 aryl, C7-19 aralkyl or 5- to 14-membered heterocyclic group having, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which may be substituted with 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) C1-6 alkyl which may be halogenated, (vi) C3-6 cycloalkyl which may be halogenated, (vii) C1-6 alkoxy which may be halogenated, (viii) C1-6 alkylthio which may be halogenated, (ix) hydroxy, (x) amino, (xi) mono-C1-6 alkylamino, (xii) di-C1-6 alkylamino, (xiii) 5- to 7-membered saturated cyclic amino which may be substituted with 1 to 3 substituents selected from the group consisting of [1] C6-14 aryl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated, (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [2] C7-19 aralkyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [3] 5 to 10 membered aromatic heterocyclic group having, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [4] C6-14 aryl-carbonyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [5] C1-6 alkyl-carbonyl which may be halogenated, and [6] C1-6 alkyl-sulfonyl, (xiv) formyl, (xv) carboxy, (xvi) carbamoyl, (xvii) C1-6 alkyl-carbonyl which may be halogenated, (xviii) C1-6 alkoxy-carbonyl, (xix) C6-10 aryl-carbonyl, (xx) C6-10 aryloxy-carbonyl, (xxi) C7-16 aralkyloxy-carbonyl, (xxii) mono-C1-6 alkyl-carbamoyl, (xxiii) di-C1-6 alkyl-carbamoyl, (xxiv) C6-10 arylcarbamoyl, (xxv) C1-6 alkylsulfonyl which may be halogenated, (xxvi) C6-10 arylsulfonyl, (xxvii) formnylamino, (xxviii) C1-6 alkyl-carboxamido which may be halogenated, (xxix) C6-10 aryl-carboxamido, (xxx) C1-6 alkoxy-carboxamido, (xxxi) C1-6 alkylsulfonylamino, (xxxii) C1-6 alkyl-carbonyloxy, (xxxiii) C6-10 aryl-carbonyloxy, (xxxiv) C1-6 alkoxy-carbonyloxy, (xxxv) mono-C1-6 alkyl-carbamoyloxy, (xxxvi) di-C1-6 alkyl-carbamoyloxy, (xxxvii) C6-10 aryl-carbamoyloxy, (xxxviii) nicotinoyloxy and (xxxix) C6-10 aryloxy, R4 is hydrogen atom or C1-6 alkyl, or R3 and R4 may form, together with the adjacent nitrogen atom, 5- to 7-membered nitrogen-containing heterocyclic ring having, in addition to carbon atom, at least one nitrogen atom, which may further have 1 to 3 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom], or C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene which may contain one or two these bivalent groups,
R1 and R2 are (1) hydrogen atom, (2) C1-6 alkyl which may substituted with 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) C1-6 alkyl which may be halogenated, (vi) C3-6 cycloalkyl which may be halogenated, (vii) C1-6 alkoxy which may be halogenated, (viii) C1-6 alkylthio which may be halogenated, (ix) hydroxy, (x) amino, (xi) mono-C1-6 alkylamino, (xii) di-C1-6 alkylamino, (xiii) formyl, (xiv) carboxy, (xv) carbamoyl, (xvi) C1-6 alkyl-carbonyl which may be halogenated, (xvii) C1-6 alkoxy-carbonyl, (xviii) mono-C1-6 alkyl-carbamoyl, (xix) di-C1-6 alkyl-carbamoyl, (xx) C1-6 alkylsulfonyl which may be halogenated, (xxi) formylamino, (xxii) C1-6 alkyl-carboxamido which may be halogenated, (xxiii) C1-6 alkoxy-carboxamido, (xxiv) C1-6 alkylsulfonylamino, (xxv) C1-6 alkyl-carbonyloxy, (xxvi) C1-6 alkoxy-carbonyloxy, (xxvii) mono-C1-6 alkyl-carbamoyloxy, (xxviii) di-C1-6 alkyl-carbamoyloxy, and (xxix) the same group as that of Ar, or
R1 and R2 may form, together with the adjacent nitrogen atom, 3- to 8-membered nitrogen-containing heterocyclic ring having, in addition to carbon atom, at least one nitrogen atom, which may further have 1 to 3 hetero atoms selected from nitrogen, sulfur atom and oxygen atom, and which may be substituted with 1 to 3 substituents selected from the group consisting of (i) C6-14 aryl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated, (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, (ii) C7-19 aralkyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, (iii) 5 to 10 membered aromatic heterocyclic group having, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, (iv) C6-14 aryl-carbonyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, (v) C1-6 alkyl-carbonyl which may be halogenated, and (vi) C1-6 alkyl-sulfonyl, and
ring A is a benzene ring, or a 5- or 6-membered aromatic heterocyclic ring which may be substituted with 1 to 3 substituents selected from the group consisting of halogen atom, C1-6 alkyl which may be halogenated, C1-6 alkoxy which may be halogenated, hydroxy and amino, in addition to the substituent represented by Arxe2x80x94Xxe2x80x94;
3. The inhibitor according to the above 1, wherein the aromatic group represented by Ar is a monocyclc aromatic group, an aromatic ring assembly group or a fused aromatic group;
4. The inhibitor according to the above 1, wherein Ar is an aromatic ring assembly group which may be substituted;
5. The inhibitor according to the above 4, wherein the aromatic ring assembly group is 2-, 3- or 4-biphenylyl;
6. The inhibitor according to the above 1, wherein Ar is phenyl, biphenylyl or naphthyl group which may be substituted with halogen atom;
7. The inhibitor according to the above 1, wherein X is [1] a group represented by the formula: xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3), [2] xe2x80x94(CH2)p2xe2x80x94 (wherein p2 is an integer of 1 to 3), [3] (CH2)p3OCONHxe2x80x94 (wherein p3 is an integer of 1 to 3), [4] CONH or [5] SO2NH;
8. The inhibitor according to the above 1, wherein X is a group represented by the formula: xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer or 1 to 3);
9. The inhibitor according to the above 1, wherein the bivalent C1-6 aliphatic hydrocarbon group of Y is a bivalent C1-3 aliphatic hydrocarbon group;
10. The inhibitor according to the above 1, wherein Y is [1] a group represented by the formula: xe2x80x94(CH2)q1CONR9(CH2)r1xe2x80x94 (wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl which may be halogenated or C1-6 alkyl-carbonyl which may be halogenated); or [2] a group represented by the formula: xe2x80x94(CH2)q2COO(CH2)r2xe2x80x94 (wherein each of q2 and r2 is an integer of 0 to 3 and their sum is not more than 3);
11. The inhibitor according to the above 1, wherein Y is a group represented by the formula: xe2x80x94(CH2)q1CONR9(CH2)r1xe2x80x94 (wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl-carbonyl);
12. The inhibitor according to the above 1, wherein each of R1 and R2 is [1] hydrogen atom or [2] C1-6 alkyl which may be substituted with carboxyl or C1-6 alkoxy-carbonyl, or R1 and R2 form, together with the adjacent nitrogen atom, a 5- or 6-membered nitrogen-containing heterocyclic ring;
13. The inhibitor according to the above 1, wherein ring A is a benzene ring or a 6-membered nitrogen-containing heterocyclic ring which may be substituted with halogen atom or C1-6 alkoxy;
14. The inhibitor according to the above 1, wherein ring A is a benzene ring, a pyridine ring or 2-pyridone ring;
15. The inhibitor according to the above 1, wherein ring A is a benzene ring or a pyridine ring;
16. The inhibitor according to the above 1, wherein Ar is C6-14 aryl or biphenylyl which may be substituted with halogen atom,
X is [1] a group represented by the formula: xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3), [2] xe2x80x94(CH2)p2xe2x80x94 (wherein p2 is an integer of 1 to 3), [3] (CH2)p3OCONHxe2x80x94 (wherein p3 is an integer of 1 to 3), [4] CONH or [5] SO2NH, Y is [1] a group represented by the formula: xe2x80x94(CH2)q1CONR9(CH2)r1xe2x80x94 (wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl-carbonyl which may be halogenated), or [2] a group represented by the formula: xe2x80x94(CH2)q2COO(CH2)r2xe2x80x94 (wherein each of q2 and r2 is an integer of 0 to 3 and their sum is not more than 3), each of R1 and R2 is [1] hydrogen atom or [2] C1-6 alkyl which may be substituted with carboxy, C1-6 alkoxy-carbonyl, or di-C1-6 alkylnitrile, or R1 and R2 form, together with the adjacent nitrogen atom, a 5- or 6-membered nitrogen-containing heterocyclic ring, and ring A is a benzene ring or a 6-membered nitrogen-containing heterocyclic ring which may be substituted with halogen atom or C1-6 alkoxy;
17. The inhibitor according to the above 1, wherein Ar is C6-14 aryl or biphenylyl which may be substituted with halogen atom, X is a group represented by the formula: xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3), CONH or SO2NH, Y is C1-3 alkylene, xe2x80x94CONH(CH2)sxe2x80x94 (wherein s is an integer of 1 to 3) or xe2x80x94COO(CH2)txe2x80x94 (wherein t is an integer of 1 to 3), each of R1 and R2 is hydrogen atom or C1-6 alkyl, or R1 and R2 form, together with the adjacent nitrogen atom, a 5- or 6-membered nitrogen-containing heterocyclic ring, and ring A is a benzene ring or a 6-membered nitrogen-containing heterocyclic ring which may be substituted with halogen atom or C1-6 alkoxy.
18. The inhibitor according to the above 1, wherein the compound is 5-chloro-N-[2-N,N-diethylamino)ethyl]-2-methoxy-4-(1-naphthoylamino)benzamide,
5-chloro-N-[2-N,N-diethylamino)ethyl]-2-methoxy-4-(2naphthoylamino)benzamide,
5-chloro-N-[2-N,N-diethylamino)ethyl]-2-methoxy-4-(1-naphthylsulfonylamino)benzamide,
5-chloro-N-[2-N,N-diethylamino)ethyl]-2-methoxy-4-(2-naphthylsulfonylamino)benzamide,
N-[3-[4-(2-naphthylmethoxy)phenyl]propyl]-N,N-dipropylamine hydrochloride,
N-[3-[4-[(2,4-dichlorobenzyl)oxy]phenyl]propyl]-N,N-dipropylamine hydrochloride,
N-[4-(2-naphthylmethoxy)phenethyl]-N,N-dipropylamine hydrochloride,
N-[4-(2,4-dichlorobenzyl)oxy]phenethyl]-N,N-dipropylamine hydrochloride,
N-[4-(4-biphenylylmethoxy)phenethyl]-N,N-dipropylamine hydrochloride,
N-[2-(2-naphthylmethoxy)phenethyl]-N,N-dipropylamine hydrochloride,
N-[3-(2-naphthylmethoxy)phenethyl]-N,N-dipropylamine hydrochloride,
N-[3-(4-biphenylylmethoxy)phenethyl]-N,N-dipropylamine hydrochloride,
N-[3-[(2,4-dichlorobenzyl)oxy]phenethyl]-N,N-dipropylamine hydrochloride,
N-[3-(1-naphthylmethoxy)phenethyl]-N,N-dipropylamine hydrochloride,
4-(4-biphenylylmethoxy)phenyl-N-(2-piperidinoethyl)acetamide,
4-(4-biphenylylmethoxy)phenyl-N-[2-(N,N-dimethylamino)ethyl]acetamide,
6-(4-biphenylylmethoxy)-N-[2-(pyrrolidine-1-yl)ethyl]nicotinamide,
1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-N-[2-(pyrrolidine-1-yl)ethyl]-3-pyridinecarboxamide,
1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-N-(2-(piperidinoethyl)-3-pyridinecarboxamide,
6-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)nicotinamide,
6-(4-biphenylylmethoxy)-N-[2-(N,N-dimethylamino)ethyl]nicotinamide,
4-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)benzamide,
4-(4-biphenylylmethoxy)-N-[(2-pyrrolidine-1-yl)ethyl]benzamide,
2-piperidinoethyl=4-(4-biphenylylethoxy)benzoate,
2-(pyrrolidin-1-yl)ethyl=4-(4-biphenylylmethoxy)benzoate,
4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)ethyl]acetamide oxalate,
4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)ethyl]acetamide maleate,
4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)ethyl]acetamide fumarate,
4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N-methylamino)ethyl]acetamide hydrochloride, ethyl]acetamide hydrochloride,
4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N-methylamino)ethyl]acetamide,
ethyl 7-[2-[4-[(4-biphenylylmethoxy)phenyl]acetylaminoethyl](methyl)amino]heptanoate,
7-[2-[4-[4-(biphenylylmethoxy)phenyl]acetylaminoethyl](methyl)amino]heptanoic acid hydrochloride,
N-(4-(2-((2-(dimethylamino)ethyl)(methyl)amino)-2-oxoethyl)phenyl)[1,1xe2x80x2-biphenyl]-4-carboxamido,
N-(2-aminoethyl)-2-(4-([1,1xe2x80x2-biphenyl]-4-ylmethoxy)phenyl)acetamide hydrochloride,
4-([1,1xe2x80x2-biphenyl]-4-ylmethoxy)-N-(2-(1-pyrrolidinyl)ethyl)benzamide,
N-(4-(2-((2-dimethylamino)ethyl)(methyl)amino)-2-oxoethyl)phenyl)[1,1xe2x80x2-biphenyl]-4-carboxamide,
N-[4-({[2-(diethylamino)ethyl]amino}carbonyl)phenyl](4-biphenylyl)carboxamide,
4-(4-biphenylyl)methoxy)-N-[2-(isopropylamino)ethyl]benzamide,
2-(N,N-diethylamino)ethyl-4-[(4-biphenylyl)carbonyl]amino]benzoate,
N-[4-({[2-(dimethylamino)ethyl]amino}carbonyl)phenyl](4-biphenylyl)carboxamide,
N-[4-{[2-(piperidinoethyl)amino]carbonyl}phenyl](4-biphenylyl)carboxamide, or
N-[4-({[2-(pyrrolidinyl)ethyl]amino}carbonyl)phenyl](4-biphenylyl)carboxamide;
19. The inhibitor according to the above 1 which is an agent for preventing or treating diseases caused by the production and/or secretion of amyloid-xcex2 protein;
20. The inhibitor according to the above 1 which is an agent for preventing or treating senile dementia, Alzheimer""s disease, Down""s syndrome, Parkinson""s disease, disease, amyloid angiopathy or disorders due to amyloid-xcex2 protein in cerebrovascular disorders caused by the production and/or secretion of amyloid-xcex2 protein;
21. A compound represented by the formula: 
xe2x80x83wherein
Arxe2x80x2 is an aromatic ring assembly group which may be substituted,
Xxe2x80x2 is [1] a group represented by the formula: xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3), [2] xe2x80x94(CH2)p2xe2x80x94 (wherein p2 is an integer of 1 to 3) or [3] CONH,
Yxe2x80x2 is [1] a group represented by the formula: xe2x80x94(CH2)q1CONR9(CH2)r1xe2x80x94 (wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl which may be halogenated or C1-6 alkyl-carbonyl which may be halogenated):, or [2] a group represented by the formula: xe2x80x94(CH2)q2COO(CH2)r2xe2x80x94 (wherein each of q2 and r2 is an integer of 0 to 3 and their sum is not more than 3),
each of R1 and R2 is hydrogen atom or C1-6 alkyl which may be substituted, or R1 and R2 may form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring, and
ring A is a monocyclic aromatic ring which may be further substituted;
22. The compound according to the above 21, wherein Arxe2x80x2 is:
an aromatic ring assembly group formed by removing any one of hydrogen atoms from an aromatic ring assembly of 2 or 3 rings of [1] C6-14 monocyclic or bi- or tricyclic aromatic hydrocarbon aromatic ring or [2] 5- to 14-membered aromatic heterocyclic ring having, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, or rings formed by the aromatic heterocyclic ring fused together with 1 or 2 benzene rings, said rings being bound to each other directly through a single bond, and the number of the bonds which bind the rings directly being smaller than the number of the rings by 1, which may be substituted with 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) C1-6 alkyl which may be halogenated, (vi) C6-10 aryloxy-C1-6 alkyl, (vii) C1-6 alkyl-C6-10 aryl-C2-6 alkenyl, (viii) C3-6 cycloalkyl which may be halogenated, (ix) C7-16 aralkyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) halogen atom, (b) C1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) C1-6 alkyl which may be halogenated, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, (x) C1-6 alkoxy which may be halogenated, (xi) C1-6 alkylthio which may be halogenated, (xii) hydroxy, (xiii) C6-10 aryloxy which may be substituted with 1 to 5 substituents selected from the group consisting of (a) halogen atom, (b) C1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) C1-6 alkyl which may be halogenated, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, (xiv) C6-10 aryl-C7-16 aralkyloxy, (xv) amino, (xvi) mono-C1-6 alkylamino, (xvii) di-C1-6 alkylamino, (xviii) 5- to 7-membered saturated cyclic amino which may be substituted with 1 to 3 substituents selected from the group consisting of [1] C6-14 aryl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [2] C7-19 aralkyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [3] 5 to 10 membered aromatic heterocyclic group having, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [4] C6-14 aryl-carbonyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C8 alkyl-carbamoyloxy, [5] C1-6 alkyl-carbonyl which may be halogenated, and [6] C1-6 alkyl-sulfonyl, (xix) acyl represented by the formula: xe2x80x94COxe2x80x94R3, xe2x80x94COxe2x80x94OR3, xe2x80x94COxe2x80x94NR3R4, xe2x80x94CSxe2x80x94NHR3, xe2x80x94SO2xe2x80x94R3a or xe2x80x94SOxe2x80x94R3a [wherein R3 is hydrogen atom, or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, a fused ring of C3-6 cycloalkyl and a benzene ring, C6-14 aryl, C7-9 aralkyl or 5- to 14-membered heterocyclic group having, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which may be substituted with 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) C1-6 alkyl which may be halogenated, (vi) C3-6 cycloalkyl which may be halogenated, (vii) C1-6 alkoxy which may be halogenated, (viii) C1-6 alkylthio which may be halogenated, (ix) hydroxy, (x) amino, (xi) mono-C1-6 alkylamino, (xii) di-C1-6 alkylamino, (xiii) 5- to 7-membered saturated cyclic amino which may be substituted with 1 to 3 substituents selected from the group consisting of [1] C6-14 aryl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated, (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (1) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [2] C7-19 g aralkyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [3] 5 to 10 membered aromatic heterocyclic group having, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k), mono-C1-6 alkylamino, (1) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [4] C6-14 aryl-carbonyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (1) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [5] C1-6 alkyl-carbonyl which may be halogenated, and [6] C1-6 alkyl-sulfonyl, (xiv) formyl, (xv) carboxy, (xvi) carbamoyl, (xvii) C1-6 alkyl-carbonyl which may be halogenated, (xviii) C1-6 alkoxy-carbonyl, (xix) C6-10 aryl-carbonyl, (xx) C6-10 aryloxy-carbonyl, (xxi) C7-16 aralkyloxy-carbonyl, (xxii) mono-C1-6 alkyl-carbamoyl, (xxiii) di-C1-6 alkyl-carbamoyl, (xxiv) C6-10 arylcarbamoyl, (xxv) C1-6 alkylsulfonyl which may be halogenated, (xxvi) C6-10 arylsulfonyl, (xxvii) formnylamino, (xxviii) C1-6 alkyl-carboxamido which may be halogenated, (xxix) C6-10 aryl-carboxamido, (xxx) C1-6 alkoxy-carboxamido, (xxxi) C1-6 alkylsulfonylamino, (xxxii) C1-6 alkyl-carbonyloxy, (xxxiii) C6-10 aryl-carbonyloxy, (xxxiv) C1-6 alkoxy-carbonyloxy, (xxxv) mono-C1-6 alkyl-carbamoyloxy, (xxxvi) di-C1-6 alkyl-carbamoyloxy, (xxxvii) C6-10 aryl-carbamoyloxy, (xxxviii) nicotinoyloxy and (xxxix) C6-10 aryloxy, R3a is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, a fused ring of C3-6 cycloalkyl and a benzene ring, C6-14 aryl, C7-19 aralkyl or 5- to 14-membered heterocyclic group having, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which may be substituted with 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) C1-6 alkyl which may be halogenated, (vi) C3-6 cycloalkyl which may be halogenated, (vii) C1-6 alkoxy which may be halogenated, (viii) C1-6 alkylthio which may be halogenated, (ix) hydroxy, (x) amino, (xi) mono-C1-6 alkylamino, (xii) di-C1-6 alkylamino, (xiii) 5- to 7-membered saturated cyclic amino which may be substituted with 1 to 3 substituents selected from the group consisting of [1] C6-14 aryl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated, (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (1) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [2] C7-19 aralkyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (1) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [3] 5 to 10 membered aromatic heterocyclic group having, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (1) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [4] C6-14 aryl-carbonyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (1) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, [5] C1-6 alkyl-carbonyl which may be halogenated, and [6] C1-6 alkyl-sulfonyl, (xiv) formyl, (xv) carboxy, (xvi) carbamoyl, (xvii) C1-6 alkyl-carbonyl which may be halogenated, (xviii) C1-6 alkoxy-carbonyl, (xix) C6-10 aryl-carbonyl, (xx) C6-10 aryloxy-carbonyl, (xxi) C1-6 aralkyloxy-carbonyl, (xxii) mono-C1-6 alkyl-carbamoyl, (xxiii) di-C1-6 alkyl-carbamoyl, (xxiv) C6-10 arylcarbamoyl, (xxv) C1-6 alkylsulfonyl which may be halogenated, (xxvi) C6-10 arylsulfonyl, (xxvii) formnylamino, (xxviii) C1-6 alkyl-carboxamido which may be halogenated, (xxix) C6-10 aryl-carboxamido, (xxx) C1-6 alkoxy-carboxamido, (xxxi) C1-6 alkylsulfonylamino, (xxxii) C1-6 alkyl-carbonyloxy, (xxxiii) C6-10 aryl-carbonyloxy, (xxxiv) C1-6 alkoxy-carbonyloxy, (xxxv) mono-C1-6 alkyl-carbamoyloxy, (xxxvi) di-C1-6 alkyl-carbamoyloxy, (xxxvii) C6-10 aryl-carbamoyloxy, (xxxviii) nicotinoyloxy and (xxxix) C6-10 aryloxy, R4 is hydrogen atom or C1-6 alkyl, or R3 and R4 may form, together with the adjacent nitrogen atom, 5- to 7-membered nitrogen-containing heterocyclic ring having, in addition to carbon atom, at least one nitrogen atom, which may further have 1 to 3 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom], (xx) acylamino represented by the formula: xe2x80x94NR5xe2x80x94COR6, xe2x80x94NR5xe2x80x94COOR6a, xe2x80x94NR5xe2x80x94SO2RR6a or xe2x80x94NR5xe2x80x94CONR6aR6b [wherein R5 is hydrogen atom or C1-6 alkyl, R6 is as defined above R3, R6a is as defined above R3a, R6b is as defined above R4] and (xxi) acyloxy represented by the formula: xe2x80x94Oxe2x80x94COR7, xe2x80x94Oxe2x80x94COOR7 or xe2x80x94Oxe2x80x94CONHR7 [wherein R7 is as defined above R3],
R1 and R2 are (1) hydrogen atom, (2) C1-6 alkyl which may substituted with 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) C1-6 alkyl which may be halogenated, (vi) C3-6 cycloalkyl which may be halogenated, (vii) C1-6 alkoxy which may be halogenated, (viii) C1-6 alkylthio which may be halogenated, (ix) hydroxy, (x) amino, (xi) mono-C1-6 alkylamino, (xii) di-C1-6 alkylamino, (xiii) formyl, (xiv) carboxy, (xv) carbamoyl, (xvi) C1-6 alkyl-carbonyl which may be halogenated, (xvii) C1-6 alkoxy-carbonyl, (xviii) mono-C1-6 alkyl-carbamoyl, (xix) di-C1-6 alkyl-carbamoyl, (xx) C1-6 alkylsulfonyl which may be halogenated, (xxi) formylamino, (xxii) C1-6 alkyl-carboxamido which may be halogenated, (xxiii) C1-6 alkoxy-carboxamido, (xxiv) C1-6 alkylsulfonylamino, (xxv) C1-6 alkyl-carbonyloxy, (xxvi) C1-6 alkoxy-carbonyloxy, (xxvii) mono-C1-6 alkyl-carbamoyloxy, (xxviii) di-C1-6 alkyl-carbamoyloxy, and (xxix) the same group as that of Ar,
R1 and R2 may form, together with the adjacent nitrogen atom, 3- to 8-membered nitrogen containing heterocyclic ring having, in addition to carbon atom, at least one nitrogen atom, which may further have 1 to 3 hetero atoms selected from nitrogen, sulfur atom and oxygen atom and which may be substituted with 1 to 3 substituents selected from the group consisting of (i) C6-14 aryl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated, (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, (ii) C7-9 aralkyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, (iii) 5 to 10 membered aromatic heterocyclic group having, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (1) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl-carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, (iv) C6-14 aryl-carbonyl which may be substituted with 1 to 5 substituents selected from the group consisting of (a) C1-6 alkyl which may be halogenated (b) halogen atom, (c) C1-3 alkylenedioxy, (d) nitro, (e) cyano, (f) C3-6 cycloalkyl which, may be halogenated, (g) C1-6 alkoxy which may be halogenated, (h) C1-6 alkylthio which may be halogenated, (i) hydroxy, (j) amino, (k) mono-C1-6 alkylamino, (l) di-C1-6 alkylamino, (m) formyl, (n) carboxy, (o) carbamoyl, (p) C1-6 alkyl carbonyl which may be halogenated, (q) C1-6 alkoxy-carbonyl, (r) mono-C1-6 alkyl-carbamoyl, (s) di-C1-6 alkyl-carbamoyl, (t) C1-6 alkylsulfonyl which may be halogenated, (u) formylamino, (v) C1-6 alkyl-carboxamido which may be halogenated, (w) C1-6 alkoxy-carboxamido, (x) C1-6 alkylsulfonylamino, (y) C1-6 alkyl-carbonyloxy, (z) C1-6 alkoxy-carbonyloxy, (aa) mono-C1-6 alkyl-carbamoyloxy and (bb) di-C1-8 alkyl-carbamoyloxy, (v) C1-6 alkyl-carbonyl which may be halogenated, and (vi) C1-6 alkyl-sulfonyl, and
ring A is a benzene ring, or a 5- or 6-membered aromatic heterocyclic ring which may be substituted with 1 to 3 substituents selected from the group consisting of halogen atom, C1-6 alkyl which may be halogenated, C1-6 alkoxy which may be halogenated, hydroxy and amino, in addition to the substituent represented by Arxe2x80x94Xxe2x80x94;
23. The compound according to the above 21, wherein the aromatic ring assembly group represented by Arxe2x80x2 is 2-, 3- or 4-biphenylyl;
24. The compound according to the above 21, wherein Xxe2x80x2 is a group represented by xe2x80x94(CH2)p1O (wherein p1 is an integer of 1 to 3);
25. The compound according to the above 21, wherein Yxe2x80x2 is a group represented by the formula: xe2x80x94(CH2)q1CONR9(CH2)r1xe2x80x94 (wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl which may be halogenated or C1-6 alkyl-carbonyl which may be halogenated);
26. The compound according to the above 21, wherein each of R1 and R2 is [1] hydrogen atom or [2] C1-6 alkyl which may be substituted with carboxy or C1-6 alkoxy-carbonyl, or R1 and R2 form, together with the adjacent nitrogen atom, a 5- or 6-membered nitrogen-containing heterocyclic ring;
27. The compound according to the above 21, wherein ring A is a benzene ring or a 6-membered nitrogen-containing aromatic heterocyclic ring which may be substituted with halogen atom or C1-6 alkoxy;
28. The compound according to the above 21, wherein ring A is a benzene ring, a pyridine ring or 2-pyridone ring;
29. The compound according to the above 21, wherein ring A is a benzene ring or a pyridine ring;
30. The compound according to the above 21, wherein Arxe2x80x2 is 2-, 3- or 4-biphenylyl, Xxe2x80x2 is [1] a group represented by the formula: xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3), [2] xe2x80x94(CH2)p2xe2x80x94 (wherein p2 is an integer of 1 to 3) or [3] CONH, Yxe2x80x2 is [1] a group represented by the formula: xe2x80x94(CH2)q1CONR9(CH2)r1xe2x80x94 (wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl which may be halogenated or C1-6 alkyl-carbonyl which may be halogenated), or [2] a group represented by the formula: xe2x80x94(CH2)q2COO(CH2)r2xe2x80x94 (wherein each of q2 and r2 is an integer of 0 to 3 and their sum is not more than 3), each of R1 and R2 is [1] hydrogen atom or [2] C1-6 alkyl which may be substituted with carboxy, C1-6 alkoxy-carbonyl or di-C1-6 alkylnitrile, or R1 and R2 may form, together with the adjacent nitrogen atom, a 5- or 6-membered, nitrogen-containing heterocyclic ring, and
ring A is a benzene ring or a 6-membered nitrogen-containing aromatic heterocyclic ring;
31. The compound according to the above 21, wherein Arxe2x80x2 is biphenylyl, Xxe2x80x2 is xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3), Yxe2x80x2 is xe2x80x94CONH(CH2)sxe2x80x94 (wherein s is an integer of 1 to 3), R1 and R2 are C1-6 alkyl, or R1 and R2 form, together with the adjacent nitrogen atom, a 5- or 6-membered nitrogen-containing heterocyclic ring, and ring A is a benzene ring or a 6-membered nitrogen-containing aromatic heterocyclic ring;
32. 4-(4-biphenylylmethoxy)phenyl-N-(2-piperidino-ethyl)acetamide,
4-(4-biphenylylmethoxy)phenyl-N-[2-(N,N-dimethylamino)-ethyl]acetamide,
6-(4-biphenylylmethoxy)-N-[2-(pyrrolidine-1-yl)ethyl]-nicotinamide,
1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-N-[2-(pyrrolidine-1-yl)ethyl]-3-pyridinecarboxamido,
1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-N-(2-(piperidinoethyl)-3-pyridinecarboxamido,
6-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)nicotinamide,
6-(4-biphenylylmethoxy)-N-[2-(N,N-dimethylamino)ethyl]-nicotinamide,
4-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)benzamide,
4-(4-biphenylylmethoxy)-N-[(2-pyrrolidine-1-yl)ethyl]-benzamide,
2-piperidinoethyl=4-(4-biphenylylethoxy)benzoate,
2-(pyrrolidin-1-yl)ethyl=4-(4-biphenylylmethoxy)benzoate,
4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)-ethyl]acetamide oxalate,
4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)-ethyl]acetamide maleate,
4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)-ethyl]acetamide fumarate,
4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N-methylamino)-ethyl]acetamide hydrochloride,
4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N-methylamino)-ethyl]acetamide,
ethyl 7-[2-[4-[(4-biphenylylmethoxy)phenyl]acetylamino-ethyl](methyl)amino]heptanoate,
7-[2-[4-[4-(biphenylylmethoxy)phenyl]acetylaminoethyl]-methyl)amino]heptanoic acid hydrochloride,
N-(4-(2-((2-(dimethylamino)ethyl)(methyl)amino)-2-oxoethyl)phenyl)[1,1xe2x80x2-biphenyl]-4-carboxamide,
N-(2-aminoethyl)-2-(4-([1,1xe2x80x2-biphenyl]-4-ylmethoxy)phenyl)-acetamide hydrochloride,
4-([1,1,xe2x80x2-biphenyl]-4-ylmethoxy)-N-(2-(1-pyrrolidinyl)-ethyl)benzamide,
N-(4-((2-([2-dimethylamino)ethyl)(methyl)amino)-2-oxoethyl)phenyl)[1,1xe2x80x2-biphenyl]-4-carboxamide,N-[4-({[2-(diethylamino)ethyl]amino}carbonyl)phenyl](4-biphenylyl)carboxamide,
4-(4-biphenylyl)methoxy)-N-[2-(isopropylamino)ethyl]-benzamide,
2-(N,N-diethylamino)ethyl-4-[(4-biphenylyl)carbonyl]amino]-benzoate,
N-[4-({[2-(dimethylamino)ethyl]amino}carbonyl)phenyl](4-biphenylyl)carboxamide,
N-[4-{[2-(piperidinoethyl)amino]carbonyl}phenyl](4-biphenylyl)carboxamide, or
N-[4-({[2-(pyrrolidinyl)ethyl]amino}carbonyl)phenyl](4-biphenylyl)carboxamide;
33. A prodrug of the compound according to the above 21.
34. A process for producing the compound according to the above 21 which comprises:
(1) reacting a compound represented by the formula: 
xe2x80x83wherein Xa is oxygen atom, sulfur atom which may be oxidized or imino which may be substituted, and other symbols are as defined in the above 21, or a salt thereof with a compound represented by the formula:
Arxe2x80x94Xbxe2x80x94Lxe2x80x83xe2x80x83(III)
xe2x80x83wherein Xb is a group corresponding to Xxe2x80x2 from which Xa is removed, L is a leaving group of hydroxy, and Xxe2x80x2 and Arxe2x80x2 are as defined in the above 21, or a salt thereof, or
(2) reacting a compound represented by the formula: 
xe2x80x83wherein each symbol is as defined in the above 21, or a salt thereof with a compound represented by the formula: 
xe2x80x83wherein each symbol is as defined in the above 21, or a salt thereof;
35. A pharmaceutical composition which comprises a compound represented by the formula: 
wherein Arxe2x80x2 is aromatic ring assembly group which may be substituted, Xxe2x80x2 is [1] a group represented by the formula: xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3), [2] xe2x80x94(CH2)p2xe2x80x94 (wherein p2 is an integer of 1 to 3) or [3] CONH, Yxe2x80x2 is [1] a group represented by the formula: xe2x80x94(CH2)q1CONR9 (CH2)r1xe2x80x94 (wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl which may be halogenated or C1-6 alkyl-carbonyl which may be halogenated), or [2] a group represented by the formula: xe2x80x94(CH2)q2COO(CH2)r2xe2x80x94 (wherein each of q2 and r2 is an integer of 0 to 3 and their sum is not more than 3), each of R1 and R2 is hydrogen atom or C1-6 alkyl which may be substituted, or R1 and R2 may form, together with the adjacent nitrogen atom, a 5- or 6-membered nitrogen-containing heterocyclic ring, and ring A is monocyclic aromatic ring which may be further substituted, or a salt or a prodrug thereof;
36. The pharmaceutical composition according to the above 35 which is an agent for preventing or treating senile dementia, Alzheimer""s disease, Down""s syndrome, Parkinson""s disease, amyloid angiopathy or disorders due to amyloid-xcex2 protein in cerebrovascular disorders caused by the production and/or secretion of amyloid-xcex2 protein;
37. A method for inhibiting the production and/or the secretion of amyloid-xcex2 protein in mammal, which comprises administering to said mammal an effective amount of a compound represented by the formula: 
wherein Ar is an aromatic group which may be substituted, X and Y are the same and different and each is a bivalent group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94CONR8xe2x80x94, SO2NR8xe2x80x94 and xe2x80x94COOxe2x80x94 (wherein R8 is hydrogen atom, a hydrocarbon group which may be substituted or acyl) or a bivalent C1-6 aliphatic hydrocarbon group which may contain one or two above bivalent groups, each of R1 and R2 is hydrogen atom or C1-6 alkyl which may be substituted, or R1 and R2 may form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring, and ring A is monocyclic aromatic ring which may be further substituted, or a salt or a prodrug thereof;
38. A method for preventing or treating senile dementia, Alzheimer""s disease, Down""s syndrome, Parkinson""s disease, amyloid angiopathy or disorders due to amyloid-xcex2 protein in cerebrovascular disorders caused by the production and/or secretion of amyloid-xcex2 protein which comprises administering an effective amount of a compound represented by the formula: 
wherein Ar is an aromatic group which may be substituted, X and Y are the same and different and each is a bivalent group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94SO2NR8xe2x80x94 and xe2x80x94COOxe2x80x94 (wherein R8 is hydrogen atom, a hydrocarbon group which may be substituted or acyl) or a bivalent C1-6 aliphatic hydrocarbon group which may contain one or two above bivalent groups, each of R1 and R2 is hydrogen atom or C1-6 alkyl which may be substituted, or R1 and R2 may form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring, and ring A is monocyclic aromatic ring which may be further substituted, or a salt or a prodrug thereof;
39. Use of a compound represented by the formula: 
wherein Ar is an aromatic group which may be substituted, X and Y are the same and different and each is a bivalent group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94SO2NR8xe2x80x94 and xe2x80x94COOxe2x80x94 (wherein R8 is hydrogen atom, a hydrocarbon group which may be substituted or acyl) or a bivalent C1-6 aliphatic hydrocarbon group which may contain one or two above bivalent groups, each of R1 and R2 is hydrogen atom or C1-6 alkyl which may be substituted, or R1 and R2 may form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring, and
ring A is monocyclic aromatic ring which may be further substituted, or a salt or a prodrug thereof, for manufacturing an inhibitor of the production and/or the secretion of amyloid-xcex2 protein; and
40. Use of a compound represented by the formula: 
wherein Ar is an aromatic group which may be substituted, X and Y are the same and different and each is a bivalent group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94SO2NR8xe2x80x94 and xe2x80x94COOxe2x80x94 (wherein R8 is hydrogen atom, a hydrocarbon group which may be substituted or acyl) or a bivalent C1-6 aliphatic hydrocarbon group which may contain one or two above bivalent groups, each of R1 and R2 is hydrogen atom or C1-6 alkyl which may be substituted, or R1 and R2 may form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring, and ring A is monocyclic aromatic ring which may be further substituted, or a salt or a prodrug thereof, for manufacturing an agent for preventing or treating senile dementia, Alzheimer""s disease, Down""s syndrome, Parkinson""s disease, amyloid angiopathy or disorders due to amyloid-xcex2 protein in cerebrovascular disorders caused by the production and/or secretion of amyloid-xcex2 protein.
As the term xe2x80x9cC1-6 alkyl which may be halogenatedxe2x80x9d used herein, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.) can be used. Examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.
As the term xe2x80x9cC3-6 cycloalkyl which may be halogenatedxe2x80x9d used herein, for example, C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.) can be used. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, etc.
As the term xe2x80x9cC1-6 alkoxy which may be halogenatedxe2x80x9d used herein, for example, C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.) can be used. Examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc. can be mentioned.
As the term xe2x80x9cC1-6 alkylthio which may be halogenatedxe2x80x9d used herein, for example, C1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.) can be used. Examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio;, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc.
As the term xe2x80x9cC1-6 alkyl-carbonyl which may be halogenatedxe2x80x9d, for example, C1-6 alkyl-carbonyl (e.g., acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.) can be used. Examples thereof include acetyl, monochloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, hexanoyl etc.
As the term xe2x80x9cC1-6 alkylsulfonylxe2x80x9d used herein, for example, C1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.) can be used. Examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.
As the term xe2x80x9cC1-6 alkyl-carboxamido which, may be halogenatedxe2x80x9d used herein, for example, C1-6 alkyl-carboxamido (e.g., acetamido, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.) can be used. Examples thereof include acetamido, trifluoroacetamido, propanamido, butanamido, etc.
In the above-mentioned formula, as the aromatic group represented by Ar, for example, a monocyclic aromatic group, an aromatic ring assembly group, a fused aromatic group, etc. can be used.
As the xe2x80x9cmonocyclic aromatic groupxe2x80x9d, for example, a monovalent group formed by removing any one of hydrogen atoms from benzene ring or a 5- or 6-membered aromatic heterocyclic ring can be used.
As the xe2x80x9c5- or 6-membered aromatic heterocyclic ringxe2x80x9d for example, a 5- or 6-membered aromatic heterocyclic ring having, in addition to carbon atom, one or more (e.g., 1 to 3, preferably 1 or 2) hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, etc. can be used. Examples thereof include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrazine, pyrimidine, pyridazine rings, etc.
Examples of the above-mentioned monocyclic aromatic group include, preferably, phenyl, 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2- or 4-imidazolyl, 3- or 4-pyrazolyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 2-, 3- or 4-pyridyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 3- or 4-pyridazinyl, etc. Among them, phenyl, etc. are preferred.
As the xe2x80x9caromatic ring assembly groupxe2x80x9d, for example, a group which is derived, by removing any one of hydrogen atoms from an assembled aromatic ring in which two or more, preferably two or three aromatic rings are directly joined to each other by single bond(s) and the number of such direct ring junctions is one less than the number of the aromatic rings involved can be used. The xe2x80x9caromatic ringxe2x80x9d includes, for example, an aromatic hydrocarbon, an aromatic heterocyclic ring, etc.
The xe2x80x9caromatic hydrocarbonxe2x80x9d includes, for example, a C6-14 monocyclic or fused polycyclic (preferably, bi- or tri- cyclic) aromatic hydrocarbon compound (e.g., benzene, naphthalene, indene, anthracene, etc.),
The xe2x80x9caromatic heterocyclic ringxe2x80x9d includes, for example, 5- to 14-membered, preferably 5- to 10-membered aromatic heterocyclic rings containing one or more (e.g., 1 to 4, preferably 1 to 2) hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, etc. Examples thereof include an aromatic heterocyclic ring, such as thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, phenoxathiin, pyrrole, imidazole, pyrazole, oxazole, isoxzaole, 1,2,4-oxadiazole, 1,3,4-oxadizaole, 1,2,4-thiadizaole, 1,3,4-thiadiazaole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, xcex2-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, furazan, phenoxazine, phthalimide, 2-, 3- or 4-pyridone, 2-, 3- or 4-quinolone, etc.; and a ring as formed through condensation of the above ring, preferably monocyclic ring, with one or more, preferably one or two aromatic rings (e.g., a benzene ring, etc.), etc.
The assembly of those aromatic rings in which the rings are directly bonded to each other via a single bond includes, for example, those to be composed of two or three, preferably two aromatic rings selected from the group consisting of a benzene ring, naphthalene ring and 5- to 10-membered (preferably 5- or 6-membered) aromatic heterocyclic ring. As preferred examples of the assembly of such aromatic rings, there are aromatic ring assembly groups composed of two or 3 aromatic rings selected from benzene, naphthalene, pyridine, pyrimidine, thiophen, furan, thiazole, isothiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, quinoline, isoquinoline, indole, benzothiophen, benzoxazole, benzthiazole and benzofuran. Specific examples thereof include 2-, 3- or 4-biphenylyl, 3-(1-naphthyl)-1,2,4-oxadiazol-5-yl, 3-(2-naphthyl)-1,2,4-oxadiazol-5-yl, 3-(2-benzofuranyl)-1,2,4-oxadiazol-5-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 3-(2-benzoxazolyl)-1,2,4-oxadiazol-2-yl, 3-(3-indolyl)-1,2,4-oxadiazol-2-yl, 3-(2-indolyl)-1,2,4-oxadiazol-2-yl, 4-phenylthiazol-2-yl, 4-(2-benzofuranyl)thizaol-2-yl, 4-phenyl-1,3-oxazol-5-yl, 5-phenylisothiazol-4-yl, 5-phenyloxazol-2-yl, 4-(2-thienyl)phenyl, 4-(3-thienyl)phenyl, 3-(3-pyridyl)phenyl, 4-(3-pyridyl)phenyl, 6-phenyl-3-pyridyl, 5-phenyl-1,3,4-oxadiazol-2-yl, 4-(2-naphthyl)phenyl, 4-(2-benzofuranyl)phenyl, 4,4xe2x80x2-terphenyl, etc. Of those, preferred are 2-, 3- or 4-biphenylyl.
As the xe2x80x9cfused aromatic groupxe2x80x9d, a monovalent group formed by removing any one of hydrogen atoms from a fused polycyclic (preferably, bi- to tetra-cyclic, more preferably bi- to tri-cyclic) aromatic hydrocarbon ring can be used. As the xe2x80x9cfused polycyclic aromatic ringxe2x80x9d, a fused polycyclic aromatic hydrocarbon, a fused polycyclic aromatic heterocyclic ring can be used.
As the xe2x80x9cfused polycyclic aromatic hydrocarbonxe2x80x9d, for example, C9-14 fused polycyclic (bi- or tri-cyclic) aromatic hydrocarbon (e.g., naphthalene, indene, anthracene, etc.), etc. can be used.
As the xe2x80x9cfused polycyclic aromatic heterocyclic ringxe2x80x9d, for example, 9- to 14-membered, preferably, 9- to 10 membered fused polycyclic aromatic heterocyclic ring, etc. can be used. Examples thereof include aromatic heterocyclic rings such as benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, isoquinoline, quinoline, indole, quinoxaline, phenanthridine, phenothiazine, phenoxazine, phthalimide, etc.
Specific examples of the above-mentioned fused aromatic group include 1-naphthyl, 2-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-benzofuranyl, 2-benzothiazolyl, 2-benzimidazolyl, 1-indolyl, 2-indolyl, 3-indolyl, etc. Among them, 1-naphthyl, 2-naphthyl, etc. are preferred.
The substituent for the aromatic group represented by Ar includes, for example, halogen atom (e.g., fluoro, chloro, bromo, iodo, etc.), C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.), nitro, cyano, C1-6 alkyl which may be halogenated, C6-10 aryloxy-C1-6 alkyl (e.g., phenoxymethyl, etc.), C1-6 alkyl-C6-10 aryl-C2-6 alkenyl (e.g., methylphenylethenyl, etc.), C3-6 cycloalkyl which may be halogenated, C7-16 aralkyl which may be substituted, C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, C6-10 aryloxy which may be substituted, C6-10 aryl-C7-16 aralkyloxy (e.g., phenylbenzyloxy, etc.), amino, mono-C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etch), 5- to 7-membered saturated cyclic amino which may be substituted, acyl, acylamino, acyloxy, etc. The xe2x80x9caromatic groupxe2x80x9d may have 1 to 5, preferably 1 to 3 substituents as mentioned above at possible positions of the aromatic ring, and when the number of substituents is two or more, those substituents may be the same as or different from one another.
Among these substituents of the aromatic group represented by Ar, as xe2x80x9cC7-16 aralkylxe2x80x9d of xe2x80x9cC7-16 aralkyl which may be substitutedxe2x80x9d, for example, benzyl, phenethyl, nephthylmethyl, etc. can be used.
As xe2x80x9cC6-10 aryloxyxe2x80x9d of xe2x80x9cC6-10 aryloxy which may be substitutedxe2x80x9d, for example, phenyloxy, naphthyloxy, etc. can be used. The xe2x80x9csubstituentxe2x80x9d which those xe2x80x9cC7-16 aralkyl which may be substitutedxe2x80x9d and xe2x80x9cC6-10 aryloxy which may be substitutedxe2x80x9d respectively may have, include, for example, 1 to 5 substituents selected from halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), formyl, carboxy, carbamoyl, optionally halogenated C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), mono-C1-6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), di-C1-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), optionally halogenated C1-6 alkylsulfonyl, formylamino, optionally halogenated C1-6 alkyl-carboxamido C1-6 alkoxy-carboxamido (e.g., methoxycarboxamido, ethoxycarboxamido, propoxycarboxamido, butoxycarboxamido, etc.) C1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), C1-6 alkyl-carbonyloxy (e.g., acetoxy, propanoyloxy, etc.), C1-6 alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C1-6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C1-8 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), etc.
Among the substituent of the aromatic group represented by Ar, the xe2x80x9c5- to 7-membered saturated cyclic aminoxe2x80x9d of xe2x80x9c5- to 7-membered saturated cyclic amino which may be substitutedxe2x80x9d includes, for example, morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, hexamethyleneimin-1-yl, etc. The xe2x80x9csubstituentsxe2x80x9d of these xe2x80x9c5- to 7-membered saturated cyclic amino which may be subsitutedxe2x80x9d include, for example, 1 to 3 substituents selected from optionally halogenated C1-6 alkyl, optionally substituted C6-14 aryl, optionally substituted C7-19 aralkyl, optionally substituted 5- to 10-membered aromatic heterocyclic group, optionally substituted C6-10 aryl-carbonyl, optionally halogenated C1-6 alkyl-carbonyl, optionally halogenated C1-6 alkylsulfonyl, etc.
The xe2x80x9cC6-14 arylxe2x80x9d of the xe2x80x9cC6-14 aryl which may be substitutedxe2x80x9d includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, etc. Preferred is phenyl.
The xe2x80x9cC7-19 aralkylxe2x80x9d of the xe2x80x9cC7-19 aralkyl which may be substitutedxe2x80x9d includes, for example, benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc. Preferred is benzyl, etc.
The xe2x80x9c5- to 10-membered aromatic heterocyclic groupxe2x80x9d of the xe2x80x9c5- to 10-membered aromatic heterocyclic group which may be substitutedxe2x80x9d includes, for example, 2-, 3- or 4-pyridyl, 1-, 2- or 3-indolyl, 2- or 3-thienyl, etc. Preferred is 2-, 3- or 4-pyridyl, etc.
The xe2x80x9cC6-10 aryl-carbonylxe2x80x9d of the xe2x80x9cC6-10 aryl-carbonyl which may be substitutedxe2x80x9d includes, for example, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.
The xe2x80x9csubstituentxe2x80x9d which these xe2x80x9cC6-14 aryl which may be substitutedxe2x80x9d, xe2x80x9cC7-19 aralkyl which may be substitutedxe2x80x9d, xe2x80x9c5- to 10-membered aromatic heterocyclic group which may be substitutedxe2x80x9d and xe2x80x9cC6-10 aryl-carbonyl which may be subsitutedxe2x80x9d respectively may have, includes, for example, 1 to 5 substituents selected from the group consisting of halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), formyl, carboxy, carbamoyl, optionally halogenated C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), mono-C1-6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etec.), di-C1-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), optionally halogenated C1-6 alkylsulfonyl, formylamino, optionally halogenated C1-6 alkyl-carboxamido, C1-6 alkoxy-carboxamido (e.g., methoxycarboxamido, ethoxycarboxamido, propoxycarboxamido, butoxycarboxamido, etc.) C1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), C1-6 alkyl-carbonyloxy (e.g., acetoxy, propanoyloxy, etc.), C1-6 alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C1-6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C1-8 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), etc.
The xe2x80x9cacylxe2x80x9d of xe2x80x9cacylxe2x80x9d, xe2x80x9cacylaminoxe2x80x9d and xe2x80x9cacyloxyxe2x80x9d as the substituent of the xe2x80x9caromatic group which may be subsitutedxe2x80x9d represented by Ar includes, for example, that represented by the formula: xe2x80x94COxe2x80x94R3, xe2x80x94COxe2x80x94OR3xe2x80x94COxe2x80x94NR3R4, xe2x80x94CSxe2x80x94NHR3, xe2x80x94SO2xe2x80x94R3a or xe2x80x94SOxe2x80x94R3a wherein R3 is (i) hydrogen atom, (ii) a hydrocarbon group which may be substituted, specifically, a heterocyclic group which may be substituted with 1 to 5 substituents selected from the group consisting of halogen atom, C1-3 alkylenedioxy, nitro, cyano, C1-6 alkyl which may be halogenated, C3-6 cycloalkyl which may be halogenated, C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, amino, mono- C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7- membered cyclic amino which may be substituted, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl which may be halogenated, C7-16 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, mono-C1-6 alkyl-carbamoyl,; di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, C1-6 alkylsulfonyl which may be halogenated, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido which may be halogenated, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-8 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, or (iii) a heterocyclic group which may be substituted, specifically, a heterocyclic group which may be substituted with 1 to 5 substituents selected from the group consisting of halogen atom, C1-3 alkylenedioxy, nitro, cyano, C1-6 alkyl which may be halogenated, C3-6 cycloalkyl which may be halogenated, C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, amino, mono- C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7- membered cyclic amino which may be substituted, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl which may be halogenated, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, C1-6 alkylsulfonyl which may be halogenated, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido which may be halogenated, C6-10 aryl-carboxamido, C6-10 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-8 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, R3a is (i) a hydrocarbon group which may be substituted, specifically, a heterocyclic group which may be substituted with 1 to 5 substituents selected from the group consisting of halogen atom, C1-3 alkylenedioxy, nitro, cyano, C1-6 alkyl which may be halogenated, C3-6 cycloalkyl which may be halogenated, C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, amino, mono- C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7- membered cyclic amino which may be substituted, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl which may be halogenated, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, C1-6 alkylsulfonyl which may be halogenated, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido which may be halogenated, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-8 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, or (iii) a heterocyclic group which may be substituted, specifically, a heterocyclic group which may be substituted with 1 to 5 substituents selected from the group consisting of halogen atom, C1-3 alkylenedioxy, nitro, cyano, C1-6 alkyl which may be halogenated, C3-6 cycloalkyl which may be halogenated, C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, amino, mono- C1-6 alkylamino, di-C1-6 alkylamino, 5- to 7- membered cyclic amino which may be substituted, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl which may be halogenated, C1-6 alkoxy-carbonyl, C6-10 aryl-carbonyl, C6-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, C1-6 alkylsulfonyl which may be halogenated, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido which may be halogenated, C6-10 aryl-carboxamido, C6-10 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-8 alkyl-carbamoyloxy, C6-10 aryl-carbamoyloxy, nicotinoyloxy and C6-10 aryloxy, R4 is hydrogen atom or C1-6 alkyl, or R3 and R4 may form, together with the adjacent nitrogen atom, a nitrogen-containing ring.
The xe2x80x9c5- to 7-membered saturated cyclic aminoxe2x80x9d as the substituent of R3 or R3a is the same as those mentioned above.
The xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d represented by R3 or R3ais a group formed by removing any one of hydrogen atoms from a hydrocarbon compound, as exemplified by acyclic or cyclic hydrocarbon group such as alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, etc. Among them, the following C1-19 acyclic or cyclic hydrocarbon group is preferred:
a) C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),
b) C2-6 alkenyl (e.g., vinyl, allyl, isopropenyl, 2-butenyl, etc.),
c) C2-6 alkynyl (e.g., ethynyl, propargyl, 2-butynyl, etc.),
d) C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), and the C3-6 cycloalkyl being optionally condensed with one a benzene ring,
e) C6-14 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, etc.), preferably phenyl,
f) C7-19 aralkyl (e.g., benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.), preferably benzyl.
The heterocyclic group represented by R3 or R3a includes, for example, a monovalent group formed by removing any one of hydrogen atoms from 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic ring containing 1 to 4 hetero atoms of 1 or 2 species selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, preferably, (i) 5- to 14-membered, preferably 5- to 10-membered aromatic heterocyclic ring, (ii) 5- to 10-membered non-aromatic heterocyclic ring or (iii) a 7- to 10-membered bridged heterocyclic ring.
The above-mentioned xe2x80x9c5- to 14-membered, preferably 5- to 10-membered aromatic heterocyclic ringxe2x80x9d includes, for example, an aromatic heterocyclic ring such as thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, phenoxathiine, pyrrole, imidazole, pyrazole, oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, xcex2-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine, phthalimide, etc.; and a ring as formed through condensation of those rings, preferably a monocyclic ring, with one or more, preferably one or two aromatic rings (e.g., a benzene ring, etc.), etc.
The above-mentioned xe2x80x9c5- to 10-membered non-aromatic heterocyclic ringxe2x80x9d includes, for example, pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, etc.
The above-mentioned xe2x80x9c7- to 10-membered bridged heterocyclic ringxe2x80x9d includes, for example, quinuclidine, 7-azabicyclo[2,2,1]heptane, etc.
Preferable examples of the xe2x80x9cheterocyclic groupxe2x80x9d include, for example, 5- to 10-membered (monocyclic or bicyclic) heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Specific examples thereof include an aromatic heterocyclic group such as 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2-, 3-, 4-, 5- or 8-quinolyl, 4-isoquinolyl, pyrazinyl, 2- or 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 2-isoindolylnyl, etc; and a non-aromatic heterocyclic group such as 1-, 2 or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholino, etc.
Among these groups, a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Specific examples thereof include 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-, 2-, or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholino, etc.
The xe2x80x9cC1-6 alkylxe2x80x9d represented by R4 includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
The xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d formed by, taken together with the adjacent nitrogen atom, R3 and R4 includes, for example, 5- to 7-membered nitrogen-containing heterocyclic ring having one nitrogen atom and optionally having 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Such examples include piperidine, morpholine, thiomorpholine, piperazine, pyrrolidine, etc.
Preferred examples of the xe2x80x9cacylxe2x80x9d as the xe2x80x9csubstituentxe2x80x9d of the xe2x80x9caromatic ringxe2x80x9d represented by Ar include formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl which; may be halogenated, C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C6-10 aryl-carbonyl which may be substituted, C6-10 aryloxy-carbonyl which may be substituted, C7-16 aralkyloxy-carbonyl which may be substituted, 5- or 6-membered heterocycle carbonyl which may be substituted, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C6-10 aryl-carbamoyl which may be substituted, 5- or 6-membered heterocycle carbamoyl which may be substituted, C1-6 alkylsulfonyl which may be halogenated, C6-10 arylsulfonyl which may be substituted, etc.
Among them, xe2x80x9cC6-10 aryl-carbonylxe2x80x9d of xe2x80x9cC6-10 aryl-carbonyl which may be substitutedxe2x80x9d includes, for example, benzoyl, 1-naphthoyl, 2-naphthoyl, etc. xe2x80x9cC6-10 aryloxy-carbonylxe2x80x9d of xe2x80x9cC6-10 aryloxy-carbonyl which may be substitutedxe2x80x9d includes, for example, phenoxycarbonyl, etc. xe2x80x9cC7-16 aralkyloxy-carbonylxe2x80x9d of xe2x80x9cC7-16 aralkyoxy-carbonyl which may be substitutedxe2x80x9d includes, for example, benzyloxycarbonyl, phenethyloxycarbonyl, etc. xe2x80x9c5- or 6-membered heterocyclic carbonylxe2x80x9d of xe2x80x9c5- or 6-membered heterocyclic carbonyl which may be substitutedxe2x80x9d includes, for example, nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl, etc. xe2x80x9cC6-10 aryl-carbamoylxe2x80x9d; of xe2x80x9cC6-10 aryl-carbamoyl which may be subsitutedxe2x80x9d includes, for example, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc. xe2x80x9c5- or 6-membered heterocyclic-carbamoylxe2x80x9d of xe2x80x9c5- or 6-membered heterocyclic carbamoyl which may be subsitutedxe2x80x9d includes, for example, 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc. xe2x80x9cC6-10 arylsulfonylxe2x80x9d of xe2x80x9cC6-10 arylsulfonyl which may be subsitutedxe2x80x9d includes, for example, benzenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, etc.
The xe2x80x9csubstituentxe2x80x9d of these xe2x80x9cC6-10 aryl-carbonyl which may be substitutedxe2x80x9d, xe2x80x9cC6-10 aryloxy-carbonyl which may be substitutedxe2x80x9d, xe2x80x9cC7-16 aralkyoxy-carbonyl which may be substitutedxe2x80x9d, xe2x80x9c5- or 6-membered heterocyclic carbonyl which may be substitutedxe2x80x9d, xe2x80x9cC6-10 aryl-carbamoyl which may be subsitutedxe2x80x9d, xe2x80x9c5- or 6-membered heterocyclic carbamoyl which may be subsitutedxe2x80x9d and xe2x80x9cC6-10 arylsulfonyl which may be subsitutedxe2x80x9d includes, for example, 1 to 5, preferably 1 to 3 substituents selected from the group consisting of halogen atom, C1-3 alkylenedioxy, nitro, cyano, C1-6 alkyl which may be halogenated, C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, formyl, carboxy, carbamoyl, C1-6 alkyl-carbonyl which may be halogenated, C1-6 alkoxy-carbonyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C1-6 alkylsulfonyl which may be halogenated, C6-10 arylsulfonyl, formylamino, C1-6 alkyl-carboxamido which may be halogenated, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy and di-C1-8 alkyl-carbamoyloxy.
The xe2x80x9cacylaminoxe2x80x9d as the xe2x80x9csubstituentxe2x80x9d of the xe2x80x9caromatic group which may be substitutedxe2x80x9d represented by the above Ar includes, for example, an amino substituted by 1 or 2 xe2x80x9cacylxe2x80x9d described in detail in the above xe2x80x9csubstituentxe2x80x9d for the xe2x80x9caromatic group which may be substitutedxe2x80x9d represented by Ar. Preferred is an acylamino of the formula: xe2x80x94NR5xe2x80x94COR6, xe2x80x94NR5xe2x80x94COOR6a, xe2x80x94NR5xe2x80x94SO2RR6a orxe2x80x94NR5xe2x80x94CONR6a R6b wherein R5 is hydrogen atom or C1-6 alkyl, R6 is as defined above with respect to R3, R6a is as defined above with respect to R3a and R6b is as defined with respect to R4, etc.
The xe2x80x9cC1-6 alkylxe2x80x9d for R5 and R6b includes the xe2x80x9cC1-6 alkylxe2x80x9d shown by R4 above.
Preferred examples of the xe2x80x9cacylaminoxe2x80x9d as the xe2x80x9csubstituentxe2x80x9d of the xe2x80x9caromatic group which may be substitutedxe2x80x9d represented by Ar include formylamino, C1-6 alkyl-carboxamido which may be halogenated, C6-10 aryl-carboxamido (e.g., phenylcarboxamido, naphthylcarboxamido, etc.), C1-6 alkoxy-carboxamido (e.g., methoxycarboxamido, ethoxycarboxamido, propoxycarboxamido, butoxycarboxamido, etc.), C1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), etc.
The above-mentioned xe2x80x9cacyloxyxe2x80x9d as the xe2x80x9csubstituentxe2x80x9d of the xe2x80x9caromatic group which may be substitutedxe2x80x9d represented by the above Ar includes, for example, an oxy substituted by one xe2x80x9cacylxe2x80x9d described in detail in the foregoing referring to the xe2x80x9csubstituentxe2x80x9d for the xe2x80x9caromatic ring assembly group which may be substitutedxe2x80x9d. Preferred is an acyloxy of the formula: xe2x80x94Oxe2x80x94COR7, xe2x80x94Oxe2x80x94COOR7 or xe2x80x94Oxe2x80x94CONHR7 wherein R7 is as defined with respect to the above R3, etc.
Preferred examples of xe2x80x9cacyloxyxe2x80x9d as the xe2x80x9csubstituentxe2x80x9d of the xe2x80x9caromatic group which may be substitutedxe2x80x9d represented by the above Ar include C1-6 alkyloxy-carbonyl (e.g., acetoxy, propanoyloxy, etc.), C6-10 aryl oxy-carbonyl which may be substituted (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy, etc.), C1-6 alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C1-6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C1-6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), C6-10 aryl-carbamoyloxy which may be substituted (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), nicotinoyloxy, etc. Preferred examples of the xe2x80x9csubstituentxe2x80x9d or these xe2x80x9cC6-10 aryl-carboxamido which may be substitutedxe2x80x9d, xe2x80x9cC6-10 aryl-carbonyloxy which may be substitutedxe2x80x9d and xe2x80x9cC6-10 aryl-carbamoyloxy which may be substitutedxe2x80x9d include the same substituents as those of the above xe2x80x9cC6-10 aryl-carbonyl which may be substitutedxe2x80x9d.
Among them, preferred Ar is the aromatic ring assembly group which may be substituted (in particular, 2-, 3- or 4-biphenylyl, etc.).
Each of X and Y is a bivalent group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2, xe2x80x94NR8xe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94SO2NR8xe2x80x94 and xe2x80x94COOxe2x80x94 (wherein R8 is hydrogen atom, a hydrocarbon group which may be substituted or acyl) or a bivalent C1-6 aliphatic hydrocarbon group which may contain one or two above bivalent groups.
Examples of the hydrocarbon group which may be subsituted represented by R8 include the same group as the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d of the above R3. Among them, C1-6 alkyl which may be halogenated, etc. are preferred.
Examples of the acyl represented by R8 include the same group as the xe2x80x9cacylxe2x80x9d as the substituent of the aromatic group represented by Ar. Among them, preferred examples thereof include formyl, carbamoyl, C1-6 alkyl-carbonyl which may be halogenated, C1-6 alkoxy-carbonyl. (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C6-10 aryl-carbonyl which may be substituted, C6-10 aryloxy-carbonyl which may be substituted, C7-16 aralkyloxy-carbonyl which may be substituted, 5- or 6-membered heterocycle carbonyl which may be substituted, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C6-10 aryl-carbamoyl which may be substituted, 5- or 6-membered heterocycle carbamoyl which may be substituted, C1-6 alkylsulfonyl which may be halogenated, C6-10 arylsulfonyl which may be substituted, etc. In particular, C1-6 alkyl-carbonyl is preferred.
The C1-6 aliphatic hydrocarbon group includes, for example, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, etc.
The C1-6 alkylene includes, for example, in addition to a straight chain alkylene such as xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94, etc., C1-3 alkylene (e.g., xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, etc.) which may have 1 to 3 C1-3 alkyl groups, etc.
The C2-6 alkenylene includes for example, in addition to a straight chain C2-6 alkenylene such as xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x942xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94,xe2x80x94(CH2)2xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)2, xe2x80x94(CH2)3xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, etc., C2-3 alkenylene (e.g., xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, etc.) which may have 1 to 3 C1-3 alkyl groups, etc.
The C2-6 alkynylene includes, for example, in addition to a straight chain C2-6 alkynylene such as xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2, xe2x80x94(CH2)2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, etc., C2-3 alkynylene (e.g., xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, etc.) having 1 to 3 C1-3 alkyl groups.
Preferred examples of the C1-6 aliphatic hydrocarbon group includes, in particular, a C1-3 aliphatic hydrocarbon group such as C1-3 alkylene, C2-3 alkenylene, C2-6 alkynylene, etc.
Examples of a bivalent C1-6 aliphatic hydrocarbon group which may contain one or two bivalent groups selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94SO2NR8xe2x80x94 and xe2x80x94COOxe2x80x94 represented by X include
(i) xe2x80x94(CH2)wOxe2x80x94, xe2x80x94(CH2)wSxe2x80x94, xe2x80x94(CH2)wCOxe2x80x94, xe2x80x94(CH2)wSOxe2x80x94, xe2x80x94(CH2)wSO2xe2x80x94, xe2x80x94(CH2)wNR8xe2x80x94, xe2x80x94(CH2)wCONR8xe2x80x94, xe2x80x94(CH2)wNR8COxe2x80x94, xe2x80x94(CH2)wSO2NR8xe2x80x94, xe2x80x94(CH2)wNR8SO2xe2x80x94, xe2x80x94(CH2)wCOOxe2x80x94,
(ii) xe2x80x94O (CH2)wxe2x80x94, xe2x80x94S(CH2)wxe2x80x94, xe2x80x94CO(CH2)wxe2x80x94, xe2x80x94SO (CH2)wxe2x80x94, xe2x80x94SO2(CH2)wxe2x80x94, xe2x80x94NR8(CH2)wxe2x80x94, xe2x80x94CONR8(CH2)wxe2x80x94, xe2x80x94NR8CO (CH2)wxe2x80x94, xe2x80x94SO2NR8(CH2)wxe2x80x94, xe2x80x94NR8SO2(CH2)wxe2x80x94, xe2x80x94COO(CH2)
(iii) xe2x80x94(CH2)w1O (CH2)w2xe2x80x94, xe2x80x94(CH2)w1S (CH2)w2xe2x80x94, xe2x80x94(CH2)w1CO(CH2)w2xe2x80x94, xe2x80x94(CH2)w1SO(CH2)w2xe2x80x94, xe2x80x94(CH2)w1SO2(CH2)w2xe2x80x94, xe2x80x94(CH2)w1NR8(CH2)w2xe2x80x94, xe2x80x94(CH2)w1CONR8(CH2)w2xe2x80x94, xe2x80x94(CH2)w1NR8CO (CH2)w2xe2x80x94, xe2x80x94(CH2)w1SO2NR8(CH2)w1xe2x80x94, xe2x80x94(CH2)w1NR8SO2(CH2)w1xe2x80x94, xe2x80x94(CH2)w1COO (CH2)w1xe2x80x94, etc.
Examples of a bivalent C1-6 aliphatic hydrocarbon group which may contain one or two above bivalent groups selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94, SO2xe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94SO2NR8xe2x80x94 and xe2x80x94COOxe2x80x94 or represented by Y include
(i) xe2x80x94O(CH2)wxe2x80x94, xe2x80x94S(CH2)wxe2x80x94, xe2x80x94CO (CH2)w1xe2x80x94xe2x80x94SO(CH2)wxe2x80x94, xe2x80x94SO2(CH2)wxe2x80x94, xe2x80x94NR8(CH2)wxe2x80x94, xe2x80x94CONR8(CH2)wxe2x80x94, xe2x80x94NR8CO(CH2)wxe2x80x94, xe2x80x94SO2NR8(CH2)wxe2x80x94, xe2x80x94NR8SO2(CH2)wxe2x80x94, xe2x80x94COO (CH2)wxe2x80x94,
(ii) xe2x80x94(CH2)w1O(CH2)w2xe2x80x94, xe2x80x94(CH2)w1S(CH2)w2xe2x80x94, xe2x80x94(CH2)w1CO(CH2)w2xe2x80x94, xe2x80x94(CH2)w1SO(CH2)w2xe2x80x94, xe2x80x94(CH2)w1SO2(CH2)w2xe2x80x94, xe2x80x94(CH2)w1NR8(CH2)w2xe2x80x94, xe2x80x94(CH2)w1CONR8(CH2)w2xe2x80x94, xe2x80x94(CH2)w1NR8CO(CH2)w2xe2x80x94, xe2x80x94(CH2)w1SO2NR8(CH2)w1xe2x80x94, xe2x80x94(CH2)w1NR8SO2(CH2)w1xe2x80x94, xe2x80x94(CH2)w1COO(CH2)w1xe2x80x94, etc.
w is an integer of 1 to 6, preferably 1 to 4, in particular 1 to 2.
Each of w1 and w2 is integer of 1 to 3, preferably 1 or 2.
In addition, preferred examples of X and Y also include
C1-5 alkylene, C2-5 alkenylene, C2-5 alkynylene, xe2x80x94CH2xe2x80x94Zxe2x80x94, xe2x80x94(CH2)2xe2x80x94Zxe2x80x94, xe2x80x94(CH2)3xe2x80x94Zxe2x80x94, xe2x80x94(CH2)4xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94CH2xe2x80x94, xe2x80x94Zxe2x80x94(CH2)2xe2x80x94, xe2x80x94Zxe2x80x94(CH2)3xe2x80x94, xe2x80x94Zxe2x80x94(CH2)4xe2x80x94, xe2x80x94Zxe2x80x94CH2xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94(CH2)2xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94(CH2)3xe2x80x94Zxe2x80x94, xe2x80x94CH2xe2x80x94Zxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Z-CH2xe2x80x94, xe2x80x94(CH2)3xe2x80x94Zxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Zxe2x80x94(CH2)2xe2x80x94 or xe2x80x94CH2xe2x80x94Zxe2x80x94(CH2)3xe2x80x94
wherein Z is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94SO2NR8xe2x80x94 or xe2x80x94COOxe2x80x94, and, when two Z""s are contained in one formula, they may be the same or different.
Among them, preferred examples of X include [1] a group represented by the formula:xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3), [2] xe2x80x94(CH2)p2xe2x80x94 (wherein p2 is an integer of 1 to 3), [3] xe2x80x94(CH2)p3OCONHxe2x80x94 (wherein p3 is an integer of 1 to 3) [4] CONH or [5] SO2NH, etc., in particular, xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3), etc.
Preferred examples of Y include [1] a group represented by the formula: xe2x80x94(CH2)q1CONR9(CH2)r1xe2x80x94 (wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl which may be halogenated or C1-6 alkyl-carbonyl which may be halogenated), or [2] a group represented by the formula: xe2x80x94(CH2)q2COO(CH2)r2xe2x80x94 (wherein each of q2 and r2 is an integer of 0 to 3 and their sum is not more than 3), etc. in particular, a group represented by the formula: xe2x80x94(CH2)q1CONR9(CH2)r1xe2x80x94 (wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl which may be halogenated or C1-6 alkyl-carbonyl which may be halogenated), etc.
The C1-6 alkyl represented by R1 and R2 includes, for example, methyl, ethyl, propyl, isopropyl, butyl; isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. In particular, methyl, ethyl, propyl, etc. are preferred.
Examples of the substituent of C1-6 alkyl represented by R1 and R2 include 1 to 5, preferably, 1 to 3 substituents selected from the group consisting of halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C3-6 cycloalkyl, optionally halogenated C1-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), formyl, carboxy, carbamoyl, optionally halogenated C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), mono-C1-6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etec.), di-C1-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), optionally halogenated C1-6 alkylsulfonyl, formylamino, optionally halogenated C1-6 alkyl-carboxamido, C1-6 alkoxy-carboxamido (e.g., methoxycarboxamido, ethoxycarboxamido, propoxycarboxamido, butoxycarboxamido, etc.) C1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), C1-6 alkyl-carbonyloxy (e.g., acetoxy, propanoyloxy, etc.), C1-6 alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C1-6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C1-8 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), optionally substituted aromatic group, etc. When two or more substituents are present, they may be the same or different. The optionally substituted aromatic group is the same as the optionally substituted aromatic group of the above Ar.
The xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d of the xe2x80x9cnitrogen-containing heterocyclic ring which may be substitutedxe2x80x9d to be formed by R1 and R2 along with the adjacent nitrogen atom includes, for example, a 3- to 8-member nitrogen-containing heterocyclic ring having one nitrogen atom and optionally having 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Specific examples thereof include aziridine, azetidine, morpholine, thiomorpholine, piperidine, piperazine, pyrrolidine, hexamethyleneimine, heptamethyleneimine, hexahydropyrimidine, 1,4-diazepam as well as unsaturated cyclic amines corresponding to those rings (e.g., 1,2,5,6-tetrahydropyridine, etc.), etc. Of those, preferred are morpholine, piperidine, piperazine, pyrrolidine, etc.
The xe2x80x9csubstituentxe2x80x9d of the xe2x80x9cnitrogen-containing heterocyclic ring which may be substitutedxe2x80x9d formed by R1 and R2 taken together with the adjacent nitrogen atom include 1 to 3 substituents which are the same as the substituents of the above xe2x80x9c5- to 7-membered saturated cyclic aminoxe2x80x9d.
Preferred examples of R1 and R2 include [1] hydrogen atom or [2] C1-6 alkyl which may be substituted by carboxy, C1-6alkoxy-carbonyl or di-C1-6 alkylnitrile, or R1 and R2 form, together with the adjacent nitrogen atom, 5- or 6-membered nitrogen-containing heterocyclic ring (e.g., piperidino, pyrolidin-1-yl, etc.).
Further, preferably, one of R1 and R2 is C1-6 alkyl which may be substituted, more preferably, both R1 and R2 are C1-6 alkyl which may be substituted.
Ring A is, for example, a benzene ring, or a 5- or 6-membered aromatic heterocyclic ring, etc.
The xe2x80x9c5- or 6-membered aromatic heterocyclic ringxe2x80x9d includes, for example, 5- or 6-membered aromatic heterocyclic ring containing one or more (e.g., 1 to 3, preferably 1 or 2) hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Specific examples thereof inculde thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, etc.
Preferred examples of ring A include a benzene ring or a 6-membered nitrogen-containing aromatic heterocyclic ring, preferably a benzene ring, a pyridine ring or 2-pyridone ring, in particular, a benzene ring or a pyridine ring.
Ring A is substituted by a group represented by the formula: Arxe2x80x94Xxe2x80x94 at a substitutable position thereof. Ring A may be further substituted, in addition to the group represented by the formula: Arxe2x80x94Xxe2x80x94. Examples of such substituent include halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy, hydroxy, amino, etc. The xe2x80x9coptionally halogenated C1-6 alkylxe2x80x9d and the xe2x80x9cOptionally halogenated C1-6 alkoxyxe2x80x9d are the same as those mentioned in detail above for the xe2x80x9coptionally halogenated C1≢alkylxe2x80x9d and the xe2x80x9coptionally halogenated C1-6 alkoxyxe2x80x9d for Ar.
In particular, as the substituent of ring A, halogen atom (e.g., chloro, etc.), C1-6 alkoxy (e.g., methoxy, etc.) are preferred.
One to three such substituents may be substituted at the substitutable positions of ring A. When the number of the substituents is two or more, those substituents may be the same as or different from one another.
Ring A is preferable a benzene ring substituted by the group of the formula: Axe2x80x94Xxe2x80x94.
In compound (I), any combination of each above-mentioned symbol can be appropriately used. Among them, the following combination is preferred.
(1) compound (I) wherein Ar is biphenylyl (e.g., 2-, 3- and 4-biphenylyl optionally substituted with halogen atom (in particular, chloro), X is [1] a group represented by the formula: xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3, preferably p1 is 1), [2] xe2x80x94(CH2)p2xe2x80x94 (wherein p2 is an integer of 1 to 3), [3] xe2x80x94(CH2)p3OCONHxe2x80x94 (wherein p3 is an integer of 1 to 3, preferably p3 is 1) [4] CONH or [5] SO2NH, Y is a group represented by the formula: xe2x80x94(CH2)q1CONR9(CH2)r1xe2x80x94 (wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl which may be halogenated or C1-6 alkyl-carbonyl which may be halogenated), or a group represented by the formula: xe2x80x94(CH2)q2COO(CH2)r2xe2x80x94 (wherein each of q2 and r2 is an integer of 0 to 3 and their sum is not more than 3) (preferably, Y is C1-3 alkylene, a group represented by the formula: xe2x80x94CONH(CH2)sxe2x80x94 (s is an integer of 1 to 3) or a group represented by the formula: xe2x80x94COO(CH2)txe2x80x94 (t is an integer of 1 to 3). In particular, r1 and r2 are preferably an integer of 1 to 3.
(2) compound (I) wherein Ar is C6-14 aryl (in particular, phenyl, 1,2-naphthyl, etc.) or biphenylyl (e.g., 2-, 3- and 4-biphenylyl optionally substituted with halogen atom (in particular, chloro), X is [1] a group represented by the formula: xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3, preferably p1 is 1), [2] xe2x80x94(CH2)p2xe2x80x94 (wherein p2 is an integer of 1 to 3), [3] xe2x80x94(CH2)p3OCONHxe2x80x94 (wherein p3 is an integer of 1 to 3, preferably p3 is 1) [4] CONH or [5] SO2NH, Y is a group represented by the formula: xe2x80x94(CH2)q1CONR9(CH2)r1xe2x80x94 (wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl which may be halogenated or C1-6 alkyl-carbonyl which may be halogenated), or a group represented by the formula: xe2x80x94(CH2)q2COO(CH2)r2xe2x80x94 (wherein each of q2 and r2 is an integer of 0 to 3 and their sum is not more than 3) (preferably, Y is C1-3 alkylene, a group represented by the formula: xe2x80x94CONH(CH2)sxe2x80x94 (s is an integer of 1 to 3) or a group represented by the formula: xe2x80x94COO(CH2)txe2x80x94 (t is an integer of 1 to 3), each of R1 and R2 is [1] hydrogen atom or [2] C1-6 alkyl (in particular C1-3 alkyl such as methyl, ethyl, propyl, etc.) which may be substituted by carboxy, C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl) or di-C1-6 alkylnitrile (e.g., dimethylnitrile, diethylnitrile), or R1 and R2 form, together with the adjacent nitrogen atom, a 5- or 6-membered nitrogen-containing heterocyclic ring (e.g., piperidino, pyrolidin-1-yl, etc.), ring A is a benzene ring, or a 6-membered aromatic heterocyclic ring which may be substituted with halogen atom (e.g., chloro, etc.) and/or C1-6 alkoxy (in particular, methoxy). Among them, r1 and r2 are preferably an integer of 1 to 3.
(3) compound (I) wherein Ar is C6-14 aryl (in particular, phenyl, 1,2-naphthyl, etc.) or biphenylyl (e.g., 2-, 3- and 4-biphenylyl) optionally substituted with halogen atom (in particular chloro), etc., X is a group represented by the formula: xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3), xe2x80x94CONHxe2x80x94, xe2x80x94SO2NHxe2x80x94 or C1-3 alkylene, Y is C1-3 alkylene, a group represented by the formula: xe2x80x94CONH(CH2)sxe2x80x94 (s is an integer of 1 to 3) or a group represented by the formula: xe2x80x94COO(CH2)txe2x80x94 (t is an integer of 1 to 3), each of R1 and R2 is hydrogen atom or C1-6 alkyl (in particular, C1-3 alkyl such as methyl, ethyl, propyl, etc.) or R1 and R2 form, together with the adjacent nitrogen atom, a 5- or 6-membered nitrogen-containing heterocyclic ring (e.g., piperidino, pyrolidin-1-yl, etc.), ring A is a benzene ring or a 6-membered aromatic heterocyclic ring which may be substituted with halogen atom (e.g., chloro, etc.) and/or C1-6 alkoxy (in particular, methoxy). In particular, r1 and r2 are preferably an integer of 1 to 3.
Especially preferred compound (I) are
(1) 5-chloro-N-[2-N,N-diethylamino)ethyl]-2-methoxy-4-(1-naphthoylamino)benzamide,
(2) 5-chloro-N-[2-N,N-diethylamino)ethyl]-2-methoxy-4-(2-naphthoylamino)benzamide,
(3) 5-chloro-N-[2-N,N-diethylamino)ethyl]-2-methoxy-4-(1-naphthylsulfonylamino)benzamide,
(4) 5-chloro-N-[2-N,N-diethylamino)ethyl]-2-methoxy-4-(2-naphthylsulfonylamino)benzamide,
(5) N-[3-[4-(2-naphthylmethoxy)phenyl]propyl]-N,N-dipropyl-amine hydrochloride,
(6) N-[3-[4-[(2,4-dichlorobenzyl)oxy]phenyl]propyl]-N,N-di-propylamine hydrochloride,
(7) N-[4-(2-naphthylmethoxy)phenethyl]-N,N-dipropylamine hydrochloride,
(8) N-[4-(2,4-dichlorobenzyl)oxy]phenethyl]-N,N-dipropyl-amine hydrochloride,
(9) N-[4-(4-biphenylylmethoxy)phenethyl]-N,N-dipropylamine hydrochloride,
(10) N-[2-(2-naphthylmethoxy)phenethyl]-N,N-dipropylamine hydrochloride,
(11) N-[3-(2-naphthylmethoxy)phenethyl]-N,N-dipropylamine hydrochloride,
(12) N-[3-(4-biphenylylmethoxy)phenethyl]-N,N-dipropylamine hydrochloride,
(13) N-[3-[(2,4-dichlorobenzyl)oxy]phenethyl]-N,N-dipropylamine hydrochloride,
(14) N-[3-(1-naphthylmethoxy)phenethyl]-N,N-dipropylamine hydrochloride,
(15) 4-(4-biphenylylmethoxy)phenyl-N-(2-piperidinoethyl)acetamide,
(16) 4-(4-biphenylylmethoxy)phenyl-N-[2-(N,N-dimethylamino)ethyl]acetamide,
(17) 6-(4-biphenylylmethoxy)-N-[2-(pyrrolidine-1-yl)ethyl]nicotinamide,
(18) 1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-N-[2-(pyrrolidine-1-yl)ethyl]-3-pyridinecarboxamide,
(19) 1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-N-(2-(piperidinoethyl)-3-pyridinecarboxamide,
(20) 6-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)-nicotinamide,
(21) 6-(4-biphenylylmethoxy)-N-[2-(N,N-dimethylamino)ethyl]nicotinamide,
(22) 4-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)benzamide,
(23) 4-(4-biphenylylmethoxy)-N-[(2-pyrrolidine-1-yl)ethyl]benzamide,
(24) 2-piperidinoethyl=4-(4-biphenylylethoxy)benzoate,
(25) 2-(pyrrolidin-1-yl)ethyl=4-(4-biphenylylmethoxy)benzoate,
(26) 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)ethyl]acetamide oxalate,
(27) 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)ethyl]acetamide maleate,
(28) 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)ethyl]acetamide fumarate,
(29) 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N-methylamino)-ethyl]acetamide hydrochloride,
(30) 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N-methylamino)-ethyl]acetamide,
(31) ethyl 7-[2-[4-[(4-biphenylylmethoxy)phenyl]acetylaminoethyl](methyl)amino]heptanoate,
(32) 7-[2-[4-[4-(biphenylylmethoxy)phenyl]acetylaminoethyl](methyl)amino]heptanoic acid hydrochloride,
(33) N-(4-(2-((2-(dimethylamino)ethyl)(methyl)amino)-2-oxoethyl)phenyl)[1,1xe2x80x2-biphenyl]-4-carboxamido,
(34) N-(2-aminoethyl)-2-(4-([1,1xe2x80x2-biphenyl]-4-ylmethoxy)phenyl)acetamide hydrochloride,
(35) 4-([1,1xe2x80x2-biphenyl]-4-ylmethoxy)-N-(2-(1-pyrrolidinyl)ethyl)benzamide,
(36) N-[4-({[2-(diethylamino)ethyl]amino}carbonyl)phenyl]-(4-biphenylyl)carboxamide,
(37) 4-(4-biphenylyl)methoxy)-N-[2-(isopropylamino)ethyl]benzamide,
(38)2-(N,N-diethylamino)ethyl-4-[(4-biphenylyl)carbonyl]-amino]benzoate,
(39) N-[4-({[2-(dimethylamino)ethyl]amino}carbonyl)phenyl]-(4-biphenylyl)carboxamide,
(40) N-[4-{[2-(piperidinoethyl)amino]carbonyl}phenyl](4-biphenylyl)carboxamide, or
(41) N-[4-({[2-(pyrrolidinyl)ethyl]amino}carbonyl)phenyl]-(4-biphenylyl)carboxamide, etc.
Among them, preferred compounds are
[1] 5-chloro-N-[2-N,N-diethylamino)ethyl]-2-methoxy-4-(1-naphthoylamino)benzamide,
[2] 5-chloro-N-[2-N,N-diethylamino)ethyl]-2-methoxy-4-(2-naphthoylamino)benzamide,
[3] 5-chloro-N-[2-N,N-diethylamino)ethyl]-2-methoxy-4-(1-naphthylsulfonylamino)benzamide,
[4] 5-chloro-N-[2-N,N-diethylamino)ethyl]-2-methoxy-4-(2-naphthylsulfonylamino)benzamide,
[5] 6-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)nicotinamide,
[6] 6-(4-biphenylylmethoxy)-N-[2-(N,N-dimethylamino)ethyl]nicotinamide,
[7] 4-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)benzamide,
[8] 4-(4-biphenylylmethoxy)-N-[(2-pyrrolidine-1-yl)ethyl]benzamide, etc.
In the above-mentioned compound (I), the compound represented by the formula (Ia) is a novel compound.
In the formula, examples of the aromatic ring assembly group which may be substituted represented by Arxe2x80x2 include the same aromatic ring assembly which may be substituted as defined with respect to the above Arxe2x80x2, in particular, biphenylyl (e.g., 2-, 3- or 4-biphenylyl, etc.).
Examples of Xxe2x80x2 include [1] a group represented by the formula: xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3), [2] xe2x80x94(CH2)p2xe2x80x94 (wherein p2 is an integer of 1 to 3) or [3] CONH, etc. in particular, xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is as defined above), etc. Preferably, p1 is 1 or 2, in particular, 1 is preferred. Preferably, p2 is 1 or 2, in particular, 1 is preferred.
Examples of Yxe2x80x2 include [1] a group represented by the formula: xe2x80x94(CH2)q1CONR9(CH2)r1xe2x80x94 (wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl which may be halogenated or C1-6 alkyl-carbonyl which may be halogenated), or [2] a group represented by the formula: xe2x80x94(CH2)q2COO(CH2)r2xe2x80x94 (wherein each of q2 and r2 is an integer of 0 to 3 and their sum is not more than 3), etc., in particular, a group represented by the formula: xe2x80x94(CH2)q1CONR9(CH2)r1xe2x80x94 (wherein each symbol is as defined above), etc.
Preferably, q1 and q2 are 0 or 1, in particular, 0 is preferred.
Preferably, r1 and r2 are an integer of 1 to 3, more preferably, 1 or 2. In particular, 1 is preferred.
The C1-6 alkyl represented by R1 and R2 includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. In particular, methyl, ethyl, propyl, etc. are preferred.
Preferred example of R9 include hydrogen atom, C1-3 alkyl which may be halogenated (in particular, methyl, ethyl, etc.) or C1-3 alkyl-carbonyl (in particular, acetyl, etc.). Hydrogen atom is particularly preferred.
Preferred examples of R1 and R2 include [1] hydrogen atom or [2] C1-6 alkyl (in particular, C1-3 alkyl such as methyl, ethyl, propyl, etc.) which may be substituted by carboxy, C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl) or di-C1-6 alkylnitrile (e.g., dimethynitrile, diethylnitrile), or R1 and R2 form, together with the adjacent nitrogen atom, a 5- or 6-membered nitrogen-containing heterocyclic ring.
Preferred examples of ring A include a benzene ring or a 6-membered nitrogen-containing aromatic heterocyclic ring, preferably a benzene ring, a pyridine ring or 2-pyridone ring, in particular, a benzene ring or a pyridine ring.
Preferred examples of compound (Ia) include that wherein Arxe2x80x2 is biphenylyl (e.g., 2-, 3- and 4-biphenylyl), Xxe2x80x2 is [1] a group represented by the formula: xe2x80x94(CH2)p1Oxe2x80x94 (wherein p1 is an integer of 1 to 3), [2] xe2x80x94(CH2)p2xe2x80x94 (wherein p2 is an integer of 1 to 3) or [3] CONH, Yxe2x80x2 is [1] a group represented by the formula: xe2x80x94(CH2)q1CONR9(CH2)r1xe2x80x94 (wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl (in particular, C1-3 alkyl) which may be halogenated or C1-6 alkyl-carbonyl (in particular, C1-3 alkyl-carbonyl such as acetyl, ethylcarbonyl, etc.) which may be halogenated), or a group represented by the formula: xe2x80x94(CH2)q2COO(CH2)r2xe2x80x94 (wherein each of q2 and r2 is an integer of 0 to 3 and their sum is not more than 3), each of R1 and R2 is [1] hydrogen atom or [2] C1-6 alkyl (in particular C1-3 alkyl such as methyl, ethyl, propyl, etc.) which may be substituted by carboxy, C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl) or di-C1-6 alkylnitrile (e.g., dimethylnitrile, diethylnitrile), or R1 and R2 form, together with the adjacent nitrogen atom, a 5- or 6-membered nitrogen-containing heterocyclic ring (e.g., piperidino, pyrrolidin-1-yl, etc.), ring A is a benzene ring or a 6-membered aromatic heterocyclic ring (in particular, a pyridine ring, 2-pyridone ring).
Further, preferred examples of compound (Ia) include that wherein Ar is biphenylyl, X is xe2x80x94(CH2)pO, Y is xe2x80x94CONH(CH2)sxe2x80x94 (s is an integer of 1 to 3), each of R1 and R2 is C1-3 alkyl (in particular, methyl, ethyl, propyl, etc.), or R1 and R2 form, together with the adjacent nitrogen atom, a 5- or 6-membered nitrogen-containing heterocyclic ring (e.g., piperidino, pyrrolidin-1-yl, etc.), ring A is a benzene ring or a 6-membered aromatic heterocyclic ring (in particular, a pyridine ring, 2-pyridone ring, etc.) which may be substituted with halogen atom (e.g., chloro, etc.) and/or C1-6 alkoxy (in particular, methoxy).
More specifically, preferred examples of compound (Ia) include, in particular,
(1) 4-(4-biphenylylmethoxy)phenyl-N-(2-piperidinoethyl)acetamide,
(2) 4-(4-biphenylylmethoxy)phenyl-N-[2-(N,N-dimethylamino)ethyl]acetamide,
(3) 6-(4-biphenylylmethoxy)-N-[2-(pyrrolidine-1-yl)ethyl]-nicotinamide,
(4) 1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-N-[2-(pyrrolidine-1-yl)ethyl]-3-pyridinecarboxamide,
(5) 1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-N-(2-(piperidinoethyl)-3-pyridinecarboxamide,
(6) 6-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)nicotinamide,
(7) 6-(4-biphenylylmethoxy)-N-[2-(N,N-dimethylamino)ethyl]nicotinamide,
(8) 4-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)benzamide,
(9) 4-(4-biphenylylmethoxy)-N-[(2-pyrrolidine-1-yl)ethyl]benzamide,
(10) 2-piperidinoethyl=4-(4-biphenylylethoxy)benzoate
(11) 2-(pyrrolidin-1-yl)ethyl=4-(4-biphenylylmethoxy)benzoate
(12) 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)ethyl]acetamide oxalate,
(13) 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)ethyl]acetamide maleate,
(14) 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)ethyl]acetamide fumarate,
(15) 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N-methylamino)ethyl]acetamide hydrochloride,
(16) 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N-methylamino)ethyl]acetamide
(17) ethyl 7-[2-[4-[(4-biphenylylmethoxy)phenyl]acetylaminoethyl](methyl)amino]heptanoate,
(18) 7-[2-[4-[4-(biphenylylmethoxy)phenyl]acetylaminoethyl](methyl)amino]heptanoic acid hydrochloride,
(19) N-(4-(2-((2-(dimethylamino)ethyl)(methyl)amino)-2-oxoethyl)phenyl)[1,1xe2x80x2-biphenyl]-4-carboxamide,
(20) N-(2-aminoethyl)-2-(4-([1,1xe2x80x2-biphenyl]-4-ylmethoxy)phenyl)acetamide hydrochloride,
(21) 4-([1,1xe2x80x2-biphenyl]-4-ylmethoxy)-N-(2-(1-pyrrolidinyl)ethyl)benzamide
(22) N-[4-({[2-(diethylamino)ethyl]amino}carbonyl)phenyl]-(4-biphenylyl)carboxamide,
(23) 4-(4-biphenylyl)methoxy)-N-[2-(isopropylamino)ethyl]benzamide
(24)2-(N,N-diethylamino)ethyl-4-[(4-biphenylyl)carbonyl]amino]benzoate
(25) N-[4-({[2-(dimethylamino)ethyl]amino}carbonyl)phenyl]-(4-biphenylyl)carboxamide,
(26) N-[4-{[2-(piperidinoethyl)amino]carbonyl}phenyl](4-biphenylyl)carboxamide,
(27) N-[4-({[2-(pyrrplidinyl)ethyl]amino}carbonyl)phenyl]-(4-biphenylyl)carboxamide, etc.
Among them, preferred compounds are
[1] 6-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)nicotinamide,
[2] 6-(4-biphenylylmethoxy)-N-[2-(N,N-dimethylamino)ethyl]nicotinamide,
[3] 4-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)benzamide,
[4] 4-(4-biphenylylmethoxy)-N-[(2-pyrrolidine-1-yl)ethyl]benzamide, etc.
As the salts of compound (I) and compound (Ia), for example, inorganic salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic or acidic amino acids can be mentioned.
Preferable examples of inorganic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salts, magnesium salts and barium salts; aluminum salts, etc. Preferred salts with organic bases are exemplified by salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine, etc. Preferred salts with inorganic acids are exemplified by salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Preferred salts with organic acids are exemplified by salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Preferred salts with basic amino acids are exemplified by salts with arginine, lysine, ornithine, etc. Preferred salts with acidic amino acids are exemplified by salts with aspiartic acid, glutamic acid, etc.
Among others, pharmaceutically acceptable salts are preferable. Preferable examples include, for example, when compound (I) or (Ia) has an acidic functional group, alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.), and ammonium salts; and when compound (I) or (Ia) has a basic functional group, inorganic salts such as hydrochloride, sulfate, phosphate and hydrobromide, or, organic salts such as acetate, maleate, fumarate, succinate, methanesulfonate, p-toluenesulfonate, citrate and tartrate.
A prodrug of compound (I), compound (Ia) or its salt (hereinafter referred to as the compound of the present invention) may be a compound that is converted into the compound of the present invention by a reaction with an enzyme, gastric acid, or the like under physiological conditions in the living body, namely, a compound that is converted into the compound of the present invention by an enzymatic oxidation, reduction, hydrolysis, or the like, and a compound that is converted into the compound of the present invention by hydrolysis with gastric acid or the like.
Examples of a prodrug of the compound of the present invention include a compound wherein an amino group in the compound of the present invention is acylated, alkylated, phosphorylated, (e.g., a compound wherein an amino group in the compound of the present invention is converted into eicosanoylamino, alanylamino, pentylaminocarbonylamino, (5-methyl-2-oxo-1,3-dioxorene-4-yl)methoxycarbonylamino, tetrahydrofuranylamino, pyrrolidylmethylamino, pivaloyloxymethylamino, tert-butylamino, etc.); a compound wherein an hydroxy group in the compound of the present invention is acylated, alkylated, phosphorylated, or converted into borate (e.g., a compound wherein hydroxy group in the compound of the present invention is converted into acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, or dimethylaminomethylcarbonyloxy, etc.); a compound wherein carboxy group of the compound of the present invention is ethyl esterification, phenyl esterification, carboxyoxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxoren-4-yl)methyl esterification, cyclohexyloxycarbonyl esterification, or conversion into methyl amide), etc. These compounds can be produced from the compound of the present invention according to any per se known method.
Further, a prodrug of the compound of the present invention may be a compound that is converted into the compound of the present invention under physiological conditions as described in xe2x80x9cDevelopment of Drugsxe2x80x9d, Volume 7, Molecular Design, Hirokawa Shoten, 1990; pages 163-198.
Further, compound (I) or (Ia) may be either anhydride or hydrate and, in case of a hydrate, it may have 1 to 3 H2O molecules.
Process for producing compound (Ia) will be explained below.
The compound (Ia) can be produced by using any per se known means. For example, the compound (Ia) wherein X contains oxygen atom, optionally oxidized sulfur atom or optionally substituted imino can be produced by the following process. Normally, xe2x80x9croom temperaturexe2x80x9d is 0 to 30xc2x0 C.
Each symbol disclosed in the following schemes is as defined above unless otherwise stated.
[Process 1]
wherein Xa is oxygen atom, optionally oxidized sulfur atom or optionally substituted imino. The xe2x80x9coptionally substituted iminoxe2x80x9d represented by Xa is the same group as xe2x80x9coptionally substituted iminoxe2x80x9d of the above R8.
(Step 1)
The Compound (II) is subjected to alkylation or acylation to obtain the compound (Ia).
The xe2x80x9calkylationxe2x80x9d and xe2x80x9cacylationxe2x80x9d may be effected in any per se known manner, for example, according to the methods described in Organic Functional Group Preparations, 2nd Ed., Academic Press Inc., 1989.
Specifically, the compound (II) is reacted with a compound of the formula: Arxe2x80x2-Xb-L (III): wherein Xb represents a group formed by removing Xa from Xxe2x80x2, and L represents a leaving group or a hydroxy, to obtain the compound (Ia)
The leaving group for L includes, for example, halogen atoms (e.g., chloro, bromo, iodo, etc.), optionally halogenated C1-6 alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), C6-10 arylsulfonyloxy which may be substituted, etc.
The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9cC6-10 arylsulfonyloxy which may be substitutedxe2x80x9d includes, for example, 1 to 3 substituents selected from the group consisting of halogen atoms, optionally halogenated C1-6 alkyl and optionally halogenated C1-6 alkoxy. Specific examples of the xe2x80x9cC6-10 arylsulfonyloxy which may be substitutedxe2x80x9d are benzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy, 2-naphthalenesulfonyloxy, etc.
In the case that L is a leaving group, for example, the compound (II) is reacted with an equivalent amount or an excessive amount of the compound (III) in an inert solvent. If desired, a base is added to the reaction system. Where Xa is optionally substituted imino, the addition of the base is not always indispensable.
The reaction temperature falls between xe2x88x9220xc2x0 C. and 100xc2x0 C., preferably between room temperature and 80xc2x0 C. The reaction time falls between 0.5 hours and 1 day.
The inert solvent includes, for example, alcohols, ethers, halogenated hydrocarbons, aromatic solvents, nitrites, amides, ketones, sulfoxides, water, etc., which may be used either singly or as a suitable mixture of two or more species. Of those, preferred are acetonitrile, N,N-dimethylformamide (DMF), acetone, ethanol, pyridine, etc.
The xe2x80x9cbasexe2x80x9d includes, for example;
(1) strong bases such as alkali metal or alkaline earth metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal or alkaline earth metal amides (e.g., lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide, etc.), alkali metal or alkaline earth metal lower-alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc.;
(2) inorganic bases such as alkali metal or alkaline earth metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonates (e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal hydrogencarbonates (e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), etc.; or
(3) organic bases such as amines e.g., triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo[5.4.0]-7-undecene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), etc., basic heterocyclic compounds, e.g., pyridine, imidazole, 2,6-lutidine, etc.
Preferably, the alkylation is effected by stirring the compound (II) with 1 to 2 equivalents of the compound (III) and 1 to 5 equivalents of a base (e.g., potassium carbonate, sodium hydride, sodium hydroxide, etc.), in acetonitrile or DMF, for 1 hour to 2 days. The preferred reaction temperature varies, depending on the base used. For example, when sodium hydride is used, the reaction temperature is preferably room temperature; and when potassium carbonate is used, the preferred reaction temperature falls between room temperature and 80xc2x0 C.
The acylation is preferably effected by stirring the compound (II) with 1 to 1.5 equivalents of the compound (III) and 1 to 5 equivalents of a base (e.g., sodium hydride, sodium hydroxide, potassium carbonate, sodium hydrogencarbonate, triethylamine, etc.), in an inert solvent (e.g., single or mixed solvent of water, ethyl acetate, DMF, acetonitrile and/or pyridine), at room temperature for 1 to 6 hours.
In the case that L is a hydroxy group, the compound (II) is subjected to Mitsunobu reaction.
The Mitsunobu reaction may be attained, for example, by stirring the compound (II) with 1 to 3 equivalents, preferably from 1.1 to 2 equivalents of the compound (III) in the presence of 1 to 2 equivalents of a triarylphosphine (e.g., triphenylphosphine, etc.) and 1 to 2 equivalents of DEAE (diethyl azodicarboxylate) in an inert solvent, for 1 to 24 hours.
The inert solvent includes, for example, ethers, etc. Preferred is tetrahydrofuran (THF).
The compound wherein Yxe2x80x2 is xe2x80x94(CH2)qCONR9(CH2)rxe2x80x94 can be produced by reacting a carboxylic acid derivative (IV) with an amine (V) according to the amidation according to the following process 2.
[Process 2]
wherein each symbol is as defined above.
(Step 2)
The xe2x80x9camidationxe2x80x9d may be effected in any per se known methods, for example, (1) by reacting the compound (IV) with amine (V) in the presence of a dehydrating condensing agent, or (2) by reacting a reactive derivative of compound (IV) with amine (V).
In the above reaction (1), the compound (IV) is reacted with 1 to 5 equivalents of amine (v) in the presence of 1 to 2 equivalents of a dehydrating condensing agent, in an inert solvent, at room temperature, for 10 to 24 hours. If desired, 1 to 1.5 equivalents of 1-hydroxybenzotriazole (HOBT) and/or 1 to 5 equivalents of a base (e.g., triethylamine, etc.) may be added to the reaction system.
The xe2x80x9cdehydrating condensing agentxe2x80x9d includes, for example, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSC), etc. Of those, preferred is WSC.
The inert solvent includes, for example, nitrites (preferably, acetonitrile), amides (preferably, DMF), halogenated hydrocarbons (preferably, dichloromethane), ethers (preferably, THF), etc., which may be used either singly or as a suitable mixture of two or more species.
In the above reaction (2), a reactive derivative of the compound (IV) is reacted with 1 to 5 equivalents, preferably 1 to 3 equivalents of amine (V) in an inert solvent at, normally, xe2x88x9220 to 50xc2x0 C., preferably at room temperature, for 5 minutes to 40 hours, preferably 1 to 18 hours. If desired, 1 to 10 equivalents, preferably 1 to 3 equivalents of a base may be in the reaction system.
The xe2x80x9creactive derivativexe2x80x9d of the compound (IV) includes, for example, its acid halides (e.g., acid chlorides, acid bromides, etc.), mixed acid anhydrides (e.g., acid anhydrides with C1-6 alkyl-carboxylic acids, C6-10 aryl-carboxylic acids or C1-6 alkyl-carbonic acids, etc.), and active esters (e.g., esters with C1-6 alcohols [e.g., methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, etc.], phenol which may be substituted, 1-hydroxybenzotriazole or N-hydroxysuccinimide, etc.).
The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9cphenol which may be substitutedxe2x80x9d includes, for example, 1 to 5 substituents selected from the group consisting of halogen atoms, nitro, optionally halogenated C1-6 alkyl and optionally halogenated C1-6 alkoxy. Specific examples of the xe2x80x9cphenol which may be substitutedxe2x80x9d are phenol, pentachlorophenol, pentafluorophenol, p-nitrophenyl, etc. The reactive derivatives are preferably acid halides.
The xe2x80x9cbasexe2x80x9d is the same as those mentioned in detail hereinabove for the step 1. Preferred are potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium butoxide, etc.), organic amines (e.g., triethylamine, pyridine, triazole, imidazole, hydroxy pyridine, etc.). The inert solvent includes, for example, alcohols, ethers, halogenated hydrocarbons, aromatic solvents, nitrites, amides, ketones, sulfoxides, water, etc., which may be used either singly or as a suitable mixture of two or more species. Of those, preferred are methanol, ethanol, acetonitrile, dichloromethane, chloroform, etc.
In the case of an active ester, for example, the ester (preferably, methyl ester or ethyl ester) is reacted with 1 to 5 equivalents of amine (V) together with catalytic amount to 2 equivalents of an organic amine (e.g., triethylamine, pyridine, triazole, imidazole, hydroxy pyridine, etc.) in an inert solvent.
The reaction temperature falls between room temperature and under refluxing (preferably 50 to 120xc2x0 C.). The preferred reaction time falls between 1 and 60 hours. As the inert solvent, alcohols (e.g., methanol, ethanol, etc.) can be used.
Carboxylic acid (IV) and amine (V) used in the reaction are commercially available or can be easily available. For example, the benoziic acid derivative can be produced by the process described in WO93/24442, etc.
Compound (Ixe2x80x2) thus obtained can be converted into the compound (I) by any per se known reaction such as hydrolysis, esterification, amidation, oxidation, reduction and the following deprotection reaction, or combination thereof.
The above xe2x80x9calcoholsxe2x80x9d includes, for example, methanol, ethanol, isopropanol, tert-butanol, etc. The above xe2x80x9cethersxe2x80x9d includes, for example, ethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, etc. The above xe2x80x9chalogenated hydrocarbonsxe2x80x9d includes, for example, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc. The above xe2x80x9caromatic solventsxe2x80x9d includes, for example, benzene, toluene, xylene, pyridine, etc. The above xe2x80x9chydrocarbonsxe2x80x9d includes, for example, hexane, pentane, cyclohexane, etc. The above xe2x80x9camidesxe2x80x9d includes, for example, N,Nxe2x80x2-dimethylformamide (DMF), N,Nxe2x80x2-dimethylacetamide, N-methylpyrrolidone, etc. The above xe2x80x9cketonesxe2x80x9d includes, for example, acetone, methyl ethyl ketone, etc. The above xe2x80x9csulfoxidesxe2x80x9d includes, for example, dimethylsulfoxide (DMSO), etc. The above xe2x80x9cnitritesxe2x80x9d includes, for example, acetonitrile, propionitrile, etc.
In the above-mentioned reactions where the starting compounds have any of amino, carboxy, hydroxy or carbonyl as their substituents, those groups may be protected by ordinary protective groups which are generally used in peptide chemistry. The protective groups may be removed after the reaction to give the objective products.
The amino-protecting group includes, for example, formyl, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), C1-6 alkyloxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), benzoyl, C7-10 aralkyl-carbonyl (e.g., benzylcarbonyl, etc.), C7-14 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, etc.), trityl, phthaloyl, N,N-dimethylaminomethylene, silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, dimethyl-t-butylsilyl, diethyl-t-butylsilyl, etc.), C2-6 alkenyl (e.g., 1-allyl, etc.), etc. These groups may be substituted by 1 to 3 substituents of halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, etc.) or nitro, etc.
The carboxy-protecting group includes, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), C7-11 aralkyl (e.g., benzyl, etc.), phenyl, trityl, silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, dimethyl-t-butylsilyl, diethyl-t-butylsilyl, etc.), C2-6 alkenyl (e.g., 1-allyl, etc.), etc. These groups may be substituted by 1 to 3 substituents of halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, etc.) or nitro, etc.
The hydroxy-protecting group includes, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, C7-10 aralkyl (e.g., benzyl, etc.), formyl, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), benzoyl, C7-10 aralkyl-carbonyl (e.g., benzylcarbonyl, etc.), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, dimethyl-t-butylsilyl, diethyl-t-butylsilyl, etc.), C2-6 alkenyl (e.g., 1-allyl, etc.), etc. These groups may be substituted by 1 to 3 substituents of halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-6 alkyl (e.g., methyl, ethyl, propyl, etc.), C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, etc.) or nitro, etc.
The carbonyl-protecting group includes, for example, cyclic acetals (e.g., 1,3-dioxorane, etc.), acyclic acetals (e.g., di-C1-6 alkylacetals, etc.), etc.
Those protective groups may be removed by any per se known methods, for example, the methods described in Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1980, etc. For example, the method of removing these protective groups, includes the methods using acids, bases, ultraviolet ray, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.; and reduction, etc.
Compound (Ia) can be isolated and purified by any known procedures, for example, through solvent extraction, pH adjustment, redistribution, crystallization, recrystallization, chromatography, etc. The starting compounds and their salts for the compound (Ia) can also be isolated and purified according to the same known procedures as above, but without any isolation procedure, they may be used in the next step while they are in reaction mixtures.
Where the compound (Ia) includes optical isomers, stereoisomers, regio isomers and rotational isomers, those are within the scope of the compound (Ia), and can be isolated as their single compound through per se known synthesis or separation. For example, where optical isomers of the compound (Ia) exist, those resolved from their mixtures through optical resolution are within the scope of the compound (Ia).
The optical isomers can be produced in any per se known manner. Specifically, optically active synthetic intermediates or mixtures of racemate of the final product are subjected to ordinary optical resolution to give the corresponding optical isomers.
For the optical resolution, employable are any per se known methods, such as a fractional recrystallization method, a chiral column method, a diastereomer method, etc.
1) Fractional Recrystallization
The method which comprises allowing a tracemate to react with an optically active compound (e.g., (+)-mandelic acid, (xe2x88x92)-mandelic acid, (+)-tartaric acid, (xe2x88x92)-tartaric acid, (+)-1-phenethylamine, (xe2x88x92)-1-phenethylamine, cinchonine, (xe2x88x92)-cinchonidine, brucine, etc.) to, give a salt, which is then isolated through fractional recrystallization, followed by, when desired, subjecting the isolated compound to neutralization to obtain free optical isomers.
2) Chiral Column Method
The method of separating a racemate or a salt thereof, which comprises utilizing a column for fractionating optical isomers (chiral column). In the case of liquid column chromatography, for example, a mixture of optical isomers is applied to a chiral column, such as ENANTIO-OVM (manufactured by Tosoh Corp.), CHIRAL SERIES (manufactured by Daicel Co.), etc., which is then eluted with water, various buffers (e.g., phosphate buffer) and organic solvents (e.g., ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.), singly or a suitable mixture of them, to isolate the individual optical isomers. In case of gas chromatography, for example, a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Science Co.), etc. is used for the fractionation.
3) Diastereomer Method
A racemic mixture is chemically reacted with an optically-active reagent to give a mixture of diastereomer, which is subjected to ordinary separation (e.g., fractional recrystallization, chromatography, etc.) to give single compounds. The thus-isolated single compounds are then chemically processed, for example, through hydrolysis to thereby remove the optically-active reagent site from the compounds to obtain optical isomers. For example, where the compound (I) has a hydroxy group or a primary or secondary amino group in the molecule, it is fused with an optically-active organic acid (e.g., MPTA [xcex1-methoxy-xcex1-(trifluoromethyl)phenyl-acetic acid], (xe2x88x92)-menthoxyacetic acid, etc.) or the like to give the corresponding ester-type or amide-type diastereomer. On the other hand, where the compound (I) has a carboxylic acid group, it is fused with an optically-active amine or alcohol reagent to give the corresponding amide-type or ester-type diastereomer. The thus-isolated diastereomer is then subjected to acidic or basic hydrolysis, through which it is converted into the optical isomer of the original compound.
Compound (I) or a salt thereof can be produced according to the above process for producing the compound (Ia) or a salt thereof, or can be producing by any per se known method or its modification.
Compound (I) has an excellent inhibitory activity of amyloid-xcex2 protein (Axcex21-40, Axcex21-41, Axcex2-42 and/or Axcex21-43, in particular Axcex21-40 and/or Axcex21-42) the production and/or secretion and thus is effective in preventing and/or treating diseases caused by amyloid-xcex2 protein. Compound (Ia) also has the inhibitory activity for the amyloid-xcex2 protein production and/or secretion.
In addition, the compound (I) has low toxicity. In particular, the compound obtained in Example 8 hereinafter shows excellent penetration in brain.
Therefore, compounds (I) are useful as safe medicines for preventing and/or treating diseases caused by amyloid-xcex2 protein, in particular, the production and/or secretion of amyloid-xcex2 protein in mammals (e.g., rat, mouse, guinea pig, rabbit, sheep, horse, pig, cattle, monkey, human being, etc.).
Examples of the diseases include senile dementia, Alzheimer""s disease, Down""s syndrome, Parkinson""s disease, disease, amyloid angiopathy and disorders caused by amyloid-xcex2 protein in cerebrovascular disorders. Among others, the compound (I) is suitable for Alzheimer""s disease.
Compound (I) can be formulated into pharmaceutical compositions by any per se known means. Directly or after mixing with suitable amounts of any desired, pharmaceutically-acceptable carriers in any per se known formulation processes, the compound (I) can be safely administered in the form of tablets (including sugar-coated tablets, film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained release preparations, etc., either orally or non-orally (for example, topically, rectally, intravenously, etc.).
In the pharmaceutical composition of the present invention, the amount of the compound (I) is about 0.1 to 100% by weight of the total weight of the composition. The dose of the composition varies depending on the subject to which the composition is administered, the administration route employed, the disorder of the subject, etc. For example, for the peroral composition for treating Alzheimer""s disease, its dose may be about 0.1 to 500 mg/adult (weighing about 60 kg) or so, preferably about 1 to 100 mg/adult or so, more preferably 5 to 100 mg/adult or so, in terms of the active ingredient [compound (I)], and this may be administered once or several times a day.
Any ordinary organic and inorganic carrier substances that are generally used in formulating medicines are usable as the carriers for formulating the pharmaceutical compositions of the present invention. For example, employable are ordinary excipients, lubricants, binders, disintegrators, etc. for formulating solid preparations; and solvents, solubilizers, suspending agents, isotonizing agents, buffers, soothing agents, etc. for formulating liquid preparations. If desired, further employable are other additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents, etc.
The excipients include, for example, lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose, light silicic anhydride, etc.
The lubricants include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc.
The binders include, for example, crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose, carboxymethyl cellulose sodium, etc.
The disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, etc.
The solvents include, for example, water for injections, alcohol, propylene glycol, macrogol, sesame oil, corn oil, etc.
The solubilizers include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.
The suspending agents include, for example, surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.
The isotonizing agents include, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.
The buffers include, for example, liquid buffers of phosphates, acetates, carbonates, citrates, etc.
The soothing agents include, for example, benzyl alcohol, etc.
The preservatives include, for example, parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
The antioxidants include, for example, sulfites, ascorbic acid, etc.
The present invention is further illustrated in detail by the following Reference Examples, Examples and Experimental Examples, but they are merely examples, which are not intended to limit the present invention and may be varied without departing from the scope of the present invention.
xe2x80x9cRoom temperaturexe2x80x9d in the following Reference Examples and Examples usually indicates about 0 to about 30xc2x0 C. For drying an organic solvent, magnesium sulfate anhydride or sodium sulfate anhydride was used. Unless otherwise stated, % indicates the percent by weight.
IR spectra were measured by diffused reflection method with Fourier-transform IR spectrophotometer.
Other symbols used in the present text indicate the following meanings.
s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
br: broad
dd: doublet of doublets
J: coupling constant
Hz: Hertz
CDCl3: deuterated chloroform
1H-NMR: proton nuclear magnetic resonance
IR: infrared spectrum
DMSO-d6: deuterated dimethyl sulfoxide
WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
HOBt: 1-hydroxy-1H-benztriazole
IPE: diisopropyl ether
DMAP: 4-dimethylaminopyridine
WSCD: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

To a solution of ethyl 4-hydroxyphenylacetic acid (3.6 g) in DMF (50 ml) were added potassium carbonate (2.5 g) and 4-phenylbenzyl chloride (4 g) sequentially. After stirring at 60xc2x0 C. for 6 hr, the reaction mixture was poured onto water and the resulting crystals were suspended in ethyl acetate. The suspension was washed with water and concentrated. The resulting crude crystals were dissolved in THF (100 ml)/ethanol (50 ml) and 2 N sodium hydroxide (20 ml) was added to the solution. The reaction mixture was heated under stirring at 60xc2x0 C. for 18 hr and concentrated. The residue was acidified with 2 N hydrochloric acid and the resulting crystals were collected by filtration and washed with ethyl ether to obtain the titled compound (5.3 g).
m.p.: 170-171xc2x0 C.
To methanol (100 ml) in an ice bath was added thionyl chloride (16 ml) followed by addition of 6-hydroxynicotinic acid (10 g).
The reaction mixture was warmed to room temperature and stirring was continued for sixty hr. After concentration, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with the combined mixture of THF and ethyl acetate.
The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was recrystallized from THF/diisopropyl ether to obtain the titled compound (3.4 g).
m.p.:164-166xc2x0 C.

A mixture of methyl 6-hydroxynicotinate (3 g), 4-biphenylylmethyl bromide (5.8 g), potassium carbonate (8.2 g), and DMF (30 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially and concentrated. The resulting crystals were washed with diisopropylether and recrystallized from ethyl acetate/hexane to obtain the titled compound (5.1 g).
m.p.:130-133xc2x0 C.

To a solution of methyl 1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylate (4.5 g) in methanol (50 ml)/THF (50 ml) was added dropwise 1N aqueous sodium hydroxide (28 ml) at room temperature. The reaction mixture was stirred at room temperature for 3 hr and concentrated. The residue was diluted with 1 N hydrochloric acid (30 ml) and extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. Diisopropylether was added to the residue and the resulting crystals were collected by filtration to obtain the titled compound (4.2 g).
m.p.: 245-250xc2x0 C.

The mixture of methyl 6-hydroxynicotinate (6 g), 4-biphenylylmethyl bromide (7.7 g), silver carbonate (4.8 g), and toluene (60 ml) was stirred at 50xc2x0 C. for 12 hr. The reaction mixture was further stirred at 100xc2x0 C. for 6 hr and filtrated.
The filtrate was concentrated. The residue was purified by alumina column chromatography (eluent; ethyl acetate) and recrystallized from ethyl acetate/hexane to obtain the titled compound (2.5 g).
m.p.:121-123xc2x0 C.

To a solution of methyl 6-(4-biphenylylmethoxy)nicotinate (2.0 g) in methanol (20 ml)/THF(40 ml) was added iN aqueous sodium hydroxide (13 ml) at room temperature. After stirring at room temperature for 4 hr the reaction mixture was diluted with 1 N hydrochloric acid (13 ml) and concentrated. The precipitate was collected by filtration and washed with water and diethyl ether sequentially to obtain the titled compound (1.6 g) as amorphous powder.
1H-NMR (DMSO-d6) xcex4: 5.48 (2H, s), 6.96 (1H, d), 7.30-7.74 (9H, m), 8.18 (1H, dd), 8.74 (1H, d).

To a solution of metoclopramide (free form, 500 mg) in pyridine (50 ml) was added 1-naphtharenecarbonyl chloride (350 mg). The reaction mixture was heated under reflux for 2 hr and cooled to room temperature. The reaction mixture was concentrated, diluted with 1 N hydrochloriclacid (100 ml), and washed with ethyl acetate. The aqueous layer was basified to pH 10 by adding 1 N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent; ethyl acetate/ethanol=4/1) to obtain the titled compound (280 mg) as amorphous powder.
1H-NMR(CDCl3) xcex4: 1.06 (6H, t), 2.50-2.70 (6H, m)., 3.52 (2H, q), 4.04 (3H, s), 7.55-7.70 (2H, m), 7.85-8.05 (4H, m), 8.31 (1H, s), 8.35-8.50 (2H, m), 8.55 (1H, s), 8.78 (1H, s).

The titled compound was prepared by the procedure similar to Reference example 7.
m.p.: 173-174xc2x0 C.
Recrystallizing solvent: ethyl acetate/diisopropyl ether.

The titled compound was prepared by the procedure similar to Reference example 7.
Amorphous powder.
1H-NMR(CDCl3) xcex4: 1.01 (6H, t, J=7.0 Hz), 2.50-2.70 (6H, m), 3.52 (2H, q, J=5.2 Hz), 3.82 (3H, s), 7.17 (1H, s), 7.44 (1H, t, J=7.6 Hz), 7.50-7.70 (2H, m), 7.89 (1H, d, J=7.6 Hz), 7.95 (1H, s), 8.01 (1H, d, J=8.0 Hz), 8.17-8.30 (2H, m), 8.71 (1H, d, J=8.0 Hz).

The titled compound was prepared by the procedure similar to Reference example 7.
m.p.: 148-149xc2x0 C.
Recrystallizing solvent: ethyl acetate/diisopropyl ether.

To a mixture of 4-[3-(N,N-dipropylamino)propyl]phenol hydrochloride (0.152 g), 2-bromomethylnaphthalene (0.165 g), and DMF (10 ml) was added potassium carbonate (0.131 g). Sodium hydride (60% oil dispersion: 0.044 g) was added to the reaction mixture under ice cooling and the reaction mixture was stirred at room temperature for one hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: hexane/ethyl acetate=4/1) and converted into its hydrochloride by 4 N hydrochloric acid/ethyl acetate solution followed by recrystallization from methanol/diisopropylether to obtain the titled compound (0.169 g).
m.p.: 130-132xc2x0 C.
The following Reference example compounds 12-20 were prepared by the method similar to Reference example 11.

(Recrystallizing solvent: methanol/diisopropylether).

m.p.: 113-115xc2x0 C.
Recrystallizing solvent: methanol/diethyl ether.

m.p.: 122-123xc2x0 C.
Recrystallizing solvent: ethanol/diethyl ether.

m.p.: 149-150xc2x0 C.
Recrystallizing solvent: ethanol/diethyl ether.

m.p.: 146-147xc2x0 C.
Recrystallizing solvent: ethanol/diethyl ether.

m.p.: 115-116xc2x0 C.
Recrystallizing solvent: ethanol/diethyl ether.

m.p.: 108-110xc2x0 C.
Recrystallizing solvent: ethanol/diethyl ether.

m.p.: 76-78xc2x0 C.
Recrystallizing solvent: ethanol/diethyl ether.

m.p.: 140-142xc2x0 C.
Recrystallizing solvent: ethyl acetate/diethyl ether.
To a solution of 3-(4-benzyloxyphenyl)propylalcohol (3.483 g) and pyridine (1.8 ml) in dichloromethane (30 ml) was added p-toluenesulfonyl chloride (2.73 g) at room temperature. The reaction mixture was stirred overnight at room temperature, diluted with water, and extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried, and concentrated. The residue was dissolved in acetone (50 ml) and sodium iodide (3.34 g) was added to the solution. The reaction mixture was heated under reflux for 3 hr and cooled. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried, and concentrated to obtain the titled compound (4.275 g).
1H-NMR (CDCl3) xcex4: 2.09(2H, m), 2.67(2H, t), 3.16(2H, t), 5.04(2H, s), 6.90(2H, d), 7.11(2H, d), 7.30-7.47(5H, m).
To a solution of 3-(4-benzyloxyphenyl)propyl iodide (1.790 g) in DMF (20 ml) were added N,N-dipropylamine (1.3 ml) and potassium carbonate (1.391 g). The reaction mixture was stirred at room temperature for 29 hr, diluted with water, and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/1) to obtain 3-(4-benzyloxyphenyl)propyl-N,N-dipropylamine (1.589 g).
To a solution of 3-(4-benzyloxyphenyl)propyl-N,N-dipropylamine (1.589 g) in methanol (30 ml) was added 10% palladium carbon (0.499 g) and hydrogenation reaction was conducted under hydrogen atmosphere at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by alumina column chromatography (eluent:hexane/ethyl acetate=1/1), converted into its hydrochloride, which was recrystallized from methanol/ethyl acetate to obtain the titled compound.
m.p.: 139-141xc2x0 C.

To a solution of ethyl trifluoroacetate (10 ml) in diethyl ether (20 ml) in an ice bath was added dropwise N-methylethylenediamine (7.4ml) for one hr. After addition, the reaction mixture was warmed to room temperature and stirred for 2 hr. Removal of ethyl ether from the reaction mixture gave the titled compound (14 g).
Oily material.
1H-NMR (CDCl3) xcex4: 2.39(3H, s), 2.77-2.83(2H, t, J=6.0 Hz), 3.40-3.16(2H, t, J=6.0 Hz).

To a solution of 2,2,2-trifluoro-N-[2-(methylamino)ethyl]acetamide (7 g) in THF (100 ml) in an ice bath was added a solution of di-tert-butylcarbamate (10.4 ml) in THF (90 ml) for one hr. After addition, the reaction mixture was warmed to room temperature and stirring was continued for further 3 hr. THF was distilled from the reaction mixture and the residue was dissolved in ethyl acetate, washed with water and saturated aqueous sodium chloride sequentially. Desiccation with sodium sulfate followed by concentration gave the crude crystals, which were further recrystallized from hexane-IPE to yield the titled compound (9.22 g).
Oily material.
1H-NMR (CDCl3) xcex4: 1.46(9H, s), 2.90(3H, s), 3.48-3.50(4H, m).

To a solution of tert-butyl(methyl)[2-[(2,2,2-trifluoroacetyl)amino]ethyl]carbamate (1 g) in methanol (10 ml) in an ice bath was added aqueous 10% potassium carbonate (5 ml). After addition, the reaction mixture was warmed to room temperature and stirring was continued for additional 20 hr. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The insoluble material was removed by filtration and the filtrate was concentrated to obtain the titled compound (451 mg).
Oily material.
1H-NMR (CDCl3) xcex4: 1.46(9H, s), 2.79-2.86(2H, t, J=6.4 Hz), 2.89(3H, s), 3.24-3.31(2H, t, J=6.6 Hz).

4-(4-Biphenylylmethoxy)phenylacetic acid (1.51 g), tert-butyl 2-aminoethyl(methyl)carbamate (826 mg), WSC (1 g), 1-hydroxybenzotriazole (798 mg), and triethylamine (2.2 ml) were added to THF (90 ml). The reaction mixture was stirred at room temperature for 20 hr and poured onto water, followed by extraction with ethyl acetate-THF (1:1). The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride sequentially, dried with sodium sulfate, and concentrated. The residue was purified by alumina column chromatography (eluent; methanol:THF=1:1) followed by recrystallization from THF-IPE gave the titled compound (888 mg).
m.p.:109-110xc2x0 C.

To a solution of 2,2,2-trifluoro-N-[2-(methylamino)ethyl]acetamide (5 g) in DMF (50 ml) were added ethyl 7-bromoheptanoate (3.6 ml) and potassium carbonate (7.7 g) and stirring was continued at room temperature for 18 hr. Potassium carbonate was removed by filtration and saturated aqueous sodium bicarbonate and water was added to the filtrate, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried with sodium sulfate, and concentrated. The residue was dissolved in toluene and purified by passing through the silica gel column (eluent; hexane to hexane-ethyl acetate (4:1) to ethyl acetate) to obtain the titled compound as a crude material (7 g).
Oily material.
1H-NMR (CDCl3) xcex4: 1.22-1.66(10H, m), 2.21(3H, s), 2.26-2.40 (4H, m), 2.50-2.55(2H, t, J=6.0 Hz), 3.35-3.51(2H, dd, J=14.2, 7.0 Hz), 4.08-4.18(2H, m).

To a solution of ethyl 7-[methyl-[2-[(2,2,2-trifluoroacetyl)amino]ethyl]amino]heptanoate (4.89 g) in ethanol (80 ml) in an ice bath was added 10% aqueous potassium carbonate (30 ml) and stirring was continued for 20 hr. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The insoluble material was removed by filtration and the filtrate was concentrated to obtain the titled compound (3 g)
Oily material.
1H-NMR (CDCl3) xcex4: 1.26-1.63 (10H, m), 2.05 (3H, s), 2.20-2.41(4H, m), 2.73-2.79 (2H, t, J=6.3 Hz), 4.07-4.18 (2H, dd, J=14.4, 7.2 Hz).

To a solution of (4-(((benzyloxy)carbonyl)amino)-phenyl)acetic acid (6 g) in THF (100 ml) were added WSC (4 G), HOBt (3 g), and N,N,N-trimethylethylenediamine (2.1 g) sequentially. Triethylamine (3 ml) was added to the reaction mixture. After stirring at room temperature overnight, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. The residue was recrystallized from IPE/ethyl acetate to obtain the titled compound (7 g).
m.p.: 109-110xc2x0 C.

To a solution of benzyl 4-(2-((2-(dimethylamino)ethyl)(methyl)amino)-2-oxoethyl)phenylcarbamate (0.7 g) in ethanol (10 ml) was added 10% Pd-C (0.2 g). The reaction mixture was hydrogenated under atmospheric pressure at room temperature for one hr. The catalyst was removed by filtration and the filtrate was concentrated to obtain the titled compound (0.43 g).
m.p.: 235-240xc2x0 C. (as dihydrochloride; recrystallized from ethanol/IPE).

To a solution of (4-([1,1xe2x80x2-biphenyl]-4-ylmethoxy)phenyl)acetic acid (2.1 g) in THF (100 ml) were added WSC (1.4 g), HOBt (1 g), and t-butyl N-(2-aminoethyl)carbamate (1 g). After stirring overnight, the reaction mixture was diluted in THF-ethyl acetate, washed with 10% aqueous potassium carbonate, dried, and concentrated. The residue was recrystallized from ethanol to obtain the titled compound (1.8 g).
m.p.: 175-176xc2x0 C.

To a solution of 4-biphenylcarboxylic acid (2.184 g) in THF (30 ml) in an ice bath were added oxalyl chloride (1.2 ml) and DMF (0.04 ml). After stirring at room temperature for 30 min, the reaction mixture was concentrated. The residue was dissolved in THF (15 ml) and was added into a solution of methyl 4-aminobenzoate (1.512 g) and triethylamine (2.1 ml) in THF (30 ml) at 0xc2x0 C. After stirring for 30 min, the reaction mixture was diluted with 10% aqueous citrate and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried, and concentrated. The resulting crude crystals were washed with diethyl ether to obtain the titled compound (2.179 g).
m.p.:247-251xc2x0 C.

To a solution of methyl 4-(4-biphenylylcarbonylamino)benzoate (1.998 g) in THF (60 ml)/methanol (20 ml) was added 1N aqueous sodium hydroxide (8 ml) and stirring was continued at room temperature for 18 hr. The reaction mixture was diluted with 1 N hydrochloric acid (10 ml) and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried, and concentrated. The resulting crude crystals were washed with diethyl ether to obtain the titled compound (1.760 g).
m.p.: greater than 320xc2x0 C.
A solution of 4-biphenylmethanol (800 g) in DMF (2.4 l) as cooled to 0xc2x0 C and thionyl chloride (380 ml) was added to the solution for 40 min. The temperature of the reaction mixture was raised to 30xc2x12xc2x0 C. and stirring was continued for additional one hr. Methyl 4-hydroxyphenylacetate (722 g) was added and stirring was continued for 20 min at this temperature. 28% Sodium methoxide (2.93 kg) was added to the solution for 70 min and stirring was continued for 6 hr while the temperature of the reaction mixture was maintained at 50xc2x12xc2x0 C. Water (3.21) was added to the reaction mixture for 25 min while the temperature of the reaction mixture was maintained at 50xc2x12xc2x0 C. which was stirred for additional one hr at same temperature and cooled to room temperature. The precipitate was collected by filtration and washed with methanol (1.6 l) and water (6.41) sequentially to obtain the titled compound (1119 g).
m.p.:115-116xc2x0 C.
A suspension of methyl 4-(4-biphenylylmethoxy)phenylacetate (1000 g), N,N-dimethylethylenediamine (795 g), and 1H-1,2,4-triazole (207 g) in methanol (2.0 l) was heated under reflux under nitrogen for 10 hr and was left to stand at room temperature over night. The reaction mixture was warmed to 60xc2x12xc2x0 C. and methanol (4.0 l) was added for 35 min. After stirring under reflux for additional one hr the reaction mixture was cooled to room temperature. The precipitate was collected by filtration and washed with methanol (2.0 l) to obtain the titled compound (1109 g).
A solution of methyl 4-(4-biphenylylmethoxy)phenylacetate (60.0 g), N,N-dimethylethylenediamine (47.7 g), and 1H-1,2,4-triazole (12.6 g) in toluene (120 ml) was stirred under nitrogen at 100xc2x0 C. for 8 hr and cooled until the temperature of the reaction mixture was reached to 60xc2x12xc2x0 C., to which ethyl acetate (240 ml) was added for 20 min. The reaction mixture was further heated under reflux for additional 30 min, left to stand at room temperature over night and stirred in an ice bath for 2 hr. The precipitate was collected by filtration and washed with ethyl acetate (120 ml) to obtain the titled compound (71.7 g).
A suspension of methyl 4-(4-biphenylylmethoxy)phenylacetate (2.00 g), N,N-dimethylethylenediamine (1.60 g), 2-hydroxypyridine (573 mg) in methanol (4.0 ml) was heated under reflux under nitrogen for 16 hr and cooled until the temperature of the reaction mixture reached to 60xc2x12xc2x0 C., to which methanol (8.0 ml) was added. The reaction mixture was heated under reflux for additional one hr and cooled to room temperature. The precipitate was collected by filtration and washed with methanol (4.0 ml to obtain the titled compound (2.18 g).
A suspension of methyl 4-(4-biphenylylmethoxy)phenylacetate (1.00 g), N,N-dimethylethylenediamine (0.80 g), and imidazole (205 mg) in methanol (2.0 ml) was heated under reflux under nitrogen for 30 min and cooled until the temperature of the reaction mixture reached to 60xc2x12xc2x0 C. Methanol (4.0 ml) was added to the reaction mixture, which was heated under reflux for additional one hr and cooled to room temperature. The precipitate was collected by filtration and washed with methanol (2.0 ml) to obtain the titled compound (1.03 g).

To a solution of 2-(4-([1,1xe2x80x2-biphenyl]-4-ylmethoxy)phenyl)-N-(2-(dimethylamino)ethyl)acetamide (0.2 g) in acetone (30 ml) was added m-chloroperbenzoic acid (0.2 g) and stirring was continued at room temperature for 18 hr. The reaction mixture was concentrated. The residue was recrystallized twice from ethyl acetate to obtain the titled compound (0.1 g).
m.p.:134-135xc2x0 C.
USPTO Backgrounds
USPTO Backgrounds