US 2013/0296551 A1 · 7-MEMBERED RING COMPOUND AND METHOD OF PRODUCTION AND PHARMACEUTICAL APPLICATION THEREOF

Abstract

A 7-membered heterocyclic compound having the formula (I), or its salt, or a solvate thereof with a chymase inhibitory action and useful for the prevention or treatment of various diseases, in which chymase is involved: a method for producing the same, and a pharmaceutical composition useful for the prevention or treatment of diseases, in which chymase is involved, including the compound of having the formula (I), or its pharmaceutically acceptable salt, or a solvate thereof are provided.

Claims4

Dependent claims

1-24. (canceled)

A compound, or its salt, or a solvate thereof, having the formula (VIa):

wherein R1, R2, and R3 are the same as defined in claim 1, P is the same as defined in claim 23,
X′ indicates methylene, or X′ forms —CH=together with R1;
P′ indicates a protective group selected from the group consisting of (1) allyl, (2) allyloxycarbonyl, (3) 9-fluorenylmethylcarbonyl, (4) linear or branched C1 to C6 alkyloxycarbonyl which may optionally be substituted with 1 to 3 halogen atoms, (5) linear or branched C1 to C6 alkylcarbonyl which may optionally be substituted with 1 to 3 halogen atoms, (6) C7 to C16 aralkyl which may optionally be substituted with 1 to 3 of (i) a halogen atom, (ii) C1 to C6 alkyl, (iii) C1 to C6 alkoxy, or (iv) nitro, (7) C5 to C16 arylcarbonyl which may optionally be substituted with 1 to 3 of (i) a halogen atom, (ii) C1 to C6 alkyl, (iii) C1 to C6 alkoxy, or (iv) nitro, (8) C7 to C16 aralkyloxycarbonyl which may optionally be substituted with 1 to 3 of (i) a halogen atom, (ii) C1 to C6 alkyl, (iii) C1 to C6 alkoxy, or (iv) nitro, and (9) C5 to C16 arylsulfonyl which may optionally be substituted with 1 to 3 of (i) a halogen atom, (ii) C1 to C6 alkyl, (iii) C1 to C6 alkoxy, or (iv) nitro, or a hydrogen atom;
R20 is (1) a halogen atom, (2) nitro, (3) cyano, (4) C1 to C6 alkyl which may optionally be substituted with 1 to 3 halogen atoms, (5) hydroxyl, or (6) C1 to C6 alkoxy which may be substituted with 1 to 3 groups selected from a halogen atom, C1 to C6 alkoxy, carboxyl, and C1 to C6 alkoxycarbonyl;
and
R21, R22, R23, and R24 are, independently, (1) a halogen atom, (2) nitro, (3) cyano, (4) C1 to C6 alkyl which may be substituted with 1 to 3 halogen atoms, (5) hydroxyl, or (6) C1 to C6 alkoxy which may optionally be substituted with 1 to 3 groups selected from a halogen atom, C1 to C6 alkoxy, carboxyl, and C1 to C6 alkoxycarbonyl, or a hydrogen atom, except for the following compounds:
(1) Compounds, wherein R20 and R24 are chlorine atoms and R21, R22, and R23 are hydrogen atoms,
(2) Compounds, wherein R20, R22, and R24 are methyl and R21 and R23 are hydrogen atoms, and
(3) Compounds, wherein R20 is a chlorine atom or bromine atom and R21, R22, R23, and R24 are hydrogen atoms.

6 more elements

A compound, or a salt thereof, having the formula

wherein
Ar indicates (1) a C6 to C14 aromatic hydrocarbon group, (2) a 5- to 8-membered aromatic heterocyclic group including 1 to 4 hetero atoms selected from a nitrogen atom, sulfur atom and oxygen atom, other than a carbon atom, or (3) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6 to C14 aromatic hydrocarbon ring,
wherein the groups (1) to (3) of the above Ar may optionally be substituted with any 1 to 5 groups selected from the group consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1 to C6 alkyl which may optionally be substituted with 1 to 3 halogen atoms, (v) C2 to C6 alkenyl which may optionally be substituted with 1 to 3 halogen atoms, (vi) C2 to C6 alkynyl which may optionally be substituted with 1 to 3 halogen atoms, (vii) C3 to C6 cycloalkyl, (viii) hydroxyl, (ix) C1 to C6 alkoxy which may optionally be substituted with 1 to 3 groups selected from a halogen atom, mono- or di-C1 to C6 alkylamino, C1 to C6 alkoxy, mono- or di-C1 to C6 alkylcarbamoyl, mono- or di-C7 to C16 aralkylcarbamoyl, mono- or di-C1 to C10 heteroaryl-C1 to C6 alkylcarbamoyl, carboxyl, and C1 to C6 alkoxycarbonyl, (x) C1 to C5 alkylenedioxy, (xi) C1 to C6 alkylthio which may optionally be substituted with 1 to 3 groups selected from a halogen atom, mono- or di-C1 to C6 alkylamino, C1 to C6 alkoxy, mono- or di-C1 to C6 alkylcarbamoyl, mono- or di-C7 to C16 aralkylcarbamoyl, mono- or di-C1 to C10 heteroaryl-C1 to C6 alkylcarbamoyl, carboxyl and C1 to C6 alkoxy-carbonyl, (xii) amino, (xiii) mono-C1 to C6 alkylamino, (xiv) di-C1 to C6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C1 to C6 alkylcarbonyl, (xvii) carboxyl, (xviii) C1 to C6 alkoxycarbonyl, (xix) carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C1 to C6 alkylcarbamoyl, (xxii) di-C1 to C6 alkylcarbamoyl, (xxiii) 5- to 6-membered cyclic aminocarbonyl, (xxiv) sulfo, (xxv) C1 to C6 alkylsulfonyl, (xxvi) C1 to C6 alkoxycarbonylamino, (xxvii) C1 to C6 alkylcarbonylamino, (xxviii) mono- or di-C1 to C6 alkylaminocarbonylamino, (xxix) aminosulfonyl, and (xxx) mono- or di-C1 to C6 alkylaminosulfonyl;
X indicates (1) a bond, (2) linear or branched C1 to C6 alkylene, (3) an oxygen atom, (4) NR13, wherein R13 indicates a hydrogen atom or a C1 to C6 alkyl group, or (5) —S(O)m— wherein m indicates an integer of 0 to 2;
R1 indicates (1) a hydrogen atom, (2) a halogen atom, or (3) C1 to C6 alkyl, or R1 forms —CH═ together with X;
R2 and R3 are independently (1) a hydrogen atom, (2) a halogen atom, or (3) C1 to C6 alkyl;
R5 and R6 are independently (1) a hydrogen atom or (2) C1 to C6 alkyl which may optionally be substituted with a group selected from the group consisting of (i) carboxyl, (ii) C1 to C6 alkoxy, (iii) C1 to C6 alkoxycarbonyl, (iv) C6 to C12 aryloxycarbonyl, (v) C1 to C10 heteroaryloxycarbonyl, and (vi) amino;
R2 and R3 and also R5 and R6 may independently form a 3- to 8-membered ring;
and
P indicates a protective group selected from the group consisting of (1) allyl, (2) allyloxycarbonyl, (3) 9-fluorenylmethylcarbonyl, (4) C1 to C6 alkyloxycarbonyl which may optionally be substituted with 1 to 3 halogen atoms, (5) C1 to C6 alkylcarbonyl which may optionally be substituted with 1 to 3 halogen atoms, (6) C7 to C16 aralkyl which may optionally be substituted with 1 to 3 groups selected from (i) a halogen atom, (ii) C1 to C6 alkyl, (iii) C1 to C6 alkoxy, and (iv) nitro, (7) C5 to C16 arylcarbonyl which may optionally be substituted with 1 to 3 groups selected from (i) a halogen atom, (ii) C1 to C6 alkyl, (iii) C1 to C6 alkoxy, and (iv) nitro, (8) C7 to C16 aralkyloxycarbonyl which may optionally be substituted with 1 to 3 groups selected from (i) a halogen atom, (ii) C1 to C6 alkyl, (iii) C1 to C6 alkoxy, and (iv) nitro, or (9) C5 to C16 arylsulfonyl which may optionally be substituted with 1 to 3 groups selected from (i) a halogen atom, (ii) C1 to C6 alkyl, (iii) C1 to C6 alkoxyl, and (iv) nitro, or R4, wherein R4 indicates a (1) a hydrogen atom, (2) C1 to C6 alkylcarbamoyl, or (3) C1 to C6 alkyl which may optionally be substituted with 1 to 3 groups selected from the group consisting of (i) carbamoyl, (ii) mono- or di-C1 to C6 alkylcarbamoyl, (iii) mono- or di-C6 to C12 arylcarbamoyl, (iv) mono- or di-C1 to C10 heteroarylcarbamoyl, (v) N—C1 to C6 alkyl-N—C6 to C12 arylcarbamoyl, (vi) N—C1 to C6 alkyl-N—C1 to C10 heteroarylcarbamoyl, (vii) mono- or di-C7 to C16 aralkylcarbamoyl, (viii) mono- or di-C1 to C10 heteroaryl-C1 to C6 alkylcarbamoyl, (ix) carboxyl, and (x) C1 to C6 alkoxycarbonyl.

7 more elements

A method of producing a compound or a solvate thereof having the formula of

wherein
Ar indicates (1) a C6 to C14 aromatic hydrocarbon group, (2) a 5- to 8-membered aromatic heterocyclic group including 1 to 4 hetero atoms selected from a nitrogen atom, sulfur atom and oxygen atom, other than a carbon atom, or (3) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6 to C14 aromatic hydrocarbon ring,
wherein the groups (1) to (3) of the above Ar may optionally be substituted with any 1 to 5 groups selected from the group consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1 to C6 alkyl which may optionally be substituted with 1 to 3 halogen atoms, (v) C2 to C6 alkenyl which may optionally be substituted with 1 to 3 halogen atoms, (vi) C2 to C6 alkynyl which may optionally be substituted with 1 to 3 halogen atoms, (vii) C3 to C6 cycloalkyl, (viii) hydroxyl, (ix) C1 to C6 alkoxy which may optionally be substituted with 1 to 3 groups selected from a halogen atom, mono- or di-C1 to C6 alkylamino, C1 to C6 alkoxy, mono- or di-C1 to C6 alkylcarbamoyl, mono- or di-C7 to C16 aralkylcarbamoyl, mono- or di-C1 to C10 heteroaryl-C1 to C6 alkylcarbamoyl, carboxyl, and C1 to C6 alkoxycarbonyl, (x) C1 to Cs alkylenedioxy, (xi) C1 to C6 alkylthio which may optionally be substituted with 1 to 3 groups selected from a halogen atom, mono- or di-C1 to C6 alkylamino, C1 to C6 alkoxy, mono- or di-C1 to C6 alkylcarbamoyl, mono- or di-C7 to C16 aralkylcarbamoyl, mono- or di-C1 to C10 heteroaryl-C1 to C6 alkylcarbamoyl, carboxyl and C1 to C6 alkoxy-carbonyl, (xii) amino, (xiii) mono-C1 to C6 alkylamino, (xiv) di-C1 to C6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C1 to C6 alkylcarbonyl, (xvii) carboxyl, (xviii) C1 to C6 alkoxycarbonyl, (xix) carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C1 to C6 alkylcarbamoyl, (xxii) di-C1 to C6 alkylcarbamoyl, (xxiii) 5- to 6-membered cyclic aminocarbonyl, (xxiv) sulfo, (xxv) C1 to C6 alkylsulfonyl, (xxvi) C1 to C6 alkoxycarbonylamino, (xxvii) C1 to C6 alkylcarbonylamino, (xxviii) mono- or di-C1 to C6 alkylaminocarbonylamino, (xxix) aminosulfonyl, and (xxx) mono- or di-C1 to C6 alkylaminosulfonyl;
X indicates (1) a bond, (2) linear or branched C1 to C6 alkylene, (3) an oxygen atom, (4) NR13, wherein R13 indicates a hydrogen atom or a C1 to C6 alkyl group, or (5) —S(O)m— wherein m indicates an integer of 0 to 2;
R1 indicates (1) a hydrogen atom, (2) a halogen atom, or (3) C1 to C6 alkyl, or R1 forms —CH═ together with X;
R2 and R3 are independently (1) a hydrogen atom, (2) a halogen atom, or (3) C1 to C6 alkyl;
R5 and R6 are independently (1) a hydrogen atom or (2) C1 to C6 alkyl which may optionally be substituted with a group selected from the group consisting of (i) carboxyl, (ii) to C6 alkoxy, (iii) C1 to C6 alkoxycarbonyl, (iv) C6 to C12 aryloxycarbonyl, (v) C1 to C10 heteroaryloxycarbonyl, and (vi) amino;
R2 and R3 and also R5 and R6 may independently form a 3- to 8-membered ring;
P indicates a protective group selected from the group consisting of (1) allyl, (2) allyloxycarbonyl, (3) 9-fluorenylmethylcarbonyl, (4) C1 to C6 alkyloxycarbonyl which may optionally be substituted with 1 to 3 halogen atoms, (5) C1 to C6 alkylcarbonyl which may optionally be substituted with 1 to 3 halogen atoms, (6) C7 to C16 aralkyl which may optionally be substituted with 1 to 3 groups selected from (i) a halogen atom, (ii) C1 to C6 alkyl, (iii) C1 to C6 alkoxy, and (iv) nitro, (7) C5 to C16 arylcarbonyl which may optionally be substituted with 1 to 3 groups selected from (i) a halogen atom, (ii) C1 to C6 alkyl, (iii) C1 to C6 alkoxy, and (iv) nitro, (8) C7 to C16 aralkyloxycarbonyl which may optionally be substituted with 1 to 3 groups selected from (i) a halogen atom, (ii) C1 to C6 alkyl, (iii) C1 to C6 alkoxy, and (iv) nitro, or (9) C5 to C16 arylsulfonyl which may optionally be substituted with 1 to 3 groups selected from (i) a halogen atom, (ii) C1 to C6 alkyl, (iii) C1 to C6 alkoxyl, and (iv) nitro, or R4,
wherein R4 indicates a (1) a hydrogen atom, (2) C1 to C6 alkylcarbamoyl, or (3) C1 to C6 alkyl which may optionally be substituted with 1 to 3 groups selected from the group consisting of (i) carbamoyl, (ii) mono- or di-C1 to C6 alkylcarbamoyl, (iii) mono- or di-C6 to C12 arylcarbamoyl, (iv) mono- or di-C1 to C10 heteroarylcarbamoyl, (v) N—C1 to C6 alkyl-N—C6 to C12 arylcarbamoyl, (vi) N—C1 to C6 alkyl-N—C1 to C10 heteroarylcarbamoyl, (vii) mono- or di-C7 to C16 aralkylcarbamoyl, (viii) mono- or di-C1 to C10 heteroaryl-C1 to C6 alkylcarbamoyl, (ix) carboxyl, and (x) C1 to C6 alkoxycarbonyl;
W indicates (1) a hydrogen atom, (2) a C6 to C14 aromatic hydrocarbon group, (3) a 5- to 8-membered aromatic heterocyclic group including 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, other than a carbon atom, (4) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6 to C14 aromatic hydrocarbon ring, and (5) C1 to C6 alkyl, or (6) a 5- to 7-membered heterocycloalkyl group which may optionally be substituted with 1 to 3 groups selected from oxo and phenyl,
wherein each of the groups (2) to (4) of the above W may optionally be substituted with 1 to 5 groups selected from the group consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1 to C6 alkyl which may optionally be substituted with a halogen atom, amino, C1 to C6 alkoxycarbonyl, C1 to C6 alkoxycarbonylamino, and carboxyl, (v) C2 to C6 alkenyl which may optionally be substituted with 1 to 3 halogen atoms, (vi) C2 to C6 alkynyl which may optionally be substituted with 1 to 3 halogen atoms, (vii) C3 to C6 cycloalkyl, (viii) hydroxyl, (ix) C1 to C6 alkoxy which may optionally be substituted with 1 to 3 groups selected from a halogen atom, hydroxyl, C1 to C6 alkoxy, amino, and mono- or di-C1 to C6 alkylamino, (x) C1 to C5 alkylenedioxy, (xi) C1 to C6 alkylthio which may optionally be substituted with 1 to 3 groups selected from a halogen atom, hydroxyl, C1 to C6 alkoxy, amino, and mono- or di-C1 to C6 alkylamino, (xii) amino, (xiii) mono-C1 to C6 alkylamino, (xiv) di-C1 to C6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C1 to C6 alkylcarbonyl, (xvii) carboxyl, (xviii) C1 to C6 alkoxycarbonyl which may optionally be substituted with a halogen atom, (xix) C7 to C16 aralkyloxycarbonyl which may optionally be substituted with a halogen atom, (xx) carbamoyl, (xxi) mono-C1 to C6 alkylcarbamoyl which may optionally be substituted with 1 to 3 groups selected from a halogen atom, hydroxyl, carboxyl, C1 to C6 alkoxy, amino, and mono- or di-C1 to C6 alkylamino, (xxii) di-C1 to C6 alkylcarbamoyl which may optionally be substituted with hydroxyl, (xxiii) 5- to 6-membered cyclic aminocarbonyl which may optionally be substituted with C1 to C6 alkoxycarbonyl, (xxiv) C6 to C10 arylcarbamoyl, (xxv) C1 to C10 heteroarylcarbamoyl, (xxvi) C7 to C16 aralkylcarbamoyl, (xxvii) C1 to C10 heteroaryl-C1 to C6 alkylcarbamoyl, (xxviii) N—C1 to C6 alkyl-N—C6 to C12 arylcarbamoyl, (xxix) C3 to C6 cycloalkylcarbamoyl, (xxx) sulfo, (xxxi) C1 to C6 alkylsulfonyl, (xxxii) C1 to C6 alkylsulfonylamino, (xxxiii) C6 to C12 arylsulfonylamino which may optionally be substituted with C1 to C6 alkyl, (xxxiv) C1 to C10 heteroarylsulfonylamino, (xxxv) C1 to C6 alkoxycarbonylamino, (xxxvi) C1 to C6 alkylcarbonylamino, (xxxvii) mono- or di-C1 to C6 alkylaminocarbonylamino, (xxxviii) C6 to C12 aryl, (xxxix) C1 to C10 heteroaryl, (xl) C6 to C10 aryloxy, (xli) C1 to C10 heteroaryloxy, (xlii) C7 to C16 aralkyloxy, (xliii) C1 to C10 heteroaryl-C1 to C6 alkyloxy, (xliv) aminosulfonyl, (xlv) mono- or di-C1 to C6 alkylaminosulfonyl, (xlvi) C7 to C16 aralkyloxycarbamoyl, and (xlvii) C1 to C10 heteroaryl-C1 to C6 alkyloxycarbamoyl;
and
Z indicates (1) a bond or (2) CR7R8 wherein R7 and R8 are, independently,
(A) a hydrogen atom,
(B) C1 to C6 alkyl which may optionally be substituted with 1 to 5 groups selected from the group consisting of (i) carboxyl, (ii) C1 to C6 alkoxycarbonyl, (iii) phenyl, (iv) hydroxyl, (v) C1 to C6 alkoxy, and (vi) a halogen atom,
(C) C6 to C12 aryl or C1 to C10 heteroaryl, which may optionally be substituted with 1 to 5 groups selected from the group consisting of (i) a halogen atom and (ii) an alkyl group which may optionally be substituted with 1 to 3 halogen atoms,
(D) C3 to C6 cycloalkyl which may optionally be substituted with 1 to 5 groups selected from (i) a halogen atom and (ii) an alkyl group which may optionally be substituted with 1 to 3 halogen atoms,
(E) —COORS wherein R9 indicates a hydrogen atom or C1 to C6 alkyl, or
(F) CONR10R11 wherein R10 and R11 are, independently,
(a) a hydrogen atom,
(b) C1 to C6 alkyl which may optionally be substituted with 1 to 3 groups selected from the group consisting of (i) a halogen atom, (ii) C3 to C6 cycloalkyl, (iii) carboxyl, (iv) C1 to C6 alkoxycarbonyl, (v) C1 to C6 alkylcarbonyl, (vi) carbamoyl, (vii) mono-C1 to C6 alkylcarbamoyl, (viii) di-C1 to C6 alkylcarbamoyl, (ix) C6 to C12 aryl, and (x) C1 to C10 heteroaryl,
(c) OR12 wherein R12 indicates a hydrogen atom or C1 to C6 alkyl, or
(d) (1) a C6 to C14 aromatic hydrocarbon group, (2) a 5- to 8-membered aromatic heterocyclic group including 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, other than a carbon atom, or (3) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6 to C14 aromatic hydrocarbon ring,
wherein each of the groups (1) to (3) may optionally be substituted with 1 to 5 groups selected from the group consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1 to C6 alkyl which may optionally be substituted with 1 to 3 halogen atoms, (v) C2 to C6 alkenyl which may optionally be substituted with 1 to 3 halogen atoms, (vi) C2 to C6 alkynyl which may optionally be substituted with 1 to 3 halogen atoms, (vii) C3 to C6 cycloalkyl, (viii) hydroxyl, (ix) C1 to C6 alkoxy which may optionally be substituted with 1 to 3 halogen atoms, (x) C1 to C5 alkylenedioxy, (xi) C1 to C6 alkylthio which may optionally be substituted with 1 to 3 halogen atoms, (xii) amino, (xiii) mono-C1 to C6 alkylamino, (xiv) di-C1 to C6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C1 to C6 alkylcarbonyl, (xvii) carboxyl, (xviii) C1 to C6 alkoxycarbonyl, (xix) carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C1 to C6 alkylcarbamoyl, (xxii) di-C1 to C6 alkylcarbamoyl, (xxiii) C6 to C10 arylcarbamoyl, (xxiv) C1 to C10 heteroarylcarbamoyl, (xxv) sulfo, (xxvi) C1 to C6 alkylsulfonyl, (xxvii) aminosulfonyl, and (xxviii) mono- or di-C1 to C6 alkylaminosulfonyl;
comprising undergoing a coupling reaction of the compound or a salt thereof having the formula (III):
with the compound or a salt thereof having the formula (IV)
wherein Q2 and Q3 independently indicate C6 to C10 aryloxy group which may optionally be substituted with 1 to 3 halogen atoms or nitro, or a halogen atom, and Y′ indicates —S(O)n— (wherein n indicates an integer of 1 or 2) or C(═O),
and the compound or salt thereof having the formula (V)

26 more elements

Dependencies are inferred from the claim text.

7-membered ring compound and method of production and pharmaceutical application thereof

Life of this patent

7-membered ring compound and method of production and pharmaceutical application thereof

Life of this patent

Abstract

Claims4