US 9,067,887 B2 · Quinolone compound

Abstract

The present invention provides a compound represented by the formula (I) wherein X is a hydrogen atom or a fluorine atom; R is a hydrogen atom or alkyl; R1 is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or (2) phenyl optionally substituted by 1 to 3 halogen atoms; R2 is alkyl, alkoxy, haloalkoxy, a halogen atom, cyano, etc.; and R3 is 7-oxo-7,8-dihydro-1,8-naphthyridinyl, 3-pyridyl, etc., or a salt thereof. The compound of the present invention has excellent antimicrobial activity against Clostridium difficile and is useful for the prevention or treatment of intestinal infection such as Clostridium difficile-associated diarrhea.

A compound represented by the formula (I)

wherein
X is a fluorine atom;
R is a hydrogen atom or alkyl;
R1 is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or (2) phenyl optionally substituted by 1 to 3 halogen atoms;
R2 is alkyl optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom and hydroxyl;
alkoxy;
haloalkoxy;
a chlorine atom;
cyano;
cyclopropyl;
nitro;
amino;
formyl;
alkenyl or alkynyl;
or
R1 and R2 are bonded to form a 5- or 6-membered ring optionally substituted by alkyl;
R3 is
(1) a fused heterocyclic group of the formula
wherein
represents a single bond or a double bond,
X1 is C(R5) or N,
R4 is a hydrogen atom or alkyl, and
R5 is (a) a hydrogen atom,
(b) a halogen atom,
(c) cyano,
(d) nitro,
(e) hydroxy,
(f) alkyl optionally substituted by 1 to 3 halogen atoms,
(g) alkenyl or alkynyl,
(h) aryl, or
(i) alkoxy optionally substituted by 1 to 3 halogen atoms,
when X1 is C(R5), R4 and R5 are optionally bonded to form a 5- or 6-membered ring optionally substituted by oxo, said fused heterocyclic group is optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom, cyano, nitro, hydroxy and alkyl,
(2) a group of the formula
wherein
X2 is C(R8) or N, and
R8, R7 and R8 are each independently,
(a) a hydrogen atom,
(b) a halogen atom,
(c) cyano,
(d) nitro,
(e) amino,
(f) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, alkoxy and amino,
(g) alkenyl,
(h) alkynyl,
(i) aryl,
(j) formyl or CH═N—OH,
(k) carboxy,
(l) carbamoyl,
(m) a 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl, or
(n) alkenyloxy,
(3) a group of the formula
wherein
X3 and X4 are N, or
X3 is N and X4 is CR″, wherein R″ is hydrogen atom, amino, hydroxy, alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of alkoxy and dimethylamino or mercapto, or
X3 is CH and X4 is N,
R′ is a hydrogen atom or alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of substituted hydroxyl and amino, and
R6 is as defined above,
(4) a group of the formula
wherein
represents a single bond or a double bond and R6 is as defined above,
(5) 3-pyridyl optionally substituted by 1 or 2 substituents selected from the group consisting of
(a) a halogen atom,
(b) cyano,
(c) nitro,
(d) hydroxy,
(e) amino,
(f) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, alkylamino, dialkylamino and hydroxy,
(g) alkenyl, alkynyl
(h) aryl,
(i) cycloalkyl,
(j) alkoxy,
(k) alkylamino,
(l) dialkylamino,
(m) phenylamino optionally substituted by 1 to 3 halogen atoms,
(n) a cyclic amino group optionally substituted by alkoxycarbonyl,
(o) formyl,
(p) carbamoyl optionally substituted by alkyl optionally substituted by hydroxy, and
(q) a 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl,
(6) 4-pyridyl optionally substituted by a halogen atom,
(7) 5-pyrimidinyl optionally substituted by 1 or 2 substituents selected from the group consisting of amino, alkylamino, dialkylamino and carboxy,
(8) 2-indolyl, 3-indolyl, 5-indolyl, 6-indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl or benzothiazolyl, each optionally substituted by 1 or 2 substituents selected from the group consisting of
(a) a halogen atom,
(b) cyano,
(c) nitro,
(d) hydroxy,
(e) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of amino, alkoxycarbonylamino, alkylamino and dialkylamino,
(f) alkoxy,
(g) formyl,
(h) carboxy, and
(j) amino optionally substituted by 1 or 2 substituents selected from the group consisting of
(i) alkoxycarbonyl,
(ii) alkylcarbonyl optionally substituted by a substituent selected from the group consisting of
(A) cycloalkyloxy optionally substituted by 1 to 3 alkyl,
(B) alkylamino,
(C) dialkylamino,
(D) a cyclic amino group optionally substituted by alkoxycarbonyl, and
(E) a halogen atom,
(iii) phenylcarbonyl optionally substituted by 1 to 3 substituents selected from the group consisting of alkyl and alkoxy,
(iv) cycloalkylcarbonyl,
(v) a 5- to 10-membered aromatic heterocyclylcarbonyl group optionally substituted by alkyl optionally substituted by 1 to 3 halogen atoms,
(vi) benzylcarbonyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and alkoxy,
(vii) arylsulfonyl optionally substituted by alkoxy,
(viii) cycloalkylalkylsulfonyl optionally substituted by 1 to 3 substituents selected from the group consisting of alkyl and oxo,
(ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group optionally substituted by 1 to 3 alkyl, and
(x) —C(═N—CN)—SR9 wherein R9 is alkyl,
(9) a group of the formula
wherein
one of Y1, Y2, Y3 and Y4 is N or N+(—O−), and the remaining three are each C(R25), C(R26) and C(R27),
W is O, S, NH or N(R23)
R23 is a hydrogen atom or alkyl, and
R24, R25, R26 and R27 are each independently,
(a) a hydrogen atom,
(b) cyano, or
(c) nitro,
(10) a group of the formula
wherein
R28 is a hydrogen atom or hydroxy, and
R29 is a hydrogen atom or alkyl,
(11) a group of the formula
wherein
X5 is C(R11) or N,
X6 is CH2, C(═O), O, S, SO2 or N(R12),
X7 is CH(R13), C(═O) or N(R14),
X8 is CH(R15) or C(═O),
R10, R12 and R14 are each independently,
(a) a hydrogen atom or
(b) alkyl, and
R11, R13 and R15 are independently,
(a) a hydrogen atom,
(b) a halogen atom,
(c) cyano,
(d) nitro,
(e) amino,
(f) alkylamino,
(g) dialkylamino,
(h) alkyl optionally substituted by hydroxy, or
(i) alkenyl,
when X5 is C(R11), R10 and R11 are optionally bonded to form a 5- or 6-membered ring optionally substituted by alkyl or oxo, and when X6 is N(R12) and X7 is CH(R13), R12 and R13 are optionally bonded to form a 5- or 6-membered ring,
(12) a group of the formula
wherein R16 is
(a) a hydrogen atom,
(b) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of cyano, alkylamino and dialkylamino,
(c) alkenyl optionally substituted by carboxy,
(d) formyl,
(e) carboxy,
(f) carbamoyl,
(g) —C(R17)═N—OH wherein R17 is a hydrogen atom, cyano or hydroxy,
(h) a 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl, alkoxycarbonyl, carboxy or phenyl, or cyano,
(13) a group of the formula
wherein
R18 is a hydrogen atom or alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and phenyl,
n is 0 or 1,
R19, R20 and R33 are each independently,
(a) a hydrogen atom,
(b) a halogen atom,
(c) cyano,
(d) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of
(i) a halogen atom
(ii) cyano,
(iii) hydroxy,
(iv) amino,
(v) alkylamino,
(vi) dialkylamino, and
(vii) a cyclic amino group optionally substituted by alkyl,
(e) alkoxy,
(f) amino optionally substituted by 1 or 2 substituents selected from the group consisting of
(i) alkylcarbonyl optionally substituted by a cyclic amino group,
(ii) alkylsulfonyl,
(iii) carbamoyl,
(iv) alkyl, cycloalkyl or cycloalkylalkyl, and
(v) 5- to 10-membered saturated heterocyclic group,
(g) carboxy,
(h) alkoxycarbonyl,
(i) carbamoyl optionally substituted by alkyl optionally substituted by amino, alkylamino, dialkylamino or alkoxycarbonylamino,
(j) formyl,
(k) a 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl,
(l) —CH═N—OR21 wherein R21 is a hydrogen atom or alkyl optionally substituted by alkylamino or dialkylamino,
(m) nitro,
(n) a 5- to 10-membered saturated heterocyclic group optionally substituted by amino,
(o) phenyl, or
(p) —NHC(SMe)=CHCN,
(14) a group of the formula
wherein
R30 is (a) a hydrogen atom,
(b) a halogen atom,
(c) cyano,
(d) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and hydroxy,
(e) alkenyl,
(f) alkynyl,
(g) alkoxy,
(h) formyl,
(i) —CH═N—OH, or
(j) carbamoyl,
(15) naphthyl or isochromenyl,
(16) quinolyl or isoquinolyl, or their oxide derivatives,
(17) a group of the formula
(18) a group of the formula
wherein
U is O or S, and
R31 is (a) a hydrogen atom,
(b) a halogen atom,
(c) alkyl optionally substituted by 1 to 3 halogen atoms,
(d) carboxy,
(e) nitro,
(f) cyano, or
(g) amino,
(19) a group of the formula
wherein
R32 is (a) a halogen atom,
(b) phenyl, or
(c) a group of the formula
(20) a group of the formula
wherein
R34 and R35 are each independently,
(a) a hydrogen atom, or
(b) aminoalkyl,
or
R34 and R35 are bonded to form a 6-membered ring optionally substituted by amino or oxo,
(21) a group of the formula
wherein R36 is
(a) a hydrogen atom,
(b) a halogen atom,
(c) nitro, or
(d) thienyl, or
(22) a group of the formula
or a salt thereof,
providing that, when R1 and R2 are bonded to form a 6-membered ring substituted by alkyl, R3 is not 4-pyridyl, quinolyl or isoquinolyl.

224 more elements

Quinolone compound

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Quinolone compound

Life of this patent

Abstract

Claims22