US 2003/0069245 A1 · Composition and antiviral activity of substituted indoleoxoacetic piperazine derivatives

Abstract

This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with indoleoxoacetyl piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.

A compound of Formula I, including pharmaceutically acceptable salts thereof,

1360
wherein:
A is selected from the group consisting of C1-6alkoxy, aryl and heteroaryl;
in which said aryl is phenyl or napthyl;
said heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoimidazolyl and benzothiazolyl;
and said aryl or heteroaryl is optionally substituted with one or two of the same or different amino, nitro, cyano, C1-6alkoxy, —C(O)NH2, halogen or trifluoromethyl;
1361
may represent a carbon-carbon bond;
R1 is hydrogen;
R2, R3, R4, and R5 are each independently selected from the group (a)-(r) consisting of:
(a) hydrogen,
(b) halogen,
(c) cyano,
(d) nitro,
(e) amino,
(f) C1-4alkylamino,
(g) di(C1-4alkyl)amino,
(h) hydroxy,
(i) C1-6alkyl optionally substituted with one to three same or different halogen, hydroxy, C1-6alkoxy, amino, C1-4alkylamino, di (C1-4alkyl)amino, cyano or nitro,
(j) C3-7cycloalkyl optionally substituted with one to three same or different halogen, hydroxy, C1-6alkoxy, amino, C1-4alkylamino, di (C1-4alkyl)amino, cyano or nitro,
(k) C1-6alkoxy,
(l) —C(O)OR7,
(m) —C(O)R8,
(n) —C(O)NR9R10,
(o) —C(═NR12)(R11),
(p) aryl, said aryl is phenyl or napthyl, and said aryl is optionally substituted with one to two of the same or different amino, C1-4alkylamino, di(C1-4alkyl)amino, cyano, C-amido, N-amido, C1-6alkoxy, C1-6thioalkoxy or halogen,
(q) heteroaryl, said heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl, and said heteroaryl is optionally substituted with one to two same or different groups selected from (aa)-(pp) consisting of:
(aa) halogen, (bb) C1-6alkyl, said C1-6alkyl optionally substituted with one to three same or different halogen, hydroxy, cyano, amino, C1-4alkylamino or di(C1-4alkyl)amino, (cc) C3-6alkenyl, (dd) C1-6alkoxy, (ee) phenyl optionally substituted with one or two same or different halogen, (ff) heteroaryl, said heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, furanyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl and tetrazolyl, and said heteroaryl optionally substituted with one or two same or different C1-4alkyl, C1-4alkoxy, halogen, amino, C1-4alkylamino and di (C1-4alkyl)amino, (gg) heteroarylC1-6alkyl-, in which the heteroaryl of said heteroaryl C1-6alkyl- is selected from the group consisting of pyridinyl, furanyl, thienyl and pyrazolyl, the heteroaryl of said heteroarylC1-6alkyl- is optionally substituted with one or two same or different C1-4alkyl, halogen or amino, and in which a carbon of the C1-6alkyl of said heteroarylC1-6alkyl- is optionally replaced by one sulfur or sulfonyl, (hh) amino, (ii) C1-4alkylamino, in which the C1-4alkyl of said C1-4alkylamino is optionally substituted with amino, C1-4alkylamino, di (C1-4alkyl)amino, morpholinyl, piperazinyl or piperidinyl, (jj) di (C1-4alkyl)amino, (kk) C3-7cycloalkylamino, (ll) —(CH2)qaC(O)R23, (mm) —CH2OC(O)Cl6alkyl, (nn) —NH—(CH2)qbC(O)R24, (oo) —CO2CH2C(O)R25, (pp) phenylmethyl, in which the phenyl of said phenylmethyl is optionally substituted with a —(CH2)qcC(O)R26;
and
(r) heteroalicyclic, said heteroalicyclic selected from the group consisting of piperazinyl, piperidinyl, morpholinyl, 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl, 4,5-dihydro-thiazol-2-yl, 5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl and 4,5-dihydro-1H-imidazol-2-yl, and said heteroalicyclic is optionally substituted with one or two same or different C1-4alkyl, C1-4alkoxy, hydroxy, cyano or amino;
R6 and R7 are each independently selected from hydrogen or C1-6 alkyl;
R8 is selected from the group consisting of C1-6alkyl, phenyl and heteroaryl in which said heteroaryl is selected from the group consisting of oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, and pyrimidinyl and said heteroaryl is optionally substituted with one to two of the same or different C1-6alkyl, amino, CO2H or CO2C1-6alkyl;
R9 and R10 are each independently selected from the group (a)-(l) consisting of:
(a) hydrogen,
(b) C1-6alkyl, said C1-6alkyl is optionally substituted with in one to two of the same or different amino, di(C,6alkyl)amino or C1-6alkoxy,
(c) C1-6alkoxy,
(d) heteroaryl, in which said heteroaryl is selected from the group consisting of pyridinyl, isoxazolyl, benzoimidazolyl, tetrazolyl, pyrazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, pyrimidinyl and isoquinolinyl and said heteroaryl is optionally substituted with one to two of the same or different C1-6alkyl or C1-6alkoxy,
(e) heteroaryl-C1-6alkyl-, in which said heteroaryl is selected from the group consisting of indolyl, imidazolyl, benzoimidazolyl, pyridinyl, pyrimidinyl, thiazolyl, triazolyl, tetrazolyl, furanyl and thienyl,
(f) heteroalicyclic, in which said heteroalicyclic is morpholinyl, piperazinyl or dihydrothiazolyl, and said heteroalicyclic is optionally substituted with a C1-6alkoxycarbonyl,
(g) morpholin-4-ylethyl,
(h) phenylsulfonyl,
(i) C1-4alkylsulfonyl,
(j) amino,
(k) (C1-6alkoxy)—C(O)NH—, and
(l) (C1-6alkyl)-NHC(O)NH;
or R9 and R10 taken together with the nitrogen to which they are attached are 4-benzylpiperazin-1-yl or 4-benzoylpiperazin-1-yl;
R11 is selected from the group consisting of hydrogen, C1-6alkoxy and NR21R22;
R12 is selected from the group consisting of hydrogen, hydroxy, NHCO2 C1-6alkyl and C1-6alkoxy, said C1-6alkoxy optionally substituted with one CO2H or CO2C1-6alkyl;
R13, R14, R15, R16, R17, R18, R19 and R20 are each independently selected from hydrogen or C1-6alkyl;
R21 and R22 are each independently selected from the group consisting of hydrogen, amino, C1-6alkyl, C3-7cycloalkyl and NHCO2C1-6alkyl;
R23, R24, R25 and R26 are each independently selected from the group consisting of hydroxy, C1-4alkyl, C1-4alkoxy optionally substituted with morpholin-4-yl or di(C1-4alkyl)amino, amino, pyrolidin-1-yl, (C1-4alkyl)amino and di(C1-4alkyl)amino;
qa, qb and qc are each independently 0 or 1;
and provided that at least one of R2, R3, R4, and R5 is selected from the group consisting of —C(O)R8, —C(O)NR9R10, —C(═NR12)(R11), aryl, heteroaryl, and heteroalicyclic when—represents a carbon-carbon bond.

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Composition and antiviral activity of substituted indoleoxoacetic piperazine derivatives

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Composition and antiviral activity of substituted indoleoxoacetic piperazine derivatives

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Abstract

Claims37