US 2010/0144735 A1 · SUBSTITUTED PIPERIDINO PHENYLOXAZOLIDINONES HAVING ANTIMICROBIAL ACTIVITY WITH IMPROVED IN VIVO EFFICACY

Substituted piperidino phenyloxazolidinones having antimicrobial activity with improved in vivo efficacy

AssigneeWockhardt Limited

InventorsPrasad Keshav Deshpande, Milind Dattatraya Sindkhedkar, Mahesh Shriram Phansalkar, Ravindra Dattatraya Yeole, Shrikant Vinayak Gupte, Yati Chugil, Nitin Shetty, Sachin Subhash Bhagwat, Milind Chintaman Shukla, Noel John De Souza, Mahesh Vithalbhai Patel

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Abstract

The present invention provides agents having antimicrobial activity for preventing and treating infectious diseases. Thus, the present invention provides novel substituted piperidino phenyloxazolidinone derivatives, processes for making compounds as well as antimicrobial compositions containing said derivatives as active ingredients and methods of treating bacterial infections with the said derivatives.

Claims24

Dependent claims

1-35. (canceled)

A compound of formula I

wherein Q is
or a pharmaceutical acceptable salt, stereoisomer or polymorph thereof,
wherein m is 1 and n is 2;
X represents OH or fluorine;
Y represents a group selected from
i) C1-C6 alkyl;
ii) substituted C1-C6 alkyl which is substituted by one or more groups selected from
a) C3-C6 cycloalkyl,
b) C1-C6 alkoxy,
c) hydroxyl;
d) alkylsulfonyloxy,
e) alkylsulfonamido,
f) arylsulfonyloxy,
g) substituted arylsulfonyloxy which is substituted by one or more groups selected from alkyl, aryl, nitro, cyano and carboxamido,
h) cyano,
i) C2-C6 alkenyl,
j) alkynyl,
k) amino,
l) substituted amino which is substituted by one or more groups selected from alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, aralkyl and cyano,
m) carbamoyloxy,
n) substituted carbamoyloxy which is substituted by one or more groups selected from alkyl, C1-C6 acyl, C1-C6 alkylsulfonyl, aryl, aralkyl and cyano,
o) substituted arylamino which is substituted by one or more groups selected from alkyl, aryl, halogen, cyano, alkyloxycarbonyl and carboxamido,
p) aryl,
q) substituted aryl which is substituted by one or more groups selected from haloalkyl, halogen, cyano, nitro, amino, mercapto, and alkoxycarbonyl,
r) heterocyclyl,
s) substituted heterocyclyl, substituted by one or more groups selected from C1-C6 alkyl, cyano and carboxamido,
t) heterocycloyl,
u) heteroaryl,
v) substituted heteroaryl which is substituted by one or more groups selected from haloalkyl, halogen, cyano, nitro, amino, mercapto, and alkoxycarbonyl,
w) one or more halogen atoms,
x) nitro,
y) azido,
z) mercapto,
aa) alkoxycarbonyl,
bb) carboxy,
cc) carboxamido,
dd) ureido, and
ee) thioureido;
iii) C3-C6 cycloalkyl;
iv) C2-C6 alkenyl;
v) C2-C6 alkynyl;
vi) aryl;
vii) heterocyclylamino;
viii) heterocyclylcarbonyl;
ix) cyano;
x) halogen;
xi) amino;
xii) substituted amino substituted by one or more groups selected from
a) alkyl,
b) aryl,
c) substituted aryl which is substituted by one or more groups selected from haloalkyl, alkoxy, halogen, cyano, nitro, amino, mercapto and alkoxycarbonyl,
d) aralkyl,
e) heteroaryl,
f) substituted heteroaryl which is substituted by one or more groups selected from haloalkyl, halogen, cyano, nitro, amino, mercapto, and alkoxycarbonyl,
g) cyano,
h) alkyloxycarbonyl,
i) aryloxycarbonyl, and
j) arylsulfonyl;
xiiii) hydrazino;
xiv) substituted hydrazino which is substituted by one or more groups selected from
a) alkyl,
b) substituted alkyl which is substituted by one or more groups selected from hydroxy, alkoxy, alkoxycarbonyl, carboxamido, cyano, and halogen,
c) alkenyl,
d) substituted alkenyl which is substituted by one or more groups selected from hydroxy, alkoxy, cyano, and halogen,
e) alkynyl,
f) substituted alkynyl which is substituted by one or more groups selected from cyano and halogen,
g) C1-C6 acyl,
h) substituted C1-C6 acyl which is substituted by one or more groups selected from cyano and halogen,
i) alkoxycarbonyl,
j) alkylsulfonyloxy,
k) substituted alkylsulfonyloxy which is substituted by one or more groups selected from hydroxy, alkoxycarbonyl, carboxamido, cyano and halogen,
l) arylsulfonyloxy,
m) substituted arylsulfonyloxy which is substituted by one or more groups selected from alkyl, alkoxycarbonyl, carboxamido, cyano, and halogen,
n) aroyl,
o) substituted aroyl substituted by one or more groups selected from alkoxy, cyano and carboxamido,
p) heterocyclyloxy,
q) heteroaroyl,
r) substituted herterocyclyloxy which is substituted by one or more groups selected from alkyl, alkoxycarbonyl, carboxamido, cyano, and halogen,
s) heteroaryl,
t) substituted heteroaryl which is substituted by one or more groups selected from alkyl, alkoxycarbonyl, carboxamido, cyano, and halogen,
u) carboxamido,
v) thiocarboxamido,
w) heterocyclylamino,
x) substituted herterocyclylamino which is substituted by one or more groups selected from alkyl, alkoxycarbonyl, carboxamido, cyano, and halogen,
y) heterocyclylmercato, and
z) substituted heterocyclylmercapto which is substituted by one or more groups selected from alkyl, alkoxycarbonyl, carboxamido, cyano, and halogen;
or
X and Y together form a 3-membered carbocylic ring or heterocyclic ring containing a hetero atom selected from oxygen and sulfur, the carbocyclic ring or heterocyclic ring optionally substituted with substituents selected from
a) cyano,
b) carboxamido, and
c) alkoxycarbonyl;
or
X and Y together form an optionally substituted, unsaturated or saturated 4 or 7 membered heterocyclic ring having 1-4 hetero atoms selected from nitrogen, oxygen, sulfur and groups selected from sulfinyl and sulfonyl where the sulfur atom as a part of heterocyclic ring wherein when the 4 or 7 membered heterocyclic ring is substituted the one or more substituents are selected from C1-C6 alkyl and substituted C1-C6 alkyl substituted by one or more groups selected from amino, acylamino, alkylsulfonamido, arylsulfonamido, alkylsulfonyloxy, arylsulfonyloxy, cyano, carboxamido and oxo;
or
A and B are each the same or different and are independently selected from
a) hydrogen,
b) C1-C6 alkyl, and
c) halogen;
wherein R2 and R3 are the same or different and are independently selected from hydrogen and halogen;
and
R4 is selected from
i) C1-C6 alkylsulphonyloxy;
ii) alkylsulfonyloxyacetamido;
iii) aminosulfonyloxy;
iv) substituted aminosulfonyloxy which is substituted by one or more groups selected from alkyl, aryl, aralkyl, cyano, alkyloxycarbonyl, and aryloxycarbonyl;
v) alkyloxysulfonyloxy;
vi) arylsulphonyloxy;
vii) amino;
viii) substituted amino which is substituted by one or more groups selected from alkyl, acyl, aryl, aralkyl, cyano, alkyloxycarbonyl, and aryloxycarbonyl;
ix) azido;
x) aminonitrilo;
xi) isocyanato;
xii) formamido;
xiii) N-hydroxyformamido;
xiv) substituted C1-C6 alkanoyloxy which is substituted by one or more groups selected from amino, alkyloxycarbonylamino and aryloxycarbonylamino;
xv) C1-C6 alkylamido;
xvi) substituted C1-C6 alkylamido which is substituted by one or more groups selected from
a) alkyloxy,
b) aryl,
c) aryloxy,
d) aralkyl,
e) aralkyloxy,
f) halogen,
g) cyano,
h) alkyloxycarbonyl, and
i) aryloxycarbonyl;
xvii) C1-C6 alkylthiocarbonylamido;
xviii) substituted C1-C6 alkylthiocarbonylamido which is substituted by one or more groups selected from
a) alkyloxy,
b) aryl,
c) aryloxy,
d) aralkyl,
e) aralkyloxy,
f) halogen,
g) cyano,
h) alkyloxycarbonyl, and
i) aryloxycarbonyl;
xix) C1-C6 alkylsulphonamido;
xx) substituted arylsulphonamido which is substituted by one or more groups selected from
a) alkyloxy,
b) aryloxy,
c) halogen,
d) cyano,
e) alkyloxycarbonyl, and
f) aryloxycarbonyl;
xxi) alkylcarbamato;
xxii) substituted alkylcarbamato which is substituted by one or more groups selected from
a) cyano,
b) halogen, and
c) amino;
xxiii) ureido;
xxiv) substituted ureido which is substituted by one or more groups selected from
a) alkyl,
b) aryl,
c) haloalkyl, and
d) cyanoalkyl;
and
xxv) substituted mercapto substituted by a C1-C6 alkyl group.

155 more elements

A compound selected from the group consisting of:

(S)—N-{3-[4-(4-Fluoro-4-methyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-cyanomethyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-carboxamidomethyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-azidomethyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-aminomethyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-(N-acetylamino)-methyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-methanesulfonamidomethyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-(N,N-dimethylamino)-methyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-hydroxymethyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-methoxymethyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-ethoxymethyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-methanesulfonyloxymethyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-fluoromethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-chloromethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Fluoro-4-iodomethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4,4-Difluoropiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-(prop-2-yn-1-yl)-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Cyano-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Cyanomethyl-4-hydroxy piperidin-1-ye-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Cyanomethyl-4-hydroxypiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-(1-Cyclopropyl-1-cyanomethyl)-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Aminocarbonyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Aminocarbonylmethyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Azidomethyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Nitromethyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-(N,N-dimethylamino)-methyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-(1-Imidazolylmethyl)-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-(1-piperazinomethyl)-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-(1-Morpholinomethyl)-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-(N,N-Dimethylpiperazinomethyl)-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide iodide salt;
(S)—N-{3-[4-(4-Hydroxymethyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Methoxymethyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Ethoxymethyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-Azidomethyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-methanesulfonamide;
(R)-{3-[4-(4-Prop-2-en-1-yl)-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-methanesulfonate;
(R)-{3-[4-(4-Hydroxymethyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-methanesulfonate;
(R)-{3-[4-(4-(3-Hydroxyprop-1-yn-1-yl)-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-methanesulfonate;
(1RS,5S)—N-{3-[4-(1-cyano-6-aza-spiro[2.5]oct-6-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(1RS,5S)—N-{3-[4-(1-cyano-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(1R,5S)—N-{3-[4-(1-cyano-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(1S,5S)—N-{3-[4-(1-cyano-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(1,1-dicyano-6-aza-spiro[2.5]oct-6-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(1,1-dicyano-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(1-carboethoxy-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(1-oxa-2-carboethoxy-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(1-thia-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(1-sulfinyl-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(R)—N-{3-[4-(4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-methanesulfonate;
(S)—N-{3-[4-(1,6-dioxa-10-aza-spiro[6.5]dodec-10-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(1,4-dioxa-10-aza-spiro[6.5]dodec-10-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(1-oxa-5-thia-10-aza-spiro[6.5]dodec-10-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(1,5-dithia-10-aza-spiro[6.5]dodec-10-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(1-thia-5-sulfinyl-10-aza-spiro[5.5]dodec-10-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-cyclopropylaminomethyl-4-hydroxy-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-azidomethyl-4-hydroxy-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(S)—N-{3-[4-(4-methanesulfonyloxymethyl-4-hydroxy-piperidin-1-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide;
(R)—N-{3-[4-(4-methansulfonyloxymethyl-4-fluoro-piperidin-1-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-methanesulfonate;
and
(S)—N-{3-[4-(4-Azidomethyl-4-hydroxy piperidin-1-yl)-3,5-difluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide.

58 more elements

Dependencies are inferred from the claim text.

Facts

Application

12/705,258Filed 12 Feb 2010

Priority

IN 924/MUM/20038 Sep 2003

Published

10 Jun 2010

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 491/10
In which the condensed system contains two hetero rings: spiro-condensed systems
A61P 31/00
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
C07D 413/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings