US 2003/0195206 A1 · 2-Oxy-benzoxazinone derivatives for the treatment of obesity

Abstract

The use of a compound comprising formula (I): 1 or a salt, ester, amide or prodrug therof in the inhibition of an enzyme whose preferred mode of action is to catalyse the hydrolysis of an ester functionality, e.g. in the control and inhibition of unwanted enzymes in products and processes. The compounds are also useful in medicine e.g. in the treatment of obesity and related conditions. The invention also relates to novel compounds within formula (I), to processes for preparing them and pharmaceutical compositions containing them. In formula (I) A is a 6-membered aromatic or heteroaromatic ring; and R1 is a branched or unbranched alkyl (optionally interrupted by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or a substituted derivative of any of the foregoing groups.

Claims53

Dependent claims

A method for the prevention or treatment of conditions which require the inhibition of an enzyme whose preferred mode of action is to catalyse the hydrolysis of an ester functionality which method comprises administering to a subject a therapeutically effective amount of a compound comprising formula (I):

113
or a pharmaceutically acceptable salt, ester, amide or prodrug therof;
in the manufacture of a medicament for the treatment of conditions which require the inhibition of an enzyme whose preferred mode of action is to catalyse the hydrolysis of an ester functionality
wherein in formula (I):
A is a 6-membered aromatic or heteroaromatic ring;
and
R1 is a branched or unbranched alkyl (optionally interrupted by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or a substituted derivative of any of the foregoing groups, wherein the substituents are one or more independently of halogen, alkyl, halosubstituted alkyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy, cyano, nitro, —C(O)R4, —CO2R5, —SOR4, —SO2R4, —NR6R7, —OR6, —SR6, —C(O)CX1X2NR6R7, —C(O)N(OH)R6, —C(O)NR5R4, —NR6C(O)R4, —CR6(NH2)CO2R6, —NHCX1X2CO2R6, —N(OH)C(O)NR6R7, —N(OH)C(O)R4,—NHC(O)NR6R7, —C(O)NHNR6R7, —C(O)N(OR5)R6, or a lipid or steroid (natural or synthetic) with the proviso that any hetero atom substituent in R1 must be separated from the exocyclic oxygen atom by at least two carbon atoms (preferably saturated);
and where:
R4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl, reduced heteroarylalkyl, —OR6, —NHCX1X2CO2R6 or —NR6R7;
R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl;
and
R6 and R7 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl or —(CH2)n(OR5)m wherein n is 1 to 12, preferably 2 to 10, wherein m is 1-3 and R5 is most preferably C2-C10 alkyl;
and
X1 and X2 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl.

11 more elements

A compound formula (IIa):

115
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof;
where:
R1a is
(ii) a C10-30 branched or unbranched alkyl, optionally substituted by one or more independently of C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl, heteroaryl, reduced heteroaryl, —C(O)R13, —CO2R13, —SOR13, —SO2R13, —NR13R14, —OR13, —SR13,—C(O)NR13R14, —NR14C(O)R13, halogen, cyano, and nitro and/or optionally interrupted by one or more oxygen atoms with the proviso that any hetero atom in R1 must be separated from the exocyclic oxygen atom (or from any other heteroatom) by at least two carbon atoms (preferably saturated);
(ii) C2-25 alkenyl, C2-25 alkynyl, C3-6 cycloalkenyl, aryl-C2-25 alkenyl, heteroaryl-C2-25alkenyl, reduced heteroaryl, reduced heteroaryl-C1-25 alkyl or a substituted derivative of any of the foregoing groups wherein the substituents are one or more independently of C1-6 alkyl, halosubstituted C1-6 alkyl, aryl, aryl-C1-6alkyl, heteroaryl, reduced heteroaryl, reduced heteroaryl-C1-6alkyl, C1-6 alkoxy, aryl-C1-6alkoxy, —C(O)R13, —CO2R13, —SOR13, —SO2R13, —NR13R14, —OR13, —SR13, —C(O)NR13R14, —NR14C(O)R13, halogen, cyano, and nitro, with the proviso that any hetero atom in R1 must be separated from the exocyclic oxygen atom (or from any other heteroatom) by at least two carbon atoms (preferably saturated);
(iii) a C2-9 alkyl group interrupted by one or more oxygen atoms and optionally substituted by one or more independently of C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl, heteroaryl, reduced heteroaryl, —C(O)R3, —CO2R3, —SOR3, —SO2R13, NR13R14, OR13, SR13, —C(O)NR13R14, —NR14C(O)R13, halogen, cyano and nitro with the proviso that any hetero atom in R1 must be separated from the exocyclic oxygen atom (or from any other heteroatom) by at least two carbon atoms (preferably saturated);
or
(iv) a C1-9 alkyl group substituted by a group selected from —C(O)R13, —CO2R13, SOR13, SO2R13, NR13R14, OR13, SR13, C(O)NR13R14, NR14C(O)R13;
tetrahydronaphthyl, pyridyl, pyrrolyl, piperidinyl, halogen, cyano, nitro, bicyclic aryl, bicyclic heteroaryl, monocyclic or bicyclic reduced heteroaryl, monocyclic heteroaryl other than imidazolyl;
(v) a phenyl group substituted by a group selected from OR17, —COR13, —CO2R13, SOR13, SO2R13, CONR13R14, NR14C(O)R13;
halosubstituted C, alkyl, aryl, arylC1-6alkyl, heteroaryl and heteroarylC1-6alkyl;
or
(vi) a bicyclic aryl, bicyclic heteroaryl, monocyclic or bicyclic reduced heteroaryl, or monocyclic heteroaryl group other than imidazolyl, optionally substituted by a group selected from OR17, —COR13, —CO2R13, SOR13, SO2R13, CONR13R14, NR14C(O)R13;
halosubstituted C1-6 alkyl, aryl, arylC1-6alkyl, heteroaryl and heteroarylC1-6alkyl;
where R13 and R14 each independently represents hydrogen, C1-10alkyl, C2-10alkenyl, C2-10 alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, aryl, arylC1-10alkyl, heteroaryl, heteroarylC1-10alkyl, reduced heteroaryl or reduced heteroaryl, C1-10alkyl, and R17 represents hydrogen or C2-10alkenyl, C2-10 alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, aryl, arylC1-10alkyl, heteroaryl, heteroarylC1-10alkyl, reduced heteroaryl or reduced heteroarylC1-10alkyl
and R8a, R9a, R10a and R11a are each independently hydrogen, halo, hydroxy, amino, nitro, cyano, thiol, C1-10alkyl, C1-10alkoxy, C1-10cycloalkyl, C1-10cycloalkoxy, C(O)R15, C(O)NR15R16, S(O)R15 or haloC1-10alkyl;
where R15 and R16 each independently represent hydrogen or C1-10alkyl with the proviso that when R8aa, R9aa, R10a, and R11a are H, R1 is not CH2CH2C1 or C3-alkenyl.

15 more elements

Dependencies are inferred from the claim text.

2-Oxy-benzoxazinone derivatives for the treatment of obesity

Life of this patent

2-Oxy-benzoxazinone derivatives for the treatment of obesity

Life of this patent

Abstract

Claims53