[go: up one dir, main page]

HK1138263A - 5-oxo-isoxazoles as inhibitors of lipases and phospholipases - Google Patents

5-oxo-isoxazoles as inhibitors of lipases and phospholipases Download PDF

Info

Publication number
HK1138263A
HK1138263A HK10103420.2A HK10103420A HK1138263A HK 1138263 A HK1138263 A HK 1138263A HK 10103420 A HK10103420 A HK 10103420A HK 1138263 A HK1138263 A HK 1138263A
Authority
HK
Hong Kong
Prior art keywords
alkyl
formula
phenyl
alkylene
substituted
Prior art date
Application number
HK10103420.2A
Other languages
Chinese (zh)
Inventor
Stefan Petry
Manfred Seidel
Gerhard Zoller
Günter Müller
Karl-Heinz Baringhaus
Hubert Heuer
Original Assignee
Sanofi-Aventis
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi-Aventis filed Critical Sanofi-Aventis
Publication of HK1138263A publication Critical patent/HK1138263A/en

Links

Description

5-oxoiso  azoles as lipase and phospholipase inhibitors
the present invention relates to 5-oxoisoxazoles of formula I, their pharmaceutically acceptable salts and their use as medicaments.
In WO 01/44211 certain 3-oxo-3H-benzo [ c ] isoxazole-1-carboxamides are described as inhibitors of acyl peptidase hydrolases.
Lowe et al describe 3-oxoisoxazole-5-urea derivatives active against hormone sensitive lipases in bioorg.Med.chem.Lett.14(2004) 3155-3159. It is stated that the examples mentioned therein with hydrogen on the amino group of the urea are inactive against hormone sensitive lipases. The examples also have no activity on endo-sebum lipase.
Compounds having an inhibitory effect on endo-sebum lipase are described in the prior art, for example, in WO2004/094394, WO2004/094393, WO2004/093872 or WO 2006/111321.
It is an object of the present invention to provide novel compounds which exhibit properties which can be applied therapeutically. In particular, it is an object of the present invention to find new compounds suitable for the treatment of elevated blood lipid concentrations, metabolic syndrome, diabetes, insulin resistance, LDL, HDL disorders or cardiovascular disorders.
It is an object of the present invention to provide compounds which inhibit endothelial lipase.
The invention relates to 5-oxoisoxazoles of formula (I), the tautomeric forms of said compounds and their physiologically tolerated salts
The meaning is as follows:
r1 is (C)5-C16) -alkyl, Y-aryl, Y-heteroaryl, wherein aryl or heteroaryl may be substituted one or more times by: F. cl, Br, I, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl, O- (C)1-C4) -alkoxy- (C)1-C4) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) Haloalkyl, O- (C)2-C4) -haloalkyl, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, O- (C)3-C8) -cycloalkyl, (C)2-C6) -alkynyl, (C)0-C8) Alkylene-aryl, O- (C)0-C8) Alkylene-aryl, S-aryl, (C)0-C8) Alkylene-heteroaryl, N (R4) (R5), SO2-CH3、SO2-NH2、SF5、COOH、COO-(C1-C6) Alkyl, CON (R6) (R7), N (R8) CO (R9), N (R10) SO2(R11)、CO(R12)、(CR13R14)x-O(R15)、O-CO-N(R16)(R17)、O-CO-(C1-C6) alkylene-CO-O- (C)1-C6) Alkyl, O-CO- (C)1-C6) alkylene-CO-OH, O-CO- (C)1-C6) alkylene-CO-N (R18) (R19), wherein the aryl or heteroaryl group may in turn be substituted one or more times by:
F、Cl、Br、I、OH、CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl, O- (C)1-C4) -alkoxy- (C)1-C4) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) -haloalkyl, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, O- (C)3-C8) -cycloalkyl, (C)2-C6) Alkynyl, N (R4a) (R5a), SO2-CH3、SF5、COOH、COO-(C1-C6) Alkyl, CON (R6a) (R7a), N (R8a) CO (R9a), N (R10a) SO2(R11a)、CO(R12a)、(CR13aR14a)x′-O(R15a)、O-CO-N(R16a)(R17a)、O-CO-(C1-C6) alkylene-CO-O- (C)1-C6) Alkyl, O-CO- (C)1-C6) alkylene-CO-OH, O-CO- (C)1-C6) -alkylene-CO-N (R18a) (R19 a);
x, x' are 0, 1, 2, 3, 4, 5, 6;
r4, R5, R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R4a, R5a, R6a, R7a, R9a, R10a, R11a, R12a, R13a, R14a, R15a, R16a, R17a, R18a, R19a are independently of one another hydrogen, (C5), (C6), R7, R9, R5 181-C8) -an alkyl group;
or a radical of the formula Ia
Wherein
W is-C (R26) (R27) -, -C (R26) (R27) -C (R28) (R29) -, -C (R26) (R27) -O-; r20, R21, R22, R23, R24, R25, R26, R27, R28 and R29 are the same or different and are hydrogen, F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、SF5、O-(C1-C6) Alkyl, O- (C)1-C4) -alkoxy- (C)1-C4) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) Haloalkyl, O- (C)2-C4) -haloalkyl, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, O- (C)3-C8) -cycloalkyl, (C)3-C8) Cycloalkenyl radical, (C)2-C6) Alkynyl, N (R30) (R31), SO2-CH3、COOH、COO-(C1-C6) Alkyl, CON (R32) (R33), N (R34) CO (R35), N (R36) SO2(R37)、CO(R38)、(CR39R40)x″-O(R41)、O-CO-N(R42)(R43)、O-CO-(C1-C6) alkylene-CO-O- (C)1-C6) Alkyl, O-CO- (C)1-C6) alkylene-CO-OH, O-CO- (C)1-C6) -alkylene-CO-N (R44) (R45);
x' is 0, 1, 2, 3, 4, 5, 6;
R30、R31、R32、R33、R34、R35、R36、R37、R38、R39、R40、R41、R42、R43、R44、R45
identical or different, is hydrogen, (C)1-C6) -an alkyl group;
or
R20 and R26 or R21 and R27 together with the carbon atoms carrying them form a monocyclic, 5-or 6-membered saturated, partially unsaturated or aromatic ring system, individual members of which may be replaced by-CHR 46-, -CR46R47-, (C-R46) -;
or
R22 and R24 or R23 and R25 together with the carbon atoms carrying them form a monocyclic, 5-or 6-membered saturated, partially unsaturated or aromatic ring system, individual members of which may be replaced by-CHR 46-, -CR46R47-, (C-R46) -;
r46 and R47 are the same or different and are F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、SF5、O-(C1-C6) Alkyl, O- (C)1-C4) -alkoxy- (C)1-C4) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) Haloalkyl, O- (C)2-C4) -haloalkyl, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, O- (C)3-C8) -cycloalkyl, (C)2-C6) Alkynyl, N (R48) (R49), SO2-CH3、COOH、COO-(C1-C6) Alkyl, CON (R50) (R51),N(R52)CO(R53)、N(R54)SO2(R55)、CO(R56)、(CR57R58)x′″-O(R59)、O-CO-N(R60)(R61)、O-CO-(C1-C6) alkylene-CO-O- (C)1-C6) Alkyl, O-CO- (C)1-C6) alkylene-CO-OH, O-CO- (C)1-C6) -alkylene-CO-N (R62) (R63);
x′″0、1、2、3、4、5、6；
R48、R49、R50、R51、R52、R53、R54、R55、R56、R57、R58、R59、R60、R61、R62、R63
identical or different, is hydrogen, (C)1-C6) -an alkyl group;
y, Z are the same or different and are (C)1-C2) Alkylene which may be substituted by F, Cl, CH3Or OH substitution;
r2 is hydrogen, (C)1-C12) -alkyl, Z-aryl, wherein aryl may be optionally substituted, (C)3-C12) -a cycloalkyl group;
r3 is (C)1-C12) Alkyl, aryl, heteroaryl, wherein aryl or heteroaryl may be optionally substituted, (C)3-C12) -a cycloalkyl group; or
R2 and R3 together with the carbon atoms carrying them form a monocyclic, saturated or partially unsaturated 4-to 8-membered ring system, individual members of which may be replaced by one to three atoms or groups selected from-CHR 64-, -CR64R65-, (C-R66) -, -NR67-, -C (═ O) -, -O-, with the proviso that two units selected from-O-may not be adjacent;
r64, R65, R66 and R67 are the same or different and are hydrogen, F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、SF5、O-(C1-C6) Alkyl, O- (C)1-C4) -alkoxy- (C)1-C4) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) Haloalkyl, O- (C)2-C4) -haloalkyl, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, O- (C)3-C8) -cycloalkyl, (C)3-C8) Cycloalkenyl radical, (C)2-C6) Alkynyl, N (R68) (R69), SO2-CH3、COOH、COO-(C1-C6) Alkyl, CON (R70) (R71), N (R72) CO (R73), N (R74) SO2(R75)、CO(R76)、(CR77R78)x″″-O(R79)、O-CO-N(R80)(R81)、O-CO-(C1-C6) alkylene-CO-O- (C)1-C6) Alkyl, O-CO- (C)1-C6) alkylene-CO-OH, O-CO- (C)1-C6) -alkylene-CO-N (R82) (R83);
x "" is 0, 1, 2, 3, 4, 5, 6;
R68、R69、R70、R71、R72、R73、R74、R75、R76、R77、R78、R79、R80、R81、R82、R83
identical or different, is hydrogen, (C)1-C6) -an alkyl group;
with the proviso that compounds in which R1 ═ cyclohexyl, R2 ═ H and R3 ═ phenyl are excluded.
Preference is given to compounds of the formula I, the tautomeric forms of the compounds and their physiologically tolerated salts, in which
R1 is (C)5-C12) -alkyl, Y-phenyl, Y-heteroaryl, wherein heteroaryl comprises one heteroatom selected from N, O, S and wherein phenyl or heteroaryl may be substituted one or more times by: F. cl, Br, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) -haloalkyl, (C)3-C8) -cycloalkyl, (C)0-C6) Alkylene-phenyl, O- (C)0-C6) Alkylene-phenyl, S-phenyl, (C)0-C8) -AAlkyl-heteroaryl, N (R4) (R5), COOH, COO- (C)1-C6) -alkyl, CON (R6) (R7), CO (R12), wherein the phenyl or heteroaryl group may in turn be substituted one or more times by:
F、Cl、OH、CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) -haloalkyl, (C)3-C8) Cycloalkyl, N (R4a) (R5a), COOH, COO- (C)1-C6) -alkyl, CON (R6a) (R7a) CO (R12 a);
x, x' are 0, 1, 2, 3, 4, 5, 6;
r4, R5, R6, R7, R12, R4a, R5a, R6a, R7a and R12a are the same or different and are hydrogen or (C)1-C8) -an alkyl group;
or a radical of the formula Ib
Wherein
W is-C (R26) (R27) -, -C (R26) (R27) -C (R28) (R29) -, -C (R26) (R27) -O-; r20, R21, R26, R27, R28 and R29
Identical or different and are hydrogen, F, Cl, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) Alkyl, CO- (C)1-C6) -an alkyl group;
or
R20, R21, R26 and R27 form together with the carbon atoms bearing them a fused benzene residue which may be substituted one or more times with: F. cl, CN, NO2、CF3、OCF3、(C1-C6) Alkyl, O- (C)1-C6) Alkyl, CO- (C)1-C6) -an alkyl group;
y, Z are the same or different and are-CH2-or-CH2-CH2-, which may be substituted by CH3Or OH once;
r2 is hydrogen, (C)1-C12) -alkyl, Z-phenyl, wherein the phenyl group may optionally be substituted, (C)3-C12) -a cycloalkyl group;
r3 is (C)1-C12) -alkyl, phenyl, heteroaryl, said heteroaryl comprising one heteroatom selected from N, O, S, wherein phenyl or heteroaryl may be optionally substituted, (C)3-C12) -a cycloalkyl group; or
R2 and R3 together with the carbon atoms carrying them form a monocyclic, saturated, 5-to 7-membered ring system, individual members of which may be replaced by one to three groups selected from-CHR 64-, -CR64R65-, (C-R66) -;
r64, R65 and R66 are the same or different and are F, Cl, OH, CF3、O-(C1-C6) Alkyl, O- (C)1-C4) -alkoxy- (C)1-C4) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) -haloalkyl, (C)3-C8) Cycloalkyl, N (R68) (R69), SO2-CH3、COOH、COO-(C1-C6) Alkyl, CON (R70) (R71), N (R72) CO (R73), CO (R76), O-CO-N (R80) (R81), O-CO- (C)1-C6) alkylene-CO-O- (C)1-C6) Alkyl, O-CO- (C)1-C6) alkylene-CO-OH, O-CO- (C)1-C6) -alkylene-CO-N (R82) (R83);
R68、R69、R70、R71、R72、R73、R76、R77、R78、R79、R80、R81、R82、R83
independently of one another, hydrogen, (C)1-C6) -an alkyl group.
Particular preference is given to compounds of the formula I, the tautomeric forms of the compounds and their physiologically tolerated salts, in which
R1 is (C)5-C8) Alkyl, Y-phenyl, Y-pyridyl, Y-thienyl, Y-furyl, Y-benzothienyl, Y-benzofuryl, where the phenyl or heteroaromatic radical may be substituted by F, Cl, Br, CF3、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)3-C6) Cycloalkyl, N (R4) (R5), COOH, COO- (C)1-C6) Alkyl, CON (R6) (R7), CO (R12) once, twice or three times and may be substituted by (C)0-C1) Alkylene-phenyl, O- (C)0-C1) Phenyl, pyrazolyl, pyridyl, thienyl, furyl, benzothienyl, benzofuryl once, where the heteroaromatic radicals or phenyl radicals can in turn be substituted once, twice or three times by: F. cl, Br, CF3、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)3-C6) Cycloalkyl, N (R4a) (R5a), COOH, COO- (C)1-C6) -alkyl, CON (R6a) (R7a), CO (R12 a);
r4, R5, R6, R7, R12, R4a, R5a, R6a, R7a, R12a are independently of each other H, (C)1-C8) -an alkyl group;
or the following groups
R20, R21, R26, R27, R28 and R29 are the same or different and are hydrogen or (C)1-C6) -alkyl, preferably hydrogen and methyl;
y is-CH2-or-CH2-CH2-, which may be substituted by CH3Once substituted;
r2 is hydrogen, (C)1-C8) -alkyl, -CH2-a phenyl group,wherein phenyl may be optionally substituted, (C)3-C8) -a cycloalkyl group;
r3 is (C)1-C8) -alkyl, phenyl, pyridyl, thienyl, wherein phenyl, pyridyl or thienyl may be optionally substituted, (C)3-C8) -a cycloalkyl group; or
R2 and R3 together with the carbon atoms carrying them form a monocyclic, saturated 6-to 7-membered ring system, the individual members of which may be replaced by one to three atoms or groups selected from-CHR 64-, -CR64R 65-;
r64 and R65 are the same or different and are F, Cl or CF3、OCF3、(C1-C6) Alkyl, O- (C)1-C6) Alkyl, N (R68) (R69), COOH, COO- (C)1-C6) -alkyl, CO-N (R70) (R71), CO (R76);
r68, R69, R70, R71 and R76 are the same or different and are hydrogen or (C)1-C6) -an alkyl group.
In a particularly preferred embodiment of the compounds of formula I,
r2 is propyl, and
r3 is methyl.
In another particularly preferred embodiment of the compounds of formula I,
r2 is hydrogen, and
r3 is phenyl, which may be substituted once by Cl.
In another particularly preferred embodiment of the compounds of formula I,
r2 and R3 taken together are-CH2-CH2-CH2-CH2-or-CH2-CH2-CH2-CH2-CH2-。
Particular preference is given to the following compounds of the formula I, the tautomeric forms of the compounds and their physiologically tolerated salts
R1 is (C)5-C7) Alkyl, Y-phenyl, Y-thienyl, Y-benzothienyl, where the phenyl or heteroaromatic radical may be substituted by F, Cl, Br, CF3、O-CH3、-CH3、-CH2CH3、-CH2-CH2-CH2-CH3Once, twice or three times and once with phenyl, pyrazolyl or thienyl,
wherein the heteroaromatic radical or phenyl radical may in turn be substituted by F, Cl, Br, CF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl substitution once, twice or three times; or the following groups
R20, R21, R26, R27, R28 and R29 are the same or different and are hydrogen or CH3；
Y is-CH2-, which may be substituted by CH3Once substituted;
r2 is hydrogen, methyl, isopropyl, cyclopropyl, phenyl, -CH2-phenyl, wherein phenyl may be substituted in the 4-position with Cl;
r3 is methyl, phenyl, pyridyl, cyclopropyl, wherein phenyl may be substituted by Cl; or
R2 and R3 taken together are-CH2-CH2-CH2-CH2-or-CH2-CH2-CH2-CH2-CH2。
The invention relates to compounds of formula (I) in the form of their salts, their racemates, racemic mixtures and pure enantiomers, as well as their diastereomers and mixtures thereof.
Substituent groups R1, R2, R3, R43, R53, R63, R73, R9 3, R10 3, R11 3, R12 3, R13 3, R14 3, R15 3, R16 3, R17 3, R18, R3, 36.
Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
Haloalkyl refers to alkyl substituted one or more times with halogen.
Aryl means phenyl, naphthyl or biphenyl.
A preferred aryl group is phenyl.
The aryl group may be substituted one or more times with suitable groups such as: F. cl, Br, I, CF3、OH、OCF3、NO2、CN、COOH、COO(C1-C6) Alkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) Alkyl radical]2、(C3-C10) -cycloalkyl, (C)1-C10) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, O- (C)1-C6) Alkyl, CO- (C)1-C6) Alkyl, O-CO- (C)1-C6) Alkyl, O-CO- (C)1-C6) Aryl, PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) -alkyl radical]2、S-(C1-C6) Alkyl, S- (CH)2)nAryl, S- (CH)2)n-heterocycle, SO- (C)1-C6) Alkyl, SO- (CH)2)nAryl, SO- (CH)2)n-heterocyclic ring, SO2-(C1-C6) Alkyl, SO2-(CH2)nAryl, SO2-(CH2)n-heterocyclic ring, SO2-NH(CH2)nAryl, SO2-NH(CH2)n-heterocyclic ring, SO2-N(C1-C6) -alkyl) (CH2)nAryl, SO2-N(C1-C6) -alkyl) (CH2)n-heterocyclic ring, SO2-N((CH2)n-aryl radicals)2、SO2-N((CH2)n- (heterocycle)2、NH-(CH2)nAryl, NH- (CH)2)n-heterocycle, N ((C)1-C6) -alkyl) (CH2)nAryl, N ((C)1-C6) -alkyl) (CH2)n-heterocycle, C (NH)2)、NH2、NH-(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、NH-CO-(C1-C6) -alkyl, NH-COO- (C)1-C6) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH- (C)1-C6) Alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, aryl, O- (CH)2)nAryl, O- (CH)2)nHeterocycles, where n can be 0 to 6, in which the aryl or heterocyclic radical can be substituted by F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2、NH(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、SO2-CH3、COOH、COO-(C1-C6) Alkyl, CONH2And 1 to 3 times of substitution.
A heterocycle is a mono-or bicyclic ring system containing from 5 to 12 ring members, at least one atom of which is a heteroatom selected from N, O and S. This definition also includes ring systems in which the heterocyclic ring is fused to the benzene nucleus. (C)5-C7) -the heterocycle is a monocyclic ring system, (C)8-C12) -a heterocycle is a bicyclic ring system.
Suitable "heterocyclic" or "heterocyclic group" are azocinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2, 3-b ] -tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, furyl, tetrazolyl, quinoxalinyl, cinnolinyl, quinoxalinyl, and thiadiazolyl, Isochroman group, isoindolyl group, isoquinolinyl (benzimidazolyl), isothiazolyl group, isoxazolyl group, morpholinyl group, naphthyridinyl group, octahydroisoquinolinyl group, oxadiazolyl group, 1, 2, 3-oxadiazolyl group, 1, 2, 4-oxadiazolyl group, 1, 2, 5-oxadiazolyl group, 1, 3, 4-oxadiazolyl group, oxazolidinyl group, oxazolyl group, oxazolidinyl group, pyrimidinyl group, phenanthridinyl group, phenanthrolinyl group, phenazinyl group, phenothiazinyl group, phenoxazinyl group, phthalazinyl group, piperazinyl group, piperidinyl group, pteridinyl group, purinyl group, pyranyl group, pyrazinyl group, pyrazolidinyl group, pyrazolinyl group, pyrazolyl group, pyridazinyl group, pyridooxazole, pyridoimidazole, pyridothiazole, pyridyl group, pyrimidinyl group, pyrrolidinyl group, pyrrolinyl group, 2H-pyrrolyl group, Pyrrolyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1, 2, 5-thiazinyl, thiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thienyl, triazolyl, tetrazolyl, and xanthyl.
Pyridyl refers to 2-, 3-and 4-pyridyl. Thienyl refers to 2-and 3-thienyl. Furyl means 2-and 3-furyl.
Also included are the corresponding N-oxides of these compounds, i.e., for example, 1-oxo-2-, 3-, or 4-pyridyl.
Heteroaryl is a subgroup of heterocycles, being mono-or bicyclic aromatic ring systems containing 5 to 12 ring members, at least one atom of which is a heteroatom selected from N, O and S.
Suitable "heteroaryl rings" or "heteroaryl groups" are, for example, benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, furanyl, furazanyl, imidazolyl, 1H-indazolyl, indolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, thiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thienyl.
Preferred heteroaryl groups are thienyl, pyridyl, furyl, pyrazolyl, benzothienyl and benzofuryl. Particularly preferred heteroaryl groups are thienyl, benzothienyl and furyl, with thienyl being particularly preferred.
The heterocyclic or heteroaromatic group may be substituted one or more times by suitable groups such as: F. cl, Br, I, CF3、OH、OCF3、NO2、CN、COOH、COO(C1-C6) Alkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) Alkyl radical]2、(C3-C10) -cycloalkyl, (C)1-C10) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, O- (C)1-C6) Alkyl, CO- (C)1-C6) Alkyl, O-CO- (C)1-C6) Alkyl, O-CO- (C)1-C6) Aryl, PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) -an alkyl group,SO2N[(C1-C6) -alkyl radical]2、S-(C1-C6) Alkyl, S- (CH)2)nAryl, S- (CH)2)n-heterocycle, SO- (C)1-C6) Alkyl, SO- (CH)2)nAryl, SO- (CH)2)n-heterocyclic ring, SO2-(C1-C6) Alkyl, SO2-(CH2)nAryl, SO2-(CH2)n-heterocyclic ring, SO2-NH(CH2)nAryl, SO2-NH(CH2)n-heterocyclic ring, SO2-N(C1-C6) -alkyl) (CH2)nAryl, SO2-N(C1-C6) -alkyl) (CH2)n-heterocyclic ring, SO2-N((CH2)n-aryl radicals)2、SO2-N((CH2)n- (heterocycle)2、NH-(CH2)nAryl, NH- (CH)2)n-heterocycle, N ((C)1-C6) -alkyl) (CH2)nAryl, N ((C)1-C6) -alkyl) (CH2)n-heterocycle, C (NH)2)、NH2、NH-(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、NH-CO-(C1-C6) -alkyl, NH-COO- (C)1-C6) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH- (C)1-C6) Alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, aryl, O- (CH)2)nAryl, O- (CH)2)nHeterocycles, where n can be 0 to 6, in which the aryl or heterocyclic radical can be substituted by F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2、NH(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、SO2-CH3、COOH、COO-(C1-C6) Alkyl, CONH2And 1 to 3 times of substitution.
Cycloalkyl radicals are understood to mean a ring system comprising one or more rings, which is in saturated or partially unsaturated (with one or two double bonds) form and which contains only carbon atoms, such as cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or adamantyl.
The cycloalkyl group may be substituted one or more times by suitable groups such as: F. cl, Br, I, CF3、OH、OCF3、NO2、CN、COOH、COO(C1-C6) Alkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) Alkyl radical]2、(C3-C10) -cycloalkyl, (C)1-C10) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, O- (C)1-C6) Alkyl, CO- (C)1-C6) Alkyl, O-CO- (C)1-C6) Alkyl, O-CO- (C)1-C6) Aryl, PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) -alkyl radical]2、S-(C1-C6) Alkyl, S- (CH)2)nAryl, S- (CH)2)n-heterocycle, SO- (C)1-C6) Alkyl, SO- (CH)2)nAryl, SO- (CH)2)n-rings, SO2-(C1-C6) Alkyl, SO2-(CH2)nAryl, SO2-(CH2)n-heterocyclic ring, SO2-NH(CH2)nAryl, SO2-NH(CH2)n-heterocyclic ring, SO2-N(C1-C6) -alkyl) (CH2)nAryl, SO2-N(C1-C6) -alkyl) (CH2)n-heterocyclic ring, SO2-N((CH2)n-aryl radicals)2、SO2-N((CH2)n- (heterocycle)2、NH-(CH2)nAryl, NH- (CH)2)n-heterocycle, N ((C)1-C6) -alkyl) (CH2)nAryl, N ((C)1-C6) -alkyl) (CH2)n-heterocycle, C (NH)2)、NH2、NH-(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、NH-CO-(C1-C6) -alkyl, NH-COO- (C)1-C6) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH- (C)1-C6) Alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, aryl, O- (CH)2)nAryl, O- (CH)2)nHeterocycles, where n can be 0 to 6, in which the aryl or heterocyclic radical can be substituted by F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2、NH(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、SO2-CH3、COOH、COO-(C1-C6) Alkyl, CONH2And 1 to 3 times of substitution.
Pharmaceutically acceptable salts are salts which are particularly suitable for pharmaceutical use because of their higher solubility in water than the original or base compound. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and salts of organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable base salts are ammonium, alkali metal salts (e.g. sodium and potassium) and alkaline earth metal salts (e.g. magnesium and calcium) and salts of tromethamine (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine.
Salts with non-pharmaceutically acceptable anions, such as trifluoroacetate, are also within the scope of the invention, as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic applications, such as in vitro applications.
The term "physiologically functional derivative" as used herein refers to any physiologically tolerable derivative of a compound of formula I of the present invention, such as an ester, which when administered to a mammal, such as a human, can form (directly or indirectly) a compound of formula I or an active metabolite thereof.
Physiologically functional derivatives also include prodrugs of the compounds of the invention, for example as described in H.Okada et al, chem.pharm.Bull.1994, 42, 57-61. These prodrugs can be metabolized in vivo to form the compounds of the invention. These prodrugs may be active or inactive themselves.
The compounds of the present invention may also exist in various polymorphic forms, for example, in amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the present invention are encompassed within the scope of the present invention and are another aspect of the present invention.
All references hereinafter to "compounds of formula I" refer to compounds of formula I as described above, and salts, solvates, and physiologically functional derivatives thereof, as described herein.
Use of
The compounds of the invention of formula I have a surprising inhibitory effect on endo-sebum lipase (EL). A preferred substrate for EL is HDL, which has anti-atherosclerotic activity. The reduction of HDL levels leads to the progression of atherosclerosis and its sequelae such as metabolic syndrome and coronary heart disease. Inhibition of EL should therefore lead to prevention of atherosclerotic conditions.
It has further been found that the inhibitory effect of the compounds of the invention of formula I is selective with respect to other lipases, such as Hormone Sensitive Lipase (HSL).
The compounds of formula I also show improved solubility in aqueous media and their activity is at least as high as that of structurally similar compounds. The compounds of the invention also have other advantageous features, such as higher metabolic stability and serum stability, compared to the compounds of the prior art.
Compounds of this type are particularly suitable for therapy and/or prophylaxis
1. Dyslipidemia and its sequelae, such as atherosclerosis, coronary heart disease, cerebrovascular disorders, etc., particularly (but not limited to) those characterized by one or more of the following factors:
high plasma triglyceride concentration, high postprandial plasma triglyceride concentration
Low HDL cholesterol concentration
Low apolipoprotein A lipoprotein concentration
High LDL cholesterol concentration
Small and dense particles of LDL cholesterol
High apolipoprotein B lipoprotein concentration
2. A variety of other conditions that may be associated with metabolic syndrome, such as:
obesity (overweight), including central obesity
Thrombosis, hypercoagulability and a phase tending to thrombosis blockage (of arteries and veins)
-hypertension
Heart failure, such as (but not limited to) heart failure following myocardial infarction, hypertensive heart disease or cardiomyopathy
Prevention of diabetes, especially type 2 diabetes, including its associated sequelae (hyperglycemia, glucose intolerance, pancreatic beta cell depletion, macrovascular and microvascular disorders)
3. Other disorders that may be involved, for example, in inflammatory responses or cell differentiation:
atherosclerosis, such as (but not limited to) coronary arteriosclerosis, including angina pectoris or myocardial infarction, stroke
Restenosis or reocclusion of blood vessels
Chronic inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis
-pancreatitis
Other inflammatory states
Retinopathy of the retina
-adipose cell tumors
Adipose cell carcinoma, such as liposarcoma
Solid tumors and neoplasms such as, but not limited to, cancers of the gastrointestinal tract, liver, biliary tract and pancreas, endocrine tumors, cancers of the lung, kidney and urinary tract, reproductive tract, prostate cancer and the like,
acute and chronic myeloproliferative diseases and lymphomas
Angiogenesis
-neurodegenerative diseases
-Alzheimer's disease
Multiple sclerosis
-Parkinson's disease
Erythrosquamous dermatoses, e.g. psoriasis
Acne vulgaris
Other dermatological and dermatological conditions modulated by PPAR
-eczema and neurodermatitis
Dermatitis, such as seborrheic dermatitis or photodermatitis
Keratitis and keratoses, such as seborrheic keratosis, senile keratosis, actinic keratosis, light-induced keratosis or follicular keratosis
Prevention of keloids and keloids
Warts, including condyloma or condyloma acuminata
Human Papillomavirus (HPV) infection, e.g. venereal papillomatosis, viral warts such as molluscum contagiosum, leukoplakia
Papulodermopathies, e.g. lichen planus
Skin cancer, such as basal cell carcinoma, melanoma or cutaneous T-cell lymphoma
Local malignant epithelial tumors, e.g. keratoderma, epidermal nevi
Chilblain
-hypertension
Syndrome X
Polycystic ovarian syndrome (PCOS)
-asthma
-osteoarthritis
Lupus Erythematosus (LE) or inflammatory arthropathy, e.g. rheumatoid arthritis
Vasculitis
Emaciation (cachexia)
Gout (gout)
Ischemia/reperfusion syndrome
-Acute Respiratory Distress Syndrome (ARDS)
Preparation
The amount of a compound of the invention necessary to achieve a desired biological effect will depend on a variety of factors, such as the particular compound selected, the intended use, the mode of administration, and the clinical condition of the patient. The daily dose is generally in the range 0.3mg to 100mg (usually 3mg to 50mg) per day per kilogram body weight, for example 3-10 mg/kg/day. The intravenous dose may be, for example, from 0.3mg to 1.0mg/kg, which may suitably be administered in an infusion of from 10ng to 100 ng/kg/minute. Suitable infusions for these purposes may contain, for example, 0.1ng to 10mg, usually 1ng to 10mg per ml. Single doses may contain, for example, from 1mg to 10g of active ingredient. Thus, ampoules for injection may contain, for example, from 1mg to 100mg, and orally administrable single-dose preparations such as tablets or capsules may contain, for example, from 0.05 to 1000mg, usually from 0.5 to 600 mg. For the treatment of the above conditions, the compounds of formula I may be used as the compounds themselves, but they are preferably in the form of a pharmaceutical composition containing an acceptable carrier. The carrier must, of course, be acceptable, i.e., compatible with the other ingredients of the composition and not deleterious to the health of the patient. The carrier may be a solid or a liquid or both, and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05 to 95% by weight of the active ingredient. Other pharmaceutically active substances, including other compounds of the invention, may also be present. The pharmaceutical compositions of the present invention may be prepared by one of the known pharmaceutical methods which essentially comprise mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
The pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of the formula I used in each case. Coated formulations and coated sustained release formulations are also encompassed within the scope of the invention. Acid and gastric juice resistant formulations are preferred. Suitable gastro-resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Pharmaceutical formulations suitable for oral administration may be in the form of discrete units such as capsules, cachets, suckable tablets or tablets, each containing a defined amount of a compound of formula I; in the form of a powder or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions may be prepared by any suitable pharmaceutical process which includes a step in which the active ingredient is contacted with a carrier, which may contain one or more other ingredients. Compositions are generally prepared by uniformly and homogenously mixing the active ingredient with a liquid and/or finely divided solid carrier, and then, if desired, shaping the product. Thus, for example, a tablet may be prepared by compressing or molding a powder or granules of the compound (and, where appropriate, one or more other ingredients). Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, glidant, inert diluent, and/or one or more surfactants/dispersants. Molded tablets may be prepared by molding in a suitable machine the compound in powder form and moistened with an inert liquid diluent.
Pharmaceutical compositions suitable for oral (sublingual) administration include suckable tablets containing a compound of formula I and a flavoring agent, typically sucrose and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These formulations are preferably administered intravenously, although administration by subcutaneous, intramuscular or intradermal injection is also possible. These formulations can preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with blood. The injectable compositions of the present invention generally comprise from 0.1 to 5% by weight of active compound.
Pharmaceutical compositions suitable for rectal administration are preferably in the form of single dose suppositories. They may be prepared by mixing a compound of formula I with one or more conventional solid carriers, for example cocoa butter, and then shaping the resulting mixture.
Pharmaceutical compositions suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, sprays, aerosols or oils. Carriers which may be used are petroleum ether, lanolin, polyethylene glycol, alcohols and combinations of two or more of these. The active ingredient is generally present at a concentration of 0.1 to 15%, for example 0.5 to 2% by weight of the composition.
Transdermal administration may also be carried out. Pharmaceutical compositions suitable for transdermal use may be in the form of a single patch suitable for prolonged intimate contact with the epidermis of a patient. Such patches suitably contain the active ingredient dissolved and/or dispersed in an adhesive or in an (where appropriate buffered) aqueous solution in a polymer. Suitable active ingredient concentrations are about 1% to 35%, preferably about 3% to 15%. The active ingredient can be released in particular by electrotransport or iontophoresis, for example pharmaceutical research, 2 (6): 318 (1986).
The compounds of the formula I are advantageous in respect of their advantageous effects on metabolic disorders. They have a beneficial effect on lipid and carbohydrate metabolism, in particular they reduce triglyceride levels and are suitable for the prevention and treatment of type II diabetes and arteriosclerosis and various sequelae thereof.
Combinations with other drugs
The compounds of the present invention may be administered alone or in combination with one or more other pharmacologically active agents. In particular, the compounds of the present invention may be administered together with an active ingredient having a pharmacological action similar to itself. For example, they can be administered in combination with active ingredients which have a good effect on metabolic disorders or disorders usually associated therewith. Examples of such drugs are
1. Hypoglycemic agents, antidiabetic agents,
2. an active ingredient for the treatment of dyslipidemia,
3. an anti-atherosclerotic medicament,
4. an anti-obesity drug, which is a drug,
5. an anti-inflammatory active ingredient, which is,
6. an active component for treating malignant tumor,
7. an active ingredient for the prevention of thrombosis,
8. an active ingredient for the treatment of hypertension,
9. active ingredients for the treatment of heart failure, and
10. an active ingredient for the treatment and/or prophylaxis of complications caused by or associated with diabetes.
11. An active ingredient for the treatment of neurodegenerative diseases,
12. an active ingredient for the treatment of central nervous system diseases,
13. active ingredients for the treatment of drug, nicotine and alcohol dependence,
14. an analgesic.
They can be used in combination with the compounds of the formula I according to the invention for a synergistic increase in particular of the therapeutic effect. The combined administration of the active ingredients can be carried out by separate administration of the active ingredients to the patient or in the form of a combination product in which a plurality of active ingredients are present in one pharmaceutical preparation.
Other active ingredients particularly suitable for the combination are: all antidiabetics mentioned in Rote Liste 2006, chapter 12; all antiobesity/appetite suppressant drugs mentioned in Rote list 2006, chapter 1; all lipid lowering drugs mentioned in Rote list 2006, chapter 58. They can be used in combination with the compounds of the formula I according to the invention for a synergistic increase in particular of the therapeutic effect. The combined administration of the active ingredients can be carried out by separate administration of the active ingredients to the patient or in the form of a combination product in which a plurality of active ingredients are present in one pharmaceutical preparation. Most of the active ingredients described below are disclosed in the United states Dictionary of selected and International Drug Names (USP Dictionary of USAN and International Drug Names), the United states pharmacopoeia (US Pharmacopeia), Rockville 2001.
Antidiabetic agents include insulin and insulin derivatives, e.g.(see www.lantus.com) orOr those described in WO 2005/005477(Novo Nordisk); rapid acting insulin (see US6,221,633); inhaled insulin, e.g. insulinOral insulin such as IN-105(Nobex) or Oral-lynTM(Generex Biotechnology); GLP-1-derivatives such as Exenatide (Exenatide), Liraglutide (Liraglutide), or those disclosed in WO 98/08871 or WO 2005/027978 to NovoNordisk A/S, WO01/04156 to Zealand, or WO 00/34331 to Beaufour-Ipsen, pramlintide acetate (Symlin; Amylin Pharmaceuticals), and orally active hypoglycemic active ingredients.
The active ingredient preferably comprises
A sulfonylurea,
(ii) a biguanide compound(s),
(ii) a group of the meglitinides,
an oxadiazolidinedione compound which is a novel compound,
the thiazolidinediones are selected from the group consisting of thiazolidinediones,
a glucosidase inhibitor,
an inhibitor of a glycogen phosphorylase enzyme, which is capable of inhibiting glycogen phosphorylase activity,
an antagonist of the activity of glucagon is disclosed,
an activator of the enzyme glucokinase and a compound of the enzyme glucokinase,
fructose-1, 6-bisphosphatase inhibitors,
glucose transporter 4(GLUT4) modulators,
a glutamine-fructose-6-phosphate aminotransferase inhibitor (GFAT),
a GLP-1 agonist,
potassium channel openers, such as those disclosed in WO 97/26265 and WO99/03861 to Novo Nordisk A/S,
dipeptidyl peptidase IV (DPP-IV) inhibitors,
an insulin sensitizer is used for preparing the insulin-containing oral liquid,
inhibitors of liver enzymes associated with the stimulation of gluconeogenesis and/or glycogenolysis,
modulators of glucose uptake, glucose transport and glucose reabsorption,
an inhibitor of 11 beta-HSD 1,
inhibitors of protein tyrosine phosphatase 1B (PTP1B),
modulators of sodium-dependent glucose transporter 1 or 2(SGLT1, SGLT2),
compounds which alter lipid metabolism, such as antihyperlipidemic active ingredients and antilipidemic active ingredients,
a compound that reduces the intake of food,
a compound that increases the production of heat,
PPAR and RXR modulators, and
active ingredients that act on the ATP-dependent potassium channel of beta cells.
In one embodiment of the invention, the compound of formula I is administered in combination with an HMGCoA reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, rosuvastatin or L-659699.
In one embodiment of the invention, the compounds of the formula I are administered in combination with cholesterol absorption inhibitors such as ezetimibe, tiquinan, pamabrin, FM-VP4 (sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech, WO 2005/042692), MD-0727(Microbia Inc., WO2005/021497) or with the compounds described in WO 2002/066464(Kotobuki pharmaceuticals, Inc.), WO2005/062824 (Merck & Co.), or WO 2005/061451 and WO2005/061452 (AstraZeneca AB)).
In one embodiment, the compounds of formula I are administered in combination with a PPAR γ agonist, such as rosiglitazone, pioglitazone, JTT-501, Gl 262570, R-483 or CS-011 (linaglitazone).
In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR α agonist, such as GW9578, GW-590735, K-111, LY-674, KRP-101 or DRF-10945.
In one embodiment of the invention, the compounds of formula I are administered in combination with a mixed PPAR α/γ agonist, for example, mogroside, tesaglitar, nagaglitar, LY-510929, ONO-5129, E-3030 or those described in WO 00/64888, WO 00/64876, WO 03/020269, WO 2004/075891, WO 2004/076402, WO 2004/075815, WO 2004/076447, WO 2004/076428, WO 2004/076401, WO 2004/076426, WO 2004/076427, WO 2006/018118, WO 2006/018115 and WO 2006/018116 or in J.P. Berger et al, TRES in Pharmacological Sciences 28(5), 244-.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR delta agonist, for example GW-501516 or a compound as described in WO 2005/097762, WO 2005/097786, WO2005/097763, WO 2006/029699.
In one embodiment of the invention, the compounds of formula I are administered in combination with Metaglidasen or with MBX-2044 or other partial PPAR γ agonists/antagonists.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, for example fenofibrate, clofibrate or bezafibrate.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor, for example, implitapide, BMS-201038, R-103757 or those described in WO 2005/085226.
In one embodiment of the invention, the compound of formula I is administered in combination with a CETP inhibitor, such as Tochester (torcetrapib) or JTT-705.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid absorption inhibitor (see, for example, US6,245,744, US6,221,897 or WO 00/61568), for example HMR 1741 or compounds such as those described in DE 102005033099.1 and DE 102005033100.9.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid absorber, for example cholestyramine, colesevelam.
In one embodiment of the invention, the compounds of formula I are administered in combination with LDL receptor inducers (see US6,342,512), such as HMR1171, HMR1586 or those compounds as described in WO 2005/097738.
In one embodiment of the invention, the compounds of the formula I and(omega-3 fatty acids; highly concentrated ethyl eicosapentaenoate and ethyl docosahexanoate) are administered in combination.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, for example avasimibe.
In one embodiment of the invention, the compounds of formula I are administered in combination with an antioxidant, such as OPC-14117, probucol, tocopherol, ascorbic acid, beta-carotene or selenium.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a vitamin, for example vitamin B6 or vitamin B12.
In one embodiment of the invention, the compounds of formula I are administered in combination with a lipoprotein lipase modulator, for example Ibrolipim (NO-1886).
In one embodiment of the invention, the compounds of formula I are administered in combination with an ATP citrate lyase inhibitor, such as SB-204990.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor, for example BMS-188494 or a compound as described in WO 2005/077907.
In one embodiment of the invention, the compounds of formula I are administered in combination with a lipoprotein (a) antagonist, such as Gemcabene (CI-1027).
In one embodiment of the invention, the compounds of formula I are administered in combination with an HM74A receptor agonist, for example nicotinic acid.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, for example orlistat or Cetilistat (Cetilistat) (ATL-962).
In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with sulfonylureas, for example tolbutamide, glyburide, glipizide or glimepiride.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a biguanide, for example metformin.
In another embodiment of the invention, the compounds of the formula I are administered in combination with meglitinides, for example repaglinide or nateglinide.
In one embodiment of the invention, the compounds of the formula I are administered in combination with thiazolidinediones, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of the research Foundation of redabersat (dr. reddy' sResearch Foundation), in particular with 5- [ [4- [ (3, 4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy ] phenyl ] methyl ] -2, 4-thiazolidinedione.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an α -glucosidase inhibitor, for example miglitol or acarbose.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of beta cells, for example tolbutamide, glibenclamide, glipizide or glimepiride or repaglinide.
In one embodiment of the invention, the compounds of the formula I are administered in combination with more than one of the above-mentioned compounds, for example in combination with sulfonylureas and metformin, in combination with sulfonylureas and acarbose, in combination with repaglinide and metformin, in combination with insulin and sulfonylureas, in combination with insulin and metformin, in combination with insulin and troglitazone, in combination with insulin and lovastatin, etc.
In one embodiment of the invention, the compounds of the formula I are administered in combination with glycogen phosphorylase inhibitors, for example PSN-357 or FR-258900 or compounds as described in WO 2003/084922, WO 2004/007455, WO2005/073229-31 or WO 2005/067932.
In one embodiment of the invention, the compounds of formula I are administered in combination with a glucagon receptor antagonist, e.g., A-770077, NNC-25-2504, or a compound as described in WO 2004/100875 or WO 2005/065680.
In one embodiment of the invention, the compounds of the formula I are reacted with glucokinase activators, for example RO-4389620, LY-2121260(WO 2004/063179), PSN-105, PSN-110, GKA-50 or, for example, Prosidion in WO 2004/072031, WO 2004/072066, WO 05/103021 or WO 06/016178, Roche in WO 00/058293, WO 00/183465, WO00/183478, WO 00/185706, WO 00/185707, WO 01/044216, GB 02385328, WO 02/008209, WO 02/014312, WO 02/46173, WO 02/48106, DE10259786, WO 03/095438, US 04067939 or WO 04/052869, Novo Nordisk in EP 1532980, WO 03/055482, WO 04/002481, WO 05/049019, WO05/066145 or WO 05/123132, Merck/Banyu in WO 03/080585, WO03/097824, WO 04/081001, WO 05/063738 or WO 05/090332, Eli Lilly in WO 04/063194 or Astra Zeneca in WO 01/020327, WO 03/000262, WO 03/000267, WO 03/015774, WO 04/045614, WO 04/046139, WO05/044801, WO 05/054200, WO 05/054233, WO 05/056530, WO 05/080359, WO 05/080360 or WO 05/121110.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a gluconeogenesis inhibitor, for example FR-225654.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an inhibitor of fructose-1, 6-bisphosphatase (FBPase), for example CS-917.
In one embodiment of the invention, the compounds of formula I are administered in combination with a glucose transporter 4(GLUT4) modulator, such as KST-48(D. -O.Lee et al: Arzneim. -Forsch.drug Res.54(12), 835 (2004)).
In one embodiment of the invention, the compounds of the formula I are administered in combination with a glutamine-fructose-6-phosphate amidotransferase inhibitor (GFAT), such as the compounds described in WO 2004/101528.
In one embodiment of the invention, the compounds of the formula I are administered in combination with dipeptidyl peptidase IV (DPP-IV) inhibitors, for example vildagliptin (LAF-237), sitagliptin (MK-0431), Saxagliptin (BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200, GW-825964X or compounds as described in WO2003/074500, WO 2003/106456, WO 2004/50658, WO 2005/058901, WO2005/012312, WO 2005/012308, PCT/EP2005/007821, PCT/EP2005/008005, PCT/EP2005/008002, PCT/EP2005/008004, PCT/EP2005/008283, DE 102005012874.2 or DE 102005012873.4.
In one embodiment of the invention, the compounds of formula I are combined with an inhibitor of 11-beta-hydroxysteroid dehydrogenase 1(11 beta-HSD 1), for example BVT-2733 or a compound as described in WO 2001/90090-94, WO2003/43999, WO 2004/112782, WO 2003/44000, WO 2003/44009, WO 2004/112779, WO 2004/113310, WO 2004/103980, WO 2004/112784, WO 2003/065983, WO 2003/104207, WO 2003/104208, WO 2004/106294, WO 2004/011410, WO 2004/033427, WO 2004/041264, WO 2004/037251, WO 2004/056744, WO 2004/065351, WO 2004/089367, WO 2004/089380, WO 2004/089470-71, WO 2004/089896, WO 2005/016877 or WO 2005/097759.
In one embodiment of the invention, the compounds of the formula I are administered in combination with inhibitors of protein tyrosine phosphatase 1B (PTP1B) as described in WO 2001/19830-31, WO 2001/17516, WO 2004/506446, WO 2005/012295, PCT/EP2005/005311, PCT/EP2005/005321, PCT/EP2005/007151, PCT/EP2005/01294 or DE 102004060542.4.
In one embodiment of the invention, the compounds of the formula I are administered in combination with modulators of the sodium-dependent glucose transporters 1 or 2(SGLT1, SGLT2), for example KGA-2727, T-1095 and SGL-0010 or as described in WO 2004/007517, WO 2004/52903, WO 2004/52902, WO 2005/121161, WO 2005/085237, JP2004359630 or in A.L.Handlon in Expert Opin. Ther. patents (2005)15(11), 1531-ion 1540.
In one embodiment of the invention, the compounds of the formula I are administered in combination with hormone-sensitive lipase (HSL) inhibitors, for example as described in WO 01/17981, WO 01/66531, WO 2004/035550, WO 2005/073199 or WO 03/051842.
In one embodiment of the invention, the compounds of the formula I are administered in combination with acetyl-coa carboxylase (ACC) inhibitors, for example as described in WO 1999/46262, WO 2003/72197, WO 2003/072197 or WO 2005/044814.
In one embodiment of the invention, the compounds of the formula I are administered in combination with inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), such as those described in WO 2004/074288.
In one embodiment of the invention, the compounds of formula I are administered in combination with a glycogen synthase 3 β (GSK-3 β) inhibitor, e.g. a compound described in US2005222220, WO 2004/046117, WO 2005/085230, WO 2005/111018, WO 2003/078403, WO 2004/022544, WO 2003/106410, WO 2005/058908, US2005038023, WO 2005/009997, US2005026984, WO 2005/000836, WO 2004/106343, EP1460075, WO 2004/014910, WO 2003/076442, WO 2005/087727 or WO 2004/046117.
In one embodiment of the invention, the compounds of formula I are administered in combination with a protein kinase C β (PKC β) inhibitor, such as Ruboxistaurin.
In one embodiment of the invention, the compounds of formula I are administered in combination with an endothelin A receptor antagonist, such as Avosentan (SPP-301).
In one embodiment of the invention, the compounds of the formula I are administered in combination with an "I-kappa B kinase" inhibitor (IKK inhibitor), such as the compounds described in WO 2001/000610, WO 2001/030774, WO 2004/022553 or WO 2005/097129.
In one embodiment of the invention, the compounds of formula I are administered in combination with a glucocorticoid receptor modulator, such as those described in WO 2005/090336.
In another embodiment of the invention, the compounds of formula I are administered in combination with: CART modulators (see, "Cocaine-amphetamine-regulated transcription affects energy metabolism, anxiety, and gastric emptying in mice (Cocaine-amphetamine-regulated transcript induction metabolism in mice)" Asakawa, A et al, Hormone and Metabolic Research (2001), 33(9), 554-); NPY antagonists such as naphthalene-1-sulfonic acid {4- [ (4-aminoquinazolin-2-ylamino) methyl ] cyclohexylmethyl } amide hydrochloride (CGP 71683A)); peptide YY3-36 (PYY3-36) or similar compounds, such as CJC-1682 (PYY3-36 bound to human serum albumin via Cys 34), CJC-1643 (PYY3-36 derivatives bound to serum albumin in vivo) or compounds as described in WO 2005/080424;
cannabinoid receptor 1 antagonists, such as rimonabant, SR147778 or those such as EP 0656354, WO 00/15609, WO 02/076949, WO 2005/080345, WO 2005/080328, WO 2005/080343, WO 2005/075450, WO 2005/080357, WO 2001/70700, WO 2003/026647-48, WO 2003/02776, WO 2003/040107, WO 2003/007887, WO 2003/027069, US6,509,367, WO 2001/32663, WO 2003/086288, WO 2003/087037, WO 2004/048317, WO 2004/058145, WO 2003/084930, WO 2003/084943, WO 2004/058744, WO 2004/013120, WO 2004/029204, WO 2004/035566, WO 2004/058249, WO 2004/058255, WO 2004/058727, WO 2004/069838, US20040214837, WO 5937, A compound described in US20040214855, US20040214856, WO 2004/096209, WO 2004/096763, WO 2004/096794, WO 2005/000809, WO 2004/099157, US20040266845, WO 2004/110453, WO 2004/108728, WO 2004/000817, WO 2005/000820, US20050009870, WO 2005/00974, WO 2004/111033-34, WO 2004/11038-39, WO 2005/016286, WO 2005/007111, WO 2005/007628, US20050054679, WO 2005/027837, WO 2005/028456, WO 2005/063761-62, WO 2005/061509 or WO 2005/077897;
MC4 agonists (e.g. 1-amino-1, 2, 3, 4-tetrahydronaphthalene-2-carboxylic acid [2- (3 a-benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydropyrazolo [4, 3-c ] pyridin-5-yl) -1- (4-chlorophenyl) -2-oxoethyl ] amide (WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141 or those such as WO 2005/060985, WO 2005/009950, WO 2004/087159, WO 2004/078717, WO 2004/078716, WO 2004/024720, US20050124652, WO 2005/051391, WO 2004/112793, WOUS20050222014, US20050176728, US20050164914, US20050124636, US 20030988, US20040167201, US 20040167401201, WO 01/91752, Compounds described in WO 2004/005324, WO 2004/037797, WO 2005/042516, WO 2005/040109, WO 2005/030797, US20040224901, WO 2005/01921, WO 2005/09184, WO 2005/000339, EP1460069, WO 2005/047253, WO 2005/047251, EP1538159, WO 2004/072076, WO 2004/072077 or WO 2006/024390;
orexin receptor antagonists (e.g., 1- (2-methylbenzoxazol-6-yl) -3- [1, 5] naphthyridin-4-ylurea hydrochloride (SB-334867-A) or those described in WO 2001/96302, WO 2001/85693, WO 2004/085403, or WO 2005/075458);
histamine H3 receptor agonists (e.g. 3-cyclohexyl-1- (4, 4-dimethyl-1, 4, 6, 7-tetrahydroimidazo [4, 5-c ] pyridin-5-yl) propan-1-one oxalate (WO 00/63208) or those compounds as described in WO 2000/64884, WO 2005/082893);
CRF antagonists (e.g., [ 2-methyl-9- (2, 4, 6-trimethylphenyl) -9H-1, 3, 9-triazafluoren-4-yl ] dipropylamine (WO 00/66585));
CRF BP antagonists (e.g., urocortin),
A urocortin agonist;
a β 3 agonist (e.g. 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2, 3-dimethyl-1H-indol-6-yloxy) ethylamino ] ethanol hydrochloride (WO 01/83451));
MSH (melanocyte-stimulating hormone) agonists;
MCH (melanin-concentrating hormone) receptor antagonists (e.g., NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430 or compounds as described in WO 2003/15769, WO 2005/085200, WO 2005/019240, WO 2004/011438, WO 2004/012648, WO 2003/015769, WO 2004/072025, WO 2005/070898, WO 2005/070925, WO 2006/018280, WO 2006/018279, WO 2004/039780, WO 2003/033476, WO 2002/006245, WO 2002/002744, WO 2003/004027 or FR 2868780);
CCK-A agonists (e.g. {2-14- (4-chloro-2, 5-dimethoxyphenyl) -5- (2-cyclohexylethyl) thiazol-2-ylcarbamoyl ] -5, 7-dimethylindol-1-yl } acetic acid trifluoroacetate (WO99/15525), SR-146131(WO 02/44150) or SSR-125180);
serotonin reuptake inhibitors (e.g., dexfenfluramine);
mixed serotonergic and noradrenergic compounds (e.g., WO 00/71549);
5-HT receptor agonists, such as 1- (3-ethylbenzofuran-7-yl) piperazine oxalate (WO 01/09111);
5-HT2C receptor agonists (e.g., APD-356, BVT-933 or such compounds as those described in WO 2000/77010, WO 2007/7001-02, WO 2005/019180, WO 2003/064423, WO 2002/42304 or WO 2005/082859);
5-HT6 receptor antagonists such as those described in WO 2005/058858;
bombesin receptor agonists (BRS-3 agonists);
a galanin receptor antagonist;
growth hormone (e.g., human growth hormone or AOD-9604);
a growth hormone releasing compound (6-benzyloxy-1- (2-diisopropylaminoethylcarbamoyl) -3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695));
growth hormone secretagogue receptor antagonists (ghrelin antagonists), such as a-778193 or those described in WO 2005/030734;
TRH agonists (see, e.g., EP 0462884);
uncoupling protein 2 or 3 modulators;
leptin agonists (see, e.g., Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential method of treating obesity (Leptin agonists as a potential approach to the treatment of obesity.) Drugs of the Future (2001), 26(9), 873-);
DA agonists (bromocriptine or Doprexin);
lipase/amylase inhibitors (such as those described in WO 00/40569);
diacylglycerol O-acyltransferase (DGAT) inhibitors as described, for example, in US2004/0224997, WO 2004/094618, WO 2000/58491, WO 2005/044250, WO 2005/072740, JP2005/206492 or WO 2005/013907;
fatty Acid Synthase (FAS) inhibitors, such as C75 or those compounds as described in WO 2004/005277;
oxyntomodulin;
oleoyl estrone
Or thyroid hormone receptor agonists, such as KB-2115 or those compounds as described in WO 2005/8279, WO 2001/72692, WO 2001/94293, WO 2003/084915, WO 2004/018421 or WO 2005/092316.
In one embodiment of the invention, the other active ingredient is leptin; see, e.g., "prospects for the therapeutic use of leptin" (Perspectives in the therapeutic use of leptin), "Salvador, Javier; Gomez-Ambrosi, Javier; fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-.
In one embodiment of the invention, the other active ingredient is dextroamphetamine or amphetamine.
In one embodiment of the invention, the other active ingredient is fenfluramine or dexfenfluramine.
In another embodiment of the invention, the other active ingredient is sibutramine.
In one embodiment of the invention, the other active ingredient is mazindol or phentermine.
In one embodiment of the invention, the compounds of the formula I are reacted with a swelling agent, preferably an insoluble swelling agent (see, for example, carob @(Zunft H J et al, Carob pulp preparation for treatment of hypercholesterolemia), ADVANCES IN THERAPY (9-10 months 2001), 18(5), 230-6). Caromax is a peptide derived from Nutrinova, Nutrition Specialties&Products containing carob gum supplied by Food ingredients GmbH, Industrie park Hoechst, 65926 Frankfurt/Main). Andcan be in one formulation or by separate administration of the compounds of the formula I andto be implemented. In this contextIt can also be administered in the form of a food product, for example in the form of a bakery product or breakfast bar (muesli bar).
In one embodiment of the invention, the compounds of the formula I are administered in combination with PDE (phosphodiesterase) inhibitors, such as those described in WO 2003/077949 or WO 2005/012485.
In one embodiment of the invention, the compounds of formula I are administered in combination with NAR-1 (nicotinic acid receptor) agonists, such as those described in WO 2004/094429.
In one embodiment of the invention, the compounds of formula I are administered in combination with CB2 (cannabinoid receptor) agonists, such as those described in US 2005/143448.
In one embodiment of the invention, the compounds of formula I are administered in combination with histamine-1 agonists, such as those described in WO 2005/101979.
In one embodiment of the invention, the compounds of formula I are administered in combination with bupropion, for example as described in WO 2006/017504.
In one embodiment of the invention, the compounds of formula I are administered in combination with an opioid receptor antagonist, such as those described in WO 2005/107806 or WO 2004/094429.
In one embodiment of the invention, the compounds of the formula I are administered in combination with neutral endopeptidase inhibitors, such as those described in WO 2002/02513, WO 2002/06492, WO 2002/040008, WO 2002/040022 or WO 2002/047670.
In one embodiment of the invention, the compounds of formula I are administered in combination with an NPY inhibitor (neuropeptide Y), such as those described in 2002/047670.
In one embodiment of the invention, the compounds of the formula I are administered in combination with sodium/hydrogen exchange inhibitors, such as those described in WO 2003/092694.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a glucocorticoid receptor modulator, such as those described in WO 2005/090336.
In one embodiment of the invention, the compounds of formula I are administered in combination with a nicotine receptor agonist, such as those described in WO 2004/094429.
In one embodiment of the invention, the compounds of formula I are administered in combination with NRI (norepinephrine reuptake inhibitor), such as those described in WO 2002/053140.
In one embodiment of the invention, the compounds of the formula I are administered in combination with MOA (E-. beta. -methoxyacrylate), for example Segeline or those described in WO 2002/053140.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an antithrombotic active ingredient, for example clopidogrel.
It is to be understood that each suitable combination of a compound of the invention with one or more of the above-mentioned compounds and optionally one or more other pharmacologically active substances is to be regarded as being within the scope of the protection given by the present invention.
Some of the above-described chemical formulas for developing code are described in detail below.
The activity of the compounds of the invention of formula I was tested in the following enzyme assay system:
EL inhibition test:
recombinant cell lines (CHO, HEK293) release EL as a secreted protein into the cell culture medium (conditioned medium) at high concentrations. After concentration, it was used as an enzyme solution.
EL Activity test
The phospholipase-specific substrate 1, 2-bis (4, 4-difluoro-5, 7-dimethyl-4-bora-3 a, 4 a-diaza-s-indacene-3-undecanoyl) -sn-glycero-3-phosphocholine (manufacturer Molecular Probes) was used to define the enzymatic activity of endothelial lipase and the action of inhibitors. The A1 ester bond of the phospholipid was enzymatically hydrolyzed, releasing the fluorescent dye Bodipy labeled fatty acid, which can be detected after separation by thin layer chromatography on HPTLC plates (silica gel 60, Merck) or directly in the reaction vessel by measuring fluorescence.
A substrate solution was prepared by dissolving 100. mu.g of 1, 2-bis (4, 4-difluoro-5, 7-dimethyl-4-bora-3 a, 4 a-diaza-s-indacene-3-undecanoyl) -sn-glycero-3-phosphocholine (Molecular Probes, manufacturer) in 100. mu.l DMSO and adding it to 2.4mg of glyceryl palmitate (Sigma) in 393. mu.l of chloroform solution containing 20mg/ml of DOP-choline (1, 2-dioleoyl-sn-glycero-3-phosphocholine). 39.3. mu.l of the lipid mixture were transferred to a new reaction vessel and the solvent was evaporated. The lipid mixture was dissolved in 4ml of 200mM TRIS-HCl, 150mM sodium chloride, pH7.4 by two sonications. The subsequent enzymatic reaction was carried out at 37 ℃ for 90 minutes. For this, 20. mu.l of substrate solution were incubated with 2. mu.l of the appropriate concentration of inhibitor (dissolved in 10% DMSO, using 10% DMSO solution as a control) and 2. mu.l of enzyme solution (conditioned medium). Mu.l of the test mixture were then spotted on HPTLC plates (silica gel 60, Merck) and the released fluorochrome was separated off with a developing reagent (ether: petroleum ether: acetic acid [ 78: 22: 1]) for detection. After evaporation of the developer, the plate is read in a fluorescence scanner. The increase in fluorochrome release in the uninhibited reaction was observed as a measure of enzyme activity.
The enzyme activity decreases as a function of the inhibitor concentration used, the concentration of inhibitor at which half-maximal enzyme activity is observed being called IC50。
Examples IC50[μM]EL
6 0.028
7 0.9
8 3.2
10 0.06
16 0.004
18 14.1
25 0.009
26 0.035
31 0.1
39 0.001
40 0.053
44 0.5
Other test models
The suitability of the compounds of the invention as active pharmaceutical ingredients can be tested by various test models. A description is given below exemplarily about the test model.
Solubility in aqueous systems
The proper solubility of a substance in an aqueous solvent system is an important prerequisite for a (reproducible) pharmacological effect. Solubility in aqueous systems can be determined by various methods. Suitable examples are the solution precipitation method ("kinetic solubility") and the method of studying the dissolution of solid samples until an equilibrium state is established ("thermodynamic solubility").
a) Dynamic solubility
A DMSO solution of the test compound (2.5 mM; 0.5. mu.L) is pipetted into 200. mu.L of an aqueous test solution (e.g., phosphate buffered saline, 10X, 1M, Sigma, adjusted to 10mM, pH7.4) in a 96-well microtiter plate and the turbidity is measured with a turbidimeter (e.g., Nephelstar Galaxy, BMG Labtech) for the resulting theoretical concentration of 6.25. mu.M of the test compound. The concentration of the test compound in the aqueous test solution was then increased to the theoretical value of 12.5. mu.M by further addition of DMSO solution (2.5 mM; 0.5. mu.L) and the turbidity measurement was repeated. The measurement procedure was completed by further addition of DMSO solution (1. mu.L, 2.5 mM; 0.5. mu.L, 10 mM; then 9X 1. mu.L, 10mM resulting in theoretical concentrations of 25. mu.M, 50. mu.M, 100. mu.M, 150. mu.M, 200. mu.M, 250. mu.M, 300. mu.M, 350. mu.M, 400. mu.M, 450. mu.M and 500. mu.M), and turbidity was measured between each sample addition.
Evaluation: the turbidity values obtained from the turbidimeter are plotted against the theoretical concentration of the test compound in the aqueous test solution. As long as a significant turbidity is found at a certain theoretical concentration (e.g., 5 times or more the control value of an aqueous test solution), a concentration level below that concentration is referred to as the solubility limit of the test compound in the test solution. Thus, the maximum possible measurement ranges are < 6.25. mu.M, 6.25-500. mu.M and > 500. mu.M.
Preferred compounds of the invention exhibit a kinetic solubility in phosphate buffer (ph7.4) of at least 12.5 μ M; more preferably at least 50. mu.M and even more preferably at least 250. mu.M.
b) Thermodynamic solubility
Integrated UV absorbance obtained from HPLC UV measurements of DMSO serial dilutions of test compounds (500 μ M, 100 μ M, 50 μ M, 10 μ M and 1 μ M) showed a linear correlation with concentration under the standard curve. The test compound (500. mu.g) was shaken with an aqueous test solution (250. mu.L) in a closed vessel (volume: 1.5mL) for 16 hours (Eppendorf Thermoshaker, 1400rpm, 25 ℃, covered with light). The sample was then centrifuged at maximum speed and the supernatant was finally filtered. The filtered supernatant samples were directly analyzed by HPLCUV measurement (see above). The samples were further analyzed after dilution (1 volume of supernatant, 39 volumes of test solution).
Evaluation: based on the established standard curve, the concentration of the test compound in the undiluted supernatant was calculated from the integrated UV absorption of the resulting supernatant sample and expressed as the solubility of the test compound in the respective aqueous test solution.
Examples of aqueous test solutions are deionized water or phosphate buffered aqueous solutions of various pH values (e.g., pH 1.2; pH 4.0; pH 6.8; pH 7.4; pH9.0), which can be prepared by standard methods from commercial solutions (phosphate buffered saline, 10X, Sigma) by dilution and adjustment with phosphoric acid or sodium hydroxide solution.
Preferred compounds of the invention exhibit a solubility in phosphate buffer (ph7.4) of at least 12.5 μ M; more preferably at least 50. mu.M and even more preferably at least 250. mu.M.
Metabolic stability
Metabolic stability was determined by incubating test compounds (5 μ M) with liver microsomes (1mg/mL protein + 0.1% w/vBSA; 1mM NADPH, 0.5% DMSO) at 37 ℃. Analysis was performed by LCMS/MS at 0 and 20 min incubation times. Further description of the test systems and reference to the test methods can be found in Plant, n.; drug Discovery Today 2004, 9(7), 328-336 and Lau, Y.Y., etc.; pharmaceutical Res.2002, 19, (11), 1606-1610.
Preparation method
The compounds of the formula I according to the invention are prepared in two steps by methods known per se.
Substituted isoxazolone compounds can be prepared by reacting the appropriately substituted acetoacetate derivative IIa with hydroxylamine as described, for example, in Bowden K., Crank C., Ross WJ., J.chem.Soc.C 1968, 172-185. Acetoacetate derivative IIa can be obtained commercially from commercial sources, or can be prepared by alkylating acetoacetate ester by known methods.
In a further step, the compounds of formula I according to the invention are prepared by acylation of unsubstituted or substituted isoxazolones II with carbamoyl chlorides III (method a) or in two steps by reacting 3-oxoisoxazolones II with phosgene or its equivalent, e.g. trichloromethyl chlorocarbonate, di-trichloromethyl carbonate or 4-nitrophenyl chloroformate and then reacting the resulting isoxazolone carboxylic acid derivatives with amines IV (method B) or by reacting isoxazolones II with the appropriate isocyanates V R1-N ═ C ═ O.
Since acids are usually liberated in these reactions, it is advisable to add bases such as pyridine, triethylamine, sodium hydroxide solution or alkali metal carbonates as promoters. The reaction can be carried out over a wide temperature range. It has generally proven advantageous to work at from 0 ℃ to the boiling point of the solvent used. Examples of the solvent used are dichloromethane, THF, DMF, toluene, ethyl acetate, n-heptane, dioxane, diethyl ether or pyridine. If anhydrous conditions are employed, strong bases such as lithium hydride, sodium hydride or potassium tert-butoxide in aprotic solvents such as THF or DMF have proven suitable.
Examples
3-cyclopropyl-2H-isoxazol-5-ones
A solution of methyl 3-cyclopropyl-3-oxopropanoate (4.8g, 34mmol) in methanol (80mL) was mixed with hydroxylamine hydrochloride (2.6g, 38mmol) and triethylamine (5.3mL, 38mmol) and the mixture was heated under reflux for 2 h. The solvent was evaporated in vacuo. Ethyl acetate was added to the residue and filtered through silica gel.
Yield: 3.2g (75.2%).
Isoxazolones bearing various substituents at the 3-position or additional substituents at the 4-position are prepared in a similar manner. In these cases, the substituted acetoacetate derivative used is either commercially available or can be prepared by alkylating acetoacetate esters by known methods.
5-oxo-5H-isoxazole-2-carboxamides
3-cyclopropyl-5-oxo-5H-isoxazol-2-thiophen-2-ylmethyl-carboxamide
A toluene solution of phosgene (20%, 1mL, 2mmol) was diluted with THF (10 mL). To this solution was added a solution of 3-cyclopropyl-2H-isoxazol-5-one (125mg, 1mmol) in THF (5mL) and to the mixture was added triethylamine (140 μ L, 1mmol), and the mixture was stirred at 25 ℃ for 8 hours. The precipitate was then filtered off and the filtrate was concentrated in vacuo. THF (10mL) was added to the residue and added to a solution of 2-thiophen-2-methylamine (113.2mg, 1mmol) in pyridine (10 mL). The mixture was stirred at 25 ℃ for 16 hours. The solvent was then evaporated in vacuo and the residue was purified by HPLC.
Yield: 66mg (25%)
Accordingly, isoxazolinones bearing various substituents at the 3 and 4 positions are converted to the corresponding 5-oxo-5H-isoxazole-2-carboxamides by reaction with various amines.
The following detailed description of the embodiments is intended to illustrate, but not limit the invention.

Claims (18)

1. A compound of the formula I, tautomeric forms of the compound and physiologically tolerable salts thereof
The meaning is as follows:
r1 is (C)5-C16) -alkyl, Y-aryl, Y-heteroaryl, wherein aryl or heteroaryl may be substituted one or more times by: F. cl, Br, I、OH、CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl, O- (C)1-C4) -alkoxy- (C)1-C4) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) Haloalkyl, O- (C)2-C4) -haloalkyl, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, O- (C)3-C8) -cycloalkyl, (C)2-C6) -alkynyl, (C)0-C8) Alkylene-aryl, O- (C)0-C8) Alkylene-aryl, S-aryl, (C)0-C8) Alkylene-heteroaryl, N (R4) (R5), SO2-CH3、SO2-NH2、SF5、COOH、COO-(C1-C6) Alkyl, CON (R6) (R7), N (R8) CO (R9), N (R10) SO2(R11)、CO(R12)、(CR13R14)x-O(R15)、O-CO-N(R16)(R17)、O-CO-(C1-C6) alkylene-CO-O- (C)1-C6) Alkyl, O-CO- (C)1-C6) alkylene-CO-OH, O-CO- (C)1-C6) alkylene-CO-N (R18) (R19), wherein the aryl or heteroaryl group may in turn be substituted one or more times by:
F、Cl、Br、I、OH、CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl, O- (C)1-C4) -alkoxy- (C)1-C4) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) -haloalkyl, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, O- (C)3-C8) -cycloalkyl, (C)2-C6) Alkynyl, N (R4a) (R5a), SO2-CH3、SF5、COOH、COO-(C1-C6) Alkyl, CON (R6a) (R7a), N (R8a) CO (R9a), N (R10a) SO2(R11a)、CO(R12a)、(CR13aR14a)x′-O(R15a)、O-CO-N(R16a)(R17a)、O-CO-(C1-C6) alkylene-CO-O-, (C1-C6) Alkyl, O-CO- (C)1-C6) alkylene-CO-OH, O-CO- (C)1-C6) -alkylene-CO-N (R18a) (R19 a);
x, x' are 0, 1, 2, 3, 4, 5, 6;
r4, R5, R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R4a, R5a, R6a, R7a, R9a, R10a, R11a, R12a, R13a, R14a, R15a, R16a, R17a, R18a, R19a are independently of one another hydrogen, (C5), (C6), R7, R9, R5 181-C8) -an alkyl group;
or a radical of the formula Ia
Wherein
W is-C (R26) (R27) -, -C (R26) (R27) -C (R28) (R29) -, -C (R26) (R27) -O-; r20, R21, R22, R23, R24, R25, R26, R27, R28 and R29 are the same or different and are hydrogen, F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、SF5、O-(C1-C6) Alkyl, O- (C)1-C4) -alkoxy- (C)1-C4) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) Haloalkyl, O- (C)2-C4) -haloalkyl, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, O- (C)3-C8) -cycloalkyl, (C)3-C8) Cycloalkenyl radical, (C)2-C6) Alkynyl, N (R30) (R31), SO2-CH3、COOH、COO-(C1-C6) Alkyl, CON (R32) (R33), N (R34) CO (R35), N (R36) SO2(R37)、CO(R38)、(CR39R40)x″-O(R41)、O-CO-N(R42)(R43)、O-CO-(C1-C6) alkylene-CO-O- (C)1-C6) Alkyl, O-CO- (C)1-C6) alkylene-CO-OH, O-CO- (C)1-C6) -alkylene-CO-N (R44) (R45);
x' is 0, 1, 2, 3, 4, 5, 6;
R30、R31、R32、R33、R34、R35、R36、R37、R38、R39、R40、R41、R42、R43、R44、R45
identical or different, is hydrogen, (C)1-C6) -an alkyl group;
or
R20 and R26 or R21 and R27 together with the carbon atoms carrying them form a monocyclic, 5-or 6-membered saturated, partially unsaturated or aromatic ring system, individual members of which may be replaced by-CHR 46-, -CR46R47-, (C-R46) -;
or
R22 and R24 or R23 and R25 together with the carbon atoms carrying them form a monocyclic, 5-or 6-membered saturated, partially unsaturated or aromatic ring system, individual members of which may be replaced by-CHR 46-, -CR46R47-, (C-R46) -;
r46 and R47 are the same or different and are F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、SF5、O-(C1-C6) Alkyl, O- (C)1-C4) -alkoxy- (C)1-C4) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) Haloalkyl, O- (C)2-C4) -haloalkyl, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, O- (C)3-C8) -cycloalkyl, (C)2-C6) Alkynyl, N (R48) (R49), SO2-CH3、COOH、COO-(C1-C6) Alkyl, CON (R50) (R51), N (R52) CO (R53), N (R54) SO2(R55)、CO(R56)、(CR57R58)x′″-O(R59)、O-CO-N(R60)(R61)、O-CO-(C1-C6) alkylene-CO-O- (C)1-C6) Alkyl, O-CO- (C)1-C6) alkylene-CO-OH, O-CO- (C)1-C6) -alkylene-CO-N (R62) (R63);
x′″0、1、2、3、4、5、6；
R48、R49、R50、R51、R52、R53、R54、R55、R56、R57、R58、R59、R60、R61、R62、R63
is the same as orDifferent from hydrogen, (C)1-C6) -an alkyl group;
y, Z are the same or different and are (C)1-C2) Alkylene which may be substituted by F, Cl, CH3Or OH substitution;
r2 is hydrogen, (C)1-C12) Alkyl, Z-aryl, wherein aryl or heteroaryl may be optionally substituted, (C)3-C12) -a cycloalkyl group;
r3 is (C)1-C12) Alkyl, aryl, heteroaryl, wherein aryl or heteroaryl may be optionally substituted, (C)3-C12) -a cycloalkyl group; or
R2 and R3 together with the carbon atoms carrying them form a monocyclic, saturated or partially unsaturated 4-to 8-membered ring system, individual members of which may be replaced by one to three atoms or groups selected from-CHR 64-, -CR64R65-, (C-R66) -, -NR67-, -C (═ O) -, -O-, with the proviso that two units selected from-O-may not be adjacent;
r64, R65, R66 and R67 are the same or different and are hydrogen, F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、SF5、O-(C1-C6) Alkyl, O- (C)1-C4) -alkoxy- (C)1-C4) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) Haloalkyl, O- (C)2-C4) -haloalkyl, (C)2-C6) -alkenyl, (C)3-C8) -cycloalkyl, O- (C)3-C8) -cycloalkyl, (C)3-C8) Cycloalkenyl radical, (C)2-C6) Alkynyl, N (R68) (R69), SO2-CH3、COOH、COO-(C1-C6) Alkyl, CON (R70) (R71), N (R72) CO (R73), N (R74) SO2(R75)、CO(R76)、(CR77R78)x″″-O(R79)、O-CO-N(R80)(R81)、O-CO-(C1-C6) alkylene-CO-O- (C)1-C6) Alkyl, O-CO- (C)1-C6) alkylene-CO-OH, O-CO- (C)1-C6) -alkylene-CO-N (R82) (R83);
x "" is 0, 1, 2, 3, 4, 5, 6;
R68、R69、R70、R71、R72、R73、R74、R75、R76、R77、R78、R79、R80、R81、R82、R83
identical or different, is hydrogen, (C)1-C6) -an alkyl group;
with the proviso that compounds in which R1 ═ cyclohexyl, R2 ═ H and R3 ═ phenyl are excluded.
2. A compound of the formula I as claimed in claim 1, in which the tautomeric forms of the compounds and their physiologically tolerable salts are
R1 is (C)5-C12) -alkyl, Y-phenyl, Y-heteroaryl, wherein heteroaryl comprises one heteroatom selected from N, O, S and wherein phenyl or heteroaryl may be substituted one or more times by: F. cl, Br, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) -haloalkyl, (C)3-C8) -cycloalkyl, (C)0-C6) Alkylene-phenyl, O- (C)0-C6) Alkylene-phenyl, S-phenyl, (C)0-C8) Alkylene-heteroaryl, N (R4) (R5), COOH, COO- (C)1-C6) -alkyl, CON (R6) (R7), CO (R12), wherein the phenyl or heteroaryl group may in turn be substituted one or more times by:
F、Cl、OH、CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl, S- (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) -haloalkyl, (C)3-C8) Cycloalkyl, N (R4a) (R5a), COOH, COO- (C)1-C6) -alkyl, CON (R6a) (R7a), CO (R12 a);
x, x' are 0, 1, 2, 3, 4, 5, 6;
R4、R5、R6、R7、R12、R4a、R5a、R6a、R7a、R12a
identical or different, is hydrogen, (C)1-C8) -an alkyl group;
or a radical of the formula Ib
Wherein
W is-C (R26) (R27) -, -C (R26) (R27) -C (R28) (R29) -, -C (R26) (R27) -O-; r20, R21, R26, R27, R28 and R29
Identical or different and are hydrogen, F, Cl, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) Alkyl, CO- (C)1-C6) -an alkyl group;
or
R20, R21, R26 and R27 form together with the carbon atoms bearing them a fused benzene residue which may be substituted one or more times with: F. cl, CN, NO2、CF3、OCF3、(C1-C6) Alkyl, O- (C)1-C6) Alkyl, CO- (C)1-C6) -an alkyl group;
y, Z are the same or different and are-CH2-or-CH2-CH2-, which may be substituted by CH3Or OH once;
r2 is hydrogen, (C)1-C12) -alkyl, Z-phenyl, wherein the phenyl group may optionally be substituted, (C)3-C12) -a cycloalkyl group;
r3 is (C)1-C12) -alkyl, phenyl, heteroaryl, said heteroaryl comprising one heteroatom selected from N, O, S, wherein phenyl or heteroaryl may be optionally substituted, (C)3-C12) -a cycloalkyl group; or
R2 and R3 together with the carbon atoms carrying them form a monocyclic, saturated, 5-to 7-membered ring system, individual members of which may be replaced by one to three groups selected from-CHR 64-, -CR64R65-, (C-R66) -;
r64, R65 and R66 are the same or different and are F, Cl, OH, CF3、O-(C1-C6) Alkyl, O- (C)1-C4) -alkoxy- (C)1-C4) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C4) -haloalkyl, (C)3-C8) Cycloalkyl, N (R68) (R69), SO2-CH3、COOH、COO-(C1-C6) Alkyl, CON (R70) (R71), N (R72) CO (R73), CO (R76), O-CO-N (R80) (R81), O-CO- (C)1-C6) alkylene-CO-O- (C)1-C6) Alkyl, O-CO- (C)1-C6) alkylene-CO-OH, O-CO- (C)1-C6) -alkylene-CO-N (R82) (R83);
R68、R69、R70、R71、R72、R73、R76、R77、R78、R79、R80、R81、R82、R83
independently of one another, hydrogen, (C)1-C6) -an alkyl group.
3. A compound of the formula I as claimed in claim 1 or 2, the tautomeric forms of the compound and the physiologically tolerable salts thereof, wherein
R1 is (C)5-C8) Alkyl, Y-phenyl, Y-pyridyl, Y-thienyl, Y-furyl, Y-benzothienyl, Y-benzofuryl, where the phenyl or heteroaromatic radical may be substituted by F, Cl, Br, CF3、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)3-C6) Cycloalkyl, N (R4) (R5), COOH, COO- (C)1-C6) Alkyl, CON (R6) (R7), CO (R12) once, twice or three times and may be substituted by (C)0-C1) Alkylene-phenyl, O- (C)0-C1) Phenyl, pyrazolyl, pyridyl, thienyl, furyl, benzothienyl, benzofuryl once, where the heteroaromatic radicals or phenyl radicals can in turn be substituted once, twice or three times by: F. cl, Br, CF3、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)3-C6) Cycloalkyl, N (R4a) (R5a), COOH, COO- (C)1-C6) -alkyl, CON (R6a) (R7a), CO (R12 a);
r4, R5, R6, R7, R12, R4a, R5a, R6a, R7a, R12a are independently of each other H, (C)1-C8) -an alkyl group;
or the following groups
R20, R21, R26, R27, R28 and R29 are the same or different and are hydrogen or (C)1-C6) -alkyl, preferably hydrogen and methyl;
y is-CH2-or-CH2-CH2-, which may be substituted by CH3Once substituted;
r2 is hydrogen, (C)1-C8) -alkyl, -CH2-phenyl, wherein phenyl may be optionally substituted, (C)3-C8) -a cycloalkyl group;
r3 is (C)1-C8) -alkyl, phenyl, pyridyl, thienyl, wherein phenyl, pyridyl or thienyl may be optionally substituted, (C)3-C8) -a cycloalkyl group; or
R2 and R3 together with the carbon atoms carrying them form a monocyclic, saturated 6-to 7-membered ring system, the individual members of which may be replaced by one to three atoms or groups selected from-CHR 64-, -CR64R 65-;
r64 and R65 are the same or different and are F, Cl or CF3、OCF3、(C1-C6) Alkyl, O- (C)1-C6) Alkyl, N (R68) (R69), COOH, COO- (C)1-C6) -alkyl, CO-N (R70) (R71), CO (R76);
r68, R69, R70, R71 and R76 are the same or different and are hydrogen or (C)1-C6) -an alkyl group.
4. A compound of formula I according to claims 1 to 3, wherein
R2 is propyl, and
r3 is methyl.
5. A compound of formula I according to claims 1 to 3, wherein
R2 is hydrogen, and
r3 is phenyl, which may be substituted once by Cl.
6. A compound of formula I according to claims 1 to 3, wherein
R2 and R3 taken together are-CH2-CH2-CH2-CH2-or-CH2-CH2-CH2-CH2-CH2-。
7. A compound of the formula I as claimed in claims 1 to 3, the tautomeric forms of the compound and the physiologically tolerable salts thereof, wherein
R1 is (C)5-C7) Alkyl, Y-phenyl, Y-thienyl, Y-benzothienyl, where the phenyl or heteroaromatic radical may be substituted by F, Cl, Br, CF3、O-CH3、-CH3、-CH2CH3、-CH2-CH2-CH2-CH3Once, twice or three times and once with phenyl, pyrazolyl or thienyl,
wherein the heteroaromatic radical or phenyl radical may in turn be substituted by F, Cl, Br, CF3、
O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl substitution once, twice or three times;
or the following groups
R20, R21, R26, R27, R28 and R29 are the same or different and are hydrogen or CH3；
Y is-CH2-, which may be substituted by CH3Once substituted;
r2 is hydrogen, methyl, isopropyl, cyclopropyl, phenyl, -CH2-phenyl, wherein phenyl may be substituted in the 4-position with Cl;
r3 is methyl, phenyl, pyridyl, cyclopropyl, wherein phenyl may be substituted by Cl; or
R2 and R3 taken together are-CH2-CH2-CH2-CH2-or-CH2-CH2-CH2-CH2-CH2。
8. Medicaments comprising one or more compounds of the formula I as claimed in claims 1 to 7.
9. Use of a compound of formula I as claimed in claims 1 to 7 for the preparation of a medicament for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders.
10. The use of a compound of the formula I as claimed in claims 1 to 7 for the preparation of medicaments for the treatment and/or prophylaxis of disorders in which insulin resistance is involved.
11. The use of compounds of the formula I as claimed in claims 1 to 7 for the preparation of medicaments for the treatment and/or prophylaxis of diabetes mellitus and the sequelae associated therewith.
12. The use of compounds of the formula I as claimed in claims 1 to 7 for the preparation of medicaments for the treatment and/or prophylaxis of dyslipidemia and its sequelae.
13. Use of a compound of formula I as claimed in claims 1 to 7 for the preparation of a medicament for the treatment and/or prevention of disorders associated with the metabolic syndrome.
14. The use of compounds of the formula I as claimed in claims 1 to 7 for the preparation of medicaments for the treatment and/or prophylaxis of disorders which are associated with a reduced HDL level.
15. Use of a compound of formula I as claimed in claims 1 to 7 for the preparation of a medicament for the treatment and/or prophylaxis of atherosclerotic disorders.
16. The use of a compound of the formula I as claimed in claims 1 to 7 in combination with at least one further active ingredient for the preparation of a medicament for the treatment and/or prophylaxis of disorders in which insulin resistance is involved.
17. A process for the preparation of a medicament comprising one or more compounds of formula I as claimed in claims 1 to 7, which process comprises mixing the compounds with a pharmaceutically acceptable carrier and converting the mixture into a form suitable for administration.
18. A process for the preparation of compounds of formula I as claimed in claims 1 to 7, which comprises reacting a 3-oxoisoxazole derivative of formula II
a) Acylation with a carbamoyl chloride of formula III;
or
b) First with phosgene or its equivalent, for example trichloromethyl chlorocarbonate, bis-trichloromethyl carbonate or 4-nitrophenyl chloroformate, and in a second step with an amine of formula IV; or
c) And formula V: reacting O-C-N-R1 isocyanate,
wherein the substituents have the meanings indicated above,
HK10103420.2A 2007-04-05 2008-03-22 5-oxo-isoxazoles as inhibitors of lipases and phospholipases HK1138263A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP07007251.7 2007-04-05

Publications (1)

Publication Number Publication Date
HK1138263A true HK1138263A (en) 2010-08-20

Family

ID=

Similar Documents

Publication Publication Date Title
US8148395B2 (en) Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
US7772268B2 (en) Diacyl indazole derivatives as lipase and phospholipase inhibitors
US7897616B2 (en) Imidazopyridin-2-one derivatives as inhibitors of lipases and phospholipases
US7718669B2 (en) Triazolopyridine derivatives as inhibitors of lipases and phospholipases
US8735437B2 (en) Imidazolidine carboxamide derivatives as lipase and phospholipase inhibitors
AU2006303552A1 (en) Carbamoylbenzotriazole derivatives as inhibitors of lipases and phospholipases
US9029400B2 (en) 5-oxoisoxazoles as inhibitors of lipases and phospholipases
HK1138263A (en) 5-oxo-isoxazoles as inhibitors of lipases and phospholipases
HK1130795A (en) Azolopyridin-3-one derivatives as inhibitors of endothelial lipase
HK1124850A (en) Diacyl indazol derivatives as lipase and phospholipase inhibitors
HK1130773A (en) Imidazopyridin-2-one derivatives as inhibitors of endothelial lipase
HK1125364A (en) Carbamoylbenzotriazole derivatives as inhibitors of lipases and phospholipases