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HK1077507B - 2,4,5-trisubstituted thiazolyl derivatives ant their antiinflammatory activity - Google Patents

2,4,5-trisubstituted thiazolyl derivatives ant their antiinflammatory activity Download PDF

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Publication number
HK1077507B
HK1077507B HK05109570.4A HK05109570A HK1077507B HK 1077507 B HK1077507 B HK 1077507B HK 05109570 A HK05109570 A HK 05109570A HK 1077507 B HK1077507 B HK 1077507B
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Hong Kong
Prior art keywords
alkyl
group
formula
amino
compound
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HK05109570.4A
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Chinese (zh)
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HK1077507A1 (en
Inventor
Christopher John Love
Jean. Pierre Frans Van Wauwe
Marc J. De Brabander
Roger Clive Moses
Mykhaylo Goncharenko
Ludwig Paul Cooymans
Nele Vandermaesen
Gaston Stanislas Marcella Diels
Anthony William Sibley
Caterina Noula
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Janssen Pharmaceutica N. V.
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Priority claimed from PCT/EP2002/008956 external-priority patent/WO2003015776A1/en
Publication of HK1077507A1 publication Critical patent/HK1077507A1/en
Publication of HK1077507B publication Critical patent/HK1077507B/en

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Description

2, 4, 5-trisubstituted thiazole derivatives and their anti-inflammatory activity
The present invention relates to 2, 4, 5-trisubstituted thiazole derivatives having properties inhibiting the production of proinflammatory cytokines. The invention also relates to a preparation method thereof and a pharmaceutical composition containing the same. The invention also relates to the use of 2, 4, 5-trisubstituted thiazole derivatives for the manufacture of a medicament for the prevention or treatment of diseases mediated by TNF-alpha and/or IL-12.
WO 00/35911 describes acetal derivatives useful as TNF- α inhibitors.
WO 96/03392 describes sulfonyl derivatives for use in the treatment of inflammation.
WO 98/01449 describes pyrimidine fused compounds for use as antiallergic and antiinflammatory agents.
US 5,249,929 describes 2-heterocyclic-5-hydroxy-1, 3-pyrimidines for use as anti-inflammatory agents.
Chem., 1969, 9(5), 186-.
EP 117,082 describes thiazole derivatives as cardiotonic, blood pressure regulating and antiulcer agents.
Chem. pharm. Bull., 1982, 30(6), 1974-1979 discloses the study of tertiary amine oxides.
WO 97/05131 describes heteroaryl carboxamides for use as agricultural and medical fungicides.
JP 91-144612 relates to isoxazoles useful as disinfectants, antiseptics, anti-inflammatory agents, germicides and virucidal agents.
Arch.pharm.1981, 314(9), 744-750 describe the synthesis and antibacterial effect of 2-aryl-4-R-5 glyoxylthiazole.
Naturforsch. B chem. Sci.1990, 45(12), 1695-.
Synthesis 1988, 3, 194-198 describes a process for introducing trifluoromethyl groups into heteroarenes by regioselective reactions.
J.Med.chem.1998, 31(6), 1197-1204 describes the synthesis of oxazole derivatives useful as hypolipidemic agents, anticholesterolemic agents and platelet aggregation inhibitors.
Chem. Ber.1982, 115(7)2494-2507 relates to a synthesis method of 1, 3-azole compounds.
DD 258165 describes quinoxaline derivatives useful as herbicides and fungicides.
Chem.1979, 19(1), 21-22 relates to heterocyclic substituted thiazoles for use as pesticides.
Indian j.chem., sect.b, 1976, 14B (7), 552-555 relate to synthetic methods and anti-inflammatory activities of dithiazole derivatives.
Justus Liebigs Ann. chem.1974, 8, 1195-A1205 describe the synthesis of thiazole compounds.
DE 1959307 relates to benzoxazole derivatives as optical brighteners.
GB 1189008 relates to benzoxazole derivatives as optical brighteners.
JP 41012946 describes benzoxazole and benzimidazole derivatives for use as optically brightened organic fibers.
Chem. Ber.1967, 100(7), 2184-2187 describe the synthesis of thiophene derivatives.
US 6,231,786 describes fluorinated azole compounds and their use in liquid crystal mixtures.
WO 01/30778 discloses thiazoles and imidazopyridines for the treatment of TNF and IL-1 mediated diseases.
WO 98/08830 and WO 98/08841 disclose thiazole derivatives having PDE IV inhibitory activity.
WO 01/64674 describes 2, 4-disubstituted thiazolyl derivatives useful as TNF-alpha and/or IL-12 inhibitors.
The compounds of the invention differ from the prior art in their structure, pharmacological activity, potency or physicochemical properties (improved chemical stability, improved solubility).
The invention relates to the use of a compound for the manufacture of a medicament for the prevention or treatment of diseases caused by THF-alpha (tumor necrosis factor-alpha) and/or IL-12 (interleukin 12), wherein the compound is a compound of formula (I), an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof,
wherein
Z is halogen; c1-6An alkyl group; hydroxy, carboxy, cyano, amino, mono-or di (C)1-6Alkyl) amino, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6Alkoxycarbonyl or C1-6Alkoxy-substituted C1-6An alkyl group; polyhalo C1-4An alkyl group; c1-4An alkoxy group; a cyano group; an amino group; an aminocarbonyl group; mono or di (C)1-6Alkyl) aminocarbonyl; c1-6An alkoxycarbonyl group; c1-6Alkylcarbonyloxy H2N-S(＝O)2-; mono or di (C)1-6Alkyl) amino-S (═ O)2；-C(＝N-Rx)NRyRz；
RxIs hydrogen, C1-6Alkyl, cyano, nitro or-S (═ O)2-NH2；
RyIs hydrogen, C1-6Alkyl radical, C2-6Alkenyl or C2-6An alkynyl group;
Rzis hydrogen or C1-6An alkyl group;
q is C3-6Cycloalkyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridinyl, wherein each ring may be optionally substituted with up to three substituents independently selected from the group consisting of: halogen; a hydroxyl group; a cyano group; a carboxyl group; an azide group; an amino group; mono or di (C)1-6Alkyl) amino; c1-6An alkylcarbonylamino group; c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; c3-6A cycloalkyl group; with hydroxy groups, C1-6Alkoxy, amino, mono-or di (C)1-4Alkyl) amino-substituted C1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylthio group; c1- 6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; aryl radical C1-6An alkoxy group; an aryloxy group; polyhalo C1-6An alkyl group; polyhalo C1-6An alkoxy group; polyhalo C1-6An alkylcarbonyl group; c1-4alkyl-S (═ O)n-or R1HN-S(＝O)n-, wherein R1Represents hydrogen or a group of formula (a-1):
wherein A is O, S or has the formula-CR2A divalent radical of ═ N-, in which CR is2Is linked to N of formula (a-1); and R is2Is hydrogen, C1-6Alkyl or C1-6An alkoxy group;
or
Q is a group of formula (b-1), (b-2) or (b-3):
wherein B is1And B2Are each independently O, NR3、CH2Or S, wherein R3Is hydrogen or C1-4An alkyl group;
B3is O or NR4Wherein R is4Is hydrogen or C1-4An alkyl group;
q is an integer of 1 to 4;
r is an integer of 1 to 3;
n is an integer of 1 or 2;
l is phenyl substituted with up to 4 substituents independently selected from: c1-6An alkoxycarbonyl group; c1-6An alkylcarbonyloxy group; an aminocarbonyl group; mono or di (C)1-6Alkyl) aminocarbonyl; c1-6alkyl-C (═ O) -NH-; c1-6alkoxy-C (═ O) -NH-; h2N-C (═ O) -NH-; mono or di (C)1-4Alkyl) amino-C (═ O) -NH-; Het-NH-; het1-NH-；-NH-C(＝N-Rx)NRyRz；-C(＝N-Rx)NRyRz；Het1(ii) a Or of the formula-X-C1-Y1-C2-Y2-C3-Y3-C4A group of-Z (c-1), wherein
X represents NR5O, S or a straight bond;
C1、C2、C3and C4Each independently represents C1-6Alkanediyl, or a direct bond;
Y1、Y2and Y3Each independently represents NR5O, S or a straight bond;
z is hydrogen, halogen, cyano, hydroxy, carboxy, -P (═ O) (OH) H, -P (═ O) (OH)2、P(＝O)(OH)CH3、-P(＝O)(OH)(OCH3)、-P(＝O)(OH)(OCH2CH3)、-P(＝O)(OH)NH2、-S(＝O)2H、-S(＝O)2(OH)、-S(＝O)2NH、-C(＝O)-NH-S(＝O)2-H, tetrazolyl, 3-hydroxy-isothiazolyl, 3-hydroxy-isoxazolyl, 3-hydroxy-thiadiazolyl, mercaptotetrazolyl, 3-mercapto-triazolyl, 3-sulfinyl-triazolyl, 3-sulfonyl-triazolyl;
R5is hydrogen, C1-6Alkyl or-C (-NH) -N (R)z)2(ii) a Wherein at R5And C in the definition of the radical of the formula (C-1)1-6Alkyl radical, C1-6Alkanediyl, C2-6Alkenediyl or C2-61-3 hydrogen atoms of the alkynediyl group may be optionally and independently substituted with: halogen, hydroxy, carboxy, -P (═ O) (OH) H, -P (═ O) (OH)2、P(＝O)(OH)CH3、-P(＝O)(OH)(OCH3)、-P(＝O)(OH)(OCH2CH3)、-P(＝O)(OH)NH2、-S(＝O)2H、-S(＝O)2(OH)、-S(＝O)2NH、-C(＝O)-NH-S(＝O)2-H, tetrazolyl, 3-hydroxy-isothiazolyl, 3-hydroxy-isoxazolyl, 3-hydroxy-thiadiazolyl, mercaptotetrazolyl, 3-mercapto-triazolyl, 3-sulfinyl-triazolyl, 3-sulfonyl-triazolyl;
or
L is a 5-or 6-membered partially saturated or aromatic monocyclic heterocycle or a partially saturated or aromatic bicyclic heterocycle wherein each of said rings may be optionally substituted with up to 3 substituents each independently selected from: c1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-; c1-6alkoxy-C (═ O) -NH-; h2N-C (═ O) -NH-; mono or di (C)1-4Alkyl) amino-C (═ O) -NH-; Het-NH-; het1-NH-；-NH-C(＝N-Rx)NRyRz；-C(＝N-Rx)NRyRz；Het1(ii) a Or of the formula-X-C1-Y1-C2-Y2-C3-Y3-C4A group of-Z (c-1), wherein
X represents NR5O, S or a straight bond;
C1、C2、C3and C4Each independently represents C1-6Alkanediyl, C2-6Alkenediyl, C2-6Alkyndiyl or a direct bond;
Y1、Y2and Y3Each independently represents NR5O, S or a straight bond;
z is hydrogen, halogen, cyano, hydroxy, carboxy, -P (═ O) (OH) H, -P (═ O) (OH)2、P(＝O)(OH)CH3、-P(＝O)(OH)(OCH3)、-P(＝O)(OH)(OCH2CH3)、-P(＝O)(OH)NH2、-S(＝O)2H、-S(＝O)2(OH)、-S(＝O)2NH、-C(＝O)-NH-S(＝O)2-H, tetrazolyl, 3-hydroxy-isothiazolyl, 3-hydroxy-isoxazolyl, 3-hydroxy-thiadiazolyl, mercaptotetrazolyl, 3-mercapto-triazolyl, 3-sulfinyl-triazolyl, 3-sulfonyl-triazolyl;
R5is hydrogen, C1-6Alkyl or-C (-NH) -N (R)z)2(ii) a Wherein at R5And C in the definition of the radical of the formula (C-1)1-6Alkyl radical, C1-6Alkanediyl, C2-6Alkenediyl or C2-61-3 hydrogen atoms of the alkynediyl group may be optionally and independently substituted with: halogen, hydroxy, carboxy, -P (═ O) (OH) H, -P (═ O) (OH)2、-P(＝O)(OH)CH3、-P(＝O)(OH)-(OCH3)、-P(＝O)(OH)(OCH2CH3)、-P(＝O)(OH)NH2、-S(＝O)2H、-S(＝O)2(OH)、-S(＝O)2NH、-C(＝O)-NH-S(＝O)2-H, tetrazolyl, 3-hydroxy-isothiazolyl, 3-hydroxy-isoxazolyl, 3-hydroxy-thiadiazolyl, mercaptotetrazolyl, 3-mercapto-triazolyl, 3-sulfinyl-triazolylAzolyl, 3-sulfonyl-triazolyl;
het is a5 or 6 membered partially saturated or aromatic monocyclic heterocycle or a partially saturated or aromatic bicyclic heterocycle wherein each of said rings may be optionally substituted with up to 3 substituents each independently selected from: halogen, hydroxy, amino, cyano, carboxy, mono-or di (C)1-6Alkyl) amino, C1-6Alkyl, with hydroxy or C1-4Alkoxy or amino or mono-or di (C)1-4Alkyl) amino-substituted C1-6Alkyl, polyhalo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-, C1-6alkoxy-C (═ O) -NH-, H2N-C (═ O) -NH-, or mono-or di (C)1-4Alkyl) amino-C (═ O) -NH-;
Het1is a saturated 6-membered heterocyclic ring selected from: piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, wherein said saturated 6-membered heterocycle may be optionally substituted by amino or optionally aryl1-4Alkyl substitution;
aryl is phenyl, optionally substituted with up to 5 substituents, each of which is independently selected from halogen, hydroxy, C1-6Alkyl, polyhalo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, cyano, nitro, amino, mono-or di (C)1-6Alkyl) amino.
The invention also relates to a compound of the formula:
n-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof,
wherein
Z is halogen; c1-6An alkyl group; hydroxy, carboxy, cyano, amino, mono-or di (C)1-6Alkyl) amino, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6Alkoxycarbonyl or C1- 6Alkoxy-substituted C1-6An alkyl group; polyhalo C1-4An alkyl group; c1-4An alkoxy group; a cyano group; an amino group; an aminocarbonyl group; mono or di (C)1-6Alkyl) aminocarbonyl; c1-6An alkoxycarbonyl group; c1-6An alkylcarbonyloxy group; h2N-S(＝O)2-; mono or di (C)1-6Alkyl) amino-S (═ O)2；-C(＝N-Rx)NRyRz；
RxIs hydrogen, C1-6Alkyl, cyano, nitro or-S (═ O)2-NH2；
RyIs hydrogen, C1-6Alkyl radical, C2-6Alkenyl or C2-6An alkynyl group;
Rzis hydrogen or C1-6An alkyl group;
q is C3-6Cycloalkyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridinyl, wherein each ring may be optionally substituted with up to three substituents independently selected from the group consisting of: halogen; a hydroxyl group; a cyano group; a carboxyl group; an azide group; an amino group; mono or di (C)1-6Alkyl) amino; c1-6An alkylcarbonylamino group; c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; c3-6A cycloalkyl group; with hydroxy groups, C1-6Alkoxy, amino, mono-or di (C)1-4Alkyl) amino-substituted C1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylthio group; c1- 6An alkylcarbonyl group; c1-6Alkoxy radicalA carbonyl group; aryl radical C1-6An alkoxy group; an aryloxy group; polyhalo C1-6An alkyl group; polyhalo C1-6An alkoxy group; polyhalo C1-6An alkylcarbonyl group; c1-4alkyl-S (═ O)n-or R1HN-S(＝O)n-, wherein R1Represents hydrogen or a group of formula (a-1):
wherein A is O, S or has the formula-CR2A divalent radical of ═ N-, in which CR is2Is linked to N of formula (a-1); and R is2Is hydrogen, C1-6Alkyl or C1-6An alkoxy group;
or
Q is a group of formula (b-1), (b-2) or (b-3):
wherein B is1And B2Are each independently O, NR3、CH2Or S, wherein R3Is hydrogen or C1-4An alkyl group;
B3is O or NR4Wherein R is4Is hydrogen or C1-4An alkyl group;
q is an integer of 1 to 4;
r is an integer of 1 to 3;
n is an integer of 1 or 2;
l is a 5-or 6-membered partially saturated or aromatic monocyclic heterocycle or a partially saturated or aromatic bicyclic heterocycle wherein each of said rings may be optionally substituted with up to 3 substituents each independently selected from: c1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono orTwo (C)1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-; c1-6alkoxy-C (═ O) -NH-; h2N-C (═ O) -NH-; mono or di (C)1-4Alkyl) amino-C (═ O) -NH-; Het-NH-; het1-NH-；-NH-C(＝N-Rx)NRyRz；-C(＝N-Rx)NRyRz；Het1(ii) a Or of the formula-X-C1-Y1-C1-Y2-C3-Y3-C4A group of-Z (c-1), wherein
X represents NR5O, S or a straight bond;
C1、C2、C3and C4Each independently represents C1-6Alkanediyl, C2-6Alkenediyl, C2-6Alkyndiyl or a direct bond;
Y1、Y2and Y3Each independently represents NR5O, S or a straight bond;
z is hydrogen, halogen, cyano, hydroxy, carboxy, -P (═ O) (OH) H, -P (═ O) (OH)2、P(＝O)(OH)CH3、-P(＝O)(OH)(OCH3)、-P(＝O)(OH)(OCH2CH3)、-P(＝O)(OH)NH2、-S(＝O)2H、-S(＝O)2(OH)、-S(＝O)2NH、-C(＝O)-NH-S(＝O)2-H, tetrazolyl, 3-hydroxy-isothiazolyl, 3-hydroxy-isoxazolyl, 3-hydroxy-thiadiazolyl, mercaptotetrazolyl, 3-mercapto-triazolyl, 3-sulfinyl-triazolyl, 3-sulfonyl-triazolyl;
R5is hydrogen, C1-6Alkyl or-C (-NH) -N (R)z)2(ii) a Wherein at R5And C in the definition of the radical of the formula (C-1)1-6Alkyl radical, C1-6Alkanediyl, C2-6Alkenediyl or C2-61-3 hydrogen atoms of the alkynediyl group may be optionally and independently substituted with: halogen, hydroxy, carboxy, -P (═ O) (OH) H, -P (═ O) (OH)2、P(＝O)(OH)CH3、-P(＝O)(OH)(OCH3)、-P(＝O)(OH)(OCH2CH3)、-P(＝O)(OH)NH2、-S(＝O)2H、-S(＝O)2(OH)、-S(＝O)2NH、-C(＝O)-NH-S(＝O)2-H, tetrazolyl, 3-hydroxy-isothiazolyl, 3-hydroxy-isoxazolyl, 3-hydroxy-thiadiazolyl, mercaptotetrazolyl, 3-mercapto-triazolyl, 3-sulfinyl-triazolyl, 3-sulfonyl-triazolyl;
het is a5 or 6 membered partially saturated or aromatic monocyclic heterocycle or a partially saturated or aromatic bicyclic heterocycle wherein each of said rings may be optionally substituted with up to 3 substituents each independently selected from: halogen, hydroxy, amino, cyano, carboxy, mono-or di (C)1-6Alkyl) amino, C1-6Alkyl, with hydroxy or C1-4Alkoxy or amino or mono-or di (C)1-4Alkyl) amino-substituted C1-6Alkyl, polyhalo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-, C1-6alkoxy-C (═ O) -NH-, H2N-C (═ O) -NH-, or mono-or di (C)1-4Alkyl) amino-C (═ O) -NH-;
Het1is a saturated 6-membered heterocyclic ring selected from: piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, wherein said saturated 6-membered heterocycle may be optionally substituted by amino or optionally aryl1-4Alkyl substitution;
aryl is phenyl, optionally substituted with up to 5 substituents, each said substituent being independently selected from halogen, hydroxy, C1-6Alkyl, polyhalo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, cyano, nitro, amino, mono-or di (C)1-6Alkyl) amino.
With the following conditions:
-when Z is methyl, Q is phenyl or phenyl substituted by halogen, methyl or ethoxy, then L is not quinoxalinyl;
-when Z is methyl, Q is phenyl or phenyl substituted in the para-position by methyl, chloro, nitro or methoxy, then L is not thiazolyl substituted by methyl or amino;
-when Z is trifluoromethyl and Q is 4-methylphenyl, then L is not 1, 2, 3-triazolyl mono-or disubstituted with methoxycarbonyl;
-L is not a substituted or unsubstituted benzoxazolyl group or a substituted or unsubstituted benzimidazolyl group;
the compound is not
The invention also relates to a compound of the formula:
n-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof,
wherein
Z is halogen; c1-6An alkyl group; by hydroxy, carboxy, cyano, amino, mono-or di (C)1-6Alkyl) amino, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6Alkoxycarbonyl or C1-6Alkoxy-substituted C1-6An alkyl group; polyhalo C1-4An alkyl group; c1-4An alkoxy group; a cyano group; an amino group; an aminocarbonyl group; mono or di (C)1-6Alkyl) aminocarbonyl; c1-6An alkoxycarbonyl group; c1-6An alkylcarbonyloxy group; h2N-S(＝O)2-; mono or di (C)1-6Alkyl) amino-S (═ O)2-；-C(＝N-Rx)NRyRz；
RxIs hydrogen, C1-6Alkyl, cyano, nitro or-S (═ O)2-NH2；
RyIs hydrogen, C1-6Alkyl radical, C2-6Alkenyl or C2-6An alkynyl group;
Rzis hydrogen or C1-6An alkyl group;
q is C3-6Cycloalkyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridinyl, wherein each ring may be optionally substituted with up to three substituents independently selected from the group consisting of: halogen; a hydroxyl group; a cyano group; a carboxyl group; an azide group; an amino group; mono or di (C)1-6Alkyl) amino; c1-6An alkylcarbonylamino group; c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; c3-6A cycloalkyl group; with hydroxy groups, C1-6Alkoxy, amino, mono-or di (C)1-4Alkyl) amino-substituted C1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylthio group; c1- 6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; aryl radical C1-6An alkoxy group; an aryloxy group; polyhalo C1-6An alkyl group; polyhalo C1-6An alkoxy group; polyhalo C1-6An alkylcarbonyl group; c1-4alkyl-S (═ O)n-or R1HN-S(＝O)n-, wherein R1Represents hydrogen or a group of formula (a-1):
wherein A is O, S or has the formula-CR2A divalent radical of ═ N-, in which CR is2Is linked to N of formula (a-1); and R is2Is hydrogen, C1-6Alkyl or C1-6An alkoxy group;
or
Q is a group of formula (b-1), (b-2) or (b-3):
wherein B is1And B2Are each independently O, NR3、CH2Or S, wherein R3Is hydrogen or C1-4An alkyl group;
B3is O or NR4Wherein R is4Is hydrogen or C1-4An alkyl group;
q is an integer of 1 to 4;
r is an integer of 1 to 3;
n is an integer of 1 or 2;
l is a 5-or 6-membered partially saturated or aromatic monocyclic heterocycle or a partially saturated or aromatic bicyclic heterocycle, wherein each of said rings may be optionally substituted with up to 3 substituents each independently selected from: c1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-; c1-6alkoxy-C (═ O) -NH-; h2N-C (═ O) -NH-; mono or di (C)1-4Alkyl) amino-C (═ O) -NH-; Het-NH-; het1-NH-；-NH-C(＝N-Rx)NRyRz；-C(＝N-Rx)NRyRz；Het1(ii) a Or of the formula-X-C1-Y1-C1-Y2-C3-Y3-C4A group of-Z (c-1), wherein
X represents NR5O, S or a straight bond;
C1、C2、C3and C4Each independently represents C1-6Alkanediyl, C2-6Alkenediyl, C2-6Alkyndiyl or a direct bond;
Y1、Y2and Y3Each independently represents NR5O, S or a straight bond;
z is hydrogen, halogen, cyano, hydroxy, carboxy, -P (═ O) (OH) H, -P (═ O) (OH)2、P(＝O)(OH)CH3、-P(＝O)(OH)(OCH3)、-P(＝O)(OH)(OCH2CH3)、-P(＝O)(OH)NH2、-S(＝O)2H、-S(＝O)2(OH)、-S(＝O)2NH、-C(＝O)-NH-S(＝O)2-H, tetrazolyl, 3-hydroxy-isothiazolyl, 3-hydroxy-isoxazolyl, 3-hydroxy-thiadiazolyl, mercaptotetrazolyl, 3-mercapto-triazolyl, 3-sulfinyl-triazolyl, 3-sulfonyl-triazolyl;
R5is hydrogen, C1-6Alkyl or-C (═ NH) -N (R)z)2(ii) a Wherein at R5And C in the definition of the radical of the formula (C-1)1-6Alkyl radical, C1-6Alkanediyl, C2-6Alkenediyl or C2-61-3 hydrogen atoms of the alkynediyl group may be optionally and independently substituted with: halogen, hydroxy, carboxy, -P (═ O) (OH) H, -P (═ O) (OH)2、P(＝O)(OH)CH3、-P(＝O)(OH)-(OCH3)、-P(＝O)(OH)(OCH2CH3)、-P(＝O)(OH)NH2、-S(＝O)2H、-S(＝O)2(OH)、-S(＝O)2NH、-C(＝O)-NH-S(＝O)2-H, tetrazolyl, 3-hydroxy-isothiazolyl, 3-hydroxy-isoxazolyl, 3-hydroxy-thiadiazolyl, mercaptotetrazolyl, 3-mercapto-triazolyl, 3-sulfinyl-triazolyl, 3-sulfonyl-triazolyl;
het is a5 or 6 membered moietyA monocyclic partially saturated or aromatic heterocycle or a bicyclic partially saturated or aromatic heterocycle wherein each of said rings may be optionally substituted with up to 3 substituents, each substituent being independently selected from: halogen, hydroxy, amino, cyano, carboxy, mono-or di (C)1-6Alkyl) amino, C1-6Alkyl, with hydroxy or C1-4Alkoxy or amino or mono-or di (C)1-4Alkyl) amino-substituted C1-6Alkyl, polyhalo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-, C1-6alkoxy-C (═ O) -NH-, H2N-C (═ O) -NH-, or mono-or di (C)1-4Alkyl) amino-C (═ O) -NH-;
Het1is a saturated 6-membered heterocyclic ring selected from: piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, wherein said saturated 6-membered heterocycle may be optionally substituted by amino or optionally aryl1-4Alkyl substitution;
aryl is phenyl, optionally substituted with up to 5 substituents, each of which is independently selected from halogen, hydroxy, C1-6Alkyl, polyhalo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, cyano, nitro, amino, mono-or di (C)1-6Alkyl) amino.
With the following conditions:
-L is not substituted phenyl;
-when Z is methyl, Q is phenyl or phenyl substituted by halogen, methyl or ethoxy, then L is not quinoxalinyl;
-when Z is methyl, Q is phenyl or phenyl substituted in the para-position by methyl, chloro, nitro or methoxy, then L is not thiazolyl substituted by methyl or amino;
the compounds used as medicaments are not the following compounds
C as a group or part of a group as used hereinbefore or hereinafter1-4Alkyl is defined as a straight or branched chain saturated hydrocarbon group containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, and the like; c as a group or part of a group1-6Alkyl is defined as a straight or branched chain saturated hydrocarbon radical containing from 1 to 6 carbon atoms, e.g. C1-4Alkyl and pentyl, hexyl, 2-methylbutyl, 3-methylpentyl and the like; c as a group or part of a group1-12Alkyl is defined as a straight or branched chain saturated hydrocarbon radical containing from 1 to 12 carbon atoms, e.g. C1-6A group defined by alkyl or heptyl, octyl, nonyl, decyl, 3-ethylpentyl, etc.; c1-6Alkanediyl is defined as a straight-chain or branched saturated divalent hydrocarbon group containing from 1 to 6 carbon atoms, such as methylene, 1, 2-ethanediyl or 1, 2-ethylene, 1, 3-propanediyl or 1, 3-propylene, 1, 4-butanediyl or 1, 4-butylene, 1, 5-pentanediyl, 1, 6-hexanediyl, and the like; c as a group or part of a group2-6Alkenyl is defined as a straight or branched chain hydrocarbon group containing 2 to 6 carbon atoms and having one double bond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, 3-methylbutenyl, and the like; c as a group or part of a group2-6Alkenediyl is defined as a straight or branched chain divalent hydrocarbon radical containing 2 to 6 carbon atoms and having one double bond such as ethenediyl, 2-buten-1, 4 diyl, and the like; c as a group or part of a group2-6Alkynyl is defined as a straight or branched chain hydrocarbon radical containing 2 to 6 carbon atoms and having a triple bond such as ethynyl, propynyl, butynyl, pentynylAlkynyl, hexynyl, 3-methylbutynyl and the like; c as a group or part of a group2-6Alkynediyl is defined as a straight or branched chain divalent hydrocarbon group containing 2 to 6 carbon atoms and having a triple bond such as ethynyl diyl, 3-pentyne-1, 5 diyl, and the like; c3-6Cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; a partially saturated monocyclic or bicyclic heterocycle represents a ring system consisting of 1 or 2 rings and containing at least one heteroatom selected from O, N or S and at least one double bond, with the proviso that the ring system is not an aromatic ring; aromatic monocyclic or bicyclic heterocycle represents an aromatic ring system consisting of 1 or 2 rings and containing at least one heteroatom selected from O, N or S; the term aromaticity is well known to the person skilled in the art and refers to a cyclic conjugated system of 4n '+ 2 electrons, i.e. containing 6, 10, 14 etc. numbers of pi-electrons (Huckel's law).
The L or Q group in the compounds of formula (I) above may be attached to the remainder of formula (I) through any suitable ring carbon or heteroatom. For example, when Q is pyridyl, it may be 2-pyridyl, 3-pyridyl or 4-pyridyl.
The lines drawn into the ring system indicate that the bond may be attached to any suitable ring atom. When the ring system is a bicyclic ring system, the bond may be attached to any suitable ring atom in either ring.
As used herein before, the term (═ O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom, and a sulfonyl moiety when both of the terms are attached to a sulfur atom.
The term halogen generally refers to fluorine, chlorine, bromine and iodine. As used hereinbefore and hereinafter polyhaloc as a group or part of a group1-6Alkyl is defined as mono-or polyhaloC1-6Alkyl, in particular methyl, bearing one or more fluorine atoms, for example difluoromethyl or trifluoromethyl. If in polyhaloC1-6To alkyl groups in the definition of alkylMore than one halogen atom in (A) may be the same or different.
When any variable occurs more than one time in any constituent, each definition is independent.
Whether used above or below, each substituent may be independently selected from a number of lists of definitions, such as substituents for L or Q, all possible combinations that are chemically feasible and result in a chemically stable molecule are contemplated. When the ring system is linked to the other part of the molecule via a linker, e.g. Het1-NH-, all possible combinations of ring systems and linkers that are chemically feasible and result in chemically stable molecules are contemplated.
When several adjacent substituents in the group of formula (c-1) represent a direct bond, it must be a single direct bond. For example, when X represents a direct bond, C1Represents CH2，Y1、C2、Y2、C3、Y3And C4Represents a direct bond and Z represents a hydrogen, then said group of formula (c-1) represents a methyl group (CH)3)。
It will be appreciated that some of the compounds of formula (I) and the N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof, may contain one or more chiral centers and exist as stereochemically isomeric forms.
The term "stereochemically isomeric forms" as used hereinabove and hereinbelow defines all the possible stereoisomers which the compounds of formula (I) and the N-oxides, addition salts, quaternary amines or physiologically functional derivatives thereof may possess. Unless otherwise indicated, the chemical designation of a compound denotes the mixture of all possible stereochemically isomeric forms, said mixtures including all diastereomers and enantiomers of the basic molecular structure as well as the individual isomers of compounds of formula (I) and their N-oxides, salts, solvates, quats which are substantially free of other isomers, i.e. wherein the content of other isomers is less than 10%, preferably less than 5%, particularly less than 2%, most preferably less than 1%. The stereochemical isomers of the compounds of formula (I) are clearly within the scope of the present invention.
Salts of the compounds of formula (I) for use in therapy are those containing a pharmaceutically acceptable counterion. However, salts of non-pharmaceutically acceptable acids and bases also have other uses, for example in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the invention.
The pharmaceutically acceptable acid and base addition salts mentioned hereinabove and hereinbelow are meant to be addition salts containing therapeutically active non-toxic acids and bases which the compounds of formula (I) are capable of forming. Pharmaceutically acceptable acid addition salts are conveniently obtained by treating the base with an appropriate acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acids, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as acetic, propionic, glycolic, lactic, pyruvic, oxalic (i.e., oxalic), malonic, succinic (i.e., succinic), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexylamine sulfonic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely, the salts may be converted to the free base by treatment with an appropriate base.
The compounds of formula (I) containing acidic protons may also be converted into their non-toxic metal or ammonium addition salts by treatment with appropriate organic and inorganic bases. Suitable base salts include, for example, ammonium salts, alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases such as aliphatic and aromatic primary, secondary and tertiary amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinine, pyridine, quinoline and isoquinoline; n, N' -dibenzylethylenediamine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as arginine, lysine, and the like. Conversely, the salt may be converted to the free acid by acid treatment.
The term addition salt as used hereinbefore also comprises the solvates which the compounds of formula (I) and their salts are able to form. Such solvates are for example hydrates, alcoholates and the like.
The term "quaternary ammonium" as used hereinbefore is defined as a quaternary ammonium salt which the compound of formula (I) is capable of forming by reaction of the basic nitrogen of the compound of formula (I) with a suitable quaternising agent, for example an optionally substituted alkyl halide, aryl halide or aralkyl halide such as methyl iodide or benzyl iodide. Other reactants having good leaving groups may also be used, such as alkyl triflates, alkyl methylsulfonates and alkyl p-toluenesulfonates. Quaternary amines have positively charged nitrogen. Pharmaceutically acceptable counterions include, for example, chloro, bromo, iodo, trifluoroacetate and acetate. The counter ion of choice may be obtained using an ion exchange resin column.
The N-oxide forms of the compounds of the present invention are meant to comprise compounds of formula (I) wherein one or several tertiary nitrogen atoms are oxidized to form the so-called N-oxide.
Some of the compounds of formula (I) also exist in their tautomeric forms. Although these forms are not specifically shown in the above formulae, they are also included in the scope of the present invention.
Specific examples of the partially saturated monocyclic or bicyclic heterocycle are pyrrolinyl, imidazolinyl, pyrazolinyl, 2, 3-dihydrobenzofuranyl, 1, 3-benzodioxolyl, 2, 3-dihydro-1, 4-benzodioxinyl, indolinyl and the like.
Specific examples of aromatic monocyclic or bicyclic heterocycles are azetyl, oxyethylidenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, cinnolinyl, quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, thienyl, and the like, Furopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, isoxazolopyridinyl, oxazolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiothienopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidyl, thiazolopyrimidyl, isoxazolopyrimidyl, oxazolopyrimidyl, pyrazolopyrimidyl, imidazopyridazinyl, pyrrolopyridazinyl, thienopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl, imidazopyridazinyl, oxadiazoopyridinyl, thiadiazolopyridinyl, and pyrazolopyridinyl, Triazolopyridinyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolyl, thiadiazolopyrimidyl, triazolopyrimidinyl, oxadiazolyl-pyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, imidazolooxazolyl, imidazothiazolyl, imidazoimidazolyl, isoxazolotriazinyl, isothiazolo-triazinyl, pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl, oxadiazozotriazinyl, thiadiazolotriazinyl, triazolotriazinyl.
An interesting embodiment of the present invention relates to the use of compounds of formula (I) wherein Q is C3-6Cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridinylEach ring is optionally substituted with up to 3 substituents independently selected from: halogen; a hydroxyl group; a cyano group; a carboxyl group; an azide group; an amino group; mono or di (C)1-6Alkyl) amino; c1-6An alkylcarbonylamino group; c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; c3-6A cycloalkyl group; with hydroxy groups, C1-6Alkoxy, amino, mono-or di (C)1-4Alkyl) amino-substituted C1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylthio group; c1- 6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; aryl radical C1-6An alkoxy group; an aryloxy group; polyhalo C1-6An alkyl group; polyhalo C1-6An alkoxy group; polyhalo C1-6An alkylcarbonyl group; c1-4alkyl-S (═ O)n-or R1HN-S(＝O)n-；
Or
Q is a group of formula (b-1), (b-2) or (b-3):
wherein X and Y are each independently O, NR33、CH2Or S, wherein R3Is hydrogen or C1-4An alkyl group;
q is an integer of 1 to 4;
z is O or NR4，R4Is hydrogen or C1-4An alkyl group;
r is an integer of 1 to 3;
z is halogen; c1-6An alkyl group; by hydroxy, carboxy, cyano, amino, mono-or di (C)1-6Alkyl) amino, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6Alkoxycarbonyl or C1-6Alkoxy-substituted C1-6An alkyl group; polyhalo C1-4An alkyl group; a cyano group; an amino group; an aminocarbonyl group; mono or di (C)1-6Alkyl) aminocarbonylA group; c1-6An alkoxycarbonyl group; c1-6An alkylcarbonyloxy group; h2N-S(＝O)2-; mono or di (C)1-6Alkyl) amino-S (═ O)2-；-C(＝N-Rx)NRyRz；
L is phenyl substituted with up to 4 substituents independently selected from: halogen, hydroxy, mercapto, amino, cyano, carboxy, mono-or di (C)1-6Alkyl) amino, C1-6Alkyl, with hydroxy or C1-4Alkoxy or amino or mono-or di (C)1-4Alkyl) amino-substituted C1-6Alkyl, polyhalo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-, C1-6alkoxy-C (═ O) -NH-, H2N-C (═ O) -NH-, mono-or di (C)1-4Alkyl) amino-C (═ O) -NH-or Het-NH-, -C (═ N-Rx)NRyRz(ii) a Or
L is a 5-or 6-membered partially saturated or aromatic monocyclic heterocycle or a partially saturated or aromatic bicyclic heterocycle, wherein each of said rings may be optionally substituted with up to 3 substituents each independently selected from: halogen, hydroxy, mercapto, amino, cyano, carboxy, mono-or di (C)1-6Alkyl) amino, C1-6Alkyl, with hydroxy or C1-4Alkoxy or amino or mono-or di (C)1-4Alkyl) amino-substituted C1-6Alkyl, polyhalo C11-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-, C1-6alkoxy-C (═ O) -NH-, H2N-C (═ O) -NH-, mono-or di (C)1-4Alkyl) amino-C (═ O) -NH-or Het-NH-, -C (═ N-Rx)NRyRz。
Another interesting embodiment of the inventionEmbodiments relate to the use of compounds of formula (I) wherein Q is C3-6Cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridinyl, each ring optionally substituted with up to 3 substituents independently selected from the group consisting of: halogen; a hydroxyl group; a cyano group; a carboxyl group; an azide group; an amino group; mono or di (C)1-6Alkyl) amino; c1-6An alkylcarbonylamino group; c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; c3-6A cycloalkyl group; with hydroxy groups, C1-6Alkoxy, amino, mono-or di (C)1-4Alkyl) amino-substituted C1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylthio group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; aryl radical C1-6An alkoxy group; an aryloxy group; polyhalo C1-6An alkyl group; polyhalo C1-6An alkoxy group; polyhalo C1-6An alkylcarbonyl group; c1-4alkyl-S (═ O)n-or R1HN-S(＝O)n-；
Or
Q is a group of formula (b-1), (b-2) or (b-3):
wherein X and Y are each independently O, NR3、CH2Or S, wherein R3Is hydrogen or C1-4An alkyl group;
q is an integer of 1 to 4;
z is O or NR4，R4Is hydrogen or C1-4An alkyl group;
r is an integer of 1 to 3;
z is halogen; c1-6An alkyl group; by hydroxy, carboxy, cyano, amino, mono-or di (C)1-6Alkyl) amino, aminocarbonyl, mono-or di (C)1-6Alkyl) ammoniaCarbonyl radical, C1-6Alkoxycarbonyl or C1-6Alkoxy-substituted C1-6An alkyl group; polyhalo C1-4An alkyl group; a cyano group; an amino group; an aminocarbonyl group; mono or di (C)1-6Alkyl) aminocarbonyl; c1-6An alkoxycarbonyl group; c1-6An alkylcarbonyloxy group; h2N-S(＝O)2-; mono or di (C)1-6Alkyl) amino-S (═ O)2-；-C(＝N-Rx)NRyRz；
L is a 5-or 6-membered partially saturated or aromatic monocyclic heterocycle or a partially saturated or aromatic bicyclic heterocycle, wherein each of said rings may be optionally substituted with up to 3 substituents each independently selected from: halogen, hydroxy, mercapto, amino, cyano, carboxy, mono-or di (C)1-6Alkyl) amino, C1-6Alkyl, with hydroxy or C1-4Alkoxy or amino or mono-or di (C)1-4Alkyl) amino-substituted C1-6Alkyl, polyhalo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-, C1-6alkoxy-C (═ O) -NH-, H2N-C (═ O) -NH-, mono-or di (C)1-4Alkyl) amino-C (═ O) -NH-or Het-NH-, -C (═ N-Rx)NRyRz。
Another interesting embodiment of the present invention relates to the use of compounds of formula (I) wherein L is a 5-or 6-membered partially saturated or aromatic monocyclic heterocycle or a partially saturated or aromatic bicyclic heterocycle, wherein each of said rings may optionally be substituted with up to 3 substituents each independently selected from the group consisting of: c1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-; c1-6alkoxy-C (═ O) -NH-; h2N-C (═ O) -NH-; mono or di (C)1-4Alkyl) amino-C (═ O) -NH-; Het-NH-; het1-NH-；-NH-C(＝N-Rx)NRyRz；-C(＝N-Rx)NRyRz；Het1(ii) a Or of the formula-X-C1-Y1-C2-Y2-C3-Y3-C4-Z (c-1).
Another interesting embodiment of the invention relates to the use of compounds of formula (I) wherein one or more of the following limitations apply:
a) q is C3-6Cycloalkyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridinyl, each ring being optionally substituted with up to 3 substituents independently selected from the group consisting of: halogen; a hydroxyl group; a cyano group; a carboxyl group; an azide group; an amino group; mono or di (C)1-6Alkyl) amino; c1-6An alkylcarbonylamino group; c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; c3-6A cycloalkyl group; with hydroxy groups, C1-6Alkoxy, amino, mono-or di (C)1-4Alkyl) amino-substituted C1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylthio group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; aryl radical C1-6An alkoxy group; an aryloxy group; polyhalo C1-6An alkyl group; polyhalo C1-6An alkoxy group; polyhalo C1-6Alkylcarbonyl or C1-4alkyl-S (═ O)n-; or Q is pyridyl substituted with up to 3 substituents independently selected from: halogen; a hydroxyl group; a cyano group; a carboxyl group; an azide group; an amino group; mono or di (C)1-6Alkyl) amino; c1-6An alkylcarbonylamino group; c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; c3-6A cycloalkyl group; with hydroxy groups, C1-6Alkoxy, amino, mono-or di (C)1-4Alkyl) amino-substituted C1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylthio group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; aryl radical C1-6An alkoxy group; an aryloxy group; polyhalo C1-6An alkyl group; polyhalo C1-6An alkoxy group; polyhalo C1-6Alkylcarbonyl or C1-4alkyl-S (═ O)n-；
b) Q is C3-6Cycloalkyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridinyl, each ring optionally substituted with up to 3 substituents independently selected from the group consisting of: halogen; a hydroxyl group; a cyano group; a carboxyl group; an azide group; an amino group; mono or di (C)1-6Alkyl) amino; c1-6An alkylcarbonylamino group; c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; c3-6A cycloalkyl group; with hydroxy groups, C1-6Alkoxy, amino, mono-or di (C)1-4Alkyl) amino-substituted C1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylthio group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; aryl radical C1-6An alkoxy group; an aryloxy group; polyhalo C1-6An alkyl group; polyhalo C1- 6An alkoxy group; polyhalo C1-6An alkylcarbonyl group; c1-4alkyl-S (═ O)n-；
c) Q is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridinyl, each ring optionally substituted with up to 3 substituents independently selected from the group consisting of: halogen; a hydroxyl group; a cyano group; a carboxyl group; an azide group; an amino group; mono or di (C)1-6Alkyl) amino; c1-6An alkylcarbonylamino group; c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; c3-6A cycloalkyl group; with hydroxy groups, C1-6Alkoxy, amino, mono-or di (C)1-4Alkyl) amino-substituted C1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylthio group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; aryl radical C1-6An alkoxy group; an aryloxy group; polyhalo C1-6An alkyl group; polyhalo C1-6An alkoxy group; polyhalo C1-6An alkylcarbonyl group; c1-4alkyl-S (═ O)n-；
d) Q is C3-6Cycloalkyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridinyl, each ring optionally substituted with up to 3 substituents independently selected from the group consisting of: halogen; a cyano group; a carboxyl group; an azide group; an amino group; mono or di (C)1-6Alkyl) amino; c1-6An alkylcarbonylamino group; c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; c3-6A cycloalkyl group; with hydroxy groups, C1-6Alkoxy, amino, mono-or di (C)1-4Alkyl) amino-substituted C1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylthio group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; aryl radical C1-6An alkoxy group; an aryloxy group; polyhalo C1-6An alkyl group; polyhalo C1-6An alkoxy group; polyhalo C1-6An alkylcarbonyl group; c1-4alkyl-S (═ O)n-；
e) Q is C3-6Cycloalkyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl or imidazopyridinyl, each ring being optionally substituted with up to 3 substituents, andthe substituents are independently selected from: halogen; a hydroxyl group; a cyano group; a carboxyl group; an azide group; an amino group; mono or di (C)1-6Alkyl) amino; c1-6An alkylcarbonylamino group; c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; c3-6A cycloalkyl group; with hydroxy groups, C1-6Alkoxy, amino, mono-or di (C)1-4Alkyl) amino-substituted C1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylthio group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; aryl radical C1-6An alkoxy group; an aryloxy group; polyhalo C1-6An alkyl group; polyhalo C1-6An alkoxy group; polyhalo C1-6An alkylcarbonyl group; c1-4alkyl-S (═ O)n-or R1HN-S(＝O)n-；
f) L is furyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, a 5-membered partially saturated heterocycle, a 6-membered partially saturated or aromatic heterocycle or a partially saturated or aromatic bicyclic heterocycle, wherein each of said rings may be optionally substituted with up to 3 substituents each independently selected from: c1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-; c1-6alkoxy-C (═ O) -NH-; h2N-C (═ O) -NH-; mono or di (C)1-4Alkyl) amino-C (═ O) -NH-; Het-NH-; het1-NH-；-NH-C(＝N-Rx)NRyRz；-C(＝N-Rx)NRyRz；Het1(ii) a Or of the formula-X-C1-Y1-C1-Y2-C3-Y3-C4-a group of Z (c-1); provided that L is not an optionally substituted quinoxalinyl group;
g) l is a 6-membered partially saturated or aromatic heterocycle, wherein each of said rings may be optionally substituted with up to 3 substituents each independently selected from: c1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono-or di (A)C1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-; c1-6alkoxy-C (═ O) -NH-; h2N-C (═ O) -NH-; mono or di (C)1-4Alkyl) amino-C (═ O) -NH-; Het-NH-; het1-NH-；-NH-C(＝N-Rx)NRyRz；-C(＝N-Rx)NRyRz；Het1(ii) a Or of the formula-X-C1-Y1-C1-Y2-C3-Y3-C4-a group of Z (c-1);
h) l is a 5-or 6-membered partially saturated or aromatic monocyclic heterocycle or a partially saturated or aromatic bicyclic heterocycle, wherein each of said rings may be optionally substituted with up to 3 substituents each independently selected from: c1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-; c1-6alkoxy-C (═ O) -NH-; h2N-C (═ O) -NH-; mono or di (C)1-4Alkyl) amino-C (═ O) -NH-; -NH-C (═ N-R)x)NRyRz；-C(＝N-Rx)NRyRz；Het1(ii) a Or of the formula-X-C1-Y1-C2-Y2-C3-Y3-C4-a group of Z (c-1);
i) l is a 5-or 6-membered partially saturated or aromatic monocyclic heterocycle or a partially saturated or aromatic bicyclic heterocycle, wherein each of said rings may be optionally substituted with up to 3 substituents each independently selected from: such as-X-C1-Y1-C2-Y2-C3-Y3-C4-a group of Z (c-1);
j) l is a 5-or 6-membered partially saturated or aromatic monocyclic heterocycle or a partially saturated or aromatic bicyclic heterocycle, wherein each of said rings may be optionally substituted with up to 3 substituents each independently selected from: such as-X-C1-Y1-C2-Y2-C3-Y3-C4-a group of Z (c-1); with the proviso that the group does not represent a hydroxyl group;
k) l is a 5-or 6-membered partially saturated or aromatic monocyclic heterocycle or a partially saturated or aromatic bicyclic heterocycle wherein each of said rings may be optionally substituted with 1 or 2 substituents independently selected from: c1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6alkyl-C (═ O) -NH-; c1-6alkoxy-C (═ O) -NH-; h2N-C (═ O) -NH-; mono or di (C)1-4Alkyl) amino-C (═ O) -NH-; Het-NH-; het1-NH-；-NH-C(＝N-Rx)NRyRz；-C(＝N-Rx)NRyRz；Het1(ii) a Or of the formula-X-C1-Y1-C1-Y2-C3-Y3-C4-a group of Z (c-1);
l) L is a 5-or 6-membered partially saturated or aromatic monocyclic heterocycle or a partially saturated or aromatic bicyclic heterocycle wherein each of said rings may be optionally substituted with up to 3 substituents each independently selected from: halogen; a hydroxyl group; a mercapto group; an amino group; a cyano group; a carboxyl group; mono or di (C)1-2Alkyl) amino optionally substituted with 1, two or three substituents independently selected from: hydroxy, amino, mono-or di (C)1-4Alkyl) amino, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkoxy, amino C1-4Alkoxy, amino C1-4Alkoxy radical C1-4Alkoxy, mono-or di (C)1-4Alkyl) amino C1-4Alkoxy, mono-or di (C)1-4Alkyl) amino C1-4Alkoxy radical C1-4An alkoxy group; c1-6An alkyl group; with hydroxy groups, C1-4Alkoxy, amino or mono-or di (C)1-4Alkyl) amino-substituted C1-6An alkyl group; polyhalo C1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylthio group; c1-6An alkoxycarbonyl group; c1-6An alkylcarbonyloxy group; an aminocarbonyl group; mono or di (C)1-6Alkyl) aminocarbonyl; c1-6alkyl-C (═ O) -NH-; c1-6alkoxy-C (═ O) -NH-; h2N-C (═ O) -NH-; mono or di (C)1-4Alkyl) amino-C (═ O) -NH-; Het-NH-; het1-NH-；-NH-C(＝N-Rx)NRyRz；-C(＝N-Rx)NRyRz(ii) a Or Het1；
m) Z is halogen; c1-6An alkyl group; by hydroxy, carboxy, cyano, amino, mono-or di (C)1-6Alkyl) amino, aminocarbonyl, mono-or di (C)1-6Alkyl) aminocarbonyl, C1-6Alkoxycarbonyl or C1-6Alkoxy-substituted C1-6An alkyl group; polyhalo C1-4An alkyl group; a cyano group; an aminocarbonyl group; mono or di (C)1-6Alkyl) aminocarbonyl; c1-6An alkoxycarbonyl group; c1-6An alkylcarbonyloxy group; h2N-S(＝O)2-; mono or di (C)1-6Alkyl) amino-S (═ O)2-；-C(＝N-Rx)NRyRz。
Another interesting embodiment of the present invention relates to the use of compounds of formula (I) wherein L is a substituted aromatic 6-membered heterocyclic ring, in particular a substituted pyrimidinyl or substituted triazinyl group, more in particular a substituted pyrimidin-4-yl group, even more in particular a pyrimidin-4-yl group substituted with 1 or 2 substituents, preferably selected from the group consisting of: amino, amino C1-6Alkylamino, hydroxy C1-6Alkylamino (e.g. 3-hydroxypropylamino), carboxy C1-6Alkylamino (such as 2-carboxyethylamino) or halogen (e.g., fluoro).
Another interesting embodiment of the present invention relates to the use of compounds of formula (I) wherein Q is phenyl; phenyl substituted with 1 or 2 substituents selected from: halogen, polyhaloC1-6An alkyl group; a pyridyl group; z is C1-6Alkyl or halogen; l is pyrimidinyl, pyrazolyl or triazolyl, each of said three rings being optionally substituted with 1 or 2 substituents selected from: halogen, amino, C1-6Alkylcarbonylamino, C1-6Alkylamino radical, C1-6Alkylthio, Het-NH-.
Another preferred embodiment of the invention relates to the use of compounds of formula (I) wherein Q is with polyhalogenated C1-6Alkyl, in particular phenyl substituted with trifluoromethyl.
Also preferred are compounds of formula (I) wherein Z is halogen or C1-6Alkyl, in particular chlorine or methyl.
Another preferred embodiment of the invention relates to the use of compounds of formula (I) wherein Q is phenyl, pyridyl, pyrrolyl, pyrazolyl or thienyl, wherein each ring may optionally be substituted by 1 or 2 substituents selected from halogen or polyhaloC1-6Alkyl is substituted by a substituent; z is C1-6Alkyl, halogen, C1-6Alkoxy, aminocarbonyl; l is pyrimidinyl, pyrazolyl, triazolyl or triazinyl, wherein each ring may be optionally substituted with 1 or 2 substituents selected from: amino group, C1-6Alkylcarbonylamino, halogen, Het-NH-, hydroxy, C1-6Alkylthio radical, C1-6Alkoxy radical, C1-6Alkyl radical, C1-12Alkylamino, mono-or di- (hydroxy C)1-12Alkyl) amino, wherein C1-12Alkyl may be further optionally substituted by hydroxy, Het1Aminocarbonyl, cyano, amino C1-12Alkylamino radical, hydroxy radical C1-12Alkoxy, -NH-C (═ NH) -NH2Carboxyl group C1-12Alkylamino or amino C1-6Alkoxy radical C1-6Alkoxy radical C1-6An alkylamino group.
Another interesting embodiment of the present invention relates to the use of compounds of formula (I) wherein Q is phenyl; phenyl substituted with 1 or 2 substituents selected from chloro, fluoro, trifluoromethyl; 2-pyridyl or 3-pyridyl; z is methyl; l is 2-amino-pyrimidin-4-yl, 2-carbonylamino-pyrimidin-4-yl, 2-methylamino-pyrimidin-4-yl, 2-methylsulfanyl-pyrimidin-4-yl, 2- [ (4-methyl-2-thiazolyl) amino ] -pyrimidin-4-yl, 2-amino-5-bromo-pyrimidin-4-yl, 2-amino-5-chloro-pyrimidin-4-yl, 4-pyrimidinyl, 3-pyrazolyl, 2-methylsulfanyl-1-methyl-1, 3, 4-triazol-5-yl.
Another interesting embodiment of the present invention relates to the use of compounds of formula (I) wherein Q is pyrrolyl; a pyrazolyl group; a thienyl group; a phenyl group; phenyl substituted with 1 or 2 substituents selected from chloro, fluoro, methyl, trifluoromethyl; 2-pyridyl; 2-pyridyl substituted with a substituent selected from the group consisting of chloro, fluoro, trifluoromethyl; a 3-pyridyl group; z is methyl, chloro, methoxy or aminocarbonyl; l is 2-amino-pyrimidin-4-yl, 2-methylcarbonylamino-pyrimidin-4-yl, 2-methylamino-pyrimidin-4-yl, 2-methylsulfanyl-pyrimidin-4-yl, 2- [ (4-methyl-2-thiazolyl) amino ] -pyrimidin-4-yl, 2-amino-5-bromo-pyrimidin-4-yl, 2-amino-5-chloro-pyrimidin-4-yl, 2-amino-5-fluoro-pyrimidin-4-yl, 2- (2-hydroxy) ethylamino-pyrimidin-4-yl, 2- (3-hydroxy) propylamino-pyrimidin-4-yl, m, 2-piperazinyl-pyrimidin-4-yl, 2- (4-methylpiperazinyl) -pyrimidin-4-yl, 2- (2-amino) ethylamino-pyrimidin-4-yl, 2- (3-amino) propylamino-pyrimidin-4-yl, 2- (6-amino) hexylamino-pyrimidin-4-yl, 2- (7-amino) heptylamino-pyrimidin-4-yl, 2- (8-amino) octylamino-pyrimidin-4-yl, 2-hydroxyamino-pyrimidin-4-yl, 2- (2-hydroxy-3 hydroxy) propylamino-pyrimidin-4-yl, 2-guanidino-pyrimidin-4-yl, substituted guanidino-amino-2- (6-amino) propylamino-pyrimidin-4-yl, 2- (morpholin-4-yl) -pyrimidin-4-yl, 2- (bis (2-hydroxy) ethyl) amino-pyrimidin-4-yl, 2- (1-methyl) piperidin-4-yl-pyrimidin-4-yl, 2- (1-benzyl) piperidin-4-yl-pyrimidin-4-yl, 2- [ (1-hydroxymethyl-2-hydroxy) ethylamino ] -pyrimidin-4-yl, 2-methyl-pyrimidin-4-yl, 2-aminocarbonyl-pyrimidin-4-yl, 2-cyano-pyrimidin-4-yl, 2- (piperidin-1-yl) -pyrimidin-4-yl, 2- (1-hydroxy) ethylamino) -pyrimidin-4-yl, 2-cyano-pyrimidin-4-yl, 2- (morpholin-4-yl) -pyrimidin-4-yl, 2- (di (2-hydroxy) ethyl) pyrimidin-4, 2-methylamino-pyrimidin-4-yl, 4-pyrimidinyl, 3-pyrazolyl, 2-methylsulfanyl-1-methyl-1, 3, 4-triazol-5-yl, 2-amino-1, 3, 5-triazin-4-yl, 2-methoxy-pyrimidin-4-yl, 2- (2-carboxy) ethylamino-pyrimidin-4-yl, 2-carboxymethylamino-pyrimidin-4-yl, 2- (2-hydroxy) ethoxy-pyrimidin-4-yl, 6-hydroxy-2-amino-pyrimidin-4-yl, 2- (2-amino) ethoxyethoxyethyl-pyrimidin-4-yl.
The most preferred compounds are compounds 9 (see table 3), 34 (see table 2), 58 (see table 2) and 84 (see table 3).
In general, the compounds of formula (I),wherein L is Ra4-pyrimidinyl substituted in position 2, wherein RaRepresents hydrogen, amino, optionally substituted C1-6Alkyl, optionally substituted mono-or di (C)1-12Alkyl) amino, Het-NH-or Het1The compound represented by the formula (I-a) can be prepared as follows: the intermediate of formula (II) is reacted with an intermediate of formula (III) or a suitable salt thereof, e.g., formamidine acetate, guanidine hydrochloride, guanidine carbonate (2:1), guanidine sulfate, guanidine hemisulfate, N- (3-hydroxypropyl) guanidine hemisulfate, 1-piperazine carboxylic acid imine sulfate (2:1), and the like, in the presence of a suitable solvent, e.g., N-dimethylformamide, dimethyl sulfoxide, an alcohol, e.g., ethanol, diethoxyethanol, 2-methoxyethanol, and the like, a suitable base, e.g., sodium methoxide, sodium ethoxide, sodium hydride, and the like. Sodium may also be used in the presence of a suitable alcohol. The reaction may be carried out at elevated temperature.
A compound of formula (I-a), wherein Z represents aminocarbonyl, said compound being represented by formula (I-a-1) and being preparable by: the intermediate of formula (II') is reacted with an intermediate of formula (III) or a suitable salt thereof, e.g., formamidine acetate, guanidine hydrochloride, guanidine carbonate (2:1), guanidine sulfate, guanidine hemisulfate, N- (3-hydroxypropyl) guanidine hemisulfate, 1-piperazine carboxylic acid imine sulfate (2:1), and the like, in the presence of a suitable solvent, e.g., N-dimethylformamide, dimethyl sulfoxide, an alcohol, e.g., ethanol, diethoxyethanol, 2-methoxyethanol, and the like, a suitable base, e.g., sodium methoxide, sodium hydride, and the like. Sodium may also be used in the presence of a suitable alcohol. The reaction may be carried out at elevated temperature.
A compound of formula (I) wherein L is Rb4-pyrimidinyl substituted in position 2, wherein Rbrepresents-NH2，Het1-NH-；Het1；-NH-C(＝NH)-N(Rz)2(ii) a With C optionally substituted by 1, 2 or 3 hydroxy groups1-12An alkoxy group; optionally substituted mono-or di (C)1-12Alkyl) amino, especially unsubstituted mono-or di (C)1-12Alkyl) amino or C thereof1-12Alkyl is optionally substituted by 1, 2 or 3 substituents selected from hydroxy, carboxy, amino C1-4Alkoxy radical C1-4Alkoxy-substituted mono-or di (C)1-12Alkyl) amino, said compound being represented by formula (I-b), can be prepared as follows: the intermediate of formula (IV) is reacted with the intermediate of formula (V), optionally at elevated temperature and optionally in the presence of a suitable solvent such as N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, alcohols such as 2-propanol, methanol/sodium methoxide and the like, and optionally in the presence of a suitable base such as disodium carbonate to form the corresponding salt, or in the presence of a suitable acid such as hydrochloric acid, acetic acid and the like, optionally in the presence of sodium hydride, for example when H-R is presentbRepresents a hydroxyl group C1-12Alkoxy, optionally under pressure.
Analogous reactions may be carried out to convert intermediates of formula (IV ') to compounds of formula (I' -b).
A compound of formula (I) wherein L is 4-pyrimidinyl substituted with cyano in the 2-position, said compound being represented by formula (I-c), may be prepared as follows: the intermediate of formula (IV) is reacted with a suitable cyanide salt, such as potassium cyanide, in the presence of a suitable solvent, such as N, N-dimethylformamide. The reaction may be carried out at elevated temperature.
A compound of formula (I) wherein L is 4-pyrimidinyl substituted with hydroxy in the 2-position, said compound being represented by formula (I-d), may be prepared as follows: the intermediate of formula (IV) is reacted with a suitable hydroxide base, such as sodium hydroxide, in the presence of a suitable solvent, such as water, tetrahydrofuran.
A compound of formula (I) wherein L is CH34-pyrimidinyl wherein S is substituted at the 2-position, said compound being represented by formula (I-e), which can be prepared as follows: the intermediate of formula (II) is reacted with thiourea in the presence of a suitable solvent, e.g. an alcohol such as ethanol and the like, a suitable alcoholate, e.g. sodium ethanolate and the like, dimethyl sulphate and a suitable base, e.g. sodium hydroxide.
A compound of formula (I) wherein L is RaAt 2 position and CH34-pyrimidinyl wherein S is substituted in position 6, said compound being represented by formula (I' -e) and being preparable as follows: the intermediate of formula (XXXV) is reacted with the intermediate of formula (III) in the presence of a suitable solvent, such as N, N-dimethylformamide. The reaction may be carried out at elevated temperature.
A compound of formula (I) wherein L is 3-pyrazolyl, which compound is represented by formula (I-f), can be prepared as follows: the intermediate of formula (II) is reacted with hydrazine monohydrate in the presence of a suitable acid, such as acetic acid.
A compound of formula (I) wherein L is a triazole substituted with a mercapto group, said compound being represented by formula (I-g), can be prepared as follows: the intermediate of formula (VII) is reacted with an intermediate of formula (VIII) therein in the presence of a suitable base, e.g. 1, 8-diazobicyclo [5, 4, 0] undec-7-ene, and a suitable solvent, e.g. an alcohol such as butanol.
A compound of formula (I) wherein L is Ra4-pyrimidinyl substituted in the 2-position and in the 6-position with hydroxy, said compound being represented by formula (I-h), can be prepared as follows: the intermediate of formula (VI) is reacted with an intermediate of formula (III) or a suitable salt thereof, e.g., formamidine acetate, guanidine hydrochloride, guanidine carbonate (2:1), guanidine sulfate, guanidine hemisulfate, N- (3-hydroxypropyl) guanidine hemisulfate, 1-piperazine carboxylic acid imine sulfate (2:1), and the like, in the presence of a suitable solvent, e.g., diethoxyethanol/sodium methoxide. The reaction may be carried out at elevated temperature.
A compound of formula (I) wherein L is Ra1, 3, 5-triazin-4-yl substituted at the 2-position, said compounds being represented by formula (I-I), can be prepared as follows: the intermediate of formula (XXX) is reacted with an intermediate of formula (III) or a suitable salt thereof, e.g., formamidine acetate, guanidine hydrochloride, guanidine carbonate (2:1), guanidine sulfate, guanidine hemisulfate, N- (3-hydroxypropyl) guanidine hemisulfate, 1-piperazine carboxylic acid imine sulfate (2:1), and the like, in the presence of 1, 1-dimethoxy-N, N-dimethyl-methylamine and in the presence of a suitable solvent, e.g., methanol/sodium methoxide.
The compounds of formula (I) may be interconverted according to functional group displacement reactions known in the art, including the reactions described hereinafter.
The compounds of formula (I) may be converted to the corresponding N-oxides according to methods known in the art for converting trivalent nitrogen to its N-oxide. The N-oxidation reaction is generally carried out by reacting the starting reactants of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides include peroxy acids such as benzoic acid or halogenated benzoic acids, for example 3-chlorobenzoic acid, peroxy alkanoic acids such as peroxyacetic acid, alkyl hydroperoxides such as t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dichloromethane and mixtures of these solvents.
Compounds of formula (I) wherein L is substituted with amino can be prepared by reaction with C in a suitable solvent such as pyridine1-6Conversion of alkyl acid chlorides to L with C1-6An alkylamide-substituted compound of formula (I).
Compounds of formula (I) wherein Q or L is substituted with cyano may be converted to compounds of formula (I) wherein Q or L is substituted with carboxy by reaction with a suitable acid such as concentrated hydrochloric acid in the presence of a suitable reaction inert solvent such as water.
Compounds of formula (I) wherein Q or L is substituted with cyano may also be converted to compounds of formula (I) wherein Q or L is substituted with aminocarbonyl by reaction with a suitable acid such as sulfuric acid in the presence of water.
C for L1-6Alkyl- (C (═ O) -NH-substituted compounds of formula (I) can be converted to compounds of formula (I) in which L is substituted with an amino group by reaction with a suitable acid such as hydrobromic acid or the like in the presence of a suitable solvent such as water.
Compounds of formula (I) wherein L is substituted with a mercapto group may be prepared by reaction with a suitable alkylating agent such as C1-6alkyl-I, e.g. CH3Conversion of-I etc. to-C for L by reaction in the presence of a suitable solvent such as an alcohol e.g. ethanol1-6Alkylthio-substituted compounds of formula (I).
Compounds of formula (I) wherein L is substituted with fluorine may be obtained by conversion of compounds of formula (I) wherein L is not substituted with fluorine by reaction with optional fluorine in the presence of 2, 6-lutidine and a suitable solvent such as N, N-dimethylformamide. The compounds of formula (I) wherein L is substituted with chlorine or bromine can be converted by reacting a compound of formula (I) wherein L is not substituted with chlorine or bromine with N-chlorosuccinimide or N-bromosuccinimide in the presence of a suitable solvent such as carbon tetrachloride.
Several methods of preparation of intermediates in the foregoing preparation are described in the following paragraphs. Many intermediates and starting materials are commercially available or known compounds that can be prepared according to conventional reaction methods well known in the art.
Intermediates of formula (II) can be prepared by reacting an intermediate of formula (IX) with (CH)3)N-CH(OCH3)2At elevated temperature, optionally in the presence of a suitable solvent such as N, N-dimethylformamide or toluene.
An intermediate of formula (IX) wherein Z represents C1-6Alkyl or C1-6Alkoxycarbonyl group, said Z being ZaAnd said intermediate is represented by formula (IX-a), may be prepared by reacting an intermediate of formula (X) with an intermediate of formula (XI) wherein W is1Represents a suitable leaving group such as: halogen, e.g. chlorine, bromine and as above ZaIs represented by C1-6Alkyl or C1-6Alkoxycarbonyl) in the presence of a suitable solvent such as an alcohol, e.g., methanol, ethanol, etc., at elevated temperature.
Intermediates of formula (IX) may also be prepared by oxidation of intermediates of formula (XII) in the presence of a suitable oxidant such as pyridinium chlorochromate in a suitable solvent such as 1, 2-dichloroethane at elevated temperature.
Intermediates of formula (XII) can be prepared by reacting an intermediate of formula (XIII) with CH3MgCl is prepared in the presence of a suitable solvent such as tetrahydrofuran.
Intermediates of formula (XIII) can be prepared by reacting an intermediate of formula (XIV), wherein W is2Represents a suitable leaving group such as: halogen such as chlorine and the like and intermediates of formula (XV) in the presence of a suitable catalyst such as palladium tetrakis-triphenylphosphine and a suitable solvent such as tetrahydrofuran and a suitable salt such as sodium carbonate in water.
Intermediates of formula (IX), wherein Z represents chlorine, said intermediates being represented by formula (IX-b), or intermediates of formula (XIII), wherein Z represents chlorine, said intermediates being represented by formula (XIII-a), can be prepared by reacting an intermediate of formula (XVI) with N, N-dimethylformamide in POCl3In the presence of a catalyst at high temperature.
Intermediates of formula (XVI) can be prepared by reacting an intermediate of formula (X) with Cl-CH2Reaction of-C (═ O) -Cl at elevated temperatureAnd (4) preparing.
Intermediates of formula (XIII-a), wherein Q represents 1-pyrrolyl, represented by formula (XIII-a-1), may be prepared by reacting 2-amino-4-chloro-5-thiazolecarboxaldehyde (CAS76874-79-8) with tetrahydro-2, 5-dimethoxy-furan (CAS 696-59-3) in the presence of a suitable acid, such as acetic acid.
In an analogous manner, 2-amino-4-methyl-5-thiazolyl-ethanone (CAS 106012-40-2) may be reacted with tetrahydro-2, 5-dimethoxy-furan in the presence of a suitable acid, such as acetic acid, to form 2-pyrrol-1-yl-4-methyl-5-thiazolyl-ethanone.
Intermediates of formula (XIII-a), wherein Q represents 1-pyrazolyl, which intermediates are represented by formula (XIII-a-2), can be prepared by reacting an intermediate of formula (XXXI) with an acid such as acetic acid in a suitable solvent such as an alcohol: for example, methanol, etc., at a high temperature.
Intermediates of formula (XXXI) can be prepared by reacting an intermediate of formula (XXXII) with pyrazole in the presence of a suitable solvent such as N, N-dimethylformamide and sodium hydride.
Intermediates of formula (XXXII) may be prepared by reacting an intermediate of formula (XXXIII) with 1, 2-ethanediol in the presence of a suitable acid, such as 4-toluenesulphonic acid, and a suitable solvent, such as toluene.
Intermediates of formula (II') can be prepared by reacting an intermediate of formula (XVII) with (CH)3)2N-CH(OCH3)2Reacting at high temperature.
Intermediates of formula (XVII) can be prepared by reacting an intermediate of formula (XVIII) with NH3In the presence of a suitable solvent such as an alcohol, e.g., methanol, and the like.
Intermediates of formula (XVIII) can be prepared by reacting an intermediate of formula (X) with CH3-C(＝O)-CHCl-C(＝O)-C(＝O)-OCH2CH3At elevated temperature in the presence of a suitable solvent such as an alcohol, e.g. ethanol or the like.
Intermediates of formula (IV) can be prepared by reacting a compound of formula (I-e) with a suitable oxidizing agent such as 3-chloroperoxybenzoic acid in the presence of a suitable solvent such as methylene chloride.
Intermediates of formula (IV ') can be prepared by reacting a compound of formula (I' -e) with a suitable oxidizing agent such as 3-chloroperoxybenzoic acid in the presence of a suitable solvent such as chloroform and a suitable base such as sodium carbonate and sodium metabisulphite.
Intermediates of formula (VI) can be prepared by reacting an intermediate of formula (IX) with CH3-C(＝O)-OC1-4Alkyl groups are prepared by reaction at elevated temperature in the presence of a suitable solvent such as tetrahydrofuran and sodium hydride.
An intermediate of formula (IX), wherein Z represents chlorine, said intermediate being represented by formula (IX-b), may be converted into an intermediate of formula (IX), wherein Z represents C, by reaction at elevated temperature with a suitable alcoholate, e.g. sodium methylate, in the presence of a suitable solvent, e.g. an alcohol, e.g. methanol1-4An alkoxy group, the intermediate being represented by the formula (IX-c).
Intermediates of formula (VII) can be prepared by reacting an intermediate of formula (IXX) with hydrazine hydrate.
Intermediates of formula (XXX) may be prepared by reacting an intermediate of formula (XXXIV) with an appropriate anhydride, such as trifluoroacetic anhydride.
Intermediates of formula (XXXIV) can be prepared by reacting an intermediate of formula (XXXV) with ammonia in the presence of oxalyl chloride and a suitable solvent such as dichloromethane and N, N-dimethylformamide.
Intermediates of formula (XXXVI) can be prepared by reacting an intermediate of formula (IX) with carbon disulfide and methyl iodide in the presence of a suitable solvent such as tetrahydrofuran and a suitable base such as potassium tert-butoxide.
An intermediate of formula (IX) wherein Q represents 4-trifluoromethylphenyl and Z represents halogen or C1-4Alkyl, said Z being of the formula ZbSaid intermediates, represented by formula (IX-c), are novel compounds and also form part of the invention.
The invention therefore also relates to compounds of the formula (IX-c),
wherein ZbRepresents halogen or C1-4An alkyl group.
Preferred compounds of the formula (IX-c) are those of ZbA compound representing halogen, in particular chlorine.
An intermediate of formula (XIII) wherein Q represents 4-trifluoromethylphenyl and Z represents halogen or C1-4Alkyl, said Z being of the formula ZbSaid intermediate represented by the formula (XIII-b), is a novel compound and also constitutes the present inventionIn the clear.
The invention therefore also relates to compounds of the formula (XIII-b),
wherein ZbRepresents halogen or C1-4An alkyl group.
Preferred compounds of the formula (XIII-b) are those ZbA compound representing halogen, in particular chlorine.
The compounds of the present invention have activity in modulating cytokine production, particularly activity in inhibiting cytokine production, more particularly activity in inhibiting pro-inflammatory cytokine production. A cytokine is any secreted polypeptide that affects the function of other cells by modulating interactions between cells in an immune or inflammatory response. Examples of cytokines include interleukin-1 (IL-1) to interleukin-23 (IL-23), tumor necrosis factor-alpha (TNF-alpha), tumor necrosis factor-beta (TNF-beta). The compounds of the invention also have inhibitory activity on the production of chemotactic cytokines responsible for the transport and activation of leukocytes. The chemotactic cytokine which is inhibited by the compound of formula (I) is MCP-1 (monocyte chemotactic protein-1).
Cytokines whose production is specifically inhibited by the compounds of formula (I) are TNF-alpha and/or interleukin-12 (IL-12).
TNF- α is produced primarily by monocytes, macrophages, T and B lymphocytes, neutrophils, mast cells, tumor cells, fibroblasts, keratinocytes, astrocytes, microglia, smooth muscle cells, and the like. This proinflammatory cytokine is at the top of a series of proinflammatory responses; it plays a key role in the cytokine network associated with many infections, inflammation and autoimmune diseases. Excessive or unregulated TNF- α production is associated with the mediation or worsening of a number of diseases, including: rheumatoid arthritis, rheumatoid spondylitis, spondylarthritis, systemic lupus erythematosus, osteoarthritis, gouty arthritis, juvenile arthritis and other joint disorders, polychondritis, scleroderma, wegener's granulomatosis, dermatomyositis, stevenson-Hohnson syndrome, idiopathic steatorrhea, endocrine ophthalmopathy, Grave's disease, alveolitis, chronic allergic pneumonia, primary biliary cirrhosis, uveitis, keratoconjunctivitis sicca, and vernal keratoconjunctivitis, allergic rhinitis, pemphigus, eosinophilia, rofury's syndrome, eosinophilic pneumonia, parasitic infection, bronchopulmonary aspergillosis, polyarteritis nodosa, eosinophilic granuloma, eosinophilic granulocytic associated disorder caused by drug response affecting the respiratory tract, septicemia, septic shock, and other joint disorders, Endotoxic shock, gram-negative sepsis, toxic shock syndrome, cerebral malaria, adult respiratory distress syndrome, bronchitis (acute, arachidic, catarrhal, chronic, asthmatic, phlonoid bronchitis), chronic obstructive or pulmonary disease, pulmonary fibrosis, pneumoconiosis (aluminopneumoconiosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, nicotinoidosis, gossypium), tuberculosis, silicosis, exacerbation of airway hyperreactivity to other drug treatments (e.g. aspirin or beta-agonist treatment), pulmonary sarcoidosis, bone resorption diseases, meningitis, reperfusion injury, graft-versus-host reaction, allograft rejection, graft rejection, fever and myalgia due to infections such as influenza, cachexia (due to e.g. bacterial, viral or parasitic infections or to loss of function or decline of body fluids or other organs, or by malignant disease; malaria and vermal cachexia; cachexia due to pituitary, thyroid, and thymus dysfunction and uremia cachexia; cachexia caused by acquired immunodeficiency syndrome (AIDS), AIDS, ARC (AIDS-related syndrome), diabetes, cancer, angiogenesis, lymphoma, kawasaki syndrome, Behcet's syndrome, canker sores, skin-related diseases such as psoriasis, eczema, burns, dermatitis, keloid formation, scar tissue formation, erythema nodosum leprosum, Crohn's disease, ulcerative colitis, inflammatory bowel disease, irritable bowel syndrome, pyresis, asthma (intrinsic, extrinsic, allergic, nonallergic, motor and occupational, and bacterial infectious asthma), wheatey infant syndrome, multiple sclerosis, parkinson's syndrome, pancreatitis, cardiac disease, congestive heart failure, myocardial infarction, acute liver failure, glomerulonephritis, therapy-related syndromes including Jarisch-herche reaction and IL-2 reaction with IL-2 anti-CD 3 antibody transfusion, hemodialysis, yellow fever vaccination related syndromes.
TNF- α is also capable of activating HIV (human immunodeficiency Virus) replication in monocytes and/or macrophages. Thus, inhibition of TNF- α production or activation helps limit HIV progression. TNF- α also plays a role in other viral infections, such as hepatitis C, CMV (cytomegalovirus), influenza and herpes viral infections including herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, EB (Epstein-Barr) virus, human herpes viruses types 6, 7 and 8, pseudorabies and rhinotracheitis.
IL-12 is mainly produced by monocytes, macrophages and dendritic cells in response to bacteria, bacterial products (lipopolysaccharides) and immune signals. IL-12 production is regulated by other cytokines and endogenous mediators produced during inflammation and immune responses. IL-12 in the immune system plays a central use. Evidence obtained from animal models and human disease suggests that inappropriate and prolonged production of IL-12 and the ability of IL-12 to induce Th1(Thelperl) cell type responses may contribute to the development and maintenance of chronic inflammatory diseases, such as rheumatoid arthritis, carrageenan-induced arthritis, allergic rhinitis, colitis, inflammatory bowel disease, Crohn's disease and multiple sclerosis, and to the development and maintenance of autoimmune diseases, such as diabetes, graft-versus-host reactions, shock or musculoskeletal and connective tissue diseases. Adverse effects also include anemia (hemolytic, aplastic, pure red cell aplastic, idiopatic thrombocytopenia), neutropenia, lymphopenia, hepatosplenomegaly due to monocyte infiltration, and pulmonary edema due to interstitial cell infiltration. Overproduction of IL-12 can accelerate the inflammatory process of a disease or the onset of a disease, such as rheumatoid arthritis, or it can also increase the severity of a disease.
Inhibition of TNF-alpha and/or IL-12 production by compounds of formula (I) may provide an interesting alternative to non-specific immunosuppressive approaches (e.g. corticosteroids) with potentially low toxicity in the treatment of chronic inflammatory and autoimmune diseases. Complex modulation of TNF- α and IL-12 production may alleviate the treated disease to a greater extent than monotherapy. The combined therapeutic effect of inhibiting both immune and inflammatory aspects of the disease may provide additional beneficial clinical effects. The compounds of the invention may also be used as co-therapeutic agents for use with immunosuppressive and/or anti-inflammatory drugs, for example as potentiators of the therapeutic activity of said drugs, to reduce the required dose or also to reduce the side effects of said drugs. Immunosuppressive and/or anti-inflammatory agents include, for example, cyclic peptides, cyclopeptolide or macrocyclic lactones immunosuppressive and/or anti-inflammatory agents, such as cyclosporins, e.g. cyclosporin a or G, tacrolimus, ascomycin, rapamycin, glucocorticosteroids, e.g. budesonide, beclomethasone, fluticasone, mometasone.
The compounds of formula (I) are useful in the prevention or treatment of cytokine mediated diseases and, therefore, prevent, inhibit or antagonize the production or activity of pro-inflammatory cytokines, such as TNF- α and/or IL-12.
TNF-alpha and/or IL-12 mediated disease refers to TNF-alpha and/or IL-12 play a role in any and all diseases and conditions, either by cytokines themselves, by cytokines produced by other cytokines, such as IL-1 or IL-6, or by some mediator released.
Due to their activity in inhibiting cytokine production, in particular their activity in inhibiting pro-inflammatory cytokine production, more in particular their activity in inhibiting TNF- α and/or IL-12, the compounds of formula (I), their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, are useful in the treatment or prevention of cytokine-mediated diseases or disorders, in particular diseases or disorders associated with an excessive or unregulated production of pro-inflammatory cytokines such as TNF- α and/or IL-12, including inflammatory diseases or autoimmune diseases. Diseases or conditions associated with excessive or unregulated production of proinflammatory cytokines include rheumatoid arthritis, rheumatoid spondylitis, spondyloarthritis, systemic lupus erythematosus, osteoarthritis, gouty arthritis, juvenile arthritis and other joint conditions, multiple chondritis, scleroderma, wegener's granulomatosis, dermatomyositis, stevens-Hohnson syndrome, idiopathic steatorrhea, endocrine ophthalmopathy, Grave's disease, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, uveitis, keratoconjunctivitis sicca and vernal keratoconjunctivitis, allergic rhinitis, pemphigus, hypereosinophilia, Loffler's syndrome, eosinophilic pneumonia, parasitic infection, bronchopulmonary aspergillosis, polyarteritis nodosa, eosinophilic granuloma, eosinophil-associated conditions caused by drug response affecting the respiratory tract, Septicemia, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, cerebral malaria, adult respiratory distress syndrome, bronchitis (acute, arachidic, catarrhal, chronic, asthmatic, phthoid bronchitis), chronic obstructive respiratory or pulmonary disease, pulmonary fibrosis, tuberculosis, pneumoconiosis (aluminosis, anthracosis, asbestosis, chalicosis, ostrich hairy pneumoconiosis, siderosis, silicosis, nicotinicosis, gossyposis), exacerbation of airway hyperreactivity to other drug treatments (e.g., aspirin or beta-agonist treatment), silicosis, pulmonary sarcoidosis, bone resorption diseases, meningitis, allergic encephalitis, reperfusion injury, graft-versus-host reaction, allograft rejection, graft rejection, musculoskeletal and connective tissue diseases, fever and myalgia due to infections such as influenza, Cachexia (due to, for example, bacterial, viral or parasitic infection or to loss or decline of bodily fluid or other organ function, or by a malignant disease; malaria and vermal cachexia; cachexia due to pituitary, thyroid and thymus dysfunction and uremic cachexia; cachexia due to acquired immunodeficiency syndrome (AIDS)), AIDS, ARC (AIDS-related syndrome), diabetes, cancer, angiogenesis, lymphoma, Kawasaki syndrome, Behcet's syndrome, canker sores, skin-related diseases such as psoriasis, eczema, burns, dermatitis, keloid formation, scar tissue formation, erythema nodosum leprosum, Crohn's disease, ulcerative colitis, inflammatory bowel disease, irritable bowel syndrome, pyresis, asthma (intrinsic, extrinsic, allergic, non-allergic, motor and infectious, and bacterial asthma) Wheezy infant syndrome, multiple sclerosis, Parkinson's syndrome, pancreatitis, heart disease, congestive heart failure, myocardial infarction, acute liver failure, glomerulonephritis, treatment-related syndromes including Jarisch-Herxheimer response and syndromes related to IL-2 infusion, anti-CD 3 antibody infusion, hemodialysis, yellow fever vaccination. HIV or other viral infections, such as hepatitis C, CMV, influenza and herpes virus infections, pseudorabies and rhinotracheitis, follicular lymphoproliferation, anemia (hemolytic, aplastic, pure red cell aplastic, idiopatic thrombocytopenia), neutropenia, lymphopenia, hepatosplenomegaly due to monocyte infiltration and pulmonary edema due to interstitial cell infiltration; or preventing these diseases. In particular, the compounds of formula (I) may be used in the treatment of rheumatoid arthritis, Crohn's disease, irritable bowel syndrome, colitis, psoriasis or multiple sclerosis.
The cytokine production inhibitory activity of the compounds of formula (I), for example, the activity of TNF- α and/or IL-12, can be demonstrated in an in vitro assay "inhibition of cytokine production in human whole blood medium". Suitable in vitro tests are "measurement of cytokines in the serum of mice challenged with LPS (lipopolysaccharide) and anti-CD 3", "inhibition of LPS-galactose induced shock in mice", "inhibition of carrageenan induced arthritis in mice".
The compounds of formula (I) may also inhibit interleukin-6 (IL-6).
The compounds of the present invention may also be used as intermediates for the preparation of other thiazole derivatives.
In view of the above pharmacological properties, the compounds of formula (I) or any subgroup thereof, their N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, may be used as medicaments. In particular, the compounds of the invention may be used for the preparation of a medicament for the treatment or prevention of cytokine mediated diseases, in particular diseases mediated by TNF-2 and/or IL-12, such as inflammatory or autoimmune diseases.
With respect to the use of compounds of formula (I), there is provided a method of treatment or prophylaxis in warm-blooded animals, including humans, suffering from cytokine mediated diseases, particularly diseases mediated by TNF-2 and/or IL-12, such as inflammatory or autoimmune diseases. Said method comprising administering, preferably orally, an effective amount of a compound of formula (I), their N-oxides, pharmaceutically acceptable addition salts, quaternary amines or possible stereochemically isomeric forms thereof, to warm-blooded animals, including humans.
The invention also provides a composition for preventing or treating cytokine mediated diseases, particularly diseases mediated by TNF-alpha and/or IL-12, comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
The compounds of the present invention, or any subgroup thereof, may be formulated into various pharmaceutical dosage forms for different purposes of administration. Suitable compositions may employ all components commonly used in systemic administration. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is intimately admixed with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. It is desirable that these pharmaceutical compositions be in unit dosage forms particularly suitable for oral administration, rectal administration, dermal administration, or administration by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols and the like when preparing oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like are used when preparing powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. For parenteral administration, the carrier will usually comprise sterile water, at least in large part, although other ingredients, such as those used to aid solubility, may also be included. For example, an injection solution can be prepared in which the carrier comprises physiological saline, a glucose solution, or a mixture of physiological saline and a glucose solution. Injectable solutions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are dosage forms that are solid preparations that are converted to liquid preparations just prior to use. In compositions suitable for dermal administration, the carrier optionally contains a penetration enhancer and/or a suitable wetting agent, optionally in combination with small amounts of suitable additives of any nature that do not cause significant adverse effects on the skin. The additives may facilitate administration to the skin and/or aid in the preparation of the desired composition. These compositions may be administered by various methods, for example in the form of transdermal patches, spot-ons, ointments. The compounds of the present invention may also be administered by inhalation or insufflation, using methods and formulations used in the art for administration via this method. Thus, the compounds of the invention may generally be administered to the lungs in the form of a solution, suspension or dry powder. Any system developed for the delivery of solutions, suspensions or dry powders by oral or nasal inhalation or insufflation is suitable for the administration of the compounds of the invention.
To facilitate dissolution of the compound of formula (I), suitable ingredients, such as cyclodextrins, may be used in the compositions of the present invention. Suitable cyclodextrins are α -, β -, γ -cyclodextrins or ethers and mixed ethers thereof, wherein one or more of the hydroxyl groups of the anhydroglucose unit in the cyclodextrin are substituted by: c1-6Alkyl, especially methyl, ethyl or isopropyl, e.g. randomly methylated beta-CD; hydroxy radical C1-6Alkyl, in particular hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy group C1-6Alkyl, in particular carboxymethyl or carboxyethyl; c1-6Alkylcarbonyl, in particular acetyl. Particularly noteworthy as complexing and/or solubilizing agents are β -CD, randomly methylated β -CD, 2, 6-dimethyl- β -CD, 2-hydroxyethyl- γ -CD, 2-hydroxypropyl- γ -CD and (2-carboxymethoxy) propyl- β -CD, especially 2-hydroxypropyl- β -CD (2-HP- β -CD).
The term mixed ether refers to cyclodextrin derivatives in which at least two cyclodextrin hydroxy groups are etherified with different groups such as hydroxypropyl and hydroxyethyl.
The average molar substitution (m.s.) was used to measure the average number of moles of alkoxy units per mole of anhydrous glucose. The average degree of substitution (d.s.) refers to the average number of hydroxyl groups substituted per anhydroglucose unit. The m.s. and d.s. values can be determined by various analytical techniques such as Nuclear Magnetic Resonance (NMR), Mass Spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, the values measured for a given cyclodextrin derivative may vary slightly. Preferably, the m.s. range is 0.125 to 10 and the d.s. range is 0.125 to 3 as measured by mass spectrometry.
Other compositions suitable for oral or rectal administration include particles consisting of a solid dispersion comprising a compound of formula (I) and one or more suitable pharmaceutically acceptable water-soluble polymers.
The term "solid dispersion" as used hereinafter is defined as a solid system (other than a liquid or gaseous state) comprising at least two components, namely a compound of formula (I) and a water-soluble polymer, wherein one component is more or less uniformly dispersed in the other component or components (if other pharmaceutically acceptable formulating agents are included, generally known in the art, such as plasticizers, preservatives and the like). When said dispersion of this component is a chemically and physically homogeneous or overall homogeneous system or a system consisting of a thermodynamically defined single phase, this solid dispersion is called a "solid solution". Solid solutions are the preferred physical system because the components therein are generally readily bioavailable to the organism to which they are administered. This advantage may be due to the ability of the solid solution to readily form a liquid solution when contacted with a liquid medium such as gastrointestinal fluids. The ease of dissolution is at least in part because the energy required to dissolve the components in the solid solution is less than the energy required to dissolve the components in the crystalline or microcrystalline solid phase.
The term "solid dispersion" also includes dispersions that are less homogeneous overall than solid solutions. Such dispersions are not chemically and physically homogeneous or contain more than one phase. For example, the term "solid dispersion" also relates to a system containing several regions or small regions in which amorphous, microcrystalline and crystalline compounds of formula (I), or amorphous, microcrystalline and crystalline water-soluble polymers, or both, are more or less homogeneously dispersed in another phase containing water-soluble polymers, or compounds of formula (I) and water-soluble polymers. The domains are in solid dispersion, have some very distinct physical characteristics, are small in size and are uniformly and randomly dispersed throughout the solid dispersion.
Various techniques exist for preparing solid dispersions including melt extrusion, spray drying and solution evaporation methods.
The solution evaporation method comprises the following steps:
a) dissolving a compound of formula (I) and a water-soluble polymer in a suitable solvent, optionally at elevated temperature;
b) heating the solution obtained in a), optionally under vacuum, until the solvent evaporates. It is also possible to pour the solution onto a large surface to form a film and evaporate the solvent therein.
In the spray drying technique, the two components may also be dissolved in a suitable solvent, and the resulting solution is then sprayed through the nozzle of a spray dryer, followed by evaporation of the solvent from the resulting droplets at elevated temperature.
The preferred solid-phase liquid preparation technique is a melt extrusion process comprising the steps of:
a) mixing a compound of formula (I) with a suitable water-soluble polymer,
b) optionally mixing an additive with the resulting mixture,
c) heating and combining the resulting mixture until a homogeneous melt is obtained,
d) extruding the resulting melt through one or more nozzles; and is
e) The melt was cooled until solidification.
The terms "melt" and "melting" should be interpreted broadly. These terms refer not only to the change from solid to liquid but also to the transition from solid to glassy or rubbery state and one component of the mixture may be more or less homogeneously contained in the other. In special cases, one component melts and the other dissolves in the melt to form a solution, which upon cooling may form a solid solution with advantageous dissolution characteristics.
After the solid dispersion is prepared as described above, the resulting product is optionally milled and sieved.
The resulting dispersion product may be milled or ground to particles having a particle size of less than 600 μm, preferably less than 400 μm and most preferably less than 125 μm.
The granules prepared as described above may be formulated into pharmaceutical preparations such as tablets and capsules using conventional techniques.
It will be appreciated that the person skilled in the art will be able to optimise the parameters of the above described solid dispersion technique, such as the most appropriate solvent, operating temperature, type of equipment used, spray drying speed, throughput rate of the melt extruder.
The water-soluble polymer in the particles is a polymer which, when dissolved in a 2% (w/v) aqueous solution at 20 ℃, has an apparent viscosity of from 1 to 5000mpa.s, more preferably from 1 to 700mpa.s, most preferably from 1 to 100 mpa.s. For example, suitable water-soluble polymers include alkyl celluloses, hydroxyalkyl alkyl celluloses, carboxyalkyl celluloses, alkali metal salts of carboxyalkyl celluloses, carboxyalkyl alkyl celluloses, carboxyalkyl cellulose esters, starches, pectins, chitin derivatives, disaccharides, oligosaccharides and polysaccharides such as trehalose, alginic acid or its alkali metal and ammonium salts, carageenan, galactomannan, tragacanth, agar, acacia, guar gum and xanthan gum, polyacrylic acid and its salts, polymethacrylic acid and its salts, methacrylate copolymers, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, combinations of polyvinyl alcohol and polyvinylpyrrolidone, polyalkylene oxides and copolymers of ethylene oxide and propylene oxide. The preferred water soluble polymer is hydroxypropyl methylcellulose.
One or more cyclodextrins may also be used as water-soluble polymer in the preparation of the above-mentioned particles, as described in WO 97/18839. The cyclodextrins include pharmaceutically acceptable substituted and unsubstituted cyclodextrins known in the art, particularly alpha, beta or gamma cyclodextrins or pharmaceutically acceptable derivatives thereof.
Substituted cyclodextrins that can be used to prepare the above particles include polyethers described in U.S. patent No. 3,459,731. Other substituted cyclodextrins being obtained by substituting one or more of the cyclodextrin hydroxy groups with a hydrogen atom by C1-6Alkyl, hydroxy C1-6Alkyl, carboxyl C1-6Alkyl, or C1-6Alkoxycarbonyl group C1-6Alkyl substituted ethers or mixed ethers thereof. These substituted cyclodextrins being in particular substituted by C1-3Alkyl, hydroxy C2-4Alkyl, or carboxyl C1-2Alkyl-substituted ethers or more particularly ethers substituted by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl.
Beta-cyclodextrin ethers are particularly useful, for example dimethyl-beta-cyclodextrin and polyethers described by M.Nogradi in "Drugs of Future", Vol.9, No.8, P.577-578(1984), for example hydroxypropyl-beta-cyclodextrin and hydroxyethyl-beta-cyclodextrin, as examples herein. Such alkyl ethers may be methyl ethers with a degree of substitution of 0.125 to 3, for example 0.3 to 2. For example, such hydroxypropyl cyclodextrins can be formed by the reaction of beta-cyclodextrin and propylene oxide and have an MS value of about 0.125 to 10, e.g., about 0.3 to 3.
Another substituted cyclodextrin is sulfobutyl cyclodextrin.
The ratio of the compound of formula (I) to the water-soluble polymer varies widely. For example, ratios of 1/100-100/1 may be used. The advantageous ratio of the compound of formula (I) to the cyclodextrin ranges from about 1/10 to 10/1. A more advantageous range of ratios is about 1/5-5/1.
It is further advantageous to prepare the compound of formula (I) in the form of nanoparticles, the amount of surface modifying agent adsorbed on the surface of the nanoparticles being sufficient to maintain an effective average particle size of less than 1000 nm. Surface modifying agents considered suitable include those surfactants which are capable of physical adsorption on the surface of the compound of formula (I) but which are not chemically bonded to said compound.
Suitable surface-modifying agents are preferably selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifying agents include nonionic and anionic surfactants.
Another attractive way of formulating the compounds of formula (I) relates to a pharmaceutical composition wherein the compound of formula (I) is incorporated in a hydrophilic polymer and the mixture is coated as a coating on a plurality of beads, thus obtaining a composition which can be conveniently prepared and which is suitable for use in the preparation of oral pharmaceutical dosage forms.
The beads comprise a round or spherical core, a coating of a hydrophilic polymer and a compound of formula (I) and optionally a sealing coating.
There are many materials suitable for use as the core of the beads, provided that the material is pharmaceutically acceptable and has the appropriate size and robustness. Examples of such materials are polymers, inorganic, organic and sugars and derivatives thereof.
It is particularly advantageous to formulate the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored and coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and various combinations thereof.
The compounds of the invention are orally active compounds and are preferably administered orally.
The precise dose and frequency of administration will depend upon the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of the disorder and the general physical condition of the particular patient and other drugs the individual may be taking, as is well known to those skilled in the art. Furthermore, it will be apparent that the effective daily dose may be reduced or increased depending on the response of the subject and/or the evaluation of the physician prescribing the compounds of the instant invention.
The compounds of formula (I) may also be used in combination with other conventional anti-inflammatory or immunosuppressive agents, such as steroids, cyclooxygenase-2 inhibitors, non-steroidal anti-inflammatory agents, TNF-alpha antibodies, such as acetylsalicylic acid, bufexamic acid, diclofenac potassium, sulindac (sulindac), diclofenac sodium, ketorolac tromethamine, tolmetin (tolmetin), ibuprofen (ibuprofen), naproxen (naproxen), naproxen sodium, tiaprofen acid, flurbiprofen (flurbiprofen), mefenamic acid, nifluminic acid, meclofenamic acid (meclofenamate), indomethacin (indomethacin), proglucumetacine, ibuprofen (ketoprofen), nabumetone (nabumetone), paracetamol (paracetamol), piroxicam (piroxicam), tenoxicam (tenoxicam), sultamide (sultamide), betamethasone (betamethasone), diclofenac (clotrimazole), naloxonol (naloxonol), naloxonol (methasone), naloxonol (clofenamate), ibuprofen (ibuprofen), betamethasone (clomethasone), clomethasone (clomethasone, Betamethasone (betamethasone), beclomethasone, budesonide (budesonide), fluticasone (fluticasone), mometasone (mometasone), dexamethasone (dexamethasone), hydrocortisone (hydrocortisone), methylprednisolone (methylprednisone), prednisolone (prednisone), triamcinolone (triamcinolone), celecoxib (celecoxib), rofecoib (rofecoxib), infliximab (infliximab), leflunomide (leflunomide), etanercept (etanercept), CPH82, methotrexate (methoxitate), sulfasalazine (sulfasalazine), lymphocyte immunoglobulin, anti-adenocyte immunoglobulin, thiopurine, cyclosporine (rapamycin), rapamycin (tacrolimus) -3.
The invention therefore also relates to a combination of a compound of formula (I) and another anti-inflammatory agent or immunosuppressant. The composition may be used as a medicament. The invention also relates to a product containing (a) a compound of formula (I) and (b) another anti-inflammatory or immunosuppressive compound as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease associated with an overproduction or a lack of modulation of cytokine production. The different drugs may be combined together with a pharmaceutically acceptable carrier into a single formulation.
Experimental part
A. Preparation of intermediate compounds
Example A1A
a) Preparation of intermediate 1a
Palladium (II) acetate (0.0003mol) and 1, 3-bis (diphenylphosphino) -propane (0.0006mol) were added to a solution of 2-chloro-5-fluoropyridine (0.01mol) in tetrahydrofuran (100ml) in an autoclave. Liquid ammonia (0.6mol) was added and carbon monoxide at 40 atm was passed in. The mixture was heated at 150 ℃ for 16 hours. After cooling to room temperature, methanol (200ml) was added, and the mixture was stirred for 1 hour. The mixture was filtered and the residue was washed with methanol. The combined filtrates were distilled to dryness under reduced pressure, and the residue and diisopropyl ether were triturated and dried under reduced pressure. Yield: 0.56g of intermediate 1a (40%).
b) Preparation of intermediate 1b
Next, 5-chloro-2-pyridinecarboxamide (0.004mol), phosphorus pentasulfide (0.004mol) and tetrahydrofuran (25ml) were heated under reflux for 2 hours. The mixture was cooled to room temperature, filtered, and the residue was washed with tetrahydrofuran. The residue was then suspended in water (20ml) and the mixture was boiled for 15 minutes. After cooling, the mixture was extracted with dichloromethane methanol 9: 1. After phase separation, the organic layer was dried (MgSO4) And the solvent was removed under reduced pressure. Yield: 0.57g of intermediate 1b (82%).
Example A1B
a) Preparation of intermediate 1
A mixture of 3-chloro-2, 4-pentanedione (0.098mol) and 4-trifluoromethylphenylthiocarboxamide (0.098mol) in ethanol (160ml) was stirred and refluxed for 16 hours. The mixture was filtered, the residue washed with ethanol and dried under reduced pressure. Yield: 17g of intermediate 1 (60%) (mp.87 ℃ -88 ℃ C.).
b) Preparation of intermediate 2
A suspension of intermediate 1 in 1, 1-dimethoxy-N, N-dimethyl-methylamine (150ml) was heated at 80 ℃ for 6 hours. The solvent was evaporated off under reduced pressure, the residue was triturated with diisopropyl ether, the mixture was filtered, the residue was washed with diisopropyl ether and dried under reduced pressure. Yield: 11.0g of intermediate 2 (92%) (mp.147 ℃ C.).
Example A1C
a) Preparation of intermediate 2a
Dimethyl carbonate (0.07mol) was added to a suspension of sodium hydride (0.07mol) in tetrahydrofuran (70ml), and the mixture was heated to 60 ℃. A solution of intermediate 1(0.035mol) in tetrahydrofuran (50ml) was added dropwise. The reaction mixture was heated at reflux for 45 minutes, cooled to room temperature, and methanol was added to destroy the remaining sodium hydride. The mixture was neutralized with acetic acid and the solvent was removed under reduced pressure. The residue was separated between ethyl acetate and water, the phases separated and the aqueous layer extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO)4) And the solvent was removed under reduced pressure. The resulting oil was triturated in ether/hexane, the mixture was filtered and the residue was washed with hexane. Yield: 10.4g of intermediate 2a (87%).
Example A2
a) Preparation of intermediate 3
Pd (PPh)3)4(0.002mol) was dissolved in tetrahydrofuran (120 ml). 2, 4-dichloro-5-thiazolecarboxaldehyde (0.02mol) was added. The reaction mixture was stirred at room temperature for 30 minA clock. Adding [4- (trifluoromethyl) phenyl]Boric acid (0.021mol) and Na2CO3/H2O (11g/80 ml). The reaction mixture was stirred and refluxed for 3 hours. The reaction mixture was cooled and water was added. CH for the mixture2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) And the solvent was removed under reduced pressure. The residue was triturated in ethanol, washed with ethanol and dried under reduced pressure. Yield: 3.2g of intermediate 3 (55%).
b) Preparation of intermediate 4
Intermediate 3(0.011mol) was dissolved in tetrahydrofuran (50ml) and cooled to-10 ℃. A solution of 3M methylmagnesium chloride in tetrahydrofuran (3.7ml, 0.011mol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. Water (3ml) was added followed by CH3COOH (1ml) (exothermic). The reaction mixture was extracted with ethyl acetate, the organic layer was separated, dried, filtered and the solvent was evaporated. Yield: 3.4g intermediate 4 (100%).
c) Preparation of intermediate 5
Intermediate 4(0.01mol) was dissolved in 1, 2-dichloroethane (40 ml). Pyridine chlorochromate (0.02mol) was added to the reaction mixture. The reaction mixture was stirred at 70 ℃ for 3 hours, cooled to room temperature, poured onto a plug of silica gel and eluted with dichloromethane. The eluate was evaporated under reduced pressure and the residue was dried under reduced pressure. Yield: 2.2g of intermediate 5 (72%) (mp.178 ℃ C.).
d) Preparation of intermediate 6
Intermediate 5(0.004mol) was dissolved in 1, 1-dimethoxy-N, N-dimethyl-methylamine (50ml) and stirred at 80 ℃ for 16 h. The reaction mixture was cooled, water was added, and the mixture was filtered. The residue was washed with water and dried under reduced pressure. Yield: 1.1g of intermediate 6 (76%) (mp.198).
Example A3A
a) Preparation of intermediate 7
2-amino-4-chloro-5-thiazolecarboxaldehyde (0.012mol) was dissolved in CH3COOH (80ml) and heating. To the hot solution was added dropwise tetrahydro-2, 5-dimethoxyfuran (0.015 mol). The reaction mixture was heated at reflux for 2 hours. The solvent was evaporated. The residue was dried under reduced pressure. Yield: 2.0g of intermediate 7 (78%).
Intermediate 7 was converted to intermediate 7' using a procedure similar to that used to convert intermediate 3 to intermediate 6 in example a 2. Yield: 57% intermediate 7' (mp.201 ℃ C.).
b) Preparation of intermediate 7a
2-amino-4-methyl-5-acetylthiazole (0.030mol) was dissolved in CH3COOH (160ml) and heating. To the hot solution was added dropwise tetrahydro-2, 5-dimethoxyfuran (0.035 mol). The reaction mixture was heated at reflux for 2 hours. The solvent was evaporated. The residue was dried under reduced pressure. Yield: 5.3g of intermediate 7a (86%).
Example A3B
a) Preparation of intermediate 7b
2, 4-dichloro-5-thiazolecarboxaldehyde (0.027mol), 1, 2-ethanediol and 4-toluenesulphonic acid were dissolved in toluene (60ml) and heated in a dean and Stark trap for 16 h. The solvent was removed under reduced pressure and the residue was chromatographed using dichloromethane as eluent. Yield: 2.0g of intermediate 7b (33%).
b) Preparation of intermediate 7c
Sodium hydride (0.009mol) was added portionwise to a suspension of pyrazole (0.009mol) in N, N-dimethylformamide (20ml) with stirring. Stirring was continued for 1 hour, then intermediate 7b was added. The mixture was stirred for 72 hours and ice water was added carefully. The mixture was filtered, and the residue was washed with water and then dried under reduced pressure. Yield: 1.7g intermediate 7c (74%).
c) Preparation of intermediate 7d
Intermediate 7c (0.0058mol) was added to a solution of acetic acid (5ml) in water (30ml), and sufficient methanol was added to dissolve it. The solution was heated to reflux for 1 hour, cooled and then filtered. The residue was washed with water and then dried under reduced pressure. Yield: 1.2g of intermediate 7d (97%).
d) Preparation of intermediate 7e
Intermediate 7d (0.0052mol) was converted to intermediate 7e (0.0028mol) using a method analogous to that used to convert intermediate 3 to intermediate 6 in example a 2. Yield: 0.8g of intermediate 7e (54%) (mp.232 ℃ C.).
Example A4
a) Preparation of intermediate 8
4-fluorophenyl thiocarboxamide (0.05mol) and chloroacetyl chloride (0.2mol) were mixed at room temperature and stirred for 10 minutes. The reaction temperature was slowly raised to 60 ℃. After 30 minutes, the reaction mixture was cooled to room temperature and then the volatile components were removed under reduced pressure. The residue was dissolved in ether, hexane was added, and the mixture was filtered. The residue was washed with diethyl ether/hexane (1/4) and then dried under reduced pressure. Yield: 8.9g intermediate 8 (77%).
b) Preparation of intermediate 9
Phosphorus oxychloride (0.44mol) was added dropwise to N, N-dimethylformamide (0.22mol) at between 0 ℃ and 5 ℃ with rapid stirring. The reaction mixture was stirred at 0 ℃ for 30 minutes, then intermediate 8(0.044mol) was added while the reaction mixture was allowed to warm to room temperature. The reaction mixture was heated to 60 ℃ for 1 hour and then heated to reflux for 90 minutes. Water was added carefully, the mixture was filtered, the residue was triturated with ether and dried under reduced pressure. Yield: 6.8g of intermediate 9 (64%).
Example A5
a) Preparation of intermediate 11
4-Trifluoromethylphenylthiocarboxamide (0.10mol) was dissolved in ethanol (150ml) and ethyl-3-chloroacetoacetonate (0.11mol) dissolved in ethanol (50ml) was added. The reaction mixture was heated to reflux for 90 minutes. The solvent was evaporated under reduced pressure and the residue was in CH2Cl2And saturated aqueous sodium bicarbonate. Phase separation, aqueous phase with CH2Cl2The extraction was performed 2 times. The combined organic phases were washed with water and brine, and dried (MgSO)4) And concentrating to dryness. The crude oily residue was triturated with hexane and chromatographed on silica gel using ethyl acetate: hexane (1:4) as eluent to give intermediate 11. Yield: 8.2g of intermediate 11 (24%) (mp.72 ℃ -74 ℃ C.).
b) Preparation of intermediate 12
A solution of ammonia in methanol (7M, 80ml) was added dropwise to a cooled suspension of intermediate 11(0.01mol) in methanol (30ml) at 0 ℃ with stirring. The reaction mixture was stirred at 0 ℃ for a further 30 minutes and then at room temperature for 16 hours. The solvent was evaporated under reduced pressure, methanol was added and most of the solvent was removed under reduced pressure. The solution was cooled to 0 ℃, filtered and the residue washed with cold methanol then hexane. The crude product was recrystallized from ethanol, water (3: 1). Yield: 81.7g of intermediate 12 (54%) (mp.196-200 ℃ C.).
c) Preparation of intermediate 13
Intermediate 12(0.002mol) and 1, 1-dimethoxy-N, N-dimethyl-methylamine (0.010mol) were mixed and the mixture was heated at 110 ℃ for 40 minutes. After the reaction mixture was cooled to room temperature, the mixture was filtered and the residue and hexane were triturated and separated. Yield: 0.84g of intermediate 13 (95%).
Example A6
Preparation of intermediate 14
Compound 37 (prepared according to B6) (0.035mol) and 3-chloroperoxybenzoic acid (0.077mol) were stirred in dichloromethane for 16 h. The reaction mixture was diluted with dichloromethane (150ml) and washed with 5% aqueous sodium metabisulphite (3 × 100ml) and then with 5% aqueous sodium carbonate (2 × 100 ml). The reaction mixture was then washed repeatedly with water until the pH of the aqueous wash was 7. Undissolved solids were filtered off. The filtrate was dried (MgSO4) Evaporated to dryness under reduced pressure and the resulting residue combined with undissolved solid. Yield: 14g of intermediate 14 (100%) (mp.223 ℃ C.).
Intermediate 14a
Prepared from compound 91 according to the procedure described above for the preparation of intermediate 14. Yield: 74% of intermediate 14 a.
Example A7
Preparation of intermediate 15
Will be provided withPrepared (from intermediate 7) in analogy to the methods of examples A2b) and c) (0.0044mol) was dissolved in methanol (50ml) and heated until complete dissolution. A30% by weight solution of sodium methoxide in methanol (0.00mol) was added. Reaction ofThe mixture was stirred at reflux for 4 hours and stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was washed twice with water and dried under reduced pressure. Yield: 0.7g intermediate 15 (71%).
Example A8
a) Preparation of intermediate 16
Oxalyl chloride (0.039mol) was added dropwise to a 0 ℃ dichloromethane suspension (200ml) of 4-methyl-2- (4-trifluoromethylphenyl) -5-thiazolecarboxylic acid (0.039mol) and N, N-dimethylformamide (1 drop) with stirring. The reaction mixture was warmed to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure, and methylene chloride (100ml) was then added. A methanol solution of ammonia (7M, 30ml) was added and the mixture was stirred for 8 hours. The mixture was filtered, the residue was washed with dichloromethane and dried under reduced pressure. Yield: 10g of intermediate 16 (90%) (mp 213 ℃ C. 216 ℃ C.).
b) Preparation of intermediate 17
Trifluoroacetic anhydride (0.0063mol) was added dropwise to a suspension of intermediate 16(0.0016mol) and pyridine (0.010mol) in dioxane at 0 ℃ with stirring. Stirring was continued for 30 minutes and the reaction mixture was allowed to warm to room temperature and stirring was continued for 16 hours. The solvent was removed under reduced pressure, the residue triturated with water and dried under reduced pressure. Yield: 0.39g of intermediate 17 (91%) (mp 90 ℃ C.).
Example A9
Preparation of intermediate 18
A solution of intermediate 1(0.020mol) in tetrahydrofuran (25ml) was added dropwise to a suspension of potassium tert-butoxide (0.040mol) in tetrahydrofuran (100ml) with stirring at room temperature. The resulting dark red solution was stirred for an additional 30 minutes. Carbon disulfide (1.5ml) was added dropwise and after 30 minutes methyl iodide (4ml) was added. The reaction mixture was stirred for 2 hours, then poured into water (11) and filtered. The residue was washed with water and dried under reduced pressure. Yield: 4.6g of intermediate 18 (59%) were used in mp.164-166 deg.C (cleaved).
Example A10
Preparation of intermediate 19
3-Chloroperoxybenzoic acid (0.0045mol) was added portionwise to a chloroform (10ml) suspension of compound 99(0.0015mol) under stirring at room temperature. Stirring was continued for 16 hours. Chloroform (50ml) and a saturated aqueous solution of sodium metabisulfite (10ml) were added successively and stirred rapidly for 15 minutes. After the gas evolution had ceased, a saturated aqueous disodium carbonate solution was added dropwise. The mixture was washed with water and the phases separated. Organic layer dried (Na)2SO4) The solvent was removed under reduced pressure. Yield: 0.60g of intermediate 19 (97%) mp.155-158 ℃.
B preparation of the Final Compound
Example B1
Preparation of Compound 9
Sodium methoxide (0.045mol) was added to a mixture of diguanidine carbonate (0.023mol) in 2-ethoxyethanol (300ml), and the mixture was stirred until a homogeneous solution was formed. Intermediate 2(0.023mol) was added and the reaction mixture was heated to reflux for 3 hours. After cooling, water was added and the mixture was filtered. The residue was washed with water and dried under reduced pressure. Yield: 5.9g Compound 9 (76%).
Alternatively used solvents are ethanol, N-dimethylformamide or dimethylsulfoxide.
Example B2
Will be provided with(0.016mol) (prepared as described in example A1B) and hydrazine monohydrate (0.018mol) were stirred and refluxed in a mixture of acetic acid (20ml) overnight. Boiling water (100ml) was added to the hot reaction mixture and the resulting solution was cooled. The mixture was filtered and the residue was recrystallized from ethanol. Yield: 2.2g Compound 28 (57%).
Example B3
a)
Will be provided with(0.016mol), prepared as described in example A1B, was added to a mixture of methyl guanidine hydrochloride (0.024mol) and sodium methoxide (0.026mol) in N, N-dimethylformamide (30 ml). The mixture was heated at 100 ℃ for 26 hours. The mixture was diluted with water (80ml) and acidified with acetic acid (2 ml). The mixture was filtered, the residue was dried and recrystallized from isooctane, toluene 3: 1. Yield: 4.4g Compound 17 (87%).
b)
Will be provided with(0.0073mol) (prepared as described in example A1B) was added to a mixture of acetamidoate (0.022mol) and sodium ethoxide (0.024mol) in ethanol (20 ml). The mixture was heated at reflux for 24 hours. A mixture of formamidinate (0.012mol) and sodium ethoxide (0.013mol) in ethanol (10ml) was added and the mixture was heated under reflux for a further 24 h. The mixture was diluted with water (30ml) and acidified with acetic acid (3 ml). The solvent was removed under reduced pressure. The residue was dried under reduced pressure and recrystallized from 1-butanol. Yield: 1.2g Compound 22 (57%).
C) Preparation of Compound 59
Sodium methoxide (0.0014mol) was added to a mixture of 3-hydroxypropyl guanidine hemisulfate (0.0014mmol) in 2-methoxyethanol. Stirring was continued for 30 min, then intermediate 7' (0.0007mol) was added. The reaction mixture was stirred at 100 ℃ for 16 hours, cooled and the solvent removed under reduced pressure. The residue was chromatographed on silica gel using dichloromethane as eluent. The residue was triturated with diisopropyl ether, filtered, washed with diisopropyl ether and dried under reduced pressure. Yield: 0.013g Compound 59 (6%).
Example B4
Preparation of Compound 35
Sodium methoxide (0.0041mol) was suspended in 2-ethoxyethanol (6ml), followed by the addition of acetamidine hydrochloride (0.0041 mol). The mixture was stirred at room temperature for 30 minutes. Intermediate 2 (prepared according to the method of example A1 Bb) (0.0018mol) was then added and the mixture was stirred at reflux for 8 hours. Sodium methoxide (0.020mol) and acetamidine hydrochloride (0.020mol) in 2-ethoxyethanol (2ml) were added. After stirring at reflux for 1 hour, the reaction mixture was cooled and poured into ice water (70 ml). The mixture was filtered and the residue was washed with water. Yield: 0.59g Compound 35 (98%).
Example B5
Preparation of Compound 36
Guanidine hydrochloride (0.0054mol) was added to a solution of sodium methoxide (0.0054mol) in ethanol (10ml), and the mixture was stirred for 30 minutes. A solution of intermediate 13 (prepared according to the method of example A5 c) (0.0018mol) in ethanol (10ml) was then added and the reaction mixture refluxed for 1 hour. After cooling, water was added, the mixture was filtered, and the residue was washed with ethanol-water. The residue was dried and recrystallized from 2-ethoxyethanol. Yield: 0.23g of Compound 36 (35%) (mp.286-287 ℃ C.).
Example B6
Intermediate 2(0.009mol) and thiourea (0.010mol) were added to a solution of potassium hydroxide (0.009mol) in ethanol (25ml) and the resulting mixture was refluxed for 5 hours. The mixture was cooled on an ice bath, filtered and the residue was washed with diethyl ether. The residue was dried under reduced pressure and then dissolved in a solution of sodium hydroxide (0.027mol) in water (40 ml). Dimethyl sulfate (0.018mol) was added dropwise at room temperature. After 2 h water (10ml) was added and the reaction mixture was extracted with diethyl ether (2 × 40 ml). The organic layers were combined, washed successively with water (10ml) and brine (10ml), and then dried (MgSO4). The solvent was removed under reduced pressure. Yield: 2.28g Compound 37 (69%).
Compound 91
Prepared from intermediate 6 following the procedure for compound 37 above. Yield: 52% Compound 91.
Example B7
a) Preparation of Compound 38
Intermediate 14 (prepared according to the method of A6) (0.001mol) was suspended in 1, 3-propanediamine (2ml) and the mixture was heated to 130 ℃ for 15 minutes. After cooling, water was added with stirring and the mixture was left for 16 hours. The mixture was filtered and the residue was washed with water. The residue was dried under reduced pressure. Yield: 0.35g Compound 38 (89%).
With a similar reaction, if the amine used is not liquid at 20 ℃, an appropriate solvent, for example N, N-dimethylformamide, is optionally used.
b) Preparation of Compound 84
Intermediate 14 (prepared according to the method of A6) (0.0005mol), 3-aminopropionic acid (0.001mol) and disodium carbonate (0.001mol) were suspended in dimethyl sulfoxide and the mixture was heated to 120 ℃ for 3 hours. After cooling to room temperature, water (6ml) was added with stirring. Stirring was continued until crystallization was complete, the mixture was filtered and the residue was dried under reduced pressure. Yield: 0.2g Compound 84 (93%).
c) Preparation of Compound 83
A solution of sodium methoxide in methanol (30 wt%, 0.2ml) was added to a solution of intermediate 14 (prepared according to the method of a 6) (0.0002mol) and methanol (0.8ml) in tetrahydrofuran (4ml) and the solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue stirred in acetonitrile (2ml) and water (4 ml). The mixture was filtered and the residue was dried under reduced pressure. Yield: 0.051g Compound 83 (73%).
d) Preparation of Compound 82
Sodium hydroxide solution (1M, 0.4ml) was added to a solution of intermediate 14 (prepared according to the method of a 6) (0.0002mol) and water (0.6ml) in tetrahydrofuran (4ml) and the solution was warmed briefly and then stirred at room temperature for 72 hours. The solvent was removed under reduced pressure and the residue stirred in acetonitrile (2ml), water (2ml) and aqueous hydrochloric acid (1M, 0.4 ml). The mixture was filtered and the residue was dried under reduced pressure. Yield: 0.058g Compound 82 (86%).
e) Preparation of Compound 40
Intermediate 14 (prepared according to the method of A6) (0.0013mol) was suspended in N, N-dimethylformamide (5ml) and potassium cyanide (0.003mol) was added. The reaction mixture was heated to 100 ℃ for 15 minutes. After cooling to room temperature, water was added and the mixture was filtered. The residue was washed with water and dried under reduced pressure. Yield: 0.43g Compound 40 (96%).
f) Preparation of Compound 70
Intermediate 14 (prepared according to the method of A6) (0.001mol) was suspended in bis- (2-hydroxyethyl) amine (5ml) and the mixture was heated to 100 ℃ for 30 min. After cooling, water was added with stirring and the mixture was filtered. The residue was washed with water and dried under reduced pressure. Yield: 0.18g Compound 70 (42%).
g) Preparation of Compound 87
Intermediate 14a (prepared according to the method of A6) (0.0001mol) was dissolved in tetrahydrofuran (4ml) and 2-aminoethanol (0.0002mol) was added. The solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue dissolved in MeOH (2 ml). The solution was acidified with 6M hydrochloric acid in 2-propanol. 2-propanol (4ml) was added and the mixture was stirred for 16 h. The mixture was filtered and the residue was dried under reduced pressure. Yield: 0.354g of Compound 87 (87%).
h) Preparation of Compound 90
Intermediate 14 (prepared according to the method of A6) (0.0005mol) was added to dimethyl sulfoxide (5ml) and the suspension was gently heated until complete dissolution. Glycine (0.001mol) and sodium carbonate (0.001mol) were added in this order. The mixture was stirred at 120 ℃ for 4 hours. Cooled to 100 ℃ and then water (5ml) was added to neutralize the solution with 1M hydrochloric acid. Water (3ml) was added and cooled to 0 ℃ with rapid stirring. The mixture was filtered and the residue was dried under reduced pressure. Yield: 0.192g of Compound 90 (92%).
i) Preparation of Compound 89
1, 2-ethanediol (1ml) was added dropwise to a mixture of sodium hydride (60% in oil, 0.0005mol) in N, N-dimethylformamide and stirring was continued for 30 minutes. Intermediate 14a (0.0002mol) was added and the reaction stirred for 20 hours. The solvent was removed under reduced pressure, dissolved in water (5ml) and neutralized with acetic acid. The mixture was slowly warmed and acetonitrile was added slowly until dissolution was complete. After cooling, the mixture is filtered, the residue is dried under reduced pressure and chromatographed on silica gel using dichloromethane/methanol 99:1 as eluent. Yield: 0.023g Compound 89 (29%).
Example B8
Preparation of Compound 81
Sodium methoxide (0.0028mol) was added to a solution of intermediate 17(0.0028mol) (prepared according to the method of example A8 b) in methanol (20ml) with stirring and stirring was continued for 16 hours.
In a separate flask, guanidine hydrochloride (0.0028mol) was suspended in methanol (15ml) and sodium methoxide (0.0028mol) was added and stirring continued for 1 hour. This solution was then added to the previously prepared solution. Stirring was continued for 16 hours. The solvent was removed under reduced pressure and 1, 1-dimethoxy-N, N-dimethyl-methylamine (0.0028mol) was added followed by sodium methoxide (0.0028mol) in methanol (5ml) and stirred for 16 h. The solvent was removed under reduced pressure, methanol (5ml) was added, and the solvent was removed again under reduced pressure. The residue was suspended in hot ethanol and the mixture was filtered while hot. The cooled filtrate was filtered and the residue was dried under reduced pressure. Yield: 0.080g of Compound 81 (7%).
Example B9
Preparation of Compound 2
A solution of acetyl chloride (1.5ml) in dichloromethane (10ml) was added dropwise to a mixture of compound 32(0.019mol) and pyridine (30 ml). The mixture was stirred at room temperature for 75 hours, water (30ml) was added and the mixture was filtered. The residue was washed with hexane and recrystallized from acetic acid. Yield: 3.55g Compound 2 (54%).
Example B10
a) Preparation of Compound 49
[1- (chloromethyl) -4-fluoro-1, 4-diazobicyclo [2.2.2] octane bis (tetrafluoroborate) salt ] ] "Selectfluor" was added to a solution of compound 9(0.0024mol) (prepared according to the method of B1) and 2, 6-lutidine (0.045mol) in N, N-dimethylformamide (5 ml). The reaction mixture was stirred at room temperature for 48 hours and the volatile components were removed under reduced pressure. The residue was chromatographed on silica gel using tetrahydrofuran, hexane 1:4 as eluent. Yield: 0.093g Compound 49 (11%).
b) Preparation of Compound 16
N-chlorosuccinimide (0.0038mol) was added to a solution of compound 9(0.0035mol) (prepared according to the method of B1) in carbon tetrachloride (30 ml). The mixture was refluxed for 5 hours and the solvent was removed under reduced pressure. The residue was suspended in water, the mixture was boiled for 5 minutes and the mixture was filtered. The residue was recrystallized from ethanol. Yield: 0.81g Compound 16 (62%).
c) Preparation of Compound 11
N-bromosuccinimide (0.0026mol) was added to a solution of Compound 6 (prepared according to the method of B1) (0.0024mol) in carbon tetrachloride (3 ml). The mixture was refluxed for 4 hours and the solvent was removed under reduced pressure. The residue was recrystallized from ethanol, water (4:1) and ethanol in this order. Yield: 0.89g Compound 11 (89%).
Example B11
Preparation of Compound 42
Compound 40 (prepared according to the method of B7 e) (0.00087mol) was dissolved in concentrated sulfuric acid (98%, 28ml) and the mixture was heated to 40 ℃. Water (0.35ml) was added slowly. After stirring for 2 hours, the reaction mixture was poured onto ice and neutralized with cold aqueous ammonia. The mixture was filtered and the residue was washed with water and then with ethanol and diethyl ether (1: 5). Yield: 0.25g of Compound 42 (79%).
Example B12
Preparation of Compound 80
A mixture of guanidine hydrochloride (0.025mol), sodium methoxide (0.025mol) and 2-ethoxyethanol (20ml) was refluxed for 15 minutes, then intermediate 2a (0.013mol) was added in one portion. Stirring was continued for 90 minutes at reflux and the solution was cooled and diluted with ethanol and water. The pH was adjusted to 3 using acetic acid. The mixture was filtered, and the residue was washed with water and then dried under reduced pressure. Yield: 3.6g Compound 80 (79%).
Example B13
Preparation of Compound 99
Sodium hydride (0.020mol) was added to a solution of guanidine hydrochloride (0.020mol) in N, N-dimethylformamide (10ml) and stirring was continued for 30 minutes. A solution of intermediate 18(0.014mol) in N, N-dimethylformamide (10ml) was added thereto, and the reaction was heated under reflux for 2 hours. The solution was cooled to 0 ℃, water (150ml) was added and the mixture was filtered. The residue was dried under reduced pressure. Yield: 1.5g Compound 99 (28%). The sample was recrystallized from acetonitrile to give compound 99 as a yellow solid (mp.178-180 ℃).
Example B14
Preparation of Compound 97
Intermediate 20(0.001mol) was dissolved in tetrahydrofuran (10ml) in an autoclave and liquid ammonia (0.6mol) was added. The autoclave was closed and the reaction was stirred at room temperature for 16 hours. The mixture was filtered and the volatile components were removed from the filtrate under reduced pressure. The residue was chromatographed on silica gel using dichloromethane methanol 99:1 as eluent. Yield: 0.15g Compound 97 (42%).
Compounds 92, 93, 94, 95, 96 and 98 were prepared analogously to the methods described in example B7a) or B7 f).
Tables 1, 2 and 3 list compounds of formula (I) prepared according to one of the examples and methods described above.
TABLE 1
Compound (I) Examples of the invention R R R R Physical data (m.p.)
1 B1 H H H H 203
2 B9 -C(＝O)-CH H 4-Cl H >280
3 B1 H H 2-Cl H 209
4 B1 H H 2-Cl 3-Cl 220
5 B1 H H 2-Cl 4-Cl
6 B1 H H 3-CF H 168
7 B1 H H 3-Cl H 175
8 B1 H H 3-F H 198
10 B1 H H 4-F H 221
11 B10c H 5-Br 3-CF H 166
12 B10c H 5-Br 3-F H 136
14 B10c H 5-Br 4-F H 169
15 B10b H 5-C1 3-CF H 174
17 B3a CH H 4-Cl H
32 B1 H H 4-Cl H
43 B1 H H 4-CH H 209
80 B12 H 6-OH 4-CF H >270
TABLE 2
TABLE 3
C. Pharmacological examples
Example c.1: in vitro inhibition of TNF-alpha production in human blood
Human whole blood stimulation
Peripheral blood drawn from healthy male donors was drawn into syringes containing heparin (12.5U heparin/ml). Blood samples were diluted three-fold in RMPI1640 medium (Life technologies, Belgium) supplemented with 2mM L-glutamine, 100U/ml penicillin and 100. mu.gMu.l of the fractions were added to a 24-well multi-well plate (Nunc, Roskilde, Denmark). Blood samples were placed in 6% CO in moisture before stimulation with 100. mu.l of lipopolysaccharide at a final concentration of 100ng/ml2Preincubation (60 min at 37 ℃) in the atmosphere with 100. mu.l of drug solvent (0.02% final concentration in RMPI 1640) or with 100. mu.l of the appropriate dose of test compound. After 6 hours, cell-free supernatants were harvested by centrifugation and stored at-20 ℃ until the presence of TNF-. alpha.was tested.
Example c.2: in vitro inhibition of IL-12p40 production in human blood
Human whole blood stimulation
Peripheral blood drawn from healthy male donors was drawn into syringes containing heparin (12.5U heparin/ml). Blood samples were diluted three times in RMPI1640 medium (Life technologies, Belgium) supplemented with 2mM L-glutamine, 100U/ml penicillin and 100. mu.g/ml streptomycin, and 300. mu.l of the fractions were added to 24-well multi-well plates (Nunc, Roskilde, Denmark). Blood samples were placed in 6% CO in moisture before stimulation with 100. mu.l of lipopolysaccharide at a final concentration of 100ng/ml2Preincubation (60 min at 37 ℃) in the atmosphere with 100. mu.l of drug solvent (0.02% final concentration in RMPI 1640) or with 100. mu.l of the appropriate dose of test compound. After 24 hours, cell-free supernatants were collected by centrifugation and stored at-20 ℃ until the presence of IL-12p40 was tested.
Example c.3: cytokine measurement
Cytokine protein concentrations were measured using a Sandwich ELISA method as described by Van Wauwe et al (1996, Inflamm Res, 45, 357-363). Murine monoclonal antibodies used as human cytokine capture antibodies were obtained from R & D Systems (Abingdon, UK) and the codes for detecting TNF- α and IL-12p40 were MAB210 and MAB611, respectively. Biotinylated goat polyclonal antibodies for detection of human cytokines were obtained from R & D Systems (BAF210, BAF 219). Cytokine concentrations were calculated from standard curves using recombinant cytokines supplied by R & D Systems.
Example c.4: in vitro inhibition of IL-12p70 production in human blood
Human whole blood stimulation
Peripheral blood drawn from healthy male donors was drawn into syringes containing heparin (12.5U heparin/ml). Blood samples were diluted three times in RMPI1640 medium (Life technologies, Belgium) supplemented with 2mM L-glutamine, 100U/ml penicillin and 100. mu.g/ml streptomycin, and 200. mu.l of the fractions were added to 96-well plates (Nunc, Roskilde, Denmark). Blood samples were incubated at 5% C in moisture before being stimulated by the addition of 25. mu.l of lipopolysaccharide at a final concentration of 100ng/ml2Pre-incubation (60 min at 37 ℃) in the atmosphere with 25. mu.l of the drug solvent (0.1% final concentration in RMPI 1640) or with 25. mu.l of the appropriate dose of the test compound. After 24 hours, cell-free supernatants were collected by centrifugation and stored at-20 ℃ until the presence of IL-12 was tested.
Example c.5: cytokine measurement
Cytokine protein concentrations were measured using a Sandwich ELISA method as described by Van Wauwe et al (1996, Inflamm Res, 45, 357-363). The cytokine concentration in the supernatant was quantified using the quantikineHS kit (by R & D HS120, Abingdon, uk) (IL12 p 70).
Table 4 shows the compounds of the invention at the tested dose of 1X 10-6、1×10-7Or 1X 10-8M inhibits the percentage of TNF-alpha and IL-12 production ("% inhibition" column).
TABLE 4

Claims (9)

1. Use of a compound for the manufacture of a medicament for the prevention or treatment of a disease mediated by TNF- α and/or IL-12, wherein the compound is of formula (I)
N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof,
wherein
Z is halogen;C1-6an alkyl group; c1-4An alkoxy group; or an aminocarbonyl group;
q is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, wherein each ring may be optionally substituted with up to three substituents each independently selected from: halogen; c1-6Alkyl or polyhalo C1-6An alkyl group;
l is pyrimidinyl, which may be optionally substituted with up to 3 substituents each independently selected from: amino group, C1-6Alkylcarbonylamino, halogen, Het1-NH-, hydroxy, C1-6Alkylthio radical, C1-6Alkoxy radical, C1-6Alkyl radical, C1-12Alkylamino, mono-or di- (hydroxy C)1-12Alkyl) amino, wherein C1-12Alkyl may also be optionally substituted with a group selected from: hydroxy, Het1Aminocarbonyl, cyano, amino C1-12Alkylamino, hydroxy C1-12Alkyloxy, -NH-C (═ NH) -NH2C carboxyl group1-12Alkylamino, or amino C1-6Alkoxy radical C1-6Alkoxy radical C1-6An alkylamino group;
Het1is a saturated 6-membered heterocyclic ring selected from: piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl wherein said saturated 6-membered heterocycle may be optionally substituted by amino or optionally by phenyl1-4Alkyl substitution.
2. Use of a compound according to claim 1, wherein Q is phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein each ring may be optionally substituted with up to three substituents, each substituent independently selected from the group consisting of: halogen; c1-6Alkyl or polyhalo C1-6An alkyl group;
z is halogen; c1-6Alkyl or aminocarbonyl;
l is pyrimidinyl, which may be optionally substituted with up to 3 substituents, each substituent independently selected from: amino group、C1-6Alkylcarbonylamino, halogen, hydroxy, C1-6Alkylthio radical, C1-6Alkoxy radical, C1-6Alkyl radical, C1-6Alkylamino, aminocarbonyl or cyano.
3. Use of a compound according to claim 1, wherein Q is phenyl, pyridyl, pyrrolyl, pyrazolyl or thienyl, wherein each ring may optionally be optionally substituted with 1 or 2 substituents each independently selected from halogen or polyhaloc1-6Alkyl is substituted by a substituent; z is C1-6Alkyl, halogen, C1-6Alkoxy, aminocarbonyl; l is pyrimidinyl, which may be optionally substituted with 1 or 2 substituents, each substituent independently selected from: amino group, C1-6Alkylcarbonylamino, halogen, Het1-NH-, hydroxy, C1-6Alkylthio radical, C1-6Alkoxy radical, C1-6Alkyl radical, C1-12Alkylamino, mono-or di- (hydroxy C)1-12Alkyl) amino, wherein C1-12Alkyl may further optionally be substituted by hydroxy, Het1Aminocarbonyl, cyano, amino C1-12Alkylamino radical, hydroxy radical C1-12Alkoxy, -NH-C (═ NH) -NH2Carboxyl group C1-12Alkylamino or amino C1-6Alkoxy radical C1-6Alkoxy radical C1-6And (4) alkyl amino substitution.
4. A compound as defined in any one of claims 1 to 3, with the proviso that:
the compound is not
5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of claim 4.
6. A process for the preparation of a composition according to claim 5, characterized in that a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 4 are homogeneously mixed.
7. A compound as defined in claim 1, having the formula (IX-c),
wherein ZbRepresents halogen or C1-4Alkyl, provided that Z isbAnd does not represent a methyl group.
8. A compound as defined in claim 1, having the formula (XIII-b),
wherein ZbRepresents halogen or C1-4Alkyl, provided that Z isbAnd does not represent a methyl group.
9. A process for the preparation of a compound according to claim 4, characterized in that:
a) reacting an intermediate of formula (II) with an intermediate of formula (III) or a suitable salt thereof in the presence of a suitable solvent and a suitable alkoxide
Wherein Q and Z are as defined in claim 1, and RaRepresents hydrogen, amino, optionally substituted C1-6Alkyl, optionally substituted mono-or di (C)1-12Alkyl) amino, Het-NH-or Het1；
b) Reacting an intermediate of formula (II') with an intermediate of formula (III) or a suitable salt thereof in the presence of a suitable solvent and a suitable alkoxide
Wherein Q is as defined in claim 1, and RaRepresents hydrogen, amino, optionally substituted C1-6Alkyl, optionally substituted mono-or di (C)1-12Alkyl) amino, Het-NH-or Het1；
c) Reacting the intermediate of formula (IV) or (IV') with the intermediate of formula (V), optionally at elevated temperature, optionally in the presence of a suitable solvent, optionally in the presence of a suitable base or a suitable acid, optionally under pressure
Wherein Q and Z are as defined in claim 1, and RaRepresents hydrogen, amino, optionally substituted C1-6Alkyl, optionally substituted mono-or di (C)1-12Alkyl) amino, Het-NH-or Het1；Rbrepresents-NH2，Het1-NH-；Het1；-NH-C(＝NH)-N(Rz)2(ii) a C optionally substituted by 1, 2 or 3 hydroxy groups1-12An alkoxy group; optionally substituted mono-or di (C)1-12Alkyl) amino, especially unsubstituted mono-or di (C)1-12Alkyl) amino or C therein1-12The alkyl group is selected from hydroxy, carboxyl, amino C1-4Alkoxy radical C1-4Mono-or di- (C) substituted by 1, 2 or 3 substituents of alkoxy1-12Alkyl) amino;
d) reacting an intermediate of formula (IV) with a suitable cyanide salt in the presence of a suitable solvent
Wherein Q and Z are as defined in claim 1;
e) reacting an intermediate of formula (IV) with a suitable hydroxide base in the presence of a suitable solvent
Wherein Q and Z are as defined in claim 1;
f) reacting an intermediate of formula (II) with thiourea in the presence of a suitable solvent, a suitable alkoxide, dimethyl sulfate and a suitable base
Wherein Q and Z are as defined in claim 1;
g) reacting an intermediate of formula (XXXVI) with an intermediate of formula (III) in the presence of a suitable solvent
Wherein Q and Z are as defined in claim 1, and RaThe definition of (a) is the same as in the above method items a) and b);
j) reacting an intermediate of formula (VI) with an intermediate of formula (III) or a suitable salt thereof in the presence of a suitable solvent
Wherein Q and Z are as defined in claim 1, and RaThe definition of (a) is the same as in the above method items a) and b);
and, if desired, converting the compounds of formula (I) into each other according to conversion methods known in the art and, if desired, further converting the compounds of formula (I) into therapeutically active non-toxic acid addition salts by acid treatment or into therapeutically active non-toxic base addition salts by base treatment, or vice versa converting acid addition salts into free bases by base treatment or converting base addition salts into free acids by acid treatment; and if necessary, a stereochemically isomeric form, a quaternary ammonium or N-oxide thereof.
HK05109570.4A 2001-08-13 2002-08-09 2,4,5-trisubstituted thiazolyl derivatives ant their antiinflammatory activity HK1077507B (en)

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