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Patent US7687637 - 5-phenylthiazole derivatives and use as Pi3 kinase inhibitors - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsCompounds of formula I in free or salt form, wherein R1, R2, R3, R4 and R5 have the meanings as indicated in the specification, are useful for treating diseases mediated by phosphatidylinositol 3-kinase. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds...http://www.google.com/patents/US7687637?utm_source=gb-gplus-sharePatent US7687637 - 5-phenylthiazole derivatives and use as Pi3 kinase inhibitorsAdvanced Patent SearchPublication numberUS7687637 B2Publication typeGrantApplication numberUS 10/504,259PCT numberPCT/EP2003/002036Publication dateMar 30, 2010Filing dateFeb 27, 2003Priority dateFeb 28, 2002Fee statusPaidAlso published asCA2477601A1, CA2477601C, CN1639139A, CN100548996C, EP1480962A1, EP1480962B1, US8129541, US20050119320, US20100093690, WO2003072557A1Publication number10504259, 504259, PCT/2003/2036, PCT/EP/2003/002036, PCT/EP/2003/02036, PCT/EP/3/002036, PCT/EP/3/02036, PCT/EP2003/002036, PCT/EP2003/02036, PCT/EP2003002036, PCT/EP200302036, PCT/EP3/002036, PCT/EP3/02036, PCT/EP3002036, PCT/EP302036, US 7687637 B2, US 7687637B2, US-B2-7687637, US7687637 B2, US7687637B2InventorsIan Bruce, Peter Finan, Catherine Leblanc, Clive McCarthy, Lewis Whitehead, Nicola Press, Graham Charles Bloomfield, Judy Hayler, Louise Kirman, Mrinalini Sachin Oza, Lena ShuklaOriginal AssigneeNovartis AgExport CitationBiBTeX, EndNote, RefManPatent Citations (22), Non-Patent Citations (11), Classifications (38), Legal Events (2) External Links: USPTO, USPTO Assignment, Espacenet5-phenylthiazole derivatives and use as Pi3 kinase inhibitorsUS 7687637 B2Abstract Compounds of formula I
in free or salt form, wherein R1, R2, R3, R4 and R5 have the meanings as indicated in the specification, are useful for treating diseases mediated by phosphatidylinositol 3-kinase. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
R1 is C1-C8-alkylcarbonyl optionally substituted by the group consisting of, hydroxy, C1-C8-alkylamino, carboxy, C1-C8-alkoxycarbonyl, nitrile, phenyl, C1-C8-haloalkyl, C1-C8-alkyl optionally substituted by hydroxy, C3-C8-cycloalkyl optionally substituted by hydroxy, C1-C8-alkoxy optionally substituted by hydroxy, phenyl substituted by hydroxy or C1-C8-alkyl and, 5- or 6-membered unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that heterocyclic ring being optionally substituted by hydroxy, C1-C8-alkyl or C1-C8-alkoxy,
R2 is C1-C3-alkyl or halogen;
R3 is hydrogen, hydroxy, amino, �SOR8, �SO2R8, �SO2NH2, �SO2NR9R10, �COR8, �CONHR8, �NHSO2R8, nitrile, carboxy, �OR8 or C1-C8-haloalkyl;
R4 is �NR12R13;
R8 is C1-C8-alkyl or C3-C8-cycloalkyl, optionally substituted by halogen, hydroxy, C1-C8-alkoxy, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino;
R9 is C1-C8-alkyl or C3-C8-cycloalkyl, optionally substituted by hydroxy, C1-C8-alkoxy, nitrile, amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl;
R10 is hydrogen or C1-C8-alkyl; or
R9 and R10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl; and
R12 and R13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl.
R1 is C1-C8-alkylcarbonyl optionally substituted by the group consisting of hydroxy, carboxy, C1-C8-alkoxycarbonyl, nitrile, phenyl, C1-C8-haloalkyl, C1-C8-alkyl optionally substituted by hydroxy, C1-C8-alkoxy optionally substituted by hydroxy, and a 5- or 6-membered unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl,
R3 is hydrogen, hydroxy, amino, �SO2R8, �SO2NH2, �SO2NR9R10, �NHSO2R8, cyano, carboxy, �OR8 or C1-C4-haloalkyl;
R8 is C1-C8-alkyl;
R9 is C1-C8-alkyl optionally substituted by hydroxy, C3-C8-cycloalkyl optionally substituted by hydroxy, C1-C8-alkoxy, nitrile, di(C1-C8-alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C8-alkyl;
R9 and R10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C8-alkyl; and
R12 and R13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C8-alkyl.
3. A compound according to claim 2, in free or salt form, wherein
R1 is C1-C4-alkylcarbonyl optionally substituted by the group consisting of hydroxy, carboxy, C1-C4-alkoxycarbonyl, nitrile, phenyl, C1-C4-haloalkyl, C1-C4-alkyl optionally substituted by hydroxy, C1-C4-alkoxy optionally substituted by hydroxy, and a 5- or 6-membered unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that heterocyclic ring being optionally substituted by C1-C4-alkyl,
R3 is hydrogen, hydroxy, amino, SO2R8, SO2NH2, SO2NR9R10, NHSO2R8, cyano, carboxy, OR8 or C1-C4-haloalkyl;
R9 is C1-C4-alkyl optionally substituted by hydroxy, C3-C5-cycloalkyl optionally substituted by hydroxy, C1-C4-alkoxy, nitrile, di(C1-C4-alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C4-alkyl;
R9 and R10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C4-alkyl; and
R12 and R13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C4-alkyl.
4. A compound of formula I according to claim 1 in free or salt form, wherein
R1 is C1-C8-alkylcarbonyl optionally substituted by the group consisting of hydroxy, C1-C8-alkylamino, carboxy, C1-C8-alkyl optionally substituted by the group consisting of hydroxy, C3-C8-cycloalkyl optionally substituted by hydroxy, C1-C8-alkoxy optionally substituted by hydroxy, C1-C8-alkoxycarbonyl, nitrile, or phenyl optionally substituted by hydroxy or C1-C8-alkyl, and a 5- or 6-membered unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that heterocyclic ring being optionally substituted by hydroxy, C1-C8-alkyl or C1-C8-alkoxy,
R3 is hydrogen, hydroxy, amino, �SOR8, �SO2R8, �SO2NH2, �SO2NR9R10, �COR8, �CONHR8, NHSO2R8, nitrile, carboxy, �OR8 or C1-C8-haloalkyl;
R1 is C1-C8-alkylcarbonyl optionally substituted by the group consisting of hydroxy, carboxy, C1-C8-alkyl optionally substituted by hydroxy, C3-C8-cycloalkyl optionally substituted by hydroxy, C1-C8-alkoxy optionally substituted by hydroxy, C1-C8-alkoxycarbonyl, nitrile, and phenyl optionally substituted by hydroxy or C1-C8-alkyl;
6. A compound of formula I according to claim 1, in free or salt form, wherein
R1 is C1-C8-alkylcarbonyl optionally substituted by the group consisting of carboxy, C1-C3-alkoxy, C1-C8-alkoxycarbonyl, or nitrile;
R3 is hydrogen, hydroxy, amino, SOR8, SO2R8, SO2NH2, SO2NR9R10, COR8, CONHR8, NHSO2R8, nitrile, carboxy, OR8 or C1-C8-haloalkyl;
R4 is NR12R13;
R9 is C1-C8-alkyl or C3-C8-cycloalkyl, optionally substituted by hydroxy, C1-C8-alkoxy, nitrile, amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino or a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl;
R9 and R10 together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl; and
R12 and R13 together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl.
R1 is C1-C8-alkylcarbonyl optionally substituted by carboxy or C1-C8-alkoxycarbonyl;
R9 is C1-C8-alkyl or C3-C8-cycloalkyl, optionally substituted by hydroxy, C1-C8-alkoxy, nitrile, di(C1-C8-alkyl)amino or a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C8-alkyl;
R9 and R10 together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C5-alkyl; and
R12 and R13 together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C8-alkyl.
8. A compound of claim 1, that is also a compound of formula XIX
in free or salt form, wherein Ra, Rb, Rc and R1 are as shown in the following table:
Ra Rb Rc R1 H H H H H H H H 9. A compound of claim 1, that is also a compound of formula XIX
Ra Rb Rc R1 H H 10. A pharmaceutical composition comprising a compound according to claim 1 in combination with at least one drug substance which is an anti-inflammatory, a bronchodilator or an antihistamine drug substance.
11. A pharmaceutical composition comprising as active ingredient a compound according to claim 1, optionally together with a pharmaceutically acceptable diluent or carrier.
12. A pharmaceutical composition comprising as active ingredient a compound according to claim 8, optionally together with a pharmaceutically acceptable diluent or carrier.
13. A pharmaceutical composition comprising as active ingredient a compound according to claim 9, optionally together with a pharmaceutically acceptable diluent or carrier.
14. A compound of claim 1, which compound has the formula:
R1 is hydrogen or aminocarbonyl optionally substituted by nitrile, or R1 is C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl either of which being optionally substituted by halogen, hydroxy, amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino, carboxy, C1-C8-alkoxycarbonyl, nitrile, phenyl, C1-C8-haloalkyl, or by C1-C8-alkyl optionally substituted by hydroxy,
or R1 is C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl either of which being optionally substituted by C3-C8-cycloalkyl optionally substituted by hydroxy,
or R1 is C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl either of which being optionally substituted by C1-C8-alkoxy optionally substituted by hydroxy,
or R1 is C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl either of which being optionally substituted by phenyl optionally substituted by hydroxy or C1-C8-alkyl,
or R1 is C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl either of which being optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C1-C8-alkyl or C1-C8-alkoxy,
or R1 is �(C═O)�(NH)a-Het where a is 0 or 1 and Het denotes a 4-, 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C1-C8-alkyl, C1-C8-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or R1 is �(C═O)�(NH)b-T where b is 0 or 1 and T denotes C3-C8-cycloalkyl or phenyl either of which being optionally substituted by hydroxy, C1-C8-alkyl, C1-C8-alkoxy, or by C1-C8-alkyl substituted by hydroxy,
one of R3 and R4 is R6 and the other is R7;
R6 is hydrogen, hydroxy, amino, �SOR8, �SO2R8, �SO2NH2, �SO2NR9R10, �COR8, �CONHR8, �NHSO2R8, nitrile, carboxy, �OR8 or C1-C8-haloalkyl;
R7 is hydrogen, R11, �OR11, halo, carboxy, �SO2R8, nitrile or C1-C8-haloalkyl, or, when R4 is R7, R7 can also be �NR12R13, R14 or �OR14;
R8 and R11 are independently C1-C8-alkyl or C3-C8-cycloalkyl, optionally substituted by halogen, hydroxy, C1-C8-alkoxy, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino;
either R9 is C1-C8-alkyl or C3-C8-cycloalkyl, optionally substituted by hydroxy, C1-C8-alkoxy, nitrile, amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl, and R10 is hydrogen or C1-C8-alkyl; or R9 and R10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl;
either R12 is C1-C8-alkyl or C3-C8-cycloalkyl optionally substituted by hydroxy, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino, and R13 is hydrogen or C1-C8-alkyl; or R12 and R13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl; and
R14 is C1-C8-alkyl optionally substituted by hydroxy or �NR12R13.
�Optionally substituted� as used herein means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter.
�Aminocarbonyl� as used herein denotes amino attached through the nitrogen atom to a carbonyl group.
�C1-C8-alkyl� denotes straight chain or branched C1-C8-alkyl, which may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched pentyl, straight or branched hexyl, straight or branched heptyl, or straight or branched octyl. Preferably, C1-C8-alkyl is C1-C4-alkyl.
�C1-C8-alkoxy� denotes straight chain or branched C1-C8-alkoxy which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight or branched pentoxy, straight or branched hexyloxy, straight or branched heptyloxy, or straight or branched octyloxy. Preferably, C1-C8-alkoxy is C1-C4-alkoxy.
�C1-C8-haloalkyl� denotes C1-C8-alkyl as hereinbefore defined substituted by one or more halogen atoms, preferably one, two or three halogen atoms, preferably fluorine or chlorine atoms. Preferably C1-C8-haloalkyl is C1-C4-alkyl substituted by one, two or three fluorine or chlorine atoms.
�C1-C8-alkylcarbonyl�, �C1-C8-alkoxycarbonyl� and �C1-C8-haloalkylcarbonyl� and denote C1-C8-alkyl, C1-C8-alkoxy or C1-C8-haloalkyl respectively as hereinbefore defined attached by a carbon atom to a carbonyl group.
�C1-C8-alkylamino� and �di(C1-C8-alkyl)amino� denote amino substituted respectively by one or two C1-C8-alkyl groups as hereinbefore defined, which may be the same or different. Preferably C1-C8-alkylamino and di(C1-C8-alkyl)amino are respectively C1-C4-alkylamino and di(C1-C4-alkyl)amino.
�Halogen� or �halo� may be fluorine, chlorine, bromine or iodine; preferably it is fluorine or chlorine.
�4, 5- or 6-membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur� as used herein may be, for example, azetidine, furan, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, morpholino, triazine, oxazine or thiazole. Preferred heterocyclic rings include piperazine, morpholino, imidazole, isotriazole, pyrazole, pyridine, furan, oxazole, isoxazole and azetidine.
Preferred compounds of the present invention include compounds of formula I in free or salt form, wherein
R1 is hydrogen or aminocarbonyl optionally substituted by nitrile,
or R1 is C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl either of which being optionally substituted by halogen, hydroxy, di(C1-C8-alkyl)amino, carboxy, C1-C8-alkoxycarbonyl, nitrile, phenyl, C1-C8-haloalkyl, or by C1-C8-alkyl optionally substituted by hydroxy,
or R1 is C1-C8-alkylaminocarbonyl optionally substituted by C3-C8-cycloalkyl,
or R1 is C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl either of which being optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl,
or R1 is �(C═O)�(NH)a-Het where a is 0 or 1 and Het denotes a 4-, 5- or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C1-C8-alkyl, C1-C8-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or R1 is �(C═O)�NH-T where T denotes C3-C8-cycloalkyl or phenyl either of which being optionally substituted by hydroxy, C1-C8-alkyl, or by C1-C8-alkyl substituted by hydroxy,
R6 is hydrogen, hydroxy, amino, �SO2R8, �SO2NH2, �SO2NR9R10, �NHSO2R8, cyano, carboxy, �OR8 or C1-C4-haloalkyl;
R7 is hydrogen, �OR11, fluorine, chlorine, bromine, nitrile or C1-C4-haloalkyl, or, when R4 is R7, R7 can also be �NR12R13 or �OR14;
R8 and R11 are independently C1-C8-alkyl;
either R9 is C1-C8-alkyl optionally substituted by hydroxy, C3-C8-cycloalkyl optionally substituted by hydroxy, C1-C8-alkoxy, nitrile, di(C1-C8-alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C8-alkyl, and R10 is hydrogen or C1-C8-alkyl; or R9 and R10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C8-alkyl;
either R12 is C1-C8-alkyl optionally substituted by di(C1-C8-alkyl)amino, and R13 is hydrogen or C1-C8-alkyl; or R12 and R13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C8-alkyl; and
R14 is C1-C8-alkyl.
Further preferred compounds of formula I in free or salt form include those wherein
or R1 is C1-C4-alkylcarbonyl or C1-C4-alkylaminocarbonyl either of which being optionally substituted by halogen, hydroxy, di(C1-C4-alkyl)amino, carboxy, C1-C4-alkoxycarbonyl, nitrile, phenyl, C1-C4-haloalkyl, or by C1-C4-alkyl optionally substituted by hydroxy,
or R1 is C1-C4-alkylaminocarbonyl optionally substituted by C3-C8-cycloalkyl,
or R1 is C1-C4-alkylcarbonyl or C1-C4-alkylaminocarbonyl either of which being optionally substituted by C1-C4-alkoxy optionally substituted by hydroxy,
or R1 is C1-C4-alkylcarbonyl or C1-C4-alkylaminocarbonyl either of which being optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C4-alkyl,
or R1 is �(C═O)�(NH)a-Het where a is 0 or 1 and Het denotes a 4-, 5- or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C1-C4-alkyl, C1-C4-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or R1 is �(C═O)�NH-T where T denotes C3-C8-cycloalkyl or phenyl either of which being optionally substituted by hydroxy, C1-C4-alkyl, or by C1-C4-alkyl substituted by hydroxy,
R6 is hydrogen, hydroxy, amino, SO2R8, SO2NH2, SO2NR9R10, NHSO2R8, nitrile, carboxy, OR8 or C1-C4-haloalkyl;
R7 is hydrogen, �OR11, fluorine, chlorine, bromine, cyano or C1-C4-haloalkyl, or, when R4 is R7, R7 can also be �NR12R13 or �OR14;
R8 and R11 are independently C1-C4-alkyl;
either R9 is C1-C4-alkyl optionally substituted by hydroxy, C3-C8-cycloalkyl optionally substituted by hydroxy, C1-C4-alkoxy, nitrile, di(C1-C4-alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C4-alkyl, and R10 is hydrogen or C1-C4-alkyl; or R9 and R10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C4-alkyl;
either R12 is C1-C4-alkyl optionally substituted by di(C1-C4-alkyl)amino, and R13 is hydrogen or C1-C4-alkyl; or R12 and R13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C4-alkyl; and
R14 is C1-4 alkyl.
In a second aspect, the present invention provides compounds of formula I in free or salt form, wherein
R1 is hydrogen, or R1 is aminocarbonyl, C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl either of which being optionally substituted by hydroxy, amino, C1-C8-alkylamino, di(C1-C8-alkyl(amino), carboxy, C1-C8-alkyl optionally substituted by hydroxy, halogen, C3-C8-cycloalkyl optionally substituted by hydroxy, C1-C8-alkoxy optionally substituted by hydroxy, C1-C8-alkoxycarbonyl, nitrile, halogen, phenyl optionally substituted by hydroxy or C1-C8-alkyl, or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C1-C8-alkyl or C1-C8-alkoxy, or R1 is �(C═O)�(NH)a-Het where a is 0 or 1 and Het denotes a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C1-C8-alkyl or C1-C8-alkoxy;
R7 is hydrogen, R11, �OR11, halo, carboxy, �SO2R8, cyano or C1-C8-haloalkyl, or, when R4 is R7, R7 can also be �NR12R13, R14 or �OR14;
Preferred compounds include compounds of formula I wherein
R1 is hydrogen, or R1 is aminocarbonyl, C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl either of which being optionally substituted by hydroxy, di(C1-C8-alkylamino), carboxy, C1-C8-alkyl optionally substituted by hydroxy, halogen, C3-C8-cycloalkyl optionally substituted by hydroxy, C1-C8-alkoxy optionally substituted by hydroxy, C1-C8-alkoxycarbonyl, nitrile, halogen, phenyl optionally substituted by hydroxy or C1-C8-alkyl, or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl or C1-C8-alkoxy, or R1 is �(C═O)�(NH)a-Het where a is 0 or 1 and Het denotes a 5- or 6-membered N-heterocyclic ring optionally substituted by hydroxy, C1-C8-alkyl or C1-C8-alkoxy;
In a third aspect, the present invention provides compounds of formula I in free or salt form, wherein
R1 is hydrogen, or C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl optionally substituted by amino, carboxy, C1-C8-alkoxy, C1-C8-alkoxycarbonyl, nitrile, halogen or a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl;
R6 is hydrogen, hydroxy, amino, SOR8, SO2R8, SO2NH2, SO2NR9R10, COR8, CONHR8, NHSO2R8, nitrile, carboxy, OR8 or C1-C8-haloalkyl;
R7 is hydrogen, R11, OR11, halo, cyano, carboxy, SO2R8, or C1-C8-haloalkyl, or, when R4 is R7, R7 can also be NR12R13, R14 or OR14;
R8 and R11 are independently C1-C8-alkyl or C3-C8-cycloalkyl, optionally substituted by halogen, hydroxy, C1-C8-alkoxy, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino; either R9 is C1-C8-alkyl or C3-C8-cycloalkyl, optionally substituted by hydroxy, C1-C8-alkoxy, nitrile, amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino or a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl, and R10 is hydrogen or C1-C8-alkyl; or R9 and R10 together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl;
either R12 is C1-C8-alkyl or C3-C8-cycloalkyl optionally substituted by hydroxy, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino, and R13 is hydrogen or C1-C8-alkyl; or R12 and R13 together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl; and
R14 is C1-C8-alkyl optionally substituted by hydroxy or NR12R13.
Preferred compounds include compounds of formula I, wherein
R1 is hydrogen, C1-C8-alkylcarbonyl, C1-C8-alkylaminocarbonyl optionally substituted by carboxy or C1-C8-alkoxycarbonyl;
R6 is hydrogen, hydroxy; amino, SO2R8, SO2NH2, SO2NR9R10, NHSO2R8, cyano, carboxy, OR8 or C1-C4-haloalkyl;
R7 is hydrogen, OR11, fluorine, chlorine, bromine, cyano or C1-C4-haloalkyl, or, when R4 is R7, R7 can also be NR12R13 or OR14;
either R9 is C1-C8-alkyl or C3-C8-cycloalkyl, optionally substituted by hydroxy, C1-C8-alkoxy, nitrile, di(C1-C8-alkyl)amino or a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C8-alkyl, and R10 is hydrogen or C1-C8-alkyl; or R9 and R10 together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C8-alkyl;
either R12 is C1-C8-alkyl optionally substituted by di(C1-C8-alkyl)amino, and R13 is hydrogen or C1-C8-alkyl; or R12 and R13 together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C1-C8-alkyl; and
The invention provides, in another aspect, a process for preparing a compound of formula I in free or salt form which comprises the steps of:
(i) (A) for the preparation of compounds of formula I where R1 is C1-C8-alkylcarbonyl, C1-C8-alkylaminocarbonyl optionally substituted by amino, carboxy, C1-C8-alkoxy, C1-C8-alkoxycarbonyl, nitrile or halogen, or a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl, reacting a compound of formula II wherein R1 and R2 are as hereinbefore defined, with a compound of formula III
wherein R3, R4 and R5 are as hereinbefore defined, in the presence of a transition metal catalyst, preferably palladium;
(B) for the preparation of compounds of formula I where R3 or R4 is �SO2NH2 or �SO2NR9R10, reacting a compound of formula IV
wherein R1, R2, R5 and R7 are as hereinbefore defined and the �SO2Cl group is meta or para to the thiazole ring, with ammonia or a compound of formula R9R10NH;
(C) for the preparation of compounds of formula I where R3 or R4 is NHSO2R8, reacting a compound of formula I where one or R3 and R4 is NH2 with a sulfonyl chloride of formula R8SO2Cl;
(D) for the preparation of compounds of formula I where R4 is NR12R13, reacting a compound of formula I where R4 is halogen and R3 is SO2R8 with a compound of formula V
where R12 and R13 are as hereinbefore defined;
(E) for the preparation of compounds of formula I where R1 is optionally substituted C1-C8-alkylaminocarbonyl, reacting a compound of formula I where R1 is hydrogen with a compound of formula VI
R5�N═C═O VI
R15�N═C═O, wherein R15 is C1-C8-alkyl optionally substituted by carboxy or C1-C8-alkoxycarbonyl;
(F) for the preparation of compounds of formula I where one of R3 and R4 is amino and the other is hydrogen or halogen and at least one of R3, R4 and R5 is halogen, halogenating a compound of formula I where R3 or R4 is amino and the other is hydrogen;
(G) reacting a compound of formula VII
wherein R2, R3, R4 and R5 are as hereinbefore defined and X is halogen, with a compound of formula VIII
(H) for the preparation of compounds of formula I where R3 or R4 is �SO2R8 and R8 is methyl, reacting a compound of formula IV wherein R1, R2, R5 and R7 are as hereinbefore defined and the �SO2Cl group is meta or para to the thiazolyl ring, with an alkali metal sulphite and an alkali metal bicarbonate, followed by reaction with bromoacetic acid or an alkyl halide, e.g. iodomethane at elevated temperature;
(I) for the preparation of compounds of formula I where R1 is C1-C8-alkylamino-carbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl or C1-C8-alkoxy, or where R1 is �(C═O)�(NH)a-Het where a is 0 and Het denotes a 4-, 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C1-C8-alkyl, C1-C8-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or where R1 is �(C═O)�(NH)b-T where b is 0 and T denotes C3-C8-cycloalkyl or phenyl either of which being optionally substituted by hydroxy, C1-C8-alkyl, C1-C8-alkoxy, or by C1-C8-alkyl substituted by hydroxy,
reacting a compound of formula I where R1 is hydrogen with a compound of formula IX
where R16 is C1-C8-alkyl substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C1-C8-alkyl or C1-C8-alkoxy, or R16 is a 4-, 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C1-C8-alkyl, C1-C8-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or R16 is C3-C8-cycloalkyl or phenyl either of which being optionally substituted by hydroxy, C1-C8-alkyl, C1-C8-alkoxy, or by C1-C8-alkyl substituted by hydroxy;
(J) for the preparation of compounds of formula I where R1 is C1-C8-alkylaminocarbonyl optionally substituted by halogen, hydroxy, amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino, carboxy, C1-C8-alkoxycarbonyl, nitrile, phenyl, C1-C8-haloalkyl, or by C1-C8-alkyl optionally substituted by hydroxy,
or R1 is C1-C8-alkylaminocarbonyl optionally substituted by C3-C8-cycloalkyl optionally substituted by hydroxy,
or R1 is C1-C8-alkylaminocarbonyl optionally substituted by C1-C8-alkoxy optionally substituted by hydroxy,
or R1 is C1-C8-alkylaminocarbonyl optionally substituted by phenyl optionally substituted by hydroxy or C1-C8-alkyl,
or R1 is C1-C8-alkylaminocarbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C1-C8-alkyl or C1-C8-alkoxy,
or R1 is �(C═O)�(NH)a-Het where a is 1 and Het denotes a 4-, 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C1-C8-alkyl, C1-C8-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or R1 is �(C═O)�(NH)b-T where b is 1 and T denotes C3-C8-cycloalkyl or phenyl either of which being optionally substituted by hydroxy, C1-C8-alkyl, C1-C8-alkoxy, or by C1-C8-alkyl substituted by hydroxy,
reacting a compound of formula X
wherein R2, R3, R4 and R5 are as hereinbefore defined, with a compound of formula XI
where R17 and R18 are selected from hydrogen, hydroxy, amino, C1-C8-alkylamino, di(C1-C8-alkyl(amino), carboxy, C1-C8-alkyl optionally substituted by hydroxy, halogen, C3-C8-cycloalkyl optionally substituted by hydroxy, C1-C8-alkoxy optionally substituted by hydroxy, C1-C8-alkoxycarbonyl, nitrile, halogen, phenyl optionally substituted by hydroxy or C1-C8-alkyl, and a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C1-C8-alkyl or C1-C8-alkoxy,
or when R1 is �(C═O)�(NH)a-Het, R17 is hydrogen and R18 is a 4-, 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, C1-C8-alkyl, C1-C8-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or when R1 is �(C═O)�(NH)b�T R17 is hydrogen and R18 is C3-C8-cycloalkyl or phenyl either of which being optionally substituted by hydroxy, C1-C8-alkyl, C1-C8-alkoxy, or by C1-C8-alkyl substituted by hydroxy; or
(K) the preparation of compounds of formula I where R1 is hydrogen, hydrolysing a compound of formula I where R1 is C1-C8-alkylcarbonyl; and
Process variant (A) may be carried out using known Suzuki reaction procedures, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in an organic solvent such as dimethoxyethane (DME) usually in the presence of aqueous alkali metal carbonate. The reaction temperature may be from room temperature to 100� C., but conveniently 80� C. The palladium catalyst may be, for example, a bis(triarylphosphine) palladium halide.
Process variant (B) may be carried out using known procedures for preparation of sulphonamides from sulfonyl chlorides, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in an aqueous solvent or an organic solvent, e.g. an ether such as dioxane, usually in the presence of an alkali metal carbonate. The reaction temperature may be from 0� C. to 100� C., but conveniently room temperature.
Process variant (C) may be carried out using known procedures for reaction of amines with sulfonyl chlorides, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in an organic solvent, e.g. dimethylformamide (DMF), usually in the presence of an alkali metal carbonate. The reaction temperature may be from 0� C. to 100� C., but conveniently room temperature.
Process variant (D) may be carried out using known procedures for reaction of aryl halides, ortho to an electron withdrawing group, with primary or secondary amines, or analogously, e.g. as hereinafter described in the Examples. It may be carried out either neat or in an organic solvent, e.g. dimethylsulphoxide. The reaction temperature may be from 100� C. to 170� C. but conveniently about 120� C. to 140� C.
Process variant (E) may be carried out using known procedures for reaction of amines with acylating agents or isocyanates, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in an organic solvent, e.g. dimethylformamide. The reaction temperature may be from 0� C. to 100� C., but conveniently room temperature.
Process variant (F) may be carried out using known procedures for halogenating anilines, or analogously, e.g. as hereinafter described in the Examples. Chlorination may be carried out using hydrogen peroxide, acetic acid and hydrochloric acid, for example as described in S. Mukhopadhyay, K. H. Chandnani and S. B. Chandalia, Organic Process Research & Development, 1999, 3, 196-200. The reaction temperature may be from 0� C. to 50� C., but conveniently room temperature. Mono-bromination may be carried out by reaction with N-bromosuccinimide (NBS) in an organic solvent, preferably dimethylsulphoxide. But mono- or di-bromination may be carried out by reaction with bromine in an organic solvent, e.g. an ether such as dioxane. In both cases the reaction the reaction temperature may be from 0� C. to 50� C., but conveniently room temperature.
Process variant (G) may be carried out using known procedures for preparing aminothiazoles, or analogously, e.g. as hereinafter described in the Examples. The halogen X is preferably bromine. The reaction may be carried out in an organic solvent, e.g. an alcohol such as ethanol. The reaction temperature may be from room temperature to the reflux temperature of the solvent, but conveniently from about 50� C. to 60� C.
Process variant (H) may be carried out using the procedure known in R. W. Brown, Journal of Organic Chemistry, 1991, 56, 4974 for converting sulfonyl halides to sulfones, or analogously, e.g. as hereinafter described in the Examples. It may be carried out with the alkali metal sulphite, e.g. sodium sulphite, and the alkali metal bicarbonate, e.g. sodium bicarbonate in water at a temperature from 20� C. to 100� C., but conveniently at about 75� C. The reaction with bromoacetic acid may be carried out at temperature from 50� C. to 150� C., but conveniently at about 100� C. An alkyl halide, e.g. iodomethane may be used in place of bromoacetic acid
Process variant (I) may be carried out using known procedures for reacting amines with carboxylic acids, or analogously, e.g. as hereinafter described in the Examples. The reaction may be carried out in an organic solvent, e.g. dichloromethane, in the presence of a coupling agent, e.g. HATU, and a base, e.g. triethylamine. The reaction temperature may be from 0� C. to 50� C., but conveniently room temperature.
Process variant (J) may be carried out using known procedures for reacting isocyanates with amines, or analogously, e.g. as hereinafter described in the Examples. The reaction may be carried out in an organic solvent, e.g. dioxane or DMF. The reaction temperature may be an elevated temperature, for example from 50� C. to 100� C., but preferably about 80� C.
Process variant (K) may be carried out using known procedures for converting alkylcarbonylamines to amines, or analogously, e.g. as hereinafter described in the Examples. The reaction may be carried out in an organic solvent, e.g. ethanol, in the presence of a base, preferably a strong base such as sodium hydroxide. The reaction temperature may be an elevated temperature, for example from 50� C. to 100� C., but preferably about 90� C.
The compounds of formula I in free or salt form can be recovered from reaction mixtures and purified in a conventional manner. Isomer mixtures can be separated into individual isomers, e.g. enantiomers, in a conventional manner, e.g. by fractional crystallisation.
Compounds of formula II may be prepared by the method known in Garreau, Bull. Soc. Chim. Fr, 1954,1048, or analogously, e.g. as hereinafter described in the Examples.
Compounds of formula IV may be prepared by reacting a compound of formula XII
wherein R1, R2, R5 and R7 are as hereinbefore defined, with nitrous acid to give a diazo compound which is then reacted with sulphur dioxide in the presence of copper chloride, for example by the method described in E. E. Gilbert, Synthesis 1969, 1-10, to give the corresponding sulfonyl chloride of formula IV.
Compounds of formula IV may also be prepared by reacting a compound of formula XIII
wherein R1, R2, R5 are as hereinbefore defined and R7 is halogen or OR11 with chlorosulfonic acid, or analogously, e.g. as described in the Examples.
Compounds of formula V are either available commercially or may be prepared by known methods.
Compounds of formula VI are either available commercially or may be prepared by known methods.
Compounds of formula VII may be prepared by reacting a compound of formula XIV
wherein R2, R3, R4 and R5 are as hereinbefore defined, with an halogenating agent, for example bromine, or analogously, e.g. as described in the Examples.
Compounds of formula VIII are commercially available or may be prepared by known methods.
Compounds of formula IX are commercially available or may be prepared by known methods.
Compounds of formula X may be prepared by reacting a compound of formula I wherein R1 is hydrogen with phosgene or analogously, e.g. as described in the Examples.
Compounds of formula XI are commercially available or may be prepared by known methods.
Compounds of formula XII may be prepared by reduction of compounds of formula XV
wherein R1, R2, R5 and R7 are as hereinbefore defined, using standard techniques known for the reduction of aromatic nitro compounds to anilines, for example catalytic hydrogenation using a transition metal catalyst, preferably palladium on carbon, in an organic solvent, e.g. ethyl acetate, under an atmosphere of hydrogen.
Compounds of formula XIII may be prepared by reacting the corresponding ketone of formula XVI
wherein R2, R3, R4 and R5 are as hereinbefore defined and X is halogen, with a compound of formula VIII wherein R1 is as hereinbefore defined, or analogously, e.g. as described in the Examples.
Compounds of formula XIV where either R3 or R4 is independently SO2NH2 or SO2NR9R10 may be prepared by reacting a compound of formula XII where R1 and R2 are as hereinbefore defined and one of R1 or R7 is hydrogen, the other being halogen or OR11, with chlorosulfonic acid followed by treatment with an amine or ammonia, or analogously, e.g. as described in the Examples.
Compounds of formula XIV may also be obtained from commercially available compounds of formula XVII
by known methods, for example as described in R. V. Heinzelman, Organic Synthesis 1963, IV, 573.
Compounds of formula XV may be prepared as described in process variant (G) or by known procedures, for example as described in J. Liebscher, E. Mitzner, Synthesis, 1985, 4, 414-417.
Compounds of formula XVI may be prepared by reacting a compound of formula XVIII
wherein R2, R5, and R7 are as hereinbefore defined, with an halogenating agent, for example bromine, or analogously, e.g. as described in the Examples.
Compounds of formula XVII where R3 is SO2CH3 are available from commercial sources or may be prepared from compounds of formula XVI where R3 is halogen, for example by the method described in A. Ulman and E. Urankar, J. Org. Chem., 1989, 54, p 4691-4692.
Compounds of formula XVIII are commercially available or may be prepared by known methods.
Compounds of the Examples hereinbelow have IC50 values below 0.6 μM in the aforementioned assay. For example the compounds of Examples 8, 48, 80, 138, 156, 165 and 178 have IC50 values of 0.009, 0.018, 0.013, 0.005, 0.002, 0.019 and 0.040 respectively.
Having regard to their anti-inflammatory activity, in particular in relation to inhibition of eosinophil activation, agents of the invention are also useful in the treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related disorders of the airways (e.g. involving morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil-related disorders of the airways consequential or concomitant to L�ffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.
Agents of the invention may also be used for the treatment of other diseases or conditions, in particular diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or aetiology, including autoimmune haematological disorders (e.g. haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary billiary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy). Other diseases or conditions which may be treated with agents of the invention include septic shock, rheumatoid arthritis, osteoarthritis, proliferative diseases such as cancer, athersclerosis, allograft rejection following transplantation, stroke, obesity, restenosis, diabetes, e.g. diabetes mellitus type I (juvenile diabetes) and diabetes mellitus type II, diarrheal diseases, ischemia/reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterised by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.
The agents of the invention are also useful as co-therapeutic agents for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs. An agent of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance. Accordingly the invention includes a combination of an agent of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory or antihistamine drug substance, said agent of the invention and said drug substance being in the same or different pharmaceutical composition. Such anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone, fluticasone, ciclesonide or mometasone, LTB4 antagonists such as those described in U.S. Pat. No. 5,451,700, LTD4 antagonists such as montelukast and zafirlukast, dopamine receptor agonists such as cabergoline, bromocriptine, ropinirole and 4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]-sulfonyl]ethyl]-amino]ethyl]-2(3H)-benzothiazolone and pharmaceutically acceptable salts thereof (the hydrochloride being Viozan��AstraZeneca), and PDE4 inhibitors such as Ariflo� (GlaxoSmith Kline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma) and PD189659 (Parke-Davis). Such bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide and tiotropium bromide, and beta-2 adrenoceptor agonists such as salbutamol, terbutaline, salmeterol and, especially, formoterol and pharmaceutically acceptable salts thereof, and compounds (in free or salt or solvate form) of formula I of PCT International patent publication No. WO 00/75114, which document is incorporated herein by reference, preferably compounds of the Examples thereof, especially a compound of formula
EXAMPLES Compounds of formula I which are also of formula XIX
are shown in the Table 1 below, the method of preparation being described thereafter. The table also shows mass spectrometry (MH+) data. The examples are in free form.
Ra Rb Rc R1 m/s MH+
466.7 (M − H+)
365 16
370 17
311 18
301 20
258 23
301 24
Preparation of Specific Examples Abbreviations used are as follows: DCM is dichloromethane, DIPEA is diisopropylethylamine DME is dimethoxyethane, HATU is O-(7-azabenzotriazol-1-yl)-N,N,-N′,N′-tetramethyl-uronium hexafluorophophate, NBS is N-bromosuccinimide and THF is tetrahydrofuran.
Example 1 N-[5-(4-Methanesulfonylamino-phenyl)-4-methyl-thiazol-2-yl]-acetamide 1a N[5-(4-Amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide N-[4-Methyl-5-(4-nitro-phenyl)-thiazol-2-yl]-acetamide (J. Liebscher, E. Mitzner, Synthesis, 1985, (4), p 414) (10.0 g, 3.6 mmol) is dissolved in ethyl acetate/THF (5/1, 600 ml) and stirred at room temperature under an atmosphere of argon. The solution is then treated with 10% palladium on carbon (10 g). The reaction mixture is purged three times with nitrogen and placed under an atmosphere of hydrogen overnight. The mixture is then filtered through Celite� filter material and the catalyst is washed with tetrahydrofuran (600 ml). The solvent is removed in vacuo to leave N-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide as an off-white solid.
1b) N-[5-(4-Methanesulfonylamino-phenyl)-4-methyl-thiazol-2-yl]-acetamide N-[5-(4-Amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (0.05 g, 0.20 mmol) is dissolved in dimethylformamide (1 ml) and treated by a solution of methylsulfonyl chloride (0.0232 g, 0.20 mmol) in dry dimethylformamide (1 ml) followed by 2M aqueous sodium carbonate solution (0.20 ml, 0.40 mmol). The reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the residue is purified by chromatography to give the title compound. MH+ (ESMS): 326.1
Example 2 N-[5-[4-(Butane-1-sulfonlamino)-phenyl]-4-methyl-thiazol-2-yl]-acetamide This is prepared as described in example 1b by replacing methylsulfonyl chloride with n-butylsulfonyl chloride. MH+ (ESMS): 368.1
Example 3 N-[4-Methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide 3a) 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride N-[5-(4-Amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 1a) (7.9 g, 31.9 mmol) in suspension in glacial acetic acid (250 ml) is treated with a 32% aqueous HCl solution (40 ml). The resulting solution is then cooled approximately to 10� C. and treated dropwise with a solution of sodium nitrite (2.2 g, 31.9 mmol) in water (2 ml). After 10 minutes the reaction mixture is added to a stirred solution of SO2/AcOH/CuCl2/H2O (200 ml) (the preparation of the reagent is described below). The reaction mixture is allowed to warm to room temperature and is stirred overnight.
The reaction mixture is then poured into water (1000 ml) and extracted with ethyl acetate (3�300 ml). The combined organic layers are washed with water (2�250 ml) followed by brine (200 ml) and dried over MgSO4. After filtration the solvent is removed in vacuo to give 4-(2-acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride. MH+ (TOF, MS ES+): 248.1
Preparation of the Reagent SO2/AcOH/CuCl2/H2O According to the reported procedure (E. E. Gilbert, Synthesis 1969, 1-10, p 6), glacial acetic acid (100 ml) vigorously stirred at room temperature is treated by bubbling SO2 gas. Once a saturated solution is achieved (approximately 10 g per 100 ml), the solution is treated with copper (II) chloride (4 g) in water (5 ml). The resulting mixture is allowed to settle to give a green solution.
3b) N-[4-Methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (3a) (3.8 g, 11.5 mmol) is dissolved in dioxane (50 ml) with stirring. Sodium carbonate (2.45 g, 23 mmol) is added followed by a solution of ammonia in dioxane (50 ml, 0.75 M). After stirring for 2 hours at room temperature diethyl ether (120 ml) is added and the solid precipitate is removed by filtration. The solid is stirred in tetrahydrofuran (200 ml) and the mixture is then filtered through Celite� filter material to remove inorganic material. Removal of the solvent affords N-[4-methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide.
Example 4 N-[5-(4-Amino-3-chloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide Following a general procedure for chlorination of anilines (S. Mukhopadhyay, K. H. Chandnani, S. B. Chandalia, Organic Process Research & Development, 1999 3, p 196) hydrogen peroxide (27% solution in water, 5.1 ml, 40 mmol) is added dropwise over 30 minutes to N-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide 1a (5.0 g, 20 mmol) stirred in acetic acid (30 ml) and concentrated hydrochloric acid (6.7 ml) at room temperature. When the addition is complete the mixture is poured onto ice water and the pH adjusted to alkaline by addition of 4M aqueous sodium hydroxide solution. The mixture is then extracted with ethyl acetate, followed by dichloromethane. The combined organic extracts are dried (MgSO4) and the product mixture is absorbed on silica. Chromatography on silica eluting with hexane�ethyl acetate (1:1) affords three fractions: The first fraction is identified as N-[5-(4-amino-3,5-dichloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 4a). MH+ (TOF, MS ES+) 316.1, 318.1, 320.1. The second fraction is identified as the title compound, N-[5-(4-amino-3-chloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 4b). MH+ (AP+): 282, 284 (3:1). The third fraction is unreacted starting material (Example 1a).
Examples 5 to 8 These products are obtained in a two step sequence from the corresponding anilines (4a, 4b, 7a, 8a) following analogous conditions to those described for the conversion of N-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 1a) to the corresponding sulfonamide (Example 3b).
Example 5 N-[5-(3-Chloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide Using N-[5-(4-amino-3-chloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 4b) affords the title compound as an orange solid. MH+ (TOF, MS ES+) 345.9, 347.9
Example 6 N-[5-(3,5-Dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide Using N-[5-(4-amino-3,5-dichloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 4a) affords the product as a white crystalline solid. MH+ (TOF, MS ES+) 380.0, 382.0, 384.0
Example 7 N-[5-(3-Bromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide 7a) N-[5-(4-Amino-3-bromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide NBS (2.52 g, 14.7 mmol) is added to a stirred solution of N-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 1a) (3.5 g, 14.7 mmol) in dry dimethylsulphoxide (50 ml) at 10� C. After 10 minutes the solution is diluted with water (200 ml) and the resulting precipitate is removed by filtration. Crystallisation from ethyl acetate�methanol affords the title compound. MH+ (TOF, MS ES+): 325.9, 328.9
7b) N-[5-(3-Bromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide The title compound is obtained from N-[5-(4-amino-3-bromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 7a) to give a cream solid. MH+ (TOF, MS ES+) 390.1, 391.1,
Example 8 N-[5-(3,5-Dibromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide 8a) N-[5-(4-Amino-3,5-dibromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide Bromine (0.083 ml, 1.6 mmol) is added dropwise over 10 minutes to a stirred solution of N-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 1a) (0.20 g, 0.81 mmol) in 1,4-dioxane (5 ml). When the addition is complete the mixture is diluted with saturated sodium hydrogen carbonate solution (30 ml) and extracted with dichloromethane (2�30 ml). The combined organic extracts are dried (MgSO4), filtered, and the solvent removed to give a dark solid. Crystallisation from methanol�dichloromethane yields the tide compound. MH+ (TOF, MS ES+): 403.7, 405.6, 407.6
8b) N-[5-(3,5-Dibromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide Using N-[5-(4-amino-3,5-dibromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide (8a) affords the title compound. MH+ (TOF, MS ES+): 467.8, 469.8, 471.8
Example 9 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-2,6-dibromo-benzenesulfonic acid This compound is obtained as a minor component in the preparation of example 5 from N-[5-(4-amino-3-bromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide; The crude product mixture obtained in the preparation of example 8 is filtered through Celite� filter material washing with tetrahydrofuran to give N-[5-(3,5-dibromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (8). Washing the Celite� filter material with ethanol then affords the title compound. M-H+(AP−) 466.7, 468.6, 470.6
Example 10 N-[4-Methyl-5-(4-methylsulfamoyl-phenyl)-thiazol-2-yl]-acetamide 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (Example 3a) (0.05 g, 0.15 mmol) is dissolved in dioxane (1 ml). The solution is treated with 2M aqueous sodium carbonate (0.15 ml, 0.24 mmol) followed by the addition of a 33% solution of methylamine in ethanol (0.08 ml, 0.6 mmol). The reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue is purified by prep LC-MS i.e. liquid chromatography mass spectrometry to give N-[4-Methyl-5-(4-methylsulfamoyl-phenyl)-thiazol-2-yl]-acetamide. MH+ (ESMS): 326.1
Examples 11 to 16 These compounds, namely N-[5-(4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Mp 279-281� C.), N-[5-(4-ethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide, N-[5-(4-cyclopropylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide, N-{5-[4-(2-hydroxy-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide, N-{5-[4-(2-cyano-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide and N-{5-[4-(2-methoxy-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide respectively, are prepared in an analogous manner to Example 10 by reaction of the appropriate amine with 4-(2-acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (3a).
Example 17 N-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide 17a) N-(4-Methyl-thiazol-2-yl)-acetamide 2-Amino-4-methylthiazole (10.0 g, 87.6 mmol) is dissolved in dry pyridine (75 ml) at room temperature. This solution is then treated dropwise with acetyl chloride (6.3 ml, 87.6 mmol). After 2 hours, the reaction mixture is poured into water (1000 ml), and extracted with ethyl acetate (3�250 ml). The combined organic layers are washed with water (2�200 ml), brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in toluene (200 ml) followed by the removal of the solvent in vacuo. The solid thus obtained is dried in vacuo to give the title compound.
17b) N-(5-Bromo-4-methyl-thiazol-2-yl)-acetamide N-(4-Methyl-thiazol-2-yl)-acetamide (Example 17a) (4.0 g, 25.6 mmol) is dissolved in glacial acetic acid (100 ml) at room temperature. This solution is then treated portionwise with N-bromosuccinimide (4.6 g, 25.6 mmol). After 48 hours the reaction mixture is poured into water (1000 ml) and extracted with ethyl acetate (3�250 ml). The combined organic layers are washed with water (200 ml), brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in toluene (100 ml) followed by the removal of the solvent in vacuo. This is repeated twice more and the resulting solid is dried in vacuo at 40� C. to give N-(5-bromo-4-methyl-thiazol-2-yl)-acetamide.
17c) N-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide N-(5-Bromo-4-methyl-thiazol-2-yl)-acetamide (Example 17b) (0.1 g, 0.43 mmol) is dissolved in DME (2 ml) at room temperature. This solution is treated with [(4-methylsulfonyl) phenyl] boronic acid (0.172 g, 0.86 mmol), followed by 2M aqueous Na2CO3 (0.63 ml, 1.29 mmol) and bis(triphenylphosphine)palladium(II)chloride (0.03 g, 0.043 mmol). The mixture is then heated at 80� C. for 4 hours. The solvent is removed in vacuo and the residue is purified by preparative LCMS to give N-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide. MH+ (ESMS): 311.0, Mp 251-253� C.
Examples 18 to 23 These compounds, namely N-[5-(4-acetyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide, N-[4-methyl-5-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-acetamide, N-[5-(4-hydroxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide, N-[5-(3,4-dimethoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide, N-[5-(3-cyano-phenyl)-4-methyl-thiazol-2-yl]-acetamide and N-[4-methyl-5-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-acetamide respectively, are prepared in an analogous manner from the appropriate boronic acid following the procedure described for Example 17.
Example 24 {3-[5-(4-Dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-acetic acid: ethyl ester 24a) 4-(2-Amino-4-methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide Concentrated hydrochloric acid (15 ml) is added to a stirred suspension of N-[5-(4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (example 11) (6.26 g, 18.5 mmol) in ethanol (120 ml). The reaction is heated at 85� C. until no starting material remains (4 hours). The reaction is allowed to cool and the solvent removed to give the hydrochloride salt as a yellow solid. Aqueous sodium hydroxide (4M) is added and the mixture is stirred vigorously for 30 minutes before extracting with chloroform followed by ethyl acetate. The combined organic extracts are dried (MgSO4), filtered and the solvent is removed to give the title compound. MH+ (TOF, MS, ES+): 427.3
24b) {3-[5-(4-Dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-acetic acid ethyl ester 4-(2-Amino-4-methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide (Example 24a) (0.083 g, 0.28 mmol) and ethyl isocyanatoacetate (0.05 ml, 0.34 mmol) are stirred in dimethylformamide at 100� C. for 3 hours. The mixture is then partitioned between 1M aqueous hydrochloric acid and ethyl acetate. The organic extract is washed with brine, dried over MgSO4 and the solvent removed in vacuo. Purification by preparative HPLC affords the title compound. MH+ (TOF, MS, ES+): 441.4
Example 25 3-{3-[5-(4-Dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid ethyl ester Using 4-(2-amino-4-methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide (Example 24a) (0.083 g, 0.28 mmol) and replacing ethyl isocyanatoacetate with ethyl 3-isocyanatopropion-ate (0.05 ml, 0.34 mmol) in the above reaction affords the title compound.
Example 26 4-(2-Amino-4-methyl-thiazol-5-yl)-2,6-dichloro-benzenesulfonamide A solution of N-[5-(3,5-dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 6) (0.70 g, 1.84 mmol) in aqueous hydrochloric acid (5M, 10 ml) and ethanol (20 ml) is heated at reflux for 90 minutes. When cool, the mixture is concentrated to remove ethanol and the aqueous solution is brought to pH 9 by addition of aqueous sodium hydroxide (4M). The product is extracted with n-butanol (50 ml) and the organic extract is dried over MgSO4. Removal of the solvent followed by chromatography on silica (eluting with ethyl acetate�hexane, 2:1 increasing to 4:1) affords the title compd. MH+ (MS, AP+): 337.8, 339.5
Example 27 2,6-Dichloro-4-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-benzenesulfonamide Ethyl isocyanate (0.015 ml, 0.19 mmol) is added to a stirred solution of 4-(2-amino-4-methyl-thiazol-5-yl)-2,6-dichloro-benzenesulfonamide (Example 26) (0.043 g, 0.127 mmol) in dry dimethylformamide (1.0 ml) under argon. After heating at 85� C. for 3 hours more ethyl isocyanate (0.015 ml, 0.19 mmol) is added and heating continued for a further hour. The reaction is concentrated in vacuo and the product is purified by chromatography on silica eluting with ethyl acetate�hexane (1:1 increasing to 4:1) to give the title compound. MH+ (TOF, MS, ES+): 408.9, 410.9, 412.8
Example 28 5-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy-benzenesulfonamide 28a) N-[5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide 4-methoxyphenylacetone (10 g, 60.9 mmol), N-acetylthiourea (7.2 g, 60.9 mmol) and iodine (15.46 g, 60.9 mmol) in pyridine (50 ml) are stirred at 70� C. for 16 hours. The mixture is concentrated and the residue is purified by chromatography on silica with iso-hexane-ethyl acetate (1:1) to give the titled compound.
28b) 5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-ylamine A solution of concentrated hydrochloric acid HCl (20 ml) in water (30 ml) is added to N-[5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 28a) (2 g, 7.63 mmol) in ethanol. After 5 hours at reflux, the reaction is poured into water (600 ml) and the pH is adjusted to 9/10 with 2.5 M NaOH. The aqueous layer is then extracted with ethyl acetate (3�200 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford 5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-ylamine.
28c) 1-Ethyl-3-[5-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]urea Ethyl isocyanate (1.2 ml, 14.18 mmol) is added to 5-(4-methoxy-phenyl)-4-methyl-thiazol-2-ylamine (Example 28b) (1.56 g, 7.09 mmol) in dioxane (100 ml). After 5 hours at 85� C. the reaction mixture is concentrated to yield 1-ethyl-3-[5-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]urea as a brown solid.
28d) 5-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy-benzenesulfonylchloride A suspension of 1-ethyl-3-[5-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]urea (Example 28c) (1.0 g, 3.44 mmol) in dichloromethane (15 ml) is added portionwise to chlorosulfonic acid (25 ml, excess) cooled at −10� C. The temperature is kept below 0� C. throughout the addition. The reaction mixture is left to warm up to room temperature. After 3 hours, the reaction mixture is poured carefully onto ice (2 litres). Once ice is melted, the aqueous layer is extracted with dichloromethane (DCM) (3�200 ml). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated to afford 5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy benzenesulfonylchloride.
28e) 5-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy-benzenesulfonamide To a stirred solution of 5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy benzenesulfonylchloride (Example 28d) (0.2 g, 0.514 mmol) in dioxane (10 ml) is added 2 M Na2CO3 (0.515 ml) followed by 0.5 M NH3 in dioxane (2.06 ml). After 2 hours at room temperature, the reaction mixture is poured into water (200 ml) then extracted with ethyl acetate (3�50 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford 5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy-benzenesulfonamide as a yellow powder.
Example 29 5-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-.N.-(2-hydroxy-ethyl)-2-methoxy-benzenesulfonamide To 5-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy benzenesulfonylchloride (Example 28d) (0.2 g, 0.514 mmol) in dioxane (10 ml) is added 2M Na2CO3 (0.515 ml) followed by ethanolamine (0.031 ml, 0.514 mmol). After 2 hours at room temperature, the reaction mixture is poured into water (150 ml)/ethylacetate (50 ml) and sonicated. The layers are separated then the aqueous layer is extracted with ethyl acetate (3�50 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford a sticky oil which is dissolved in a minimum amount of DCM/methanol and dried at reduced pressure to afford 5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-N-(2-hydroxy-ethyl)-2-methoxy-benzenesulfonamide as a yellow foam.
Example 30 N-[5-(4-Methoxy-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide 30a) 2-Methoxy-5-(2-oxo-propyl)-benzenesulfonamide 4-methoxyphenylacetone (5 g, 30 mmol) is added dropwise to chlorosulfonic acid (14.25 ml, 0.21 mol) at below 0� C. and the mixture is stirred at room temperature for 2 hours. The mixture is poured into crushed ice and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried over Na2SO4. After removal of the solvent, the residue is dissolved in tetrahydrofuran (50 ml) and concentrated ammonia (8 ml) is added dropwise. The mixture is stirred at room temperature overnight and concentrated. To the residue is added water, the precipitates are collected by filtration and recrystallised from methanol to give the titled compound.
30b) 5-(1-Bromo-2-oxo-propyl)-2-methoxy-benzenesulfonamide 2-Methoxy-5-(2-oxo-propyl)-benzenesulfonamide (Example 30a) (0.5 g, 2.05 mmol) in dry THF (15 ml) is added dropwise to a solution of 2-carboxyethyltriphenylphosphonium perbromide (1.24 g, 2.15 mmol) in dry THF (10 ml). The mixture is stirred at room temperature for 3 hours, filtered and then concentrated. The residue is purified by chromatography on silica with hexane-ethyl acetate (1:1) to give the titled compound.
30c) N-[5-(4-Methoxy-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide 5-(1-Bromo-2-oxo-propyl)-2-methoxy-benzenesulfonamide (Example 30b) (0.2 g, 0.64 mmol) and N-acetylthiourea (0.075 g, 0.64 mmol) in ethanol (3 ml) are stirred at 70� C. for 4 hours. The mixture is concentrated and the residue is recrystallised from ethanol to give an off-white solid. MH+ (ESMS): Mp 341.9� C.
Example 31 N-{5-[3-(2-Dimethylamino-ethylsulfamoyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamide 31a) N-[5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide 4-methoxyphenylacetone (10 g, 60.9 mmol), N-acetylthiourea (7.2 g, 60.9 mmol), iodine (15.46 g, 60.9 mmol) in pyridine (50 ml) are stirred at 70� C. for 16 hours. The mixture is concentrated and the residue is purified by chromatography on silica with hexane-ethyl acetate (1:1) to give the titled compound.
31b) N-{5-[3-(2-Dimethylamino-ethylsulfamoyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamide To N-[5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 28a) (0.0947 g, 0.361 mmol) is added at 0� C. chlorosulfonic acid (3 ml) followed by dichloromethane (1 ml). The reaction mixture is stirred below 0� C. for 2 hours then poured into crushed ice and extracted with dichloromethane (3�5 ml). The organic layers are combined and dried over MgSO4. The solvent is removed to give 5-(2-acetylamino-4-methyl-thiazol-5-yl)-2-methoxy-benzenesulfonyl chloride, which is dissolved into dioxane (2 ml). To this solution is added N,N-dimethyl-ethylenediamine (0.0636 g, 0.72 mmol) and 2M Na2CO3 (0.5 ml). The reaction mixture is stirred at room temperature for 2 hours. The mixture is concentrated and the residue is taken into water (2 ml) and extracted with dichloromethane (3�5 ml). The combined organic layers are dried over MgSO4. After filtration the solvent is removed in vacuo to give the titled compound which is dried overnight in vacuum oven at 25� C. MH+ (ESMS): Mp 413.0� C.
Examples 32 to 40 These compounds namely N-{5-[4-methoxy-3-(2-methoxy-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide, N-{5-[4-methoxy-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide, N-{5-[3-(3-dimethylamino-propylsulfamoyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamide, N-(5-{3-[(2-dimethylamino-ethyl)-methyl-sulfamoyl]-4-methoxy-phenyl}-4-methyl-thiazol-2-yl)-acetamide, N-{5-[4-methoxy-3-(3-morpholin-4-yl-propylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide, N-{5-(4-methoxy-3-[3-(4-methyl-piperazin-1-yl)-propylsulfamoyl]-phenyl}-4-methyl-thiazol-2-yl)-acetamide, N-{5-[4-methoxy-3-(2-pyrrolidin-1-yl-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide, N-{5-[4-methoxy-3-(3-methoxy-propylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide and N-{5-[3-(2-hydroxy-ethylsulfamoyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamide respectively, are prepared by replacing N,N-dimethylethylenediamine with the appropriate amine in the above procedure described for the preparation of N-{5-[3-(2-dimethylamino-ethylsulfamoyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamide (Example 31b) to afford the title compounds.
Example 41 N-[5-(3-Methanesulfonyl-4-methoxy-phenyl)-4-methyl-thiazol-2]-acetamide 41a) 5-(2-Acetylamino-4-methyl-thiazol-5-yl)-2-methoxy-benzenesulfonyl chloride To chlorosulfonic acid (25 ml, excess), cooled at −10� C., is added portionwise a suspension of N-[5-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 31a) (1.0 g, 3.8 mmol) in DCM (10 ml). The temperature is kept below 0� C. throughout the addition. The reaction mixture is left to warm up to room temperature. After 2 hours, the reaction mixture is poured carefully onto ice (500 ml). Once the ice is melted, the aqueous layer is extracted with DCM (3�200 ml). The combined organic layers are washed with brine (150 ml), dried over MgSO4, filtered and concentrated to afford 5-(2-acetylamino-4-methyl-thiazol-5-yl)-2-methoxybenzene-sulfonyl chloride.
41b) N-[5-(3-Methanesulfonyl-4-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide To a stirred solution of sodium sulfite (1.05 g, 8.31 mmol) and sodium hydrogen carbonate (0.71 g, 8.31 mmol) in water (10 ml) at 70� C. is added a solution of 5-(2-acetylamino-4-methyl-thiazol-5-yl)-2-methoxy-benzenesulfonyl chloride (Example 41a) (1.5 g, 4.16 mmol) in 1,4-dioxane (20 ml). After 30 minutes, the reaction mixture is concentrated to yield the sodium sulfinate intermediate as an off-white solid. To the sulfinate intermediate (0.5 g, 1.43 mmol) in DMF (10 ml) is added iodomethane (0.09 ml, 1.43 mmol). After 2 hours at 40� C., the reaction mixture is poured into water (250 ml) and extracted with ethyl acetate (3�50 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford N-[5-(3-methanesulfonyl-4-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide.
Examples 42 to 44 These compounds, namely N-{5-[3-(2-hydroxy-ethanesulfonyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamide, N-{5-[3-(3-hydroxy-propane-1-sulfonyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamide, and N-[5-(3-Cyanomethanesulfonyl-4-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide respectively, are synthesised following the same procedure as 41, replacing methyl iodide in the above procedure with the appropriate alkyl iodide
Example 45 N-[5-(3-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide N-[4-Methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-acetamide (Example 49b) is converted into the aniline using the procedure described in Example 1a and this material is converted into the title compound following the procedure described in Example 41b.
Example 46 N-[5-(3-Cyanomethanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide N-[4-Methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-acetamide (49b) is converted into the aniline using the procedure described in Example 1a and this material is converted into the title compound following the procedure described in Example 41b, replacing methyl iodide in this procedure with iodoacetonitrile.
Example 47 N-[5-(4-Fluoro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide 47a) 2-Fluoro-5-(2-oxo-propyl)-benzenesulfonyl chloride To chlorosulfonic acid (25 ml, excess) cooled at −10� C. is added dropwise 4-fluorophenyl acetone (1.0 g, 6.57 mmol). The temperature is kept below 0� C. throughout the addition. The reaction mixture is then left to warm up to room temperature overnight. The reaction mixture is poured carefully onto ice (1500 ml). Once ice is melted, the aqueous layer is extracted with DCM (3�250 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford the titled compound as an off-white solid.
47b) 1-(4-Fluoro-3-methanesulfonyl-phenyl)-propan-2-one To a stirred solution of sodium sulfite (0.5 g, 3.99 mmol) and sodium hydrogen carbonate (0.34 g, 3.99 mmol) in water (10 ml) at 70� C. is added a solution of 2-fluoro-5-(2-oxo-propyl)-benzenesulfonyl chloride (Example 47a) (0.5 g, 1.99 mmol) in 1,4-dioxane (20 ml). After 1 hour, the reaction mixture is concentrated to yield the sulfinate intermediate. To the sulfinate intermediate (0.47 g, 1.97 mmol) in DMF (20 ml) is added iodomethane (0.12 ml, 1.97 mmol). After 1 hour at 40� C., the reaction mixture is poured into water (400 ml) and extracted with ethyl acetate (3�100 ml). The combined organic layers are dried over MgSO4, filtered and concentrated. The residue is left overnight in the vacuum oven to afford the titled compound as a viscous oil.
47c) 1-Bromo-1-(4-Fluoro-3-methanesulfonyl-phenyl)-propan-2-one To 1-(4-fluoro-3-methanesulfonyl-phenyl)-propan-2-one (Example 47b) (0.23 g, 1 mmol) in dry THF (5 ml) is added under inert atmosphere and dropwise a solution of 2-carboxethyltriphenylphosphonium tribromide (0.6 g, 1.05 mmol). After 2.5 hours at room temperature the reaction mixture is filtered then concentrated to give a viscous orange oil which is purified by chromatography eluting with isohexane-ethyl acetate (4:1 then 2:1) to give the titled compound.
47d) N-[5-(4-Fluoro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide A mixture of 1-bromo-1-(4-fluoro-3-methanesulfonyl-phenyl)-propan-2-one (Example 47c) (0.17 g, 0.55 mmol) and N-acetylthiourea (0.065 g, 0.55 mmol) in ethanol is heated at 70� C. for 3 hours then at room temperature over two days. The reaction mixture is poured into water (200 ml) and extracted with ethyl acetate (3�50 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford a viscous solid. This solid in a minimum amount of ethyl acetate is sonicated to give a suspension which is then heated until all solid has dissolved then left to cool to room temperature overnight. The white crystalline solid is filtered off to afford the titled compound.
Example 48 N-[5-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide The title compound is prepared following the same route as N-[5-(4-Fluoro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 47) by replacing 4-fluorophenyl acetone with 4-chlorophenyl acetone.
Example 49 N-[4-Methyl-5-(3-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide 49a) 1-Bromo-1-(3-nitro-phenyl)-propan-2-one A stirred solution of 3-nitrophenylacetone (0.5 g, 13.9 mmol) in THF (10 ml) at room temperature is treated with polymer supported pyridine hydrobromide perbromide (1.4 g, 2 mmol Br3 −/g). The reaction mixture is stirred overnight, then filtered and concentrated in vacuo. The residue is purified by chromatography on silica with iso-hexane-ethyl acetate (6:1) to give the titled compound.
49b) N-[4-Methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-acetamide A mixture of 1-bromo-1-(3-nitro-phenyl)-propan-2-one (Example 49a) (0.5 g, 1.94 mmol) and N-acetylthiourea (0.23 g, 1.94 mmol) in ethanol (10 ml) is stirred at 70� C. for 2 hours. After cooling the reaction to room temperature, the precipitated product is removed by filtration and dried under vacuum to give the titled compound (0.28 g).
49c) N-[4-Methyl-5-(3-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide N-[4-Methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-acetamide (Example 49b) is converted into the aniline using the procedure described in Example 1a and this material is converted into the corresponding sulfonamide following the procedure described in Example 3.
Examples 50 to 54 These compounds, namely N-{4-methyl-5-[3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-thiazol-2-yl}-acetamide, N-{5-[3-(3-dimethylamino-propylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide, N-{4-methyl-5-[3-(3-morpholin-4-yl-propylsulfamoyl)-phenyl]-thiazol-2-yl}-acetamide, N-{5-[3-(3-methoxy-propylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide and N-{5-[3-(2-hydroxy-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide respectively, are prepared as described for Example 49 by replacing ammonia in the final reaction with the appropriate amine.
Example 55 N-(3-Dimethylamino-propyl)-3-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]benzenesulfonamide The title compound was prepared from Example 51 using hydrolysis conditions described in example 26 followed by reaction with ethyl isocyanate as described in Example 27.
Example 56 N-[5-(4-Fluoro-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide The title compound is prepared from 4-fluorophenyl acetone via 2-fluoro-5-(2-oxo-propyl)-benzenesulfonyl chloride (Example 47a) following an identical sequence of reactions used for the synthesis of N-[5-(4-methoxy-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 30) from 4-methoxyphenyl acetone.
Example 57 N-[5-(4-Chloro-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide Replacing 4-fluorophenyl acetone with 4-chlorophenyl acetone in the above procedure (Example 56) affords the title compound.
Example 58 5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (Example 3a) (0.5 g, 1.5 mmol) in dioxane (2 ml) is added dropwise to a stirred solution of sodium sulfite (0.378 g, 3.0 mmol) and sodium hydrogen carbonate (0.252 g, 3.0 mmol) in water at 75� C. After 1 hour at 75� C., bromoacetic acid (0.417 g, 3.0 mmol) is added and heating continued for 1 hour at 100� C. Sodium hydroxide (0.24 g, 6.0 mmol) in water (0.25 ml) is then added and the mixture is heated with stirring at 91� C. for 16 hours. The reaction mixture is allowed to cool, diluted with water (100 ml) and extracted with dichloromethane (3�75 ml). The combined organic extracts are washed with brine (75 ml), dried (MgSO4), filtered, and the solvent removed to give the title compound. MH+ 268.9.
Example 59 1-Ethyl-3-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea Ethyl isocyanate (0.09 ml, 1.1 mmol) is added to a stirred solution of 5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 58) (0.10 g, 0.37 mmol) in dimethylformamide (1.0 ml). The mixture is heated at 85� C. for 90 minutes followed by removal of the solvent. The residue is crystallised from ethyl acetate�methanol to afford the title compound. MH+ 340.0.
Ex. 60 {3-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-acetic acid ethyl ester Replacing ethyl isocyanate in Example 59 with ethyl isocyanoacetate affords the title compound as a white solid. MH+ 398
Example 61 {3-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-acetic acid Aqueous sodium hydroxide (2M, 0.5 ml) is added to a stirred solution of {3-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-acetic acid ethyl ester (Example 60) (0.14 g, 0.00035 mmol) in methanol (2 ml). After stirring at room temperature for 18 hours the solvent is removed and dilute HCl is added. The resulting yellow solid is removed by filtration and recrystallised from ethanol to afford the title compound. MH+ 370.0
Example 62 3-{3-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid Replacing ethyl isocyanate in Example 59 with ethyl 3-isocyanatopropionate affords {3-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid ethyl ester as a white solid. This is treated with aqueous sodium hydroxide for 18 hours as described in Example 61 to afford the title compound as a white solid. MH+ 384.0
Example 63 N-[5-(3-Bromo-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide N-[5-(4-amino-3-bromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 7a) (1.0 g, 3.07 mmol) is converted into the corresponding sulfonyl chloride by the procedure described for the conversion of aniline (Example 1a) to sulfonyl chloride (Example 3a). A sample of this crude sulfonyl chloride (1.0 g, 2.4 mmol) is dissolved in dioxane (5 ml) and the resulting solution is added to a stirred solution of sodium sulfite (0.615 g, 4.9 mmol) and sodium hydrogen carbonate (0.41 g, 4.9 mmol) in water (5 ml) at 75� C. After 1 hour at 75� C. bromoacetic acid (0.679 g, 4.9 mmol) is added. The reaction is stirred for an additional 6 hours at 75� C. When cool the mixture is diluted with water (200 ml) and extracted with dichloromethane (3�100 ml). The combined organic extracts are washed with brine (100 ml, dried (MgSO4) and the solvent removed. Purification by chromatography on silica (EtOAc) affords the title compound.
Example 64 N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide 64a) 3-Fluoro-4-methanesulfonyl-benzaldehyde Methane sulfinic acid sodium salt (20.1 g, 200 mmol) is added to a stirred solution of 3,4-difluorobenzaldehyde (22.5 g, 158 mmol) in dry DMSO (200 ml) at 75� C. After 2 hours the reaction is poured onto ice-water (200 ml). The precipitate is filtered, washed with water and dissolved in chloroform (400 ml). The organic extract is washed with water (2�200 ml), dried over MgSO4, filtered, and the solvent is removed to give the title compd as a white solid.
64b) 2-Fluoro-1-methanesulfonyl-4-(2-nitro-propenyl)-benzene A stirred mixture of 3-fluoro-4-methanesulfonyl-benzaldehyde (Example 64a) (24 g, 0.119 mol), nitroethane (70 ml, 0.97 mol) and ammonium acetate (2.75 g, 35 mmol) is heated at reflux under argon for 24 hours. The mixture is concentrated to give an oil which is dissolved in chloroform (200 ml) and washed with water (2�200 ml), followed by brine (100 ml). The organic extract is dried (MgSO4), filtered and the solvent removed to give the product as an orange oil. This was used immediately in the next step.
64c) 1-(3-Fluoro-4-methanesulfonyl-phenyl)-propan-2-one Iron powder (25 g, 0.45 mol) is added to a stirred mixture of freshly prepared 2-fluoro-1-methanesulfonyl-4-(2-nitro-propenyl)-benzene (Example 64b) (29 g, 0.112 mol) in THF (50 ml). Water (110 ml) is added and the mixture is heated to 60� C. Concentrated hydrochloric acid (50 ml) is added slowly over 1 h at 60-90� C. The reaction is then stirred at 100� C. for 20 hours then diluted with cold water (500 ml) and filtered through Celite� filter material washing with chloroform (500 ml). The organic extract is washed with water (200 ml) followed by brine (200 ml). After drying (MgSO4) the mixture is absorbed on silica and purified by chromatography, eluting with hexane�ethyl acetate (1:1) to give the title compound.
64d) N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide 1-(3-Fluoro-4-methanesulfonyl-phenyl)-propan-2-one (Example 64c) (1.0 g, 4.34 mmol) is dissolved in dioxane (35 ml) and the solution is cooled to 10� C. at which point the mixture is semi frozen. Bromine (0.067 ml, 1.2 mmol, 0.3 eq.) is added slowly and the mixture is stirred for an additional 15 min in a semi frozen state. The mixture is then allowed to warm to room temperature and the solvent is removed to give a brown oil containing starting material and 1-bromo-1-(3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one. This material is dissolved in ethanol (30 ml) and N-acetylthiourea (0.369 g, 3.1 mmol) is added in one portion. The mixture is stirred at 60� C. for 30 minutes then allowed to cool whereupon the product crystallised. Filtration affords the title compound as a white solid.
Example 65 N-[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide The title compound is prepared by an analogous procedure to N-[5-(3-fluoro-4-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) by replacing 3,4-difluoro-benzaldehyde with 3-fluoro-4-trifluoromethylbenzaldehyde.
Example 66 N-[5-(3-Chloro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide The title compound is prepared by an analogous procedure to N-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) by replacing 3,4-difluorobenzaldehyde with 3,4-dichlorobenzaldehyde.
Example 67 N-{5-[4-Methanesulfonyl-3-(4-methyl-piperazin-1-yl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide A stirred mixture of N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) (0.05 g, 0.15 mmol) and 1-methylpiperazine (0.1 ml, 0.9 mmol) in dry DMSO (1 ml) is heated under argon at 115� C. for 1 hour. The solvent is removed and water (30 ml) is added. The product is extracted with ethyl acetate (2�30 ml) and the combined organic extracts are washed with brine (20 ml) and dried (MgSO4). Removal of the solvent and trituration with diethyl ether affords the title compound as a yellow solid.
Examples 68 to 71 These compounds, namely N-(5-{3-[(2-dimethylamino-ethyl)-methyl-amino]-4-methane-sulfonyl-phenyl}-4-methyl-thiazol-2-yl)-acetamide, N-{5-[3-(3-dimethylamino-propylamino)-4-methanesulfonyl-phenyl]-4-methyl-thiazol-2-yl}-acetamide, N-{5-[3-(2-diethylamino-ethyl-amino)-4-methanesulfonyl-phenyl]-4-methyl-thiazol-2-yl}-acetamide and N-(5-{3-[(2-diethyl-amino-ethyl)-methyl-amino]-4-methanesulfonyl-phenyl}-4-methyl-thiazol-2-yl)-acetamide respectively, are prepared by the same procedure as Example 67, replacing 1-methylpiperazine in this example with the appropriate amine.
Example 72 5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine This material is prepared from N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) using hydrolysis conditions described in Example 26.
Example 73 1-Ethyl-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea A mixture of 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (0.40 g, 1.4 mmol) and ethyl isocyanate (0.121 ml, 1.5 mmol) in dry DMF (3 ml) is heated at 85� C. for 1 hour. The solvent is removed and the product is purified by chromatography on silica eluting with hexane�ethyl acetate (1:1) to give the title compound.
Example 74 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzoic acid 74a) 3-(1-Bromo-2-oxo-propyl)-benzoic acid A stirred solution of 4-(2-oxopropyl)benzoic acid (1.0 g, 5.6 mmol) in THF (30 ml) at room temperature is treated with polymer supported pyridine hydrobromide perbromide (2.8 g, 2 mmol Br3 −/g). After 3 hours at room temperature, the reaction mixture is filtered through Celite� filter material and the solvent removed under vacuum to give the titled compound.
74b) 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzoic acid A mixture of 3-(1-bromo-2-oxo-propyl)-benzoic acid (1.4 g, 5.4 mmol) and N-acetylthiourea (0.64 g, 5.4 mmol) in ethanol is stirred at 70� C. for 2 hours. The reaction mixture is cooled to room temperature. The precipitated product is removed by and dried under vacuum to give the titled compound.
Example 75 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-N-(2-hydroxy-ethyl)-benzamide To 4-(2-acetylamino-4-methyl-thiazol-5-yl)-benzoic acid (Example 74b) (0.1 g, 0.36 mmol) in DMF (1 ml) is added HATU (0.14 g, 0.36 mmol) followed by DIPEA (0.07 ml, 0.36 mmol) and ethanolamine (0.022 ml, 0.36 mmol). After 5 hours, the reaction mixture is filtered and the precipitated product is washed with ethanol and dried under vacuum to give the titled compound.
Example 76 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-N-(2-cyano-ethyl)-benzamide The title compound is prepared following the procedure outlined in Example 75 by replacing ethanolamine with 3-aminopropionitrile.
Agents of the invention also include compounds of formula XIX where Ra, Rb, Rc and R1 are as shown in the Table 2 below, the method of preparation being described thereafter. The table also shows mass spectrometry (MH+) data. The examples are in free form.
Ra Rb Rc R1 ms MH+
Preparation of Specific Examples Abbreviations used are as follows: DCM is dichloromethane, DIPEA is diisopropylethylamine DME is dimethoxyethane, HATU is O-(7-azabenzotriazol-1-yl)-N,N,-N′, N′-tetramethyl-uronium hexafluorophosphate, NBS is N-bromosuccinimide and THF is tetrahydrofuran.
Example 77 1-(5-{3-[(2-Dimethylamino-ethyl)-methyl-amino]-4-methanesulfonyl-phenyl}-4-methyl-thiazol-2-yl)-3-ethyl-urea A stirred mixture of 1-Ethyl-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea (Example 73) (0.05 g, 0.14 mmol) and N,N,N′-Trimethylethylenediamine (0.25 ml, 2.1 mmol) in dry DMSO (0.5 ml) is heated under argon at 120� C. for 2 hours. The solvent is in vacuo removed and the product is purified by chromatography on silica eluting with ethanol-triethylamine (98:1) to give the titled compound. MH+: 440.1051
Example78 N-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-2-tetrazol-1-yl-acetamide 5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 58) (0.08 g, 0.3 mmol) is added to a solution of HATU (0.113 g, 0.3 mmol) and 1-tetrazole acetic acid (0.039 g, 0.31 mmol) in DCM. Triethylamine (0.104 ml, 0.75 mmol) is then added and the reaction mixture is left to stir at room temperature overnight. The product is purified by chromatography on silica eluting with methanol�DCM (96:4) to give the titled compound.
Example 79 N-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-2-pyridin-3-yl-acetamide This is prepared as described in Example 78 by replacing 1-tetrazole acetic acid with 3-pyridineacetic acid.
Example 82 N-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-2-pyridin-4-yl-acetamide This is prepared as described in Example 78 by replacing 1-tetrazole acetic acid with 4-pyridineacetic acid.
Example 80 N-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide A stirred mixture of N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) (0.1 g, 0.30 mmol), imidazole (0.069 g, 0.90 mmol) and caesium carbonate (0.198 g, 0.60 mmol) in dry DMSO is heated under argon at 140� C. for 2 hours. The solvent is removed and water (30 ml) is added. The product is extracted with ethyl acetate (2�30 ml) and the combined organic extracts are washed with brine (20 ml) and dried (MgSO4). Removal of the solvent and trituration with methanol affords the titled compound as an orange solid. MH+: 377.9721
Examples 81, 84 to 87, 103 and 104 The compounds, namely N-[5-(4-methanesulfonyl-3-[1,2,4]triazol-1-yl-phenyl)-4-methyl-thiazol-2-yl]-acetamide, N-{5-[4-methanesulfonyl-3-(4-methyl-imidazol-1-yl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide, N-{5-[4-methanesulfonyl-3-(2-methyl-imidazol-1-yl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide, N-{5-[3-(2-ethyl-imidazol-1-yl)-4-methanesulfonyl-phenyl]-4-methyl-thiazol-2-yl}-acetamide, N-{5-[4-methanesulfonyl-3-(4-methyl-pyrazol-1-yl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide, N-{5-[4-methanesulfonyl-3-(2-propyl-imidazol-1-yl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide and N-{5-[3-(2-isopropyl-imidazol-1-yl)-4-methanesulfonyl-phenyl]-4-methyl-thiazol-2-yl}-acetamide respectively, are prepared by the same procedure as Example 80 replacing 1-methylpiperazine in this example with the appropriate 5-membered ring nitrogen heterocycle.
Example 83 5-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine This compound is made via an analogous procedure to N-[5-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Ex. 48) by replacing N-acetylthiourea with thiourea.
Example 88 1-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)-urea 88a) 5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole 5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) (1.74 mmol, 0.5 g) is added to acetonitrile (15 ml) and treated with phosgene (20% solution in toluene, 6.99 mmol, 3.7 ml). The reaction mixture is heated to reflux (85� C.) for 30 minutes. After cooling to room temperature the solvent is removed in vacuo to leave 5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole as an orange solid.
88b) 1-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)-urea 5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole (88a)(0.58 mmol, 0.183 g) is dissolved in dioxane (5 ml) and treated with 2-aminoethanol (0.64 mmol, 0.039 ml) under argon. The reaction mixture is stirred and heated to 80� C. for 1 hour. The solvent is then removed and the residue dissolved in EtOAc and washed with water (2�20 ml) followed by brine (20 ml) and dried over MgSO4. After filtration, the solvent is removed in vacuo and the residue purified by chromatography on silica eluting with ethyl acetate�methanol (9:1) to give the title compound.
Examples 89, 91 to 94 and 96 These compounds, namely 1-(2-cyano-ethyl)-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea, 1-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(3-hydroxy-propyl)-urea, 1-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-2-ylmethyl-urea, 1-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-2-yl-ethyl)-urea, 1-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-pyridin-3-yl-ethyl)-urea and 1-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(4-hydroxy-butyl)-urea respectively are prepared by the same procedure as Example 88 replacing 2-aminoethanol (part 88b) in this example with the appropriate amine.
Examples 97, 99 to 101 and 105 to 116 The compounds namely, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-propyl-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-furan-2-ylmethyl-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-cyano-ethyl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2,5-dimethyl-2H-pyrazol-3-yl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-2-ylmethyl-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-isopropyl-urea, 1-butyl-3-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-cyclobutyl-urea, azetidine-1-carboxylic acid [5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-4-ylmethyl-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-3-ylmethyl-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(3-imidazol-1-yl-propyl)-urea, pyrrolidine-1-carboxylic acid [5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-cycopropylmethyl-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-furan-3-ylmethyl-urea respectively are prepared by the same procedure as Example 88 replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 83) and by replacing 2-aminoethanol (part 88b) with the appropriate amine.
Examples 117 to 147 The compounds namely, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(3-hydroxy-propyl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-((S)-1-hydroxymethyl-propyl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(4-hydroxy-cyclohexyl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-((R)-2-hydroxy-1-methyl-ethyl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-((S)-2-hydroxy-1-methyl-ethyl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-[2-(2-hydroxy-ethoxy)-ethyl]-urea, 1-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(3-diethylamino-propyl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-3-yl-urea, 1-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-4-yl-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-methyl-2H-pyrazol-3-yl)-urea, 1-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(5-methyl-isoxazol-3-ylmethyl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(4,6-dimethyl-pyridin-2-yl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(6-methyl-pyridin-2-yl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-((S)-2-hydroxy-2-phenyl-ethyl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(3-hydroxymethyl-2-methyl-phenyl)-urea, 1-((R)-sec-butyl)-3-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(6-methoxy-pyridin-3-yl)-urea, 1-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-methoxy-pyridin-3-yl)-urea, 1-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(3,3,3-trifluoro-propyl)-urea, [5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-methyl-urea, 3-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-1-(2-hydroxy-ethyl)-1-methyl-urea, (R)-3-hydroxy-pyrrolidine-1-carboxylic acid [5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(4-hydroxy-butyl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(5-hydroxy-pentyl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(1H-pyrazol-3-yl)-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-cyclopropyl-urea, 1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-ethyl-urea and 3-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-1,1-dimethyl-urea respectively, are prepared by the same procedure as Example 88 replacing 2-aminoethanol (part 88b) in this example with the appropriate amine and by replacing dioxane with dimethyl formamide.
Example 90 N-[5-(3,4-Bis-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide This is isolated as a minor by product in the synthesis of N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) when excess methane sulfinic acid sodium salt is added in the first step of the synthesis (64a). The resulting aldehyde is converted into the title compound by the procedure described in parts 64b-d.
Example 95 N-[5-(3,5-Difluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide The title compound is made via an analogous procedure to N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) by replacing 3,4-difluorobenzaldehyde in part 64a of the procedure with 3,4,5-trifluorobenzaldehyde.
Example 98 3-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-N-(2-hydroxy-ethyl)-benzenesulfonamide 98a) 1-Bromo-1-(3-nitro-phenyl)-propan-2-one A stirred solution of 3-nitrophenylacetone (2.5 g, 14.0 mmol) in dry THF (50 ml) at room temperature is treated with polymer supported pyridine hydrobromide perbromide (7.0 g, 14.0 mmol) and left to stir overnight. The reaction mixture is then filtered and the solvent removed in vacuo. The residue is purified by chromatography on silica eluting with 1:4 ethyl acetate�hexane to give the titled compound.
98b) 4-Methyl-5-(3-nitro-phenyl)-thiazol-2-ylamine A stirred solution of 1-Bromo-1-(3-nitro-phenyl)-propan-2-one (98a) (2.4 g, 9.3 mmol) in ethanol (20 ml) at room temperature is treated with thiourea (0.71 g, 9.3 mmol). The reaction mixture is heated to 70� C. for 10 minutes. The resulting precipitate is removed by filtration and dried under vacuum to give the titled compound.
98c) 1-Ethyl-3-[4-methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-urea The title compound is made via an analogous procedure to Example 88 by, first of all, replacing 5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (part 88a) with 4-Methyl-5-(3-nitro-phenyl)-thiazol-2-ylamine and secondly, by replacing 2-aminoethanol with ethylamine (part 88b).
98d) 1-[5-(3-amino-phenyl)-4-methyl-thiazol-2-yl]-3-ethyl-urea A stirred solution of 1-Ethyl-3-[4-methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-urea (98c) (0.55 g, 1.8 mmol) in THF (25 ml) and EtOAc (50 ml) under Argon is treated with 10% palladium on carbon (1.0 g). The reaction mixture was placed under an atmosphere of hydrogen for 2 hours. The mixture was then filtered through Celite� filter material and the solvent removed in vacuo to yield the titled compound.
98e) 3-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-N-(2-hydroxy-ethyl)-benzenesulfonamide The titled compound is made via an analogous procedure to N-[4-methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide (Example 3) by replacing N-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide with 1-[5-(3-amino-phenyl)-4-methyl-thiazol-2-yl]-3-ethyl-urea (part 3a) and by replacing ammonia with ethanolamine (part 3b).
Example 102 N-[5-(3,5-Dichloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide The title compound is made via an analogous procedure to N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64d) by replacing 1-(3-Fluoro-4-methanesulfonyl-phenyl)-propan-2-one with 1-(3,5-Dichloro-phenyl)-propan-2-one.
Example 148 5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine A stirred solution of N-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 80) (0.80 g, 2.13 mmol) in ethanol (15 ml) and 7M aqueous HCl (20 ml) is heated at 90� C. for 2 hours. The solution is allowed to cool, brought to pH 10 by addition of aqueous NaOH and extracted with n-butanol. The organic extract is dried (MgSO4), the solvent is removed and the residue is triturated with ethanol to give the titled compound as a yellow solid.
Ex. 149 5-[4-Methanesulfonyl-3-(2-propyl-imidazol-1-yl)-phenyl]-4-methyl-thiazol-2-ylamine This is prepared by an analogous procedure to Ex. 148, replacing N-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (example 4) with N-{5-[4-methane-sulfonyl-3-(2-propyl-imidazol-1-yl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide (Ex. 103).
Example 150 1-(2-Cyano-ethyl)-3-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea 150a) Imidazole-1-carboxylic acid [5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide Sodium hydride (60% dispersion in oil, 0.137 g, 3.42 mmol) is added to a stirred suspension of 5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (148) (1.04 g, 3.1 mmol) in dry dimethylformamide (10 ml) at room temperature under argon. 1,1′-Carbonyl diimidazole (0.757 g, 4.67 mmol) is added and the stirred suspension is heated to 40� C. for 1 h. The reaction mixture is cooled and the resulting solid filtered and washed with DCM and ether to afford the title compound.
150b) 1-(2-Cyano-ethyl)-3-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea The titled compound is prepared by the same procedure as example 88, replacing 2-aminoethanol (part 88b) in this example with 3-aminopropionitrile and replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole (88a) with Imidazole-1-carboxylic acid [5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide (150a)
Examples 151 to 155 These compounds, namely 1-(3-hydroxy-propyl)-3-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea, 1-(4-hydroxy-butyl)-3-[5-(3-imidazol-1-yl-4-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea, 1-cyano-3-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea, 1-(2-cyano-ethyl)-3-[5-(3-imidazol-1-yl-4-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-1-methyl-urea and 1-(2-cyano-ethyl)-1-ethyl-3-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea respectively are prepared by the same procedure as Example 150 by replacing 3-aminopropionitrile (part 150b) in that Example with the appropriate amine.
Example 156 N-{5-[4-Chloro-3-(2-hydroxy-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide The title compound is made via an analogous procedure to N-[5-(4-Methoxy-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 30) by replacing 4-methoxyphenyl acetone (in example 30a) with 4-chlorophenyl acetone; and ammonia with 2-amino ethanol.
Agents of the invention also include compounds of formula XIX where Ra, Rb, Rc and R1 are as shown in the Table 3 below, the method of preparation being described thereafter. The table also shows mass spectrometry (MH+) data. The examples are in free form.
Preparation of Specific Examples Example 157 2-Chloro-N-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide 5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148) (0.537 g, 1.60 mmol) and chloroacetyl chloride (5 ml) are heated together for 2 hours. The reaction mixture is allowed to cool to room temperature and the solid filtered and washed with saturated sodium bicarbonate solution (3�100 ml) and water (2�50 ml) to yield the titled compound.
Example 158 N-[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-2-methoxy-acetamide 158a) 5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine The title compound is prepared by an analogous procedure to N-[5-(3-fluoro-4-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) by replacing 3,4-difluorobenz-aldehyde with 3-fluoro-4-trifluoromethylbenzaldehyde (part 64a) and by replacing N-acetal-thiourea with thiourea (part 64d).
158b) N-[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-2-methoxy-acetamide 5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine (158a) (0.1 g, 0.3 mmol) is added to a solution of HATU (0.226 g, 0.6 mmol), methoxyacetic acid (0.046 ml, 0.6 mmol) and DIPEA (0.1 ml, 0.6 mmol) in DMF (7.5 ml). The reaction mixture was left to stir for 3 days at room temperature. The reaction mixture is filtered through basic alumina. The solvent is removed in vacuo and the product is purified by chromatography on silica eluting with ethyl acetate-hexane (3:1) to give the titled compound.
Example 159 N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-propionamide 5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) (1 g, 3.39 mmol) is suspended in propionic anhydride (12.5 ml) and heated to 70� C. for 1 hour. The reaction mixture is cooled to room temperature and the solvent removed in vacuo. The solid is triturated with ether to yield the titled compound.
Example 160 N-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-propionamide The title compound is prepared via an analogous procedure to N-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 80) by replacing N-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in this example with N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-propionamide (159).
Example 161 N-[5-(4-Fluoro-3-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide 161a) 1-(4-Fluoro-3-methoxy-phenyl)-propan-2-one The title compound is prepared via an analogous procedure to 1-((3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one (64c) (steps 64b-64c) by replacing 3-fluoro-4-methanesulfonyl-benzaldehyde in step 64b with 4-fluoro-3-methoxy-benzaldehyde.
161b) 1-bromo-1-(4-fluoro-3-methoxy-phenyl)-propan-2-one A stirred solution of 1-(4-fluoro-3-methoxy-phenyl)-propan-2-one (161a) (0.5 g, 2.74 mmol) in dry THF (5 ml) is treated dropwise with a solution of 2-carboxyethyltriphenylphosphonium perbromide (1.66 g, 2.88 mmol) in THF. The reaction mixture is allowed to stir at room temperature for 1.5 hours and then filtered. The filtrate is concentrated in vacuo to yield the titled compound.
161c) N-[5-(4-Fluoro-3-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide 1-Bromo-1-(4-fluoro-3-methoxy-phenyl)-propan-2-one (161b) (0.72 g, 2.74 mmol) is dissolved in ethanol (20 ml) and N-acetylthiourea (0.324 g, 2.72 mmol) is added in one portion. The mixture is stirred at 80� C. overnight then allowed to cool whereupon the product crystallised. Filtration affords the title compound as a white solid.
Example 162 3-Hydroxy-azetidine-1-carboxylic acid [5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide 162a) 1-Benzhydryl-3-(tert-butyl-diphenyl-silanyloxy)-azetidine A stirred solution of 1-Benzhydrylazetan-3-ol (2.0 g, 8.4 mmol) in DMF (20 ml) at 0� C. is treated with imidazole (0.57 g, 8.4 mmol) and t-butylchlorodiphenyl silane (2.31 g, 8.4 mmol). The reaction mixture is allowed to warm up to room temperature and stirred overnight. The mixture is poured into water (250 ml) and extracted with EtOAc (3�100 ml). The combined organic extracts are washed with water (2�100 ml), brine (100 ml) and dried over MgSO4. The solvent is removed in vacuo to yield the titled compound.
162b) 3-(tert-Butyl-diphenyl-silanyloxy)-azetidine A stirred solution of 1-benzhydryl-3-(tert-butyl-diphenyl-silanyloxy)-azetidine (162a) (4.0 g, 8.4 mmol) in DCE (60 ml) at room temperature is treated with 1-chloroethylchloroformate (1.2 ml, 10.9 mmol) and the reaction mixture is heated to 80� C. After 2 hours, the solvent is removed in vacuo and the residue is dissolved in methanol (60 ml) and heated to reflux. After 1 h the reaction mixture is poured into water (250 ml), acidified with hydrochloric acid (1M solution) and washed with EtOAc (3�75 ml). The aqueous solution is basified with saturated sodium bicarbonate solution and extracted with EtOAc (3�75 ml). The combined organic layers are washed with water (2�50 ml), brine (50 ml), dried over MgSO4. The solvent is removed in vacuo to yield the titled compound.
162c) 3-(tert-Butyl-diphenyl-silanyloxy)-azetidine-1-carboxylic acid [5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazole-2-yl]amide A stirred solution of 5-(4-chloro-3-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole [prepared by the same procedure as example 88a replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) in this example with 5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 83)] (0.2 g, 0.61 mmol) in DMF is treated with 3-(tert-butyl-diphenyl-silanyloxy)-azetidine (162b) (0.25 g, 0.8 mmol) and the reaction mixture is heated to 120� C. After 30 minutes, the reaction is complete. The product is purified by chromatography on silica eluting with ethyl acetate-hexane (1:2) to give the titled compound.
162d) 3-Hydroxy-azetidine-1-carboxylic acid [5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide A stirred solution of 3-(tert-butyl-diphenyl-silanyloxy)-azetidine-1-carboxylic acid [5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazole-2-yl]amide (162c) (0.15 g, 0.23 mmol) in THF (2 ml) at room temperature is treated with tetrabutylammonium fluoride (1.0 M in THF, 0.23 ml, 0.23 mmol). After 30 minutes, the reaction was complete. Purification by preparative LC-MS affords the titled compound.
Example 163 1-[5-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(6-morpholin-4-yl-pyridin-3-yl)-urea The title compound is prepared by the same procedure as 1-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)-urea (Example 88) replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 83) and by replacing 2-aminoethanol (part 88b) with 6-morpholinopyridin-3-amine.
Example 164 4-{3-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester 5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72), (0.1 g, 0.31 mmol) DIPEA (0.039 ml, 0.34 mmol), ethyl-4-isocyanatobutyrate (0.046 ml, 0.31 mmol) in DCM (2 ml) are heated together at reflux overnight. The reaction mixture is diluted with DCM (20 ml) and washed with 1M hydrochloric acid (15 ml), water (2�15 ml), brine (15 ml), dried over MgSO4, filtered and concentrated in vacuo to yield the titled compound as an off white solid.
Example 165 3-{3-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid ethyl ester The title compound is prepared by the same procedure as 4-{3-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Example 166 3-{3-[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid ethyl ester The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine (158a) and replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Example 167 4-{3-[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine (158a).
Example 168 3-{3-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid ethyl ester The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148) and replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Example 169 4-{3-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148).
Example 170 3-{3-[5-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid ethyl ester The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 83) and replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Example 171 3-{3-[5-(3,5-Dichloro-4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid ethyl ester 171a) N-[5-(3,5-Dichloro-4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide The title compound is prepared by an analagous procedure to N-[5-(3,5-dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 6) by replacing ammonia with dimethylamine.
171b) 4-(2-Amino-4-methyl-thiazol-5-yl)-2,6-dichloro-N,N-dimethyl-benzenesulfonamide The title compound is prepared by the same procedure as 4-(2-amino-4-methyl-thiazol-5-yl)-2,6-dichloro-benzenesulfonamide (Example 26) by replacing N-[5-(3,5-dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 6) with N-[5-(3,5-dichloro-4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (171a).
171c) 3-{3-[5-(3,5-Dichloro-4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido)}-propionic acid ethyl ester The title compound is prepared by the same procedure as 4-{3-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 4-(2-amino-4-methyl-thiazol-5-yl)-2,6-dichloro-N,N-dimethyl-benzenesulfonamide (171b) and replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Example 172 4-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylcarbamoyl]-butyric acid methyl ester Methyl-4-(chloroformyl) butyrate (4.0 mmol) is added to a stirred solution of 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) (0.77 g, 2.69 mmol) and heated to 60� C. for 1.5 hours. The reaction mixture is allowed to cool to room temperature and the solvent removed in vacuo. The residue is washed with saturated sodium bicarbonate solution (2�50 ml) and water (1�50 ml). The product is extracted with ethyl acetate (2�50 ml) and the combined organic extracts dried (MgSO4). Removal of the solvent followed by recrystallisation from ethyl acetate affords the tided compound.
Example 173 3-{3-[5-(4-Dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid To a stirred solution of 3-{3-[5-(4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid ethyl ester (Example 24) in methanol (5 ml) is added dropwise sodium hydroxide (2M, 3 ml) over 2 minutes. The reaction mixture is heated at reflux overnight and then allowed to cool to room temperature. The mixture is neutralised with hydrochloric acid (2M, 3 ml) and the resulting precipitate is filtered, washed with water (20 ml) and dried in vacuo to yield the titled compound.
Example 174 1-{5-[4-Chloro-3-(4-methyl-2-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-yl}-3-ethyl-urea 174a) 2-Chloro-5-(2-oxopropyl)-benzenesulphonyl chloride To chlorosulfonic acid (25 ml, excess) cooled at −10� C. is added dropwise 4-chlorophenyl acetone (1.0 g, 5.93 mmol). The temperature is kept below 0� C. throughout the addition. The reaction mixture is then left to warm up to room temperature overnight. The reaction mixture is poured carefully onto ice (1500 ml). Once the ice is melted, the aqueous layer is extracted with dichloromethane (3�250 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford the titled compound as an off-white solid.
174b) 1-[4-Chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propan-2-one 2-Chloro-5-(2-oxopropyl)-benzenesulphonyl chloride (174a) (2.0 g, 7.5 mmol) is dissolved in dioxan (50 ml) with stirring. Sodium carbonate (7.5 ml, 2M solution, 2 eq.) is added followed by 1-methyl piperazine (0.75 g, 7.5 mmol). After 30 min the reaction mixture is poured onto water (250 ml) and extracted with ethyl acetate (3�100 ml). The combined organic extracts are washed with water (2�100 ml) followed by brine (100 ml) and dried (MgSO4). After filtration the solvent is removed and the product is purified by chromatography on silica, eluting with ethyl acetate/hexane (1:2) to afford the titled compound.
174c) 1-Bromo-1-[4-chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propan-2-one A stirred solution of 1-[4-chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propan-2-one (174b) (0.5 g, 1.22 mmol) in dry THF (5 ml) is treated dropwise with a solution of 2-carboxyethyltriphenylphosphonium perbromide (0.84 g, 1.44 mmol) in THF. The reaction mixture is allowed to stir at room temperature for 1.5 hours and then filtered. The filtrate is concentrated in vacuo to yield the titled compound.
174d) 5-[4-Chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-ylamine The title compound is prepared as an HBr salt by the same procedure as N-[5-(4-fluoro-3-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (161c) by replacing 1-bromo-1-(4-fluoro-3-methoxy-phenyl)-propan-2-one (161b) with 1-bromo-1-[4-chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propan-2-one (171c) and N-acetylthiourea with thiourea.
174e) 1-{5-[4-Chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-yl}-3-ethyl-urea A stirred solution of 5-[4-Chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-ylamine hydrobromide (174d) (0.1 g, 0.26 mmol) in DMF (1 ml) at room temperature is treated with DIPEA (0.07 g, 0.52 mmol) and ethyl isocyanate (0.025 ml, 0.33 mmol). The reaction mixture is heated to 120� C. for 1 hour and then allowed to cool to room temperature. Purification by preparative LC-MS affords the titled compound.
Example 175 N-[5-(3-Cyano-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide The titled compound was prepared by an identical procedure to N-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) replacing 3,4-difluorobenzaldehyde in this procedure with 2-fluoro-5-formylbenzonitrile.
Examples 176 3-{3-[5-(3-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid ethyl ester 176a) 1-(4-Chloro-3-methanesulphonyl-phenyl)-propan-2-one A stirred solution of 2-Chloro-5-(2-oxo-propyl)-benzenesulphonyl chloride (prepared as described in Example 174a) (20.0 g, 74.9 mmol) in dioxane (300 ml) at room temperature is treated with a solution of sodium sulphite (18.9 g, 150 mmol) and sodium hydrogen carbonate (12.6 g, 150 mmol) in water (200 ml). The reaction mixture is heated to 75� C. for 10 minutes and then allowed to cool to room temperature. The solvent is removed in vacuo and the residue dissolved in DMF (200 ml). The solution is stirred at room temperature and treated with iodomethane (21.2 g, 150 mmol). After stirring for 20 minutes, the reaction mixture is diluted with water (1000 ml) and extracted with ethyl acetate (3�250 ml). The combined organic layers are washed with water (2�200 ml), brine (100 ml), dried over MgSO4 and concentrated in vacuo to yield the titled compound.
176b) 1-(3-Methanesulphonyl-phenyl)-propan-2-one A solution of 1-(4-chloro-3-methanesulphonyl-phenyl)-propan-2-one (5.49 g, 22.28 mmol) in methanol (250 ml) is stirred under hydrogen in the presence of 10% Pd on carbon (3 g) for 2 hours. The reaction mixture is filtered and concentrated in vacuo to yield a yellow oil of the titled compound.
176c) 1-Bromo-1-(3-methanesulphonyl-phenyl)-propanone A stirred solution of 1-(3-methanesulphonyl-phenyl)-propan-2-one (176b) (0.25 g, 1.18 mmol) in dioxane (10 ml) at 5� C. is treated with bromine (0.131 g, 0.82 mmol) added in two portions. The reaction is stirred and allowed to warm up to room temperature. The solvent is removed in vacuo to yield an orange oil of the titled compound.
176d) 5-(3-Methanesulphonyl-phenyl)-4-methyl-thiazol-2-ylamine hydrobromide A stirred solution of 1-bromo-1-(3-methanesulphonyl-phenyl)-propanone (176c) (0.32 g, 1.01 mmol) is treated with thiourea (0.067 g, 0.88 mmol) added in one portion. The reaction mixture is allowed to stir at room temperature over two days. The product precipitates out and is filtered to yield the title compound as while solid.
176e) 3-{3-[5-(3-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid ethyl ester A stirred suspension of 5-(3-methanesulphonyl-phenyl)-4-methyl-thiazol-2-ylamine hydrobromide (176d) (0.172 g, 0.64 mmol) in DCM (15 ml) is treated with Hunigs base (0.45 ml, 2.36 mmol) followed by ethyl-3-isocyanatopropionate (0.092 g, 0.64 mmol). The reaction mixture is stirred and heated to 60� C. for 10 hours and then the solvent in removed in vacuo. The product is purified by chromatography on silica to give the titled compound
Examples 177 [5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea 177a) Imidazole-1-carboxylic acid [5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide The title compound is prepared by the same procedure as imidazole-1-carboxylic acid [5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide (Example 150a) by replacing 5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148) with 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72)
177b) [5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea The title compound is prepared by the same procedure as 1-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)-urea (Example 88) by replacing 2-aminoethanol (part 88b) in this example with ammonia.
Examples 178 1-[2-(5-Ethyl-oxazol-2-yl)-ethyl]-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea The title compound is prepared by the same procedure as -[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea (Example 177) by replacing ammonia (part 177b) with the hydrochloride salt of 2-(5-Ethyl-oxazol-2-yl)-ethylamine (details of preparation procedure follows below), by replacing dioxane with DMF and by using triethylamine as a base.
2-(5-Ethyl-oxazol-2-yl)-ethylamine) Step 1) [2-(2-Hydroxy-butylcarbamoyl)-ethyl]-carbamic acid benzyl ester A mixture comprising Z-Beta-Ala-OH (9.0 g, 40.3 mmol), EDCI.HCl (10.0 g, 52.4 mmol), hyrdoxybenzotriazole (5.45 g, 40.3 mmol), triethylamine (7.3 ml, 52.4 mmol) in DCM (150 ml) is stirred at 0� C. for 30 minutes. 1-Amino-2-butanol (4.2 ml, 44.3 mmol) is added in one portion and stirring is continued for 1 hour. The reaction mixture is diluted with water (150 ml) and extracted with dichloromethane (2�150 ml) The organic layers are combined, dried over MgSO4, filtered and concentrated in vacuo to yield a crude white solid. The product is purified by chromatography on silica eluting with ethanol-ethyl acetate (1:10) to give the titled compound.
Step 2) [2-(2-Oxo-butylcarbamoyl)-ethyl]-carbamic acid benzyl ester To a stirred solution of oxalyl chloride (2 M in DCM) (13.35 ml, 26.5 mmol) in dry DCM at −78� C. is added dropwise DMSO (2.5 ml, 35.4 mmol). After stirring for 15 minutes, the reaction mixture is treated with a solution of [2-(2-hydroxy-butylcarbamoyl)-ethyl]-carbamic acid benzyl ester (step 1) (6.5 g, 22.1 mol) in dry DCM (40 ml). Triethylamine (13 ml) is added after 1 hour and after stirring at −78� C. for 90 minutes, the reaction mixture is allowed to warm to room temperature. The reaction is diluted with DCM (100 ml) and washed with HCl (1M, 200 ml), saturated sodium bicarbonate solution (200 ml), water (200 ml) and brine (200 ml). The organic portion is dried over MgSO4, filtered and concentrated in vacuo to yield the titled compound as a white solid.
Step 3) [2-(5-Ethyl-oxazol-2-yl)-ethyl]-carbamic acid benzyl ester To a stirred suspension of polymer supported triphenylphosphene (19.6 g, 58.9 mmol) in DCM (250 ml) is added iodine (14.95 g, 58.9 mmol). After stirring at room temperature for 10 minutes, the mixture is treated with triethylamine (16.4 ml, 117.5 mmol) followed by a solution of [2-(2-oxo-butylcarbamoyl)-ethyl]-carbamic acid benzyl ester (step 2) (6.88 g, 23.5 mmol) in DCM (50 ml). The reaction mixture is stirred overnight and then filtered through celite, washed through with DCM (500 ml) and the solvent removed in vacuo to yield the titled compound as a brown solid.
Step 4) 2-(5-Ethyl-oxazol-2-yl)-ethylamine (hydrochloride salt) A solution of [2-(5-ethyl-oxazol-2-yl)-ethyl]-carbamic acid benzyl ester (step 3) (0.41 g, 1.49 mmol), 2M HCl (0.75 ml) in ethanol (40 ml) is stirred under hydrogen in the presence of 10% Pd on carbon (0.041 g) for 5 hours. The reaction mixture is filtered and concentrated in vacuo to yield the titled compound.
Examples 179 1-[2-(4-Ethyl-oxazol-2-yl)-ethyl]-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea The title compound is prepared by the same procedure as 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea (Example 178) by replacing 2-(5-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4) with the hydrochloride salt of 2-(4-ethyl-oxazol-2-yl)-ethylamine. This is prepared by the same procedure as 2-(5-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4) by replacing 1-amino-2-butanol (step 1) with 2-amino-1-butanol.
Example 180 1-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-[2-(5-methyl-oxazol-2-yl)-ethyl]-urea The title compound is prepared by the same procedure as 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea (Example 178) by replacing 2-(5-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4) with the hydrochloride salt of 2-(5-methyl-oxazol-2-yl)ethylamine. This is prepared by the same procedure as 2-(5-ethyl-oxazol-2-yl)ethylamine hydrochloride (step 4) by replacing 1-amino-2-butanol (step 1) with 1-amino-2-propanol.
Example 181 1-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-[2-(4-methyl-oxazol-2-yl)-ethyl]-urea The title compound is prepared by the same procedure as 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea (Example 178) by replacing 2-(5-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4) with the hydrochloride salt of 2-(4-methyl-oxazol-2-yl)ethylamine. This is prepared by the same procedure as 2-(5-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4) by replacing 1-amino-2-butanol (step 1) with 2-amino-1-propanol.
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J., vol. 324, pp. 489-495 (1997).* Cited by examinerClassifications U.S. Classification548/195International ClassificationA61P35/00, A61K31/5377, A61K31/496, A61P9/00, C07D277/44, C07D417/04, A61P37/06, A61P37/08, A61P9/10, C07D277/20, A61P43/00, A61K31/427, A61K31/4439, A61P3/10, A61P3/04, A61P7/08, C07D277/48, A61P31/04, A61P17/06, A61P19/02, A61P1/04, C07D277/46, A61K31/426, A61P11/00, C07D277/42, C07D417/12, A61P29/00Cooperative ClassificationC07D277/40, C07D417/04, C07D417/12, C07D277/46, C07D277/48European ClassificationC07D417/12, C07D417/04, C07D277/40, C07D277/46, C07D277/48Legal EventsDateCodeEventDescriptionSep 4, 2013FPAYFee paymentYear of fee payment: 4Dec 17, 2009ASAssignmentOwner name: NOVARTIS AG, SWITZERLANDFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BRUCE, IAN;FINAN, PETER;LEBLANC, CATHERINE;AND OTHERS;REEL/FRAME:023669/0226;SIGNING DATES FROM 20040731 TO 20040811Owner name: NOVARTIS AG,SWITZERLANDFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BRUCE, IAN;FINAN, PETER;LEBLANC, CATHERINE AND OTHERS;SIGNED BETWEEN 20040731 AND 20040811;US-ASSIGNMENT DATABASE UPDATED:20100330;REEL/FRAME:23669/226Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BRUCE, IAN;FINAN, PETER;LEBLANC, CATHERINE;AND OTHERS;SIGNING DATES FROM 20040731 TO 20040811;REEL/FRAME:023669/0226RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services