HK1111359B - Processes for the preparation of isothiazole derivatives - Google Patents
Processes for the preparation of isothiazole derivatives Download PDFInfo
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- HK1111359B HK1111359B HK08102078.3A HK08102078A HK1111359B HK 1111359 B HK1111359 B HK 1111359B HK 08102078 A HK08102078 A HK 08102078A HK 1111359 B HK1111359 B HK 1111359B
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Description
Background
The present invention relates to a process for the preparation of isothiazole derivatives which are useful in the treatment of hyperproliferative disorders, such as cancer, in mammals. Polypeptide growth factors, such as Vascular Endothelial Growth Factor (VEGF) having high affinity for the receptor containing the human kinase insertion region (KDR) or the murine fetal liver kinase 1(FLK-1), are known to be associated with endothelial cell proliferation, more specifically angiogenesis and vasculogenesis. The present invention provides methods for preparing compounds capable of binding to or modulating the KDR/FLK-1 receptor. The compounds are useful for treating diseases associated with angiogenesis or vasculogenesis, such as diabetes, diabetic retinopathy, hemangioma, gliosis, melanoma, Kaposi's sarcoma, and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancers.
The invention also relates to a process for the preparation of intermediates which can be converted into the above-mentioned isothiazole derivatives, and to the intermediates prepared. Methods for preparing isothiazole derivatives and intermediates thereof have been disclosed in international patent publication WO 99/62890 published on 9.12.1999 and in U.S. patent nos. 6235764, 6380214 and 6548526 issued on 22.5.2001, 30.4.2002 and 15.4.2003, respectively. A process for preparing 3-alkoxyisothiazole derivatives as herbicides is disclosed in U.S. Pat. No.4059433 issued on 11/22/1977. Methods for preparing 5-amino-3-hydroxy (alkoxy, amino) isothiazoles have been disclosed in chemische belichte (1964), 97(11), 3106-17.
Summary of The Invention
The present invention relates to processes for the preparation of compounds of formula I or pharmaceutically acceptable salts, prodrugs, hydrates and solvates thereof,
wherein the content of the first and second substances,
R1is H, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, -C (O) (C)1-C10Alkyl), - (CH)2)t(C6-C10Aryl), - (CH)2)t(4-10 membered heterocycle), -C (O) (CH)2)t(C6-C10Aryl) or-C (O) (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0-5; the alkyl group optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R1Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; 1 or 2 carbon atoms in the above heterocyclic moiety are optionally substituted with an oxo group (═ O); r is as defined above1The radicals (other than H) being optionally substituted by 1-3R4Substituted by radicals;
R2is selected from among R1The substituents, -SO2(CH2)t(C6-C10Aryl), -SO2(CH2)t(4-to 10-membered heterocycle) and OR5T is an integer of 0to 5, and the above R2Optionally substituted by 1-3R4Substituted by radicals;
or, R1And R2May be taken together with the nitrogen to which they are attached to form a 4-to 10-membered saturated monocyclic ring orPolycyclic or 5-10 membered heteroaromatic ring wherein the saturated ring and heteroaromatic ring are other than R1And R2Optionally containing, in addition to the nitrogen attached, 1 or 2 substituents selected from the group consisting of O, S and-N (R)6) -a heteroatom moiety of said-N (R)6) -optionally is ═ N-or-N ═ with R1And R2Taken together as the heteroaryl group, the saturated ring, optionally partially unsaturated by introduction of a 1 or 2 carbon-carbon double bond, is partially unsaturated with a heteroaromatic ring (including the-N (R)6) R of (A-C)6Radical) is optionally substituted by 1 to 3R4Substituted by radicals;
R3is H, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, - (CH)2)t(C6-C10Aryl) or- (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0-5; the alkyl group optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R3Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; 1 or 2 carbon atoms in the above heterocyclic moiety are optionally substituted with an oxo group (═ O); r is as defined above3Of radical- (CH)2)t-optionally comprising a carbon-carbon double or triple bond, wherein t is an integer from 2 to 5, and R as defined above3Optionally substituted by 1-5R4Substituted by radicals;
each R4Independently selected from halogen, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR5、-NR6C(O)OR5、-NR6SO2R5、-SO2NR5R6、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-S(O)jR7(where j is an integer of 0to 2), -NR5(CR6R7)tOR6、-(CH2)t(C6-C10Aryl), -SO2(CH2)t(C6-C10Aryl), -S (CH)2)t(C6-C10Aryl), -O (CH)2)t(C6-C10Aryl), - (CH)2)t(4-10 membered heterocycle) and- (CR6R7)mOR6Wherein m is an integer of 1 to 5, and t is an integer of 0to 5; the alkyl group optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R4Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; 1 or 2 carbon atoms in the above heterocyclic moiety are optionally substituted with an oxo group (═ O); r is as defined above4The alkyl, aryl and heterocyclic moieties of the group are optionally substituted with 1-3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6SO2R5、-SO2NR5R6、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-(CR6R7)mOR6(where m is an integer of 1 to 5), OR5And in R5The substituents listed in the definition of (1);
each R5Independently selected from H, C1-C10Alkyl, - (CH)2)t(C6-C10Aryl) and- (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0-5; the alkyl group optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R5Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; r is as defined above5The radicals (other than H) being optionally substituted by 1-3Substituted with substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6C(O)R7、-C(O)NR6R7、-NR6R7Hydroxy, C1-C6Alkyl and C1-C6An alkoxy group;
each R6And R7Independently is H or C1-C6An alkyl group;
the process comprises reacting a compound of formula II with an ammonia source in a solvent to obtain a compound of formula I.
Wherein R is8Is H, C1-C10Alkyl, -C (O) (C)1-C10Alkyl), -C (O) (C)6-C10Aryl), -C (O) (4-10 membered heterocycle), -CH2)t(C6-C10Aryl), - (CH)2)t(4-10 membered heterocycle), -C (O) O (C)1-C10Alkyl), -C (O) O (C)6-C10Aryl), -C (O) O (4-10 membered heterocycle), where t is an integer from 0to 5; said aryl and heterocyclic ring R8Radicals optionally condensed to C6-C10On the aryl group; the above-mentioned aryl and heterocyclic ring R8Optionally substituted with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6Alkoxy radical, C1-C6Alkyl and nitro; r1、R2、R3、R4、R5、R6And R7As defined above for the compounds of formula I,
the reaction is preferably carried out at a temperature between about-50 ℃ and about 150 ℃ and a pressure between about atmospheric pressure and about 200psi, more preferably between about 50 ℃ and about 70 ℃ and about 10 to about 40psi, still more preferably between about 30 ℃ and about 50 ℃ and about 45 to about 80 psi. The source of ammonia is preferably anhydrous ammonia, but the source of ammonia is not critical to the invention. Other non-limiting sources of ammonia include ammonium hydroxide, liquid ammonia, ammonium chloride, sodium amide, and formamide.
The reaction is preferably carried out in the presence of a solvent, such as C1-C4Alcohols (e.g., methanol, ethanol, propanol, and 2-propanol), dipolar aprotic solvents (e.g., dimethyl sulfoxide, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone), ethers (e.g., tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, dioxane, 2-methyltetrahydrofuran), water, or a mixture of at least two of the foregoing. Tetrahydrofuran and methanol or mixtures thereof are particularly preferred.
One embodiment of the invention relates to the following methods and compounds: wherein R is2Is H, R1Is C optionally substituted by 1 or 2 substituents1-C10Alkyl, said substituents being independently selected from-NR5R6、-NR5(CR6R7)tOR6And- (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0to 5. In another embodiment, R1Selected from propyl, butyl, pentyl and hexyl, and may optionally be substituted by dimethylamino, hydroxy, pyrrolidinyl, morpholinyl and ethyl- (2-hydroxy-ethyl) -amino, R2Is H.
In another embodiment, R2Is H, R1Is- (CH)2)t(4-10 membered heterocycle) wherein t is an integer of 0-5, said heterocycle optionally being fused to C6-C10Aryl radical, C5-C8On a saturated cyclic group or a 4-to 10-membered heterocyclic group, R1Radical (including the R1Any fused part of the radicals) may be substituted by 1 or 2 substituents independently selected from C1-C4Alkyl, hydroxy and hydroxymethyl.
In another embodiment, R2Is H, R14-to 10-membered heterocyclic moiety of radical (when R is1When the variable t of the group is 2 to 5) may be morpholinyl, pyrroleAlkyl, imidazolyl, piperazinyl, piperidinyl and 2, 5-diaza-bicyclo [2.2.1]Any one of hept-2-yl, R1Optionally substituted with hydroxy, hydroxymethyl and methyl.
One embodiment of the invention relates to the following methods and compounds: wherein R is3Is- (CH)2)t(C6-C10Aryl) group, wherein t is an integer of 1 to 3, R3Optionally substituted by 1-4R4And (4) substituting the group. In another embodiment, R3Is benzyl optionally substituted with 1-4 halo substituents.
In a preferred embodiment, the invention relates to the following methods and compounds: wherein R is2Is H, R1Is- (CH)2)4-1-pyrrolidine, R3Is 2, 6-difluoro-4-bromobenzyl, R8Is methyl. Preferably, in this embodiment, the compound of formula II is reacted with anhydrous ammonia in methanol at 50-70 deg.C, 10-40 psi. Still more preferably, in this embodiment, the compound of formula II is reacted with anhydrous ammonia in methanol and tetrahydrofuran at 30-50 deg.C, 45-80 psi.
Another embodiment of the present invention relates to those methods wherein the compound of formula I is selected from:
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- {3- [3- (4-methyl-piperazin-1-yl) propyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3-4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
hydrochloride salt of 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [ - (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3-hydroxy-5-piperidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (5-hydroxy-6-piperidin-1-yl) -hexyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 3, 6-trifluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (4-dimethylamino-butyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-dimethylamino-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-hydroxy-5-isopropylamino-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-isopropylamino-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [4- (4-methyl-piperazin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5[3- (4-imidazol-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-1-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-dimethylamino-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-dimethylamino-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-imidazol-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-difluoro-benzyloxy) -5- (3- {3- [ ethyl- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- (3- {3- [ ethyl- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- [3- (3-methylamino-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-amino-propyl) -3-methyl-ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (4-diethylamino-butyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (3-chloro-2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-dimethylamino-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- (3- {4- [ bis- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
and pharmaceutically acceptable salts, prodrugs, hydrates, and solvates of said compounds.
In a particularly preferred embodiment, the present invention relates to those processes wherein the compound of formula I is 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide and pharmaceutically acceptable salts, prodrugs, hydrates and solvates thereof.
The invention also relates to a process for preparing a compound of formula II or a pharmaceutically acceptable salt thereof;
wherein R is1、R2、R3、R4、R5、R6、R7And R8As defined above for formula I; the method comprises the following steps
(1) Reacting a compound of formula IV with a carbonyl source, with or without the addition of a base, and then adding a compound of formula III in a solvent to obtain a compound of formula II,
wherein R is3、R4、R5、R6、R7And R8As defined above for formula II,
HNR1R2 III
wherein R is1And R2As defined above for formula II; or
(2) Reacting a compound of formula III with a carbonyl source, with or without the addition of a base, and then adding a compound of formula IV in a solvent to obtain a compound of formula II.
The carbonyl source can be any suitable carbonyl source known to those skilled in the art. In one embodiment, the carbonyl source is represented by the formula
R’OCOX’
Wherein R' is C1-C4Alkyl or C6-C10Aryl and X' is a leaving group, for example chloro. Alternatively, non-limiting examples of suitable carbonyl sources include 1, 1' -carbonyldiimidazole, di-tert-butyl dicarbonate in the presence of 4-dimethylaminopyridine, and phosgene or its equivalents such as diphosgene or triphosgene.
The reaction may be carried out at a temperature of from about-78 ℃ to about 100 ℃, preferably from about 15 ℃ to about 25 ℃.
The reaction may use any suitable base known to those skilled in the art. Non-limiting examples of suitable bases include tertiary amines (e.g., triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine), alkali metal carbonates and alkali metal bicarbonates.
The reaction may take place in any suitable solvent known to those skilled in the art. Preferably, the reaction is carried out in the presence of the following solvents and mixtures thereof: halogenated hydrocarbon solvents such as dichloromethane or chloroform; ethers such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and 2-methyltetrahydrofuran; dipolar aprotic solvents, for example, dimethyl sulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone and dimethylacetamide.
In a preferred embodiment, the compound of formula IV is treated with triphosgene and triethylamine in dichloromethane at a temperature of about-78 ℃ to about 20 ℃ followed by addition of the compound of formula III, preferably wherein R is added1Is H and R2Is- (CH)2)4-1-pyrrolidinyl of a compound of formula III to obtain a compound of formula II.
In a more preferred embodiment, the present invention relates to those processes wherein the compound of formula II is 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester.
In a more preferred embodiment, the temperature is from about-10 ℃ to about 10 ℃ in tetrahydrofuranTreatment of furans with 1, 1' -carbonyldiimidazole wherein R1Is H and R2Is- (CH)2)4-1-pyrrolidinyl of a compound of formula III, the resulting product being added to a compound of formula IV in dimethyl sulfoxide and potassium carbonate at a temperature of about 15 ℃ to about 25 ℃ to give a compound of formula II, which is preferably 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido)]-isothiazole-4-carboxylic acid methyl ester.
Another embodiment of the present invention relates to those processes wherein the compound of formula II is selected from:
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
5- {3- [3- (4-methyl-piperazin-1-yl) propyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid methyl ester;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3-4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl-ureido) -isothiazole-4-carboxylic acid methyl ester;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (2-fluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
hydrochloride of 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [ - (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3-hydroxy-5-piperidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (5-hydroxy-6-piperidin-1-yl) -hexyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (4-bromo-2, 3, 6-trifluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
5- [3- (4-dimethylamino-butyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
5- [3- (3-dimethylamino-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
5- [3- (3-hydroxy-5-isopropylamino-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
5- [3- (3-isopropylamino-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
5- {3- [4- (4-methyl-piperazin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5[3- (4-imidazol-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-1-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid methyl ester;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-dimethylamino-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-dimethylamino-propyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (4-bromo-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-imidazol-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 3, 6-difluoro-benzyloxy) -5- (3- {3- [ ethyl- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- (3- {3- [ ethyl- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -isothiazole-4-carboxylic acid methyl ester;
5- [3- (3-methylamino-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
5- [3- (3-amino-propyl) -3-methyl-ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
5- [3- (4-diethylamino-butyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (3-chloro-2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-dimethylamino-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
5- (3- {4- [ bis- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid methyl ester;
and pharmaceutically acceptable salts thereof.
The invention also relates to a process for preparing a compound of formula IV or a pharmaceutically acceptable salt thereof
Wherein R is3、R4、R5、R6、R7And R8As defined above;
the process comprises reacting a compound of formula V with an ammonia source in a solvent to obtain a compound of formula IV,
wherein R is3、R4、R5、R6、R7And R8As defined above; r9Is C1-C10Alkyl radical, C6-C10Aryl, 4-10 membered heterocyclic ring, said aryl and heterocyclic ring R9Radicals optionally condensed to C6-C10On the aryl group; the above-mentioned aryl and heterocyclic ring R9Optionally independently substituted with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6Alkoxy radical, C1-C6Alkyl and nitro; n is 0, 1 or 2.
The reaction is preferably carried out at a temperature between about-50 ℃ and about 150 ℃ and a pressure between about atmospheric pressure and about 200psi, more preferably between about 20 ℃ and about 60 ℃ and about atmospheric pressure to about 50psi, and even more preferably between about 40 ℃ and about 50 ℃ and about 45 to about 55 psi. The source of ammonia is preferably anhydrous ammonia, but the source of ammonia is not critical to the invention. Other non-limiting sources of ammonia include ammonium hydroxide and liquid ammonia.
The reaction is preferably carried out in the presence of a solvent, such as water, C1-C4Alcohols (e.g., methanol, ethanol, propanol, and isopropanol), ethers (e.g., tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, dioxane, 2-methyltetrahydrofuran), dipolar aprotic solvents (e.g., dimethyl sulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone, and dimethylacetamide).
One embodiment of the invention relates to a method comprising: wherein the compound of formula V is reacted with a source of ammonia in a solvent to give a compound of formula IV, wherein R is3Is- (CH)2)t(C6-C10Aryl) group, wherein t is an integer of 1 to 3, R3Optionally substituted by 1-4R4And (4) substituting the group. In another embodiment R3And the group is benzyl optionally substituted with 1 to 4 halo substituents.
In a preferred embodiment, the present invention relates to the following methods and compounds: wherein the compound of formula V is reacted with a source of ammonia in a solvent to give a compound of formula IVA compound of formula (I) wherein R3Is 2, 6-difluoro-4-bromobenzyl, R8Is methyl, R9Is methyl and n is 2. Preferably, in this embodiment, the compound of formula V is reacted with anhydrous ammonia in methanol or dimethyl sulfoxide at 20-60 deg.C and at atmospheric pressure-50 psi. Still more preferably, in this embodiment, the compound of formula V is reacted with anhydrous ammonia in tetrahydrofuran at 40-50 deg.C and 45-55 psi.
In a particularly preferred embodiment, the present invention relates to those processes wherein the compound of formula IV is 5-amino-3- (4-bromo-2, 6-difluoro-benzyloxy) -isothiazole-4-carboxylic acid methyl ester.
The invention also relates to a process for preparing a compound of formula V or a pharmaceutically acceptable salt thereof,
wherein R is3、R4、R5、R6、R7、R8And R9As defined above; n is 0, 1 or 2;
the process comprises reacting a compound of formula VII with a compound of formula VI in a solvent to give a compound of formula V
Wherein n and R8And R9As defined above;
R3X VI
wherein R is3As defined above, X is halogen (e.g. chlorine, bromine or iodine), hydroxy, C1-C4Alkyl sulfonates, aryl sulfonates (e.g. tosylate, nitrobenzenesulfonate, benzenesulfonate)Bromobenzenesulfonate), or imidates (e.g., trichloromethyl imidate);
the reaction is carried out in acid, alkali or Mitsunobu reagent R'3P and R "oc (o) N ═ nc (o) OR", wherein each R' and R "is independently C1-C4Alkyl or C6-C10Aryl, and wherein said R 'and R' alkyl and aryl groups are optionally substituted with 1-3R10Substituted by radicals;
R10is C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, nitro, trifluoromethyl, trifluoromethoxy, -OR5、-NR6C(O)OR5、-NR6SO2R5、-SO2NR5R6、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-S(O)jR7(where j is an integer of 0to 2), -NR5(CR6R7)tOR6、-(CH2)t(C6-C10Aryl), -SO2(CH2)t(C6-C10Aryl), -S (CH)2)t(C6-C10Aryl), -O (CH)2)t(C6-C10Aryl), - (CH)2)t(4-10 membered heterocycle) and- (CR6R7)mOR6Wherein m is an integer of 1 to 5, and t is an integer of 0to 5; said C is1-C10Alkyl optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; the- (CH)2)t(C6-C10Aryl), -SO2(CH2)t(C6-C10Aryl), -S (CH)2)t(C6-C10Aryl), -O (CH)2)t(C6-C10Aryl) and- (CH)2)t(4-10 membered heterocyclic) group optionally fused to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; 1 or 2 carbon atoms in the above heterocyclic moiety are optionally substituted with an oxo group (═ O); r is as defined above10The alkyl, aryl and heterocyclic moieties of the group are optionally substituted with 1-3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, -NR6SO2R5、-SO2NR5R6、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-(CR6R7)mOR6(where m is an integer of 1 to 5), OR5And in R5Wherein R is a substituent listed in the definition of (1)5、R6And R7As defined above, provided that R5、R6And R7And cannot be H. When X is halogen or sulfonate, a base is generally used. Non-limiting examples of suitable bases include alkali metal carbonates, alkali metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydroxides, alkali metal C1-C4Alkoxides, alkali metal hydrides and tertiary amines, e.g. triethylamine, diisopropylethylamine, 1, 8-diazabicyclo- [5.4.0]Undec-7-ene ("DBU") and 1, 5-diazabicyclo- [4.3.0]Non-5-ene ("DBN"). When X is an imidate, an acid is generally used. Non-limiting examples of acids include mineral acids such as hydrochloric acid and sulfuric acid; bronsted acids such as trifluoromethanesulfonic acid; or Lewis acids, e.g. trimethylsilyl trifluoromethanesulfonate, transition metal chlorides (e.g. SnCl)4、TiCl4)、BF3Etherates and triflates of the lanthanide series (e.g. Sc (OTf)3And Ln (OTf)3). When X is hydroxyl, it is preferred to use Mitsunobu reagent R'3P and R "OC (O) OR". In preferred reagents, R' is C1-C4Alkyl or C1-C4Aryl radical, R' is C1-C4Alkyl or C1-C4And (4) an aryl group. In a more preferred reagent, R' is phenyl and R "is ethyl or isopropyl.
The reaction may be carried out at a temperature of from about-20 ℃ to about 100 ℃, preferably from about 15 ℃ to about 35 ℃.
The reaction may also be carried out in the presence of a solvent. Preferably, when X is halogen, sulfonate or hydroxyl, the solvent is a halogenated hydrocarbon solvent, such as dichloromethane or chloroform; ethers such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether or 2-methyltetrahydrofuran; or dipolar aprotic solvents such as dimethyl sulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone and dimethylacetamide. Preferably, when X is an imidate, the solvent is a polar solvent, for example nitromethane, acetonitrile or 2, 2, 2-trifluoromethanol or a halogenated hydrocarbon solvent such as dichloromethane or chloroform.
A preferred embodiment of the invention relates to the following method: wherein a compound of formula VII is reacted with a compound of formula VI (wherein X is an aryl sulfonate) in the presence of an alkali metal carbonate base in a dipolar aprotic solvent to give a compound of formula V. It is particularly preferred when R3Is 2, 6-difluoro-4-bromobenzyl, X is p-toluenesulfonate, R8Is methyl, R9When the number is methyl and n is 2, the alkali metal carbonate base is potassium carbonate, and the solvent is dimethyl sulfoxide. This preferred process can be carried out at a temperature of from about 15 ℃ to about 35 ℃.
In a particularly preferred embodiment, the present invention relates to those processes wherein the compound of formula V is 3- (4-bromo-2, 6-difluoro-benzyloxy) -5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester.
The invention also relates to compounds of formula IIa, IVa or Va, which are useful for preparing isothiazole derivatives of formula I, which are useful for binding or modulating the KDR/FLK-1 receptor.
The present invention relates to compounds of formula IIa or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R1is H, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, -C (O) (C)1-C10Alkyl), - (CH)2)t(C6-C10Aryl), - (CH)2)t(4-10 membered heterocycle), -C (O) (CH)2)t(C6-C10Aryl) or-C (O) (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0-5; the alkyl group optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R1Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; 1 or 2 carbon atoms in the above heterocyclic moiety are optionally substituted with an oxo group (═ O); r is as defined above1The radicals (other than H) being optionally substituted by 1-3R4Substituted by radicals;
R2is selected from among R1The substituents, -SO2(CH2)t(C6-C10Aryl), -SO2(CH2)t(4-to 10-membered heterocycle) and OR5T is an integer of 0to 5, and the above R2Optionally substituted by 1-3R4Substituted by radicals;
or, R1And R2May be taken together with the nitrogen to which they are attached to form a 4-10 membered saturated monocyclic or polycyclic or 5-10 membered heteroaromatic ring, wherein the saturated ring and heteroaromatic ring are other than R1And R2Optionally containing, in addition to the nitrogen attached, 1 or 2 substituents selected from the group consisting of O, S and-N (R)6) -a heteroatom moiety of said-N (R)6) -optionally is ═ N-or-N ═ with R1And R2Taken together as the heteroaryl group, the saturated ring, optionally partially unsaturated by introduction of a 1 or 2 carbon-carbon double bond, is partially unsaturated with a heteroaromatic ring (including the-N (R)6) R of (A-C)6Base) is optionally substituted by 1-3R4Substituted by radicals;
R3is H, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, - (CH)2)t(C6-C10Aryl) or- (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0-5; the alkyl group optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R3Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; 1 or 2 carbon atoms in the above heterocyclic moiety are optionally substituted with an oxo group (═ O); r is as defined above3Of radical- (CH)2)t-the moiety optionally comprises a carbon-carbon double or triple bond, wherein t is an integer from 2 to 5, and R as defined above3Optionally substituted by 1-5R4Substituted by radicals;
each R4Independently selected from halogen, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR5、-NR6C(O)OR5、-NR6SO2R5、-SO2NR5R6、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-S(O)jR7(where j is an integer of 0to 2), -NR5(CR6R7)tOR6、-(CH2)t(C6-C10Aryl), -SO2(CH2)t(C6-C10Aryl), -S (CH)2)t(C6-C10Aryl), -O (CH)2)t(C6-C10Aryl), - (CH)2)t(4-10 membered heterocycle) and- (CR6R7)mOR6Wherein m is an integer of 1 to 5, and t is an integer of 0to 5; the alkyl group may beOptionally containing 1 or 2 groups selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R4Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; 1 or 2 carbon atoms in the above heterocyclic moiety are optionally substituted with an oxo group (═ O); r is as defined above4The alkyl, aryl and heterocyclic moieties of the group are optionally substituted with 1-3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6SO2R5、-SO2NR5R6、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-(CR6R7)mOR6(where m is an integer of 1 to 5), OR5And in R3The substituents listed in the definition of (1);
each R5Independently selected from H, C1-C10Alkyl, - (CH)2)t(C6-C10Aryl) and- (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0-5; the alkyl group optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R5Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; r is as defined above5The group (other than H) is optionally substituted with 1-3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6C(O)R7、-C(O)NR6R7、-NR6R7Hydroxy, C1-C6Alkyl and C1-C6An alkoxy group;
each R6And R7Independently is H or C1-C6An alkyl group;
R8is H, C1-C10Alkyl, -C (O) (C)1-C10Alkyl), -C (O) (C)6-C10Aryl), -C (O) (4-10 membered heterocycle), -CH2)t(C6-C10Aryl), - (CH)2)t(4-10 membered heterocycle), -C (O) O (C)1-C10Alkyl), -C (O) O (C)6-C10Aryl), -C (O) O (4-10 membered heterocycle), where t is an integer from 0to 5; said aryl and heterocyclic ring R8Radicals optionally condensed to C6-C10On the aryl group; the above-mentioned aryl and heterocyclic ring R8Optionally substituted with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6Alkoxy radical, C1-C6Alkyl and nitro, with the proviso that when R1Is H while R is2Is pyrrolidin-1-ylbutyl and at the same time R3Is C1-C3When alkyl, R8Is not ethyl.
One embodiment of the present invention relates to compounds of formula IIa, wherein R is2Is H, R1Is C optionally substituted by 1 or 2 substituents1-C10Alkyl, said substituents being independently selected from-NR5R6、-NR5(CR6R7)tOR6And- (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0to 5. In another embodiment, R1Selected from propyl, butyl, pentyl and hexyl, and may optionally be substituted by dimethylamino, hydroxy, pyrrolidinyl, morpholinyl and ethyl- (2-hydroxy-ethyl) -amino, R2Is H.
In another embodiment, the invention relates to a compound of formula IIa wherein R is2Is H, R1Is- (CH)2)t(4-10 membered heterocycle) wherein t is an integer of 0-5, said heterocycle optionally being fused to C6-C10Aryl radical, C5-C8On a saturated cyclic group or a 4-to 10-membered heterocyclic group, R1Radical (including the R1Any fused part of the radicals) may be substituted by 1 or 2 substituents independently selected from C1-C4Alkyl, hydroxy and hydroxymethyl. In this embodiment, preferably, R1The 4-to 10-membered heterocyclic moiety of (A) is selected from morpholinyl, pyrrolidinyl, imidazolyl, piperazinyl, piperidinyl and 2, 5-diaza-bicyclo [2.2.1]]One of the hept-2-yl radicals, R1Optionally substituted by hydroxy, hydroxymethyl and methyl, R1The variable t of the base is 2 to 5.
One embodiment of the present invention relates to compounds of formula IIa, wherein R is3Is- (CH)2)t(C6-C10Aryl) group, wherein t is an integer of 1 to 3, R3Optionally substituted by 1-4R4And (4) substituting the group. In this embodiment, preferably, R3Is benzyl optionally substituted with 1-4 halo substituents.
In a preferred embodiment, the invention relates to compounds of the formula IIa, in which R is2Is H, R1Is- (CH)2)4-1-pyrrolidine, R3Is 2, 6-difluoro-4-bromobenzyl, R8Is methyl.
Another embodiment of the invention relates to a compound of formula IVa or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R3is H, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, - (CH)2)t(C6-C10Aryl) or- (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0-5; the alkyl group optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R3Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; 1 or 2 carbon atoms in the above heterocyclic moiety are optionally substituted with an oxo group (═ O); r is as defined above3Of radical- (CH)2)t-the moiety optionally comprises a carbon-carbon double or triple bond, wherein t is an integer from 2 to 5, and R as defined above3Optionally substituted by 1-5R4Substituted by radicals;
each R4Independently selected from halogen, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR5、-NR6C(O)OR5、-NR6SO2R5、-SO2NR5R6、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-S(O)jR7(where j is an integer of 0to 2), -NR5(CR6R7)tOR6、-(CH2)t(C6-C10Aryl), -SO2(CH2)t(C6-C10Aryl), -S (CH)2)t(C6-C10Aryl), -O (CH)2)t(C6-C10Aryl), - (CH)2)t(4-10 membered heterocycle) and- (CR6R7)mOR6Wherein m is an integer of 1 to 5, and t is an integer of 0to 5; the alkyl group optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R4Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; 1 or 2 carbon atoms in the above heterocyclic moiety are optionally substituted with an oxo group (═ O); r is as defined above4The alkyl, aryl and heterocyclic moieties of the group are optionally substituted with 1-3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6SO2R5、-SO2NR5R6、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-(CR6R7)mOR6(where m is an integer of 1 to 5), OR5And in R5The substituents listed in the definition of (1);
each R5Independently selected from H, C1-C10Alkyl, - (CH)2)t(C6-C10Aryl) and- (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0-5; the alkyl group optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R5Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; r is as defined above5The group (other than H) is optionally substituted with 1-3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6C(O)R7、-C(O)NR6R7、-NR6R7Hydroxy, C1-C6Alkyl and C1-C6An alkoxy group;
each R6And R7Independently is H or C1-C6An alkyl group;
R8is H, C1-C10Alkyl, -C (O) (C)1-C10Alkyl), -C (O) (C)6-C10Aryl), -C (O) (4-10 membered heterocycle), -CH2)t(C6-C10Aryl), - (CH)2)t(4-10 membered heterocycle), -C (O) O (C)1-C10Alkyl), -C (O) O (C)6-C10Aryl), -C (O) O (4-10 membered heterocycle), where t is an integer from 0to 5; said aryl and heterocyclic ring R8Radicals optionally condensed to C6-C10On the aryl group; the above-mentioned aryl and heterocyclic ring R8Optionally substituted with 1-2 substituents, saidThe substituents are independently selected from halogen, trifluoromethyl, C1-C6Alkoxy radical, C1-C6Alkyl and nitro, with the proviso that when R3Is C1-C3When alkyl, R8Is not ethyl.
In a preferred compound of formula IVa, R3Is- (CH)2)t(C6-C10Aryl) group, wherein t is an integer of 1 to 3, R3Optionally substituted by 1-4R4Is substituted, more preferably R3Is benzyl optionally substituted with 1-4 halo substituents.
In a preferred embodiment, the invention relates to compounds of formula IVa, wherein R3Is 2, 6-difluoro-4-bromobenzyl, R8Is methyl.
Another embodiment of the invention is directed to a compound of formula Va or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R3is H, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, - (CH)2)t(C6-C10Aryl) or- (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0-5; the alkyl group optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R3Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; 1 or 2 carbon atoms in the above heterocyclic moiety are optionally substituted with an oxo group (═ O); r is as defined above3Of radical- (CH)2)t-part optionally comprising carbon-a carbon double or triple bond, wherein t is an integer from 2 to 5, R as defined above3Optionally substituted by 1-5R4Substituted by radicals;
each R4Independently selected from halogen, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR5、-NR6C(O)OR5、-NR6SO2R5、-SO2NR5R6、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-S(O)jR7(where j is an integer of 0to 2), -NR5(CR6R7)tOR6、-(CH2)t(C6-C10Aryl), -SO2(CH2)t(C6-C10Aryl), -S (CH)2)t(C6-C10Aryl), -O (CH)2)t(C6-C10Aryl), - (CH)2)t(4-10 membered heterocycle) and- (CR6R7)mOR6Wherein m is an integer of 1 to 5, and t is an integer of 0to 5; the alkyl group optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R4Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; 1 or 2 carbon atoms in the above heterocyclic moiety are optionally substituted with an oxo group (═ O); r is as defined above4The alkyl, aryl and heterocyclic moieties of the group are optionally substituted with 1-3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6SO2R5、-SO2NR5R6、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-(CR6R7)mOR6(wherein m is an integer of 1 to 5),OR5And in R5The substituents listed in the definition of (1);
each R5Independently selected from H, C1-C10Alkyl, - (CH)2)t(C6-C10Aryl) and- (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0-5; the alkyl group optionally contains 1 or 2 substituents selected from O, S and-N (R)6) -with the proviso that two O atoms, two S atoms, or an O atom and an S atom are not directly attached to each other; said aryl and heterocyclic ring R5Radicals optionally condensed to C6-C10Aryl radical, C5-C8Saturated cyclic groups or 4-to 10-membered heterocyclic groups; r is as defined above5The group (other than H) is optionally substituted with 1-3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6C(O)R7、-C(O)NR6R7、-NR6R7Hydroxy, C1-C6Alkyl and C1-C6An alkoxy group;
each R6And R7Independently is H or C1-C6An alkyl group;
R8is H, C1-C10Alkyl, -C (O) (C)1-C10Alkyl), -C (O) (C)6-C10Aryl), -C (O) (4-10 membered heterocycle), -CH2)t(C6-C10Aryl), - (CH)2)t(4-10 membered heterocycle), -C (O) O (C)1-C10Alkyl), -C (O) O (C)6-C10Aryl), -C (O) O (4-10 membered heterocycle), where t is an integer from 0to 5; said aryl and heterocyclic ring R8Radicals optionally condensed to C6-C10On the aryl group; the above-mentioned aryl and heterocyclic ring R8Optionally substituted with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6Alkoxy radical, C1-C6Alkyl and nitro;
R9is C1-C10Alkyl radical, C6-C10Aryl, 4-10 membered heterocyclic ring, said aryl and heterocyclic ring R9Radicals optionally condensed to C6-C10On the aryl group; the above-mentioned aryl and heterocyclic ring R9Optionally independently substituted with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6Alkoxy radical, C1-C6Alkyl and nitro;
n is 1 or 2.
In a preferred compound of formula Va, R3Is- (CH)2)t(C6-C10Aryl) group, wherein t is an integer of 1 to 3, R3Optionally substituted by 1-4R4Is substituted, more preferably R3Is benzyl optionally substituted with 1-4 halo substituents, more preferably, R8And R9Is methyl.
In a more preferred embodiment, the invention relates to a compound of formula Va, wherein n is 2 and R is3Is 2, 6-difluoro-4-bromobenzyl, R8Is methyl, R9Is methyl.
In one embodiment, the compound of formula I as defined above is prepared by reacting a compound of formula IIa with a source of ammonia in a solvent.
In another embodiment, the compound of formula II as defined above is prepared by: reacting a compound of formula IVa with a carbonyl source in a solvent, with or without the addition of a base, followed by the addition of a compound of formula III as defined above; alternatively, the compound of formula III is reacted with a carbonyl source in a solvent with or without the addition of a base, followed by the addition of the compound of formula IV to provide the compound of formula II.
In another embodiment, the compound of formula IV as defined above is prepared by reacting a compound of formula Va with a source of ammonia in a solvent.
In the present invention, the term "halogen" includes fluorine, chlorine, bromine or iodine unless otherwise specified. Preferred halogen substituents are fluorine, chlorine and bromine.
The term "alkyl" as used herein, unless otherwise specified, includes saturated monovalent hydrocarbon radicals having straight, cyclic, or branched moieties. It is understood that in the alkyl group, at least three carbon atoms are required for the cyclic moiety.
The term "alkenyl", as used herein, unless otherwise indicated, includes monovalent hydrocarbon radicals having at least one carbon-carbon double bond and also having straight, cyclic, or branched moieties as defined in the definition of "alkyl" above.
The term "alkynyl", as used herein, unless otherwise specified, includes monovalent hydrocarbon radicals having at least one carbon-carbon triple bond and also having straight, cyclic or branched moieties as defined in the definition of "alkyl" above.
The term "alkoxy" as used herein, unless otherwise indicated, includes O-alkyl, wherein "alkyl" is as defined above.
The term "aryl" as used herein, unless otherwise indicated, includes organic groups derived from aromatic hydrocarbons by the loss of one hydrogen atom, such as phenyl or naphthyl.
As used herein, unless otherwise indicated, the term "heteroaryl" includes organic groups derived from a heteroaromatic ring wherein one or more heteroatoms independently selected from O, S and N are absent from a carbon atom. Heteroaryl must have at least 5 atoms in its ring system and is independently substituted by 0-2 halogen atoms, trifluoromethyl, C1-C6Alkoxy radical, C1-C6Alkyl and nitro are optionally substituted.
As used herein, unless otherwise indicated, the term "4-10 membered heterocyclic" includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms selected from O, S and N, wherein each heterocyclic group has 4-10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. One example of a 4-membered heterocyclic groupAn example is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl (thioxanyl), piperazinyl, azetidinyl, oxetanyl (oxolanyl), thietanyl, homopiperidinyl, oxepanyl (oxolanyl), thietanyl (thietanyl), oxazepinyl (oxazepinyl), diazepinyl (diazepinyl), thiazepinyl (thiazepinyl), 1, 2, 3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl (dioxanyl), 1, 3-dioxolanyl, pyrazolinyl, dithianyl (dithianyl), dithiolan (dithiolan), dihydropyranyl, dihydrothienyl, Dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-diazabicyclo [3.1.0 ]]Hexyl, 3-diazabicyclo [4.1.0]A heptyl radical,3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl (furyl), thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuryl, o-naphthyridinyl (cinnolinyl), indazolyl, indolizinyl (indolizinyl), phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl (pteridinyl), purinyl (purinyl), oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furylpyridinyl. The aforementioned groups derived from the compounds listed above may be C-linked or N-linked (if possible). For example, a group derived from pyrrole may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked).
As used herein, unless otherwise indicated, the term "saturated cyclic group" includes non-aryl, fully saturated cyclic moieties in which alkyl is as defined above.
The term "pharmaceutically acceptable salt" as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of the present invention. The essentially basic compounds of the present invention are capable of forming a wide variety of salts with a variety of inorganic and organic acids. The acids which can be used for the preparation of pharmaceutically acceptable addition salts of the basic compounds of the invention are acids which form non-toxic acid addition salts, i.e. salts comprising a pharmacologically acceptable anion, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucarate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate)).
The acidic in nature compounds of the present invention are capable of forming basic salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, particularly sodium and potassium salts.
The term "solvate" as used herein includes a compound of the invention or a salt thereof, and also includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for topical administration to humans.
The term "hydrate" as used herein refers to a compound of the present invention or a salt thereof, and also includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
Certain compounds of the invention may have asymmetric centers and thus exhibit different enantiomeric forms. The present invention relates to the use of all optical isomers and stereoisomers of the compounds of the invention and mixtures thereof. The compounds of the invention may also be presented as tautomers. The present invention relates to the use of all such tautomers and mixtures thereof.
The invention also includes isotopically-labeled compounds, and pharmaceutically acceptable salts thereof, which are identical to those recited in formulas I, II, IIa, IV, IVa, V, and Va except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, for example2H、3H、13C、14C、15N、18O、17O、35S、18F and36and (4) Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example, in which a radioactive isotope is incorporated (e.g., by3H、13C) Are suitable for use in drug and/or stromal tissue distribution studies. Tritium (i.e. tritium3H) And carbon-14 (i.e.14C) Isotopes are particularly preferred because they are easy to prepare and detect. Also, with heavier isotopes (e.g. deuterium, i.e. of2H) Substitution may provide particular therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Isotopically labeled compounds of formula I of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples below, substituting a readily available isotopically labeled reagent for an non-isotopically labeled reagent.
Compounds of formula I having a free amino, amido, hydroxy or carboxy group can be converted into prodrugs. Prodrugs include compounds that: wherein an amino acid residue or a polypeptide chain of two or more (e.g. two, three or four) amino acid residues is covalently bonded via an amide or ester bond to a free amino, hydroxyl or carboxylic acid group of the compound of formula I. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids typically represented by three letters, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline (norvalin), β -alanine, γ -aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
The invention also includes other types of prodrugs. For example, the free carboxyl groups may be derivatized as amides or alkyl esters. Groups to which the amide and ester moieties may be bonded include, but are not limited to, ether, amine, and carboxylic acid functional groups. Groups from which the free hydroxyl group can be derived include, but are not limited to, hemisuccinate, phosphate, dimethylaminoacetate and hydroxymethyloxycarbonyl phosphate, as described in d.fleisher, r.bong, b.h.stewart, Advanced Drug Delivery Reviews (1996)19, 115. Also included are carbamate prodrugs of hydroxy and amino groups, as well as carbonate prodrugs and sulfates of hydroxy groups. The present invention also includes derivatizing the hydroxyl groups as (acyloxy) methyl and (acyloxy) ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or wherein the acyl group is an amino acid ester as described above. Prodrugs of this type are described in r.p. robinson et al, j.medicinal chemistry (1996)39, 10.
The patents, patent applications, published international applications and scientific publications referred to in this patent application are incorporated herein by reference in their entirety.
Detailed Description
The compounds of formula I are useful as agents that bind to or modulate the KDR/FLK-1 receptor and are therefore useful in the treatment of hyperproliferative disorders, such as cancer, in mammals.
A first aspect of the process of the present invention relates to the preparation of isothiazole derivatives of formula I. The compounds of formula I may be prepared according to the following reaction schemes and discussions. Unless otherwise stated, the followingR in the reaction schemes and related discussion1、R2、R3、R4、R5、R6、R7、R8、R9And R10As defined above.
Scheme 1
Referring to scheme 1 above, compounds of formula I can be prepared as follows: malonic acid diester (XIII) is treated with a base and carbon disulfide (reaction a) and then with an alkylating agent to provide an (alkyl) sulfanyl-vinyl thiol anion (XI) (reaction b). Amination of the (alkyl) sulfanyl-vinylthiol anion by an electrophilic aminating agent gives 5- (alkyl) sulfanyl isothiazole (VIII) (reaction c). Oxidation of isothiazole (VIII) with an oxidizing agent in a suitable solvent to give 5- (alkyl) sulfonyl isothiazole when n ═ 2; when n is 1, 5- (alkyl) sulfinyl isothiazole (VII) is obtained (reaction d). Alternatively, isothiazole (VIII) may be protected with a suitable Protecting Group (PG) to give a compound of formula X (reaction e), which is then treated with an oxidizing agent in a suitable solvent to prepare a compound of formula IX (reaction f). The compound of formula IX is then deprotected to give 5- (alkyl) sulfonylisothiazole or 5- (alkyl) sulfinylisothiazole (VII). This mechanism is illustrated in scheme 2 below.
Scheme 2
Referring to scheme 1, 5- (alkyl) sulfonyl/sulfinyl isothiazole (VII) is treated with a compound of formula R, typically under basic conditions3Treatment of compounds of X (VI)To obtain isothiazole (V) having an alkoxy functional group at position 3 of the isothiazole (reaction h). Surprisingly, this reaction is particularly advantageous when compound VI is a tosylate and the reaction conditions include the presence of a base in a dipolar aprotic solvent. The reaction under these conditions proceeds with very high O: N selectivity when alkylation occurs on the hydroxyl group rather than on the nitrogen atom of the isothiazole ring. Under appropriate conditions, the O: N selectivity approaches 35: 1.
The alkylation of various substituted 3-hydroxyisothiazoles has been reported in the literature. Wherein various electrophiles (alkyl halides, alkyl sulfates, diazomethane), solvents (water, acetone, DMSO, DMF, MeCN, DME) and bases (NaOH, K) are used2CO3、Li2CO3、Ag2CO3) However, mixtures of O-and N-alkylated products were all observed. For example, Tetrahedron, 1970: (26) an exhaustive study of 3-hydroxyisothiazole alkylation was reported in 2497-2506:
| RX | M | DMSO(O∶N) | DMF(O∶N) | MeCN(O∶N) | DME(O∶N) |
| Mel | K | 46∶54 | 41∶59 | 40∶60 | 20∶80 |
| Ag | 68∶32 | ||||
| Li | 34∶66 | 17∶83 | |||
| Etl | K | 25∶25 | 77∶23 | 70∶30 | 50∶50 |
| RX | M | DMSO(O∶N) | DMF(O∶N) | MeCN(O∶N) | DME(O∶N) |
| Li | 55∶45 | ||||
| PrBr | K | 78∶22 | 80∶20 | 80∶20 | |
| iPrBr | K | 88∶12 | 86∶14 | ||
| BnCl | K | 68∶32 | 59∶41 | 45∶55 | 34∶66 |
other references which describe the reaction of 3-hydroxyisothiazolidinylation with lower selectivity to O: N include:
the alkylation step (reaction h) in the process of the present invention is carried out with a very high O: N selectivity, i.e., an O: N selectivity of about 35: 1 for the conditions described in the experimental procedure of example 7 discussed below, which is much higher than the selectivity ratios disclosed in the references cited herein.
Referring to scheme 1, the alkylated isothiazole (V) is treated with a source of ammonia in a suitable solvent to convert the sulfonyl/sulfinyl group at position (5) of the isothiazole to the primary amine (IV) (reaction I). The compound of formula IV can be combined with a secondary amine and a carbonyl source in a suitable solvent, with or without the addition of a base, to replace the primary amine with a ureido group at the 5-position (5) of the isothiazole to provide the compound of formula II. A second treatment with an ammonia source converts the alkyl ester to an amide to provide the compound of formula I.
The starting materials used in scheme 1 are readily commercially available or may be conveniently prepared using methods well known in the art.
In each reaction discussed or illustrated in these schemes, the pressure is not critical unless otherwise indicated. Pressures of about 0.5 to about 5 atmospheres are generally acceptable, and for convenience, ambient pressure, i.e., about 1 atmosphere, is preferred.
The following examples and methods of preparation further illustrate and exemplify the compounds of the present invention, methods of preparing such compounds, and methods of the present invention. It should be understood that the scope of the present invention is not limited in any way by the following examples and preparation methods. In the examples below, molecules with a single chiral center exist as a racemic mixture, unless otherwise indicated. Unless otherwise indicated, molecules having two or more chiral centers exist as racemic mixtures of diastereomers. The single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
The invention is illustrated by the following examples. It should be understood, however, that the invention is not limited to the specific details of these examples.
Example 1
Preparation of 2, 2-bis-methoxycarbonyl-1-methylthio-vinylthiol anion
Acetonitrile (240mL, 6 volumes) was added to the reaction vessel followed by 1, 8-diazabicyclo- [5.4.0] undec-7-ene (2.1 equivalents, 96.8 g). The mixture was cooled to 5 ℃ under nitrogen atmosphere. Dimethyl malonate (1.0 eq, 40.0g) was added over 10-15 minutes. The mixture was held at 5 ℃ for 30-45 minutes. Carbon disulfide (1.0 eq, 23.1g) was added over 10-15 minutes, and the mixture was then held at 5 ℃ for 60-70 minutes. Dimethyl sulfate (1.05 eq, 40.1g) was added over 10-15 minutes, and the mixture was then held at 5 ℃ for 16 hours. The mixture containing the 2, 2-bis-methoxycarbonyl-1-methylthio-vinylthiol anion is finally heated to 25 ℃ over 30 minutes and held at 25 ℃ for 1-2 hours.
Example 2
Preparation of 3-hydroxy-5-methylsulfanyl-isothiazole-4-carboxylic acid methyl ester
In another reaction vessel were added water (280mL, 7 volumes) and sodium bicarbonate (1.5 eq, 38.2 g). The water/sodium bicarbonate mixture was cooled to 5 ℃ under nitrogen atmosphere. hydroxylamine-O-sulfonic acid (1.2 eq, 41.1g) was added over 5 minutes and the mixture was stirred for 15-30 minutes. The 2, 2-bis-methoxycarbonyl-1-methylthio-vinylthiol anion/acetonitrile solution obtained in example 1 was added over 60 to 70 minutes. The mixture was heated to 25 ℃ over 1 hour and then held at 25 ℃ for 16 hours. Most of the acetonitrile was removed by vacuum distillation (130Torr, 50 ℃). The residue was cooled to room temperature and acidified to a pH of about 1 by addition of 37% hydrochloric acid (32 mL). The solid was granulated for 16 hours at 25 ℃. The slurry was filtered and the filter cake was washed with water (3X 100mL), once with 200mL of 1: 3 ethyl acetate to hexane (v/v) and once with 100mL of 1: 3 ethyl acetate to hexane (v/v). The wet cake (50.5g) was dried in a vacuum oven for 16 hours to give 45.4g (yield 73%) of methyl 3-hydroxy-5-methylsulfanyl-isothiazole-4-carboxylate.1H NMR：(DMSO-d6)：δ11.92(s，1H)；3.74(s，3H)；2.53(s，3H).MS：(API-ES pos)206(M+H)+Reference.
Example 3
Preparation of 3-methoxycarbonyloxy-5-methylthio-isothiazole-4-carboxylic acid methyl ester
To the flask was added 3-hydroxy-5-methylsulfanyl-isothiazole-4-carboxylic acid methyl ester (1.00 eq, 10.0g) and dichloromethane (100mL, 10 vol) and held at 25 ℃ under nitrogen. Triethylamine (1.0 eq, 6.7mL, 4.88g) was added. An orange solution formed which was cooled to 0 ℃. Methyl chloroformate (1.0 eq, 3.74mL, 4.56g) was added over 3 minutes. The mixture was stirred at 25 ℃ for 2h, then washed with water (50mL, 5 volumes) followed by brine (50mL, 5 volumes). The solvent was replaced with acetonitrile (100mL, 10 volumes) to give a brown slurry containing 3-methoxycarbonyloxy-5-methylthio-isothiazole-4-carboxylic acid methyl ester.
Example 4
Preparation of 5-methanesulfonyl-3-methoxycarbonyloxy-isothiazole-4-carboxylic acid methyl ester
The slurry of methyl 3-methoxycarbonyloxy-5-methylthio-isothiazole-4-carboxylate was cooled to 0 ℃ and urea hydrogen peroxide addition compound (2.8 eq, 12.8g) was added. Trifluoroacetic anhydride (2.8 eq, 19.2mL, 28.4g) was added dropwise over 20 minutes. The mixture was stirred at 0 ℃ for 45 minutes, quenched with a solution of sodium bisulfite (2.0 equiv., 10.0g) in water (90mL, 9 volumes), and stirred at 25 ℃. Most of the acetonitrile was removed under vacuum and the aqueous residue was extracted once with 100mL of dichloromethane and once with 50mL of dichloromethane to give methyl 5-methanesulfonyl-3-methoxycarbonyloxy-isothiazole-4-carboxylate.
Example 5
Preparation of 3-hydroxy-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester
The 5-methanesulfonyl-3-methoxycarbonyloxy-isothiazole-4-carboxylic acid methyl ester/dichloromethane extracts were combined and then replaced with methanol (150mL, 15 volumes). A solution of 98% sulfuric acid (50mL, 5 vol) in water (100mL, 10 vol) was added, and the mixture was then heated at 65 ℃ for 6 hours. The foam slurry changed over time to a clear solution containing a small amount of insoluble white solids. The mixture was cooled to 25 ℃ and stirred for 16 hours. Most of the methanol was removed under vacuum. The aqueous residue was extracted once with 100mL of dichloromethane and then twice with 50mL of dichloromethane. The combined dichloromethane extracts were dried over anhydrous magnesium sulfate and then filtered. The dichloromethane was replaced with hexane (100mL, 10 volumes) and then stirred at 25 ℃ until a solid formed. The solid was filtered, and the filter cake was washed with hexane and then dried to obtain 9.27g of methyl 3-hydroxy-5-methanesulfonyl-isothiazole-4-carboxylate (yield 80%).1H NMR：(DMSO-d6)：δ13.07(s，1H)；3.83(s，3H)；3.55(s，3H).MS：(API-ES pos)：238(M+H)+，206(M-MeO)+Reference.
Example 6
Preparation of toluene-4-sulfonic acid 4-bromo-2, 6-difluoro-benzyl ester
In a flask under nitrogen, (4-bromo-2, 6-difluoro-phenyl) -methanol (1.10 equivalents, 19.1g) was added to dichloromethane (185mL, 10 volumes), followed by p-toluenesulfonic anhydride (1.1 equivalents, 28.9 g). The mixture was cooled to 0 ℃ and triethylamine (1.2 eq, 13.0mL, 9.47g) was then added dropwise over 20 minutes. The mixture was heated to 25 ℃ and stirred for 1 hour. The mixture was then washed once with 185mL of 1N hydrochloric acid and once with 92.5mL of 1N hydrochloric acid. The organic layer containing toluene-4-sulfonic acid 4-bromo-2, 6-difluoro-benzyl ester was concentrated to about 55-60 mL.
Example 7
Preparation of 3- (4-bromo-2, 6-difluoro-benzyloxy) -5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester
In another vessel, to dimethyl sulfoxide (185mL, 10 volumes) was added methyl 3-hydroxy-5-methanesulfonyl-isothiazole-4-carboxylate (1.00 eq, 18.5g) followed by potassium carbonate (1.0 eq, 10.8 g). The toluene-4-sulfonic acid 4-bromo-2, 6-difluoro-benzyl ester/dichloromethane solution obtained in example 6 was added dropwise over 1 hour to a 3-hydroxy-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester/potassium carbonate/dimethyl sulfoxide slurry. The mixture was stirred at 25 ℃ for 16.5 hours. Dichloromethane (185mL, 10 volumes) and water (185mL, 10 volumes) were then added and the layers were separated. The organic layer was dried over magnesium sulfate and then filtered. The dichloromethane was removed under vacuum leaving an orange paste. The orange paste was diluted with 10 volumes of 1: 1 EtOAc: hexane (v/v) and then slurried at 25 ℃ for 16 hours. The mixture was filtered and the filter cake was washed with 50-60mL of 1: 1 EtOAc: hexane (v/v) and then dried to give 24.22g of methyl 3- (4-bromo-2, 6-difluoro-benzyloxy) -5-methanesulfonyl-isothiazole-4-carboxylate (yield 70%).1H NMR：(DMSO-d6)：δ7.57(m，2H)；5.46(s，2H)；3.80(s，3H)；3.57(s，3H).MS(API-ES pos)：442/444(M+H)+205/207(1, 5-difluoro-3-bromophosphonium ion), reference.
Example 8
Preparation of 5-amino-3- (4-bromo-2, 6-difluoro-benzyloxy) -iso-isomerThiazole-4-carboxylic acid methyl ester
In a 1L autoclave, to tetrahydrofuran (840mL, 30 volumes) was added 3- (4-bromo-2, 6-difluoro-benzyloxy) -5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester (1.00 eq, 28.0 g). The vessel was evacuated, heated to 50 ℃ and then placed under 45psi of anhydrous ammonia. The mixture was stirred at 600rpm for 3 days, then at 1000rpm for another 21 hours. The mixture was cooled to 25 ℃, purged with nitrogen, and then tetrahydrofuran was removed with a rotary evaporator. To the residue was added a 60: 40 acetonitrile/water (v/v) solution (240mL, 10 volumes relative to theoretical product mass). The slurry was heated to 70 ℃ over 1 hour and then stirred at 25 ℃ overnight. The slurry was filtered and the filter cake was then rinsed with 60: 40 acetonitrile/water (v/v) (40 mL). The solid was dried under vacuum to give 21.55g of methyl 5-amino-3- (4-bromo-2, 6-difluoro-benzyloxy) -isothiazole-4-carboxylate (yield 90%).1HNMR：(DMSO-d6)：δ7.87(s，2H)；7.52(m，2H)；5.26(s，2H)；3.60(s，3H).MS(API-ES pos)：379/381(M+H)+205/207(1, 5-difluoro-3-bromophosphonium ion), reference.
Example 9
Preparation of imidazole-1-carboxylic acid (4-pyrrolidin-1-yl-butyl) -amide
In a flask under nitrogen, 4-pyrrolidin-1-yl-butylamine (1.3 eq, 10.1g) was added to tetrahydrofuran (105mL, 5 vol). The mixture was cooled to 0 ℃ and 1, 1' -carbonyldiimidazole (1.3 eq, 11.6g) was then added. The mixture was stirred at 0 ℃ for 20 minutes, then heated to 20 ℃ over 10 minutes and held at 20 ℃ for 30 minutes.
Example 10
Preparation of 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido]-isothiazol-4-
Carboxylic acid methyl ester
To the imidazole-1-carboxylic acid (4-pyrrolidin-1-yl-butyl) -amide/tetrahydrofuran mixture was added dimethyl sulfoxide (105mL, 5 volumes) and the tetrahydrofuran was removed by vacuum distillation. The mixture was cooled to 20 ℃ then 5-amino-3- (4-bromo-2, 6-difluoro-benzyloxy) -isothiazole-4-carboxylic acid methyl ester (1.00 eq, 21.0g) was added followed by potassium carbonate (2.0 eq, 15.2 g). The mixture was stirred at 20 ℃ for 21.5 hours. Then ethyl acetate (210mL, 10 volumes) and water (210mL, 10 volumes) were added sequentially. The slurry was stirred at 20 ℃ for 3-4 hours. The solid was filtered and the filter cake was rinsed with ethyl acetate (63.0mL, 3 volumes). The solid was dried in a vacuum oven for 17 hours to give 27.36g of 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido]Methyl (yield 90%) isothiazole-4-carboxylate.1H NMR：(DMSO-d6)：δ10.38(s，1H)；8.11(m，1H)；7.54(m，2H)；5.30(s，2H)；3.70(s，3H)；3.12(m，2H)；2.48(m，6H)；1.63(m，4H)；1.44(m，4H).MS(API-ES pos)：547/549(M+H)+Reference.
Example 11
Preparation of 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido]-isothiazol-4-
Carboxylic acid amides
In a 1L autoclave, 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido]Methyl-isothiazole-4-carboxylate (1.00 eq, 27.0g) was slurried in methanol (270mL, 10 vol) and tetrahydrofuran (270mL, 10 vol). The mixture was cooled to 0 ℃ and then stirred at 600 rpm. Anhydrous ammonia gas was carefully charged, keeping the temperature below 10 ℃. After maintaining a steady pressure of about 10psi, the mixture was heated to 40 ℃. The pressure was raised to about 45 psi. The pressure was adjusted to 50psi and then stirred at 600rpm for 90 hours at 40 ℃. The stirring rate was then adjusted to 1000rpm and stirred for an additional 24 hours. The ammonia was removed by vacuum, the mixture was cooled to 20 ℃ and transferred out of the reactor. The mixture was filtered to remove insoluble solids (not related to the product). The filtrate was diluted with 2-propanol (270mL, 10 volumes) and then tetrahydrofuran and methanol were distilled at atmospheric pressure. Additional 2-propanol (135mL, 5 volumes) was added and the mixture was then distilled to a total volume of about 250 mL. The slurry was cooled to 20 ℃ and then stirred for 18 hours. The solid was filtered and then dried under vacuum to give 19.9g of 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido-group]Isothiazole-4-carboxylic acid amide (yield 76%).1H NMR(DMSO-d6)：δ10.98(s，1H)；8.18(m，1H)；7.55(m，3H)；6.80(s，1H)；5.41(s，2H)；3.08(m，2H)；2.47(m，6H)；1.62(m，4H)；1.42(m，4H).MS(API-ES pos)：532/534(M+H)+Reference.
Claims (11)
1. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R1、R2are each independently selected from H and- (CH)2)t(5-membered heterocycle), wherein t is 4, said heterocycle comprising one nitrogen atom as heteroatom;
R3is- (CH)2)t(C6-C10Aryl) wherein t is 1; r is as defined above3Radical is substituted by 3R4Substituted by radicals;
each R4Independently selected from halogen;
the process comprising reacting a compound of formula II with a source of ammonia in a solvent to obtain a compound of formula I,
wherein R is8Is C1-C10An alkyl group; r1、R2、R3As defined above for the compounds of formula I.
2. The method of claim 1, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
and pharmaceutically acceptable salts of said compounds.
3. The process according to claim 1, wherein the compound of formula II is prepared by:
(1) reacting a compound of formula IV with a carbonyl source, with or without the addition of a base, and then adding a compound of formula III in a solvent to obtain a compound of formula II,
wherein R is3And R8As defined above for formula II,
HNR1R2 III
wherein R is1And R2As defined above for formula II; or
(2) Reacting a compound of formula III with a carbonyl source, with or without the addition of a base, and then adding a compound of formula IV in a solvent to obtain a compound of formula II.
4. The process of claim 3, wherein the compound of formula II is 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester.
5. The method of claim 3, wherein the compound of formula II is selected from the group consisting of:
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester.
6. A process according to claim 3, wherein the compound of formula IV is prepared by:
reacting a compound of formula V with an ammonia source in a solvent to obtain a compound of formula IV,
wherein R is3And R8As defined in formula IV;
R9is C1-C10An alkyl group; n is 2.
7. The process of claim 6, wherein the compound of formula IV is methyl 5-amino-3- (4-bromo-2, 6-difluoro-benzyloxy) -isothiazole-4-carboxylate.
8. The process according to claim 6, wherein the compound of formula V is prepared by:
reacting a compound of formula VII with a compound of formula VI in a dipolar aprotic solvent to give a compound of formula V
Wherein n and R8And R9As defined in formula V;
R3X VI
wherein R is3As defined in formula V, X is tosyl,
the reaction is carried out in the presence of a base.
9. The process of claim 8, wherein formula V is 3- (4-bromo-2, 6-difluoro-benzyloxy) -5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester.
10. A compound of formula IIa or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R1、R2are each independently selected from H and- (CH)2)t(5-membered heterocycle), wherein t is 4, said heterocycle comprising one nitrogen atom as heteroatom;
R3is- (CH)2)t(C6-C10Aryl) wherein t is 1; r is as defined above3Radical is substituted by 3R4Substituted by radicals;
each R4Independently selected from halogen;
R8is C1-C10An alkyl group.
11. The compound of formula IIa according to claim 10, which is 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid methyl ester.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60454204P | 2004-08-26 | 2004-08-26 | |
| US60/604,542 | 2004-08-26 | ||
| PCT/US2005/027398 WO2006026034A2 (en) | 2004-08-26 | 2005-08-02 | Processes for the preparation of isothiazole derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1111359A1 HK1111359A1 (en) | 2008-08-08 |
| HK1111359B true HK1111359B (en) | 2011-05-06 |
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