MXPA99007030A - Sulfonyl urea derivatives and their use in the control of interleukin-1 activity - Google Patents
Sulfonyl urea derivatives and their use in the control of interleukin-1 activityInfo
- Publication number
- MXPA99007030A MXPA99007030A MXPA/A/1999/007030A MX9907030A MXPA99007030A MX PA99007030 A MXPA99007030 A MX PA99007030A MX 9907030 A MX9907030 A MX 9907030A MX PA99007030 A MXPA99007030 A MX PA99007030A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- hydroxy
- hydrogen
- group
- halo
- Prior art date
Links
- 108010002352 Interleukin-1 Proteins 0.000 title claims abstract description 26
- 102000000589 Interleukin-1 Human genes 0.000 title description 23
- 230000000694 effects Effects 0.000 title description 4
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 125000003118 aryl group Chemical group 0.000 claims abstract description 44
- 230000001154 acute Effects 0.000 claims abstract description 12
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 11
- 206010061218 Inflammation Diseases 0.000 claims abstract description 8
- 208000009525 Myocarditis Diseases 0.000 claims abstract description 8
- 230000004054 inflammatory process Effects 0.000 claims abstract description 8
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims abstract description 6
- 206010003246 Arthritis Diseases 0.000 claims abstract description 6
- 206010003816 Autoimmune disease Diseases 0.000 claims abstract description 6
- 206010006895 Cachexia Diseases 0.000 claims abstract description 6
- 208000003167 Cholangitis Diseases 0.000 claims abstract description 6
- 206010009887 Colitis Diseases 0.000 claims abstract description 6
- 208000006313 Delayed Hypersensitivity Diseases 0.000 claims abstract description 6
- 208000009190 Disseminated Intravascular Coagulation Diseases 0.000 claims abstract description 6
- 206010014599 Encephalitis Diseases 0.000 claims abstract description 6
- 206010018364 Glomerulonephritis Diseases 0.000 claims abstract description 6
- 206010022114 Injury Diseases 0.000 claims abstract description 6
- 208000006897 Interstitial Lung Disease Diseases 0.000 claims abstract description 6
- 208000002260 Keloid Diseases 0.000 claims abstract description 6
- 210000001117 Keloid Anatomy 0.000 claims abstract description 6
- 206010023330 Keloid scar Diseases 0.000 claims abstract description 6
- 241000124008 Mammalia Species 0.000 claims abstract description 6
- 206010033645 Pancreatitis Diseases 0.000 claims abstract description 6
- 208000008494 Pericarditis Diseases 0.000 claims abstract description 6
- 206010063837 Reperfusion injury Diseases 0.000 claims abstract description 6
- 208000007893 Salpingitis Diseases 0.000 claims abstract description 6
- 206010040070 Septic shock Diseases 0.000 claims abstract description 6
- 206010042953 Systemic sclerosis Diseases 0.000 claims abstract description 6
- 206010052779 Transplant rejections Diseases 0.000 claims abstract description 6
- 206010047115 Vasculitis Diseases 0.000 claims abstract description 6
- 230000003305 autocrine Effects 0.000 claims abstract description 6
- 230000001684 chronic Effects 0.000 claims abstract description 6
- 238000005755 formation reaction Methods 0.000 claims abstract description 6
- 201000004044 liver cirrhosis Diseases 0.000 claims abstract description 6
- 201000009906 meningitis Diseases 0.000 claims abstract description 6
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 6
- 238000009527 percussion Methods 0.000 claims abstract description 6
- 230000036303 septic shock Effects 0.000 claims abstract description 6
- 201000009594 systemic scleroderma Diseases 0.000 claims abstract description 6
- 206010014665 Endocarditis Diseases 0.000 claims abstract description 5
- 208000006454 Hepatitis Diseases 0.000 claims abstract description 5
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 5
- 239000003102 growth factor Substances 0.000 claims abstract description 5
- 231100000283 hepatitis Toxicity 0.000 claims abstract description 5
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 4
- 201000001320 atherosclerosis Diseases 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 147
- -1 (d-CeJalkoxy Chemical group 0.000 claims description 121
- 239000001257 hydrogen Substances 0.000 claims description 92
- 229910052739 hydrogen Inorganic materials 0.000 claims description 92
- 238000002360 preparation method Methods 0.000 claims description 64
- 125000005843 halogen group Chemical group 0.000 claims description 60
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 42
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 41
- 125000003545 alkoxy group Chemical group 0.000 claims description 40
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
- 239000001301 oxygen Substances 0.000 claims description 28
- 229910052760 oxygen Inorganic materials 0.000 claims description 28
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 28
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 150000002431 hydrogen Chemical group 0.000 claims description 19
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 239000011593 sulfur Substances 0.000 claims description 18
- 239000004202 carbamide Substances 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000003282 alkyl amino group Chemical group 0.000 claims description 15
- 125000004414 alkyl thio group Chemical group 0.000 claims description 15
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 125000004442 acylamino group Chemical group 0.000 claims description 9
- 125000004423 acyloxy group Chemical group 0.000 claims description 9
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 8
- 125000005110 aryl thio group Chemical group 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 125000005035 acylthio group Chemical group 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- 125000005936 piperidyl group Chemical group 0.000 claims description 6
- 206010001897 Alzheimer's disease Diseases 0.000 claims description 5
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 5
- 125000001769 aryl amino group Chemical group 0.000 claims description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 5
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 5
- 201000008838 periodontal disease Diseases 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000005145 cycloalkylaminosulfonyl group Chemical group 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052720 vanadium Inorganic materials 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- RZNNEQHIXCRCKM-UHFFFAOYSA-N 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide Chemical compound CC(C)(O)C1=COC(S(N)(=O)=O)=C1 RZNNEQHIXCRCKM-UHFFFAOYSA-N 0.000 claims description 3
- 206010012601 Diabetes mellitus Diseases 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- HLEOGYNUFBFPQF-UHFFFAOYSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(2-hydroxypropan-2-yl)thiophen-2-yl]sulfonylurea Chemical compound CC(C)(O)C1=CSC(S(=O)(=O)NC(=O)NC=2C=3CCCC=3C=C3CCCC3=2)=C1 HLEOGYNUFBFPQF-UHFFFAOYSA-N 0.000 claims description 2
- DDRGGWOWUJRBRH-UHFFFAOYSA-N 1-(4-acetylthiophen-2-yl)sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound CC(=O)C1=CSC(S(=O)(=O)NC(=O)NC=2C=3CCCC=3C=C3CCCC3=2)=C1 DDRGGWOWUJRBRH-UHFFFAOYSA-N 0.000 claims description 2
- YUSFXGQGPSLKHV-UHFFFAOYSA-N 1-[4-chloro-2,6-di(propan-2-yl)phenyl]-3-(1H-indol-6-ylsulfonyl)urea Chemical compound CC(C)C1=CC(Cl)=CC(C(C)C)=C1NC(=O)NS(=O)(=O)C1=CC=C(C=CN2)C2=C1 YUSFXGQGPSLKHV-UHFFFAOYSA-N 0.000 claims description 2
- NMPXFRKPFCOTDU-UHFFFAOYSA-N 1-[4-chloro-2,6-di(propan-2-yl)phenyl]-3-[(5-fluoro-1H-indol-6-yl)sulfonyl]urea Chemical compound CC(C)C1=CC(Cl)=CC(C(C)C)=C1NC(=O)NS(=O)(=O)C(C(=C1)F)=CC2=C1C=CN2 NMPXFRKPFCOTDU-UHFFFAOYSA-N 0.000 claims description 2
- WYOJYANQSVFZJC-UHFFFAOYSA-N 1-[4-chloro-2,6-di(propan-2-yl)phenyl]-3-[3-(methylsulfamoyl)phenyl]sulfonylurea Chemical compound CNS(=O)(=O)C1=CC=CC(S(=O)(=O)NC(=O)NC=2C(=CC(Cl)=CC=2C(C)C)C(C)C)=C1 WYOJYANQSVFZJC-UHFFFAOYSA-N 0.000 claims description 2
- UTUTZQKQYZYYKW-UHFFFAOYSA-N 1-[4-fluoro-2,6-di(propan-2-yl)phenyl]-3-[3-(2-hydroxypropan-2-yl)phenyl]sulfonylurea Chemical compound CC(C)C1=CC(F)=CC(C(C)C)=C1NC(=O)NS(=O)(=O)C1=CC=CC(C(C)(C)O)=C1 UTUTZQKQYZYYKW-UHFFFAOYSA-N 0.000 claims description 2
- 229910014585 C2-Ce Inorganic materials 0.000 claims description 2
- 101710004852 CHR11 Proteins 0.000 claims description 2
- 101700034590 CHR12 Proteins 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 2
- 125000005605 benzo group Chemical group 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000005349 heteroarylcycloalkyl group Chemical group 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 3
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims 1
- YEEZKYANFBMVNG-UHFFFAOYSA-N 1-(3H-benzimidazol-5-ylsulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound C1=C2NC=NC2=CC(S(=O)(=O)NC(NC=2C=3CCCC=3C=C3CCCC3=2)=O)=C1 YEEZKYANFBMVNG-UHFFFAOYSA-N 0.000 claims 1
- GGWYDFQWIFFOSI-UHFFFAOYSA-N 1-(4-acetylfuran-2-yl)sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound CC(=O)C1=COC(S(=O)(=O)NC(=O)NC=2C=3CCCC=3C=C3CCCC3=2)=C1 GGWYDFQWIFFOSI-UHFFFAOYSA-N 0.000 claims 1
- MRKXXRUHPFFURP-UHFFFAOYSA-N 1-[2,6-di(propan-2-yl)phenyl]-3-[4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonylurea Chemical compound CC(C)C1=CC=CC(C(C)C)=C1NC(=O)NS(=O)(=O)C1=CC(C(C)(C)O)=CO1 MRKXXRUHPFFURP-UHFFFAOYSA-N 0.000 claims 1
- YRSBLSHMKVQWHP-UHFFFAOYSA-N 1-[4-chloro-2,6-di(propan-2-yl)phenyl]-3-[3-(2-hydroxypropan-2-yl)phenyl]sulfonylurea Chemical compound CC(C)C1=CC(Cl)=CC(C(C)C)=C1NC(=O)NS(=O)(=O)C1=CC=CC(C(C)(C)O)=C1 YRSBLSHMKVQWHP-UHFFFAOYSA-N 0.000 claims 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 1
- 125000002877 alkyl aryl group Chemical group 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
- 201000000023 osteosclerosis Diseases 0.000 claims 1
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- 201000000028 adult respiratory distress syndrome Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- 239000000243 solution Substances 0.000 description 88
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
- 239000000203 mixture Substances 0.000 description 51
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- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- LYAWGVFUGRUFEO-UHFFFAOYSA-N 5-chloro-2-isocyanato-1,3-di(propan-2-yl)benzene Chemical compound CC(C)C1=CC(Cl)=CC(C(C)C)=C1N=C=O LYAWGVFUGRUFEO-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 33
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- 239000007787 solid Substances 0.000 description 27
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- FEUFNKALUGDEMQ-UHFFFAOYSA-N 2-isocyanato-1,3-di(propan-2-yl)benzene Chemical compound CC(C)C1=CC=CC(C(C)C)=C1N=C=O FEUFNKALUGDEMQ-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 20
- 210000004027 cells Anatomy 0.000 description 18
- 239000008079 hexane Substances 0.000 description 18
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- UYBZBDIWTYRSAW-UHFFFAOYSA-N 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene Chemical compound O=C=NC1=C2CCCC2=CC2=C1CCC2 UYBZBDIWTYRSAW-UHFFFAOYSA-N 0.000 description 11
- 239000002609 media Substances 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
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- 229910002027 silica gel Inorganic materials 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
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- 238000007792 addition Methods 0.000 description 6
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- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 6
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- MGPHDXOVGHRZJB-UHFFFAOYSA-N 3-methylsulfanylbenzenesulfonamide Chemical compound CSC1=CC=CC(S(N)(=O)=O)=C1 MGPHDXOVGHRZJB-UHFFFAOYSA-N 0.000 description 5
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Abstract
A compound of formula (I) wherein R1 and R2 are as defined in the description, R2 being an aromatic group, useful in the treatment and condition selected from the group consisting of the group meningitis and salpingitis, septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome, acute or chronic inflammation, arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease, auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis, periodonate diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, keloid formation tumors which produce IL-1 as an autocrine growth factor, cachexia, Alzeimer's disease, percussion injury, depression, atherosclerosis, osteoporosis in a mammal, including a human.
Description
DERIVATIVES OF SULFONIL UREA
BACKGROUND OF THE INVENTION
This invention relates to substituted urea derivatives useful in the treatment of inflammation in joints, central nervous system, gastrointestinal tract, endocardium, pericardium, lung, eyes, ears, skin and urogenital system. More particularly, this invention relates to substituted aryl and heteroaryl sulfonyl ureas which are useful inhibitors of the transformation and release of interleukin-1a and interleukin-1β. The consideration of IL-1 as an important mediator of inflammation is based on numerous studies demonstrating this proinflammatory activity of the cytokine. In vivo, these effects manifest as a stimulation of cartilage resorption, an induction of leukocyte recruitment and acute phase response, and the production of fever and a shock-type state. The changes mediated by the binding of IL-1 to its receptor, include the regulation of the adhesion of molecules and chemokines, the stimulation of the synthesis of metalloproteases, the increased synthesis of cyclooxygenase-2 and phospholipase A2, increasing, in this way , the production of prostaglandins, the induction of nitric oxide synthase, thus increasing the production of nitric oxide and the stimulation of the synthesis of I L-6, resulting in changes in the synthesis of watery phase proteins. In response to the stimuli
Inflammatory, two different forms of 1L-1 (IL-1 a and IL-β) are produced by monocytes and macrophages. The initial translation product of human IL-1β is a 31 kDa polypeptide, which is incompetent to bind IL-1 receptors on target cells. In order to promote its biological activity, prolL-1 ß must, first, be excised by a thiol protease, in order to generate a mature 17 kDa polypeptide species. This protease, interleukin-1 convertase (ICE), is a member of a new family of cytosolic proteases that require an aspartic acid residue in the P1 subsite of their substrates. In contrast to prolL-1 ß, prolL-1a of 31 kDa is competent to bind to IL-1 receptors; however, this cytokine is also transformed into a 1 JkDa species by a protease other than ICE. Both forms of IL-1 are synthesized without signal sequences and, as a result, these cytokines accumulate within the cytoplasm of monocytes and macrophages activated by LPS. Therefore, unlike most secreted cytokines that are transformed through the traditional secretory apparatus of the cell involving the endoplasmic reticulum and the Golgi apparatus, IL-1 must gain access to the extracellular compartment through a new secretory way. The mechanical elements of this path remain unknown. However, recent studies have shown that the synthesis of IL-1β is not matched with its secretion. The agents that serve as a stimulus to promote the transformation
post-translation of IL-1β (both proteolytic cleavage by ICE and release of mature 1 J kDa species) include ATP, cytolytic T cells, and ionophores such as nigericin. Importantly, mu peritoneal macrophobes activated by LPS also require, in vivo, a secondary stimulus to promote an effective release of mature IL-1β, and ATP has been shown to serve this purpose. Accordingly, the production of IL-1β is highly regulated, both in vitro and in vivo, by the requirement of separate stimuli to promote transcription, translation and maturation / post-translational release. Therapeutic routes that aspire to inhibit ICE as a way of regulating the production of IL-1 are likely to be equally limited, since ICE inhibitors: 1) do not block the release of prolL-1β, which could be transformed extracellularly by other proteases, in order to generate a biologically mature active cytokine species, and 2) do not decrease the production of IL-1a by activated monocytes / macrophages. Accordingly, a therapeutic route that prevents activation of the transformation and post-translational release of IL-1 is likely to provide efficacy superior to that of an ICE inhibitor by blocking the externalization of both species cytokines Mammalian cells capable of producing IL-1 include, but are not limited to, caratinocytes, endothelial cells, mesangial cells, thymic epithelial cells, dermal fibroblasts, chondrocytes,
astrocytes, glioma cells, mononuclear phagocytes, granulacytes, T and B lymphocytes and NK cells. The activities of interleukin-1 are numerous. Subcutaneous injection of IL-1 produces fever, insomnia, anorexia, generalized myalgias, arthralgia, headache, and, under increased exposure, hypotension. Likewise, neutrophil margination and maximum extravascular infiltration of polymorphonuclear leukocytes (PMN) have been observed. Likewise, IL-1 stimulates chondrocytes to release metalloproteases from the matrix, resulting in degradation of the cartilage matrix. Accordingly, the disease states in which inhibitors of the transformation and release of IL-1 of formula I can be useful as therapeutic agents, include, but are not limited to, infectious diseases in which there is active infection anywhere on the body, such as meningitis and salpingitis; complication of infections that include septic shock, disseminated intravascular coagulation, and / or respiratory distress syndrome in adults; acute or chronic inflammation due to antigens, antibodies and / or deposition of supplements; inflammatory conditions that include arthritis, cholangitis, colitis, encephalitis, endocarrditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis. Immuno-active diseases that can respond to IL-1 transformation and release inhibitors of formula I, include, but are not
limited to them, the states involving T cells and / or macrophages such as acute and delayed hypersensitivity, graft rejection, and host disease versus grafting, autoimmune diseases include type 1 diabetes mellitus and multiple sclerosis. Likewise, inhibitors of the transformation and inhibition of IL-1 of formula I may be useful in the treatment of bone and cartilage resorption, as well as in diseases that result in excessive deposition of extracellular matrix. Such diseases include periodontal diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis and keloid formation. Likewise, inhibitors of the transformation and release of IL-1 of formula I may be useful in the treatment of certain tumors that produce IL-1 as an autocrine growth factor and in the prevention of cachexia associated with certain tumors. . Similarly, inhibitors of IL-1 transformation and release of formula I may be useful in the treatment of neuronal diseases with an inflammatory component, including, but not limited to, Alzheimer's disease, depression, and depression. percussion injury. Inhibitors of the transformation and release of IL-1 may also be useful in the treatment of cardiovascular diseases, in which the recruitment of monocytes within the subendothelial space plays a role, such as the development of atherosclerotic plaques.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein: R1 is (C -? - C6) alkyl optionally substituted by (C -? - C6) alkylamino, (C -? - C6) alkylthio, (C? -C6) alkoxy, trifluoromethyl, (C6-C? 0) aryl, (C5-C9) heteroaryl, (C6-C10) arylamino, (C6-C? 0) arylthio, (C6-C-? 0) aryloxy, (C5-C9) ) heteroarylamino, (C5-C9) heteroarylthio, (C5-C9) heteroaryloxy, (C-C-io) aryl (C6-C? o) -aryl (C3-C6) cycloalkyl, hydroxy (C? -C6) alkyl, (C? -C6) alkyl (hydroxymethylene), piperazinyl, (C? -C -io) aryl (CrC6) alkoxy, (C5-C9) heteroaryl (C? -C6) alkoxy, (CrC6) acylamino, (C -? - C6) acylthio, (CrC6) acyloxy, (C -? - C6) alkylsulfinyl, (C6-C10) arylsulfinyl, (C? -C6) alkylsulfonyl, (C6-C-? O) arylsulfonyl, amino, (C? -C6) ) alkylamino or ((Ci-Cβ) alkyl) 2 amino; or R1 and R2 are each independently of a group of the formula:
II
wherein the dashed lines represent optional double bonds; n is 0, 1, 2 or 3; A, B, D, E and G are each independently, oxygen, sulfur, nitrogen or CR5R6, wherein R5 and Rd are each independently selected from hydrogen, (C -C6) alkyl optionally substituted by one or two groups selected from (d-Cß) alkylamino, (CrC6) alkylthio, (C? -C6) alkoxy, hydroxy, cyano, perfluoro (C? -C6) alkyl, (C6-C10? 0) aryl, (C5-) C9) heteroaryl, (C6-C? 0) arylamino, (C6-C? O) arylthio, (Ce-Cio) aryloxy wherein the aryl group is optionally substituted by (C-C6) alkoxy, (C? -C6) acyl, carboxy, hydroxy or halo; (C5-C9) heteroarylamino, (C5-C9) heteroarylthio, (C5-C9) heteroaryloxy, (C6-C? 0) aryl (Cedo) aryl, (C3-C6) cycloalkyl, hydroxy, piperazinyl, (Ce-C or ) aryl (C -CT) alkoxy, (C5-C9) heteroaryl (C-C6) alkoxy, (Ci-Ce) acylamino, (Ci-Cß) acylthio, (Ci-Cβ) acyloxy, (C?-C6) alkylsulfinyl , (C6-C? O) arylsulfinyl, (Ci-C?) Alkylsulfonyl, (Cedo) arylsulfonyl, amino (Ci-C?) Alkylamino or ((Ci-C?) Alkyl) 2-amino; halo, cyano, amino, hydroxy, perfluoro (C? -C6) alkyl, perfluoro (C? -C6) alkoxy, (C2-Ce) alkenyl, carboxy (C2-C6) alkenyl, (C2-C6) alkynyl, (C ? -C6) alkylamino, ((C1-Cβ) alkyl) 2-amino, (d-C6) alkylsulfonylamido, (C? -C6) alkylsulfinyl, aminosulfonyl, (C-C) alkylaminosulfonyl, ((C? -C6) alkyl2) aminosulfonyl , (C? -C6) alkylthio, (d-C?) Alkoxy, perfluoro (d-C6) alkyl, (C6-C? O) aryl, (C5-C9) heteroaryl, (C6-C? 0) arylamino, ( Ce-Cι) arylthio, (Ce-Cι) aryl (C? -C6) alkoxy, (C5-Cg) heteroarylamino, (C5-C9) heteroarylthyl, (C5-C9) heteroaryloxy, (C3-Ce) cycloalkyl, (C ? -C6) alkyl (hydroxymethylene), piperidyl, pyridinyl, thienyl, furanyl, (d-C6) alkylpiperidyl, (C? -C6) acylamino, (CI-CT) acylthio, (CI-CT)
acyloxy, R7 (C? -Ce) alkyl wherein R7 is (CI-CT) acylpiperazino, (Ce-Cio) arylpiperazino, (C5-C9) heteroarylpiperazino, (d-C) alkylpiperazino, (Ce-Cio) aryl ( Ci-Cß) alkylpiperazine, (C5-C9) heteroaryl (d-Cß) alkylpiperazine, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (d-C6) alkylpiperidyl
(Ce-Cι) arylpiperidyl, (C5-C9) heteroarylpiperidyl, (d-C6) alkylpiperidyl (C Cβ) alkyl, (C6-C? 0) arylpiperidyl (C?-C6) alkyl, (C5-C9) heteroarylpiperidyl (d) -Cβ) alkyl or (C? -C6) acylpiperidyl; or a group of the formula:
wherein: s is 0 to 6; t is 0 or 1; X is oxygen or NR8 in R8 is hydrogen, (C? -C6) alkyl or (C3-C7) cycloalkyl (d-Ce) alkyl; Y is hydrogen, hydroxy, (C? -C6) alkyl, optionally substituted by halo, hydroxy or cyano; (d-Cß) alkoxy, cyano, (C2-C6) alkynyl, (C6-C? 0) aryl wherein the aryl group is optionally substituted by halo, hydroxy, carboxy, (C? -C6) alkyl, (d -Cβ) alkoxy; perfluoro (C6C6) alkyl, (C6C6) alkoxy (C6C6) alkyl or NR9R10 wherein R9 and R10 are each independently selected from the group consisting of hydrogen, (dC6) alkyl optionally substituted by (d-C6) alkylpiperidyl, (C6-do) arylpiperidyl (C5-C9) heteroarylpiperidyl, (C6-C? 0) aryl, (C5-C9) heteroaryl or (C3-C6) cycloalkyl; piperidyl, (Ci-Cß) alkylpiperidyl, (C6-C? 0) arylpiperidyl, (C5-C9) heteroarylpi-
Peridyl, (C? -C6) acylpiperidyl, (C6-C? 0) aryl, (C5-C9) heteroaryl, (C3-C6) cycloalkyl, R11 (C2-C6) alkyl, (C1-C5) alkyl (CHR11) (d-C6) alkyl wherein R11 is hydroxy, (C? -C6) acyloxy, (C? -C6) alkoxy, piperazino, (C? -C6) acylamino, (CrC6) alkylthio, (C6-C? ) arylthio, (C6-C? 0) alkylsulfinyl, (C6-C? 0) arylsulfinyl, (C? -C6) alkylsulfoxyl, (C6-C? 0) arylsulfoxyl, amino, (C? -C6) alkylamino, (( Cr C6) alkyl) 2-amino, (C? -C6) acylpiperazine, (C? -C6) alkylpiperazine, (C6-C? 0) aryl (C? -C6) alkylpiperazine, (C5-C9) heteroaryl (d-C6) alkyipiperazine, morpholino, thiomorpholino, pyperidino or pyrrolidino; R 2 (C? -C6) alkyl, (C1-C5) alkyl (CHR12) (C-C6) alkyl wherein R12 is piperidyl or (d-C6) alkylpiperidyl; and CH (R13) COR14 wherein R14 is as defined below and R13 is hydrogen, (d-C6) alkyl, (Ce-Cι) aryl (C?-C6) alkyl, (C5-C9) heteroaryl (C?-C6) alkyl, (C?-C6) alkylthio (d-C6) alkyl, (C6-C? 0) arylthio (d-C6) alkyl, (d-C6) alkylsulfinyl (C? -C6) alkyl, (C6-C? 0) arylsulfinyl (C? -C6) alkyl, (d-C6) alkylsulfonyl (C? -C6) alkyl, (C6-C? 0) arylsulfonyl (C? -C6) alkyl, hydroxy (C? -C6) alkyl, amino (C? -C6) alkyl, (C? -C6) alkylamino (C6C6) alkyl, ((C6C6) alkylamino) 2 (dC6) alkyl, R15R16NCO (C6C6) alkyl or R15OCO (C6C6) alkyl in R5 and R16 are each one of them independently selected from the group consisting of hydrogen, (d-C6) alkyl, (Ce-Cι) aryl (C? -C6) alkyl and (C5-C9) heteroaryl (d-C6) alkyl; and R14 is R17O or R17R18N wherein R17 and R18 are each independently selected from the group consisting of hydrogen, (dC?) alkyl, (Ce-C o) aryl (Ci-C?) alkyl and (C5-C9) ) heteroaryl (d-C6) alkyl; Or a group of formula:
wherein: u is 0, 1 or 2; R19 is hydrogen, (d-C6) alkyl or perfluoro (CI-CT) alkyl; R 20 is hydrogen, (d-Cß) alkyl, (Ci-Cß) carboxyalkyl or (C6-C 0) aryl (d-Cß) alkyl; or a group of the formula:
in which: a is 0, 1 or 2; b is O, or 1;
c is 1, 2 or 3; * d is 0 or 1; e is 0, 1, or 2; J and L are each independently oxygen or sulfur; R21 is hydrogen, hydroxy, fluoro, (d-C6) alkyl, (d-Cß) alkoxy, halo (Ci-Cß) alkyl, amino, (d-Cß) acylamino or NR26R27 are each independently selected from hydrogen, (d-C6) alkyl or (C6-do) aryl; and R22 is hydrogen, (d-C6) alkyl optionally substituted by hydroxy, halo, (d-Cß) alkylthio, (C6C6) alkylsulfinyl or (C C) alkylsulfonyl; or when n is 1 and B and D are both CR5, the two groups R5 can be taken together with the carbons to which they are attached to form a group of the formula:
wherein the dashed lines represent optional double bonds; m is 0 or 1; Y
T, U, V and W are each independently oxygen, sulfur, CO, nitrogen or CR5R6 in which R5 and R6 are as defined above; or when A and B, or when n is 1 and B and D, or D and E, or E and G, are both CR5, the two groups R5 can be taken together with the adjacent carbons to which they are bound to form a group (C5-C6) cycloalkyl optionally substituted by hydroxy or a benzo group; or when n is 1 and D and E are both CR5, the two groups R5 can be taken together with the adjacent carbons to which they are attached to form a group of the formula:
wherein the dashed line represents an optional double bond; R23 is hydrogen, (C? -C6) alkyl, halo, amino or (C? -C6) alkoxy; J is C or SO; K is oxygen, NR24 in which R24 is hydroxy, (Ci-Cβ) alkoxy or (Cedo) aryl (Ci-Ce) alkoxy; or hydroxy; or R25SO2 wherein R25 is defined as above for R1 or (C3-C7) cycloalkylamino; Y
with the proviso that the groups of the formulas II and VI can not have two oxygens, two sulfur or one oxygen and one sulfur defined in adjacent positions; with the proviso that R2 must be aromatic; with the proviso that when either a or e is 0, in another it must be 1; with the proviso that when b and d are 1, the sum of a, c and e can not be 6 or 7; and with the proviso that when A, B, D, E, G, T, U, V and W represent a sp2 carbon, there is no R6. The term "alkyl", as used herein, unless indicated to the contrary, includes saturated monovalent hydrocarbon radicals containing linear, branched or cyclic parts or combinations thereof. The term "alkoxy," as used herein, includes O-alkyl groups, wherein "alkyl" is as defined above. The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by the removal of a hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3. substituents selected from the body consisting of fluoro, chloro, trifluoromethyl, (C? -C6) alkoxy, (Ce-Cio) aryloxy, trifluoromethoxy, difluoromethoxy and (d-C6) alkyl. The term "heteroaryl" as used herein, unless
Indicate otherwise, include an organic radical derived from a
aromatic heterocyclic compound by the removal of a hydrogen, such as pyridyl, furyl, pyroyl, thienyl, isothiazolinium, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrmidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl, optionally substituted by 1 or 2 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (Ci-Cß) alkoxy, (Ce-Cι) aryloxy, trifluoromethoxy, d-fluoromethoxy and (Ci-Ce) alkyl. The term "acilo"as used herein, unless otherwise indicated, includes a radical of the general formula RCO, wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy and the terms "alkyl" or "aryl" are as defined above. The term "acyloxy", as used herein, includes O-acyl group in which "acyl" is as defined above. Preferred compounds of formula I, including those in which R 1 is a group of the formula:
wherein the dashed lines represent double bonds; n is 0 or 1;
A is CR5, wherein R5 is hydrogen or halo; B and E are both independently CR5, wherein R5 is hydrogen, cyano, halo, (C-CT) alkyl optionally substituted by one or two hydroxy; (C3-C7) cycloalkylaminosulfonyl, (Ci-Cβ) alkylaminosulfonyl, or a group of the formula:
where: s is 0; t is 0; and Y is hydrogen, (d-Cβ) alkyl, optionally substituted by halo; or (C -C6) alkoxy (d-C6) alkyl; or a group of the formula:
where: a is 0 or 1; b is O or 1; c is 1 or 2; d is O or 1; e is O or 1; J and L are each independently oxygen or sulfur; R21 is hydrogen, hydroxy or (C? -C6) alkyl, optionally substituted by halo; and R22 is hydrogen or (Ci-Cβ) alkyl optionally substituted by hydroxy, halo, (d-Cß) alkylthio, (d-C6) alkylsulfinyl or (d-C6) alkylsulfonyl; or a group of the formula:
wherein: u is 0 or 1; R 19 is (C C β) alkyl or trifluoromethyl; and R20 is hydrogen; D is CR5, wherein R5 is hydrogen, (CrC6) alkyl or halo;
G is CR5, wherein R5 is oxygen, sulfur or CR5, wherein R5 is hydrogen or halo; or when n is 1 and B and D are both CR5, the two groups R5 can be taken together with the carbons to which they are attached to form a group of the formula:
wherein the dashed lines represent double bonds; m is 0; T is oxygen, nitrogen or CR5, wherein R5 is hydrogen; U is CO or CR5, wherein R5 is hydrogen; and W is nitrogen or CR5, where R5 is hydrogen; or when it is 1 and D and E are both CR5, the two groups R5 can be taken together with the adjacent carbons to which they are joined to form a group of the formula:
wherein the dashed line represents an optional double bond; R23 is hydrogen or (C1-C6) alkyl; J is C or SO; K is oxygen, NR24, wherein R24 is hydroxy; or hydroxy. Other preferred compounds of Formula I include those in which R2 is a group of the Formula:
wherein the dashed lines represent optional double bonds; n is 1, A is CR 5, wherein R 5 is halo or (C -C 6) alkyl; B is CR5, wherein R5 is hydrogen or halo; D is CR 5, wherein R 5 is hydrogen, halo cyano, or a group of the Formula:
in which:
s is 0; t is 0; and Y is NH2; E is CR5, wherein R5 is hydrogen or halo; and G is CR5, wherein R5 is halo or (C1-C6) alkyl; or when A and B, or E and G, are both CR5, the two groups R5 can be taken together with the adjacent carbons to which they are attached to form a (C5-C6) alkyl group. Other preferred compounds of Formula I include those in which R 1 is a group of the Formula;
wherein the dashed lines represent double bonds; n is 0 or 1; A is CR5, wherein R5 is hydrogen or halo; B and E are both independently CR 5, wherein R 5 is hydrogen, cyano, halo, (Ci-Cβ) alkyl optionally substituted by one or two hydroxy; (C3-C) cycloalkylamino-sulfonyl, (C6C) alkylaminosulfonyl, or a group of the Formula:
where: s is 0; t is 0; and Y is hydrogen, (d-C6) alkyl optionally substituted by halo; or (C? -C6) alkoxy (d-C?) alkyl; Or a group of the Formula:
in which: a is 0 or 1; b is 0 or 1;
c is 1 or 2; d is O or 1; e is O or 1; J and L are each independently oxygen or sulfur; R21 is hydrogen, hydroxy or (C? -C6) aluyl optionally substituted by halo; and R22 is hydrogen or (d-C6) alkyl optionally substituted by hydroxy, halo, (d-C) alkylthio, (C6C6) alkylsulfinyl or (dC) alkylsulfonyl; or a group of the Formula:
wherein: u is 0 or 1, R19 is (C? -C6) alkyl or trifluoromethyl; and R20 is hydrogen; D is CR5, wherein R5 is hydrogen, (C? -C6) alkyl or halo; G is CR5, wherein R5 is oxygen, sulfur or CR5, wherein R5 is hydrogen or halo;
or when n is 1 and B and D are both CR5, the two groups R5 can be taken together with the carbons to which they are attached to form a group of the Formula:
wherein the dashed lines represent optional double bonds; m is O; T is oxygen, nitrogen or CR5, wherein R5 is hydrogen; U is CO or CR5, wherein R5 is hydrogen; and W is nitrogen or CR5, wherein R5 is hydrogen; or when n is 1 and D and E are both CR5, the two groups R5 can be taken together with the adjacent carbons to which they are attached to form a group of the Formula:
vp
wherein the dashed line represents an optional double bond; R23 is hydrogen or (d-Cß) alkyl; J is C or SO; K is oxygen, NR24 in which R24 is hydroxy; or hydroxy; and R2 is a group of the Formula:
wherein the dashed lines represent optional double bonds; n in 1; A is CR5, wherein R5 is halo or (C6C6) alkyl; B is CR5, wherein R5 is hydrogen or halo; D is CR 5, wherein R 5 is hydrogen, halo, cyano or a group of the Formula:
where: s is 0; t is 0; and Y is NH2; E is CR5, wherein R5 is hydrogen or halo; and G is CR5, wherein R5 is halo or (d-C6) alkyl; 0 when A and B, or E and G, are both CR5, the two groups R5 can be taken together with the adjacent carbons with which they are joined to form a group (CS-CT) cycloalkyl. Specific preferred compounds of Formula I include the following: 1- (4-chloro-2,6-diisopropyl-phenyl) -3- [3- (1-hydroxy-1-methyl-ethyl) -benzenesulfonyl-urea; 1 - (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methyl-ethyl) furan-2-sulfonyl] urea; 1 - (1, 2,3,5,6, 7-hexahydro-4-aza-s-indacen-8-yl) -3- [4- (1-hydroxy-1-methyl-ethyl) furan-2 sulfonyl] urea; 1 - (1, 2,3,5,6J-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methyl-ethyl) thiophene-2-sulfonyl] urea; 1 - (4- [1, 3] dioxalan-2-yl-furan-2-sulfonyl) -3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1- (2,6-diisopropylphenyl) 3- [4- (1-hydroxy-1-methyl-ethyl) furan-2-sulfonyljurea;
1 - . 1 - . 1 - (2,6-diisopropylpheni) -3- [4- (1-hydroxy-1-methyl-ethyl) thiophene-2-sulfonyljurea; 1- (4-acetyl-thiophene-2-sulfonyl) -3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1- (1 H-benzoimidazole-5-sulfonyl) -3- (1, 2,3,5,6,7-haxahydro-s-ndacen-4-yl) urea; 1 - (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methyl-ethyl) thiophene-2-sulfonyl] urea; 1- (8-chloro-1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methyl-ethyl) furan-2 -sulphonyl] urea; 1- (4-acetyl-furan-2-sulfonyl) -3- (1, 2,3,5,6,7-hexanidro-s-indacen-4-yl) urea; 1- (8-fluoro-1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methyl-ethyl) furan-2- sulfonyl] urea; 1- (4-Fluoro-2,6-diisopropyl-phenyl) -3- [3- (1-hydroxy-1-methyl-ethyl) -benzenesulfonyl] -urea; 1- (6-Fluoro-1 H-benzoimidazole-5-sulfonyl) -3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1- (4-chloro-2,6-diisopropyl-phenyl) -3- (1 H -indole-6-sulfonyl) urea; 1- (4-chloro-2,6-diisopropyl-phenyl) -3- (5-fluoro-1 H -indole-6-sulfonyl) urea; 1- [1, 2,3,5,6,7-hexahydro-s-indacen-u-yl) -3- (1 H -indole-6-sulfonyl) urea;
1- (5-fluoro-1 H -indole-6-sulfonyl) -3- (1, 2,3,5,6,7-hexahydro-5-indacen-4-yl) urea; 1- [4-chloro-2,6-diisopropyI-phenyl] -3- [2-fluoro-5- (2-methyl- (1, 3) dioxolan-2-yl) benzenesulfonyl] urea; 3- [3- [4-chloro-2,6-diisopropyl-phenyl] ureidosulfonyl] -N-methyl-benzenesulfonamide; 1 - [2-fluoro-5- (2-methyl- (1, 3) dioxolan-2-yl) benzenesulfonyl] -3-1, 2,3,5,6,7-hexahydro-indacen-4- il) urea; and 3- [3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) ureidosulfonyl] -N-methyl-benzenesulfonamide. Likewise, the present invention relates to a pharmaceutical composition for the treatment of meningitis and salpingitis, septic shock, disseminated intravascular coagulation, and / or respiratory distress syndrome in adults, acute or chronic inflammation, arthritis, cholangitis, colitis. , encephalitis, endocarditis, glomerulonephritis, hapatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, acute and delayed hypersensitivity, graft rejection, and host disease versus graft, autoimmune diseases that include type 1 diabetes mellitus and multiple sclerosis, periodontal diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, keloid formation, tumors that produce IL-1 as an autocrine growth factor, cachexia, Alzheimer's disease, percussion injury, depression, atherosclerosis (including cardiomyopathy, myocarditis and heart failure) and
osteoporosis in a mammal, including a human, comprising the administration of an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, effective in said treatments or inhibition and a pharmaceutically acceptable carrier. Likewise, the present invention relates to a method for the treatment of a condition selected from the group of meningitis and salpingitis, septic shock, disseminated intravascular coagulation, and / or respiratory distress syndrome in adults, acute or chronic inflammation, arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, acute and delayed hypersensitivity, graft rejection, and host disease versus graft, autoimmune diseases including diabetes mellitus Type 1 and multiple sclerosis, periodontal diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, keloid formation, tumors that produce IL-1 as an autocrine growth factor, cachexia, Alzheimer's disease, percussion injury, depression, atherosclerosis (including cardiomyopathy, myocarditis and cardiac insufficiency aca) and osteoporosis in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically thereof, effective in treating such condition acceptable salt.
DETAILED DESCRIPTION OF THE INVENTION
The following reaction schemes illustrate the preparation of the present invention. Unless otherwise indicated, n A, B, D, E and G in the reaction schemes and in the discussion that follows are as defined above.
PREPARATION A
XII
XI
PREPARATION B
XIV
XIII
PREPARATION C
XVI
XV
PREPARATION D
XVIII
XVII
SCHEME 1
VIII
In reaction 1 of preparation A, the compound of formula XII was converted to the corresponding isocyanate compound of formula XI by the reaction of XII with triphosgene in the presence of a base, such as triethylamine, diisopropylethylamine or 1,8-diazabicyclo [5.4.0.] Undec-7-ene, and an aprotic solvent, such as tetrahydrofuran, benzene or methylene chloride. The mixture was stirred and heated to reflux for a period of time
comprised between about 1 hour to about 3 hours, preferably about 2 hours. In reaction 1 of preparation B, the compound of the formula
XIV was converted to the corresponding sulfonamide compound of formula XIII by the addition of an alkyl lithium, such as n-butyl-, sec-butyl- or tert-butyl lithium, to a stirred solution of XIV in a polar solvent, such as tetrahydrofuran, at a temperature comprised between about -70 ° C to about -85 ° C, preferably about -78 ° C. After about 15 minutes, liquid sulfur dioxide was added to the reaction mixture thus formed, stirred at about -78 ° C for 5 minutes, and then heated to room temperature for a period of time comprised between about 1 hour to about 3 hours, preferably about 2 hours. Then, the mixture (a) was concentrated in vacuo, and treated either with a coloring reagent, such as N-chlorosuccinimide in a polar solvent; such as methylene chloride, followed by treatment with gaseous or aqueous ammonia, or (b) was treated with hydroxylamino or sulphonic acid in water in the presence of a buffer, such as sodium acetate. In reaction 1 of preparation C, the compound of formula XVI was converted to the corresponding sulfonamide compound of the formula
XV by adding a solution of sodium nitrate in water to a stirred solution of XVI in a mixture of acetic acid and hydrochloric acid. Next, saturated acetic acid was added with gaseous sulfur dioxide
followed by cuprous chloride. The reaction mixture thus formed was stirred at a temperature between about -10 ° C to about 10 ° C, preferably about 0 ° C, for a period of time from about 1 hour to about 3 hours, preferably about 2 hours. Next, the resulting sulfonyl chloride was treated with gaseous or aqueous ammonia bubbled through a solution of the sulfonyl chloride in an aprotic solvent, such as methylene chloride or ether. In reaction 1 of preparation D, the compound of formula XVIII was converted to the corresponding sulfonamide compound of formula XVII by the reaction of XVIII with chlorosulfonic acid in a polar aprotic solvent, such as chloroform at a temperature comprised between approximately - 10 ° C to about 10 ° C, preferably about 0 ° C. The reaction mixture thus formed was heated to approximately 60 ° C. After a period of time from about 1.5 hours to about 2.5 hours, preferably 2 hours, the reaction mixture was once again cooled to a temperature of about 0 ° C and poured onto ice. Next, the resulting sulfonyl chloride was treated with gaseous or aqueous ammonia bubbled through a solution of the sulfonyl chloride in an aprotic solvent such as methylene chloride or ether. In reaction 1 of scheme 1, the isocyanate compound of formula X and the sulfonamide compound of formula IX were converted to the
corresponding sulfonyl urea compound of the formula VII by the reaction of IX and X in the presence of a base, such as sodium hydride, sodium hydroxide, triethylamine or 1,8-diazabicyclo [5. 4. 0] un-dec-7-ene, and a polar solvent, such as tetrahydrofuran, acetone or dimethylformamide. The reaction mixture thus formed was heated to reflux for a period of time from about 10 hours to about 14 hours, preferably 12 hours.
INHIBITION OF ATP LIBERATION INDUCED BY IL-1 B
Mononuclear cells from 100 ml of isolated blood were purified using LSM (Organon Teknika). Heparinized blood (1.5 ml of 1000 units / ml of heparin for Apotheconis injectin was added to each heparinized blood) was diluted with 20 ml of medium (RMI 1640, 5% FBS, penicillin / streptomycin 1%, HEPES 25 mM, pH 7.3). Thirty ml of the diluted blood was layered on 15 ml of LSM (Organon Teknika) in a 50 ml conical polypropylene centrifuge tube. The tubes were centrifuged at 1200 rpm for 30 minutes in a Sorvall bench-top centrifuge at room temperature. The mononuclear cells located at the plasma interface and LSM were separated, diluted with medium in order to achieve a final volume of 50 ml, and collected by centrifugation as indicated above. The supernatant was discarded and the cell pellet was washed 2 times with 50 ml of medium. Before
from the second wash, 10 μl of sample was extracted from the suspended cells for counting; based on this count, the washed cells were diluted with the medium to a final concentration of 2.0 x 106 cells / ml. To each 96-well plate cavity 0.1 ml of the cell suspension was added. The monocytes were allowed to adhere for 2 hours and then the non-adherent cells were removed by aspiration and the cell units were washed twice with 100 μl of medium. To each well was added 100 μl of medium, and the cells were incubated overnight at 37 ° C in a 5% carbon dioxide incubator. The next day, 25 μl of 50 mg / ml LPS (medium) was added to each well and the cells were activated for 2 hours at 37 ° C. The test agents were diluted with dimethyl sulfoxide to a final concentration of 10 mM. From this mother solution, the compounds were diluted, first, 1: 50 [5 μl of 10 mM stock solution + 245 μl of Chase Medium (RPMI 1640, 25 mM HEPES, pH 6.9, 1% FBS, 1% penicillin / streptomycin, 10 ng / ml of LPS and 50 mM sodium bicarbonate.] A second dilution was prepared by diluting 10 μl of the 200 μM assay agent to 90 μl of Chase Medium, giving a final concentration of the 20 μM assay agent, at this point, the concentration of the dimethyl sulfoxide was 0.2% The monocytes activated with LPS were washed once with 100 μl of Chase Medium and then 100 μl of Chase Medium (0.2% dimethyl sulfoxide content) was added to each cavity. To the cavities
Appropriate, 0.01 1 ml of the 20 μM assay agent solutions were added, and the monocytes were incubated for 30 minutes at 37 ° C. At this point, 2 mM ATP was introduced by the addition of 12 μl of a 20 mM stock solution (previously adjusted to pH 7.2 with sodium hydroxide) and the cells were incubated for an additional 3 hour period at 37 ° C. The 96-well plates were centrifuged for 10 minutes at 2000 rpm in a benchtop Sorvall centrifuge in order to remove the cells and cell debris. A 90 μl aliquot was removed from each supernatant and transferred to a 96-well round bottom plate, and this plate was centrifuged a second time in order to ensure that all cell debris had been removed. Thirty μl of the resulting supernatant were added to each well of an ELISA plate.
IL-1 ß, which, likewise, contained 70 μl of PBS and 1% FBS. The plate
ELISA was incubated overnight at 4 ° C. The ELISA plate (R & D Systems) was manipulated following the instructions of the game.
Data calculation and analysis: The proportion of immunoreactivity of IL-1β in the samples of Medio Chase was calculated as follows:% control = (XB) /) (TOT-B) x 100 in which: X OD = 450 nm from the cavity of the test compound.
B = OD at 450 nm of the blank reagent cavities of the ELISA plate. TOT = OD at 450 nm of the cells that were treated only with 0.2% dimethyl sulfoxide. The compounds of the present invention can be administered in a wide variety of different dosage forms; In general, the therapeutically effective compounds of this invention are present in said dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used, together with various disintegrants such as starch (and, preferably, corn starch, potato or tapioca), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for compaction purposes. Similarly, solid compositions of a similar type such as gelatin capsule fillers may be used; Preferred materials related thereto also include milk sugar or lactose, as well as polyethylene glycols of high molecular weight. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may
combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying and / or suspending agents, as well as, together with diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration (for intramuscular, intraperitoneal, subcutaneous and intravenous use) a sterile injectable solution of the active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention may be used either in sesame or peanut oil, or aqueous propylene glycol. The aqueous solutions should be adequately adjusted and buffered, preferably at a pH above 8, if necessary, and, first, the liquid diluent made isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art. The present invention is illustrated by the following examples, but is not limited to the details thereof.
PREPRARE \ CION A 3-tert-Butylsulfamoyl-Benzenesulfonyl Chloride
A solution of 1.46 grams (20 moles) of t-butylamine and 2.02 grams (20 mmoles) of triethylamine in tetrahydrofuran was added dropwise to a solution of 5.5. grams (20 mmoles) of 1,3-benzenedisulfonyl chloride in tetrahydrofuran. The reaction was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo. The residue was purified on silica gel, eluting with methylene chloride, afforded 3.86 grams of the title compound as an oil.
PREPARATION B Terc-buti 1-amide methylamide of benzene-1,3-disulfonic acid
Five ml of a 33% solution of methylamine in ethanol was added to a solution of 1.8 grams (7 ml) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. The mixture was stirred for 2 hours. The ethyl acetate layer was separated and concentrated in vacuo. The residue was purified on silica gel, eluting with 5% methanol in dichloromethane, yielding 1.32 grams of the title compound as a white solid.
PREPARATION C Tert-butyl-amide dimethylamide of benzene-1,3-disulfonic acid
Dimethylamine gas was allowed to bubble for 3 minutes into a solution of 1.8 grams (7 ml) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. Water was added and the mixture was stirred at room temperature for 1 hour. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo to a solid, which was triturated with hexane / isopropyl ether to give 1.59 grams of the title compound, mp. 100-102 ° C.
PREPARCJON D Amide tert-butyl amide benzene-1,3-disulfonic acid
ml of concentrated ammonium hydroxide was added to a solution of 1 gram (3.2 mmol) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. It was stirred vigorously for 8 hours. The ethyl acetate layer was separated, dried over magnesium sulfate in vacuo to give 320 mg of the title compound as a white solid. P.fus. 151 -154 ° C.
PREPARATION E Tert-butyl-amide cyclopropylamide of benzene-1,3-disulfonic acid
A mixture of 5 mL of cyclopropylamine and 10 mL of water was added to a solution of 1 grams (3.9 mmol) of 3-tert-butylsulfamoyl-benzenesulfonyl in ethyl acetate. The mixture was stirred at room temperature for 2 hours. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo to an oil, which was crystallized from isopropyl ether to give 839 mg of the title compound as a solid.
PREPARATION F Tert-butylamide cyclobutylamide benzene-1,3-disulfonic acid
Using a procedure similar to that described in Preparation E, 4 mL of cyclobutylamide was added to 1 grams (3.9 mmol) of 3-tert-butylsulfamoyl-benzenesulfonium chloride, yielding 813 mg of the title compound.
PREPARATION G Methylamide of benzene-1 acid. 3-disulfonic
A solution of 1.3 grams (4.3 mmoles) of tert-butylamide methylamide of benzene-1,3-disulfonic acid in 15 ml of trifluoroacetic acid containing 1 drop of anisole was stirred at room temperature for 12 hours. The trifluoroacetic acid was evaporated in vacuo and the residue was triturated with methylene chloride to provide 330 mg of the title compound, mp 124-126 ° C. The compounds of the epigraphs of the H-J preparations were prepared by a procedure analogous to that described in Preparation G, using the indicated starting material.
PREPARATION H Amine dimethylamide benzene-1,3-disulfonic acid
Tert-butyl-amide dimethylamide of benzene-1,3-disulfonic acid. P.fus: 166-167 ° C.
PREPARATION I Cyclopropylamide amide benzene-1,3-disulfonic acid
Tert-butyl-amide cyclopropylamide of benzene-1,3-disulfonic acid. P.fus: 120-121 ° C.
PREPARATION J Cyclobutylamide amide of benzene-1,3-disulfonic acid
Tert-butyl-amide cyclobutylamide of benzene-1,3-disulfonic acid. P.fus: 128-130 ° C.
PREPARATION K 3-Methylsulfanyl-benzenesulfonamide
A solution of 1.6 M n-butyllithium (12.5 ml, 20 mmol) in hexane was added to a solution of m-bromothioanisole (4.06 grams, 20 mmol). The solution thus formed was stirred at -78 ° C for 3 hours. Next, sulfur dioxide was bubbled into the reaction until it became acidic. The reaction was allowed to warm to room temperature overnight. A solution of N-chlorosuccinimide (2.4 grams, 78 mmol) in methylene chloride was added and after stirring for 1 hour at room temperature, it was evaporated in tetrahydrofuran. The residue is
it was suspended in methylene chloride and filtered. The filtrate was mixed with concentrated ammonium hydroxide and stirred at room temperature for 1 hour. The methylene chloride layer was dried and evaporated. The residue was triturated with methylene chloride, yielding 1.5 grams of the title compound. P.fus .: 126-127 ° C.
PREPARATION L 3-Methanesulfinyl-benzenesulfonamide
A mixture of 3-methylsulfanyl-benzenesulfonamide (406 mg, 2 mmol) and N-chlorosuccinimide (268 mg, 2 mmol) in methanol was stirred at room temperature for 8 hours. The methanol was evaporated and the residue was suspended with methylene chloride and filtered. The filtrate was evaporated, yielding 250 mg of the title compound as a white solid.
PREPARATION M 3-Methanesulfonyl-benzenesulfonamide
To a solution of 3-methylsulfanyl-benzenesulfonamide (500 mg,
2. 5 mmole) in acetone, an aqueous solution of OXONER (3.2 grams, 5 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction was evaporated to dryness in vacuo. The residue was triturated with
acetone and filtered. The filtrate was evaporated, providing 460 mg of the title compound.
PREPARATION N 1 - (3-Bromophenyl) cyclobutanol
To a solution of 1,3-dibromobenzene (2.36 grams, 10 mmol) in tetrahydrofuran at -78 ° C, a 1.6 M solution of n-butyllithium (6.3 mL, 10 mmol) in hexane was added and stirred for 4 hours. hours. Then, cyclobutanone (700 mg, 10 mmol) was added in a single portion. After stirring for 2 hours at -78 ° C, the reaction was quenched with 2 N hydrochloric acid. The reaction was warmed to room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was dried and evaporated, yielding 2.5 grams of crude product, which was purified on silica gel, eluting with 50% methylene chloride in hexane, yielding 1.5 grams of the title compound.
PREPARATION OR 3- (1-Hydroxycyclobutyl) benzenesulfonamide
A solution of 1.6 M n-butyllithium (8 ml, 12.8 mmol) in hexane was added a solution of 1- (3-bromo-phenyl) cyclobutanol (1.44 grams, 6.4 mmol) in tetrahydronyl chloride. 78 ° C. After 30 minutes, the reaction
it was allowed to warm 0 ° C. Sulfur dioxide was bubbled into the reaction mixture and stirred for an additional 30 minutes. The tetrahydrofuran was evaporated and an aqueous solution of sodium acetate (4.1 grams, 50 mmol) and hydroxylaminosulfonic acid (1.85 grams,
16 mmol). After stirring at room temperature for 2 hours, the reaction was acidified with 2N hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate was dried over sodium sulfate and evaporated.
The residue was purified on silica gel with dichloromethane / ether to give 70 mg of the title compound.
PREPARATION P 1- (3-Bromophenyl) cyclopentanol
Using a procedure similar to that of preparation N, from 2.36 grams of 1,3-dibromobenzene, 6.3 ml of 1.6 M n-butyl-lithium and 840 mg of cyclopentanone, 1.56 grams of 1- (3-bromophenyl) were obtained. in the form of cyclopentanol in the form of an oil.
PREPARATION Q 3- (1-Hydroxycyclopentyl) -6-benzenesulfonamide
Using a procedure similar to that of preparation O, from 1.5 grams of 1- (3-bromophenyl) cyclopentanol, 7.9 ml of 1.6 M n-butyllithium,
1. 85 grams of hydroxylamino-O-sulfonic acid and 4.1 grams of NaOAc, 220 mg of 3- (1-hydroxycyclopentyl) benzenesulfonamide was obtained, as a white solid from diclomethane. P.fus .; 146-148 ° C.
PREPARATION R 1- (3-Bromophenyl) cyclohexanol
Using a procedure similar to that of preparation N, from 20 grams (85 mmol of 1,3-dibromo-benzene, 53 ml of 1.6 M n-butyl-lithium in hexane and 8.3 grams of cyclohexanone, 4.9 grams of 1- (3-bromophenyl) cyclohexanol in the form of a white solid.
PREPARATION S 3- (1-Hydroxycyclohexyl) benzenesulfonamide
A 1.6 M solution of n-butyllithium (12.35 mL, 19.8 mmol) in hexane was added to a solution of 1- (3-bromophenyl) cyclohexanol (2.4 grams, 9.4 mmol) in tetrahydrofuran at -78 ° C. The reaction was stirred for 1 hour and then sulfur dioxide was bubbled into the solution until it became acidic by wetting the pH paper. The reaction was allowed to warm to room temperature over 12 hours. N-chlorosuccinimide (1.38 grams, 10.3 mmol), dissolved in dichloromethane, was added and the reaction was stirred for 2 hours. Tetrahydrofuran and the residue were evaporated
it was suspended with methylene chloride and filtered. The filtrate was evaporated until
2. 1 gram of 3- (1-hydroxycyclohexyl) benzenesulfonyl chloride in the form of a brown oil. This was dissolved in methylene chloride and added, dropwise, to 20 ml of liquid ammonia. The ammonia was allowed to evaporate and the residue was purified on silica gel with dichloromethane / methanol to give 250 mg of the title compound as a white solid. The compounds of the epigraphs of the T-V preparations were prepared by a procedure analogous to that described in the preparation
K, using the indicated starting material.
PREPARATION T 3- (2-Methyl-M .31d-oxolan-2-yl) benzenesulfonamide
2- (3-Bromophenyl) -2-methyl- [1, 3] dioxolane. P.fus .: 96-98 ° C.
PREPARATION U 3 - ri. 31 Dioxolan-2-yl benzenesulfonamide
2- (3-Bromophenyl) - [1, 3] dioxolane. P.fus .: 55-58 ° C.
PREPARATION V 2-Fluoride-5- (2-methyl-ri, 31-d¡oxolan-2-yl) benzenesulfonamide
2- [3-Bromo-4-fluorophenyl] -2-methyl- [1, 3] dioxolane. P.fus .: 149- 150 ° C.
PREPARATION W (2- r4-Bromo-2-n¡trofen¡p vinyl) dimethyl amine
A solution of 27 grams (0.125 moles) of 4-bromo-1-methyl-2-nitrobenzene and 1 ml (0.31 moles) of N, N-dimethylformamide dimethyl acetal in 120 ml of DMF was heated at 80 ° C for 2 hours. hours. After cooling, the reaction was poured into water and extracted with ethyl acetate. It was then dried over sodium sulfate and evaporated to give 36 grams of the title compound as a purple solid.
PREPARATION X (2- r4-Bromo-2-nitrophenin ethylidene) hydrazide of acetic acid i A solution of 36 grams of crude (2- [4-bromo-2-nitrophenyl] vinyl) dimethylamine in 75 ml of dimethylformamide was cooled to 0 ° C. A solution of 26 grams of semicarbacide hydrochloride in 200 ml of water was added. Then, 20 ml of concentrated hydrochloric acid was added.
The resulting solution was allowed to warm to room temperature.
A tan precipitate was filtered, washed with water and dried.
PREPARATION AND 6-bromo-1 H-indole
A solution of 375 grams of iron (II) sulfate heptahydrate in 700 ml of water was added to a suspension of 35 grams of (2- [4-bromo-2-nitrophenyl] ethylidene) hydrazide of crude acetic acid in 300 ml of concentrated ammonium hydroxide. The mechanically stirred mixture was refluxed for 4 hours and then cooled and filtered. The precipitate was triturated several times with hot ethyl acetate. The combined ethyl acetate layers were dried and evaporated to give 18 grams of the title compound.
PREPARATION Z 1 H-Indole-6-sulfonic acid amide
To a suspension of 3.5 grams (0.03 mole) of 35% KH in mineral oil in ether at 0 ° C, a solution of 6.0 grams (0.03 mole) of 6-bromo-1 H-indole was added dropwise. . After stirring for 1 hour, the light yellow solution was cooled to -78 ° C. 36.5 ml (0.06 moles) of a 1.7 m solution of t-butyl lithium in pentane were added dropwise.
After stirring for 1 hour at -78 ° C, SO2 (gas) was bubbled into the solution for 5 minutes. The reaction was allowed to warm to room temperature overnight. One solution was added in a single portion
4. 1 grams (0.03 moles) of N-chlorosuccinimide. After stirring
1 hour, the reaction was filtered to remove the succinimide and the filtrate was evaporated to a yellow solid. This was dissolved in tetrahydrofuran and added to 20 ml of liquid ammonia. The reaction was allowed to warm to room temperature. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated, yielding 1.4 grams of the title compound.
PREPARATION AA 5-Fluoro-2,3-dihydro-1 H-indole
A solution of 6.8 grams (0.05 moles) of 5-fluoro-1 H-indole in
50 ml of ether, cooled to 0 ° C under nitrogen. 507 ml of a 0.15 M solution of borohydride in zinc in ether were added dropwise. The reaction was allowed to stir for 48 hours. The reaction was quenched with dilute hydrochloric acid. The pH was adjusted to 8.0 with dilute sodium hydroxide. The ether layer was separated, dried and evaporated, yielding 7 grams of the title compound.
PREPARATION BB 1 - (5-Fluoro-2,3-dihydro-indolyl) etonone
Acetyl chloride (3 ml) was added dropwise to a solution of 7 grams of crude 5-fluoro-2,3-dihydro-1 H-indole and 3 ml of triethylamine in 100 ml of CH 2 Cl 2 at 0 ° C. . After 2 hours, the reaction was diluted with water. The methylene chloride layer was separated, dried and evaporated, giving 7.3 grams of the crude product, which was purified on silica gel, eluting by hexane / ethyl acetate, yielding 3.3 grams of the title compound.
PREPARATION CC 1-Acetyl-5-fluoro-2,3-dihydro-1 H-indol-6-sulfonic acid amide
Chlorosulfonic acid (35 ml) was cooled to 0 ° C under nitrogen. 3 grams (0.016 moles) of 1- (5-fluoro-2,3-dihydro-indolyl) ethanone were added in portions. The reaction was heated at 50 ° C for 3 hours, cooled and poured on ice. The resulting white precipitate was separated by filtration and dissolved in methylene chloride. A concentrated ammonium hydroxide solution was added and the mixture was stirred at room temperature for 1 hour. The volatiles were evaporated in vacuo and dilute hydrochloric acid was added. The precipitate was filtered and washed with water, yielding 3.6 grams of the title compound.
PREPARATION DD 5-Fluoro-2,3-dihydro-1 H-indole-6-sulfonic acid amide
A mixture of 3.6 grams of 1-acetyl-5-fluoro-2,3-dihydro-1 H-indole-6-sulfonic acid amide and 30 ml of 2N sodium hydroxide were heated at 100 ° C for 3 hours. The reaction was cooled and the pH adjusted to 7.0 with acetic acid. The resulting precipitate was filtered, yielding 3.0 grams of the title compound.
PREPARATION EE 5-Fluoro-1 H-indol-6-sulfonic acid amide
A mixture of 3 grams of manganese dioxide and 3 grams of 5-fluoro-2,3-dihydro-1 H-indole-6-sulfonic acid amide in 30 ml of dioxane was heated at 50 ° C for 1 night. The reaction was filtered and the filtrate was evaporated, affording the crude product, quai, purified on silica gel, eluting with methylene chloride / ethyl acetate, -providing 1.1 grams of the title compound. P. fus. 181-182 ° C.
PREPARATION FF 2- (3-Bromophenyl) propan-2-ol
To a stirred solution of methylmagnesium bromide (60 ml of a 3.0 M solution in diethyl ether) at 0 ° C, a solution of 3-bromoacetophenone (29.8 g) in 75 ml of diethyl ether was added dropwise. After the addition was complete, the mixture was stirred for 0.5 hour and poured into water. The aqueous phase was acidified with 1 M hydrochloric acid and extracted with three portions of diethyl ether. The combined ether layers were washed with saturated sodium bicarbonate and concentrated to provide 30.4 grams of the title compound. 1H NMR 7.72 (ar s, 1), 7.49 (d, 1, J = 7.8), 7.37 (d, 1, J = 7.9), 7.25 (dd, 1, J = 7.8, 7.9), 4.19 (s, 1), 1.50 (brs, 6).
PREPARATION GG 2- (3-Aminosulfonylphenyl) propan-2-ol
To a stirred solution of 2- (3-bromophenyl) propan-2-ol (30 grams) in tetrahydrofuran (1.5 I) at -78 ° C, methyl lithium (10 ml of a 1.4 M solution in diethyl ether was added. ). The solution was stirred at -78 ° C for 15 minutes and then, butyllithium (61 ml of a 2.5 M solution in hexane) was added. The solution was stirred for 15 minutes at -78 ° C, at which time, a suspension formed. To this suspension liquefied sulfur dioxide (approximately 5 equivalents) was added in a single portion. The suspension
it was stirred at -78 ° C for 5 minutes and then warmed to room temperature and stirred for an additional 2 hours. The mixture was concentrated in vacuo to give a yellow solid, which was taken up in water (418 ml). To the aqueous solution was added sodium acetate (190 grams) and hydroxylamino-O-sulfonic acid (47.3 grams) and the solution was stirred overnight. The mixture was extracted with ethyl acetate and the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography (2: 1, ethyl acetate / hexane) provided 27 grams of the title compound, p. fus 107.2-108.2 ° C.
PREPARATION HH 4-Chloro-2,6-diisopropylaniline
To a stirred solution of 2,6-diisopropylaniline (47 grams) in dimethylformamide (886 ml) was added N-chlorosuccinimide (37.3 grams) and the mixture was stirred overnight. The resulting dark red solution was poured into water (12 L) and extracted with diethyl ether. The combined ether extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting dark red oil was purified by filtration through silica gel, eluting with 6: 1 hexane / methylene chloride, providing 32
grams of the compound of the epigraph. 1 H NMR 7.02 (s, 2), 3.71 (ar s, 2), 2.91
(qq, 2, J = 6.9 Hz), 1 .27 (d, 6, J = 6.9 Hz), 1.27 (d, 6, J = 6.9 Hz),
PREPARATION II 4-Chloro-2,6-diisopropylphenyl isocyanate
To a stirred solution of 4-chloro-2,6-disopropylamine (32 grams) and triethylamine (7.8 ml) in tetrahydrofuran (505 ml), triphosgene (14.9 grams) was added. The mixture was refluxed for 2 hours with stirring. Then, the tetrahydrofuran was removed in vacuo and the resulting oil was taken up in pentane and filtered through silica gel, yielding 33.3 grams of the product. 1 H NMR 7.18 (s, 2), 3.22 (qq, 2, J = 7.1 Hz), 1.25 (d, 6, J = 7.1 Hz), 1.25 (d, 6, J = 7.1 Hz).
PREPARATION JJ 2-r3-rrr (4-chloro-2,6-disopropylphenylamino) amino-1-carbonyl-1-amino-sulphonylphenyl] -propan-2-ol]
To a stirred solution of 2- (3-aminosulfonylphenyl) propan-2-ol (26.5 grams) in tetrahydrofuran was added sodium hydride (5.2 grams of a 60% dispersion in mineral oil) in several portions. Once the evolution of hydrogen was complete, 4-chloro-2,6-disio-propylphenylisocyanate (30.8 grams) was added in one portion, and the resulting mixture
it was heated to reflux for 12 hours. Then, the mixture was cooled to room temperature and concentrated in vacuo. The resulting foam was dissolved in water, basified with 1N sodium hydroxide, extracted with two portions of
1: 1 ether / hexane. The aqueous layer was acidified with 1 N hydrochloric acid, and the resulting white solid was filtered, washed with water and dried. This gave 50 grams of a white solid, which was recrystallized from ethyl acetate / dry hexane to give the title compound, mp. 160.5-162. 0 ° C.
PREPARATION KK 5-nitroisophthaloyl chloride
To a stirred solution of 5-nitroisophthalic acid (10 grams) in methylene chloride (943 ml), oxalyl chloride (12.3 ml) and N, N-dimethylformamide (1 drop) were added. The reaction mixture was stirred at room temperature overnight. Solvent removal in vacuo afforded 10.63 grams of the title compound. 1 H NMR 9.17 (s, 2), 9.07 (s, 1).
PREPARATION LL 3,5-Diacetylnitrobenzene
Magnesium shavings (2.27 grams) were stirred with ethanol (12 ml) and carbon tetrachloride (1 drop). Upon complete evolution of hydrogen, dimethyl malonate (15.19 grams) in diethyl ether (30 ml) was added and the mixture was refluxed until all the magnesium was consumed. 5-Nitroisophthaloyl chloride (10 grams) in tetrahydrofuran (29 ml) was added to the mixture and the reflux was continued for an additional period of 16 hours. The mixture was cooled in an ice bath and acidified with 10% sulfuric acid. The aqueous phase was extracted with ethyl acetate and the organic phase was concentrated in vacuo. The oily residue was taken up in acetic acid (72 ml) and water (14 ml) and sulfuric acid (4 ml) was added. The mixture was kept under vigorous reflux for 12 hours and then cooled in an ice bath. The mixture was neutralized with 3 M sodium hydroxide and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo to provide 7.54 grams of the title compound. 1 H NMR 8.90 (s, 2), 8.86 (s, 1), 2J8 (s, 6).
PREPARATION MM 3,5-Diacetylaniline
To a stirred solution of tin (II) chloride dihydrate (32.87 grams) in concentrated hydrochloric acid (93 ml) at 50 ° C, 3,5-diacetylnitrobenzene (7.54 grams) was added. The heat was removed immediately and an exotherm occurred. The mixture was stirred for 5 minutes, cooled in an ice bath and neutralized with saturated potassium carbonate solution. The aqueous phase was extracted with several portions of ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo to give 3.01 grams of the title compound. 1 H NMR 7.77 (s, 1), 7.48 (s, 2), 5.16 (br s, 2), 2.55 (s, 6).
PREPARATION NN 3, 5-DiacetH benzenesulfonamide
To a stirred solution of 3,5-diacetylaniline (3.00 grams) in a mixture of acetic acid (17 ml) and hydrochloric acid (5 J ml), a solution of sodium nitrate (1.27 grams) in 2.1 ml of water was added. The solution was stirred for 20 minutes. Fourteen ml of acetic acid were saturated with gaseous sulfur dioxide, and this mixture was added to the reaction, followed by cuprous chloride (0.63 grams). There was a significant foaming. The reaction mixture was stirred for one hour, diluted with water, and extracted
with three portions of ethyl acetate. The combined ethyl acetate extracts were washed with water and concentrated. The resulting oil was taken up in diethyl ether, and gaseous ammonia was bubbled through the solution. The resulting suspension was filtered, and the solid was taken up in acetone and filtered in order to remove the ammonium chloride. Removal of acetone in vacuo gave 1.48 grams of the title compound., P. fus 179.2- 180. 7 ° C.
PREPARATION OO 1 -r3-f G G (4-Chloro-2,6-diisopropylphenylamino) carbonyl] aminol-sulfonyl-5-acetylphenyl ethan-1-one
The title compound was prepared as described in Procedure AA from 3,5-diacetylbenzenesulfonamide (0.35 grams), 4-chloro-2,6-diisopropylphenylisocyanate (0.37 grams) and sodium hydride (0.06 grams of a dispersion). 60% in mineral oil), in tetrahydrofuran (4 ml). This provided 0.28 grams of the title compound, p.fus. 201.9-203. 4 ° C.
PREPARATION PP 3-Chloro-1-indan-5-yl-propan-1 -one
To a stirred solution of indan (300 grams) and 3-chloropropionyl chloride (323 grams) in methylene chloride (2 I) at 0 ° C, aluminum chloride (376 grams) was added over a period of 3 hours. hours. After the addition was complete, the cooling bath was removed and the mixture was warmed to room temperature and stirred until the evolution of hydrogen chloride ceased. The reaction was stopped by pouring it onto a mixture of 3.5 kg of ice and 700 ml of concentrated hydrochloric acid. The layers were separated, and the aqueous phase was extracted with methylene chloride. The combined methylene chloride layers were washed with water, sodium bicarbonate solution and brine. The organic phase was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from hexane, yielding 282 grams of a yellow solid, e.g. fus 63.5-65.1 ° C.
PREPARATION QQ 3.5,6,7-Tetrahydro-2H-s-indacen-1 -one
Concentrated sulfuric acid (550 ml) was added dropwise, with stirring over a period of 2 hours, to 137 grams of 3-chloro-1-indan-5-yl-propan-1-one. The resulting thick black solution was heated to 90 ° C until the evolution of hydrogen chloride ceased
(usually 1-4 hours). The mixture was then cooled to room temperature and poured onto 5 kg of ice. The resulting suspension was stirred overnight and filtered. The solid was washed with water until the water flowed transparent through the filter. Then, the tan solid was dried in vacuo and recrystallized from hexane, yielding 90 grams of the title compound, p.fus. 72.4-74.8 ° C.
PREPARATION RR 1, 2,3,5,6,7-Hexahydro-s-indacene
A mixture of 3,5,6,7-tetrahydro-2H-s-indacen-1-one (90 grams), ethanol (1 m), 10% palladium on carbon (1-2 grams) and concentrated hydrochloric acid ( 50 ml), was hydrogenated on a Parr shaker at room temperature until the evolution of hydrogen ceased. The mixture was filtered through a pad of Celite. The filler was washed with 1 l of diethyl ether. The filtrate was diluted with water and the organic phase was separated. The aqueous phase was extracted with 1 L of ether, and the combined ether extracts were washed with water, and saturated with sodium bicarbonate solution and brine. The ether extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting pale yellow solid was recrystallized from methanol, yielding 61 grams of the title compound as colorless crystals, p.f. 56.6-58.5 ° C.
PREPARATION SS 1 - (1, 2,3,5,6,7-Hexahydro-s-indacen-4-yl) ethanone
To a stirred solution of 1, 2,3,5,6,7-hexahydro-s-indacene (30 grams) and acetyl chloride (14.2 ml) in 120 ml of benzene at 0 ° C, 30 grams of chloride was added. of aluminum over a period of 1 hour. The cooling bath was removed and the solution was warmed to room temperature and stirred for 4 hours. Then, the deep red mixture was poured onto a mixture of 270 grams of ice and 50 ml of concentrated hydrochloric acid. The layers were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow solid, which was recrystallized from hexane to provide 34 grams of the title compound, p. .fus. 69.1-76.1 ° C.
PREPARATION TT Oxide of 1 - (1, 2,3,5,6J-hexahydro-s-indacen-4-yl) ethanone
A mixture of 1- (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) ethanone
(33 grams), ethanol (250 ml), hydroxylamine hydrochloride (58.5 grams) and pyridine (80 ml), was heated to reflux for a period of 12 hours. Then, the mixture was cooled to room temperature and concentrated in
empty. Then. The residue was treated with 500 ml of water and extracted with chloroform-methanol. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give 32 grams of the title compound as a mixture of the E and Z isomers, p. Fus. 178.6-182.3 ° C.
PREPARATION US N- (1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) acetamide
A mixture of 1- (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) ethanone oxime (85 grams) in 270 ml of trifluoroacetic acid was added dropwise to a stirred solution of 90 ml of trifluoroacetic acid over a period of 1/2 hour. The resulting purple solution was then refluxed for 1 hour. The solution was cooled to room temperature and the trifluoroacetic acid was removed in vacuo. The dark colored solid was triturated with ethyl acetate / hexanes to give 85 grams of a gray solid, which was used without further purification, p.f. 257.4-259.1 ° C.
PREPARATION W 1, 2,3,5,6, 7-Hexahydro-s-indacen-4-yl-amine
A suspension of N- (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) acetamide (1 10 grams) in 1 ml of 25% sulfuric acid was treated with
enough ethanol to obtain a solution (approximately 11 ml). The resulting solution was heated to reflux for a period of two days. The resulting black solution was treated with refluxing charcoal, filtered hot and cooled to 0 ° C. Then, the solution was carefully neutralized with 20% sodium hydroxide solution. Then, the resulting suspension was filtered and washed with water, until the filtrate flowed neutral. Then, the tan solid was isolated and dried in vacuo to give 80 grams of the title compound, p.f. 94.5-96.6 ° C, which was used without further purification. If necessary, the title compound can be recrystallized from methanol to give a white solid.
PREPARATION WW 1,2,3,5,6,7, -Hexahidro-s-indaceno
To a stirred solution of 1, 2,3,5,6,7-hexahydro-s-indacen-4-yl-amine (77 grams) in tetrahydrofuran (1.5 I) and triethylamine (68.3 ml), triphosgene (43.9) was added. grams) in a single portion. The mixture was refluxed for 1/2 hour and then cooled to room temperature. The tetrahydrofuran was removed under reduced pressure, and the residue was taken up in pentane and filtered through a plug of silica gel. Removal of pentane in vacuo gave 80 grams of a white solid, p.f. 35.0-36.2 ° C.
PREPARATION XX 3-f 1-Hydroxy-1-methyethylphenuran
To a stirred solution of 24.97 ml of methyl magnesium bromide (3M solution in diethyl ether) at 0 ° C, 4.82 ml of ethyl 3-furoate in diethyl ether was added. The mixture was heated gently using a hot water bath for 30 minutes. After heating was complete, the mixture was poured onto ice-water, carefully acidified using a buffered solution, and extracted with diethyl ether. The ether extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The tertiary furan alcohol was purified using flash column chromatography with hexane / ethyl acetate 6: 1. Recovery: 2.89 grams (64%). 1 H NMR (400 MHz, acetone-d 6) delta 1.45 (s, 3 H), 1.46 (s, 3 H), 3.89 (s s, 1 H), 6.45 (s s, 1 H), 7.41 (s s, 1 H ), 7.42 (ar, r 1 H).
PREPARATION YY 2-Aminosulfonyl-3- (1-hydroxy-1-methyl-di-furan)
To a stirred mixture of 2.89 grams of the tertiary furan alcohol in THF at -78 ° C, 17.1 ml of methyl lithium (1.4 M solution in diethyl ether) was added, followed 5 minutes after 18.51 ml of sec-butyl lithium (solution 1.3 M in cyclohexanes). The mixture was continued stirring 78 ° C
for 40 minutes and 5.02 ml of liquid SO2 was added. The temperature was maintained at -78 ° C for 5 minutes and then heated to room temperature with continued stirring for 2 hours. The THF was then removed in vacuo and the lithium sulphinate was dissolved in 76.4 ml of water, followed by the addition of 7J8 grams of hydroxylamine-O-sulfonic acid and 31 grams of sodium acetate. This mixture was stirred at room temperature for 1 night and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The sulfonamide was purified using flash column chromatography with 2: 1 hexane / ethyl acetate. Recovery: 1.91 grams (41%), p.fus. 110.1-111.6 ° C.
PREPARATION ZZ 3- (1-Hydroxy-1-methyl-di-thiofen)
To a stirred solution of 3.17 ml of methyl magnesium bromide (3M solution in diethyl ether) at 0 ° C, 1 gram of 3-acetylthiophene in diethyl ether was added. Then, the mixture was allowed to stir for 30 minutes while heating to room temperature. After the end of this period, the mixture was poured onto ice-water, acidified and extracted with diethyl ether. The ether extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. Recovery:
800 mg (71%). 1 H NMR (400 MHz, acetone-d 6) delta 1.50 (s, 6H), 400 (br s.
1 H), 7.15 (dd, 1 H, J = 1 .4, 5), 7.23 (m, 1 H), 7.33 (dd, 1 H, J = 3.1, 5).
PREPARATION AAA 2-Aminosulfonyl-3- (1-hydroxy-1-methylphenylthiophene)
To a stirred mixture of 800 ml of the thiophene tertiary alcohol in THF at 78 ° C, 4.22 ml of methyl lithium (1.4 M solution in diethyl ether) was added, followed 5 minutes later by 4.55 ml of sec-butyl lithium ( 1.3 M solution in cyclohexanes). The mixture was continued stirring at -78 ° C for 40 minutes and 1.23 ml of liquid SO2 was added. The temperature was maintained at -78 ° C for 5 minutes and then heated to room temperature with continued stirring for 2 hours. Then, the THF was removed in vacuo and the lithium sulfinate was dissolved in 19 ml of water, followed by the addition of 1.9 grams of hydroxylamine-O-sulfonic acid and 7.76 grams of sodium acetate. This mixture was stirred at room temperature overnight and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The sulfonamide was purified using flash column chromatography with 2: 1 hexane / ethyl acetate. Recovery: 600 mg (48%), p.fus. 1 14.3-1 15.1 ° C.
EXAMPLE 1 1 - (4-Chloro-2,6-diisopropyl-phenyO-3-r3- (1-hydroxy-1-methylethyl) benzenesulfonylurea
To a stirred solution of 2- (3-aminosulfonylphenyl) propane-2-ol
(26.5 grams) in tetrahydrofuran, sodium hydride (5.2 grams of a 60% dispersion in mineral oil) was added in several portions. After the evolution of hydrogen was complete, 4-chloro-2,6-diisopropylphenylisocyanate (30.8 grams) was added in a single portion, and the resulting mixture was heated to reflux for 12 hours. Then the mixture was cooled to room temperature and concentrated in vacuum. The resulting foam was dissolved in water, basified with 1N sodium hydroxide and extracted with two portions of a 1: 1 ether / hexane ratio. The aqueous layer was acidified with 1 N hydrochloric acid, and the resulting white solid was filtered, washed with water and dried. This gave 50 grams of a white solid, which was recrystallized from ethyl acetate / dry hexane to give the title compound, mp 160.5-162.0 ° C. The compounds of Examples 2-130 were prepared by a procedure analogous to that described in Example 1 using the reagents indicated.
EXAMPLE 2 1- (4-Chloro-2,6-diisopropyl-phenyl) -3-r3- (1-hydroxycyclopentyl) -benzenesulfonylurea
3- (1-Hydroxycyclopentyl) -bezenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P.fus. 155 ° C.
EXAMPLE 3 1- (4-Chloro-2,6-diisopropyl-phenyl) -3-r3-methylsulfamoyl-benzenesulfonipurea
3-Methylsulfamoyl-becenosulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P.fus. 125-128 ° C.
EXAMPLE 4 1- (4-Chloro-2,6-diisopropyl-phenyl) -3-r3-methylsulfamoyl-benzenesulfonylurea
3-Dlmethylsulfamoyl-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P.fus. 101-106 ° C.
EXAMPLE 5 1- (4-Chloro-2,6-diisopropyl-phenyl) -3-r3-cyclopropylsulfamoyl-benzenesulfonylurea
3-Cyclopropyl-iso-fluoro-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 170-174 ° C.
EXAMPLE 6 1- (4-Chloro-2,6-diisopropyl-phenyl) -3-r3-cyclobutylsulfamoyl-benzenesulfonylurea
3-Cyclobutylsulfamoyl-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 140-143 ° C.
EXAMPLE 7 1- (4-Chloro-2,6-diisopropyl-phenyl) -3-f3-methylsulfanyl-benzenesulfonylurea
3-Methylsulfanyl-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 125-126 ° C.
EXAMPLE 8 1- (4-Chloro-2,6-diisopropyl-phen »0-3-r3-methanesulfinyl-benzenesulfoninurea
3-Methylsulfinyl-benzenesulfonamide; 4-chloro-2,6-disopropyl-phenyl isocyanate. P. fus. 226-227 ° C. 3-Methylsulfanyl-benzenesulfonamide; 4-Cyano-2,6-diisopropyl-phenyl isocyanate. P. fus. ° C.
EXAMPLE 9 1- (4-Chloro-2,6-diisopropyl-phenyl) -3-r3-methanesulfonyl-benzenesulonnurea
3-Methylsulfonyl-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. ° C.
EXAMPLE 10 1- (4-Chloro-2,6-diisopropyl-phenyD-3-r3- (1-hydroxycyclobutyl) -benzenesulfonylurea
3- (1-Hydroxycyclobutyl) -benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl socianate. P. fus. 155-157 ° C.
EXAMPLE 11 1- (4-Chloro-2,6-diisopropyl-phenyl) -3-r3- (1-hydroxycyclopentyl) -benzenesulfonylurea
3- (1-Hydroxycyclopentyl) -benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenylisocyanate. P. fus. 155 ° C.
EXAMPLE 12 1- (4-Chloro-2,6-diisopropyl-phenyD-3-r3- (1-hydroxycyclopentylbenzenesulfonylurea
3- (1-Hydroxycyclohexyl) -benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 172-176 ° C.
EXAMPLE 13 1- (4-Chloro-2,6-diisopropyl-phenin-3-r3- (2-methyl-p, 31-dioxolan-2-yl) -benzenesulfonylurea
3- (2-Methyl- [1,3] dioxolan-2-yl) -benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 155-157 ° C.
EXAMPLE 14 1- (4-Chloro-2,6-diisopropyl-phenyD-3-r3-H, 31-dioxolan-2-yl-benzenesulfonylurea)
3 - ([1, 3] Dioxolan-2-yl) -benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 145-147 ° C.
EXAMPLE 15 1-r4-Chloro-2,6-diisopropyl-phenin-3- (2-fluoro-5- (2-methyl-p.31-dioxolan-2-benzenesulfonylurea)
3- (2-Fluor-5- (2-methyl- [1, 3] dioxolan-2-yl) -benzenesulfonamide; 4-chloro-2,6-düsopropyl-phenyl isocyanate, P. fus. 168-170 ° C.
EXAMPLE 16 1-r 2-Fluor-5- (2-methyl-p. 31-dioxolan-2-y-benzenesulfonip-3- (1.2.3.5.6.7- hexahydro-5-indacen-4-yl) urea
EXAMPLE 17 January -f4-Chloro-2.6-diisopropyl-phenyl) -3-n H -indole-ß-sulfonillurea
3- (1 H -indole-6-sulfonamide) -benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 220-221 ° C.
EXAMPLE 18 1 - (1, 2,3,5,6,7-Hexahydro-5-indacen-4-yl) -3-H H -indole-6-sulfoninurea
EXAMPLE 19 1- (4-Chloro-2,6-disisopropii-phenyl) -3- (5-fluoro-1H-indole-6-sulfonyl) -urea
3- (5-Fluor-1 H-indol-6-suphonamide) -benzenesulfonamide; 4-chloro-2,6-düsopropyl-phenyl socianate. P. fus. 226-227 ° C.
EXAMPLE 20 1-r5-Fluor-1 H-indol-6-sulfonip-3- (1,2,3,5,6,7-hexahydro-5-indacen-4-urea)
EXAMPLE 21 1- (4-Chloro-2,6-diisopropyl-phenyl) -3-r3- (1-hydroxy-ethyl) -5-trifluoromethyl-benzenesulfonylurea
3- (1-Hydroxy-ethyl) -5-trifluoromethyl-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl socianate. P. fus. 168.9-170.0 ° C.
EXAMPLE 22 1- (3-Acetyl-5-trifluoromethyl-benzenesulfonin-3- (4-chloro-2,6-diisopropyl-phenylPurea
3-Acetyl-5-trifluoromethyl-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 157.4-158.9 ° C.
EXAMPLE 23 1- (4-Chloro-2,6-diisopropii-phenyl-3-r3- (1-hydroxy-ethyl-4-methyl-benzenesulfonylurea
3- (1-Hydroxy-ethyl) -4-methyl-benzenesulfonamide; 4-chloro-2,6-disipropyl-phenyl socianate. P. fus. 155.2-158.2 ° C.
EXAMPLE 24 1- (3-Acetyl-4-methyl-bencenosulfoniP-3- (4-chloro-2,6-diisopropyl-phenyl) -urea
3-Acetyl-4-methyl-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 152.5-154.6 ° C.
EXAMPLE 25 1-r3,5-Bis- (1-hydroxy-etiPenzenesulfonin-3- (4-chloro-2,6-diisopropylpheniPurea
3,5-Bys- (1-hydroxy-ethyl) benzenesulfonamide; 4-Chloro-2,6-düsopropyl-phenyl socianate. P fus. 175.3-176.8 ° C.
EXAMPLE 26 1 - (4-Chloro-2β-diisopropyl-phenyl-3-r3- (1-hydroxy-ethyl-5-iodo-benzenesulfonylurea
3- (1-Hydroxy-ethyl) -5-iodo-benzenesulfonamide; 4-chloro-2,6-düsopropyl-phenyl isocyanate. P. fus. 184.4-186.6 ° C.
EXAMPLE 27 1- (3-Acetyl-5-vodo-bencenosulfoniP-3- (4-chloro-2,6-diisopropyl-feniPurea
3-Acetyl-5-iodo-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 187.6-188.9 ° C.
EXAMPLE 28 1- (4-Chloro-2,6-diisopropyl-phenyl-3-r4-fluoro-3- (1-hydroxyethylP-benzenesulfonylurea
4-Fluor-3- (1-hydroxy-ethyl) -benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl socianate. P. fus. 149.7-151.8 ° C.
EXAMPLE 29 1 - (3-Acetyl-4-fluoro-benzenesulfoniP-3- (4-chloro-2,6-diisopropyl-phenyl) urea
3-Acetyl-4- (fluoro-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate, P. fus 171.8-173.4 ° C.
EXAMPLE 30 1- (4-Acetyl-thiophene-2-sulfoniP-3- (4-chloro-2,6-d¡isopropil-phenyl) urea
4-Acetyl-thiophene-2-sulfonamide; 4-chloro-2,6-diisopropyl-phenyl socianate. P. fus. 169.7-171.8 ° C.
EXAMPLE 31 1- (4-Chloro-2,6-diiopropyl-phen-P-3-r4- (1-hydroxy-etiP-thiophene-2-sulfoninurea
4- (1-Hydroxy-ethyl) -thiophene-2-sulfonamide; 4-chloro-2,6-diisopropyl-phenyl sodanate. P fus. 164.5-166.6 ° C.
EXAMPLE 32 1- (4-Chloro-2,6-diisopropyl-phenyl-3-r3- (2-hydroxyimino-propiP-benzenesulfonylurea
3- (2-Hydroxyminopropyl) -benzenesulfonyl; 4-chloro-2,6-düsopropyl-phenyl isocyanate. P. fus. 153.8-156.7 ° C.
EXAMPLE 33 1- (4-Chloro-2,6-d¡¡-propyl-phenyl-3-F3- (2-hydroxy-propiP-benzenesulfonylurea
3- (2-Hydroxy-propyl) -benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl sodanate. P. fus. 148.7-149.9 ° C.
EXAMPLE 34 1- (4-Chloro-2,6-diisopropyl-phenyl-3-r3- (2-oxo-propiP-benzenesulfoninurea
3- (2-Oxo-propyl) -benzenesulfonamide; 4-chloro-2,6-dusopropyl-phenyl isocyanate. P. fus. 154.8-156.6 ° C.
EXAMPLE 35 1- (2, ß-Diisopropyl-phenyP-3- (3-propionyl-benzenesulfonophen-P-urea
3-Propionyl-benzenesulfonamide; 2,6-diisopropyl-phenylisocyanate.
P. fus. 151.7-152.8 ° C.
EXAMPLE 36 1- (3-Acetyl-4-methoxy-benzenesulfoniP-3- (4-chloro-216-diisopropyl-pheniPurea
3-Acetyl-4-methoxy-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 214.2-215.1 ° C.
EXAMPLE 37 1- (4-Chloro-2,6-diisopropyl-phenyl) -3-r3- (1-hydroxy-et.P-4-methoxy-benzenesulfonylurea)
3- (1-Hydroxy-ethyl) -4-methoxy-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 164.9-166.1 ° C.
EXAMPLE 38 1- (4-Chloro-2,6-phenylpropyl-phenyl-3-r3- (1-hydroxy-propyl-benzenesulfonylurea
3- (1-Hydroxy-propyl) -benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl-socianate, F, 218.4-220.3 ° C.
EXAMPLE 39 1- (4-Chloro-2,6-diisopropyl-phenyl-3- (3-propionyl-benzene-sulfoninurea
3-Propionii-benzenesulfonamide; 4-chloro-2,6-diisopriol-phenyl socianate. P. fus. 149.1-152.2 ° C.
EXAMPLE 40 1- (4-Chloro-2,6-diisopropyl-phenyl-3-r3- (1-hydroxy-etiP-benzenesulfoninurea
3- (1-Hydroxy-ethyl) -benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 151.8-154.3 ° C.
EXAMPLE 41 1- (5-Acetyl-2-methoxy-benzenesulfonyl) -3- (4-bromo-2,6-diiso-propylene-urea)
-Acetyl-2-methoxy-benzenesulfonamide; 4-bromo-2,6-diisopropyl-phenyl socianate. P. fus. 185.1-186.5 ° C.
EXAMPLE 42 1- (5-Acetyl-2-methoxy-benzenesulfoniP-3- (2,6-diisopropyl-pheniPurea
-Acetyl-2-methoxy-benzenesulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 199.7-201.3 ° C.
EXAMPLE 43 1- (3-Acetyl-benzenesulfonyl) -3- (4-chloro-2,6-diisopropyl-pheniPurea
3-Acetyl-benzenesuifonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 163.1 -165.6 ° C.
EXAMPLE 44 1- (4-Chloro-2,6-diisopropyl-phenyl-3-r3- (1-hydroxyimino-etiP-benzenesulfonylurea
3- (1-Hydroxyimino-ethyl) -benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl socianate. P. fus. 158.4-160.0 ° C.
EXAMPLE 45 1 - (4-Bromo-2,6-diisopropyl-phenyl-3- (6-methyl-1,1-dioxo-1-thiochroman-7-sulfonium-Purea
6-Methyl-1, 1-dioxo-1-thiochroman-7-sulfonamide; 4-bromo-2,6-diisopropyl-phenyl isocyanate. P. fus. 250.4-251. 9 ° C.
EXAMPLE 46 1 - (2,6-Diisopropyl-phenyD-3- (6-methyl-1,1-dioxo-1-thiochroman-7-sulfoniumPurea
6-Methyl-1, 1-dioxo-1-thiochroman-7-sulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 242.7-245.2 ° C.
EXAMPLE 47 1- (2,6-Diisopropyl-pheniP-3-r3- (1-hydroxy-etiP-benzenesulfoniPurea
3- (1-Hydroxy-ethyl) -benzenesulfonamide; 2,6-diisopropyl-phenyl socianate. P. fus. 122.6-124.0 ° C.
EXAMPLE 48 1 - (4-Bromo-2,6-diisopropyl-phenyl-3-f3- (1-hydroxy-etiP-benzenesulfoniPurea
3- (1-Hydroxy-ethyl) -benzenesulfonamide; 4-bromo-2,6-diisopropyl-phenyl isocyanate. P. fus. 142.5-144.8 ° C.
EXAMPLE 49 1 - (3-Acetyl-benzenesulfoniP-3- (4-bromo-2,6-diisopropyl-pheniPurea
3-Acetyl-benzenesulfonamide; 4-bromo-2,6-düsopropyl-phenyl socianate. P. fus. 231.4-233.6 ° C.
EXAMPLE 50 1 - (3-Acetyl-4-hydroxy-benzenesulfoniP-3- (2,6-diisopropyl-phenylPurea
3-Acetyl-4-hydroxy-benzenesulfonamide; 2,6-diisopropyl-phenyl socianate. P. fus. 196.6-198.9 ° C.
EXAMPLE 51 1 - (3-Acetyl-4-methoxy-benzenesulfoniP-3- (2,6-diisopropyl-pheniPurea
3-Acetyl-4-methoxy-benzenesulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 203.4-205.7 ° C.
EXAMPLE 52 1- (3-Acetyl-benzenesulfonyl) -3- (2-sec-butyl-6-ethyl-phenyl) -urea
3-Acetyl-benzenesulfonamide; 2-sec-butyl-6-ethyl-phenyl isocyanate. P. fus. 136.3-138.9 ° C.
EXAMPLE 53 1 - (3-Acetyl-benzenesulfoniP-3- (2-isopropyl-6-methyl-phenyl-urea)
3-Acetyl-benzenesulfonamide; 2-iso-propyl-6-methyl-phenyl isocyanate. P. fus. 136.8-138.9 ° C.
EXAMPLE 54 1 - (3-Acetyl-benzenesulfoniP-3- (2-tert-butyl-6-methyl-phenyl-urea)
3-Acetyl-benzenesulfonamide; 2-tert-butyl-6-methyl-phenyl isocyanate. P. fus. 155.4-157.7 ° C.
EXAMPLE 55 1- (3-Acetyl-benzenesulfoniP-3- (2-ethyl-6-isopropyl-phenyl-urea)
3-Acetyl-benzenesulfonamide; 2-ethyl-6-isopropyl-phenyl socianate. P. fus. 127.1-128.5 ° C.
EXAMPLE 56 1 - (3-Acetyl-benzenesulfoniP-3- (2,6-diisopropyl-pheniPurea
3-Acetyl-benzenesulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 151.6-153.5 ° C.
EXAMPLE 57 1- (4-Acetyl-2,6-diisopropyl-phenyl) -3- (3,5-diacetyl-benzenesulfonyl) urea
3,5-Diacetyl-benzenesulfonamide; 4-acetyl-2,6-diisopropyl-phenyl isocyanate. P. fus. 154.0-156.4 ° C.
EXAMPLE 58 4-r3- (3,5-Diacetyl-benzenesulfonyl-ureido1-3,5-diisopropyl-benzamide
3,5-Diacetyl-benzenesulfonamide; 4-isocyanato-3,5-diisopropyl-benzamide. P. fus. 198.5-199.8 ° C.
EXAMPLE 59 1 - (4-Chloro-2,6-diisopropyl-phenyl-3-r3- (2,2,2-trifluoro-1-hydroxy-etiP-benzenesulfonylurea
3- (2,2,2-Trifluoro-1-hydroxy-ethyl) -benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl socianate. P. fus. 129.6-131.5 ° C.
EXAMPLE 60 1- (4-Chloro-2,6-diisopropyl-phenyl-3- (3-trifluoroacetyl-benzenesulfoniumPurea
3-Trifluoroacetyl-benzenesulfonamide; 4-chloro-2,6-düsopropyl-phenyl isocyanate. P. fus. 88.4-89.1 ° C.
EXAMPLE 61 1- (4-Chloro-2,6-diisopropyl-phenyl-3-r3- (1-hydroxy-2-methoxy-etiP-benzenesulfonylurea
3- (1-Hydroxy-2-methoxy-ethyl) -benzenesulfonamide; 4-chloro-2,6-düsopropyl-phenyl socianate. P. fus. 108.7-109.2 ° C.
EXAMPLE 62 1- (4-Chloro-2,6-diisopropyl-phenyl-3- (3-methoxyacetyl-benzenesulfonium) Purea
3-Methoxy acetyl-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 121.2-122.1 ° C.
EXAMPLE 63 4-f3-r3- (1-Hydroxy-etiP-benzenesulfonin-ureido1-3,5-diisopropyl-benzamide
3- (1-Hydroxy-ethyl-benzenesulfonamide; 4-isocyanato-3,5-düsopropyl-benzamide, Fr. 204.6-205.9 ° C.
EXAMPLE 64 1 - (4-Cyano-2,6-diisopropylpheniP-3-r3-r3- (1-hydroxy-etiP-benzenesulfonylurea
3- (1-Hydroxy-ethyl) -benzenesulfonamide; 4-cyano-2,6-diisopropyl-phenyl socianate. P. fus. 191.3-194.0 ° C.
EXAMPLE 65 1 - (4-Chloro-2,6-diisopropyl-phen-P-3-f3- (1-hydroxy-2-methyl-propiP-benzenesulfonylurea
3- (1-Hydroxy-2-methyl-propyl) -benzenesulfonamide; 4-chloro-2,6-diesopropyl phenyl isocyanate. P. fus. 152.3-153.0 ° C.
EXAMPLE 66 1 - (4-Chloro-2,6-diisopropyl-phenyl-3- (3-isobutyryl-benzene-sulfonium)
3-lsobutyryl-benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 170.2-171.4 ° C.
EXAMPLE 67 1- (2,6-Diisopropyl-4-thiophene-3-phenyp-3-r3- (1-hydroxy-etiP-benzenesulfonylurea
3- (1-Hydroxy-ethyl) -benzenesulfonamide; 2,6-düsopropyl-4-thiophen-3-yl-phenol socianato. P. fus. 137.0-139.4 ° C.
EXAMPLE 68 1 - (2,6-Diisopropyl-4-thiophen-2-yl-phenyD-3-r3- (1-hydroxy-ethyl) -benzenesulfonylurea
3- (1-Hydroxy-ethyl) -benzenesulfonamide; 2,6-diisopropyl-4-thiophen-2-yl-phenyl isocyanate. P. fus. 98.4-99.9 ° C.
EXAMPLE 69 1- (3,5-Diisopropyl-biphenyl-4-iP-3-r3- (1-hydroxy-etiP-benzenesulfonipurea
3- (1-Hydroxy-ethyl) -benzenesulfonamide; 3,5-diisopropyl-biphenyl 4-isocyanate. P. fus. 127.4-128.6 ° C.
EXAMPLE 70 1- (4-Chloro-2,6-diisopropyl-phenyl-3- (8-hydroxy-5,6,8-tetrahydro-naphthalene-2-sulfonium-Purea
8-Hydroxy-5,6J, 8-tetrahydro-naphthalene-2-sulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 136.8-138.2 ° C.
EXAMPLE 71 1-Chloro-S.e-diisopropyl-phenyl-S-fd-oxo-S.e.J.d-tetrahydro-naphthalene-S-sulfonylurea
8-Oxo-5,6J, 8-tetrahydro-naphthalene-2-sulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 180.0-182.4 ° C.
EXAMPLE 72 1- (4-Chloro-2,6-diisopropyl-phenyP-3- (8-hydroxyimino-5,6,7,8-tetrahydro-naphthalene-2-sulfonylurea
8-Hydroxyimino-5,6,7,8-tetrahydro-naphthalene-2-sulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 162.5-164.2 ° C.
EXAMPLE 73 1- (4-Bromo-2,6-diisopropyl-phenyP-3- (8-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-sulfoniumPurea
8-Hydroxy-5,6,7,8-tetrahydro-naphthalene-2-sulfonamide; 4-bromo-2,6-diisopropyl-phenyl isocyanate. P. fus. 164.0-165.8 ° C.
EXAMPLE 74 1- (2,6-D8-isopropyl-phenyl-3- (8-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-sulfonium-Purea
8-Hydroxy-5,6J, 8-tetrahydro-naphthalene-2-sulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 120.0-122.6 ° C.
EXAMPLE 75 1- (2,6-Diisopropyl-phenyP-3- (8-hydroxyimino-5,6,7,8-tetrahydro-naphthalene-2-sulfoniumPurea
8-Hydroxymethyl-5,6J, 8-tetrahydro-naphthalene-2-sulfonamide; 2,6-diisopropyl-phenyl socianate. P. fus. 139.2-140.0 ° C.
EXAMPLE 76 1- (4-Bromo-2,6-diisopropyl-phenyP-3- (8-hydroxyimino-5,6,7,8-tetrahydro-naphthalene-2-sulfonium)
8-Hydroxyimino-5,6,7,8-tetrahydro-naphthalene-2-sulfonamide; Isocyanate of 4-bromo-2,6-diisopropyl-phenyl. P. fus. 168.6-169.2 ° C.
EXAMPLE 77 1- (4-Bromo-2,6-diisopropyl-phenyl-3- (8-oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonium-Purea
8-Oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonamide; 4-bromo-2,6-diisopropyl-phenyl isocyanate. P. fus. 208.0-208.8 ° C.
EXAMPLE 78 1- (2,6-Diisopropyl-phenyl-3- (8-oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonium Purea
8-Oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. Fus. 197.4-198.0 ° C.
EXAMPLE 79 3-r3- (4-Bromo-2,6-disopropyl-phenyl) -urethodosulfonylbenzamide
3-Sulfonamido-benzamide; 4-bromo-2,6-diisopropyl-phenyl isocyanate. P. fus. 180.0-180.6 ° C.
EXAMPLE 80 (1- (4-Chloro-2,6-diisopropyl-phenyl-3-r3- (1,2-dihydroxy-etiP-benzenesulfonylurea
3- (1,2-Dihydroxy-ethyl) -benzenesulfonamide; 4-chloro-2,6-diisopropyl-phenyl socianate. P. fus. 169.7-171.2 °.
EXAMPLE 81 3-r3- (2,6-Diisopropyl-phenyP-ureidosulfonylbenzamide
3-Sulfonamido-benzamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 182.3-184.1 ° C.
EXAMPLE 82 3-f3- (4-Bromo-2,6-diisopropyl-phenylP-ureidosulfonyl-N-methyl-benzamide
3-Sulfonamido-N-methyl-benzamide; 4-bromo-2,6-diisopropyl-phenyl isocyanate. P. fus. 243.8-245.1 ° C.
EXAMPLE 83 3-r3- (2,6-Diisopropyl-phenyl) -ureidosulfonyl-1-N-methyl-benzamide
3-Sulfonamido-N-methyl-benzamide; 2,6-diisopropyl-phenyl socianate. P. fus. 236.2-237.2 ° C.
EXAMPLE 84 1- (5-Acetyl-2-bromo-benzenesulfoniP-3- (4-bromo-2,6-diissopropyl-phenylurea)
-Acetyl-2-bromo-benzenesulfonamide; 4-bromo-2,6-diisopropyl-phenyl socianate. P. fus. 177.2-179.1 ° C.
EXAMPLE 85 1-r2-Chloro-5- (1-hydroxy-etiP-benzenesulfonyl-3- (2,6-diisopropyl-phenylurea)
2-Chloro-5- (1-hydroxy-ethyl) -benzenesulfonamide; 2,6-diisopropyl-phenyl socianate. P. fus. 154.0-156.0 ° C.
EXAMPLE 86 1-r2-Chloro-5- (1-hydroxy-etiP-benzenesulfonyl-3- (4-bromo-2,6-diisopropyl-phenyl)
2-Chloro-5- (1-hydroxy-ethyl) -benzenesulfonamide; 4-bromo-2,6-diisopropyl-phenyl isocyanate. P. fus. 144.3-146.2 ° C.
EXAMPLE 87 1-f2-Chloro-5- (1-hydroxyimino-etiP-benzenesulfon-p-3-2,6-d¡¡propylphen-Phe
2-Chloro-5- (1-hydroxy-ethyl) -benzenesulfonamide; 2,6-düsopropyl-phenyl isocyanate. P. fus. 156.6-158.0 ° C.
EXAMPLE 88 1-r 2 -chloro-5- (1-hydroxyimino-etiP-benzenesulfonyl-3- (4-bromo-2,6-diisopropyl-phenylurea)
2-Chloro-5- (1-hydroxyimino-etiI) -benzenesulfonamide; Socianato de
4-bromo-2,6-diisopropyl-phenyl. P. fus. 185.0-186.2 ° C.
EXAMPLE 89 1-r5-Acetyl-2-chloro-benzenesulfon-p -3- (2,6-diisopropyl-phenylPurea)
-Acetyl-2-chloro-benzenesulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 180.7-182.3 ° C.
EXAMPLE 90 1- (5-Acetyl-2-chloro-benzenesulfonin-3- (4-bromo-2,6-diisopropyl-phenyl-urea)
-Acetyl-2-chloro-benzenesulfonamide; 4-bromo-2,6-diisopropyl-phenyl socianate. P. fus. 175.2-176.5 ° C.
EXAMPLE 91 3-r3- (2,6-Diisopropyl-pheny P-ureidosulfonin-N, N-dimethyl-benzamide
3-Sulfonamido-N, N-dimetii-benzamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 21 1 .8-212.6 ° C.
EXAMPLE 92 3-r3- (4-Bromo-2,6-diisopropyl-phenylP-ureidosulfonyl-N, N-dimethyl-benzamide
3-Sulfonamido-N, N-d-methyl-benzamide; 4-bromo-2,6-düsopropyl-phenyl isocyanate. P. fus. 225.7-227.6 ° C.
EXAMPLE 93 1 - (2,6-Diisopropyl-phenyD-3- (3-formyl-benzenesulfonium)
3-Formyl-benzenesulfonamide; 2,6-diisopropyl-phenyl socianate. P. fus. 108.3-109.0 ° C.
EXAMPLE 94 1- (2,6-Diisopropyl (hydroxyimino-metiP-benzenesulfoniPurea
3- (Hydroxyimino-methyl) -benzenesulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 107.0-108.1 ° C.
EXAMPLE 95 1- (2,6-Diisopropyl-phenyl-3-r3- (1-methoxyimino-etiP-benzenesulfoniPurea
3- (1-Methoxyimino-ethyl) -benzenesulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 164.9-165.9 ° C.
EXAMPLE 96 1 -r3- (1-Benzyloxyimino-etiP-benzenesulfonin-3- (2,6-diisopropyl-pheniPurea
3- (1-Benzyloxyimino-ethyl) -benzenesulfonamide; 2,6-diisopropyl-phenyl socianate. P. fus. 136.5-139.0 ° C.
EXAMPLE 97 1- (2,6-Diisopropyl-pheniP-3-r3- (1-ethoxy-amino-etiP-benzene-sulphonurea)
3- (1-Ethoxyimino-ethyl) -benzenesulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus.156.9-158.4 ° C.
EXAMPLE 98 Acid (1 - {3-r3- (2,6-diisopropyl-phenyD-ureidosulfoniP-pheny-) - ethyl-denoamino-oxaacetic acid
3-Sulfonamido-phenyl- (1-ethyl-denoaminooxy) acetic acid;
2,6-diisopropyl-phenyl socianate. P. fus. 107.1-107.7 ° C.
EXAMPLE 99 (1- (2,6-diisopropyl-phenyl-3-r3- (1-hydroxyimino-etiP-benzenesulfoniPurea
3- (1-Hydroxyimino-ethyl) benzenesulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 131.0-132.6 ° C.
EXAMPLE 100 1 - (2,6-Diisopropyl-phenyP-3- (3-methanesulfonyl-benzenesulfoniumPurea
3-Methanesulfonyl-benzenesulfonamide; 2,6-düsopropyl-phenylene isocyanate: P. fus. 99.5-100.6 ° C.
EXAMPLE 101 1 - (2,6-Diisopropyl-phenyP-3- (3-methanesulfinyl-benzenesulfoniumPurea
3-Methanesulfinyl-benzenesulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 217.4-221.0 ° C.
EXAMPLE 102 3-r3- (2,6-Diisopropyl-phenyl) -ureidosulfonyl-benzenesulfonamide
3-Sulfonamido-benzenesulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 131.4-133.5 ° C.
EXAMPLE 103 1- (4-Bromo-2,6-diisopropyl-phenyl-3- (3-formyl-benzenesulfonium) Purea
3-Formyl-benzenesulfonamide; 4-bromo-2,6-diisopropyl-phenyl isocyanate. P. fus. 127.2-128.6 ° C.
EXAMPLE 104 1-r3- (2-Acetyl-phenoxymethiP-benzenesulfonin-3- (2,6-diisopropyl-phenylPurea
3- (2-Acetyl-phenoxymethyl) -benzenesulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 124.2-125 ° C.
EXAMPLE 105 1-f3- (1-amino-2-D-benzenesulfonip-3- (2,6-diisopropyl-phenylurea) hydrochloride
3- (1-Amino-ethyl) -benzenesulfonamide hydrochloride; 2,6-diisopropyl-phenyl socianate. P. fus. 210.6-212.9 ° C.
EXAMPLE 106 1- (2,6-Diisopropyl-phenylP-3- (3-furan-2-yl-benzenesulfonyl-urea)
3-Furan-2-yl-benzenesulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 196.6-198.0 ° C.
EXAMPLE 107 1 - (2,6-Diisopropyl-phenyp-3- (4-furan-2-iP-benzenesulfoniP-urea
4-Furan-2-yl-benzenesulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 201.5-202.7 ° C.
EXAMPLE 108 1 - (1, 2,3,5,6,7-Hexahydro-s-indacen-4-iD-3-r4- (1-hydroxyimino-etiP-thiophene-2-sulfonylurea
4- (1- (Hydroxy-amino-ethyl) -thiophene-2-sulfonamide; 4-isocyanato-1, 2,3,5,6,7-hexahydro-s-indacene, P. fus. 261.8-266.1 ° C.
EXAMPLE 109 1- (4-Acetyl-thiophene-2-sulfoniP-3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-iPurea
4-acetyl-thiophene-2-sulfonamide; 4-isocyanato-1, 2,3,5,6,7-hexahydro-s-indacene. P. fus. 270.2-272.3 ° C.
EXAMPLE 110 1 - (1, 2,3,5,6,7-Hexahydro-s-indacen-4-iP-3-r5- (1-hydroxy-1-methyl-etSP-thiophene-3-sulfoninurea
- (1-Hydroxy-1-methyl-ethyl) -thiophene-3-sulfonamide; 4-isocyanato-1, 2,3,5,6,7-hexahydro-s-indacene. P. fus. 149.5-154.8 ° C.
EXAMPLE 111 1 - (2,6-Diisopropyl-phenyD-3-r4- (1-hydroxy-1-methyl-2-phenylphene-2-sulfonipurea
4- (1-Hydroxy-1-methyl-ethyl) -thiophene-2-sulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 124.6-127.4 ° C.
EXAMPLE 112 1 - (2,6-Diisopropyl-phenyl-3-r4- (1-hydroxy-1-methyl-eti-Pfuran-2-sulfonipurea
4- (1-Hydroxy-1-methyl-ethyl) -furan-2-sulfonamide; 2,6-diisopropyl-phenyl isocyanate. P. fus. 121.3-124.4 ° C.
EXAMPLE 113 1 - (1, 2,3,5,6,7-Hexahydro-s-indacen-4-iP-3-r4- (1-hydroxy-1-methyl-etiP-thiophene-2-sulfoninurea
4- (1-Hydroxy-1-methyl-ethyl) -thiophene-2-sulfonamide; 4-isocyanato-1, 2,3,5,6,7-hexahydro-s-indacene. P. fus. 133.1-134.0 ° C.
EXAMPLE 114 1 - (1.2.3,5,6.7-Hexahydro-s-indacen-4-iP-3-r4- (1-hydroxy-1-methyl-etiD-furan-2-sulfonylurea
4-1-Hydroxy-1-methyl-ethyl) -furan-2-sulfonamide; 4-isocyanato-1, 2,3,5,6,7-hexahydro-s-indacene. P. fus. 153.8-154.4 ° C.
EXAMPLE 115 1 - (8-Chloro-1, 2,3,5,6,7-hexahydro-s-indacen-4-iP-3-r4- (1-hydroxy-1-methyl-yl-P-furan-2- sulfonylurea
4- (1-Hydroxy-1-methyl-ethyl) -furan-2-sulfonamide; 4-chloro-8-isocyanato-1, 2,3,5,6J-hexahydro-s-indacene. P. fus. 163J ° C (decomposed).
EXAMPLE 116 1- (4-Formyl-furan-2-sulfoniP-3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-iPurea
4-Formyl-furan-2-sulfonamide; 4-isocyanato-1, 2,3,5,6,7-hexahydro-s-indacene. P.fus. 281.3-284.1 ° C.
EXAMPLE 117 1 - (1, 2,3,5,6,7-Hexahydro-s-indacen-4-iP-3- (4-hydroxymethyl-thiophene-2-sulfoniumPurea
4-Hydroxymethyl-thiophene-2-sulfonamide; 4-isocyanato-1, 2,3,5,6,7-hexahydro-s-indacene. P.fus. 273.9-275.8 ° C.
EXAMPLE 118 1- (4-Formyl-thiophene-2-sulfoniP-3- (1, 2,3,4,6,7-hexahydro-s-indacen-4-iPurea
4-Formyl-thiophene-2-sulfonamide; 4-isocyanato-1, 2,3,5,6,7-hexahydro-s-indacene. P.fus. 146.3-148.9 ° C.
EXAMPLE 119 1-f4-Chloro-2,6-diisopropyl-phenyl-3-r4- (1-hydroxyimino-etiP-thiophene-2-sulfonylurea)
4- (1-Hydroxyimino-ethyl) -thiophene-2-sulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P.fus. 184.7-187.8 ° C.
EXAMPLE 120 1 - (4-Chloro-2,6-diisopropyl-phenyl-3-r5- (1-hydroxy-1-m eti I -eti P-furan -2-sulfonylurea
- (1-Hydroxy-1-methyl-ethyl) -furan-2-sulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P.fus. 1 16.0-1 17.9 ° C.
EXAMPLE 121 1- (4-Chloro-2,6-diisopropyl-phenyl-3-r4-1-hydroxy-1-methyl-etiP-furan-2-sulfonylurea)
4- (1-Hydroxy-1-methyl-ethyl) -furan-2-sulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P.fus. 127.4-129.2 °.
EXAMPLE 122 1- (4-Chloro-2,6-diisopropyl-phenyl-3-r4- (1-hydroxy-1-methyl-ethyl-thiophene-2-sulfonylurea)
4- (1-Hydroxy-1-methyl-ethyl) -thiophene-2-sulfonamide; 4-chloro-2,6-diisopropyl-phenyl isocyanate. P. fus. 131.2-133.6 ° c.
EXAMPLE 123 Sodium salt of 1- (4-chloro-2,6-diisopropyl-phenyl-3-r5- (1-hydroxy-1-methyl-etiP-thiophene-2-sulfoninurea
- (1-Hydroxy-1-methyl-ethyl) -thiophene-2-sulfonamide; 4-chloro-2,6-diisopropyl-phenyl socianate. P.fus. 270.3-271.9 ° C.
EXAMPLE 124 1 - (4-p. 31 Dioxolan-2-yl-thiophene-2-sulfoniP-3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) urea
4- [1 -, 3] Dioxolan-2-yl-thiophene-2-sulfonamide; 4-Isocyanate-1, 2,3,5,6,7-hexahydro-s-indacene. P.fus. 224.7-226.6 ° C.
EXAMPLE 125 1 - (4-H, 31 Dioxolan-2-yl-furan-2-sulfoniP-3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-i Purea
4- [1, 3] Dioxolan-2-yl-furan-2-sulfonamide; 4-isocyanato-1, 2,3,5,6,7-hexahydro-s-indacene. P.fus. 183.5 ° C. (decomposition).
EXAMPLE 126 1-r3- (4-, 5-Dihydro-1 H-imidazol-2-iPbenzenesulfonyl-3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-iPurea
3- (4,5, -Dihydro-1 H-imidazol-2-yl) -benzenesulfonamide; 4-isodanate-1, 2,3,5,6J-hexahydro-s-indacene. P. fus.241.0 ° C (decomposition).
EXAMPLE 127 1 - (1 H-Benzoimidazol-5-sulfoniP-3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-Purea
1 H-benzoimidazole-5-sulfonamide; 4-isocyanato-1, 2,3,5,6,7-hexahydro-s-indacene. P.fus. 239.0 ° C (decomposition).
EXAMPLE 128 1 - (1, 2,3,5,6,7-Hexahydro-s-indacen-4-iP-3-r3-f 1 -hydroxyimino-etiP-benzenesulfonylurea
3- (1-Hydroxyimino-ethyl) -benzenesulfonamide; 4-isocyanato-1, 2,3,5,6,7-hexahydro-s-indacene. P.fus. 249.8 ° C (decomposition).
EXAMPLE 129 1- (4-Chloro-2,6-diisopropyl-phenyl-3-f3-tert-butylsulfamoyl-benzenesuifonylurea)
Amide tert-butyl-amide of benzene-1,3-disulfonic acid: 5-chloro-2-isocyanato-1,3-diisopropyl-benzene.
EXAMPLE 130 1- (4-Chloro-2,6-diisopropylpheniP-3-r3-sulfamoyl-benzenesulfonylurea)
Using a procedure similar to that of preparation G, from 200 mg (0.38 mmol) of 1- (4-chloro-2,6-diisopropyl-phenyl) -3- [3-tert-butylsulfamoyl-benzenesulfonyl] urea, 92 were obtained. mg of the title compound as a white solid. P.fus .: 172-177 ° C.
Claims (8)
1. - A compound of the formula: I or a pharmaceutically acceptable salt thereof, wherein: R1 is (C-r Β-Chalkyl optionally substituted by (C ?Ce) alkylamino, (C ?Ce) alkylthio, (d-CeJalkoxy, trifluoromethyl, (C6-C? 0) aryl, (Cs-Cg-heteroaryloxy, (C6-C? o) arylamino, (Ce-C? o) arylthio, (C6-C-? o) aryloxy, ( Cs-Cgjheteroarylamino, (C5-C9) heteroarylthio, (Cs-Cg-heteroaryloxy, (C6-C? O) aryl (C6-C? O) -aryl, (C3-C6) cycloalkyl, hydroxy Ci-Cealkyl, (C? C6) alkyl (hydroxymethylene), piperazinyl, (C6-C? O) aryl (C-C6) alkoxy, (C5-C9) heteroaryl (C? -C6) alkoxy, (Ci-C6) acylamino, (C? -Ce) ) acylthio, (C? -C6) acyloxy, (C? -Ce) alkylsulfinyl, (C? -C?) arylsulfinyl, (C? -Ce) alkylsulfonyl, (C6-C0) arylsulfonyl, amino, (Cr C6) alkylamino or ((CrC6) alkyl) 2 amino; or R1 and R2 are each independently a group of the formula: wherein the dashed lines represent optional double bonds; n is 0, 1, 2 or 3; A, B, D, E and G are each independently, oxygen, sulfur, nitrogen or CR5R6, wherein R5 and R6 are each independently selected from hydrogen, (C ^ CeCalkyl optionally substituted by one or two groups selected from (d-Ce) alkylamino, (C -? - Ce) alkylthio, (C? -C6) alkoxy, hydroxy, cyano, perfluoro (C? - C6) alkyl, (C6-C? 0) ar It, (C5-C9) heteroary, (C6-C-? O) arylamino, (C6-C? O) arylthio, (C6-C? O) aryloxy in which the aryl group is optionally substituted by (C-i-Ce) alkoxy, (C? -Ce) acyl, carboxy, hydroxy or halo; (C5-C9) heteroarylamino, (C5-Cg) heteroarylthio, (C5-Cg) heteroaryloxy, (C6-C? O) aryl (C6-C? O) aryl, (C3-Ce) cycloalkyl, hydroxy, piperacinyl, ( C6-C? O) aryl (C? -Ce) alkoxy, (C5-Cg) heteroaryl (C? -C6) alkoxy, (C? -C6) acylamino, (C? -Ce) acylthio, (C? -C6) ) acyloxy, (C1-C6) alkylsulfinyl, (C6-C? o) arylsulfinyl, (C? -Ce) alkylsulfonyl, (C6-C? 0) arylsulfonyl, amino, (C? -C6) alkylamino or ((C? -Ce) alkyl) 2amino; halo, cyano, amino hydroxy, perfluoro (C? -C6) alkyl, perfluoro (C? -C6) alkoxy, (C2-C6) alkenyl, carboxy (C2-Ce) alkenyl, (C2-C6) alkynyl, ( C -C6) alkylamino, ((Cr Ce) alk) 2amino, (C? -Ce) alkylsulfonylamido, (C? -Ce) alkylsulfinyl, aminosulfonyl, (Ci-Cejalkylaminosulfonyl, ((C? -Ce) alkyl ) aminosulfonyl, (d-Ce) alkylthio, (C? -Ce) alkoxy, perfluoro (C -? - C6) alkyl, (C6-C? 0) aryl, (C5-C9) heteroaryl, (C6-C10) ar Lamino, (C6-C? O) arithium, (C6-C? O) aryl (C? -Ce) alkoxy, (C5-Cg) heteroarylamine, (C5-Cg) heteroarylthyl, (C5-Cg) heteroaryloxy, ( C3-C6) cycloalkyl, (C? -Ce) alkyl (hydroxymethylene), piperidyl, pyridinyl, thienyl, furanyl, (Ci-Cejalkylpiperidyl, (C? -C6) acylamino, (C? -Ce) acylthio, (C? C6) acyloxy, R7 (C? -Ce) alkyl wherein R7 is (C1-C6) acylpiperacino, (C6-C? O) arylpiperazin, (C5-Cg) heteroarylpiperazine, (C? -C6) alkylpiperazine, (C6-C? 0) aryl (C?-Ce) alkylpiperazine, (C5-Cg) heteroaryl (C1-C6) alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C? -C6) alkylpiperidyl (CT-C? o) arylpiperidyl, (C5-Cg) heteroarylpiperidyl, (C? -C6) alkylpiperidyl (C? -Ce) alkyl, (C6-C? O) arylpiperidyl (C? -Ce) alkyl, (C5-C9) heteroarylpiperidyl (C? -Ce) alkyl or (d- C6) acylpiperidyl; or a group of the formula: wherein: s is 0 to 6; t is 0 or 1; X is oxygen or NR in which R is hydrogen, (CrC6) alkyl or (C3-C7) cycloalkyl (C? -C6) alkyl; Y is hydrogen, hydroxy, (C -? - C6) alkyl, optionally substituted by halo, hydroxy or cyano; (Cr C-alkoxy, cyano, (C2-C6) alkynyl, (C6-C? O) aryl wherein the aryl group is optionally substituted by halo, hydroxy, carboxy, (C? -Ce) alkyl, C6) alkoxy, perfluoro (C6C6) alkyl, (C6C6) alkoxy (C6C6) alkyl or NR9R10 wherein R9 and R10 are each independently selected from the group consisting of hydrogen, (C? -C6) alkyl optionally substituted by (C? -C6) alkylpiperidyl, (C6-C? O) arylpiperidyl (C5-Cg) heteroalrilpiperidyl, (C? -C?) Aryl, (C5-Cg) heteroaryl or (C3-C6) cycloalkyl, piperidyl, (CiC? alkylchipperidyl, (C6-C? o) arylpiperidyl, (C5-Cg) heteroarylpiperidyl, C6) aclpiperidyl, (C6-C? O) aryl, (C5-C9) heteroaryl, (C3-Ce) c-chloroalkyl, R11 (C2-C6) alkyl, (C? -C5) alkyl (CHR11 ) (d-Ce) alkyl wherein R11 is hydroxy, (Ci- Ce) acyloxy, (CrC6) aloxy, piperazino, (d-dOacylamino, (C? -Ce) alkyl, (C6-C-? o) arylthio , (Ce-C? O) alkylsulfinyl, (Ce-C? O) arylsulfinyl, (C? -C6) alkylsulfoxyl, (C6-C? O) arylsulfoxy, amino, (C? -C6) alkylamino, ((C? -C6) alkyl) 2-amino, (d-Ce) acylpiperazine, (CrC6) alkylpiperazine, (C6-C10) aryl (C? -C6) alkylpiperazine (C5-Cg) heteroaryl (d-C6) alkylpperazin, morpholino, thiomorpholino, piperidino or pyrrolidino; R12 (d-C6) alkyl, (d-C5) alkyl (CHR12) (C? -Cβ) alkyl in which R12 is piperidyl or (C? -C6) alkylpiperidyl; and CH (R13) COR14 wherein R14 is as defined below and R13 is hydrogen, (C? -C6) alkyl, (C6-doJari d-CeJalkyl, (C5-Cg) heteroaryl (d-C6) alkyl , (d-C6) alkylthio (C? -C6) alkyl, (Ce-Cic arylthioid-CeJalkyl, (dd alkylsulfini d-CeJalkyl, (C6-C? o) arylsulfinyl (C -? - C6) alkyl , (C? -C6) alkylsulfonyl (C? -Ce) alkyl, (C6-Cio-arylsulfon-d-Cejalkyl, hydroxy (C-C) alkyl, aminoC-CeCalkyl, (Ci- Ce) alkylamino (C? -Ce) alkyl, ((C? -C6) alkyllam) 2 (d-C6) alkyl, R15R16NCO (d-C6) alkyl or R15OCO (C? -C6) alkyl wherein R15 and R16 are each independently selected from the group consisting of hydrogen, (C? -C6) alkyl, (C6-C10) aryl (C -? - C6) alkyl and (C5-Cg) heteroaryl (C? -C6) alkyl; and R14 is R17O or R17R18N wherein R17 and R18 are each independently selected from the group consisting of hydrogen, (d-C6) alkyl, (C6-C? o) aryl (C? -C6) alkyl and ( C5-Cg) heteroaryl (C6-C6) alkyl; or a group of the formula: wherein: u is 0, 1 or 2; R19 is hydrogen, (CrC6) alkyl or perfluoro (d-C6) alkyl; R20 is hydrogen, (d-C6) alkyl, (C? -Ce) carboxyalkyl or (C6-C? O) aryl (C? -C6) alkyl; or a group of the formula: wherein: a is 0, 1 or 2; b is 0 or 1; c is 1, 2 or 3; d is 0 or 1; e is 0, 1 or 2; J and L are each independently oxygen or sulfur; R21 is hydrogen, hydroxy, fluoro, (C? -C6) alkyl, (dC? Jalcoxy, halo (C? -Ce) alkyl, amino, (CrC6) acylamino or NR26R27 are each independently selected from hydrogen, (C C6) alkyl or (C6-C10) aryl, and R22 is hydrogen, (C? -C6) alkyl optionally substituted by hydroxy, halo, (d-C6) alkylthio, (d-C6) alkylsulfinyl or (d-C6) ) alkylsulfonyl, or when n is 1 and B and D are both CR5, the two groups R5 can be taken together with the carbons to which they are attached to form a group of the formula: wherein the dashed lines represent optional double bonds; m is 0 or 1; and T, U, V and W are each independently oxygen, sulfur, CO, nitrogen or CR5R6 in which R5 and R6 are as defined above; or when A and B, or when n is l. and B and D, or D and E, or E and G, are both CR5, the two groups R5 can be taken together with the adjacent carbons to which they are attached to form a group (C5-Cß-cycloalkyl optionally substituted by hydroxy or a group benzo, or when n is 1 and D and E are both CR5, the two groups R5 can be taken together with the adjacent carbons to which they are attached to form a group of the formula: wherein the dashed line represents an optional double bond; R23 is hydrogen, (dC6) alkyl, halo, amino or (CrC6) alkoxy; J is C or SO; K is oxygen, NRi in which R4 is hydroxy, (C6C6) alkoxy or (C6-C6o) ar1 (C6C6) alkoxy; or hydroxy; or R25S02 wherein R25 is defined as above for R1 or (C3-C) cycloalkylamino; and with the proviso that the groups of formulas II and VI can not have two oxygens, two sulfur or one oxygen and one sulfur defined in adjacent positions; with the proviso that R2 must be aromatic; with the proviso that when either a or e is 0, the other must be 1; with the proviso that when b and d are 1, the sum of a, c and e can not be 6 or 7; and with the proviso that when A, B, D, E, G, T, U, V and W represent a sp2 carbon, there is no R6.
2. A compound according to claim 1, wherein R1 is a group of the formula: wherein the dashed lines represent double bonds; n is 0 or 1; A is CR5, wherein R5 is hydrogen or halo; B and E are both independently CR5, wherein R5 is hydrogen, cyano, halo, (dC6) alkyl optionally substituted by one or two hydroxy; (C3-C) cycloalkylamino-sulfonyl, (d-C6) alkylaminosulfonyl, or a group of the formula: where: s is 0; t is 0: and Y is hydrogen, (d-Ce) alkyi, optionally substituted by halo; or (C -? - C6) alkoxy (d-C6) alkyl; or a group of the formula: wherein: a is 0 or 1; b is 0 or 1; c is 1 or 2: d is 0 or 1; e is 0 or 1; J and L are each independently oxygen or sulfur; R21 is hydrogen, hydroxy or (C6C6) alkyl, optionally substituted by halo; and R22 is hydrogen or (C? -Ce) alkyl optionally substituted by hydroxy, halo, (d-C6) alkylthio, (C? -C6) alkylsulfinyl or (d-C6) alkylsulfonyl; or a group of the formula: wherein: u is 0 or 1; R19 is (C? -C6) alkyl or trifluoromethyl; and R20 is hydrogen; D is CR 5, wherein R 5 is hydrogen, (d-C 6) aikyl or halo; G is CR5, wherein R5 is oxygen, sulfur or CR5, wherein R5 is hydrogen or halo; or when n is 1 and B and D are both CR5, the two groups R5 can be taken together with the adjacent carbons to which they are attached to form a group of the formula: wherein the dashed lines represent double bonds; m is 0; T is oxygen, nitrogen or CR5, wherein R5 is hydrogen; U is CO or CR5, wherein R5 is hydrogen; and W is nitrogen or CR5, wherein R5 is hydrogen; or when n is 1 and D and E are both CR5, the two groups R5 can be taken together with the carbons to which they are attached to form a group of the formula: wherein the dashed line represents an optional double bond; R23 is hydrogen or (C? -Ce) alkyl; J is C or SO; K is oxygen, NR24, wherein R24 is hydroxy; or hydroxy.
3. A compound according to claim 1, wherein R2 is a group of the formula: in which the dashed lines represent optional double links; n is 1; A is CR5, wherein R5 is halo or (C6C6) alkyl; B is CR5, wherein R5 is hydrogen or halo; D is CR 5, wherein R 5 is hydrogen, halo, cyano, or a group of the formula: where: s is 0; t is 0; and Y is NH2; E is CR5, wherein R5 is hydrogen or halo; and G is CR5, wherein R5 is halo or (alkyl), or when A and B, or E and G, are both CR5, the two groups R5 can be taken together with the adjacent Carbons to which they are attached to form a group (C5-C-chalkyl.
4. - A compound according to claim 1, wherein
R1 is a group of the formula; in which the dashed lines represent double reaches; n is 0 or 1; A is CR5, wherein R5 is hydrogen or halo; B and E are both independently CR5, wherein R5 is hydrogen, cyano, halo (C6C6) alkyl optionally substituted by one or two hydroxy; (C3-C) cycloalkylamino-sulfonyl, (d-C6) alkylaminosulfonyl, or a group of the formula: where: s is 0; t is 0; and Y is hydrogen, (C -? - C6) alkyl optionally substituted by halo; or (C? -C6) alkoxy (d-C6) alkyl; or a group of the formula: where: aes0ó 1; kissed 1; ces 1 or 2; d is 0 or 1; ees0ó 1; J and L are each independently oxygen or sulfur; R2 is hydrogen, hydroxy or (C1-C6) alkyl optionally substituted by halo; and R22 is hydrogen or (C6C6) alkyl optionally substituted by hydroxy, halo, (dC6) alkylthio, (C6C6) alkylsulfinyl or (C6C6) alkylsulfonyl; or a group of the formula: wherein: u is 0 or 1, R19 is (d-C6) alkyl or trifluoromethyl; and R20 is hydrogen; D is CR5, wherein R5 is hydrogen, (dC6) alkyl or halo; G is CR5, wherein R5 is oxygen, sulfur or CR5, wherein R5 is hydrogen or halo; or when n is 1 and B and D are both CR5, the two groups R5 can be taken together with the carbons to which they are attached to form a group of the formula:
SAW wherein the dashed lines represent optional double bonds; m is 0;
T is oxygen, nitrogen or CR5, wherein R5 is hydrogen; U is CO or CR5, wherein R5 is hydrogen; and W is nitrogen or CR5, wherein R5 is hydrogen; or when n is 1 and D and E, both are CR5, the two groups R5 can be taken together with the adjacent carbons to which they are attached to form a group of the formula: wherein the dashed line represents an optional double bond; R23 is hydrogen or (d-Cß) alkyl; J is C or SO; K is oxygen, NR24 in which R24 is hydroxy; or hydroxy; and R2 is a group of the formula: wherein the dashed lines represent optional double bonds; n is 1; A is CR5, wherein R5 is halo or (dC6) alkyl; B is CR5, wherein R5 is hydrogen or halo; D is CR 5, wherein R 5 is hydrogen, halo, cyano or a group of the formula: where: s is 0; t is 0; and Y is NH2; E is CR5, wherein R5 is hydrogen or halo; and G is CR5, wherein R5 is halo or (d-C6) alkyl; or when A and B, or E and G, are both CR5, the two groups R5 can be taken together with the adjacent carbons with which they are bonded to form a (C5-Ce) cycloalkyl group. 5. A compound according to claim 1, said compound being selected from the group consisting of: 1- (4-chloro-2,6-diisopropyl-phenyl) -3- [3- (1-hydroxy-1 - methyl-ethyl) benzenesulfonyl] urea; 1 - (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methyl-ethyl) furan-2-sulfonii] urea; 1- (1, 2,3,5,6,7-hexahydro-4-aza-s-indacen-8-iI) -3- [4- (1-hydroxy-1-methyl-ethyl) furan-2- sulfonyl] urea; 1 - (1, 2,3,5,6J-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methyl-ethyl) thiophene-2-sulfonyl] urea; 1- (4- [1, 3] dioxalan-2-yl-furan-2-sulfonyl) -3-1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1- (2,6-diisopropylphenyl) 3- [4- (1-hydroxy-1-methyl-ethyl) furan-2-sulfonyl] urea, 1- (2,6-diisopropyiphenyl) -3- [4- (1 -hydroxy-1-methyl-ethyl) thiophene-2-sulfonyl] urea; 1- (4-acetyl-thiophene-2-sulfonyl) -3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1- (1 H-benzoimidazole-5-sulfonyl) -3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1 - (1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) -3- [4- (1 - hydroxy-1-methyl-ethyl) thiophene-2-sulfonyl] urea; 1 - (8-chloro-1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methyl-2-yl) furan-2 sulfonyl] urea; 1- (4-acetyl-furan-2-sulfonyl) -3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1 - (8-fIuor-1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methyl-ethyl) furan-2 -sulphonyl] urea; 1- (4-Fluoro-2,6-diisopropyl-phenyl) -3- [3- (1-hydroxy-1-methyl-ethyl) benzenesulfonyl] urea; 1- (6-Fluoro-1 H-benzoimidazole-5-sulfonyl) -3- (1, 2,3,5,6J-hexahydro-s-indacen-4-yl) urea; 1 - . 1- (4-chloro-2,6-diisopropyl-phenyl) -3- (1 H -indole-6-sulfonyl) urea; 1- (4-chloro-2,6-diisopropyl-phenyl) -3- (5-fluoro-1 H -indole-6-sulfonyl) urea; 1 - [1, 2,3,5,6,7-hexahydro-s-indacen-u-yl) -3- (1 H -indole-6-sulfonyl) urea; 1 - (5-Fluoro-1 H -indole-6-sulfonyl) -3- (1, 2,3,5,6,7-hexahydro-5-indacen-4-yl) urea; 1 - [4-chloro-2,6-diisopropyl-phenyl] -3- [2-fIuor-5- (2-methyl- (1,3) dioxolan-2-yl) benzenesulfonyl] urea; 3- [3- [4-chloro-2,6-diisopropyl-phenyl] ureidosulfonyl] -N-methyl-benzenesulfonamide; 1- [2-fluoro-5- (2-methyl- (1,3) dioxalan-2-yl) benzenesulfonyl] -3-1, 2,3,5,6,7-hexahydro-indacen-4-yl) urea; and 3- [3- (1, 2,3,5,6,7-hexahydro-s-indacen-4-yl) ureidosulfonyl] N-methyl-benzenesulfonamide. 6.- A pharmaceutical composition for the treatment of meningitis and salpingitis, septic shock, disseminated intravascular coagulation, and / or respiratory distress syndrome in adults, acute or chronic inflammation, arthritis, cholangitis, colitis, encephalitis, endocarditis , glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury vasculitis, acute and delayed hypersensitivity, graft rejection, and host disease versus graft, autoimmune diseases including diabetes mellitus type 1 and multiple sclerosis, periodontal diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, keloid formation, tumors that produce IL-1 as an autocrine growth factor, cachexia, Alzheimer's disease, percussion injury, depression atherosclerosis and osteoporosis in a mammal, including a human, comprising the administration of an amount of a compound of claim 1, or a pharmaceutically acceptable sai thereof, effective in said treatments or inhibition and a pharmaceutically acceptable carrier. 7. The use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a condition selected from the group of meningitis and salpingitis, septic shock, disseminated intravascular coagulation, and / or respiratory distress syndrome in adults, acute or chronic inflammation, arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, acute and delayed hypersensitivity, graft rejection, and host disease versus graft, autoimmune diseases including diabetes mellitus type 1 and multiple sclerosis, periodontal diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, keloid formation, tumors that produce IL-1 as a factor of autocrine growth, cachexia, Alzheimer's disease, percussion injury, depression, ater Osteosclerosis and osteoporosis in a mammal, including a human.
8. - The compound 4- (1-hydroxy-1-methyl-ethyl) -furan-2-sulfonamide.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/036,979 | 1997-01-29 |
Publications (1)
Publication Number | Publication Date |
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MXPA99007030A true MXPA99007030A (en) | 2000-02-02 |
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