MXPA98008586A - Derivatives of n- (amidinofenil) -n '- (substituent) -3h-2,4-benzodiazepin-3-ona as factor inhibitors - Google Patents
Derivatives of n- (amidinofenil) -n '- (substituent) -3h-2,4-benzodiazepin-3-ona as factor inhibitorsInfo
- Publication number
- MXPA98008586A MXPA98008586A MXPA/A/1998/008586A MX9808586A MXPA98008586A MX PA98008586 A MXPA98008586 A MX PA98008586A MX 9808586 A MX9808586 A MX 9808586A MX PA98008586 A MXPA98008586 A MX PA98008586A
- Authority
- MX
- Mexico
- Prior art keywords
- cycloheptylurea
- amidinophenyl
- piperidin
- phenyl
- substituted
- Prior art date
Links
- 230000002401 inhibitory effect Effects 0.000 title abstract description 50
- 239000003112 inhibitor Substances 0.000 title abstract description 30
- -1 amidinophenyl Chemical group 0.000 claims abstract description 311
- 150000001875 compounds Chemical class 0.000 claims description 162
- SZGLLXJFYCJRPP-UHFFFAOYSA-N cycloheptylurea Chemical compound NC(=O)NC1CCCCCC1 SZGLLXJFYCJRPP-UHFFFAOYSA-N 0.000 claims description 119
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 64
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 60
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 50
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 47
- 239000011780 sodium chloride Substances 0.000 claims description 43
- 150000003839 salts Chemical group 0.000 claims description 38
- 235000013877 carbamide Nutrition 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 229960000539 carbamide Drugs 0.000 claims description 33
- 239000004202 carbamide Substances 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 108020004021 3-ketosteroid receptors Proteins 0.000 claims description 29
- 108020000002 NR3 subfamily Proteins 0.000 claims description 29
- 125000005842 heteroatoms Chemical group 0.000 claims description 26
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 21
- 125000002947 alkylene group Chemical group 0.000 claims description 20
- 125000002837 carbocyclic group Chemical group 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 14
- 125000004429 atoms Chemical group 0.000 claims description 12
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- BPEXTIMJLDWDTL-UHFFFAOYSA-N N-(2-methylphenyl)acetamide Chemical compound CC(=O)NC1=CC=CC=C1C BPEXTIMJLDWDTL-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 claims description 7
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 4
- 150000001555 benzenes Chemical group 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- JROHQJUUCHIMDT-UHFFFAOYSA-N 3-(1-benzylpiperidin-3-yl)-1-(3-carbamimidoylphenyl)-1-cycloheptylurea Chemical compound NC(=N)C1=CC=CC(N(C2CCCCCC2)C(=O)NC2CN(CC=3C=CC=CC=3)CCC2)=C1 JROHQJUUCHIMDT-UHFFFAOYSA-N 0.000 claims description 3
- YKRRGDYFZAEQLQ-UHFFFAOYSA-N 3-[1-(3-aminophenyl)sulfonylpiperidin-4-yl]-1-(3-carbamimidoylphenyl)-1-cycloheptylurea Chemical compound NC(=N)C1=CC=CC(N(C2CCCCCC2)C(=O)NC2CCN(CC2)S(=O)(=O)C=2C=C(N)C=CC=2)=C1 YKRRGDYFZAEQLQ-UHFFFAOYSA-N 0.000 claims description 3
- GJEXEJGHDBDTSC-UHFFFAOYSA-M [3-carbamimidoyl-N-[[4-[2-(sulfinatoamino)phenyl]phenyl]carbamoyl]anilino]cycloheptane Chemical compound NC(=N)C1=CC=CC(N(C2CCCCCC2)C(=O)NC=2C=CC(=CC=2)C=2C(=CC=CC=2)NS([O-])=O)=C1 GJEXEJGHDBDTSC-UHFFFAOYSA-M 0.000 claims description 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000005874 benzothiadiazolyl group Chemical group 0.000 claims description 3
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- FNQJDLTXOVEEFB-UHFFFAOYSA-N 1,2,3-benzothiadiazole Chemical compound C1=CC=C2SN=NC2=C1 FNQJDLTXOVEEFB-UHFFFAOYSA-N 0.000 claims description 2
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1,2,3-triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 2
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 claims description 2
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 claims description 2
- UDGKZGLPXCRRAM-UHFFFAOYSA-N 1,2,5-thiadiazole Chemical compound C=1C=NSN=1 UDGKZGLPXCRRAM-UHFFFAOYSA-N 0.000 claims description 2
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 claims description 2
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 claims description 2
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 claims description 2
- OKGNASCFNLKPHV-UHFFFAOYSA-N 1-(3-carbamimidoylphenyl)-1-cycloheptyl-3-(1-thiophen-2-ylsulfonylpiperidin-4-yl)urea Chemical compound NC(=N)C1=CC=CC(N(C2CCCCCC2)C(=O)NC2CCN(CC2)S(=O)(=O)C=2SC=CC=2)=C1 OKGNASCFNLKPHV-UHFFFAOYSA-N 0.000 claims description 2
- JFOOYKFSRNYDPA-UHFFFAOYSA-N 1-(3-carbamimidoylphenyl)-1-cycloheptyl-3-[1-(2-methylpyridin-3-yl)piperidin-4-yl]urea Chemical compound CC1=NC=CC=C1N1CCC(NC(=O)N(C2CCCCCC2)C=2C=C(C=CC=2)C(N)=N)CC1 JFOOYKFSRNYDPA-UHFFFAOYSA-N 0.000 claims description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 1H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 2
- 239000005964 Acibenzolar-S-methyl Substances 0.000 claims description 2
- KTZQTRPPVKQPFO-UHFFFAOYSA-N Benzisoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 claims description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N Benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N Benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N Benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 2
- BCMCBBGGLRIHSE-UHFFFAOYSA-N Benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 2
- YLLQRJRUPZEECK-UHFFFAOYSA-N C1CC(NC(=O)N(C2CCCCCC2)C=2C=C(C=CC=2)C(N)=N)CCN1C1(C)NC=CC=C1 Chemical compound C1CC(NC(=O)N(C2CCCCCC2)C=2C=C(C=CC=2)C(N)=N)CCN1C1(C)NC=CC=C1 YLLQRJRUPZEECK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- JKFAIQOWCVVSKC-UHFFFAOYSA-N Furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 claims description 2
- IDDYFTIITUZJJU-UHFFFAOYSA-N N-[2-[4-[[(3-carbamimidoylphenyl)-cycloheptylcarbamoyl]amino]piperidin-1-yl]sulfonyl-4-methyl-1,3-thiazol-5-yl]acetamide Chemical compound CC1=C(NC(=O)C)SC(S(=O)(=O)N2CCC(CC2)NC(=O)N(C2CCCCCC2)C=2C=C(C=CC=2)C(N)=N)=N1 IDDYFTIITUZJJU-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
- 125000004854 thiadizolyl group Chemical group 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims 1
- NXTDOTYNPKMTDR-UHFFFAOYSA-N 1-(3-carbamimidoylphenyl)-1-cycloheptyl-3-(1-quinolin-8-ylsulfonylpiperidin-4-yl)urea Chemical compound NC(=N)C1=CC=CC(N(C2CCCCCC2)C(=O)NC2CCN(CC2)S(=O)(=O)C=2C3=NC=CC=C3C=CC=2)=C1 NXTDOTYNPKMTDR-UHFFFAOYSA-N 0.000 claims 1
- VERRWDNRYQUDOR-UHFFFAOYSA-N 1-(3-carbamimidoylphenyl)-1-cycloheptyl-3-[1-(2-fluorophenyl)sulfonylpiperidin-4-yl]urea Chemical compound NC(=N)C1=CC=CC(N(C2CCCCCC2)C(=O)NC2CCN(CC2)S(=O)(=O)C=2C(=CC=CC=2)F)=C1 VERRWDNRYQUDOR-UHFFFAOYSA-N 0.000 claims 1
- ZFJFCNVCTVRUDI-UHFFFAOYSA-N 1-(3-carbamimidoylphenyl)-3-[1-(5-chlorothiophen-2-yl)sulfonylpiperidin-4-yl]-1-cycloheptylurea Chemical compound NC(=N)C1=CC=CC(N(C2CCCCCC2)C(=O)NC2CCN(CC2)S(=O)(=O)C=2SC(Cl)=CC=2)=C1 ZFJFCNVCTVRUDI-UHFFFAOYSA-N 0.000 claims 1
- NZBQJABZPUIEDM-UHFFFAOYSA-N 3-(1-benzylpiperidin-4-yl)-1-(3-carbamimidoylphenyl)-1-cycloheptylurea Chemical compound NC(=N)C1=CC=CC(N(C2CCCCCC2)C(=O)NC2CCN(CC=3C=CC=CC=3)CC2)=C1 NZBQJABZPUIEDM-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 219
- 239000000203 mixture Substances 0.000 description 126
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 104
- 238000006243 chemical reaction Methods 0.000 description 98
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 84
- 239000000243 solution Substances 0.000 description 83
- 239000002904 solvent Substances 0.000 description 83
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 73
- 239000000047 product Substances 0.000 description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 66
- 238000002360 preparation method Methods 0.000 description 63
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
- 239000000463 material Substances 0.000 description 35
- 235000002639 sodium chloride Nutrition 0.000 description 35
- 239000002585 base Substances 0.000 description 34
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 34
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 33
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
- 108010074860 Factor Xa Proteins 0.000 description 27
- 239000000543 intermediate Substances 0.000 description 27
- 238000000034 method Methods 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 229940045136 Urea Drugs 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 25
- 150000001412 amines Chemical class 0.000 description 24
- 239000012267 brine Substances 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 229940086542 triethylamine Drugs 0.000 description 24
- 239000008079 hexane Substances 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- 239000003795 chemical substances by application Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 238000010992 reflux Methods 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 21
- 238000005755 formation reaction Methods 0.000 description 21
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- 229940002612 prodrugs Drugs 0.000 description 20
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- 239000000010 aprotic solvent Substances 0.000 description 18
- 125000004122 cyclic group Chemical group 0.000 description 18
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 17
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
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- 238000007792 addition Methods 0.000 description 14
- 150000003141 primary amines Chemical class 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- NKCXQMYPWXSLIZ-PSRDDEIFSA-N (2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[2-[[(2S)-6-amino-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]-3-m Chemical compound O=C([C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)[C@@H](C)O)[C@@H](C)O)C(C)C)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O NKCXQMYPWXSLIZ-PSRDDEIFSA-N 0.000 description 13
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- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000005804 alkylation reaction Methods 0.000 description 12
- 239000003146 anticoagulant agent Substances 0.000 description 12
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 12
- 238000010828 elution Methods 0.000 description 12
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- 239000000758 substrate Substances 0.000 description 12
- 150000001299 aldehydes Chemical class 0.000 description 11
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 239000003054 catalyst Substances 0.000 description 11
- 239000003480 eluent Substances 0.000 description 11
- KXKVLQRXCPHEJC-UHFFFAOYSA-N Methyl acetate Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 10
- IQPQWNKOIGAROB-UHFFFAOYSA-N [N-]=C=O Chemical compound [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 description 10
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- 230000000875 corresponding Effects 0.000 description 10
- 230000001808 coupling Effects 0.000 description 10
- 238000010168 coupling process Methods 0.000 description 10
- 238000005859 coupling reaction Methods 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
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- 238000005932 reductive alkylation reaction Methods 0.000 description 10
- RISRZABJWBDINO-UHFFFAOYSA-N 1-(3-cyanophenyl)-1-cycloheptyl-3-piperidin-4-ylurea Chemical compound C1CCCCCC1N(C=1C=C(C=CC=1)C#N)C(=O)NC1CCNCC1 RISRZABJWBDINO-UHFFFAOYSA-N 0.000 description 9
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
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- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical class C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 229910052716 thallium Inorganic materials 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- VNNLHYZDXIBHKZ-UHFFFAOYSA-N thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CS1 VNNLHYZDXIBHKZ-UHFFFAOYSA-N 0.000 description 1
- KQDJZZWCYTXUDE-UHFFFAOYSA-M thiophene;chloride Chemical compound [Cl-].C=1C=CSC=1 KQDJZZWCYTXUDE-UHFFFAOYSA-M 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 229940117960 vanillin Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
Abstract
The present invention describes N- (amidinophenyl) cyclourea analogues of the formula (I), which are useful as factor inhibitors
Description
DERIVATIVES OF N- (AMIDINOFENIL) -N '- (SUBSTITUENT) -3H-2, 4-BENZODIAZEPIN-3-ONA AS FACTOR XA INHIBITORS
FIELD OF THE INVENTION
This invention relates generally to analogues of
N- (amidinophenyl) cyclourea, which are inhibitors of the factor
Xa, pharmaceutical compositions containing the same, and methods of using same as anticoagulant agents for the treatment and prevention of thromboembolic disorders.
BACKGROUND OF THE INVENTION
Bovy et al, U.S. Patent No. 5,430,043 describes phenyl amidines of the formula:
Ref. 28548 which are reported to be inhibitors for platelet aggregation. However, there is no mention of factor Xa inhibition.
Himmelsbach et al, CA 2,105,934, is directed to cyclic ureas of the formula:
where, among the number of choices, X can be a carbonyl, and can be a C2-4 alkylene, Ra can be A-B-C and Rb can be -D-E-F. The group F is selected from -C02R, phosphono, tetrazolyl, and R8C0-0-CHR9-0-C0-. The compounds described by the above formula are claimed to have inhibition of aggregation and / or properties for fibrinogen binding. The inhibition of factor Xa is not discussed.
Lam et al, WO 94/19329, reports cyclic carbonyls, which may be cyclic ureas of the formula:
wherein at least one of R4, R4a, R7, and R7a is different from hydrogen. Compounds of this type are said to be useful as inhibitors of HIV protease. N- (amidinophenyl) cyclo -reases are not suggested as factor Xa inhibitors.
Curie et al, WO 96/36639, shows amidine derivatives of the formula:
wherein A may be a cyclic urea of 6 members, which may be useful as inhibitors for antiplatelet aggregation. However, Y is nitrate, nitrite, or a nitric oxide donation group. The present compounds, in contrast, do not contain the nitric oxide donation groups of WO 96/36639.
Klinger et al, WO 94/21607, illustrates heterocyclic compounds of the formula:
wherein, with the judicious selection of variables, Z1 can be a carbonyl, A can be NR1, R1 can be an amidino-substituted phenyl, and B and Z2 each can be CH2. However, the present compounds do not include the right-side chain shown above.
Mohán et al, WO 96/38421, describes cyclic N, N-di (arylmethyl) urea derivatives of the formula:
wherein R7 and R8 may be combined to form a benzene ring and the double bond shown may be absent, which may be useful as factor Xa inhibitors. These compounds are preferably substituted bis-amidino. However, the presently claimed compounds are not bis-benzyl or substituted bis-amidino.
Chakravarty et al, WO 95/03044, discusses benzimidazoles substituted with phenoxyphenylacetic acid derivatives of the formula:
wherein R 12 can be a substituted aryl group. But, this reference does not consider amidino-phenyl groups. In addition, the present compounds do not contain the above variable Z, which is defined as a carbonyl, sulfonyl, or phosphoryl group.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, maintains a central position that unites the mechanisms of intrinsic and extrinsic activation in the final common path of blood coagulation. The generation of thrombin, the final serine protease in the path to generate a fibrin clot, from its precursor is amplified by the formation of the prothrombinase complex (factor Xa, factor V, Ca2 + and phospholipid). Since it is estimated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation, Thromb Res. 1979, 15, 617-629), the inhibition of factor Xa may be more efficient than the inactivation of thrombin in the interruption of the blood coagulation system.
Therefore, effective and specific inhibitors of factor Xa are necessary as valuable therapeutic agents potentially for the treatment of thromboembolic disorders. Therefore, it is desirable to discover new factor Xa inhibitors.
BRIEF DESCRIPTION OF THE INVENTION
Accordingly, an object of the present invention is to provide novel N- (amidinophenyl) cyclourea factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof. same.
These and other objects, which will become apparent during the following detailed description, have been achieved by the discovery of the inventors that the compounds of the formula (I):
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R1, R2, m and n are defined below, are effective inhibitors of factor Xa.
DETAILED DESCRIPTION OF THE PREFERRED MODALITIES
(1) Therefore, in a first embodiment, the present invention provides novel compounds of the formula I:
or stereoisomers or pharmaceutically acceptable salt forms thereof, wherein;
one of D and D1 is selected from CN, C (= NRX1) NR12R13, NHC (= NR11) NR1R13, NR12CH kNR11), C (0) NR12R13, and (CH2) tNR12R13 and the other is H;
R1 is selected from H, (, CH2) rOR3, halo, C1-4 alkyl, (CH2) rNR4R '
(CH2) rC02H, (CH2) rC (= 0) R4 (CH2 rNR4C < = 0) R4 (CH2) rS02R5
(CH2) rNR4S02R5;
R2 is selected from H, = 0, C1-4 alkyl substituted with 0, 1, or 2 R7, C2-6 alkenyl substituted with 0, 1, or 2 R7, (CH2) rOR3, (CH2) rC (0) R4 , (CH2) rOC (0) R4, (CH2) rNR3R3 ', (CH2) rNR3C (O) R4,
(CH2) rS02R5, (CH2) rNR3S02R5, carbocyclic residue C3_? 0 substituted with 0-2 Rfi; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
R2a is absent;
alternatively, R2 and R2a may be present on adjacent carbon atoms and combine to form a benzene ring substituted with 0-2 R10 or a 5-6 member aromatic heterocycle containing 0-2 heteroatoms selected from the group consisting of N, O and S and substituted with 0-2 R10a;
R3 and R3 'are independently selected from H, C1-4 alkyl, benzyl and phenyl;
R3 and R3 'can be taken together to form a 5- or 6-membered ring substituted with 0-2 R6;
R and R are independently selected from H, OR 3, C 1-4 alkyl, phenyl and NR 3 R 3 ';
R5 is selected from C? -4 alkyl, phenyl and NR3R3 ';
Z is selected from a bond, C? -4 alkylene, (CH2) rO (CH2) r,
(CH2) 2NR3 (CH2) r, (CH2) rC (0) (CH2) r, (CH2) rC (O) 0 (CH2) r, (CH2) 2OC (0) (CH2) r, (CH2) rC (0) NR3 (CH2) r, (CH2) 2NR3C (O) (CH2) r, (CH2) 2OC (0) 0 (CH2) r, (CH2) 2OC (0) NR3 (CH2) r, (CH2) 2NR3C (O) O (CH2) r,
(CH2) 2NR3C (0) NR3 (CH2) r, (CH2) rS (0) p (CH2) r, (CH2) rS02NR3 (CH2) r,
(CH2) 2NR3S02 (CH2) r, and (CH2) 2NR3S02NR3 (CH2) r;
A is selected from;
C3.10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
B is selected from:
XY, NR3R3 ', C (0) NR3R3', S02NR3R3 ', benzyl substituted with 0-2 R6, C3-? 0 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
X is selected from C1-4 alkylene, -C (O) -, -C (0) CR3R3 '- CR3R3'C (0) -, -C (0) 0-, -C (0) 0CR3R3'-, -CR3R3'C (O) O-, -0C (0) - OC (0) CR3R3'-, -CR3R3'0C (0) -, -S (0) p-, -S (O) pCR3R3 '- , -CR3R3'S (O) p -S (0) 2NR3-, -NR3S (0) 2-, -NR3S (0) 2CR3R3'-, -CR3R3'S (O) 2NR3- -NR3S (0) 2NR3-, -C (0) NR3-, -NR3C (0) -, -C (O) NR3CR3R3 '--NR3C (0) CR3R3'-, -CR3R3'C (O) NR3-, -CR3R3'NR3C (O) -, - NR3C (O) O-OC (0) NR3-, -NR3C (0) NR3-, -NR3-, -NR3CR3R3'-, -CR3R3'NR3-, O, -CR3R3 '? -, -OCR3R3'-, S, -CR3R3'S-, and -SCR3R3'-;
And it is selected from:
C4_4 alkyl substituted with 0-2 R6, C3-? 0 carbocyclic residue substituted with 0-2 R6, and 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and ft S replaced with 0-2 R6;
R is selected from H, OH, CF3, (CH2) nOR, halo, C1-4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (0) R3, NR3C (0) R3', NR3C ( 0) NR3R3 ', S02NR3R3', NR3SOzNR3R3 ', NR3S02- alkylo C? -4, S02-phenyl, and NR3S02R8;
R7 is selected from:
C3-10 carbocyclic residue substituted with 0-2 R6; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6;
R8 is selected from:
C3-10 carbocyclic residue substituted with 0-2 R9; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R9;
R9 is selected from H, OH, (CH2) nOR3, halo, C1-4 alkyl / CN, N02, (CH2) rNR3R3 ', (CH2) rC (0) R3, NR3C (0) R3', NR3C (O) NR3R3 ', S02NR3R3', NR3S02NR3R3 ', and NR3S02-C1-4alkyl;
R10 is selected from H, OR3, halo, C1-4alkyl, CN, N02, NR3R3 ', NR3C (0) R3', NR3C (0) 0R3 ', NR3S02-phenyl, and NR3S02-C1-4alkyl;
R10a is selected from H and C1-4alkyl if it is a substituent on the nitrogen atom;
R10a is selected from H, C? -4 alkyl, NR3R3 ', NR3C (0) R3', NR3C (0) 0R3 ', NR3S02-phenyl, and NR3S02-C1-4 alkyl if it is a substituent on the carbon atom;
R 11 is selected from H, OH, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-4 alkoxycarbonyl, C 6 -? Aryloxy, C 6 -? Aryloxycarbonyl or C 6 -? 0 arylmethylcarbonyl, C 1-6 alkylcarbonyloxy 4 C 1 -4 alkoxycarbonyl, C 6 -α arylcarbonyloxy or C 1 -4 alkoxycarbonyl, C 1 -6 alkylaminocarbonyl, phenylaminocarbonyl, and C 4 -4 alkoxycarbonyl of phenyl;
R 12 is selected from H, C 1-6 alkyl and (CH 2) n-phenyl;
R13 is selected from H, C? -6 alkyl and (CH2) n-phenyl;
n is selected from 0, 1, 2, and 3;
m is selected from 0 and 1;
p is selected from 0, 1, and 2;
q is selected from 1, 2, 3, 4, and 5; Y,
r is selected from 0, 1, and 2.
(2) In a preferred embodiment, the present invention provides compounds of the formula I, wherein:
D is C (= NH) NH2;
D 'is H;
R1 is selected from H, (CH2) rOR3, halo, (CH2) rNR4R4 ', (CH2) rC02H, (CH2) rC (= 0) R4, (CH2) rNR4C (= 0) R4, (CH2) rS02R5, and (CH2) rNHS02R5;
R2 is selected from H, = 0, (CH2) rOR3, (CH2) rC (0) R4, (CH2) r0C (O) R4, (CH2) rNR3R3 ', (CH2) rNR3C (0) R4, (CH2) rS02R5, (CH2) rNR3S02R5, C3-10 carbocyclic residue substituted with 0-2 R6; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
R4 and R4 'are independently selected from H, OR3, C? -4 alkyl, and NR3R3';
R5 is selected from C? -4 alkyl, and NR3R3 ';
Z is selected from a bond, alkylene C? _4, (CH2) rC (0) (CH2) r, (CH2) rC (0) NR3 (CH2) r, (CH2) 2NR3C (0) (CH2) r, ( CH2) 2OC (O) NR3 (CH2) r, (CH2) 2NR3C (0) 0 (CH2) r, (CH2) 2NR3C (0) NR3 (CH2) r, (CH2) rS (O) p (CH2) r , (CH2) rS02NR3 (CH2) r, (CH2) 2NR3S02 (CH2) r, and (CH2) 2NR3S02NR3 (CH2) r; Y,
X is selected from alkylene C? -4, -C (O) -, -C (O) CR3R3 '-, -CR3R3'C (0) -, -C (0) 0-, -C (0) OCR3R3' -, -CR3R3'C (0) O-, -0C (0) -, -0C (0) CR3R3'-, -CR3R3'0C (0) -, -S (0) p-, -S (O. ) pCR3R3 '-, -CR3R3'S (O) p-, -S (0) 2NR3-, -C (0) NR3-, -NR3C (0) -, -NR3C (0) 0-, -0C (0) NR3 -, -NR3C (0) NR3-, -NR3-, -NR3CR3R3'-, -CR3R3'NR3-, O, -CR3R3 '? -, and -OCR3R3'-.
(3) In a further preferred embodiment, the present invention provides compounds of the formula I, wherein:
R1 is selected from H, OR3, (CH2) OR3, halo, NRR4 ', (CH2) NR4R4', C (= 0) R4, NHC (= 0) R4, (CH2) NHC (= 0) R4, S02R5, (CH2) S02R5, NHS02R5, and (CH2) NHS02R5;
R2 is selected from H, = 0, OR3, C (0) R4, (CH2) C (0) R4, 0C (0) R4,
NR4R4 'NR3C (0) and NR4S02R5;
A is selected from:
C5-6 carbocyclic residue substituted with 0-1 R6, and 5-6 member heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N and O substituted with 0-1 R6;
B is selected from: Y, X-Y, and NR2R2a;
And it is selected from one of the following carboxylic and heterocyclic systems, which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2-oxadiazole, 1,2,4-oxadiazole, 1, 2, 5-oxadiazole, 1, 3, 4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1, 2, 5-thiadiazole, 1,3,4-thiadiazole, 1 2,3-triazole, 1, 2,4-triazole, 1, 2, 5-triazole, 1,3-triazole, benzofuran, benzothiofuran, indole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, isoindazole, and benzothiadiazole;
And it can also be selected from the following bicyclic heteroaryl ring systems:
K is selected from O, S, NH, and N;
X is selected from -CH2-, -C (0) -, -C (0) CHR3-, -CHR3C (0) -, -S (0) p-, -S (0) pCR3R3'-, -CHR3S ( 0) p-, -S (0) 2NR3-, -C (0) NR3-, -NR3C (0) -, -NR3-, -NR3CHR3-, and -CHR3NR3;
R6 is selected from H, OH, CF3, (CH2) n0R3, halo, C? -4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (0) R3, NR3C (0) R3', S02NR3R3 ', S02-phenyl, NR3S02-C1-4 alkyl, and NR3S02R8;
R is selected from:
C5-s carbocyclic residue substituted with 0-2 R9; and, 5-6 member heterocyclic system containing from
1-3 heteroatoms selected from the group consisting of N, 0, and
S substituted with 0-2 R9;
R9 is selected from H, OH, (CH2) n0R3, halo, Cx.4 alkyl / CN, N02, (CH2) rNR3R3 ', (CH2) rC (0) R3, NR3C (0) R3', NR3C (0) NR3R3 ', S02NR3R3', NR3S02NR3R3 ', and NR3S02-C1-4alkyl; Y,
p is 2
(4) In an identical more preferred embodiment, the present invention provides compounds of the formula I, wherein:
Z is selected from a bond, C? -4 alkylene, (CH2) rC (0) (CH2) r / (CH2) rC (0) NR3 (CH2) r, (CH2) 2NR3C (0) (CH2) r, (CH2) 2NR3C (O) NR3 (CH2) r, and (CH2) rS (CH2) r;
X se. select from -CH2-, -C (0) -, -C (0) CHR3-, -CHR3C (0) -, -S (0) p-, -S (0) pCR3R3'-, -CHR3S (0) p-, -S (0) 2NR3-, -C (0) NR3-, and -NR3C (0) -;
R is selected from H, OH, CF3, (CH2) nOR, halo, C? -4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (O) R3, NR3C (0) R3', S02NR3R3 ',
S02-f enyl, and NR3S02- alkylo C? -4;
m is 1; Y,
r is selected from 0 and 1.
(5) In a further preferred embodiment, the present invention provides compounds of the formula I, wherein:
R3 and R3 'are independently selected from H and alkyl
-1-4 /
Z is selected from a bond, C? -4 alkylene, (CH2) rC (0) NR3 (CH2) r, (CH2) 2NR3C (0) (CH2) r, and (CH2) 2NR3C (O) NR3 (CH2) r;
A is selected from phenyl substituted with 0-1 R6 and a 6-membered heterocyclic system containing 1 atom of N and 0-1 atom of 0 and substituted with 0-1 R6;
X is selected from -CH2-, -S (0) p-, -S (O) PCR3R3'-, -S (0) 2NR3-, -C (0) NR3-, and;
Y is selected from phenyl, i-propyl, quinolinyl, thiadizolyl, benzothiadiazolyl, thiophenyl, pyridyl, cyclohexyl, and naphthyl, each of which is substituted with 0-2 R6; Y,
n is selected from 0, 1, and 2.
(6) In an identical additional preferred embodiment, the present invention provides compounds of the formula I, wherein:
R3 and R3 'are independently selected from H and methyl;
Z is selected from a bond, CH2, -CH2CH2-, -CH2CH2CH2- and -CH2CH2CH2CH2-;
A is selected from phenyl substituted with 0-1 R6, and piperidinyl substituted with 0-1 R6; Y,
n is 2
(7) In a particularly preferred embodiment, the present invention provides compounds selected from:
N- (3-amidinophenyl) -N 1 - ((4- ((2-sulfonamido) phenyl) phenyl) -methyl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (1-benzylpiperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- (picolin-2-yl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- (picolin-3-yl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- (picolin-4-yl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (1- (a-phenethyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- ((phenyl) methane) sulfonyl) -piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- (phenyl) sulfsnylpiperidin-4-yl) -cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (1- (quinolin-8-yl) sulfonylpiperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (1- (2-fluorophenyl) sulfonylpiperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- (4-acetamidophenyl) sulfonyl-piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- (2-aminophenyl) sulfonylpiperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- (3-aminophenyl) sulfonylpiperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- (4-aminophenyl) sulfonylpiperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- ((2-aminophenyl) methane) sulfonyl) -piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- ((2-acetamido-phenyl) methane) -sulfonylpiperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- ((thiophen-2-yl) sulfonyl) piperidin-4-yl) -cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (1- ((5-chlorothiophen-2-yl) sulfonyl) -piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- ((5-carbomethoxythiophen-2-yl) sulfonyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- ((benzo-2,3,1-thiadiazo-4-yl) sulfonyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- ((cyclohexyl) sulfamido) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (1- ((isopropyl) sulfamido) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- ((phenyl) sulfamido) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- ((isopropyl) sulfonyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (1- ((5-amino-4-methylthiazol-2-yl) sulfonyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (1- ((5-acetamido-4-methylthiazol-2-yl) sulfonyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (1- (6-carbomethoxyphenyl-sulfonyl) piperidin-4-yl) -cycloheptylurea;
N- (3-amidinophenyl) -N '- (2-pyridylmethyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (3-pyridylmethyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (4-pyridylmethyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (phenyl-N 1 '-methylsulfamido) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- ((4-phenylsulfonylthiophen-2-yl) sulfonyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (4-pyridylmethylsulfonyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (thiophen-2-ylsulfonyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (4-fluorobenzylsulfonyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (2-pyridylsulfonyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (2-trifluoromethyl-phenylsulfonyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (2-phenylisopropylsulfonyl) piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- ((1- ((phenyl) -1,1-dimethyl) methane) sulfonyl) -piperidin-4-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (methyl ((phenyl-methane) carbamide) morpholin-3-yl)) cycloheptylurea;
N- (3-amidinophenyl) -N '- (methyl ((thiophen-2-yl) sulfonyl) morpholin-3-yl)) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (methyl ((phenyl-methane) sulfonyl) morpholin-3-yl)) cycloheptylurea;
N- (3-amidinophenyl) -N '- ((N-benzyl) piperidin-3-yl) cycloheptylurea;
N- (3-amidinophenyl) -N1 - ((N- (benzyl) sulfonyl) -piperidin-3-yl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - ((N- (thiophen-2-yl) sulfonyl) piperidin-3-yl) cycloheptylurea;
N- (3-amidinophenyl) -N '- (4- (2-sulfonamido-phenyl) phenyl) cycloheptylurea;
N- (3-amidinophenyl) -N 1 - (5- (2-sulfonamido-phenyl) pyridin-2-yl) cycloheptylurea; Y,
N- (3-amidinophenyl) -N '- (methyl (4- (2-sulfonamidophenyl) phenyl)) cycloheptylurea;
or stereoisomers or pharmaceutically acceptable salt forms thereof.
(8) In another preferred embodiment, the present invention provides compounds, wherein:
n is 2; Y
R2 and R2a are on adjacent carbon atoms and combine to form a benzene ring substituted with 0-2 Rxo or a 5-6 membered aromatic heterocycle containing 0-2 heteroatoms selected from the group consisting of N, O, and S and replaced with 0-2 R10a.
(9) In another more preferred embodiment, the present invention provides novel compounds of formula II:
or stereoisomers or pharmaceutically acceptable salt forms thereof, wherein;
Ring N contains 0-2 N atoms and is substituted with 0-2 R10; Y,
D is selected from CN, C (= NR1X) NR12R13, NHC (= NR11) NR12R13, NR12CH (= NR1X), C (0) NR12R13, and (CH2) tNR12R13.
(10) In another, more identical, preferred embodiment, the present invention provides compounds of the formula II, wherein:
D is C (= NH) NH2;
R1 is selected from H, (CH2) rOR3, halo, (CH2) rNR4R4 ', (CH2) rC02H, (CH2) rC (= 0) R4, (CH2) rNR4C (= 0) R4, (CH2) rS02R5, and (CH2) rNHS02R5;
R4 and R4 'are independently selected from H, OR3, C1-4 alkyl, and NR3R3';
R5 is selected from C1-4 alkyl, and NR3R3 ';
Z is selected from a bond, C1-4 alkylene, (CH2) rC (0) (CH) r,
(CH2) rC (0) NR3 (CH2) r, (CH2) 2NR3C (0) (CH2) r, (CH2) 2OC (O) NR3 (CH2) r,
(CH2) 2NR3C (0) 0 (CH2) r, (CH2) 2NR3C (0) NR3 (CH2) r, (CH2) rS (0) p (CH2) r, and (CH2) rS02NR3 (CH2) r; and, X is selected from alkylene C? -4, -C (0) -, -C (O) CR3R3'-,
• -CR3R3'C (0) -, -C (0) 0-, -C (0) OCR3R3'-, -CR3R3'C (0) O-, -OC (O) -,
-OC (0) CR3R3'-, -CR3R3'0C (0) -, -S (0) p-, -S (0) pCR3R3'-, -CR3R3'S (0) p-,
-C (0) NR3-, -NR3C (0) -, -NR3C (0) 0-, -0C (0) NR3-, -NR3C (O) NR3-, -NR3-, -NR3CR3R3'-, -CR3R3 'NR3-, O, -CR3R3'? -, and -OCR3R3'-.
(11) In still another preferred embodiment, the present invention provides compounds of the formula II, wherein:
Z is selected from a bond, C? - alkylene, C (0) NR3 (CH2) r, S (0) 2, S (0) 2CH2, and (CH2) rS02NR3 (CH2) r;
A is selected from phenyl substituted with 0-1 R6 and a 6-membered heterocyclic system containing an N atom and substituted with 0-1 R6; Y,
X is selected from C1-4 alkylene, -C (0) -, -C (0) CR3R3'-, -CR3R3'C (0) -, -S (0) p-, -S (0) pCR3R3'- , -C (0) NR3-, and, -NR3-.
(12) In another identical additional preferred embodiment, the present invention provides compounds selected from:
1,2,4,5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -3H-2,4-benzodiazepin-3-one;
1,2,4,5-tetrahydro-2- (thiophen-2-yl) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -3H-2,4-benzodiazepin-3-one;
1,2,4,5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -7,8-dimethoxy-3H-2,4-benzodiazepine- 3-one; -Y,
1,2,4,5-tetrahydro-2- (thiophen-2-yl) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -7,8-dimethoxy-3H-2,4-benzodiazepine -3-one;
In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.
In a third embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a salt or form of pharmaceutically acceptable prodrug thereof.
DEFINITIONS
The compounds described herein can have asymmetric centers. The compounds of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis of optically active starting materials. Many geometric isomers of olefins, C = N double bonds, and the like may also occur in the compounds described herein, and all similar stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stoichiometry or isomeric form is specifically indicated.
The term "substituted" as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection of the indicated group, since the normal valence of the designated atom is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (ie, = 0), then 2 hydrogens are replaced in the atom.
When any variable (for example, R6) is presented more than once in any constituent or formula for a compound, its definition in each case is independent of its definition in each two cases. Therefore, for example, if a group shows that it can be substituted with 0-2 R6, then the group can optionally be replaced with up to two groups R6 and R6 in each case independently selected from the definition of R6. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such a substituent can be attached to any atom in the ring. When a substituent is listed without indicating the atom via which such a substituent is attached to the rest of the compound of a given formula, then such a substituent may be attached via any atom in such a substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.
As used herein, "C? -6 alkyl" means that it includes both straight and branched chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; "alkenyl" means that it includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds, which may occur at any point along the chain, such as ethenyl, propenyl, and the like.
"halo" or "halogen" as used herein, refers to fluoro, chloro, bromo, and iodo; and "counterion" is used to represent a negatively charged, small species, such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, the term "carbocycle" or "carbocyclic residue" means any monocyclic or bicyclic 3 to 7 member or bicyclic or tricyclic member of 7 to 13 members, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl; [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane (decalin), [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term "heterocycle" or "heterocyclic system" means a 5- or 7-membered monocyclic or bicyclic or a 7 to 10 membered bicyclic heterocyclic ring, which is saturated, partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S and which includes any bicyclic group in which any of the heterocyclic rings defined above are fused to a ring of benzene. The nitrogen and sulfur heteroatoms can optionally be oxidized. The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein can be substituted on a carbon atom or on a nitrogen atom if the resulting compound is stable. If it is specifically shown, that a nitrogen atom in the heterocycle can optionally be quaternized again. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. As used herein, the term "aromatic heterocyclic system" means a 5- or 7-membered monocyclic or bicyclic or a 7- to 10-membered bicyclic aromatic heterocyclic ring, which consists of carbon atoms and from 1 to 4 heteroatoms in a manner independently selected from the group consisting of N, 0 and S. It is preferred that the total number of S and O atoms in the heterocycle is not greater than 1.
Examples of the heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H, 6H-1, 5, 2-dithiazinyl, ft 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1, 2, 5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzthiazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, benzothiadiazolyl, carbazolyl, 4aH-carbazolyl, β- carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2, 3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 2, 5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthroline, fenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl , purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinquinlidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1, 2,5-thiadiazinyl, 1, 2, 3-thiadiazolyl, 1,2-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl , thienoimidazolyl, thiophenyl, triazinyl, 1, 2, 3-triazolyl, 1, 2,4-triazolyl, 1, 2, 5-triazolyl, 1, 3, 4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are the fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of the judgment of the physician, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.
As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, wherein the parent compound is modified by making acid or base salts thereof. Examples of the pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; organic or alkali salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, of non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from organic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the main compound, which contains a basic or acid part by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, it is preferred in a non-aqueous medium similar to ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. The lists of appropriate salts are found in Remington's Pharmaceutical Sciences, Seventeenth Edition; Mack Publishing Company, Easton, PA, 1985, p. 1418, the discovery of which by the same is incorporated by reference.
The term "prodrugs" means that it includes any of the covalently linked carriers, which release the active major drug according to formula (I) in vivo when such a prodrug is administered to a mammalian subject. The prodrugs of a compound of the formula (I) are prepared by modifying the functional groups present in the compound in such a way that the modifications are divided, either in the routine manipulation or in vivo, to the main compound. Prodrugs include compounds of the formula (I), wherein a hydroxy, amino, or sulfhydryl group is attached to any group which, when the prodrug or compound of the formula (I) is administered to a mammalian subject, is divided to form a free hydroxyl group, free amino, or free sulfhydryl, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. Preferred prodrugs are prodrugs of amidine, where D is C (= NR?:?) NH2, and R11 is selected from OH, C1-4 alkoxy, aryloxy Ce.10, alkoxycarbonyl C1-, aryloxycarbonyl C6-10, arylmethylcarbonyl C6 -?, C 1-4 alkoxycarbonyloxy C 1-4 alkoxycarbonyl and C 1-6 arylcarbonyloxy or C 1-4 alkoxycarbonyl. The most preferred prodrugs are where R 11 is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.
The term "stable compound" and "stable structure" mean that it indicates a compound that is sufficiently strong to survive isolation to a useful degree of purity from the reaction mixture, and formulation into an effective therapeutic agent.
SINTESTS
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the synthetic organic chemistry art, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those methods described below. Each of the references cited below are therefore incorporated herein by reference. All temperatures are reported in degrees Celsius.
The compounds of Formula 1 can be prepared using the reactions and techniques described below. The reactions are carried out in a suitable solvent for the reagents and materials used and appropriate for the transformations that are carried out. It will be understood by those experts in the technique of organic synthesis that the functionality present in the molecule must be consistent with the proposed transformations. This will sometimes require a judgment to modify the order of the synthesis steps or to select a particular process scheme over another to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protection group used for the protection of the reactive functional groups present in the compounds described in this invention. An authoritative description describing the many alternatives for the experienced physician is in Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).
Two general approaches can be used for the preparation of the cyclic ureas of this invention. The first comprises the bimolecular cyclizations for the cyclic urea, as shown in Scheme I, the second uses the internal unimolecular cyclizations of Scheme II.
Scheme I: Bimolecular cyclization routes for a cyclic urea precursor to Formula 1. Route A
Route A of Scheme I illustrates the bis-alkylation of a N, N '-disubstituted urea with a substituted alkane on both terminals with an appropriate leaving group (L.G.), such as a halogen or sulfonate ester. The flexibility of this approach also allows bis-alkylation with an alkene or R2-substituted alkane, which is again substituted in both terminals with an appropriate leaving group (L.G.). Such alkylating agents are either commercially available, for example, 1,4-dibromobutane and its lower homologs, found in the literature, for example, the isopropylidene ether of 1,4-diiodide-2,3-dihydroxybutane (Deluca and Magnus, J. Chem. Soc. (Perkin Trans.I), 2661 (1991), and Hoye and Suhadolnik, Tetrahedron, 42 (11) 2855 (1986)), or can be prepared by a physician skilled in the art using standard chemical methods.
The N, N '-substituted urea can be generated from two primary amines, one of which must be a Q, R1-substituted aniline, where Q is a functional group from which an amidine should be easily generated such as the nitrile; in some special cases Q can be tolerated as a protected mono- or diacyl- or carbamoyl amidine. The second primary amine, H2N-ZAB, can be any amine considered appropriate within the limits of Formula 1. This amine can be commercially available, for example 1-benzyl-4-aminopiperidine, found in the literature, for example the lt-butoxycarbonyl-4-aminopiperidine (Mach et al., J. Med. Chem., 36 (23), 3707 (1993)), or may be prepared by a physician skilled in the art using standard chemical methods.
The two primary amines described above can be attached to the desired N, N'-disubstituted urea by selecting one for transformation to the corresponding isocyanate in situ by stirring with phosgene or its equivalent, such as trichloromethyl chloroformate or p-nitrophenylchloroformate in the presence of a trialkylamine base and a dry aprotic solvent such as dimethylformamide, dioxane, benzene or a chlorinated alkane. The temperature of this reaction can be varied from -10 ° C to the point of reflux of the solvent (Takeda et al., Tetrahedron Lett., 24 (42) 4569 (1983), Cortez et al., Synth. Commun., 21 (2) 285 (1991)). Alternatively, the desired isocyanate may be commercially available, such as 3-cyanophenyl isocyanate, in which case convenience dictates that this substrate be used. The conditions for the direct reaction of a preformed isocyanate are similar to those described above with the caveat that the phosgene equivalent is necessary, and that the trialkylamine base can be omitted (Shiau et al., J. Heterocyclic Chem., 26, 595 (1989)).
Ring formation in Route A is achieved by alkylation of the N, N '-substituted urea with the dihalogenated alkylating agent (Curtis, Aust. J. Chem., 41, 585 (1988), Htay et al., Tetrahedron Lett., 79, (1976), Sulsky et al., Synth. Commun., 19, 1871 (1989)) or disulfonated (Ayyana et al., Chem. Ind. (London), 599 (1988)) described above. Typically, the disubstituted urea is added at room temperature or lower to a mixture of at least two equivalents of strong base, such as sodium hydride, potassium t-butoxide or an alkyl lithium in an appropriate anhydrous solvent, such as tetrahydrofuran, dimethylformamide, t-butanol, toluene or dimethylsulfoxide. After the deprotonation is complete, a solution of the alkylating agent in the selected solvent is added slowly to the disubstituted urea at room temperature or lower; when the addition is complete, the reaction can be continued at room temperature or lower or heated to the reflux temperature of the solvent, depending on the reactivity of the alkylated / urea disubstituted agent pair and the authorization of the skilled physician.
Route B of Scheme I illustrates the use of an appropriately substituted diamine and phosgene or its equivalent to generate a cyclic urea precursor to Formula 1. The required diamine can be generated by two approaches. The first approach utilizes a Q, R1-substituted aniline, which binds with a secondary amine protected with N-acyl or N-carbamoyl, where G is a halogen leaving group or sulfonate ester for a standard aniline alkylation Q, R1-substituted or G should be an appropriate aldehyde for the reductive alkylation of the Q, R1-substituted aniline. The second approach to the formation of diamine binds an N-acyl or N-carbamoyl-protected N-alkylated R1-substituted aniline, where G is as described above, with a primary amine H2N-ZAB by a reductive or standard alkylation .
Both protected secondary amines are available by similar chemistry. The selected aniline or primary amine H2N-Z-A-B is protected with an N-acyl or N-carbamoyl protecting group according to a method specified in Greene and Wuts; N-t-butoxycarbamoyl is useful for this application. Then this protected amine can be cleanly mono-alkylated with one of the dihalogenated or disulfonylated alkylation agents recommended for Route A (Reed et al., Tetrahedron Lett., 79 (45) 5725 (1988)). Alternatively, the protected amine may be mono-alkylated with a protected haloalcohol. Both alkylations are easily achieved in anhydrous aprotic solvents, such as toluene, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide at temperatures ranging from -78 ° C to the reflux temperature of the selected solvent with a strong base, such as sodium hydride, t -potassium butoxide or an alkyl lithium. In the case where G is a protected alcohol, the protecting group is removed and an aldehyde is generated by oxidation of Moffatt (Pfitzner and Moffatt, J. Amer. Chem. Soc., 87, 5661 (1965)) or through the use of pyridinium chlorochromate (Corey and Suggs, Tetrahedron Lett., 2647 (1975)) or pyridinium dichromate in dichloromethane (Coates and Corrigan, Chem. Ind. (London), 1594 (1969)).
The required diamine can then be prepared by stirring the alkylating agent with the secondary amine component either neat or in an aprotic solvent such as toluene, tetrahydrofuran, dimethylformamide or dimethylsulfoxide. The temperature of the reaction can range from -78 ° C to the reflux temperature of the selected solvent. A strong base, such as sodium hydride, potassium t-butoxide or an alkyl lithium or a weaker trialkylamine base may be used, depending on the reactivity of the components. As an alternative, when G is an aldehyde, a reductive alkylation of the primary amine component is possible. The direct method comprises the use of a borohydride reducing agent, more preferably sodium or lithium cyanoborohydride, in a mixture of aldehyde and amine components in an alcohol solvent (Borch et al., J. Amer. Chem. Soc. ., 93, 2897 (1971)). A stepwise method comprises the generation of an imine / enamine intermediate by azeotropic removal of water from a hot mixture of aldehyde and primary amine component in an appropriate solvent, such as benzene at reflux temperature. Then the imine / enamine intermediate can be isolated and reduced by palladium catalyst under an atmosphere of hydrogen gas at ambient pressure or higher or reduced by borohydride reagents under conditions similar to those preferred for the direct method. The required diamine is generated by the removal of the protection group according to a method recommended in Greene and Wuts.
The diamine formed above is reacted with phosgene or its equivalent, such as trichloromethyl chloroformate or p-nitrophenylchloroformate in the presence of an excess of a trialkylamine base and a dry, aprotic solvent such as dimethylformamide, dioxane, toluene, benzene , or a chlorinated alkane to form a cyclic urea precursor to Formula 1. The temperature of this reaction can be varied from -10 ° C to the point of reflux of the solvent.
Scheme II: Unimolecular cyclization routes for cyclic urea precursors to Formula 1. Two alternatives, Route C Route D, for the preparation of the precursors of Formula 1 by a unimolecular cyclization method are shown in Scheme II . In Route C it begins with the alkylation of an Q, R1-substituted aniline with a halogenated alkylalcohol, such as 4-bromobutan-l-ol or its homologs, or a protected version thereof, such as methoxymethyl ether of 4 -bromobutan-1-ol, either pure or in an anhydrous solvent, such as dimethylformamide, benzene, tetrahydrofuran, hexamethylphosphorotriamide, or dimethylsulfoxide. This reaction can be promoted by heating the mixture to the point of reflux of the solvent. Depending on the reactivity of the non-base substrate, or a strong base, such as sodium hydride, potassium t-butoxide or an alkyl lithium, or a weak base, such as potassium carbonate or a trialkylamine, may be necessary . The alkylation product is reacted with an isocyanate OCN-ZAB generated from the amine NH2-ZAB by the same method described above for Route A of Scheme I to give an alcohol or alcohol protected from product, which can be transformed to a halogenated or sulfonyl ester analogue by cyclization for a cyclic urea precursor to Formula 1.
Following deprotection according to an appropriate method found in Greene Wuts (if necessary), the halogenation of the primary alcohol can be carried out with a variety of reagents, such as pure thionyl chloride, triphenylphosphine in carbon tetrachloride ( Lee Downie, Tetrahedron, 23,359 (1967)), or triphenylphosphine with N-chloro- or N-bromosuccinimide in dimethylformamide. Also the alternative sulfonyl ester is readily prepared from an appropriate sulfonyl chloride, such as the commercially available p-toluenesulfonyl chloride or methanesulfonyl chloride, in a variety of anhydrous aprotic solvents, such as pyridine, benzene, tetrahydrofuran or a chlorinated hydrocarbon, with or without cooling, with or without a trialkylamine base.
Ring closure for a cyclic urea precursor to Formula 1 has been found to occur spontaneously in some cases, but may be favored in an anhydrous solvent, such as dimethylformamide, benzene, tetrahydrofuran, hexamethylphosphorotriamide, or dimethyl sulfoxide, heating the mixture to the point of reflux of the solvent. Depending on the reactivity of the non-base substrate, or a strong base, such as sodium hydride, potassium t-butoxide or an alkyl lithium, or a weak base, such as potassium carbonate or a trialkylamine, may be necessary .
Route D of Scheme II may be advantageous over Route C because of the availability of starting materials, such as commercially produced l-benzyl-4-aminopiperidine for the NH2-ZAB component, 2-bromoethanol for the haloalcohol component , the 3-cyanophenyl isocyanate for the isocyanate component. In any respect, the chemistry described in Route C is applicable to an analogous reaction in Route D with the appropriate modifications for the particular materials included.
In formula 1 the radical Z serves as a linking group interposed between the structure of the cyclic urea the radical
A-B For the purposes of this discussion it is recognized that there are variations of Z, ie where Z = a bond or alkylene C? -4 or a portion of the defined bond, which for synthetic purposes are better incorporated as a substituent of A. It is also assumed for the purpose of this discussion the analog of A used in all respects contains an orthogonal protection group, which is compatible with the suggested chemistry. In addition, this protection group can be deleted to provide a substituent that can be used to generate an X group.
Scheme III: The preparation of H2N-Z-A, where Z = functional group -CH2CH2-0-.
"O-P.G.
The preparation of Z shown in Scheme III begins with the O-protected derivative of 2-aminoethanol. The t-butyldimethylsilyl analog is recommended for this purpose and is shown in the literature (see WO 9504277 and WO 9205186). However, a worker skilled in the art recognizes that the approaches discussed herein are not limited to this particular analog of 2-aminoethanol. Then the O-protected 2-aminoethanol can be protected as the N-t-butoxycarbonyl analog and selectively O-deprotected according to the procedures found in Greene and Wuts. Then the resulting 2- (N-t-butoxycarbamoyl) ethanol (1) can be reacted with various analogs of A to give the desired group Z.
Product 2 is the result of the reaction of the chlorocarbonate analog of A with 1 in a variety of solvents
• aprotic, such as chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78 ° C to room temperature. The carbonyl chloride analog of A (A (CH2) r0C (0) Cl) is obtainable by the reaction of an appropriate alcohol analogue of A with phosgene or one of its equivalents in a variety of aprotic solvents, such as a chlorocarbon , tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78 to room temperature.
The product 3 is prepared by reaction of the acid chloride of an appropriate acid analogue of A with 1 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from - 78 ° C to room temperature. The acid chloride can be obtained by reaction of the acid analogue of A with phosphorous oxychloride, phosphorous pentachloride, thionyl chloride or oxalyl chloride with or without a non-polar aprotic solvent, such as a chlorocarbon, benzene or toluene at temperatures ranging from 0 ° C to the point of reflux of the solvent or pure reagent.
The product 4 can be prepared by the reaction of a carbamoyl chloride analogue of A with 1 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from - 78 ° C to room temperature. The carbamoyl chloride analog of A
(A (CH2) rNR3C (0) Cl) is obtainable by reaction of an appropriate amine analogue of A with phosgene or one of its equivalents in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78CC to room temperature.
The product 5 is obtainable by the reaction of an analogue of A substituted with an appropriate leaving group with the alkoxide generated from 2 by treatment of 2 with a strong base, such as sodium or potassium hydride or a thallium alkoxide in an aprotic solvent, such as dimethylformamide, tetrahydrofuran or dimethyl sulfoxide at a temperature ranging from 0 to 120 ° C. The leaving group of A is more conveniently generated from an appropriate alcohol analog of A. The function of the alcohol can be used to prepare a sulfonate ester from a sulfonyl chloride in a chlorocarbon solvent with a trialkylamine base or pyridine; alternatively the halogen can be generated from a variety of reagents, triphenyl phosphine and carbon tetrabromide, pentabromide or phosphorous chloride, and thionyl chloride, to mention a few.
Scheme IV: Preparation of H2N-Z-A, where Z = functional group
-CH2CH2-NR3 -
NH 2 / ^ O-PG
PG-I * NR5C02 (CH2), A 12 PG-. A- (CH2) ßC (0) CI A (CH2) rS02CI pG, ~ NR3C02 (CH2) A -NR3C02 (CH2) A 7 11 A- (CH2) £ (0) C1 A- (CH2), - CH = 0 or A- (CH2U-.G. A (CH2) fNR3C (0) CI NR3C02 (CH2), A PG-C ~ NR3C02 (CH2)? 10 PG-. VNR3C02 (CH2)) A
The series of analogs in Scheme IV can be prepared from the protected amino alcohol 6 to give the products 7 to 12 by methods similar to a large part of those described for Scheme III. Compound 6 is prepared from 2-amino- (O-t-butyldimethylsilyl) ethanol by reductive amination of the primary amine by a variety of methods. The primary amine can be reacted with an aldehyde or ketone under dehydration conditions to form an imine or enamine intermediate, which is then reduced to the N-alkyl derivative using palladium catalyst under an atmosphere of hydrogen in an appropriate solvent. Alternatively, the reductive alkylation can be carried out by a mixture of the ketone and the aldehyde and the amine with the sodium cyanoborohydride or lithium in methanol or ethanol as the solvent.
It is understood that the products 7 to 12 need to have the terminal protected oxygen transformed to the primary amine either at its stage or after processing with the group B. This can conveniently be achieved by the deprotection of the primary alcohol. The function of the alcohol can then be used to prepare a sulfonate ester from a sulfonyl chloride in a chlorocarbon solvent with a trialkylamine base or in pyridine; alternatively a halogen can be generated from a variety of reagents, triphenyl phosphine and carbon tetrabromide, pentabromide or phosphorous chloride, and thionyl chloride, to mention a few. Then the resulting leaving group is displaced with a mixture of sodium azide in dimethylformamide at an elevated temperature to form the primary azide. The azide can then be reduced to the amine by catalytic hydrogenation in an alcohol solvent with palladium catalyst under an atmosphere of hydrogen gas at pressures ranging from ambient pressure to 65 psi; An alternative method to effect this transformation comprises refluxing the azide intermediate with the triphenylphosphine in benzene or toluene and hydrolyzing the resulting intermediate with aqueous acid.
The product 7 of Scheme IV is the result of the reaction of the chlorocarbonate analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from - 78 CC to room temperature. The product 8 is prepared by the reaction of the acid chloride of an appropriate acid analogue of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78 ° C to room temperature. The product 9 can be prepared by the reaction of a carbamoyl chloride analogue of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from - 78 ° C to room temperature.
The product 10 can be obtained from 7 by two routes, conventional alkylation or reductive alkylation. If 6 is a primary amine, then reductive alkylation is recommended. The primary amine 6 can be reacted with an aldehyde or ketone analogue of A under dehydration conditions to form an imine or enamine intermediate, which is then reduced to the N-alkyl derivative using palladium catalyst under a hydrogen atmosphere in an appropriate solvent. Alternatively, the reductive alkylation can be carried out by a mixture of the ketone or aldehyde and the amine with lithium or sodium cyanoborohydride in methanol or ethanol as the solvent. The aldehyde or ketone analog of A is readily accessible from the appropriate alcohol by oxidation of S ern, Moffat or Jones. In the case where 6 is a secondary amine product 10 is obtainable by the reaction of an analogue of A substituted with an appropriate leaving group with 7 in the presence of a weak base, such as trialkylamine or solid sodium or potassium carbonate. in an aprotic solvent, such as dimethylformamide, acetone, tetrahydrofuran or dimethyl sulfoxide at a temperature ranging from 0 ° C to 120 ° C.
The product 11 is prepared by the reaction of the sulfonyl chloride of an appropriate analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from - 78 ° C to room temperature. The sulfonyl chloride analog of A is obtainable via the sulfonic acid of A, which can be prepared by heating a halogen analogue of A in an aqueous sodium sulfite. The sulfonyl chloride of A can be prepared by reacting sulfonic acid with phosphorous oxychloridephosphorous pentachloride, thionyl chloride or oxalyl chloride with or without a non-polar aprotic solvent, such as a chlorocarbon, benzene or toluene at temperatures ranging from 0 ° C to the point of reflux of the solvent or pure reagent. The product 12 is prepared by the reaction of the sulfamoyl chloride of an appropriate analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from - 78 ° C to room temperature.
Scheme V; Preparation of the compounds of Formula 1 wherein Z = - (CH2) 1-2C (0) -0 (CH2) r-, - (CE2) 1.2C (0) -NR3 (CH2) r- and
- (CH2) 2S02-NR3 (CH2) r-.
Scheme V shows the preparation of Z variations that are not easily prepared by the strategies in Schemes III and IV. Compound 13 is obtainable by the routes developed in Schemes I and II by replacing the primary amine NH2ZAB with O-t-butyldimethylsilyl-2-aminoethanol or its propanol homologue. Jones oxidation of 13 gives the corresponding carboxylic acid, which is then transformed to acid chloride 14 by one of the methods shown in the above discussion. Ester 15 is prepared by reaction of 14 with an alcohol derivative of A under conditions similar to those described for the preparation of ester 2 in the Scheme
III. Amide 16 is obtainable by the reaction of 14 with an amine derived from A under conditions similar to those used for the formation of amide 8 found in Scheme IV. The sulfonyl chloride 17 of Scheme V is prepared by the alcohol to halide route to sulfonic acid to sulfonyl chloride discussed for the sulfonyl analogs of the Scheme
IV. Reaction of 17 with an amine derivative of A under conditions used for the formation of 11 in Scheme IV gives sulfonamide 18 of Scheme V.
Scheme VI: Methods to incorporate B, where B = X-Y.
PG-NH-Z-A PG-NH-Z-A-B
In Scheme VI two approaches for the incorporation of group B are shown; in each case it is assumed that the starting structures are appropriately protected to accommodate the chemistry that follows. It is also understood that both approaches can not be equivalent and, for purposes of compatibility with the chemistry that follows, one approach may have certain advantages over the other. It is further assumed that groups A and B have been selected as being derivatives of A and B that contain functionality appropriate for the contemplated chemistry.
Groups A and B are obtainable either through commercial sources, known in the literature or easily synthesized by adapting standard procedures known to physicians skilled in the technique of organic synthesis. The required reactive functional groups appended to the analogues of A and B are also obtainable either from commercial sources, known in the literature or easily synthesized by adapting the standard procedures known to physicians skilled in the art of the art. Organic synthesis. In the tables that follow, the chemistry required to effect the coupling of A and B is shown.
Table 1: Preparation of Amide, Ester, Urea, Sulfonamide and Sulfamide bonds between A and B.
-. 25 -CR3R3'S02C1 a secondary NH A-CR3R3'S02-Y as part of a ring or chain
The chemistry of Table 1 can be carried out in aprotic solvents, such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from -20 ° C to the point of reflux of the solvent and with or without a trialkylamine base .
Table 2: Preparation of ketone bonds between A and B.
Rxn. if A contains: then the one to give the next
No. Substituent product A-X -Y: Y reagent is:
1 A-C (0) C1 BrMg-Y A-C (O) -Y
The coupling chemistry of Table 2 can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from a halogen analogue of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0 ° C to the point of reflux of the solvent. The Grignard reagent can be reacted directly under very controlled conditions, ie low temperature (-20 ° C or lower) and with a large excess of acid chloride or with a complex of copper bromide - catalytic dimethyl sulphide or stoichiometric in dimethyl sulfide as a solvent or with a variant thereof. Other available methods include the transformation of the Grignard reagent to the cadmium reagent and coupling according to the Carson and Prout method (Org Syn. Col. Vol. 3 (1955) 601) or a coupling mediated by Fe (acac) 3 according to Fiandanese et al. (Tetrahedron Lett., (1984) 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboue, Tetrahedron Lett., 33 (31), (1992) 4437).
Table 3: Preparation of ether and thioether bonds between A and B.
The ether and thioether linkages of Table 3 can be prepared by reacting the two components in a polar aprotic solvent, such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base, such as potassium carbonate, sodium hydride or potassium t-butoxide at a temperature that fluctuates from room temperature to the point of reflux of the solvent used.
Table 4: Preparation of -SO- and -S02- linkages from thioethers of Table 3. The thioethers of Table 3 serve as a convenient starting material for the preparation of the sulphide and sulfone analogues of Table 4. A The combination of the wet alumina and the oxone provides a reliable reagent for the oxidation of the thioether to the sulfoxide, while the oxidation of the m-chloroperbenzoic will give the sulfone.
Scheme VII: Preparation of the analogues where
Z = -C (0) - or -so2
A cyclic urea precursor of Formula 1, which is suitable for the preparation of analogs where Z = -CÍO) - or -S02- can be synthesized by an adaptation of the chemistry shown in Scheme I. The approach in Scheme VII establishes the use of an N-hydrazino-alkyl bromide as the alkylating agent for the aniline derivative. The alkylation product is then deprotected according to a method proscribed by Greene and Wutts and cyclized by treatment of the resulting diamine with phosgene or one of its equivalents. The resulting cyclic urea can be treated with a strong base, such as sodium hydride or potassium t-butoxide in an aprotic solvent similar to dimethyl formamide, dimethylsulfoxide or toluene. This mixture is rapidly cooled with a mixture of acid chloride or sulfonyl chloride of A-B at a temperature ranging from -78 ° C to the point of reflux of the solvent.
Scheme VIII: The Pinner method to transform the cyclic urea precursor where Z = -CN to Formula 1.
The final transformation of the cyclic urea precursor of Formula 1 prepared in Schemes I through VII to Formula 1 is shown in Scheme VIII. The preferred method is first described by Pinner and Klein (Ber, 10, 1889 (1877); for a more recent review see: Decroix, J. Chem. Res., 134 (1978)). By this method the nitrile is dissolved in an anhydrous alcohol or a mixture of 1 equivalent or more of an alcohol and an anhydrous aprotic cosolvent, such as a chlorohydrocarbon or a selected alcohol acetate ester (ie, methyl acetate for alcohol) of methyl). Typically, this mixture is cooled down to room temperature and dry hydrogen chloride gas is added slowly to the reaction mixture until the solvent is saturated. This saturated solution is sealed and stirred at room temperature or lower to form an imidate intermediate, which is isolated and characterized. The imidate is then dissolved in a dry alcohol solvent and an excess of ammonia in the form of gas, a standardized ammonia / alcohol solution, solid ammonium acetate or ammonium carbonate is added. The unpurified compound is conveniently purified by reverse phase HPLC or recrystallization to give the cyclic urea defined by Formula 1.
Scheme IX shows the general route for the preparation of the 5-membered aryl- or heteroaryl-fused examples of Formula II. The preparation of the biaryl amine intermediate can be carried out by the palladium catalyzed coupling of the substituted aniline to the triflate ester according to the method of Louie et al., (J. Org. Chem. 1997, 62, 1268-1273) .
Scheme IX: Preparation of the precursors for the 5-membered heteroaryl-fused examples of Formula II
Formula II
Then the aniline nitrogen can be protected as a carbamate, the nitro group is reduced to the amine. This amine can be coupled with the group Z-A-B in which Z incorporates a carbonyl group, such as an aldehyde, which can be used as a reactive partner in a reductive alkylation of the newly generated amine. Then the reactive intermediate can be processed according to the technique described for Route B of Scheme I.
Scheme X: Preparation of the precursors for the 6-membered aryl- or heteroaryl-fused examples of Formula II
I Formula II Route B
Formula II
The steps which can be used for the regiocontrolled preparation of both isomers of the 6-membered aryl- or heteroaryl-fused examples of Formula II are shown in Routes A and B of Scheme X. A regioisomer is obtainable by applying the Chemistry developed by Louie et al. for the triflate of the salicylate ester in Route A. Following the protection of the resulting biaryl amine, the ester can be reduced by lithium borohydride or some other compatible hydride reducing agent and then further processed as shown in FIG. Route B of Scheme I.
The alternative regioisomer of the Formula II contemplated by this invention can be prepared according to Route B of Scheme X. To carry out the palladium catalyzed coupling of the group H2N-ZAB with the triflate salicylate ester, the conditions reported are optimal. by Wolfe and Buchwald
(Pd (OAc) 2, BiNAP, NaO-t-Bu, toluene, J. Org. Chem. 1997, 62,
1264-1267). Then the coupling product of the amine is appropriately N-protected and the functionality of the ester is reduced to the benzyl alcohol. Then this intermediary is also treated according to the methods shown in Scheme I, Route B.
Scheme XI: Preparation of the precursors for the 7-membered aryl- or heteroaryl-fused examples of Formula II
Scheme XI describes the route used to prepare a precursor for a regioisomer of the 7-membered aryl- or heteroaryl-fused example of Formula II. The breaking point is usually the aryl- or heteroarylester substituted by 2-cyano. The reduction of the lithium aluminum hydride of these compounds leads to the corresponding amino alcohol, which can then be selectively O-protected with a silyl protecting group, preferably the t-butyldimethylsilyl group. This material is now ready for reductive alkylation by a group Z-A-B, in which Z- contains a carbonyl compound, such as a cyclic aldehyde, ketone or ketone. Based on experience, this transformation can be best accomplished by using a mixture of sodium cyanoborohydride and zinc chloride in tetrahydrofuran solvent. Following the reductive alkylation, the resulting secondary amine is reacted with an aryl isocyanate in an inert solvent, such as dimethylformamide. Then the product of the isocyanate addition can be O-deprotected, and the benzyl alcohol is converted to the benzyl chloride with a mixture of methanesulfonyl chloride and triethylamine in chloroform or dichloromethane. The benzyl chloride is then cyclized to the 7-membered ring precursor to Formula II with the sodium hydride in dimethylformamide at 0 ° C.
Scheme XII: Preparation of the precursors for alternative regioisomers of examples of 7-membered aryl- or heteroaryl-fused members of Formula II.
Route A
Route B
Scheme I ~ | j1a B - - Fópmla II
Routes for alternative regioisomers by examples of aryl- or heteroaryl-fused 7-members of Formula II are shown in Scheme XII. In Route A, phenethylnitro triflate can be subjected to palladium catalyzed coupling with the aniline analogue according to the procedure of Louie et al. Then the coupled product is N-protected, usually as a carbamate or amide, then the nitro group is reduced to the amine by catalytic hydrogenation or with tin (II) chloride in aqueous solvent or alcohol. Then a Z-A-B group in which Z- incorporates a carbonyl functionality can be used as an associate in a reductive alkylation with the function of the primary amine under the conditions previously described. The intermediary can then be subjected to the chemistry described in Scheme I, Route B to obtain a compound of Formula II. Route B describes the coupling of a protected phenethyl triflate with an amine containing the group Z-A-B under the conditions recommended by Wolfe and Buch ald. This product is then N-protected as an appropriate carbamate or amide and then processed by the chemistry described in Route B of Scheme I.
Other features of the invention will become apparent in the course of the following descriptions of the exemplary embodiments, which are given for illustration of the invention and are not intended to be limiting thereof.
The synthesis of the representative compounds according to the invention is described in more detail below with reference to the following specific examples, but not limiting.
The abbreviations used in the Examples are defined as follows: "° C" for degrees Celsius, "d" for doublet, "dd" for doublet of doublets, "DAST" for trifluoride of diethylaminosulfur, "eq" for equivalent or equivalents, " g "for gram or grams," mg "for milligram or milligrams," mL "for milliliter or milliliters," H "for hydrogen or hydrogens," hr "for hour or hours," m "for multiplet," M "for molar , "min" for minute or minutes, "MHz" for megahertz, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance spectroscopy, "t" for triplet, "TLC" for layer chromatography fine.
EXAMPLE 1
Preparation of N- (3-amidinophenyl) -N1 - (1-benzylpiperidin-4-yl) cyclopentylurea
4- (2-Hydroxyethyl) amino-1-benzylpiperidine: A mixture of
4-amino-1-benzylpiperidine (1.0 g, 5.3 mmol, 1.1 mL) and bromoethanol (0.662 g, 5.3 mmol, 0.375 mL) is stirred under an N2 atmosphere for 18 hours at room temperature. This material is used directly in the next step (1.82 g). LRMS (M + H) + m / z 235.
N- (3-Cyanophenyl) -N 1 - (2-hydroxyethyl) -N 1 - (1-benzylpiperidin-4-yl) urea: To a stirred solution of 4- (2-hydroxyethyl) -amino-1-benzylpiperidine ( 1.82 g), and triethylamine (0.789 g, 7.8 mmol) in DMF (50 mL) is added 3-cyano-phenylisocyanate (1.12 g, 7.8 mmol). This mixture is heated at 60 ° C for 18 hours under an atmosphere of N2. The reaction is diluted with water and extracted with ethyl acetate, dried over MgSO4, filtered and concentrated to give the desired product, N- (3-cyanophenyl) -N '- (2-hydroxyethyl) -N1- (1-) benzylpiperidin-4-yl) urea (2.04 g, 5.3 mmol). LRMS (M + H) + m / z 379.
N- (3-Cyanophenyl) -N 1 - (1-benzylpiperidin-4-yl) cyclopentylurea: To a stirred solution of N- (3-cyano-phenyl) -N 1 - (2-hydroxyethyl) -N '- (1-benzylphenyl) iperidin-4-yl) urea (2.04 g, 5.3 mmol) in chloroform at -10 ° C is added to a few drops of pyridine, followed by thionyl chloride (0.702 g, 5.9 mmol). This mixture is stirred for 2 hours, then heated to reflux for 1 hour. Concentrate in vacuo, dissolve in ethanol (50 mL) and add a solution of potassium hydroxide (10%) in ethanol (15 mL) and reflux for 2 hours. The mixture is cooled, then evaporated; it is dissolved in ethyl acetate, washed with water and brine, then dried (MgSO4). After removal of the solvent, the residue is purified by silica gel chromatography using ethyl acetate as eluent. 0.59 g of N- (3-cyanophenyl) -N '- (1-benzylpiperidin-4-yl) cyclopentylurea is obtained. LRMS (M + H) + m / z 361.
N- (3-Amidophenyl) -N1- (1-benzylpiperidin-4-yl) cyclopentylurea: A stirred solution of N- (3-cyano-phenyl) -N1- (1-benzylpiperidin-4-yl) cyclopentylurea (56 mg) in Anhydrous methanol (10 mL) is cooled to 0 ° C and saturated with dry hydrogen chloride gas. This mixture is tightly capped and stirred at room temperature for 18 hours. The solution is evaporated to dryness and the residual hydrogen chloride gas is removed by pumping over the imidate salt for 18 hours. The imidate is dissolved in anhydrous methanol (10 mL) and ammonium acetate (100 mg) is added. The mixture is stirred at room temperature for 24 hours, then evaporated to give 55 mg of unpurified product. Purification of this material by reverse phase HPLC gives 26 mg of N- (3-amidinophenyl) -N 1 - (1-benzylpiperidin-4-yl) cyclopentylurea as the bis-trifluoroacetic acid salt; HRMS: Calculated 378.229386, found 378.229774; XE NMR (CD3OD) d: 2.05-2.21 (m, 4H), 3.18 (dd, 2H, J = ll Hz, J = 6.0 Hz), 3.58 (dd, 4H, J = ll Hz, J = 6.0 Hz), 3.98 (t, 2H, J = 7.5 Hz), 4.02 (m, 1H), 4.32 (s, 1H), 7.45 (m, 7H), 7.81 (d, 1H, J = 7.5 Hz), 8.01 (s, 1H) ).
EXAMPLE 2
Preparation of N- (3-amidinofenyl) -N '- (1-benzylpiperidin-4-yl) cyclohexylurea
4- (3-Hydroxypropyl) amino-1-benzylpiperidine: This material is prepared in the same manner as its lower homologue 4- (2-hydroxyethyl) amino-1-benzylpiperidine using 3-bromopropanol rather than 2-bromoethanol.
N- (3-Amidophenyl) -N '- (1-benzylpiperidin-4-yl) cyclohexylurea: This material is prepared from 4- (3-hydroxypropyl) -amino-1-benzylpiperidine by the same route used in the synthesis of N- (3-amidinophenyl) -N '- (1-benzylpiperidin-4-yl) cyclopentylurea. 26 mg of the desired product is obtained as the bis-trifluoroacetic acid salt after purification by reverse phase HPLC. LRMS (M + 2H) 2+ m / z 196.7, (M + H) + m / z
392; K NMR (CD3OD): d 2.23 (m, 6H), 3.21 (bt, 2H), 3.58
(t, 2H, J = 5.12 Hz), 3.62 (m, 2H), 4.39 (m, 3H), 4.53 (t, 2H, J = 5.12 Hz), 7.51 (m, 5H), 7.62-7.78 (m, 3H), 7.81 (s, 1H).
EXAMPLE 3
Preparation of N- (3-amidinophenyl) -N'-f4- to idinophenyl) iclohept lurea
N- (3-cyanophenyl) -N '- (4-cyanophenyl) urea: m-cyanoaniline
(0.5 g, 3.38 mmol) and p-cyanophenylisocyanate (0.49 g, 3.38 mmol) are dissolved in dimethylformamide (8 mL) and triethylamine.
(1 mL). The reaction is stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is washed with water (3x), brine, dried (MgSO4) and concentrated to give an amorphous solid. This is triturated to a white crystalline solid with ethyl ether. This solid is filtered and washed with ether to give N- (3-cyanophenyl) -N '- (4-cyanophenyl) urea as a white powder
(0.92 g, mp 183-5 ° C); LRMS (M + H) + m / z 280, (M + NH 4) + m / z 297;
X H NMR (DMS0-d 6): 9.32 (s, 1 H), 9.21 (s, 1 H), 7.97 (s, 1 H),
7. 75-7.6 (m, 5H), 7.55-7.4 (m, 2H).
N- (3-cyano-phenyl) -N '- (4-cyanophenyl) cycloheptylurea: N- (3-cyanophenyl) -N1- (4-cyanophenyl) urea (0.25 g, 0.95 mmol) is dissolved in DMF (2 ml) and add to a cold slurry of sodium hydride (0.80 g, 2.0 mmol, washed with hexane to remove the mineral oil) in dimethylformamide (25 mL) under a nitrogen atmosphere. After stirring for 15 minutes, 1,4-dibromobutane (0.25 g, 0.95 mmol) is added slowly. The reaction is stirred at 0 ° C for 1 hour and then allowed to warm to 75 ° C for 3 hours. Additional sodium hydride is added to the reaction and the reaction is heated to 75 ° C for an additional 6 hours. The reaction is allowed to cool to room temperature, poured into IN HCl and extracted with ethyl acetate. The organic layer is washed with water and brine, then dried (MgSO) and concentrated to give a viscous oil. The oil is purified by flash chromatography on silica gel eluting with methylene chloride: ethyl acetate 95: 5 to give N- (3-cyanophenyl) -N '- (4-cyanophenyl) cycloheptylurea as an oil (0.075. gm, 0.24 mmoles); LRMS (M + H) + m / z 317; XH NMR (CDC13): 7.7-7.45 (m, 6H), 7.4 (d, 2H), 3.82 (m, 4H), 1.95 (m, 4H).
N- (3-amidinophenyl) -N '- (4-amidinophenyl) cycloheptylurea: Dry hydrogen chloride gas is bubbled through an ice-cooled solution of N- (3-cyanophenyl) -N 1 - (4-cyanophenyl) ) cycloheptylurea (0.065 g, 0.21 mmol) in anhydrous ethanol (5 ml) under a nitrogen atmosphere for 15 minutes. The reaction is stopped and allowed to warm to room temperature and stirred overnight. The reaction is concentrated in vacuo to give a white amorphous solid. This is dissolved in anhydrous ethanol (5 ml) and ammonium carbonate (0.118 g, 1.23 mmol) is added. The reaction is stirred under a nitrogen atmosphere at room temperature overnight. The reaction mixture is concentrated in vacuo to give a white solid. The product is purified by HPLC on a C-18 Vydec® column eluting with a mixture A of solvent (acetonitrile: water: TFA 80: 20: 0.3) and a mixture B of solvent (water: TFA 99.7: 0.3) using a gradient that begins with A: B at 3:97 and changes to A.-B at 70:30 for 20 minutes. The largest fraction is concentrated to give N- (3-amidinophenyl) -N '- (4-amidinophenyl) cycloheptylurea as a white solid (m.p. 204-206 ° C); LRMS (M + H) + m / z 351, (M + 2H) +2 m / z 176.2; HRMS: calculated 351.1933, found 351.1936; XH NMR (DMSO-d6): 9.4 (bs, 2H), 9.2 (broad s, 2H), 9.18 (broad s, 2H), 7.95 (broad s, 2H), 7.8-7.5 (m, 6H), 7.47 ( d, 2H), 3.9 (bd, 4H), 1.83 (m, 4H).
EXAMPLE 4
Preparation of N- (3-amidinophenyl) -N '- ((4-amidinophenyl) methyl) cycloheptylurea
N- (3-cyanophenyl) -N1 - ((4-cyanophenyl) methyl) urea: A mixture of m-cyanophenyl isocyanate (2.0 g, 13.9 mmol) and triethylamine
(3.09 g, 30.5 mmol) in dimethylformamide (30 ml) is cooled to 0 ° C and p-cyanobenzylamine hydrogen chloride (2.3 g, 13.9 mmol) in dimethylformamide (10 ml) is added dropwise. The reaction is allowed to liquefy at room temperature and is stirred for 18 hours. The reaction is poured into water and extracted with ethyl acetate. The ethyl acetate extract is washed with IN HCl and brine, then dried (Na 2 SO 4) and evaporated. The crude product is purified by flash chromatography on silica gel with hexane: ethyl acetate 1: 1 as eluent; 0.54 g of pure N- (3-cyano-phenyl) -N '- ((4-cyanophenyl) methyl) urea is obtained; LRMS (M + H) + m / z 294.
fc N- (3-cyano-phenyl) -N '- ((4-cyanophenyl) methyl) cycloheptylurea: To a suspension of sodium hydride (0.29 g of a 60% suspension in mineral oil, 7.28 mmole) in dimethylformamide (45 ml ) at room temperature is added a solution of dimethylformamide (5 ml) of N- (3-cyanophenyl) -N '- ((4-cyanophenyl) -methyl) urea (0.67 g, 2.43 mmol). This mixture is stirred for 30 minutes before 1,4-dibromobutane (1.05 g, "4.85 mmol) in dimethylformamide (10 ml) is added over 20 minutes, then the reaction is heated at 70 ° C for 1 hour, then from which time the analysis by thin layer chromatography (hexane: ethyl acetate 1: 2) shows that all the starting urea has been consumed.The cold reaction mixture is poured into ice water and extracted with ethyl acetate (3x) The extract is washed with IN HCl and brine, then dried (Na 2 SO 4) and evaporated The crude product is purified by flash chromatography on a column of silica gel with hexane: ethyl acetate 1: 1 as eluent. 0.47 g of pure N- (3-cyano-phenyl) -N '- ((4-cyanophenyl) methyl) cycloheptyl-urea is obtained: LRMS: (M + H) + m / z 331.
N- (3-amidinophenyl) -N '- ((4-amidinophenyl) methyl) cycloheptylurea: The N- (3-cyano-phenyl) -N1 - ((4-cyanophenyl) methyl) cycloheptylurea (0.47 g, 1.42 mmol) is dissolved in a mixture of anhydrous chloroform (25 ml) and anhydrous methanol (10 ml). This solution is cooled to 0 ° C and slowly saturated with dry hydrogen chloride gas. The reaction vessel is securely capped and stored in a refrigerator for 18 hours; the solvent is removed under vacuum and 0.59 g of the imidate is obtained as the hydrogen chloride salt; LRMS: (M + H) + m / z 396.
The imidate prepared above (0.59 g) is stirred in anhydrous methanol (25 ml) with ammonium carbonate (0.72 g, 7.49 mmol). After 72 hours, the solvent is removed under vacuum and the residue dissolved in water. The aqueous solution is washed with ethyl ether (3x), then the water is removed by lyophilization. The product is purified by HPLC on a C-18 Vydec® column that elutes with a mixture A of solvent (water: TFA 99.5: 0.5) and a mixture B of solvent (acetonitrile: TFA 99.5: 0.5) using a gradient that begins with A at 100% and change to B at 100% for 50 minutes. The fractions containing pure N- (3-amidinophenyl) -N '- ((4-amidinophenyl) methyl) cycloheptylurea are collected and lyophilized to give 0.027 g of the material; HRMS (M + H) +: calculated 365.208985, found 365.209496.
EXAMPLE 5
Preparation of N- (3-amidinophenyl) -N '- (1-amidinopiperidin-4-yl) cycloheptylurea
N- (3-Cyanophenyl) -N1- (1-benzylpiperidin-4-yl) urea: The m-cyanophenyl isocyanate (1.0 g, 6.94 mmol) is dissolved in dimethylformamide (15 ml) and triethylamine (2 ml) under a nitrogen atmosphere, then 4-amino-1-benzyl-piperidine (1.32 g, 6.94 mmol) is added slowly. The reaction is stirred at room temperature for 1 hour and then at 70 ° C for 2 hours. The reaction is allowed to cool to room temperature and divided between water and ethyl acetate. The organic layer is washed with water (2x) and brine, then dried (MgSO 4) and concentrated to give a white amorphous solid. The solid is triturated with ethyl ether to give a white powder. The solids are filtered, washed with ethyl ether and dried to give N- (3-cyanophenyl) -N 1 - (1-benzylpiperidin-4-yl) cycloheptylurea as a white powder, (1.7 g, 74%, mp 165-6. ° C); LRMS (M + H) + m / z 335; XH NMR (CDC13): 7.62 (s, 1H), 7.57 (d, 1H), 7.15-7.2 (M, 7H), 7.15 (s, 1H), 5.05 (d, 1H), 3.65 (m, 1H), 3.5 (s, 2H), 2.85 (m, 2H), 2.1 (m, 2H), 1.95 (m, 2H), 1.45 (m, 2H).
N- (3-Cyanophenyl) -N1- (1-benzylpiperidin-4-yl) cycloheptylurea: N- (3-cyanophenyl) -N '- (1-benzylpiperidin-4-yl) urea (0.5 g, 1.49 mmol) it is dissolved in DMF (25 ml) and 1.4 dibromobutane (0.33 g, 1.49 mmol) is added under a nitrogen atmosphere. The reaction is heated to 70 ° C and sodium hydride (0.131 gm, 3.3 mmol) is added in portions for 20 minutes. The reaction is heated for 4 hours, then allowed to cool to room temperature. When it is cooled, it is poured into water and extracted with ethyl acetate. The organic layer is washed with water (2x) and brine, then dried (MgSO4) and concentrated to give a viscous oil. The crude oil is purified by flash chromatography on silica gel eluting with methylene chloride: ethyl acetate 40:60 to give N- (3-cyano-phenyl) -N '- (1-benzylpiperidin-4-yl) cycloheptylurea as an oil (0.37 g, 64%); LRMS (M + H) + m / z 389.4; H NMR (CDC13): 7.4-7.25 (m, 9H), 3.9 (m, 1H), 3.57 (m, 2H), 3.42 (s, 2H), 3.25 (m, 2H), 2.87 (m, 2H), 2.03 (m, 2H), 1.8-1.5 (m, 8H).
N- (3-Cyanophenyl) -N '- (piperidin-4-yl) cycloheptylurea: N- (3-cyanophenyl) -N' - (1-benzylpiperidin-4-yl) cycloheptylurea (0.1 g,
0. 26 mmol) is dissolved in ethanol (10 ml) and cyclohexene (2 ml). Palladium hydroxide catalyst (0.05 g) is added and the reaction is heated to reflux under a nitrogen atmosphere. After 30 minutes, the reaction is allowed to cool to room temperature, filtered and concentrated to give a viscous oil. The crude product is purified by flash chromatography on silica gel, which elutes with methylene chloride: methanol 85:15 with 3% triethylamine. The product, N- (3-cyano-phenyl) -N1- (piperidin-4-yl) cycloheptylurea, is concentrated to give an oil which is crystallized with ethyl ether (0.05 g, 48%, mp 157-8 ° C); LRMS (M + H) + m / z 299; H NMR (CDC13): 7.5-7.3 (m, 4H), 4.05 (m, 1H), 3.60 (m, 2H), 3.32 (m, 2H), 3.17 (m, 2H), 2.72 (m, 2H), 2.0-1.6 (m, 8H).
N- (3-Cyanophenyl) -N1 - (l-amidinopiperidin-4-yl) cycloheptylurea: The
N- (3-cyano-phenyl) -N 1 - (piperidin-4-yl) cycloheptylurea (0.05 g, 0.126 mmol) is dissolved in pyridine (2 ml) and 3,5-dimethylpyrazole-1-carboxamidine is added under a nitrogen atmosphere.
(0.037 g, 0.188 mmol). The reaction is heated to 110 ° C for 6 hours, then allowed to cool and concentrated to give a viscous amber oil. The product is purified by HPLC on a C-18 Vydec® column eluting with a mixture A of solvent
(acetonitrile: water: TFA 80: 20: 0.3) and a mixture B of solvent
(water: TFA 99.7: 0.3) using a gradient that begins with A: B of
3:97 and changing to A: B from 70:30 for 15 minutes. The product eluted at 13.8 minutes is concentrated to give N- (3-cyanophenyl) -N '- (1-amidinopiperidin-4-yl) cycloheptylurea as an amorphous solid (0.036 g); LRMS (M + H) + m / z 341.
N- (3-Amidinophenyl) -N1- (1-amidinopiperidin-4-yl) cycloheptylurea: Dry hydrogen chloride gas is bubbled through a cold ice solution of N- (3-cyanophenyl) -N 1 - (1 -amidinopiperidin-4-yl) cyclo-heptylurea (0.03 g, 0.075 mmol) in anhydrous ethanol (5 ml) for 15 minutes. The reaction is capped, allowed to warm to room temperature and stirred for 24 hours. The reaction is concentrated to give a viscous residue, which is dissolved in anhydrous ethanol and ammonium carbonate (0.06 g, 0.63 mmol) is added. The reaction is stirred overnight at room temperature and then concentrated in vacuo. The unpurified product appears to be about a 1: 2 ratio of the desired product to the starting material. The pure N- (3-amidinophenyl) -N '- (l-amidinopiperidin-4-yl) cycloheptylurea is isolated by HPLC on a C-18 Vydec® column eluting with a mixture A of solvent (acetonitrile: water: TFA 80 : 20: 0.3) and a mixture B of solvent (water: TFA 99.7: 0.3) using a gradient that begins with A: B of 3:97 and that changes to A: B of 70:30 for 20 minutes, to give two major fractions: N- (3-amidinophenyl) -N '- (1-amidinopiperidin-4-yl) cycloheptylurea, the desired product eluted at 13.3 minutes, (8.2 mg); LRMS (M + 2H) +2 m / z 179.8; HRMS: calculated 358.2355, found 358.2349; X H NMR (DMSO-de): 9.25 (s, 2 H), 9.0 (s, 2 H), 7.55-7.4 (m, 4 H), 7.32 (s, 4 H), 3.95 (m, 3 H), 3.65 (m, 2 H) ), 3.25 (m, 2H), 3.07 (m, 2H), 1.8-1.6 (m, 8H).
The second fraction, which elutes at 18.1 minutes, is the starting material N- (3-cyanophenyl) -N '- (1-amidinopiperidin-4-yl) cycloheptylurea (16.6 mg); LRMS (M + H) + m / z 341.1; HRMS: calculated 341.20898, found 3341.2077; X H NMR (DMS0-d 6): 7.6 (s, 1 H), 7.5-7.4 (m, 3 H), 7.3 (s, 4 H), 4.0-3.9 (m, 3 H), 3.6 (m, 2 H), 3.25 (m , 2H), 3.05 (m, 2H), 1.8-1.55 (m, 8H).
EXAMPLE 6
Preparation of N- (3-amidinophenyl) -N '- (1-benzylpiperidin-4-yl) cycloheptylurea
N- (3-Amidinophenyl) -N '- (1-benzylpiperidin-4-yl) cycloheptylurea: Dry hydrogen chloride gas is bubbled through an ice-cooled solution of N- (3-cyanophenyl) -N 1 - (1-benzylpiperidin-4-yl) cycloheptylurea (0.03 g, 0.077 mmol) in anhydrous ethanol (10 ml) under a nitrogen atmosphere for 15 minutes. The reaction is capped, allowed to warm to room temperature and stirred for 24 hours. The reaction is concentrated to a solid and dissolved in anhydrous ethanol (5 ml) and ammonium carbonate (0.023 g, 0.23 mmol) is added. The reaction mixture is stirred at room temperature overnight, then concentrated in vacuo. The N- (3-amidinophenyl) -N1- (1-benzylpiperidin-4-yl) cycloheptylurea is purified by HPLC on a C-18 Vydec® column eluting with a mixture A of solvent (acetonitrile: water: TFA 80:20 : 0.3) and a mixture B of solvent (water: TFA 99.7: 0.3) using a gradient that starts with A: B of 3:97 and changes to A: B of 70:30 for 15 minutes. The largest fraction eluting at 15 minutes is concentrated to give N- (3-amidinophenyl) -N 1 - (1-benzylpiperidin-4-yl) cycloheptylurea as an amorphous solid; LRMS (M + H) + m / z 406, (M + 2H) +2 m / z 203.8; X H NMR (DMSO-dg): 9.52 (broad s, 1H), 9.27 (s, 2H), 9.02 (s, 2H), 7.5 (m, 9H), 4.3 (m, 2H), 3.95 (m, 1H) , 3.67 (m, 2H), 3.42 (m, 2H), 3.2 (m, 2H), 3.1 (m, 2H), 2.05-1.6 (m, 8H).
EXAMPLE 7
Preparation of N- (3 -amidinofenyl) -N '- (1- (a-f-eethyl) piperidin-4-yl) cjcloheptylurea
N- (3-amidinophenyl) -N '- (1- (a-phenethyl) piperidin-4-yl) cycloheptylurea: N- (3-amidinophenyl) -N' - (1- (a-phenethyl) piperidin-4 -yl) cycloheptylurea is prepared by a method analogous to the preparation of N- (3-amidinophenyl) -N1 - (1-benzylpiperidin-4-yl) cycloheptylurea starting with 4-amino-1- (a-phenethyl) piperidine rather than 4-amino-1-benzylpiperidine; HRMS: calculated 420.276336, found 420.276129; XH NMR (CD3OD) d: 1.78 (d, 3H, J = 6.95 Hz), 1.79
(m, 4H), 2.05 (m, 4H), 2.89 (m, 3H), 3.38 (m, 2H), 3.76 (m, 2H), 3.82 (broad d, 2H), 3.92 (m, 1H), 4.42 (q, 1H, J = 6.95 Hz), 7.42
(s broad, 5H), 7.52 (s broad, 3H), 7.60 (s, 1H).
EXAMPLE 8
Preparation of N- (3-amidinophenyl) -N '- (1- ((phenyl) methane) sulfonyl) -piperidin-4-yl) cycloheptylurea
N- (3-Cyanophenyl) -N1 - (1- (t-butoxycarbonyl) piperidin-4-yl) urea: A mixture of 4-amino-N- (t-butoxycarbonyl) piperidine (0.133 mol, 30.5 g, prepared by the method of Mach, RH et al., J.
Med. Chem. (1993) 36 (23), 3707-20) and triethylamine
(1.5 equivalents, 0.2 moles, 20.2 g, 27.8 ml) in dimethylformamide (230 ml) is cooled to 0 ° C and m-cyanophenylisocyanate (1.1 equivalents, 0.146 mmoles,
21. 1 g) in dimethylformamide (70 ml). The reaction is stirred at room temperature for 18 hours. It is poured into water and extracted with ethyl acetate (3x). The ethyl acetate extracts are washed with IN HCl and brine, then dried (NaS04) and evaporated to give 43.56 g of unpurified material. The pure N- (3-cyanophenyl) -N '- (1- (t-butoxycarbonyl) piperidin-4-yl) urea is isolated by flash chromatography on silica gel (1.2 kg), eluted with hexane: acetate of ethyl 2: 1 (6 L), then hexane: ethyl acetate 1: 1 and collected in 800 ml fractions. Fractions 9 to 14 contain pure product, 21.69 g of production.
N- (3-Cyanophenyl) -N '- (1- (t-butoxycarbonyl) piperidin-4-yl) cycloheptylurea: A mixture of sodium hydride (2.44 g of a 60% suspension in mineral oil, 60.9 mmoles) and dimethylformamide (350 ml) is stirred at room temperature for 5 minutes, then N- (3-cyano-phenyl) -N '- (1- (t-butoxycarbonyl) -piperidin-4-yl) is added in drops. urea (7.0 g, 20.3 mmol) in dimethylformamide (30 ml). This mixture is stirred at room temperature for 30 minutes after which time the gas emission ceases. Slowly, 1,4-dibromobutane (8.79 g, 40.6 mmoles) in dimethylformamide (20 ml) is added over 25 minutes. Following the addition of the alkylating agent, the reaction mixture is heated at 70 ° -80 ° C for 3 hours, then stirred at room temperature for 18 hours. The reaction mixture is poured into water (1 L) and extracted with ethyl acetate (4 x 250 ml). The ethyl acetate extracts are washed with brine (6x), dried (Na2SO4) and evaporated to give 10.58 g of crude product. The pure N- (3-cyano-phenyl) -N '- (1- (t-butoxycarbonyl) -piperidin-4-yl) cycloheptylurea is isolated by medium pressure chromatography on a column of silica gel (600 g) eluting with hexane : ethyl acetate 2: 1 to give 3.20 g of pure product.
N- (3-Cyanophenyl) -N '- (piperidin-4-yl) cycloheptylurea: N- (3-cyanophenyl) -N' - (1- (t-butoxycarbonyl) piperidin-4-yl) cycloheptylurea (3.2 g , 7.76 mmole) is stirred in dichloromethane (40 ml) and trifluoroacetic acid (40 ml) at room temperature for 1.5 hours. The reaction mixture is evaporated and the residue is absorbed in water. The aqueous suspension is made basic (pH 11) by the dropwise addition of an aqueous solution of sodium hydroxide (50%). The basic aqueous suspension is extracted with ethyl acetate (2x); the ethyl acetate extracts are washed with brine, dried (Na 2 SO 4), and evaporated to give N- (3-cyano-phenyl) -N 1 - (piperidin-4-yl) cycloheptylurea (2.17 g, 7.28 mmol, 94%). This sample is in all respects identical to the sample of N- (3-cyanophenyl) -N '- (piperidin-4-yl) cycloheptylurea prepared in Example 5.
N- (3-Cyanophenyl) -N 1 - (1- ((phenyl) methane) sulfonyl) piperidin-4-yl) cycloheptylurea: N- (3-cyanophenyl) -N 1 - (piperidin-4-yl) cycloheptylurea (2.07 g, 6.95 mmol) in tetrahydrofuran (100 ml) with triethylamine (7.64 mmol, 0.77 g, 1.1 ml) is cooled to 0 ° C and a-toluenesulfonyl chloride (1.46 g, 7.64 mmol) in tetrahydrofuran (60 g) is added dropwise. ml). The reaction is allowed to cool to room temperature and is stirred for 18 hours. The solvent is removed in vacuo and the residue is partitioned between water and ethyl acetate: acetone 5: 1. The organic layer is washed with IN HCl and IN NaOH, then brine. Dry (Na2SO4) and evaporate to give 2.63 g of the crude product, Purification by medium pressure liquid chromatography on a silica gel column (350 g) gives N- (3-cyanophenyl) -N '- (1- ((phenyl) methane) -sulfonyl) piperidin-4-yl) cycloheptylurea (1.81 g, 4.0 mmol, 58%, mp 203-204 ° C); HRMS (M + H) +: calc 453.196038, found 453.198085.
N- (3-amidinophenyl) -N1 - (1- ((phenyl) methane) sulfonyl) -piperidin-4-yl) cycloheptylurea: A solution of N- (3-cyanophenyl) -N '- (1- ((phenyl) ) methane) -sulfonyl) piperidin-4-yl) cycloheptylurea (1.15 g, 2.54 mmol) in anhydrous methyl acetate (300 ml) is cooled to 0 ° C and anhydrous methanol (0.81 g, 25.4 mmol, 1.02 ml) is added. . The cold solution is saturated with dry hydrogen chloride gas, then tightly capped and allowed to stir at room temperature for 18 hours. Analytical thin-layer chromatography (5% methanol in chloroform) shows the complete consumption of the starting nitrile. The methyl acetate solution is diluted with ethyl ether (1.7 L), then the crystals are allowed to form in the refrigerator for 18 hours. After this time, precipitation of the imidate is completed and the intermediate product is isolated as the hydrogen chloride salt by filtration. The solid imidate is pumped for several hours to remove any residual HCl and the product is protected from moisture. This procedure gives 1.27 g of imidate hydrochloride (2.43 mmol, 96%, m.p. 131-134 ° C).
The imidate prepared above (1.27 g, 2.43 mmol) is dissolved in dry methanol (50 ml) and 2N ammonia in methanol solution (24.3 mmoles, 12.15 ml) is added. This reaction is capped and stirred at room temperature for 24 hours. After this time, the solvent is removed under vacuum and 1.27 g of unpurified product is isolated. The largest contaminant (approximately 50%) is the corresponding amide. This mixture is separated by HPLC on a C-18 Vydec® column eluting with a mixture A of solvent (water: TFA 99.5: 0.5) and a mixture B of solvent (acetonitrile: TFA 99.5: 0.5) using a gradient starting with A at 100% and changing to B at 100% for 50 minutes. The desired product, N- (3-amidinophenyl) -N1 - (1- ((phenyl) methane) sulfonyl) -piperidin-4-yl) cycloheptylurea, is isolated in 30 minutes; after the collection of the fractions and lyophilization, 0.30 g of unpurified product is obtained as the trifluoroacetic acid salt (0.5 mmoles, 20%, mp 208-209 ° C); HRMS (M + H) +: calculated 470.222587, found 470.219813. The following Examples 9 to 12 are prepared essentially by the same preparative methods as described above for Example 8; the only changes involve the sulfonylation or acylation of the common intermediate N- (3-cyanophenyl) -N 1 - (piperidin-4-yl) cycloheptylurea. In such a case, however, the same procedure using the appropriate sulfonylating or acylating agent in tetrahydrofuran with triethylamine is used.
EXAMPLE 9
Preparation of N- (3-amidinophenyl) -N1 - (l-benzoylpiperidin-4-yl) cycloheptylurea
N- (3-amidinophenyl) -N'- (l-benzoylpiperidin-4-yl) cycloheptylurea: In this case, the title compound is prepared by acylation of N- (3-cyano-phenyl) -N 1 - (piperidin-4) -yl) cycloheptylurea with the benzoyl chloride, followed by the formation of amidine as described above; HRMS (M + H) +: calculated 421.223966, found 421.222804.
EXAMPLE 10
Preparation of N- (3-amidinophenyl) -N '- (1- ((phenyl) methane) carbonylpiperidin-4-yl) cycloheptylurea N- (3-amidinophenyl) -N1- (1- ((phenyl) methane) carbonylpiperidin- 4-yl) cycloheptylurea: In this case, the title compound is prepared by acylation of N- (3-cyanophenyl) -N1 - (piperidin-4-yl) cycloheptylurea with phenylacetyl chloride, followed by amidine formation as described above; HRMS (M + H) +: calc 434.255601, found 434.255065.
EXAMPLE 11
Preparation of N- (3-amidinophenyl) -N '- (1- (phenyl) sulfonylpiperidin-4-yl) cycloheptylurea
N- (3-amidinophenyl) -N1- (1- (phenyl) sulfonylpiperidin-4-yl) cycloheptylurea: In this case, the title compound is prepared by acylation of N- (3-cyanophenyl) -N '- ( piperidin-4-yl) cycloheptylurea with the benzoyl chloride, followed by the formation of the amidine as described above; HRMS (M + H) +: calc 456.206937, found 456.204189.
EXAMPLE 12
Preparation of N- (3-amidinophenyl) -N '- (1- (4-acetamidophenyl) sulfonylpiperidin-4-yl) cycloheptylurea
N- (3-amidinophenyl) -N '- (1- (4-acetamidophenyl) sulfonylpiperidin-4-yl) cycloheptylurea: In this case, the title compound is prepared by sulfonylating the N- (3-cyano-phenyl) -N '- (piperidin-4-yl) cycloheptylurea with (4-acetamidophenyl) -sulphonyl chloride, followed by the formation of amidine as described above; HRMS (M + H) +: calculated 513.228401, found 513.226577.
EXAMPLE 13
Preparation of N- (3-amidinophenyl) -N '- (1- (2-aminophenyl) sulfonylpiperidin-4-yl) cycloheptylurea
N- (3-amidinophenyl) -N 1 - (1- (2-nitrophenyl) sulfonylpiperidin-4-yl) cycloheptylurea: N- (3-cyanophenyl) -N '- (piperidin-4-yl) cycloheptylurea (1.5 g, 5.03 mmol) in tetrahydrofuran (30 ml) and triethylamine (1.02 g, 10.06 mmol) is cooled to 0 ° C. A solution of (2-nitrophenyl) sulfonyl chloride (1.3 g, 5.86 mmol) in tetrahydrofuran (5 ml) is added in drops and the reaction is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with IN HCl and brine, then dried (Na 2 SO 4) and evaporated. The pure N- (3-cyanophenyl) -N 1 - (1- (2-nitrophenyl) sulfonylpiperidin-4-yl) cycloheptylurea is isolated by flash chromatography on silica gel, first eluting with hexane: ethyl acetate 2: 1 , then hexane: ethyl acetate 1: 1. 0.71 g of the title compound is obtained; LRMS (M + H) + m / z 484.
N- (3-cyanophenyl) -N '- (1- (2-aminophenyl) sulfonylpiperidin-4-yl) cycloheptylurea: N- (3-cyanophenyl) -N' - (1- (2-nitrophenyl) sulfonylpiperidin-4 -yl) cycloheptylurea (0.71 g, 1.47 mmoles) in ethanol (90 ml) and water (10 ml) is stirred with zinc powder (3.2 g, 48.6 mmoles) and calcium chloride (0.11 g, 0.95 mmoles). This mixture is refluxed for 3 hours, then filtered hot through a pad of Celite® and evaporated; 0.59 g of N- (3-cyano-phenyl) -N 1 - (1- (2-aminophenyl) sulfonylpiperidin-4-yl) cycloheptylurea is obtained; LRMS (M + H) + m / z 454.
N- (3-amidinophenyl) -N '- (1- (2-aminophenyl) sulfonylpiperidin-4-iD-cycloheptylurea: N- (3-cyanophenyl) -N' - (1- (2-aminophenyl) sulfonylpiperidin-4-yl ) cycloheptylurea (0.20 g, 0.44 mmol) in anhydrous chloroform (25 ml) and anhydrous methanol (10 ml) is cooled to 0 ° C and saturated with dry hydrogen chloride gas. stir at ambient temperature for 18 hours The intermediate imidate is obtained as the hydrogen chloride salt (0.23 g) by the removal of the solvent and residual hydrogen chloride in vacuum, LRMS (M + H) + m / z 486.
The imidate prepared above (0.23 g) and a 2N solution of ammonia in methanol (1.5 ml) are stirred in a tightly capped flask at room temperature for 18 hours. A mixture of the desired amidine and the corresponding amide is obtained after the removal of the solvent. This mixture is separated by HPLC on a C-18 Vydec® column eluting with a mixture A of solvent (water: TFA 99.5: 0.5) and a mixture B of solvent (acetonitrile: TFA 99.5: 0.5) using a gradient starting with A at 100% and changing to B at 100% for 50 minutes. 38 mg of the desired product N- (3-amidinophenyl) -N1 - (1- (2-aminsphenyl) sulfonyl-piperidin-4-yl) cycloheptylurea is obtained; HRMS (M + H) +: calculated 471.217836, found 471.218097.
The corresponding amine byproduct N- (3-amidophenyl) -N '- (1- (2-aminophenyl) sulfonyl-piperidin-4-yl) cycloheptylurea is also isolated (46 mg); HRMS (M + H) +: calc. 472.201852, found 472.202530.
The following Examples 14 to 16 are prepared essentially by the same preparative methods as described above for Example 13; the only changes involve the sulfonylation of the common intermediate N- (3-cyanophenyl) -N '- (piperidin-4-yl) cycloheptylurea. In each case, however, the same procedure using the appropriate sulfonylating agent in tetrahydrofuran with triethylamine is used.
EXAMPLE 14
* Preparation of N- (3-amidinophenyl) -N '- (1- (3-aminophenyl) sulfonylpiperidin-4-yl) cycloheptylurea
N- (3-amidinophenyl) -N1 - (1- (3-aminophenyl) sulfonylpiperidin-4-yl) c-cloheptylurea: In this case the title compound is prepared by sulfonylating the N- (3-cyanophenyl) -N ' - (piperidin-4-yl) cycloheptylurea with 3-nitrophenylsulfonyl chloride. This product is reduced by a mixture of zinc powder and calcium chloride in aqueous ethanol, followed by the formation of the amidine as described above to give the title compound; HRMS (M + H) +: calculated 471.217836, found 471.219532.
EXAMPLE 15
Preparation of N- (3-amidinophenyl) -N '- (1- (4-aminophenyl) sulfonylpiperidin-4-yl) cycloheptylurea
N- (3-amidinophenyl) -N '- (1- (4-aminophenyl) sulfonylpiperidin-4-yl) cycloheptylurea: In this case the title compound is prepared by sulfonylating the N- (3-cyanophenyl) -N 1 - (piperidin-4-yl) cycloheptylurea with 3-nitrophenylsulfonyl chloride. This product is reduced by a mixture of zinc powder and calcium chloride in aqueous ethanol, followed by the formation of the amidine as described above to give the title compound; HRMS (M + H) +: calculated 471.217836, found 471.217059.
EXAMPLE 16
Preparation of N- (3-amidinophenyl) -N '- (1- ((2-aminophenyl) methane) sulfonyl) -piperidin-4-yl) cycloheptylurea N- (3-amidinophenyl) -N 1 - (1- ((2 -aminophenyl) methane) sulfonyl) -piperidin-4-yl) cycloheptylurea: In this case the title compound is prepared by sulfonylating the N- (3-cyano-phenyl) -N '- (piperidin-4-yl) cycloheptylurea with the ((2-nitrophenyl) methane) sulfonyl chloride. This product is reduced by a mixture of zinc powder and calcium chloride in aqueous ethanol, followed by the formation of the amidine as described above to give the title compound; HRMS (M + H) +: calculated 485.233486, found 485.235037.
EXAMPLE 17
Preparation of N- (3-amidinophenyl) -N '- (1- ((2 -acetamido-phenyl) ethane) sulfonylpiperidin-4-yl) cycloheptylurea
N- (3-Cyanophenyl) -N '- (1- ((2-aminophenyl) methane) sulfonylpiperidin-4-yl) cycloheptylurea: This material is prepared by sulfonylating the N- (3-cyano-phenyl) -N 1 - (piperidin -4-yl) cycloheptylurea with ((2-nitrophenyl) methane) sulfonyl chloride in tetrahydrofuran and triethyl amine, as described for EXAMPLE 16. The reduction of the nitro group using zinc dust and calcium chloride in ethanol aqueous N- (3-cyanophenyl) -N1 - (1- ((2-aminophenyl) methane) sulfonyl-piperidin-4-yl) cycloheptylurea; LRMS (M + H) + m / z 468.
N- (3-Cyanophenyl) -N1 - (1- ((2-acetamidophenyl) methane) sulfonyl-piperidin-4-yl) cycloheptylurea: N- (3-cyano-phenyl) -N1 - (1- ((2-aminophenyl) ) methane) sulfonylpiperidin-4-yl) cycloheptylurea (0.296 g), 0.63 mmole) in chloroform (30 ml) and triethylamine (0.13 g, 1.27 mmole) is cooled to 0 ° C and acetyl chloride (0.06 g, 0.76 mmole) is added. The reaction is allowed to warm to room temperature and is stirred for 6 hours. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate and washed with IN HCl and brine, then dried (Na 2 SO 4) and evaporated. Purification by flash chromatography of silica gel with 5% methanol in chloroform gives 194 mg of N- (3-cyano-phenyl) -N1 - (1- ((2-acetamido-phenyl) methane) sulfonyl-piperidin-4 -yl) cycloheptylurea; LRMS (M + H) + m / z 510.
N- (3-amidinophenyl) -N1 - (1- ((2-acetamidophenyl) methane) -sulfonylpiperidin-4-yl) cycloheptylurea: N- (3-cyanophenyl) -N '- (1- ((2-acetamidophenyl) ) methane) sulfonyl-piperidin-4-yl) cycloheptylurea (0.194 g, 0.38 mmol) in anhydrous methyl acetate (25 ml) and anhydrous methanol (10 ml) is cooled to 0 ° C and saturated with dry hydrogen chloride gas . The reaction vessel is capped securely and stirred at room temperature for 18 hours. The intermediate imidate is obtained as the hydrogen chloride salt (0.174 g) by the removal of the solvent and the residual hydrogen chloride in vacuum; LRMS (M + H) + m / z 542.
The imidate prepared above (0.174 g) and a solution of ammonium acetate (0.15 g) in methanol (10 ml) are stirred at room temperature for 18 hours. A mixture of the desired amidine and the corresponding amide is obtained after the removal of the solvent. This mixture is separated by HPLC on a C-18 Vydec® column eluting with a mixture A of solvent (water: TFA 99.5: 0.5) and a mixture B of solvent (acetonitrile: TFA 99.5: 0.5) using a gradient starting with A at 100% and changing to B at 100% for 50 minutes. 9.6 mg of the desired product N- (3-amidinophenyl) -N1 - (1- ((2-acetamidophenyl) methane) -sulfonylpiperidin-4-yl) cycloheptylurea is obtained; HRMS (M + H) +: calculated 527.244051, found 527.246420.
The corresponding amine byproduct N- (3-amidophenyl) -N1 - (1- ((2-acetamidophenyl) methane) -sulfonylpiperidin-4-yl) cycloheptylurea is also isolated (8.5 mg); HRMS (M + H) +: calculated 528.228066, found 528.236184.
EXAMPLE 18
Preparation of 1- (l-benzoylpiperidin-4-yl) -3- (3-amidinophenyl) -5- ethenyl-2-imidazolidinone
1- (L-butyloxycarbonylpiperidin-4-yl) -3- (3-amidinophenyl) -5-ethenyl-2-imidazolidinone: A mixture of N- (3-cyanophenyl) -N '- (1- (t-butoxycarbonyl) -piperidin-4-yl) urea (0.50 g, 1.45 mmol) and sodium hydride (0.20 g of a 60% suspension in mineral oil, 8.3 mmol) in dimethylformamide is stirred at room temperature for 30 minutes, then added cis -1, 4-dichloro-2-butene (0.18 g, 1.44 mmoles). This mixture is heated at 70 ° C for 4 hours, after which time an addition of 0.2 g of 60% sodium hydride and 0.04 g of cis-1,4-dichloro-2-butene is added. The mixture is heated to 70 ° C during an addition of 2 hours during which time the remaining starting material is consumed. The reaction is diluted with brine (50 ml) and extracted with ethyl acetate (3x). The ethyl acetate extracts are washed with brine, then dried (Na 2 SO 4) and evaporated. The residue is purified by flash chromatography on silica gel, eluting with hexane: ethyl acetate 2: 1 to give 0.20 g of 1- (lt-butoxycarbonylpiperidin-4-yl) -3- (3-amidinophenyl) - 5-ethenyl-2-imidazolidinone; LRMS (M + H) + m / z 397.
1- (piperidin-4-yl) -3- (3-amidinophenyl) -5-ethenyl-2-imidazolidinone: 1- (lt-Butoxycarbonylpiperidin-4-yl) -3- (3-amidinophenyl) -5-ethenyl- 2-imidazolidinone (1.32 g, 3.3 mmol) is stirred in dichloromethane: trifluoroacetic acid 1: 1 (30 ml) for 4 hours. This solvent is removed in vacuo, and 1.35 g of 1- (piperidin-4-yl) -3- (3-amidinophenyl) -5-ethenyl-2-imidazolidinone is obtained as the trifluoroacetic acid salt; LRMS (M + H) + m / z 297.
1- (1-benzoylpiperidin-4-yl) -3- (3-cyano-phenyl) -5-ethenyl-2-imidazolidinone: The free base of 1- (piperidin-4-yl) -3- (3-amidinophenyl) - 5-ethenyl-2-imidazolidinone (1.99 g, 6.72 mmol) in tetrahydrofuran (50 ml) and triethylamine (1.36 g, 13.44 mmol) is cooled to 0 ° C and benzoyl chloride in tetrahydrofuran (10 ml) is added. After 4 hours the reaction is completed; The solvent is removed under vacuum and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with IN HCl and brine, then dried (Na 2 SO 4) and evaporated. The desired product is isolated by flash chromatography using silica gel and ethyl acetate 2: 1 as eluent. 0.63 g of pure 1- (l-benzoylpiperidin-4-yl) -3- (3-cyanophenyl) -5-ethenyl-2-imidazolidinone is obtained; LRMS (M + H) + m / z 401.
1- (1-Benzoylpiperidin-4-yl) -3- (3-amidinophenyl) -5-ethenyl-2-imidazolidinone: 1- (1-Benzoylpiperidin-4-yl) -3- (3-cyano-phenyl) -5- Ethenyl-2-imidazolidinone (0.30 g, 0.75 mmol) in chloroform: anhydrous 4: 1 methanol (25 ml) is cooled to 0 ° C and saturated with dry hydrogen chloride gas. The reaction vessel is capped securely, then allowed to stand at 10 ° C for 72 hours. The solvent is removed in vacuo to give 0.33 g of the imidate as the hydrogen chloride salt (0.75 mmole); LRMS (M + H) + m / z 433.
The imidate prepared above (0.33 g, 0.75 mmol) is dissolved in anhydrous methanol (10 ml) and ammonium carbonate is added.
(0.36 g, 3.76 mmol). This mixture is stirred at room temperature for 18 hours, then the solvent is removed in vacuo. The residue is dissolved in water (10 ml) and washed with diethyl ether (3x). The aqueous layer is lyophilized and the unpurified product is purified by HPLC on a C-18 Vydec® column eluting with a mixture A of solvent (water: TFA 99.5: 0.5) and a mixture B of solvent (aceconitrile: TFA 99.5: 0.5) using a gradient that starts with A at 100% and changes to B at 100% for 50 minutes. The fractions containing pure 1- (1-benzoylpiperidin-4-yl) -3- (3-amidinophenyl) -5-ethenyl-2-imidazolidinone are collected and lyophilized to give 0.090 g of the material; HRMS (M + H) +: calculated 418.224300, found 418.223792.
The following examples 19 and 20 are prepared essentially by the same preparative methods as described above for Example 18; the only changes involve the sulfonylation of the common intermediate 1- (piperidin-4-yl) -3- (3-amidinophenyl) -5-ethenyl-2-imidazolidinone. In each case, however, the same procedure using the appropriate acylation or sulfonylating agent in tetrahydrofuran with triethylamine is used.
EXAMPLE 19
Preparation of 1- (1- ((phenyl) methane) sulfonyl) piperidin-4-yl) -3- (3 -amidinof ni) -5-etheni-2-imidazolidinone
In this case, the title compound is prepared by sulfonylating the 1- (piperidin-4-yl) -3- (3-amidinophenyl) -5-ethenyl-2-imidazolidinone with the a-toluenesulfonyl chloride in tetrahydrofuran with triethylamine , followed by the formation of amidine as described above; HRMS (M + H) +: calc. 468.206937, found 468.204978.
EXAMPLE 20
Preparation of 1- (1-phenylsulfonylpiperidin-4-yl) -3- (3-amidinophenyl) -5-ethenyl-2-imidazolidinone
In this case, the title compound is prepared by sulfonylating the 1- (piperidin-4-yl) -3- (3-amidinophenyl) -5-ethenyl-2-imidazolidinone with the phenylsulfonyl chloride in tetrahydrofuran with triethylamine, followed by the formation of amidine as described above; HRMS (M + H) +: calc 454.191287, found 454.191418.
EXAMPLE 21
Preparation of 1.2.4.5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -3H-2, 4-benzodiazepin-3 -one
N- [Methyl (2- ((t-butyldimethylsilyloxy) methyl) phenyl)] - N - [(N-carbo-t-butoxy) piperidin-4-yl] amine: A solution of methyl-2-cyanobenzoate (10 g , 62.11 mmol) in ethyl ether (300 mL) is added dropwise to a slurry of lithium aluminum hydride in ethyl ether (200 mL). After the addition is complete, more ether (200 mL) is added and the mixture is heated at reflux for 2 hours. The reaction mixture is rapidly cooled by the careful addition of successive amounts of water (7.1 mL), IN sodium hydroxide solution (7.1 mL) and water (21.3 mL). The reaction is filtered and evaporated to give 6.96 g (50.8 mmol) of 2- (aminomethyl) benzyl alcohol. This material is continuous without further purification.
The above material is dissolved in tetrahydrofuran (140 mL) and cooled to 0 ° C. To this mixture is added imidazole (1.3 equivalents, 4.5 g, 66.04 mmoles) and t-butyldimethylsilyl chloride (1.05 equivalents, 8.04 g, 53.34 mmoles). The reaction mixture is stirred at room temperature for 18 hours, then diluted with water (500 mL) and extracted with ethyl ether (3 x 150 mL). The ether extract is dried (MgSO4) and evaporated to give 10.78 g (41 mmol) of the t-butyldimethyl-silyl ether of 2- (aminomethyl) benzyl alcohol.
To a mixture of the t-butyldimethylsilyl ether prepared above (7.77 g, 29.5 mmoles) and N- (carbo-t-butoxy) piperidin-4-one (5.88 g, 29.5 mmoles) in methanol at 0 ° C is added chloride. zinc (4.02 g, 29.5 mmol), followed by sodium cyanoborohydride (2.04 g, 32.45 mmol). The reaction is allowed to liquefy at room temperature and stirred for 18 hours. After this time, the reaction is estimated to be complete by TLC (20% methanol in chloroform); the solvent is removed by vacuum distillation and the residue is partitioned between ethyl acetate and 1N hydrochloric acid solution. The ethyl acetate layer is washed with brine and dried (MgSO 4), then evaporated to give 11.66 g (26.87 mmol) of N- [methyl (2- ((t-butyldimethylsilyloxy) methyl) phenyl)] - N- [(N '-carbo-t-butoxy) piperidin-4-yl] amine.
N- [Methyl (2- (chloromethyl) phenyl)] - N - [(N '-carbo-t-butoxy) piperidin-4-yl] - (3-cyano) benzamide: A mixture of 11.66 g (26.87 mmol) of N- [methyl (2- ((t-butyldimethylsilyloxy) -methyl) phenyl)] - N - [(N-carbo-t-butoxy) piperidin-4-yl] amine and 3-cyanophenyl isocyanate (3.87 g, 26.87 mmoles) in dimethylformamide (100 mL) is stirred at room temperature for 24 hours. The reaction is estimated to be complete by TLC (5% methanol in chloroform) and diluted with brine (500 mL). The suspension is extracted with ethyl acetate (150 mL) and the ethyl acetate extracts are washed with brine (5 x 100 mL), then dried (MgSO 4) and evaporated to give 14.54 g of unpurified material. This material is then purified by elution from a column of 400 grams of silica gel with a mixture of ethyl acetate and hexane; the material isolated from the eluent is 11.66 g (20.17 mmoles) of the pure isocyanate addition product.
A solution of tetrahydrofuran (200 mL) of the purified isocyanate addition product (11.5 g, 20 mmol) is treated with solid tetra-n-butylammonium fluoride (5.75 g, 22 mmol). The reaction is complete in 30 minutes (TLC, hexane: ethyl acetate 1: 1) after which the solvent is removed by vacuum distillation and the residue is partitioned between ethyl acetate and water. The ethyl acetate layer is dried (MgSO 4) and evaporated to give 13.23 g of the distilled benzyl alcohol contaminated with a silyl, fluoro- or silyloxy-secondary product from the divided protection group. This material is assuto contain a quantitative production of the desired benzyl alcohol (20 mmol) and dissolve in chloroform (300 mL). The cold solution (0 ° C) is treated with triethylamine (2.23 g, 3.1 mL, 22 mmol), followed by the dropwise addition of methanesulfonyl chloride (2.29 g, 1.55 mL, 20 mmol) in chloroform (50 mL). The reaction is allowed to liquefy at room temperature "and stirred for 18 hours.The reaction is washed with sodium hydrogen sulfate solution (2 x 150 ml), then dried and evaporated to give 10.25 g of crude product such as sodium chloride. benzyl, a portion of this material
(about 5 g) is further purified by elution from a column of 400 g of silica gel with hexane: ethyl acetate 3: 1. N- [Methyl (2- (chloromethyl) phenyl)] - N - [(N '-carbo-t-butoxy) piperidin-4-yl] - (3-cyano) benzamide pure (3.1 g, 6.43 mmol) is isolated from the eluent as a white solid, mp : 165-170 ° C.
1,2,4, 5-tetrahydro-2- (piperidin-4-yl) -4- (3-cyano-phenyl) -3H-2,4-benzodiazepin-3-one: N- [methyl (2- (chloro -methyl) phenyl)] - N - [(N * -carbo-t-butoxy) piperidin-4-yl] - (3-cyano) benzamide (3.1 g, 6.43 mmol) is dissolved in dimethylformamide (30 mL), it is cooled to 0 ° C and a 60% suspension of sodium hydride in mineral oil (0.52 g of suspension, 12.46 mmoles) is added. The reaction is complete after 2 hours at 0 ° C; it is diluted with water (150 mL) and extracted with ethyl acetate (3 x 50 mL). The ethyl acetate solution is washed with brine (5 x 50 mL), then dried and evaporated. The production of the cyclized product is 2.7 g (6.05 mmoles); This material is contaminated with a small amount of mineral oil, but it is continued until the next step without further purification.
The t-butoxycarbonyl protection group in the product prepared above (2.7 g, 6.05 mmol) is removed by treatment with 4 N hydrogen chloride in dioxane (15 mL) at 0 ° C for 3 hours. The reaction mixture is purged with nitrogen gas, then evaporated. The residue is dissolved in water (50 mL) and washed with ethyl ether (2 x 25 mL). The water solution is made basic (pH 12) with 10% sodium hydroxide solution and the product is extracted with ethyl acetate (3 x 50 mL). The ethyl acetate solution is washed with IN aqueous sodium hydroxide, then dried (MgSO 4) and evaporated to give 1.62 g (4.68 mmol) of 1,2,4,5-tetrahydro-2- (piperidin-4-yl). ) -4- (3-cyano-phenyl) -3H-2,4-benzodiazepin-3-one as a tan solid, mp 115.8 ° C; HRMS for C 21 H 23 N 40 (M + H) +: calculated 347.187187, found 347.184824.
1,2,4,5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-cyano-phenyl) -3H-2,4-benzodiazepin-3-one: A solution of 1, 2, 4, 5-tetrahydro-2- (piperidin-4-yl) -4- (3-cyanophenyl) -3H-2,4-benzodiazepin-3-one (0.805 g, 2.33 mmol) in tetrahydrofuran ( 50 mL) is cooled to 0 ° C and triethylamine (0.26 g, 0.36 mL, 2.6 mmol) is added. To this mixture is added dropwise a solution of tetrahydrofuran (25 mL) of benzylsulfonyl chloride (0.5 g, 2.6 mmol). The reaction mixture is allowed to liquefy at room temperature and stirred for 24 hours. TLC indicates that the reaction is complete (10% methanol in chloroform). The mixture is evaporated and the residue is suspended in a 3: 1 mixture of water: hydrogen chloride solution IN. The product solidifies, the suspension is filtered and the resulting powder is dried by air, to give 0.89 g of unpurified product. This material is further purified by flash chromatography with a column of silica gel (80 g) and eluting with hexane: ethyl acetate 2: 1, then 1: 1. From the eluent is isolated 0.41 g (0.82 mmoles) of 1,2,4,5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-cyanophenyl) -3H -2, 4-benzodiazepin-3-one pure, mp: 205-207 ° C.
1,2,4,5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -3H-2,4-benzodiazepin-3-one: A solution of 0.41 g (0.82 mmol) of 1, 2, 4, 5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-cyanophenyl) -3H-2, 4- Pure benzodiazepin-3-one in chloroform (10 mL) is added to a saturated solution of gaseous hydrogen chloride, dried in dry methanol (10 mL) and chloroform (50 mL) at -78 ° C. The reaction vessel is tightly capped and allowed to liquefy at room temperature; this mixture is maintained in this way for 18 hours. After this time, the excess hydrogen chloride gas is removed from the reaction mixture by pumping with a stream of dry nitrogen gas; then the solution is evaporated and pumped for several hours to remove traces of free hydrogen chloride gas. The resulting imidate is detected by LRMS: m / z
(M + H) + = 533. This material is dissolved in a solution of dry chloroform (20 mL) and 2.0M ammonia in methanol (5 mL, 10 mmol), the reaction vessel is tightly capped and stirred at room temperature for 6 days . The reaction mixture is evaporated and approximately 0.45 g of the amidine product contaminated with the amide side product is obtained. This mixture is purified by HPLC, which elutes with an aqueous phase of 0.05% trifluoroacetic acid in water and an organic phase of 0.05% trifluoroacetic acid in acetonitrile. The product, 1,2,4,5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -3H-2,4-benzodiazepin-3-one (0.11 g, 0.17 mmol), is isolated as the trifluoroacetic acid salt by lyophilization of the appropriate fractions; mp: 210-211 ° C; purity > 99.5% (HPLC); HRMS for C28H31N5S? 3, calculated 518.222587, found 518.221085.
EXAMPLE 22
Preparation of 1.2, 4.5-tetrahydro-2- (thiophen-2-yl) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -3H-2,4-benzodiazepin-3-one
Intermediate 1, 2, 4, 5-tetrahydro-2- (piperidin-4-yl) -4- (3-cyanophenyl) -3H-2,4-benzodiazepin-3-one is sulfonylated with the thiophene chloride. 2-yl) sulfonyl according to the procedure shown for the preparation of 1,2,4,5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-cyanophenyl) -3H-2, 4-benzodiazepin-3-one in EXAMPLE 21.
The title compound is obtained via the imidate according to the procedure for 1, 2, 4, 5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -3H-2,4-benzodiazepin-3-one from EXAMPLE 21 starting with the intermediate prepared above. LRMS: m / z = 509; p.f = 119-120 ° C.
EXAMPLE 23
Preparation of 1.2.4.5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -7,8-dimethoxy-3H-2,4-benzodiazepin-3-one
Intermediate 1, 2, 4, 5-tetrahydro-2- (piperidin-4-yl) -4- (3-cyanophenyl) -7,8-dimethoxy-3H-2,4-benzodiazepin-3-one is prepared from methyl 3, 4-dimethoxy-6-cyanobenzoate according to the procedure for the preparation of 1, 2, 4, 5-tetrahydro-2- (piperidin-4-yl) -4- (3-cyanophenyl) - 3H-2, 4-benzodiazepin-3-one in EXAMPLE 21.
The intermediate 1,2,4,5-tetrahydro-2- (piperidin-4-yl) -4- (3-cyanophenyl) -7,8-dimethoxy-3H-2,4-benzodiazepin-3-one is sulfonylated with the benzylsulfonyl chloride according to the procedure shown for the preparation of 1, 2, 4, 5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-cyano-phenyl) - 3H-2, 4-benzodiazepin-3-one in EXAMPLE 21.
The title compound is obtained via the imidate according to the procedure for 1, 2, 4, 5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -3H-2, 4-benzodiazepin-3-one from EXAMPLE 21 starting with the intermediate prepared above. HRMS: (M + H) + for C3oH35'N5? 5S, calculated 578.243716, found 578.245119.
EXAMPLE 24
Preparation of 1,2,4, 5-tetra-idro-2- (thiophen-2-yl) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -7,8-dimethoxy-3H-2,4-benzodiazepin- 3-one
Intermediate 1, 2, 4, 5-tetrahydro-2- (piperidin-4-yl) -4- (3-cyano-phenyl) -7,8-dimethoxy-3H-2,4-benzodiazepin-3-one is prepared from methyl 3, 4-dimethoxy-6-cyanobenzoate according to the procedure for the preparation of 1, 2, 4, 5-tetrahydro-2- (piperidin-4-yl) -4- (3-cyanophenyl) - 3H-2, 4-benzodiazepin-3-one in EXAMPLE 21.
The intermediate 1, 2, 4, 5-tetrahydro-2- (piperidin-4-yl) -4- (3-cyanophenyl) -7,8-dimethoxy-3H-2,4-benzodiazepin-3-one is sulfonylated with the (thiophene-2-yl) sulfonyl chloride according to the procedure shown for the preparation of 1,2,4,5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4 - (3-cyanophenyl) -3H-2,4-benzodiazepin-3-one in EXAMPLE 21.
The title compound is obtained via the imidate according to the procedure for 1, 2, 4, 5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -3H-2, 4-benzodiazepin-3-one from EXAMPLE 21 starting with the intermediate prepared above. HRMS: (M + H) + for C27H31N505S2, calculated 570.184488, found 570.186900.
EXAMPLES 25 to 55 (shown in Table 7)
Examples 25 to 55 are prepared essentially by the same preparative methods as described above for Example 8; the only changes involve the sulfonylation, alkylation or acylation of the common intermediate N- (3-cyanophenyl) -N "- (piperidin-4-yl) cycloheptylurea.In each case, the same procedure using sulfonyl chloride, chloride is used. of sulfamoyl, alkyl chloride or appropriate acyl chloride in tetrahydrofuran with triethylamine Following the formation of the imidate, the reaction with methanolic ammonia to give the amidine product is carried out as described in Example 13.
An exceptional case is the preparation of Example 28; this product is obtained as a by-product of the amidine formation of Example 29. During the step of methanolic ammonia competing with the deacylation of Example 29 leads to the formation of Example 28. Both Examples 28 and 29 are obtained pure and homogeneous by HPLC purification of the mixture obtained during the formation of the amidine under standard preparative HPLC purification conditions.
EXAMPLE 56
Preparation of N- (3-amidinophenyl) -N '- ((1- ((phenyl) -1, 1-dimethyl) ethane.) Sulfonyl) -piperidin-4-yl) cycloheptylurea
The title compound is prepared from the N- (3-cyanophenyl) -N '- (1- ((phenyl) methane) sulfonyl) piperidin-4-yl) cycloheptylurea found in Example 8.
The N- (3-cyanophenyl) -N '- (1- ((phenyl) methane) sulfonyl) piperidin-4-yl) cycloheptylurea (1.94 g, 4.29 mmol) in dimethylformamide (25 mL) is cooled to -10 ° C. and a solution of potassium t-butoxide ÍM in tetrahydrofuran (12.9 mL, 12.9 mmoles) is added dropwise. The reaction is stirred for 15 minutes at -10 ° C, then methyl iodide (1.83 g, 12.9 mmol) is added. After 2 hours the reaction is completed by TLC; The reaction mixture is poured into water (200 mL), then extracted with ethyl acetate (3 x 50 mL). The ethyl acetate extracts are washed with water (5 x 50 mL), dried (MgSO 4) and evaporated to give 0.55 g of N- (3-cyanophenyl) -N '- ((1- ((phenyl) -1 , 1-dimethyl) methane) -sulfonyl) -piperidin-4-yl) cycloheptylurea; LRMS (M + NH4) + m / z = 498.
To 0.55 g of N- (3-cyanophenyl) -N '- ((1- ((phenyl) -1,1-dimethyl) methane) -sulfonyl) -piperidin-4-yl) cycloheptylurea (1.14 mmole) in pyridine ( 20 mL) with triethylamine (1 mL) is passed a stream of gaseous hydrogen sulfide for 30 minutes. The reaction mixture is tightly covered and allowed to stand for 18 hours. The solution is then poured into a solution of IN hydrochloric acid (250 mL) and extracted with ethyl acetate (3 x 50 mL). The ethyl acetate solution is dried and evaporated to give 0.53 g (1.03 mmol) of N- (3-thioamidophenyl) -N '- ((1- ((phenyl) -1,1-dimethyl) methane) -sulfonyl) -piperidin-4-iD-cycloheptylurea; LRMS (M + H) + m / z = 515.
The product prepared above, 0.53 g (1.03 mmol) of N- (3-thioamidophenyl) -N1 - ((1- ((phenyl) -1, 1-dimethyl) methane) -sulfonyl) -piperidin-4-yl) cycloheptylurea , stir in methyl iodide (10 mL) for 2 hours. Then the reaction is evaporated to give 0.62 g (1.03 mmol) of the thioimidate.
The thioimidate (0.62 g, 1.03 mmol) is stirred with ammonium acetate (0.45 g, 5.9 mmol) in methanol (20 mL) and heated at 60 ° C for 2 hours. The reaction is then evaporated, the residue is stirred in dichloromethane, the insoluble material is removed by filtration and the dichloromethane solution is evaporated to give about 0.5 g of unpurified amidine. This material is purified by HPLC (gradient elution with a mixture of 0.05% trifluoroacetic acid and trifluoroacetic acid in acetonitrile) to give 0.143 g of the title compound following lyophilization of the appropriate fractions; HRMS
(M + H) +: calculated 489.253887, found 498.252412.
EXAMPLE 57
Preparation of N- (3-amidinophenyl) -N '- (methyl ((phenylmethyl) carbamide) morpholin-3-yl)) cycloheptylurea
3- (Aminomethyl) morpholine of N-benzyl: 3- (chloro-methyl) morpholine of N-benzyl (10 g, 44.3 mmol) in dimethylformamide (200 mL) with sodium azide (8.64 g, 133 mmol) and iodide of potassium (0.73 g) is heated at 100 ° C for 72 hours. The reaction is poured into water (1 L) and extracted with ethyl acetate (3 x 150 mL). The ethyl acetate layer is washed with water (5 x 150 mL), then dried (MgSO 4) and evaporated to give 9.28 g of material. This is further purified by flash chromatography using hexane: ethyl acetate 3: 1 as eluent. 7.89 g of the pure azide is obtained.
The material prepared above is dissolved in methanol (300 mL) and palladium hydroxide catalyst (l.Og) is added. This mixture is stirred under an atmosphere of hydrogen gas at ambient pressure for 2 hours, after which the selective reduction of the azide group is completed. The reaction mixture is purged with nitrogen gas and the catalyst is removed by filtration through a pad of Celite. After removal of the solvent, 5.80 g of 3- (aminomethyl) morpholine of N-benzyl (28.1 mmol) are obtained; LRMS (M + H) + m / z = 207.
N- (3-cyanophenyl) -N '- (methyl (N-methyl (phenyl)) morpholin-3-yl)) cycloheptylurea: A mixture of 5.80 g of 3- (aminomethyl) morpholine of N-benzyl (28.1 mmol) and 3-cyano-phenocyanate isocyanate (4.46 g, 31 mmol) in dimethylformamide (100 mL) is stirred at room temperature for 18 hours. The reaction is diluted with water (500 mL), then extracted with ethyl acetate (3 x 100 mL). The ethyl acetate solution is washed with water (5 x 100 mL), dried (MgSO 4) and evaporated to give 9.49 g of urea (27.1 mmol); LRMS (M + H) + m / z = 351.
To a mixture of sodium hydride (3.25 g of a 60% suspension in mineral oil, 81.3 mmol) in dimethylformamide (450 mL) is added in drops 9.49 g of the urea (27.1 mmol) prepared above as a solution in dimethylformamide ( 50 mL). This mixture is stirred for 30 minutes, then 1.71 g of 1,4-dibromobutane (54.2 mmol) in dimethylformamide (40 ml) is slowly added. The reaction is heated to 70 ° C for 6 hours, then poured into water (2 L) and extracted with ethyl acetate (3 x 250 mL). The ethyl acetate extract is washed with water (5 x 250 mL), dried (MgSO 4) and evaporated. The residue is purified by flash chromatography using hexane: ethyl acetate 2: 1 as eluent. 7.59 g of N- (3-cyanophenyl) -N '- (methyl (N-methyl (phenyl)) morpholin-3-yl)) cycloheptylurea is obtained; LRMS (M + H) + m / z = 405.
N- (3-cyano-phenyl) -N '- (methyl (morpholin-3-yl)) cycloheptylurea: A N- (3-cyanophenyl) -N 1 - (methyl (N-methyl (phenyl)) morpholin-3-yl) cycloheptylurea (4.66 g, 11.55 mmol) in dichloromethane (100 mL) is added 1-chloroethyl chloroformate (1.81 g, 12.7 mmol) in dichloromethane (10 mL). After 2 hours, the reaction is completed by TLC; the solvent is removed by evaporation in vacuo and replaced by methanol (60 mL). The mixture is refluxed for 1 hour, then the solvent is evaporated to give 3.53 g of N- (3-cyanophenyl) -N1- (methyl (morpholin-3-yl)) cycloheptyl-urea; LRMS (M + H) + m / z - 315.
N- (3-cyanophenyl) -N '- (methyl ((phenylmethane) carbamide) -morpholin-3-yl)) cycloheptylurea: A 1.0 g of N- (3-cyanophenyl) -N' - (methyl (morpholine-3) -yl)) cycloheptylurea (3.18 mmol) in tetrahydrofuran (30 mL) with triethylamine (0.68 g, 6.7 mmol) at 0 ° C is added phenylacetyl chloride (0.54 g, 3.5 mmol) in tetrahydrofuran (10 mL). The mixture is allowed to liquefy at room temperature and stir for 18 hours. After this time, the solvent is removed by evaporation in vacuo and the residue is purified by flash chromatography with 10% methanol in chloroform used as eluent. 1.17 g (2.7 mmol) of N- (3-cyanophenyl) -N1 - (methyl ((phenyl-methane) carbamide) morpholin-3-yl)) cycloheptylurea is obtained as product; LRMS (M + H) + m / z = 433.
N- (3-amidinophenyl) -N '- (methyl ((phenyl-methane) carbamide) -morpholin-3-yl)) cycloheptylurea: To a saturated solution of gaseous hydrogen chloride in dry chloroform (20 mL) and dry methanol (8 mL) at -78 ° C a chloroform solution (5 mL) of 1.17 g (2.7 mmol) of N- (3-cyano-phenyl) -N 1 - (methyl ((phenyl-methane) carbamide) morpholine is added dropwise. -3-yl)) cycloheptylurea. This mixture is tightly capped, allowed to liquefy at room temperature and stirred for 18 hours. The solvent is removed under vacuum to give 1.04 g of the corresponding imidate; LRMS (M + H) + m / z = 465.
The imidate prepared above is dissolved in 2M ammonia in methanol solution (6.72 mmol, 3.36 mL), the flask is capped securely and the mixture is stirred at room temperature for 18 hours. After this time, the solvent is removed in vacuo and the residue (approximately 1.2 g) is purified by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) to give 0.12 g of N- (3-amidinophenyl) -N '- (methyl ((phenyl-methane) carbamide) -morpholin-3-yl)) cycloheptylurea; m.p. 49-53 ° C; HRMS (M + H) +: calculated 450.250515, found 450.251817.
EXAMPLE 58
Preparation of N- (3-amidinophenyl) -N1 - (methyl ((thiophene-2-yl) sulfonyl) morpholin-3-yl)) cycloheptylurea
This compound is prepared by the same methods used for Example 57. Starting with the common intermediate N- (3-cyanophenyl) -N 1 - (methyl (morpholin-3-yl)) cycloheptylurea, this material is sulfonylated with the chloride ( thiophen-2-yl) sulfonyl using the same conditions for the acylation described above. 0.75 g of the sulfonylation product is obtained following purification by flash chromatography using a gradient of hexane: ethyl acetate 2: 1 to hexane: ethyl acetate 1: 2 as a gradient; LRMS (M + H) + m / z = 461.
The imidate and accordingly, the N- (3-amidinophenyl) -N '- (methyl ((thiophen-2-yl) sulfonyl) morpholin-3-yl)) cycloheptylurea amidine are obtained as described above. Following the purification by HPLC, 0.32 g of the title compound is isolated; mp 78-83 ° C; HRMS (M + H) +: calculated 478.158273, found 478.156983.
EXAMPLE 59
Preparation of N- (3-amidinophenyl) -N '- (methyl ((phenylmethyl) sulfonyl) morpholin-3-yl)) cycloheptylurea
This compound is prepared by the same methods used for Example 57. Starting with the common intermediate N- (3-cyanophenyl) -N '- (methyl (morpholin-3-yl)) cycloheptylurea, this material is sulfonylated with the (phenyl) methylsulfonyl using the same conditions for the acylation described above. 0.68 g of the sulfonylation product is obtained following purification by flash chromatography using a gradient of hexane: ethyl acetate 1: 1 to hexane: ethyl acetate 1: 3 as a gradient; LRMS (M + H) + m / z = 469.
The imidate and therefore the N- (3-amidinophenyl) -N '- (methyl ((phenylmethane) sulfonyl) morpholin-3-yl)) cycloheptylurea amidine are obtained as described above. Following purification by HPLC, 0.102 g of the title compound is isolated; m.p. 45-53 ° C; HRMS (M + H) +: calculated 486.217502, found 486.217928.
EXAMPLE 60
Preparation of N- (3-amidinophenyl) -N '- (N-benzyl) piperidin-3-yl) cycloheptylurea
N-benzyl 3-aminopiperidine: To 10.0 g of N-benzyl 3-hydroxypiperidine hydrogen chloride salt (44 mmol) in chloroform (200 mL) with triethylamine (9.34 g, 92.4 mmol) at 0 ° C is added in drops methanesulfonyl chloride (5.54 g, 48.4 mmol) in chloroform (10 mL). The reaction mixture is allowed to liquefy at room temperature and is stirred for 72 hours. After this time, the solvent is removed in vacuo, the residue is dissolved in ethyl acetate (200 mL) and washed with water (200 mL). The organic solution is dried (MgSO4) and evaporated to give 9.1 g (33.8 mmol) of the mesitylate.
The material prepared above is dissolved in dimethylformamide (200 mL) and stirred at 100 ° C with sodium azide (11 g, 170 mmol). After 48 hours, the reaction is completed by TLC; it is diluted with brine (200 mL) and extracted with ethyl acetate (3 x 100 mL). The ethyl acetate extracts are washed with water (5 x 100 mL), then dried and evaporated to give 6.12 g of the azide; LRMS (M + H) + m / z = 217.
The azide (6.12 g, 28.4 mmol) in methanol (250 ml) with palladium hydroxide catalyst (1.0 g) is stirred under an atmosphere of hydrogen gas at ambient pressure for 1.25 hours. After this time the selective reduction of azide is completed. The reaction mixture is purged with nitrogen gas and the catalyst is removed by filtration through a pad of Celite. The solvent is removed by vacuum distillation to give 4.3 g of 3-aminopiperidine of N-benzyl; LRMS (M + H) + m / z = 191.
N- (3-cyanophenyl) -N1 - ((N-benzyl) piperidin-3-yl) cycloheptylurea: A mixture of 4.3 g of 3-aminopiperidine of N-benzyl (22.6 mmoles) and 3-cyanophenyl isocyanate (3.58 g) , 24.9 mmol) in dimethylformamide (100 mL) is stirred at room temperature for 18 hours. The reaction is diluted with water (500 mL) and extracted with ethyl acetate (3 x 150 mL). The organic solution is washed with water (5 x 150 mL), dried and evaporated. This material is further purified by flash chromatography on silica gel using a gradient of ethyl acetate: hexane 1: 1 to 3: 1. 3.18 g of pure urea (9.52 mmol) is obtained; LRMS (M + H) + m / z = 335.
To 1.14 g of sodium hydride (60% suspension, 28.6 mmol) in dimethylformamide (160 mL) is added a solution of dimethylformamide (20 mL) of urea (3.18 g, 9.52 mmol). After 30 minutes, 1,4-dibromobutane fc (4.32 g, 20 mmol) in dimethylformamide (10 mL) is added dropwise, then the mixture is heated to 70 ° C for 3 hours. The reaction is diluted with water (700 mL) and extracted with ethyl acetate (3 x 100 mL). The organic solution is washed with water (5 x 100 mL), dried (MgSO 4) and evaporated. The residue is purified by flash chromatography on silica gel using a gradient elution of 5 to 10% methanol in chloroform. 3.17 g of N- (3-cyanophenyl) -N1 - ((N-benzyl) piperidin-3-yl) cycloheptyl-urea is obtained; LRMS (M + H) + m / z = 389.
N- (3-amidinophenyl) -N '- ((N-benzyl) piperidin-3-yl) cycloheptyl-urea: To a saturated solution of hydrogen chloride gas in dry methanol (8 mL) and dry chloroform (15 mL) ) at -78 ° C is added a chloroform solution (5 mL) of N- (3-cyanophenyl) -N1 - ((N-benzyl) piperidin-3-yl) cycloheptyl-urea (0.5 g, 1.29 mmol). The reaction mixture is capped securely and allowed to stir at room temperature for 18 hours. After this time, the solvent is removed under vacuum and 0.49 g of the imidate hydrochloride salt is obtained; LRMS (M + H) + m / z = 422.
The imidate obtained above is dissolved in 2M ammonia in methanol
(1.75 mL, 3.5 mmol). The reaction vessel is capped securely and the mixture is stirred at room temperature for 18 hours. After this time, the solvent is removed in vacuo and the residue is purified by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) to give 0.015 g of N- (3 -amidinophenyl) -N1 - ((N-benzyl) piperidin-3-yl) cycloheptylurea pure; HRMS (M + H) +: calculated 406.260686, found 406.259064.
EXAMPLE 61
Preparation of N- (3-amidinof nyl) -N '- ((N- (benzyl) sulfonyl) -piperidin-3-yl) cycloheptylurea
N- (3-cyanophenyl) -N '- (piperidin-3-yl)) cycloheptylurea: A mixture of N- (3-cyano-phenyl) -N1 - ((N-benzyl) piperidin-3-yl) cycloheptyl-urea ( prepared in Example 60, 2.7 g, 6.98 mmol) and a-chloroethyl chloroformate (1.09 g, 7.65 mmol) is stirred at room temperature for 2.5 hours, after which the reaction is complete as estimated by TLC. The solvent is removed by evaporation in vacuo and replaced with methanol (40 mL). The reaction is heated to reflux until all the newly formed intermediate is consumed as indicated by TLC. Evaporation of the solvent gives 2.49 g of N- (3-cyano-phenyl) -N1- (piperidin-3-yl) -cycloheptylurea; LRMS (M + H) + m / z = 299.
N- (3-cyano-phenyl) -N "- ((N- (benzyl) sulfonyl) piperidin-3-yl) cycloheptylurea: A N- (3-cyano-phenyl) -N1- (piperidin-3-yl) -cycloheptylurea (1.2 g , 4.03 mmol) and triethylamine (0.85 g, 8.46 mmol) in tetrahydrofuran (30 mL) at 0 ° C is added benzylsulfonyl chloride (0.92 g, 4.83 mmol) in tetrahydrofuran solution (10 mL) .The reaction is allowed to liquefy The reaction mixture is evaporated and the residue is dissolved in ethyl acetate (100 mL) The organic solution is washed with IN sodium hydroxide solution (100 mL), IN hydrochloric acid (100 mL) and saturated sodium hydrogen carbonate (100 mL) The solution is dried (MgSO4) and evaporated to give 0.99 g (2.19 mmol) of N- (3-cyanophenyl) -N1 - ((N- (benzyl)). -sulfonyl) piperidin-3-yl) cycloheptylurea; LRMS (M + H) + m / z = 453.
N- (3-amidinophenyl) -N1 - ((N- (benzyl) sulfonyl) piperidin-3-yl) cycloheptylurea: To a saturated solution at -78 ° C of hydrogen chloride gas in dry chloroform (20 mL) and methanol (10 mL) is added 0.99 g (2.19 mmoles) of N- (3-cyanophenyl) -N '- ((N- (benzyl) -sulfonyl) piperidin-3-yl) cycloheptylurea in chloroform (5 mL). The reaction vessel is capped securely, allowed to liquefy at room temperature and stirred for
18 hours. After this time, the solvent is removed by evaporation under vacuum and 1.04 g of the imidate is obtained as the hydrogen chloride salt; LRMS (M + H) + m / z = 485.
The imidate prepared above is dissolved in 2M ammonia in methanol solution (3.22 mL, 6.44 mmol). The reaction is capped securely and stirred for 18 hours. Following the removal of the solvent and purification by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile), 0.316 g of N (-3-amidinophenyl) -N '- (( N- (benzyl) -sulfonyl) piperidin-3-yl) cycloheptylurea; HRMS (M + H) +: calculated 470.225587, found 470.221857.
Additionally, 0.066 g of the amide side product, N- (3-amidophenyl) -N '- ((N- (benzyl) sulfonyl) piperidin-3-yl) cycloheptylurea, is isolated as a slower elution maximum.
EXAMPLE 62
Preparation of N- (3-amidinophenyl) -N '- ((N- (thiophen-2-yl) sulfonyl) piperidin-3-yl) cycloheptylurea
This compound is prepared by the same methods used for EXAMPLE 61. Starting with the common intermediate N- (3-cyanophenyl) -N 1 - (piperidin-3-yl) cycloheptylurea, this material is sulfonylated with thiophene-2-chloride. il) sulfonyl using the same conditions for the sulfonylation described above. 0.87 g of the sulfonylation product is obtained following purification by flash chromatography using a gradient of hexane: ethyl acetate 2: 1 to hexane: ethyl acetate 1: 1 as a gradient; LRMS (M + H) + m / z = 445.
The imidate and accordingly, the N- (3-amidinophenyl) -N1 - ((N- (thiophen-2-yl) sulfonyl) piperidin-3-yl) cycloheptylurea amidine are obtained as described above. Following the purification by HPLC, 0.234 g of the title compound is isolated; HRMS (M + H) +: calc 462.163359, found 462.164841.
Additionally, 0.045 g of the secondary amide product, N- (3-amidophenyl) -N '- ((N- (thiophen-2-yl) sulfonyl) piperidin-3-yl) cycloheptylurea, is isolated as a slowest elution maximum.; HRMS (M + H) +: calc. 463.147374, found 463.146300.
EXAMPLE 63
Preparation of N- (3-amidinophenyl) -N '- (4- (2-sulfonamido-phenyl) phenyD.cycloheptyl rea
N- (3-cyano-phenyl) -N 1 - (4-bromophenyl) cycloheptylurea: A mixture of isocyanate. of 3-cyanophenyl (3.76 g, 26.1 mmoles) and 4-bromoaniline (4.5 g, 26.1 mmoles) in tetrahydrofuran: chloroform 1: 1 (100 mL). After 72 hours at room temperature, the product is isolated by filtration, the filtrate is washed with cold chloroform and dried with air to give 6.6 g of N- (3-cyano-phenyl) -N1- (4-bromophenyl) urea (21). mmoles).
To 1.41 g of sodium hydride (60% suspension, 33.6 mmol) in dimethylformamide (300 mL) is added a solution of dimethylformamide (20 mL) of 6.6 g of N- (3-cyano-phenyl) -N1- (4-bromophenyl) ) urea (21 mmoles). After 30 minutes, it is added
1, 4-dibromobu an (6.2 g, 28.6 mmoles) in dimethylformamide
(10 mL), then the mixture is heated to 60 ° C for 2 hours and then stirred at room temperature for 18 hours. The reaction is diluted with water (700 mL) and extracted with ethyl acetate (3 x 100 mL). The organic solution is washed with water (5 x
100 mL), dried (MgSO 4) and evaporated. The residue is purified by flash chromatography on silica gel using a gradient elution of 5 to 10% methanol in chloroform.
3.68 g of N- (3-cyanophenyl) -N1- (4-bromophenyl) cycloheptylurea is obtained.
N- (3-cyanophenyl) -N '- (4- (2- ((Nt-butyl) sulfonamido) phenyl) -phenyl) cycloheptylurea: A mixture of N- (3-cyanophenyl) -N1- (4-bromophenyl) ) cycloheptylurea (4.0 g, 10.81 mmol), 2- ((Nt-butyl) sulfonamido) phenylboronic acid (3.9 g, 15.2 mmol), tetrabutylammonium bromide (0.203 g) and sodium carbonate (2.47 g) in benzene (170 mL) ) is completely purged with dry nitrogen gas. Tetrakis (triphenylphosphine) palladium (0) ^ catalyst (0.635 g) is added and the mixture is heated under reflux under a nitrogen atmosphere for 18 hours. The benzene solution is washed with water (3 x 100 mL) and brine (100 mL), then dried (MgSO 4) and evaporated. The crude product is triturated with n-butylchloride, filtered and dried with air to give 3.92 g of N- (3-cyanophenyl) -N1 - (4- (2- ((Nt-butyl) su-fonamido) phenyl) phenyl) cycloheptylurea.
N- (3-amidinophenyl) -N '- (4- (2-sulfonamidophenyl) phenyl) -cycloheptylurea: A solution of 3.0 g of N- (3-cyano-phenyl) -N1 - (4- (.2- ((Nt) -butyl) sulfonamido) phenyl) phenyl) cycloheptyl urea (5.98 mmol) in dry methanol (40 mL) and dry chloroform (300 mL) is saturated with hydrogen chloride gas with cooling in. ice. This solution is tightly capped and stirred for 18 hours at room temperature. The solvent is removed by evaporation and the residue is dissolved in 2M ammonia in methanol (60 mmol, 30 mL). This solution is stirred in a tightly capped reaction vessel for 48 hours at room temperature. After this time, the solvent is removed under vacuum and 2.28 g of unpurified product is obtained. A portion (0.735 g) of this material is purified by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) to give 0.396 g of N- (3-amidinophenyl) -N1 - (pure 4- (2-sulfonamidophenyl) -phenyl) -cycloheptylurea; p.f. 163-166ßC; HRMS (M + H) +: calc 464.175637, found 464.177525.
EXAMPLE 64
Preparation of N- (3-amidinophenyl) -N '- (5- (2-sulfonamido-phenyl) pyridin-2-yl) cycloheptylurea
Example 64 is prepared by a procedure similar to that used for Example 63 with the exception that 2-amino-5-bromopyridine is replaced by 4-bromoaniline in the initial step. 0.043 g of N- (3-amidinophenyl) -N '- (5- (2-sulfonamido-phenyl) pyridin-2-yl) cycloheptylurea is obtained as a bis-trifluoroacetate salt; mp 75-79 ° C; HRMS (M + H) +: calc. 465.170886, found 465.170759.
EXAMPLE 65
Preparation of N- (3-amidinophenyl) -N '- (methyl (4- (2-sulfonamidophenyl) phenyl)) cycloheptylurea
N- (3-cyano phenyl) -N '- (methyl (4-bromo) phenyl) urea: A mixture of 4-bromobenzyl amine (3.81 g, 20 mmol) and 3-cyanophenyl isocyanate (2.65 g, 18.4 mmol) in dimethylformamide (60 mL) is stirred at room temperature for 48 hours. The reaction is partitioned between a solution of IN hydrochloric acid (200 mL) and ethyl acetate (200 mL). The ethyl acetate solution is washed with water (5 x 100 mL), then dried (MgSO 4) and evaporated to give 5.33 g of N- (3-cyanophenyl) -N 1 - (methyl (4-bromo) phenyl) urea .
N- (3-cyanophenyl) -N '- (methyl (4-bromophenyl)) cycloheptylurea: To 1.82 g of sodium hydride (60% suspension, 45.3 mmol) in dimethylformamide (270 mL) is added a solution of dimethylformamide ( 30 mL) of the N- (3-cyanophenyl) -N1- (methyl (4-bromo) phenyl) urea (4.98 g, 15.1 mmol). After 30 minutes, 1,4-dibromobutane (6.52 g, 30.2 mmol) in dimethylformamide (10 mL) is added dropwise. This mixture is heated to 70 ° C for 3 hours, then cooled to room temperature and stirred for 48 hours. The reaction is diluted with water (1 L) and extracted with ethyl acetate (4 x 250 mL). The organic solution is washed with water (5 x 150 mL), dried (MgSO) and evaporated. The residue is purified by flash chromatography on silica gel eluting with 1% methanol in chloroform. 2.3 g of N- (3-cyano-phenyl) -N1- (methyl (4-bromophenyl)) cycloheptylurea are obtained.
N- (3-cyanophenyl) -N '- (methyl (4- (2- (Nt-butyl) sulfonamido-phenyl) phenyl) cycloheptylurea: A mixture of N- (3-cyano-phenyl) -N 1 - (methyl (4-) bromophenyl)) cycloheptylurea (1.24 g, 3.2 mmol), 2- ((Nt-butyl) sulfonamido) phenylboronic acid (1.17 g, 4.5 mmol), tetrabutylammonium bromide (0.06 g) and sodium carbonate (0.73 g) in Benzene (50 mL) and water (5 mL) are completely purged with dry nitrogen gas, Tetrakis (triphenylphosphine) palladium (0) catalyst (0.188 g) is added and the mixture is refluxed under a nitrogen atmosphere for 18 hours. The benzene solution is washed with water (3 x 100 mL) and brine (100 mL), then dried (MgSO 4) and evaporated to give 2.0 g of crude product. Recrystallization with acetone gives 0.80 g of N- (3-cyanophenyl) -N 1 - (methyl (4- (2- (Nt-butyl) sulfonamido-phenyl) phenyl)) cycloheptylurea, mp 177-179 ° C.
An additional 0.365 g of the product is recovered from the mother liquors by silica gel chromatography using 1% methanol in chloroform as eluent.
N- (3-cyanophenyl) -N '- (methyl (4- (2-sulfonamido-phenyl) phenyl)) cycloheptylurea: A solution of 1.17 g of N- (3-cyano-phenyl) -N' - (methyl ( 4- (2- (Nt-butyl) sulfonamido-phenyl) phenyl)) cycloheptylurea (2.27 mmol) in trifluoroacetic acid (30 mL) is heated at reflux for 1 hour. The reaction is evaporated and the residue is suspended in a 10% sodium hydroxide solution (30 mL). The suspension is extracted with ethyl acetate (50 mL), the extracts are washed with a solution of 10% sodium hydroxide (2 x 25 mL) and brine (25 mL). The solution is dried (MgSO4) and evaporated to give 0.72 g of the product without purification. This material is purified by column chromatography using a gradient of 1.5 to 2.5% methanol in chloroform. 0.55 g of N- (3-cyanophenyl) -N 1 - (methyl (4- (2-sulfonamidophenyl) phenyl)) cycloheptylurea is obtained.
N- (3-amidinophenyl) -N 1 - (methyl (4- (2-sulfonamidophenyl) -phenyl)) cycloheptylurea: A solution of 0.55 g of N- (3-cyanophenyl) -N 1 - (methyl (4- (2- sulfonamidophenyl) -phenyl)) cycloheptylurea (1.2 mmol) in dry methyl acetate
(70 mL) and dry methanol (0.192 g, 0.24 mL, 6.0 mmol) is cooled to 0 ° C and saturated with dry hydrogen chloride gas. The reaction is tightly capped and stirred at room temperature for 18 hours. Precipitation of the imidate product is initiated by the addition of ethyl ether (70 mL) to the cold solution. The solid is isolated by filtration and kept under vacuum for 18 hours to remove the last traces of hydrogen chloride gas; 0.50 g of the imidate is obtained as the hydrogen chloride salt.
The above imidate is triturated for 18 hours in a methanol solution (20 mL) of ammonium acetate (0.462 g, 6 mmol). The reaction is evaporated and partitioned between ethyl acetate (50 mL) and IN hydrochloric acid (50 mL). The ethyl acetate solution is dried and evaporated to give 0.16 g of the amide side product. The lyophilization of the hydrochloric acid solution gives 0.39 g of the unpurified amidine. Purification of this material by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) gives 0.258 g of N- (3-amidinophenyl) -N '- (methyl) (2-sulfonamidophenyl) phenyl)) cycloheptylurea as the salt of "trifluoroacetic acid; mp 90-94 ° C; HRMS (M + H) +: calculated 478.191671, found 478.191287.
Table 5 Table 6
Table 7
* Unless otherwise indicated, group B is replaced in A in the position for a Z, if present, and cyclourea.
Table 8
Table 9
Table 10
Table 11 Table 12 Table 13
Table 14
Table 15 1439 NHS02CH3 bond "thiophen-2-ylmethylsulfonyl
1440 NHS02CH3 bond thiophen-2-ylmethyl Table 16
Table 17
Table 18
Table 19
^ B is substituted in the position para for Z in A. Table 20
* B is substituted in the position for a Z in A. Table 21
* B is substituted in the position for a Z in A.
Table 22
* B is replaced in the position for a Z in A. Table 23
* "B is replaced in the position for a Z in A. Example 24
* B is substituted in the position for a Z in A. Table 25 *
• Each entry in Table 25 is intended to correspond individually to each of the formula a-m.
UTILITY
The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes cardiovascular or cerebrovascular venous thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, attack of paralysis, atherosclerosis, venous thrombosis. , thrombosis of the deep venous system, trobophlebitis, arterial embolism, coronary and cerebral artery thrombosis, cerebral embolism, kidney embolisms, and lung embolisms.
The anticoagulant effect of the compounds of the present invention is believed to be due to the inhibition of factor Xa. The effectiveness of the compounds of the present invention as inhibitors of factor Xa is determined using purified human factor Xa and the synthetic substrate. The proportion of the hydrolysis of factor Xa of the chromogenic substrate S2222
(kabi Pharmacia, Franklin, OH) is measured both in the absence and presence of the compounds of the present invention. The hydrolysis of the substrate results in the release of pNA, which is monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the ratio of the absorbance change to 405 nM in the presence of the inhibitor is indicative of the inhibition of the enzyme. The results of this test are expressed as inhibitory constant, Ki.
The determinations of factor Xa are made in a 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant, K-, for the hydrolysis of the substrate is determined at 25 ° C using the method of Lineweaver and Burk. Ki # values are determined by allowing human factor Xa 0.2-0.5 nM (Enzyme Research Laboratories, South Bend, IN) to react with the substrate (0.20 mM - 1 mM) in the presence of the inhibitor. The reactions are allowed to run for 30 minutes and the velocities (ratio of absorbance change against time) are measured in the 25-30 minute time cycle. The following relationship is used to calculate the values of K:
(v0-vs) / vs = l / (Ki (1+ S / K)
where :
v0 is the speed of the control in the absence of the inhibitor; vs is the speed in the presence of the inhibitor; I is the concentration of the inhibitor; Ki is the dissociation constant of the enzyme complex: inhibitor; S is the concentration of the substrate; Km is the constant of Michaelis.
Using the methodology described above, a number of compounds of the present invention are found to inhibit a
Ki of less than or equal to 1 μm, thereby confirming the usefulness of the compounds of the present invention as effective factor Xa inhibitors.
The antitrobotic effect of the compounds of the present invention can be demonstrated in a rat model with vena cava thrombosis. In this model, Spragüe-Da ley ley rats weighing 350-450 grams anesthetized with a mixture of xylazine (10 mg / kg intramuscular) and ketamine (110 mg / kg intramuscular) are used. A carotid artery, a jugular vein and a femoral vein are cannulated by the blood sample, drug infusion and hypotonic saline injection, respectively. The abdominal vena cava is isolated and all its lateral branches are linked from below the left renal vein. Thrombus formation is induced by the rapid injection of one milliliter of hypotonic saline (0.225%) into the vena cava. This is followed 15 seconds later by a 15-minute intestinal stasis of an isolated segment (approximately 1 cm) of the vena cava. The thrombus formed in the vena cava is eliminated and immediately weighed.
The test compounds or vehicle are given as continuous intravenous infusions or orally starting one hour before the injection of hypotonic saline. Blood samples from the artery (1.5 ml) for determination of coagulation times are collected before and one hour after infusion or oral dosing of the test compounds or vehicle. The percentage of inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.
The compounds of the formula (I) are also considered to be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Due to their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforementioned class of enzymes.
Some compounds of the present invention are shown to be inhibitors of serine protease direct thrombin action because of their facility to inhibit the separation of small molecule substrates by thrombin in a purified system. In vitro inhibition constants are determined by the method described by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990), incorporated herein by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, TX) is monitored spectrophotometrically. The addition of an inhibitor to the test mixture results in a decrease in absorbance and is indicative of the inhibition of thrombin. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, IN) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, is incubated with several Substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, the thrombin activity is analyzed by monitoring the proportion of the increase in absorbance at 405 nm, which seems adequate for the hydrolysis of the substrate. The inhibition constants are derived from reciprocal graphs of the reaction rate as a function of substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention are evaluated and found to inhibit a Ki of less than 5 μm, thereby confirming the usefulness of the compounds of the invention as effective thrombin inhibitors.
The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anticoagulant or coagulation inhibitory agents, antiplatelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.
The compounds are administered to a mammal in a therapeutically effective amount. By the term "therapeutically effective amount" is meant an amount of a compound of Formula I which, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate thromboembolic disease condition or progression of the illness.
By the term "administered in combination" or "combination therapy" is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component can be administered at the same time or sequentially in any order at different points in time. Therefore, each component can be administered separately but sufficiently closely in time to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory agents) that can be used in combination with the compounds of this invention include warfarin and heparin, as well as other factor Xa inhibitors, such as those described in the publications identified above under Background of the Invention .
The term antiplatelet agents (or platelet inhibitory agents), as used herein, means agents that inhibit platelet function, such as by inhibiting platelet aggregation, adhesion or granular secretion. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including salts or prodrugs pharmaceutically acceptable thereof. Of the NSAIDS, aspirin (acetylsalicylic acid or ASA), and piroxicam are preferred. Other suitable antiplatelet agents include ticlopidine, including the pharmaceutically acceptable salts or prodrugs thereof. Also ticlopidine is a preferred compound since it is known to be moderate in the gastrointestinal tract in use. Still other suitable platelet inhibiting agents include the Ilb / Illa complex antagonists, the thromboxan-A2-receptor antagonists and the thromboxan-A2-synthetase inhibitors, as well as the pharmaceutically acceptable salts or prodrugs thereof.
The term thrombin inhibitors (or antithrombin agents), as used herein, means inhibitors of the serine protease thrombin. Due to the inhibition of thrombin, a number of thrombin-mediated processes are interrupted, such as thrombin-mediated platelet activation (i.e., for example, platelet aggregation, and / or granular secretion of inhibitor-1). activator of plasminogen and / or serotonin) and / or fibrin formation. A number of thrombin inhibitors are known to one skilled in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including the pharmaceutically acceptable salts or prodrugs thereof. The boroarginine and boropeptide derivatives include the N-acetyl and boronic acid peptide derivatives, such as the C-terminal α-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes appropriate derivatives or analogs of hirudin, referred to herein as hirulogos, such as disulfatohirudin. The boropeptide thrombin inhibitors include the compounds described in Kettner et al. , U.S. Patent No. 5,187,157 and the European Patent Application Publication Number 293 881 A2, the discoveries of which are incorporated by reference. Other suitable boroarginine derivatives and inhibitors of the boropeptide thrombin include those described in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471,651 A2, the discoveries of which are therefore incorporated by reference.
The term thrombolytic agents (or fibrinolytics)
(or thrombolytics or fibrinolytics), as used herein, means agents that cause lysis of blood clots (thrombus).
Such agents include the tissue plasminogen activator, anistreplase, urokinase or streptokinase, including the pharmaceutically acceptable salts or prodrugs thereof. The term "anistreplase", as used herein, refers to the anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated by reference. The term urokinase, as used herein, means both dual or single chain urokinase, the latter also referred to herein as prourokinase.
The administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may provide an efficacy advantage over the compounds and agents alone, and may remain so as long as the use of lower doses of each is allowed. A lower dosage minimizes the potential of the side effects, therefore it provides an increase in the safety margin.
The compounds of the present invention are also useful as reference or standard compounds, for example as a standard or quality control, in tests or assays comprising the inhibition of factor Xa. Such compounds can be provided in a commercial type, for example, for use in pharmaceutical research comprising factor Xa. For example, a compound of the present invention should be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This assures the experimenter that the assay is properly started and provides a basis for comparison, especially if the test compound is a derivative of the reference compound. When new assays or protocols are developed, the compounds according to the present invention should be used to test their effectiveness.
The compounds of the present invention can also be used in diagnostic assays comprising factor Xa. For example, the presence of factor Xa in an unknown sample must be determined by the addition of the chromogenic substrate S2222 to a series of solutions containing the test sample and optionally one of the compounds of the present invention. If the production of pNA is observed in the solutions containing the test sample, but no compound of the present invention, then one must conclude that factor Xa is present.
Dosage-, ñn and Formulation
The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or delayed release formulations), pills, powders, granules, elixirs, medicinal solutions, suspensions, syrups and emulsions. They may also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously, or intramuscularly, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage regimen for the compounds of the present invention, from source, will vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and frequency of symptoms; the class of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, control, or arrest the progress of thromboembolic disorder.
As a general guide, the daily oral dosage of each active ingredient, when used for the indicated effects, will fluctuate between approximately 0.001 to 1000 mg / kg of body weight, preferably between approximately 0.01 to 100 mg / kg of weight of the body per day, and more preferably between about 1.0 to 20 mg / kg / day. Intravenously, the most preferred doses will range from about 1 to about 10 mg / kg / minute during a constant proportion infusion. The compounds of this invention can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three, or four times daily.
The compounds of this invention can be administered in intranasal form via topical use of appropriate intranasal vehicles, or transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration, from source, will be continuous rather than intermittent throughout the dosage regimen.
The compounds are typically administered in a mixture with suitable diluents, excipients, or pharmaceutical carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected with respect to the intended form of administration, ie oral, tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an inert carrier, pharmaceutically acceptable, non-toxic, oral, such as lactose, starch, sucrose, glucose, cellulose methyl, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in the liquid form, the oral drug components can be combined with any pharmaceutically acceptable, non-toxic, oral inert carrier, such as ethanol, glycerol, water, and the like. In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents, and colorants can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. similar. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
The compounds of the present invention can also be linked with soluble polymers as objective drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyethylene-polylysine oxide substituted with palmitoyl residues. In addition, the compounds of the present invention can be attached to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, polyepsilon caprolactone, polyhydroxybutyric acid , polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and amphiphilic or crosslinked block copolymers of hydrogels.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
Gelatin capsules may contain the active ingredient and powder carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide continuous release of medication over a period of time. The compressed tablets can be coated sugar or coated film to hide any unpleasant taste and protect the tablet from the atmosphere, or enterically coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration may contain coloration and taste to increase patient acceptance.
In general, water, an appropriate oil, saline, aqueous dextrose (glucose), and sugar solutions and glycols, such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, appropriate stabilizing agents, and if necessary, buffer substances. Antioxidant agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Citric acid and its salts and sodium EDTA are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
Representative useful pharmaceutical dosage forms for administration of the compounds of this invention may be illustrated as follows:
Capsules
A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules, each with
100 milligrams of active ingredient in powder, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams of magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestible oil, such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump in gelatin to form soft gelatine capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.
Tablets
A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings can be applied to increase the acceptability or absorption of delay.
Injectable
A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume of propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
Suspension
An aqueous suspension is prepared for oral administration so that each 5 mL contains 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution,
U.S.P., and 0.025 mL vanillin.
Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of body weight of the patient . For a tablet dosage form, the compounds of this invention can generally be presented in an amount of about 5 to 10 milligrams per dosage unit, and the second anticoagulant in an amount of about 1 to 5 milligrams per dosage unit.
Where the compounds of Formula I are administered in combination with an antiplatelet agent, as a general guide, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the antiplatelet agent, preferably about 0.1 to 1 milligram of the compound of Formula I and about 1 to 3 milligrams of the antiplatelet agents, per kilogram of body weight of the patient.
Where the compounds of Formula I are administered in combination with a thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligram of the compound of Formula I, per kilogram of body weight of the patient and, in the case of the agents With thrombolytics, the usual dosage of the thrombolytic agent when administered alone can be reduced by about 70-80% when administered with a compound of Formula I.
Where two or more of the aforementioned second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a daily dosage typically and typical dosage form can be reduced relative to the usual dosage of the agent when administer alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.
Particularly when it is provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that physical contact between the active ingredients is combined in a single dosage unit through the active ingredients. it is minimized (that is, it is reduced). For example, an active ingredient can be enterically coated. Due to the enteric coating of one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract, such that one of these components is not release in the stomach but rather be released in the intestines. One of the active ingredients can also be coated with a material, which affects a sustained release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. In addition, the additionally maintained-released component can be enteric coated such that the release of this component occurs only in the intestine. Still another approach comprises the formulation of a combination product in which one component is coated with a sustained release and / or enteric polymer, and the other component is also coated with a polymer, such as a lower viscosity grade of methylcellulose of hydroxypropyl (HPMC) or other suitable materials known in the art, to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.
As well as these, other ways of minimizing contact between the components of the combination products of the present invention, if administered in a single dosage form or administered in separate forms but at the same time by the same mode, will be readily apparent. for those skilled in the art, once protected with the present discovery.
Obviously, numerous modifications and variants of the present invention are possible in the clarity of the above teachings. It is therefore understood that within the scope of the amended claims, the invention may be practiced otherwise than as specifically described herein.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following is claimed as property.
Claims (20)
1. A compound of the formula I: or stereoisomer or pharmaceutically acceptable salt form thereof, characterized in that: one of D and D1 is selected from CN, C (= NRX1) NR12R13, NHC (= NR11) NR12R13, NR12CH (= NR1: L), C (0) NR12R13, and (CH2) t R12R13 and the other is H; R1 is selected from H, (CH2) rOR3, halo, C4-4 alkyl, (CH2) rNR4R4 ', (CH2) rC02H, (CH2) rC (= 0) R4, (CH2) rNR4C (= 0) R4, (CH2) rS02R5, and (CH2) rNR4S02R5; R2 is selected from H, = 0, C1-alkyl substituted with 0, 1, or 2 R7, C2-6 alkenyl substituted with 0, 1, or 2 R7, (CH2) rOR3, (CH2) rC (0) R4 ( CH2) rOC (0) R4 (CH2) rNRJRJ (CH2) rNR3C (0) R4 (CH2) rS02R5, (CH2) rNR3S02R5, carbocyclic residue C3-? 0 substituted with 0-2 R6; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6; R2a is absent; alternatively, R2 and R a may be present on adjacent carbon atoms and combine to form a benzene ring substituted with 0-2 R10 or a 5-6 membered aromatic heterocycle containing 0-2 heteroatoms selected from the group consisting of N , O and S and substituted with 0-2 R10; R3 and R3 'are independently selected from H, C? -4 alkyl, benzyl and phenyl; R3 and R3 'can be taken together to form a 5- or 6-membered ring substituted with 0-2 R6; R4 and R4 'are independently selected from H, OR3, C? -4 alkyl, phenyl and NR3R3'; R5 is selected from C? -4 alkyl, phenyl and NR3R3 ', - Z is selected from a bond, alkylene Ci-4, (CH2) r0 (CH2) r (CH2) 2NR3 (CH2) r, (CH2) rC (0) (CH2) r, (CH2) rC (O) O (CH2) r (CH2) 2OC (0) (CH2) r, (CH2) rC (0) NR3 (CH2) r / (CH2) 2NR3C (O) (CH2) r (CH2) 2OC (0) 0 (CH2) r, (CH2) 2OC (0) NR3 (CH2) r, (CH2) 2NR3C (O) O (CH2) r (CH2) 2NR3C (0) NR3 (CH2) r , (CH2) rS (0) p (CH2) r, (CH2) rS02NR3 (CH2) r (CH2) 2NR3S02 (CH2) r, and (CH2) 2NR3S02NR3 (CH2) r; A is selected from: C3-? 0 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; B is selected from: XY, NR3R3 ', C (0) NR3R3', S02NR3R3 ', benzyl substituted with 0-2 R6, C3-? 0 carbocyclic residue substituted with 0-2 Rs, and 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; X is selected from alkylene C? _4, -C (0) -, -C (O) CR3R3'-, -CR3R3'C (0) -, -C (0) 0-, -C (0) OCR3R3 '- , -CR3R3'C (0) O-, -0C (0) -, -OC (0) CR3R3'-, -CR3R3 '? C (0) -, -S (0) p-, -S (0) pCR3R3'-, -CR3R3'S (O) p-, -S (0) 2NR3-, -NR3S (0) 2-, -NR3S (0) 2CR3R3'-, -CR3R3'S (O) 2NR3-, -NR3S (0) 2NR3-, -C (0) NR3-, -NR3C (0) -, -C (O) NR3CR3R3'-, -NR3C (0) CR3R3'-, -CR3R3'C (0) NR3-, -CR3R3'NR3C (O) -, -NR3C (0) 0-, -OC (0) NR3-, -NR3C (0) NR3 -, -NR3-, -NR3CR3R3'-, -CR3R3'NR3-, O, -CR3R3 '? -, -OCR3R3'-, S, -CR3R3'S-, and -SCR3R3'-; And it is selected from: C? -alkyl substituted with 0-2 R6, C3-? 0 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; Rs is selected from H, OH, CF3, (CH2) nOR3, halo, C4_4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (0) R3, NR3C (0) R3', NR3C ( O) NR3R3 ', S02NR3R3', NR3S02NR3R3 ', NR3S02-C1-4alkyl, S02-phenyl, and NR3S02R8; R7 is selected from: C3-? 0 carbocyclic residue substituted with 0-2 R6; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; R8 is selected from: C3.10 carbocyclic residue substituted with 0-2 R9; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R9; R9 is selected from H, OH, (CH2) nOR3, halo, C? -4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (0) R3, NR3C (0) R3', NR3C (O ) NR3R3 ', S02NR3R3', NR3S02NR3R3 ', and NR3S02-C1-4alkyl; R10 is selected from H, OR3, halo, C1-4alkyl CN, N02, NR3R3 ', NR3C (0) R3', NR3C (0) OR3 ', NR3S02-phenyl, and NR3S02-C1-4alkyl; R10a is selected from H and C? -4 alkyl if it is a substituent on the nitrogen atom; R10a is selected from H, C? -4 alkyl, NR3R3 ', NR3C (0) R3', NR3C (0) OR3 ', NR3S02-phenyl, and NR3S02-C alquilo .4 alkyl if it is a substituent on the carbon atom; R 11 is selected from H, OH, C 1-6 alkyl, C 1-6 alkylcarbonyl / C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 6 - 0 aryloxy, aryloxycarbonyl C6-? O / C6-10 arylmethylcarbonyl, alkylsarbonyloxy Cj._4 alkoxycarbonyl C1-, arylcarbonyloxyC6-? Or alkoxycarbonyl C? _4, alkylaminocarbonyl C1-6, phenylaminocarbonyl, and alkoxycarbonyl Ci-4 phenyl; R12 is selected from H, C6-C6 alkyl and (CH2) n-phenyl; R13 is selected from H, C6_6 alkyl and (CH2) n-phenyl; n is selected from 0, 1, 2, and 3; m is selected from 0 and 1; p is selected from 0, 1, and 2; q is selected from 1, 2, 3, 4, and 5; Y, r is selected from 0, 1, and 2.
2. A compound according to claim 1, characterized in that: D is C (= NH) NH2; D1 is H; R1 is selected from H, (CH2) rOR3, halo, (CH2) rNRR4 ', (CH2) rC02H, (CH2) rC (= 0) R4, (CH2) rNR4C (= 0) R4, (CH2) rS02R5, and (CH2) rNHS02R5; R2 is selected from H, = 0, (CH2) rOR3, (CH2) rC (0) R4, (CH2) r0C (0) R4, (CH2) rNR3R3 ', (CH2) rNR3C (0) R4, (CH2) rS02R5, (CH2) rNR3S02R5, C3_10 carbocyclic residue substituted with 0-2 R6; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; R4 and R4 'are independently selected from H, OR3, C1-4 alkyl, and NR3R3'; R5 is selected from C C4 alkyl, »and NR3R3 '; Z is selected from a bond, C? -4 alkylene, (CH2) rC (O) (CH2) r, (CH2) rC (0) NR3 (CH2) r, (CH2) 2NR3C (0) (CH2) r, (CH2) 2OC (O) NR3 (CH2) r, (CH2) 2NR3C (0) 0 (CH2) r, (CH2) 2NR3C (0) NR3 (CH2) r, (CH2) rS (O) p (CH2) r, (CH2) rS02NR3 (CH2) r, (CH2) 2NR3S02 (CH2) r, and (CH2) 2NR3S02NR3 (CH2) r; Y, X is selected from alkylene C? -4, -C (O) -, -C (O) CR3R3'-, -CR3R3'C (0) -7-C (0) 0-, -C (0) OCR3R3 ' -, -CR3R3'C (0) O-, -0C (0) -, -OC (0) CR3R3'-, -CR3R3'0C (0) -, -S (0) p-, -S (0) pCR3R3 '-, -CR3R3'S (0) p-, -S (0) 2NR3-, -C (0) NR3-, -NR3C (0) -, -NR3C (0) 0-, -OC (0) NR3- , -NR3C (0) NR-, -NRJ -NR3CR3R3 '-CR3R3NR3-, O, -CR3R3'? -, and -OCR3R3 '
3. A compound according to claim 2, characterized in that: R1 is selected from H, OR3, (CH2) OR3, halo, NR4R4 ', (CH2) NR4R4', C (= 0) R4, (CH2) C (= 0) R4, NHC (= 0) R4, (CH2) ) NHC (= 0) R4, S02R5, (CH2) S02R5, NHS02R5, and (CH2) NHS02R5; R2 is selected from H, = 0, OR3, C (0) R4, (CH2) C (0) R4, 0C (0) R4, NRR4 ', NR3C (0) R4, and NR4S02R5; A is selected from: C5.6 carbocyclic residue substituted with 0-1 R6, and 5-6 member heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N and O substituted with 0-1 R6; B is selected from: Y, X-Y, and NR2R2a; And it is selected from one of the following carbocyclic and heterocyclic systems, which are substituted with 0-2 R4; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1, 2, 5-oxadiazole, 1, 3, 4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1, 2, 5-thiadiazole, 1,3,4-thiadiazole, 1 2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3-triazole, benzofuran, benzothiofuran, indole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, isoindazole, and benzothiadiazole; And you can also select from the following bicyclic heteroaryl ring systems: K is selected from O, S, NH, and N; X is selected from -CH2-, -C (0) -, -C (0) CHR3-, -CHR3C (0) -, -S (0) p-, -S (0) pCR3R3'-, -CHR3S ( 0) p-, -S (0) 2NR3-, -C (0) NR3-, -NR3C (0) -, -NR3-, -NR3CHR3-, and -CHR3NR3; R6 is selected from H, OH, CF3, (CH2) nOR3, halo, C? -4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (0) R3, NR3C (0) R3', S02NR3R3 ', S02-f enyl, NR3S02-C? _4 alkyl, and NR3S02R8; R8 is selected from: C3-6 carbocyclic residue substituted with 0-2 R9; and, 5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R9; R9 is selected from H, OH, (CH2) nOR3, halo, C? _4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (0) R3, NR3C (0) R3', NR3C (0) NR3R3 ', S02NR3R3', NR3S02NR3R3 ', and NR3S02-C? _4 alkyl; Y, p is 2
4. A compound according to claim 3, characterized in that: Z is selected from a bond, C al alkylene, 4, (CH 2) rC (0) (CH 2) r # (CH 2) rC (0) NR 3 (CH 2) r, (CH 2) 2 NR 3 C (O) (CH 2) r , (CH2) 2NR3C (0) NR3 (CH2) r, and (CH2) rS (CH2) r; X is selected from -CH2-, -C (O) -, -C (0) CHR3-, -CHR3C (0) -, -S (0) p-, -S (0) PCR3R3'-, -CHR3S ( 0) p-, -S (0) 2NR3-, -C (0) NR3-, and -NR3C (0) -; R6 is selected from H, OH, CF3, (CH2) pOR3, halo, C1-4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (0) R3, NR3C (0) R3', S02NR3R3 ' , S02-phenyl, and NR3S02-C? -4 / -m alkyl is 1; Y, r is selected from 0 and 1,
5. A compound according to claim 4, characterized in that: R3 and R3 'are independently selected from H and alkyl Z is selected from a bond, C4-4 alkylene, (CH2) rC (0) NR3 (CH2) r, (CH2) 2NR3C (0) (CH2) r, and (CH2) 2NR3C (O) NR3 (CH2) r; A is selected from phenyl substituted with 0-1 Rs and a 6-membered heterocyclic system containing 1 atom of N'y 0-1 atoms of 0 and substituted with 0-1 R6; X is selected from -CH2-, -S (0) p-, -S (0) PCR3R3'-, -S (0) 2NR3-, -C (0) NR3-, and; Y is selected from phenyl, i-propyl, quinolinyl, thiadizolyl, benzothiadiazolyl, thiophenyl, pyridyl, cyclohexyl, and naphthyl, each of which is substituted with 0-2 Rs; Y, n is selected from 0, 1, and 2.
«6. A compound according to claim 5, characterized in that: R3 and R3 'are independently selected from H and methyl; Z is selected from a bond, CH2, -CH2CH2-, -CH2CH2CH2- and -CH2CH2CH2CH2-; A is selected from phenyl substituted with 0-1 R6, and piperidinyl substituted with 0-1 R6; Y, n is 2
7. A compound according to claim 6, characterized in that the compound is selected from: N- (3-amidinophenyl) -N '- ((4- ((2-sulfonamido) phenyl) phenyl) -methyl) cycloheptylurea; N- (3-amidinophenyl) -N '- (1-benzylpiperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (1- (picolin-2-yl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (1- (picolin-3-yl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (1- (picolin-4-yl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (1- (a-phenethyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (1- ((phenyl) methane) sulfonyl) -piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (1- (phenyl) sulfonylpiperidin-4-yl) -cycloheptylurea; N- (3-amidinophenyl) -N '- (1- (quinolin-8-yl) sulfonylpiperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (1- (2-fluorophenyl) sulfonylpiperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (1- (4-acetamidophenyl) sulfonyl-piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (1- (2-aminophenyl) sulfonylpiperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (1- (3-aminophenyl) sulfonylpiperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (1- (4-aminophenyl) sulfonylpiperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (1- ((2-aminophenyl) methane) sulfonyl) -piperidin-4-yl) cycloheptylurea; N- (3-amidinesphenyl) -N 1 - (1- ((acetamido-phenyl) methane) -sulfonylpiperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (1- ((thiophen-2-yl) sulfonyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (1- ((5-chlorothiophen-2-yl) sulfonyl) -piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (1- ((5-carbomethoxythiophen-2-yl) sulfonyl) iperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (1- ((benzo-2, l-3-thiadiazo-4-yl) sulfonyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (1- ((cyclohexyl) sulfamido) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (1- ((isopropyl) sulfamido) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (1- ((phenyl) sulfamido) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (1- ((isopropyl) sulfonyl) piperidin-4-yl) cycloheptylurea; 'N- (3-amidinophenyl) -N' - (1- ((5-amino-4-methylthiazol-2-yl) sulfonyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (1- ((5-acetamido-4-methylthiazol-2-yl) sulfonyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (1- (6-carbomethoxyphenyl-sulfonyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (2-pyridylmethyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (3-pyridylmethyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (4-pyridylmethyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (phenyl-N 1' -methylsulfamido) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N1 - ((4-phenylsulfonylthiophen-2-yl) sulfonyl) -piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (4-pyridylmethylsulfonyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (thiophen-2-ylsulfonyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (4-fluorobenzylsulfonyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (2-pyridylsulfonyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (2-trifluoromethyl-phenylsulfonyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (2-phenylisopropylsulfonyl) piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- ((1- ((phenyl) -1,1-dimethyl) methane) sulfonyl) -piperidin-4-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (methyl ((phenyl-methane) carbamide) morpholin-3-yl)) cycloheptylurea; , N- (3-amidinophenyl) -N '- (methyl ((thiophen-2-yl) sulfonyl) morpholin-3-yl)) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (methyl ((phenyl-methane) sulfonyl) morpholin-3-yl)) cycloheptylurea; N- (3-amidinophenyl) -N '- ((N-benzyl) piperidin-3-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- ((N- (benzyl) sulfonyl) -piperidin-3-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- ((N- (thiophen-2-yl) sulfonyl) piperidin-3-yl) cycloheptylurea; N- (3-amidinophenyl) -N '- (4- (2-sulfonamido-phenyl) phenyl) cycloheptylurea; N- (3-amidinophenyl) -N 1 - (5- (2-sulfonamido-phenyl) pyridin-2-yl) cycloheptylurea; and, N- (3-amidinophenyl) -N 1 - (methyl (4- (2-sulfonamidophenyl) phenyl)) cycloheptylurea; or stereoisomers or pharmaceutically acceptable salt forms thereof.
8. A compound according to claim 1, characterized in that: n is 2; Y R and R a are on adjacent carbon atoms and combine to form a benzene ring substituted with 0-2 R10 or a 5-6 member aromatic heterocycle containing 0-2 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10a.
9. A compound according to claim 8, characterized in that the compound is of the formula II: II characterized in that ring N contains 0-2 N atoms and is substituted with 0-2 R10; Y, D is selected from CN, C (= NR11) NR12R13, NHC (= NRX1) NR12R13, NRJ "! CH (= NRiJ-), C (0) NR" R, and (CH2) tNR "R.
10. A compound according to claim 9, characterized in that: D is C (= NH) NH2; R1 is selected from H, (CH2) rOR3, halo, (CH2) rNR4R ', (CH2) rC02H, (CH2) rC (= 0) R4, (CH2) rNR4C (= 0) R4, (CH2) rS02R5, and (CH2) rNHS02R5; R4 and R4 'are independently selected from H, OR3, C1-4 alkyl, and NR3R3'; R5 is selected from C? -4 alkyl, and NR3R3 'Z is selected from a bond, C? -4 alkylene, (CH2) rC (0) (CH2) r, (CH2) rC (0) NR3 (CH2) r, (CH2) 2NR3C (0) (CH2) r, (CH2) 20C (O) NR3 (CH2) r, (CH2) 2NR3C (0) 0 (CH2) r, (CH2) 2NR3C (0) NR3 (CH2) r, (CH2) rS (O) p (CH2) r, and (CH2) rS02NR3 (CH2) r; Y, X is selected from alkylene C? -4, -C (0) -, -C (0) CR3R3'-, -CR3R3'C (0) -, -C (0) 0-, -C (0) OCR3R3 ' -, -CR3R3'C (O) 0-, -0C (0) -, -OC (0) CR3R3"-, -CR3R3'0C (0) -, -S (0) p-, -S (0) pCR3R3'-, -CR3R3'S (0) p-, -C (0) NR3-, -NR3C (0) -, -NR3C (0) 0-, -0C (0) NR3-, -NR3C (0) NR3- , -NR3-, -NR3CR3R3'-, -CR3R3'NR3-, 0, -CR3R3 '? -, and -OCR3R3'-.
11. A compound according to claim 10, characterized in that: Z is selected from a bond, C1-4alkylene, C (0) NR3 (CH2) r, S (0) 2, S (0) 2CH2, and (CH2) rS02NR3 (CH2) r; A is selected from phenyl substituted with 0-1 R6 and a 6-membered heterocyclic system containing an N atom and substituted with 0-1 R6; Y, X is selected from alkylene C? -4, -C (0) -, -C (O) CR3R3'-, -CR3R3'C (0) -, -S (0) p-, -S (0) pCR3R3 ' -, -C (0) NR3-, and, -NR3-.
12. A compound according to claim 11, characterized in that the compound is selected from: 1,2,4,5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -3H-2,4-benzodiazepin-3-one; 1,2,4,5-tetrahydro-2- (thiophen-2-yl) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -3H-2,4-benzodiazepin-3-one; 1,2,4,5-tetrahydro-2- ((phenyl) methane) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -7,8-dimethoxy-3H-2,4-benzodiazepin- 3-one; Y, 1,2,4,5-tetrahydro-2- (thiophen-2-yl) -sulfonyl) piperidin-4-yl) -4- (3-amidinophenyl) -7,8-dimethoxy-3H-2,4-benzodiazepine -3-one;
13. A pharmaceutical composition, characterized in that it comprises: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition, characterized in that it comprises: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition, characterized in that it comprises: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition, characterized in that it comprises: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 9 or a pharmaceutically acceptable salt thereof.
17. A method for treating or preventing a thromboembolic disorder, characterized in that it comprises: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
18. A method to treat or prevent a. thromboembolic disorder, characterized in that it comprises: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
19. A method for treating or preventing a thromboembolic disorder, characterized in that it comprises: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof.
20. A method for treating or preventing a thromboembolic disorder, characterized in that it comprises: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 9 or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US015684 | 1996-04-17 | ||
US647127 | 1996-05-09 | ||
US042532 | 1997-04-01 | ||
US08838246 | 1997-04-16 |
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MXPA98008586A true MXPA98008586A (en) | 2000-01-01 |
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