HRP20010737A2 - N-cyanomethylamides as protease inhibitors - Google Patents
N-cyanomethylamides as protease inhibitors Download PDFInfo
- Publication number
- HRP20010737A2 HRP20010737A2 HR20010737A HRP20010737A HRP20010737A2 HR P20010737 A2 HRP20010737 A2 HR P20010737A2 HR 20010737 A HR20010737 A HR 20010737A HR P20010737 A HRP20010737 A HR P20010737A HR P20010737 A2 HRP20010737 A2 HR P20010737A2
- Authority
- HR
- Croatia
- Prior art keywords
- alkyl
- compound
- benzamide
- substituted
- halo
- Prior art date
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- DFNYGALUNNFWKJ-UHFFFAOYSA-N aminoacetonitrile Chemical class NCC#N DFNYGALUNNFWKJ-UHFFFAOYSA-N 0.000 title abstract description 34
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 56
- 150000003839 salts Chemical class 0.000 claims abstract description 51
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims description 488
- 125000000217 alkyl group Chemical group 0.000 claims description 246
- -1 trimethylene, tetramethylene Chemical group 0.000 claims description 144
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 117
- 229910052739 hydrogen Inorganic materials 0.000 claims description 107
- 239000001257 hydrogen Substances 0.000 claims description 105
- 125000003118 aryl group Chemical group 0.000 claims description 101
- 239000000203 mixture Substances 0.000 claims description 99
- 125000005842 heteroatom Chemical group 0.000 claims description 91
- 239000002253 acid Substances 0.000 claims description 90
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 87
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 79
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 65
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 55
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 50
- 125000004432 carbon atom Chemical group C* 0.000 claims description 43
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 36
- 201000010099 disease Diseases 0.000 claims description 33
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 32
- 229910052799 carbon Inorganic materials 0.000 claims description 29
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 29
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 29
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 24
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 23
- 150000007513 acids Chemical class 0.000 claims description 23
- 125000001118 alkylidene group Chemical group 0.000 claims description 20
- 239000000651 prodrug Substances 0.000 claims description 20
- 229940002612 prodrug Drugs 0.000 claims description 20
- 125000001072 heteroaryl group Chemical class 0.000 claims description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
- 125000002723 alicyclic group Chemical group 0.000 claims description 17
- 125000000592 heterocycloalkyl group Chemical class 0.000 claims description 17
- 241001465754 Metazoa Species 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 15
- 150000002148 esters Chemical class 0.000 claims description 14
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- 102000005927 Cysteine Proteases Human genes 0.000 claims description 11
- 108010005843 Cysteine Proteases Proteins 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical class 0.000 claims description 10
- 230000009471 action Effects 0.000 claims description 9
- 108090000625 Cathepsin K Proteins 0.000 claims description 8
- 102000004171 Cathepsin K Human genes 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 7
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 230000007170 pathology Effects 0.000 claims description 6
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 claims description 6
- 208000001132 Osteoporosis Diseases 0.000 claims description 5
- 239000000556 agonist Substances 0.000 claims description 5
- 102000015694 estrogen receptors Human genes 0.000 claims description 5
- 108010038795 estrogen receptors Proteins 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- PAYGMRRPBHYIMA-UHFFFAOYSA-N sodium;trihydrate Chemical compound O.O.O.[Na] PAYGMRRPBHYIMA-UHFFFAOYSA-N 0.000 claims description 5
- 239000004305 biphenyl Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 125000006267 biphenyl group Chemical group 0.000 claims description 4
- 125000004956 cyclohexylene group Chemical group 0.000 claims description 4
- KOUXXQSBRWTPSF-UHFFFAOYSA-N n-[1-(cyanomethylamino)-4-methyl-1-oxopentan-2-yl]-3-(pyridin-2-ylcarbamoylamino)benzamide Chemical compound N#CCNC(=O)C(CC(C)C)NC(=O)C1=CC=CC(NC(=O)NC=2N=CC=CC=2)=C1 KOUXXQSBRWTPSF-UHFFFAOYSA-N 0.000 claims description 4
- ZVXVCSFLPDQOFS-UHFFFAOYSA-N n-[1-(cyanomethylamino)-4-methyl-1-oxopentan-2-yl]-4-(piperidin-4-ylcarbamoylamino)benzamide Chemical compound C1=CC(C(=O)NC(CC(C)C)C(=O)NCC#N)=CC=C1NC(=O)NC1CCNCC1 ZVXVCSFLPDQOFS-UHFFFAOYSA-N 0.000 claims description 4
- TYJLGELUBBAGKK-UHFFFAOYSA-N n-[1-(cyanomethylcarbamoyl)cyclohexyl]-4-(2-morpholin-4-yl-1,3-thiazol-4-yl)benzamide Chemical compound C=1C=C(C=2N=C(SC=2)N2CCOCC2)C=CC=1C(=O)NC1(C(=O)NCC#N)CCCCC1 TYJLGELUBBAGKK-UHFFFAOYSA-N 0.000 claims description 4
- HJOXUKZNYOVXDZ-UHFFFAOYSA-N n-[1-(cyanomethylcarbamoyl)cyclohexyl]-4-(2-piperazin-1-yl-1,3-thiazol-4-yl)benzamide Chemical compound C=1C=C(C=2N=C(SC=2)N2CCNCC2)C=CC=1C(=O)NC1(C(=O)NCC#N)CCCCC1 HJOXUKZNYOVXDZ-UHFFFAOYSA-N 0.000 claims description 4
- JVPVQZVJMIEJPE-UHFFFAOYSA-N n-[1-(cyanomethylcarbamoyl)cyclohexyl]-4-[2-(piperazin-1-ylmethyl)-1,3-thiazol-4-yl]benzamide Chemical compound C=1C=C(C=2N=C(CN3CCNCC3)SC=2)C=CC=1C(=O)NC1(C(=O)NCC#N)CCCCC1 JVPVQZVJMIEJPE-UHFFFAOYSA-N 0.000 claims description 4
- SIPOTAOXKMZPFX-UHFFFAOYSA-N n-[1-(cyanomethylcarbamoyl)cyclohexyl]-4-[2-(piperidin-4-ylamino)-1,3-thiazol-4-yl]benzamide Chemical compound C=1C=C(C=2N=C(NC3CCNCC3)SC=2)C=CC=1C(=O)NC1(C(=O)NCC#N)CCCCC1 SIPOTAOXKMZPFX-UHFFFAOYSA-N 0.000 claims description 4
- WIJNHFXLYZGIJV-UHFFFAOYSA-N n-[1-[(4-cyanooxan-4-yl)carbamoyl]cyclohexyl]-4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide Chemical compound C1CN(C)CCN1C1=NC(C=2C=CC(=CC=2)C(=O)NC2(CCCCC2)C(=O)NC2(CCOCC2)C#N)=CS1 WIJNHFXLYZGIJV-UHFFFAOYSA-N 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- OSXJMKADIOMXMP-IBGZPJMESA-N n-[(2s)-1-(cyanomethylamino)-4-methyl-1-oxopent-4-en-2-yl]-4-[2-(pyridin-4-ylamino)-1,3-thiazol-4-yl]benzamide Chemical compound C1=CC(C(=O)N[C@@H](CC(=C)C)C(=O)NCC#N)=CC=C1C1=CSC(NC=2C=CN=CC=2)=N1 OSXJMKADIOMXMP-IBGZPJMESA-N 0.000 claims description 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- KVKJSQQQFLTFKO-UHFFFAOYSA-N C1=CC(C(=O)NC(CC(C)C)C(=O)NCC#N)=CC=C1NC(=O)N1CCC(N(C)C)CC1 Chemical compound C1=CC(C(=O)NC(CC(C)C)C(=O)NCC#N)=CC=C1NC(=O)N1CCC(N(C)C)CC1 KVKJSQQQFLTFKO-UHFFFAOYSA-N 0.000 claims description 2
- NFGODEMQGQNUKK-UHFFFAOYSA-M [6-(diethylamino)-9-(2-octadecoxycarbonylphenyl)xanthen-3-ylidene]-diethylazanium;chloride Chemical group [Cl-].CCCCCCCCCCCCCCCCCCOC(=O)C1=CC=CC=C1C1=C2C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C21 NFGODEMQGQNUKK-UHFFFAOYSA-M 0.000 claims description 2
- KCNKJCHARANTIP-SNAWJCMRSA-N allyl-{4-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-but-2-enyl}-methyl-amine Chemical group C=1OC2=CC(OC/C=C/CN(CC=C)C)=CC=C2C=1C1=CC=C(Br)C=C1 KCNKJCHARANTIP-SNAWJCMRSA-N 0.000 claims description 2
- 125000004980 cyclopropylene group Chemical group 0.000 claims description 2
- VULXDFLCVUUTAQ-FQEVSTJZSA-N n-[(2s)-1-[(1-cyanocyclopropyl)amino]-4-methyl-1-oxopentan-2-yl]-4-[2-(piperazin-1-ylmethyl)-1,3-thiazol-4-yl]benzamide Chemical compound N([C@@H](CC(C)C)C(=O)NC1(CC1)C#N)C(=O)C(C=C1)=CC=C1C(N=1)=CSC=1CN1CCNCC1 VULXDFLCVUUTAQ-FQEVSTJZSA-N 0.000 claims description 2
- ZKTHKRQXMDNCKL-UHFFFAOYSA-N n-[1-(cyanomethylamino)-4-methyl-1-oxopentan-2-yl]-3-(3-morpholin-4-ylpropylcarbamoylamino)benzamide Chemical compound N#CCNC(=O)C(CC(C)C)NC(=O)C1=CC=CC(NC(=O)NCCCN2CCOCC2)=C1 ZKTHKRQXMDNCKL-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000002852 cysteine proteinase inhibitor Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 2
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 359
- 238000005160 1H NMR spectroscopy Methods 0.000 description 173
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 68
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 62
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 59
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 56
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 30
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 27
- 239000007787 solid Substances 0.000 description 27
- 125000006239 protecting group Chemical group 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- 150000003254 radicals Chemical class 0.000 description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 239000011347 resin Substances 0.000 description 16
- 229920005989 resin Polymers 0.000 description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- GQHJCLXWRQHKPT-SSDOTTSWSA-N (2R)-2-amino-N-(cyanomethyl)-4-methylpentanamide Chemical compound C(#N)CNC([C@H](N)CC(C)C)=O GQHJCLXWRQHKPT-SSDOTTSWSA-N 0.000 description 13
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 125000004429 atom Chemical group 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 150000003842 bromide salts Chemical class 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- ZZUXTLHHXTUBKA-UHFFFAOYSA-N 3-amino-n-[1-(cyanomethylamino)-4-methyl-1-oxopentan-2-yl]benzamide Chemical compound N#CCNC(=O)C(CC(C)C)NC(=O)C1=CC=CC(N)=C1 ZZUXTLHHXTUBKA-UHFFFAOYSA-N 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000012131 assay buffer Substances 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000012085 test solution Substances 0.000 description 8
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
- XFKYKTBPRBZDFG-UHFFFAOYSA-N 2-aminoacetonitrile;hydrochloride Chemical compound Cl.NCC#N XFKYKTBPRBZDFG-UHFFFAOYSA-N 0.000 description 7
- 238000010790 dilution Methods 0.000 description 7
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- 230000000694 effects Effects 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 125000000923 (C1-C30) alkyl group Chemical group 0.000 description 6
- OJPFWONQJWTJTI-UHFFFAOYSA-N 4-amino-N-[1-(cyanomethylamino)-4-methyl-1-oxopentan-2-yl]benzamide Chemical compound N#CCNC(=O)C(CC(C)C)NC(=O)C1=CC=C(N)C=C1 OJPFWONQJWTJTI-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 108090000712 Cathepsin B Proteins 0.000 description 6
- 102000004225 Cathepsin B Human genes 0.000 description 6
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical class N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
- SKOLWUPSYHWYAM-UHFFFAOYSA-N carbonodithioic O,S-acid Chemical compound SC(S)=O SKOLWUPSYHWYAM-UHFFFAOYSA-N 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 230000001575 pathological effect Effects 0.000 description 6
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- UPUZGXILYFKSGE-UHFFFAOYSA-N quinoxaline-2-carboxylic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CN=C21 UPUZGXILYFKSGE-UHFFFAOYSA-N 0.000 description 1
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- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- JNDZDNXOXWGQII-UHFFFAOYSA-N tert-butyl 4-[4-[(4-methoxycarbonylpiperidin-1-yl)methyl]-1,3-thiazol-2-yl]piperidine-1-carboxylate Chemical compound C1CC(C(=O)OC)CCN1CC1=CSC(C2CCN(CC2)C(=O)OC(C)(C)C)=N1 JNDZDNXOXWGQII-UHFFFAOYSA-N 0.000 description 1
- GPCSKWXTSPEMSU-UHFFFAOYSA-N tert-butyl 4-[[2-(4-methoxycarbonylanilino)-1,3-thiazol-4-yl]methyl]piperazine-1-carboxylate Chemical compound C1=CC(C(=O)OC)=CC=C1NC1=NC(CN2CCN(CC2)C(=O)OC(C)(C)C)=CS1 GPCSKWXTSPEMSU-UHFFFAOYSA-N 0.000 description 1
- JBKRAGACGOPWFP-UHFFFAOYSA-N tert-butyl 4-carbamothioylpiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1 JBKRAGACGOPWFP-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
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- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
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- C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Description
Izum
Ova prijava se odnosi na spojeve i pripravke za liječenje bolesti povezanih s djelovanjem cistein proteaze, osobito bolesti povezanih s djelovanjem katepsina B, K, L ili S.
Opis stanja
Cistein proteaze predstavljaju razred peptidaza koje imaju cisteinski ostatak na katalitičkom mjestu enzima. Cistein proteaze su povezane s normalnom razgradnjom i procesiranjem proteina. Međutim, odstupanje od normalnog djelovanja cistein proteaza, npr. zbog povećane ekspresije ili pojačane aktivacije, može dovesti do patoloških posljedica. Zbog ovoga, neke cistein proteaze su povezane s brojnim bolesnim stanjima, uključujući artritis, mišićnu distrofiju, upalu, tumorsku invaziju, glomerulonefritis, malariju, bolest periodonta, metakromatsku leukodistrofiju i druge. Na primjer, povišene vrijednosti katepsina B i preraspodjela enzima nalaze se kod tumora, upućujući na ulogu ovog enzima u tumorskoj invaziji i metastaziranju. Usto, poremećeno djelovanje katepsina B dovodi se u vezu s bolestima kao što su reumatoidni artritis, osteoartritis, infekcije s pneumocistis carinii, akutni pankreatitis, upalna bolest dišnih puteva, te poremećaj kostiju i zglobova.
Jaka ekspresija katepsina K u osteoklastima i multinuklearnim stanicama koje su srodne osteoklastima i njegovo snažno kolagenolitičko djelovanje upućuju na uključenost enzima u resorpciju kosti posredovanu osteoklastima, a time i u koštane poremećaje poput onih koji se javljaju u osteoporozi. Pored toga, ekspresija katepsina K u plućima i njegovo elastinolitičko djelovanje upućuju na ulogu tog enzima i u plućnim bolestima.
Katepsin L je povezan s normalnom lizosomskom proteolizom, kao i s nekim bolesnim stanjima, uključujući, bez ograničenja, metastaze melanoma. Katepsin S je povezan s Alzheimerovom bolešću i nekim autoimunim bolestima, uključujući, bez ograničenja, juvenilni dijabetes, multiplu sklerozu, pemfigus vulgaris, Gravesovu bolest, mijasteniju gravis, sistemski eritematodni lupus, reumatoidni artritis i Hashimotov tireoiditis; alergijske poremećaje, uključujući, bez ograničenja, astmu; kao i alogene imunosne odgovore, uključujući, bez ograničenja, odbacivanje presadaka organa ili presadaka tkiva.
Obzirom na broj bolesti u kojima je uočeno kako pojačano djelovanje cistein proteaze doprinosi patologiji i/ili znakovlju bolesti, molekule za koje je dokazano kako sprječavaju djelovanje ovog razreda enzima, osobito molekule koje su inhibitori katepsina B, K, L i/ili S, će biti korisne kao sredstva za liječenje.
Kratak opis izuma
Prijava se odnosi na spojeve Formule I:
[image]
u kojima:
R1 je skupina Formule (a) ili (b):
[image]
pri čemu:
X1 i X2 su neovisno -C(O)- ili -CH2S(O)2-;
R5 i R6 su neovisno vodik, (C1-6)alkil ili kako je dolje definirano;
R7 i R8 su neovisno vodik, (C1-6)alkil ili kako je dolje definirano;
R9 i R10 su neovisno (i) (C1-6)alkil neobavezno supstituiran s cijano, halo, halo-supstituirani (C1-3)alkil, nitro, -NR12R12, -NR12C(O)OR12, -NR12C(O)NR12R12, -NR12C(NR12)NR12R12, -OR12, -SR12, -C(O)OR12, -OC(O)R12, -C(O)NR12R12, -S(O)2NR12R12, -P(O)(OR12)OR12, -OP(O)(OR12)OR12, -NR12C(O)R13, -S(O)R13, -S(O)2R13, -C(O)R13, -OR14, -SR14, -S(O)R14, -S(O)2R14, -C(O)R14, -C(O)OR14, -OC(O)R14, -NR14R15, -NR15C(O)R14, -NR15C(O)OR14, -C(O)NR14R15, -S(O)2NR14R15, -NR15C(O)NR14R15 ili -NR15C(NR15)NR14R15, pri čemu je R12 pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil, R13 je (C1-6)alkil ili halo-supstituirani(C1-3)alkil, R14 je (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, (C9-12) policikloaril(C0-6)alkil ili hetero(C8-12)policikloaril(C0-6)alkil, R15 je vodik ili (C1-6)alkil, pri čemu je unutar R14 spomenuti cikloalkilni, heterocikloalkilni, arilni, heteroarilni, policikloarilni ili heteropolicikloarilni prsten neobavezno supstituiran skupinom odabranom između -R16, -X3OR16, -X3SR16, -X3S(O)R16, -X3S(O)2R16, -X3C(O)R16, -X3C(O)OR16, -X3OC(O)R16, -X3NR16R17, -X3NR17C(O)R16, -X3NR17C(O)OR16, -X3C(O)NR16R17, -X3S(O)2NR16R17, -X3NR17C(O)NR16R17 ili -X3NR17C(NR17)NR16R17, pri čemu je X3 veza ili (C1-6)alkilen, R16 je vodik ili (C1-6)alkil, a R17 je (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, (C9-12)policikloaril(C0-6)alkil ili hetero(C8-12)policikloaril(C0-6)alkil, ili (ii) skupina odabrana između (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, (C9-12)policikloaril(C0-6)alkil i hetero(C8-12)policikloaril(C0-6)alkil, pri čemu je spomenuti cikloalkilni, heterocikloalkilni, arilni, heteroarilni, policikloarilni ili heteropolicikloarilni prsten neobavezno supstituiran skupinom odabranom između -R16, -X3OR16, -X3SR16, -X3S(O)R16, -X3S(O)2R16, -X3C(O)R16, -X3C(O)OR16, -X3OC(O)R16, -X3NR16R17, -X3NR17C(O)R16, -X3NR17C(O)OR16, -X3C(O)NR16R17, -X3S(O)2NR16R17, -X3NR17C(O)NR16R17 ili -
X3NR17C(NR17)NR16R17, pri čemu su X3, R16 i R17 kao što su gore definirani; pri čemu unutar R9 i/ili R10 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu su X3, R12 i R13 kao što su gore definirani; ili
R9 zajedno s R7 i/ili R10 zajedno s R8 tvore trimetilen, tetrametilen ili fenilen-1,2-dimetilen, neobavezno supstituiran s hidroksi, okso, (C1-4)alkil ili metilen; ili
R9 i R5 zajedno s ugljikovim atomom na koji su oba vezani i/ili R10 i R6 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen; a
R11 je -X4X5R18, pri čemu je X4 -C(O)-, -C(O)C(O)- ili -S(O)2-, X5 je veza, -O- ili –NR19-, pri čemu je R19 vodik ili (C1-6)alkil, R18 je (i) (C1-6)alkil neobavezno
supstituiran s cijano, halo, halo-supstituirani (C1-3)alkil, nitro, -NR14R14, -NR14C(O)OR14, -NR14C(O)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(O)OR14, -C(O)NR14R14, -S(O)2NR14R14, -P(O)(OR14)OR14, -OP(O)(OR14)OR14, -NR14C(O)R15, -S(O)R15, -S(O)2R15, -C(O)R15, -OR20, -SR20, -S(O)R20, -S(O)2R20, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -NR20R21, -NR21C(O)R20, -NR21C(O)OR20, -NR21C(O)NR20R21 ili -NR21C(NR21)NR20R21, pri čemu su R14 i R15 kako je gore definirano, R20 je (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, (C9-12)policikloaril(C0-6)alkil ili hetero(C8-12)policikloaril(C0-6)alkil, R21 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil, ili (ii) (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, difenil(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, dihetero(C5-6)aril(C0-6)alkil, (C9-12)policikloaril(C0-6)alkil ili hetero(C8-12)policikloaril(C0-6)alkil, pri čemu spomenuti cikloalkilni, heterocikloalkilni, arilni, difenilni, heteroarilni, diheteroarilni, policikloarilni ili heteropolicikloarilni prsten može biti supstituiran s –R22, -X3OR22, -X3SR22, -X3S(O)R22, -X3S(O)2R22, -X3C(O)R22, -X3C(O)OR22, -X3C(O)NR22R23, -X3NR22R23, -X3NR23C(O)R22, -X3NR23C(O)OR22, -X3NR23S(O)2R22-X3NR23C(O)NR22R23 ili -X3NR23C(NR23)NR22R23, pri čemu je X3 kako je gore definirano, R22 je(C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, (C9-12)policikloaril(C0-6)alkil ili hetero(C8-12)policikloaril(C0-6)alkil, R23 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil; pri čemu unutar R11 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu su X3, R12 i R13 kao što su gore definirani;
R2 je vodik ili (C1-6)alkil;
R3 je vodik, (C1-6)alkil ili kako je dolje definirano; a
R4 je (i) cijano, -C(O)OR12 ili (C1-6)alkil, pri čemu je spomenuti alkil neobavezno supstituiran s cijano, halo, halo-supstituirani (C1-3)alkil, nitro, -NR12R12, -NR12C(O)OR12, -NR12C(O)NR12R12, -NR12C(NR12)NR12R12, -OR12, -SR12, -C(O)OR12, -O(C)OR12, -C(O)NR12R12, -S(O)2NR12R12, -P(O)(OR12)OR12, -OP(O)(OR12)OR12, -NR12C(O)R13, -S(O)R13, -S(O)2R13, -C(O)R13, -OR14, -SR14, -S(O)R14, -S(O)2R14, -C(O)R14, -C(O)OR14, -OC(O)R14, -NR14R15, -NR15C(O)R14, -NR15C(O)OR14, -C(O)NR14R15, -S(O)2NR14R15, -NR15C(O)NR14R15 ili -NR15C(NR15)NR14R15, pri čemu su R12, R13 i R14 kao što je gore definirano, ili (ii) skupina odabrana između (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, (C9-12)policikloaril(C0-6)alkil i hetero(C8-12)policikloaril(C0-6)alkil, pri čemu je spomenuti cikloalkilni, heterocikloalkilni, arilni, heteroarilni, policikloarilni ili heteropolicikloarilni prsten neobavezno supstituiran sa skupinom odabranom između -R16, -X3OR16, -X3SR16, -X3S(O)R16, -X3S(O)2R16, -X3C(O)R16, -X3C(O)OR16, -X3OC(O)R16, -X3NR16R17, -X3NR17C(O)R16, -X3NR17C(O)OR16, -X3C(O)NR16R17, -X3S(O)2NR16R17, -X3NR17C(O)NR16R17 ili -X3NR17C(NR17)NR16R17, pri čemu su X3, R16 i R17 kako je gore definirano, pri čemu unutar R4 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu su X3, R12 i R13 kao što su gore definirani, ili
R4 zajedno s R2 tvore trimetilen, tetrametilen ili fenilen-1,2-dimetilen, neobavezno supstituiran s hidroksi, okso, (C1-4)alkil ili metilen; ili
R4 i R3 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen, pri čemu je spomenuti cikloalkilen ili heterocikloalkilen neobavezno supstituiran s 1 do 3 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu su X3, R12 i R13 kao što su gore definirani; i N-oksidni derivati, prolijek derivati, zaštićeni derivati, pojedinačni izomeri i smjese izomera; i njihove farmaceutski prihvatljive soli.
U drugom posebnom obliku, ovaj izum se odnosi na spojeve Formule II:
[image]
pri čemu:
X1 je odabran između -C(O)-, -S(O)-, -C(S)-, -S(O)2- i -P(O)2-;
R1 i R2 su neovisno vodik ili (C1-6)alkil;
R3 i R4 su neovisno vodik ili (C1-6)alkil, ili R3 i R4 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen;
R5 i R6 su neovisno vodik ili (C1-6)alkil, ili R5 i R6 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen; a
R7 je –X2X3R9, pri čemu je X2 -C(O)-, -S(O)-, -C(S)-, -S(O)2- ili -P(O)2-, X3 je veza, -O- ili -NR10-, pri čemu je R10 vodik ili (C1-6)alkil, R9 je (C3-6)cikloalkil(C0-6)alkil, hetero(C3-6)cikloalkil(C0-6)alkil, fenil(C0-6)alkil ili hetero(C5-6)aril(C0-6)alkil, pri čemu je unutar R9 spomenuti cikloalkil, heterocikloalkil, fenil ili heteroaril supstituiran s -R12, -X4NR11R12, -X4NR11C(O)R12, -X4NR11C(O)OR12, -X4NR11C(O)NR11R12, -X4NR11C(NR11)NR11R12, -X4OR12, -X4SR12, -X4S(O)R12, -X4S(O)2R12, -X4C(O)R12, -X4C(O)OR12, -X4OC(O)R12, -X4C(O)NR11R12, -X4OC(O)NR11R12, -X4S(O)2NR11R12, -X4P(O)(OR11)OR12 ili -X4OP(O)(OR11)OR12, pri čemu je X4 veza ili (C1-6)alkilen, R11 je pri svakoj pojavi vodik ili (C1-6)alkil, a R12 je (C3-6)cikloalkil(C0-6)alkil, hetero(C3-6)cikloalkil(C0-6)alkil, fenil(C0-6)alkil ili hetero(C5-6)aril(C0-6)alkil, pri čemu je unutar R12 spomenuti cikloalkil, heterocikloalkil, fenil ili heteroaril supstituiran s –R13, -X4NR11R13, -X4NR11C(O)R13, -X4NR11C(O)OR13, -X4NR11C(O)NR11R13, -X4NR11C(NR11)NR11R13, -X4OR13, -X4SR13, -X4S(O)R13, -X4S(O)2R13, -X4C(O)R13, -X4C(O)OR13, -X4OC(O)R13, -X4C(O)NR11R13, -X4OC(O)NR11R13, -X4S(O)2NR11R13, -X4P(O)(OR11)OR13 ili -X4OP(O)(OR11)OR13, pri čemu su X4 i R11 kako su gore definirani, R13 je (C3-6)cikloalkil(C0-6)alkil, hetero(C3-6)cikloalkil(C0-6)alkil, fenil(C0-6)alkil ili hetero(C5-6)aril(C0-6)alkil, pri čemu unutar R7 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(O)(OR5)OR14, -X5OP(O)(OR5)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 i -X5C(O)R15, pri čemu je X5 veza ili (C1-6)alkilen, R14 je pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil; R15 je (C1-6)alkil ili halo-supstituirani (C1-3)alkil; i N-oksidni derivati, prolijek derivati, zaštićeni derivati, pojedinačni izomeri i smjese izomera; i njihove farmaceutski prihvatljive soli.
Treći aspekt izuma je farmaceutski pripravak koji sadrži spoj Formule I ili njegov N-oksidni derivat, prolijek derivat, pojedinačni izomer ili smjesu izomera, ili njihovu farmaceutski prihvatljivu sol u smjesi s jednim ili više prikladnih ekscipijensa.
Četvrti aspekt izuma je postupak za liječenje bolesti u životinje u koje inhibiranje cistein proteaze može spriječiti, zaustaviti ili ublažiti patologiju i/ili znakovlje bolesti, a taj postupak obuhvaća primjenu na životinju terapijski učinkovite količine spoja Formule I ili njegovog N-oksidnog derivata, prolijek derivata, pojedinačnog izomera ili smjese izomera, ili njihovih farmaceutski prihvatljivih soli.
Peti aspekt izuma su postupci za pripravu spojeva Formule I i njihovih N-oksidnih derivata, prolijek derivata, zaštićenih derivata, pojedinačnih izomera ili smjese izomera, ili njihovih farmaceutski prihvatljivih soli, kakvi su opisani u “Detaljnom opisu izuma”.
Detaljan opis izuma
Definicije:
Ukoliko nije drugačije naznačeno, slijedeći izrazi korišteni u specifikaciji i zahtjevima određeni su za potrebe ove Prijave, a imaju slijedeća značenja:
"Aliciklički" označuje spoj koji ima ugljikove atome poredane u strukturu zatvorenog nearomatskog prstena, ima svojstva slična alifaticima i može biti zasićen ili djelomično nezasićen s dvije ili više dvostrukih ili trostrukih veza.
"Alifatski" označuje spoj koji ima ugljikove atome u nerazgranatom ili razgranatom lancu i može biti zasićen ili djelomično nezasićen s dvije ili više dvostrukih i trostrukih veza.
"Alkil" samostalno označuje nerazgranati ili razgranati, zasićeni ili nezasićeni alifatski radikal s naznačenim brojem ugljikovih atoma (na pr., (C1-6)alkil uključuje metil, etil, propil, izopropil, butil, sek-butil, izobutil, terc-butil, vinil, alil, 1-propenil, izopropenil, 1-butenil, 2-butenil, 3-butenil, 2-metilalil, etinil, 1-propinil, 2-propinil i druge). Alkil kao dio većeg radikala (na pr. kao arilalkil) označuje nerazgranati ili razgranati, zasićeni ili nezasićeni alifatski dvovaljani radikal s naznačenim brojem atoma ili, kada ima 0 atoma, označuje vezu (na pr. (C0-3)alkil u (C3-12)cikloalkil(C0-3)alkil znači vezu, metilen, etilen, trimetilen, 1-metiletilen i slično).
"Alkilen", ako nije drugačije naznačeno, označuje nerazgranati ili razgranati, zasićeni ili nezasićeni, alifatski dvovaljani radikal s naznačenim brojem ugljikovih atoma (na pr., (C1-6 alkilen uključuje metilen (-CH2-), etilen (-CH2CH2-), trimetilen (-CH2CH2CH2-), 2-metiltrimetilen (-CH2CH(CH3)CH2-), tetrametilen (-CH2CH2CH2CH2-), 2-butenilen (-CH2CH=CHCH2-), 2-metiltetrametilen (-CH2CH(CH3)CH2CH2-), pentametilen (-CH2CH2CH2CH2CH2-) i slično). Na primjer, prikazan je primjer u kojem je R5 vodik, a R9 zajedno s R7 tvori neobavezno supstituirani trimetilen:
[image]
u kojem je R neobavezna hidroksi ili okso skupina, a X1 i R11 su kao što su definirani u Sažetku izuma.
"Alkiliden" označuje nerazgranati ili razgranati, zasićeni ili nezasićeni, alifatski dvovaljani radikal s naznačenim brojem ugljikovih atoma (na pr. (C1-6)alkiliden uključuje metilen (=CH2), etiliden (=CHCH3), izopropiliden (=C(CH3)2), propiliden (=CHCH2CH3), aliliden (=CHCH=CH2), i slično).
"Amino" označuje radikal -NH2. Ako nije drugačije naznačeno, spojevi izuma koji sadrže amino dijelove uključuju i njihove zaštitne derivate. Prikladne zaštitne skupine za amino dijelove uključuju acetil, terc-butoksikarbonil, benziloksikarbonil i slično.
"Životinjski" uključuje ljude i druge sisavce (na pr., pse, mačke, kuniće, stoku, konje, ovce, goveda, svinje, jelene itd.) i nesisavce (na pr., ptice itd.).
"Aril" označuje monociklički ili biciklički prstenski sklop (stopljen ili vezan jednostrukom vezom) koji sadrži naznačeni ukupni broj ugljikovih atoma prstena, pri čemu je svaki prsten sastavljen od 6 ugljikovih atoma prstena i aromatski je, ili kada je stopljen s drugim prstenom tvori aromatski sklop prstena. Na primjer, (C6-12)aril uključuje fenil, naftil i bifenilil.
"Aromatski" označuje spoj u kojem atomi koji ga tvore oblikuju nezasićeni prstenski sustav, svi atomi u prstenskom sustavu su sp2 hibridizirani, a ukupan broj pi elektrona je jednak 4n+2.
"Karbamoil" označuje radikal -C(O)NH2. Ako nije drugačije naznačeno, spojevi izuma koji sadrže karbamoilne dijelove uključuju i njihove zaštićene derivate. Prikladne zaštitne skupine za karbamoilne dijelove uključuju acetil, terc-butoksikarbonil, benziloksikarbonil i slično, a unutar područja izuma potpadaju i nezaštićeni i zaštićeni derivati.
"Karboksi" označuje radikal -C(O)OH. Ako nije drugačije naznačeno, spojevi izuma koji sadrže karboksi dijelove uključuju i njihove zaštićene derivate. Prikladne zaštitne skupine za karboksi dijelove uključuju benzil, terc-butil i slično.
"Cikloalkil" označuje zasićeni ili djelomično nezasićeni monociklički prsten, biciklički sklop prstena (izravno vezanih jednostrukom vezom ili stopljenih) ili premošteni policiklički sklop prstena koji sadrži naznačeni broj ugljikovih atoma prstena, i bilo koji njihov karbociklički ketonski, tioketonski ili iminoketonski derivat (na pr., (C3-12)cikloalkil uključuje ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheksenil, 2,5-cikloheksadienil, bicikloheksilil, ciklopentilcikloheksil, biciklo[2.2.2] oktil, adamantan-1-il, dekahidronaftalenil, oksocikloheksil, dioksocikloheksil, tiocikloheksil, 2-oksobiciklo[2.2.1]hept-1-il, itd.).
"Cikloalkilen" označuje zasićeni ili djelomično nezasićeni monociklički prsten ili premošteni policiklički sklop prstena koji sadrži naznačeni broj ugljikovih atoma prstena, i bilo koji njihov karbociklički ketonski, tioketonski ili iminoketonski derivat Na primjer, slučaj kada R9 i R5 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen uključuje, bez ograničenja, slijedeće:
[image]
pri čemu su X1 i R7 definirani kao u Sažetku izuma.
"Bolest" specifično uključuje svako nezdravo stanje životinje ili njezinog dijela, uključujući i nezdravo stanje koje može biti uzrokovano ili povezano s medicinskim ili veterinarskim liječenjem te životinje, tj. “nuspojavu” takvog liječenja.
"Gvanidino" označuje radikal -NHC(NH)NH2. Ako nije drugačije naznačeno, spojevi izuma koji sadrže guanidinske dijelove uključuju i njihove zaštićene derivate. Prikladne zaštitne skupine za amino dijelove uključuju acetil, terc-butoksikarbonil, benziloksikarbonil i slično.
"Halo" označuje fluoro, kloro, bromo ili jodo.
"Halo-supstituirani alkil", kao skupina ili dio skupine, označuje "alkil" supstituiran jednim ili više "halo" atoma, u značenju definiranom u ovoj Prijavi. Halo-supstituirani alkil uključuje haloalkil, dihaloalkil, trihaloalkil, perhaloalkil i slično (na pr. halo-supstituirani (C1-3)alkil uključuje klorometil, diklorometil, difluorometil, trifluorometil, 2,2,2-trifluoroetil, perfluoroetil, 2,2,2-trifluoro-1,1-dikloroetil i slično).
"Heteroaril" označuje aril, kao što je definiran u ovoj Prijavi, s time da su jedan ili više ugljikovih atoma prstena zamijenjeni heteroatomskim dijelom odabranim između -N=, -NR-, -O- ili -S-, pri čemu R je vodik, (C1-6)alkil ili zaštitna skupina, a svaki sadržani prsten sastoji se od 5 do 6 atoma-članova prstena. Na primjer, hetero(C5-12) aril, u značenju u kojem se koristi u ovoj Prijavi, uključuje benzofuril, benzooksazolil, benzotiazolil, [2,4’] bipiridinilil, karbazolil, karbolinil, kromenil, cinolinil, furazanil, furil, imidazolil, indazolil, indolil, indolizinil, izobenzofuril, izokromenil, izooksazolil, izokvinolil, izotiazolil, naftiridinil, oksazolil, perimidinil, 2-fenilpiridil, ftalazinil, pteridinil, purinil, pirazinil, piradazinil, pirazolil, piridil, pirimidinil, pirolizinil, pirolidinil, pirolil, piranil, kvinazolinil, kvinolizinil, kvinolil, kvinoksalinil, tetrazolil, tiazolil, 4-tiazol-4-ilfenil, tienil, ksantenil i slično. Prikladne zaštitne skupine uključuju terc-butoksikarbonil, benziloksikarbonil, benzil, 4-metoksibenzil, 2-nitrobenzil i slično.
"Heterocikloalkil" označuje cikloalkil, kako je ovdje definiran, s time da su jedan ili više ugljikovih atoma prstena zamijenjeni heteroatomskim dijelom odabranim između -N=, -NR-, -O-, -S- ili -S(O)2, pri čemu R je vodik, (C1-6)alkil ili zaštitna skupina, i bilo koji njihov karbociklički ketonski, tioketonski ili iminoketonski derivat (na pr. izraz hetero(C5-12)cikloalkil uključuje [1,4’]bipiperidinilil, dihidrooksazolil, morfolinil, 1-morfolin-4-ilpiperidinil, piperazinil, piperidil, pirazolidinil, pirazolinil, pirolinil, pirolidinil, kvinuklidinil i slično). Prikladne zaštitne skupine uključuju terc-butoksikarbonil, benziloksikarbonil, benzil, 4-metoksibenzil, 2-nitrobenzil i slično. Na primjer, spoj Formule I u kojem je R1 piperidin-4-ilkarbonil može postojati kao nezaštićeni ili kao zaštićeni derivat, na pr. gdje je R1 1-terc-butoksikarbonilpiperidin-4-ilkarbonil, pri čemu oba ta derivata potpadaju u područje izuma.
"Heterocikloalkilen" označuje cikloalkilen, kao što je definiran u ovoj Prijavi, s time da su jedan ili više ugljikovih atoma prstena zamijenjeni heteroatomskim dijelom odabranim između -N=, -NR-, -O-, -S- ili -S(O)2, pri čemu je R vodik ili (C1-6)alkil. Na primjer, slučaj kada R3 i R4 zajedno s ugljikovim atomom na koji su oba vezani tvore hetero(C3-8)cikloalkilen uključuje, bez ograničenja, slijedeće:
[image]
pri čemu je R vodik, (C1-6)alkil ili zaštitna skupina, a R2 je definiran kao u Sažetku izuma.
"Heteropolicikloaril" označuje policikloaril, kako je ovdje definiran, osim što su jedan ili više ugljikovih atoma prstena zamijenjeni heteroatomskim dijelom odabranim između -N=, -NR-, -O-, -S- ili -S(O)2-, pri čemu R je vodik, (C1-6)alkil ili zaštitna skupina, i bilo koji njihov karbociklički ketonski, tioketonski ili iminoketonski derivat (na pr., hetero(C8-12)policikloaril uključuje 3,4-dihidro-2H-kvinolinil, 5,6,7,8-tetrahidrokvinolinil, 3,4-dihidro-2H-[1,8]naftiridinil, morfolinilpiridil, piperidinilfenil, 1,2,3,4,5,6-heksahidro-[2,2’]bipiridinilil, 2,4-diokso-3,4-dihidro-2H-kvinazolinil, 3-okso-2,3-dihidrobenzo[1,4]oksazinil itd.).
"Heteroatomski dio" uključuje -N=, -NR-, -O-, -S- ili -S(O)2-, pri čemu R je vodik, (C1-6)alkil ili zaštitna skupina.
"Hidroksi" označuje radikal -OH. Ako nije drugačije naznačeno, spojevi izuma koji sadrže hidroksi radikale uključuju i njihove zaštićene derivate. Prikladne zaštitne skupine za hidroksi dijelove uključuju benzil i slične. Na primjer, spoj Formule I pri čemu R9 sadrži hidroksi dio postoji kao nezaštićeni ili zaštićeni derivat, na pr., pri čemu je R9 benziloksibenzil, a oba ta derivata pripadaju području izuma.
"Iminoketonski derivat" označuje derivat koji sadrži dio -C(NR)-, pri čemu je R vodik ili (C1-6)alkil.
"Izomeri" označuju spojeve Formule I koji imaju jednake molekulske formule, ali se razlikuju po svojoj prirodi ili slijedu vezanja svojih atoma ili rasporedu atoma u prostoru. Izomeri koji se razlikuju po rasporedu svojih atoma u prostoru zovu se "stereoizomeri". Stereoizomeri koji nisu zrcalna slika jedan drugoga zovu se "dijastereomeri", a stereoizomeri koji nisu preklopive zrcalne slike zovu se "enantiomeri" ili ponekad "optički izomeri". Ugljikov atom vezan na četiri različita supstituenta zove se “kiralno središte”. Spoj s jednim kiralnim središtem i dva enantiomerička oblika suprotne kiralnosti zove se "racemička smjesa". Spoj koji ima više od jednog kiralnog središta ima 2n-1 enantiomeričke parove, pri čemu je n broj kiralnih središta. Spojevi s više od jednog kiralnog središta mogu postojati kao pojedinačni dijastereomeri ili kao smjesa dijastereomera, što se naziva "dijastereomerička smjesa". Kada postoji jedno kiralno središte, stereoizomer se može prepoznati po apsolutnoj konfiguraciji tog kiralnog središta. Apsolutna konfiguracija odnosi se na prostorni raspored supstituenata vezanih na kiralno središte. Enantiomeri se prepoznaju po apsolutnoj konfiguraciji svojih kiralnih središta, a opisuju se R- i S- sekvencijskim pravilima prema Cahnu, Ingoldu i Prelogu. Konvencije za stereokemijsko nazivlje, postupke određivanja stereokemije i razdvajanja stereoizomera dobro su poznate u struci (na pr, vidi “Advanced Organic Chemistry”, 3. izd., March, Jery, John Wiley & Sons, New York, 1985). Razumljivo je kako nazivi i ilustracije korištene u ovoj Prijavi za opis spojeva Formule I obuhvaćaju sve moguće stereoizomere. Tako, na primjer, naziv 1-(1-cijano-1-metiletilkarbamoil)-3-metilbutilkarbamat uključuje i 1S-(1-cijano-1-metiletilkarbamoil)-3-metilbutilkarbamat i 1R-(1-cijano-1-metiletilkarbamoil)-3-metilbutilkarbamat, kao i svaku njihovu smjesu, racemičku ili drugu.
"Ketonski derivat" označuje derivat koji sadrži dio -C(O)-.
"Metilen" označuje dvovaljani radikal -CH2- ili CH2:, pri čemu njegove slobodne valencije mogu biti vezane na različite atome ili na isti atom. Na primjer, slučaj u kojem R9 zajedno s R7 tvori trimetilen supstituirani metilen uključuje slijedeće:
[image]
pri čemu su X1 i R11 definirani kao u Sažetku izuma, a može se odnositi na 2,2-metilen, odnosno na 1,2-metilen.
"Nitro" označuje radikal -NO2.
"Neobavezan" ili "neobavezno" označuje da se spominjani događaj ili okolnost može ili ne mora dogoditi, a opis uključuje oba slučaja, i kada se događaj ili okolnost dogodila, i kada se događaj ili okolnost nije dogodila. Na primjer, izraz "bilo kojih 1 do 3 atoma bilo kojeg aromatskog prstena s dostupnim valencijama koji sadrži R6 mogu biti neobavezno neovisno supstituirani” znači da spomenuti aromatski prsten može, ali ne mora biti supstituiran, a u oba slučaja potpada u područje izuma.
"N-oksidni derivati" označuje derivate spoja Formule I u kojem su dušikovi atomi u oksidiranom stanju (tj., O←N) i koji posjeduje željeni farmakološki učinak.
"Okso" označuje radikal :O.
"Patologija" bolesti označuje osnovnu prirodu, uzroke i razvoj bolesti, kao i strukturne i funkcijske promjene koje nastaju zbog patološkog procesa.
"Farmaceutski prihvatljiv" znači koristan za pripravu farmaceutskog pripravka koji je općenito siguran, neotrovan i nije niti biološki niti na koji drugi način nepoželjan, a uključuje prihvatljivost za veterinarsku uporabu, kao i farmaceutsku uporabu za ljude.
"Farmaceutski prihvatljive soli" znače soli spoja Formule I koje su farmaceutski prihvatljive, kao što je gore definirano, i koje posjeduju željenu farmakološku aktivnost. Takve soli uključuju kisele adicijske soli dobivene od neorganskih kiselina, kao što su kloridna kiselina, bromidna kiselina, sulfatna kiselina, nitratna kiselina, fosfatna kiselina i slične; ili od organskih kiselina, kao što su octena kiselina, propionska kiselina, heksanska kiselina, heptanska kiselina, ciklopentanpropionska kiselina, glikolna kiselina, piruvična kiselina, mliječna kiselina, malonska kiselina, sukcinilna kiselina, malična kiselina. maleinska kiselina, fumarna kiselina, vinska kiselina, limunska kiselina, benzojeva kiselina, o-(4-hidroksibenzoil)benzojeva kiselina, cinaminska kiselina, mandelična kiselina, metansulfonska kiselina, etansulfonska kiselina, 1,2-etandisulfonska kiselina, 2-hidroksietansulfonska kiselina, benzensulfonska kiselina, p-klorobenzensulfonska kiselina, 2-naftalensulfonska kiselina, p-toluensulfonska kiselina, kamforsulfonska kiselina, 4-metilbiciklo[2.2.2]okt-2-en-1-karboksilna kiselina, glukoheptonska kiselina, 4,4’-metilenbis(3-hidroksi-2-en-1-karboksilna kiselina), 3-fenilpropionska kiselina, trimetiloctena kiselina, tercijarna butiloctena kiselina, lauril sulfatna kiselina, glukonska kiselina, glutaminska kiselina, hidroksinaftojeva kiselina, salicilna kiselina, stearinska kiselina, mukonska kiselina i slično.
Farmaceutski prihvatljive soli uključuju i bazne adicijske soli koje se mogu dobiti kada postojeći kiselinski protoni mogu reagirati s neorganskim ili organskim bazama. Prihvatljive neorganske baze uključuju natrij hidroksid, natrij karbonat, kalij hidroksid, amonij hidroksid, aluminij hidroksid i kalcij hidroksid. Prihvatljive organske baze uključuju etanolamin, dietanolamin, trietanolamin, trometamin, N-metilglukamin i druge.
“Fenilen-1,2-dimetilen" označuje dvovaljani radikal -CH2C6H4CH2-, pri čemu su metilenski dijelovi vezani na položajima 1- i 2- fenilenskog dijela. Na primjer, skupina Formule (a), pri čemu R9 zajedno s R7 tvori neobavezno supstituirani fenilen-1,2-dimetilen ilustrira slijedeća formula:
[image]
u kojoj je R neobavezno hidroksi ili (C1-4)alkilna skupina, a X1 i R11 su kao što su definirani u Sažetku izuma.
"Policikloaril" označuje biciklički sklop prstena (izravno vezan na jednostuku vezu ili stopljen) koji sadrži naznačen broj ugljikovih atoma-članova prstena, pri čemu je najmanje jedan, ali ne svi, stopljeni prsteni koji sadrže radikal aromatski, ili bilo koji njihov karbociklički ketonski, tioketonski ili iminoketonski derivat (na pr., (C9-12)policikloaril uključuje indanil, indenil, 1,2,3,4-tetrahidronaftalenil, 1,2-dihidronaftalenil, cikloheksilfenil, fenilcikloheksil, 2,4-diokso-1,2,3,4-tetrahidronaftalenil i slično).
"Prolijek derivati" označuje derivate spojeva Formule I koji se in vivo pretvaraju u odgovarajući nederivirani oblik spoja Formule (I).
"Zaštićeni derivati" znače derivate spojeva Formule I u kojima je reaktivno mjesto/mjesta blokirana zaštitnim skupinama. Zaštićeni derivati spojeva Formule I korisni su u pripravi spojeva Formule I ili u njima samima mogu biti aktivni cistein proteazni inhibitori. Sveobuhvatan popis prikladnih zaštitnih skupina može se pronaći u TW Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
"Terapijski učinkovita količina" označuje onu količinu koja je, kada se primijeni na životinju radi liječenja bolesti, dovoljna za postizanje učinka takvog liječenja bolesti.
"Tioketonski derivat" označuje derivat koji sadrži spoj -C(S)-.
"Liječenje" ili "tretiranje" označuje svaku primjenu spoja ovog izuma i uključuje:
(1) sprječavanje pojave bolesti u životinje koja je predisponirana za bolest, ali još nije razvila patološka obilježja ili znakovlje bolesti,
(2) suzbijanje bolesti u životinje koja je razvila ili pokazuje patološka obilježja ili znakovlje bolesti (tj., zaustavljanje daljnjeg razvoja patoloških obilježja i/ili znakovlja), ili
(3) ublažavanje bolesti u životinje koja je razvila ili pokazuje patološka obilježja ili znakovlje bolesti (tj., povlačenje patoloških obilježja i/ili znakovlja).
"Ureido" označuje radikal-NHC(O)NH2. Ako nije drugačije naznačeno, spojevi izuma koji sadrže ureido dijelove uključuju i njihove zaštićene derivate. Prikladne zaštitne skupine za ureido dijelove uključuju acetil, terc-butoksikarbonil, benziloksikarbonil i slično. Na primjer, spoj Formule I pri čemu R9 sadrži ureido spoj može postojati bilo kao nezaštićeni, bilo kao zaštićeni derivat i slično, a oba ta derivata potpadaju u područje izuma.
Specifični oblici
Iako je u Sažetku izuma prikazana najšira definicija, preporučuju se pojedini aspekti izuma. Preporučeni aspekti izuma su spojevi Formule I u kojima:
R1 je skupina Formule (a), pri čemu je unutar Formule (a):
X1 je -C(O)-;
R5 je vodik, (C1-6)alkil ili kako je definirano zajedno s R9;
R7 je vodik, (C1-6)alkil ili kako je definirano zajedno s R9;
R9 je (i) (C1-6)alkil neobavezno supstituiran s halo-supstituirani (C1-3)alkil, -OR12 ili -NR12C(NR12)NR12R12, pri čemu je R12 pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil, ili (ii) (C6-12)aril(C0-6)alkil, ili
R9 zajedno s R7 tvori trimetilen neobavezno supstituiran s okso, (C1-4)alkil ili metilen; ili
R9 i R5 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen; a
R11 je -X4X5R18, pri čemu je X4 -C(O)-, X5 je veza, -O- ili –SO2-, pri čemu je R18 (i) (C1-6)alkil neobavezno supstituiran s -C(O)NR20R21 ili –NR21C(O)R20, pri čemu je R20 (C6-12)aril(C0-6)alkil, a R21 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil, ili (ii) (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil ili hetero(C8-12)policikloaril(C0-6)alkil, pri čemu spomenuti heterocikloalkilni, arilni, heteroarilni ili heteropolicikloarilni prsten može biti supstituiran s –R22, -X3OR22, -X3NR22R23, -X3NR17C(O)R16, -X3NR23C(O)OR22, -X3NR23S(O)2R22, -X3S(O)2R22, -X3C(O)R22 ili -X3NR23C(O)NR22R23, pri čemu je X3 veza ili (C1-6)alkilen, R22 je hetero(C3-12)cikloalkil(C0-6)alkil, R23 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil; pri čemu unutar R11 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu je X3 veza ili (C1-6)alkilen, R12 je pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil, a R13 je (C1-6)alkil ili halo-supstituirani (C1-3)alkil;
R3 je vodik, (C1-6)alkil ili kako je definirano zajedno s R4; a
R4 je (i) vodik, cijano, -C(O)OR12 ili (C1-6)alkil, pri čemu je spomenuti alkil neobavezno supstituiran s -C(O)OR12, -O(C)OR12, pri čemu je R12 pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil, ili (ii) (C6-10)aril(C0-3)alkil, ili
R4 zajedno s R2 tvore trimetilen, ili
R4 i R3 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen, pri čemu su spomenuti (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen neobavezno supstituirani s (C1-6)alkil.
Preporučeni aspekt izuma su spojevi Formule I u kojima:
R1 je skupina Formule (a), pri čemu unutar Formule (a):
X1 je -C(O)-;
R5 je vodik ili kako je definirano zajedno s R9;
R7 je vodik;
R9 je (i) (C1-6)alkil ili
R9 i R5 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen; a
R11 je -X4X5R18, pri čemu je X4 -C(O)-, a R18 je (C6-12)aril(C0-6)alkil ili hetero(C5-12)aril(C0-6)alkil, pri čemu spomenuti arilni ili heteroarilni prsten može biti supstituiran s –R22, -X3OR22, -X3NR22R23, -X3NR17C(O)R16, -X3NR23C(O)OR22, -X3NR23S(O)2R22, -X3S(O)2R22, -X3C(O)R22 ili -X3NR23C(O)NR22R23, pri čemu je X3 veza ili (C1-6)alkilen, R22 je hetero(C3-12)cikloalkil(C0-6)alkil, R23 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil; pri čemu unutar R11 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu je X3 veza ili (C1-6)alkilen, R12 je pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil, a R13 je (C1-6)alkil ili halo-supstituirani (C1-3)alkil;
R3 je vodik ili kako je definirano zajedno s R4; a
R4 je (i) vodik, ili
R4 i R3 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen, pri čemu su spomenuti (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen neobavezno supstituirani s (C1-6)alkil.
Preporučeni aspekt izuma su spojevi Formule I u kojima:
R1 je skupina Formule (a), pri čemu unutar Formule (a):
X1 je -C(O)-;
R5 je vodik ili kako je definirano zajedno s R9;
R7 je vodik;
R9 je (i) (C1-6)alkil ili
R9 i R5 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen; a
R11 je -X4X5R18, pri čemu je X4 -C(O)-, a R18 je fenil, pri čemu spomenuti fenilni prsten može biti supstituiran s –R22, -X3OR22, -X3NR22R23, -X3NR17C(O)R16, -X3NR23C(O)OR22, -X3NR23S(O)2R22, -X3S(O)2R22, -X3C(O)R22 ili -X3NR23C(O)NR22R23, pri čemu je X3 veza ili (C1-6)alkilen, R22 je hetero(C3-12)cikloalkil(C0-6)alkil, R23 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil; pri čemu unutar R11 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu je X3 veza ili (C1-6)alkilen, R12 je pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil, a R13 je (C1-6)alkil ili halo-supstituirani (C1-3)alkil;
R3 je vodik ili kako je definirano zajedno s R4; a
R4 je (i) vodik, ili
R4 i R3 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen, pri čemu su spomenuti (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen neobavezno supstituirani s (C1-6)alkil.
Pozivanje na gore prikazane preporučene oblike uključuje sve kombinacije pojedinih i preporučenih skupina.
Nadalje, preporučeni su spojevi Formule I, odabrani iz skupine koja se sastoji od:
N-[1-(cijanometil-karbamoil)-3-metil-butil]-3-[3-(3-morfolin-4-il-propil)ureido]-benzamid; i
N-[1-(cijanometil-karbamoil)-3-metil-butil]-3-(3-piridin-2-il-ureido)-benzamid;
N-[1S-(cijanometil-karbamoil)-3-metil-butil]-4-(3-piridin-4-ilmetil-ureido)-benzamid;
N-[1-(cijanometil-karbamoil)-3-metil-butil]-4-(3-piperidin-4-il-ureido)-benzamid;
N-[1-S-(dicijanometil-karbamoil)-3-metil-butil]-4-morfolin-4-il-benzamid;
4-dimetilamino-piperidin-1-karboksilna kiselina{4-[1-(cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-amid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(4-metilpiperazin-1-il)-benzamid;
N-[1-cijanometilkarbamoil-3-metilbutil-4-(2-gvanidinotiazo1-4-il)]benzamid;
{4-[1-S-(cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-karbamilna kiselina, 3-piridin-4-il-propilester; i
N-[1-(cijanometil-karbamoil)-3-metil-butil]-4-{3-[2-(3H-imidazo1-4-il)-etil]-ureido}-benzamid.
Preporučeni aspekt izuma su spojevi Formule II, u kojima:
X1 je odabran između -C(O)-;
R1 i R2 su vodici:
R3 je izobutil i R4 je vodik, ili R3 i R4 zajedno s ugljikovim atomom na koji su oba vezani tvore ciklopropilen ili cikloheksilen;
R5 i R6 su vodici, ili R5 i R6 zajedno s ugljikovim atomom na koji su oba vezani tvore cikloheksilen ili (C6)heterocikloalkilen; a
R7 je –X2X3R9, pri čemu je X2 -C(O)-, X3 je veza, a R9 je fenil, pri čemu je unutar R9 spomenuti fenil supstituiran s –R12, -X4NR11R12, -X4NR11C(O)R12, -X4NR11C(O)OR12, -X4NR11C(O)NR11R12, -X4NR11C(NR11)NR11R12, -X4OR12, -X4SR12, -X4S(O)R12, -X4S(O)2R12, -X4C(O)R12, -X4C(O)OR12, -X4OC(O)R12, -X4C(O)NR11R12, -X4OC(O)NR11R12,-X4S(O)2NR11R12, -X4P(O)(OR11)OR12, -X4OP(O)(OR11)OR12, pri čemu je X4 veza ili (C1-6)alkilen, R11 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil, a R12 je hetero(C3-6)cikloalkil(C0-6)alkil, fenil(C0-6)alkil ili hetero(C5-6)aril(C0-6)alkil, pri čemu je unutar R12 spomenuti heterocikloalkil, fenil ili heteroaril supstituiran s –R13, -X4NR11R13, -X4NR11C(O)R13, -X4NR11C(O)OR13, -X4NR11C(O)NR11R13, -X4NR11C(NR11)NR11R13, -X4OR13, -X4SR13, -X4S(O)R13, -X4S(O)2R13, -X4C(O)R13, -X4C(O)OR13, -X4OC(O)R13, -X4C(O)NR11R13, -X4OC(O)NR11R13, -X4S(O)2NR11R13, -X4P(O)(OR11)OR13 ili -X4OP(O)(OR11)OR13, pri čemu su X4 i R11 kako su gore definirani, R13 je (C3-6)cikloalkil(C0-6)alkil, hetero(C3-6)cikloalkil(C0-6)alkil, fenil(C0-6)alkil ili hetero(C5-6)aril(C0-6)alkil, pri čemu unutar R7 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(O)(OR5)OR14, -X5OP(O)(OR5)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 i -X5C(O)R15, pri čemu je X5 veza ili (C1-6)alkilen, R14 je pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil; R15 je (C1-6)alkil ili halo-supstituirani (C1-3)alkil.
Nadalje, preporučeni su spojevi Formule II, odabrani iz skupine koja se sastoji od:
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-pirid-4-ilamino)tiazol-4-ilbenzamid;
4-[3-(1-benzilpiperidin-4-il)ureido]-N-(1S-cijanometilkarbamoil-3-metilbutil)benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[4-(2-morfolin-4-iletil)piperazin-1-il]benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-pirid-4-iltiazol-4-il)benzamid;
4-[3-(1-benzilpirolidin-3S-il)-3-metilureido]-N-(1S-cijanometilkarbamoil-3-metilbutil)benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(4-pirid-4-ilpiperazin-1-il)benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(1-metilpiridin-4-ilamino)tiazol-4-il]benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(1-metilpiridin-4-il)tiazol-4-il]benzamid;
N-[(S)-1-(cijanometil-karbamoil)-3-metil-but-3-enil]-4-[2-(piridin-4-ilamino)-tiazol-4-il]-benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(1-alilpirid-4-il)tiazol-4-il]benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-piperidin-4-ilaminotiazol-4-il)benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-piperazin-1-iltiazol-4-il)benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(4-metilpiperazin-1-il)tiazol-4-il]benzamid;
N-[1S-(1-cijanociklopropilkarbamoil)-3-metilbutil]-4-(2-piperazin-1-il-tiazol-4-il)benzamid;
N-[1S-(1-cijanociklopropilkarbamoil)-3-metilbutil]-4-[2-(4-metilpiperazin-1-il)tiazol-4-il]benzamid;
N-[1S-(1-cijanociklopropilkarbamoil)-3-metilbutil]-4-(2-piperidin-4-ilaminothiazol-4-il)benzamid;
N-(1-cijanometilkarbamoilcikloheksil)-4-(2-piperazin-1-iltiazol-4-il)benzamid;
N-[1-(cijanometil-karbamoil)-cikloheksil]-4-[2-(piperidin-4-ilamino)-tiazol-4-il]-benzamid;
N-(1R-cijanometilkarbamoil-3-metilbutil)-4-(2-morfolin-4-iltiazol)-4-il)benzamid;
N-(1-cijanometilkarbamoilcikloheksil]-4-[2-(4-metilpiperazin-1-il)tiazol-4-il]benzamid;
N-[1-(4-cijanotetrahidropiran-4-ilkarbamoil)cikloheksil]-4-[2-(4-metilpiperazin-1-il)tiazol-4-il]benzamid;
N-(1-cijanometilkarbamoilcikloheksil)-4-(2-morfolin-4-iltiazol-4-il)benzamid;
N-(1-cijanometilkarbamoilcikloheksil)-4-(2-piperazin-1-ilmetiltiazol-4-il)benzamid;
terc-butil 4-(4-{4-[1S-(1-cijanociklopropilkarbamoil)-3-metilbutilkarbamoil]fenil}tiazol-2-ilmetil)piperazin-1-karboksilat;
N-[(S)-1-(1-cijano-ciklopropilkarbamoil)-3-metil-butil]-4-(2-piperazin-1-ilmetil-tiazol-4-il)-benzamid; i
N-(1S-cijanometilkarbamoil-3-metilbutil]-4-(4-morfolin-4-ilmetiltiazol-2-ilamino)benzamid.
Farmakologija i uporaba
Spojevi izuma su inhibitori cistein proteaze; točnije, spojevi izuma inhibiraju djelovanje katepsina B, L, K i/ili S, i kao takvi su korisni za liječenje bolesti u kojima djelovanje katepsina B, L, K i/ili S doprinosi patologiji i/ili znakovlju bolesti. Na primjer, spojevi izuma su korisni za liječenje tumorske invazije i metastaza, osobito kao protuangiogenička sredstva, reumatoidnog artritisa, osteoartritisa, infekcije s pneumocistis carinii, akutnog pankreatitisa, upalne bolesti dišnih puteva, te poremećaja kostiju i zglobova. Nadalje, spojevi izuma korisni su u liječenju poremećaja bolesti resorpcije kostiju, na pr. osteoporoze. Spojevi izuma također su korisni u liječenju autoimunosnih poremećaja, uključujući, bez ograničenja, juvenilni dijabetes, multiplu sklerozu, pemfigus vulgaris, Gravesovu bolest, mijasteniju gravis, sistemski eritematodni lupus, reumatoidni artritis i Hashimotov tireoiditis, alergijske poremećaje, uključujući, bez ograničenja, astmu, kao i alogene imunosne odgovore, uključujući, bez ograničenja, odbacivanje presadaka organa ili presadaka tkiva.
Djelovanje spojeva izuma kao inhibitora cistein proteaze može se odrediti postupcima koji su poznati prosječno upućenima u struku. Poznati su prikladni in vitro testovi za mjerenje proteazne aktivnosti i njezine inhibicije ispitivanim spojevima. Tipično, test mjeri proteazom induciranu hidrolizu supstrata koji ima peptidnu osnovu. Pojedinosti testova za mjerenje aktivnosti u inhibiranju proteaza iznijeti su u Primjerima 10, 11, 12 i 13, u nastavku.
Nazivlje
Spojevi Formule I, međuspojevi i početne tvari korištene za njihovu pripravu nazivaju se prema IUPAC pravilima za nazivlje, pri čemu su pojedine skupine nabrojane po redoslijedu važnosti: kiseline, esteri, amidi itd. Alternativno, spojevi su imenovani pomoću programa AutoNom 4.0 (Beilstein Information Systems, Inc.). Na primjer, spoj Formule I u kojem je R1 benziloksikarbonilaminobutiril, a R2, R3 i R4 su vodici; dakle, spoj slijedeće strukture:
[image]
nazvan je benzil (S)-1-cijanometilkarbamoil-3-metilbutilkarbamat ili [(S)-1-(cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, benzil ester; a spoj Formule I u kojem je R1 4-(2-met-4-iltiazolil)benzoilaminobutiril, a R2, R3 i R4 su vodici; dakle, spoj slijedeće strukture:
[image]
nazvan je N-(1-cijanometilkarbamoil-3-metilbutil)-4-(2-metiltiazol-4-il)benzamid ili N-[(S)-1-(cijanometil-karbamoil)-3-metil-butil]-4-(2-metil-tiazol-4-il)-benzamid; a spoj Formule I u kojem je R1 4-(2-met-4-iltiazolil)benzoilaminobutiril, a R2, R3 i R4 su vodici; dakle, spoj slijedeće strukture:
[image]
nazvan je etil 4-{4-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]tiazol-2-ilamino}piperidin-1-karboksilat ili 4-(4-{4-[(S)-1-(cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-tiazol-2-ilamino)-piperidin-1-karboksilna kiselina, etil ester.
Primjena i farmaceutski pripravci
Općenito, spojevi Formule I bit će primijenjeni u terapijski učinkovitim količinama putem bilo kojeg od uobičajenih i prihvatljivih načina poznatih u struci, bilo pojedinačno, bilo u kombinaciji s drugim terapijskim sredstvom. Terapijski učinkovita količina može u širokim granicama varirati, ovisno o težini bolesti, dobi i relativnom zdravlju pojedinca, snazi korištenog spoja i drugim čimbenicima. Na primjer, terapijski učinkovita količina spoja Formule I može biti u rasponu od 0.1 mikrograma po kilogramu tjelesne težine (μg/kg) na dan, pa do 10 miligrama po kilogramu tjelesne težine (mg/kg) na dan, a tipično od 1 μg/kg/dan do 1 mg/kg/dan. Stoga, terapijski učinkovita količina za čovjeka od 80 kg može biti u rasponu od 10 μg/dan do 100 mg/dan, tipično 0.1 mg/dan do 10 mg/dan. Općenito, stručnjak prosječnog znanja će moći, radeći prema osobnom znanju i opisu ove Prijave, ocijeniti terapijski učinkovitu količinu spoja Formule I za liječenje određene bolesti.
Spojevi Formule I mogu se primijeniti kao farmaceutski pripravci jednim od slijedećih puteva: peroralni, sistemski (na pr. transdermalni, intranazalni ili u supozitorijima) ili parenteralni (na pr., intramuskularni, intravenski ili potkožni). Spojevi mogu biti u obliku tableta, pilula, kapsula, polukrutina, prašaka, pripravaka s produljenim otpuštanjem, otopina, suspenzija, eliksira, aerosola, ili bilo koji drugi prikladni pripravci, a općenito se sastoje od spoja Formule I u kombinaciji s najmanje jednim farmaceutski prihvatljivim ekscipijensom. Prikladni ekscipijensi su neotrovne, pomoćne tvari koje nemaju nepovoljan učinak na djelotvornost liječenja aktivnim sastojkom. Takvi ekscipijensi mogu biti kruti, tekući ili polukruti, ili, u slučaju aerosolnog pripravka, plinoviti ekscipijens koji je općenito dostupan upućenome u struku.
Kruti farmaceutski ekscipijensi uključuju škrob, celulozu, talk, glukozu, laktozu, saharozu, želatinu, slad, rižu, brašno, kredu, silika gel, magnezij stearat, natrij stearat, glicerol monostearat, natrij klorid, sušeno obrano mlijeko i slično. Tekući i polukruti ekscipijensi mogu se odabrati između vode, etanola, glicerola, propilen glikola i različitih ulja, uključujući petrolejsko, životinjsko, biljno ili sintetičko (na pr., kikirikijevo ulje, sojino ulje, mineralno ulje, sezamovo ulje i dr.). Preporučeni tekući nosači, osobito otopine za injiciranje, uključuju vodu, fiziološku otopinu, vodenu dekstrozu i glikole.
Količina spoja Formule I u pripravku može varirati u širokim granicama ovisno o tipu pripravka, veličini jedinice za doziranje, vrste ekscipijensa i drugih čimbenika koji su poznati upućenome u farmaceutske znanosti. Općenito, pripravak spoja Formule I za liječenje određene bolesti sadržavat će od 0.01 mas% do 10 mas%, preporučljivo 0.3 mas% do 1 mas%, aktivnog sastojka, a ostalo će biti ekscipijens, odnosno ekscipijensi. Preporučljivo, farmaceutski pripravak se primijenjuje kao pojedinačni oblik jedinice za doziranje za trajno liječenje ili kao pojedinačni oblik jedinice za doziranje po potrebi, kada se osobito zahtijeva smirivanje simptoma. Reprezentativni farmaceutski pripravci koji sadrže spoj Formule I su opisani u Primjeru 17.
Spojevi Formule I mogu se primjenjivati samostalno ili u kombinaciji s drugim spojevima Formule I, ili u kombinaciji s jednim ili više aktivnih sastojaka. Na primjer, spojevi Formule I mogu se primjenjivati u kombinaciji s terapijski aktivnom količinom bisfosfonske kiseline ili kiselog esterskog derivata ili bilo koje njihove farmaceutski prihvatljive soli. Prikladne bisfosfonske kiseline i kiseli esterski derivati uključuju spojeve kojima odgovara slijedeća formula:
[image]
pri čemu je X11 veza ili (C1-7)alkilen, svaki R43 je neovisno vodik ili (C1-30)alkil, R44 i R45 su neovisno odabrani iz skupine koja se sastoji od vodika, halo, neobavezno supstituiranog (C1-30)alkil, (C3-30)cikloalkil, hetero(C5-30)cikloalkil, neobavezno supstituiran s(C6-10)aril, hetero(C6-10)aril, -NR46R46, -OR46, -SR46, pri čemu je svaki R46 neovisno vodik, (C1-10)alkil, (C3-10)cikloalkil, neobavezno supstituiran s (C6-10)aril, s time da R44 i R45 ne budu oba odabrani između vodika ili hidroksi kada je X11 veza; ili R44 i R45 zajedno tvore (C2-9)alkilen; pri čemu (C3-10)cikloalkil uključuje adamantil i slično, hetero(C5-10)cikloalkil uključuje pirolidinil i slično, (C6-10)aril uključuje fenil i naftil, a hetero(C6-10)aril uključuje kvinolil, izokvinolil, piridil, furil, imidazolil, imidazopiridil i slično.
Slučajevi u kojima su R44 i/ili R45 supstituirani (C1-30)alkil mogu uključivati, bez ograničenja, (C1-30)alkil supstituiran s hetero(C5-10)cikloalkil, (C6-10)aril, hetero(C6-10)aril, -NR47R47, -OR47 i -SR47, pri čemu je svaki R47 neovisno vodik ili (C1-10)alkil; pri čemu hetero(C5-10)cikloalkil uključuje pirolidinil i slično, (C6-10)aril uključuje fenil i naftil, a hetero(C6-10)aril uključuje kvinolil, izokvinolil, piridil, furil, imidazolil, imidazopiridil i slično. Prikladne neobavezno supstituirane arilne skupine uključuju, bez ograničenja, halo-supstituirani fenil.
Neograničavajući razred bisfosfonskih kiselina i njihovih kiselih esterskih derivata prikladnih za primjenu u kombinaciji sa spojevima Formule I uključuju one u kojima je R44 odabran iz skupine koja se sastoji od vodika, hidroksi ili halo, a R45 je odabran iz skupine koja se sastoji od neobavezno supstituiranog (C1-30)alkil, halo i -SR46, pri čemu je R46 (C1-10)alkil ili fenil.
Neograničavajući podrazred bisfosfonskih kiselina i njihovih kiselih esterskih derivata prikladnih za primjenu u kombinaciji sa spojevima Formule I uključuju one u kojima je R44 odabran iz skupine koja se sastoji od vodika, hidroksi i kloro, a R45 je odabran iz skupine koja se sastoji od neobavezno supstituiranog (C1-30)alkil, kloro i klorofeniltio.
Neograničavajući primjer bisfosfonskih kiselina prikladnih za primjenu u kombinaciji sa spojevima Formule I uključuju onaj gdje je X11 je veza, svaki R43 je vodik, R44 je hidroksi, a R45 je 3-aminopropil, i to 4-amino-1-hidroksibutiliden-1,1-bisfosfonska kiselina (aka alendronska kiselina), ili njezina mononatrij trihidratna sol, to jest 4-amino-1-hidroksibutiliden-1,1-bisfosfonat mononatrij trihidrat (aka alendronat mononatrij trihidrat), opisan u SAD patentima 4922007 autora Kieczykowskog i sur., od 1. svibnja 1990.; 5019651 autora Kieczykowskog i sur., od 28. svibnja 1991.; 5510517 autora Dauera i sur., od 23. travnja 1996.; 5648491 autora Dauera i sur., od 15. srpnja 1997.; svi ovi patenti uključeni su ovdje u cijelosti kao reference.
Daljnji neograničavajući primjeri bisfosfonskih kiselina prikladnih za primjenu u kombinaciji sa spojevima Formule I uključuju slijedeće:
cikloheptilaminometilen-1,1-bisfosfonska kiselina (aka cimadronska kiselina); opisana u SAD patentu br. 4970335, autora Isomure i sur, od 13. studenoga 1990;
1,1-diklorometilen-1,1-difosfonska kiselina (aka klodronska kiselina); i njena dinatrijeva sol, to jest klodronat dinatrij, opisan u belgijskom patentu 672205 (1966) i J Org Chem 32, 4111 (1967);
1-hidroksi-3-pirolidin-1-ilpropiliden-1,1-bisfosfonska kiselina (aka EB-1053);
1-hidroksietiliden-1,1-difosfonska kiselina (aka etidronska kiselina);
1-hidroksi-3-(N-metil-N-pentilamino)propiliden-1,1-bisfosfonska kiselina (aka ibandronska kiselina), opisana u SAD patentu br. 4927814 od 22. svibnja 1990;
6-amino-1-hidroksiheksiliden-1,1-bisfosfonska kiselina (aka neridronska kiselina);
3-(dimetilamino)-1-hidroksipropiliden-1,1-bisfosfonska kiselina (aka olpadronska kiselina);
3-amino-1-hidroksipropiliden-1,1-bisfosfonska kiselina (akapamidronska kiselina);
2-pirid-2-iletiliden-1,1-bisfosfonska kiselina (aka piridronska kiselina),opisana u SAD patentu br. 4761406;
1-hidroksi-2-pirid-3-iletiliden-1,1-bisfosfonska kiselina (aka rizedronska kiselina);
4-klorofeniltiometilenbisfosfonska kiselina (aka tiludronska kiselina), opisana u SAD patentu br. 4876248 autora Breliere-a i sur., od 24. listopada 1989; i
1-hidroksi-2-(1H-imidazol-1-il)etiliden-1,1-bisfosfonska kiselina (aka zoledronska kiselina); svi ovi patenti, kao i drugi dokumenti koji se odnose na ovu materiju, uključeni su ovdje u cijelosti kao reference.
Neograničavajući podrazred bisfosfonskih kiselina prikladnih za primjenu u kombinaciji sa spojevima Formule I uključuju one odabrane iz skupine koja se sastoji od alendronske kiseline, cimadronske kiseline, klodronske kiseline, tiludronske kiseline, etidronske kiseline, ibandronske kiseline, rizedronske kiseline, piridronske kiseline, pamidronske kiseline, zolendronske kiseline, njihovih farmaceutski prihvatljivih soli i smjesa. Daljnji primjer bisfosfonske kiseline prikladne za primjenu u kombinaciji sa spojevima Formule I je alendronska kiselina ili njezina farmaceutski prihvatljiva sol ili smjese. Daljni neograničavajući primjer je alendronat mononatrij trihidrat.
Spojevi Formule I mogu se primjenjivati u kombinaciji s terapijski aktivnom količinom agonista estrogenskih receptora. Neograničavajući primjeri agonista estrogenskih receptora prikladnih za primjenu u kombinaciji sa spojevima Formule I uključuju prirodne estrogene poput estradiola, estrona i estriola, ili sintetičke agoniste estrogenskih receptora poput [6-hidroksi-2-(4-hidroksifenil)benzo[b]tien-3-il][4-(2-piperidin-1-iletoksi)fenil]metanon (aka raloksifen) i {2-[4-(1,2-difenilbut-1-enil)fenoksi]etil}dimetilamin (aka tamoksifen). Neograničavajući podrazred agonista estrogenskih receptora prikladnih za primjenu u kombinaciji sa spojevima Formule I uključuju djelomične agoniste estrogenskih receptora (tj. agoniste estrogenskih receptora s miješanim agonističko/antagonističkim svojstvima), koji se ponekad nazivaju i modulatori estrogenskih receptora. Djelomični agonisti estrogenskih receptora mogu izazvati tkivno selektivne estrogenske agonističke učinke. Tamoksifen, na primjer, selektivno izaziva estrogenski agonistički učinak na kost u ljudi. Dodatni prikladni djelomični agonisti estrogenskih receptora opisani su u Tissue-Selective Actions Of Estrogen Analogs, Bone vol. 17, br. 4, listopad 1995., 181S-190S. Neki 3-[4-(2-fenilindol-1-ilmetil)fenil]akrilamidi, opisani u SAD patentu 5985910 autora Millera i sur., od 16. studenoga 1999.; benzotifenski spojevi, opisani u SAD patentu 5985897 autora Meuhl-a i sur., od 16. studenoga 1999.; naftilni spojevi, opisani u SAD patentu 5952350 autora Cullinana i sur., od 14. rujna 1999.; supstituirani benzotiofenski spojevi, opisani u SAD patentu 5962475 Schmida i sur., od 4. listopada 1999., su prikladni djelomični agonisti estrogenskih receptora za primjenu sa spojevima Formule I; svi ovi patenti, kao i drugi dokumenti koji se odnose na ovu materiju, uključeni su ovdje u cijelosti kao reference.
Točnije, farmaceutski pripravak ovog izuma može sadržavati terapijski učinkovitu količinu spoja Formule I u kombinaciji s jednim ili više aktivnih sastojaka odabranih iz skupine koja se sastoji od (i) terapijski učinkovite količine bisfosfonske kiseline ili njezinog kiselog estera ili njihove farmaceutski prihvatljive soli i (ii) terapijski učinkovite količine agonista estrogenskih receptora ili njegove farmaceutski prihvatljive soli; i jednog ili više farmaceutski prihvatljivih ekscipijensa. Neograničavajući primjeri takvih bisfosfonskih kiselina uključuju 1,1-diklorometilen-1,1-difosfonsku kiselinu, 1-hidroksi-3-pirolidin-1-ilpropiliden-1,1-bisfosfonsku kiselinu, 1-hidroksietiliden-1,1-difosfonsku kiselinu, 1-hidroksi-3-(N-metil-N-pentilamino)propiliden-1,1-bisfosfonsku kiselinu, 6-amino-1-hidroksiheksiliden-1,1-bisfosfonsku kiselinu, 3-(dimetilamino)-1-hidroksipropiliden-1,1-bisfosfonsku kiselinu, 3-amino-1-hidroksipropiliden-1,1-bisfosfonsku kiselinu, 2-pirid-2-iletiliden-1,1-bisfosfonsku kiselinu, 1-hidroksi-2-pirid-3-iletiliden-1,1-bisfosfonsku kiselinu, 4-klorofeniltiometilenbisfosfonsku kiselinu i 1-hidroksi-2-(1H-imidazol-1-il)etiliden-1,1-bisfosfonsku kiselinu ili njihove kisele estere, ili njihove farmaceutski prihvatljive soli; osobito 1,1-diklorometilen-1,1-difosfonsku kiselinu ili njezina farmaceutski prihvatljiva sol, preporučljivo 1,1-diklorometilen-1,1-difosfonat mononatrij trihidrat.
Kemija
Postupci za pripravu spojeva Formule I:
Spojevi Formule I mogu se pripraviti postupcima prema slijedećoj Shemi 1:
Shema 1
[image]
na kojoj je Y vodik ili aktivirajuća skupina (na pr., 2,5-dioksopirolidin-1-il (NBS) i slično), a R1, R2, R3 i R4 su definirani kao u Sažetku izuma.
Spojevi Formule I mogu se pripraviti reakcijom spoja Formule 2, ili njegovog zaštićenog derivata, sa spojem Formule R1OY, ili njegovog zaštićenog derivata, i potom neobaveznom deprotekcijom. Reakcija se provodi u nazočnosti prikladnog acilacijskog katalizatora (na pr., trietilamina) i u prikladnom otapalu (na pr., acetonitril, N, N-dimetilformamid (DMF), metilen klorid ili bilo koja njihova prikladna kombinacija) na 10 do 30°C, preporučljivo na oko 25°C, a za dovršenje zahtijeva 24 do 30 sati. Kada je Y vodik, reakcija se može izvesti u nazočnosti prikladnog sredstva za spajanje (na pr., benzotriazol-1-iloksitrispirolidinofosfonij heksafluorofosfat (PyBOP®), 1-(3-dimetilaminopropil)-3-etilkarbodiimid hidroklorid (EDC), O-benzotriazol-1-il-N,N,N',N'-tetrametiluronij heksafluorofosfat (HBTU), 1,3-dicikloheksilkarbodiimid (DCC), ili slično) i baze (na pr., N,N-diizopropiletilamin, trietilamin, ili slično), a dovršenje zahtijeva 2 do 15 sati. Alternativno, kada je Y vodik, reakcija se može provesti obradom spoja Formule R1OH s N-metilmorfolinom i izobutil kloroformatom u prikladnom otapalu (na pr., THF ili slično) na između 0 i 5°C, tijekom 30 minuta do jednog sata, a potom uvođenjem spoja Formule 2 u reakcijsku smjesu i ostavljanjem reakcije da se nastavi 12 do 15 sati.
Deprotekcija se može postići bilo kojim sredstvom koje uklanja zaštitnu skupinu i daje željeni proizvod u razumnom prinosu. Opsežan opis tehnika primjenjivih za stvaranje zaštitnih skupina i njihovo uklanjanje može se naći u TW Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc., 1981. Opsežan opis priprave spoja Formule I prema Shemi 1 iznijet je u Primjerima 4, 5, 6 i 8 koji slijede.
Alternativno, spojevi Formule I mogu se pripraviti reagiranjem spoja Formule 2 sa spojem formule R1-SS, pri čemu je SS prikladna kruta potpora (na pr., tiofenolna smola ili slično). Reakcija se može provesti u nazočnosti prikladnog acilacijskog katalizatora (na pr., 4-dimetilaminopiridina ili slično) u prikladnom otapalu (na pr., suhom pirimidinu ili slično), a za dovršenje je potrebno 60 do 70 sati. Podroban opis priprave spoja Formule I prema gore opisanim postupcima prikazan je u Primjeru 9 u kasnijem tekstu.
Spojevi Formule I mogu se pripraviti postupcima prema slijedećoj reakcijskoj Shemi 2:
Shema 2
[image]
na kojoj su R1, R2, R3 i R4 definirani kao u Sažetku izuma.
Spojevi Formule I mogu se pripraviti obradom spoja Formule 3, ili njegovog zaštićenog derivata, s amonijakom, čime se dobije odgovarajući amid, potom reakcijom amida s prikladnim sredstvom za dehidriranje (na pr. trifluoroocteni anhidrid, cijanurični klorid, tionil klorid, fosfonil klorid i slični) i neobaveznom deprotekcijom. Reakcija s amonijakom provodi se u prikladnom otapalu (na pr., metanol) na između 0 i 5°C, a za dovršenje je potrebno 6 do 10 dana. Reakcija sa sredstvom za dehidriranje provodi se u nazočnosti prikladne baze (na pr. trietilamin) i u prikladnom otapalu (na pr. tetrahidrofuran (THF) i slično), na između 0 i 50°C, a dovršenje zahtijeva 1 do 2 sata. Opsežan opis priprave spoja Formule I prema Shemi 2 iznijet je u Primjerima 7 i 8 koji slijede.
Dodatni postupci za pripravu spojeva Formule I
Spoj Formule I može se pripraviti kao farmaceutski prihvatljiva kisela adicijska sol, reakcijom spoja u obliku slobodne baze s farmaceutski prihvatljivom neorganskom ili organskom kiselinom. Alternativno, farmaceutski prihvatljiva bazna adicijska sol spoja Formule I može se pripraviti reakcijom slobodnog kiselinskog oblika spoja s farmaceutski prihvatljivom neorganskom ili organskom bazom. Neorganske i organske kiseline i baze prikladne za pripravu farmaceutski prihvatljivih soli spojeva Formule I prikazani su u odjeljku s definicijama ove prijave. Alternativno, solni oblici spojeva Formule I mogu se pripraviti pomoću soli početne tvari ili međuspojeva.
Slobodni kiseli ili slobodni bazični oblici spojeva Formule I mogu se pripraviti iz odgovarajućih baznih adicijskih soli ili kiselinskih adicijskih soli. Na primjer, spoj Formule I u obliku kisele adicijske soli može se prevesti u odgovarajuću slobodnu bazu izlaganjem prikladnoj bazi (na pr. otopina amonij hidroksida, natrij hidroksida itd.). Spoj formule I u obliku bazne adicijske soli može se prevesti u odgovarajuću slobodnu kiselinu izlaganjem prikladnoj kiselini (na pr. kloridna kiselina itd.).
N-oksidi spojeva Formule I mogu se pripraviti postupcima koji su poznati prosječno upućenima u struku.Na primjer, N-oksidi se mogu pripraviti obradom neoksidiranog oblika spoja Formule I s oksidirajućim sredstvom (na pr. trifluoroperoctena kiselina, permaleinska kiselina, perbenzojeva kiselina, peroctena kiselina, meta-kloroperoksibenzojeva kiselina itd.) u prikladnom inertnom organskom otapalu (na pr. halogeniranom ugljikovodiku, kao što je metilen klorid), na približno 0°C. Alternativno, N-oksidi spojeva Formule I mogu se pripraviti od N-oksida odgovarajuće početne tvari.
Spojevi Formule I u neoksidiranom obliku mogu se pripraviti od N-oksida spojeva Formule I, obradom s reducirajućim sredstvom (na pr. sumpor, sumporni dioksid, trifenil fosfin, litij borohidrid, natrij borohidrid, fosfor triklorid, tribromid itd.) u prikladno inertnom organskom otapalu (na pr. acetonitril, etanol, vodeni dioksan itd.) na 0 do 80°C.
Prolijek derivati spojeva Formule I mogu se pripraviti postupcima koji su poznati prosječno upućenima u struku (za više pojedinosti, vidi Saulnier i sur. (1994), Bioorganic and Medicinal Chemistry Letters. 4: 1985). Na primjer, odgovarajući prolijekovi se mogu pripraviti reakcijom nederiviranog spoja Formule I s prikladnim karbamilirajućim sredstvom (na pr. 1,1-aciloksialkilkarbonokloridat, para-nitrofenil karbonat itd.)
Zaštićeni derivati spojeva Formule I mogu se pripraviti postupcima koji su poznati prosječno upućenima u struku. Opsežan opis tehnika primjenjivih za stvaranje zaštitnih skupina i njihovo uklanjanje može se naći u TW Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc., 1981.
Spojevi Formule I mogu se pripraviti u obliku svojih pojedinačnih stereoizomera, reakcijom racemičke smjese spoja s optički aktivnim sredstvom za otapanje, čime se dobije par dijasteroizomeričkih spojeva, razdvajanjem dijastereomera i ponovnim dobivanjem optički čistog enantiomera. Iako se razdvajanje enantiomera može provesti pomoću kovalentnih dijastereomeričkih derivata spojeva Formule I, prednost se daje kompleksima koji mogu disocirati (na pr. kristalne dijastereoizomeričke soli). Dijastereomeri imaju različita fizikalna svojstva (na pr. talište, vrelište, topljivost, reaktivnost itd.) i mogu se lako razdvojiti zahvaljujući tim razlikama. Dijastereomeri se mogu razdvojiti kromatografijom ili, preporučljivo, tehnikama razdvajanja/odjeljivanja temeljenima na razlikama u topljivosti. Tako se dobije optički čisti enantiomer, zajedno sa sredstvom za razdvajanje, bilo kojim praktičnim načinom koji neće dovesti do racemiziranja. Opsežniji opis tehnika primjenjivih za razdvajanje stereoizomera spojeva iz njihovih racemičkih smjesa može se naći u Jean Jacques Andre Collet, Samuel H. Wilen. Enantiomers, Racemates and Resolutions. Honh Wiley & Sons, Inc. (1981).
U sažetku, predmet ovog izuma je postupak za pripravu spoja Formule I, koji obuhvaća:
(A) reakciju spoja Formule 2.
[image]
ili njegovog zaštićenog derivata, sa spojem formule R1OY, ili njegovog zaštićenog derivata, pri čemu je Y vodik ili aktivirajuća skupina, a R1, R2, R3 i R4 su definirani kao u Sažetku izuma; ili
(B) reakciju spoja Formule 3:
[image]
s amonijakom, čime se dobije odgovarajući amid, potom reakcijom amida s trifluorooctenim anhidridom, pri čemu su R1, R2, R3 i R4 definirani kao u Sažetku izuma;
(C) neobaveznu deprotekciju zaštićenog derivata spoja Formule I, čime se dobije odgovarajući nezaštićeni derivat;
(D) neobavezno prevođenje spoja Formule I u farmaceutski prihvatljivu sol;
(E) neobavezno prevođenje spoja Formule I iz oblika soli u ne-solni oblik;
(F) neobavezno prevođenje neoksidiranog oblika spoja Formule I u farmaceutski prihvatljiv N-oksid;
(G) neobavezno prevođenje N-oksidnog oblika spoja Formule I u neoksidirani oblik;
(H) neobavezno prevođenje nederiviranog spoja Formule I u farmaceutski prolijek derivat; i
(I) neobavezno prevođenje prolijek derivata spoja Formule I u nederivirani oblik.
Postupak za pripravu međuspojeva
Spojevi Formule 2 mogu se pripraviti reakcijom spoja Formule 4:
[image]
u kojoj je R19 amino zaštitna skupina, a svaki R2, R3 i R4 su definirani kao u Sažetku izuma, s tionil kloridom, te potom deprotekcija. Reakcija s tionil kloridom provodi se u nazočnosti prikladne baze (na pr. trietilamin) i u prikladnom otapalu (na pr. DMF) na između 0 i 5°C, a za dovršenje reakcije potrebno je 30 minuta do sat vremena. Alternativno, spojevi Formule 2 mogu se pripraviti reakcijom spoja Formule 4 s trifluorooctenim anhidridom. Deprotekcija se može postići bilo kojim načinom koji uklanja zaštitnu skupinu i daje željeni proizvod u razumnom prinosu. Podroban opis priprave spoja Formule 2 prema gore opisanoj proceduri prikazan je u Primjeru 1 u nastavku.
Spojevi Formule 4 mogu se pripraviti obradom odgovarajućeg alkanoil halida s amonijakom. Obrada se provodi u prikladnom otapalu (na pr. diklorometan, 5%-tna vodena otopina natrij karbonata i slično, ili bilo koja njihova prikladna kombinacija) na 10 do 30°C, a za dovršenje je potrebno 30 minuta do jedan sat.
Alkanoil halidni međuspojevi mogu se pripraviti od odgovarajuće alkanoilne kiseline, obradom s tionil kloridom u prikladnom otapalu (na pr. diklorometan) u dušiku, tijekom 30 minuta do jedan sat. Podroban opis priprave spoja Formule 2 prema gore opisanoj proceduri prikazan je u Primjeru 1 u nastavku.
Spojevi formule R1-SS mogu se pripraviti reakcijom spoja Formule 5(a) ili 5(b):
[image]
u kojem je R19 amino zaštitna skupina (na pr. terc-butoksikarbonil, fluoren-9-ilmetoksikarbonil ili slični), a X1, X2, X3, R5 i R7 su definirani za Formulu I u Sažetku izuma, s prikladnom krutom potpornom smolom (na pr. Wangova (4-benziloksibenzil alkohol) smola, tiofenolna smola i slične), i deprotekcijom, kojom se dobije spoj Formule 6(a), odnosno 6(b):
[image]
u kojem je SS kruta potpora, te potom reakcijom spoja Formule 6(a) ili 6(b) sa spojem formule R6OH (na pr. benzojeva kiselina, indol-5-karboksilna kiselina, metansulfonska kiselina i slične).
Reakcija između spoja Formule 5(a) ili 5(b) i smole provodi se u nazočnosti prikladnog vežućeg sredstva (na pr. benzotriazol-1-iloksitrispirolidinofosfonij heksafluorofosfat, diizopropilkarbodiimid (DIC), PyBOP®, EDC, HBTU, DCC i slični) i acilacijskog katalizatora (na pr. N,N-diizopropiletilamin, trietilamin, 4-dimetilaminopiridin, 1-hidroksibenzotriazol hidrat ili slično) u prikladnom otapalu (na pr. metilen klorid, DMF ili slično), a za dovršenje zahtijeva približno 3 do 20 sati. Deprotekcija se može provesti bilo kojim sredstvom koje uklanja zaštitnu skupinu i daje željeni proizvod u razumnom prinosu. Reakcija između spoja Formule 6(a) ili 6(b) se može provesti s prikladnim vežućim sredstvom i acilacijskim katalizatorom. Podroban opis priprave spoja formule R1-SS prema gore opisanoj proceduri prikazan je u Primjerima 2(A-C) i 4(A-C) u nastavku.
Spojevi formule R1OH mogu se pripraviti obradom spoja formule R1-SS sa prikladnom kiselinom (na pr. trifluorooctena kiselina ili slično) u prikladnom otapalu (na pr. metilen klorid ili slično). Alternativno, spojevi formule R1OH u kojima je X1 -C(O)-, a X2 je -CHR9-, mogu se pripraviti alkiliranjem organometalnog spoja Formule 7(a) ili 7(b):
[image]
sa spojem formule R9L, pri čemu je L odlazeća skupina, a X3, X4, R5, R6, R7 i R9 su definirani kao u Formuli I u Sažetku izuma, potom prevođenjem dobivenog etil estera u odgovarajuću kiselinu. Alkiliranje se provodi u prikladnom otapalu (na pr. THF) na -78°C do 0°C, a za dovršenje zahtijeva 1 do 2 sata. Prevođenje kiseline može se postići obradom estera litij hidroksidom tijekom približno 15 sati. Organometalni spoj se dobiva obradom odgovarajućeg organo spoja s odgovarajućom bazom (na pr. N,N-diizopropiletilamin, trietilamin i slično) i n-butillitijem ili terc-butillitijem na -80°C do -70°C, preporučljivo na oko -78°C, tijekom približno 30 minuta do jedan sat. Podroban opis priprave spoja formule R1OH prema gore opisanoj proceduri prikazan je u Primjeru 3 u nastavku.
Primjeri:
Spojevi Formule 2:
REFERENCA 1
2S -Amino-4-fenilbutironitril
Smjesa koja se sastoji od 2S-flouren-9-ilmetoksikarbonilamino-3-fenilpropionske kiseline (2 g, 5 mmol), tionil klorida (4 mL) i diklormetana (10 mL) se drži u refluksu u dušiku tijekom 30 minuta, te potom koncentrira. Ostatak se suspendira u 50% dietil eter/heksanu. Kruti dijelovi se prikupe filtriranjem, ispiru s vodom i suše (fosfor pentoksid) u vakuumskom desikatoru, čime se dobije 2S-flouren-9-ilmetoksikarbonilamino-3-fenilpropionil klorid (1.83 g, 4.35 mmol) u obliku bijele krute tvari, t.t. 120-122°C. Protonska NMR (300 MHz, CDCl3): δ 7.78 (d, J = 7 Hz, 2H), δ 7.59 (d, J = 7 Hz, 2H), δ 7.17 -7.45 (m, 9 H), δ 5.21 (bd, J = 7 Hz, 1H), δ 4.52 (m, 3H), δ 4.26 (t, J = 7 Hz, 1H), δ 2. 73 (m, 2H), δ 2.37 (m, 1H), δ 2.09 (m, 1H).
Smjesa koja se sastoji od 2S-flouren-9-ilmetoksikarbonilamino-3-fenilpropionil klorida (0.484 g. 1.15 mol), diklorometana (10 mL), 5% vodene otopine natrij karbonata (10 mL) i koncentriranog vodenog amonijaka (84 μL, 1.27 mmol) se energično miješa do stvaranja bijelog precipitata. Precipitat se prikupi filtriranjem, ispire s vodom i suši (fosfor pentoksid) u vakuumsom desikatoru, čime se dobije 2S-flouren-9-ilmetoksikarbonilamino-3-fenilpropionamid (0.375 g. 0.93 mmol) u obliku bijele krute tvari, t.t. 159-161 °C (dekomp.). Protonska NMR (300 MHz, DMSO-d6): δ 7.85 (d, J = 7.5 Hz, 2H), δ 7.71 (m, 2H), δ 7.50 (d, J = 8 Hz, 1H), δ 6.99-7.40 (m, 10H), δ 4.24 (m, 3H), δ 3.88 (m, 1H), δ 2.46 -2.65 (m, 2H), δ 1.70 -1.94 (m, 2H).
2S-Flouren-9-ilmetoksikarbonilamino-3-fenilpropionamid (0.235 g, 0.59 mmol) se otopi u hladnom DMF (5 mL, 0 do 5°C), potom se otopini dodaju trietilamin (0.33 mL, 2.35 mmol) i tionil klorid (0.59 mL, 1.17 mmol). Smjesa se hladi na između 0 i 5°C tijekom 30 minuta i potom se doda metanol (10 kapi). Smjesa se koncentrira in vacuo, a ostatak se usitni s 50% etil acetat/heksanima. Kruti dijelovi se prikupe filtriranjem, a proizvod se pročisti silika gel kromatografijom pomoću 20% etil acetat/heksana, čime se dobije flouren-9-ilmetil 1S-cijano-3-fenilpropilkarbamat (94 mg, 0.25 mmol) u obliku žutog praška, t.t. 110-113°C. Protonska NMR (300 MHz, DMSO-d6): δ 8.21 (d, J = 7 Hz, 1H), δ 7.85 (d, J = 7.5 Hz, 2H), δ 7.66 (d, J = 7.5 Hz, 2H), δ 7.14 -7.41 (m, 9H), δ 4.39 (d, J = 6 Hz, 3H), δ 4.22 (t, J = 6 Hz, 1H), δ 2.62 (t, J = 7.5 Hz, 2H), δ 2.00 (prividni q, J = 7.5 Hz, 2H). MS (electrospray): mH+ 383.
Smjesa koja se sastoji od flouren-9-ilmetil 1S-cijano-3-fenilpropilkarbamata (89 mg, 0.23 mmol), piperidina (0.2 mL) i bezvodnog DMF (1 mL) se miješa na sobnoj temperaturi tijekom 30 minuta, a zatim koncentrira. Proizvod se pročisti iz ostatka silika gel kromatografijom pomoću 2.5% metanol/diklorometana, čime se dobije 2S-amino-4-fenilbutironitril (27 mg, 0.17 mmol) u obliku ulja. Protonska NMR (300 MHz, CDCl3): δ 7.25 (m, 5H), δ 3.62 (t, J = 6 Hz, 1H), δ 2.83 (m, 2H), δ 2.08 (m, 2H). MS (electrospray): mH+ 161 (100%).
REFERENCA 2
2-benzoilamino-3-(2,6-diklorofenil)propionska kiselina
Otopina koja se sastoji od N,N-diizopropilamina (3.97 mL, 22.8 mmol) u suhom THF (57 mL) se hladi na -78 °C u dušiku, a potom se otopine n-butillitija u heksanima (14.25 mL, 22.8 mmol) i etil benzoilaminoacetata (2.37 g, 11.4 mmol) u suhom THF (23 mL) uzastopno dodaju kap po kap. Smjesa se miješa 1 sat, a zatim se kap po kap dodaje otopina sastavljena od 2,6-diklorobenzil bromida (1.87 g, 11.4 mmol) u suhom THF (2 mL). Smjesa se miješa 1 sat na -78 °C, a potom se ostavi 30 minuta da se ugrije. Smjesa se potom gasi s vodom (8 mL) i ekstrahira s etil acetatom (2 x 54 mL). Pomiješani ekstrakti se ispiru s 1M kloridnom kiselinom (1 x 27 mL) i zasićenom otopinom natrij klorida (1 x 27 mL), suše (Na2SO4) i koncentriraju na kružnom isparivaču. Proizvod se pročisti iz ostatka flash stupcem (silika gel, 10:90 do 50:50 vol/vol EtOAc-heksan), čime se dobije sirovi etil 2-benzoilamino-3-(2,6-diklorofenil)propionat. Propionatni ester se obradi s litij hidroksidom (118.8 mg, 4.96 mmol) u etanolu (12 mL) i vodi (50 mL) tijekom 15 sati. Smjesa se potom razrijedi s 1M kloridnom kiselinom (12 mL) i etil acetatom (24 mL). Vodeni sloj se izdvoji i ekstrahira s etil acetatom (2 x 4 mL). Pomiješani organski slojevi se ispiru sa zasićenom otopinom natrij klorida (25 mL), suše (Na2SO4), filtriraju i koncentriraju na kružnom isparivaču, čime se dobije 2-benzoilamino-3-(2,6-diklorofenil)propionska kiselina.
REFERENCA 3
2S- benzoilamino-3-(4-benziloksifenil)propionil-SS
Wangova smola (200-400 mesh, 300 mg) se ispire dva puta sa suhim DMF, a zatim pomiješa s otopinom sastavljenom od 3-(4-benziloksifenil)- 2-(9H-fluoren-9-ilmetoksikarbonilamino)propionske kiseline (0.51 g, 1.03 mmol, otopljene u minimalnoj količini suhog DMF), PyBOP® (0.54 g, 1.03 mmol) i N,N-diizopropiletilamina (0.18 mL. 1.03 mmol). Smjesa se protresa, a zatim se ostavi slijegati 3 sata. Smola se odijeli iz otopinske faze i ispire dva puta s DMF, čime se dobije 3-(4-benziloksifenil)-2-(9H -fluoren-9-ilmetoksikarbonilamino)propionil-SS.
3-(4-benziloksifenil)-2-(9H -fluoren-9-ilmetoksikarbonilamino)propionil-SS se obradi s 20% (vol/vol) piperidina u DMF u tri dijela, za 3, 7 i 20 minuta uz protresanje smjese i uklanjanje otopinske faze nakon svake obrade. Smola se zatim tri puta ispire s DMF, po jednom s metanolom, DMF i metanolom, a zatim ponovno tri puta s DMF, čime se dobije 2-amino-3-(4-benziloksifenil)propionil-SS. Smjesa sastavljena od 2-amino-3-(4-benziloksifenil)propionil-SS se pomiješa s benzojevom kiselinom (125.8 mg, 1.03 mmol, otopljena u minimalnoj količini suhog DMF), PyBOP® (0.54 g, 1.03 mmol) i N,N-diizopropiletilaminom (0.18 mL, 1.03 mmol), protresa i potom ostavi slijegati tijekom 3 sata. Smola se razdijeli, ispire po dva puta s DMF, metanolom i metilen kloridom, čime se dobije 2S-benzoilamino-3-(4-benziloksifenil)propionil-SS.
REFERENCA 4
4-[2-(4-aminobenzoilamino)-4-metilvaleriloksi]-SS
Otopina sastavljena od 2-terc-butoksikarbonilamino-4-metilvalerične kiseline, monohidrata (7 g, 28 mmol) u toluenu (50 mL) se koncentrira. Ostatak se otopi u metilen kloridu, a zatim se doda DIC (4.4 mL, 28 mmol). Smjesa se pomiješa sa suspenzijom tiofenolne smole (5 g. 1.4 mmol/g punjenja) u metilen kloridu (50 mL), a zatim se smjesi doda 4-dimetilaminopiridin (0.34 g, 2.8 mmol). Smjesa se protresa 14 sati i filtrira. Smola se ispire po dva puta s metilen kloridom, 15% trimetilaminom u metilen kloridu i metanolom, te suši, čime se dobije 4-terc-butoksikarbonil-4-metilvaleril-SS (6.4 g. 1 mmol/g punjenja) u obliku žute krute tvari.
4-[terc-Butoksikarbonil-4-metilvaleril-SS (6.6 g) se obrađuje s 50:48:2 (vol/vol) trifluorooctena kiselina/metilen klorid/anisolom (50 mL) jedan sat. Smola se izolira i ispire po dva puta s metilen kloridom, 15% trimetilaminom u metilen kloridu i metanolom, te suši, čime se dobije 4-[4-metilvaleriloksi]-SS (5.8 g, 1.38 mmol/g punjenja).
Smjesa sastavljena od 4-terc-butoksikarbonilaminometilbenzojeve kiseline (0.38 g, 1.5 mmol), 1-hidroksibenzotriazol hidrata (0.2 g), HBTU (0.57 g, 1.5 mmol), 4-[4-metilvaleriloksi]-SS (0.4 g, 0.55 mmol), diizopropiletilamina (0.26 mL, 1.5 mmol) i dimetilformamida (10 mL) se zatali u staklene ampule i protresa 16 sati. Smola se izolira filtriranjem smjese i ispire po dva puta s dimetilformamidom, metilen kloridom, metanolom i 1,4-dioksanom, čime se dobije 4-[2-(4-terc-butoksikarbonilaminobenzoilamino)-4-metil valeriloksi]-SS.
4-[2-(4-terc-butoksikarbonilaminobenzoilamino)-4-metilvaleriloksi]-SS se obradi s 50:48:2 (vol/vol) trifluorooctena kiselina/metilen klorid/anisolom, čime se dobije 4-[2-(4-aminobenzoilamino)-4-metilvaleriloksi]-SS.
Postupcima kao u Referenci 4 dobiju se slijedeći spojevi:
4-[2-(3-dimetilaminopirid-4-ilkarbonilamino)valeriloksi]-SS;
4-{2-[6-(1H-imidazol-1-il)pirid-3-ilkarbonilamino]valeriloksi}-SS;
4-[2-(6-dimetilaminopirid-3-ilkarbonilamino)valeriloksi]-SS;
4-{2-[6-(4-metilpiperazin-1-il)pirid-3-ilkarbonilamino]valeriloksi} -SS;
4-[2-(2-pirolidin-1-ilpirid-4-ilkarbonilamino)valeriloksi]-SS;
4-[2-(6-morfolin-4-ilpirid-3-ilkarbonilamino)valeriloksi]-SS;
4-[2-(6-piperidin-1-ilpirid-3-ilkarbonilamino)valeriloksi]-SS;
4-[2-(6-pirolidin-1-ilpirid-3-ilkarbonilamino)valeriloksi]-SS;
4-[2-(2-piperidin-1-ilpirid-4-ilkarbonilamino)valeriloksi]-SS;
4-[2-(2-morfolin-4-ilpirid-4-ilkarbonilamino)valeriloksi]-SS;
4-{2-[2-(1H-imidazol-1-ilpirid-4-ilkarbonilamino]valeriloksi} -SS;
4-{2-[2-(4-metilpiperazin-1-il)pirid-4-ilkarbonilamino]valeriloksi} -SS;
4-[2-(3-dimetilaminometilbenzoilamino)valeriloksi]-SS;
4-[2-(3-piperidin-1-ilmetilbenzoilamino)valeriloksi]-SS;
4-[2-(4-hidroksi-3-morfolin-4-ilmetilbenzoilamino)valeriloksi]-SS; i
4-[2-(4-terc-butoksikarbonilaminometilbenzoilamino)valeriloksi]-SS; pri čemu je SS Wangova smola.
REFERENCA 5
2S-benzoilamino-3-(4-benziloksifenil)propionska kiselina
2S-benzoilamino-3-(4-benziloksifenil)propionil-SS pripravljena kao u Primjeru 3 se obrađuje s 90:10 (vol/vol) trifluorooctena kiselina/metilen kloridom tijekom jednog sata. Smjesa se filtrira i smola se poniješa s metilen kloridom. Smjesa se protresa, ostavi se slijegati 10 minuta i potom se filtrira. Pomiješani filtrati se koncentriraju na kružnom isparivaču, čime se dobije sirovi 2S-benzoilamino-3-(4-benziloksifenil) propionska kiselina, koja se koristi bez pročišćavanja.
REFERENCA 6
2-amino- N -cijanometil-4-metilpentanamid
Otopina sastavljena od 2-terc-butoksikarbonilamino-4-metilvalerične kiseline (5 g, 30 mmol) u DMF (20 mL) se hladi u ledenoj kupelji, potom se otopini uzastopno dodaju aminoacetonitril hidroklorid (3 g, 30 mmol), PyBOP® (11.25 g, 21 mmol) i trietilamin (6 mL, 60 mmol). Smjesa se miješa 2 sata, a zatim koncentrira u vakuumu. Ostatak se razdijeli između etil acetata (50 mL) i zasićenog natrij bikarbonata (40 mL). Organski sloj se odvoji, ispire vodom, 1M kloridnom kiselinom (20 mL), vodom i otopinom soli, suši (MgSO4) i koncentrira pri smanjenom tlaku. Proizvod se pročisti iz ostatka pomoću sloja silike s etil acetatom kao sredstvom za ispiranje, čime se dobije terc-butil 1-cijanometilkarbamoil-3-metilbutilkarbamat.
Smjesa koja se sastoji od terc-butil 1-cijanometilkarbamoil-3-metilbutilkarbamata i bezvodne p-toluensulfonske kiseline (3 eq.) u metilen kloridu (20 mL) se miješa približno 12 sati. Smjesa se filtrira, prikupljena kruta tvar se usitni nekoliko puta s eterom kako bi se uklonio višak kiseline i potom suši u vakuumu, čime se dobije sol 2-amino-N-cijanometil-4-metilpentanamid p-toluensulfonske kiseline.
PRIMJER 1
Benzil (S)-1-cijanometilkarbamoil-3-metilbutilkarbamat
(Spoj 1)
[image]
Smjesa koja se sastoji od 2.5-dioksopirolidin-1-il 2-benziloksikarbonilamino-4-metilvalerata (39.6 g. 0.109 mol), aminoacetonitril hidroklorida (10.1 g, 0.109 mol), trietilamina (61 mL, 0.436 mol), DMF (40 mL) i acetonitrila (360 mL) se miješa na sobnoj temperaturi 27 sati. Smjesa se filtrira, koncentrira do volumena od 100 mL i ulije u ledenu vodu (1000 mL). Smjesa se miješa do pojave precipitata. Precipitat se prikupi, ispire s vodom i suši. Suhi proizvod se rekristalizira iz 55% etanol/vode (80 mL). Kristali se prikupe i rekristaliziraju iz 65% etanol/vode (70 mL). Kristali se prikupe i suše, čime se dobije benzil (S)-1-cijanometilkarbamoil-3-metilbutilkarbamat (21.1 g, 0.067 mol) u obliku bijelih iglica, t.t. 120-121 °C. Protonska NMR (300 MHz, DMSO-d6): δ 8.68 (t, J = 6 Hz, 1H), δ 7.54 (d, J = 8 Hz, 1H), δ 7.33 (m, 5H), δ 5.00 (Abq, 2H), δ 4.09 (d, J = 6 Hz, 2H), δ 4.03 (m, 1H), δ 1.24 -1.64 (m, 3H), δ 0.84 (prividni t, J = 7 Hz, 6H). MS (electrospray): mH+ 303.9 (100%). Izrač. za C16H21N3O3 : C, 63.35; H, 6.98; N, 13.85. Nađeno: C, 63.55; H, 7.01; N, 13.74.
Postupcima kao u Primjeru 1 dobiju se slijedeći spojevi Formule I:
benzil 1S-cijanometilkarbamoil-2-metilbutilkarbamat (Spoj 2); Protonska NMR (300 MHz, DMSO-d6): δ 8. 72 (bt, 1H), δ 7.50 (d, J = 8Hz, 1H), δ 7.35 (s, 5H), δ 5.02 (s, 2H), δ 4.13 (m, 2H), δ 3.85 (prividni t, 1H), δ 1. 75 (m, 1H), δ 1.42 (m, 1H), δ 1.14 (m, 1H), δ 0.80 (m, 6H).
PRIMJER 2
2-cijanometilkarbamoilpiperidin-2-karboksilat
(Spoj 3)
[image]
Smjesa koja se sastoji od 1-benziloksikarbonilpiperidin-2-karboksilne kiseline (0.425 g, 1.61 mmol), aminoacetonitril hidroklorida (0.149 g, 1.61 mmol), PyBOP® (0.838 g, 1.61 mmol), N,N-diizopropiletilamina (0.84 mL, 4.83 mmol) i DMF (10 mL) se miješa na sobnoj temperaturi 2.5 sata. Smjesa se koncentrira, a ostatak se prenese u diklorometan. Diklorometanska smjesa se ispire s 1N kloridnom kiselinom, vodom i vodenim natrij bikarbonatom, suši (MgSO4), filtrira i koncentrira. Proizvod se pročisti iz ostatka silika gel kromatografijom pomoću 5% metanola u diklorometanu, čime se dobije 2-cijanometilkarbamoilpiperidin-2-karboksilat (435 mg, 1.53 mmol) u obliku ulja. Protonska NMR (300 MHz, DMSO-d6): δ 8.65 (bs, 1H), δ 7.34 (bs, 5H), δ 5.05 (bs, 2H), δ 4.64 (d, J = 4 Hz, 1H), δ 4.11 (d, J = 5.4 Hz, 2H), δ 3.87 (prividni d, J = 12 Hz, 1H), δ 3.02 (m, 1H), δ 2.03 (m, 1H), δ 1.55 (prividni d, J = 8 Hz, 3H), δ 1.06 -1.20 (m, 2H); MS (electrospray): mH+301.9.
Postupcima kao u Primjeru 2 dobiju se slijedeći spojevi Formule I:
N-(1-cijanometilkarbamoil-3-metilbutil)-3-(2-gvanidinotiazol-4-il)benzamid (Spoj 4); Protonska NMR (300 MHz, DMSO-d6): δ 8.77 (bt, 1H), δ 8.71 (d, J = 7 Hz, 1H), δ 8.36 (bs, 1H), δ 8.11 (d, J = 7 Hz, 1H), δ 7.88 (m, 2H), δ 7.54 (t, J = 7Hz, 1H), δ 4.52 (m, 1H), δ 4.12 (d, J = 6Hz, 2H), δ 1.50 -1.78 (m, 3H), δ 0.88 (dd, 6H); MS (electrospray): mH+ 414 (100%);
benzil (S)-1-(N-cijanometil)-N-metilkarbamoil-3-metilbutilkarbamat (Spoj 5); Protonska NMR (300 MHz,CD3OD): δ 7.70 (d, J = 7Hz, 1H), δ 7.41 (m, 5H), δ 5.02 (s, 2H), δ 4.43 (m, 3H), δ 3.14 (s, 3H), δ 1.24 -1.68 (m, 3H), δ 0.88 (dd, 6H); MS (PCI): mH+318;
N-(1S-cijanometilkarbamoil-3-metilbutil)piperidin-4-karboksamid (Spoj 6); Protonska NMR (300 MHz, CD3OD): δ 8.72 (bt, 1H), δ 8.57 (bs, 2H), δ 8.19 (d, J = 7Hz, 1H), δ 4.32 (m, 1H), δ 4.11 (d, J = 6Hz, 2H), δ 2.80 -3.18 (m, 3H), δ 1.36 -1.80 (m, 9H), δ 0.86 (dd, 6H); 13C NMR (67.9 MHz, CDCl3): δ 173.8, 173.5, 118.1, 51.1, 42.9, 42.8, 39.2, 27.6, 25.9, 25.1, 24.8, 23.5, 21.8; MS (electrospray): mH+ 281 (100%); benzil 1S-cijanometilkarbamoilpentilkarbamat (Spoj 7); Protonska NMR (300MHz,DMSO-d6): δ 8.65 (bt, 1H), δ 7.55 (d, J = 7Hz, 1H), δ 7.41 (bs, 5H), δ 5.00 (Abq, 2H), δ 4.08 (d, J = 6Hz, 2H), δ 3.97 (m, 1H), δ 1.52 (m, 2H), δ 1.24 (m, 4H), δ 0.81 (bs, 3H);
benzil 1S-cijanometilkarbamoil-2-naft-2-iletilkarbamat (Spoj 8); Protonska NMR (300 MHz, DMSO-d6): δ 8.81 (bt, 1H), δ 7.84 (m, 4H), δ 7.48 (m, 3H), δ 7.21 (m, 5H), δ 4.95 (Abq, 2H), δ 4.40 (m, 1H), δ 4.12 (d, J = 7Hz, 2H), δ 3.08 (m, 2H);
N-(1S-cijanometilkarbamoilmetilbutilindol)-4-karboksamid (Spoj 9); Protonska NMR (300 MHz, DMSO-d6): δ 11.34 (s, 1H), δ 8.67 (bt, 1H), δ 8.30 (d, J = 7Hz, 1H), δ 7.54 (t, J = 6Hz, 2H), δ 7.46 (s, 1H), δ 7.17 (t, J = 6Hz, 1H), δ 6.88 (s, 1H), δ 4.56 (m, 1H), δ 4.12 (d, J = 5Hz, 2H), δ 1.60 (m, 3H), δ 0.90 (prividni t, 6H);
N-(1S-cijanometilkarbamoilmetilbutilindol)-6-karboksamid (Spoj 10); Protonska NMR (300 MHz, DMSO-d6): δ 11.45 (s, 1H), δ 8. 70 (bt, 1H), δ 8.48 (d, J = 5Hz, 1H), δ 8.01 (s, 1H), δ 7.57 (s, 2H), δ 7.49 (s, 1H), δ 6.48 (s, 1H), δ 4.53 (m, 1H), δ 4.12 (d, J = 5Hz, 2H), δ 1.47- 1.80 (m, 3H), δ 0.89 (m, 6H);
N-(1-cijanometilkarbamoil-3-metilbutil)-3-(4-metilpiperazin-1-ilmetil)benzamid (Spoj 11); i
N-[3-(1-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]-4-metilpiperazin-1-karboksamid (Spoj 12).
PRIMJER 3
Benzil 2S-cijanometilkarbonil-4-metilpirolidin-1-karboksilat
(Spoj 13)
[image]
Otopina sastavljena od 1-benziloksikarbonilpirolidin-2S-karboksilne kiseline (183 mg, 0. 70 mmol) u THF (10mL) se hladi na između 0 i 5 °C, potom se dodaju N-metilmorfolin (70 mg, 0. 70 mmol) i izobutil kloroformat (105 mg, 0.77 mmol). Smjesa se miješa na niskoj temperaturi 30 minuta, potom se dodaju aminoacetonitril hidroklorid (71 mg, 0.77 mmol) i N-metilmorfolin (140 mg, 1.4 mmol). Reakcija se ostavi napredovati dodatnih 12 sati, a potom se filtrira. Filtrat se koncentrira, a ostatak se razdijeli između diklorometana i 1N vodene kloridne kiseline. Organska faza se odvoji, ispire sa zasićenim natrij bikarbonatom i zasićenim natrij kloridom, suši (MgSO4), filtrira i koncentrira. Proizvod se pročisti iz ostatka silika kromatografijom pomoću 5% metanola u diklorometanu, čime se dobije benzil 2S-cijanometilkarbonil-4-metilpirolidin-1-karboksilat (42.0 mg, 0.14 mmol) u obliku bezbojnog ulja. Protonska NMR (300 MHz, DMSO-d6): δ 8.71 (m, 1H), δ 7.42 (m, 5H), δ 5.07 (m, 2H), δ 4.12 (m, 3H), δ 3.74 (m, 1H), δ 2.93 (prividni q, 1H), δ 2.08 -2.50 (m, 3H), δ 1.45 (m, 1H), δ 0.95 (2d, 3H). 13C NMR (67.9 MHz, CD3OD): δ 173.4, 173.0, 155.0, 154.1, 137.4, 137.3, 129.0, 128.9, 127.7 , 118.0, 66.6, 60.9, 60.5, 54.6, 54.2, 39.5, 33.1, 32.4, 27.6, 27.5, 17.4, 17.3.
Postupcima kao u Primjeru 3 dobiju se slijedeći spojevi Formule I: benzil 2S-cijanometilkarbamoil-3-azabiciklo[3.1.0]heksan-3-karboksilat (Spoj 14); Protonska NMR (300 MHz, DMSO-d6): δ 8.92 (m, 1H), δ 7.40 (m, 5H), δ 5.02 (m, 2H), δ 4.18 (dd, J = 5, 14Hz, 2H), δ 3.58 (m, 2H), δ 1.60 (m, 2H), δ 0.85 (m, 1H); i
N-(1S-cijanometilkarbamoilmetibutil) benzamid (Spoj 15); Protonska NMR (300 MHz, DMSO-d6): δ 8. 74 (bt, 1H), δ 8.53 (d, J = 7Hz, 1H), δ 7.94 (d, J = 6Hz, 2H), δ 7.49 (m, 3H), δ 4.48 (m, 1H), δ 4.11 (d, J = 6Hz, 2H), δ 1.45 -1.75 (m, 3H), δ 0.88 (dd, 6H);
PRIMJER 4
4-Aminometil-N-(1-cijanometilkarbamoil-3-metilbutil) benzamid
(Spoj 16)
[image]
Suspenzija sastavljena od 4-[2-(4-aminobenzoilamino)-4-metilvaleriloksi]-SS, pripravljene kao u Primjeru 4, aminoacetonitril hidroklorida (3 mg, 3.2 mmol) i 4-dimetilaminopiridina (20 mg, mmol) u suhom pirimidinu (8 mL) se zatali u polietilenske cjevčice i protresa 60 sati. Smjesa se filtrira, a smola se ispire piridinom i metanolom. Pomiješani filtrat se koncentrira in vacuo, a ostatak se otopi u 50:50 (vol/vol) voda/acetonitrilu. Otopina se filtrira i proizvod se pročisti iz otopine pomoću RP-HPLC, čime se dobije 4-aminometil-N-(1-cijanometilkarbamoil-3-metilbutil)benzamid (71 mg, 0.23 mmol) u obliku bijele krute tvari.
1H NMR (270 MHz, DMSO-d6): δ 0.86 (d, 3, J = 6.2 Hz), δ 0.90 (d, 3, J = 5.9 Hz), δ 1.48-1.77(m,3), δ 4.10-4.14 (m,4), δ 4.50 (m, 1), δ 7.53 (d,2,J=7.9Hz), δ 7.95 (d, 2, J = 8.2 Hz), δ 8.25 (2, br), δ 8.61 (d, 1, J = 7.9 Hz), δ 8. 77 (t, 1, J = 5.4 Hz). ESI-MS m/z 303 (M+1).
Postupcima kao u Primjeru 4 dobiju se slijedeći spojevi Formule I:
N-(1 S-cijanometilkarbamoil- 3-metilbutil)- 2-dimetilaminoizonikotinamid (Spoj 17); 1H NMR (270 MHz, DMSO-d6): δ 0.86 (d, 3, J = 5.2 Hz), δ 0.90 (d, 3, J = 4.7 Hz), δ 1.52 -1.74 (m, 3), δ 3.15 (s, 6), δ 4.14 (d, 2, J = 4.9 Hz), δ 4.51 (m, 1), δ 7.08 (d, 1, J = 5. 7 Hz), δ 7.26 (s, 1), δ 8.12 (d, 1J = 5.9 Hz), δ 8.81 (t, 1, J = 5.0 Hz), δ 8.89 (d, 1, J = 7.7 Hz); ESI-MS m/z 318 (M+1);
N-(1S-cijanometilkarbamoil-3-metilbutil)-6-imidazol-1-ilnikotinamid (Spoj 18); 1H NMR (270 MHz, DMSO-d6): δ 0.88 (d, 3, J = 4.9 Hz), δ 0.92 (d, 3, J = 5.1 Hz), δ 1.55 -1.74 (m, 3), δ 4.14 (d, 2, J = 5.4 Hz), δ 4.54 (m, 1), δ 7.61 (s, 1), δ 8.07 (d, 1, J = 8.7 Hz), δ 8.33 (s, 1), δ 8.54 (d, 1, J = 8.3 Hz), δ 8.81 (t, 1, J = 5.3 Hz), δ 8.92 (d, 1, J = 7.3 Hz), δ 9.02 (s, 1), δ 9.42 (s, 1); ESI-MS m/z 341 (M+1);
N-(1S-cijanometilkarbamoil-3-metilbutil)6-dimetilaminonikotinamid (Spoj 19); 1H NMR (270 MHz, DMSO-d6): δ 0.85 (d, 3, J = 5.2 Hz), δ 0.89 (d, 3, J = 5.2 Hz), δ 1.52 -1.67 (m, 3), δ 3.15 (s, 6), δ 4.12 (d, 2, J = 4.9 Hz), δ 4.48 (m, 1), δ 6.91 (d, 1, J = 8.9 Hz), δ 8.12 (d, 1, J = 9.3 Hz), δ 8.48 (d, 1, J = 7.1 Hz), δ 8.55 (s, 1), δ 8.72 (t, 1, J = 5.0 Hz); ESI-MS m/z 318 (M+1);
N-(1S-cijanometilkarbamoil-3-metilbutil)-6-(4-metilpiperazin-1-il)nikotinamid (Spoj 20); 1H NMR (270 MHz, DMSO-d6): δ 0.84 (d, 3, J = 5.9 Hz), δ 0.89 (d, 3, J = 5.9 Hz), δ 1.50 -1.73 (m, 3), δ 2.84 (s, 3), δ 3.02 -3.23 (m, 4), δ 3.51 (d, 2, J = 10.8 Hz), δ 4.12 (d, 2, J = 5.5 Hz), δ 4.46 -4.56 (m, 3), δ 7.00 (d, 1, J = 9.1 Hz), δ 8.10 (dd, 1, J = 2.4, 8.9 Hz), δ 8.42 (d, 1, J = 7.9 Hz), δ 8.70 (d, 1, J=2.2 Hz), δ 8.73 (t, 1, J = 5.8 Hz), δ 9.88 (br. s, NH+); ESI-MS m/z 373 (M+1);
N-(1S-cijanometilkarbamoil-3-metilbutil)-2-pirolidin-1-ilizonikotinamid (Spoj 21); 1H NMR (270 MHz, DMSO-d6): δ 0.86 (d, 3, J = 5.4 Hz), δ 0.90 (d, 3, J = 5.6 Hz), δ 1.53 -1.69 (m, 3), δ 2.02 (br. s, 4), δ 3.55 (br. s, 4), δ 4.14 (d, 2, J = 5.2 Hz), δ 4.52 (m, 1), δ 7.13 (d, 1, J = 6.4 Hz), δ 7.32 (s, 1), δ 8.08 (d, 1, J = 6.4 Hz), δ 8.87 (t, 1, J = 5.4 Hz), δ 9.04 (d, 1, J = 7.9 Hz); ESI-MS m/z 344 (M+1);
N-(1S-cijanometilkarbamoil-3-metilbutil)-6-morfolin-4-ilnikotinamid (Spoj 22); 1H NMR (270 MHz, DMSO-d6): δ 0.84 (d, 3, J = 5. 7 Hz), δ 0.89 (d, 3, J = 5.9 Hz), δ 1.50 -1.72 (m, 3), δ 3.56 (t, 4, J = 4.5 Hz), δ 3.68 (t, 4, J = 4.5 Hz), δ 4.11 (d, 2, J = 5.2 Hz), δ 4.47 (m, 1), δ 6.89 (d, 1, J = 9.1 Hz), δ 8.06 (dd, 1, J = 2.2, 8.9 Hz), δ 8.38 (d, 1, J = 8.1 Hz), δ 8.65 -8.69 (m, 2); ESI-MS m/z 360 (M+1);
N-[1S-cijanometilkarbamoil-3-metilbutil]-3,4,5,6- tetrahidro-2H-[1,2’]bipiridinil-5'-karboksamid (Spoj 23); 1H NMR (270 MHz, DMSO-d6): δ 0.84 (d, 3, J = 3.3 Hz), δ 0.89 (d, 3, J = 5.9 Hz), δ 1.49 -1.72 (m, 9), δ 3.65 (br. s, 4), δ 4.11 (d, 2, J = 5.4 Hz), δ 4.48 (m, 1), δ 7.03 (d, 1, J = 8.9 Hz), δ 8.09 (d, 1, J = 9. 7 Hz), δ 8.44 (d, 2, J = 7.6 Hz), δ 8.56 (s, 1), δ 8.70 (t, 1, J =5.4 Hz); ESI-MS m/z 358 (M+1);
N-[1S-cijanometilkarbamoil-3-metilbutil]-6-pirolidin-1-ilnikotinamid (Spoj 24); 1H NMR (270 MHz, DMSO-d6): δ 0.85 (d, 3, J = 5. 7 Hz), δ 0.89 (d, 3, J=5.9Hz), δ 1.50-1.71 (m, 3), δ 2.00 (m, 4), δ 3.50 (m, 4), δ 4.12(d, 2, J=5.4 Hz), δ 4.48 (m, 1), δ 6.84 (br. s, 1), δ 8.16 (d, 1, J = 10.1 Hz), δ 8.51 (m, 2), δ 8.75 (t, 1, J = 5.9 Hz); ESI-MS m/z 344 (M+1);
N-[1S-cijanometilkarbamoil-3-metilbutil]-3,4,5,6- tetrahidro-2H-[1,2’]bipiridinil-4'-karboksamid (Spoj 25); 1H NMR (270 MHz, DMSO-d6): δ 0.85 (d, 3, J = 5. 7 Hz), δ 0.90 (d, 3, J = 5.7 Hz), δ 1.55 -1.73 (m, 9), δ 3.64 (br. s, 4), δ 4.13 (d, 2, J=5.4 Hz), δ 4.51 (m, 1), δ 7.08 (d, 1, J=5.9 Hz), δ 7.45 (s, 1), δ 8.11 (d, 1, J = 5.9 Hz), δ 8.83 (t, 1, J = 6.2 Hz), δ 8.92 (d, 1, J = 7.9 Hz); ESI-MS m/z 358 (M+1); N-[1S-cijanometilkarbamoil-3-metilbutil-2-morfolin-4-il]-izonikotinamid (Spoj 26); 1H NMR (270 MHz, DMSO-d6): δ 0.85 (d, 3, J = 5.7 Hz), δ 0.90 (d, 3, J = 5.7 Hz), δ 1.52 -1.73 (m, 3), δ 3.52 (t, 4, J = 4.6 Hz), δ 3.73 (t, 4, J = 4.6 Hz), δ 4.13 (d,2, J=5.4 Hz), δ 4.51 (m, 1), δ 7.12 (d, 1, J=5.4 Hz), δ 7.31 (s, 1), δ 8.21 (d, 1, J = 5.4 Hz), δ 8.78 (m, 2); ESI-MS m/z 360 (M+1);
N-[1S-cijanometilkarbamoil-3-metilbutil-2-imidazol-4-il]-izonikotinamid (Spoj 27); 1H NMR (270 MHz, DMSO-d6): δ 0.88 (d, 3, J = 5.9 Hz), δ 0.92 (d, 3, J = 5.9 Hz), δ 1.55 -1.72 (m, 3), δ 4.16 (d, 2, J = 5.7 Hz), δ 4.56 (m, 1), δ 7.71 (s, 1), δ 7.96 (d, 1, J = 5.2 Hz), δ 8.33 (s, 1), 8.37 (s, 1), δ 8.76 (d, 1, J = 5.1 Hz), δ 8.90 (t, 1, J = 5.4 Hz), δ 9.04 (d, 1, J = 7.9 Hz), δ 9.58 (s, 1); ESI-MS m/z 341 (M+1);
N-[1S-cijanometilkarbamoil-3-metilbutil-2-(4-metilpiperazin-1-il)]-izonikotinamid (Spoj 28); 1H NMR (270 MHz, DMSO-d6): δ 0.86 (d, 3, J = 5.9 Hz), δ 0.91 (d, 3, J = 5.9 Hz), δ 1.54 -1.74 (m, 3), δ 2.85 (s, 3), δ 3.05 -3.24 (m, 4), δ 3.53 (d, 2, J = 10.9 Hz), δ 4.14 (d, 2, J = 5.4 Hz), δ 4.43 -4.56 (m, 3), δ 7.18 (d, 1, J = 5.2Hz), δ 7.33 (s, 1), δ 8.27 (d, 1, J =4.9Hz), δ 8.75 (d, 1, J = 7.9 Hz), δ 8.81 (t, 1, J = 5.1 Hz), δ 9.9 (br. s, NH+); ESI-MS m/z 373 (M+1);
N-[1S-cijanometilkarbamoil-3-metilbutil-3-dimetilaminometil]benzamid (Spoj 29); 1H NMR (270 MHz, DMSO-d6): δ 0.86 (d, 3, J = 6.2 Hz), δ 0.91 (d, 3, J = 6.2 Hz), δ 1.52 -1.71 (m, 3), δ 2.74 (s, 6), δ 4.13 (d, 2, J = 5.7 Hz), δ 4.33 (d, 2, J = 4. 7 Hz), δ 4.53 (m, 1), δ 7.58 (t, 1 , J = 7.6 Hz), δ 7.65 (d, 1 , J = 7.7 Hz), δ 8.00 (s, 1), 8.02 (d, 1, J=9.1 Hz), δ 8.65 (d, 1, J=7.0 Hz), δ 8.80 (t, 1, J=5.4Hz), δ 9.68 (br.s, NH+). ESI-MS m/z 331 (M+ 1);
N-[1S-cijanometilkarbamoil-3-metilbutil-3-piperidin-1-ilmetil]benzamid (Spoj 30); 1H NMR (270 MHz, DMSO-d6): δ 0.86 (d, 3, J = 6.2 Hz), δ 0.91 (d, 3, J = 6.2 Hz), δ 1.32 -1.84 (m, 9), δ 2.90 (m,2), δ 3.31 (m, 2), 4.13 (d, 2, J = 5.7 Hz), δ 4.34 (s, 2), δ 4.53 (m, 1), δ 7.58 (t, 1, J = 7.7 Hz), δ 7.65 (d, 1, J = 6.9 Hz), δ 8.01 (s, 1), 8.03 (d, 1, J = 9.1 Hz), δ 8.65 (d, 1, J = 7.7 Hz), δ 8.79 (t, 1, J = 5.4 Hz), δ 9.38 (br. s, NH+); ESI-MS m/z 371 (M+1);
N-[1S-cijanometilkarbamoil-3-metilbutil]4-hidroksi-3-morfolin-4-ilmetilbenzamid (Spoj 31); 1H NMR (270 MHz, DMSO-d6): δ 0.85 (d, 3, J = 6.2 Hz), δ 0.90 (d, 3, J = 6.2 Hz), δ 1.48 -1.75 (m, 3), δ 3.1 B 3.3 (m, 4), δ 3.60 B 3.68 (m, 2), δ 3.89 B 3.97 (m, 2), δ 4.12 (d, 2, J = 5.4 Hz), δ 4.30 (s, 2), δ 4.50 (m, 1), δ 6.97 (d, 1, J = 8.4 Hz), δ 7.92 (d, 1, J = 8.7 Hz), δ 7.97 (s, 1), δ 8.36 (d, 1, J = 7.9 Hz), δ 8.75 (t, 1, J = 5.2 Hz), δ 9.7 (br. s, NH+), δ 10.9 (br. s, OH); ESI-MS m/z 389 (M+1); i
terc-butil ester 4-[1S-cijanometilkarbamoil-3-metilbutilkarbamoilbenzil]karbamat (Spoj 32); 1H NMR (270 MHz, DMSO-d6): δ 0.85 (d, 3, J = 6.0 Hz), δ 0.89 (d, 3, J = 6.2 Hz), δ 1.39 (s, 9), δ 1.50 -1.75 (m, 3), δ 4.11 (d, 2, J = 5.6 Hz), δ 4.15 (s, 2), 4.48 (m, 1), δ 7.30 (d, 2, J = 7.9 Hz), δ 7.47 (t, NH, J = 5.9 Hz), δ 7.85 (d, 2, J = 7.9 Hz), δ 8.50 (d, 1, J = 7.8 Hz), δ 8.69 (t, 1, J = 5.7 Hz); ESI-MS m/z 403 (M+1).
PRIMJER 5
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-metiltiazol-4-il)] benzamid
(Spoj 33)
[image]
Smjesa koja se sastoji od 2-amino-N-cijanometil-4-metilpentanamid p-toluensulfonske kiseline, kisele soli (0.75 g, 2.3 mmol), 4-(2-metiltiazol-4-il)benzojeve kiseline (0.5 g, 2.3 mmol), PyBOP® (1.2 g, 2.3 mmol) and trietilamina (1 mL, 5 mmol) u 10 mL DMF se miješa 1 sat. Smjesa se koncentrira pri smanjenom tlaku, a ostatak se razdijeli između etil acetata (20 mL) i zasićene otopine natrij bikarbonata(20 mL). Organski sloj se odvoji , ispire vodom i otopinom soli, suši (MgSO4) i koncentrira pri smanjenom tlaku. Proizvod se pročisti iz ostatka flash kromatografijom na silika gelu pomoću 66% etil acetata u heksanu. čime se dobije N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-metiltiazol-4-il)benzamid (0.5 g, 1.4 mmol). 1H NMR (DMSO-d6, ppm): δ 0.81 (m, 6 H), δ 1.55 (m, 3H), δ 2.81 (s, 3 H), δ 4.01 (m, 2H), δ 4.17 (m, 1H), δ 8.01 (m, 5 H), δ 8.41 (d, 1H), δ 9.01 (m, 1H); ES-Ms: 371.1 (M+H+).
Postupcima kao u Primjeru 5 dobiju se slijedeći spojevi Formule I:
N-(1-cijanometilkarbamoil-3-metilbutil-1H-benzoimidazol-5-karboksamid (Spoj 34): 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6H), δ 1.42 (m, 3 H), δ 4.21 (s, 2H), δ 4.81 (m, 1H), δ 7.6 (d, 1H), δ 8.01 (d, 1H), δ 8.23 (s, 1H), δ 8.81 (s, 1H), δ 9.2 (s, 1H); ES-Ms: 314.1 (M+H+);
N-(1-cijanometilkarbamoil-3-metilbutil)pirazin-2-karboksamid (Spoj 35); 1H NMR (DMSO-d6, ppm): δ 0.91 (d, 6 H), δ 1.41 (m, 3H), δ 4.21 (s, 2H), δ 4.61 (m, 1H), δ 8.81 (m, 4 H), δ 9.2 (s, 1H); ES-Ms: 276.1 (M+H+);
N-(1-cijanometilkarbamoil-3-metilbutil)-4-dimetilaminobenzamid (Spoj 36); 1H NMR (DMSO-d6, ppm): δ 0.89 (d, 6H), δ 1.51 (m, 3 H), δ 4.11 (s, 2H), δ 4.72 (m, 1H), δ 6.81 (d, 2H), δ 7.81 (d, 2 H), δ 8.31 (s, 1H), δ 9.2 (s, 1H); ES-Ms: 317.3 (M+H+);
N-(1-cijanometilkarbamoil-3-metilbutil)-3-dimetilaminobenzamid (Spoj 37); 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6H), δ 1.45 (m, 3H), δ 4.22 (s, 2 H), δ 4.85 (m, 1H), δ 7.11 (m, 1H), δ 7.41 (m, 3 H), δ 8.31 (s, 1H), δ 8.81 (s, 1H); S-Ms: 317.3 (M+H+);
N-(1-cijanometilkarbamoil-3-metilbutil)benzodioksol-5-karboksamid (Spoj 38); 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.45 (m, 3 H), δ 4.21 (s, 2 H), δ 4.81 (m, 1H), δ 6.03 (s, 2 H), δ 7.01 (d, 1H), δ 7.41 (m, 3 H), δ 8.41 (s, 1H), δ 8.81 (s, 1H); ES-Ms: 318.3 (M+H+);
N-(1-cijanometilkarbamoil-3-metilbutil)-piridin-4-karboksamid
(Spoj 39); 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.42 (m, 3 H), δ 4.01 (s, 2 H), δ 4.81 (m, 1H), δ 6.03 (s, 2 H), δ 8.01 (d, 2H), δ 8.41 (s, 1H), δ 8.81 (m, 3 H), δ 9.03 (s, 1H); ES-Ms: 275.3 (M+H+);
N-(1-cijanometilkarbamoil-3-metilbutil)-N’-benzotazol-6-ilureido
(Spoj 40); 1H NMR (DMSO-d6, ppm): δ 0.81 (d, 6 H), δ 1.48 (m, 3 H), δ 4.26 (s, 2 H), δ 4.31 (m, 1H), δ 7.23 (d, 1H), δ 7.91 (dd, 2 H), δ 8.13 (s, 1H), δ 8.81 (s, 2 H), δ 9.11 (s, 1H); ES-Ms: 346.1 (M+H+);
N-(1-cijanometilkarbamoil-3-metilbutil)-N’-pirid-4-ilmetilureido
(Spoj 41); 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.42 (m, 3 H), δ 4.21 (s, 2H), δ 4.31 (m, 1H), δ 7.81 (d, 2H), δ 7.91 (dd, 2H), δ 8.81 (d, 2 H), δ 8.91 (s, 2H), δ 9.11 (s, 1H); MS (electrospray): mH+ 304.1;
N-(1-cijanometilkarbamoil-3-metilbutil)-4-metilpiperazin-1-karboksamid
(Spoj 42); 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.42 (m, 3 H), δ 3.01 (m, 4 H), δ 3.72 (m, 4 H), δ 4.21 (s, 2 H), δ 4.31 (m, 1H), δ 7.81 (d, 1H), δ 7.91 (d, 1H), δ 8.81 (d, 1H); MS (electrospray): mH+ 296.0;
N-(1-cijanometilkarbamoil-3-metilbutil)-N’-pirid-3-ilureido
(Spoj 43); 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.42 (m, 3 H), δ 4.21 (s, 2 H), δ 4.31 (m, 1H), δ 7.81 (m, 2 H), δ 7.11 (m, 1H), δ 8.19 (m, 1H), δ 9.13 (m, 3 H); MS (electrospray): mH+ 290.0;
N-(1-cijanometilkarbamoil-3-metilbutil)-N’-metil-N’-(1-benzilpirolidin-3-il) ureido (Spoj 44); Protonska NMR (300 MHz, DMSO-d6): δ 8.77 (bt, 1H), δ 8.44 (m, 3H), δ 7.63 (bd, 1H), δ 7.30 (m, 1H), δ 4.25 (m, 1H), δ 4.11 (m, 2H), δ 3.50 (ABq, 2H), δ 1.40 -1.60 (m, 3H), δ 0.81 (m, 6H); MS (electrospray): mH+ 289 (100%); i
4-benzil-N-(1-cijanometilkarbamoil-3-metilbutil)piperazin-1-karboksamid
(Spoj 45); 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.42 (m, 3 H), δ 2.01 (m, 2 H), δ 2.21 (m, 1H), δ 3.01 (m, 2 H), δ 2.81 (s, 3 H), δ 3.01 (m, 1H), δ 3.21 (m, 2 H), δ 3.72 (m, 6 H), δ 4.21 (s, 2 H), δ 4.31 (m, 1H), δ 7.27 (m, 5 H), δ 8.81 (m, 1H); MS (electrospray): mH+ 386.2.
PRIMJER 6
Benzil 1S-(1-cijano-1-metiletilkarbamoil)-3-metilbutilkarbamat
(Spoj 46)
[image]
Otopina sastavljena od metil 2-(1S-benziloksikarbonilamino-3-metilvalerilamino)-2-metilpropionata (0.911 g, 2.5 mmol) u bezvodnom metanolu (10 mL) se hladi na između 0 i 5°C, pa se uvodi plinoviti amonijak do povećanja volumena otopine na približno 3 mL. Reakcijska posuda se zatali i otopina se ostavi slijegati na temperaturi okoline 168 sati. Nakon toga se otopina koncentrira, a proizvod se pročisti iz ostatka silika kromatografijom pomoću 5% metanola u diklorometanu, čime se dobije benzil 1S-karbamoilmetilkarbamoil-3-metilbutilkarbamat (514 mg, 1.48 mmol) u obliku bijele krute tvari, t.t. 93-94°C. Protonska NMR (300 MHz, DMSO-d6): δ 7.99 (s, 1H), δ 7.51 (d, J = 7 Hz, 1H), δ 7.32 (bs, 5H), δ 6.92 (bs, 2H), δ 4.99 (s, 2H), δ 3.97 (m, 1H), δ 1.58 (m, 1H), δ 1.39 (m, 2H), δ 1.33 (s, 3H), δ 1.31 (s, 3H), δ 0.83 (prividni t, J = 7 Hz, 6H).
Smjesa koja se sastoji od benzil 1S-karbamoilmetilkarbamoil-3-metilbutilkarbamata (0.175 g, 0.5 mmol) i trietilamina (141 μL, 1.5 mmol) u bezvodnom tetrahidrofuranu (15 mL) se hladi na između 0 i 5°C, doda se trifluoroocteni anhidrid (210 μL, 1 mmol). Smjesa se drži na između 0 i 5°C tijekom 1 sat, a potom se doda izopropanol (3 kapi). Smjesa se koncentrira i proizvod se pročisti iz ostatka silika kromatografijom pomoću 2% metanola u diklorometanu, čime se dobije benzil-1S-(1-cijano-1-metiletilkarbamoil)-3-metilbutilkarbamat (106 mg, 0.32 mmol) u obliku bijele pjene. Protonska NMR (300 MHz, DMSO-d6): δ 8.48 (s, 1H), δ 7.43 (d, J = 7 Hz, 1H), 7.32 (bs, 5H), δ 4.99 (s, 2H), δ 4.02 (m, 1H), δ 1.53 (s, 3H), δ 1.51 (s, 3H), δ 1.20 -1.60 (m, 3H), δ 0.83 (t, J = 6 Hz, 6H). MS (electrospray): mH+ 332 (100%).
Postupcima kao u Primjeru 6 dobiju se slijedeći spojevi Formule I:
benzil 1S-(1S-cijano-3-fenilpropilkarbamoil)-3-metilbutilkarbamat (Spoj 47); Protonska NMR (300 MHz, CDCl3): δ 7.05 -7.30 (m, 10H), δ 5.29 (m, 1H), δ 5.08 (m, 2H), δ 4.76 (prividni q, J = 7.5 Hz, 1H), δ 4.17 (m, 1H), δ 2.74 (m, 3H), δ 2.03 (m, 2H), δ 1.42 -1.68 (m, 3H), δ 0.90 (bs, 6H). 13C NMR (67.9 MHz, CDCl3): δ 171.8, 156.6. 139.2, 135.9, 128.9, 128.5. 126.8, 118.3, 67.6, 53.3, 41.0, 40.2, 34.5, 31.6, 24.7, 22.9, 22.0; MS (electrospray): mH+ 408 (100%);
3-aminometil-N-(1S-cijanometilkarbamoil-3-metibutil)benzamid
(Spoj 48); 13C NMR (67.9 MHz, D20): δ 175.5, 170.6, 134.0, 133.4, 132.8, 129.7, 128.1, 128.0, 116.9, 53.3, 42.8, 39.7, 27.7, 24.6. 22.2, 20.8; MS (electrospray): mH+ 303 (100%);
benzil 2S-cijanometilkarbamoilpirolidin-1-karboksilat (Spoj 49); t.t. 136-137°C; Protonska NMR (300 MHz, DMSO-d6): δ 8.77 (m, 1H), δ 7.30 (m, 5H), δ 5.00 (m, 2H), δ 4.19, m (1H), δ 4.10 (t, J = 6 Hz, 2H), δ 3.39 (m, 2H), δ 2.08 (m, 1H), δ 1.79 (m, 3H); MS (electrospray): mH+ 288 (100%);
benzil 2R-cijanometilkarbamoilpirolidin-1-karboksilat (Spoj 50); t.t. 135-136°C; Protonska NMR (300 MHz, DMSO-d6): δ 8. 77 (m, 1H), δ 7.30 (m, 5H), δ 5.00 (m, 2H), δ 4.19, m (1H), δ 4.10 (t, J = 6 Hz, 2H), δ 3.39 (m, 2H), δ 2.08 (m, 1H), δ 1.79 (m, 3H); MS (electrospray): mH+ 288 (100%);
N-(1S-cijanometilkarbonil-3-metilbutil)piridin-3-karboksamid
((Spoj 51); t.t. 173-174°C; Protonska NMR (300 MHz, DMSO-d6): δ 9.04 (d, J = 2 Hz, 1H), δ 8. 70 (m, 3H), δ 8.20 (m, 1H), δ 7.49 (m, 1H), δ 4.49 (m, 1H), δ 4.11 (d, J = 6 Hz, 2H), δ 1.45 -1.78 (m, 3H), δ 0.87 (dd. 6H); MS (electrospray): mH+ 275 (100%);
benzil 1S-(1-cijanociklopropilkarbamoil)-3-metilbutilkarbamat
(Spoj 52); Protonska NMR (300 MHz, CD3OD): δ 7.33 (m, 6H), δ 5.07 (s, 2H), δ 4.06 (m, 1H), δ 1.65 (m, 1H), δ 1.47 (m, 4H), δ 1.86 (m, 2H), δ 0.93 (t, J = 6 Hz, 6H); MS (electrospray): mH+ 330 (100%);
N-(1 S-cijanometilkarbamoilmetilbutilindol)-5-karboksamid (Spoj 53);
t.t. 225-226°C; Protonska NMR (300 MHz, DMSO-d6): δ 11.31 (s, 1H), δ 8.63 (t, J = 6 Hz, 1H), δ 8.35 (d, J = 7 Hz, 1H), δ 8.20 (s, 1H), δ 7.66 (d, J = 8 Hz, 1H), δ 7.41 (m, 2H), δ 6.52 (s, 1H), δ 4.50 (m, 1H), δ 4.10 (d, J = 6 Hz, 2H), δ 1.48 -1.79 (m, 3H), δ 0.86 (m, 6H); MS (electrospray): mH+ 313;
N -(1S-cijanometilkarbamoilmetilbutil-2,3-dihidroindol)-5-karboksamid
(Spoj 54); Protonska NMR (300 MHz, DMSO-d6): δ 8.59 (7 , J = 6 Hz, 1H), δ 8.11 (d, J = 7 Hz, 1H), δ 7.65 (s, 1H), δ 7.58 (d, J = 7 Hz, 1H), δ 6.57 (d, J = 7 Hz, 1H), δ 4.44 (m, 1H), δ 4.08 (d, J = 6 Hz, 2H), δ 3.51 (t, J = 8 Hz, 2H), δ 2.97 (t, J = 8 Hz, 2H), δ 1.58 (m, 3H), δ 0.87 (m, 6H); MS (electrospray): mH+ 315 (100%);
benzil 1R-cijanometilkarbamoil-3-metilbutilkarbamat (Spoj 55);
t.t. 120-121 °C; Protonska NMR (300 MHz, DMSO-d6): δ 8.68 (t, J = 6 Hz, 1H), δ 7.54 (d, J = 7 Hz, 1H), δ 7.33 (bs, 5H), δ 4.99 (ABq, 2H), δ 4.09 (d, J = 5 Hz, 2H), δ 4.00 (m, 1H), δ 1.28 -1.65 (m, 3H), δ 0.83 (prividni t, J = 7 Hz, 6H); MS (electrospray): mH+ 304 (100%);
benzil 1S-(1S-cijanoetilkarbamoil)-3-metilbutilkarbamat (Spoj 56);
Protonska NMR (300 MHz, DMSO-d6): δ 8.76 (d, J = 7 Hz, 1H), δ 7.51 (d, J = 5 Hz, 1H), δ 7.34 (bs, 5H), δ 5.01 (ABq, 2H), δ 4. 74 (m, 1H), δ 4.01 (m, 1H), δ 1.23 -1.65 (m, 6H), δ 0.86 (prividni t, J = 6 Hz, 6H); 13C NMR (67.9 MHz, DMSO-d6): δ 173.0, 137.5, 128.9, 128.4, 128.2, 120.8, 66.0, 53.1, 39.7, 24.7, 23.5, 21.9, 18.6; MS (electrospray): mH+ 318 (100%);
benzil 1S-(2S-cijanopirolidin-1-ilkarbonil)-3-metilbutilkarbamat
(Spoj 57); Protonska NMR (300 MHz, CD3OD): δ 7.32 (bs, 5H), δ 5.06 (s, 2H), δ 4. 75 (m, 1H), δ 4.40 (m, 1H), δ 3. 70 (m, 2H), δ 2.05 -2.17 (m, 4H), δ l.39 -1.83 (m, 3H), δ 0.96 (m, 6H); 13C NMR (67.9 MHz, CD3OD): δ 172. 7 , 157.5, 137.0, 128.2, 127.7 , 127.5, 118.2, 66.4, 51.3, 47.4, 46.4, 39.8, 29.5, 25.0, 24.6, 22.3, 20.5; MS (electrospray): mH+344 (100%);
terc-butil 3-(1 S-cijanometilkarbamoil-3-metilbutilkarbamoil)benzilkarbamat
(Spoj 58); Protonska NMR (300 MHz, DMSO-d6): δ 8.71 (bt, 1H), δ 8.54 (d, J = 8 Hz, 1H), δ 7.77 (bs, 2H), δ 7.39 (m, 3H), δ 4.52 (m, 1H), δ 4.16 (d, J = 6 Hz, 2H), δ 4.11 (d, J = 6 Hz, 2H), δ 1.43 -1.78 (m, 2H), δ 1.38 (bs, 10H), δ 0.87 (dd, 6H);
2S-(1S-benziloksikarbonilamino-3-metilbutilkarbonilamino)-2-cijanoetil acetat
(Spoj 59); Protonska NMR (300 MHz, DMSO-d6): δ 8.89 (d, J = 7 Hz, 1H), δ 7.52 (d, J = 8 Hz, 1H), δ 7.32 (bs, 5H), δ 5.00 (m, 3H), δ 4.20 (d, J = 6 Hz, 2H), δ 4.03 (m, 1H), δ 2.03 (s, 3H), δ 1.28 -1.66 (m, 3H), δ 0.84 (prividni t, 6H). MS (electrospray): mH+ 376 (100%);
2-(2-acetilaminoacetilamino)-N-cijanometil-4-metilpentanamid
(Spoj 61); Protonska NMR (300 MHz, DMSO-d6): δ 8.66 (bt, 1H), δ 8.08 (m, 2H), δ 4.27 (m, 1H), δ 4.10 (d, J = 6 Hz, 2H), δ 3.70 (d, J = 6 Hz, 2H), δ l.83 (s, 3H), δ 1.38 -1.64 (m, 3H), δ 0.85 (dd, 6H); MS (electrospray): mH+ 269 (100%);
benzil 1S-(1S-cijano- 3- metilbutilkarbamoil)- 3-metilbutilkarbamat
(Spoj 62); Protonska NMR (300 MHz, DMSO-d6): δ 8. 71 (d, J = 7 Hz, 1H), δ 7.51 (d, J = 8 Hz, 1H), δ 7.32 (s, 5H), δ 4.99 (s, 2H), δ 4.68 (m, 1H), δ 3.98 (m, 1H), δ 1.30 -1.74 (m, 6H), δ 0.83 (m, 12H); MS (electrospray): mH+ 360;
N-(1S-cijanometilkarbamoil-3-metilbutil)-2,3,4-trihidro-1H-kvinolinkarboksamid (Spoj 63); Protonska NMR (300 MHz, DMSO-d6): δ 8.58 (bt, 1H), δ 7.96 (d, J = 7 Hz, 1H), δ 7.45 (m, 2H), δ 6.38 (d, J = 7 Hz, 1H), δ 4.44 (m, 1H), δ 4.07 (d, J = 6 Hz, 2H), δ 3.60 (t, J = 7 Hz, 2H), δ 2.95 -3.16 (m, 4H), δ 1.41 -1.80 (m, 3H), δ 0.84 (m, 6H); MS (electrospray): mH+ 329;
N-(1s-cijanometilkarbamoil-3-metilbutil)-4-aminosulfonilbenzamid (Spoj 64); t.t. 191-194 °C; protonska NMR (300 MHz, DMSO-d6): δ 8.77 (m, 2H), δ 8.04 (d, J = 6 Hz, 2H), δ 7.88 (d, J = 6 Hz, 2H), δ 7.50 (s, 2H), δ 4.49 (m, 1H), δ 4.12 (m, 2H), δ 1.50 -1.74 (m, 3H), δ 0.86 (m, 6H); MS (electrospray): mH+ 353 (100%);
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-fenilbutiramid (Spoj 65);
Protonska NMR (300 MHz, DMSO-d6): δ 8.64 (bt, 1H), δ 8.04 (d, J = 8 Hz, 1H), δ 7.10 -7.28 (m, 5H), δ 4.26 (m, 1H), δ 4.08 (m, 2H), δ 2.52 (t, J = 7 Hz, 2H), δ 2.12 (t, J = 7 Hz, 2H), δ 1.78 (m, 2H), δ 1.32 -1.60 (m, 3H), δ 0.83 (m, 6H); MS (electrospray): mH+ 316 (100%);
N-(1 S-cijanometilkarbamoil-3-metilbutil)-3-metiltiofen-2-karboksamid (Spoj 66); t.t. 132-134 °C; Protonska NMR (300 MHz, DMSO-d6): δ 8.72 (bt, 1H), δ 8.04 (d, J = 8 Hz, 1H), δ 7.55 (d, J = 5 Hz, 1H), δ 6.95 (d, J = 5Hz, 1H), δ 4.41 (m, 1H), δ 4.12 (m, 2H), δ 2.39 (s, 3H), δ 1.42 -1.75 (m, 3H), δ 0.86 (m, 6H). MS (electrospray): mH+ 294 (100%);
N-[1-cijanometilkarbamoil-3-metilbutil-4-(2-gvanidinotiazol-4-il)]benzamid (Spoj 67); 1H NMR (DMSO-d6, ppm): δ 0.96(m, 6 H), δ 1.65 (m, 3 H), δ 4.01 (m, 2 H), δ 4.17 (m, 1H), δ 8.03 (m, 5 H), δ 8.31 (m, 2 H), δ 8.73 (d, 1 H), δ 8.91 (d, 1 H); MS (electrospray): mH+ 414.1;
N-[1s-cijanometilkarbamoil-3-metilbutil-3-pirid-3-ilakrilamid (Spoj 68); 1H NMR (DMSO-d6, ppm): δ 0.96 (m, 6 H), δ 1.55 (m, 3 H), δ 4.01 (m, 2 H), δ 4.17 (m, 1H), δ 6.85 (d, 1 H), δ 7.54 (d, 1 H), δ 7.66 (d, 1 H), δ 8.22 (d, 1 H), δ 8.81 (d, 1 H), δ 8.84 (m, 1H); MS (electrospray): mH+ 301.0;
N-[1S-cijanometilkarbamoil-3-metilbutil-3-(1H-imidazol-4-il)akrilamid
(Spoj 69); 1H NMR (DMSO-d6, ppm): δ 0.96 (m, 6 H), δ 1.55 (m, 3 H), δ 4.01 (m, 2 H), δ 4.17 (m,1H), δ 6.71 (d, 2 H), δ 7.33 (d, 1 H), δ 7.95 (s, 1 H), δ 8.81 (d, 1 H), δ 9.01 (m, 1 H); MS (electrospray): mH+ 290.1;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-N’,N'-dimetilaminobenzamid N'-oksid (Spoj 70); Protonska NMR (300 MHz, CD3OD): δ 8.10 (m, 4H), δ 4.65 (m, 1H), δ 4.17 (s, 2H), δ 3.97 (s, 6H), δ 1.58 -1.90 (m, 3H), δ 0.98 (m, 6H); MS (electrospray): mH+ 333 (100%);
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(1H-imidazol-2-il)benzamid
(Spoj 71); t.t. 246-247 °C; Protonska NMR (300 MHz, DMSO-d6): δ 12.66 (s, 1 H), δ 8.70 (bb, 1H), δ 8.57 (d, J = 7 Hz, 1H), δ 7.98 (bs, 4H), δ 4.49 (m, 1H), δ 4.10 (m, 2H), δ 1.50 -1.75 (m, 3H), δ 0.87 (m, 6H); MS (electrospray): mH+ 340 (100%);
N-(1S-cijanometilkarbamoil-4-metilpentil)-4-dietilaminobenzamid
(Spoj 72); 1H NMR (DMSO-d6, ppm): δ 0.96 (mt, 6 H), δ 1.11 (m, 6 H), δ 1.85 (m, 3 H), δ 3.3 (m, 4 H), δ 4.01 (m, 2 H), δ 4.17 (m, 1 H), δ 6.71 (m, 2 H), δ 7.53 (m, 2 H), δ 8.05 (s, 1 H), δ 8.81 (d, 1 H); MS (electrospray): mH+ 359.0;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-morfolin-4-ilbenzamid
(Spoj 73); 1H NMR (DMSO-d6, ppm): δ 0.96 (m, 6 H), δ 1.65 (m, 3 H), δ 3.31 (m, 4 H), δ 3.72 (m, 4 H), δ 4.01 (m, 2 H), δ 4.17 (m, 1H), δ 7.01 (d, 2 H), δ 7.63 (d, 2 H), δ 8.81 (d, 1 H), δ 9.01 (m, 1 H); MS (electrospray): mH+ 359.1;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(4-metilpiperazin-1-il)benzamid
(Spoj 74); 1H NMR (DMSO-d6, ppm): δ 0.96 (m, 6 H), δ 1.65 (m, 3 H), δ 2.81 (s, 3 H), δ 3.31 (m, 4 H), δ 3.81 (m, 4 H), δ 4.01 (m, 2 H), δ 4.17 (m, 1H), δ 7.01 (d, 2 H), δ 7.73 (d, 2 H), δ 8.41 (d, 1 H), δ 9.01 (m, 1 H); MS (electrospray): mH+ 372.1;
N-(1S-cijanometilkarbamoil-3-metilbutil)-3-(1H-imidazol-2-il)benzamid
(Spoj 75); Protonska NMR (300 MHz, DMSO-d6): δ 8.83 (bt, 1H), δ 8.76 (d, J = 8 Hz, 1H), δ 8.50 (s, 1H), δ 8.13 (m, 2H), δ 7.78 (m, 3H), δ 4.52 (m, 1H), δ 4.13 (d, J = 6Hz, 2H), δ 1.50 -1.74 (m, 3H), δ 0.88 (m, 6H); MS (electrospray): mH+ 340 (100%);
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-pirol-1-ilbenzamid
(Spoj 76); 1H NMR (DMSO-d6, ppm): δ 0.96 (m, 6 H), δ 1.65 (m, 3 H), δ 2.81 (s, 3 H), δ 3.31 (m, 4 H), δ 3.81 (m, 4 H), δ 4.01 (m, 2 H), δ 4.17 (m, 1H), δ 6.03 (s, 2 H), δ 7.31 (d, 2 H), δ 7.73 (d, 2 H), δ 8.01 (d, 2 H), δ 8.81 (d, 1 H), δ 9.01 (m, 1H); MS (electrospray): mH+ 338.1;
benzil 1-cijanometilkarbamoil-4-gvanidinobutil)karbamat (Spoj 77); 1H NMR (DMSO-d6, ppm): δ 1.65 (m, 4 H), δ 2.91 (m, 2 H), δ 4.01 (m, 2 H), δ 4.17 (m, 1H), δ 5.03 (s, 2 H), δ 7.31 (s, 5 H), δ 7.73 (d, 1H), δ 8.01 (d, 2 H), δ 8.81 (d, 1H), δ 9.01 (m, 1H); MS (electrospray): mH+ 347.1;
N-cijanometil-2-(1H-indol-3-ilacetilamino)-4-metilpentanamid
(Spoj 78); Protonska NMR (300 MHz, DMSO-d6): δ 10.74 (bs, 1H), δ 8.63 (bt, 1H), δ 8.11 (d, J=8 Hz, 1H), δ 7.41 (d, J=8 Hz, 1H), δ 7.21 (d, J=8 Hz, 1H), δ 7.06 (s, 1H), δ 6.94 (t, J = 7 Hz, 1H), δ 6.84 (t, J = 7 Hz, 1H), δ 4.18 (m, 1H), δ 4.00 (m, 2H), δ 3.44 (Abq, 2H), δ 1.25- 1.53 (m, 3H), δ 0.67 (m, 6H), MS(electrospray): mH+ 327 (100%);
N-cijanometil-4-metil-2-(3-pirid-2-ilmetilureido)pentanamid
(Spoj 79); 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.42 (m, 3 H), δ 4.21 (s, 2 H), δ 4.31 (m, 1H), δ 6.81 (m, 2 H), δ 7.81 (m, 2 H), δ 8.21 (m, 1H), δ 8.81 (m, 2 H); MS (electrospray): mH+ 304.0;
N-(1-cijanometilkarbamoil-3-metilbutil)-[1,4’]bipiperidinil-1’-karboksamid
(Spoj 80); 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.42 (m, 3 H), δ 3.01 (m, 2 H), δ 3.72 (m, 6 H), δ 4.21 (s, 2 H), δ 4.31 (m, 1H), δ 7.27 (s, 5 H), δ 8.81 (m, 1H); MS (electrospray): mH+ 364.2;
N-(1-cijanometilkarbamoil-3-metilbutil)-4-dietilaminobenzamid (spoj 81); 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.61 (m, 6 H), δ 1.42 (m, 3 H), δ 3.78 (m, 4 H), δ 4.21 (s, 2 H), δ 4.81 (m, 1H), δ 6.81 (d, 2 H), δ 7.81 (d, 2 H), δ 8.31 (s, 1H), δ 9.2 (s, 1H); MS (electrospray): mH+ 345.3;
N-(1-cijanometilkarbamoil-3-metilbutil)-4-fluorobenzamid (Spoj 82);
1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.62 (m, 6 H), δ 4.21 (s, 2 H), δ 4.81 (m, 1H), δ 6.81 (d, 2 H), δ 7.81 (d, 2 H), δ 8.31 (s, 1H), δ 9.2 (s, 1H); MS (electrospray): mH+ 292.0;
N-(1-cijanometilkarbamoil-3-metilbutil)-4-hidroksibenzamid (Spoj 83);
1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.62 (m, 3 H), δ 4.21 (s, 2 H), δ 4.81 (m, 1H), δ 6.81 (d, 2 H), δ 7.81 (d, 2 H), δ 8.31 (s, 1H), δ 9.2 (s, 1H); MS (electrospray): mH+ 292.0;
N-(1-cijanometilkarbamoil-3-metilbutil)-3-hidroksibenzamid (Spoj 84);
1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.62 (m, 6 H), δ 4.21 (s, 2 H), δ 4.81 (m, 1H), δ 6.81 (m, 1H), δ 7.21 (m, 4 H), δ 8.31 (s, 1H), δ 9.2 (s, 1H); MS (electrospray): mH+ 290.0;
N-(1-cijanometilkarbamoil-3-metilbutil)-4-gvanidinobenzamid
(Spoj 85); 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.62 (m, 6 H), δ 3.30 (m, 2 H), δ 4.21 (s, 2 H), δ 4.81 (m, 1H), δ 7.3 (d, 2 H), δ 7.62 (m, 1H), δ 7.91 (d, 2 H), δ 8.31 (s, 1H), δ 9.2 (s, 1H); MS (electrospray): mH+ 331.0;
N-(1-cijanometilkarbamoil-3-metilbutil)-2-pirid-4-iltiazol-5-karboksamid (Spoj 86); 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.1 (m, 6 H), δ 4.21 (s, 2 H), δ 4.81 (m, 1H), δ 7.81 (m, 1H), δ 8.31 (m, 2 H), δ 8.81 (m, 2 H), δ 9.2 (s, 1H); MS (electrospray): mH+ 358.0;
N-(1-cijanometilkarbamoil-3-metilbutil)-2-pirid-3-iltiazol-5-karboksamid (Spoj 87); 1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.1 (m, 6 H), δ 4.21 (s, 2 H), δ 4.81 (m, 1H), δ 8.21 (m, 2 H), δ 8.51 (m, 1H), δ 8.81 (m,2 H), δ 9.2 (s, 1H); MS (electrospray): mH+ 358.0;
6-amino-N-(1-cijanometilkarbamoil-3-metilbutil)nikotinamid (Spoj 88);
1H NMR (DMSO-d6, ppm): δ 0.86 (d, 6 H), δ 1.62 (m, 6 H), δ 4.21 (s, 2 H), δ 4.81 (m, 1H), δ 6.81 (m, 1H), δ 7.21 (m, 4 H), δ 8.31 (s, 1H), δ 9.2 (s, 1H); MS (electrospray): mH+ 290.0;
benzil 1-cijanometilkarbamoil-4,4,4-trifluoro-3-metilbutilkarbamat
(Spoj 89); 1H NMR (DMSO-d6, ppm): δ 1.01 (m, 3 H), δ 3.02 (m, 3 H), δ 4.21 (s, 2 H), δ 5.01 (s, 2 H), δ 5.12 (m, 1H), δ 7.21 (m, 5 H), δ 8.01 (s, 1H), δ 9.21 (s, 1H); MS (electrospray): mH+ 358.2;
benzil 1-cijanometilkarbamoil-1,3-dimetilbutilkarbamat (Spoj 90); 1H
NMR (DMSO-d6, ppm): δ 0.86 (m, 6 H), δ 1.81 (m, 2 H), δ 4.01 (m, 3 H), δ 5.01 (s, 2 H), δ 7.21 (m, 5 H), δ 8.01 (s, 1H), δ 9.21 (s, 1H); MS (electrospray): mH+ 318.2;
benzil 1-cijanometilkarbamoil-2,2-dimetilpropilkarbamat (Spoj 91); 1H
NMR (DMSO-d6, ppm): δ 0.96 (s, 9 H), δ 3.88 (m, 1H), δ 4.01 (s, 2 H), δ 5.01 (s, 2 H), δ 7.21 (m, 5 H), δ 8.01 (s, 1H), δ 9.21 (s, 1H); MS (electrospray): mH+ 304.2;
benzil 1-cijanometilkarbamoil-3,3-dimetilbutilkarbamat (Spoj 92);
1H NMR (DMSO-d6, ppm): δ 0.96 (s, 9 H), δ 1.55 (m, 2 H), δ 4.01 (m, 3 H), δ 5.01 (m, 2 H), δ 7.27 (m, 5 H), δ 8.01 (s, 1H), δ 9.21 (s, 1H); MS (electrospray): mH+ 318.2;
benzil (cijanometilkarbamoil)(fenil)metilkarbamat (Spoj 93); 1H NMR (DMSO-d6, ppm): δ 0.96 (s, 9 H), δ 1.55 (m, 2 H), δ 4.01 (m, 3 H), δ 5.01 (m, 2 H), δ 7.27 (m, 5 H), δ 8.01 (s, 1H), δ 9.21 (s, 1H); MS (electrospray): mH+ 324.2;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-dimetilaminonaftalen-1-karboksamid (Spoj 94); t.t. 161-162 °C; Protonska NMR (300 MHz, DMSO-d6): δ 8.88 (bt, 1H), δ 8.74 (d, J = 8 Hz, 1H), δ 8.24 -8.37 (m, 2H), δ 7.60 -7.71 (m, 3H), δ 7.20 (d, J = 8Hz, 1H), δ 4.64 (m, 1H), δ 4.29 (m, 2H), δ 2.94 (s, 6H), δ 1.57 -1.83 (m, 3H), δ 1.02 (prividni t, 6H); MS (electrospray): mH+ 367 (100%); i
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-dimetilamino-2-hidroksibenzamid (Spoj 95); t.t. 171-173 °C; Protonska NMR (300 MHz, DMSO-d6): δ 12.57 (bs, 1H), δ 8.73 (bt, 1H), δ 8.40 (d, J = 7 Hz, 1H), δ 7.76 (d, J = 8 Hz, 1H), δ 6.24 (dd, J = 2, 8 Hz, 1H), δ 6.01 (d, J = 2 Hz, 1H), δ 4.47 (m, 1H), δ 4.10 (m, 2H), δ 2.92 (s, 6H), δ 1.47-1.72 (m, 3H), δ 0.87 (m, 6H); MS (electrospray): mH+ 333 (100%).
Postupcima koji su analogni gore opisanim primjerima, dobiju se slijedeći spojevi Formule I:
benzil 1-[1-(1-cijanometilkarbamoil-2-feniletilkarbamoil)-3-metilbutilkarbamoil]-2-metilpropilkarbamat (Spoj 96);
N-benzil-N-(1S-cijanometilkarbamoil)-3-metilbutilureido (Spoj 97);
Protonska NMR (270 MHz, DMSO-d6): δ 8.78 (t, 1H), 7.2-7.40 (m, 5H). 6.46 (t, 1H), 6.23 (d, 1H), 4.11-4.29 (m, 5H), 1.35-1.67 (m, 3H), 0.88 (prividni t, 6H). LCMS (electrospray)mH+ 303 (100%);
benzil 1S-[(cijano)(fenil)metilkarbamoil]-3-metilbutilkarbamat
(Spoj 98); Protonska NMR (300 MHz, DMSO-d6): δ 9.42 (2d, 1H), 7.57 (m, 1H), 7.35-7.50 (m, 10H), 6.15 (2d, 1H), 5.02 (ABq, 2H), 4.08 (m, 1H), 1.32-1.61 (m, 3H), 0.90 (m, 6H);
benzil (S)-N-(1-cijanometilkarbamoil-3-metilbutil)-N-metilkarbamat
(Spoj 99); Protonska NMR (300 MHz, DMSO-d6): δ 8.78 (bt, 1H), 7.4 (bs, 5H), _5.05 (m, 2H), 4.56_(m, 1H), 4.10 (d, 2H). 2.75 (s, 3H), 1.3-1.72 (m, 3H), 0.86 (m, 6H), MS (CI): mH+ 318;
benzil 2S-cijanometilkarbamoil-4-oksopirolidin-1-karboksilat
(Spoj 100); Protonska NMR (270 MHz, DMSO-d6): δ 8.99_(t, 1H), 7.34 (m, 5H), 5.12 (ABq, 2H), 4.68 (prividni t, 1H), 4.15 (m, 2H), 3.79-4.02 (m, 2H), 3.15 (m, 1H), 2.39 (m, 1H);
N-(1S-cijanometilkarbamoilpentil)benzensulfonamid (Spoj 101); Proton
NMR (270 MHz, DMSO-d6): δ 8.66, 8.60 (2t's, 1H), 8.10, 8.14 (2d's. 1H), 7.51-7.91 (m, 5H), 4.11, 3.98 (2d's, 2H), 3.73, 3.62 (2m's, 1H), 0.71-1.50 (m, 9H). APT 13C NMR (67 MHz, DMSO-d6): δ 172.6, 172.1, 171.2, 141.7, 141.4, 132.9. 129.5, 129.3, 127.0, 118.0, 117.8. 56.4, 52.6, 33.0, 32.5, 32.1, 27.6, 27.5, 22.2, 22.0, 14.4, 14.2;
benzil 2S-cijanometilkarbamoil-4-etilpirol-1-karboksilat (Spoj 102);
Protonska NMR (300 MHz, DMSO-d6): δ 8.78 (m, 1H), 7.37 (m, 5H), 5.04 (m, 2H), 3.95- 4.40 (m, 3H), 3.74 (prividni t, 1H), 2.94 (m, 1H), 2.40 (m, 1H), 2.03 (m, 1H), 1.4 (m, 3H), 0.78 (m, 3H). APT 13C NMR (67 MHz, DMSO-d6): δ 173.7, 173.3, 129.0, 128.9, 128.4, 128.2, 127.7, 118.1, 66.6, 60.7, 60.3, 53.1, 52.6, 39.5, 37.6, 27.6, 25.6, 12.9;
N-(1S-cijanometilkarbamoilmetilbutil-1-metilindol)-4-karboksamid
(Spoj 103); Protonska NMR (300 MHz, DMSO-d6): δ 8.74 (t, 1H), 8.44 (d, 1H), 8.20 (s, 1H), 7.75 (d, 1H), 7.48 (d, 1H), 7.43 (d, 1H), 6.56 (d, 1H), 4.53 (m, 1H), 4.16 (d, 2H), 3.84 (s, 3H), 1.47-1.77 (m, 3H), 0.88 (m, 6H);
N-1-(N-cijanometil-N-metilkarbamoil)-3-metilbutil-4-metilsulfonamid (Spoj 104);
benzil 1S-cijanometilkarbamoil-4-hidroksi-4-metilpirolidin-1-karboksilat
(Spoj 105); Protonska NMR (300 MHz, DMSO-d6): δ 8.65_(m, 1H). 7.36 (m, 5H), 5.03 (m, 2H), 4.2 (m, 1H), 4.09 (m, 2H), 3.35 (m, 2H), 2.1 (m, 1H), 1.91 (m, 1H), 1.22 (s, 3H). LCMS (electrospray)mH+ 302 (100%);
benzil 2S-cijanometilkarbonil-4-metilenpirolidin-1-karboksilat
(Spoj 106); Protonska NMR (300 MHz, DMSO-d6): δ 8.80 (m, 1H), 7.42 (m, 5H), 5.04 (m, 4H), 4.45 (m, 1H), 4.09 (m, 4H), 2.96 (m, 1H), 2.45 (m, 1H);
N-(1-cijanometilkarbamoil-2-metilpropilbenzamid (Spoj 107); Protonska NMR (300 MHz, DMSO-d6): δ 8.82 (t, 1H), 8.47 (d, 1H), 7.9 (d, 2H), 7.46 (m, 3H), 4.2 (m, 3H), 2.12 (m, 1H), 0.92 (prividni t, 6H);
N-(1-cijanometilkarbamoilpentil)benzamid (Spoj 108); Protonska NMR (300 MHz, DMSO-d6): δ 8.7 (t, 1H), 8.55 (d, 1H), 7.84 (d, 2H), 7.0 (m, 3H), 4.43 (m, 1H), 4.12 (d, 2H), 1.35-1.9 (m, 6H), 0.89 (t, 3H);
benzil 1S-cijanometilkarbamoil-2-hidroksipropilkarbamat (Spoj 109);
Protonska NMR (300 MHz, DMSO-d6): δ 8.55 (t, 1H), 7.42 (m, 5H), 7.08 (d, 1H), 5.03 (ABq, 2H), 4.18 (m, 2H), 3.95 (d, 2H), 1.04 (d, 3H). MS (APCI): mH+ 292;
benzil 1S-(N-cijanometil-N-metilkarbamoil-2-metilbutilkarbamat
(Spoj 112); Protonska NMR (270 MHz, CDCl3): δ 7.31 (m, 5H), 5.51 (bd, 1H), 5.07 (ABq, 2H), 4.55 (m, 2H), 4.06 (d, 1H), 3.23 (s, 3H), 1.40-1.77 (m, 2H), 1.04-1.27 (m, 1H), 0.88 (m, 6H);
benzil 1S-(N-cijanometil-N-metilkarbamoilpentilkarbamat (Spoj 113);
Protonska NMR (270 MHz, CDCl3): δ 7.33 (s, 5H), 5.51 (bd, 1H), 5.08 (ABq, 2H), 4.65 (m, 1H), 4.51 (d, 1H), 4.14 (d, 1H), 3.21 (s, 3H), 1.51-1.77 (m, 2H), 1.32 (m, 4H), 0.88 (t, 3H);
(S)-N-(1-cijanometilkarbamoil-3-metilbutil)acetamid (Spoj 114); Protonska NMR (270 MHz, DMSO-d6): δ 8.69 (t, 1H), 8.10 (d, 1H), 4.24 (prividni q, 1H), 4.10 (d, 2H), 1.84 (s, 3H), 1.40-1.50 (m, 3H), 0.84 (m, 6H). LCMS (electrospray): mH+212;
N-(1S-cijanometilkarbamoil-3-metilbutil)-kvinolin-6-karboksamid (Spoj 115);
4-amino-N-(1S-cijanometilkarbamoil-3-metilbutil)benzamid (Spoj 116);
pirid-3-ilmetil 1S-cijanometilkarbamoil-3-metilbutilkarbamat
(Spoj 117); Protonska NMR (300 MHz, DMSO-d6): 8.77 (bb, 1H), 8.44 (m, 3H), 7.63 (m, 1H), 7.32 (m, 1H), 4.25 (m, 1H), 4.11 (m, 2H), 3.50 (ABq, 2H), 1.40-1.60 (m, 3H), 0.84 (dd, 6H); MS (electrospray): mH+ 289 (100%);
N-(1S-cijanometilkarbamoil)-3-metilbutil-4-(1H-imidazol-4-il)benzamid
(Spoj 118); 1H NMR (DMSO): δ 0.85-0.91 ppm (d,d, 6 H), 1.45-1.8 ppm (m, 3 H), 2.99-3.02 ppm (m, 1H), 4.12-4.14 ppm (d, 2 H), 4.5-4.6 (m, 1H), 7.89-7.92 ppm (d, 2 H), 8.02-8.05 ppm (d, 2 H), 8.22 ppm (s, 1H), 8.62-8.65 ppm (d, 1H), 8.72-8.77 ppm (t, 1H), 9.07 ppm (s, 1H); LC/MS (339.9 M+H+);
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-imidazol-1-ilbenzamid
(Spoj 119);
N-(1-cijanometilkarbamoil-2-metilpropil)-4-(2-gvanidinotiazol-4-il)benzamid (spoj 120); 1H NMR (DMSO-d6): 1.04 (m, 6H), 1.95 (m, 1H), 4.11 (m, 2H), 4.17 (m, 1H), 8.03 (m, 5H), 8.31 (m, 2H), 8.73 (d, 1H), 8.91 (d, 1H); ES-Ms: 400.1 (M+H+);
N-(1-cijanometilkarbamoil-2-feniletil)-4-(2-gvanidinotiazol-4-il)benzamid
(Spoj 121); 1H NMR (DMSO-d6): 1.04 3.01 (m, 1H), 4.01 (m, 2H), 4.17 (m, 1H), 7.12 (m, 5H), 8.03 (m, 5H), 8.31 (m, 2H), 8.73 (d, 1H), 8.91 (d, 1H); ES-Ms: 448.3 (M+H+);
N-(1-cijanometilkarbamoil-2-metilbutil)-4-(4-metilpiperazin-1-il)benzamid (spoj 122); 1H NMR (DMSO-d6): 1.04 0.95 (m, 6H), 1.15 -1.35 (m, 3H), 2.81 (s, 3H), 3.31 (m, 4H), 3.81 (m, 4H), 4.01 (m, 2H), 4.17 (m, IH), 7.01 (d, 2H), 7.73 (d, 2H), 8.41 (d, 1H), 9.01 (m, 1H); ES-Ms: 372.3 (M+H+);
N-(1-cijanometilkarbamoil-2-feniletil)-4-(4-metilpiperazin-1-il)benzamid (spoj 123); 1H NMR (DMSO): δ 2.22 ppm (s, 3 H), δ 2.43 ppm (m, 4 H), δ 3.15- 3.25 ppm (m, 4 H), δ 4.12-4.13 ppm (d, 2 H), δ 4.55-4.7 (m, 1H), δ 6.9-6.93 ppm (d, 2 H), δ 7.1-7.3 ppm (m, 5 H), δ 7.67-7.71 ppm (d, 2 H), δ 8.35-8.38 ppm (d, 1H), δ 8.7- 8.8 (t, 1H); LC/MS (406 M+H+);
N-(1-cijanometilkarbamoil-2-metilpropil)-4-(4-metilpiperazin-1-il)benzamid
(Spoj 124); 1H NMR (DMSO): δ 0.86-0.91 ppm (t, 6 H), δ 1.79-1.85 ppm (m, 31H), δ 2.3 ppm (s, 3 H), δ 2.5-2. 7 ppm (m, 4 H), δ 3.12-3.16 ppm (m, 4 H), δ 4.12-4.14 ppm (d, 2 H), δ 4.2-4.3 (m, 2 H), δ 6.93-6.96 ppm (d, 2 H), δ 7.77- 7.8 ppm (d, 2 H), δ 8.06-8.10 ppm (d, 1H), δ 8.74-8.76 ppm (t, 1H); LC/MS (358 M+H+);
N -(1-cijanometilkarbamoil)-3-metilbutil)-4-(2-dimetilaminotiazol-4-il)benzamid (Spoj 125); 1H NMR (DMSO-d6): 1.04): 0.96 (m, 6H), 1.85 (m, 3H), 3.32 (s, 6H), 4.01 (m, 2H), 4.37 (m, 2H), 7.02 (m, 1H), 7.51 (d, 2H), 8.03 (d, 2H), 8.83 (d, 2H), 10.11 (m, 1H); ES-Ms: 400.1 (M+H+);
4-(2-aminotiazol-4-il)-N-(1-cijanometilkarbamoil-3-metilbutil)benzamid
(Spoj 126); 1H NMR (DMSO-d6): 1.04): 0.91 (m, 6H), 1.78 (m, 3H), 4.01 (m, 2H), 4.27 (m, 2H), 7.02 (m, 1H), 7.31 (d, 2H), 7.83 (d, 2H), 8.53 (d, 2H), 9.81 (m, 2H); ES-Ms: 372.1 (M+H+);
N-(1-cijanometilkarbamoil-3-metilbutil)-3-dimetilaminometil-1H-indol-5- karboksamid (Spoj 127);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, izobutil ester (Spoj 128);
N-[1-S-(Cijanometil-karbamoil)-2-metil-butil]-4-dimetilamino-benzamid (Spoj 129);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, piridin-4-ilmetil ester (Spoj 130); HNMR (Cl3CD): 8.55 (2H, m), 7.22 (3H, m), 5.53 (1H, d), 5.09 (2H, m), 4.15 (1H, m), 4.12 (2H, m), 1.65 (3H, m), 0.89 (6H, m);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, piridin-3-ilmetil ester (Spoj 131); HNMR (Cl3CD): 8.54 (2H, m), 7.65 (1H, d), 7.28 (2H, m), 5.61 (1H, d), 5.09 (2H, s), 4.15 (1H, m), 4.10 (2H, d), 1.52 (3H, m), 0.89 (6H, m);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, piridin-2-ilmetil ester (Spoj 132); HNMR (Cl3CD): 8.56 (1H, m), 7.67 (1H, t), 7.28 (4H, m), 5.20 (2H, m), 4.21 (1H, m), 4.13 (2H, m), 1.57 (3H, m), 0.91 (6H, m);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 4-fluoro-benzil ester (Spoj 133); HNMR (Cl3CD): 7.27 (2H, m), 7.06 (2H, t), 6.90 (1H, bs), 5.18 (1H, m), 5.05 (2H, m), 4.18 (1H, m), 4.12 (2H, d), 1.60 (3H, m), 0.91 (6H, t);
1-S-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-(2-piridin-4-il-etilamino)-benzamid (Spoj 134); 1H NMR (DMSO): δ 0.81-0.94 ppm (d,d, 6 H), δ 1.45-1.8 ppm (m, 3 H), δ 3.12-3.19 ppm (t, 2H), δ 3.4-3.51 ppm (t,m, 2 H), δ 4.08-4.09 ppm (d, 2 H), δ 4.45-4.51 ppm (m, 1H), δ 6.58-6.61 ppm (d, 2 H), δ 7.69-7.72 ppm (d, 2 H), δ 7.94-7.96 ppm (d, 2 H), δ 8.6-8.7 ppm (t,m, 1H), δ 8.80-8.82 ppm (d, 2 H); LC/MS (394 M+H+);
1-S-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-fenilamino-benzamid
(Spoj 135); 1H NMR (DMSO): δ 0.79-0.94 ppm (m, 6 H), δ 1.45-1.8 ppm (m, 3 H), δ 4.08-4.12 ppm (m, 2 H), δ 4.4-4.51 ppm (m, 1H), δ 7.2-7.33 ppm (m, 2 H), δ 7.79- 8.0 ppm (m, 2 H), δ 8.55-8.6 ppm (m, 1H), δ 8.6-8.72 ppm (m, 1H);
1-S-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-[(piridin-3-ilmetil)-amino]-benzamid (Spoj 136);
1-S-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-[(piridin-2-ilmetil)-amino]-benzamid (Spoj 137); 1H NMR (DMSO): δ 0.75-0.94 ppm (d,d, 6 H), δ 1.45-1.8 ppm (m, 3 H), δ 4.08-4.09 ppm (s, 2 H), δ 4.42-4.47 ppm (m, 1H), δ 4.61 ppm (s, 2 H), δ 6.60-6.63 ppm (d, 2 H), δ 7.66-7.71 ppm (m, 4 H), δ 8.15-8.24 ppm (m, 2 H), δ 8.71- 8.73 ppm (d, 1H). LC/MS (380.1 M+H+);
But-2-endiojeva kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid fenilamid (Spoj 138);
4-Metil-piperazin-1-karboksilna kiselina{4-[1-S-(cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-amid (Spoj 139);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 2-(4-metil-tiazol-5-il)-etil ester (Spoj 140);
1-S-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-(1H-[1,2,4]triazol-3-ilamino)-benzamid (Spoj 141); 1H NMR (DMSO): δ 0.8-1.0 ppm (m, 6 H), δ 1.10-1.2 ppm (m, 1H), δ 1.5-1.7 ppm (m, 3 H), δ 4.12-4.2 ppm (m, 2 H), δ 4.4-4.50 ppm (m, 1H), δ 7.6-7.68 ppm (m, 1H), δ 7.72-7.8 ppm (m, 1H), δ 7.9-8.1 ppm (m, 2 H), δ 8.7-8.8 ppm (m, 1H); LC/MS (356 M+H+);
1-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(piridin-4-ilmetoksi)-benzamid (Spoj 142); 1H NMR (DMSO): δ 0.83-0.88 ppm (m, 6 H), δ 1.45-1.74 ppm (m, 3 H), δ 4.09-4.10 ppm (m, 2 H), δ 4.44-4.48 ppm (m, 1H), δ 5.46 ppm (s, 2 H), δ 7.10-7.13 ppm (m, 2 H), δ 7.84-7.95 ppm (m, 4 H), δ 8.78-8.84 ppm (m, 2 H); LC/MS (380.91 M+H+);
1-[1-(Cijanometil-karbamoil)-3-metil-butil]-2-nitro-benzamid
(Spoj 143); 1H-NMR (DMSO-d6): δ 9.2 (d, 1H) δ 8.9 (t, 1H) δ 8.2 (d, 1H) δ 7.9 (m, 3H) δ 4.4 (d, 2H) δ 1.6-2.0 (m, 3H), δ 1.1 (m, J = 10 Hz, 6H); MS (electrospray): mH+ 318.8 (100%);
[1-R-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 1-metil-piperidin-2-ilmetil ester (Spoj 144);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-metoksi-benzamid (Spoj 145); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.56-1.89 (m, 3 H), 3.81 (s, 3 H), 4.17 (m, 2 H), 4.47 (m, 1H), 7.28 (m, 2 H), 8.11 (d, 2 H), 8.51 9m, 1H), 8.89 (m, 1H). ES-Ms: 303.1 (M+H+);
[1-R-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, furan-2-ilmetil ester (Spoj 146); HNMR (Cl3CD): 7.55 (1H, m), 7.38 (1H, m), 6.37 (1H, m), 6.33 (1H, m), 5.66 (1H, d), 5.00 (2H, dd), 4.25 (1H, m), 4.10 (2H, d), 1.60 (3H, m), 0.90 (6H, m);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-piridin-4-il-propoksi)-benzamid (Spoj 147);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-3-(4-metil-piperazin-1-sulfonil)-benzamid (Spoj 148);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(4-metil-piperazin-1-ilmetil)-benzamid (Spoj 149);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-[1-(4-metil-piperazin-1-il)-etil]-benzamid (Spoj 150);
2-Amino-N-[1-(cijanometil-karbamoil)-3-metil-butil]-benzamid (Spoj 151); 1H-NMR (DMSO-d6): δ 8.7 (t, 1H) δ 8.3 (d, 1H) δ 7.7 (d, 1H) δ 7.2 (t, 1H) δ_6.8 (d, 1H) δ 6.6 (t, 1H) δ 4.2 (d, 2H) δ 1.6-1.8 (m, 3H) δ 0.9 (q, 6H); MS (electrospray)mH+ 288.7 (100%);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, tiofen-3-ilmetil ester (Spoj 152); HNMR (Cl3CD): 7.17 (2H, m), 7.05 (1H, m), 5.44 (1H, d), 5.08 (2H, m), 4.20 (1H, m), 4.08 (2H, d), 1.60 (3H, m), 0.91 (6H, m);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-3-(4-metil-piperazin-1-karbonil)-benzamid (Spoj 153);
N-{4-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-izonikotinamid (Spoj 154); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.56-1.89 (m, 3 H), 4.17-4.33 (m, 3 H), 7.89-8.13 (m, 6 H), 8.81 (m, 2 H), 8.51 (m, 1H), 9.01 (m, 1H), 11.10 (m, 1H). ES-Ms: 394.1 (M+H+);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(2-piridin-3-il-acetilamino)-benzamid (Spoj 155); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.56-1.89 (m, 3 H), 4.11 (s, 2 H), 4.17 (s, 2 H), 4.43 (m, 1H), 7.89-8.13 (m, 4 H), 8.61 (m, 2 H), 8.81 (m, 3 H), 11.10 (m, 1H). ES-Ms: 408.1 (M+H+);
[1-S-(Cijanometil-karbamoil)-2-metil-butil]-karbamska kiselina, terc-butil ester (Spoj 156);
[1-R-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, tiofen-2-ilmetil ester (Spoj 157); HNMR (Cl3CD): 7.32 (1H, m), 7.07 (1H, m), 6.98 (1H, m), 5.26 (2H, s), 5.10 (1H, m), 4.14 (2H, m), 1.66 (3H, m), 0.91 (6H, m);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(4-metil-piperazin-1-sulfonil)-benzamid (Spoj 158);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(4-metil-piperazin-1-karbonil)-benzamid (Spoj 159);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-piridin-4-ilmetil-ureido)-benzamid (Spoj 160); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.56-1.89 (m, 3 H), 4.11 (s, 2 H), 4.13 (m, 1H), 4.17 (s, 2 H), 7.89-8.13 (m, 4 H), 8.41 (m, 2 H), 8.81 (m, 3 H), 9.10 (m, 2 H), 10.15 (m, 1H). ES-Ms: 408.1 (M+H+);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 3-piridin-4-il-propil ester (Spoj 161); HNMR (Cl3CD): 8.50 (2H, d), 7.15 (2H, d), 7.08 (1H, m), 5.14 (1H, d), 4.16 (2H, d), 4.10 (2H, t), 2.69 (2H, t), 1.96 (2H, m), 1.60 (3H, m), 0.92 (6H, m);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 3-piridin-3-il-propil ester (Spoj 162); 1HNMR (dmso-d6): 8.65 (1H, t), 8.41 (2H, m), 7.63 (1H, d), 7.40 (1H, d), 7.31 (1H, m), 4.11 (2H, d), 4.00 (1H, m), 3.94 (2H, t), 2.65 (2H, t), 1.86 (2H, m), 1.50 (3H, m), 0.87 (6H, m);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 2-[(piridin-4-karbonil)-amino]-etil ester (Spoj 163); 1HNMR (dmso-d6): 9.00 (1H, t), 8.84 (2H, m), 8.65 (1H, t), 7.91 (2H, d), 7.42 (1H, d), 4.12 (4H, m), 4.0 (1H, m), 3.50 (2H, m), 1.60 (1H, m), 1.43 (2H, m), 0.83 (6H, m);
4-Amino-N-[1-R-(cijanometil-karbamoil)-3-metil-butil]-benzamid (Spoj 164);
N-[1-(Cijanometil-karbamoil)-2-metil-butil]-4-(2-piridin-4-il-etilamino)-benzamid (Spoj 166);
Ciklopropankarboksilna kiselina, [1-S-(Cijanometil-karbamoil)-2-metil-butil]-amid (Spoj 167);
Ciklopropankarboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 168);
4-Amino-N-[1-(cijanometil-karbamoil)-2-metil-butil]-benzamid (Spoj 169);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-piridin-3-il-propoksi)-benzamid (Spoj 170); 1H NMR (DMSO): δ 0.84-0.91 ppm (d,d, 6 H), δ 1.49-1.8 ppm (m, 3 H), δ 1.98-2.11 ppm (m, 2 H), δ 2.72-2.8 ppm (m, 2 H), δ 2.88 ppm (s, 1H), δ 3.98-4.09 ppm (m, 2 H), δ 4.10-4.12 ppm (d, 2 H), δ 4.47-4.54 (m, 1H), δ 6.97-7.01 ppm (d, 2 H), δ 7.29-7.33 ppm (m, 1H), δ 7.65-7.68 ppm (d, m 1H), δ 7.86-7.90 ppm (d, 2 H), δ 8.35-8.41 ppm (m, 2 H), δ 8.45-8.46 ppm (m, 1H), δ 8.64-8.68 ppm (t, 1H); LC/MS (409.4 M+H+);
3- Amino-N-[1-(Cijanometil-karbamoil)-3-metil-butil]-benzamid (Spoj 171);
1,3-bis-{4-[1-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-urea(Spoj 172);
N-[1-S-(Cijanometil-karbamoil)-2-metil-butil]-4-(piridin-4-ilmetoksi)-benzamid (Spoj 173);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(piridin-2-ilmetoksi)-benzamid (Spoj 174); 1H NMR (DMSO): δ 0.84-0.91 ppm (d,d, 6 H), δ 1.49-1.8 ppm (m, 3 H), δ 4.10-4.12 ppm (d, 2 H), δ 4.4-4.52 (m, 1H), δ 5.25 ppm (s, 2 H), δ 7.08-7.11 ppm (d, 2 H), δ 7.34-7.37 ppm (m, 1H), δ 7.50-7.53 ppm (d, 1H), δ 7.8-7.90 ppm (m, 3 H), δ 8.38-8.41 ppm (d, 1H), δ 8.55-8.60 ppm (d,m, 1H), δ 8.64-8.68 ppm (t, 1H); LC/MS (381.02 M+H+);
5-Kloro-N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-2-nitro-benzamid
(Spoj 175); 1H-NMR (DMSO-d6): δ 9.3 (d, 1H) δ 9.0 (m, 1H) δ 8.3 (d 1H) δ 8.0 (m, 2H) δ 4.4 (d, 2H) δ 1.6-2.0 (m, 3H) δ 1.1 (m, 6H); MS (electrospray): mH+ 353.8 (100%);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(2-piridin-2-il-etoksi)-benzamid (Spoj 176);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(2-pirolidin-1-il-etoksi)-benzamid (Spoj 177); 1H NMR (DMSO): δ 0.84-0.94 ppm (d,d, 6 H), δ 1.4-1.8 ppm (m, 3 H), δ 1.8-1.91 ppm (m, 2H), δ 1.98-2.10 ppm (m, 2 H), δ 3.01-3.2 ppm (m, 2 H), δ 4.11-4.13 ppm (d, 2 H), δ 4.34-4.36 (d, 2 H), δ 4.45-4.6 ppm (m, 1H), δ 7.05-7.09 ppm (d, 2 H), δ 7.91-7.95 ppm (d, 2 H), δ 8.42-8.45 ppm (d, 1H), δ 8.69-8.75 ppm (t, 1H); LC/MS (386.6 M+H+);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(piridin-3-ilmetoksi)-benzamid (Spoj 178); 1H NMR (DMSO): δ 0.84-0.91 ppm (d,d, 6 H), δ 1.5-1.8 ppm (m, 3 H), δ 4.1-4.12 ppm (d, 2 H), δ 4.44-4.55 ppm (m, 1H), δ 5.23 (s, 2 H), δ 7.09-7.12 ppm (d, 2 H), δ 7.42-7.45 ppm (m, 1H), δ 7.87-7.94 ppm (m, 3 H), δ 8.39- 8.42 ppm (d, 1H), δ 8.54-8.56 ppm (m, 1H), δ 8.65-8.70 ppm (m, 2 H); LC/MS (380.4 M+H+);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 4-(3-piridin-4-il-propoksi)-benzil ester (Spoj 179); 1HNMR (dmso-d6): 8.67 (1H, t), 8.45 (2H, m), 7.48 (2H, d), 7.26 (4H, m), 6.90 (2H, d), 4.93 (2H, dd), 4.11 (2H, d), 4.00 (3H, m), 2.75 (2H, t), 2.01 (2H, m), 1.50 (3H, m), 0.85 (6H, m);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 4-(piridin-4-ilmetoksi)-benzil ester (Spoj 180); 1HNMR (dmso-d6): 8.68 (1H, t), 8.56 (2H, m), 7.48 (1H, d), 7.42 (2H, d), 7.30 (2H, d), 7.01 (2H, d), 5.19 (2H, s), 4.94 (2H. dd), 4.11 (2H, d), 4.01 (1H, m), 1.50 (3H, m), 0.84 (6H, m);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-3-nitro-benzamid (Spoj 181);
N-[1-S-(Cijanometil-karbamoil)-2-metil-butil]-3-nitro-benzamid (Spoj 182);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-piridin-3-il-benzamid
(Spoj 183); 1HNMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.56-1.89 (m, 3 H), 4.13 (m, 2 H), 4.17 (m, 1H), 7.76-7.81 (m, 6 H), 8.51 (m, 1H), 8.86 (m, 3 H), 9.18 (m, 1H), ES-Ms: 351.3 (M+H+);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-piridin-2-il-propoksi)-benzamid (Spoj 184); 1H NMR (DMSO): δ 0.81-0.94 ppm (d,d, 6 H), δ 1.5-1.8 ppm (m, 3 H), δ 2.1-2.2 ppm (m, 2H), δ 2.85-2.95 ppm (t, 2 H), δ 4.07-4.19 ppm (m, 4 H), δ 4.47-4.51 ppm (m, 1H), δ 6.96-7.00 ppm (d, 2 H), δ 7.15-7.24 ppm (m, 1H), δ 7.25-7.3 ppm (d, t.H), δ 7.66-7.74 ppm (t,d, 1H), δ 7.84-7.9 ppm (d, 2 H), δ 8.37-8.40 ppm (d, 1H), δ 8.48-8.51 ppm (d,m, 1H), δ 8.63-8.70 ppm (t, 1H); LC/MS (408.4 M+H+);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-3-(piridin-3-sulfonilamino)-benzamid (Spoj 185); 1H-NMR (DMSO-d6): δ 10.6 (s, 1H) δ 9.0-8.6 (m, 3H) δ 8.5 (s, 1H) δ 8.2 (d, 1H) δ 7.6 (m, 3H) δ 7.3 (m, 2H) δ 4.1 (d, 2H) δ 1.4-1.7 (m, 3H) δ 0.9 (m, 6H); MS (electrospray): mH+ 429.5 (100%);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 1-metil-piridin-4-ilmetil ester, jodidna sol (Spoj 186); 1HNMR (dmso-d6): 8.96 (2H, d), 8.77 (1H, t), 7.98 (2H, d), 7.92 (1H, d), 5.35 (2H, m), 4.31 (3H, s), 4.13 (2H, d), 4.04 (1H, m), 1.50 (3H, m), 0.88 (6H, m);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 3-(1-metil-piridin-3-il)-propil ester, jodidna sol (Spoj 187); 1HNMR (dmso-d6): 8.92 (1H, s), 8.84 (1H, d), 8.69 (1H, t), 8.44 (1H, d), 8.05 (1H, m), 7.37 (1H, d), 4.31 (3H, s), 4.12 (2H, d), 4.00 (3H, m), 2.85 (2H, t), 1.95 (2H, m), 1.50 (3H, m), 0.86 (6H, m);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 3-(1-cijanometil-piridin-3-il)-propil ester, jodidna sol (Spoj 188); 1HNMR (dmso-d6): 9.12 (1H, s), 9.05 (1H, d), 8.70 (1H, t), 8.62 (1H, d), 8.18 (1H, m), 7.37 (1H, d), 5.93 (2H, s), 4.12 (2H, d), 4.00 (3H, m), 2.89 (2H, m), 1.96 (2H, m), 1.50 (3H, m), 0.86 (6H, m);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 4-(piridin-3-iloksi)-benzil ester (Spoj 189); 1HNMR (dmso-d6): 8.69 (1H, t), 8.37 (2H, m), 7.55 (1H, d), 7.42 (4H, m), 7.07 (2H, d), 5.01 (2H, dd), 4.11 (2H, d), 4.02 (1H, m), 1.50 3H, m), 0.85 (6H, m);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-3-(4-metoksi-benzensulfonilamino)-benzamid (Spoj 190); 1H-NMR (DMSO-d6): δ 10.3 (s, 1H) δ 8.7 (t, 1H) δ 8.5 (d, 1H) δ 7.0-7.7 (m, 8H) δ 4.4 (m, 1H) δ 4.2 (d, 2H) δ 1.5-1.7 (m, 3H) δ 0.9 (m, 6H); MS (electrospray): mH+ 459.4 (100%);
N-{3-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-sukcinilna kiselina, metil ester (Spoj 191);
N-{3-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-sukcinilna kiselina, (Spoj 192);
5-Piridin-2-il-tiofen-2-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 193);
N-{3-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-sukcinilna kiselina, (Spoj 194);
1,3-bis-{3-[1-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-urea(Spoj 195);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-3-(naftalen-1-sulfonilamino)-benzamid (Spoj 196); 1H-NMR (DMSO-d6): δ 10.6 (s, 1H) δ 8.7 (t, 1H) δ 8.6 (d, 1H) δ 8.46 (s, 1H) δ 8.1 (m, 3H) δ 7.8 (m, 1H) δ 7.5-7.8 (m, 4H) δ 7.45 (m, 1H) δ 7.25 (m 2H) δ 4.4 (m, 1H) δ 4.1 (d, 2H) δ 1.4-1.7 (m, 3H) δ 0.8 (q, J = 11 Hz, 6 H); MS (electrospray)mH+ 479.2 (100%);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-3-(4-fluoro-benzensulfonilamino)-benzamid (Spoj 197); 1H-NMR (DMSO-d6): δ 10.5 (s, 1H) δ 8.7 (t, 1H) δ 8.5 (d, 1H) δ 7.8 (m, 2 H) δ 7.6 (m, 2H) δ 7.2-7.5 (m (br)4 H), δ 4.2 (m, 1H) δ 4.1 (d, 2H) δ 1.4-1.7 (m, 3H) δ 0.9 (q, J = 12 Hz, 6H); MS (electrospray)mH+ 447.4 (100%);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-3-metoksi-benzamid
(Spoj 198); 1H NMR (DMSO): δ 0.81-0.94 ppm (m, 6 H), δ 1.44-1.80 ppm (m, 3 H), δ 3.8 ppm (s, 3 H), δ 4.10-4.14 ppm (d, 2 H), δ 4.47-4.55 ppm (m, 1 H), δ 7.01-7.13 ppm (d,d, 1H), δ 7.27- 7.52 ppm (m, 4 H), δ 8.47-8.6 ppm (d, 1H), δ 8.6-8. 74 ppm (t, 1 H); LC/MS (303.4 M+H+);
{4-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-karbamska kiselina, 2-pirolidin-1-il-etil ester (Spoj 199); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.26-1.89 (m, 7 H), 3.31 (m, 2 H), 3.56-3.71 (m, 6 H), 4.09 (s, 2 H), 4.13 (m, 2 H), 4.17 (m, 1H), 7.76 (m, 2 H), 7.81 (m, 2 H), 8.51 (m, 1H), 8.86 (m, 1H), 9.88 (m, 1H), 10.15 (m, 1H). ES-Ms: 430.3 (M+H+);
{4-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-karbamska kiselina, 3-piridin-4-il-propil ester (Spoj 200); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.26-1.89 (m, 3 H), 2.01 (m, 2 H), 3.01 (m, 2 H), 4.17 (m, 4 H), 4.57 (m, 1H), 7.56 (m, 2 H), 7.81 (m, 4 H), 8.51 (m, 1H), 8.86 (m, 3 H), 9.88 (m, 1H). ES-Ms: 452.1 (M+H+);
{4-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-karbamska kiselina, 3-piridin-3-il-propil ester (Spoj 201); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.26-1.89 (m, 3 H), 2.01 (m, 2 H), 3.01 (m, 2 H), 4.17 (m, 4 H), 4.57 (m, 1H), 7.66 (m, 2 H), 7.91 (m, 4 H), 8.31 (m, 1H), 8.51 (m, 1H), 8.86 (m, 3 H), 9.98 (m, 1H). ES-Ms: 452.1 (M+H+);
{4-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-karbamska kiselina 3-piridin-2-il-propil ester (Spoj 202); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.26-1.89 (m, 3 H), 2.01 (m, 2 H), 3.01 (m, 2 H), 4.17 (m, 4 H), 4.57 (m, 1H), 7.56-7.91 (m, 6 H), 8.31 (m, 1H), 8.51 (m, 1H), 8.86 (m, 2 H), 9.98 (m, 1H). ES-Ms: 452.1 (M+H+);
{4-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-karbamska kiselina, 1-metil-piperidin-3-il-metil ester (Spoj 203); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.26-1.89 (m, 8 H), 2.01 (m, 2 H), 3.51 (m, 7 H), 3.71 (m, 2 H), 4.17 (m, 4 H), 4.57 (m, 1H), 7.66 (m, 2 H), 7.91 (m, 2 H), 8.11 (m, 1H), 8.31 (m, 1H), 9.16 (m, 1H), 9.98 (m, 1H). ES-Ms: 453.9 (M+H+);
{4-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-karbamska kiselina, 1-metil-piperidin-2-il-metil ester (Spoj 204); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.26-1.89 (m, 9 H), 2.01 (m, 2 H), 3.51 (m, 6 H), 3.71 (m, 2 H), 4.17 (m, 4 H), 4.57 (m, 1H), 7.56 (m, 2 H), 7.91 (m, 2 H), 8.21 (m, 1H), 8.31 (m, 1H), 9.36 (m, 1H), 9.98 (m, 1H). ES-Ms: 453.9 (M+H+);
{4-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-karbamska kiselina, piridin-2-ilmetil ester (Spoj 205); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.26-1.89 (m, 3 H), 4.17 (m, 2 H), 4.57 (m, 1H), 5.12 (s, 2 H), 7.56-8.01 (m, 6 H), 8.51 (m, 1H), 8.81 (m, 2 H), 9.98 (m, 1H). ES-Ms: 424.1 (M+H+);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(piridin-3-iloksi)-benzamid (Spoj 206); 1H NMR (DMSO): δ 0.86-0.94 ppm (m, 6 H), δ 1.42-1.8 ppm (m, 3 H), δ 4.1 ppm (m, 2 H), δ 4.5 ppm (m, 1H), δ 7.09-7.15 ppm (m, 2 H), δ 7.44-7.6 ppm (m, 2 H), δ 7.95-8.0 ppm (d,m 2 H), δ 8.4 ppm (m, 1H), δ 8.5 ppm (m, 1H), δ 8.7 ppm (m, 1H). LC/MS (366.2 M+H+);
{4-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-karbamska kiselina, 2-piridin-2-il-etil ester (Spoj 207); ES-Ms: 438.4 (M+H+);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 1-metil-piridin-3-ilmetil ester, jodidna sol (Spoj 208); 1HNMR (dmso-d6): 8.98 (1H, s), 8.92 (1H, m), 8.76 (1H, m), 8.48 (1H, d), 8.15 (1H, m), 7.76 (1H, m), 5.20 (2H, m), 4.32 (3H, s), 4.11 (2H, m), 4.08 1H, m), 1.50 (3H, m), 0.90 (6H, m);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 1-karbamoilmetil-piridin-3-ilmetil ester bromidna sol (Spoj 209); 1HNMR (dmso-d6): 9.03 (0.5 H, s), 8.97 (0.5 H, d), 8.89 (1H, m), 8.59 (1H, d), 8.20 (1H, m), 8.12 (1H, s), 7.68 (1H, m), 7.65 (1H, bs), 7.30 (1H, bs), 5.40 (1H, s), 5.13 (1H), 4.15 2H, d), 4.00 (1H, m), 3.80 (2H, s), 1.50 (3H, m), 0.95 (6H, m);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-piperidin-4-il-ureido)-benzamid (Spoj 210);
[1-S-(Cijanometil-karbamoil)-3-metil-butil]-karbamska kiselina, 5-piridin-2-il-tiofen-2-ilmetil ester (Spoj 211); HNMR (Cl3CD): 8.51 (1H, m), 7.85 (2H, m), 7.42 (1H, m), 7.34 (1H, s), 7.20 (1H, m), 7.10 (2H, m), 5.22 (2H, m), 4.30 (3H, m), 1.70 (3H, m), 0.90 (6H, m);
4-Piridin-4-il-piperazin-1-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 212);
2-(2-Nitro-fenil)-tiazol-4-karboksilna kiselina, [1-R-(cijanometil-karbamoil)-2-naftalen-2-il-etil]-amid (Spoj 213);
Morfolin-4-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-2-naftalen-2-il-etil]-amid (Spoj 214);
Benzofuran-2-karboksilna kiselina, [1-(cijanometil-karbamoil)-3-metil-butil]-amid (spoj 215); 1HNMR (dmso-d6): 8.80 (1H, m), 7.79 (1H, d), 7.67 (3H, m), 7.48 (1H, m), 7.35 (1H, t), 4.53 (1H, m), 4.14 (2H, m), 1.65 (3H, m), 0.90 (6H, m);
Morfolin-4-karboksilna kiselina, {4-[1-(cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-amid (Spoj 216);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-[3-(3-morfolin-4-il-propil)-ureido]-benzamid (Spoj 217);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-piridin-3-ilmetil-ureido)-benzamid (Spoj 218);
N-[1-(cijanometil-karbamoil)-3-metil-butil]-4-[3-(1h-[1,2,4]triazol-3-il)-ureido]-benzamid (spoj 219);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-(3,3-dimetil-ureido)-benzamid (Spoj 220);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-piridin-2-il-ureido)-benzamid (Spoj 221);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-piridin-3-il-ureido)-benzamid (Spoj 222);
Kvinolin-2-karboksilna kiselina, [1-R-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 223); 1HNMR (dmso-d6): 8.88 (2H, m), 8.60 (1H, d), 8.15 (3H, m), 8.09 (1H, m), 7.74 (1H, m), 4.66 (1H. m), 4.17 (2H, d), 1.80 (1H, m), 1.65 (2H, m), 0.92 (6H, m);
Kvinolin-4-karboksilna kiselina, [1-R-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 224); 1HNMR (dmso-d6): 9.06 (1H, d), 9.01 (1H, d), 8.87 (1H, t), 8.16 (1H, d), 8.08 (1H, d), 7.81 (1H, m), 7.67 (1H, m), 7.58 (1H, d), 4.61 (1H, m), 4.22 (2H, d), 1.60 (3H, m), 0.94 (6H, m);
N-[1-S-(Cijanometil-karbamoil)-2-naftalen-2-il-etil]-4-morfolin-4-il-benzamid (Spoj 225);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-[1,3,4]tiadiazol-2-il-ureido)-benzamid (Spoj 226);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-tiazol-2-il-ureido)-benzamid (Spoj 227);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-furan-2-ilmetil-ureido)-benzamid (Spoj 228);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-{3-[2-(1H-indol-3-il)-etil]-ureido}-benzamid (Spoj 229);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-piridin-2-ilmetil-ureido)-benzamid (Spoj 230);
Tiomorfolin-4-karboksilna kiselina, {4-[1-(cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-amid (Spoj 231);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-ureido-benzamid (Spoj 232);
{4-[1-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-karbamska kiselina, metil ester (Spoj 233);
N-[1-(cijanometil-karbamoil)-3-metil-butil]-3-ureido-benzamid (spoj 234);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-3-(3,3-dimetil-ureido)-benzamid (Spoj 235);
Morfolin-4-karboksilna kiselina, {3-[1-(cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-amid (Spoj 236);
Tiomorfolin-4-karboksilna kiselina, {3-[1-(cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-amid (Spoj 237);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-3-[3-(3-morfolin-4-il-propil)-ureido-benzamid (Spoj 238);
N-[1-(cijanometil-karbamoil)-3-metil-butil]-3-(3-piridin-2-il-ureido)-benzamid (spoj 239);
N-[1-(cijanometil-karbamoil)-3-metil-butil]-3-(3-piridin-3-il-ureido)-benzamid (spoj 240);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-3-(3-piridin-4-ilmetil-ureido)-benzamid (Spoj 241);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-3-(3-furan-2-ilmetil-ureido)-benzamid (Spoj 242);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-3-{3-[2-(1H-indol-3-il)-etil]-ureido}-benzamid (Spoj 243);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-3-{3-[2-(1H-imidazol-4-il)-etil]-ureido}-benzamid (Spoj 244);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-{3-[2-(3H-imidazol-4-il)-etil]-ureido}-benzamid (Spoj 245);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-4-[3-(5-metil-pirazin-2-ilmetil)-ureido]-benzamid (Spoj 246);
4-Dimetilamino-piperidin-1-karboksilna kiselina, {3-[1-(cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}amid (Spoj 247);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-3-(3-piridin-2-ilmetil-ureido)-benzamid (Spoj 248);
N-[1-(Cijanometil-karbamoil)-3-metil-butil]-3-(3-piridin-3-ilmetil-ureido)-benzamid (Spoj 249);
4-(1-Aza-biciklo[2.2.2]okt-1-ilmetil)-N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-benzamid, bromidna sol (Spoj 250); 1HNMR (dmso-d6): 8.78 (1H, t), 8.69 (1H, d), 8.05 (2H, d), 7.61 (2H, d), 4.57 (1H, m), 4.48 (2H, s), 4.14 (2H, d), 3.47 (6H, m), 2.04 (1H, bs), 1.85 (6H, m), 1.60 (3H, m), 0.89 (6H, m);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-hidroksimetil-piridin-1-ilmetil)-benzamid, bromidna sol (Spoj 251); 1HNMR (dmso-d6): 9.16 (1H, s), 8.70 (1H, d), 8.54 (1H, d), 8.16 (1H, t), 7.99 (2H, d), 7.65 (2H, d), 5.95 (2H, s), 4.72 (2H, s), 4.50 (1H, m), 4.12 (2H, d), 1.60 (3H, m), 0.88 (6H, m);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(4-metil-morfolin-4-ilmetil)-benzamid, bromidna sol (Spoj 252); 1HNMR (dmso-d6): 9.30 (1H, m), 9.20 (1H, m), 8.14 (2H, d), 7.66 (2H, d), 4.74 (2H, bs), 4.57 (1H, m), 4.11 (2H, bs), 3.97 (2H, bs), 3.56 (2H, bs), 3.38 (4H, s), 3.07 (3H. bs), 1.80 (1H, m), 1.56 (2H, m), 0.88 (6H, m);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-(3-dimetilamino-fenoksi)-benzamid (Spoj 253); 1H NMR (DMSO): δ 0.81-0.89 ppm (d,d, 6 H), δ 1.46-1.73 ppm (m, 3 H), δ 2.85 ppm (s, 6 H), δ 4.08-4.1 ppm (d, 2 H), δ 4.42-4.5 (m, 1 H), δ 6.24- 6.27 ppm (d, 1H), δ 6.275 ppm (s, 1H), δ 6.5-6.53 ppm (d, 1H), δ 6.97- 7.00 ppm (d, 2 H), δ 7.14-7.17 ppm (t, 1H), δ 7.88-7.91 ppm (d, 2 H), δ 8.43-8.48 ppm (d, 1H), δ 8.65-8.68 ppm (t, 1H); LC/MS (408.2 M+H+);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-3-(3-piridin-3-il-propoksi)-benzamid (Spoj 254); 1H NMR (DMSO): δ 0.84-0.89 ppm (d,d, 6 H), δ 1.46-1.74 ppm (m, 3 H), δ 1.95-2.07 ppm (m, 2 H), δ 2.73-2.78 ppm (t, 2 H), δ 3.97-4.03 ppm (m, 2 H), δ 4.08-4.10 ppm (d, 2 H), δ 4.43-4.5 (m, 1H), δ 7.06- 7.08 ppm (d, 1H), δ 7.26-7.37 ppm (m, 2 H), δ 7.63-7.66 ppm (m, 1H), δ 8.36-8.38 ppm (m, 1H), δ 8.43 ppm (s, 1H), δ 8.52-8.55 ppm (d, 1H), δ 8.66-8.69 ppm (m, 1H); LC/MS (408.4 M+H+);
Izokvinolin-1-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 255); 1HNMR (dmso-d6): 8.96 (1H, d), 8.88 (1H, t), 8.07 (2H, m), 7.84 (1H, t), 7.74 (1H, t), 4.64 (1H, m), 4.21 (2H, d), 1.65 (3H, m), 0.93 (6H, m);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-4-piridin-1-ilmetil-benzamid, jodidna sol (Spoj 256); 1HNMR (dmso-d6): 9.20 (2H, d), 8.65 (1H, t), 8.20 (2H, t), 7.98 (2H, d), 7.62 (2H, d), 5.92 (2H, s), 4.50 (1H, m), 4.12 (2H, s), 1.50 (3H, m), 0.89 (6H, m);
Izokvinolin-3-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 257); 1HNMR (dmso-d6): 9.42 (1H, s), 8.85 (2H, m), 8.58 (1H, s), 8.27 (1H, d), 8.22 (1H, d), 7.86 (2H, m), 4.67 (1H. m), 4.17 (2H, d), 1.77 (1H. m), 1.61 (2H. m). 0.92 (6H, m);
4-Dimetilamino-piperidin-1-karboksilna kiselina, {4-[1-(cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-amid (Spoj 258);
N-[1-S-(Cijanometil-karbamoil)-3-metil-but-3-enil]-4-fluoro-benzamid (Spoj 259);
5-(3-Trifluorometil-fenil)-furan-2-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 260); 1H NMR (DMSO): δ 0.8-1.0 ppm (m, 6 H), δ 1.55-1.85 ppm (m, 3 H), δ 4.14-4.16 ppm (d, 2 H), δ 4.5-4.6 ppm (m, 1H), δ 7.3-7.4 ppm (d,d. 2 H), δ 7.7-7.8 ppm (m, 2 H), δ 8.25-8.34 ppm (m, 2 H), δ 8.7-8.9 ppm (m, 2 H);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-3-fenoksi-benzamid (Spoj 261); 1H NMR (DMSO): δ 0.0.86-0.96 ppm (m, 6 H), δ 1.42-1.8 ppm (m, 3 H), δ 4.0-4.17 ppm (m, 2 H), δ 4.5 ppm (m, 1H), δ 6.97-7.04 ppm (m, 2 H), δ 7.12-7.19 ppm (m, 2 H), δ 7.39-7.58 ppm (m 4 H), δ 7.61-7.73 ppm (m, 1H), δ 8.56-8.73 ppm (m, 1H); LC/MS (366 M+H+);
N-[1-(cijanometil-karbamoil)-3-metil-but-3-enil]-4-morfolin-4-il-benzamid (spoj 262);
2-(2-Nitro-fenil)-tiazol-4-karboksilna kiselina, [1-S-(Cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 263); 1H NMR (DMSO): δ 0.86-0.88 ppm (m, 6 H), δ 1.5-1.7 ppm (m, 3 H), δ 4.09-4.20 ppm (m, 2 H), δ 4.39-4.55 ppm (m, 1H). δ 7.73-7.88 ppm (m, 2 H), δ 7.87-7.99 ppm (m, 1H), δ 7.98-8.12 ppm (m 2 H), δ 8.75-8.87 ppm (m, 1H); LC/MS (402 M+H+);
2-Benzo[1,3]dioksol-5-il-oksazol-4-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 264); 1HNMR (dmso-d6): 8.81 (1H, t), 8.69 (1H. s), 8.22 (1H, d), 7.61 (1H, d), 7.53 (1H, s), 7.12 (1H, d), 6.16 (2H, s), 4.57 (1H, m), 4.15 (2H, d), 1.60 (3H, m), 0.90 (6H, m);
Piridin-2-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 265); 1HNMR (dmso-d6): 8.83 (1H, t), 8.70 (2H, m), 8.02 (2H, m), 7.66 (1H, m), 4.59 (1H. m), 4.15 (2H, d), 1.74 (1H, m), 1.58 (2H, m), 0.90 (6H, m);
{4-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-karbamska kiselina, 2-morfolin-4-il-etil ester (Spoj 266); ES-Ms: 446.4 (M+H+);
4-Metil-2-S-[3-(4-fenil-tiazol-2-il)-ureido]-pentanojeva kiselina, cijanometil-amid (Spoj 267); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.26-1.89 (m, 3 H), 4.17 (m, 2 H), 4.57 (m, 1H), 5.12 (s, 2 H), 7.36-7.61 (m, 6 H), 7.81 (m, 2 H). ES-Ms: 372.1 (M+H+);
2-(3-Nitro-fenil)-tiazol-4-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 268); 1H NMR (DMSO): δ 0.86-0.91 ppm (m, 6 H), δ 1.56-1.64 ppm (m, 2 H), δ 1.74-1.80 ppm (m, 1H), δ 4.11-4.4 ppm (d, 2 H), δ 4.5-4.6 ppm (m, 1H), δ 7.79-7.85 ppm (m, 1H), δ 8.28-8.39 ppm (m, 1H), δ 8.41-8.52 ppm (m, 2 H), δ 8.57-8.68 ppm (m, 1H), δ 8.7-8.9 ppm (m, 2 H); LC/MS (423.8 M+Na+);
4-Hidroksi-kvinolin-2-karboksilna kiselina, [1-R-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 269);
6-Hidroksi-piridin-2-karboksilna kiselina, [1-R-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 270); 1HNMR (dmso-d6): 11.00 (1H, s), 8.95 (1H, bs), 7.79 (1H, bs), 6.84 (1H, bs), 4.55 (1H, bs), 4.16 (2H, m), 1.58 (3H. m), 0.90 (6H, m);
Kvinoksalin-2-karboksilna kiselina, [1-R-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 271); 1HNMR (dmso-d6): 9.48 (1H, s), 9.00 (1H, d), 8.85 (1H, t), 8.25 (2H, m), 8/02 (2H, m), 4.66 (1H, m), 4.17 (2H, m), 1.84 (1H, m), 1.65 (2H, m), 0.93 (6H, m);
3-Hidroksi-piridin-2-karboksilna kiselina, [1-R-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 272); 1HNMR (dmso-d6): 9.03 (1H. d), 8.84 (1H. t), 8.21 (1H, d), 7.56 (1H, dd). 7.45 (1H, d), 4.57 (1H, m), 4.16 (2H, d), 1.78 (1H, m), 1.60 (2H, m), 0.90(6H, m);
8-Hidroksi-kvinolin-2-karboksilna kiselina, [1-R-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 273); 1HNMR (dmso-d6): 9.68 (1H, d), 8.52 (1H, d), 8.15 (1H, d), 7.54 (2H, m), 7.20 (1H, d), 4.65 (1H, m), 4.15 (2H, s), 1.71 (3H, m), 0.92 (6H, m);
N-[1-S-(Cijanometil-karbamoil)-3-metil-butil]-3-(2-dimetilamino-tiazol-5-il)-benzamid (Spoj 274);
4’-Trifluorometil-bifenil-2-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 275); 1H NMR (DMSO): δ 0.66-0.74 ppm (m, 6 H), δ 1.06-1.28 ppm (m, 2 H), δ 1.35-1.45 (m, 1H), δ 2.75 (m, 1H), δ 4.09-4.12 ppm (m, 2 H), δ 4.17-4.25 ppm (m, 1H), δ 7.32-7.61 ppm (m, 8 H), δ 7.7-7.76 ppm (m, 2 H), δ 7.78 ppm (m 1H), δ 8.48-8.51 ppm (m, 1H), δ 8.6-8.65 ppm (m, 1H); LC/MS (440.2 M+Na+);
{4-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}karbamska kiselina, 1-metil-pirolidin-2-ilmetil ester (Spoj 276); ES-Ms: 429.4 (M+H+);
{4-[1-S-(Cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}karbamska kiselina, 2-(1-metil-pirolidin-2-il)-etil ester (Spoj 277); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.26-1.89 (m, 9 H), 2.01 (m, 2 H), 3.51 (m, 6 H), 4.17 (m, 2 H), 4.57 (m, 1H), 7.56 (m, 2 H), 7.91 (m, 2 H), 8.21 (m, 1H), 8.31 (m, 1H). ES-Ms: 443.9 (M+H+);
2-(Piridin-4-ilamino)-tiazol-4-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 278);
N-[1-S-(Dicijanometil-karbamoil)-3-metil-butil]-4-morfolin-4-il-benzamid (Spoj 279);
2-(3-Amino-fenil)-tiazol-4-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 280); 1H NMR (DMSO): δ 0.78-0.94 ppm (m, 6 H), δ 1.5-1.75 ppm (m, 3 H), δ 4.12-4.14 ppm (d, 2 H), δ 4.51-4.59 ppm (m, 1H), δ 5.37 ppm (m, 1H), δ 6.67 -6.69 ppm (m, 1H), δ 7.11-7.20 ppm (m, 2 H), δ 8.24-8.28 ppm (m, 1H), δ 8.8-8.85 ppm (m, 1H); LC/MS (371.6 M+H+);
2-(2-Amino-fenil)-tiazol-4-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 281); 1H NMR (DMSO): δ 0.81-0.94 ppm (m, 6 H), δ 1.52-1.65 ppm (m, 2 H), δ 1.74-1.82 ppm (m, 1H), δ 4.10-4.14 ppm (m, 2 H), δ 4.47- 4.55 ppm (m, 1H), δ 6.55-6.6 ppm (t, 1H), δ 6.83-6.86 ppm (m, 1H), δ 7.11-7.17 ppm (t,m 1H), δ 7.51- 7.56 ppm (d, 1H). δ 8.2 ppm (m, 1H), δ 8.66-8.71 ppm (m, 2 H); LC/MS (372.2 M+H+);
2-Piridin-3-il-benzooksazol-6-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid (Spoj 282); 1HNMR (dmso-d6): 9.40 (1H, d), 8.85 (1H, m), 0.75 (2H, m), 0.58 (1H, m), 8.40 (1H, s), 8.05 (1H, d), 7.94 (1H, d), 7.70 (1H, m), 4.56 (1H, m), 4.15 (2H, d), 1.70 (3H, m), 0.92 (6H, m);
2-(1-Metil-piridin-3-il)- benzooksazol-6-karboksilna kiselina, [1-S-(cijanometil-karbamoil)-3-metil-butil]-amid, jodidna sol (Spoj 283); 1HNMR (dmso-d6): 9.91 (1H, s), 9.25 (1H, d), 9.19 (1H, d), 8.82 (2H, m), 8.42 (1H, s), 8.37 (1H, m), 8.13 (1H, d), 8.05 (1H, d), 4.57 (1H, m), 4.51 (3H, s), 4.16 (2H, m), 1.70 (3H, m), 0.92 (6H, m);
4-Metil-2-S-[4-(4-nitro-fenil)-tiazol-2-ilamino]-pentanojeva kiselina, cijanometil-amid (Spoj 284);
4-Metil-2-S-(4-fenil-tiazol-2-ilamino)-pentanojeva kiselina, cijanometil-amid (Spoj 285);
4-Metil-2-S-(4-piridin-3-il-tiazol-2-ilamino)-pentanojeva kiselina, cijanometil-amid(Spoj 286);
4-Metil-2-S-(4-piridin-4-il-tiazol-2-ilamino)-pentanojeva kiselina, cijanometil-amid(Spoj 287);
[1-(Cijanometil-karbamoil)-ciklopropil]-karbamska kiselina, benzil ester (Spoj 288);
[1-(Cijanometil-karbamoil)-ciklopentil]-karbamska kiselina, benzil ester (Spoj 289);
[1-(Cijanometil-karbamoil)-cikloheksil]-karbamska kiselina, benzil ester (Spoj 290);
4-Metil-2-S-[4-(3-nitro-fenil)-tiazol-2-ilamino]-pentanojeva kiselina, cijanometil-amid (Spoj 291);
2-S-[4-(3-Amino-fenil)-tiazol-2-ilamino]-4-metil-pentanojeva kiselina, cijanometil-amid (Spoj 292);
Octena kiselina, 2-[1-S-(cijanometil-karbamoil)-3-metil-butilamino]-tiazol-4-ilmetil ester (Spoj 293);
N-[1-(Cijanometil-karbamoil)-ciklopropil]-4-morfolin-4-il-benzamid (Spoj 294); 1H NMR (DMSO-d6), δ 8.71 (s, 1H), δ 8.44 (s, 1H), δ 7.77 (d, 2H), δ 6.93 (d, 2H), δ 4.02 (d, 2H), δ 3.70 (s, br, 4H), δ 3.17 (s, br, 4H), δ 1.33 (s, br, 2H), δ 0.98 (s, br, 2H);
[1-(Cijanometil-karbamoil)-cikloheksil]-karbamska kiselina, terc-butil ester (Spoj 295); 1H NMR (DMSO-d6) δ 8.09 (s, 1H), δ 6.76 (s, 1H), δ 4.00 (d, 2H), δ 1.88-1.07 (m, 19H); MS: M+H+ = 282.0;
2-[4-S-(2,5-Dikloro-tiofen-3-il)-tiazol-2-ilamino]-4-metil-pentanojeva kiselina, cijanometil-amid (Spoj 296);
{2-[1-S-(Cijanometil-karbamoil)-3-metil-butilamino]-tiazol-4-il}-octena kiselina, etil ester (Spoj 297);
N-[1-(Cijanometil-karbamoil)-cikloheksil]-4morfolin-4-il-benzamid (Spoj 298); 1H NMR (DMSO-d6), δ 8.11 (s, 1H), δ 7.76 (d, 2H), δ 7.65 (s, 1H), δ 6.93 (d, 2H), δ 4.02 (d, 2H), δ 3.70 (s, br, 4H), δ 3.17 (s, br, 4H), δ 2.15-1.04 (m, 10H): MS: M+H+ = 370.6;
N-[1-S-(1-Cijano-2-okso-propilkarbamoil)-3-metil-butil]-4-morfolin-4-il-benzamid (Spoj 299);
Bifenil-3-karboksilna kiselina, [1-(1-cijano-2-okso-propilkarbamoil)-3-metil-butil]-amid (Spoj 300);
[1-S-(1-Cijano-2-okso-propilkarbamoil)-3-metil-butil]-karbamska kiselina, benzil ester (Spoj 301);
(3-{2-[1-S-(Cijanometil-karbamoil)-3-metil-butilamino]-tiazol-4-il}-fenil)-karbamska kiselina, alil ester (Spoj 302);
{2-[1-S-(Cijanometil-karbamoil)-3-metil-butilamino]-tiazol-4-il}-octena kiselina, (Spoj 303);
N-[1-(Cijanometil-karbamoil)-cikloheksil]-4-dimetilamino-benzamid
(Spoj 304); 1H NMR (DMSO-d6), δ 8.13 (s, 1H), δ 7.73 (d, 2H), δ 7.57 (s, 1H), δ 6.68 (d, 2H), δ 4.23-4.05 (s,br, 6H), δ 4.02 (s, 2H), δ 2.93 (s, br, 6H), δ 2.17-1.03 (m, 10H); MS: M+H+ = 329.4;
1-(3-Fenil-propionilamino)-cikloheksankarboksilna kiselina, cijanometil-amid
(Spoj 305); 1H NMR (DMSO-d6), δ 8.04 (s, 1H), δ 7.65 (s, 1H), δ 7.20 (m, 5H), δ 4.00 (d, 2H), δ 4.02 (s, 2H), δ 2.77 (t, 2H), δ 2.45 (s,br, 2H), δ 1.95-1.07 (m, 10H); MS: M+H+ = 314.0;
N-[1-(Cijanometil-karbamoil)-cikloheksil]-4-(4-metil-piperazin-1-il)-benzamid (Spoj 306); 1H NMR (DMSO-d6), δ 8.14(s, 1H), δ 7.80 (d, 2H), δ 7.73 (s, 1H), δ 7.01 (d, 2H), δ 4.08-3.80 (m, 4H), δ 3.76-3.32 (m, 2H), δ 3.20-2.91 (m, 4H), δ 2.84 (s, 3H), δ 2.17-1.09 (m, 10H); MS: M+H+ = 384.2;
3-Bromo-N-[1-(cijanometil-karbamoil)-cikloheksil]-benzamid (Spoj 307);
1H NMR (DMSO-d6), δ 8.27-8.14 (m, 2H), δ 8.08 (s, 1H), δ 7.82 (d, 1H), δ 7.71 (d, 1H), δ 7.40 (t, 1H), δ 4.02 (d, 2H), δ 2.15-1.10 (m, 10H); MS: M+H+ = 364.0 i 366.2;
N-[1-S-(1-Cijano-ciklopropilkarbamoil)-3-metil-butil]-4-(4-metil-piperazin-1-il)benzamid (Spoj 308);
Bifenil-3-karboksilna kiselina, [1-(cijanometil-karbamoil)-cikloheksil]-amid
(Spoj 309); 1H NMR (DMSO-d6), δ 8.22 (s,br, 1H), δ 8.14 (d, 2H), δ 7.81 (t, 2H), δ 7.72 (d, 2H), δ 7.58-7.33 (m, 4H), δ 4.01 (d, 2H), δ 2.17-1.13 (m, 10H): MS: M+H+ = 362.0;
[1-S-(1-Cijano-ciklobutilkarbamoil)-3-metil-butil]-karbamska kiselina, benzil ester (Spoj 310);
[1-S-(1-Cijano-ciklobutilkarbamoil)-3-metil-butil]-karbamska kiselina, terc-butil ester (Spoj 311);
N-[1-S-(4-Cijano-tetrahidro-piran-4-ilkarbamoil)-3-metil-butil]-4-morfolin-4-il-benzamid (Spoj 312); 1H NMR (DMSO-d6, ppm): 0.86 (m, 6 H), 1.26-1.89 (m, 7 H), 2.61 (m, 4 H), 3.51 (m, 8 H), 4.57 (m, 1H), 7.56 (m, 2 H), 7.91 (m, 2 H), 8.41 (m, 1H). ES-Ms:428.9 (M+H+);
N-[1-(1-Cijano-ciklopropilkarbamoil)-cikloheksil]-4-morfolin-4-il-benzamid (Spoj 313); 1H NMR (DMSO-d6), δ 8.35(s, 1H), δ 7.72 (d, 2H), δ 7.55 (s, 1H), δ 6.92 (d, 2H), δ 3.93 (s, br, 7H), δ 3.70 (s, br, 4H), δ 3.17 (s, br, 4H), δ 2.00-0.9 (m, 14H); MS: M+H+ = 397.0;
4-Amino-N-[1-(cijanometil-karbamoil)-cikloheksil]-benzamid (Spoj 314);
N-[1-(Cijanometil-karbamoil)-cikloheksil]-4-(4-metil-piperazin-1-sulfonil)-benzamid (Spoj 315);
N-[1-(Cijanometil-karbamoil)-cikloheksil]-4-(4-metil-piperazin-1-karbonil)-benzamid (Spoj 316);
4-Metil-piperazin-1-karboksilna kiselina, {4-[1-(cijanometil-karbamoil)-cikloheksilkarbamoil]-fenil}-amid (Spoj 317);
N-[1-S-(1-Cijano-ciklobutilkarbamoil)-3-metil-butil]-4-morfolin-4-il-benzamid (Spoj 318);
4-[4-(4-Metil-piperazin-1-il)-benzoilamino]-tetrahidro-piran-4-karboksilna kiselina, cijanometil-amid (Spoj 319); 1H NMR (DMSO-d6, ppm): 1.76-1.89 (m, 4 H), 2.81 (s, 3 H), 2.91-3.31 (m, 4 H), 3.47-3.66 (m, 6 H), 4.07 (m, 4 H), 7.16 (m, 2 H), 7.81 (m, 2 H), 8.11 (m, 1H), 8.41 (m, 1H), ES-Ms: 386.0 (M+H+);
N-[1-(1-Cijano-ciklopropilkarbamoil)-cikloheksil]-6-(4-metil-piperazin-1-il)-nikotinamid (Spoj 320); 1H NMR (DMSO-d6), δ 8.63(s, 1H), δ 8.41 (s, 1H), δ 8.03 (d, 1H), δ 7.80 (s, 1H), δ 6.95 (d, 2H), δ 4.49 (d, 2H), δ 4.20-3.71 (s, br, 2H), δ 3.49 (d, 2H), δ 3.24-2.94 (m, 4H), δ 2.56 (s, 3H), δ 2.00-0.90 (m, 14H); MS: M+H = 411.2;
N-[1-S-(1-Cijano-ciklobutilkarbamoil)-3-metil-butil]-4-(4-metil-piperazin-1-il)-benzamid (Spoj 321);
[1-(1-Cijano-ciklopropilkarbamoil)-cikloheksil]-karbamska kiselina, terc-butil ester
(Spoj 322); 1H NMR (DMSO-d6), δ 8.37(s, 1H), δ 6.64 (s, 1H), δ 1.81-0.90 (m, 23H); MS: M+H = 380.0;
[1-S-(4-Cijano-tetrahidro-tiopiran-4-ilkarbamoil)-3-metil-butil]-karbamska kiselina, benzil ester (Spoj 323); 1H NMR (DMSO-d6), δ 8.48(s, 1H), δ 7.48 (d, 1H), δ 7.31 (s, 5H), δ 4.99 (s, 2H), δ 4.05 (m, 1H), δ 2.78-2.57 (m, 4H), δ 2.39 (m, 2H), δ 1.95 (m, 2H), δ 1.67-1.18 (m, 3H), δ 0.94-.074 (m, 6H); MS: M+H = 390.2;
[1-S-(1-Cijano-4-metil-cikloheksilkarbamoil)-3-metil-butil]-karbamska kiselina, benzil ester (Spoj 324); 1H NMR (DMSO-d6), δ 8.44 i δ 8.16 (s, 1H), δ 7.46 (m, 1H), δ 7.31 (s, 5H), δ 4.99 (s, 2H), δ 4.04 (m, 1H), δ 2.28 (d, 2H), δ 1.80-0.95 (m, 10H), δ 0.92-0.71 (m, 9H): MS: M+ H = 386.2;
[1-S-(1-Cijano-3-metil-cikloheksilkarbamoil)-3-metil-butil]-karbamska kiselina, benzil ester (Spoj 325); 1H NMR (DMSO-d6), δ 8.44 (s, 1H), δ 7.44 (d, 1H), δ 7.31 (s, br, 5H), δ 4.99 (s, 2H), δ 4.02 (m, 1H), δ 2.28 (d, 2H), δ 1.78-0.95 (m, 10H), δ 0.92-0.71 (m, 9H): MS:M+ H+ = 386.0;
2-(4-morfolin-4-il-benzoilamino)-biciklo[2.2.1]heptan-2-karboksilna kiselina, cijanometil-amid (Spoj 326);
[1-S-(4-Cijano-1,1-diokso-heksahidro-116-tiopiran-4-ilkarbamoil)-3-metil-butil]-karbamska kiselina, benzil ester (Spoj 327); 1H NMR (DMSO-d6), δ 8.69 (s, 1H), δ 7.58 (d, 1H), δ 7.31 (s, br, 5H), δ 4.99 (s, 2H), δ 4.02 (m, 1H), δ 3.21 (s, br, 4H), δ 2.69-2.35 (m, 4H), δ 1.69-1.17 (m, 3H), δ 0.85 (m, 6H); MS: M+ H+ = 421.8;
4-{4-[1-(Cijanometil-karbamoil)-cikloheksilkarbamoil]-benzensulfonil}-piperazin-1-karboksilna kiselina, terc-butil ester (Spoj 328);
[1-S-(4-Cijano-tetrahidro-piran-4-ilkarbamoil)-3-metil-butil]-karbamska kiselina, benzil ester (Spoj 329); i
[1-(4-Cijano-1-metil-piperidin-4-ilkarbamoil)-3-metil-butil]-karbamska kiselina, benzil ester (Spoj 330).
REFERENCA 7
4-(2-pirid-3-ilaminotiazol-4-il)benzojeva kiselina
Otopina 4-bromoacetilbenzojeve kiseline (2.2 g, 10 mmol) u etanolu (50 mL) se obradi s pirid-3-iltiourejom (1.53 g, 1 mmol) i smjesa se drži u refluksu 3 h. Krute tvari se prikupe filtriranjem, ispiru eterom i suše, čime se dobije 4-(2-pirid-3-ilaminotiazol-4-il)benzojeva kiselina (2.2 g, 74%-tni prinos). LC-MS: FAB LC-MS. 298.2 (M+H+).
Postupcima kao u Referenci 7 dobije se 4-[2-(4-metilpiperazin-1-il)tiazol-4-il] benzojeva kiselina LC-MS: FAB LC-MS 304.2 (M+H+).
REFERENCA 8
terc -Butil 4-metil-2S-[4-(2-pirid-3-ilamino)tiazol-4-il]benzoilaminopentanoat
Smjesa 4-(2-pirid-3-ilaminotiazol-4-il)benzojeve kiseline (10 g, 33.6 mmol), dobivene kao u Referenci 7, terc-butil 2S-amino-4-metilpentanoat (7.5 g, 33.3 mmol), HBTU (13.3 g, 33.3 mmol) i trietilamin (10.0 mL, 67.0 mmol) se miješaju približno 12 sati, i zatim razrijede s natrij bikarbonatom (50 mL) i etil acetatom (300 mL). Organski sloj se odvoji, uzastopno ispire s vodom i otopinom soli, suši preko bezvodnog magenzij sulfata i koncentrira pri smanjenom tlaku. Ostatak se otopi u etilacetatu i heksanu i proizvod se rekristalizira, čime se dobije terc-butil 4-metil-2S-[4-(2-pirid-3-ilamino)tiazol-4-il]benzoilaminopentanoat (10 g, 62%-tni prinos). LC-MS: 467.1 M+H+.
REFERENCA 9
1-amino-N-cijanometilcikloheksankarboksamid, sol metansulfonske kiseline
1-benziloksikarbonilaminocikloheksankarboksilna kiselina (5.0 g, 21.0 mmol) se prenese u dmf (40 mL). Smjesa se hladi u ledenoj kupelji, a zatim uzastopno obradi s aminoacetonitril hidrokloridom (3.8 g, 42 mmol), HATU (8.25 g, 21 mmol) i trietilaminom (8.0 mL, 63 mmol). Reakcija se ostavi napredovati 4 sata, a potom se smjesa koncentrira u vakuumu. Ostatak se obradi sa zasićenom otopinom nahco3 (40 mL) i etil acetatom (150 mL). Organski sloj se razdvoji, uzastopno ispire vodom, 1 m kloridnom kiselinom (20 mL), vodom i otopinom soli, suši preko bezvodnog mgso4 i koncentrira pri smanjenom tlaku. Slobodna baza proizvoda se pročisti iz ostatka pomoću sloja silike s etil acetatom kao sredstvom za razrjeđivanje. Slobodna baza proizvoda se prenese u diklormetan (20 mL) i metansulfonsku kiselinu (3.0 eq) i smjesa se miješa približno 12 sati. Smjesa se koncentrira, a ostatak se usitni s eterom (100 mL) i suši u vakuumu, čime se dobije 1-amino-N-cijanometilcikloheksankarboksamid, sol metansulfonske kiseline (5.5 g, 100%-tni prinos). LC-MS: 182.2, M+H+.
REFERENCA 10
4-[2-(4-terc-butoksikarbonilpiperazin-1-il)tiazol-4-ilmetoksi]benzojeva kiselina
Otopina terc-butil-4-tiokarbamoilpiperazin-1-karboksilata (650 mg, 2.65 mmol) i 1,3-dikloroacetona (672 mg, 5.3 mmol) u 1,2-dikloroetanu se obradi s natrij bikarbonatom (22 mg, 2.65 mmol). Reakcijska smjesa se miješa na 70°C 18 sati, potom razrijedi s kloroformom. Razrjeđenje se ispire vodom i otopinom soli, suši preko natrij sulfata i koncentrira. Proizvod se pročisti iz ostatka na stupcu silika gela, pomoću etil acetat/heksana (3/7) kao sredstva za ispiranje, čime se dobije terc-butil 4-(4-klorometiltiazol-2-il)piperazin-1-karboksilat (830 mg, 100%-tni prinos). HNMR (dmso-d6): 6.92 (1H, s), 4.57 (2H, s), 3.40 (8H, m), 1.42 (9H, s).
Otopina terc-butil 4-(4-klorometiltiazol-2-il)piperazin-1-karboksilata (820 mg, 2.58 mmol) i metil 4-hidroksibenzoata (395 mg, 2.58 mmol) u DMF se obradi s kalij karbonatom (360 mg, 2.6 mmol). Smjesa se miješa na 70°C približno 12 sati, a zatim koncentrira u vakuumu. Ostatak se razdijeli između etil acetata i vode, organska faza se odvoji, ispire otopinom soli, suši preko natrij sulfata i koncentrira. Ostatak se kristalizira iz smjese etil acetat/heksana, čime se dobije terc-butil 4-[4-(4-metoksikarbonil-fenoksimetil)tiazol-2-il]piperazin-1-karboksilat (830 mg, 74%-tni prinos). HNMR (dmso-d6): 7.91 (2H, d), 7.13 (2H, d), 6.91 (1H, s), 5.00 (2H, s). 3.81 (3H, s), 3.41 (8H, m), 1.41 (9H, s).
Otopina terc-butil 4-[4-(4-metoksikarbonilfenoksimetil)tiazol-2-il]piperazin-1-karboksilata (820 mg. 1.89 mmol) u metanolu (30 mL) i THF (10 mL) se obradi s otopinom natrij hidroksida (226 mg, 5.67 mmol) u vodi (10 mL). Smjesa se miješa na 55°C 8 sati, a zatim koncentrira isparavanjem. Vodena otopina se razrijedi vodom (10 mL) i razrjeđenje se zakiseli s razrjeđenom kloridnom kiselinom. Dobivena kruta tvar se prikupi filtriranjem, čime se dobije 4-[2-(4-terc-butoksikarbonilpiperazin-1-il)tiazol-4-ilmetoksi]benzojeva kiselina (800 mg, 100%-tni prinos). HNMR (dmso-d6): 7.88 (2H, d), 7.09 (2H, d), 6.91 (1H, s), 4.99 (2H, s), 3.44 (8H, m), 1.41 (9H, s).
Postupcima kao u Referenci 10 dobije se 4-(4-morfolin-4-ilmetiltiazol-2- ilamino)benzojeva kiselina
REFERENCA 11
terc-butil 4-[4-(4-metoksikarbonilpiperidin-1-ilmetil)tiazol-2-il]piperazin-1-karboksilat
Otopina terc-butil 4-(4-klorometiltiazol-2-il)piperazin-1-karboksilata (860 mg, 2.7 mmol) i metil piperidin-4-karboksilata (539 mg, 3 mmol) u DMF se obradi s kalij karbonatom (414 mg, 3 mmol). Smjesa se miješa na 70°C 18 sati, a zatim koncentrira u vakuumu. Proizvod se pročisti iz ostatka flash kromatografijom na silika gelu, čime se dobije terc-butil 4-[4-(4-metoksikarbonilpiperidin-1-ilmetil)tiazol-2-il]piperazin-1-karboksilat (575 mg, 50%-tni prinos). HNMR (dmso-d6): 6.58 (1H, s), 3.59 (2H, s), 3.42 (4H, m), 3.34 (4H, m), 3.32 (3H, s), 2.78 (2H, m), 2.28 (1H, m), 2.02 (2H, m), 1.77 (2H, m), 1.57 (2H, m), 1.41 (3H, s).
Postupcima kao u Referenci 11 dobiju se slijedeći spojevi:
terc-butil 4-[2-(4-metoksikarbonilfenilamino)tiazol-4-ilmetil]piperazin-1-karboksilat; HNMR (dmso-d6): 10.6 (1H, s), 7.90 (2H, d), 7.70 (2H, d), 6.78 (1H, s), 3.80 (3H, s), 3.51 (2H, s), 3.32 (4H, m), 2.42 (4H, m), 1.41 (9H, s); i
terc-butil 4-cijanometil-piperazin-1-karboksilat; HNMR (dmso-d6): 3. 75 (2H, s), 3.34 (4H, t), 2.41 (4H, t), 1.40 (9H, s).
REFERENCA 12
1-[2-(4-terc-butoksikarbonilpiperazin-1-il)tiazol-4-ilmetil]piperidin-4-karboksilna kiselina
Otopina terc-butil-4-[4-(4-metoksikarbonilpiperidin-1-ilmetil)tiazol-2-il]piperidin-1-karboksilata (560 mg, 1.31 mmol), dobivena kao u Referenci 11, u metanolu (30 mL) se obradi na sobnoj temperaturi s otopinom natrij hidroksida (79 mg, 1.97 mmol) u vodi (10 mL). Smjesa se grije na 50°C tijekom 3 sata i koncentrira do suhoće, čime se dobije 1-[2-(4-terc-butoksikarbonilpiperazin-1-il)tiazol-4-ilmetil]piperidin-4-karboksilna kiselina
Postupcima kao u Referenci 12 dobiju se slijedeći spojevi:
4-[2-(1-terc-butoksikarbonilpiperazin-1-il)metiltiazol-4-ilamino]piperadinkarboksilna kiselina
REFERENCA 13
terc-Butil 4-tiokarbamoilmetilpiperazin-1-karboksilat
U otopinu terc-butil-4-cijanometilpiperazin-1-karboksilata (4.5 g, 0.020 mol) u 3:1 smjesi trietilamin/piridina (40 mL) na sobnoj temperaturi se puštaju mjehurići vodikovog sulfida tijekom 30 minuta. Reakcijska smjesa se miješa 18 sati na sobnoj temperaturi, a zatim koncentrira u vakuumu. Ostatak se obradi sa 1:4 smjesom etil acetat/heksana i dobivena otopina se prikupi filtriranjem i ispire sa smjesom etil acetat/heksana, čime se dobije terc-Butil 4-tiokarbamoilmetilpiperazin-1-karboksilat (3.93 g, 75%). HNMR (dmso-d6): 9.87 (1H, bs), 9.07 (1H, bs), 3.35 (4H, t), 2.34 (4H, t), 1.29 (9H, s); LC/MS: M+1: 259.6.
REFERENCA 14
4-[2-(1-etoksikarbonilpiperidin-4-ilamino)tiazol-4-il] benzojeva kiselina
Otopina etil 4-aminopiperidin-1-karboksilata (4.3 g, 0.025 mol) u suhom THF se hladi na 0°C i potom obradi s trietilaminom (3.83 mL, 27.5 mol) i tiofosgenom (2.1 mL, 27.5 mmol). Smjesa se miješa 1.5 sati na sobnoj temperaturi, hladi na 0° C i zatim obradi s otopinom amonij hidroksida (7.7 mL, 28% u vodi). Smjesa se miješa približno 12 sati, a zatim koncentrira isparavanjem. Ostatak se prenese u etilacetat i smjesa se obradi sa zasićenom otopinom NaHCO3 i otopinom soli. Organska faza se odijeli, suši preko natrij sulfata, a zatim koncentrira do suhoće. Ostatak se prenese u dietil eter i dobivena kruta tvar se prikupi filtriranjem i ispire dietil eterom, čime se dobije etil 4-tioureidopiperidin-1-karboksilat (4.18 g, 72% V). HNMR (dmso-d6): 7.57 (1H, d), 6.9 (1H, s), 4.05 (1H, bs), 4.02 (2H, q), 3.86 (2H, d), 2.89 (2H, bs), 1.82 (2H, bs), 1.20 (2H, m), 1.17 (3H, t).
Otopina etil-4-tioureidopiperidin-1-karboksilata (3.8 g, 0.0164 mol) i 4-(2-bromoacetil)benzojeve kiseline (4 g, 0.0164 mmol) u THF (100 mL) se grije na 70 °C 2 sata, hladi na sobnoj temperaturi i potom razrijedi s dietil eterom. Dobivena kruta tvar se prikupi filtriranjem i ispire s dietil eterom, čime se dobije 4-[2-(1-etoksikarbonilpiperidin-4-ilamino)tiazol-4-il]benzojeva kiselina (4.32 g, 70%-tni prinos) u obliku prljavobijele krute tvari. HNMR (dmso-d6): 7.93 (4H, m), 7.27 (1H, s), 4.05 (2H, q), 3.82 (3H, m), 3.04 (2H, m), 2.02 (2H, m), 1.41 (2H, m), 1.18 (3H, t). LC/MS: M+1: 376.
Postupcima kao u Referenci 14 dobiju se slijedeći spojevi:
metil 3-(4-pirid-4-iltiazol-2-ilamino)benzojeva kiselina. HNMR (dmso-d6): 11.00 (1H, s), 8.89 (2H, d), 8.46 (2H, d), 8.38 (1H, s), 7.99 (2H, AB sustav, d), 7.88 (2H, AB sustav, d), 3.83 (3H, s), 3.50 (1H, bs);
4-[2-(4-terc-butoksikarbonilpiperazin-1-il)tiazol-4-il]benzojeva kiselina; HNMR (dmso-d6): 7.96 (4H, s), 7.50 (1H, s), 3.48 (8H, s), 1.42 (9H, s); i
4-[2-(4-terc-butoksikarbonilpiperazin-1-ilmetil)tiazol-4-il]benzojeva kiselina; HNMR (dmso-d6): 8.47 (1H, s), 8.12 (2H, d), 8.03 (2H, d), 4.00 (2H, bs), 3.51 (4H, t), 3.08 (4H, bs), 1.41 (9H, s); LC/MS (M+1): 404.
REFERENCA 15
4-[2-(1-terc-butoksikarbonilpiperidin-4-ilamino)tiazol-4-il]benzojeva kiselina
Otopina 4-[2-(1-etoksikarbonilpiperidin-4-ilamino)tiazol-4-il]benzojeve kiseline (1 g, 2.66 mmol), dobivena u Referenci 14, u 30%-tnoj bromidnoj kiselini u octenoj kiselini se grije u zataljenoj posudi na 60°C približno 12 sati, a potom se hladi na sobnu temperaturu. Dobivena kruta tvar se prikupi filtriranjem i ispire dietil eterom, čime se dobije 4-(2-piperidin-4-ilaminotiazol-4-il)benzojeva kiselina, hidrobromid (660 mg, 64%). HNMR (dmso-d6): 7.94 (4H, s), 7.31 (1H, s), 4.50 (2H, bs), 3.92 (1H, bs), 3.28 (2H, m), 3.07 (2H, m), 2.15 (2H, m), 1.69 (2H, m). LC/MS: M+1: 304.
Otopina 4-(2-piperidin-4-ilaminotiazol-4-il)benzojeve kiseline, hidrobromida (600 mg, 1.56 mmol) i natrij hidroksida (125 mg, 3.12 mmol) u THF/vodi (30 mL) se obradi s bis(1,1-dimetiletil)dikarbonatom (375 mg, 1.71 mmol). Smjesa se miješa približno 12 sati na sobnoj temperaturi, a zatim koncentrira na kružnom isparivaču. Ostatak se razrijedi vodom i smjesa se zakiseli do pH 3 razrijeđenom kloridnom kiselinom i ekstrahira etil acetatom. Ekstrakt se ispire otopinom soli i suši preko Na2(SO)4 čime se dobije 4-[2-(1-terc-butoksikarbonilpiperidin-4-ilamino)tiazol-4-il]benzojeva kiselina (680 mg, 100%-tni prinos). HNMR (dmso-d6): 7.93 (4H, s), 7.73 (1H, d), 7.26 (1H, s), 3.84 (2H, m), 3.76 (1H, m), 2.97 (2H, m), 1.97 (2H, m), 1.46 (9H, s), 1.28 (2H, m).
REFERENCA 16
3-(4-pirid-4-iltiazol-2-ilamino)benzojeva kiselina
Otopina metil 3-(4-pirid-4-iltiazol-2-ilamino)benzoata (500 mg, 1.27 mmol) u 3/2 smjesi metanol/THF (100 mL) se obradi s vodenom otopinom natrij hidroksida (240 mg, 6 mmol, 20 mL). Reakcijska smjesa se miješa na 40°C približno 12 sati, a zatim koncentrira. Ostatak se razrijedi vodom (20 mL) i razrijeđena otopina se zakiseli do pH 5 s razrijeđenom kloridnom kiselinom. Dobivena kruta tvar se prikupi filtriranjem i ispire vodom, čime se dobije 3-(4-pirid-4-iltiazol-2-ilamino)benzojeva kiselina (328 mg, 87%-tni prinos). HNMR (dmso-d6): 10.80 (1H, s), 8.63 (2H, m), 7.90 (7H, m). LC/MS: M+1: 297.86.
PRIMJER 7
N-(1S-Cijanometilkarbamoil-2-metilbutil)-4-(2-pirid-3-iltiazol-4-il)benzamid
(Spoj 331)
[image]
Otopina 4-(2-pirid-3-iltiazol-4-il)benzojeve kiseline (1.7 g, 6.03 mmol), N-cijanometil-2S-amino-3-metilpentanamid metansulfonata (1.60 g, 6.03 mmol) i PyBOP (3.14 g, 6.03 mmol) u DMF (20 mL) se obradi s 4-metilmorfolinom (2.44 g, 24.14 mmol) i smjesa se potom miješa na sobnoj temperaturi 3 sata. Smjesa se obradi s 10% vodenim kalij karbonatom (50 mL) i miješa dodatnih 30 minuta, ekstrahira s etil acetatom (100 mL), ispire zasićenom vodenom NaHCO3 (50 mL), suši preko MgSO4, filtrira, ispari i filtrira kroz kratak sloj silika gela (50-100% etil acetat/diklorometan). Najčišće frakcije se dalje pročišćavaju pomoću HPLC, čime se dobije N-(1S-cijanometilkarbamoil-2-metilbutil)-4-(2-pirid-3-iltiazol-4-il)benzamid (89 mg, 13%-tni prinos).
PRIMJER 8
N-(1S-cijanometilkarbamoil-3-metilbut-3-enil)-4-(2-pirid-3-iltiazol-4-il)benzamid
(Spoj 332)
[image]
Otopina 4-(2-pirid-3-iltiazol-4-il)benzojeve kiseline (0.381 g, 1.35 mmol), N-cijanometil-2S-amino-4-metilpent-4-enamid metansulfonata (0.355 g, 1.35 mmol) i HBTU (0.511 g, 1.35 mmol) u DMF (10 mL) se obradi s 4-metilmorfolinom (0.445 mL, 4.04 mmol) i smjesa se miješa na sobnoj temperaturi približno 12 sati. Otopina se ulije u 4:1:2:3 smjesu etil acetat/THF/voda/otopina soli (100 mL) i organska faza se odijeli, uzastopno ispire sa zasićenim vodenim NaHCO3 (50 mL) i otopinom soli (50 mL), suši preko MgSO4, filtrira i ispari do suhoće. Ostatak se pročisti na kratkom sloju silika gela pomoću etil acetata kao mobilne faze, čime se dobije N-(1S-cijanometilkarbamoil-3-metilbut-3-enil)-4-(2-pirid-3-iltiazol-4-il)benzamid (100 mg, 17%-tni prinos). MS (M+1): 432. NMR (d6- DMSO): 1.74 (3H, s); 2.51-2.54 (2H, m*); 4.16 (2H, d, J = 5.4 Hz); 4.71 (1H, m*); 4.79 (2H, d, J =9Hz); 7.61 (1H, dd, J = 8,5 Hz); 8.02 (2H, d, J = 7.7 Hz); 8.19 (2H, d, J = 7.7 Hz); 8.46 (2H, s, d*); 8.65 (1H, d, J = 7 Hz); 8.72 (1H, d, J = 4.7 Hz); 8.79 (1H, t, J = 5.4 Hz); 9.26 (1H, s).
PRIMJER 9
N-(1S-cijanometilkarbamoil-3-metilbutil-4-(2-pirid-3-ilaminotiazol-4-il)benzamid
(Spoj 333)
[image]
terc-Butil 4-metil-2S-[4-(2-pirid-3-ilamino)tiazol-4-il]benzoilaminopentanoat (10 g, 20 mmol), dobiven kao u Primjeru 8, se prenese u HCl/dioksan (4.0 M, 50 mL, 200 mmol) i smjesa se miješa preko noći. Smjesa se razrijedi s eterom i krute tvari se prikupe filtriranjem i potom suše u vakuumu, čime se dobije 4-metil-2S-[4-(2-pirid-3-ilamino)tiazol-4-il]benzoilaminopentanojeva kiselina, hidroklorid (12 g, 100%-tni prinos). LC-MS: 411.1, M+H.
4-Metil-2S-[4-(2-pirid-3-ilamino)tiazol-4-il]benzoilaminopentanojeva kiselina, hidroklorid (5 g, 10.1 mmol) se prenese u DMF (50 mL) i dobivena otopina se obradi uzastopno s aminoacetonitril hidrokloridom (1.8 g, 20 mmol), PyBop (5.2 g, 10.1 mmol) i trietilaminom (6 mL, 40 mmol). Smjesa se miješa približno 12 sati, a potom razrijedi s natrij bikarbonatom (30 mL) i etil acetatom (200 mL). Organski sloj se odijeli, uzastopno ispire vodom i otopinom soli, suši preko bezvodnog magnezij sulfata i koncentrira pri smanjenom tlaku. Ostatak se usitni s acetonom i eterom, čime se dobije N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-pirid-3-ilaminotiazol-4-il]benzamid (1.5 g, 30%-tni prinos). 1H NMR (DMSO-d6, ppm): 0.96 (m, 6 H), 1.75 (m, 3 H), 4.31 (m, 1H), 4.47 (m, 2 H), 7.82-8.03 (m, 5 H), 8.31 (m, 2 H), 8.53 (m, 1H), 8.73 (d, 1H), 8.91 (d, 1H), 9.11 (m, 1H), 11.01 (m, 1H). ES-Ms: 449.3 (M+H+).
Postupcima kao u Primjeru 9 dobiju se slijedeći spojevi Formule I:
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-pirid-3-iltiazol-4-il)benzamid (Spoj 334); 1H NMR (DMSO-d6, ppm): 0.91 (m, 6 H), 1.75 (m, 3 H), 4.11 (m, 2H), 4.47 (m, 1H), 7.51 (m, 1H), 7.81 (m, 2 H), 8.03 (m, 2 H), 8.33 (d, 2 H), 8.91 (m, 3 H), 9.11 (m, 1H); ES-Ms: 434.3 (M+H+);
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-pirid-4-ilamino)tiazol-4-ilbenzamid (Spoj 335); 1H NMR (DMSO-d6, ppm):): 0.91 (m, 6 H), 1.65 (m, 3H), 4.01 (m, 2 H), 4.37 (m, 1H), 7.82-8.03 (m, 7H), 8.73 (m, 3 H), 8.91 (m, 1H); ES-Ms: 448.9 (M+H+);
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-pirid-4-iltiazol-4-il)benzamid (Spoj 336); 1H NMR (DMSO-d6, ppm): 0.91 (m, 6 H), 1.55-72 (m, 3 H), 4.17 (m, 2 H), 4.31 (m, 1H), 8.03-8.63 (m, 7 H), 8.83 (m, 2 H), 8.91 (m, 1H), 8.98-9.11 (m, 2 H); ES-Ms: 443.9 (M+H+);
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-pirid-2-ilamino)tiazol-4-ilbenzamid (Spoj 337); 1H NMR (DMSO-d6, ppm): 0.91 (m, 6 H), 1.65 (m, 3 H), 4.01 (m, 2 H), 4.37 (m, 1H), 6.91-7.11 (m, 2 H), 7.60 (m, 1H), 7.11 (m, 1H), 7.59 (d, 1H), 7.72 (d, 1H), 8.03 (m, 4 H), 8.32 (m, 1H), 8.59 (m, 1H), 8.73 (m, 1H); ES-Ms: 448.9 (M+H+);
N-{4-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]tiazol-2-il}izonikotinamid (Spoj 338); 1H NMR (DMSO-d6, ppm): 0.95 (m, 6 H), 1.65-1.78 (m, 3H), 4.17 (m, 3H), 8.01-8.15 (m, 5H), 8.60-8.79 (m, 4H); ES-Ms: 477.2 (M+H+);
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[4-(2-morfolin-4-iletil)piperazin-1-il]benzamid (Spoj 339); 1H NMR (DMSO-d6, ppm): 0.95 (m, 6 H), 1.65-1.78 (m, 3 H), 3.11-3.67 (m, 16H), 3.78-3.85 (m, 4H), 4.17 (s, 2H), 4.45 (m, 1H), 7.01 (d, 2H), 8.01 (d, 2H), 8.40 (m,1H), 8.79 (m,1H); ES-Ms: 471.2 (M+H+);
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(4-pirid-4-ilpiperazin-1-il)benzamid (Spoj 340); 1H NMR (DMSO-d6, ppm): 0.95 (m, 6 H), 1.65-1.78 (m, 3 H), 3.67-3.87 (m, 8 H), 4.17 (s, 2 H), 4.38 (m, 1H), 6.81 (d, 2 H), 7.21 (d, 2 H), 7.78 (d, 2 H), 8.20 (d, 2 H), 8.79 (m, 1H); ES-Ms: 435.2 (M+H+);
N[1S-(l-cijanociklopropilkarbamoil)-3-metilbutil]-4-[2-(4-metilpiperazin-1-il)tiazol-4-il]benzamid (Spoj 341); 1H NMR (DMSO-d6, ppm): 0.91 (m, 6 H), 1.55-1.72 (m, 3 H), 2.81 (s, 3 H), 3.21-3.87 (m, 8 H), 4.17 (m, 2 H), 4.31 (m, 1H), 7.51 (s, 1H), 8.03 (m, 4 H), 8.83 (m, 2 H), 8.61 (m, 1H), 9.11 (m, 1H); ES-Ms: 480.9 (M+H+); i
N-(1R-cijanometilkarbamoil-3-metilbutil)-4-(2-morfolin-4-iltiazol-4-il)benzamid (Spoj 342); 1H NMR (DMSO-d6, ppm): 0.91 (m, 6 H), 1.55-1.72 (m, 3 H), 3.15-3.27 (m, 4 H), 3.61-3.87 (m, 4 H), 4.17 (m, 2 H), 4.51 (m, 1H), 7.51 (s, 1H), 7.72 (m, 1H), 8.03 (m, 4 H), 8.61 (m, 1H), 8.81 (m, 1H); ES-Ms: 441.2 (M+H+).
PRIMJER 10
N-(1-Cijanometilkarbamoilcikloheksil]-4-[2-(4-metilpiperazin-1-il)tiazol-4-il]benzamid, sol trifluorooctene kiseline
(Spoj 343)
[image]
Otopina 4-[2-(4-metilpiperazin-1-il)tiazol-4-il]benzojeve kiseline (330 mg, 1 mmol), dobivena kao u Referenci 7, u DMF (10 mL) se uzastopno obradi s trifluorooctenom kiselinom, 1-amino-N-cijanometilcikloheksankarboksamid, sol metansulfonske kiseline (300 mg, 1.0 mmol), dobivena kao u Referenci 9, trietilaminom (0.5 mL, 3 mmol) i HATU (400 mg, 1 mmol). Otopina se miješa približno 12 sati i potom razrijedi s etil acetatom (50 mL) i zasićenim natrij bikarbonatom (20 mL). Etil acetatni sloj se odijeli i koncentrira. Proizvod se pročisti iz ostatka preparativnom HPLC obrnute faze, čime se dobije N-(1-cijanometilkarbamoilcikloheksil]-4-[2-(4-metilpiperazin-1-il)tiazol-4-il]benzamid, sol trifluorooctene kiseline (200 mg, 40 %). 1H NMR (DMSO-d6, ppm): 1.55-1.72 (m, 6 H), 2.11-2.23 (m, 2 H), 2.81 (s, 3 H), 3.21-3.67 (m, 6 H), 4.89-4.13 (m, 5 H), 7.51 (s, 1H), 8.03 (m, 4 H), 8.13 (m, 1H). ES- Ms: 466.4 (M+H+).
Postupcima kao u Primjeru 10, dobiju se slijedeći spojevi Formule I:
N-[1-(4-cijanotetrahidropiran-4-ilkarbamoil)cikloheksil]-4-[2-(4-metilpiperazin 1-il)tiazol-4-il]benzamid (Spoj 344); 1H NMR (DMSO- d6, ppm): 1.25-1.42 (m, 4H), 1.55-1.91 (m, 6 H), 2.81 (s, 3 H), 3.11-3.87 (m, 10H), 4.17-4.23 (m, 2H), 7.51 (s, 1H), 7.88 (m, 5 H); ES-Ms: 537.1 (M+H+); i
N-(1-cijanometilkarbamoilcikloheksil)-4-(2-morfolin-4-iltiazol-4-il)benzamid (Spoj 345); 1H NMR (DMSO-d6, ppm): 1.51-1.74 (m, 6 H), 2.11-2.23 (m, 4H), 3.21-3.67 (m, 8H), 4.17-4.23 (m, 2H), 7.51 (s, 1H), 8.03 (m, 4 H), 8.13 (m, 1H); ES- Ms: 454.0 (M+H+).
PRIMJER 11
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(1-metilpirid-3-il)tiazol-4-il]benzamid, jodidna sol
(Spoj 346)
[image]
Otopina N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-pirid-3-iltiazol-4-il)benzamida (80 mg, 0.184 mmol), dobivena kao u Referenci 12, u acetonitrilu (1 mL) se obradi s metil jodidom (115 μL, 1.84 mmol, 10 eq.) koji se dodaje kap po kap. Reakcijska smjesa se miješa približno 72 sata, a zatim koncentrira do suhoće. Ostatak se obradi s etil eterom. Kruta tvar se prikupi filtriranjem i ispire istim dietil eterom, čime se dobije otapalo N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(1-metilpirid-3-il)tiazol-4-il]benzamid, jodidna sol (85 mg, 80%-tni prinos). HNMR (dmso-d6): 9.74 (1H, s), 9.15 (1H, d), 9.07 (1H, d), 8.78 (1H, t), 8.68 (1H, d), 8.65 (1H, s), 8.24 (3H, m), 8.07 (2H, d), 4.58 (1H, m), 4.48 (3H, s), 4.15 (2H, d), 1.70 (3H, m), 0.91 (6H, m). M: 448).
Postupcima kao u Primjeru 11, dobiju se slijedeći spojevi Formule I:
4-[2-(1-karbamoilmetilpiridin-3-il)tiazol-4-il]-N-(1S-cijanometilkarbamoil-3-metilbutil)benzamid, bromidna sol (Spoj 347); HNMR (dmso-d6): 9.78 (1H, s), 9.21 (1H, d), 9.06 (1H, d), 8.78 (1H, t), 8.68 (1H, d), 8.66 (1H, s), 8.33 (1H, dd), 8.24 (2H, d), 8.08 (3H, m), 7.79 (1H, s), 5.55 (2H, s), 4.55 (1H, m), 4.15 (2H, d), 1.70 (3H, m), 0.91 (6H, m). M: 491); LC/MS, M: 491;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(1-metilpiridin-4-ilamino)tiazol-4-il]benzamid, jodidna sol (Spoj 348); HNMR (dmso-d6): 8.76 (1H, t), 8.63 (3H, m), 8.10 (3H, m), 8.03 (2H, d), 7.97 (1H, s), 4.57 (1H, m), 4.15 (2H, d), 4.14 (3H, s), 1.70 (3H, m), 0.91 (6H, m);
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(1-metilpiridin-4-il)tiazol-4-il]benzamid, jodidna sol (Spoj 349); HNMR (dmso-d6): 9.09 (2H, d), 8.83 (1H, s), 8.73 (2H, d), 8.25 (2H, d), 8.08 (2H, d), 4.58 (1H, m), 4.52 (3H, s), 4.16 (2H, s), 1.70 (3H, m), 0.92 (6H, m); i
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(1-alilpirid-4-il)tiazol-4-il]benzamid, bromidna sol (Spoj 350).
PRIMJER 12
Etil 4-{4-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]tiazol-2-ilamino}piperidin-1-karboksilat
(Spoj 351)
[image]
Otopina 4-[2-(1-terc-butoksikarbonilpiperidin-4-ilamino)tiazol-4-il]benzojeve kiseline (751 mg, 2 mmol), dobivena kao u Referenci 15, i metan sufonatna sol 2S-amino-N-cijanometil-4-metilpentanamida (560 mg, 2 mmol) u DMF (10 mL) se obradi s PyBOP (1.04 mg, 2 mmol) i diizopropiletilaminom (715 μL, 4.1 mmol) na sobnoj temperaturi. Smjesa se miješa preko noći, a zatim koncentrira u vakuumu. Ostatak se otopi u etil acetatu i otopina se ispire uzastopno sa zasićenom otopinom NaHCO3 i otopinom soli, suši na natrij sulfatu i koncentrira. Proizvod se pročisti iz ostatka pomoću silika gel stupca, pomoću etil acetat/heksana kao sredstva za ispiranje, čime se dobije etil 4-{4-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]tiazol-2-ilamino}piperidin-1-karboksilat (815 mg, 77%-tni prinos). HNMR (dmso-d6): 8.71 (1H, t), 8.54 (1H, d), 7.91 (4H, AB sustav, dd), 7.74 (1H, d), 7.23 (1H, s), 4.52 (1H, m), 4.13 (2H, t), 4.04 (2H, q), 3.90 (2H, m), 3.76 (1H, m), 3.04 (2H, m), 1.98 (2H, m), 1.65 (3H, m), 1.38 (2H, m), 1.18 (3H, t), 0.89 (6H, m). LC/MS: M+1: 527.
Postupcima kao u Primjeru 12, dobije se etil 4-{4-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]tiazol-2-ilamino}piperidin-1-karboksilat (Spoj 252); HNMR (dmso-d6): 8.71 (1H, t), 8.54 (1H, d), 7.91 (4H, dd), 7.73 (1H, d), 7.23 (1H, s), 4.52 (1H, m), 4.13 (2H, m), 3.85 (2H, m), 3.75 (1H, m), 3.00 (2H, m), 1.95 (2H, m), 1.70 (3H, m), 1.40 (9H, s), 1.37 (2H, m), 0.88 (6H, m); LC/MS: M+1: 555;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(4-pirid-4-iltiazol-2-ilamino)benzamid (Spoj 353); HNMR (dmso-d6): 10.6 (1H, s), 8.67 (1H, t), 8.63 (2H, AB sustav, d), 8.38 (1H, d), 7.95 (2H, AB sustav, d), 7.88 (2H, AB sustav, d), 7.82 (2H, AB sustav), d), 7.81 (1H, s), 4.49 (1H, m), 4.13 (2H, d), 1.70 (3H, m), 0.89 (6H, m); LC-MS: M+1: 449;
terc-butil 4-{4-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]tiazol-2-il}piperazin-1-karboksilat (Spoj 354); HNMR (dmso-d6): 8.72 (1H, t), 8.57 (1H, d), 7.94 (4H, s), 7.48 (1H, s), 4.52 (1H, m), 4.13 (2H, d), 3.48 (8H, s), 1.65 (3H, m), 0.89 (6H, m). LC/MS: M+1: 541;
terc-butil 4-{4-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenoksimetil]tiazol-2-il}piperazin-1-karboksilat (Spoj 355); HNMR (dmso-d6): 8.66 (1H, t), 8.40 (1H, d), 7.89 (2H, d), 7.08 (2H, d), 6.90 (1H, s), 4.99 (2H, s), 4.48 (1H, m), 4.11 (2H, d), 3.41 (8H, m), 1.65 (3H, m), 0.88 (6H, m);
terc-butil 4-{4-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)piperidin-1-ilmetil]tiazol-2-il}piperazin-1-karboksilat (Spoj 356); HNMR (dmso-d6): 8.71 (1H, t), 8.17 (1H, d), 7.03 (1H, s), 4.26 (1H, m), 4.16 (2H, bs), 4.11 (2H, d), 3.79 (4H, bs), 3.45 (4H, bs), 2.97 (2H, bs), 2.43 (1H, m), 1.85 (3H, m), 1.46 (3H, m), 1.41 (9H, s); LC/MS: M+1: 562.4;
N-(1S-cijanometilkarbamoil-3-metilbutil]-4-(4-morfolin-4-ilmetiltiazol-2-ilamino)benzamid (Spoj 357); HNMR (dmso-d6): 10.7 (1H, s), 8.72 (1H, t), 8.39 (1H, d), 7.91 (2H, d), 7.71 (2H, d), 7.19 (1H, s), 4.50 (1H, m), 4.34 (2H, s), 4.12 (2H, m), 3.59 (8H, m), 165 (3H, m), 0.89 (6H, m); LC/MS: M+1: 471;
terc-butil 4-{2-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil}fenilamino]tiazol-4-ilmetil}piperazin-1-karboksilat (Spoj 358);
terc-butil 4-(4-{4-[1S-(1-cijanociklopropilkarbamoil)-3-metilbutilkarbamoil]fenil}tiazol-2-il)piperazin-1-karboksilat (Spoj 359); HNMR (dmso-d6): 8.98 (1H, s), 8.51 (1H, d), 7.92 (4H, m), 7.47 (1H, s), 4.44 (1H, m), 3.48 (8H, s), 1.65 (2H, m), 1.48 (3H, m), 1.43 (9H, s), 1.12 (2H, m), 0.89 (6H, m); LC/MS: M+1: 567.5;
terc-butil 4-(4-{4-[1S-(N-cijanometil-N-metilkarbamoil)-3-metilbutilkarbamoil]fenil}tiazol-2-il)piperazin-1-karboksilat (Spoj 360); HNMR (dmso-d6): 8.70 (1H, d), 7.92 (4H, s), 7.47 (1H, s), 4.93 (1H, m), 4.41 (2H, m), 3.48 (8H, s), 3.20 i 2.91 (3H, s), 1.75 (2H, m), 1.42 (1H, m), 1.42 (9H, s), 0.93 (6H, bs); LC/MS: M+1: 555.5;
N-[1S-(N-cijanometil-N-metilkarbamoil)-3-metilbutil]-4-[2-(4-metilpiperazin-1-il)tiazol-4-il] benzamid (Spoj 361); HNMR (dmso-d6): 8.71 (1H, d), 7.98 i 7.95 (4H, m), 7.60 i 7.58 (1H, s), 4.93 (1H, m), 4.42 (2H, m), 4.12 (2H, m), 3.53 (6H, m), 2.87 (3H, s), 1.74 (2H, m), 1.45 (1H, m), 0.93 (6H, m); LC/MS: M+1: 468.4; i
terc-butil 4-(4-{4-[1S-(1-cijanociklopropilkarbamoil)-3-metilbutilkarbamoil]fenil}tiazol-2-ilmetil)piperazin-1-karboksilat (Spoj 362); HNMR (dmso-d6): 8.22 (1H, s), 8.00 (5H, m), 4.45 (1H, m), 3.92 (2H, s), 3.36 (4H, m), 2.50 (4H, m),), 1.65 (2H, m), 1.48 (3H, m), 1.40 (9H, s), 1.12 (2H, m), 0.89 (6H, m).
PRIMJER 13
terc-butil 4-{4-[4-(1-cijanometilkarbamoilcikloheksilkarbamoil)fenil]tiazol-2-il}piperazin-1-karboksilat
(Spoj 363)
[image]
Otopina 1-amino-N-cijanometilcikloheksankarboksamida (500 mg, 1.8 mmol), dobivena kao u Referenci 9, i 4-[2-(4-terc-butoksikarbonilpiperazin-1-il)tiazol-4-il]benzojeve kiseline (702 mg, 1 mmol), dobivena kao u Referenci 14, u DMF se obradi s diizopropiletilaminom (940 μL, 5.4 mmol) i HATU (685 mg, 1.8 mmol). Smjesa se miješa približno 12 sati na sobnoj temperaturi, a zatim koncentrira u vakuumu. Ostatak se otopi u etil acetatu i otopina se ispire uzastopno s zasićenom otopinom NaHCO3, vodom i otopinom soli, suši preko Na2SO4 i koncentrira. Proizvod se pročisti iz ostatka kroz silika gel, čime se dobije terc-butil 4-{4-[4-(1-cijanometilkarbamoilcikloheksilkarbamoil)fenil]tiazol-2-il}piperazin-1-karboksilat (350 mg, 35%-tni prinos) u obliku pjene. HNMR (dmso-d6): 8.31 (1H, t), 8.09 (1H. s), 8.02 (4H, dd), 7.57 (1H, s), 4.15 (2H, d), 3.58 (8H, s), 2.13 (2H, m), 1.76 (2H, m), 1.53 (4H, m), 1.43 (9H, s), 1.40 (2H, m). LC/MS: M+1: 553. Postupcima kao u Primjeru 13 dobije se terc-butil 4-(4-{4-[1-cijanometilkarbamoil)cikloheksilkarbamoil]fenil}tiazol-2-ilmetil)piperazin-1-karboksilat (Spoj 364); HNMR (dmso-d6): 8.22 (1H, m), 8.00 (4H, m), 7.47 (1H, d), 4.04 (2H, m), 3.92 (2H, s), 3.37 (4H, m), 2.50 (4H, m), 2.13 (2H, m), 1.75 (2H, m), 1.54 (5H, m), 1.40 (9H, s), 1.40 (2H, m); LC/MS: M+1: 567.4
PRIMJER 14
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-piperidin-4-ilaminotiazol-4-il)benzamid, sol metansulfonske kiseline
(Spoj 365)
[image]
Otopina etil 4-{4-[4-(1S-cijanometilkarbamoil- 3-metilbutilkarbamoil)fenil]tiazol-2-ilamino}piperidin-1-karboksilata (290 mg, 0.52 mmol), pripravljena kao u Primjeru 12, u suhom THF (5 mL) se obradi s metansulfonskom kiselinom (135 μL, 2.08 mmol, 4 eq) na sobnoj temperaturi. Smjesa se miješa preko noći i potom razrijedi dietil eterom. Dobivena kruta tvar se prikupi filtriranjem i usitni s nekoliko porcija dietil etera. Proizvod se pročisti iz sirove krute tvari pomoću preparativne TLC obrnute faze, uz pomoć smjese acetonitril/voda (8/2) kao mobilne faze, čime se dobije N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-piperidin-4-ilaminotiazol-4-il)benzamid, sol metansulfonske kiseline (90 mg, 31%-tni prinos). HNMR (dmso-d6): 8.73 (1H, t), 8.54 (1H, d), 7.92 (4H, s), 7.85 (1H, d), 7.27 (1H, s), 4.51 (1H, m), 4.13 (2H, t), 3.88 (1H, m), 3.25 (2H, m), 3.03 (2H, m), 2.30 (3H, s), 2.15 (2H, m), 1.65 (5H, m), 0.89 (6H, m). LC/MS: M+1: 455.
Postupcima kao u Primjer 14 dobiju se slijedeći spojevi Formule I:
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-piperazin-1-iltiazol-4-il)benzamid (Spoj 366); HNMR (dmso-d6): 8.96 (1H, bs), 8.74 (1H, t), 8.58 (1H, d), 7.95 (4H, s), 7.56 (1H, s), 4.52 (1H, m), 4.13 (2H, d), 3.71 (4H, m), 3.28 (4H, bs), 1.65 (3H, m), 0.89 (6H, m);
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-piperazin-1-iltiazol-4-ilmetoksi)benzamid (Spoj 367); HNMR (dmso-d6): 8.67 (1H, t), 8.40 (1H, d), 7.89 (2H, d), 7.07 (2H, d), 6.99 (1H, s), 4.99 (1H, s), 4.48 (1H, m), 4.11 (2H, d), 3.56 (4H, m), 3.18 (4H, m), 1.65 (3H, m), 0.89 (6H, m); LC/MS: M+1: 471;
N-(1S-cijanometilkarbamoil-3-metilbutil)-1-(2-piperazin-1-iltiazol-4-ilmetil)piperidin-4-karboksamid (Spoj 368); HNMR (dmso-d6): 9.10 (1H, bs), 8.67 (1H, t), 8.15 (1H, s), 7.09 (1H, s), 4.25 (1H, m), 4.10 (2H, d), 3.63 (2H, bs), 3.35 (4H, bs), 3.24 (4H, m), 2.92 (2H, bs), 2.36 (7H, m)), 1.80 (3H, m), 1.44 (3H, m), 0.83 (6H, m); LC/MS: M+1: 462.3;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(4-piperazin-1-ilmetiltiazol-2-ilamino)benzamid (Spoj 369); HNMR (dmso-d6): 10.4 (1H, s), 8.68 (1H, t), 8.48 (1H, bs), 8.35 (1H, d), 7.88 (2H, d), 7.67 (2H, d), 4.48 (1H, m), 4.12 (2H, d), 3.58 (2H, s), 3.10 (4H, bs), 2.69 (4H, bs), 2.34 (6H, s), 1.65 (3H, m), 0.88 (6H, m);
N-[1S-(1-cijanociklopropilkarbamoil)-3-metilbutil]-4-(2-piperazin-1-il-tiazol-4-il)benzamid (Spoj 370); HNMR (dmso-d6): 8.99 (1H, s), 8.52 (1H, d). 7.94 (4H, s), 7.53 (1H, s). 4.44 (1H, m), 3.65 (4H, m), 3.20 (4H, m), 1.65 (2H, m), 1.47 (3H, m), 1.11 (2H, m), 0.88 (6H, m); LC/MS: M+1: 467.2;
N!-[1S-(N-cijanometil-N-metilkarbamoil)-3-metilbutil]-4-(2-piperazin-1-iltiazol-4-il)benzamid (Spoj 371); HNMR (dmso-d6): 8.69 (1H, d), 7.94 (4H, m), 7.53 (1H, s), 4.93 (1H, m), 4.41 (2H, dd), 3.66 (4H, m), 3.30 (4H, m), 3.20 i 2.90 (3H, s), 1.70 (2H, m), 1.45 (1H, m), 0.93 (6H, m); LC/MS: M+1: 455.1;
N-(1-cijanometilkarbamoilcikloheksil)-4-(2-piperazin-1-iltiazol-4-il)benzamid (Spoj 372); HNMR (dmso-d6): 8.90 (1H, bs), 8.21 (1H, m), 7.94 (5H, m), 7.56 (1H, d), 4.06 (2H, d), 3.71 (4H, m), 3.29 (4H, bs), 2.13 (2H, m), 1.76 (2H, m), 1.54 (5H, m), 1.29 (1H, m). LC/MS: M+1: 453.2; i
N-(1-cijanometilkarbamoilcikloheksil)-4-(2-piperazin-1-ilmetiltiazol-4-il)benzamid (Spoj 373); HNMR (dmso-d6): 8.26 (1H,s), 8.24 (1H, d), 8.05 (1H, s), 4.06 (2H, d), 4.01 (2H, s), 3.15 (4H, m), 2.77 (4H, m), 2.15 (2H, m), 1.75 (2H, m), 1.54 (5H, m), 1.30 (1H, m). LC/MS: M+1: 467.2.
PRIMJER 15
Etil-4-{4-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]tiazol-2-il}piperazin-1-karboksilat
(Spoj 374)
[image]
Otopina N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-piperazin-1-iltiazol-4-il)benzamida (200 mg, 0.35 mmol), dobivena kao u Primjeru 14, u 5:1 smjesi suhog THF/DMF se obradi s diizopropiletilaminom (146 μL, 0.84 mmol) i etil kloroformatom (40 mL, 0.42 mmol). Smjesa se miješa 16 sati na sobnoj temperaturi i potom razrijedi s etil acetatom. Razrjeđenje se zakiseli s 1 N kloridnom kiselinom, ispire otopinom soli, suši preko natrij sulfata i koncentrira. Sirovi proizvod se pročisti iz ostatka preparativnom TLC, čime se dobije etil-4-{4-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]tiazol-2-il}piperazin-1-karboksilat. HNMR (dmso-d6): 8.73 (1H, t), 8.57 (1H, d), 7.94 (4H, s), 7.48 (1H, s), 4.53 (1H, m), 4.13 (2H, d), 4.08 (2H, q), 3.52 (8H, m), 1.65 (3H, m), 1.21 (3H, t) 0.89 (6H, m).
PRIMJER 16
N-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]-4-benzilpiperazin-1-karboksamid, sol trifluorooctene kiseline
(Spoj 383)
[image]
Otopina 4-amino-N-(1S-cijanometilkarbamoil-3-metilbutil)benzamida (1.7 g, 6 mmol) u diklorometanu (120 mL) i acetonitrilu (60 mL) se grije i obradi s vodenom otopinom natrij bikarbonata (100 mL). Smjesa se hladi na 0°C uz energično miješanje, a zatim se kratko ostavi slijegati na dva sloja. Donji sloj se obradi jednom s 20%-tnom otopinom fosgena u toluenu (10 mL, 18 mmol). Smjesa se energično miješa 10 minuta na 0°C. Jedna dvanaestina smjese se doda otopini 1-benzilpiperazina (0.17 mL, 10 mmol) u acetonitrilu (5 mL) i nakon 20 h miješanja smjesa se ekstrahira diklorometanom. Ekstrakt se suši preko bezvodnog natrij sulfata, filtrira, i ispari. Sirovi proizvod se pročisti pomoću HPLC obrnute faze na C-18 stupcu, čime se dobije N-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]-4-benzilpiperazin-1-karboksamid, sol trifluorooctene kiseline (u obliku bijele krute tvari (0.14 g, 46%-tni prinos). 1H NMR (270 MHz, DMSO-d6) δ 0.84 (d, 3), 0.88 (d, 3), 1.47 -1.75 (m, 3), 3.1-3.4 (m, 6), 4.10 (t, 2), 4.2 -4.3 (m, 2), 4.35 (br. s, 2), 4.48 (m, 1), 7.48 (br. s, 5), 7.52 (d, 2), 7.82 (d, 2), 8.36 (d, 1 NH), 8.68 (t, 1 NH), 9.01 (s, 1 NH), 10.1 (br. s, 1); ESI-MS m/z 491.4 (M+1).
Postupcima kao u Primjeru 16 dobiju se slijedeći spojevi Formula 1:
3-[3-(1-benzilpirolidin-3-il)-3-metilureido]-N-(1S-cijanometilkarbamoil)-3-metilbutil)benzamid (Spoj 375); 1H NMR (270 MHz, DMSO-d6, smjesa dijastereomera) δ 0.86 (d, 3), 0.90 (d, 3), 1.47 -1.77 (m, 3), 2.0 -2.4 (m, 2), 2.95 i 2.97 (s, 3), 3.1- 3.7 (m, 4), 4.12 (d, 2), 4.25 -4.53 (m, 3), 4.7 -4.9 (m, 1), 7.30 -7.37 (m, 1), 7.45 -7.53 (m, 6), 7.91 (s, 1), 8.47 (d, 1), 8.59 (s, 1), 8.72 (m, 1); ESI-MS m/z 505.2 (M+1);
N-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]-4-(2-morfolin-4-iletil)piperazin-1-karboksamid (Spoj 376); 1H NMR (270 MHz, DMSO-d6) δ 0.89 (d, 3), 0.91 (d, 3), 1.48 -1.75 (m, 3), 2.9 -3.2 (m, 12), 3.6 -3.8 (m, 8), 4.12 (d, 2), 4.51 (m, 1), 7.34 (t, 1), 7.54 (d, 1), 7.68 (dd, 1), 7.89 (t, 1), 8.47 (d, 1 NH), 8.71 (t, 1 NH), 8.81 (s, 1 NH); ESI-MS m/z 514.2 (M+1);
N-[3-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]-4-(2-morfolin-4-iletil)piperazin-1-karboksamid (Spoj 377); 1H NMR (270 MHz, DMSO-d6) δ 0.87 (d, 3), 0.90 (d, 3), 1.48 -1.76 (m, 3), 2.9 -3.2 (m, 12), 3.6 -3.8 (m, 8), 4.12 (d, 2), 4.48 (m, 1), 7.55 (d, 2), 7.83 (d, 2), 8.36 (d, 1 NH), 8.70 (t, 1 NH), 8.91 (s, 1 NH); ESI-MS m/z 514.2 (M+1);
4-[3-(1-benzilpiperidin-4-il)ureido]-N-(1S-cijanometilkarbamoil-3-metilbutil)benzamid (Spoj 378); 1H NMR (270 MHz, DMSO-d6) δ 0.82 (d, 3), 0.86 (d, 3), 1.45 -1.73 (m, 5), 1.88 -2.06 (m, 2), 3.0 -3.1 (m, 2), 3.30 -3.37 (m, 2), 3.7 -3.9 (m, 1), 4.09 (d, 2), 4.2 -4.3 (m, 2), 4.44 (m, 1), 6.60 (d, 1 NH), 7.42 (d, 2), 7.46 (m, 5), 7.78 (d, 2), 8.31 (d, 1), 8.66 (m, 1), 8.73 (m, 1); ESI-MS m/z 505.2 (M+1);
4-[3-(1-benzilpirolidin-3S-il)-3-metilureido]-N-(1S-cijanometilkarbamoil-3-metilbutil)benzamid, sol trifluorooctene kiseline (Spoj 379); 1H NMR (270 MHz, DMSO-d6, smjesa rotomera) δ 0.87 (d, 3), 0.91 (d, 3), 1.48 -1.75 (m, 3), 2.0 -2.4 (m, 2), 2.96 i 2.99 (s, 3), 3.1 -3.7 (m, 4), 4.13 (d, 2), 4.25 -4.53 (m, 3), 4.82 -4.92 (m, 1), 7.47 -7.58 (m, 7), 7.82 -7.86 (m, 2), 8.37 (d, 1 NH), 8.66 -8.71 (m, 2), 9.94 (br. s, 1); ESI-MS m/z 505.1 (M+1);
4-[3-(1-benzilpirolidin-3R-il)-3-metilureido]-N-(1S-cijanometilkarbamoil-3-metilbutil)benzamid, sol trifluorooctene kiseline (Spoj 380); 1H NMR (270 MHz, DMSO-d6, smjesa rotomera) δ 0.87 (d, 3), 0.91 (d, 3), 1.48 -1.76 (m, 3), 2.0-2.4 (m, 2), 2.96 i 2.99 (s, 3), 3.1 -3.7 (m, 4), 4.13 (d, 2), 4.35 -4.53 (m, 3), 4.8 -4.9 (m, 1), 7.47 -7.57 (m, 7), 7.82 -7.86 (m, 2), 8.37 (d, 1 NH), 8.66 -8.71 (m, 2), 9.9 (br. s, 1); ESI-MS m/z 505.1 (M+1);
N-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]-4-pirimidin-2-ilpiperazin-1-karboksamid (Spoj 381); 1H NMR (270 MHz, DMSO-d6) δ 0.87 (d, 3), 0.91 (d, 3), 1.48 -1. 75 (m, 3), 3.55 -3.58 (m, 4), 3.77 -3.80 (m, 4), 4.12 (d, 2), 4.48 (m, 1), 6.68 (t, 1), 7.58 (d, 2), 7.84 (d, 2), 8.37 (d, 1 NH), 8.40 (d, 2), 8.68 (t, 1 NH), 8.88 (s, 1 NH); ESI-MS m/z 479 (M+1);
N-[4-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]-4-(2-okso-2-pirolidin-1-iletil)piperazin-1-karboksamid (Spoj 382); 1H NMR (270 MHz, DMSO-d6) δ 0.86 (d, 3), 0.91 (d, 3), 1.49 -1.98 (m, 7), 3.0 -3.6 (m, 8), 4.12 (t, 2), 4.22 (br. s, 4), 4.48 (m, 1), 7.55 (d, 2), 7.86 (d, 2), 8.38 (d, 1 NH), 8.70 (t, 1 NH), 9.04 (s, 1 NH); ESI-MS m/z 512.3 (M+1);
N-[3-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]-4-pirimidin-2-ilpiperazin-1-karboksamid (Spoj 384); 1H NMR (270 MHz, DMSO-d6) δ 0.86 (d, 3), 0.90 (d, 3), 1.47 -1.77 (m, 3), 3.52 -3.56 (m, 4), 3.75 -3.79 (m, 4), 4.11-4.13 (t, 3), 4.50 (m, 1), 6.66 (t, 1), 7.32 (t, 1), 7.50 (d, 1), 7.69 (d, 1), 7.91 (s, 1), 8.39 (d, 2), 8.45 (d, 1 NH), 8.68 (t, 1 NH), 8.78 (s, 1 NH); ESI-MS m/z 479.3 (M+1);
N-[3-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil}-4-(2-okso-2-pirolidin-1-iletil)piperazin-1-karboksamid, sol trifluorooctene kiseline (Spoj 385); 1H NMR (270 MHz, DMSO-d6) δ 0.87 (d, 3), 0.91 (d, 3), 1.49 -1.98 (m, 7), 3.0 -3.6 (m, 8), 4.13 (d, 2), 4.21 (br. s, 4), 4.50 (m, 1), 7.36 (t, 1), 7.56 (d, 1), 7.69 (d, 1), 7.89 (s, 1), 8.48 (d, 1 NH), 8.72 (t, 1 NH), 8.95 (s, 1 NH), 10.1 (br. s, 1); ESI-MS m/z 512.4 (M+1);
N-[3-(1S-cijanometilkarbamoil-3-metilbutilkarbamoil)fenil]-4-benzilpiperazin-1-karboksamid, sol trifluorooctene kiseline (Spoj 386); 1H NMR (270 MHz, DMSO-d6) δ 0.87 (d, 3), 0.91 (d, 3), 1.47 -1.78 (m, 3), 3.0 -3.2 (m, 4), 3.36 - 3.40 (m, 2), 4.13 (d, 2), 4.2 -4.3 (m, 2), 4.38 (br. s, 2), 4.51 (m, 1), 7.36 (t, 1), 7.51 (br. s, 5), 7.56 (d, 1), 7.69 (d, 1), 7.89 (s, 1), 8.48 (d, 1 NH), 8.72 (t, 1 NH), 8.93 (s, 1 NH), 9.8 (br. s, 1); ESI-MS m/z 491.4 (M+1); i
3-[3-(1-benzilpiperidin-4-il)ureido]-N-(1S-cijanometilkarbamoil-3-metilbutil)benzamid, sol trifluorooctene kiseline (Spoj 387); 1H NMR (270 MHz, DMSO-d6) δ 0.87 (d, 3), 0.91 (d, 3), 1.45 -1.78 (m, 5), 1.93 -2.11 (m, 2), 3.02- 3.15 (m, 2), 3.30 -3.37 (m, 2), 3.7 -3.9 (m, 1), 4.13 (d, 2), 4.29 -4.38 (m, 2), 4.48 (m, 1), 6.54 (d, 1 NH), 7.31 (t, 1), 7.46 (d, 1), 7.50 (br. s, 5), 7.59 (d, 1), 7.80 (s, 1), 8.47 (d, 1 NH), 8.59 (s, 1 NH), 8.70 (t, 1 NH), 9.46 (br. s, 1); ESI-MS m/z 505.4 (M+1).
Postupcima koji su analogni gore opisanima, dobiju se slijedeći spojevi Formule I:
4-(2-pirid-3-iltiazol-4-il)benzil 1S-cijanometilkarbamoil-3-metilbutilkarbamat (Spoj 388);
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(4-metilpiperazin-1-il)tiazol-4il]benzamid (Spoj 389);
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[N-metil-N-(4-pirid-4-iltiazol-2-il)amino]benzamid (Spoj 390);
terc-butil 4-{4-[4-(1-cijanometilkarbamoilcikloheksilkarbamoil)fenoksimetil]tiazol-2-il}piperazin-1-karboksilat (Spoj 391); NMR (u DMSO-d6): δ 8.14 (m, 1H), δ 7.87-7.78 (m, 3H), δ 7.1-7.0 (m, 2H). δ 6.87 (s, 1H), δ 4.95 (s, 1H), δ 4.00 (s, br, 2H), δ 3.81- 3.48 (m, 8H), δ 1.71-1.31 (m, 19H); MS: M+ H+ = 583.2;
terc-butil 4-(4-{4-[1S-(1-cijanociklopropilkarbamoil)-3-metilbutilkarbamoil]fenil}tiazol-2-ilamino)piperidin-1-karboksilat (Spoj 392); 1H NMR (DMSO): 8.97 (s, 1H), 8.49 (d, 1H), 7.90 (s, 4H), 7.73 (d, 1H), 7.23 (s, 1H), 4.43 (m, 1H), 3.85 (d, 2H), 3.75 (m, 1H), 2.98 (m, 2H), 1.97 (m, 2H), 1.81 (m, 1H), 1.68 (m, 2H), 1.48 (dd, 2H), 1.41 (br s, 11H), 1.11 (dd, 2H), 0.89 (m, 6H); MS: (m=z) 581.4;
N-[1S-(1-cijanociklopropilkarbamoil)-3-metilbutil]-4-(2-piperidin-4-ilaminotiazol-4-il)benzamid (Spoj 393); 1H NMR (DMSO): 8.99 (s, 1H), 8.50 (d, 1H), 7.91 (s, 4H), 7.87 (d, 1H), 7.27 (s, 1H), 4.43 (m, 1H), 3.89 (m, 1H), 3.32 (m, 2H), 3.04 (m, 2H), 2.33 (s, 3H), 2.16 (m, 2H), 1.72 (m,5H), 1.48 (dd, 2H), 1.11 (dd, 2H), 0.89 (m, 6H); MS: (m=z) 481.0;
terc-butil 4-{4-[4-(1-cijanometilkarbamoilcikloheksilkarbamoil)fenil]tiazol-2-ilamino}piperidin-1-karboksilat (Spoj 394); NMR (u DMSO-d6): δ 8.31-7.76 (m, 6H), δ 7.2 (s, 1H), δ 4.20-3.60 (m, 23H), δ 2.94 (s, br, 1H), δ 2.12-1.05 (m, 21H); MS: M+ H+ = 567.4;
N-[1-(cijanometil-karbamoil)-2-metil-butil]-4-[2-(piridin-3-ilamino)-tiazol-4-il]-benzamid (Spoj 395); MS: 449 (M+1); 1H NMR (DMSO-d6): 0.9 (6H, t +d), 1.23 (1H, m), 1.52 (1H, m), 2.00 (1H, m, 4.2 (2H, br d), 4.3 (1H, t, 7Hz), 7.64 (1H, s), 7.7 (1H, m), 7.95-8.1 (4H, 2xd, J=7 Hz), 8.4-8.6 (3H, m*), 8.86 (1H, t), 9.25 (1H, br s), 11.06 (1H, s);
N-[1-(cijanometil-karbamoil)-cikloheksil]-4-[2-(piperidin-4-ilamino)-tiazol-4-il]-benzamid (Spoj 396); NMR (u DMSO-d6): δ 8.23- 7.76 (m, 6H), δ 7.24 (s, 1H), δ 4.0 (d, 2H), δ 3.82 (s, br, 1H), δ 3.6-2.8 (m, 43H), δ 2.28 (s, 8H), δ 2.2- 1.14 (m, 10H); MS: --H+ = 465.0;
4-(4-{4-[1-(cijanometil-karbamoil)-cikloheksilkarbamoil]fenil}-tiazol-2-ilamino)-piperidin-1-karboksilna kiselina, etil ester (Spoj 397);
(S)-4-metil-2-[4-(4-morfolin-4-il-fenil)-tiazol-2-ilamino]-pentanojeva kiselina, cijanometil-amid (Spoj 398);
(S)-4-metil-2-[4-(4-pirolidin-1-il-fenil)-tiazol-2-ilamino]-pentanojeva kiselina, cijanometil-amid (Spoj 399);
(S)-4-metil-2-[4-(3-fenilsulfonilureidofenil)tiazol-2-ilamino)-pentanojeva kiselina, cijanometil-amid (Spoj 400);
(S)-4-metil-2-{4-[3-(3-fenil-ureido)-fenil]-tiazol-2-ilamino}-pentanojeva kiselina, cijanometil-amid (Spoj 401);
(S)-4-metil-2-(4-{3-[3-(4-fenoksi-fenil)-ureido]-fenil}-tiazol-2-ilamino)-pentanojeva kiselina, cijanometil-amid (Spoj 402);
(S)-4-metil-2-(4-{3-[3-((R)-1-fenil-etil)-ureido]-fenil}-tiazol-2-ilamino)-pentanojeva kiselina, cijanometil-amid (Spoj 403);
N-[1-(cijanometil-karbamoil)-cikloheksil]-4-(2-piridin-4-il-tiazol-4-il)-benzamid (Spoj 404); NMR (u DMSO-d6): δ 8.78 (d, 2H), δ 8.55 (s, 1H), δ 8.22 (m, 1H), δ 8.15 (d, 2H), δ 8.11-8.05 (m, 3H), δ 7.99 (d, 2H), δ 4.0-4.06 (m, 2H), δ 3.69 (s, br, 3H), δ 2.11 (d, 2H), δ 1.75 (m, 2H), δ 1.52 (s, br, 5H), δ 1.26 (s, br, 1H); MS: M+ H+ = 446.4;
(3-{2-[(S)-1-(cijanometil-karbamoil)-3-metil-butilamino]-tiazol-4-il}-fenil)-karbamska kiselina, 3,4-dikloro-benzil ester (Spoj 405);
N-[(S)-1-(1-cijano-ciklopropilkarbamoil)-3-metil-butil]-4-(2-(piperazin-1-ilmetil-tiazol-4-il)-benzamid (Spoj 406);
N-[(S)-1-(cijanometil-karbamoil)-3-metil-but-3-enil]-4-[2-(piridin-4-ilamino)-tiazol-4-il]-benzamid (Spoj 407);
N-[(S)-1-(cijanometil-karbamoil)-2-naftalen-2-il-etil]-4-[2-(piridin-4-ilamino)-tiazol-5-il]-benzamid (Spoj 408);
N-[(S)-1-(cijanometil-karbamoil)-2-naftalen-2-il-etil]-4-[2-(piridin-4-ilamino)-tiazol-4-il]-benzamid (Spoj 410); i
N-[(cijanometil-karbamoil)-dimetilamino-etil]-4-(2-piridin-4-il-tiazol-4-il)-benzamid.
Postupcima koji su analogni izloženima u ovoj Prijavi , dobiju se spojevi Formule I koji su predstavljeni elementima A, B i C, prikazanima u Tablici 1 koja slijedi.
TABLICA 1
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Iako svaka kombinacija elemenata A, B i C može predstavljati spojeve izuma, neke se kombinacije preporučuju. Na primjer, preporučuju se slijedeće kombinacije:
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PRIMJER 17
Test s katepsinom B
Otopine ispitivanih spojeva u različitim koncentracijama pripravljene su u 10 μL dimetil sulfoksida (DMSO) i potom razrijeđene u testnom puferu (40 μL, sadrži: N,N-bis(2-hidroksietil)-2-aminoetansulfonska kiselina (BES), 50 mM (pH 6); polioksietilensorbitan monolaurat, 0.05%; i ditiotreitol (DTT), 2.5 mM). Ljudski katepsin B (0.025 pmol u 25 μL testnog pufera) se doda razrjeđenjima. Testne otopine se miješaju 5-10 sekundi na ploči za protresanje, pokriju i inkubiraju 30 minuta na sobnoj temperaturi. Z-FR-AMC (20 nmol u 25 μL testnog pufera) se doda ispitivanim otopinama i hidroliza se spektrofotometrijski prati na (λ 460 nm) tijekom 5 minuta. Prividne inhibicijske konstante (Ki) su izračunate iz krivulje enzimske progresije, pomoću standardnih matematičkih modela.
Spojevi izuma ispitani su prema gore opisanom testu i opaženo je kako ispoljavaju inhibicijsko djelovanje na katepsin B.
PRIMJER 18
Test s katepsinom K
Otopine ispitivanih spojeva u različitim koncentracijama pripravljene su u 10 μL dimetil sulfoksida (DMSO) i potom razrijeđene u testnom puferu (40 μL, sadrži: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; i DTT, 2.5 mM). Ljudski katepsin K (0.0906 pmol u 25 μL testnog pufera) se doda razrjeđenjima. Testne otopine se miješaju 5-10 sekundi na ploči za protresanje, pokriju i inkubiraju 30 minuta na sobnoj temperaturi. Z-Phe-Arg-AMC (4 nmol u 25 μL testnog pufera) se doda ispitivanim otopinama i hidroliza se spektrofotometrijski prati na (λ 460 nm) tijekom 5 minuta. Prividne inhibicijske konstante (Ki) su izračunate iz krivulje enzimske progresije, pomoću standardnih matematičkih modela.
Spojevi izuma ispitani su gore opisanim testom i opaženo je kako ispoljavaju inhibicijsko djelovanje na katepsin K.
PRIMJER 19
Test s katepsinom L
Otopine ispitivanih spojeva u različitim koncentracijama pripravljene su u 10 μL dimetil sulfoksida (DMSO) i potom razrijeđene u testnom puferu (40 μL, sadrži: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; i DTT, 2.5 mM). Ljudski katepsin L (0.05 pmol u 25 μL testnog pufera) se doda razrjeđenjima. Testne otopine se miješaju 5-10 sekundi na ploči za protresanje, pokriju i inkubiraju 30 minuta na sobnoj temperaturi. Z-Phe-Arg-AMC (1 nmol u 25 μL testnog pufera) se doda ispitivanim otopinama i hidroliza se spektrofotometrijski prati na (λ 460 nm) tijekom 5 minuta. Prividne inhibicijske konstante (Ki) su izračunate iz krivulje enzimske progresije, pomoću standardnih matematičkih modela.
Spojevi izuma ispitani su gore opisanim testom i opaženo je kako ispoljavaju inhibicijsko djelovanje na katepsin L.
PRIMJER 20
Test s katepsinom S
Otopine ispitivanih spojeva u različitim koncentracijama pripravljene su u 10 μL dimetil sulfoksida (DMSO) i potom razrijeđene u testnom puferu (40 μL, sadrži: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; i NaCl, 100 mM). Ljudski katepsin S (0.158 pmol u 25 μL testnog pufera) se doda razrjeđenjima. Testne otopine se miješaju 5-10 sekundi na ploči za protresanje, pokriju i inkubiraju 30 minuta na sobnoj temperaturi. Z-Val-Val-Arg-AMC (9 nmol u 25 μL testnog pufera) se doda ispitivanim otopinama i hidroliza se spektrofotometrijski prati na (λ 460 nm) tijekom 5 minuta.
Prividne inhibicijske konstante (Ki) su izračunate iz krivulje enzimske progresije, pomoću standardnih matematičkih modela.
Spojevi izuma ispitani su gore opisanim testom i opaženo je kako ispoljavaju inhibicijsko djelovanje na katepsin S.
PRIMJER 21
Primjeri farmaceutskih pripravaka koji sadrže spoj Formule I
PERORALNI PRIPRAVAK
Spoj Formule I 10-100 mg
Monohidrat limunske kiseline 105 mg
Natij hidroksid 18 mg
Aroma
Voda dopuniti do 100 mL
INTRAVENSKI PRIPRAVAK
Spoj Formule I 0.1-10 mg
Dekstroza monohidrat nadopuniti do izotoničnosti
Monohidrat limunske kiseline 1.05 mg
Natij hidroksid 0.18 mg
Voda za injekcije dopuniti do 1.0 mL
PRIPRAVAK U OBLIKU TABLETE
Spoj Formule I 1%
Mikrokristalna celuloza 73%
Stearinska kiselina 25%
Koloidna silika 1%
Dobivene tablete su korisne za primjenu prema postupcima izuma za liječenje ili sprječavanje bolesnih stanja posredovanih katepsinom, kao što je osteoporoza.
Claims (28)
1. Spoj Formule I:
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naznačen time, što:
R1 je skupina Formule (a) ili (b):
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pri čemu:
X1 i X2 su neovisno -C(O)- ili -CH2S(O)2-;
R5 i R6 su neovisno vodik, (C1-6)alkil ili kako je dolje definirano;
R7 i R8 su neovisno vodik, (C1-6)alkil ili kako je dolje definirano;
R9 i R10 su neovisno (i) (C1-6)alkil neobavezno supstituiran s cijano, halo, halo-supstituirani (C1-3)alkil, nitro, -NR12R12, -NR12C(O)OR12, -NR12C(O)NR12R12, -NR12C(NR12)NR12R12, -OR12, -SR12, -C(O)OR12, -OC(O)R12, -C(O)NR12R12, -S(O)2NR12R12, -P(O)(OR12)OR12, -OP(O)(OR12)OR12, -NR12C(O)R13, -S(O)R13, -S(O)2R13, -C(O)R13, -OR14, -SR14, -S(O)R14, -S(O)2R14, -C(O)R14, -C(O)OR14, -OC(O)R14, -NR14R15, -NR15C(O)R14, -NR15C(O)OR14, -C(O)NR14R15, -S(O)2NR14R15, -NR15C(O)NR14R15 ili -NR15C(NR15)NR14R15, pri čemu je R12 pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil, R13 je (C1-6)alkil ili halo-supstituirani(C1-3)alkil, R14 je (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, (C9-12) policikloaril(C0-6)alkil ili hetero(C8-12)policikloaril(C0-6)alkil, R15 je vodik ili (C1-6)alkil, pri čemu je unutar R14 spomenuti cikloalkilni, heterocikloalkilni, arilni, heteroarilni, policikloarilni ili heteropolicikloarilni prsten neobavezno supstituiran skupinom odabranom između -R16, -X3OR16, -X3SR16, -X3S(O)R16, -X3S(O)2R16, -X3C(O)R16, -X3C(O)OR16, -X3OC(O)R16, -X3NR16R17, -X3NR17C(O)R16, -X3NR17C(O)OR16, -X3C(O)NR16R17, -X3S(O)2NR16R17, -X3NR17C(O)NR16R17 ili -X3NR17C(NR17)NR16R17, pri čemu je X3 veza ili (C1-6)alkilen, R16 je vodik ili (C1-6)alkil, a R17 je (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, (C9-12)policikloaril(C0-6)alkil ili hetero(C8-12)policikloaril(C0-6)alkil, ili (ii) skupina odabrana između (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, (C9-12)policikloaril(C0-6)alkil i hetero(C8-12)policikloaril(C0-6)alkil, pri čemu je spomenuti cikloalkilni, heterocikloalkilni, arilni, heteroarilni, policikloarilni ili heteropolicikloarilni prsten neobavezno supstituiran skupinom odabranom između -R16, -X3OR16, -X3SR16, -X3S(O)R16, -X3S(O)2R16, -X3C(O)R16, -X3C(O)OR16, -X3OC(O)R16, -X3NR16R17, -X3NR17C(O)R16, -X3NR17C(O)OR16, -X3C(O)NR16R17, -X3S(O)2NR16R17, -X3NR17C(O)NR16R17 ili -X3NR17C(NR17)NR16R17, pri čemu su X3, R16 i R17 kao što su gore definirani; pri čemu unutar R9 i/ili R10 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu su X3, R12 i R13 kao što su gore definirani; ili
R9 zajedno s R7 i/ili R10 zajedno s R8 tvore trimetilen, tetrametilen ili fenilen-1,2-dimetilen, neobavezno supstituiran s hidroksi, okso, (C1-4)alkil ili metilen; ili
R9 i R5 zajedno s ugljikovim atomom na koji su oba vezani i/ili R10 i R6 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen; a
R11 je -X4X5R18, pri čemu je X4 -C(O)-, -C(O)C(O)- ili -S(O)2-, X5 je veza, -O- ili –NR19-, pri čemu je R19 vodik ili (C1-6)alkil, R18 je (i) (C1-6)alkil neobavezno supstituiran s cijano, halo, halo-supstituirani (C1-3)alkil, nitro, -NR14R14, -NR14C(O)OR14, -NR14C(O)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(O)OR14, -C(O)NR14R14, -S(O)2NR14R14, -P(O)(OR14)OR14, -OP(O)(OR14)OR14, -NR14C(O)R15, -S(O)R15, -S(O)2R15, -C(O)R15, -OR20, -SR20, -S(O)R20, -S(O)2R20, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -NR20R21, -NR21C(O)R20, -NR21C(O)OR20, -NR21C(O)NR20R21 ili -NR21C(NR21)NR20R21, pri čemu su R14 i R15 kako je gore definirano, R20 je (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, (C9-12)policikloaril(C0-6)alkil ili hetero(C8-12)policikloaril(C0-6)alkil, R21 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil, ili (ii) (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, difenil(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, dihetero(C5-6)aril(C0-6)alkil, (C9-12)policikloaril(C0-6)alkil ili hetero(C8-12)policikloaril(C0-6)alkil, pri čemu spomenuti cikloalkilni, heterocikloalkilni, arilni, difenilni, heteroarilni, diheteroarilni, policikloarilni ili heteropolicikloarilni prsten može biti supstituiran s –R22, -X3OR22, -X3SR22, -X3S(O)R22, -X3S(O)2R22, -X3C(O)R22, -X3C(O)OR22, -X3C(O)NR22R23, -X3NR22R23, -X3NR23C(O)R22, -X3NR23C(O)OR22, -X3NR23S(O)2R22-X3NR23C(O)NR22R23 ili -X3NR23C(NR23)NR22R23, pri čemu je X3 kako je gore definirano, R22 je(C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, (C9-12)policikloaril(C0-6)alkil ili hetero(C8-12)policikloaril(C0-6)alkil, R23 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil; pri čemu unutar R11 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu su X3, R12 i R13 kao što su gore definirani;
R2 je vodik ili (C1-6)alkil;
R3 je vodik, (C1-6)alkil ili kako je dolje definirano; a
R4 je (i) cijano, -C(O)OR12 ili (C1-6)alkil, pri čemu je spomenuti alkil neobavezno supstituiran s cijano, halo, halo-supstituirani (C1-3)alkil, nitro, -NR12R12, -NR12C(O)OR12, -NR12C(O)NR12R12, -NR12C(NR12)NR12R12, -OR12, -SR12, -C(O)OR12, -O(C)OR12, -C(O)NR12R12, -S(O)2NR12R12, -P(O)(OR12)OR12, -OP(O)(OR12)OR12, -NR12C(O)R13, -S(O)R13, -S(O)2R13, -C(O)R13, -OR14, -SR14, -S(O)R14, -S(O)2R14, -C(O)R14, -C(O)OR14, -OC(O)R14, -NR14R15, -NR15C(O)R14, -NR15C(O)OR14, -C(O)NR14R15, -S(O)2NR14R15, -NR15C(O)NR14R15 ili -NR15C(NR15)NR14R15, pri čemu su R12, R13 i R14 kao što je gore definirano, ili (ii) skupina odabrana između (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil, (C9-12)policikloaril(C0-6)alkil i hetero(C8-12)policikloaril(C0-6)alkil, pri čemu je spomenuti cikloalkilni, heterocikloalkilni, arilni, heteroarilni, policikloarilni ili heteropolicikloarilni prsten neobavezno supstituiran sa skupinom odabranom između -R16, -X3OR16, -X3SR16, -X3S(O)R16, -X3S(O)2R16, -X3C(O)R16, -X3C(O)OR16, -X3OC(O)R16, -X3NR16R17, -X3NR17C(O)R16, -X3NR17C(O)OR16, -X3C(O)NR16R17, -X3S(O)2NR16R17, -X3NR17C(O)NR16R17 ili -X3NR17C(NR17)NR16R17, pri čemu su X3, R16 i R17 kako je gore definirano, pri čemu unutar R4 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu su X3, R12 i R13 kao što su gore definirani, ili
R4 zajedno s R2 tvore trimetilen, tetrametilen ili fenilen-1,2-dimetilen, neobavezno supstituiran s hidroksi, okso, (C1-4)alkil ili metilen; ili
R4 i R3 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen, pri čemu je spomenuti cikloalkilen ili heterocikloalkilen neobavezno supstituiran s 1 do 3 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu su X3, R12 i R13 kao što su gore definirani; i N-oksidni derivati, prolijek derivati, zaštićeni derivati, pojedinačni izomeri i smjese izomera; i njihove farmaceutski prihvatljive soli.
2. Spoj iz Zahtjeva 1, naznačen time, što
R1 je skupina Formule (a), pri čemu je unutar Formule (a):
X1 je -C(O)-;
R5 je vodik, (C1-6)alkil ili kako je definirano zajedno s R9;
R7 je vodik, (C1-6)alkil ili kako je definirano zajedno s R9;
R9 je (i) (C1-6)alkil neobavezno supstituiran s halo-supstituirani (C1-3)alkil, -OR12 ili -NR12C(NR12)NR12R12, pri čemu je R12 pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil, ili (ii) (C6-12)aril(C0-6)alkil, ili
R9 zajedno s R7 tvori trimetilen neobavezno supstituiran s okso, (C1-4)alkil ili metilen; ili
R9 i R5 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen; a
R11 je -X4X5R18, pri čemu je X4 -C(O)-, X5 je veza, -O- ili –SO2-, pri čemu je R18 (i) (C1-6)alkil neobavezno supstituiran s -C(O)NR20R21 ili –NR21C(O)R20, pri čemu je R20 (C6-12)aril(C0-6)alkil, a R21 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil, ili (ii) (C3-12)cikloalkil(C0-6)alkil, hetero(C3-12)cikloalkil(C0-6)alkil, (C6-12)aril(C0-6)alkil, hetero(C5-12)aril(C0-6)alkil ili hetero(C8-12)policikloaril(C0-6)alkil, pri čemu spomenuti heterocikloalkilni, arilni, heteroarilni ili heteropolicikloarilni prsten može biti supstituiran s –R22, -X3OR22, -X3NR22R23, -X3NR17C(O)R16, -X3NR23C(O)OR22, -X3NR23S(O)2R22, -X3S(O)2R22, -X3C(O)R22 ili -X3NR23C(O)NR22R23, pri čemu je X3 veza ili (C1-6)alkilen, R22 je hetero(C3-12)cikloalkil(C0-6)alkil, R23 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil; pri čemu unutar R11 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu je X3 veza ili (C1-6)alkilen, R12 je pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil, a R13 je (C1-6)alkil ili halo-supstituirani (C1-3)alkil;
R3 je vodik, (C1-6)alkil ili kako je definirano zajedno s R4; a
R4 je (i) vodik, cijano, -C(O)OR12 ili (C1-6)alkil, pri čemu je spomenuti alkil neobavezno supstituiran s -C(O)OR12, -O(C)OR12, pri čemu je R12 pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil, ili (ii) (C6-10)aril(C0-3)alkil, ili
R4 zajedno s R2 tvore trimetilen, ili
R4 i R3 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen, pri čemu su spomenuti (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen neobavezno supstituirani s (C1-6)alkil; i N-oksidni derivati, prolijek derivati, zaštićeni derivati, pojedinačni izomeri i smjese izomera; i njihove farmaceutski prihvatljive soli.
3. Spoj iz Zahtjeva 2, naznačen time, što:
R1 je skupina Formule (a), pri čemu unutar Formule (a):
X1 je -C(O)-;
R5 je vodik ili kako je definirano zajedno s R9;
R7 je vodik;
R9 je (i) (C1-6)alkil ili
R9 i R5 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen; a
R11 je -X4X5R18, pri čemu je X4 -C(O)-, a R18 je (C6-12)aril(C0-6)alkil ili hetero(C5-12)aril(C0-6)alkil, pri čemu spomenuti arilni ili heteroarilni prsten može biti supstituiran s –R22, -X3OR22, -X3NR22R23, -X3NR17C(O)R16, -X3NR23C(O)OR22, -X3NR23S(O)2R22, -X3S(O)2R22, -X3C(O)R22 ili -X3NR23C(O)NR22R23, pri čemu je X3 veza ili (C1-6)alkilen, R22 je hetero(C3-12)cikloalkil(C0-6)alkil, R23 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil; pri čemu unutar R11 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu je X3 veza ili (C1-6)alkilen, R12 je pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil, a R13 je (C1-6)alkil ili halo-supstituirani (C1-3)alkil;
R3 je vodik ili kako je definirano zajedno s R4; a
R4 je (i) vodik, ili
R4 i R3 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen, pri čemu su spomenuti (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen neobavezno supstituirani s (C1-6)alkil; i N-oksidni derivati, prolijek derivati, zaštićeni derivati, pojedinačni izomeri i smjese izomera; i njihove farmaceutski prihvatljive soli.
4. Spoj iz Zahtjeva 3, naznačen time, što:
R1 je skupina Formule (a), pri čemu unutar Formule (a):
X1 je -C(O)-;
R5 je vodik ili kako je definirano zajedno s R9;
R7 je vodik;
R9 je (i) (C1-6)alkil ili
R9 i R5 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen; a
R11 je -X4X5R18, pri čemu je X4 -C(O)-, a R18 je fenil, pri čemu spomenuti fenilni prsten može biti supstituiran s –R22, -X3OR22, -X3NR22R23, -X3NR17C(O)R16, -X3NR23C(O)OR22, -X3NR23S(O)2R22, -X3S(O)2R22, -X3C(O)R22 ili -X3NR23C(O)NR22R23, pri čemu je X3 veza ili (C1-6)alkilen, R22 je hetero(C3-12)cikloalkil(C0-6)alkil, R23 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil; pri čemu unutar R11 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X3NR12R12, -X3NR12C(O)OR12, -X3NR12C(O)NR12R12, -X3NR12C(NR12)NR12R12, -X3OR12, -X3SR12, -X3C(O)OR12, -X3C(O)NR12R12, -X3S(O)2NR12R12, -X3P(O)(OR3)OR12, -X3OP(O)(OR3)OR12, -X3NR12C(O)R13, -X3S(O)R13, -X3S(O)2R13 i -X3C(O)R13, pri čemu je X3 veza ili (C1-6)alkilen, R12 je pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil, a R13 je (C1-6)alkil ili halo-supstituirani (C1-3)alkil;
R3 je vodik ili kako je definirano zajedno s R4; a
R4 je (i) vodik, ili
R4 i R3 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen, pri čemu su spomenuti (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen neobavezno supstituirani s (C1-6)alkil; i N-oksidni derivati, prolijek derivati, zaštićeni derivati, pojedinačni izomeri i smjese izomera; i njihove farmaceutski prihvatljive soli.
5. Spoj iz Zahtjeva 4, naznačen time, što je odabran iz skupine koja se sastoji od:
N-[1-(cijanometil-karbamoil)-3-metil-butil]-3-[3-(3-morfolin-4-il-propil)ureido]-benzamid; i
N-[1-(cijanometil-karbamoil)-3-metil-butil]-3-(3-piridin-2-il-ureido)-benzamid;
N-[1S-(cijanometil-karbamoil)-3-metil-butil]-4-(3-piridin-4-ilmetil-ureido)-benzamid;
N-[1-(cijanometil-karbamoil)-3-metil-butil]-4-(3-piperidin-4-il-ureido)-benzamid;
N-[1-S-(dicijanometil-karbamoil)-3-metil-butil]-4-morfolin-4-il-benzamid;
4-dimetilamino-piperidin-1-karboksilna kiselina{4-[1-(cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-amid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(4-metilpiperazin-1-il)-benzamid;
N-[1-cijanometilkarbamoil-3-metilbutil-4-(2-gvanidinotiazo1-4-il)]benzamid;
{4-[1-S-(cijanometil-karbamoil)-3-metil-butilkarbamoil]-fenil}-karbamilna kiselina,
3-piridin-4-il-propilester; i
N-[1-(cijanometil-karbamoil)-3-metil-butil]-4-{3-[2-(3H-imidazo1-4-il)-etil]-ureido}-benzamid; i N-oksidni derivati, prolijek derivati, zaštićeni derivati, pojedinačni izomeri i smjese izomera; i njihove farmaceutski prihvatljive soli.
6. Spoj Formule II:
[image]
naznačen time, što:
X1 je odabran između -C(O)-, -S(O)-, -C(S)-, -S(O)2- i -P(O)2-;
R1 i R2 su neovisno vodik ili (C1-6)alkil;
R3 i R4 su neovisno vodik ili (C1-6)alkil, ili R3 i R4 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen;
R5 i R6 su neovisno vodik ili (C1-6)alkil, ili R5 i R6 zajedno s ugljikovim atomom na koji su oba vezani tvore (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen; a
R7 je –X2X3R9, pri čemu je X2 -C(O)-, -S(O)-, -C(S)-, -S(O)2- ili -P(O)2-, X3 je veza, -O- ili -NR10-, pri čemu je R10 vodik ili (C1-6)alkil, R9 je (C3-6)cikloalkil(C0-6)alkil, hetero(C3-6)cikloalkil(C0-6)alkil, fenil(C0-6)alkil ili hetero(C5-6)aril(C0-6)alkil, pri čemu je unutar R9 spomenuti cikloalkil, heterocikloalkil, fenil ili heteroaril supstituiran s -R12, -X4NR11R12, -X4NR11C(O)R12, -X4NR11C(O)OR12, -X4NR11C(O)NR11R12, -X4NR11C(NR11)NR11R12, -X4OR12, -X4SR12, -X4S(O)R12, -X4S(O)2R12, -X4C(O)R12, -X4C(O)OR12, -X4OC(O)R12, -X4C(O)NR11R12, -X4OC(O)NR11R12, -X4S(O)2NR11R12, -X4P(O)(OR11)OR12 ili -X4OP(O)(OR11)OR12, pri čemu je X4 veza ili (C1-6)alkilen, R11 je pri svakoj pojavi vodik ili (C1-6)alkil, a R12 je (C3-6)cikloalkil(C0-6)alkil, hetero(C3-6)cikloalkil(C0-6)alkil, fenil(C0-6)alkil ili hetero(C5-6)aril(C0-6)alkil, pri čemu je unutar R12 spomenuti cikloalkil, heterocikloalkil, fenil ili heteroaril supstituiran s –R13, -X4NR11R13, -X4NR11C(O)R13, -X4NR11C(O)OR13, -X4NR11C(O)NR11R13, -X4NR11C(NR11)NR11R13, -X4OR13, -X4SR13, -X4S(O)R13, -X4S(O)2R13, -X4C(O)R13, X4C(O)OR13, -X4OC(O)R13, -X4C(O)NR11R13, -X4OC(O)NR11R13, -X4S(O)2NR11R13, -X4P(O)(OR11)OR13 ili -X4OP(O)(OR11)OR13, pri čemu su X4 i R11 kako su gore definirani, R13 je (C3-6)cikloalkil(C0-6)alkil, hetero(C3-6)cikloalkil(C0-6)alkil, fenil(C0-6)alkil ili hetero(C5-6)aril(C0-6)alkil, pri čemu unutar R7 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(O)(OR5)OR14, -X5OP(O)(OR5)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 i -X5C(O)R15, pri čemu je X5 veza ili (C1-6)alkilen, R14 je pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil; R15 je (C1-6)alkil ili halo-supstituirani (C1-3)alkil; i N-oksidni derivati, prolijek derivati, zaštićeni derivati, pojedinačni izomeri i smjese izomera; i njihove farmaceutski prihvatljive soli.
7. Spoj iz Zahtjeva 6, naznačen time, što:
X1 je odabran između -C(O)-;
R1 i R2 su vodici:
R3 je izobutil i R4 je vodik, ili R3 i R4 zajedno s ugljikovim atomom na koji su oba vezani tvore ciklopropilen ili cikloheksilen;
R5 i R6 su vodici, ili R5 i R6 zajedno s ugljikovim atomom na koji su oba vezani tvore cikloheksilen ili (C6)heterocikloalkilen; a
R7 je –X2X3R9, pri čemu je X2 -C(O)-, X3 je veza, a R9 je fenil, pri čemu je unutar R9 spomenuti fenil supstituiran s -R12, -X4NR11R12, -X4NR11C(O)R12, -X4NR11C(O)OR12, -X4NR11C(O)NR11R12, -X4NR11C(NR11)NR11R12, -X4OR12, -X4SR12, -X4S(O)R12, -X4S(O)2R12, -X4C(O)R12, -X4C(O)OR12, -X4OC(O)R12, -X4C(O)NR11R12, -X4OC(O)NR11R12,-X4S(O)2NR11R12, -X4P(O)(OR11)OR12, -X4OP(O)(OR11)OR12, pri čemu je X4 veza ili (C1-6)alkilen, R11 je pri svakoj pojavi neovisno vodik ili (C1-6)alkil, a R12 je hetero(C3-6)cikloalkil(C0-6)alkil, fenil(C0-6)alkil ili hetero(C5-6)aril(C0-6)alkil, pri čemu je unutar R12 spomenuti heterocikloalkil, fenil ili heteroaril supstituiran s –R13, -X4NR11R13, -X4NR11C(O)R13, -X4NR11C(O)OR13, -X4NR11C(O)NR11R13, -X4NR11C(NR11)NR11R13, -X4OR13, -X4SR13, -X4S(O)R13, -X4S(O)2R13, -X4C(O)R13, -X4C(O)OR13, -X4OC(O)R13, -X4C(O)NR11R13, -X4OC(O)NR11R13, -X4S(O)2NR11R13, -X4P(O)(OR11)OR13 ili -X4OP(O)(OR11)OR13, pri čemu su X4 i R11 kako su gore definirani, R13 je (C3-6)cikloalkil(C0-6)alkil, hetero(C3-6)cikloalkil(C0-6)alkil, fenil(C0-6)alkil ili hetero(C5-6)aril(C0-6)alkil, pri čemu unutar R7 bilo koji od nazočnih alicikličkih ili aromatskih prstenskih sustava može biti dalje supstituiran s 1 do 5 radikala neovisno odabranih između (C1-6)alkil, (C1-6)alkiliden, cijano, halo, halo-supstituirani (C1-4)alkil, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(O)(OR5)OR14, -X5OP(O)(OR5)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 i -X5C(O)R15, pri čemu je X5 veza ili (C1-6)alkilen, R14 je pri svakoj pojavi neovisno vodik, (C1-6)alkil ili halo-supstituirani (C1-3)alkil; R15 je (C1-6)alkil ili halo-supstituirani (C1-3)alkil; i N-oksidni derivati, prolijek derivati, zaštićeni derivati, pojedinačni izomeri i smjese izomera; i njihove farmaceutski prihvatljive soli.
8. Spoj iz Zahtjeva 7, naznačen time, što je odabran iz skupine koja se sastoji od:
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-pirid-4-ilamino)tiazol-4-ilbenzamid;
4-[3-(1-benzilpiperidin-4-il)ureido]-N-(1S-cijanometilkarbamoil-3-metilbutil)benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[4-(2-morfolin-4-iletil)piperazin-1-il]benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-pirid-4-iltiazol-4-il)benzamid;
4-[3-(1-benzilpirolidin-3S-il)-3-metilureido]-N-(1S-cijanometilkarbamoil-3-metilbutil)benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(4-pirid-4-ilpiperazin-1-il)benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(1-metilpiridin-4-ilamino)tiazol-4-il]benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(1-metilpiridin-4-il)tiazol-4-il]benzamid;
N-[(S)-1-(cijanometil-karbamoil)-3-metil-but-3-enil]-4-[2-(piridin-4-ilamino)-tiazol-4-il]-benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(1-alilpirid-4-il)tiazol-4-il]benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-piperidin-4-ilaminotiazol-4-il)benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-(2-piperazin-1-iltiazol-4-il)benzamid;
N-(1S-cijanometilkarbamoil-3-metilbutil)-4-[2-(4-metilpiperazin-1-il)tiazol-4-il]benzamid;
N-[1S-(1-cijanociklopropilkarbamoil)-3-metilbutil]-4-(2-piperazin-1-il-tiazol-4-il)benzamid;
N-[1S-(1-cijanociklopropilkarbamoil)-3-metilbutil]-4-[2-(4-metilpiperazin-1-il)tiazol-4-il]benzamid;
N-[1S-(1-cijanociklopropilkarbamoil)-3-metilbutil]-4-(2-piperidin-4-ilaminothiazol-4-il)benzamid;
N-(1-cijanometilkarbamoilcikloheksil)-4-(2-piperazin-1-iltiazol-4-il)benzamid;
N-[1-(cijanometil-karbamoil)-cikloheksil]-4-[2-(piperidin-4-ilamino)-tiazol-4-il]-benzamid;
N-(1R-cijanometilkarbamoil-3-metilbutil)-4-(2-morfolin-4-iltiazol)-4-il)benzamid;
N-(1-cijanometilkarbamoilcikloheksil]-4-[2-(4-metilpiperazin-1-il)tiazol-4-il]benzamid;
N-[1-(4-cijanotetrahidropiran-4-ilkarbamoil)cikloheksil]-4-[2-(4-metilpiperazin-1-il)tiazol-4-il]benzamid;
N-(1-cijanometilkarbamoilcikloheksil)-4-(2-morfolin-4-iltiazol-4-il)benzamid;
N-(1-cijanometilkarbamoilcikloheksil)-4-(2-piperazin-1-ilmetiltiazol-4-il)benzamid;
terc-butil 4-(4-{4-[1S-(1-cijanociklopropilkarbamoil)-3-metilbutilkarbamoil]fenil}tiazol-2-ilmetil)piperazin-1-karboksilat;
N-[(S)-1-(1-cijano-ciklopropilkarbamoil)-3-metil-butil]-4-(2-piperazin-1-ilmetil-tiazol-4-il)-benzamid; i
N-(1S-cijanometilkarbamoil-3-metilbutil]-4-(4-morfolin-4-ilmetiltiazol-2-ilamino)benzamid; i N-oksidni derivati, prolijek derivati, zaštićeni derivati, pojedinačni izomeri i smjese izomera; i njihove farmaceutski prihvatljive soli.
9. Farmaceutski pripravak, naznačen time, što sadrži terapijski učinkovitu količinu spoja iz Zahtjeva 1 u kombinaciji s farmaceutski prihvatljivim ekscipijensom.
10. Pripravak iz Zahtjeva 9, naznačen time, što dalje sadrži jedan ili više aktivnih sastojaka odabranih iz skupine koja se sastoji od (i) terapijski učinkovite količine bisfosfonske kiseline ili njezinog kiselog estera ili njihove farmaceutski prihvatljive soli i (ii) terapijski učinkovite količine agonista estrogenskih receptora ili njegove farmaceutski prihvatljive soli.
11. Pripravak iz Zahtjeva 10, naznačen time, što je bisfosfonska kiselina odabrana iz skupine koja se sastoji od 1,1-diklorometilen-1,1-difosfonske kiseline, 1-hidroksi-3-pirolidin-1-ilpropiliden-1,1-bisfosfonske kiseline, 1-hidroksietiliden-1,1-difosfonske kiseline, 1-hidroksi-3-(N-metil-N-pentilamino)propiliden-1,1-bisfosfonske kiseline, 6-amino-1-hidroksiheksiliden-1,1-bisfosfonske kiseline, 3-(dimetilamino)-1-hidroksipropiliden-1,1-bisfosfonske kiseline, 3-amino-1-hidroksipropiliden-1,1-bisfosfonske kiseline, 2-pirid-2-iletiliden-1,1-bisfosfonske kiseline, 1-hidroksi-2-pirid-3-iletiliden-1,1-bisfosfonske kiseline, 4-klorofeniltiometilenbisfosfonske kiseline i 1-hidroksi-2-(1H-imidazol-1-il)etiliden-1,1-bisfosfonske kiseline ili njihovih kiselih estera, ili njihovih farmaceutski prihvatljivih soli.
12. Pripravak iz Zahtjeva 11, naznačen time, što je bisfosfonska kiselina 1,1-diklorometilen-1,1-difosfonska kiselina ili njezina farmaceutski prihvatljiva sol.
13. Pripravak iz Zahtjeva 12, naznačen time, što predstavlja 1,1-diklorometilen-1,1-difosfonat mononatrij trihidrat.
14. Farmaceutski pripravak, naznačen time, što sadrži terapijski učinkovitu količinu spoja iz Zahtjeva 6 u kombinaciji s farmaceutski prihvatljivim ekscipijensom.
15. Pripravak iz Zahtjeva 14, naznačen time, što dalje sadrži jedan ili više aktivnih sastojaka odabranih iz skupine koja se sastoji od (i) terapijski učinkovite količine bisfosfonske kiseline ili njezinog kiselog estera ili njihove farmaceutski prihvatljive soli i (ii) terapijski učinkovite količine agonista estrogenskih receptora ili njegove farmaceutski prihvatljive soli.
16. Pripravak iz Zahtjeva 15, naznačen time, što je bisfosfonska kiselina odabrana iz skupine koja se sastoji od 1,1-diklorometilen-1,1-difosfonske kiseline, 1-hidroksi-3-pirolidin-1-ilpropiliden-1,1-bisfosfonske kiseline, 1-hidroksietiliden-1,1-difosfonske kiseline, 1-hidroksi-3-(N-metil-N-pentilamino)propiliden-1,1-bisfosfonske kiseline, 6-amino-1-hidroksiheksiliden-1,1-bisfosfonske kiseline, 3-(dimetilamino)-1-hidroksipropiliden-1,1-bisfosfonske kiseline, 3-amino-1-hidroksipropiliden-1,1-bisfosfonske kiseline, 2-pirid-2-iletiliden-1,1-bisfosfonske kiseline, 1-hidroksi-2-pirid-3-iletiliden-1,1-bisfosfonske kiseline, 4-klorofeniltiometilenbisfosfonske kiseline i 1-hidroksi-2-(1H-imidazol-1-il)etiliden-1,1-bisfosfonske kiseline ili njihovih kiselih estera, ili njihovih farmaceutski prihvatljivih soli.
17. Pripravak iz Zahtjeva 16, naznačen time, što je bisfosfonska kiselina 1,1-diklorometilen-1,1-difosfonska kiselina ili njezina farmaceutski prihvatljiva sol.
18. Pripravak iz Zahtjeva 17, naznačen time, što predstavlja 1,1-diklorometilen-1,1-difosfonat mononatrij trihidrat.
19. Postupak za liječenje bolesti u životinje u koje djelovanje cistein proteaze doprinosi patologiji i/ili znakovlju bolesti, naznačen time, što obuhvaća primjenu na životinju terapijski učinkovite količine spoja iz Zahtjeva 1; ili N-oksidnog derivata, prolijek derivata, zaštićenog derivata, pojedinačnog izomera ili smjese izomera, ili njegove farmaceutski prihvatljive soli.
20. Postupak iz Zahtjeva 19, naznačen time, što je bolest osteoporoza.
21. Postupak iz Zahtjeva 20, naznačen time, što je životinja čovjek.
22. Postupak iz Zahtjeva 21, naznačen time, što je čovjek žena u postmenopauzi.
23. Postupak iz Zahtjeva 22, naznačen time, što je cistein proteaza katepsin K.
24. Postupak za liječenje bolesti u životinje u koje djelovanje cistein proteaze doprinosi patologiji i/ili znakovlju bolesti, naznačen time, što obuhvaća primjenu na životinju terapijski učinkovite količine spoja iz Zahtjeva 6; ili N-oksidnog derivata, prolijek derivata, zaštićenog derivata, pojedinačnog izomera ili smjese izomera, ili njegove farmaceutski prihvatljive soli.
25. Postupak iz Zahtjeva 24, naznačen time, što je bolest osteoporoza.
26. Postupak iz Zahtjeva 25, naznačen time, što je životinja čovjek.
27. Postupak iz Zahtjeva 26, naznačen time, što je čovjek žena u postmenopauzi.
28. Postupak iz Zahtjeva 27, naznačen time, što je cistein proteaza katepsin K.
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