HRP970391A2 - Phosphinate based inhibitors of matrix metalloproteases - Google Patents
Phosphinate based inhibitors of matrix metalloproteasesInfo
- Publication number
- HRP970391A2 HRP970391A2 HR60/021,959A HRP970391A HRP970391A2 HR P970391 A2 HRP970391 A2 HR P970391A2 HR P970391 A HRP970391 A HR P970391A HR P970391 A2 HRP970391 A2 HR P970391A2
- Authority
- HR
- Croatia
- Prior art keywords
- alkyl
- methylcarbamoyl
- phosphinic acid
- dimethyl
- benzyl
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title description 17
- 239000011159 matrix material Substances 0.000 title description 3
- 102000005741 Metalloproteases Human genes 0.000 title description 2
- 108010006035 Metalloproteases Proteins 0.000 title description 2
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 72
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 37
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 27
- 102000003390 tumor necrosis factor Human genes 0.000 claims description 27
- -1 hydroxy, amino Chemical group 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 19
- 230000005764 inhibitory process Effects 0.000 claims description 16
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 14
- 102000002274 Matrix Metalloproteinases Human genes 0.000 claims description 14
- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims description 14
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 241000124008 Mammalia Species 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 8
- KATBPZLMXQIZLF-UHFFFAOYSA-N (4-benzylphenyl)methyl-[2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-4-methylpentyl]phosphinic acid Chemical compound C1=CC(CP(O)(=O)CC(CC(C)C)C(=O)NC(C(=O)NC)C(C)(C)C)=CC=C1CC1=CC=CC=C1 KATBPZLMXQIZLF-UHFFFAOYSA-N 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 208000025865 Ulcer Diseases 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 230000036269 ulceration Effects 0.000 claims description 7
- 206010040047 Sepsis Diseases 0.000 claims description 6
- 206010040070 Septic Shock Diseases 0.000 claims description 6
- 206010003246 arthritis Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 208000028169 periodontal disease Diseases 0.000 claims description 6
- 230000036303 septic shock Effects 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 5
- 208000030507 AIDS Diseases 0.000 claims description 5
- 206010014989 Epidermolysis bullosa Diseases 0.000 claims description 5
- 206010039705 Scleritis Diseases 0.000 claims description 5
- 229940035676 analgesics Drugs 0.000 claims description 5
- 239000000730 antalgic agent Substances 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 231100000433 cytotoxic Toxicity 0.000 claims description 5
- 230000001472 cytotoxic effect Effects 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 208000037803 restenosis Diseases 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 4
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 229910005965 SO 2 Inorganic materials 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 4
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 208000002780 macular degeneration Diseases 0.000 claims description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 4
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- LQDHQVJPGDBOJR-UHFFFAOYSA-N (4-benzylphenyl)methyl-[2-(cyclohexylmethyl)-3-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]amino]-3-oxopropyl]phosphinic acid Chemical compound C=1C=C(CC=2C=CC=CC=2)C=CC=1CP(O)(=O)CC(C(=O)NC(C(=O)NC)C(C)(C)C)CC1CCCCC1 LQDHQVJPGDBOJR-UHFFFAOYSA-N 0.000 claims description 2
- UTSFQPTVPZNJJH-UHFFFAOYSA-N (4-benzylphenyl)methyl-[2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-4-phenylbutyl]phosphinic acid Chemical compound C=1C=C(CC=2C=CC=CC=2)C=CC=1CP(O)(=O)CC(C(=O)NC(C(=O)NC)C(C)(C)C)CCC1=CC=CC=C1 UTSFQPTVPZNJJH-UHFFFAOYSA-N 0.000 claims description 2
- IHXYDMMVEDLUPK-UHFFFAOYSA-N (4-benzylphenyl)methyl-[2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-5,5,5-trifluoropentyl]phosphinic acid Chemical compound C1=CC(CP(O)(=O)CC(CCC(F)(F)F)C(=O)NC(C(=O)NC)C(C)(C)C)=CC=C1CC1=CC=CC=C1 IHXYDMMVEDLUPK-UHFFFAOYSA-N 0.000 claims description 2
- XCUQHJJAOKKHJS-UHFFFAOYSA-N (4-benzylphenyl)methyl-[2-[[3-(4-methoxyphenyl)-1-(methylamino)-1-oxopropan-2-yl]carbamoyl]-4-methylpentyl]phosphinic acid Chemical compound C=1C=C(CC=2C=CC=CC=2)C=CC=1CP(O)(=O)CC(CC(C)C)C(=O)NC(C(=O)NC)CC1=CC=C(OC)C=C1 XCUQHJJAOKKHJS-UHFFFAOYSA-N 0.000 claims description 2
- NQECQHIRGFLISY-UHFFFAOYSA-N (4-benzylphenyl)methyl-[2-[[3-(4-methoxyphenyl)-1-(methylamino)-1-oxopropan-2-yl]carbamoyl]-6-phenoxyhexyl]phosphinic acid Chemical compound C=1C=CC=CC=1OCCCCC(CP(O)(=O)CC=1C=CC(CC=2C=CC=CC=2)=CC=1)C(=O)NC(C(=O)NC)CC1=CC=C(OC)C=C1 NQECQHIRGFLISY-UHFFFAOYSA-N 0.000 claims description 2
- JAAFICSMUDJNQS-UHFFFAOYSA-N (5-benzylpyridin-2-yl)methyl-[2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-4-methylpentyl]phosphinic acid Chemical compound C1=NC(CP(O)(=O)CC(CC(C)C)C(=O)NC(C(=O)NC)C(C)(C)C)=CC=C1CC1=CC=CC=C1 JAAFICSMUDJNQS-UHFFFAOYSA-N 0.000 claims description 2
- KVOARZLBLIHNAH-UHFFFAOYSA-N (5-benzylthiophen-2-yl)methyl-[2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-4-methylpentyl]phosphinic acid Chemical compound S1C(CP(O)(=O)CC(CC(C)C)C(=O)NC(C(=O)NC)C(C)(C)C)=CC=C1CC1=CC=CC=C1 KVOARZLBLIHNAH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- TTZWROSODOHYKZ-UHFFFAOYSA-N [2-(cyclobutylmethyl)-3-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]amino]-3-oxopropyl]-[[4-[(2-fluorophenyl)methyl]phenyl]methyl]phosphinic acid Chemical compound C=1C=C(CC=2C(=CC=CC=2)F)C=CC=1CP(O)(=O)CC(C(=O)NC(C(=O)NC)C(C)(C)C)CC1CCC1 TTZWROSODOHYKZ-UHFFFAOYSA-N 0.000 claims description 2
- LKOQZTZLLAIOGB-UHFFFAOYSA-N [2-(cyclopropylmethyl)-3-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]amino]-3-oxopropyl]-[[4-[(2-fluorophenyl)methyl]phenyl]methyl]phosphinic acid Chemical compound C=1C=C(CC=2C(=CC=CC=2)F)C=CC=1CP(O)(=O)CC(C(=O)NC(C(=O)NC)C(C)(C)C)CC1CC1 LKOQZTZLLAIOGB-UHFFFAOYSA-N 0.000 claims description 2
- YLNWMQOPZKKAIQ-UHFFFAOYSA-N [2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-4-methylpentyl]-[[4-(2-methylpropyl)phenyl]methyl]phosphinic acid Chemical compound CNC(=O)C(C(C)(C)C)NC(=O)C(CC(C)C)CP(O)(=O)CC1=CC=C(CC(C)C)C=C1 YLNWMQOPZKKAIQ-UHFFFAOYSA-N 0.000 claims description 2
- VNYKUPXVMBIHEO-UHFFFAOYSA-N [2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-4-methylpentyl]-[[4-[(3-fluorophenyl)methyl]phenyl]methyl]phosphinic acid Chemical compound C1=CC(CP(O)(=O)CC(CC(C)C)C(=O)NC(C(=O)NC)C(C)(C)C)=CC=C1CC1=CC=CC(F)=C1 VNYKUPXVMBIHEO-UHFFFAOYSA-N 0.000 claims description 2
- OWXGCYPTRHGHPT-UHFFFAOYSA-N [2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-4-methylpentyl]-[[4-[(4-fluorophenyl)methyl]phenyl]methyl]phosphinic acid Chemical compound C1=CC(CP(O)(=O)CC(CC(C)C)C(=O)NC(C(=O)NC)C(C)(C)C)=CC=C1CC1=CC=C(F)C=C1 OWXGCYPTRHGHPT-UHFFFAOYSA-N 0.000 claims description 2
- YQHBOKCURQRVCG-UHFFFAOYSA-N [2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-5,5,5-trifluoropentyl]-[[4-[(2-fluorophenyl)methyl]phenyl]methyl]phosphinic acid Chemical compound C1=CC(CP(O)(=O)CC(CCC(F)(F)F)C(=O)NC(C(=O)NC)C(C)(C)C)=CC=C1CC1=CC=CC=C1F YQHBOKCURQRVCG-UHFFFAOYSA-N 0.000 claims description 2
- BQHQFSSBHXZZQD-UHFFFAOYSA-N [4-(cyclohexylmethyl)phenyl]methyl-[2-[[3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-4-methylpentyl]phosphinic acid Chemical compound C1=CC(CP(O)(=O)CC(CC(C)C)C(=O)NC(C(=O)NC)C(C)(C)C)=CC=C1CC1CCCCC1 BQHQFSSBHXZZQD-UHFFFAOYSA-N 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- VWYWYCIQBGGPKK-UHFFFAOYSA-N benzyl-[2-[[3-(4-methoxyphenyl)-1-(methylamino)-1-oxopropan-2-yl]carbamoyl]-6-phenoxyhexyl]phosphinic acid Chemical compound C=1C=CC=CC=1OCCCCC(CP(O)(=O)CC=1C=CC=CC=1)C(=O)NC(C(=O)NC)CC1=CC=C(OC)C=C1 VWYWYCIQBGGPKK-UHFFFAOYSA-N 0.000 claims description 2
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000004437 phosphorous atom Chemical group 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
- 108060005980 Collagenase Proteins 0.000 description 17
- 102000029816 Collagenase Human genes 0.000 description 17
- 229960002424 collagenase Drugs 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 239000000758 substrate Substances 0.000 description 14
- 229910052717 sulfur Inorganic materials 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
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- 239000011541 reaction mixture Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
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- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 7
- 102000004142 Trypsin Human genes 0.000 description 7
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- 239000000010 aprotic solvent Substances 0.000 description 7
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- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 description 6
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
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- XZIHYPJFCNCLDP-UHFFFAOYSA-N 1-benzyl-4-(bromomethyl)benzene Chemical compound C1=CC(CBr)=CC=C1CC1=CC=CC=C1 XZIHYPJFCNCLDP-UHFFFAOYSA-N 0.000 description 3
- ARLZJQLYNLYIRF-UHFFFAOYSA-N 2-[[(3-aminophenyl)methyl-methoxyphosphoryl]methyl]-n-[3-(4-methoxyphenyl)-1-(methylamino)-1-oxopropan-2-yl]-4-methylpentanamide Chemical compound C=1C=CC(N)=CC=1CP(=O)(OC)CC(CC(C)C)C(=O)NC(C(=O)NC)CC1=CC=C(OC)C=C1 ARLZJQLYNLYIRF-UHFFFAOYSA-N 0.000 description 3
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
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- 239000011707 mineral Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- JBPFKDKEKCXAPN-UHFFFAOYSA-N n,n-diethyl-2-(propyliminomethylideneamino)ethanamine;hydrochloride Chemical compound Cl.CCCN=C=NCCN(CC)CC JBPFKDKEKCXAPN-UHFFFAOYSA-N 0.000 description 1
- DDEHDRBJXWPVCW-UHFFFAOYSA-N n-[3-(4-methoxyphenyl)-1-(methylamino)-1-oxopropan-2-yl]-2-[[methoxy-[[3-[(2,2,2-trifluoroacetyl)amino]phenyl]methyl]phosphoryl]methyl]-4-methylpentanamide Chemical compound C=1C=CC(NC(=O)C(F)(F)F)=CC=1CP(=O)(OC)CC(CC(C)C)C(=O)NC(C(=O)NC)CC1=CC=C(OC)C=C1 DDEHDRBJXWPVCW-UHFFFAOYSA-N 0.000 description 1
- LMOIFBLHHSUDGN-UHFFFAOYSA-N n-[4-[[methoxy-[2-[[3-(4-methoxyphenyl)-1-(methylamino)-1-oxopropan-2-yl]carbamoyl]-4-methylpentyl]phosphoryl]methyl]phenyl]benzamide Chemical compound C=1C=C(NC(=O)C=2C=CC=CC=2)C=CC=1CP(=O)(OC)CC(CC(C)C)C(=O)NC(C(=O)NC)CC1=CC=C(OC)C=C1 LMOIFBLHHSUDGN-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108010052605 prostromelysin Proteins 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- DRDCQJADRSJFFD-UHFFFAOYSA-N tris-hydroxymethyl-methyl-ammonium Chemical class OC[N+](C)(CO)CO DRDCQJADRSJFFD-UHFFFAOYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
- C07F9/306—Arylalkanephosphinic acids, e.g. Ar-(CH2)n-P(=X)(R)(XH), (X = O,S, Se; n>=1)
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- C—CHEMISTRY; METALLURGY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65525—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring
- C07F9/65527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring condensed with carbocyclic rings or carbocyclic ring systems
Description
Stanje thenike
Opisani izum odnosi se na derivate na bazi fosfinata koji su inhibitori matričnih metaloproteinaza ili faktora tumorne nekroze (TNF), i kao takvi su primjenjivi u tretiranju stanja odabranog iz grupe koju čine artritis, karcinom, tkivna ulceracija, restenozis, periodontalno oboljenje, epidermolizis bulosa, skleritis i druga oboljenja koja su okarakterizirana pomoću matrične metaloproteinazne aktivnosti, AIDS, sepsis, sepstički šok i druga oboljenja koja obuhvaćaju proizvodnju TNF-a. Dodatno, spojevi opisanog izuma mogu se koristiti u kombiniranoj terapiji sa standardnim ne-steroidnim anti-inflamatornim lijekovima (ovdje kasnije označenim NSAID'S) i analgeticima, i u kombinaciji sa citotoksičnim lijekovima, takvim kao što su daunomicin, cis-platinim, etopozid, taksol, taksoter i drugi alkaloidi, takvi kao što su vinkristin, u tretiranju karcinoma.
Ovaj izum se također odnosi na postupak koji koristi takve spojeve u tretiranju takvih oboljenja kod sisavaca, naročito kod ljudi, i na farmaceutske preparate koji se koriste u postupku tretiranja.
Postoje brojni enzimi koji utiču na raskidanje strukturnih proteina i koji su strukturno slični metaloproteazama. Matrične - degradirajuće metaloproteinaze, takve kao što su želatinaza, stromelizin i kolagenaza imaju učešća u tkivnoj matričnoj degradaciji (na primjer kolagenski kolaps) i učestvuju u mnogim patološkim stanjima koja obuhvaćaju nenormalno vezivno tkivo i bazni membranski matrični metabolizam, takav kao što je artritis (na primjer osteoartritis i reumatoidni artritis), tkivna ulceracija (na primjer kornealna, epidermalna i stomačna ulceracija), nenormalno zalječenje rana, periodontalno oboljenje, oboljenje kostiju (na primjer, Paget-ovo oboljenje i osteoporozis), metastaza ili invazija tumora, kao i HIV-infekcija (J. Leuk. Biol. 52 (2): 244 - 248, 1992).
Poznato je da faktor tumorne nekroze u mnogim infektivnim i autoimunim oboljenjima (W. Friers, FEBS Letters, 1991, 285, 199). Dalje, pokazano je da je TNF primarni uzročnik inflamatornog odgovora opaženog kod sepse i sepstičnog šoka (C. E. Spooner et al., Clinical Immunology and Immunopatholoy, 1992, 62 S 11).
Kratki pregled izuma
Opisani izum se odnosi na spoj formule I:
[image]
ili njegovu farmaceutski prihvatljivu sol, gdje
Ar je fenil, piridil, pirimidinil, pirazinil, piridazinil, tienil, furil, pirolil, oksazolil, tiazolil, izoksazolil, izotiazolil ili imadazolil;
R1 i R16 su svaki nezavisno vodik, (C1-C6) alkil, (trifluorometil)2 (C1-C6) alkil, perfluoro (C1-C6) alkil, perfluoro (C1-C6) alkil (C1-C6) alkil, difluorometoksi, trifluorometoksi, (C3-C7) cikloalkil (C1-C6) alkil, (C6-C10) aril
(C1-C6) alkil, (C6-C10) alriloksi (C1-C6) alkil ili (C6-C10) aril (C1-C6) alkoksi (C1-C6) alkil;
R2 je (C1-C6) alkil ili (C6-C10) aril (C1-C6) alkil po izboru supstituiran sa hidroksi, amino, halo, (C1-C6) alkil,
(C1-C6) alkoksi, (trifluorometil)2 (C1-C6) alkil, perfluoro (C1-C6) alkil, perfluoro (C1-C6) alkil (C1-C6) alkil, difluorometoksi, trifluorometoksi, karboksi ili karboksamoil grupom;
R3 je (C1-C6) alkil ili (C6-C10) aril;
R4 je vodik, (C1-C6) alkil, (C1-C6) alkoksi, (C3-C7) cikloalkil (C1-C6) alkil, (C1-C6) alkilsulfonil, (C6-C10) aril, (C6-C10) ariloksi, (C6-C10) arilsulfonil, (C6-C10) aril (C1-C6) alkil, (C6-C10) aril (C1-C6) alkoksi, (C6-C10) aril
(C1-C6) alkilsulfonil, N-ftalimido, (C6-C10) aril NHCO, (C6-C10) aril NHSO2, R7OOC, R7R8NCO, R7R8NSO2 gdje su R7 i R8 svaki nezavisno vodik, (C1-C6) alkil ili (C6-C10) aril (C1-C6) alkil; (C1-C6) alkil CR9R10, (C6-C10) aril CR9R10, (C6-C10) aril (C1-C6) alkil CR9R10 gdje su R9 i R10 svaki nezavisno fluoro, (C1-C6) alkil ili (C1-C6) alkoksi; ili
R9 i R10 mogu biti uzeti zajedno sa ugljikom na koji su vezani radi formiranja grupe formule:
[image]
gdje
a je 0, 1 ili 2; b je 0 ili l; c je1, 2 ili 3; d je 0 ili 1; e je 0, 1 ili 2;
R5 i R6 su svaki nezavisno vodik, (C1-C6) alkil, (C1-C6) alkoksi, halo, (trifluorometil)2 (C1-C6) alkil, perfluoro (C1-C6) alkil, perfluoro (C1-C6) alkil (C1-C6) alkil, difluorometoksi, trifluorometoksi, (C1-C6) alkiltio, (C1-C6) alkilsulfinil ili (C1-C6) alkilsulfonil ; ili
R1 i R16 mogu biti uzeti zajedno sa ugljikom na koji su vezani radi formiranja (C1-C6) cikloalkil grupe koja je po izboru supstituirana sa (C1-C6) alkil, (C1-C6) alkoksi, (C6-C10) aril (C1-C6) alkil, (C6-C10) aril (C1-C6) alkil ili
(C6-C10) ariloksi grupom; ili
R5 i R6, kada su pripojeni na susedne ugljične položaje, mogu biti uzeti zajedno radi formiranja grupe formule:
[image]
gdje isprekidane linije predstavljaju po izboru dvostruke veze;
h je 1 ili 2;
f i g su svaki nezavisno 0, 1 ili 2;
Y i Z su svaki nezavisno CH2, O, CO, SO2, CH2CH2, CH2O, CH2S, CH2NH, CH2CO, CH2SO2, NHCO ili NHSO2; i
R11 je vodik, halo, (C1-C6) alkil, (C1-C6) alkoksi, (trifluorometil)2 (C1-C6) alkil, perfluoro (C1-C6) alkil, perfluoro (C1-C6) alkil (C1-C6) alkil, difluorometoksi ili trifluorometoksi;
uz ograničenje da kada jedan između a i e je 0, onaj drugi mora biti 1 ; uz ograničenje da kada b i d su 1, zbroj a, c i e ne može biti 5, 6 ili 7 ; uz ograničenje da kada b i d su 0, zbroj a, c i e ne može biti 7; uz ograničenje da metilenski ugljik spojen na atom fosfora mora biti spojen na ugljični atom Ar-prstena; i uz ograničenje da R5 i R6 moraju biti pripojeni na atome ugljika na Ar-prstenu.
Termin "alkil" kako je ovdje korišten, ako nije drugačije naglašeno, uključuje zasićene monovalentne ugljikovodične radikale koji imaju normalne, račvaste ili ciklične grupe ili njihove kombinacije.
Termin "alkoksi " kako je ovdje korišteno, uključuje O-alkil grupe gdje je "alkil " definiran naprijed.
Termin "aril" kako je ovdje korišteno, ako nije drugačije naglašeno, uključuje organski radikal izveden iz aromatičnog ugljika pomoću uklanjanja jednog vodika, takav kao fenil ili naftil, po izboru supstituiran sa 1 do 3 supstituenata odabranih iz grupe koju čine, fluoro, kloro, trifluorometil, (C1-C6) alkoksi, (C6-C10) ariloksi, trifluorometoksi, difluorometoksi i (C1-C6) alkil.
Spoj formule I može imati čiralne centre i stoga postoji u različitim enantiomernim oblicima. Ovaj izum se odnosi na sve optičke izomere i stereoizomere spojeva formule I, i na njihove smjese.
Poželjni spojevi formule I uključuju ona gdje je Ar fenil ili trienil.
Drugi poželjni spojevi formule I uključuju one gdje je R1 2-metilpropil, trifluorometil, ciklopropilmetil, ciklobutilmetil, fenoksibutil, cikloheksilmetil ili feniletil.
Drugi poželjni spojevi formule I uključuju ona gdje je R2 (C1-C6) alkil ili 4-metoksibenzil.
Drugi poželjni spojevi formule I uključuju ona gdje je R3 metil.
Drugi poželjni spojevi formule I uključuju ona gdje je R4 benzil, 2-klorobenzil, 2-fluorobenzil, 3-fluorobenzil ili 4-fluorobenzil.
Još poželjniji spojevi formule I uključuju ona gdje je Ar fenil ili tienil; R1 je 2- metilpropil, trifluorometiletil, ciklopropilmetil, ciklobutilmetil, fenoskibutil, cikloheksilmetil ili feniletil; R2 je (C1-C6) alkil ili 4-metoksibenzil; R3 je metil; i R4 je benzil, 2-klorobenzil, 2-fluorobenzil, 3-fluorobenzil ili 4-fluorobenzil.
Specifični poželjni spojevi formule I uključuju slijedeće spojeve:
(4-benzilbenzil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-fosfinska kiselina;
(4-benzilbenzil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-5, 5, 5-trifluoropentil]-fosfinska kiselina;
[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-[4-(3-fluorobenzil)-benzil]-fosfinska kiselina;
Benzil-{2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-6-fenoksiheksil}-fosfinska kiselina;
(4-benzilbenzil)-{2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-6-fenoksiheksil}-fosfinska kiselina;
(4-benzilbenzil)-{3-(cikloheksil-2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-propil}-fosfinska kiselina;
(4-benzilbenzil)-[3-cikloheksil-2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-propil]-fosfinska kiselina;
(4-benzilbenzil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-fenilbutil]-fosfinska kiselina;
(4-cikloheksilmetilbenzil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)4-metilpentil]-fosfinska kiselina;
[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-(4-izobutilbenzil)-fosfinska kiselina;
[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-[4-(4-fluorobenzil)-benzil]-fosfinska kiselina;
[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-[4-(2-fluorobenzil)-benzil]-fosfinska kiselina;
(4-benzilbenzil)-{2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metilpentil}-fosfinska kiselina;
[4-(2-klorobenzil)benzil]-[2-(2, 2-dimetil-1-metilkarbamoil-1-propilkarbamoil)-4-metilpentil]-fosfinska kiselina;
(5-benzil-piridin-2-ilmetil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-fosfinska kiselina;
[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-5,5,5-trifluoro-pentil]-[4-(2-fluoro-benzil)-benzil]-fosfinska kiselina;
[3-ciklopropil-2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-propil]-[4-(2-fluoro-benzil)-benzil]-fosfinska kiselina;
[3-ciklobutil-2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-propil]-[4-(2-fluoro-benzil)-benzil]-fosfinska kiselina; i
(5-benzil-tiofen-2-ilmetil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-fosfinska kiselina.
Opisani se izum također odnosi na farmaceutski preparat za (a) tretiranje stanja odabranog iz grupe koju čine artritis, karcinom, sinergija sa citotoksičnim antikarcinomnim agensima, tkivna ulceracija, makularna degeneracija, restenozis, periodontalno oboljenje, epidermolizis bulosa, skleritis u kombinaciji sa standardnim NSAIN'S i analgeticima i druga oboljenja koja su okarakterizirana pomoću matrične metaloproteinazne aktivnosti, AIDS, sepsa, septički šok i druga oboljenja koja obuhvaćaju proizvodnju faktora tumorne nekroze (TNF), ili (b) inhibiciju matričnih metaloproteinaza ili proizvodnje faktora tumorne nekroze (TNF) kod sisavaca, uključujući i ljude, koji obuhvaća količinu spoja formule I ili njegove farmaceutski prihvatljive soli efikasne u takvim tretmanima i farmaceutski prihvatljiv nosač.
Opisani se izum također odnosi na postupak za inhibiciju (a) matričnih metaloproteinaza, ili (b) proizvodnje faktora tumorne nekroze (TNF) kod sisavaca, uključujući i ljude, koji obuhvaća primjenu kod spomenutih sisavaca efikasne količine spoja formule I ili njegove farmaceutski prihvatljive soli.
Opisani izum također se odnosi na postupak za tretiranje stanja odabranog iz grupe koju čine artritis, karcinom, sinergija sa citotoksičnim antikarcinomnim agensima, tkivna ulceracija, makularna degeneracija, restenozis, periodontalno oboljenje, epidermolizis bulosa, skleritis u kombinaciji sa standardnim NSAIN'S i analgetiicima i druga oboljenja koja su okarakterizirana pomoću matrične metaloproteinazne aktivnosti, AIDS, sepsa, septički šok i druga oboljenja koja obuhvaćaju proizvodnju faktora tumorne nekroze (TNF) kod sisavaca, uključujući i ljude, koji obuhvaća primjenu kod spomenutih sisavaca količine spoja formule I ili njegove farmaceutski prihvatljive soli efikasne u tretiranju takvog stanja.
Detaljni opis izuma
Slijedeće reakcijske sheme ilustriraju dobivanje spoja opisanog izuma. Ako nije drugačije naglašeno R1, R2, R3, R4, R5, R6 i Ar u reakcijskim shemama i diskusiji koja slijedi su kao što je definirano naprijed.
Shema 1
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Shema 2
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U reakcijskoj shemi 1, spoj formule VI prevodi se u odgovarajuću (2-benziloksikarbonil)-fosfinsku kiselinu, spoj formule V pomoću reagiranja spoja VI sa bis-trimetilsililfosfonitom u aprotičnom rastvaraču, takvom kao što je metilen klorid. Reakcijska smjesa se miješa na sobnoj temperaturi tokom vremenskog perioda između oko 8 sati do oko 48 sati, poželjno oko 18 sati.
U reakcijskoj shemi 1, spoj formule V prevodi se u odgovarajući spoj formule IV pomoću reagiranja spoja V sa arilmetilhalidom formule:
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i N,O-bis(trimetilsilil)acetamidom u inertnom aprotičnom rastvaraču, takvom kao što je metilen klorid. Reakcijska smjesa se miješa na sobnoj temperaturi ili se zagrijava na refluksoru tokom vremenskog perioda između oko 18 sati i oko 72 sata, poželjno oko 24 sati. Višak trimetilsilildiazometana u smjesi pri odnosu 7:3 toluena i metanola tada se doda tako izgrađenom sirovom reakcijskom proizvodu tokom vremenskog perioda između oko 15 minuta i oko 2 sata, poželjno oko 30 minuta.
U reakciji 3 sheme 1, spoj formule IV prevodi se u odgovarajući spoj formule III pomoću (1) hidrogenacije spoja formule IV u prisustvu katalizatora, takvog kao što je 5 % paladija na barij sulfatu i protičnog rastvarača, takvog kao što je metanol, pod pritiskom između oko 30 psiga do oko 60 psiga, poželjno oko 45 psiga, tokom vremenskog perioda između oko 15 minuta i oko 3 sata, poželjno oko 1 sata, (2) reagiranja intermedijera tako izgrađenog sa hidroksisukcinimidom i 2-dietilaminoetil propil karbodiimid hidrokloridom u polarnom aprotičnom rastvaraču, takvom kao što je dimetilformamid, na sobnoj temperaturi, tokom vremenskog perioda između oko 8 sati i oko 48 sati, poželjno oko 20 sati, i (3) reagiranja 2,5-dioksopirolidin-1-il intermedijera tako izgrađenog sa aminom formule :
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U aprotičnom rastvaraču, takvom kao što je metilen klorid, na sobnoj temperaturi, tokom vremenskog perioda između oko 16 sati i oko 48 sati, poželjno 18 sati.
U reakciji 4 sheme 1, spoj formule III prevodi se u odgovarajući spoj formule I pomoću tretiranja spoja formule III sa 10 %-tnim vodenim rastvorom trifluorooctetne kiseline. Reakcijska smjesa se miješa na sobnoj temperaturi, tokom vremenskog perioda između oko 30 minuta i oko 24 sata, poželjno oko 2 sata.
Shema 2 predstavlja alternativni postupak za dobivanje spoja formule IV.
U reakciji 1 sheme 2, spoj formule V prevodi se u odgovarajući spoj formule VIII pomoću reagiranja spoja V sa 2-(trimetilsilil) etoksimetil kloridom i N,O-bis(trimetilsilil) acetamidom u inertnom aprotičnom rastvaraču, takvom kao što je metilen klorid. Reakcijska smjesa miješa se na temperaturi između oko 20 °C do oko 40 °C, poželjno oko 25 °C, tokom vremenskog perioda između oko 8 sati do oko 48 sati, poželjno oko 18 sati. Višak trimetilsilildiazometana u smjesi pri odnosu 7:3 toluen : metanol, tada se doda tako formiranom reakcijskom proizvodu.
U reakciji 2, sheme 2, spoj formule VIII prevodi se u odgovarajući spoj formule VII pomoću reagiranja spoja VIII sa bor trifluorid dietil eteratom u inertnom aprotičnom rastvaraču, takvom kao što je metilen klorid. Reakcijska smjesa se miješa na temperaturi između oko 0 °C do oko 40 °C, poželjno oko 25 °C, tokom vremenskog perioda između oko 1 sata do oko 8 sati, poželjno oko 3 sata.
U reakciji 3 sheme 2, spoj formule VII prevodi se u odgovarajući spoj formule VI pomoću reagiranja spoja VII sa ugljen tetrabromidom u prisustvu trifenilfosfina i dietil azodikarboksilata u inertnom aprotičnom rastvaraču, takvom kao što je metilen klorid. Reakcijska smjesa miješa se na temperaturi između oko 0 °C i oko 40 °C, poželjno oko 25 °C, tokom vremenskog perioda između oko 2 sata i oko 24 sata, poželjno oko 4 sata.
U reakcijskoj shemi 2, spoj formule VI prevodi se u odgovarajući spoj formule IV pomoću reagiranja spoja VI sa arilhalidom formule:
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gdje je X bromo ili jodo u prisustvu n-butil litija i bakar(1) jodida u inertnom aprotičnom rastvaraču, takvom kao što je tetrahidrofuran. Reakcijska smjesa miješa se na temperaturi između oko -70 °C do oko 60 °C, poželjno oko 0 °C, tokom vremenskog perioda između oko 1 sata do oko 48 sati, poželjno oko 18 sati.
Farmaceutski prihvatljive soli kiselinskih spojeva izuma su soli izgrađene sa bazama, uglavnom kationske soli takve kao što su soli alkalnih i zemnoalkalnih metala, takvih kao što su natrij, litij, kalij, kalcij, magnezij kao i amonijeve soli, takve kao što su amonij, trimetil amonij, dietilamonij i tris-(hidroksimetil)-metilamonij soli.
Slično, kiselinske adicijske soli, takve kao što su soli mineralnih kiselina, organskih karboksilnih i organskih sulfonskih kiselina, na primjer, klorovodične kiseline, metansulfonske kiseline, maleinske kiseline, također je moguće da sadrže baznu grupu, takvu kao što je piridil kao sastavni dio strukture.
Sposobnost spojeva formule I ili njihovih farmaceutski prihvatljivih soli (ovdje kasnije označenih kao spojeva opisanog izuma) da inhibiraju matrične mettaloproteinaze ili proizvodnju faktora tumorne nekroze (TNF) i stoga, pokažu svoju efikasnost za tretiranje oboljenja koja su okaraktarizirana pomoću matrične metaloproetinaze ili proizvodnje faktora tumorne nekroze prikazana je pomoću slijedećih in vitro testova ispitivanja.
BIOLOŠKO ISPITIVANJE
Inhibicija humane kolagenaze (MMP-1)
Humana rekombinantna kolagenaza aktivira se sa tripsinom uz korištenje slijedećeg odnosa: 10 µg tripsina na 100 g kolagenaze. Tripsin i kolagenaza inkubiraju se na sobnoj temperaturi tokom 10 minuta i tada se doda petostruki višak (50 µg/10 µg trispina) tripsinskog inhibitora soje.
10 mM rastvori podloge inhibitora izgrade se u dimetil sulfoskidu i tada se razblaže uz korištenje slijedeće sheme:
10 mM � 120µM � 12µM � 1,2µM � 0,12µM
Dvadeset pet mikrolitara svake koncentracije tada se doda u triplikatu u odgovarajuća okna mikrofluorne ploče od 96 okana. Konačna koncentracija inhibitora biti će 1:4 razblažena poslije dodavanja enzima i supstrata. Pozitivne kontrole (enzim, bez inhibitora) postave se u okna D1 - D6 a slijepe se probe (bez enzima, bez inhibitora) postave u okna D7 - D12.
Kolagenaza se razblaži do 400 ng/ml i tada se doda 25 µl u odgovarajuća okna mikrofluorne ploče. Konačna koncentracija kolagenaze u ispitiavnju je 100 ng/ml.
Supstrat (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) napravi se kao 5 mM podloga u dimetil sulfoksidu, i tada se razblaži do 20 µM u spremniku za ispitivanje. Ispitivanje otpočinje pomoću dodavanja 50 µl supstrata po oknu mikrofluorne ploče radi dobivanja konačne koncentracije od 10 µM.
Očitavanja fluorescencije (360 nm ekscitacija, 460 nm emisija) vrše se u vremenu 0 i zatim na 20 minutnim intervalima. Ispitivanje se vrši na sobnoj temperaturi sa vremenom trajanja ispitivanja od obično 3 sata.
Fluorescencija prema vremenu tada se prikaže za slijepe probe i uzorke koji sadrže kolagenazu (podaci iz triplikatnih određivanja se uzimaju kao prosječne vrijednosti). Vremenska točka koja daje dobar signal (slijepa proba) i ona na linearnom dijelu krivulje (obično na oko 120 minuta) odabrane su za određivanje IC50 vrijednosti. Vrijeme nula se koristi kao slijepa proba za svaki spoj na svakoj koncentraciji i ove vrijednosti se oduzimaju od podataka za 120 minuta. Podaci se prikazuju kao koncentracija inhibitora prema postotku kontrole (inhibitorska fluorescencija podijeljena sa fluorescencijom same kolagenaze � 100). IC50 vrijednosti određuju se iz koncentracije inhibitora koja daje signal koji je 50 % kontrolnog.
Ako se pokaže da su IC50 vrijednosti manje od 0,03 µM, tada se inhibitori ispituju pri koncentracijama od 0,3 µM, 0,03 µM i 0,003 µM.
Inhibicija želatinaze (MMP-2)
Inhibicija želatinazne aktivnosti vrši se uz korištenje Dnp-Pro-Cha-Gly-Cys(Me)His-Ala-Lys(NMA)-NH2 supstrata (10 µM) pod istim uvjetima kao inhibicija humane kolagenaze (MMP-1).
72 kD želatinaza aktivira se sa 1 mM APMA (p-aminofenil merkuri acetatom) tokom 15 sati na 4 °C i razblaži se radi dobivanja konačne koncentracije pri ispitivanju od 100 ng/ml. Inhibitori se razblaže kao za inhibiciju humane kolagenaze (MMP-1) radi dobivanja konačnih koncentracija u ispitivanju od 30 µM, 3 µM, 0,3 µM i 0,03 µM. Svaka se koncentracija korsiti u triplikatu.
Očitavanja fluorescencije (360 nm ekscitacija, 460 nm emisija) vrše se u vremenu 0 i zatim na 20 minutnim intervalima tokom 4 sata.
IC50 vrijednosti određuju se kao za inhibiciju humane kolagenaze (MMP-1). Ako se pokaže da su IC50 vrijednosti manje od 0,03 µM, tada se inhibitori ispituju pri koncentracijama od 0,3 µM, 0,03 µM i 0,003 µM.
Inhibicija stromelizinske aktivnosti (MMP-3)
Inhibicija stromelizinske aktivnosti je bazirana na modificiranom spektrofotometrijskom ispitivanju koje su opisali Weingarten H. i Feder J., Spectrophotometric Assay for Vertebrate Collagenase, Anal. Biochem. 147, 437- 440 (1985). Hidroliza tio peptolidnog supstrata [Ac-Pro-Leu-Gly-SCH[CH2CH(CH3)2]CO-Leu-Gly-OC2H2]daje merkaptanski fragment koji može biti praćen u prisustvu Ellman-ovog reagensa.
Humani rekombinantni prostromelizin aktivira se sa tripsinom uz korištenje slijedećeg odnosa: 1 µg od 10 mg/ml trpsinske podloge na 26 µg stromelizina. Tripsin i stromelizin inkubiraju se na 37 °C tokom 15 minuta, što je praćeno inkubiranjem 10 µl od 10 mg/ml tripsinskog inhibitora tokom 10 minuta na 37 °C, radi zaustavljanja tripsinske aktivnosti.
Ispitivanja se vrše u spremniku za ispitivanje ukupnog volumena od 250 µl (200 mM natrij klorida, 50 mM MES i 10 mM kalcij klorida, pH 6,0) u mikrolitarskim pločama sa 96 okana. Aktivirani stromelizin razblaži se u spremniku za ispitivanje do 25 µg/ml. Ellman-ov reagens (3-karboksi-4-nitrofenil disulfid) pravi se kao 1M podloga u dimetil formamidu i razblaži se do 5 mM u spremniku za ispitivanje sa 50 µl po oknu, radi dobivanja 1 mM konačne koncentracije.
10 mM rastvori podloge izgrade se u dimetil sulfoksidu i serijski se razblaže u spremniku za ispitivanje, tako da dodavanje 50 µL u odgovarajuća okna daje konačne koncentracije od 0,3 µM, 0,3 µM, 0,003 µuM i 0,0003 µM. Sve se radi u triplikatu.
300 mM dimetil sulfoksidni rastvor podloge peptidnog supstarta razblaži se do 15 mM u spremniku za ispitivanje i ispitivanje počinje sa dodavanjem 50 µl u svako okno radi postizanja konačne koncentracije od 3 mM supstrata. Slijepe probe sadrže peptidni supstrat i Ellman-ov rastvor bez enzima. Formiranje proizvoda prati se na 405 nm sa Molecular Devices UVmax čitačem ploča.
IC50 vrijednosti određuju se na isti način kao za kolagenazu.
Inhibicija MMP-13
Humani rekombinantni MMP-13 aktivira se sa 2mM APMA-om (p-aminofenil merkuri acetat) tokom 1,5 sata na 37 °C i razblaži se do 400 ng/ml u spremniku za ispitivanje (50 mM Tris, pH 7,5, 200 mM natrij klorid, 5 mM kalicij klorid, 20 µM cink klorid, 0,02 % brij-a). Pri ispitivanju enzim se razblaži u odnosu 1:4 pomoću dodavanja inhibitora i supstrata radi dobivanja konačne koncentracije za ispitivanje od 100 ng/ml.
10 mM rastvori podloge inhibitora izgrade se u dimetil sulfoksidu i tada se razblaže u spremniku za ispitivanje kao po navedenoj shemi za razblaživanje inhibitora za inhibiciju humane kolagenaze (MMP-1). Dvadeset pet mikrolitara svake koncentracije doda se u triplikatu na mikrofluornu ploču. Konačne koncentracije pri ispitivanju su 30 µM, 3µM, 0,3 µM i 0,03 µM.
Supstrat (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) pripremi se kao za inhibiciju humane kolagenaze (MMP-1) i svakom oknu se doda 50 µl radi dobivanja konačne koncentracije za ispitivanje od 10 µM. Očitavanja fluorescencije (360 nm ekscitacija; 450 nm emisija) tada se vrše u vremenu 0 i zatim na svakih 5 minuta tokom 1 sata.
Pozitivne kontrole sadrže enzim i supstrat bez inhibitora, a slijepe probe sadrže samo supstrat.
IC50 vrijednosti određuju se kao za inhibiciju humane kolagenaze (MMP-1). Ako se pokaže da su IC50 vrijednosti manje od 0,03 µM, inhibitori se tada ispituju pri koncentracijama od 0,3 µM, 0,03 µM, 003 µM i 0,0003 µM.
Inhibicija proizvodnje TNF
Sposobnost spojeva ili njegovih farmaceutski prihvatljivih soli da inhibiraju proizvodnju TNF i stoga, pokazivanja njihove efikasnosti za tretiranje oboljenja koja obuhvaćaju proizvodnju TNF, pokazana je pomoću slijedećeg in vitro ispitivanja.
Humane mononuklearne ćelije se izoliraju iz anti-koagulirane humane krvi uz korištenje jednostupanjske Ficoll-hypaque tehnike. (2) Humane mononuklearne ćelije se isperu tri puta u Hanks-ovom ravnotežnom rastvoru soli (HBSS) sa dvovalentnim kationima i resuspendiraju se do gustoće od 2 � 106 ćelija/ml u HBSS koji sadrži 1 % BSA. Diferencijalni brojevi se određuju uz korištenje Abbot Cell Dyn 3500 analizatora. Na ovaj način pokazano je da monociti čine od 17 do 24 % svih ćelija u ovim preparatima.
180 µl ćelijske suspenzije izdvoji se na ravno dno ploča sa 96 okana (Costar). Dodavanja spoja i LPS (100 ng/ml konačne koncentracije) daje konačni volumen od 200 µl. Sve se ponavlja u triplikatu. Poslije četiri sata inkubacije na 37 °C u vlažnom CO2 inkubatoru, ploče se uklone i centrifugiraju (10 minuta na oko 250 � g) i supernatanti se uklone i ispituju na TNF� uz korištenje opreme R&D ELISA Kit.
Za primjenu kod sisavaca, uključujući i ljude, za inhibiciju matričnih metaloproteinaza ili inhibiciju proizvodnje faktora tumorne nekroze (TNF), mogu se koristiti razni uobičajeni načini primjene uključujući oralni, parenteralni i topikalni. Općenito, aktivni spoj biti će primjenjivan oralno i pareneteralno pri dozama između oko 0,1 i 25 mg/kg tjelesne mase subjekta koji se tretira na dan, poželjno od oko 0,3 do 5 mg/kg. Međutim, izvjesno variranje u dozi biti će potrebno izvesti zavisno od stanja subjekta koji se tretira. Osoba odgovorna za primjenu, u svakom će slučaju odrediti odgovarajuću dozu za svaki individualni subjekt.
Spojevi opisanog izuma mogu se primjenjivati u širokom varijetetu različitih doznih oblika. Općenito, terapeutski efikasni spojevi ovog izuma prisutni su u takvim doznim oblicima pri koncentracijskim nivoima koji idu od oko 5,0 do oko 70 masenih postotaka.
Za oralnu primjenu, tablete koje sadrže različite ekscipijente, takve kao što su mikrokristalna celuloza, natrij citrat, kalcij karbonat, dikalcij fosfat i glicin mogu se koristiti zajedno sa različitim dizintegrantima, takvim kao što su škrob (i poželjno škrob kukuruza, krompira ili tapioke), alginska kiselina i izvjesni kompleksni silikati, zajedno sa granulacijskim vezivima, takvim kao što su polivinilpirolidon, saharoza, želatina i akacija. Dodatno agensi za podmazivanje, takvi kao što su magnezij stearat, natrij lauril sulfat i talk, često su vrlo korisni za svrhe tabletiranja. Čvrsti preparati sličnog tipa mogu se također koristiti kao punila u želatinskim kapsulama; poželjni materijali u vezi sa ovim također uključuju laktozu ili mliječni šećer, isto kao i polietilen glikole visoke molekulske mase. Kada se žele vodene suspenzije i/ili eliksiri za oralnu primjenu, aktivni sastojak može biti sjedinjen sa različitim agensima za ukus ili zaslađivanje, sa obojenim materijama ili bojama, i (ako se želi) emulgirajućim i/ili suspendirajućim agensima, zajedno sa takvim razblaživačima kao što su voda, etanol, propilen glikol, glicerin i njihove različite kombinacije. U slučaju primjene kod životinja, prikladno je da budu sadržani u hrani za životinje ili pijućoj vodi u koncentraciji od 5 do 5000 ppm, poželjno 25 do 500 ppm.
Za parenteralnu primjenu, na primjer, za intramuskularno, intraperitonelno, podkožno i intarvensko korištenje, obično se priprema sterilni injektibilni rastvor aktivnog sastojka. Rastvori terapeutskog spoja opisanog izuma bilo u sezamovom bilo u ulju kikirikija ili vodenom propilen glikolu mogu se koristiti. Vodeni rastvori trebaju biti prikladno podešeni i spremljeni, poželjno na pH vrijednost veću od 8, i ako je potrebno tekući razblaživač prvo treba osigurati izotoničnost sa krvlju ovih rastvora. Ovi vodeni rastvori prikladni su za svrhe intravenskog injektiranja. Uljani rastvori prikladni su za svrhe intrazglobnog, intramuskularnog i potkožnog injektiranja. Dobivanje svih ovih rastvora pod sterilnim uvjetima lako se postiže pomoću standardnih farmaceutskih tehnika, koje su dobro poznate stručnjacima u ovoj oblasti tehnike. U slučaju životinja, spojevi se mogu primjenjivati intramuskularno ili potkožno pri doznim nivoima od oko 0,1 do 50 mg/kg/dan, prikladno od 0,2 do 10 mg/kg/dan u jednoj dozi ili podijeljeno u do tri doze na dan.
Opisani izum je ilustriran pomoću slijedećih primjera, ali nije ograničen na njihove detalje.
Primjer 1
S,S i R,S (4-benzilbenzil)[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-fosfinska kiselina
Stupanj A: 4-benzilbenzil bromid (2,75 grama, 10,0 mmola) i trietilsilan (2,33 grama, 20 mmola) u trifluorooctetnoj kiselini (4,56 grama, 40 mmola) zagrijavaju se na 60 °C tokom 18 sati. Ohlađena se smjesa razblaži sa etil acetatom (50 ml) i pažljivo ispere sa zasićenim rastvorom natrij bikarbonata (2 � 50 ml). Poslije sušenja sa magnezij sulfatom, ekstrakt se profiltrira i koncentrira. Ostatak se kromatografira (0,5:99,5 do 2:98 - etil acetat : heksan) radi dobivanja 1,37 grama (52 %) 4-benzilbenzil bromida u obliku bezbojnog ulja.
Stupanj B: (2-benziloksikarbonil-4-metilpentil)-fosfinska kiselina (1,14 grama, 4,0 mmola), 4-benzilbenzil bromid (1,31 grama, 5,0 mmola) i N,O-bis(trimetilsilil) acetamid (2,44 grama, 12 mmola) sjedine se u suhom metilen kloridu (40 ml). Smjesa se degazira sa strujom suhog dušika, tada se miješa na sobnoj temperaturi tokom 18 sati i refluksira se tokom 24 sata. Ohlađen rastvor tretira se radi zaustavljanja reakcije sa 1N klorovodičnom kiselinom (25 ml). Metilen kloridni sloj se odvoji i ispere sa 1N klorovodičnom kiselinom (2 � 25 ml), osuši se sa magnezij sulfatom, profiltrira i koncentrira do dobivanja zamućenog ulja. Ovo se rastvori u smjesi metanol (10 ml) / toluen (40 ml) i tretira se sa viškom trimetilsilildiazometana (komercijalni heksanski rastvor). Poslije 30 minuta višak trimetilsilil-diazo-metana se razloži sa octenom kiselinom. Rastvor se koncentrira do ulja koje se kromatografira (75:25 - etil acetat : heksan) radi dobivanja 1,18 grama (62 %) benzil estra 2-[(4-benzi)metoksi-fosfinoilmetil]-4-metilpentanoinske kiseline u obliku bezbojnog ulja.
Stupanj C: Benzil estar 2-[(4-benzilbenzil)metoksi-fosfinoilmetil]-4- metilpentanoinske kiseline (650 mg, 1,36 mmola) hidrogenizira se na 45 psiga na sobnoj temperaturi u metanolu (50 ml) iznad 5 % paladija na barij sulfatu (650 mg) tokom 1 sata. Katalizator se odfiltrira i ispere sa metanolom. Filtrat se koncentrira i tragovi metanola se uklone pomoću dvostrukog razblaživanja uzorka sa metilen kloridom i re-koncentriranja. Intermedijerna 2-[(4-benzilbenzil)metoksi-fosfinoilmetil]-4-metilenpentanoinska kiselina rastvori se u suhom dimetilformamidu (14 ml) i hidroksisukcinamidu (235 mg, 2,04 mmola) i doda se dimetilaminopropiletilkarbodiimid hidroklorid (391 mg, 2,04 mmola). Poslije miješanja na sobnoj temperaturi tokom 20 sati, rastvor se razblaži sa etrom (50 ml) i ispere sa 1N klorovodičnom kiselinom (50 ml, 2 � 25 ml) i zasićenim rastvorom natrij bikarbonata (25 ml) i osuši se sa magnezij sulfatom. Poslije filtracije i koncentriranja dobiva se 566 mg (86%) 2,5-diokso-pirolidin-1-il estra 2-[(4-benzilbenzil)metoksi-fosfinoilmetil]-4-metilpentanoinske kiseline u obliku ulja.
Stupanj D: 2,5-diokso-pirolidin-1-il estar 2-[(4-benzilbenzil)metoksi-fosfinoilmetil]4-metilpentanoinske kiseline (120 mg, 0,25 mmola), (S)-2-amino-3,3-N-trimetilbutiramid hidroklorid (25 mg, 0,30 mmola) i diizopropiletilamin (39 mg, 0,30 mmola) sjedine se i miješaju zajedno tokom 18 sati na sobnoj temperaturi u suhom metilen kloridu (10 ml). Dodatno (S)-2-amino-3,3-N-trimetil-butiramid hidroklorid (25 mg, 0,30 mmola) i diizopropiletilamin (39 mg, 0,30 mmola) dodaju se reakcijskoj smjesi. Poslije četiri dana, rastvor se ispere sa IN klorovodičnom kiselinom (2 � 10 ml) sa zasićenim rastvorom natrij bikarbonata (2 � 10 ml) i osuši se sa magnezij sulfatom. Poslije filtriranja i koncentriranja ostatak se kromatografira (3:97 - metanol : kloroform) radi dobivanja 77 mg (60 %) metil estra (4-benzilbenzil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-fosfinske kiseline.
Stupanj E: Metil estar (4-benzilbenzil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-fosfinske kiseline (77 mg, 0,15 mmola) rastvori se u 10 %-tnom vodenom rastvoru trifluorooctene kiseline (6 ml). Poslije 4 sata na sobnoj temperaturi, reakcijska smjesa se koncentrira. Zaostala voda se ukloni pomoću dvostrukog razblaživanja sa toluenom i re-koncentrira radi dobivanja 75 mg (100%) spoja iz naslova u obliku tvrdog stakla koje je bilo 63:37 smjesa S,S i R,S izomera, po istom redoslijedu. Maseni spektar m/e: M+ + 1501, M+ + Na+ 523, M+ + K+ 540, M+ + 2Na+ 555. HPLC retencijska vremena: 13,00/15,90 minute.
Spojevi u tablicama 1 - 4 dobiveni su pomoću postupka analognog onom opisanom u primjeru 1.
Tablica 1
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Tablica 2
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Tablica 3
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Tablica 4
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Primjer 65
S, S i R, S (4-benzoilaminobenzil)-{2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metilpentil}fosfinska kiselina
Stupanj A: Benzil estar 2-[metoksi-(4-nitrobenzil)-fosfinoilmetil]-4-metilpentanoinske kiseline (dobiven iz 4-nitrobenzil bromida i (2-benziloksikrabonil-4-metilpentil)-fosfinske kiseline pomoću procedure opisane u primjeru 1, Stupanj B) (900 mg, 2,08 mmola) u smjesi etanola (25 ml) i vode (6 ml) tretira se sa koncentriranom klorovodičnom kiselinom (tri kapi) i željeznim prahom (1,14 grama, 20 mmola) na refluksoru. Poslije dva sata ohlađena smjesa se profiltrira kroz diatomejsku zemlju. Filtrat se koncentrira i ostatak se kromatografira (etil acetat) radi dobivanja 444 mg (53 %) benzil estra 2-[(4-aminobenzil)metoksi-fosfinoilmetil]-4-metilpentanoisnke kiseline kao žuto ulje.
Stupanj B. Benzil estar 2-[(4-aminobenzil)metoksi-fosfinoilmetil]-4-metilpentanoinske kiseline (230 mg, 0,57 mmola), benzoil klorid (96 mg, 0,68 mmola) i trietilamin (69 mg, 0,68 mmola) sjedine se u hladnom (ledena kupka) kloroformu (10 ml). Poslije miješanja tokom 1 sata na temperaturi ledene kupke, reakcijska smjesa se razblaži sa kloroformom (150 ml) i ispere se sa vodom (20 ml), 1N klorovodičnom kiselinom (2 � 20 ml) i zasićenim rastvorom natrij bikarbonata (2 � 20 ml) i osuši se sa magnezij sulfatom. Poslije filtriranja i koncentriranja žuti ostatak se kromatografira (etil acetat) radi dobivanja 190 mg (66 %) benzil estra 2-[(4-benzoilaminobenzil)metoksi-fosfinoilmetil]-4-metilpentanoinske kiseline u obliku blago žutog ulja.
Stupanj C: Benzil estar 2-[(4-benzoilaminobenzil)metoksi-fosfinoilmetil]-4-metilpentanoinske kiseline (226 mg, 0,44 mmola) hidrogenizira se na pritisku od 50 psiga na sobnoj temperaturi u metanolu (20 ml) preko 5 % paladija na ugljiku (300 mg) tokom dva sata. Katalizator se odfiltrira i ispere sa metanolom. Filtrat se koncentrira radi dobivanja 154 mg (83 %) 2-[(4-benzoil aminobenzil)metoksi-fosfinoilmetil]-4-metilpentanoinske kiseline u obliku ulja.
Stupanj D: 2-[(4-benzoil aminobenzil)metoksi-fosfinoilmetil]-4-metilpentanoinska kiselina (154 mg, 0,37 mmola), (S)-2-amino-3-(4-metoksifenil)-N-metilpropionamid (100 mg, 0,41 mmola), benzotriazol-1-iloksi-tris(dimetilamino)fosfonij heksafluorofosfat (180 mg, 0,41 mmola) i diizopropiletilamin (238 mg, 1,85 mmola) miješaju se zajedno u suhom metilen kloridu (10 ml) tokom 18 sati.
Reakcijska smjesa se korncentrira i razblaži sa etil acetatom 9100 ml). Ovaj rastvor se ispere sa 1N klorovodičnom kiselinom (20 ml) i zasićenim rastvorom natrij bikarbonata (20 ml) i osuši se sa magnezij sulfatom. Filtriranje i koncentriranje daje sirovi proizvod koji se pročišćava pomoću kromatografije (10:90 - metanol : metilen klorid) radi dobivanja 153 mg (68 %) metil estra (4-benzoilaminobenzil){2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metilpentil}-fosfinske kiseline u obliku bijele čvrste supstance.
Stupanj E: Pomoću procedure opisane u primjeru 1, Stupanj E metil estar (4-benzoilaminobenzil){2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metilpentil}-fosfinske kiseline (153 mg, 0,25 mmola) prevede se u 100 mg (67 %) spoja iz naslova u obliku čvrste supstance koja je 50:50 smjesa S,S i R,S izomera, po istom redoslijedu. Maseni spektar m/e: M+ + H+ 594, M+ + Na+ 616. HPLC retencijska vremena: 8,32/10,33 minute.
Spojevi u tablici 5 dobiveni su pomoću postupka analognog onom opisanom u primjeru 65.
Tablica 5
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Primjer 73
S,S i R,S [4-(1,3-diokso-1,3-dihidroizoindol-2-il)benzil]{2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metilpentil}-fosfinska kiselina
Stupanj A: Benzil estar 2-[(4-aminobenzil)metoksi-fosfinoilmetil]-4-metilpentanoinske kiseline (koji je dobiven u primjeru 2, Stupanj A) (242 mg, 0,60 mmola) i ftalni anhidrid (133 mg, 0,90 mmola) u octenoj kiselini (10 ml) refluksiraju se tokom jednog sata. Ohlađena reakcijska smjesa se koncentrira i ostatak se rastvori u etil acetatu (100 ml). Ovaj rastvor se ispere sa zasićenim rastvorom natrij bikarbonata (3 � 20 ml) i osuši se sa magnezij sulfatom. Filtriranje i koncentriranje daje blijedo žuto ulje koje se pročišćava pomoću kromatografije (etil acetat) radi dobivanja 162 mg (51 %) benzil estra 2-{[4-(1,3-diokso-1,3-dihidroizoindol-2-il)benzil] metoksi-fosfinoil metil}-4-metilpentanoinske kiseline u obliku žute čvrste supstance.
Stupanj B: Pomoću procedura opisanih u primjeru 2, Stupnji C - E, benzil estar 2-{[4-(1,3-diokso-1,3-dihidroizoindol-2-il)benzil] metoksi-fosfinoil metil}-4-metilpentanoinske kiseline (269 mg, 0,50 mmola) prevodi se u 61 mg (20%, tri stupnja) spojevi u obliku bijele čvrste supstance koja je bila 50:50 smjesa S,S i R,S izomera, po istom redoslijedu. Maseni spektar m/e: M+ + H+ 620, M+ + Na+ 642. HPLC retencijska vremena: 10,12/11,92 minute.
Spojevi u tablici 6 dobiveni su pomoću postupka analognog onom opisanom u primjeru 73.
Tablica 6
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Primjer 77
S,S i R,S (3-aminobenzil)-{2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metilpentil}-fosfinska kiselina
Stupanj A: Metil estar {2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metilpentil}-[3-(2,2,2-trifluoro acetil amino)benzil]-fosfinske kiseline (koji je dobiven iz odgovarajućih polaznih materija uz korištenje procedura opisanih u primjeru 2, Stupanjevi A - D) (105 mg, 0,18 mmola) tretiraju se sa kalij karbonatom (242 mg, 1,75 mmola) u 10 %-tnom vodenom metanolu (10 ml) tokom 18 sati. Doda se 1N natrij hidroksid (1 ml) i poslije tri sata reakcijska smjesa se koncentrira i dodaju se etil acetat (25 ml) i voda (5 ml). Etil acetatni sloj se ukloni i voda se ekstrahira sa etil acetatom (3 � 20 ml). Sjedinjeni etil acetatni ekstrakti se osuše sa magnezij sulfatom i profiltriraju. Filtrat se koncentrira radi dobivanja 56 mg (64 %) metil estra (3-aminobenzil){2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metil pentil}-fosfinske kiseline u obliku blago žutog ulja.
Stupanj B: Pomoću procedure opisane u primjeru l, Stupanj E metil estar (3-aminobenzil){2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metilpentil}-fosfinske kiseline (56 mg, 0,11 mmola) prevodi se u 40 mg (74 %) spoja iz naslova u obliku bijele čvrste supstance koja je bila 44:56 smjesa S,S i R,S izomera, po istom redoslijedu. Maseni spektar m/e: M+ + H+ 490. HPLC retencijska vremena (20 % do 80 % gradijent): 6,17/8,94 minute.
Primjer 78
S,S i R,S (3-benzilaminobenzil)-{2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metilpentil}-fosfinska kiselina
Stupanj A: Metil estar (3-aminobenzil){2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metilpentil}-fosfinske kiseline (koji je dobiven kao što je opisano u primjeru 4, Stupanj A) (150 mg, 0,30 mmola), benzaldehid (38 mg, 0,36 mmola), natrij cijanoborohidrid (23 mg, 0,357 mmola) i octena kiselina (1 kap) u metanolu, miješaju se na sobnoj temperaturi tokom tri sata. Reagiranje se zaustavlja sa 1N klorovodičnom kiselinom (nekoliko mililitara) i reakcijska smjesa se koncentrira. Ostatak se rastvori u etil acetatu (20 ml) i ispere se sa 1N klorovodičnom kiselinom (20 ml), zasićenim rastvorom natrij bikarbonata (20 ml) i osuši se sa magnezij sulfatom. Filtriranje i koncentriranje daje sirovi proizvod koji se pročišćava pomoću kromatografije (3:97 - metanol : metilen klorid) radi dobivanja 133 mg (75 %) metil estra (3-benzilaminobenzil)-{2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metilpentil}-fosfinske kiseline u obliku ulja.
Stupanj B: Pomoću procedure opisane u primjeru l, Stupanj E metil estar (3-benzilaminobenzil)-{2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metilpentil}-fosfinske kiseline (133 mg, 0,22 mmola) prevodi se u 100 mg (64 %) spoja iz naslova u obliku bijele čvrste supstance koja je bila smjesa S,S i R,S izomera, po istom redoslijedu. Maseni spektar m/e: M+ + H+ 580, M+ + Na+ 602. HPLC retencijska vremena: 7,29/9,61 minute.
Primjer 79
Razdvajanje S,S i R,S (4-benzilbenzil)-[2-(2,2-dimetil-1-metilkarbamoil-propil karbamoil)-4-metilpentil]-fosfinske kiseline
Smjesa S,S i R,S (4-benzilbenzil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-fosfinske kiseline (dobivene kao što je opisano u primjeru 1) (609 mg) se kromatogarfira na preparativnoj reverzno faznoj (C-18) koloni koja se eluira prvo sa 40 %-tnim vodenim acetonitrilom koji sadrži 0,1 % trifluorooctene kiseline i tada sa 50 %-tnim vodenim acetonitrilom koji sadrži 0,1 % trifluorooctene kiseline. Ovo daje skoro potpuno razdvajanje dva diastereomera.
Koncentriranje frakcija koje sadrže dvije čiste komponente daje
304 mg S,S (4-benzilbenzil)[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-fosfinske kiseline, u obliku bijele čvrste supstance:
1HNMR (CD3OD) d 0,83 (d, 3H, J=6,9 Hz), 0,89 (d, 3H, J=6,9 Hz), 1,02 (s, 9H), 1,32 (m,1H), 1,42(m, 1H), 1,53 (m,1H), 1,67 (m, 1H), 1,99 (m, 1H), 2,69 (s, 3H), 2,81 (m, 1H), 3,10 (d, 2H, J=17,1 Hz), 3,94 (s, 2H), 4,08 (s, 1H), 7,1 - 7,3 (m, 9H); maseni spektar m/e: 501 M+ + H+; HPLC retencijsko vrijeme: 12,96 minute;
i 208 mg R;S (4-benzilbenzil)[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-fosfinske kiseline, u obliku bijele čvrste supstance:
1HNMR (CD3OD) d 0,86 (d, 3H, J=6,9 Hz), 0,91 (d, 3H, J=6,9 Hz), 1,02 (s, 9H), 1,22 (m, 1H), 1,4 - 1,7 (m, 3H), 2,00 (m, 1H), 2,64 (s, 3H), 2,85 (m, 1H), 3,10 (d, 2H, J=17,1 Hz), 3,94 (s, 2H), 4,13(s, 1H), 7,1 - 7,3 (m, 9H); maseni spektar m/e: 501 M+ + H+; HPLC retencijsko vrijeme: 15,84 minute.
Spojevi u tablici 7 razdvojeni su pomoću postupka koji je analogan onom opisanom u primjeru 79.
Tablica 7
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Claims (11)
1. Spoj formule I:
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ili njegova farmaceutski prihvatljiva sol, naznačen time, što
Ar je fenil, piridil, pirimidinil, pirazinil, piridazinil, tienil, furil, pirolil, oksazolil, tiazolil, izoksazolil, izotiazolil ili imadazolil;
R1 i R16 su svaki nezavisno vodik, (C1-C6) alkil, (trifluorometil)2 (C1-C6) alkil, perfluoro(C1-C6) alkil, perfluoro(C1-C6) alkil (C1-C6) alkil, difluorometoksi, trifluorometoksi, (C3-C7) cikloalkil (C1-C6) alkil, (C6-C10) aril (C1-C6) alkil, (C6-C10) alriloksi (C1-C6) alkil ili (C6-C10) aril (C1-C6) alkoksi (C1-C6) alkil;
R2 je (C1-C6) alkil ili (C6-C10) aril (C1-C6) alkil po izboru supstituiran sa hidroksi, amino, halo, (C1-C6) alkil,
(C1-C6) alkoksi, (trifluorometil)2 (C1-C6) alkil, perfluoro (C1-C6) alkil, perfluoro (C1-C6) alkil (C1-C6) alkil, difluorometoksi, trifluorometoksi, karboksi ili karboksamoil grupom;
R3 je (C1-C6) alkil ili (C6-C10) aril;
R4 je vodik, (C1-C6) alkil, (C1-C6) alkoksi, (C3-C7) cikloalkil (C1-C6) alkil, (C1-C6) alkilsulfonil, (C6-C10) aril, (C6-C10) ariloksi, (C6-C10) arilsulfonil, (C6-C10) aril (C1-C6) alkil, (C6-C10) aril (C1-C6) alkoksi, (C6-C10) aril
(C1-C6) alkilsulfonil, N-ftalimido, (C6-C10) aril NHCO, (C6-C10) aril NHSO2, R7OOC, R7R8NCO, R7R8NSO2 gdje R7 i R8 su svaki nezavisno vodik, (C1-C6) alkil ili (C6-C10) aril (C1-C6) alkil; (C1-C6) alkil CR9R10, (C6-C10) aril CR9R10, (C6-C10) aril (C1-C6) alkil CR9R10 gdje R9 i R10 su svaki nezavisno fluoro, (C1-C6) alkil ili (C1-C6) alkoksi; ili
R9 i R10 mogu biti uzeti zajedno sa ugljikom na koji su vezani radi formiranja grupe formule:
[image]
gdje
a je 0, 1 ili 2; b je 0 ili l; c je l, 2 ili 3; d je 0 ili l, i e je 0, 1 ili 2;
R5 i R6 su svaki nezavisno vodik, (C1-C6) alkil, (C1-C6) alkoksi, halo, (trifluorometil)2 (C1-C6) alkil, perfluoro (C1-C6) alkil, perfluoro (C1-C6) alkil (C1-C6) alkil, difluorometoksi, trifluorometoksi, (C1-C6) alkiltio, (C1-C6) alkilsulfinil ili (C1-C6) alkilsulfonil; ili
R1 i R16 mogu biti uzeti zajedno sa ugljikom na koji su vezani radi formiranja (C3-C7) cikloalkil grupe koja je po izboru supstituirana sa (C1-C6) alkil, (C1-C6) alkoksi, (C6-C10) aril (C1-C6)alkil, (C6-C10) aril (C1-C6) alkil ili
(C6-C10) ariloksi grupom; ili
R5 i R6, kada su pripojeni na susjedne ugljične položaje, mogu biti uzeti zajedno radi formiranja grupe formule:
[image]
gdje isprekidane linije predstavljaju po izboru dvostruke veze;
h je 1 ili 2;
f i g su svaki nezavisno 0, 1 ili 2;
Y i Z su svaki nezavisno CH2, O, CO, SO2, CH2CH2, CH2O, CH2S, CH2NH, CH2CO, CH2SO2, NHCO ili NHSO2; i
R11 je vodik, halo, (C1-C6) alkil, (C1-C6) alkoksi, (trifluorometil)2 (C1-C6) alkil, perfluoro (C1-C6) alkil, perfluoro (C1-C6) alkil(C1-C6) alkil, difluorometoksi ili trifluorometoksi;
uz ograničenje da kada jedan između a i e je 0, onaj drugi mora biti 1; uz ograničenje da kada b i d su l, zbroj a, c i e ne može biti 5, 6 ili 7; uz ograničenje da kada b i d su 0, zbroj a, c i e ne može biti 7; uz ograničenje da metilenski ugljik spojen na atom fosfora mora biti spojen na ugljični atom Ar-prstena; i uz ograničenje da R5 i R6 moraju biti pripojeni na atome ugljika na Ar prstenu.
2. Spoj prema zahtjevu 1, naznačen time što je Ar fenil ili tienil.
3. Spoj prema zahtjevu 1, naznačen time što je R1 2-metilpropil, trifluorometil, ciklopropilmetil, ciklobutilmetil, fenoksibutil, cikloheksilmetil ili feniletil.
4. Spoj prema zahtjevu 1, naznačen time što je R2 (C1-C6) alkil ili 4-metoksibenzil.
5. Spoj prema zahtjevu 1, naznačen time što je R3 metil.
6. Spoj prema zahtjevu 1, naznačen time što je R4 vodik, benzil, 2-klorobenzil, 2- fluorobenzil, 3-fluorobenzil ili 4-fluorobenzil.
7. Spoj prema zahtjevu 1, naznačen time što: Ar je fenil ili tienil; R1 je 2-metilpropil, trifluorometil, ciklopropilmetil, ciklobutilmetil, fenksibutil, cikloheksilmetil ili feniletil; R2 je (C1-C6) alkoksi ili 4-metoksibenzil; R3 je metil i R4 je vodik, benzil, 2-klorobenzil, 2-fluorobenzil, 3-fluorobenzil ili 4-fluorobenzil.
8. Spoj prema zahtjevu 1, naznačen time što se spomenuti spoj bira iz grupe koju čine:
(4-benzilbenzil)-[2-(2, 2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-fosfinska kiselina;
(4-benzilbenzil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-5,5,5- trifluoropentil]-fosfinska kiselina;
[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-[4-(3-fluorobenzil)-benzil]-fosfinska kiselina;
Benzil-{2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-6-fenoksiheksil}-fosfinska kiselina;
(4-benzilbenzil)-{2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-6-fenoksiheksil}-fosfinska kiselina;
(4-benzilbenzil)-{3-(cikloheksil-2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-propil}-fosfinska kiselina;
(4-benzilbenzil)-[3-cikloheksil-2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-propil]-fosfinska kiselina;
(4-benzilbenzil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-fenilbutil]-fosfinska kiselina;
(4-cikloheksilmetilbenzil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-fosfinska kiselina;
[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-(4-izobutilbenzil)-fosfinska kiselina;
[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-[4-(4-fluorobenzil)-benzil]-fosfinska kiselina;
[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-[4-(2-fluorobenzil)-benzil]-fosfnska kiselina;
(4-benzilbenzil)-{2-[2-(4-metoksifenil)-1-metilkarbamoil-etilkarbamoil]-4-metilpentil}-fosfinska kiselina;
[4-(2-klorobenzil)-benzil]-[2-(2,2-dimetil-1-metilkarbamoil-1-propilkarbamoil)-4-metilpentil]-fosfnska kiselina;
(5-benzil-piridin-2-ilmetil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-fosfinska kiselina;
[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-5,5,5-trifluoro-pentil]-[4-(2-fluoro-benzil)-benzil]-fosfinska kiselina;
[3-ciklopropil-2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-propil]-[4-(2-fluoro-benzil)-benzil]-fosfinska kiselina;
[3-ciklobutil-2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-propil]-[4-(2-fluoro-benzil)-benzil]-fosfinska kiselina; i
(5-benzil-tiofen-2-ilmetil)-[2-(2,2-dimetil-1-metilkarbamoil-propilkarbamoil)-4-metilpentil]-fosfinska kiselina.
9. Farmaceutski preparat za (a) tretiranje stanja odabranog iz grupe koju čine artritis, karcinom, sinergija sa citotoksičnim antikarcinomnim agensima, tkivna ulceracija, makularna degeneracija, restenozis, periodontalno oboljenje, epidermolizis bulosa, skleritis u kombinaciji sa standarnim NSAIN'S i analgeticima i druga oboljenja koja su okarakterizirana pomoću matrične metaloproteinazne aktivnosti, AIDS, sepsa, sepstički šok i druga oboljenja koja obuhvaćaju proizvodnju faktora tumorne nekroze (TNF) ili (b) inhibiciju matričnih metaloproteinaza ili proizvodnje faktora tumorne nekroze (TNF) kod sisavaca uključujući i ljude, naznačen time što obuhvaća količinu spoja prema zahtjevu 1, efikasnu u takvim tretmanima i farmaceutski prihvatljiv nosač.
10. Postupak za inhibiciju (a) matričnih metaloproteinaza ili (b) proizvodnje faktora tumorne nekroze (TNF) kod sisavaca, uključujući i ljude, naznačen time što obuhvaća primjenu kod spomenutih sisavaca efikasne količine spoja prema zahtjevu l.
11. Postupak za tretiranje stanja odabranog iz grupe koju čine artritis, karcinom, sinergija sa citotoksičnim antikarcinomnim agensima, tkivna ulceracija, makularna degeneracija, restenozis, periodontalno oboljenje, epidermolizis bulosa, skleritis u kombinaciji sa standarnim NSAIN'S i analgeticima i druga oboljenja koja su okarakterizirana pomoću matrične metaloproteinazne aktivnosti, AIDS, sepsa, sepstički šok i druga oboljenja koja obuhvaćaju proizvodnju faktora tumorne nekroze (TNF) kod sisavaca, uključujući i ljude, naznačen time što obuhvaća primjenu kod spomenutih sisavaca količine spoja prema zahtjevu 1, efikasnu u tretiranju takvog stanja.
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Publication number | Priority date | Publication date | Assignee | Title |
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ZW23187A1 (en) * | 1986-12-15 | 1988-06-29 | Hoffmann La Roche | Phosphinic acid derivatives |
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UA48121C2 (uk) * | 1993-11-04 | 2002-08-15 | Сінтекс (С.Ш.А.) Інк. | Інгібітори матричних металопротеаз і фармацетична композиція на їх основі |
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