MXPA00010886A - SUCCINAMIDE INHIBITORS OF INTERLEUKIN-1&bgr;CONVERTING ENZYME - Google Patents
SUCCINAMIDE INHIBITORS OF INTERLEUKIN-1&bgr;CONVERTING ENZYMEInfo
- Publication number
- MXPA00010886A MXPA00010886A MXPA/A/2000/010886A MXPA00010886A MXPA00010886A MX PA00010886 A MXPA00010886 A MX PA00010886A MX PA00010886 A MXPA00010886 A MX PA00010886A MX PA00010886 A MXPA00010886 A MX PA00010886A
- Authority
- MX
- Mexico
- Prior art keywords
- methyl
- oxo
- acid
- butyrylamino
- met
- Prior art date
Links
- 108090000790 Enzymes Proteins 0.000 title claims description 12
- 102000004190 Enzymes Human genes 0.000 title claims description 12
- 239000003112 inhibitor Substances 0.000 title description 16
- 102000000589 Interleukin-1 Human genes 0.000 title description 3
- 108010002352 Interleukin-1 Proteins 0.000 title description 3
- SNCZNSNPXMPCGN-UHFFFAOYSA-N butanediamide Chemical compound NC(=O)CCC(N)=O SNCZNSNPXMPCGN-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 105
- 200000000018 inflammatory disease Diseases 0.000 claims abstract description 15
- 206010001897 Alzheimer's disease Diseases 0.000 claims abstract description 11
- 206010040070 Septic shock Diseases 0.000 claims abstract description 11
- 230000036303 septic shock Effects 0.000 claims abstract description 11
- 206010063837 Reperfusion injury Diseases 0.000 claims abstract description 10
- 206010040550 Shigella infection Diseases 0.000 claims abstract description 10
- 201000005113 shigellosis Diseases 0.000 claims abstract description 10
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 8
- 206010039073 Rheumatoid arthritis Diseases 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- -1 3-phenyl-propylcarbamoyl Chemical group 0.000 claims description 261
- 239000002253 acid Substances 0.000 claims description 179
- 239000001257 hydrogen Substances 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 230000002401 inhibitory effect Effects 0.000 claims description 28
- 229910052717 sulfur Inorganic materials 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 239000011780 sodium chloride Substances 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000004494 ethyl ester group Chemical group 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 11
- 102000003777 Interleukin-1 beta Human genes 0.000 claims description 9
- 108090000193 Interleukin-1 beta Proteins 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 8
- 108090000426 Caspase 1 Proteins 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 102100006374 CASP1 Human genes 0.000 claims description 5
- 208000002551 Irritable Bowel Syndrome Diseases 0.000 claims description 5
- 125000001072 heteroaryl group Chemical class 0.000 claims description 5
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- QDXQAOGNBCOEQX-UHFFFAOYSA-N 1-methylcyclohexa-1,4-diene Chemical compound CC1=CCC=CC1 QDXQAOGNBCOEQX-UHFFFAOYSA-N 0.000 claims description 3
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical class [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- JYNYDTMJAHHXBP-UHFFFAOYSA-N CCOC1OC(=O)CC1NC(=O)C(CC(=O)NCCn1nnc2ccccc12)C(C)C Chemical compound CCOC1OC(=O)CC1NC(=O)C(CC(=O)NCCn1nnc2ccccc12)C(C)C JYNYDTMJAHHXBP-UHFFFAOYSA-N 0.000 claims description 2
- UGTYMRFUKGANOY-UHFFFAOYSA-N N-(2-ethoxy-5-oxooxolan-3-yl)-N'-(4-phenylbutyl)-2-propan-2-ylbutanediamide Chemical compound CCOC1OC(=O)CC1NC(=O)C(C(C)C)CC(=O)NCCCCC1=CC=CC=C1 UGTYMRFUKGANOY-UHFFFAOYSA-N 0.000 claims description 2
- OMUHWSWPEYIRFO-UHFFFAOYSA-N 3-[[4-[2-(1-methylindol-3-yl)ethylamino]-4-oxo-2-propan-2-ylbutanoyl]amino]-4-oxobutanoic acid Chemical compound C1=CC=C2C(CCNC(=O)CC(C(C)C)C(=O)NC(CC(O)=O)C=O)=CN(C)C2=C1 OMUHWSWPEYIRFO-UHFFFAOYSA-N 0.000 claims 1
- RGFKJRWDZOGFEG-UHFFFAOYSA-N 5-ethoxydihydro-2(3H)-furanone Chemical compound CCOC1CCC(=O)O1 RGFKJRWDZOGFEG-UHFFFAOYSA-N 0.000 claims 1
- HTYQBBRNIGCYTI-UHFFFAOYSA-N CCOC1OC(=O)CC1N(CCC1=CNC2=CC=CC=C12)C(=O)C(CC(N)=O)C(C)C Chemical compound CCOC1OC(=O)CC1N(CCC1=CNC2=CC=CC=C12)C(=O)C(CC(N)=O)C(C)C HTYQBBRNIGCYTI-UHFFFAOYSA-N 0.000 claims 1
- YDWTYXJTNLPSNQ-UHFFFAOYSA-N N-(2-ethoxy-5-oxooxolan-3-yl)-N'-[2-(6-methoxy-1H-indol-3-yl)ethyl]-2-propan-2-ylbutanediamide Chemical compound CCOC1OC(=O)CC1NC(=O)C(C(C)C)CC(=O)NCCC1=CNC2=CC(OC)=CC=C12 YDWTYXJTNLPSNQ-UHFFFAOYSA-N 0.000 claims 1
- UIUJIQZEACWQSV-UHFFFAOYSA-N Succinic semialdehyde Chemical compound OC(=O)CCC=O UIUJIQZEACWQSV-UHFFFAOYSA-N 0.000 claims 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims 1
- 206010021972 Inflammatory bowel disease Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 118
- 239000000243 solution Substances 0.000 description 118
- 239000007787 solid Substances 0.000 description 103
- 238000004458 analytical method Methods 0.000 description 76
- 235000019439 ethyl acetate Nutrition 0.000 description 58
- 239000000203 mixture Substances 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 239000000284 extract Substances 0.000 description 32
- 239000012267 brine Substances 0.000 description 31
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 28
- 238000000034 method Methods 0.000 description 27
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 20
- 239000008079 hexane Substances 0.000 description 20
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 19
- 239000003921 oil Substances 0.000 description 18
- 235000019198 oils Nutrition 0.000 description 18
- 150000002148 esters Chemical class 0.000 description 17
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- 239000012047 saturated solution Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 8
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 210000004027 cells Anatomy 0.000 description 6
- 230000000875 corresponding Effects 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000001384 succinic acid Substances 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 5
- 230000035492 administration Effects 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- VHJLVAABSRFDPM-UHFFFAOYSA-N 1,4-dimercaptobutane-2,3-diol Chemical compound SCC(O)C(O)CS VHJLVAABSRFDPM-UHFFFAOYSA-N 0.000 description 4
- IAOZJIPTCAWIRG-QWRGUYRKSA-N Aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 4
- 102100003814 CASP3 Human genes 0.000 description 4
- 102100014427 CASP4 Human genes 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 235000010357 aspartame Nutrition 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000003000 nontoxic Effects 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000005897 peptide coupling reaction Methods 0.000 description 4
- 159000000001 potassium salts Chemical class 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrugs Drugs 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- RKAFKUROUOLPOL-YFKPBYRVSA-N (2S)-2-propan-2-ylbutanedioic acid Chemical compound CC(C)[C@@H](C(O)=O)CC(O)=O RKAFKUROUOLPOL-YFKPBYRVSA-N 0.000 description 3
- RXRYTKIKGQNMCZ-UHFFFAOYSA-M 2-methyl-2-(sulfinatocarbamoyloxy)propane Chemical compound CC(C)(C)OC(=O)NS([O-])=O RXRYTKIKGQNMCZ-UHFFFAOYSA-M 0.000 description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- FXXACINHVKSMDR-UHFFFAOYSA-N Acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- 108091005771 Peptidases Proteins 0.000 description 3
- 102000035443 Peptidases Human genes 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000004432 carbon atoms Chemical group C* 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- YXHKONLOYHBTNS-UHFFFAOYSA-N diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000005842 heteroatoms Chemical group 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 230000035939 shock Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- AWJWWPYNMMJWAJ-ZDUSSCGKSA-N (2S)-4-oxo-4-(2-phenoxyethylamino)-2-propan-2-ylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)CC(=O)NCCOC1=CC=CC=C1 AWJWWPYNMMJWAJ-ZDUSSCGKSA-N 0.000 description 2
- YBUPWRYTXGAWJX-RXMQYKEDSA-N (4S)-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)[C@H]1COC(=O)N1 YBUPWRYTXGAWJX-RXMQYKEDSA-N 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N 1-[(1S,2R,3R,4S,5R,6R)-3-carbamimidamido-6-{[(2R,3R,4R,5S)-3-{[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy}-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy}-2,4,5-trihydroxycyclohexyl]guanidine Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N 2-Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
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- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000019189 interleukin-1 beta production Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000000302 ischemic Effects 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical class CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M laurate Chemical class CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical class [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000005487 naphthalate group Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000002314 neuroinflammatory Effects 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical class [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical class [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical class CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N palmityl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- GODHIFXMNKQHEI-UHFFFAOYSA-N pentanoic acid;hydrochloride Chemical compound Cl.CCCCC(O)=O GODHIFXMNKQHEI-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 230000002441 reversible Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 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
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 238000005059 solid analysis Methods 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical class CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical class [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003443 succinic acid derivatives Chemical class 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical class [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- 229940095064 tartrate Drugs 0.000 description 1
- BGXVADAFIXBNPZ-UHFFFAOYSA-N tert-butyl N-(2-phenylethylsulfonyl)carbamate Chemical compound CC(C)(C)OC(=O)NS(=O)(=O)CCC1=CC=CC=C1 BGXVADAFIXBNPZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical class CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical class CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
The present invention provides compounds ofFormula (I), pharmaceutical compositions comprising a compound of Formula (I), and methods of treatment of stroke;inflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease;septic shock;reperfusion injury;Alzheimer's disease;shigellosis;and multiple sclerosis.
Description
INHIBITORS SUCCINAMIDE DE LA ENZIMA CONVERTIDQRA OF INTERLEUKIN-1ß
This invention relates to a series of succinamide compounds that inhibits the interleukin-1β converting enzyme. This invention also relates to pharmaceutically acceptable compositions containing a compound that is an inhibitor of the interleukin-1β converting enzyme and a method for using the compositions for the treatment of attacks, inflammatory diseases, septic shock, reperfusion injury. , of Alzheimer's disease and shigellosis.
BACKGROUND OF THE INVENTION The protease-1β interleukin (also known as the converting enzyme interleukin-1β, ICE or Caspase 1) acts on pro-interleukin-1β (pro-IL-1ß) to produce interleukin-1β (IL-) lß), which is an inflammatory cytokine (Kostura MJ et al., Proc. Nat. Acad. Sci. 1989; 86: 5227-5231 and Black RA et al., FEBS Let. 1989; 247: 386-391). Several diseases are associated with the activity of interleukin-1. Examples of diseases in which interleukin-1 is involved include inflammatory diseases such as rheumatoid arthritis and irritable bowel disease and neurol-inflammatory diseases such as shock, multiple sclerosis and Alzheimer's disease (Dinarello CA E? R Cytokine Netw., 1994; 5: 517). Other diseases include septic shock, reperfusion injury and shigellosis. Agents that modulate IL-1ß activity have been shown to have beneficial effects in vivo. For example, compounds that are interleukin-1 receptor antagonists have been shown to inhibit excitotoxic and ischemic damage in rat brains (ie, Relton JK et al., Brain Research Bull? 1992; 29: 243-246). .
Additionally, ICE inhibitors demonstrated that they reduce inflammation and pyrexia in rats (Elford P R et al, British Journal of Pharmacology 1995, 115 601-6Q6)
ICE inhibitors can also inhibit other cistern proteases in the ICE family. Recently, the nomenclature of these cistern proteases from the ICE family (also known as Caspasas with ICE known as Caspasa-1) has also been defined. The following proteases are members representative of this class of enzymes using the nomenclature described in Alnemn et al, Cell 1996.87 171 Caspase-2 (also known as lch-1), Caspase-3 (also known as CPP32, Yama and apopain), Caspase-4 ( also known as TX, lch-2 and ICE rel-ll), Caspasa-5 (also known as ICE rel-lll), Caspasa-6 (also known as Mch2), Caspasa-7 (also known as Mch3), Caspasa- 8 (also known as FLICE and Mch5), Caspasa-9 (also known as ICE-LAP6 and Mch6), Caspasa-10 (also known as Mch4) It is recognized that members of this family of enzymes play a key biological role in the inflammation and apoptosis (programmed death cell) (Thomb erry N A et al, Perspectives m Drug Discovery and Design 1994, 2 389-399)
In addition to these effects in IL-1ß production, ICEs have shown that they play a role in the production of interferon-? inflammatory mediator (Ghayur et al, Nature 1997,386 (6625) 619-623) The ICE processes of the inactive pro-forma induction factor interferon-? (IGIF, Interleukin-18) to activate IGIF, a protein that induces the production of interferon-? by T cells and natural destructive cells Interferon-α has been implicated in the pathogenesis of diseases such as inflammatory diseases and septic shock Therefore it is expected that ICE inhibitors have beneficial effects in such diseases through the effects on the interferon-?
Most of the ICE inhibitors described in the art are based on peptides (for example, Dolle R et al, J Mßd Chem 1994,37 563).
recently reported the use of pyridone or pyrimidone based on peptidomimetic inhibitors (Dolle R. Et al., WO 9526958, 1995, Dolle R. et al., J. Med. Chem. 1996; 39: 2438 and Semple G. et al., Bioorg. Med. Chem. Lett. 1997; 7: 1337). X-ray crystallography and the molecular model have shown that pyridone-based inhibitors are appropriate replacements for P2-P3 found in peptide-based inhibitors (Golee J. et al., Bioorg, Med.Chem.Lett., 1997; 7: 2181-2186). WO 9526958 describes the use of plrimidone based on ICE inhibitors. As well as having some activity in in vitro models, the compounds described in WO 9526958 have been reported to have an IC50 ratio in vivo from 0.1 to 10 μm, reflecting the percentage of inhibition of the release of IL-1β. While these values reflect certain activity, the search for better ICE inhibitors is desired for the treatment of such diseases as inflammation, Alzheimer's disease, shock and septic shock.
SUMMARY OF THE INVENTION The present invention provides compounds of Formula I
where
each R 'is independently hydrogen or CrC6 alkyl; R1 and R2 independently are hydrogen, Ct-C6 alkyl?
-OH, aryl- (CH2) n, - (CH2) n-substituted aryl, - (CH2) p -? - aryl, - (CH2) "-? - substituted aryl, - (CH2)" - S-aryl, - (CH2) nS-substituted aryl, heteroaryl- (CH2) "- S, - (CH2) nS-heteroary substituted, - (CH2)" - NR'-aryl, - (CH2) "- NR'-substituted aryl , - (CH2) "- NR'-heteroaryl, - (CH2) n-NR'-substituted heteroaryl, - (CH2)" -heteroaryl or - (CH2) "-substituted heteroaryl; each n is independently 0 to 6;
R3 is hydrogen or alkyl 0 -, - Ce, R4 is Ci-Cß alkyl or hydrogen and X is hydrogen, O I - (CH2) n-N > S- (CH2) n-aryl, I I R'O or I - (CH2) a-N-S- (CH2) n-substituted aryl,
I I R'O
- (CH2) "- S- (CH2)" - aplo, - (CH2) n-S- (CH2) "- aplo substituted,
and the pharmaceutically acceptable salts thereof. In a preferred embodiment of the compounds of Formula I, R 'is hydrogen or methyl In another preferred embodiment,
each R 'is hydrogen. In another preferred embodiment, R3 is hydrogen and R4 is methyl, ethyl or isopropyl. In another preferred embodiment,
R1 is hydrogen or methyl and R2 is - (CH2) "- phenyl, hydrogen, (CH2)" -? - phenyl, -OH, - (CH2) "- benzimidazoyl, - (CH2) n-indolyl or - (CH2) "-phenol.
In another preferred embodiment, Y is
In another preferred embodiment, where
X is hydrogen,
O i -CH2-NH-S-CH2CH2-phenyl,? OR
-CH2-S-CH2CH2CH2-phenyl,
In a more preferred embodiment, the present invention provides compounds of Formula I
where
each R 'independently is hydrogen or methyl; each n independently is 2 to 3; R1 and R2 are independently hydrogen. - (CH2) n-phenyl, - (CH2) "-? - phenyl, -OH,
- (CH2 n
CH2CH2- 0- ^,
- «" Wr? - '
• < CH2) »- 1? | T ^
Ra, Rb and Rc are independently halogen, C?-C6 alkyl or hydrogen;
R3 is hydrogen; R4 is methyl, ethyl or isopropyl and X is hydrogen,
O I -CH2-NH-s-CH2CH2-fe1.no, I o
- 2-S-CH CH2CH2-phenyl,
and pharmaceutically acceptable salts thereof In a preferred embodiment of Formula I, R1 is hydrogen and R2 is - (CH2) "- indolyl,
- (CH2) "-? Ndol? L substituted, - (CH2)" - NH-phen? L, - (CH2) "-? - phen? L, - (CH2)" - tetrazohl, - (CH2) "- phenol, - (CH2) n-phenol substituted, - (CH2) n-benz? m? dazol? l substituted, - (CH2) n-benztpazol? l, - (CH2) n-? ndazol? l , - (CH2) "- benz? M? Dazol?, - (CH2)" - p? R? D? L, - (CH2) "- naft? L, or - (CH2) n-qu? Nol? In a more preferred embodiment, the present invention provides the compounds 3- (2-Met? l-3-phenet? lcarbamo? l-prop? on? lam? no) -4-oxo-5- (2 -phen? -ethanesulfon? lam? no) -pentane? co, 3- (2-Carbamo? lmet? l-3-met? l-but? plam? no) -5- (7,7-d? methyl-2-oxo-b? c? clo [2 2 1] hept-1? -methanesulfon? lam? no) -4-oxo-pentane? co, 5- (7,7-D? l-2-oxo-b? c? clo [2 2 1] hept-1? -methanesulfon? lam? no) -3- [3-met? l-2- (phenet? lcarbamo? l-met? l) -but? plam? no] -4-oxo-pentane? co, 3- (2-Carbamo? lmet? l-3-met? l-but? plam? no) -4-oxo-5- (2- phen-l-ethanesulfonyl-amine) -pentane? co, 3- [3-Met? l-2- (phenet? lcarbamo? l-met? l) -but? r? lam? no] - 4-oxo-5- (2-phenyl? -ethanesulfon? Lam? No) -pentane? Co,
- (7,7-D? Met? Lb? C? Clo [22 1] hept-l? Methanesulfon? Lam? No) -3- [3-met? L-2- (phenet? Lcarbamo? -met? l) -but? r? lam? no] -4-oxo-pentane? co, Acid (S, S) -3-. { 3-Met? L-2 - [(3-phen? L-prop? Lcarbamo? L) -met? L] -but? R? Lam? No} -4-oxo-butinco, Acid 3-. { 3-Met? L-2 - [(3-phenoxy? -et? Lcarbamo? L) -met? L] -but? Plam? No} -4- oxo-butipco,
- (7,7-D? -methyl-2-oxo-b? C? Clo [22 1] hept-1-? Arnetanosulfon? Lam? No) -3- acid. { 3-met? L-2 - [(2-phenox? -et? Lcarbamo? L) -met? L] -but? Plam? No) -4-oxo-pentanoic acid, 3- [3-Met? L- 2- (fenet? Lcarbamo? L-met? L) -but? Plam? No] -4-oxo-5- (3-phen? L-prop? Lsulfan? L) -pentano? Co, Acid 5- (7 , 7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-l? -methanesulfon? Lam? No) -3-. { 3-met? L-2- [(met? L-phenet? L-carbamo? L) -met? L] -but? Plam? No} -4-oxopentane? Co, 5- (7,7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-l? -methanesulfon? Lam? No) -3- acid. { 3-met? L-2 - [(3-phen? L-prop? Lcarbamo? L) -met? L] -but? Plam? No} -4-oxo-pentane? Co, Acid 3-. { 3-Met? L-2 - [(3-phen? L-prop? Lcarbamo? L) -met? L] -but? Plam? No} -4-oxo-5- (2-oxo-2H-chroman-6-? Lox?) - pentane? Co, 5- [3- (1H-? M? Dazol-2-? L) -naphthalene-2 acid -? lox?] - 3-. { 3-met? L-2 - [(3-phen? L-prop? Lcarbamo? L) -met? L] -but? Plam? No} -4-oxo-pentane? Co, 5- (7 7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-1? -methanesulfon? Lam? No) -3- (2-hydroxycarbamo? Lrnet? L-3-met? L-but? Plam? No) -4-oxo-pentane? Co, 5- (7,7-D? Met? L-2) acid oxo-b? c? clo [2 2 1] hept-1-? lmethanesulfon? lam? no) -3- (2- { [2- (1H-? ndol-3-? l) -et? lcarbamo ? -met? l.} -3-met? l-but? plam? no) -4-oxo-pentane? co, 5- (7,7-D? met? l-2-oxo- b? c? clo [2 2 1] hept-l? -methanesulfon? lam? no) -3-. { 3-met? L-2 - [[3- (4-h? Drox? Phen? L) -prop? Lcarbamo? L] -met? L] -but? R? Lam? No} -4-oxo-pentane? Co, 5- (7,7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-l? -methanesulfon? Lam? No) -3 acid - (2- { [2- (1H-? Ndol-3-? L) -et? Lcarbarmo? L] met? L.}. -3-met? L-but? R? Lam? No) - 4-oxo-pentane? Co,
- (7,7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-1-l? Methanesulfon? Lam? No) -3- (3-met? L-2) acid - { [2- (1-met? L-1H-? Ndol-3-? L) -et? Lcarbamo? L] -met? L.}. -but? Plam? No) -4-oxo- pentane? co, 5- (7,7-D? met? l-2-oxo-b? c? clo [2 2 1] hept-1-? lmethanesulfon? lam? no) -3- (3-met) ? l-2- { [2- (7-met? l-1 H-? ndol-3-? l) -et? lcarbamo? l] -met? l) -but? r? lam? no) -4-oxo-pentane? Co, 5- (7,7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-l? Methanesulfon? Lam? No) -3 acid - (2- { [2- (6-fluoro-1H-? Ndol-3-? L) -et? Lcarbamo? L] -met? L.}. -3-met? L-but? Plam? no) -4-oxo-pentane? co,
- (7,7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-1-l? Methanesulfon? Lam? No) -3- [3-met? L-2 acid - (. {met? l- [2- (1-met? l-1H-? ndol-3-? l) -et? l] -carbamo? l.]. -met? l) -but? plam ? no] -4-oxo-pentane? co,
Acid 3-. { 2 - [(2-Benzo? M? Dazol-1-? L-et? Lcarbamo? L) -met? L] -3-met? L-but? R? Lam? No} -5- (7,7-d? Met? L-2-oxo-b? C? Clo [2 2 1] hept-1? -methanesulfon? Lam? No) -4-oxo-pentane? Co, Acid 5 - (7,7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-1-? Lmethanesulfon? Lam? No) -3- (3-met? L-2- { [2- (1H-tetrazol-5? L) -et? Lcarbamo? L] -met? L.]. -but? Plam? No) -4-oxo-pentane? Co, Acid 5- (7 , 7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-1-? Lmethanesulfon? Lam? No) -4-oxo-3-. { 2 - [(3-phenyl? -propylcarbamoyl) -met? L] -but? R? Lam? No} pentane, Acid 5- (7,7-D? met? l-2-oxo-b? c? clo [22 1] hept-l? -methanesulfon? lam? no) -3- (2-. {[2- (1-met? L-1H-? Ndol-3-? L) -et? Lcarbamo? L] -met? L.}.-But? Plam? No) -4-oxo-pentane? co, Acid 3 - (3-Met? l-2- { [2- (1-met? l-1H-? ndol-3? l) -et? lcarbamo? l] met? l.}. - but? plam? no) -4-oxo-butipco, 3- [3-Met? l-2- ( { met? l- [2- (1 -met? l-1 H-? ndol- 3-? L) -et? L] -carbamo? L.) -met? L) -but? R? Lam? No] -4-oxo-but? R? Co, Acid 3-. { 2 - [(2-Benzo? M? Dazol-1-? L-et? Lcarbamo? L) -met? L] -3-met? L-but? Plam? No} -4-oxo-butipco, 5- (7,7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-l? -methanesulfon? Lam? No) -3- ( 2- { [3- (4-h? Drox? -fen? L) -prop? Lcarbamo? L-met? L.] -3-met? L-but? Plam? No) -4-oxo -pentano? co,
- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2- [(2-pyridin-4-yl-etylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2- [(2-naphthalene-2-yl-ethylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2- [(3-pyridin-4-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2- [(3-quinolin-2-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2- [(3-naphthalene-2-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2- [(3-pyridin-3-yl-propylcarbamoyl) -methyl] butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2- [(2-naphthalene-2-yl-ethylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (3-methyl-2- { [2- (7-methyl-1H-indole -3-yl) -ethylcarbamoyl] -methyl] -.-butylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (2- { [2- (6-fluoro-1 H-indole-3-) acid il) -ethylcarbamoyl] -methyl] -3-methyl-butyrylamino) -4-oxo-pentanoic acid; 3- [3-Methyl-2- ( {methyl- [2- (1-methyl-1 H -indol-3-yl) -ethyl] carbamoyl} -methyl) -butyrylamino-4- acid oxo-butyric; 3- (3-Methyl-2. {[[Methyl- (2-phenoxy-ethyl) -carbamoyl] -methyl] -.-butyrylamino) -4-oxo-butyric acid; 3- (2- { [2- (5,6-Dimethyl-benzoimidazol-1-yl) -ethylcarbamoyl] -methyl] -3-methyl-butylamino) -4-oxo-butyric acid, salt of trifluoroacetate;
- (7,7-D? Met? L -b? C? Clo [2 2 1] hept-1-? Lemtanosulfon? Lam? No) -3- acid. { 3-met? L-2 - [(3-phen? L-prop? Lcarbamo? L) -met? L] -but? Plam? No} -4-oxo-pentane? Co, 5- (7,7-D? Met? Lb? C? Clo [22 1] hept-1-? Lmethanesulfon? Lam? No) -3- (2- { [2- (1H-? Ndol-3-? L) -et? Lcarbamo? L] -met? L.}. -3-met? L-but? Plam? No) -4-oxo-pentane? Co, 5- (7,7-D? Met? L-2-oxo-b? C? Clo [22 1] hept-l? -methanesulfon? Lam? No) -3- acid. { 3-met? L-2- [(3-p? R? D? N-4-? L-prop? Lcarbamo? L) -met? L] -but? R? Lam? No} -4-oxo-pentane? Co, 5- (7,7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-1? -methanesulfon? Lam? No) -3-. { 3-met? L-2 - [(3-qu? Nol? N-2-? L-prop? Lcarbamo? L) -met? L] -but? Plam? No} -4-oxo-pentane? Co, 5- (7,7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-l? Methanesulfon? Lam? No) -3 acid -. { 3-met? L-2 - [(3-naphthalene-1-? L-prop? Lcarbamo? L) -met? L] -but? Plam? No} -4-oxo-pentane? Co, 5- (7,7-D? Met? L-2-oxo-b? C? Clo [22 1] hept-l? Methanesulfon? Lam? No) -3- acid . { 3-met? L-2 - [(3-p? Pd? N -3? L-prop? Lcarbamo? L) -met? L] -but? Plam? No} -4-oxo-pentane? Co, Acid 3-. { 2 - [(2-Benzo? M? Dazol-1-? L-et? Lcarbamo? L) -met? L] -3-met? L-but? Plam? No} -5- (7,7-d? Met? L-2-oxo-b? C? Clo [2 2 1] hept-1-? -methanesulfon? Lam? No) -4-oxo-pentane? Co, Acid 5 - (7,7-D? Met? L-2-oxo-b? C? Clo [2 1] hept-1-? L methanesulfon? Lam? No) -3- (3-met? L-2-. { . [2- (1-met? L-1 H-? Ndol-3-? L) -et? Lcarbamo? L] -met? L.}.-But? R? Lam? No) -4-oxo- pentane? co,
- (7,7-D? -methyl-2-oxo-b? C? Clo [22 1] hept-l? -methanesulfon? Lam? No) -3- acid. { 3-met? L-2 - [(2-p? Pd? N-4-? L-et? Lcarbamo? L) -met? L] -but? Plam? No} -4-oxo-pentane? Co, 3- (2- { [2- (5-Acet? L-1H-? Ndol-3-? L) -et? Lcarbamo? L] -met? L} -3-met? L-but? Plam? No) -5- (7,7-d? Met? L-2-oxo-b? C? Clo [2 2 1] hept-1-? L methanesulfon? lam? no) -4-oxo-pentane? co,
- (7,7-d? Met? L-2-oxo-b? C? Clo [22 1] hept-1-l? Methanesulfon? Lam? No) -3- (3-met? L-2) acid [[2- (1 H-tetrazol-5? L) -et? Lcarbamo? L] -met? L.]. -but? R? Lam? No) -4-oxo-pentane? Co, N4- ( 2-Benzo? M? Dazol-1-? L-et? L) -N1- (2-ethoxy? -5-oxo-tetrahydro-furan-3-? L) -2-? Soprop? L-suc namide, N 1 - (2-Ethoxy? -5-oxo-tetrahydro-furan-3-? l) -N 4 - [2- (1 H-? ndol-3? l) -et? l] -2 -? soprop? l-succmamide,
N1- (2-Etox? -5-oxo-tetrahydro-furan-3-? L) -2-? Soprop? L-N4- [2- (1-met? L-1H-? Ndol-3- ?) -et? l] -succinamide, N4- [2- (5,6-D? chloro-benzo? m? dazol-1-? l) -et? l] -N1- (2-ethoxy? 5-oxo-tetrahydro-furan-3-? L) -2-? Soprop? L-succ? Nam? Da, N - (2-Ethoxy? -5-oxo-tetrahydro-furan-3-? l) -2-? soprop? l-N4- (2-phenox? -et? l) -succ? nam? da,
N - (2-Etox? -5-oxo-tetrahydro-furan-3-? L) -2-? Soprop? L-N4- [2- (6-methox? -1H-? Ndol-3-? l) -et? l] -succ? nam? da, N4- (2-Benzotpazol-1-? l-et? l) -N1- (2-ethoxy? -5-oxo-tetrahydro-furan-3) -? l) -2-? soprop? l-succinamide, N1- (2-Etox? -5-oxo-tetrahydro-furan-3-? l) -N4- (2-? ndazol-1-? -et? l) -2-? soprop? l-sucanamide, N1- (2-Etox? -5-oxo-tetrahydro-furan-3-? l) -2-? soprop? l-N4- (2 -fen? lam? no-et? l) -succinamide, Ni- (2-Ethoxy? -5-oxo-tetrahydro-furan-3-? l) -N4- [2- (6-fluor-1H- βdol-3- l l) -et? l] -2-? soprop? l-succinamide, N1- (2-Etox? -5-oxo-tetrahydro-furan-3-? l) -N4- [ 2- (7-met? L-1H-? Ndol-3-? L) -et? L] -2-? Soprop? L-succinamide, N1- (2-ethoxy? -5-oxo-tetrahydro-? furan-3-? l) -2-? soprop? l-N4- [2- (2-met? l-benzo? m? dazol-1-? l] -succ? nam? da, N1- (2- Etox? -5-oxo-tetrahydro-furan-3-? L) -2-? Soprop? L-N4- [3- (3,4,5-tr? Methox? -phen?) -prop? l] -succ? nam? da, N1- (2-Etox? -5-oxo-tetrahydro-furan-3-? l) -2-? soprop? lN - [2- (phen? l) -et ? l] -succ? nam? da,
N1- (2-ethoxy? -5-oxo-tetrahydro-furan-3-? L) -2-? Soprop? L-N4- [4- (phen? L) -but? L] -succ? Nam ?gives,
N '- (2-Etox? -5-oxo-tetrahydro-furan-3-? L) -N4- (2-? Ndol-1-? L-et? L) -2-? Soprop? L- succinamide,
N1- (2-Ethoxy? -5-oxo-tetrahydro-furan-3-? L) -2-? Soprop? L-N4- [4- (phen? L) -prop? L] -succmamide, N1 - (2-Ethoxy? -5-oxo-tetrahydro-furan-3-? L) -N4- [2- (5-fluoro-1H-? Ndol-3-? L) -et? L] -2 -isopropyl-succinamide, acid 3-. { 2 - [(2-Benzo? M? Dazol-1-? L-et? Lcarbamo? L) -met? L] -3-met? L-but? Plam? No} -4-oxo-butyl, Acid (3- (3-Met? L-2- { [2- (1 -met? L-1 H-? Ndol-3? L) -et? Lcarbamo? ] -met? l.}.-but? plam? no) -4-oxo-butyl, Acid 3 (2- { [2- (5-Fluoro-1 -met? l-1 H-? ndol- 3-? L) -et? Lcarbamo? L] -met? L.}. -3-met? L-but? Plam? No) -4-oxo-butyr? Co, Acid 3- (2- { [2- (5,6-D? Chloro-benzo? M? Dazol-1-? L) -et? Lcarbamo? L] -met? L.]. -3-met? L-but? Plam? No) -4-oxo-butyric acid, 3- (2- { [(2-Benzo? M? Dazol-1-? L-et? L) -met? L-carbamo? L] -met? L acid .} - 3-methyl-butyl-lamethyl) -4-oxo-butyric acid, 3- ({2 - [(2-Benzotr? Azol-1-yl-et? lcarbamo? l) -met? l] -3-met? l-but? r? lam? no.}. -4-oxo-butpic acid, 3- { 2 - [(2-lndazol-1-? l-et? lcarbamo? l) -met? l] -3-met? l-but? r? lam? no.}. -4-oxo-butyr? co,
3- [2- ( { [2- (5,6-D? Met? L-benzo? M? Dazol-1-? L) -et? L] -met? Lcarbamo? L.]. met? l) -3-met? l-but? r? lam? no] 4-oxo-butyl, Acid 3- [2- ( { [2- (2-Met? l-benzo? m? dazol -1 -? L) -et? L] -met? Lcarbamo? L.). -met? L) -3-met? L-but? R? Lam? No] 4-oxo-butyl, Acid 3- ( 3-met? L-2- { [3- (3,4,5-tr? Methox? -fen? L) -prop? Lcarbamo? L] -met? L.}. -but? Plam? No ) -4-oxo-butípco, Ethyl ester of acid 3-. { 3-Met? L-2 - [(2-phenoxy? -et? Lcarbamo? L) -met? L] -but? Plam? No} -4-oxo-butyric,
Ethyl ester of 3-C-ano-3- acid. { 3-met? L-2 - [(2-phenoxy? -et? Lcarbamo? L) -met? L] -butiplaminoj-propionic acid and 3-C? Ano-3- acid. { 3-met? L-2 - [(2-phenox? -et? Lcarbamo? L) -met? L] -but? Plam? No} -prop? on? co
A pharmaceutical composition comprising a compound of Formula I is also provided. A method for treating or preventing the attack is also provided, the method comprising administering to a patient having or having had or been in danger of having an attack, a Therapeutically effective amount of a compound of Formula I A method for treating inflammatory diseases is also provided, the method comprises administering to a patient having an inflammatory disease, a therapeutically effective amount of a compound of Formula I
In a preferred embodiment of the method for treating inflammatory diseases, the inflammatory disease is rheumatoid arthritis or irritable bowel disease. A method for treating septic shock is also provided, the method comprising administering to a patient having septic shock, an amount Therapeutically effective of a compound of Formula I A method for the treatment of reperfusion damage is also provided, the method comprises administering to a patient having reperfusion injury, a therapeutically effective amount of a compound of Formula I Also provided a method for treating Alzheimer's disease, the method comprises administering to a patient having Alzheimer's disease, a therapeutically effective amount of a compound of Formula I. A method for treating shigellosis is also provided, the method comprising administration to a patient who has shigellosis, a therapeutically effective amount of a compound of Formula I
A method for treating multiple sclerosis is also provided, the method comprising administering to a patient having multiple sclerosis a therapeutically effective amount of a compound of the formula I A method is also provided for inhibiting the heteromeric converting enzyme. 1ß, the method comprises administering to a patient in need of the inhibition of the heteromeric converting enzyme-1β a therapeutically effective amount of a compound of Formula I
DETAILED DESCRIPTION OF THE INVENTION The term "alkyl" means a long or branched hydrocarbon chain. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl and hexyl. Preferred alkyls are C C6 alkyl
The term "alkoxy" means an alkyl group linked to a carbon atom. Representative examples of the alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy and isobutoxy. The term "halogen" includes chlorine, fluorine, bromine and iodine. The term " "alkenyl" means a long or branched hydrocarbon chain having one or more carbon-carbon double bonds The term "alkynyl" means a long or branched hydrocarbon chain having one or more triple carbon-carbon bonds The term "aplo2" means a aromatic hydrocarbon Representative examples of the aplo groups include phenyl and naphthyl The term "heteroatom" includes oxygen, nitrogen and sulfur The term "hetero-pyl" means an aplo group in which one or more carbon atoms of the aromatic hydrocarbon has been replaced with a heteroatom Examples of heteroaryl radicals include, but are not limited to, pipdyl, imidazolyl,
pyrrolyl, benzimidazolyl, tetrazolyl, benzotriazolyl, indazolyl, thienyl, furyl, pyranyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, naphthyridinyl and isoxazolyl. The term "cycloalkyl" means a cyclic hydrocarbon. Examples of the cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The symbol "-" means a link. The term "patient" means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep and pigs.
The term "substituted" means that the organic base radical has one or more substituents. For example, substituted cyclohexyl means a cydohexyl radical having one or more substituents. Substitutes include, but are not limited to, halogen, O O
I II -CF3, Cl-C8 alkyl, -CN, CF3, -NO2, alkyl -COCj-Cß, alkyl -NHCOC1-C5,
Or I alkyl CCl-Cβ, -NHj, -O-phenyl-alkyl-NHCl-Cg, -N-chloroCi-Csh-alkyl-SC-C6, alkyl-OCrCß and -OH. Particularly preferred substituents include but are not limited to O
II-tert-butyl, methyl, -OH, -NH2, -SCH3, -CN, -0CH3, alkyl -COCj-Ce O
II alkyl -NHCOCj-Cg, bromine, fluorine and chlorine. The term "cycloalkenyl" means a cycloalkyl group having at least one carbon-carbon double bond. Examples of the alkenyl groups include cyclopentane, cyclobutane and cyclohexane.
The term "heterocycle" or "heterocycloalkyl" means a cycloalkyl group in which one or more carbon atoms are replaced with a heteroatom. Examples of the heterocycles include, but are not limited to pyrrolidinyl, piperidinyl and piperazinyl.
The compounds of Formula I can be administered to a patient either alone or as part of a pharmaceutically acceptable composition. The compositions can be administered to patients such as humans and animals, orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally and transvesicularly, locally (powders, ointments or drops) or as a nasal spray or oral. Compositions suitable for parenteral injection may comprise sterile aqueous or non-aqueous pharmaceutically acceptable solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents or carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and the like), appropriate mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as oleate. of ethyl. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. The prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid and the like. It would also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can
caused by the use of absorption retarding agents, for example, aluminum monostearate and gelatin. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dose forms, the active compound is mixed with at least one common inert excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, such as, for example, glycerol; (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, tapioca or potato starch, alginic acid, certain complexes of silicates and sodium carbonate. (e) retarders in solution, such as paraffin; (f) absorption accelerators, such as, for example, quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (h) absorbers, such as, for example, kaolin and bentonite and (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may comprise stabilizing agents.
Solid compositions of a similar type can also be employed as fillers in hard and soft gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings or layers, such as enteric layers and others well known in the art. They may contain opacifying agents and may also be of said composition that release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of encapsulation compositions that can be used are polymeric substances and waxes. The active compounds may also be in micro-encapsulated form, sl is appropriate, with one or more of the excipients mentioned above. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as for example ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzonate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures of these substances and the like. In addition to such inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying and suspending agents, flavors, sweeteners and odoring agents. The suspensions, in addition to the active agents, may contain suspending agents, such as, for example, ethers, ethers, ethers, sorbitan esters and
polyethylene sorbitol, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances and the like. Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at normal but liquid temperatures at body temperature and therefore, they melt in the vaginal cavity or rectum and release the active component. Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays and inhalants. The active component is mixed under sterile conditions with a physiologically acceptable carrier and any condom, stabilizer or propellant may be required. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also contemplated within the scope of this invention. The compounds of the present invention can be administered to a patient at dose levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dose in the range of about 0.01 to about 100 mg / kg of body weight per day is preferred. The specific dose used, however, may vary. For example, the dose may depend on a number of factors including the requirements of the patient, the severity of the condition being treated and the pharmacological activity of the compound being used. The determination of optimal doses for a particular patient is well known to those skilled in the art. The terms pharmaceutically acceptable salts, esters, amides and prodrugs as used herein refer to those carboxylate salts, amino acids
of addition salts, esters, amides and prodrugs of the compounds of the present invention which are within the scope of medical judgment, suitable for use in contact with the tissues of patients without toxicity, irritation, excessive allergic response and the like, commensurable with a reasonable risk / benefit ratio and the effectiveness for its proposed use, as well as amphoteric forms, where possible, of the compounds of the invention. The term "salts" refers to the relatively non-toxic organic and inorganic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the isolation and final purification of the compounds or by reacting separately the purified compound in its free base form with an appropriate inorganic and organic acid and isolating the salt thus formed. Representative salts include the salts of hydrobromide, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate , tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium. , methylamine, diethyl amine, trimethylamine, ethylamine and the like. (See, for example, Berge S.M. et al., "Pharmaceutical Salts," J. Pharm, Sci. 1977; 66: 1-19, which is incorporated herein by reference). Examples of non-toxic pharmaceutically acceptable esters of the compounds of this invention include the CrCß alkyl esters wherein the alkyl group is a long or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl, alkyl esters
C1-C4 which are preferred. The esters of the compounds of the present invention can be prepared in accordance with conventional methods. Examples of pharmaceutically acceptable non-toxic amides of the compounds of this invention derived from ammonia, primary C?-C6 alkyl amines and secondary C6-dialkyl amines wherein the alkyl groups are long or branched chain. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing a nitrogen atom. Amides derived from ammonia, primary C1-C3 alkyl amines and secondary C1-C2 dialkyl amines are preferred. The amides of the compounds of the invention can be prepared in accordance with conventional methods. The term "prodrug" refers to compounds that rapidly transform in vivo to produce the parent compound of the above formula, for example, by hydrolysis in the blood. A full discussion is provided in Higuchi T. and Stella V.,
"Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical
Association and Pergamon Press, 1987, both are incorporated herein by reference. In addition, the compounds of the present invention can exist in their unsolvated forms, as well as in their solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention. The compounds of the present invention can exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compounds, that is, each asymmetric carbon can have the R or S configuration. It is contemplated that all stereoisomeric forms of the compounds thus as the
mixtures thereof, including racemic mixtures, form part of this invention. The compounds of the present invention are administered to a patient in need of ICE inhibition. In general, patients in need of ICE inhibition are those patients who have a disease or condition in which ICE plays a role. Examples of such diseases include, but are not limited to, inflammatory diseases such as rheumatoid arthritis and irritable bowel syndrome, neuroinflammatory diseases such as seizures and shock. Other diseases include reperfusion damage, Alzheimer's disease and shigellosis. A "therapeutically effective amount" is an amount of a compound of Formula I that when administered to a patient having a disease that can be treated with a compound of Formula I lessens the symptoms of the disease. A therapeutically effective amount of a compound of Formula I can be readily determined by one skilled in the art by administering a compound of Formula I to a patient and observing the results. An illustration of the preparation of the compounds of the present invention is given in Schemes I-VI I.
Scheme I
Scheme II
Scheme lll
Scheme IV
2. LiOH hydrolysis of methyl ester 3. Bromine methyl ketone formation
4. Displacement with the potassium salt of the nucleophile J. CFj yi
Scheme V
Scheme VI
Scheme Vil
Those skilled in the art will recognize that the starting materials may vary and that additional steps involved in producing the compounds are included in the present invention as demonstrated by the following examples. As shown in Scheme I, acylation of an appropriate amine with itaconic anhydride provides the desired acrylic acid, which is hydrogenated to produce the respective propionic acid. The acid is subsequently coupled to an appropriate amino acid under standard conditions of peptide coupling, such as, for example, HOBT and EDCI in the presence of a base such as 4-methylmorpholine to produce the desired succinic ester. The methyl ester is subsequently hydrolyzed with a base such as sodium hydroxide. The t-butyl ester of the resulting acid is subsequently transformed into bromomethyl ketone by, for example, forming the mixed anhydride of the acid, treating the anhydride mixed with diazomethane and subsequently brominating with HBr in acetic acid. Displacement of the bromine with the potassium salt of N-Boc sulfonamide results in the desired sulfonyl compound. The t-butyl ester subsequently hydrolyzes the acid in the presence of an acid such as, for example, trifluoroacetic acid. As shown in Scheme II, (4S) - (-) - 4-isopropyl-2-oxazolidinone is acylated with an acid chloride in the presence of the base to form the desired oxazolidinone, which is subsequently alkylated in the presence of the base with t-butyl bromoacetate. The resulting N-acyloxazolidinone is subsequently hydrolyzed to t-butyl succinic acid ester essentially by the procedure described in Tet. Lett. 1987: 28: 6141-6144. The acid is subsequently coupled to the ester 4-benzyl ester 1-allyl of (S) -2-amino-succinic acid under standard conditions of peptide coupling as defined above in Scheme I. The t-butyl ester of this product subsequently is separated and the acid is treated with O-benzylhydroxylamine under conditions similar to the coupling of the peptide to provide the desired benzyloxy carbamoyl. The allyl ester
subsequently it is essentially separated by the procedure described in Tet. Lett. 1995,36: 5741-5744 and the resulting acid is transformed to the bromomethyl ketone as described above in Scheme I. The bromine is supplied with the potassium salt of N-Boc sulfonamide, the Boc group was separated with acid and the ester benzyl on, for example, Pd / C Raney nickel to produce the desired pentanoic acid. In Scheme II, the benzyl ester of succinic acid (product 3) in Scheme II was formed from the benzyl alcohol in the presence of a dehydrating agent, such as, for example, EDCI and the t-butyl ester subsequently hydrolyzed with an acid. The benzyl ester of succinic acid was subsequently coupled to an appropriate amine under standard conditions of peptide coupling as described in Scheme I and the benzyl ester is subsequently removed via hydrogenation as described in Scheme II to produce butyric acid. The acid is subsequently coupled to the amino alcohol shown in Step 5 and the resulting alcohol is subsequently oxidized to the essential aldehyde by the procedure described by Dess and Martin in J. Org. Chem. 1993: 58.2899 and in J. Org. Chem. 1983: K48: 4156-4158. The final product is obtained under hydrolysis of the t-butyl ester with an acid. As shown in Scheme IV, the succinic acid of Scheme II (product 3) is coupled to the amino ester of Step 1 under similar conditions of the peptide to those described above in Scheme 1. The ester is hydrolyzed with the base, such as, for example, lithium hydroxide and the resulting acid is converted to bromomethyl ketone as described above in Scheme II. The bromine is replaced with the potassium salt of an appropriate nucleophile and the t-butyl ester is hydrolyzed with the acid to produce the desired product. As shown in Scheme VI, the benzyloxycarbonyl (Cbz) protecting the dietary acetal group of Cbz-Asp (? TBu) is removed by hydrogenolysis using 20% Pd / C as a catalyst. This amine is coupled to monocyclic succinic acid
protected from Scheme II (product 3) under standard peptide conditions such as, for example, HOBT and EDCI in the presence of a base such as 4-methylmorpholine. The removal of the t-butyl groups can be achieved with, for example, trifluoroacetic acid in dichloromethane to provide the cyclic O-ethylacetal. The coupling of this acid under standard conditions of peptide coupling, as established above, for example, with several amine provides the desired product. It is observed that the compounds containing the cyclic structure
They can exist in equilibrium with the open chain form.
-COH Both forms of open or cyclical chain are part of the
CH
II present invention.
As shown in Scheme VII, hydrolysis of the cyclic O-ethylacetal acid of Scheme V (product 4) for example, in hydrochloric acid diluted in acetonitrile yields the aldehyde acid. The description in this application of all articles and references including patents are incorporated herein by reference. The starting materials and the various intermediates can be obtained from commercial sources, prepared from commercially available organic compounds or prepared using the well-known synthetic methods. The examples presented below are to illustrate the particular embodiments of the invention and in no way limit the scope of the description including the claims.
EXAMPLE 1 3- (2-Methyl-3-phenethylcarbamoyl-propionylamino) -4-oxo-5- (2-phenyl-ethanesulfonylamino) -pentanoic acid
Step A: A solution of itaconic anhydride (5.00 g, 44.6 mmol) and phenethylamine (5.95 g, 49.1 mmol) in 100 mL of acetonite was stirred at room temperature under nitrogen for 72 hours. The mixture (solid forms) was concentrated, then partitioned between EtOAc and 1 N HCl. The organic extract was washed with brine, dried (MgSO 4), concentrated and the residue was crystallized from diethyl ether to give 5.24 g (50%). 2- (phenethylcarbamoyl-methyl) -acrylic acid as a white solid: mp 133-140 ° C. MS (APCI) m / z 234.2 (M + 1, 67.4%) and 216.2 (M-17, 100%). Analysis calculated for C 3 H 15 N 3 (233,269): C, 66.94; H, 6.48; N, 6.00. Found: C, 66.74; H, 6.56; N, 6.00.
Step B: A solution of 2- (phenethylcarbamoyl-methylene) -acrylic acid (2.76 g, 11.8 mmol,
Example 1, Step A) in 100 ml of THF was treated with 5% Pd / C (0.2 g) and hydrogen at room temperature and 52 psig of hydrogen for 2.5 hours. The mixture was filtered and
concentrated to give 2.39 g (86%) of 2- (phenethylcarbamoyl-methyl) -propionic acid as a grayish solid. MS (APCI) m / z 236.0 (M + 1, 100%). Analysis calculated for C? 3 H17N03 (235285): C, 66.36; H, 7.28; N, 5.95. Found: C, 65.31; H, 7.05; N, 5.80.
Step C: A mixture of 2- (phenethylcarbamoyl-methyl) -propionic acid (1.63 g, 6.93 mmol, Example 1, Step B), H-Asp (? TBu) -? Me-HCl (1.83 g, 7.64 mmol, purchased in Bachem
Bioscience Inc.), 1-hydroxybenzotriazole hydrate (H0BT * H20, 1.17 g, 7.64 mmol), N-ethyl-N '- (3-dimethylaminopropyl) -carboylidene hydrochloride (EDCI-HCI, 1.46 g, 7.62 mmol) and
4-Methylmorpholine (0.95 ml, 8.64 mmol) in 100 ml of dichloromethane was stirred at room temperature for 24 hours. The mixture was concentrated, then partitioned between EtOAc and saturated NaHC 3 solution. The organic extract was washed with brine solutions and
KH2P0 saturated, dried (MgSO4), filtered, concentrated and chromatographed (silica gel, 25% hexanes / 75% EtOAc) to give 2.54 g (87%) of 4-tert-butyl ester 1-methyl ester of 2- acid (2-methyl-3-phenethylcarbamoyl-propionylamino) -succinic, as a waxy white solid. MS (APCI) m / z 420.9 (M, 100%) Analysis calculated for C22H32N2? 6 (420.510): C, 62.84, H, 7.67; N, 6.66. Found: C, 62.68; H, 769; N, 6.54.
Step D A solution of 2- (2-methyl-3-phenethylcarbamoyl-propionylamino) -succinic acid 4-tert-butyl ester-1-methyl ester (2.11 g, 5.01 mmol, Example 1, Step C) and hydroxide solution NaOH 0.1 N (60.1 ml, 6.01 mmol) in 60 ml of ethanol was stirred at room temperature for 12 hours. The solution was concentrated, acidified with saturated KH2P0 solution to pH-5 and extracted with chloroform (2x100 ml). The combined chloroform extract was dried (MgSO4), filtered and concentrated to give 2.23 g (-100%) of 2- (2-methyl-3-phenethylcarbamoyl-propionylamino) -succinic acid 4-tert-butyl ester, as a colorless oil, which was used without further purification. A solution of 2- (2-methyl-3-phenethylcarbamoyl-propionylamino) -succinic acid 4-tert-butyl ester, (2.23 g, 5.49 mmol) and 4-methylmorpholine (0.61 ml, 5.73 mmol) in 50 ml of THF in a 250 ml round bottom flask with Claro-Seal splice was cooled to ca. -45 ° C (acetonitrile-Dry Ice suspension) and treated with isobutyl chloroformate (0.75 ml, 5.78 mmol). The solid was immediately formed and the mixture was stirred for 15 minutes, then treated with a 0.25 to 0.5 M diazomethane in an ether solution (55 ml, 27.5 mmol, generated from Diazaid and freshly distilled). The cold bath was removed, the pale yellow solution was stirred at room temperature for 2 hours, cooled to 0 ° C and treated dropwise with a solution of 48% hydrobromic acid (10 ml, 184 mmol) in 10 ml of water. acetic acid. The colorless solution was stirred at room temperature for 30 minutes, then it was partitioned between EtOAc and water (-200 ml of each). The organic extract was washed with water, saturated solutions of NaHCO 3 and brine, dried (MgSO 4), filtered and concentrated to give 1.40 g (53%) of tert-butyl ester of 5-bromo-2- (2- methyl-3-phenethylcarbamoyl-propionylamino) -4-oxo-pentanoic acid, as a pale yellow solid.
Step E A solution of 1,1-dimethylethyl [(2-phenylethyl) sulfonyl] carbamate (0.47 g, 1.66 mmol) in 3.0 ml of DMF at room temperature under nitrogen was treated with potassium tert-butoxide (0.21 g, 1.66 mmol). ). The sample was stirred at room temperature for 1 hour, cooled to 0 ° C, then treated cor. 2- (2-methyl-3-phenethylcarbamoyl-propionlamino) -5-bromo-4-oxo-pentanoic acid tert-butyl ester (0.67 g, 1.38 mmol, Example 1, Step D). The sample was heated to room temperature overnight. The sample was partitioned between EtOAc and saturated NaHCO 3 solution. The organic extract was washed with saturated NaHCO 3 solutions and brine, dried (MgSO 4), filtered and concentrated. The residue was chromatographed (silica gel, 50% hexanes / 50% EtOAc) to give 0.43 g (52%) of 1,1-dimethylethyl-5 [[(1,1-dimethylethoxy) carbonyl] [(2-phenylethyl) sulfonyl] ] amino] -3 - [[2-methyl-1,4-dioxo-4 - [(2-phenylethyl) amino] butyl] amino] -4-oxo-pentanoic acid as a pale yellow foamy solid.
Step F A solution of 3- (2-methyl-3-phenethylcarbamoyl-propionylamino) -4-oxo-5 - [(2-phenyl-ethanesulfonyl) -N-Boc-amino] -pentanoic acid 5-tert-butyl ester. , (0.40 g, 0.58 mmol, Example 1, Step E) and trifluoroacetic acid (10 ml) in 20 ml of dichloromethane was stirred at room temperature for 2 hours. The solution was concentrated to a yellow oil. Diethyl ether (-50 ml) was added and the oil solidified. The sample was stirred at room temperature overnight, filtered, washed with fresh ether and dried under vacuum to give 0.28 g (89%) of 3- (2-methyl-3-phenethylcarbamoyl-propionylamino) -4-oxo acid. -5- (2-phenyl-ethanesulfonylamino) -pentanoic acid as a white solid. MS (APCI) m / z 532.1 (M +, 100%). Analysis calculated for C26H33N3? 7S (531,633): C, 58.74; H, 6.26; N, 7.90.
Found: C, 58.38; H, 6.23; N. 7.71.
EXAMPLE 2 3- (2-Carbamoylmethyl-3-methyl-butyrylamino) -5- (7,7-dimethyl-2-oxo-blciclo [2.2.1] hept-1-ylmethanesulfonylamino) -4-oxo-pentanoic acid
Step A A solution of (4S) - (-) - 4-isopropyl-2-oxazolidinone (19.85 g, 0.154 mol) in 400 ml of THF at -78 ° C under N2 was treated dropwise with lithium n-butyl ( 64.5 ml, 0.161 mol, 2.5 M solution in hexanes) resulting in solid formation. The mixture was stirred at -78 ° C for 30 minutes, then treated with drip addition of / so-valeryl chloride (20.6 ml, 0.169 mol). The reaction was slowly warmed to room temperature overnight. The sample was concentrated and then partitioned between EtOAc and a saturated KH2P0 solution. The organic extract was washed with brine, dried (MgSO 4) and the resulting yellow oil was chromatographed (MPLC, silica gel, 10% EtOAc in hexanes) to give 29 8 g (91%) of (S) -4-isopropyl. -3- (3-Methyl-butyryl) -oxazolidin-2-one as a pale yellow oil.
Step B: A solution of (S) -4-isopropyl-3- (3-methyl-butyryl) -oxazolidin-2-one (20.8 g, 97.5 mmol, Example 2, Step A) in 500 mL of THF a- 78 ° C under N2 was treated by dripping with
sodium amide bis (trimethylsilyl) (107 ml, 107 mmol, 1.0 M solution in THF). The solution was stirred at -78 ° C for 30 minutes, then trickled with a solution of rt-butyl bromoacetate (18.0 ml, 121.9 mmol) in 100 ml of THF. The sample was stirred at -78 ° C for 1 hour, then quenched by dropwise addition of a saturated KH2P04 solution (-125 ml). The mixture was warmed to room temperature, concentrated (to remove the majority of THF), then extracted with ether. The organic extract was washed with saturated solutions of NaHCO 3 and brine, dried (MgSO 4), concentrated and crystallized from ether-naphtha to give 21.1 g (66%) of tert-butyl ester of acid [(S- (R *, R *)] - 3- (4-isopropyl-2-oxo-oxazolidine-3-carbonyl) -4-methyl-pentanoic acid as a white solid Analysis calculated for C17H29N05 (327.424): C, 62.36; H, 8.93; N, 4.28 Found: C, 62.30; H, 9.07; N, 4.09.
Step C Hydrolysis of the N-acyloxazolidone was accomplished using lithium hydroperoxide after the Evans D.A. procedure. et al. (Tet., Lett., 1987; 28: 6141-6144). To a stirring solution at 0 ° C of tert-butyl acid ester [(S- (R *, R *)] - 3- (4-isopropyl-2-oxo-oxazolidine-3-carbonyl) -4 methyl-pentanoic acid (9.05 g, 27.64 mmol, Example 2, Step B) in 250 mL of THF was added by dripping peroxide and hydrogen (14.1 mL, 138 mmol, 30% strength solution in water) followed by a solution of 1.0 M lithium hydroxide (55.3 mL, 55.3 mmol) The reaction was slowly warmed to room temperature overnight, the reaction was concentrated to remove most of the THF and then the basic solution was washed with CH2CI2 (2x100 mL). The aqueous phase was cooled, acidified with saturated KH2P0 solution to pH ~ 5 and extracted into EtOAc The organic extract was washed with brine solution, dried (MgSO4) and concentrated to give 5.66 g (95%) of ester 4-tert-butyl
(S) -2-? Sopropylsuccinic acid as a colorless oil, which was used are further purification.
Step D A mixture of 4-tert-butyl ester of (S) -2-isopropyl succinic acid (10.77 g, 49.80 mmol, Example 2, Step C), (S) -2-amino-succinic acid hydrochloride ester 4-benzyl ester 1-allyl (14.93 g, 4981 mmol), H0BT-H20 (8.4 g, 54.8 mmol), EDCI-HCl (10.5 g, 54.8 mmol) and 4-methylmoproline (8.2 mL, 74.6 mmol) in 250 mL of CH2CI2 was stirred at room temperature for 12 hours. The mixture was concentrated, then partitioned between EtOAc and saturated NaHCO 3 solution. The EtOAc extract was washed with saturated solutions of KH2P04 and brine, dried (MgSO4), filtered, concentrated and chromatographed (MPLC, silica gel, 20% EtOAc in hexanes) to give 19.21 g (84%) of 4-ester. [S - (R *, R *)] - 2- (2-tert-butoxycarbonylmethyl-3-methyl-butyrylamino) -succinic acid benzyl ester as pale yellow oil.
Step E A solution of 4-benzyl ester 1-allyl ester of [S- (R *, R *)] - 2- (2-tert-butoxycarbonylmethyl-3-methyl-butyrylamino) -succinic acid (9.3 g, 23.0 mmol , Example 2, Step D) and trifluoroacetic acid (35 ml) in 35 ml of CH 2 Cl 2 was stirred at room temperature under N 2 for 2 hours. The sample was concentrated, redissolved in CH2CI2, then treated with EDCI-HCI (8.8 g, 46.0 mmol), H0BT-H20 (6.2 g, 46.0 mmol) and O-benzylhydroxylamine hydrochloride (7.3 g, 46.0 mmol). 4-Methylmorpholine (11.6 g, 115 mol) was added dropwise and the reaction mixture was stirred at room temperature overnight. The sample was diluted with CH 2 Cl 2 and washed successively with 5% HCl and saturated NaHC 3 solutions. The organic extract was dried (Na 2 S 4) and concentrated to yield 10.25 g (88%) of the ester 4-tert-butyl ester 1-2- [2-
(benzyloxycarbamoyl-methyl) -3-methyl-butyrylamino! -succinic acid as a white solid which was carried out in the next step without further purification.
Step F The allyl ester is separated using the procedure of Dessolin M. et al., (7ef.
Lett. nineteen ninety five; 36: 5741-5744). A solution at 0 ° C under N 2 of 2- [2- (benzyloxycarbamoyl-methyl) -3-methyl-butyrylamino] -succinic acid 4-tert-butyl ester 1-allyl ester (10.25 g, 19.7 mmol, Example 2, Step E) and palladium tetrakis (triphenylphosphine) (0) (0.462 g, 0.40 mmol) in CH2Cl2 was treated dropwise with phenylsilane (4.26 g, 39.4 mmol). The reaction mixture was warmed to room temperature over a period of 1 hour, then washed with saturated KH2P? 4 solution. The organic layer was extracted with 0.5 N NaOH. The aqueous basic phase was acidified with concentrated HCl and extracted with EtAOc. The organic extract was dried (Na2SO4), filtered and concentrated to yield 6.2 g (72%) of the 4-benzyl ester of substituted succinic acid as a white foamy solid. To a solution of the above acid (6.0 g, 12.8 mmol) and 4-methylmofoline (1.3 g, 12.8 mmol) in THF (50 mL) at -42 ° C was added dropwise isobutyl chloroformate (1.8 g, 12.8 mmol). After stirring for 30 minutes, the reaction mixture was added to a solution of diazomethane in diethyl ester (-0.5 M, 200 ml) at 0 ° C. The reaction mixture was stirred for 2 hours at room temperature, then cooled at 0 ° C. A solution of 48% HBr (20 ml) and HOAC (20 ml) was added dropwise and the reaction was stirred for 30 minutes at 0 ° C. The sample was diluted with diethyl ether and washed with water. water (2x) and a saturated solution of NaHCO3 (2x). The organic layer was dried (Na2SO4) and concentrated. The residue was dissolved in CH2Cl2 and the product was precipitated with hexanes. The solid was collected by filtration, washed well with hexanes and dried to yield 1.5
g (15%) of 3- [2-benzyloxycarbamoyl-methyl) -3-methyl-butyrylamino] -5-bromo-4-oxo-pentanoic acid as a white solid.
Step GA a solution of (S) -1,1-dimethylethyl [[(7,7-dimethyl-2-oxo-bicyclo [2.2.1] hept-1-yl) methyl] sulfonyl] carbamate (0.273 g, 0.82 mmol) DMF anhydride (3 ml) was added potassium tert-butoxide (0.092 g, 0.82 mmol). The reaction was stirred under a nitrogen atmosphere for 1 hour. This solution was subsequently added dropwise to a solution of 3- [2- (benzyloxycarbamoyl-methyl) -3-methyl-butyrylamino] -5-bromo-4-oxo-pentanoic acid benzyl ester solution (0.400 g, 0.75 mmol, Example 2, Step F) in DMF anhydride (3 ml) and the reaction was stirred overnight. The sample was diluted with EtOAc and washed with brine (2x). The EtOAc layer was dried (Na2S4) and concentrated. The residue was chromatographed (silica gel, 40% EtOAc / 60% hexanes) to yield 0.271 g of phenylmethyl-5 - [[(1,1-dimethylethoxy) carbonyl] - [[(7,7-dimethyl-2-oxo-bicyclo [ 2.2.1] hept-1-yl) methyl] sulfonyl] amino] -3 - [[2- (1-methylethyl) -1,4-dioxo-4 - [(phenylmethoxy) amino] butyl] amino] - 4-oxopentanoate as a white foamy solid. The sample was treated with 50% trifluoroacetic acid in CH2Cl2 (6 ml) for 1 hour. The sample was diluted with CH2Cl2 and washed with a saturated solution of NaHCO3. The organic layer was dried (Na2SO4) and concentrated to give 0.237 g of a white solid which was carried in the next step without further purification.Step H: To a solution of the above compound (0.237 g, Example 2, Step G) in 75 ml of
THF was added 10% Pd / C (0.50 g) and the mixture was hydrogen in 50 psi H2, at room temperature for 3 hours. The reaction mixture was filtered and Raney Nickel (0.10 g) was added. The reaction mixture is again hydrogen at 50 psi for 15 hours. The sample was filtered and the
filtered was concentrated. The residue was partitioned between EtOAc and a saturated solution of NaHCO 3. The aqueous layer was separated, acidified with HCl and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to yield 0.065 g of 3- (2-carbamoylmethyl-3-methyl-butyrylamino) -5- (7,7-d? Methyl-2-oxo-bic? Clo [ 2.2.1] hept-1-ylmethanesulfonylamine) -4-oxo-pentanoic acid (Compound 2) as a pink solid. Analysis calculated for C22H35N308S x 0.27 C4H802 (525.392): C, 52.76; H, 7.13; N, 8.00 Found: C, 52.36; H, 7.06; N, 7.65. The following compounds can be prepared according to the procedure of Example 2.
EXAMPLE 3 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- [3-methyl-2- (phenylcarbamoyl-methyl) -butyrylamino] -4-oxo acid -pentanoic
A dark foamy solid. MS (APCI) m / z 606.4 (M +, 25.0%), 346.3 (100%). Analysis calculated for C30H43N3? 8S x 0.50 H2? (614,764): C, 58.61; H, 7.21; N, 6.84. Found: C, 58.62; H, 7.18; N, 6.41.
EXAMPLE 4 3- (2-Carbamoylmethyl-3-methyl-butyrylamino) -4-oxo-5- (2-phenyl-ethanesulfonyl-amino) -pentanoic acid
MS (APCI) m / z 456.3 (M + 1, 74.7%), 242.2 (100%). Analysis calculated for C20H29N3? 7S x 0.13 CF3C02H (470.357): C, 51.74; H, 6.24; N, 8.93. Found: C, 51.70; H, 5.97; N, 8.61.
EXAMPLE 5 3- [3-Methyl-2- (phenethylcarbamoyl-methyl) -butyrylamino] -4-oxo-5 (2-phenyl-ethanesulfonylamino) -pentanoic acid
A white solid. MS (APCI) m / z 560.4 (M + 1, 50.7%), 346.3 (100%). Analysis calculated for C28H37N307S (564,551): C, 59.57; H, 6.70; N, 7.44.
Found: C, 59.56; H, 6.52; N, 7.41.
EXAMPLE 6 5- (7,7-Dimethyl-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- [3-methyl-2- (phenethylcarbamoyl-methyl) -butyrylamino] -4-oxo-pentanoic acid
A grayish solid. Analysis calculated for C30H 5N3? 7S (591.773): C, 60.89; H, 7.66; N, 7.10. Found: C, 60.61; H, 7.65; N, 7.03. The resulting N-Boc sulfonamide was prepared by a Wolff-Kishner reduction of (1S) - (+) - 10-camphorsulfonamide followed by acylation with di- (t-butyl) -dicarbonate in accordance with the procedure of Example 2, Step B. Neustadt R. (Tet.Lett., 1994; 35; 379-380).
EXAMPLE 7 (S, S) -3-Methyl - [(3-phenyl-propylcarbamoyl) -methyl] -butyrylamine acid} -4-oxo-butyric
Step A: A mixture of (S) -2-isopropyl-succinic acid 4-tert-butyl ester (14.5 g, 67.0 mmol, Example 2, Step C), EDCI-HCl (15.4 g, 80.3 mmol), benzyl alcohol ( 8.7 ml, 84.1 mmol) and 4-dimethylaminopyridine (1.5 g, 12.3 mmol) in 500 ml of CH2Cl2 was stirred at room temperature for 12 hours. The sample was concentrated, then it was partitioned between EtOAc and a saturated solution of NaHCO3. The organic extract was washed with saturated KH2P0 solutions and brine, dried (MgSO4), filtered and concentrated. The resulting yellow oil was chromatographed (MPLC, silica gel, 10% EtOAc in hexanes) yielding 15.6 g (76%) of (S) -2-isopropyl-succinic acid 4-tert-butyl ester-1-benzyl ester as a colorless oil. MS (APCI) m / z 307.2 (M + 1, 92.2%), 252.2 (M-54, 90.9%) and 251.1 (M-55, 100%). The tert-butyl ester was hydrolyzed with 20% trifluoroacetic acid in CH 2 Cl 2 at room temperature to give (1) -2-isopropyl-succinic acid-1-benzyl ester as a pale yellow oil. MS (APCI) m / z 251.1 (M + 1, 100%).
Step B: A mixture of 1-benzyl ester of (S) -2-isopropyl-succinic acid (3.45 g, 13.78 mmol, Example 3, Step A), 3-phenyl-1-propylamine (2.15 mL, 15.12 mmol), H ? BT-H2? (2.32 g, 15.15 mmol), EDCI [CI] (2.91 g, 15.18 mmol) and 4-methylmorpholine 2.3 mL (20.65 mmol) in 100 mL of CH2CI2 was stirred at room temperature for 12 hours. The sample was concentrated and then partitioned between EtOAc and saturated NaHCO3 solution. The organic extract was washed with saturated KH 2 P 4 solutions and brine, dried (MgSO 4), filtered and concentrated to give 5.0 g (98%) of benzyl ester of (S) -2- (phenpropylcarbamoylmethyl) -3 acid. -methylbutyric as a pale yellow oil.
MS (APCI) m / z 369.2 (M + 2, 100%), 368.2 (M + 1, 97.4%). Hydrogenation of (S) -2- (phenpropylcarbamoylmethyl) -3-methylbutyric acid benzyl ester with 20% Pd / C in EtOH at balloon pressure gave (S) -2- (phenylpropylcarbamoylmethyl) - 3-methylbutyric as a colorless oil. (MS (APCI) m / z 279.1 (M + 2, 83.1%), 278.1 (M + 1, 83.1%) and 260.1 (M-17, 100%).
Step C A mixture of (S) -2- (phenyl-propylcarbamoyl-methyl) -3-methylbutyric acid (2.04 g, 7.34 mmol, Example 3, Step B), tert-butyl ester of 3-amino-4-tert-butyl ester -hydroxy-butyric acid (1.71 g, 8.08 mmol), H0BT-H20 (1.24 g, 8.10 mmol), EDCI-HCl (1.55 g, 8.08 mmol) and 4-methylmorpholine in 50 mL of CH2Cl2 were stirred at room temperature for 12 hours. The sample is concentrated and then divided between EtOAc and saturated NaHC 3 solution. The organic extract was washed with saturated solutions of KH2P04 and brine, dried (MgSO4), filtered and concentrated. The sample was chromatographed (MPLC, silica gel, 25% hexanes / EtOAc) to give 1.64 g, (52%) of tert-butyl ester of (S, S) -3- acid. { 3-methyl-2 - [(3-phenyl-propylcarbamoyl) -methyl] -butyrylamino} -4-hydroxy-butyric as a white foamy solid. MS (APCI) m / z 436.3 (M + 2, 100%) and 435.3 (M + 1, 83.1%).
Stage D A solution of tert-butyl ester of (S, S) -3 ~ acid. { 3-methyl-2 - [(3-phenyl-propylcarbamoyl) -methyl] -butyrylamino} -4-hydroxy-butyric acid (1.54 g, 3.54 mmol, Example 3, Step C) and Dess-Martin reagent (2.26 g, 5.33 mmol, prepared following the procedure of RE Ireland and L. Liu (J. Org. Chem.; 58: 2899) in 100 ml of CH2Cl2 was stirred at room temperature for 2 hours.The sample was treated respectively using the procedure of DB Dess and JC Martin (J. Org. Chem. 1983; 48: 4156-4158) to give
1. 16 g (77%) of tert-butyl ester of (S; S) -3- acid. { 3-methyl-2 - [(3-phenyl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-butyric as a white waxy solid. MS (APCI) m / z 434.3 (M + 2, 83.1%) and 433.3 (M + 1, 100%). Analysis calculated for C 24 H 36 N 2 5 5 x 0.50 H20 (441,573): C, 65.28; H, 8.45; N, 6.34. Found: C, 65.31; H, 8.13; N, 6.16.
Step E A solution of tert-butyl ester of (S,) - 3- acid. { 3-methyl-2 - [(3-phenyl] -propylcarbamoyl) -methyl-butyrylamino} -4-oxo-butyr? Co (1.10 g, 2.54 mmol, Example 3, Step D) and 5.0 ml of trifluoroacetic acid in 20 ml of CH2Cl2 was stirred at room temperature for 1 hour. The solution was concentrated and then partitioned between EtOAc and saturated KH2P04 solution. The organic extract was washed with saturated solutions of KH2P0 and brine, dried (MgSO4), filtered and concentrated to give 0.83 g (86%) of acid (S, S) -3-. { 3-methyl-2 - [(3-phenyl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-butyric as a greyish foamy solid (Compound 7). MS (APCI) m / z 377.2 (M + 1, 100%). Analysis calculated for C2oH28N2? 5 x 0.25 H20 (380960): C, 63.06; H, 7.54; N, 7.35. Found-C, 63.08; H, 7 25; N, 6.98. The following compounds can be prepared according to the procedure described in Example 7.
EXAMPLE 8 Acid 3-. { 3-Methyl-2 - [(3-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -4-oxo-butyric
A sparkling white solid. MS (APCI) m / z 379.1 (M + 1, 100%). Analysis calculated for C19H26N2? 6 x 0.50 H20 (387.437): C, 58.90; H, 7.02; N, 7.23. Found: C, 58.91; H, 6.78; N, 7.02.
EXAMPLE 9 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylethanesulfonylamino) -3- acid. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentane
Step A: A mixture of (S) -2- (3-phenoxy-ethylcarbamoyl-methyl) -3-methylbutyric acid (3.51 g, 12.5 mmol, prepared using the methodology described in Example 3, Steps A and B), H - Asp (? TBu)? Me x HCl (3.31 g, 13.82 mmol), HOBT x H2? (2.12 g, 13 82 mmol),
.; .
EDCI? CI (12.65 g, 13.82 mmol) and 4-methylmorpholine (2.9 mL, 26.38 mmol) in 100 mL of CH2CI2 was stirred at room temperature for 12 hours. The sample was concentrated and then partitioned between EtOAc and saturated NaHCO3 solution. The organic extract was washed with saturated KH2P04 solutions and brine, dried (MgSO4), filtered and concentrated. The sample was chromatographed (MPLC, silica gel, 25% hexanes / 75% EtOAc) to give 4.70 g (81%) of ester 1-methyl ester 4-tert-butyl acid (S, S) -2-. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -succinic as a white solid. MS (APCI) m / z 465.2 (M + 1, 100%). Analysis calculated for C 24 H 36 N 207 (464,564): C, 62.05; H, 7.81; N, 6.03. Found: C, 62.07; H, 7.85; N, 5.97.
Step B: To a stirring solution at room temperature of ester 1-methyl ester 4-tert-butyl acid (S, S) -2-. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} Succinic (4.18 g, 9.00 mmol, Example 4, Step A) in 100 mL of THF was added dropwise a solution of 0.2 M lithium hydroxide (47.3 mL, 9.46 mmol). The sample was stirred for 30 minutes, acidified with saturated KH2P0 solution, concentrated (to remove the majority of THF) and extracted with EtOAc. The organic extract was washed with brine solution, dried (MgSO 4), filtered and concentrated to give a pale yellow oil. The sample was crystallized from CH 2 Cl 2 hexanes to give 1.96 g (48%) of 4-tert-butyl ester of (S, S) -2- acid. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -succinic as a white solid. MS (APCI) m / z 451.2 (M + 1, 100%). Analysis calculated for C 23 H 34 N 2 O 7 (450,537): C, 61.32; H, 7.61; N, 6.22.
Found: C, 61.29; H, 7.71; N, 6.08.
Step C Using the procedure described in the Example, Step D, the 4-tert-butyl ester of the acid (S, S) -2-. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrilamino} -succinic (2.92 g, 6.47 mmol) was converted to 3.25 g (95.2%) of tert-butyl ester of (S, S) -5-bromo-3- acid. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic, as a grayish solid. MS (APCI) m / z 529.1 / 527.1 (M + 1, 100 / 98.7%).
Step DA a stirring solution at room temperature of N-Boc camphorsulfonamide (1.04 g, 3.14 mmol, prepared from (1S) - (+) - 10-camphorsulfonamide after the acylation procedure of Step B. Neustadt R., Tel. Lett. 1994; 35: 379-380) in 5.0 ml of DMF was added in one portion of (potassium ert-butoxide (0.35 g, 3.13 mmol) .The sample was stirred at room temperature for 30 minutes, cooled at 0 ° C, it was subsequently treated in one portion with tert-butyl ester of (S, S) -5-bromo-3-. {3-met? l-2 - [(2-phenoxy-et! lcarbamoyl) -methyl] -butyryllamide.) -4-oxo-pentane-1C (1.50 g, 2.84 mmol, Example 4, Step C.) The sample was slowly heated to room temperature. overnight The sample was partitioned between EtOAc and saturated KH2P04 solution The organic extract was washed with brine solution, dried (MgSO), filtered, concentrated and chromatographed (MPLC, silica gel, 50% hexanes / 50% EtOAc) to give 1.43 g (64%) of 1, 1 -dimethylethyl 5 - [[(1, 1 -dimethylethoxy) carbonyl] [[((7,7-dimethyl-2-oxo-bicyclo [2.2.1] hept-1-yl) methyl] sulfonyl] amino] -3 - [[2- (1-methylethyl) -1, 4 -dioxo-4 - [(2-phenoxyethyl) amino] butyl] amino] -4-oxopentanoate as a white foamy solid. MS (APCI) m / z 778.3 (M + 1, 100%).
Step E: A solution of 1,1-dimethylethyl 5 - [[(1,1-dimethylethoxy) carbonyl] [[(7,7-dimethyl-2-oxo-bicyclo [2.2.1] hept-1-yl) methyl] sulfonyl] amino] -3 - [[2- (1-methylethyl) -1,4-dioxo-4 - [(2-phenoxyethyl) amino] butyl] amino] -4-oxopentanoate (1.38 g, 1.77 mmol, Example 4 , Step D) and 10 ml of trifluoroacetic acid in 20 ml of CH 2 Cl 2 was stirred at room temperature for 1 hour. The solution was concentrated to a foamy solid. The solid was dissolved in a 0.1 M sodium hydroxide solution and washed with EtOAc (25 mL). The basic aqueous phase (pH-10-11) was acidified with a saturated solution of KH2P04 to pH ~ 5.0 and extracted with EtOAc. The organic extract was washed with brine solution, dried (MgSO 4), filtered and concentrated to give 0.57 g (52%) of 5- (7,7-dimethyl-2-oxo-bicyclo [2.2.1] hepty- 1-ylmethanesulfonylamino) -3-. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic as a white foamy solid (Compound 9). MS (APCI) m / z 622.1 (M + 1, 40.3%) and 362.1 (100%). Analysis calculated for C30H43N3? 9S (621.756): C, 57.95; H, 6.97; N, 6.76. Found: C, 57.63; H, 7.15; N, 6.59. The following compounds can be prepared according to the procedure of Example 9.
EXAMPLE 10
3- [3-Methyl-2- (phenethylcarbamoyl-methyl) -butyrylamino] -4-oxo-5- (3-phenyl-propylsulfanyl) -pentanoic acid
A white solid. MS (APCI) m / z 527.2 (M + 1, 100%). Analysis calculated for C 29 H 38 N 2 5 5 S (526,701): C, 66.13; H, 7.27; N, 5.32. Found: C, 65.99; H, 7.24; N, 5.20.
EXAMPLE 11 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [(methyl-phenethyl-carbamoyl) -methyl] -butyriamlamino} -4-oxopentanoic
A sparkling grayish solid. MS (APCI) m / z 620.2 (M + 1, 40.3%), 360.2 (100%). Analysis calculated for C3? H45N3? 8S x 0.70 H20 (632.394): C, 58.88; H, 7.40; N, 6.64. Found: C, 58.89; H, 7.48; N, 6.39.
? -. at ^ ---.
EXAMPLE 12 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [(3-phenyl-propylcarbamoyl) -methyl] -butyrylamino} -4 -oxo-pentanoic
A sparkling white solid. MS (APCI) m / z 602.2 (M + 1, 37.7%), 360.2 (100%). Analysis calculated for C31H45N3? 8S x 0.50 H20 (628.791): C, 59.22; H, 7.37; N, 6.68. Found: C, 59.22; H, 7.37; N, 6.50.
EXAMPLE 13 Acid 3-. { 3-Methyl-2 - [(3-phenyl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-5- (2-oxo-2H-chroman-6-yloxy) -pentanoic acid
A dark solid. MS (APCI) m / z 551.2 (M + 1, 62.3%), 345.2 (100%). Analysis calculated for C8HM ^ ODS X 0.50 H20 (559.622):
C, 64.39; H, 6.30; N, 5.01. Found: C, 64.39; H, 6.18; N, 5.00.
EXAMPLE 14 5- [3- (1H-lmidazol-2-yl) -naphthalen-2-yloxy] -3- acid. { 3-methyl-2 - [(3-phenyl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic
Analysis calculated for C ^ H ^ N-Oe x CF3CO2HXH2O (730.745): C, 59.17; H, 5.66; N, 7.67. Found: C, 58.84; H, 5.61; N, 768. EXAMPLE 15 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (2-hydroxycarbamoylmethyl-3-methyl-butyrylamino) -4 acid -oxo-pentanoic
Step A Using the procedure described in Example 2, Step F, the ester 4-benzyl ester
1 - . 1-acid ring [S- (R *, R *)] - 2- (2-tert-butox? Carbon? Lmet? L-3-met? L-but? R? Lam? No) -succ? N ?co
(10 68 g, 23 52 mmol, Example 2, Step D) was converted to 7 70 g (78%) of 4-benzyl ester of the acid [S- (R *, R *)] - 2- (2 -tert-butox? carbon? lmet? l-3-met? l-but? plam? no) -succ? n? co as a solid white MS (APCI) m / z 422 3 (M + 1, 12 1% ) and 366 2 (M-55, 100%) Analysis calculated for C22H31N07 (421 495) C, 62 69, H 741, N, 3 32 Found C, 62 42, H, 7 33, N, 3 17
Step B Using the procedure described in Example 1, Step D, the 4-benzyl ester of the acid [S- (R *, R *)] -2- (2-tert-butox? Carbon? Lmet? L- 3-met? L-but? Plam? No) -succ? N? Co (6 08 g, 14 43 mmol, Example 4, Step A) was converted to 462 g (64%) of benzyl ester of the acid [S- (R *, R *)] - 5-bromo-3- (2-tert-butox? Carbon? Lmet? L-3-met? L-but? Plam? No) -4-oxo-pentane? Co as a solid white MS (APCI) m / z 498 2/500 2 (M + 1, 76 5/74 7%) and 442 2/444 2 (M-55, 100/97 1%)
Analysis calculated for C23H32BrN? 6 (498424) C, 55 43, H, 647, N, 2 81 Found C 55 28, H, 6 33, N, 2 77
Step CA a solution of (S) -1, 1-d? Met? Let? L [[(7,7-d? Met? L-2-oxob? C? Clo [2 2 1] hept-1-? l) methanol] sulfonyl] carbamate (0 82 g, 2 60 mmol) in DMF anhydride (4 ml) was added potassium tert-butoxide (0 307 g, 2 74 mmol) The reaction was stirred under an atmosphere from
Nitrogen for 30 minutes This solution was subsequently added dropwise to a solution of benzyl ester of the acid [S- (R * R *)] - 5-bromo-3- (2-tert-butox-carbon? lmet? l-3 -met? l-but? r? lam? no) -4-oxo-pentane? co (1 18 g, 2 37 mmol, Example 5, Step B) in DMF anhydride (4 ml) and the reaction was stirred all over overnight The sample was diluted with EtOAc and washed with brine (2x). The EtOAc layer was dried (Na2SO) and concentrated. The residue was chromatographed (silica gel.EtOAc 20% in hexanes) to yield 0850 g of phenolmet. l-5 - [[(1 1-d? met? letox?) carbon? l] - [[(7,7-d? met? l-2-oxob? c? clo [22 1] hept-1- ? l) met? l] sulfon? l] am? no] -3 - [[4- (1, 1-d? met? letox?) - 2- (1-met? let? l) -1 4- d? oxobut? l] am? no-4-oxopentanoate as a white foamy solid
Step D The phenolmet? L-5 - [[(1,1-d? Met? Letox?) Carbon? L] - [[(7 7-d? Met? L-2-oxob? C? Clo [ 22 1] hept-1-? L) met? L] sulfon? L] am? No] -3 - [[4- (1,1-d? Met? Letox?) - 2- (1-met? Let ? -1) -1,4-d? oxobut? l] am? no-4-oxopentanoate (0 850 g 1 15 mmol, Example 5, Step C) was treated with tr? fluoroacetic acid / CH2Cl2 (1145). ml) for 1 hour The sample was concentrated to give an oily residue which was carried out in the next step without further purification The residue was dissolved in 20 ml of CH CI2 and treated with EDCI-HCI (0441 g, 2 3 mmol), H0BT-H20 (0311 g, 23 mmol) and β-benzyl-hydroxamine hydrochloride (0276 g, 1.73 mmol). 4-Met? Lmorpholine was added dropwise ( 0 506 g, 50 mmol) and the reaction mixture was stirred at room temperature overnight The sample was diluted with EtOAc and washed successively with 5% HC and saturated NaHCO 3 solutions The organic extract was dried (Na 2 S 4) and concentrated The residue was chromatographed (silica gel, 10% EtOAc in hexanes) to yield 0400 g of benzyl ester of 3- [2- (benzyl? carbamo? l-met? l) -3-met? but? plam? no] -5- (7 7-d? met? l-2-oxo-b? c? clo [2 2 1] hept-1-? lmethanesulfon? lam? no) -4-oxo-pentanoic like a white solid
Step EA a solution of 3- [2- (benzyloxycarbamoyl-methyl) -3-methyl-butyrylamino] -5- (7,7-dimethyl-2-oxo-bicyclo [2.2.1] hept-1- benzyl ester solution] ylmethanesulfonylamino) -4-oxo-pentanoic acid (0.237 g, Example 5, Step D) in 75 ml of THF was added 10% Pd / C (0.50 g) and the mixture was hydrogenated at 50 psi of hydrogen, at room temperature for 5 hours. hours. The reaction mixture was filtered and concentrated. The residue was partitioned between EtOAc and a 0.5 N NaOH solution. The aqueous layer was acidified with HCl and extracted with EtOAc. The organic extract was dried (Na2SO4) and concentrated and the residue was triturated in ether / hexanes. The solid was collected by filtration and dried to give 5- (7,7-dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (2-hydroxycarbamoylmethyl-3-methyl-butyrylamino) acid. -4-oxo-pentanoic acid (Compound 15). MS (APCI) m / z 518.1 (M + 1, 100%). Analysis calculated for C22H35N3? 9S x 0.45 C H8? 2 x 0.59 H20 (567,880): C, 50.34; H, 7.06; N, 7.40. Found: C, 50.34; H, 6.80; N, 7.40. The following compounds can be prepared according to the procedure described in Example 15.
EXAMPLE 16 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (2- { [2- (1 H -indol-3-yl) - acid ethylcarbamoyl] -methyl.} - 3-methyl-butyrylamino) -4-oxo-pentanoic acid
A sparkling white solid. MS (APCI) m / z 645.3 (M + 1, 79.2%) and 285.1 (100%). Analysis calculated for C32H, 4N408S x 0.85 H20 (660.107): C, 58.23; H, 6.98; N, 8.49. Found: C, 58.23; H, 6.74; N, 8.26.
EXAMPLE 17 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [[3- (4-hydroxyphenyl) -propylcarbamoyl] -methyl] -butyrylamino} -4-oxo-pentanoic
A grayish solid. MS (APCI) m / z 636.2 (M + 1, 36.1%) and 376.1 (100%). Analysis calculated for C31H45N3? 9S x 0.40 H20 (642.989): C, 57.91; H, 7.18; N, 6.54. Found: C, 58.10; H, 7.46; N, 6.14. In a process analogous to Example 2 using appropriate starting materials, the corresponding compounds can be prepared (Example 18 to 20).
EXAMPLE 18 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- 3-methyl-2 - [[2-naphthalene-2-yl-ethylcarbamoyl) - methyl] -butyrylamino} -4-oxo-pentanoic
A white solid. MS (APCI) m / z 656.2 (M + 1, 31.2%) and 217.1 (100%). Analysis calculated for C ^ H ^ NÜaS x 0.90 H20 (672.031) C, 60.77; H, 7.02; N, 6.25. Found: C, 60.80; H, 6.95; N, 5.93.
EXAMPLE 19 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (3-methyl-2 { [2- (7-methyl-1) acid H-indol-3-yl) -ethylcarbamoyl] -methyl.}. -butyrylamino) -4-oxo-pentanoic acid
A solid rose. MS (APCI) m / z 659.3 (M + 1, 31.2%), 399.2 (100%). Analysis calculated for C33H46N4? 8S x 0.20 H20 (662.424): C, 59.84; H, 7.06; N, 8.46. Found: C, 59.98; H, 7.35; N, 8.08.
EXAMPLE 20 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (2 { [2- (6-fluoro-1H-indole-3) acid -yl) -ethylcarbamoyl] -methyl.} - 3-methyl-butylamino) -4-oxo-pentanoic acid
A sparkling grayish solid. MS (APCI) miz 663.3 (M + 1, 14.1%), 403.2 (100%). Analysis calculated for C32H43FN4? 8S x 0.90 H2? (678,998): C, 56.61; H, 6.65; N, 8.25. Found: C, 56.92; H, 6 78; N, 7.86.
In a process analogous to Example 7 using appropriate starting materials the corresponding compounds can be prepared (Examples 21 to 23).
EXAMPLE 21 3- [3-Methyl-2- (. {Methyl- [2- (1-methyl-1 H -indol-3-yl) -ethyl] -carbamoyl} -methyl) -butyrylamino] - acid 4-oxo-butyric
A sparkling grayish solid. MS (APCI) m / z 428.3 (M + 1, 100%). Analysis calculated for C23H31N3? 5 x 0.35 CF3C0 H (469.429): C, 60.64; H, 6.73; N, 8.95. Found: C, 60.46; H, 6.93; N, 8.78.
EXAMPLE 22 3- [3-Methyl-2- acid. { [methyl- (2-phenoxy-ethyl) -carbamoyl] -methyl} -butyrylamino) -4-oxo-butyric
A sparkling white solid. MS (APCI) miz 393.2 (M + 1, 100%). Analysis calculated for C20H28N2? 6 x 0.85 H20 (407.769): C, 58.91; H, 7.34; N, 6.87.
Found: C, 58.87; H, 7.02; N, 6.59.
EXAMPLE 23 3- (2 - ([2- (5,6-Dimethyl-benzoimidazol-1-yl) -ethylcarbamoyl] -methyl] -3-methyl-butyrylamino) -4-oxo-butyric acid, salt of trifluoroacetate
A white solid. MS (APCI) m / z 431.1 (M + 1, 35.7%), 190.2 (100%). Analysis calculated for C22H30N4? 5 x 1.30 CF3C02H (578.740): C, 51.06; H, 5.45; N, 9.68. Found: C, 51.03; H, 5.50; N, 9.38.
In a process analogous to Example 9 using appropriate starting materials, the corresponding compounds can be prepared (Examples 24 to 25).
EXAMPLE 24 5- (7,7-Dimethyl-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [(3-phenyl-propylcarbamoyl) -methyl] -butyrylamino} -4 -oxo-pentanoic
A grayish solid. MS (APCI) miz 606.1 (M + 1), 360.1 (100%). Analysis calculated for C3? H47N3? 7S x 0.25 CF3C02H (634.306): C, 59.65; H, 7.51; N, 6.62. Found: C, 59.73; H, 7.67; N, 6.27.
EXAMPLE 25 5- (7,7-Dimethyl-bicyclo [2.2.1] hept-1-ylmethanesulfonyl-amino) -3- (2 { [2- (1H-indol-3-yl) -ethylcarbamoyl] acid] -methyl-butyrylamino) -4-oxo-pentanoic acid
A dark solid. MS (APCI) miz 645.2 (M + 1), 399.1 (100%). Analysis calculated for C33H48N4? 7S x 0.34 CF3C02H (683.605): C, 59.18; H, 7.13; N, 8.20. Found: C, 59.34; H, 7.13; N, 7.81. In a process analogous to Example 15 using appropriate starting materials
the corresponding compounds can be prepared (Examples 26 to 34).
EXAMPLE 26 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-l-methanesulfonylamino) -3- acid. { 3-methyl-2 - [(3-pyridin-4-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic
A grayish solid. MS (APCI) miz 621.1 (M + 1, 5.1%), 261.1 (100%). Analysis calculated for C30H44N4? 8S x 1.26 CF3C02H (764.442): C, 51.10; H, 5.97; N, 7.33. Found: C, 51.06; H, 6.06; N, 7.08.
EXAMPLE 27 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [(3-quinolin-2-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic
A grayish solid.
MS (APCI) miz 671.3 (M + 1, 70.5%), 158.1 (100%). Analysis calculated for x 0 95 H2? (687,946): C, 59.36; H, 7.02; N, 8.14. Found. C, 59.60; H, 6.71; N, 7.75.
EXAMPLE 28 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [(3-naphthalene-1-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic
A grayish solid. MS (APCI) miz 670.3 (M + 1, 79.2%), 410.2 (100%). Analysis calculated for C 35 H 47 N 3 8 8 S x 0.90 EtOAc (749,141): C, 61.89; H, 7.29; N, 5.61. Found: C, 61.90, H, 7.28; N, 5.57.
EXAMPLE 29 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2- [(3-pyridin-3-yl-propylcarbamoyl) -methyl] -butyrylamino} -4 -oxo-pentanoic
---Y.
A grayish solid. MS (APCI) miz 621.1 (M + 1, 6.5%), 261.1 (100%). Analysis calculated for C30H44N4? 8S x 1.20 CF3C02H (757.600): C, 51.37; H, 6.23; N, 7.34. Found: C, 51.37; H, 6.01; N, 7.40.
EXAMPLE 30 Acid 3 { 2 - [(2-Benzoimidazol-1-yl-ethylcarbamoyl) -methyl] -3-methyl-butyrylamino} -5- (7,7-dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -4-oxo-pentanoic acid
A sparkling white solid. MS (APCI) miz 646.2 (M + 1, 10.4%), 286.1 (100%). Analysis calculated for C31H43N5? 8S x 1.46 CF3C? 2H (812.256): C, 50.16; H, 5.52; N, 8.62. Found: C, 50.18; H, 5.73; N, 8.46.
EXAMPLE 31 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (3-methyl-2 { [2- (1-methyl-1) acid H-indol-3-yl) -ethylcarbamoyl] -methyl.} - butyrylamino) -4-oxo-pentanoic acid
A white solid. MS (APCI) miz 659.2 (M + 1, 41.6%), 399.1 (100%). Analysis calculated for C33H 6N? 8S x 0.17 CF3C? 2H (678.205): C, 59.05; H, 6.86; N, 8.26. Found: C, 59.07; H, 6.95; N, 7.98.
EXAMPLE 32 5- (7,7-D-Methoxy-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamine) -3- acid. { 3-methyl-2 - ([2-pyridin-4-yl-ethylcarbamoyl) -methyl-butyrylamino} -4-oxo-pentanoic
A white solid. MS (APCI) miz 608.2 (M + 2, 64.9%), 607.2 (M + 1, 54.5%), 347.2 (100%). Analysis calculated for C29H42N4? 8S x 1.66 CF3C02H (796.024): C, 48.77; H, 5.53; N, 7.04. Found: C, 49.12; H, 5.43; N, 6.60.
EXAMPLE 33 3- (2- { [2- (5-Acetyl-1H-indol-3-yl) -ethylcarbamoyl] -methyl] -3-methyl-butyrylamino) -5- acid (7.7-) dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -4-oxo-pentanoic acid A white solid. MS (APCI) miz 687.3, (M + 1, 18.7%), 327.2 (100%). Analysis calculated for C: MH46N409S X 0.75 H20 (700.343): C, 58.31; H, 6.84; N, 8.00 Found: C, 58.51; H, 6.88; N, 7.61.
EXAMPLE 34 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (3-methyl-2- { [2- (1H-tetrazole-5) acid -yl) -ethylcarbamoyl] -methyl] -butyrylamino) -4-oxo-pentanoic acid
A gray solid. MS (APCI) miz 596.3, (M + 1, 24.7%), 113.2 (100%). Analysis calculated for C25H39N7? 9S x CF3C02H x 0.27 EtOAc (731.733):
C, 46.09; H, 5.88; N, 13.40. Found: C, 46.08; H, 5.78; N, 13.37.
EXAMPLE 35 N4- (2-Benzoimidazol-1-yl-ethyl) -N1- (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-succinamide
Step A A solution of N-benzyloxycarbonyl-3-amino-4-oxo-butanoic acid ß-tert-butyl diethyl acetal ester (24.1 g, 63.2 mmol, prepared from Cbz-Asp (? TBu) -? H following the procedure of Chapman KT (Bioorganic &Medicinal Chemistry Letters 1992; 2: 613-618) in 150 ml of ethanol was treated with 1.0 g of 20% Pd / C.The sample was hydrogenated at room temperature and 51 psig of H2 3.5 hours The sample was filtered and concentrated to give 15.8 g (-100%) of 3-amino-4-oxo-butanoic acid β-tert-butyl diethyl acetal ester as a yellow liquid MS (APCI) m / z 248.1 (M + 1, 100%).
Step B: A mixture of 3-amino-4-oxo-butanoic acid β-tert-butyl diethyl acetal ester (15.8 g, 63.9 mmol, Example 35, Step A), 4-tert-butyl ester of (S) - acid 2-isopropyl-succinic (15.2 g, 70.3 mmol, Example 2, Step C), EDCI x HCl (13.5 g, 70.4 mmol),
HOBT x H20 (10.8 g, 70.5 mmol) and 4-methylmoproline (8.8 ml, 80.0 mmol) in 250 ml of CH 2 Cl 2 was stirred at room temperature for 12 hours. The solution was concentrated, then partitioned between EtOAc and saturated NaHCO 3 solution. The organic extract was washed with saturated KH2P04 solutions and brine, dried (MgSO4), filtered and concentrated. The resulting dark brown oil was chromatographed (MPLC, silica gel, 100% CH 2 Cl 2 to MeOH in CH 2 Cl 2) to give 13.9 g (49%) of 3- (2-tert-butoxycarbonylmethyl) -β-tert-butyl diethyl acetal ester. 3-methyl-butyrylamino) -4-oxo-butanoic as a pale yellow oil. MS (APCI) miz 224.1 (100%).
Step CA a solution of 3- (2-tert-butoxycarbonylmethyl-3-methyl-butyrylamino) -4-oxo-butanoic acid ß-tert-butyl diethyl acetal ester (8.3 g, 18.6 mmol, Example 35, Step B) 100 ml of CH CI was treated with 20 ml of trifluoroacetic acid. The solution was stirred at room temperature for 2 hours, concentrated, then partitioned between EtOAc and saturated solution of KH P04. The organic extract was washed with brine solution, dried (MgSO 4), filtered and concentrated to give 3.8 g (71%) of N- (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) acid. -2-isopropyl-succinamic as a yellow oil. MS (APCI) miz 228.1 (M + 1, 100%).
Step D: A mixture of N- (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-succinamic acid (3.8 g, 13.1 mmol, Example 35, Step C), 1- (2- aminoethyl) benzimidazole (3.2 g, 19.8 mmol, prepared from benzimidazole using the procedure of Table AM et al., Synthetic Communications, 1991; 21: 535-544), EDCI x HCl (3.0 g, 15.8 mmol) and N- methylmorpholine (2.2 ml, 20.0 mmol) in 100 ml of CH2Cl2 was stirred at room temperature
for 12 hours. The solution was concentrated, then partitioned between EtOAc and saturated NaHCO 3 solution. The organic extract was washed with saturated solutions of KH2P0 and brine, dried (MgSO4), filtered and concentrated The resulting dark oily solid was chromatographed (MPLC, silica gel, 5% MeOH in CH2Cl2) to give 2.8 g (49%) of N4- (2-benzo-midazol-1-yl-ethyl) -N1- (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-sucinamide as a white foamy solid. MS (APCI) miz 432.2, (M + 2, 100%). Analysis calculated for C 22 H 30 N 4 5 5 (430,508): C, 61.38; H, 7.02; N, 13.01. Found: C, 61.18; H, 6.95; N, 13.05.
In a process analogous to Example 35 using appropriate starting materials, the corresponding compounds can be prepared (Example 36 to 52). The initial 2-aryl-ethylamines that were not commercially available were prepared following the procedure of Table A.M. et al., Synthetic Communications
1991; 21,535-544.
EXAMPLE 36 N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -N4- [2- (1H-indol-3-yl) -ethyl] -2-isopropyl-succinamide
A grayish solid. MS (APCI) miz 430.3, (M + 1, 100%). Analysis calculated for C 3 H 31 N 3 5 5 x 0.25 H 20 (434,024): C, 63.65; H, 7.32; N, 9.68. Found: C, 63.68; H, 7.34; N, 9.36
EXAMPLE 37 N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N4- [2- (1-methyl-1H-indol-3-yl) -et L] -succinamide
A grayish solid. MS (APCI) m / z 444.3, (M + 1, 53.5%), 299.2 (100%). Analysis calculated for C2 H33N3? 5 (443,548): C, 64.99; H, 7.50; N, 9.47. Found: C, 65.16, H, 7.47; N, 9.40.
EXAMPLE 38 N - [2- (5,6-Dichloro-benzoimidazol-1-yl) -ethyl] -N1- (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-succinamide
A solid white MS (APCI) miz 430.3, (M + 1, 100%). Analysis calculated for C 22 H 28 Cl 2 N 4 5 5 (499,398): C, 52.91; H, 5.65; N, 11.22. Found-C, 52.91, H, 5.70; N, 11.07.
EXAMPLE 39 N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N4- (-phenoxy-ethyl) -succinamide
MS solid white (APCI) miz 407.2, (M + 1, 66.2%), 262.1 (100%). Analysis calculated for C2iH30N2? 6 (406.483): C, 62.05, H, 7.44; N, 6.89. Found: C, 62.29; H, 7.49; N, 6.74.
EXAMPLE 40 N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N - [2- (6-methoxy-1H-indol-3-H) -ethyl-succinamide
A grayish solid. MS (APCI) miz 460.1, (M + 1, 100%). Analysis calculated for C2 H33N3? 6 (459 547): C, 62.73, H, 7.24; N, 9.14. Found-C, 63.11; H, 7.02; N, 9.11.
EXAMPLE 41 N4- (2-Benzotriazol-1-yl-ethyl) -N1- (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-succinamide
A yellow solid. MS (APCI) miz 432.1, (M + 1, 100%). Analysis calculated for C2iH29N505 (431.496): C, 58.46; H, 6.77; N, 16.23. Found: C, 56.96; H, 6.45; N, 15.64.
EXAMPLE 42 N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -N4- (2-indazol-1-yl-ethyl) -2-isopropyl-succinamide
A yellow solid. MS (APCI) miz 431.2, (M + 1, 100%). Analysis calculated for C 22 H 30 N 5 (430,508): C, 61.38; H, 7.02; N, 13.01. Found: C, 60.91; H, 7.16; N, 12.81.
EXAMPLE 43 N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N4- (2-phenylamino-ethyl) -succinamide
A grayish solid MS (APCI) / z 406.1, (M + 1, 100%). Analysis calculated for C2? H31N3? 5 x 0.15 H20 (408.201): C, 61.79, H, 7.73; N, 10.29. Found: C, 61.77; H, 7.56; N, 10.20.
EXAMPLE 44 N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -N4- [2- (6-fluoro-1H-indol-3-yl) -ethyl] -2-isopropyl-succinamide
A white solid. MS (APCI) miz 446.1, (M-1, 100%). Analysis calculated for C23H3oFN3? 5 (447.511): C, 61.73; H, 6.76; N, 9.39. Found. C, 62.22; H, 6.59; N, 10.45
EXAMPLE 45 N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -N4- [2- (7-methyl-1H-indol-3-yl) -ethyl] -2-isopropyl-succinamide
A white solid. MS (APCI) miz 442.1, (M-1, 100%). Analysis calculated for C 24 H 33 N 30 (443,548): C, 64.99; H, 7.50; N, 9.47. Found: C, 65.28; H, 7.65; N, 9.46.
EXAMPLE 46 N1- (2-Ethoxy-5-oxotetrahydro-furan-3-yl) -2-isopropyl-N - [2- (2-methyl-benzoimidazol-1-yl) -ethyl] -succinamide
A sparkling grayish solid. MS (APCI) miz 446.2, (M + 2, 55.9%), 445.2, (M + 1, 51.5%), 300.1, (100%). Analysis calculated for C23H32N40 x 0.50 H20 (453.543): C, 60.91; H, 7.33; N, 12.35. Found: C, 60.94; H, 7.04; N, 12 05.
EXAMPLE 47 N - (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N 4 - [3- (3,4,5-trimethoxy-phenyl) -propyl] -succinamide
A white solid. MS (APCI) miz 495.1.2, (M + 1, 100%). Analysis calculated for C25H38N208 (494.590): C, 60.71; H, 7 74; N, 5 66. Found: C, 60.47; H, 7.85; N, 5 77.
EXAMPLE 48 N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N4- [2- (phenyl) -ethyl] -succinamide
A white solid. MS (APCI) miz 389.1, (M-1, 100%). Analysis calculated for C2iH30N2? 5 (390484): C, 64.60; H, 7.74; N, 7.17. Found: C, 64.50; H, 7.90; N, 6.83
EXAMPLE 49 N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N4- [4- (phenyl) -butyl] -succinamide
A soft white solid. MS (APCI) m / z 419.1 (M + 1, 100%). Analysis calculated for C 23 H 34 N 20 (418,538): C, 6601; H, 8.19, N, 6.69. Found: C, 65.91; H, 8.21; N, 6.50.
EXAMPLE 50 N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -N4- (2-indol-1-yl-ethyl-2-isopropyl-succinamide)
A solid dark reddish brown. MS (APCI) m / z 430.1, (M + 1, 100%). Analysis calculated for C23H31N3? 5 (429.521): C, 64.32; H, 7.28; N, 9.78. Found: C, 64.68; H, 7.02; N, 10.07.
EXAMPLE 51 N - (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N 4 - [4- (phenyl) -propyl] -succinamide
A dark solid. MS (APCI) miz 405.1, (M + 1, 100%). Analysis calculated for C22H32N2O5 (404.511):
C, 65.32; H, 7.97, N, 6.93. Found: C, 66.27; H, 8.07; N, 7.21.
EXAMPLE 52 N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -N4- [2- (5-fluoro-1H-indol-3-yl) -ethyl] -2-isopropyl-succinamide
A grayish solid. MS (APCI) miz 446.1, (M + 1, 100%). Analysis calculated for C23H30FN3? 5 (447.511): C, 61.73; H, 6.76; N, 9.39. Found: C, 61.35; H, 6.78; N, 9.36.
EXAMPLE 53 Acid 3-. { 2 - [(2-Benzoimidazol-1-ethyl-ethylcarbamoyl) -methyl] -3-methyl-butyrylamino} -4-oxo-butyric
A solution of N4- (2-benzoimidazol-1-yl-ethyl) -N1- (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-succinamide (1.25 g, 2.54 mmol, Example 35, Step D) in 25 ml of acetonitrile was treated with 25 ml of a 5% HCl solution. The sample was stirred for 1 hour, then concentrated in a grayish solid. The sample was washed with acetone, filtered and dried under vacuum to give 1.10 g of 3- acid. { 2 - [(2-benzoimidazol-1-yl-ethylcarbamoyl) -methyl] -3-methyl-butyrylamino} -4-oxo-butyric acid, hydrochloride as a white solid, mp 134-141 ° C, dec. MS (APCI) miz 403.3, (M + 1, 100%). Analysis calculated for C20H26N4? 5x HCl x 1.18 H2? (460,173): C, 52.50; H, 6.43; N, 12.18. Found: C, 52.21; H, 6.70; N, 11.52. In a process analogous to Example 53 using appropriate starting materials, the corresponding compounds can be prepared (Examples 54 to 62). EXAMPLE 54 3- (3-Methyl-2- { [2- (1-methyl-1 H -indol-3-yl) -ethylcarbamoyl] -methyl]. Butyrylamino) -4-oxo- Butyric
The reaction mixture was basified, extracted, then chromatographed (MPLC, silica gel, 20% CF3C02H-20% acetone in CH2Cl2) to give the title compound as a gray solid. MS (APCI) / z 416.2, (M + 1, 32.5%), 398.1 (M-17, 100%).
»*?
Analysis calculated for C22H29N3? 5x 0.05 CF3C02H (421.195): C, 63.02; H, 6.95; N, 9.98. Found: C, 63 16; H, 6.84; N, 9.62.
EXAMPLE 55 3- (2- { [2- (5-Fluoro-1-methyl-1 H -indol-3-yl) -ethylcarbamoyl] -methyl] -3-methyl-butyrylamino) - 4-oxo-butyric
The reaction mixture was basified, extracted, then chromatographed (MPLC, silica gel, HC? 1H 2% -acetone 20% in CH2Cl2) to give the title compound as a white solid. MS (APCI) m / z 434.2, (M + 1, 100%) Analysis calculated for C 22 H 28 FN 3 5 5 x 0.96 HC02H (477,669): C, 57.73; H, 6.31; N, 8.80. Found: C, 57.73; H, 6.39; N, 8.65.
EXAMPLE 56 3- (2- { [2- (5,6-Dichloro-benzoimidazol-1-yl) -ethylcarbamoyl] -methyl] -3-methyl-butyrylamino) -4-oxo-butyric acid
«•.
A white solid. MS (APCI) miz 254.1 / 356.1 / 358.1, (M + 1, 100 / 48.6 / 14.3%). Analysis calculated for C2oH2 CI2N4? 5x HCl x 0.50 H20 (516,813). C, 46.48; H, 5.07; N, 10.84. Found: C, 46.56; H, 5.31; N, 10.17.
EXAMPLE 57 3- (2-. {[[(2-Benzoimidazol-1-yl-ethyl] -methyl-carbamoyl] -methyl] -3-methyl-butyl-amino acid) -4 -oxo-butyric
A beige solid. MS (APCI) miz 417.2, (M + 1, 100%)
Analysis calculated for C2? H28N4? 5 2.57 HCl (510.186). C, 49.44; H, 6.04; N, 10.98. Found: C, 49.46; H, 6.41; N, 10.63.
EXAMPLE 58 Acid 3 { 2 - [(2-Benzotriazol-1-yl-ethylcarbamoyl) -methyl] -3-methyl-butylamino} -4-oxo-butyric
MS (APCI) miz 404.0, (M + 1, 100%). Analysis calculated for C19H25 505 x 1.54 HCl x 0.59 H20 (470.221). C, 48.53; H, 5.94; N, 14.89. Found: C, 48.54; H, 5.94; N, 14.51.
EXAMPLE 59 Acid 3-. { 2 - [(2-ldazol-1-ethyl-ethylcarbamoyl) -methyl] -3-methyl-butyrylamino} -4-oxo-butyric
A grayish solid. MS (APCI) miz 403.1, (M + 1, 100%). Analysis calculated for C20H26N4? 5x 1.34 HCl x 1.22 H20 (473.290). C, 50.76; H, 6.34; N, 11.84. Found: C, 50.75; H, 6.34; N, 11.71.
EXAMPLE 60 3- [2- ( { [2- (5,6-Dimethyl-benzoimidazol-1-yl) -ethyl] -methylcarbamoyl} -methyl) -3-methyl-butyrylamino] 4-oxo- Butyric
A white solid. MS (APCI) miz 443.1, (M-1, 100%). Analysis calculated for C23H32N4? 5x 2.0 HCl x 0.35 H20 (523.763): C, 52.74; H, 6.68; N, 10.70. Found: C, 52.75; H, 6.88; N, 10.39.
EXAMPLE 61 3- [2- (. {2- (2-Methyl-benzoamidazol-1-yl) -ethyl] -methylcarbamoyl} - methyl) -3-methyl-butyrylamino] 4-oxo- Butyric
A grayish solid. MS (APCI) miz 415.1, (M-1, 100%). Analysis calculated for C2, H28N4? 5 1.1 HCl (456.588): C, 55.24 H, 6.42; N, 12.27. Found: C, 55.14; H, 6.64; N, 11.01.
EXAMPLE 62 3- (3-Methyl-2- {[[3- (3,4,5-trimethoxy-phenyl) -propylcarbamoyl] -methyl} - butyrylamino) -4-oxo-butyric acid
A white solid. MS (APCI) miz 467.1, (M + 1, 100%). Analysis calculated for C23H34N2? 8 x 0.70 H20 (479.147): C, 57.66; H, 7.45; N, 5.85. Found: C, 57.44; H, 7.13; N, 5.72.
EXAMPLE 63 Ethyl ester of 3- acid. { 3-Methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -4-oxo-butyric
Step A: A mixture of 1-benzyl ester of (S) -2-isopropyl-succinic acid (10.1 g, 40.2 mmol, Example 3, Step A), 2-phenoxy-1-ethylamine (6.1 g, 44.2 mmol), HOBT x H20 (7.7 g, 50.2 mmol), EDCI x HCl (9.6 g, 50.2 mmol) and N-methylmorpholine (6.6 mL, 60.0 mmol) in 100 mL of CH 2 Cl 2, was stirred at room temperature for 12 hours The sample was concentrated, subsequently, it was partitioned between EtOAc and saturated NaHCO 3 solution. The organic extract was washed with saturated KH2P04 solutions and brine, dried (MgSO4), filtered and concentrated. The resulting brown liquid was chromatographed (MPLC, silica gel, 80% hexanes-20% EtOAc to 50% hexanes-50% EtOAc) to give 12.3 g (83%) of benzyl ester of the acid (S) -2- [(2-Phenoxy-ethylcarbamoyl) -methyl] -3-methyl-butyric as a pale yellow liquid MS (APCI) miz 370.0 (M + 1, 100%). Hydrogenation of the (S) -2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -3-methyl-butyric acid benzyl ester (12.3 g, 32.2 mmol) with 20% Pd / C in 100 ml of ethanol a Balloon pressure provided 9.6 g (-100%) of (S) -2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -3-methyl-butyric acid as a pale yellow oil. MS (APCI) miz 280.0 (M + 1, 100%).
Step B A mixture of (S) -2 - [(2-phenoxy-ethylcarbamoll) -methyl] -3-methyl-butyric acid (4.8 g, 17 2 mmol, Example 63, Step A), 3-amino-4 acid Ethyl ester pentanoic acid hydrochloride (3.8 g, 21.2 mmol, prepared using the procedure of Hauser FM et al., J. Org. Chem. 1987; 52: 5041-5044), HOBT x H2? (3.3 g, 21.5 mmol), EDCI x HCl (4.1 g, 21.5 mmol) and N-methylmorpholine (4.7 mL, 42.7 mmol) in 150 mL of CH2Cl2 was stirred at room temperature for 12 hours. The sample was concentrated, then partitioned between EtOAc and saturated NaHCO 3 solution, The organic extract was washed with saturated solutions of KH 2 PO and brine, dried (MgSO 4), filtered and concentrated The resulting yellow oily solid was chromatographed (MPLC, silica gel , 25% hexanes - 75% EtOAc) to give 4.2 g (60%) of ethyl ester of 3- acid. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -4-Pentenoic as a pale yellow waxy solid. MS (APCI) miz 405.1 (M + 1, 100%).
Stage C The ozone gas bubbled through a solution at -78 ° C of ethyl ester of 3- acid. { 3-methyl-2 - [(2-phenoxy-et? Lcarbamoyl) -methyl] -butyrylamino} -4-pentenoic acid (4.2 g, 10.3 mmol, Example 63, Step B) in 100 ml of CH2Cl2 until a blue color formed. The reaction was warmed to -78 ° C by the dropwise addition of dimethyl sulfide (2.3 mL, 31.3 mmol). The sample was concentrated, then partitioned between EtOAc and saturated NaHCO3 solution. The organic extract was washed with saturated solutions of KH2P04 and brine, dried (MgSO4), filtered, concentrated and chromatographed (MPLC, silica gel, 25% hexanes - 75% EtOAc) to give ethyl ester of 3- acid. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamine} -4-oxo-butyric as a white solid. MS (APCI) miz 407.1, (M + 1, 100%). Analysis calculated for C21H3oN2? 6 x 0.17 H20 (409.546):
,. »? -
C, 61.59; H, 7.47; N, 6.84. Found: C, 61.57; H, 7.46; N, 6.69.
EXAMPLE 64 Ethyl ester of 3-Cyano-3- acid. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -propionic
Step A A solution of 4-amino-3 - [(benzyloxycarbonyl) -amino] -4-oxo-butanoic acid (8.9 g, 33.6 mmol) and 10 drops of concentrated sulfuric acid in 250 mL of ethanol was refluxed for 12 hours. The solution was cooled, concentrated, then partitioned between EtOAc and saturated NaHCO 3 solution, The organic extract was washed with saturated solutions of KH 2 PO 4 and brine, dried (MgSO 4), filtered and concentrated to give 4.7 g (48%) of ester. ethyl 4-amino-3 - [(benzyloxycarbonyl) -amino] -4-oxo-butanoic acid as a white solid. MS (APCI) miz 292.0, (M + 1, 100%). Analysis calculated for C14Hl8N205 (294.310): C, 57.14; H, 6.16; N, 9.52. Found: C, 57.28; H, 6.11; N, 9.45.
Hydrogenation of the ethyl ester of 4-amino-3 - [(benzyl] carbonyl] -am [no] -4-oxo-butanoic acid (2 1 g, 74 mmol) with 20% Pd / C % in 100 ml of ethanol at balloon pressure gave 1 2 g (-100%) of ethyl ester of 3-4-d? am? no-4-oxo-butane? co as a colorless oily solid 5 MS (APCI ) miz 161 1 (M + 1, 100%)
Step B: A mixture of (S) -2 - [(2-phenoxy? -et? Lcarbamo? L) -met? L] -3-met? L-butpic acid (2.5 g, 90 mmol, Example 63, Step A), ethyl ester of 3,4-d? Am? No-4-oxo-butane? Co (1 2 g,
74 mmol, Example 64, Step A), HOBT x H20 (1 4 g, 9 3 mmol), EDCI x HCl (3.6 g, 18.6 mmol) and N-methylmorpholine (2 mL, 19 mmol) in 100 ml of CH2CI2 was stirred at room temperature for 12 hours The sample was concentrated, then partitioned between EtOAc and saturated NaHCO3 solution, The organic extract was washed with saturated KH2P04 solutions and brine, dried (MgSO), filtered and concentrated The grayish oily solid
The resulting sample was chromatographed (MPLC, silica gel, 5% methanol in chloroform) to give 0 35 g (11%) of ethyl ester of 3-acid. { 3-met? L-2 - [(2-phenox? -et? Lcarbamo? L) -met? L] -but? Plam? No} -4- oxo-butpic as a solid white MS (APCI) miz 420 1 (M-1, 30 9%), 374 1 (100%) Analysis calculated for C2? H31N3? 6 (421 498) 20 C, 5984, H, 741, N, 9 97 Found C, 6023, H, 7 38, N, 990
Step C To a stirring solution at 0 ° C under N2 of ethyl ester of 4-amino-3- acid. { 3- 5 met? L-2 - [(2-phenoxy? -et? Lcarbamo? L) -met? L] -but? Plam? No} -4-oxo-butyr? Co (0 35 g, 0 83 mmol,
Example 64, Step B) and tetylamino (0 29 mL, 208 mmol) in 50 mL of THF was added by
Trifluoroacetic anhydride drip (0.14 ml, 0.99 mmol). The sample was stirred at 0 ° C for 1 hour, then it was warmed to 0 ° C by dropwise addition of saturated NaNCO 3 solution (-10 ml). The sample was concentrated, then extracted with EtOAc. The organic extract was washed with saturated KH 2 P 4 solutions and brine, dried (MgSO 4), filtered and concentrated. Chromatography (MPLC, silica gel, 25% hexanes-EtOAc 75%) yielded 0.21 g (63%) of 3-cyano-3- ethyl ester. { 3-methyl-2 - [(2-phenoxy-et? Lcarbamoyl) -methyl] -butyrylamide] -propionic as a white solid. MS (APCI) miz 404.1, (M + 1, 100%). Analysis calculated for C21H29N306 x 0.35 H20 (409.788): C, 61.55; H, 7.30; N, 1025. Found: C, 61.73; H, 7.23; N, 9.87.
EXAMPLE 65 3-Cyano-3- Acid. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -propionic
Step A: A solution of (S) -2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -3-methyl-butyric acid (1.67 g,
. 99 mmol. Example 63, Step A), H-Asp (? TBu) -? Me? CI (1.58 g, 6.59 mmol), H0BT-H20
(1.00 g, 6.53 mmol), EDCI [CI] (1.26 g, 6.57 mmol) and N-methylmorpholine (1.50 mL, 13.64 mmol) in 50 mL of CH2CI2 was stirred at room temperature for 12 hours. The sample was concentrated, then it was divided between EtOAc and saturated NaHCO 3 solution,
Organic extract was washed with saturated KH2P0 solutions and brine, dried (MgSO4), filtered and concentrated. The resulting yellow oil was chromatographed (MPLC, silica gel, 25% hexanes / 75% EtOAc) to give 1.69 g (61%) of 1-methyl ester-4-tert-butyl ester of 2- acid. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -succinic as a white waxy solid. MS (APCI) miz 465.2, (M + 1, 100%).
Step B A solution of ester 1-methyl ester 4-tert-butyl acid 2-. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} Sucucin (1.69 g, 3.65 mmol, Example 65, Step A), in 20 ml of THF was treated at room temperature with 1.0 M lithium hydroxide solution (4.4 ml, 4.40 mmol). The nebulous sample was stirred at room temperature for 1 hour, acidified with saturated KH2P0 solution (-50 ml), concentrated (to remove the majority of THF), then extracted with EtOAc. The organic extract was washed with brine solution, dried (MgSO 4) and filtered to give 1.38 g (84%) of 4-tert-butyl ester of 2- acid. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -succinic as a white solid. MS (APCI) miz 451.2 (M-1, 76.5%), 179.1 (100%). Analysis calculated for C ^ H ^ N? O? x 0.20 H20 (454.140): C, 60.83; H, 7.64; N, 6.17. Found: C, 60.84; H, 7.63; N, 5.98.
Step C To a stirring solution of 4-tert-butyl ester of 2- acid. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} succinic (1.00 g, 2.23 mmol, Example 65, Step B) and N-methylmorpholine (0.31 mL, 2.82 mmol) in 25 mL of CH2Cl2 at ca. -45 ° C (Dry Ice-CH3CN suspension) was added dropwise with iso-butyl chloroformate (0.32 ml, 2.47
mmol). The sample was stirred for 15 minutes, then it was tempered by the dropwise addition of a concentrated ammonium hydroxide solution (15 ml). The sample was warmed to room temperature, concentrated, then extracted with EtOAc. The organic extract was washed with brine solution, dried (MgSO 4) and filtered to give 1.12 g (> 100%) of 3-tert-butyl ester. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] butyrylamine} -4-oxo-butanoic as a white solid. MS (APCI) miz 448.1, (M-1, 92.6%), 374.0 (100%). The above primary amine was dehydrated using the same conditions as those described in Example 64, Step C, subsequently chromatographed (MPLC, silica gel 25% hexanes / 75% EtOAc) to give 0.64 g (62%) of tert-butyl ester of 3-cyano-3- acid. { 3-methyl-2 - [(2-phenoxy? -ethylcarbamoyl) -met? L] -butyrylamino} -propion? co as a white solid. MS (APCI) miz 305.1 (100%).
Stage D A solution of tert-butyl ester of 3-cyano-3- acid. { 3-methyl-2 - [(2-phenoxy-et? Lcarbamoyl) -methyl] -butiplamino} -propionic (0.64 g, 1.48 mmol, Example 65, Step C) and 5.0 ml of trifluoroacetic acid in 25 ml of CH 2 Cl 2 was stirred at room temperature for 1 hour. The solution was concentrated, then partitioned between EtOAc and saturated KH2P04 solution. The organic extract was washed with brine solution, dried (MgSO), filtered and concentrated to a pale yellow oil. Diethyl ester (-50 ml) was added and the oil solidified slowly. The sample was filtered and dried under vacuum to give 0.28 g (49%) of 3-cyano-3- acid. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -propionic as a white solid. MS (APCI) m / z 377.0 (M + 2, 100%). Analysis calculated for C19H26N3? 5 x 1.20 H20 (397.047): C, 57.48; H, 6.96; N, 10.58.
Found: C, 57.53; H, 6.68; N, 10.28.
BIOLOGICAL TESTS
INHIBITION STUDIES The compounds of Formula I are inhibitors of ICE as demonstrated by measuring K, (μM) and IC50 (μM) using the protocol described herein. Serial dilutions of each compound of the invention were prepared using an 8-fold initial dilution of a DMSO solution in HGE (100 mM HEPES, 20% v / v glycerol, 0.5 mM EDTA), followed by seven dilutions of 2- you see in HGE + DMSO 12.5%. Ten microliters of diluted solutions or vehicle (HGE + 12.5% DMSO) were placed in triplicate in a 96-well concentration plate. The enzyme was diluted in a test stabilizer (HGE, 5mM STT, 15 μM AC-Tyr-Val-Ala-Asp-AMC, 0.5 nM final enzyme concentration, preheated to 30 ° C) and this reaction mixture was added to the plate in 90 μl / dish. Hydrolysis of the substrate was monitored for 300 seconds at 30 ° C using 385 and 460 nm emission and excitation filters, respectively. The curves in triplicate were averaged and the slopes were evaluated by linear regression. To evaluate K "the traces of the inhibition percentage against the inhibition concentration were fixed by non-linear regression to a reversible, competition model:
g 7o, In .h.i.b.ic .ió.n = _ 100. [I]
where the competition factor is (1 + [S] / KM) = 2.
Dose Test Response (IC50) Calorimeter ICE Diluted inhibitor solutions were prepared by serially diluting twice from a primary solution whose concentration was selected (based on filtration results or previous attempts in the evaluation of IC50) to achieve approximately 95% inhibition in most concentrated plate. The aliquots of each dilution were transferred to a concentration plate in triplicate.
The ICE enzyme was diluted to approximately 24 nM in HGE stabilizer (100 mM HEPES pH 7.5, 0.5 mM EDTA, 20% glycerol, 0.1% Bovine Serum Albumin (BSA) and activated by the addition of dithiothreitol (DTT) to a final concentration of 5 mM The activated enzyme subsequently formed aliquots in the plates containing the inhibitor or the vehicle and the plate was preincubated for 60 minutes at room temperature Substrate (Ac-Tyr-Val-Ala-Asp-pNA) add to each dish to a final concentration of 50 μM and the plates are placed in the plate reader of concentration heated to 25 ° C. Starting 5 minutes after the addition of the substrate, the absorbance of the plates (405 nm) is monitored for 1 hour and the activity was calculated as the main proportion of change in absorbance during this interval.
IC50 Determinations-PBMC Cell Test In addition to the evidence that the compounds of Formula I are inhibitors of ICE, they are provided by their ability to produce IL-1β in human peripheral blood mononuclear cells (PMMCs) as described herein. . The PBMC were isolated from heparinized blood by centrifugation in a ficoll pad, then washed three times with stabilized phosphate saline. The PMMCs are suspended in a medium containing RPMI 1640 with glutamine, penicillin, streptomycin and 2% human AB serum, then plated at 106 cells per dish in 96-well flat lower plates. PBMCs are stimulated
overnight with 10 ng / ml llpopolysaccharide (LPS, strand E. Coli 0111: B4; Calbiochem) in the presence or absence of a compound of Formula I. The medium is collected and the maturity level of 1L-1β is determined using an ELISA kit from R &D Systems. Cells are cultured for an additional 4 hours in the presence of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltettrazolium bromide (MTT) to determine viability.
Dosage-Response Test (IC50) Calorimetric lch-2 Inhibition of the lch-2 enzyme was achieved as described above for ICE, except that the enzyme is used at 64 nM and 60 μM of the specific substrate lch-2 Ac-Leu-2 Glu-Val-Asp-pNA that is used in place of the ICE substrate Ac-Tyr-Val-Ala-Asp-pNA. The results of these tests are shown in the following Table 2.
TABLE 2 Example No. ICEK¡ ICEIC50 PBMC IC50 ICH2 IC50
(μM) (μM) (μM) (Caspasa 4) (KM) l 1.60 14.50 82.50 88.96
2 0.106 ° -79 < A 6.25 3.31
3 0.045 0.40 ** 3.00 4.65
4 2.18 16.80 65.00 9.72
0.336 3.55 35.00 9.02
6 0.142 1.060 3.25 9.59
7 0.115 0.444 6.00 20.72
S 0.0150 0.54 3.75 - 9 0.0234 0.053 2.10 4.22
! 0 0.539 3.270 21.50 25.74
U 0.058 0.440 5.50 15.69
12 0.0128 0.061 1.20 1.71
13 0.0067 0.052 2.35 0.25
14 0.1066 0.0087 19.00 - 15 0.441 2.050 17.50 13.08
16 0.0025 0.0051 0.35 1.47
17 0.0329 0.0790 2.25 4.68
18 0.0236 0.0894 2.05 3.01
19 0.0009 0.0085 0.40 2.38
0.0015 0.0110 2.45 61.97
21 0.0280 0.130 7.50 209.07
22 0.1330 1.6700 19.00 - 23 0.0029 0.014S 3.60 4.43
24 0.0207 0.3600 1.60 8.66
0.0058 0.0483 1.10 3.54
26 0.0266 0.1360 2.00 9.91
27 .0.0175 0.1470 1.00 9.93
28 0.0061 0.2540 0.55 5.58
29 0.0245 0.1130 1.90 4.79
0.0011 0.0052 0.41 3.14
31 0.0004 0.0059 0-24 1-24
32 0.0260 0.4580 3.30 14.12
33 0.006S 0.0230 1.60 3.09
34 0.0166 0.1150 2.60 1.10
Example No. ICEKj ICBIC50 PBMCIC50 ICH2 IC50
(μM) (μM) (μM) (Caspase 4) (μM)
0.0511 1.0600 5.50 - 36 0.6300 0.599 & 1.30 101.17
37 0.0297 0.5810 2.00 127.60
38 0.0164 0.3770 3.40 18.73
39 0.4465 13-2000 5.00 - 40 0.0354 1.1500 2.90 - 41 0.4090 13.0000 17.50 - 42 0.1910 1.7300 7.50 - 43 0.0981 2-2800 7.50 - 44 0.0475 1-2200 2.50 -
45 0.0370 0.7500 2.60 173.83
46 0.0284 0.4380 6.50 366.57
47 1.9300 112.0000 11.00 - 48 1.0060 59.9000 13.50 -
49 2.1500 123.0000 - - 50 0.0538 0.9240 2.00 - 51 0.259 15.00 16.25 -
52 0.0185 0.4855 0.75 - 53 0.0200 0.0737 8.30 32.51
S4 0.0040 0.0370 2.85 11.13
55 0.0079 0.0370 5.30 11.48
56 0.0044 0.0286 3.25 4.02
57 0.0229 0.2270 3.75 38.03
58 0.0318 0.3360 7.75 10.63
59 0.0332 0.0566 3.75 10.40
60 0.0092 0.4680 5.00 12.71
61 0.0047 0.0233 2.90 - 62 0.274 2.560 23.00 63 6.92 197.00 14.50 64 > I00 - > 100 - 65 107.00 - • > 100 -
The following abbreviations are used through this patent application:
HEPES 4- (2-Hydroxymethyl) -1-piperazine ethane sulfonic acid
DTT Dithiothreitol EDTA Acid ethylene diamine tetra acetic Ac Acetyl Glu Glutamic acid LEU Leucine Tyr Tyrosine Val Valine Ala Alanine Asp Aspartic acid AMC 7-amino-4-methyl cu amino pNA For nitroaniline pf Melting point EtOAc Ethyl acetate MS Mass spectrum THF Tetrahydrofuran t-Bu Tert-butyl Me Methyl DMF Dimethylformamide MPLC Medium pressure liquid chromatography psig Pounds per square inch (calibration) HOBt 1-Hydroxybenzotriazole EDCI N-ethyl-N'-dimethylaminopropylcarbodiimide
Claims (35)
1. A compound of Formula I each R 'is independently hydrogen or Ci-Cß alkyl; R1 and R2 independently are hydrogen, C? -C6 alkyl, -OH, aryl- (CH2) ", - (CH2) n-substituted aryl, - (CH2)" -? - aryl - (CH2) n -? - substituted aryl, - (CH2) "- S-aryl, - (CH2) n-S-substituted aryl, - (CH2) n-S-heteroaryl, - (CH2)" - S-substituted heteroaryl, - (CH2) n-NR'-aryl, - (CH2) n-NR'-substituted aryl, - (CH2) "- NR'-heteroaryl, - (CH2) n-NR'-substituted heteroaryl, - (CH2) n-heteroaryl or - (CH2) "-substituted heteroaryl; each n is independently 0 to 6; R 3 is hydrogen or C Cß alkyl; R4 is C, -Cβ or hydrogen alkyl and X is hydrogen, OI - (CH2) nN.S- (CH2) n-aryl, II R'O or I - (CH2) nNS- (CH2) n-aryl replaced, I i R'O - (CH2) n-S- (CH2) "- aryl, - (CH2) n-S- (CH2)" - substituted aryl, - (CH ^ ^ 0 - « and the pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, wherein R 'is hydrogen or methyl.
3. A compound according to claim 1, wherein each R 'is hydrogen.
4. A compound according to claim 1, wherein R3 is hydrogen and R4 is methyl, ethyl or isopropyl.
5. A compound according to claim 1 wherein R1 is hydrogen or methyl and R2 is - (CH2) n-phenyl, hydrogen, (CH2) n -? - phenol, -OH, - (CH2) "- benzimidazole, - (CH2)" - indolyl or - (CH2) "- phenol.
6. A compound according to claim 1, wherein
7. A compound according to claim 1, wherein X is hydrogen, O I -CH2-NH-S-CH2CH2-phenyl, J O -CH2-S-CH2CH2CH2-phenyl,
8 A compound of Formula I: Or alkyl Cj-Cg each R 'independently is hydrogen or methyl; each n independently is 2 to 3; R and R2 are independently hydrogen. - (CH2) "- phenyl, - (CH2)" -? - phenyl, -OH, - (^ - ^. - (CH2 -OH; Ra, R and Rc are independently halogen, alkyl or hydrogen; R3 is hydrogen; R4 is methyl, ethyl or isopropyl and X is hydrogen, O I -CH2-NH-S-CH2CH2-phenyl, I o -CH2-S-CH2CH2CH2-phenyl, and the pharmaceutically acceptable salts thereof.
9. A compound according to claim 1, wherein R1 is hydrogen and R2 is - (CH2) "- indolyl, - (CH2)" - NH-phenyl, - (CH2) "-? - phenyl, - (CH2) n-indolyl substituted, - (CH2) n-tetrazolyl , - (CH2) n-phenyl, - (CH2) "- substituted phenyl, - (CH2) n-benz? Midazolyl substituted, - (CH2) n-benztriazolyl, - (CH2) n-indazolyl, - (CH2) n -benzimidazolyl, - (CH2) "- pyridyl, - (CH2)" - naphthyl, or - (CH2) "- quinolinyl.
10 The compound Acid 3- (2-Met? L-3-phenet? Lcarbamo? L-prop? On? Lam? No) -4-oxo-5- (2-phenyl? -ethanesulfon? Lam?) - pentane? co, 3- (2-Carbamo? lmet? l-3-met? l-but? plam? no) -5- (7,7-d? met? l-2-oxo-b? c? clo [2 2 1] hept-1-? lmethanesulfon? lam? no) -4-oxo-pentane? co, 5- (7,7-D? met? l-2-oxo-b? c? clo [ 2 2 1] hept-1-? Lmethanesulfon? Lam? No) -3- [3-met? L-2- (phenet? Lcarbamo? L-met? L) -but? Plam? No] -4-oxo- pentane? co, 3- (2-Carbamo? lmet? l-3-met? l-but? plam? no) -4-oxo-5- (2-phen? l-ethanesulfon? l-am? no) -pentano? co, 3- [3-Met? l-2- (phenet? lcarbamo? l-met? l) -but? plam? no] -4-oxo-5- (2-phene-ethanesulfon) acid lam? no) -pentane? co, 5- (7,7-D? met? lb? c? clo [22 1] hept-1-? lmethanesulfon? lam? no) -3- [3-met? l-2- (fenet? lcarbamo? l-met? l) -but? plam? no] -4-oxo-pentane? co, Acid (S, S) -3-. { 3-Met? L-2 - [(3-phen? L-prop? Lcarbamo? L) -met? L] -but? R? Lam? No} -4-oxo-but? R? Co, Acid 3-. { 3-Met? L-2 - [(3-phenoxy? -et? Lcarbamo? L) -met? L] -but? Plam? No} -4- oxo-butipco, 5- (7,7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-1-? Arnetanosulfon? Lam? No) -3- acid. { 3-met? L-2 - [(2-phenox? -et? Lcarbamo? L) -met? L] -but? R? Lam? No) -4-oxo-pentane? Co, Acid 3- [3- Met? L-2- (fenet? Lcarbamo? L-met? L) -but? Plam? No] -4-oxo-5- (3-.en? L-prop? Lsulfan? L) -pentano? Co, 5- (7,7-D? Met? L-2-oxo-b? C? Clo [2 2 1] heptyl-l? Methanesulfon? Lam? No) -3- acid. { 3-met? L-2- [(met? L-phenet? L-carbamo? L) -met? L] -but? Plam? No} -4-oxopentane? Co, 5- (7,7-D? Met? L-2-oxo-b? C? Clo [2 2 1] hept-l? -methanesulfon? Lam? No) -3- acid. { 3-met? L-2 - [(3-phen? L-prop? Lcarbamo? L) -met? L] -but? R? Lam? No} -4-oxo-pentane? Co, Acid 3-. { 3-Met? L-2 - [(3-phen? L-prop? Lcarbamo? L) -met? L] -but? Plam? No} -4-oxo-5- (2-oxo-2H-chroman-6-? Lox?) - pentane? Co, 5- [3- (1 H -imidazol-2-yl) -naphthalene-2-yloxy] -3- acid. { 3-methyl-2 - [(3-phenyl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (2-hydroxycarbamoyl-phenyl-3-methyl-butyrylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (2 { [2- (1H-indol-3-yl) -ethylcarbamoyl] -methyl] -3-methyl-butyrylamino) -4-oxo-pentanoic or 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [[3- (4-hydroxyphenyl) -propylcarbamoyl] -methyl] -butyrylamino} -4-oxo-pentanoic;
11. The compound: 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (2- { [2- (1 H-indol-3-yl) ) -ethylcarbarmoyl] methyl.} - 3-methyl-butyrylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-l-methanesulfonylamino) -3- (2 { [2- (1 H -indol-3-yl) -ethylcarbamoyl] acid] -methyl.} - butyrylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (3-methyl-2- { [2- (1-methyl-1H -indol-3-yl) -ethylcarbamoyl] -methyl] -.-butyrylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (3-methyl-2- { [2- (7-methyl-1 H-) acid indol-3-yl) -ethylcarbamoyl] -methyl] -.-butyrylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (2- { [2- (6-fluoro-1 H-indole-3-) acid il) -ethylcarbamoyl] -methyl] -3-methyl-butyrylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonyl-amino) -3- [3-methyl-2- (. {Methyl- [2- (1 - methyl-1 H-indol-3-yl) -ethyl] -carbamoyl] -methyl) -butyrylamino] -4-oxo-pentanoic acid; Acid 3-. { 2 - [(2-Benzoimidazol-1-yl-ethylcarbamoyl) -methyl] -3-methyl-butylamino} -5- (7,7-dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (3-methyl-2- { [2- (1H-tetrazol-5-yl) acid ) -ethylcarbamoyl] -methyl] - butyrylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -4-oxo-3- acid. { 2 - [(3-phenyl-propylcarbamoyl) -methyl] -butyrylamino} -pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (2- { [2- (1-methyl-1 H-indole-3- il) -ethylcarbamoyl] -methyl.}. -butyrylamino) -4-oxo-pentanoic acid, 3- (3-Methyl-2- {. [2- (1-methyl-1H-indol-3-yl) - ethylcarbamoyl] methyl.}. - butyrylamino) -4-oxo-butyric; 3- [3-Methyl-2- (. {Methyl- [2- (1-methyl-1 H -indol-3-yl) -ethyl] -carbamoyl} -methyl) -butyrylamino] -4- acid oxo-butyric; Acid 3-. { 2 - [(2-Benzoxydazol-1-yl-ethylcarbamoyl) -methyl] -3-methyl-butyrylamino} -4-oxo-butyric; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (2 { [3- (4-hydroxy-phenyl) -propylcarbamoyl-methyl acid} - 3-methyl-butyrylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [(2-pyridin-4-yl-ethylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2- [(2-naphthalene-2-yl-ethylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-Methyl-2 - [(3-pyridin-4-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [(3-quinolin-2-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-D? Methyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [(3-naphthalene-2-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic or 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [(3-pyridin-3-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic.
12. The compound: 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [(2-naphthalene-2-yl-ethylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-blciclo [2.2.1] hept-1-llmethanesulfonylamino) -3- (3-methyl-2- { [2- (7-methyl-1 H-) acid indol-3-yl) -ethylcarbamoyl] -methyl.}. -butyrylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (2- { [2- (6-fluoro-1H-indol-3-yl) acid ) -ethylcarbamoyl] -methyl] -3-methyl-butyrylamino) -4-oxo-pentanoic acid; 3- [3-Methyl-2- (. {Methyl- [2- (1-methyl-1H-indol-3-yl) -ethyl] carbamoyl} -methyl) -butylarylamide] -4- oxo-butyric; 3- (3-Methyl-2-. {[[Methyl- (2-phenoxy-ethyl) -carbamoyl] -methyl] -.-butyrylamino) -4-oxo-butyric acid; 3- (2- { [2- (5,6-Dimethyl-benzoimidazol-1-yl) -ethylcarbamoyl] -methyl] -3-methyl-butyrylamino) -4-oxo-butyric acid, trifluoroacetate salt; 5- (7,7-Dimethyl-bicyclo [2.2.1] hept-1-methanesulfonyl-amino) -3- acid. { 3-methyl-2 - [(3-phenyl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (2- { [2- (1 H -indol-3-yl) -etylcarbamoyl] - methyl.} - 3-methyl-butyrylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [(3-pyridin-4-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-l-methanesulfonylamino) -3- acid. { 3-methyl-2- [(3-quinolin-2-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [(3-naphthalene-1-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- acid. { 3-methyl-2 - [(3-pyridin-3-yl-propylcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic or acid 3-. { 2 - [(2-Benzoimidazol-1-ethyl-ethylcarbamoyl) -methyl] -3-methyl-butyrylamino} -5- (7,7-dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -4-oxo-pentanoic acid.
13. The compound: 5- (7,7-Dimethyl-2-oxo-bicyclo [.2.1] hept-1-ylmethanesulfonylamino) -3- (3-methyl-2- { [2- (1-methyl-1) H-indol-3-yl) -ethylcarbamoll] -methyl] -.-butyrylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimetyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonamino) -3- acid. { 3-Met l-2 - [(2-pyridin-4-yl-etlcarbamoyl) -methyl] -butyrylamino} -4-oxo-pentanoic; 3- (2- { [2- (5-Acetyl-1 H-indol-3-yl) -ethylcarbamoll] -methyl} -3-methyl-butyrylamino) -5- (7,7-dimethyl) acid -2-oxo-bicyclo [22.1] hept-1-ylmethanesulfonylamino) -4-oxo-pentanoic acid; 5- (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1-ylmethanesulfonylamino) -3- (3-methyl-2 - [[2- (1H-tetrazol-5-yl) -ethylcarbamoic acid] L] -methyl] -butyrylamino) -4-oxo-pentanoic acid; N 4 - (2-Benzoimidazol-1-yl-ethyl) -N 1 - (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-lsopropyl-succinamide; N - (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -N - [2- (1 H -indol-3-yl) -ethyl] -2-isopropyl-succinamide; N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N4- [2- (1-meth? L-1H-indol-3-yl) -ethyl] -succinamide; N 4 - [2- (5,6-Dichloro-benzolmidazol-1-yl) -ethyl] -N 1 - (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-succinamide; N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N4- (2-phenoxy-et? L) -succinamide or N1- (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N4- [2- (6-methoxy-1H-indol-3-yl) -ethyl] -succinamide.
14. The compound: N4- (2-Benzotriazol-1-yl-ethyl) -N1- (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl- succinamide; N 1 - (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -N 4 - (2-indazol-1-yl-ethyl) -2-isopropyl-succinamide; N 1 - (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N 4 - (2-phenylamino-ethyl) -succinamide; N 1 - (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -N 4 - [2- (6-fluoro-1 H -indol-3-yl) -ethyl] -2-isopropyl-succinamide; N 1 - (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -N 4 - [2- (7-methyl-1 H -indol-3-yl) -ethyl] -2-isopropyl-succinamide; N 1 - (2-ethoxy-5-oxotetrahydro-furan-3-yl) -2-isopropyl-N 4 - [2- (2-methyl-benzoimidazol-1-yl] -succinimide; N 1 - (2-Ethoxy-5- oxo-tetrahydro-furan-3-yl) -2-isopropyl-N - [3- (3,4,5-trimethoxy-phenyl) -propyryl-succinamide; N1- (2-Ethoxy-5-oxo-tetrahydrofuran) -3-yl) -2-isopropyl-N4- [2- (phenyl) -ethyl] -succinamide; N1- (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N4- [4- (phenyl) -butyl] -succinamide or N 1 - (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -N 4 - (2-indol-1-yl-ethyl) -2-isopropyl-succinamide.
15. The compound: N 1 - (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -2-isopropyl-N 4 - [4- (phenyl) -propyl] -succlnamide; N 1 - (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -N 4 - [2- (5-fluoro-1 H -indol-3-yl) -ethyl] -2-lsopropyl-succinamide; Acid 3-. { 2 - [(2-Benzoimidazol-1-yl-ethylcarbamoyl) -methyl] -3-methyl-butyrylamino} -4-oxo-butyric; Acid (3- (3-Methyl-2- {[2- (1-methyl-1 H -indol-3-yl) -ethylcarbamoyl] -methyl} - butyrylamino) -4-oxo-butyric acid; 3- (2- { [2- (5-Fluoro-1-methyl-1 H-indol-3-yl) -ethylcarbamoyl] -methyl} -3-methyl-butyrylamino) -4-oxo-butyric; 3- (2- { [2- (5,6-Dichloro-benzoimidazol-1-yl) -ethylcarbamoyl] -methyl] -3-methyl-butyrylamino) -4-oxo-butyric acid; - (2- {[[2-Benzoimidazol-1-yl-ethyl) -methyl-carbamoyl] -methyl} -3-methyl-butyrylamino) -4-oxo-butyric acid: 3- {2} - [(2-Benzotriazol-1-yl-ethylcarbamoyl) -methyl] -3-methyl-butyrylamino] -4-oxo-butyric acid: 3- {2 - [(2-lndazol-1-yl- ethylcarbamoyl) -methyl] -3-methyl-butyrylamino} -4-oxo-butyric acid, 3- [2- ( { [2- (5,6-D-methyl-benzoimidazol-1-yl) - ethyl] -methylcarbamoyl.} - methyl) -3-methyl-butyrylamino] 4-oxo-butyric acid 3- [2- ( { [2- (2-Methyl-benzoimidazol-1-yl) -etll] -methyl rbamoyl.} - methyl) -3-methyl-butyrylamino] -4-oxo-butyric acid 3- (3-methyl-2- { [3- (3,4,5-trimethoxy-phenyl) -propylcarbamoyl] -methyl.}. -butyrylamino) -4-oxo-butyric; Acid ethyl ester 3-. { 3-Methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -4-oxo-butyric; Ethyl ester of 3-Cyano-3- acid. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylaminoj-propionic or 3-Cyano-3- acid. { 3-methyl-2 - [(2-phenoxy-ethylcarbamoyl) -methyl] -butyrylamino} -propionic
16. A pharmaceutical composition comprising a compound according to claim 1.
17. A pharmaceutical composition comprising a compound according to claim 8.
18. A method for treating or preventing the attack, the method comprises administering to a patient having, having had or being at risk of having an attack, a therapeutically effective amount of a compound according to claim 1.
19. A method for treating or preventing the attack, the method comprises administering to a patient having, having had or being at risk of having an attack of a therapeutically effective amount of a compound according to claim 8.
20. A method for treating inflammatory diseases, the method comprises administering to a patient having an inflammatory disease a therapeutically effective amount of a compound according to claim 1.
21. A method for treating inflammatory diseases, the method comprises administering to a patient having an inflammatory disease a therapeutically effective amount of a compound according to claim 8.
22. The method according to claim 20, wherein the inflammatory disease is rheumatoid arthritis or irritable bowel syndrome.
23. The method according to claim 21, wherein the inflammatory disease is rheumatoid arthritis or irritable bowel syndrome.
24. A method of treating septic shock, the method comprises administering to a patient having septic shock a therapeutically effective amount of a compound according to claim 1.
25. A method of treatment for septic shock, the method comprises administering to a patient having septic shock a therapeutically effective amount of a compound according to claim 8.
26. A method of treatment for reperfusion injury, the method comprises administering to a patient having reperfusion injury a therapeutically effective amount of a compound according to claim 1.
27. A method of treatment for reperfusion injury, the method comprises administering to a patient having reperfusion injury a therapeutically effective amount of a compound according to claim 8.
28. A method of treating Alzheimer's disease, the method comprises administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound according to claim 1.
29. A method of treating Alzheimer's disease, the method comprises administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound according to claim 8.
30. A method of treating shigellosis, the method comprises administering to a patient having shigellosis a therapeutically effective amount of a compound according to claim 1.
31. A method of treating shigellosis, the method comprises administering to a patient having shigellosis a therapeutically effective amount of a compound according to claim 8.
32. A method of treating multiple sclerosis, the method comprises administering to a patient having multiple sclerosis a therapeutically effective amount of a compound according to claim 1.
33. A method of treating multiple sclerosis, the method comprises administering to a patient having multiple sclerosis a therapeutically effective amount of a compound according to claim 8.
34. A method of inhibition of the converting enzyme of interleukin-1β, the method comprises administering to a patient in need of inhibition of the interleukin-1β-converting enzyme, a therapeutically effective amount of a compound according to claim 1.
35. A method of inhibition of the interleukin-1β-converting enzyme, the method comprises administering to a patient in need of Inhibition of the interleukin-1β-converting enzyme, a therapeutically effective amount of a compound according to claim 8.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/084,320 | 1998-05-05 |
Publications (1)
Publication Number | Publication Date |
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MXPA00010886A true MXPA00010886A (en) | 2001-07-31 |
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