MXPA99001831A - Novel peptide derivatives having thiazolyl-alanine residue - Google Patents
Novel peptide derivatives having thiazolyl-alanine residueInfo
- Publication number
- MXPA99001831A MXPA99001831A MXPA/A/1999/001831A MX9901831A MXPA99001831A MX PA99001831 A MXPA99001831 A MX PA99001831A MX 9901831 A MX9901831 A MX 9901831A MX PA99001831 A MXPA99001831 A MX PA99001831A
- Authority
- MX
- Mexico
- Prior art keywords
- optionally substituted
- compound
- mmol
- formula
- thiazolyl
- Prior art date
Links
- WBZIGVCQRXJYQD-YFKPBYRVSA-N (2S)-2-amino-3-(1,3-thiazol-4-yl)propanoic acid Chemical group OC(=O)[C@@H](N)CC1=CSC=N1 WBZIGVCQRXJYQD-YFKPBYRVSA-N 0.000 title description 2
- 239000011780 sodium chloride Substances 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 230000000694 effects Effects 0.000 claims abstract description 20
- 230000003213 activating Effects 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 256
- 239000000203 mixture Substances 0.000 claims description 109
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 30
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 210000004369 Blood Anatomy 0.000 claims description 14
- 241000700159 Rattus Species 0.000 claims description 14
- 239000008280 blood Substances 0.000 claims description 14
- 150000002431 hydrogen Chemical group 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 12
- 239000008103 glucose Substances 0.000 claims description 12
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 239000011593 sulfur Substances 0.000 claims description 9
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims description 4
- 229910014033 C-OH Inorganic materials 0.000 claims description 2
- 229910014570 C—OH Inorganic materials 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims 1
- 150000002466 imines Chemical class 0.000 claims 1
- 150000002926 oxygen Chemical class 0.000 claims 1
- 229960004373 Acetylcholine Drugs 0.000 abstract description 11
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 abstract description 11
- 150000004677 hydrates Chemical class 0.000 abstract description 4
- 230000000891 anti-reserpine Effects 0.000 abstract description 2
- 230000001965 increased Effects 0.000 abstract description 2
- 230000004899 motility Effects 0.000 abstract description 2
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 abstract 2
- 229960000854 protirelin Drugs 0.000 abstract 1
- 230000003578 releasing Effects 0.000 abstract 1
- 230000002269 spontaneous Effects 0.000 abstract 1
- 230000002459 sustained Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 100
- -1 n-propenyl Chemical group 0.000 description 88
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 71
- 238000002360 preparation method Methods 0.000 description 62
- 238000000034 method Methods 0.000 description 59
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 44
- 239000011541 reaction mixture Substances 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 125000000217 alkyl group Chemical group 0.000 description 33
- 239000004615 ingredient Substances 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 238000001556 precipitation Methods 0.000 description 31
- 239000000706 filtrate Substances 0.000 description 29
- 238000001816 cooling Methods 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 21
- 238000009472 formulation Methods 0.000 description 20
- 239000008187 granular material Substances 0.000 description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 18
- 238000000921 elemental analysis Methods 0.000 description 17
- XNSAINXGIQZQOO-SDDRHHMPSA-N (2S)-N-[(2S)-1-[(2R)-2-carbamoylpyrrolidin-1-yl]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide Chemical compound NC(=O)[C@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SDDRHHMPSA-N 0.000 description 16
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 16
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 16
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-hydroxy-Succinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000008101 lactose Substances 0.000 description 16
- 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 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 13
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 13
- 239000010410 layer Substances 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 229920002261 Corn starch Polymers 0.000 description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 11
- 239000008120 corn starch Substances 0.000 description 11
- 235000019359 magnesium stearate Nutrition 0.000 description 11
- 239000008108 microcrystalline cellulose Substances 0.000 description 11
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 11
- 229940016286 microcrystalline cellulose Drugs 0.000 description 11
- 101700067048 CDC13 Proteins 0.000 description 10
- 102100009392 TRH Human genes 0.000 description 10
- 108060008623 TRH Proteins 0.000 description 10
- 229940034199 Thyrotropin-Releasing Hormone Drugs 0.000 description 10
- 239000000627 Thyrotropin-Releasing Hormone Substances 0.000 description 10
- 239000000499 gel Substances 0.000 description 10
- 238000002523 gelfiltration Methods 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 9
- 229960003147 reserpine Drugs 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 210000003169 Central Nervous System Anatomy 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 230000036760 body temperature Effects 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 125000003107 substituted aryl group Chemical group 0.000 description 7
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 6
- RVXBTZJECMMZSB-QMMMGPOBSA-N (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(1,3-thiazol-4-yl)propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CSC=N1 RVXBTZJECMMZSB-QMMMGPOBSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 206010021113 Hypothermia Diseases 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 230000002631 hypothermal Effects 0.000 description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 6
- 229920000609 methyl cellulose Polymers 0.000 description 6
- 239000001923 methylcellulose Substances 0.000 description 6
- 235000010981 methylcellulose Nutrition 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 229940113083 morpholine Drugs 0.000 description 5
- 238000010647 peptide synthesis reaction Methods 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 239000011877 solvent mixture Substances 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 229920003114 HPC-L Polymers 0.000 description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 125000004423 acyloxy group Chemical group 0.000 description 4
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- OCUQILXOPJOUAM-WDSKDSINSA-N (2S)-1-[(2S)-2-aminopropanoyl]pyrrolidine-2-carboxamide Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(N)=O OCUQILXOPJOUAM-WDSKDSINSA-N 0.000 description 3
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 3
- 210000004556 Brain Anatomy 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 210000003710 Cerebral Cortex Anatomy 0.000 description 3
- ULYZAYCEDJDHCC-UHFFFAOYSA-N Isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 3
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 description 3
- CJUMAFVKTCBCJK-UHFFFAOYSA-N N-benzyloxycarbonylglycine Chemical compound OC(=O)CNC(=O)OCC1=CC=CC=C1 CJUMAFVKTCBCJK-UHFFFAOYSA-N 0.000 description 3
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000003372 histidine group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
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- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
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- 238000000185 intracerebroventricular Methods 0.000 description 1
- KPJPHPFMCOKUMW-UHFFFAOYSA-N iodomethane Chemical group I[CH2] KPJPHPFMCOKUMW-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
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- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 1
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- PKXDNQMIUVUJGQ-QMMMGPOBSA-N morpholin-4-yl-[(2S)-pyrrolidin-2-yl]methanone Chemical compound C1COCCN1C(=O)[C@@H]1CCCN1 PKXDNQMIUVUJGQ-QMMMGPOBSA-N 0.000 description 1
- XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 1
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- 125000004370 n-butenyl group Chemical group [H]\C([H])=C(/[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
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- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
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- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
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Abstract
Peptide derivatives represented by general formula (I), pharmacologically acceptable salts thereof or hydrates of the same having improved central activating effects such as sustained acetylcholine-releasing effect, antireserpine effect and spontaneous motility increasing effect as compared with the publicly known TRH and TRH derivatives.
Description
NEW DERIVATIVES OF PEPTIDES THAT HAVE THE RESIDUE OF TIAZOLIL-ALANINA
Technical field
This invention relates to new peptide derivatives having the residue of 3- (4-thiazolyl or 5-thiazolyl) -alanine and having an activation effect of the central nervous system. The compound of this invention is useful as a medicament.
Background Art
The compound of this invention is derived from L-pyroglutamyl-L-his tidyl-L-prolineamide (p-Glu-His-Pro-NH2), known as TRH (thyrotropin-releasing hormone) isolated from the hypothalamus.
TRH is a hormone consisting of 3 amino acid residues isolated from the hypothalamus, and seems to show continuous activities through
REF .: 29500 of a TRH receiver. It is known that not only promotes the secretion of TSH (thyroid stimulating hormone) and prolactin, but also has the following activities; activation of the cerebral nervous system such as motor stimulating activity, etc., sympathetic activity such as elevation of blood pressure, respiratory stimulation, etc., spinal activity such as motor nerve stimulation, etc., central nervous activity such as antidepression, etc. , and peripheral activity such as suppression of gastrin secretion, stimulation of glucagon secretion, etc. Since HRT has several activities, it has been investigated in clinical use, and is being used as an intravenous injection to treat spinocerebellar degeneration for the purpose of improving motility disturbances and cognitive disturbances accompanied by functional brain disturbances (Sofue , Kanaza a, Ogawa, "Neuropeptide" '91, Medicalrevie).
However, there are several problems that prevent the clinical application of HRT. The typical problems are described later:
1) HRT shows very short half-life activity in blood and it is required to be administered frequently, because it is digested by enzymes such as pyroglutamine peptidase, TRH amidase, etc. in a living body.
2) Excess TSH secretion is caused by the repeated administration of TRH due to the stimulating activity of TSH secretion.
3) A small amount of TRH is transferred into the brain by peripheral administration due to its low hydrophobicity.
To resolve the above problems that relate to HRT, the development of TRH derivatives that have more potent activity than TRH has been attempted in view of central nervous system activation (for example, stimulation to wake up, anti-activity). reserpine (hyperthermia), locomotor increase, increased spinal reflexes, potentiation of dopamine action, antianesthetic action, etc.) and have a long duration of action. Such compounds reported today are illustrated below.
For example, 1-met il-L-4, 5-dihydroorot il-L-hist idyl-L-prolineamide (JP-B 2-36574), 2,3,4,5-tetrahydro-2-oxo are known. -L-5 furancarbonyl-L-histidyl-L-prolineamide (JP-A 52-116465), (IS, 2R) -2-met i 1-4 -oxocyclopentyl carbonyl-L-histidyl-L-prolineamide (JP- B-3- 236397), orotyl-L-histidyl-L-prolineamide (JP-B 59-36612), TRH-SR (Eur. J. Pharmacol., 271, 357 (1994)), etc.
However, the previous derivatives of TRH do not have sufficient continuous action.
Additionally, the intravenous injection of these compounds makes it difficult to improve the complications for the periodic administration of these and QOL (quality of life) of the patients who have the motor disturbance.
BRIEF DESCRIPTION OF THE INVENTION
In the above situation, the inventors of the present invention found that the compounds had superior known activity to TRH and its derivatives in relation to the activation of the central nervous system, for example, prolonged release of the action of acetylcholine, anti-reserpine action and increase in locomotive activity. The present invention relates to
a) A peptide derivative of the formula (I)
wherein A is 4-thiazolyl or 5-thiazolyl wherein the nitrogen in the thiazolyl ring could be quaternary nitrogen which is formed with optionally substituted alkyl or alkenyl, X is a bond, oxygen or sulfur, m is an integer from 0 to 4, Y is-optionally substituted alkyl, optionally substituted carboxy, cyano, or the substituent represented by the formula:
Or R 1 -CN PV wherein R 1 and R 2 are independently hydrogen or optionally substituted alkyl or R 1 and R 2 taken together could form a non-aromatic heterocyclic ring, adjacent to the nitrogen which could contain oxygen, nitrogen or sulfur and could be substituted, Z is the substituent represented by the formula:
wherein R is hydrogen, optionally substituted alkyl, optionally substituted carboxy or optionally substituted acyl, R4 and R5 are each "independently hydrogen or optionally substituted alkyl and W is - (CH2) n- wherein n is 0, 1, 2 or 3 , oxygen, sulfur or optionally substituted imino, the substituent represented by the formula:
its pharmaceutically acceptable salt or hydrate thereof
A peptide derivative of the formula (II)
wherein X, Y, Z and m are as defined above, and the nitrogen in the thiazolyl ring could be quaternary nitrogen which is formed with optionally substituted alkyl or alkenyl, its pharmaceutically acceptable salt or hydrate thereof.
A peptide derivative of the formula
(III
wherein X, Y, Z and m are as defined above, and the nitrogen in the thiazolyl ring could be quaternary nitrogen which is formed with optionally substituted alkyl or alkenyl, its pharmaceutically acceptable salt or hydrate thereof.
d) A peptide derivative of the formula (IV)
wherein, X, Y, m, R3, R4 and R5 are as defined above, their pharmaceutically acceptable salt or hydrate thereof.
e) A peptide derivative of the formula (V):
wherein Y is as defined above, its pharmaceutically acceptable salt or hydrate thereof.
f) A peptide derivative of the formula (VI)
wherein Y is as defined above, its pharmaceutically acceptable salt or hydrate thereof.
g) A peptide derivative - from any of a) to d) wherein m is 1 or 2, with the proviso that X is not a bond when m is 1, its pharmaceutically acceptable salt or hydrate thereof.
h) A peptide derivative of any of a) to d) wherein m is 1 and Y is optionally substituted alkyl, optionally substituted carboxy or optionally substituted carbamoyl, its pharmaceutically acceptable salt or hydrate thereof.
i) A peptide derivative of any of a) to d) wherein m is 2 or 3 and Y is optionally substituted alkyl, optionally substituted carboxy, optionally substituted carbamoyl, its pharmaceutically acceptable salt or hydrate thereof.
j) A pharmaceutical composition containing any of compounds a) to i) as an active ingredient.
k) A composition for activating the central nervous system containing any of the compounds of a) to i) as an active ingredient.
1) A derivative of TRH having such an effect in the ratio represented by the blood glucose level of the active substance group administered / the blood glucose level of the administered group of physiological saline is 0.7 to 1.3 in the rat to which an effective amount thereof is administered intravenously to exhibit the main activity.
All the compounds represented by the above formula have higher activation activity of the central nervous system. Specifically, compounds having the substituent shown in formula (IV) are preferable.
1) A peptide derivative wherein W is oxygen, X is oxygen or sulfur, Y is carbamoyl or optionally substituted alkyl, m is 1, R is hydrogen, R4 is optionally substituted alkyl and R5 is hydrogen, its pharmaceutically acceptable salt or hydrate Of the same.
2) A peptide derivative wherein it is oxygen, X is a bond, Y is carbamoyl or optionally substituted alkyl, m is 2, R3 is hydrogen, R4 is alkyl, and R5 is hydrogen, its pharmaceutically acceptable salt or hydrate thereof .
As the additional preferred compounds, the compounds having the substituents shown below in formula (IV) are exemplified.
1 ') A peptide derivative wherein W is oxygen, X is sulfur, Y is carbamoyl or alkyl, m is 1, R3 is hydrogen, R4 is alkyl and R5 is hydrophenone, its pharmaceutically acceptable salt or hydrate thereof. .
2 ') A peptide derivative wherein W is oxygen, X is a bond, Y is carbamoyl or alkyl, m is 2, R3 is hydrogen, R4 is alkyl and R5 is hydrogen, its pharmaceutically stable salt or hydrate thereof.
As the additional preferred compounds, the compounds having the substituents shown in the formula (IV) are exemplified.
1") A peptide derivative wherein it is oxygen, X is sulfur, Y is carbamoyl or straight or branched chain alkyl C? -C6, m is 1, R3 is hydrogen, R4 is straight or branched chain alkyl? C3 and R5 is hydrogen, its pharmaceutically acceptable salt or hydrate thereof.
2") A peptide derivative wherein it is oxygen, X is a bond, Y is carbamoyl or straight or branched chain alkyl Ci-Ce, m is 2, R3 is hydrogen, R4 is straight or branched chain alkyl Cx-C3 and R5 is hydrogen, its pharmaceutically acceptable salt or hydrate thereof.
As a preferable configuration, the configuration represented by the formula (IV)
(when one of R4 and R5 is hydrogen, the configuration shows the configuration apart from that shown in the formula).
The term "halogen" used herein means fluorine, chlorine, bromine and iodine.
The term "alkyl" used herein includes C de-C6 straight or branched chain alkyl and C3-C6 cyclic alkyl. Preferably, C?-C6 straight or branched chain alkyl is exemplified. More preferably, C3-C3 straight or branched chain alkyl is exemplified. Examples of alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopentyl and the like.
The term "alkenyl" used herein includes straight or branched chain alkenyl C2-Cs. Linear or branched chain alkenyl are preferably exemplified. More preferably, straight or branched chain alkenyl C2-Cs are exemplified. Examples of alkenyl are n-propenyl, n-butenyl, n-hexenyl and the like.
The term "aryl" used herein includes fused or monocyclic ring aromatic hydrocarbons. Preferably, monocyclic aromatic hydrocarbons are exemplified. Examples of aryl are phenyl, naphthyl and the like.
The term "heteroaryl" includes a 5-6 membered aromatic heterocyclic group containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, could be fused to a carboxylic ring or other heterocyclic ring and could be substituted in any possible position. Examples of the heteroaryl are pyrrolyl (eg, 1-pyrrolyl), indole (eg, 2-indolyl), carbazolyl (eg, 3-carbazolyl), imidazolyl (eg, 4). imidazolyl), pyrazolyl (eg, 1-pyrazolyl), benzimide zolyl (eg, 2-benzimidazolyl), indazolyl (eg, 3-indazolyl) indolizinolyl (P e 6-indolizinolyl), pyridyl (e.g., 4-pyridyl), quinolyl (e.g., 5-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), acridinyl (e.g., 1-acridinyl), fenanthyridinyl (p. eg, 2-phenyl-iridinyl), pyridazinyl (eg, 3-pi ridazinyl), pyrimidinyl (eg, 4-pyrimidinyl), pyrazinyl (eg, 2-pyrazinyl), cinolinyl (p. eg, 3-cinolinyl), talazinyl (eg, 2-1 ala zini lo), quina zolini lo (eg, 2-quinazolini lo), isoxazolyl (eg, 3-isoxazole) lo), benzisoxazole (eg, 3-benzisoxazole ilo), oxazolyl (eg, 2 -oxa zolyl), benzoxazolyl (eg, 2-benzoxazolyl), benzoxadiazolyl (e.g. , -benzoxadiazoli lo), is otiazolyl (p. ex. , 3-i sothiazolyl), benzisothiazolyl (e.g., 2-benzisothiazolyl), thiazolyl (e.g., 2-thiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), furyl (p. eg, 3-furyl), benzofuryl (eg, 3-benzofuryl), thienyl. (e.g., 2-thienyl), benzothienyl (e.g., 2-benzothienyl), tetrazolyl, and the like.
The term "non-aromatic heterocyclic group" used herein means a non-aromatic 5- to 7-membered heterocyclic group containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, and could be linked in any position possible. Examples of the non-aromatic heterocyclic group are morpholino, piperidino, 1-pyrrolidinyl, 2-pyrrolin-3-yl and the like.
The term "acyl" used herein includes alkanoyl of which the alkyl part is the "alkyl" mentioned above and aroyl of which the aryl part is the "aryl" mentioned above. Examples of acyl are acetyl, benzoyl and the like.
The term "alkyloxy" used herein includes alkyloxy of which the alkyl part is the "optionally substituted alkyl" mentioned above. Examples of alkyloxy are methyloxy, ethyloxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy, tert-butyloxy and the like.
The term "optionally substituted alkyl" for R1 and R2 used herein includes the above-mentioned "alkyl" which is optionally substituted in any possible position with one or more substituents, for example, hydroxy, alkyloxy (eg, methoxy and ethoxy) , mercapto, alkylthio (eg, methylthio), cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), halogen (eg, fluorine, chlorine, bromine and iodine), carboxy, carbamoyl, alkyl C'-C20 oxycarbonyl (eg, methoxycarbonyl, iso-propyloxycarbonyl, tetradecyloxycarbonyl and pentadecanyloxycarbonyl), aryloxycarbonyl (eg, phenyloxycarbonyl), nitro, cyano, SOpRA (p is an integer from 1 to 3 and RA is hydrogen or alkyl), PO (OH) 2 or PO (0) OH which is optionally substituted with alkyl, substituted or unsubstituted amino (e.g., methylamino, dimethylamino and carbamoylamino), optionally substituted aryl (e.g. ., phenyl and tolyl), optionally substituted heteroaryl, a heterocyclic group not a optionally substituted, aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, arylcarbonyl, non-aromatic heterocyclic carbonyl, hydrazino, hydroxyamino, alkyloxyamino and formyl. Examples of optionally substituted alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, isopropyloxycarbonylmethyl, tetradecanyloxycarbonylmethyl, pentanylcarbonylammonium and Similar. Preferred substituents are C1-C20 alkyloxycarbonyl and phenyl.
The term "optionally substituted alkyl" for Y, R3, R4 and R5 used herein includes the above-mentioned "alkyl" which is optionally substituted in any possible position with one or more substituents, eg, hydroxy, alkyloxy (eg, methoxy and ethoxy), mercapto, alkylthio (eg, methylthio), cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), halogen (eg, fluorine, chlorine, bromine and iodine), carboxy , carbamoyl, alkyloxycarbonyl (eg, methoxycarbonyl and ethoxycarbonyl), aryloxycarbonyl (eg phenyloxycarbonyl), nitro, cyano, SOpRA (p is an integer from 1 to 3, and RA is hydrogen or alkyl), PO (OH) or PO (0) OH which is optionally substituted with alkyl, substituted or unsubstituted amino (e.g., methylamino, dimethylamino and carbamoylamino), optionally substituted aryl (e.g., phenyl and tolyl "), heteroalyl optionally substituted and an optionally substituted non-aromatic heterocyclic group, aryloxy, acyloxy, aci oxycarbonyl, alkylcarbonyl, non-aromatic heterocyclic carbonyl, heterocyclic imino, hydrazino, hydroxyamino, alkyloxyamino and formyl. For example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, hydroxymethyl, tert-butylcarbonyloxymethyl, morpholinomethyl, piperidinomet ilo, N-methyl-1-piperazinylmethyl, ethylcarbonylmethyl, morpholinocarbonylmethyl, acetyloxymethyl, and the like are exemplified. As a preferable substituent, phenyl, hydroxy, alkylcarbonyloxy, morpholino, piperidino, piperazinyl substituted with N-alkyl, alkylcarbonyl, morpholcarbonyl and acyloxy are exemplified.
The term "optionally substituted alkyl" for nitrogen in the thiazolyl ring used herein "includes Ci-C3 straight or branched chain alkyl which is optionally substituted by phenyl optionally substituted with halogen or alkyl, For example, methyl, ethyl, n- is exemplified. propyl, n-butyl, benzyl, -met-ilbenzyl.
The terms "optionally substituted aryl", "heteroaryl optionally substituted" and "optionally substituted nonaromatic heterocyclic group" used herein include the "aryl", "heteroaryl" and "aromatic heterocyclic group" mentioned above, respectively, which are optionally substituted with one or more substituents, for example, hydroxy, alkyloxy (eg, methoxy and ethoxy), mercapto, alkylthio (eg, methylthio), halogen (e.g., fluorine, chlorine, bromine and iodine) , carboxy, (p. g., methoxycarbonyl and ethoxycarbonyl), nitro, cyano, haloalkyl (p. g., trifluoromethyl), aryloxy (p. g., phenyloxy), substituted amino or unsubstituted (p. g., methylamino , dimethylamino, diethylamino and lidenamino beci), guanizino, alkyl (p. g., methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-bu'tilo, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, ter-pentyl, cyclopropyl, cyclobutyl, and cyclopentyl), alkenyl (eg, vinyl) and propenyl), alkynyl (p. ex. , Ethynyl and ynyl phenyleth), alkanoyl (p. G., Formyl, acetyl and propionyl), acyloxy (p. G., Acetyloxy) acylamino, alkylsulfonyl (p. G., Methylsulfonyl), phenyl, benzyl, an azo group ( e.g., phenylazo), optionally substituted heteroaryl (e.g., 3-pyridyl), optionally substituted ureido (e.g., ureido and phenylureido) and the like.
The substituents for "optionally substituted carboxy" of Y are, for example, C1-C20 alkyl? straight or branched chain, cyclic C3-C8 alkyl and aryl. In addition, these alkyls and aryls are optionally substituted with one or more substituents that are exemplified as those for the "optionally substituted alkyl" and "optionally substituted aryl" above. Examples of "optionally substituted ca'rboxi" are carboxy, alkyloxycarbonyl and aryloxycarbonyl, for example, methoxycarbonyl, iso-propi loxicarbonilo, hexyloxycarbonyl, decyloxycarbonyl, phenyloxycarbonyl, tetradecyloxycarbonyl, icosaniloxicarbonilo, phenoxymethyl carbonyl, benzyloxycarbonyl, tolyloxycarbonyl and the like. As a preferable substituent, linear or branched chain C 1 -C 20 alkyl and benzyl are exemplified.
Substituents for "optionally substituted carbamoyl" of Y are, for example, straight or branched chain C 1 -C 6 alkyl (eg, methyl, ethyl, n-propyl and iso-propyl). In addition, this alkyl optionally substituted with one or more substituents that are exemplified as those for the "optionally substituted alkyl" above. Examples of "optionally substituted carbamoyl" are carbamoyl, methylcarbamoyl, etylcarbamoyl, n-propylcarbamoyl, methylcarbamoyl, benzylcarbamoyl, iso-propylbxycarbonylmethylcarbamoyl, tetradecanyloxycarbonylmethylcarbamoyl, benzyloxycarbonylmethylcarbonyl, acetyloxymethylcarbamoyl, acetlcarbamoyl and the like. As a preferred substituent, C1-C20alkyloxycarbonylalkyl and acyloxyalkyl are exemplified.
The substituents for "optionally substituted carboxy" of R3 are, for example, the "optionally substituted alkyl" mentioned above and "optionally substituted aryl". Examples of the "optionally substituted carboxy" are carboxy, alkyloxycarbonyl and aryloxycarbonyl, for example, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, phenyloxymethylcarbonyl, tolyoxycarbonyl and the like.
The term "optionally substituted acyl" used herein includes alkanoyl of which the alkyl part is the "optionally substituted alkyl" mentioned above and aroyl of which the aryl part is the "optionally substituted aryl" mentioned above. Examples of "optionally substituted acyl" are toluoyl and imino.
The term "optionally substituted imino" used herein includes imino which is optionally substituted with the "optionally substituted lower alkyl" mentioned above, "optionally substituted aryl", alkyloxycarbonyl, and the like.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the effect of the release of acetylcholine in the cerebral cortex where the test compound is administered orally to rats (the horizontal axis shows the course of time and the vertical axis shows a concentration of acetylcholine in the cerebral cortex).
Figure 2 shows the transition of the blood glucose level by intravenous injection to rats (the horizontal axis shows the course of time and the vertical axis shows the level of glucose in the blood).
The Best Way to Carry Out the Invention
The compounds of this invention are capable of being synthesized by means of the following methods A and B as a usual method for the synthesis of the peptide. Substituents, for example, Y and the like, are capable of being introduced by alkylation, acylation, terefication, etc. then the tripeptide was synthesized in the same manner as in method A or B.
The compound represented by the formula
VII
O O il H H ll Z-C-N-C-C-OH (VII) .CH A "
wherein A and Z are defined above, and the compound of the formula (VIII) ':
where A, X, Y and m are as defined above, which are new intermediaries for methods A and B.
(Method A)
where A, X, Y, Z and m are as defined above.
(Method B)
where A, X, Y, Z and m are as defined above.
Methods A and B are to obtain the main compound of the tripeptide (I) using the amino acid derivatives represented by the formulas (IX), (X) and (XI) as a starter material. In method A the compound (IX) is reacted with the compound (X) to give the compound (VII), which is further reacted with the compound (XI) - In the method B the compound (X) is made reacting with the compound (XI) to give the compound (VIII), which is then reacted with the compound (IX). Each reaction is carried out according to a usual peptide synthesis reaction, for example, the method described in "The peptide", vol 1, "Peptide Synthesis", Nobuo Izumiya. Maruzen and similar.
As a usual peptide synthesis reaction, the methods of a condensing agent such as N, N-dicyclohexylcarbodiimide (DCC) and the like, the azide method, the acid chloride method, the acid anhydride method, are exemplified. the activated ester method and the like. When the initiator material has a substituent that interferes with this peptide synthesis reaction, for example, amino, carboxy, hydroxy, etc., the substituent may be pre-protected according to the method of "Protective Groups in Organic Synthesis" Theodora. Green (John Wiley and Sons), and then check out at the appropriate stage.
Examples of a protective amino group are t-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, phthaloyl, t r i f luoroacetyl and the like.
Examples of a carboxy protecting group are esters such as methyl ester, ethyl ester, benzyl ester, t-butyl ester, 2- (trimethyl-ilsi-1-yl) -yl ester, etc.
How the method to activate the carboxy that refers to the reactions of the compounds (VII),
(IX) and (X), the following methods are exemplified; 1) the method for giving the activated esters such as N-hydroxysuccinimide ester, N-hydroxybenzotiazole ester, p-nitrophenol ester and the like, 2) the method for acidifying chlorides using chlorinating agents such as phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride and the like, 3) the method for giving azides, 4) the method for giving acid anhydrides. These methods are capable of being carried out in the presence or absence of a deoxydi zant e in a suitable solvent such as N, N-dimethyl formamide, acetonitrile, tetrahydrofuran, methylene chloride and the like at -50 ° C under reflux.
The active carboxylic acid derivatives which are produced by the above methods are isolated and are capable of reacting with the compounds (VIII), (X) and (XI) having an amino group with reference to this reaction. Without isolating the active carboxylic acid derivatives in the above methods, the compounds (VIII), (X) and (XI) having an amino group with reference to this reaction could be added to the reaction solution of the above methods. The 1-hydroxybenzotriazole could be added to the reaction mixture to accelerate these reactions.
In this manner, the compounds of this invention are capable of being synthesized from the amino acid derivatives of the compounds (IX.), (X) and (XI) by two peptide synthesis reactions. The initiator material of the amino acid derivatives is capable of being obtained as the known natural compounds and easily synthesized therefrom. The compound (IX) is capable of being synthesized according to the methods described in J. Med. Vhem., 33, 2130 (1990). Int. J. Peptide Protein Res., 14, 216 (1979), Chem, Lett., 1171 (1982) and Tetrahedron Lett., 36, 6569 '1995). The compound (X) is capable of being synthesized according to the methods described in Synthetic Commun., 20, 3507
(1990) and EP 417454. The compound (XI) is capable of being synthesized according to the method described in J. Med. Chem., 24, 692 (1981).
The term "the compounds of this invention" used herein includes the pharmaceutically acceptable salts or hydrates of the compounds. For example, salts with alkali metals (eg, lithium, sodium and potassium), ferrous alkaline metals (eg, magnesium and calcium), ammonium, organic bases, amino acids, mineral acids (eg. ., hydrochloric acid, hydrobromic acid, forphoric acid and sulfuric acid), or organic acids (eg, acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid and p-toluenesulfonic acid) and hydrates thereof. These salts and hydrates can be formed by the usual method.
The compound of this invention is a derivative of TRH from which the histidine residue is converted to the residue of 3- (4-tiazolyl) alanine or 3- (5-tiazolyl) alanine and has strong, continuous and selective action in the central nervous system. The administration of TRH and conventional TRH derivatives suitably increases the level of glucose in the blood and allows adequate fall by rebound, which is not observed in the compound of this invention. This fact could lead to the least side effect.
Because the compound of this invention has effects of superior hyperthermia and locomotor arousal by activation of neurons such as the dopamine system, norepinephrine system and the acetylcholine system in the brain, it is useful for the treatment of disorders accompanied with dysfunction. of these nervous systems. Especially, as it accentuously activates the neuronal acetylcholine system in the cerebral cortex, it could be useful as a therapeutic agent of disorders such as motor disturbance, disturbance of consciousness, senile dementia, drowsiness, decreased concentration, speech dysfunction and the like. which are accompanied by neuron acetylcholine dysfunction.
When the compound of this invention is administered to a person for the treatment or prevention of the above diseases, it can be administered by oral administration such as powders, granules, tablets, capsules, small pills and liquid medicine, or by parenteral administration such as injections, suppositories, percutaneous formulations, insufflation or the like. An effective amount of the compound of this invention is formulated by being mixed with the medical mixture such as excipients, penetrating binders, disintegrators, lubricants and the like if necessary. When parenteral injection is prepared, the compound of this invention and an appropriate vehicle are sterilized to prepare.
An appropriate dose varies with the conditions of the patients, a route of administration, their age and their body weight. In the case of oral administration to the adult, the dose can be in general between 0.1-100 mg / kg / day, preferably 1-20 mg / kg / day.
The following examples are provided to further illustrate the present invention and are not considered as limiting the scope thereof.
The abbreviations described later in the following examples are used.
c-: Cyclo Me: methyl Et: ethyl Pr: propyl Bu: butyl Pen: pent i 1o Hex: hexyl Ph: phenyl Ac: acetyl BOC: tert-butyloxycarbonyl Bzl: benzyl Chz: benzyloxycarbonyl p-TsOH: acid p -duluenesulfonic DCC: N, N-dicyclohexylcarbodiimide HOBT: 1-hydroxibezotriazole
that 2
Example 1-process 1
Preparation of N- (tert-butoxycarbonyl) -3- (4 • thiazolyl) -L-alanyl-L-prolineamide (1)
N- (tert-butyloxycarbonyl) -3- (4-thiazolyl) -L-alanine (8.17 g, 30 mmol) which was synthesized according to the method described in the literature (Synthetic Commun., 20.3507 (1990) and L-prolineamide (3.42 g, 30 mmol) were dissolved in
(100 ml) of N, N-dimet and formamide. To this solution was added the dicyclohexylcarbodiimide solution (DCC, 6.81 g, 33 mmol) in
(10 ml) of N, N-dimethylformamide and 1-hydroxybenzothiazole (405 mg, 3 mmol) under ice-cooling with stirring and the resulting mixture was stirred overnight at room temperature. To the reaction mixture was added (200 ml) of ethyl acetate and the precipitation that appeared was filtered. The filtrate was concentrated in vacuo. The residue (15.98 g) was subjected to column chromatography with silica gel (chloroform: methanol = 98: 2 to 97: 3) to give compound (1) (10.01 g, 90.6%).
The compounds (2) and (3) were synthesized in a manner similar to that described in the above method. The results were shown in table 1.
Table 1
Example 1-process 2
Preparation of 3- (4-thia zolyl) -L-alaninyl-L-prolineamide dihydrochloride (4)
To a solution of the compound (1, 5.53 g, 15 mmol) in (30 ml) of ethyl acetate was added a solution of 4N hydrochloride in ethyl acetate (75 ml, 300 mmol) under ice-cooling and the resulting mixture was stirred for 2.5ha at the same temperature. To the reaction mixture was added (400 ml) of diethyl ether and the precipitation that appeared was filtered. The precipitation was washed with diethyl ether and dried in vacuo with the vacuum pump to give 6.67 g of the compound (4). This compound was used in the next reaction without purification.
The compounds (5) and (6) were synthesized in a manner similar to that described in the above method. The results were shown in table 2.
Table 2
Example 1-process 3
Preparation of L-pyroglutamyl-3- (4-tia zolyl) -L-prolineamide dihydrochloride (1-1)
The L-pyroglutamic acid (1.76 g, 13.64 mmol) and N-hydroxysuccinimide (1.73 g, 15 mmol) were dissolved in (50 ml) of N, -dimethyl ilformamide. To this solution was added the solution of DCC (3.09 g, 15 mmol) in (10 ml) of, N-dimethylformamide under cooling with ice and the resulting mixture was stirred for 2 h at the same temperature. The 3- (4-tiazolyl) -L-alanyl-L-prolineamide dihydrochloride (4) (6.67 g, 15 mmol) and (4.6 mL, 33 mmol) of triethylamine were successively added to the solution and the reaction mixture. it stirred throughout the night. Then, the precipitation that appeared was filtered, acid sodium carbonate was added to the filtrate. It will adjust to pH 8. The reaction mixture was subjected to gel filtration column chromatography (MCI gel CHP-20P, 200 ml aq MeOH) to give the compound (1-1) (2.54 g, 49%) .
Compounds (1-2) to (1-12) were synthesized in a manner similar to that described in the above method. The results were shown in Tables 3 to 6.
Table 3
1518, t, J = 7 Hz), 4.42 1444, and 4.34 (1H 1263 total, m), 4.17 (1H, m), 3.80 (1H, m), 3.1-3.6 (3H, m), 1.8-2.5 ( 8H, m) (KBr) (CD3OD) 8.95 (1H, 3301, d, J = l.8 Hz), 2936, 7.43 and 7.37 (1H 1685, total, d, J = 1.8 1518, Hz), 5.05 (1H, 1419, t, J = 6.8 Hz), -87.6 1330, 4.99 (1H, d, (c = l .012 -3 1-2 4 - 1 iazolylate 1262 J = 8.6 Hz), 4.86 H20, (1H, m), 4.45 23 ° C) (1H, d, J = 8.6 Hz), 4.18 (1H, dd, J = 5, 8.6 Hz), 3.1-3.5 (4H, m), 1.9-2.5 (4H, m) (KBr) (CD3OD) 8.86 (1H, 3393, s) , 7.75 and 7.71 3081, (1H total, d, 1684, J = 0.6 Hz), 4.90 -53.6 1639, (1H, m), 4.42 (c = l .002 -3 1-3 5-t? Aolol CH: 1540, (1H, dd, J = 4.5, MeOH, 1443, 8.4 Hz), 4.18 23 ° C) 1247 (1H, dd, J = 4.8, 8.7 Hz), 3.95- 3.60 (2H, m), 3.50 (1H, dd.
Table 4
(3H total, s), 1.8-2. (4H, m) (KBr) (CD30D) 8.93 3313, (1H, d, J = 1.8 2931, Hz), 7.39 (1H 1720, total, d, J = 1.8 1675, Hz), 5.02 (1H, 1517, t, J = 6.8 Hz), 1468, 4.95 (1H, d, 1435, J = 8.8 Hz), 4.86 -37.3 1305, (1H, m), 4.46 (c = l .005 -3 1-5 4-t ? azolyl 1125 (1H, d, J = 8.8 H20, Hz), 4.09 (1H, 23 ° C) dd, J = 4.4, 7.2 Hz), 3.1-3.5 (4H, m), 3.06 (3H, s), 2.97 (1H, dd, J = 7.2, 16.6 Hz), 2.78 (1H, dd, J = 4.2, 16.6 Hz) (KBr) [CD3OD) 8.87 3318, (1H, s), 7.67 and 1720, 7.73 (1H total , 1675, s), 4.90 (1H, -12 1523, m), 4.42 (1H, (c = l .011 1448, dd, J = 4.4, 8.2 -3 1-6 5-1 alanolyl CH; MeOH, 1356 , Hz), 4.09 (1H, 23 ° C) 1304, dd, J = 3.6, 7 1270 Hz), 3.70 (2H, m), 3.49 (1H, dd, J = 4.2, 15.4 Hz), 3.21 (1H, Table 5
1229 (2H, m), 3.93 (1H, d, J = 5.4 Hz), 3.78 (1H, m), 3.1-3.6 (3H, m), 1.7-2.3 (4H, m), 1.45 (3H, d, J = 6.6 Hz) (KBr) (CD3OD) 8.95 3397, (1H, d, J = 1.8 2980, Hz), 7.43 and 2932, 7.36 (1H, d, 1752, J = l.8 Hz), 5.07 1677, (1H, t, J = 6.6 1649, Hz), 4.98 (1H, -58.8 1519, d, J = 8.6 Hz), (c = l .010 1-8 4 -thiazolyl 1413, 4.86 (1H, m), HO, 1227 4.4-4.6 (1H, 23'C) m), 4.45 (1H, d, J = 8.6 Hz), 3.95 (1H, d, J = 5 Hz), 3.1- 3.5 (4H, m), 1.46 (3H, d, J = 6.2 Hz) (KBr) (CD3OD) 8.89 3397, (1H, s), 7.76 and -25.8 1753, 7.71 (1H total, (c = l .009 1677, s), 4.90 (2H ,
9-3 1-9 5-t-azolyl CH; H; 0.1639, m), 4.43 (1H, 23 ° C) 1527, dd, J = 5.4, 6.3 1446, Hz), 3.93 (1H, 1403, d, J = 5.4 Hz), Table 6
Example 13
Preparation of L-2-oxo-oxazolidin-4-yl-carboni 1-3- (4-thiazolyl) -L-alanyl-L-prolineamide (1-13)
The compound (1-13) was obtained in a manner similar to that described in the method of Example 1-3.
Example 14
Preparation of t rans-L-N-benzyl-5-met il-2-oxo-oxa zolidin-l -carboni 1-3- (4-thiazolyl) -L-alanyl-L-prolineamide (1-14).
(1) Benzyl ester of trans-L-5-met il-2-oxo-oxazolidine-4-carboxylic acid (706 mg, 3 mmol) which was synthesized according to the method described in Tetrahedron Lett., 36.6569 ( 1995) was dissolved in, N-dimet ilformamide (8 ml). After the solution was added benzyl bromide (0.39 ml, 3.28 mmol), sodium hydrate (120 mg, 3 mmol) at 60% was added to the mixture for 5 min with stirring. The mixture was stirred for 3 h at room temperature. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was washed with water, dried with magnesium sulfate and concentrated in vacuo. The residue was subjected to column B Lobar © (Merck inc.) And the fractions that were eluted with toluene: acetone = 30: 1 were collected to produce benzyl ester of trans-LN-benzyl-1-5-methyl-2-oxo acid -oxazolidin-4-carboxylic acid (859 mg, 88%) as a colorless oil.
NMR (CDC13): 7.1-7.5 (10H, m), 5.17 (2H, s), 4.92
(1H, d, J = 14.6 Hz), 4.56 (1H, m), 4.14 (1H, d,
J = 14.6 Hz), 3.63 (1H, d, J = 5.2 Hz), 1.39 (3H, d, J = 6.4 Hz).
The compound (850 mg, 2.61 mmol) obtained in the above process was dissolved in the solvent mixture of tetrahydrofuran (18 ml) and (2.7 ml). To the mixture was added the lithium hydroxide solution monohydrate (548 mg, 13.1 mmol) in water (10 ml) and the resulting mixture was stirred for 30 min at room temperature. The reaction mixture was poured into cold water and extracted with diethyl ether three times. To the alkaline layer 5N hydrochloric acid (3 ml) was added to adjust the pH to 1 and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water, dried with magnesium sulfate and concentrated in vacuo. The residue (574 mg, 93.5%) was recrystallized from acetone-hexane to give the trans-L-N-benzyl-5-methyl-yl-2-oxo-oxazolidin-carboxylic acid (493 mg, 80.3%).
p.f: 127 ° C
[a] D = -7.8 (c = 1.003, CHC13, 24 ° C)
IR (KBr) cm "1: 2716, 2601, 1740, 1692, 1497, 1442, 1421, 1339, 1248, 1201, 1186, 1078.
IR (CHC13) cm "1: 1758, 1496, 1455, 1415, 1227, 1223, 1212, 1205.
NMR (DMSO-d6): 7.2-7.5 (5H, m), 4.69 (1H, d, J = 15.4 Hz), 4.62 (1H, m), 4.15 (1H, d, J = 15.4 Hz), 3.71 (1H , d, J = 4.4 Hz), 1.32 (3H, d, J = 6.2 Hz).me.
Elemental analysis (C? 2H? 3N0)
Cale: C, 61.27; H, 5.57; N, 5.96.
Found: C, 61.30; H, 5.61; N, 5.91.
The compound (1-14) was obtained in a manner similar to that described in example 1-3.
Example 15
Preparation of trans-L-N-5-dimethyl-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-thiazolyl) -L-alanyl-L-prolineamide (1-15)
To a solution of benzyl ester of trans -L-5-met i 1 -2-oxo-oxazolidin-carboxylic acid (488 mg, 2.075 mmol) in (6 ml) of N, N-dimethylformamide was added iodomethane ( 0.17 ml, 2.73 mmol) under cooling with ice under a nitrogen atmosphere with stirring. Subsequently, 60% sodium hydrate (83 mg, 2.075 mmol) was added to the mixture for 10 min. The reaction mixture was stirred for 3 h at the same temperature. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was washed with water, dried with magnesium sulfate and concentrated in vacuo. The residue (503 mg) was subjected to column B Lobar®
(Merck inc.) And fractions that were eluted with toluene: acetone 30: 1 were collected to produce benzyl ester of trans-LN, 5-dimethyl-2-oxo-oxa zolidin-carboxylic acid (444 mg, 85.8%) as a colorless oil.
NMR (CDC13): 7.37 (5H, m), 5.27 (1H, d, J = 12.2 Hz), 5.20 (1H, d, J = 12.2 Hz), 4.51 (1H, m), 3.86 (1H, d, J = 5.4 Hz), 2.92 (3H, s), 1.50 (3H, d, J = 6.2 Hz).
A solution of the compound (551 mg, 2.21 mmol) which was obtained from the above process in the solvent mixture of methanol (10 ml) -water (1 ml) was hydrogenated using 5% Pd / C (150 mg) for 1 hr. room temperature. The catalyst was filtered and the filtrate was concentrated in vacuo to obtain trans-L-N-5-dimethyl-2-oxo-oxazolidin-4-carboxylic acid (345 mg, 98%).
p.f: 125-127 ° C [a] D = -11.1 ° (c = 1.005, MeOH, 24 ° C)
IR (KBr) CITG1: 3433, 2585, 1743, 1697, 1483, 1443, 1408, 1227, 1034.
NMR (DMSO-d6): 4.51 (1H, m), 3.99 (1H, d, J = 5.4 Hz), 2.79 (3H, s), 1.38 (3H, d, J = 6.2 Hz).
Elementary analysis (C6HsN04)
Cale: C, 45.28; H, 5.70; N, 8.80.
Found: C, 45.40; H, 5.63; N, 8.74.
The compound (1-15) was obtained in a manner similar to that described in the method of Example 1-3. The results were shown in Table 7.
Table 7
Example 16
Preparation of 4 - [2-L-pyrogyl amyl-2 - iodide. { (S) -2-carbamoylpyrrolidin-1-ylcarbonyl} ethyl] -3 -iodide met il t iazol io (1-16)
To the solution of compound (1-1) (5 g, 13.18 mmol) in acetonitrile (500 ml) was added iodomethane (67 ml, 1.07 mmol) and the resulting mixture was heated to reflux in an oil bath (80 ° C). for 20h. After the reaction mixture was cooled to 0 ° C, the supernatant liquid was removed by decantation. The precipitate was washed with cold acetonitrile and diethyl ether was added. The crystalline powder was collected by filtration to give 6.64 g of compound (1-16) as a yellow powder.
Using a procedure analogous to that described above, compounds (I-17) to (1-27) were synthesized. The results were shown in Table 8 to 10.
Table 8 Table 9
Table 10
Example 28
Preparation of 5- [2-L-pyroglutamyl-2- iodide. { (S) -2-carbamoylpyrrolidin-1-ylcarbonyl} ethyl] -3-methyl thiazolium (1-28)
Compound (1-28) 56.4% yield was obtained in a manner similar to that described in the method of Example 16 using the compound (I-3) as a starter material.
a, = -40.6 ° C (c = 1.001, MeOH, 21 ° C)
IR (KBr) crn "1: 3412, 1667, 1639, 1533, 1439, 1262.
NMR (CD30D): 8.20 and 8.21 (1H total, s), 5.02 (1H, dd, J = 6.7 Hz), 4.41 (1H, dd, J = 4, 8.4 Hz), 4.25 (1H, dd, J = 3 , 5.8 Hz), 4.22 (3H, s), 3.68 (2H, m), 3.53 (1H, dd, J = 7.15 Hz), 3.34 (1H, dd, J = 6, 15 Hz), 1.8-2.4 (4H, m), 2.02 (4H, m).
Elemental analysis (C? 7H24N5041 S 3H20;
Cale: C, 35.48; H, 5.25; N, 12.17; I, 22.05; S, 5.57.
Found: C, 35.36; H, 5.15; N, 12.43; I, 21.97; S, 5.75.
CbzNHCH, COOH ProceB ° ich, NHCH, COOR "" Pr? CeSO ^ >
H.NCH OOR6 p-TsOH process 1"" 1 »Or process 3-iv,, .." process
H O
NHCH2COOR6 Example 29 - process 1
Preparation of tetradecyl L-prolyl glycinate (10)
(i) To a solution of glycine of N-benzyloxycarbonyl (3 g, 14.3 mmol), tert-decadic alcohol (3.7 g, 14.3 mmol) and N, N-dimethylaminopyridine (87 mg, 10.3 mmol) in ethyl acetate. ethyl acetate (100 ml) was added DCC (2.98 g, 2.34 mmol) and the resulting mixture was stirred for 2 h at room temperature. After the precipitation that appeared was filtered, the filtrate was concentrated in vacuo. The residue was washed with ethanol to give tetradecyl ester of N-benzyloxycarbonylglycine (7) (3.46 g, 59.5%) as a crystal.
p.f: 57-58 ° C
NMR (CDC13): 7.36 (5H, s), 5.22 (1H, m), 5.13 (2H, s), 4.14 (2H, t, J = 6.6 Hz), 3.84 (2H, d, J = 5.4 Hz), 1.60 (2H, m), 1.26 (22H, br. S), 0.88 (3H, t, J = 6.6 Hz). Elemental Analysis (C24H39N04) Cale: C, 71.07; H, 9.69; N, 3.45.
Found: C, 70.94; H, 9.60; N, 3.74.
(ü) A solution of compound (7) and p-toluenesulfonic acid hydrate (1.4 g, 7.39 mmol) in mixed water (2 ml) -methanol (70 ml) was hydrogenated using 5% Pd / C (500 mg) for 3 h at room temperature. Then the catalyst was filtered, and the filtrate was concentrated in vacuo. The residue was recrystallized from ethyl acetate to give tetradecanylglycinate p-toluensul fonate (2.76 g, 84%) (8).
mp: 85.5-86.5 ° C NMR (CD30D): 7.70 (2H, d, J = 8.2 Hz), 7.23 (2H, d, J = 8.2 Hz), 4.43 (2H, d, J = 6.6 Hz), 3.82 ( 2H, s), 2.37 (3H, s), 1.65 (2H, m), 1.29 (22H, m), 0.90 (3H, t, J = 6.6 Hz).
Elementary analysis (C23H41NSO5)
Cale: C, 62.12; H, 9.29; N, 3.15; S, 7.21.
Found: C, 61.90; H, 9.15; N, 3.18 7.72
(iii) To a solution of compound (8) (2.06 g, 4.64 mmol), N- (t-butyloxycarbonyl) -L-proline (1 g, 4.64 mmol), N-hydroxybenzot riazol (18 mg, 0.139 mmol ) and triethylamine (0.71 ml). in N, N-dimethyl-ilformamide (30 ml) was added DCC (1 g, 4.87 mmol) and the resulting mixture was stirred for 18 h at room temperature. After the precipitation that appeared was filtered, the filtrate was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with water, dried with magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography with silica gel (toluene: ethyl acetate 3: 1) to give N- (tert-butyloxycarbonyl) -L-prolyl-glycinate tetradecyl (9) (1.94 g, 89.4%) .
[": -54.40 (c = 1.008, CHC13, 23 ° c;
NMR (CDC13): 4.31 (1H, m), 4.13 (2H, t, J = 6.6 Hz), 4.05 (2H, dd, J = 5.8, 7.7 Hz), 3.45 (2H, m), 1.90
(2H, m), 1.47 (9H, s), 1.26 (22H, br, s), 0.88 (3H, t, J = 7 Hz).
Elemental analysis (C26H48N2O5)
Cale: C, 66.63 10.32 N, 5.9:
Found: C, 66.62; H, 10.24; N, 6.05
(iv) To a suspension of compound (9) (1.47 g, 3.02 mmol) in trifluoroacetic acid (14 ml) was stirred for 2 h under ice-cooling. The reaction mixture was diluted with toluene and the resulting mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and sodium acid carbonate aq. The organic layer was washed with water and concentrated in vacuo to give 1.08 g of tetradecyl L-glycinate (10) as a powder.
The compounds (11) and (12) were synthesized in a similar manner described in the above method. The results were shown in Table 11.
Table 11
Example 29-process 2
Preparation of N- (tert-butyloxycarbonyl) -3- (4-thiazolyl) -L-alanyl-L-tetra-ethyl-prolyglycinate (13) To a solution of N- (tert-butoxycarbonyl) -3- (4-thiazolyl) -L-alanine (1. 480 mg, 1.76 mmol) which was synthesized according to the method described in the literature (Synthic Commun., 20, 3507, (1990)), compound (10) (650 mg, 1.76 mmol) and N-hydroxybenzotriazole (70 mg, 0.528 mmol) in N, N-dimethyl-ilformamide (20 ml) was added DCC (380 mg, 1848 mmol) and the resulting mixture was stirred overnight at room temperature . After the precipitation that appeared was filtered, the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the precipitation that appeared was filtered again. The filtrate was concentrated in vacuo. The residue was subjected to silica gel column chromatography (ethyl acetate: toluene = 9: 1) to give 1.02 g of compound (13).
The compounds (14) and (15) were synthesized in a manner similar to that described in the above method. The results were shown in Table 12.
Table 12
Example 29-process 3
Preparation of tetradecyl 3- (4-tiazolyl) -L-alanyl-L-propyl glycinate hydrochloride (16)
To a solution of compound (13) (1.2 g, 1.92 mmol) in ethyl acetate (20 ml) was added 4N hydrogen chloride solution in ethyl acetate (20 ml) under ice-cooling and the resulting mixture was stirred for 2 h at the same temperature. The reaction mixture was concentrated in vacuo to give compound (16) (1.27 g, quantitative). This compound was used in the next reaction without further purification.
Example 30-process 3
Preparation of 3- (4-tiazolyl) - L-alanyl-L-prolyl-glycinate isopropyl hydrochloride (17)
In a manner similar to that described in the method of Example 29-2, compound (17) (590 mg, quantitative) was obtained by de-tert-butoxycarbonylation of compound (14) (580 mg, 1.24 mmol). This compound was used in the next reaction without purification.
Example 31-process 3
Preparation of benzyl 3- (4-tiazolyl) L-alanyl-L-prolyl glycinate hydrochloride (18)
In a manner similar to that described in the method of Example 29-3, compound (18) (700 mg, quantitative) was obtained by de-tert-butoxycarbonylation of compound (15) (750 mg, 1.45 mmol). This compound was used in the next reaction without purification.
Example 29-process 4
Preparation of cis -L-5-met i 1-oxo-oxazolidin-4-ylcarbonyl-3- (4-t-yolyl) -L-alanyl-L-propy 1-tetradecyl glycinate (1-29) cis-5-methyl-2-oxazolidin-4-yl carboxylic acid (139 mg, 0.96 mmol), which was synthesized according to the method described in Chem. Lett., 1982, 1171, and N-hydroxysuccinimide was dissolved ( 110 mg, 0.96 mmol) in N, N-dimethylformamide (2 ml). To this solution was added DCC (200 mg, 0.97 mmol) and the resulting mixture was stirred for 2 h at room temperature. To the reaction mixture was added the free base of compound (16) prepared by filtering the salt which precipitated by adding triethylamine (0.53 ml, 3.8 mmol) to the solution of compound (16) (635 mg, 0.96 mmol) in N , -dimet ilformamide (15 ml) under cooling with ice. The reaction mixture was stirred for 72 h at room temperature. After it appeared the precipitation was filtered and the filtrate was concentrated in vacuo. The solvent mixture of methanol: water = 3: 1 was added to the residue and the precipitation that appeared was filtered. The filtrate was subjected to a gel filtration column chromatography (MCI Gel CHP 20P 200 ml, methanol-water) and successively to silica gel column chromatography (chloroform-methanol = 7: 1) to give 381 mg of the compound (1-29).
The compound (1-30) and (1-31) were synthesized in a manner similar to that of the method described above. The results were shown in Table 3.
Example 32
Preparation of cis -L-5-met il-2-oxo-oxazolidin-4-ylcarbonyl-3- (4-thiazolyl) -L-alanyl-L-propi 1-glycine (1-32)
To a solution of compound (1-31) (500 mg, 0.919 mmol), lithium hydroxide (193 mg, 4.56 mmol) was added to the mixture of methanol (20 ml) -water solvents (20 ml). The resulting mixture was stirred for 30 minutes at room temperature. After the reaction mixture was neutralized by adding dilute hydrochloric acid, the mixture was concentrated in vacuo. The residue was subjected to a gel filtration column chromatography (MCI Gel CHP 20P 200 ml, methanol-water) and further lyophilized to give 218 mg of the compound (1-32) the result was shown in Table 13.
Table 13 CH (CH3) -68.7 8.78 (1H, d, J = 1.8 (c = 0.504, Hz), 7.22 (1H, d, MeOH, J = 2 Hz), 5.54 (1H, 25 ° C) d, J = 8.2 Hz), 4.67 (2H, m), 4.41 (1H, dd, J = 7.4, 17.6 Hz), 4.14 (2H, t, J = 7 Hz), 3.74 (1H, -4 1-30 dd, J = 5.5, 17.6 Hz), 3.50 (1H, m), 3.30 (2H, m), 2.97 (1H, m), 1.45 (9H, s), 2.30 (1H, m), 1.95 (3H, m), 1.27 (22H, m), 0.89 (3H, t, J = 6.6 Hz). CH-Ph-61.8 8.88 (1H, s), (c = 0.508, 7.42 (1H, s), 7.35 MeOH, (5H, m), 5.18 (2H, 23 ° C) s), 4.95 (2H m), 4.47 (1H, dd, -4 1-31 J = 4.2, 8.6 Hz), 4.33 (1H, d, J = 8.7 Hz), 4.07 (1H, d, J = 17.7 Hz), 3.99 (1H, d, J = 17.7
Example 33
The preparation of L-pyroglutamyl-3- (4-thiazolyl) -L-alanyl-L-prolyl-glycinate tetradecyl (1-33)
In a manner similar to that described in the method of Example 29-4, N-hydroxysuccinimide ester of L-pyroglutamic acid which were prepared by the reaction of L-pyroglutamic acid (124 mg, 0.96 mmol), N-hydroxysuccinimide ( 110 mg, 0.96 mmol), and DCC (200 mg, 0.97 mmol), was reacted with the free base of compound (16), which was prepared by compound (16) (635 mg, 0.96 mmol) and triethylamine ( 0.53 ml, 3.84 mmol) to give 497 mg (81.7%) of the compound (1-33).
a] D = -52.4 (c 0.508, MeOH, 23 C '
NMR (CD3OD): 8.95 (1H, d, J = 2.1 Hz), 7.44 (1H, d, J = 2.1 Hz), 4.92 (1H, t, J = 6.9 Hz), 4.49 (1H, dd, J = 3.6 , 8.5 Hz), 4.14 (3H, m), 3.97 (2H, s), 3.75 (1H, m), 3.40 (1H, m), 3.20 (2H, m), 2.4-1.8 (8H, m), 1.62 (2H m), 1.32 (22H, m), 0.89 (3H, t, J = 6.9 Hz).
Elemental Analysis (C32H5iN506S 0.4H2O)
Cale: C, 59.96; H, 8.14; N, 10.92; S, 5.00.
Found: C, 59.97; H, N 11.02 5.07
p
Example 34-process 1
Preparation of benzyl cis-L-3-ethoxycarbonyl-5-methyl-il-oxo-oxa-oxo-carboxylate (19) A solution of benzyl ester of cis-5-methyl-2-oxo-oxazolidin-4-carboxylic acid (706 mg, 3 mmol) which was synthesized according to the method described in Chem. Lett., 1982, 1171 in tetrahydrofuran (12 ml) was cooled in a dry ice-acetone bath (-50 ° C) under an atmosphere of nitrogen. To the solution was added potassium tert-butoxide (337 mg, 3 mmol) and the resulting mixture was stirred for 20 min at the same temperature. To the mixture was added dropwise a solution of ethyl chlorocarbonate (0.46 ml, 4.83 mmol) in tetrahydrofuran (2 ml) for 10 min. The reaction mixture was stirred for 3 h at -50 to -14 ° C (bath temperature). The reaction mixture was partitioned between ice and ethyl acetate. The organic layer was washed with water, dried with magnesium sulfate and concentrated in vacuo. The residue was subjected to Lober® column (Merck inc.) And recrystallized from diethyl ether-hexane to give 847 mg of compound (19) as colorless needle crystals.
Example 34-process 2
Preparation of cis-L-3-ethoxycarbonyl-5-met il-2-oxo-oxazolidin-4-carboxylic acid (20)
A solution of compound (19) (718 mg, 2.34 mmol) in 50% aqueous methanol (3 ml) was hydrogenated using 5% Pd / C (200 mg) for 2 h at room temperature. The catalyst was filtered and the filtrate was concentrated in vacuo to give 516 mg of the compound (20) as a powder.
Example 35-process 1
Preparation of cis-L-3-pivaloyloxymethyl-5-methyl-methyl-2-oxo-oxa zolidin-carboxy benzyl (21)
In a manner similar to that described in the method of Example 34-1, the benzyl ester of cis-L-5-met il-2-oxo-oxazolidin-4-carboxylic acid (706 mg, 3 mmol) was subjected to pivaloi L-carboxylation with pivalic iodomethyl acid (1.19 g, 4.92 mmol) in the presence of potassium tert-butoxide (337 mg, 3 mmol) in tetrahydrofuran (12 mL) to give 893 mg of the compound (21) as colorless needle crystals.
Example 35-process 2
Preparation of cis-L-3-pivaloyloxymethyl-5-methyl-2-oxo-oxazolidin-4-carboxylic acid (22)
In a manner similar to that described in the method of Example 34-2, compound (21) (892 mg, 2.55 mmol) was subjected to de-benzylesterification by hydrogenation in the presence of 5% Pd / C (250 mg) in aqueous methanol to give 642 mg of the compound (22) as colorless needle crystals.
Example 36-process 1
Preparation of benzyl ester of cis-L-5-methyl-N- (4-morpholinylcarbonylmethyl) -2-oxo-oxazolidin-4-carboxylic acid (23)
In a manner similar to that described in the method of Example 34-1, to a solution of benzyl ester of cis-L-5-methyl-2-oxo-oxazolidin-4-carboxylic acid (706 mg, 3 mmol) in THF (14 ml) was added potassium tert-butoxide (337 mg, 3 mmol) at -53 C under a nitrogen atmosphere and the resulting mixture was stirred for 20 min at the same temperature. A solution of N-iodoacet and Imor folin (1.15 g) was added to the reaction mixture., 4.51 mmol) in THF (1 ml) and the resulting mixture was stirred for 4h from -53 ° C to -15 ° C. The reaction mixture was partitioned between ethyl acetate and sodium thiosulfate aq. Cooled. The organic layer was washed with water, dried with magnesium sulfate and concentrated in vacuo. The residue was subjected to Lober® column (Merck inc.) And fractions were eluted with toluene: acetone = 5: 1 were collected to yield compound (23) (873 mg) as crystals.
Example 36-process 2
Preparation of cis-L-5-met il-N- (4 • morpholinylcarbonylmethyl) -2-oxo-oxazolidin-4-carboxylic acid (24)
In a manner similar to that described in the method of Example 34-2, compound (23) (846 mg, 2.33 mmol) was subjected to de-benzyl etherification by hydrogenation in the presence of 5% Pd / C (250 mg) in aqueous methanol to give 740 mg of the compound (24) as colorless needle crystals.
Example 37-process 1
Preparation of benzyl ester of cis-L-5-methyl-N- (4-morpholinocarbonyl) -2-oxo-oxazolidin-4-carboxylic acid (25)
In a manner similar to that described in the method of Example 34-1, the benzyl ester of cis-L-5-methyl-2-oxo-oxa-zolidin-4-carboxylic acid (470 mg, 2 mmol) was reacted with 4-morpholine-carbonyl chloride (0.35 ml, 3 mmol) in the presence of potassium tert-butoxide (224 mg, 2 mmol) in THF to give 630 mg of the compound (25).
Example 37-process 2
Preparation of cis-L-5-met il-N- (4-morpholylcarbonylmethyl) -2-oxo-oxazolidin-4-carboxylic acid (26)
In a manner similar to that described in the method of Example 34-2, compound (25) (1.08 g, 3.10 mmol) was subjected to de-benzyl etherification by hydrogenation in the presence of 5% Pd / C (200 mg) in aqueous methanol to give 706 mg of the compound (26).
Example 38-process 1
Preparation of benzyl ester of cis-L-5-methyl-N- (4-oxo-butyl) -2-oxo-oxazolidin-4-carboxylic acid (27)
In a manner similar to that described in the method of Example 34-1, the benzyl ester of cis-L-5-methyl-2-oxo-oxazolidin-carboxylic acid (3 g, 12.9 mmol) was reacted with l- iodo-2-butanone (3.83 g, 19.3 mmol) in the presence of potassium tert-butoxide (1.45 g, 12.9 mmol) in THF to give 2.15 g of the compound (27).
Example 38-process 2
Preparation of cis-L-5-met il-N- (2-oxo-butyl) -2 -oxo-oxa-zolidin-4-carboxylic acid (28)
In a manner similar to that described in the method of Example 34-2, compound (27) (1.67 g, 5.47 mmol) was subjected to de-benzylesterification by hydrogenation in the presence of 5% Pd / C (480 mg) in aqueous methanol to give 0.65 g of the compound (28). The above results were shown in Tables 14 and 15.
Table 14
22 C) J = ll.2 Hz), 5.30 (1H, d, J = 12 Hz), 5.24 (1H, d, J = 11.2 Hz), 5.20 (1H, d, J = 12 Hz), 4.79 (1H, m), .58 (1H, d, J = 8.8 Hz), 1.23 (3H, d, J = 6.4 Hz), 1.20 (9H, s). (DMSO-de): 5.31 (1H, d, J = ll Hz), 5.17 (1H, d, J = ll Hz), -32.0 4.89 (1H, dq, (c = l .07, -2 22 CH: OC (O) -CMe3 J = 8".6, 6.8 MeOH, Hz), 4.48-22 ° C) (1H, d, J = 8.6 Hz), 1.26 (3H, d, J = 6.8 Hz), 1.14 (9H , s) -112.1 (CDC13): 7.38 -1 23 Bzl (c = l .09, (5H, s), 5.29 h CCN (1H, d, J = 12 MeOH,
Table 15 (CDCI3): 7.37 (5H, s), 5.30 (1H, d, J = ll .6 Hz), -68.4 5.15 (1H, d, / ~ (c = 1.012 J = ll .6 Hz), -1 25 -CN Bzl CHC13 5.00 (1H, d, 25 ° C) J = 8.3 Hz), 4.89 (1H, m), 3.8-3.4 (8H, m), 1.26 (3H, d, J = 6.4 Hz) . (CD3OD): 4.99 (1H, m), 4.87 -48.8 (1H, d, J = 6 (c = 0.510 Hz), 3.72-26 -CN O MeOH, (4H, m), 3.54 26 ° C) ( 4H, m), 1.38 (3H, d, J = 6 Hz). (CDCl 3): 7.37 (5H, s), 5.20 (2H, dd, -129.5 OJ = 11.6 Hz), (c = 1. OH -1 27 H -C-Et Bzl 4.91 (1H, m), CHCl3 , 4.73 (1H, d, 26 ° C) J = 9 Hz), 4.54 (1H, d, J = 19.2 Hz),
Example 34-process 3
Preparation of cis-L-3-ethoxycarbonyl-5-methyl-2-oxo-oxazolidin-4-ylcarbonyl-3- (4-thiazolyl) -L-alanyl-L-prolineamide (1-34)
To the compound (20) (236 mg, 1.08 mmol) was added oxazolyl chloride (0.15 ml, 1.72 mmol) and N, N-dimethyl formamide (2 drops) and the resulting mixture was stirred for 2.5 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (3 ml) and a solution of 3- (4-thiazolyl) -L-alanyl-L-prolineamide (6688 mg, 1.2 mmol) and triethylamine (0.61 ml, 4.35 mmol) was added to the solution. in N, N-dimethylformamide (9 ml) under ice-cooling with stirring. The reaction mixture was stirred overnight at room temperature. After the precipitation was filtered, the filtrate was concentrated in vacuo. The residue was then dissolved in water and the solution was subjected to gel filtration column chromatography (MCI Gel CHP-20P, 200 ml, methanol-water) to give the crude compound (248 mg). The crude compound was subjected to column chromatography on silica gel (chloroform: methanol = 9: 1) to give 188 mg of compound (1-34).
The compound (1-35) to (1-39) were synthesized in a manner similar to that described in the above method. The results were shown in Tables 16 and 17. When compounds 1-36, 38 and 39 were synthesized, DCC was used in place of the oxalyl chloride as an activating agent.
Table 16 4.41 (1H, dd, J = 4.2, 8.7 Hz), 4.20 (2H, q.3 = 1.2 Hz), 3.88 (1H, m), 3.48 (1H, m), 3.40 (1H, dd, 3 = 6.9, 14.7 Hz), 2.19 (1H, m), 1.99- (3H, m), 1.37 and 1.30 (3H total, d, J = 6.3 Hz), 1.25 and 1.20 (3H total, t, 7.2 Hz). (CD3OD): 8.97 and 8.94 (1H total, d, -66.3 3 = 2.1 Hz), (c = 7.48 and 7.40 212-35-3 1-35 CH: 0C (O) -C e: 0.514, (1H total, d,: i3 MeOH, 3 = 2.1 Hz), 22.5 ° C) 5.33 and 5.31 (1H total, d, J = ll .1 Hz), 5.03 (1H, t, 11)
J = 6.9 Hz), 5.01 and 4.96 (1H total, d, J = ll .1 Hz), 4.84 (1H, m), 4.58 and 4.54 (1H total, d, J = 8.7 Hz), 4.41 and 4.32 (1H , dd, J = 3.9, 8.1 Hz), 3.89 (1H, m), 3.52 (1H, m), 3.41 (1H, dd, J = 6.6, 14.7 Hz), 3.22 (1H total, dd, J = 7.2, 14.7 Hz), 2.29 (1H, m), 2.00 (3H, m), 1.30 and 1.25 (3H total, d, J = 6.6 Hz) and 1.96 (9H total, s).
Table 17 (1H, d, J = 17.2 Hz), 386 (1H, m), 3.86 (1H, d, J = 17.2 Hz), 3.3-3.7 (10H,), 3.18 (1H, dd, J = 7.8, 14.4 Hz), 1.8-2.3 (4H, m), 12.4 and 1.17 (3H total, d, 3 = 6 Hz). (CD3OD): 8.93 and 8.72 (1H total, d, J = l.8 7.48 and 7.39 (1H total, d, -69.7 J = 1.8 Hz), (c = 0.505 1-37 -CN CH- 4.9- 5.1 (3H, MeOH, m), 4.42 (1H, 26 ° C) dd, J = 4.4, 8.4 Hz), 3.85 (1H, m), 3.70 (4H, m), 3.50 (4H, m), 1.8- 2.3 (4H, m), 1.28 (3H, d, J = 5.8 Hz). (CD3OD): 8.96 and 8.98 (1H total, d, 3 = 2.1 Hz), 7.35 and 7.43 (1H total, d, 3 = 2.1 Hz), 5.02 (1H, dd, J = 6.6 Hz), 4.92 (1H, m), 4.48 and 4.49 (1H, total, -80.4 d, 3 = 4.4 Hz), O (c = l .012 38-3 I-3Í H2C-C-Et CH- 4.40 (1H, dd, MeOH, 3 = 4.2, 8.4-26 ° C) Hz), 4.34 (1H, d, J = 18.6 Hz), 3.76 (1H, d) , J = 18.6 Hz), 3.85 (1H, m), 3.51 (1H, m), 3.38 (1H, dd, J = 6.6, 14.9 Hz), 3.17 (1H, dd, J = 6.6, 14.9?
Preparation of cis-L-3-morpholinomethyl-5-methyl-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-thiazolyl) -L-alanyl-L-prolineamide (1-40)
To a solution of ethanol (3.6 ml) of compound (1-10) (237 mg, 0.6 mmol) was added morpholine (180 mg, 2.07 mmol) and 37% formalin (0.22 ml) and the resulting mixture was stirred for 3 h in an oil bath (60 ° C). The reaction mixture was concentrated in vacuo. The residue was dissolved in a mixture of chloroform and methanol solvents and the solution was subjected to alumina column chromatography (chloroform: methanol = 97: 3) to give the fractions containing the objective compound (258 mg). The fractions were dissolved in methanol and a large amount of diethyl ether was added to the solution. The precipitation that appeared was filtered to give 195 mg of the compound (1-40).
The compound (1-41) was synthesized in a manner similar to that described in the above method. The results were shown in Table 18.
Example 42
Preparation of cis-L-3- (N-methypipiperazinyl) methyl-5-methyl-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-tiazolyl) -L-alanyl-L-prolineamide hydrochloride (1-43)
i) In a manner similar to that described in the method of Example 40, compound (1-10) (395 mg, 1 mmol) was treated with N-methyl-piperazine (0.2 ml, 2.34 mmol) and 37% formalin ( 0.24 ml) in ethanol (10 ml) to form the Mannich base, giving 350 mg of the compound (1-42) which was the free base of the compound (1-43).
The detailed result was shown in Table ^ 18.
ii) After compound (1-42) (120 mg, 0.244 mmol) was dissolved in methanol (1 ml), a solution of 4N hydrogen chloride in ethyl acetate (0.15 ml) was added to this solution. Subsequently, diethyl ether was added to the mixture and the precipitation that appeared was filtered to give 138 mg of the compound (1-43).
[a] D = -82 ° (c = 0.51, H20, 23 ° C)
IR (KBr) cm_1: 3412, 1764, 1677, 1647, 1544, 1446, 1342, 1298, 1221.
Elemental analysis (C22H32N605S 1.8HC1 0.3Et20
1. 2H20)
Cale. C, 46.28; H, 6.56; N, 13.96; Cl, 10.60; S, 5.33.
Found: C, 46.08; H, 6.38; N, 14.27; Cl, 10.88; S, 5.37.
Table 1
Do not . not . of [ot] D NMR E] emplo compue sto (CD3OD): 8.98 and 8.96 (1H total, d, J = l.8 Hz), 7.43 and 7.36 -61 (1H total, d, (c = 0.503 J = l .8 Hz),
40 1-40 H2C-NOH: 0, 5.08 (1H, dd, 23.5 ° C) J = 6.0), 7.8 Hz), 4.84 (1H,), 4.46 (1H, d, J = 8.4 Hz), 4.42 (1H , dd, J = 3.9, 8.4 Hz), 4.07 (1H, d, J = 12.6 Hz), 3.91 (1H, m), 3.63 (5H, m) 3.56 (1H, d, J = 12.6 Hz), 3.41 ( 1H, dd, J = 6.0, 14.4 Hz), 3.19 (1H, dd, J = 6.0, 14.4 Hz), 2.47 (4Hm), 2.21 (1H, m), 2.01 (2H, m), 1.30 and 1.24 ( 3H total, d, J = 6.9 Hz "). (CD30D): 8.98 and 8.96 (1H total, d, 3 = 2 -69.1 Hz), 7.43 and (c = 0.966 41 1-41 H 7.36 (1H H: 0 , total, d, 3 = 2 23.5 ° C) Hz), 5.07 (1H, dd, 3 = 6 .4, 8.2 Hz), 4.80 (1H, m), .44 (1H, d, J = 8.6 Hz) , 4.11 and 4.10 (1H total, d, J = 13 Hz), 3.90 (1H,), 3.56 (5H, d, J = 13 Hz), 3.51 (1H, m), 3.40 (1H, dd, 3 = 6 .4, 14.4 Hz), 2.3-2.6 (8H, m), 2.27 and 2.15 (3H total, s), 2.20 (1H,), 2.01 (2H, m), 1.29 and 1.24 (3H total, d, 3 = 6 .2 Hz). (DMSO-de): 9.06 and 9.02 -62.3 (1H total, d, / \ (c = 0.514 42 1-42 HX - N N- Me 3 = 2 Hz), 8.81 H20, and 8.59 (1H 23.5 ° C) total , d, J = 8 Hz), 7.43 (1H, d, 3 = 2 Hz), 7.34
(1H, br, s), 7.16 and 6.90
(1H, br, s), 4.96 (1H, m), 4.74 (1H,), 4.50 and 4.37
(1H total, d, J = 8.2 Hz), 4.22 (1H, m), 3.95 (1H, d, J = 12.8 Hz), 3.72 (1H,), 3.60 (1H, m), 3.26 (1H, d, J = 12.8 Hz), 3.20 (1H, dd, J = 5.14 Hz), 3.04 (1H, dd, J = 9.8, 14 Hz), 2.31 (4H, m), 1.6-2.1 (4H, m), 1.40 ( 6H, m), 1.16 and 1.09 (3H total, d, 3 = 6 Hz).
Example 44 and 45-process 1
Preparation of cis-L-5-met il-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-thiazolyl) -L-alanine (29) A solution of cis-L-5-met il- 2-oxo-oxazolidin-4-carboxylic acid (1.08 g, 7.5 mmol) in N, N-dimethylformamide (30 ml) was added n-hydroxysuccinimide (650 mg, 8.25 mmol) and DCC (1.70 g, 8.25 mmol) and The resulting mixture was stirred for 3 h at room temperature. After the precipitation appeared it was filtered, 3- (4-thiazolyl) -L-alanine trifluoroacetate (4.64 g, 7.5 mmol) and triethylamine (5.23 mL, 37.5 mmol) were added to the filtrate. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated in vacuo. The residue was subjected to gel filtration column chromatography (MCI GEL CHP-20P, 200 ml, MeOH, aq.) And to column chromatography on silica gel (chloroform: methanol = 10: 1) to give 890 mg (39.7 g. %) of the compound (29).
NMR (CD30D): 9.02 (1H, d, J = 1.8 Hz), 8.46 (1H, d, J = 7.8 Hz), 7.74 (1H, s), 7.38 (1H, d, J = 1 .8 Hz),
4. 77 (1H, dq, J = 8.7, 6.6 Hz), 4.66 (1H, m), 4.21
(1H, d, J = 8.7 Hz), 3.24 (1H, dd, J = 5.1, 15 Hz), 3.13 (1H, dd, J = 8.4, 15 Hz), 1.13 (3H, d, J = 6.6
Hz).
Elemental analysis (CuH? 3N305S 0.2H2O)
Cale. C, 43.62; H, 4.46; N, 13.87; Cl, 10.59.
Found: C, 43.66; H, 4.45; N, 13.73; S, 10.39.
Example 44 and 45-process 2
Preparation of cis-L-5-met il-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-thiazolyl) -L-alanyl-prolineamide (1-10)
To a solution of compound (29) (150 mg, 0.5 mmol) and N-hydroxysuccinimide (63 mg, 0.55 mmol) in N, N-dimethylformamide (5 mL) was added DCC (14 mg, 0.55 mmol) under cooling with ice and the resulting mixture was stirred for 60 min. Subsequently, L-prolineamide (63 mg, 0.55 mmol) was added to the mixture and the resulting mixture was stirred for an additional 16 h at room temperature. After the filtration appeared it was filtered, the filtrate was concentrated in vacuo. The residue was dissolved in water and subjected to column chromatography by gel filtration MCL GEL CHP-20P, 200 ml, aq MeOH) to give 164 mg (82.8%) of the same compound which are synthesized in Example 10- 3.
Example 44 and 45-process 3
Preparation of cis-L-3-acetoxymethyl-5-met-il-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-thiazolyl) -L-alanyl-N- (acetoxymethyl) -L-prolineamide (1-44) and cis-L-3-acetoxymethyl-5-methyl-2-oxo-oxazolidin-4-l-carbonyl-3- (4-t-aiazolyl) -L-alanyl-L-prolineamide (1-45) )
A solution of compound (1-10) (198 mg, 0.5 mmol) in ethanol (1 ml) was added 0.1 ml of the triethylamine solution (0.5 ml) in ethanol (10 ml) and 37% formalin (0.13 ml, 1.6 mmol) and the resulting mixture was heated to reflux in the oil bath (105 ° C) for 2 h. The reaction mixture was concentrated in vacuo. After the residue was dissolved in pyridine (9 ml), acetic anhydride (0.9 ml) was added to the mixture and kept for 1 h at room temperature. After toluene was added to the reaction mixture, the resulting mixture was concentrated in vacuo. The residue was subjected to column chromatography on silica gel (chloroform: methanol = 19: 1) to give 143 mg of compound (1-44) and 71 mg of compound (1-45).
Example 46
Preparation of cis-L-3-acetoyl-5-methyl-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-thiazolyl) L-alanyl-L-prolineamide (1-46).
After the compound (1-10) (125 mg, 0.316 mmol) was dissolved in pyridine (5 ml), acetic anhydride (0.6 ml) was added to the mixture and the resulting mixture was kept for 16 h at room temperature. Additionally, acetic anhydride (0.6 ml) was added to the mixture and the resulting mixture was kept for 2 days at room temperature. After toluene was added to the reaction mixture, the mixture was concentrated in vacuo. The residue was subjected to column chromatography on silica gel (chloroform: methanol = 19: 1) to give 94 mg of compound (1-46).
Example 47
Preparation of cis-L-3-acetoxy-5-met i 1-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-thiazolyl) -L-alanyl-Lt ia zol idin-4-carboxamide (1 -47)
In a manner similar to that described in the method of Example 44 and 45-3, then compound (1-11) (210 mg, 0.5 mmol) was subjected to hydroxymethylation by treatment with 37% formalin (0.13 ml) and triethylamine (0.05 ml), the resulting compound was acetylated by treatment with acetic anhydride-pyridine to give 140 mg of compound (1-47).
The previous results were shown in Table 19.
Table 19
(1H total, d, J = 8.4 Hz), 4.31 (1H, dd, 3 = 4. 2, 8.4 Hz), 3.86 (1H, m), 3.42 (1H,), 3.35 (1H, m), 3.20 ( 1H, dd, J = 6.9, 14.7 Hz), 1.8-2.3 (4H, m), 2.05 (3H, s), 2.04 (3H, s), 1.29 and 1.24 (3H total, d, J = 6.6 Hz). (CD30D): 8.97 and 8.94 (1H, d, J = l.8 Hz), 7.47 and 7.39 (1H, total d, J = l.8 Hz), 5.31 and 5.29 (1H total, d, J = ll. 2), 5.04 (1H, t, J = 6.9 Hz), 5.01 and 4.98 (1H total, d, J = ll.l Hz),. 4.80 (1H, m), 4.59 and 4.56
1-45 CH20Ac CH2 (1H, d, J = 8.7 Hz), 4.41 and 4.30 (1H, dd, J = 3.9, 8.4 Hz) 3.87 (1H, m), 3.50 (1H, m), 3.40 (1H, dd , J = 14.1, 6.6 Hz), 3.22 (1H, dd, 3 = .9, 14.1 Hz), 1.7-2.3 (4H, m), 2.05 (3H, s), 1.30 and 1.24 (3H total, d, 3 = 6 .6 Hz). (CD3OD): 8.94 and 8.93 (1H
1-46 Ac CH2 total, d, J = 1.8 Hz), 7.47 and 7.38 (1H total, d,
p
Example 48 - process 1
Preparation of benzyl ester of N- (tert-butyl-butyloxycarbonyl) -3- (4-thiazolyl) -L-alanyl-L-proline (30)
A solution of N- (tert-butyloxycarbonyl) -3- (4-thiazolyl) -L-alanine (2.72 g, 10 mmol), L-prolin benzyl hydrochloric acid ester (2.42 g, 10 mmol) and HOBT (135 mg, 1 mmol) in tetrahydrofuran
(60 ml) was added triethylamine (1.4 ml, 10 mmol) and DCC (2.43 g, 11.8 mmol) and the resulting mixture was stirred. for 18h at room temperature. After the precipitation appeared it was filtered, the filtrate was concentrated in vacuo. The residue (5.5 g) was subjected to column chromatography on silica gel with column C Lobar® (Merck inc.) (Toluene: acetone = 9: 1) to give 4.16 g of the compound (30).
Example 48-process 2
Preparation of benzyl ester of 3- (4-thiazolyl) -L-alanyl-L-proline hydrochloride
To a solution of compound (30) (3 g, 6.528 mmol) in ethyl acetate (10 ml) was added a solution of 4N hydrogen chloride in ethyl acetate (33 ml) under ice-cooling and the resulting mixture was stirred for 3h. Diethyl ether was added to the reaction mixture and the precipitation that appeared was filtered to give 2.77 g of the compound (32). This compound was used in the next reaction without purification.
The compounds (31) and (33) are synthesized in a manner similar to that described in the above method. The results were shown in Table 20.
Table 20
Example 48-process 3
Preparation of benzyl ester of cis-L-5-met il-2-oxo-oxazolidin-4-ylcarbonyl-3- (4-thiazolyl) -L-alanyl-L-proline (1-48)
A solution of cis-L-5-met il-2-oxo-oxazolin-4-carboxylic acid (316 mg, 2.17 mmol) and N-hydroxysuccini ida (249 mg, 2.17 mmol) in N, N-dimethylformamide (5 ml DCC (448 mg, 2.17 mmol) was added and the resulting mixture was stirred for 4 h at room temperature. After the precipitation appeared it was filtered, to the filtrate was added 865 mg (2.17 mmol) of the compound (32) and triethylamine (1.21 ml, 8.7 mmol). The reaction mixture was stirred for 16 h at room temperature. After the precipitation appeared filtered, the filtrate was concentrated in vacuo. The residue was subjected to gel filtration column chromatography (MCL GEL CHP-20P, 200 ml, aq MeOH) and to silica gel column chromatography to give 496 mg of compound (1-48).
The compound (1-49) was synthesized in a manner similar to that described in the above method. The results were shown in Table 21.
Example 50
Preparation of cis-L-5-met il-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-t-aiazolyl) -L-alanyl-L-proline (1-50)
A solution of the compound (1-48) (1.99 g,
4. 09 mmol) in 50% aqueous methanol was added lithium hydroxide (858 mg, 20.45 mmol) and the resulting mixture was stirred for 35 min at room temperature. After the reaction mixture was neutralized by adding IN hydrochloric acid (20.4 ml), the resulting mixture was concentrated in vacuo to about half the volume. The aqueous solution was washed twice with ethyl acetate. The aqueous layer was subjected to gel filtration column chromatography (MCI GEL CHP-20P, 200 mL, aq MeOH) to give 1.29 g of compound (1-50). The result was shown in Table 21.
Table 21
Example 51-process 1
Preparation of 4 - (N-benzyloxycarboni 1-L-prolyl) mor folin (34)
A solution of N-benzyloxycarbonyl-L-proline
(5 g, 20.06 mmol), morpholine (1.92 ml, 20.06 mmol) and N-hydroxysuccinimide (2.31 g, 20.06 mmol) in
N, N-dimethyl-ilformamide (100 ml) was added DCC (4.14 g, 20.06 mmol) and the resulting mixture was stirred for 4 h at room temperature. After the precipitation was filtered, the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the resulting precipitation was filtered. The filtrate was then washed with dilute hydrochloric acid, sodium hydrogen carbonate aq.
Saturated and water, the organic layer was dried with magnesium sulfate and concentrated in vacuo. The residue was crystallized from the solvent mixture of ethyl acetate-hexane to give the compound
(34) (4.44 g, 69.5%).
mp: 142-143 C.
[': = -1 0 ° (c = 1, CHC13, 23 ° C;
IR (CHC13) cm-1: 1700 1660, 1420
NMR (CDCl 3): 7.35 (5H, m), 5.12 (2H, m), 4.59 and 4.70 (1H total, dd, J = 3.6, 8.4 Hz), 3.20-3.90 (10H, m), 1.80-2.30 (4H , m).
Elemental analysis (Ci7H22N204.
Cale. C, 64.13; H, 6.96; N, 8.80,
Found: C, 53.99; H, 6.94; N, 8.81
Example 51-process 2
Preparation of 4-L-prolyl-morpholine p-toluenesulfonate (35) A solution of compound (35) (3.6 g, 11.31 mmol) in methanol (50 ml) -water (10 ml) was hydrogenated using 5% Pd / C (1.6 g) and p-toluensulonic acid (2.15 g, 11.31 mmol) for 3 h at room temperature. The catalyst was filtered and the filtrate was concentrated in vacuo to obtain compound (35) (4.31 g, 100%).
mp: 130-131 ° C
NMR (CD3OD): 7.70 (2H, m), 7.24 (2H, m), 4.65 (1H dd, J = 6.2, 8.4 Hz), 3.20-3.80 (10H, m), 1.80-2.60 (4H, m), 2.37 (3H, s).
Elemental analysis (C16H24N2O5S
Cale. C, 53.92 H, 6.79 N 7.86 9.00
Found: C, 53.91; H, 6.73; N, 7.97; S, 8.99
Example 51-process 3
Preparation of 4 - [N-. { N- (tert-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl} -L-prolyl] morpholine (36)
In a manner similar to that described in the synthesis method of compound (34), compound (35) (2.7 g, 7.57 mmol) was condensed with N- (tert-butoxycarbonyl) -3- (4-thiazolyl) -L -alanine (2.03 g, 7.57 mmol) in the presence of HOBT (200 mg, 1498 mmol), triethylamine (2.1 ml, 14.98 mmol) and DCC (1.55 g, 7.49 mmol) in N, N-dimet i 1 formamide. The product was subjected to column chromatography on silica gel (chloroform: methanol = 50: 1) to give the compound (36) (2.23 g, 67.1%).
[a] D = -23.1 ° (c = 0.91, CHC13, 25 ° C)
IR (CHC13) cm "1: 3433, 1707, 1644, 1501, 1441, 1232, 1167, 1115.
NMR (CDCl 3): 8.76 (1H, d, J = 2 Hz), 5.46 (1H, d, J = 9 Hz), 4.83 (2Hm), 3.40-4.00 (10H, m), 3.35 (1H, dd, J = 5, 14.6 Hz), 3.08 (1H, dd, J = 7.8, 14.6 Hz), 1.70-2.30 (4H, m), 1.37 (9H, s).
Elemental analysis (C2oH3oN405S 0.5H2O)
Cale. C, 53.67; H, 6.98; N, 12.52; S, 7.16.
Found: C, 53.71; H, 7.07; N, 12.34; S, 7.17.
Example 51-process 4
Preparation of 4- [N-] hydrochloride. { 3- (4-thiazolyl) -L-alanyl} -L-prolyl] morpholine (37)
To a solution of compound (36) (1.5 g, -3.42 mmol) in ethyl acetate (17 ml) was added a solution of 4N hydrochloric acid in ethyl acetate (17 ml) under ice-cooling and the resulting mixture was stirred for 3 h at the same temperature with stirring. The precipitation that appeared was filtered and washed with ethyl acetate to give compound (37) (1.33 g, 94.4%).
[] D = -39.1 ° (c = 1, MeOH, 25 ° C)
IR (CHC13) cm "1: 3429, 1741, 1654, 1610, 1465, 1370, 1238, 1111.
NMR (CDC13): 9.86 (1H, d, J = 2 Hz), 8.06 (1H, d, J = 2 Hz), 4.98 (1H dd, J = 6.0, 8.4 Hz), 4.76 (1H, t, J = 5.4 Hz), 3.40-4.00 (12H, m) 1.80-2.40 (4H, m).
Example 51-process 5
Preparation of 4 - [,. { N- (cis-L-5-met il-2-oxo-oxazolidin-4-yl-carbonyl) -3- (4-thiazolyl) -L-alanyl} -L-prolyl] morpholine (1-51)
In a manner similar to that described in the method of synthesis of compound (34), cis-L-5-met i 1-2 -oxo-oxa zolidin-4-carboxylic acid (300 mg, 2.07 mmol) was condensed with compound (37) (850 mg, 2.07 mmol) in the presence of N-hydroxysuccinimide (240 mg, 2.07 mmol), DCC (470 mg, 2.28 mmol) and triethylamine (1.16 mL, 8.28 mmol) in N, N-dimethylformamide to give 560 mg of the compound (1-51). The result was shown in Table 22.
Example 52
Preparation of cis-L-met il-2-oxo-oxazolidin-4-yl-carbonyl-3- (-thiazolyl) -L-alanyl-N- (tert-butyl) * -L-prolineamide (1-52) )
In a manner similar to that described in the synthesis method of compound (34), compound (1-50) (300 mg, 0.76 mmol) was condensed with tert-butylamine (110 mg, 1.52 mmol) in the presence of N- hydroxysuccinamide (87 mg, 0.76 mmol) and DCC (170 mg, 0.84 mmol) in N, N-dimethylformamide to give 210 mg of the compound (I-52).
In a manner similar to that described in the above method, the compound (1-53) was synthesized.
The previous results were shown in Table 22.
Table 22
Do not . not . of! o!] D NMR Composite (CD3OD): 8.94 and 8.98 (1H total, d, 3 = 2 Hz), 7.32 and 7.42 (1H total, d, 3 = 2 Hz), 5.09 (1H, dd , J = 4.6, 9.4 Hz), 4.70-5.00 -55.9 (2H, m), 4.30 and 4.33 (c = 0.50! 51-5 1-51 (1H total, d, J = 8.6 O MeOH, Hz), 3.50 -4.10 (10H, 26 ° C) m), 3.38 (1H, dd, 3 = .6, 15 Hz), 3.15 (1H, dd, J = 9.4, 15 Hz), 1.60-2.40 (4H,), 1.17 and 1.21 (3H total, d, J = 6.6 Hz). (CD3OD): 8.95 and 8.97 (1H total, d, J = 1.8 Hz), 7.57 and 7.71 (1H total, s), 7.34 and -53.7 7.42 (1H total, d, (c = 0.50Í J = l .8 Hz), 5.06 (1H,
1-52 t-BuNH MeOH, dd, J = 5.4, 8.1 Hz), 25 ° C) 4.90 (1H, m), 4.34 (1H, t, J = 8.7 Hz), 4.31 (1H, d, J = 8.7 Hz), 3.60-3.91 (2H, m), 3.37 (1H, dd,
Example 54-process 1
Preparation of 5-met i 1-2-oxo-l, 3-dioxolen-4-ylmethyl ester of N- (tert-butoxycarbonyl) -L-proline
A solution of 4-hydroxymethyl-1-5-met il-2-oxo-1,3-dioxolene (651 mg, 5 mmol) which was synthesized according to the method described in
Synthetic Commun., 22, 1277 (1992), tert-butyloxycarbonyl-L-proline (1.07 g, 5 mmol) and 4-dimethylaminopyridine (61 mg, 0.5 mmol) in THF (20 ml) was added DCC (1.14 g, 5.5 mmol) and the resulting mixture was stirred for 16 h at room temperature. After the precipitation appeared it was filtered, the filtrate was concentrated in vacuo. The residue was subjected to column chromatography on silica gel (hexane: acetone = 4: 1) to give compound (38) (1.33 g, 81.2%).
NMR (CDC13): 4.8-5.0 (2H, m), 4.2-4.4 (lH, m), 3.3-3.6 (2H, m), 2.19 and 2.17 (3H total, s), 1.93 (2H, m), 1.66 (2H, m), 1.45-1.39 (9H, s).
Example 54-process 2
Preparation of 5-met il-2-oxo-1, 3-dioxolen-4-ylmethyl ester of L-proline thiofluoroacetate (39) "
The trifluoroacetic acid 82.5 ml) was added to the compound (38) (360 mg, 1.1 mmol) under cooling with ice and the resulting mixture was maintained for 45 min. Toluene was added to the reaction mixture and the mixture was concentrated in vacuo to give 490 mg of the compound (39). This compound was used in the next reaction without purification.
NMR (CDC13): 5.03 (1H, d, J = 14.1 Hz), 4.97 (1H, d, J = 14.1 Hz), 4.53 (1H, m), 3.52 (2H, m), 2.51 (1H, m), 2.18 (3H, m), 2.18 (3H, s).
Example 54-process 3
Preparation of cis-L-5-methyl-2-oxo-oxazolidin-4-yl-carbonyl-3- (-thiazolyl) -L-alanyl-L-proline 5-me ti 1-L-proline 5-met i 1-2 -oxo-1, 3-dioxolen-4-i lmet il ester (1-54)
In a manner similar to that described in the synthesis method of compound (34), compound (29) (299 mg, 1 mmol) was condensed with compound (39) (130 mg, 0.76 mmol) in the presence of
N-hydroxysuccinimide (127 mg, 1.1 mmol), DCC (227 mg, 1.1 mmol) and triethylamine (0.56 mL, 4 mmol) in
N, N-dimethylformamide to give 162 (30%) of the compound (1-54). The chemical formula was shown later.
[] D = -56.2 ° (c = 0.502 H20, 26 ° C)
NMR (CD3OD): 8.97 and 8.96 (1H total, d, J = 2.1 Hz), 7.39 and 7.32 (1H total, d, J = 2.1 Hz), 5.09 (1H, m), 4.96 * 2H, s), 4.90 (1H, m), 4.46 (t, 1H, m), 4.31 (1H, t, J = 8.7 Hz), 3.92 (1H, m), 3.61 (1H, m), 3.29 (1H, dd, J = 5.4 , 14.7 Hz), 3.16 (1H, dd, J = 8.4, 14.7 Hz), 2.27 (1H, m), 2.17 (3H, s), 2.00 (3H, m), 1.23 and 1.18 (3H total, d, J = 6.6 Hz). Elemental analysis C21H24N4O9S 1.1H20) Cale. C, 47.74; H, 5.00; N, 10.60; S, 6.07. Found: C, 47.78; H, 5.04; N, 10.67; S, 5.97
Example 55-process 1
Preparation of N- (tert-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl-2S-cyanopyrrolidine (40)
2S-cyanopyrrolidine p-toluenesulfonate (440 mg, 1.62 mmol) which was synthesized according to
Bioorg. Med. Chem. Lett., 6, 1163 (1996) was condensed with N- (tert-butoxycarbonyl) -3- (4-thiazolyl) -L-alanine (440 mg, 1.62 mmol) in the presence of N-hydroxysuccinimide (190 mg, 1.62 mmol), DCC (370 mg, 1.78 mmol) and triethylamine
(0.46 ml, 3.24 mmol) to give 180 mg (31.5%) of the compound (40).
[] D = -37.2 ° (c = 0.503 CHC13, 26 ° C).
IR (Nujol) cpT1: 2246, 1697, 1645, 1162.
NMR (CDC13): 8.79 (1H, d, J = 2 Hz), 7.15 (1H, d, J = 2 Hz), 5.41 (1H, d, J = 8.2 Hz), 4.79 (1H, dd, J = 7 , 8.2 Hz), 4.72 (1H, dd, J = 3.6, 6.9 Hz), 3.62 (1H, m), 3.35 (1H, m), 3.22 (2H, d, J = 7 Hz), 1.90-2.3 (4H , m), 1.40 (9H, s). Elemental Analysis C? H22 N4? 3S) Cale. C, 54.84; H, 6.33; N, 15.99; S, 9.15.
Found: C, 54.64; H, 6.30; N, 15.80; S, 8.95.
Example 55-process 2
Preparation of 3- (4'-thiazolyl) -L-alanyl-2 (S) -cyanopyrrolidine trifluoroacetate (41)
Trifluoroacetic acid (5 ml) was added to compound (40) (500 mg, 1.43 mmol) under cooling with ice and the resulting mixture was stirred for 90 min. Toluene was added to the reaction mixture and the mixture was concentrated in vacuo to give 970 mg of the compound (41). This compound was used in the next reaction without purification.
NMR (CDCl 3): 8.85 (1H, d, J = 2 Hz), 7.31 (1H, d, J = 2 Hz), 4.78 (1H, dd, J = 4.8, 6.6 Hz), 4.62 (1H, t, J = 6.6 Hz), 3.10-3.70 (4H, m), 1.80-2.3 (4H, m).
Example 55-process 3
Preparation of cis-L-5-met il-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-thiazolyl) -L-alanyl -2 (S) -cyanopyrrolidine (1-55)
In a manner similar to that described in the synthesis method for compound (34), cis-L-5-me t -yl-2-oxo-oxa zolidin-4-carboxylic acid (210 mg, 1.43 mmol) was condensed. with compound (41) (970 mg, 1.43 mmol) in the presence of N-hydroxysuccinimide (160 mg, 1.43 mmol, DCC (320 mg, 1.57 mmol) and triethylamine (0.6 mL, 4.29 mmol) in N, N-dimethylformamide to 330 mg of the compound (I-55) The result was shown in Table 23.
E j emp lo 56
Preparation of cis-L-5-methyl-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-thiazolyl) -L-alanyl-L-prolinol (1-56)
In a manner similar to that described in the synthesis method of compound (34), compound (29) (299 mg, 1 mmol) was condensed with L-prolinol (101"mg, 1 mmol) in the presence of N-hydroxysuccinimide. (127 mg, 1.1 mmol, DCC (227 mg, 1.1 mmol) and triethylamine (0.15 mL, 1.1 mmol) in N, -dimethylformamide to give 162 mg of the compound (1-56) The result is shown in Table 23. Table 23
(3H, d, J = 6.3 Hz) (CD3OD): 8.98 and 8.95 (1H total, d, J = 2.1 Hz), 7.36 and 7.35 (1H, d, J = 2.1 Hz), 5.21 and 5.06 (1H, t , J = 7.5 Hz), 4.91 (1H, m), -10.7o 4.37 and 4.35 (1H total, d, (c = 0.506 J = 8.7 Hz), 4.06 (1H, m), 6 1-56 -CH- 0H H20, 3.7-3.9 (1H, m), 3.51 26 ° C) (1H, dd, J = 3.9, 10.8 Hz), 3.43 (1H, dd, J = 6.3, 10.8 Hz), 3.40 (1H, m) , 3.25 (2H, m), 1.6-2.0 (4H, m), 1.25 and 1.22 (3H total, d, J = 6.3 Hz).
BOCHN ^ COOH H2N ^ COOH = process 1_ = process 2 ^ _ P-TsOH 4; S ^ N 42 '^^ N
S ^ N
Example 57-process 1
Preparation of 3- (4 'thia zolyl) -L-alanine p-toluenesulfonate (43)
Trifluoroacetic acid (80 ml) was added to N- (tert-butoxycarbonyl) -3- (4-thiazolyl) -L-alanine
(42, 21.79, 80 mmol) which was synthesized according to the method described in the literature (Synth.
Commun., 20, 3507 (1990)) and the resulting mixture was stirred for 2 h under cooling with ice. Subsequently, the mixture was added. { p-toluenesulfonic acid hydrate (15.22 g, 80 mmol) and the resulting mixture was stirred for 30 min at room temperature. The reaction mixture was condensed in vacuo. To the residue was added water and methanol, and the excess trifluoroacetic acid was removed by concentration in vacuo. To the residue, diethyl ether was added and the precipitate that appeared was filtered to give 29.8 g (quantitative) of the compound (43).
NMR (CD3OD): 9.01 (1H, d, J = 1.8 Hz), 7.70 (2H, m), 7.46 (1H, d, J = 1.8 Hz), 7.23 (2H, m), 4.38 (1H, dd, J = 4.8 and 7.6 Hz), 3.45 (2H, m), 2.37 (3H, s).
Example 57-process 2
Preparation of diphenylmethersyl p-toluensul fonate of 3- (-thiazolyl) -L-alanine
To a solution of 38.85 g of the compound (43)
(112.8 mmol) in ethanol (200 ml) - THF (600 ml) was added di phenyldiazomethane (39 g, 201 mmol) little by little during 30 min at room temperature with stirring. After the reaction mixture was stirred for 1 h at room temperature, diphenyldiazomethane (10 g, 51.5 mmol) was added to the mixture and the resulting mixture was stirred for 1 h. To the reaction mixture was added acetic acid (0.1 ml) to quench the excess reagent and the mixture was concentrated in vacuo. The residue (92 g) was crystallized by adding ether (1 L) to give 49.05 g (96.1%) of the compound (44).
Pf: 139 - 140 ° C
[] D = -34.7 ° (c = 1.006, CHC13, 23 ° C)
IR (KBr) cm'-: 1753, 1602, 1512, 1496, 1260, 1224, 1171, 1124, 1036, 1012.
NMR (CD3OD): 8.92 (1H, d, J = 2 Hz), 7.70 (2H, m), 7.2-7.4 (13H, m), 6.91 (1H, s), 7.62 (1H, t, J = 5.8 Hz ), 3.47 (2H, d, J = 5.8 Hz), 2.36 (3H, s).
Elemental Analysis (C26H26N205S2) Cale: C, 61.16; H, 5.13; N, 5.49; S, 12.56.
Found: C, 61.14; H, 5.32; N, 5.41; S, 12.46.
Example 57-process 3
Preparation of diphenylmethether of cis-L-5-methyl-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-thiazolyl) -L-alanine (45)
A solution of 13.95 g (96.14 mmol) of cis -L-5-methyl-2-oxo-oxa-idol-4-carboxylic acid, 49.09 g (96.14 mmol) of compound (44), 2.6 g (19.23 mmol) of N-hydroxybenzot ria zol and 14.1 ml
(101 mmol) of triethylamine in THF (1 L) was added DCC (20.83 g, 101 mmol) under cooling with ice. After the mixture was stirred for 10 min at the same temperature, the cooling bath was stirred and the reaction mixture was stirred for 20 h at room temperature. After the precipitation appeared it was filtered, the filtrate was concentrated in vacuo to give the oily residue (82.7 g). The residue was dissolved in ethyl acetate (700 ml) with heating and the precipitation that appeared was filtered. The filtrate was washed with aq. Sodium carbonate. and water. Then methanol (20 ml) was added to the organic layer, the organic layer was dried with magnesium sulfate and concentrated in vacuo. The precipitated crystal was filtered and washed with ethyl acetate-ether (2.3) to give 35.69 g (79.8%) of the compound (45). After the mother liquor was concentrated in vacuo, the residue was crystallized from ethyl acetate-ether to give 2.62 g (5.9%) of the compound (45).
mp: 176-177 ° C
[x; = -39.2 (c = 1.007, CHC13, 24 C)
IR (KBr) cm - "i1: 1739, 1681, 1508, 1453, 1386, 1237, 1193, 1089.
NMR (CDC13): 8.71 (1H, d, J = 1.8 Hz), 8.180 (1H, d, J = 7.8 Hz), 7.2-7.4 (10H, m), 6.82 (1H, s), 6.6 (1H, d , J = 1.8 Hz), 5.79 (1H, s), 5.12 (1H, m), 4.35 (1H, dd, J = 1.8 and 9.0 Hz), 3.40 (1H, dd, J = 5.7 and 15 Hz), 3.29 (1H, dd, J = 4.5 and 15 Hz), 1.27 (3H, d, J = 6.3 Hz).
Elementary analysis (C24H23N30sS)
Cale. C, 61.92; H, 4.98; N, 9.03; S, 6.89.
Found: C, 61.95; H, 5.01; N, 8.94; S, 6.62.
Example 57-process 4
Preparation of cis-L-5-methyl-2-oxo-oxa zol idin-4 -i 1 -carboni 1-3- (4-thiazolyl) -L-alanine (46)
The anisole (240 ml) and trifluoroacetic acid (120 ml) was added to 41.24 g (88.59 mmol) of the compound (45) under ice-cooling and the resulting mixture was stirred for 15 min. After the cooling bath was removed, the mixture was stirred for 2.5 h at room temperature. The reaction mixture was concentrated in vacuo to give the oily residue. To the residue was added ether (500 ml) and the precipitation that appeared was filtered as a powder. The powder was dissolved in water (50 ml) -methanol (300 ml) with heating and the precipitation that appeared was filtered. The filtrate was concentrated in vacuo. To the residue was added the seed crystal and the methanol and the resulting mixture was kept for 3 days at room temperature. The precipitated crystal was filtered to give 14.89 g (56.1%) of the compound (46). The mother liquor was concentrated in vacuo and the residue was crystallized from methanol-ether to give 10.3 h (38%) of the compound (46).
mp: 214-215 C.
IR (KBr) cm_1: 1753, 1707, 1655, 1548, 1529, 1409, 1343, 1264, 1236, 1102, 1092.
NMR (DMS0-d6): 9.02 (1H, d, J = 1.8 Hz), 8.46 (1H, d, J = 7.8, Hz), 7.74 (1H, s), 7.38 (1H, d, J = 1.8 Hz) , 4.77 (1H, dq, J = 6.6 and 8.7 Hz), 4.66 (1H, m), 4.21 (1H, d, J = 8.7 Hz), 3.24 (1H, dd, J = 5.1 and 15 Hz), 3.13 ( 1H, dd, J = 8.4 and 15 Hz), 1.13 (3H, d, J = 6.6 Hz).
Elemental analysis (C ?? H? 3N305S)
Cale. C, 44.14; H, 4.38; N, 14.04; S, 10.71.
Found: C, 43.94; H, 4.478; N, 14.09; S, 10.58.
Example 57 process 5
Preparation of cis-L-5-met il-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-thiazolyl) -L-alanyl-2 (R) -met-ilpyrrolidine (1-57)
(Method A) To a suspension of .12.1 (40.48 mM) of compound (46) and N-hydroxysuccinimide (4.66 g, 40.48 M) in THF (242. ml) was added DCC (8.35 g, 40.48 mM) under cooling with ice and the resulting mixture was stirred for 30 min. The cooling bath was removed and the reaction mixture was further stirred for 2 h at room temperature. To a suspension of (R) - (+) -2-metilpyrrolidine hydrochloride (5.42 g) which was synthesized according to the method described in the literature (Tetrahedron, 27, 2599 (1971)) and triethylamine (8.46 ml). , 60.72 mM) in THF (121 ml) was added the solution containing N-hydroxysuccinimide ester of the compound (46) at room temperature. The reaction mixture was stirred for an additional 15 h. After the precipitation appeared it was filtered, the filtrate was concentrated in vacuo. The residue (24.6 g) was subjected to gel filtration column chromatography (MCI Gel CHP-20P, 600 ml). Fractions that were eluted with 40% aqueous methanol were collected to give 8.87 g of the crude compound (I-57). After the crude compound was subjected to column chromatography on silica gel (chloroform-methanol), the purified compound was dried by freezing to give 5.37 g (35.7%) of the compound (1-57).
mp: 192-194 ° C
[OÍ] 1.9 (c = 1.005, H20, 25 c:
IR (KBr) cm - i1: 1755, 1675, 1625, 1541, 1516, 1448, 1232, 1097.
NMR (CD30D): 8.97 (1H, t, J = 2.1 Hz), 7.34 (1H, t, J = 2.1 Hz), 5.19 and 5.04 (1H total, each t, J = 7.5 Hz), 4.92 (1H, dq , J = 6.6 and 8.7 Hz), 4.36 and 4.35 (1H, d, J = 8.7 Hz), 4.07 and 3.92 (1H total, each), 3.78 (1H, m), 3.42 (1H, m), 3.22 (2H ,), 1.5-2.0 (4H, m), 1.28 and 1.22 (3H total, each d, J = 6.6 Hz), 1.21 and 1.02 (3H total, each d, J = 6.6 Hz).
Elemental analysis (C? 6H22N4? 4S H20)
Cale. C, 49.99; H, 6.29; N, 14.57; S, 8.34 Found: C, 49.99; H, 6.29; N, 14.79. 8.36
(Method B) To a solution of 10 g (33.41 mol) of compound (46) and N-hydroxysuccinimide (4.04 g, 35.08 mM) in DMF (45 ml) -THF (360 ml) was added DCC (7.24 g, 35.08). mM) under cooling with ice and the resulting mixture was stirred for 4 h. To this reaction was added a solution of p-toluenesulfonate of (R) - (+) -2-methylpyrrolidine (8.6 g) which was synthesized according to the method described in the literature (Helv. Chim. Acta. 34. 2202 1951 )) and triethylamine (9.32 ml, 66.82 mmol) in THF (11 ml) under cooling. After the mixture was stirred for 4 h at the same temperature, the cooling bath was removed and the mixture was stirred for 48 h. After the precipitation was filtered, the filtrate was concentrated in vacuo. The residue (38 g) was dissolved in water (220 ml) and the precipitation that appeared was filtered. The filtrate was subjected to gel filtration column chromatography (MCI Gel CHP-20P, 600 ml). Fractions that were eluted with 40% aqueous methanol were collected and crystallized from water to give 6.94 g (56.7%) of the same compound (1-56) as the compound that had been synthesized in Method A.
2
Example 58-process 1
Preparation of 3- (4'-thiazolyl) -DL-ale p-toluenesulfonate (48)
17. 16 g (70 mmol) of 3- (4-thiazolyl) -DL-ale hydrochloride (47) was dissolved in purified water (100 ml) and the resulting mixture adsorbed on the ion exchange resin column Amberlite IR -120B (inc. Organ) (120 ml, Type H). The column was washed with water and the fractions were eluted with ammonia-water to yield the free base of the compound (47) (11.04 g) •
NMR (D20): 8.98 (1H, d, J = 1.8 Hz), 7.42 (1H, d, J = 1.8 Hz), 4.08 (1H, dd, J = 4.8 and 7.8 Hz), 3.45 (1H, dd, J = 4.8 and 15.3 Hz), 3.33 (1H, dd, J = 7.8 and 15.3 Hz).
After the free base (11.04 g) was suspended in water (50 ml), a solution of p-toluenesulfonic acid hydrate (12.19 g) in water (50 ml) was added to the suspension. The mixture was concentrated in vacuo to give the syrup residue (24.43 g). To the residue was added methanol (10 ml) and ether (300 ml) and the precipitated crystal was filtered to give 21.84 (98.9%) of the compound (48).
NMR (CD3OD): 9.00 (1H, d, J = 2.1 Hz), 7.71 (2H, m), 7.46 (1H, J = 2.1 Hz), 7.23 (2H, m), 4.37 (1H, dd, J = 4.5 and 7.5 Hz), 3.50 (1H, dd, J = 4.5 and 15.9 Hz), 3.38 (1H, dd, J = 7.5 and 15.9 Hz), 2.36 (3H, s).
Example 58-process 2
Preparation of diphenyl ester p-toluensul fonate of 3- (4-tia zolyl) -DL-ale (49)
After 21.84 (123.6 mmol) of the compound (48) was dissolved in ethanol (200 ml) and THF (100 ml) with heating, diphenyldiazomethane (24 g, 123.6 mmol) was added gradually to the solution under ice-cooling for 30 minutes. min. The cooling bath was removed and the mixture was stirred for 1 h at room temperature. To the reaction mixture was added acetic acid (0.1 ml) to quench the excess reagent and the mixture was concentrated in vacuo. The residue was crystallized from ether and ethanol to yield 31.63 g (97.7%) of the compound (49).
mp: 148-149 ° C
IR (KBr) cm - "i-1: 1755, 1607, 1516, 1493, 1216, 1202, 1181, 1125, 1088, 1066, 1036, 1011.
NMR (CD3OD): 8.92 (1H, d, J = 2.1 Hz), 7.70 (2H, m), 7.2-7.4 (13H, m), 6.91 (1H, s), 4.62 (1H, t, J = 6 Hz ), 3.47 (2H, d, J = 6 Hz), 2.36 (3H, s).
Elementary Analysis (C2óH26Nz? 5, S2)
Cale: C, 61.16; H, 5.13; N, 5.49; S, 12.56
Found: C, 60.98; H, 5.06; N, 5.45; S, 12.40 Example 58-process 3
Preparation of diphenylmethyl ester of cis-L-5-methyl-2-oxo-oxazolidin-4-yl-carbonyl-3- (4-thiazolyl) -L-ale (45) and diphenylmethyl ester of cis-L-5-methyl -2-oxo-oxazolidin-4-carbonyl-3- (4-thiazolyl) -L-ale (50).
In a manner similar to that described in process 3 above, cis-L-5-methyl-2-oxo-oxazolin-4-carboxylic acid (8.14 g, 56.07 mmol) was condensed with 28.63 g (56.07 mmol) of the compound
(49) using DCC (12.15 g, 58.87 mmol) in the presence of N-hydroxybenzotriazole (1.52 g), 11.21 mmol) and triethylamine (8.21 mL, 58.87 mmol) in the solvent mixture of DMF (100 mL) - THF (580 mL). After the precipitation that appeared was filtered, the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (400 ml) with heating and the precipitation that appeared was filtered. The filtrate was washed with aq. Sodium carbonate. and water. After the ethyl acetate layer was kept overnight and the precipitated crystal was filtered, the crystal was recrystallized from ethyl acetate-methanol to give 4.6 g (17.6%) of the compound (50).
MP: 203-204 ° C
[] D = + 27.5 ° (c = l, DMF, 22 ° C)
IR (KBr) crn "1: 1754, 1738, 1664, 1523, 1381, 1228, 1171, 1100.
NMR (DMSO-d6): 9.02 (1H, d, J = 1.8 Hz), 8.67 (1H, d, J = 7.8 Hz), 7.82 (1H, s), 7.2-7.4 (1H, m), 6.79 (1H, s), 5.00 (1H, m), 4.68 (1H, m), 4.19 (1H, d,
J = 8.4 Hz), 3.2-3.4 (1H,, m), 3.16 (1H, dd, J = 9.3 and 14.4 Hz), 0.81 (3H, d, J = 6.3 Hz).
Elementary Analysis (C24H23N305S)
Cale: C, 61.92; H, 4.98; N, 9.03; S, 6.89.
Found: C, 61.60; H, 5.04; N, 9.22; S, 6.96.
The mother liquor obtained by collecting the crystals was concentrated in vacuo, the precipitated crystal was filtered to give 17.26 g (76.1%) of the mixture of the compounds (50) and (45). The mixture was crystallized from methanol-ethyl acetate to yield 3.92 g (15%) of the compound (50). After the mother liquor was concentrated in vacuo, the residue was crystallized from acetone ether to give 6.21 g (23.7%) of the same compound (45) as the compound that had been synthesized in Example 57 - process 3.
Example 58-process 4 * Preparation of cis-L-5-met il-2-oxo-oxazolidin-4-yl-carbonyl-3- (-thiazolyl) -D-alanine (51)
In a manner similar to that described in the method of Example 57-process 4, 4.1 g (8.81 mmol) of compound (50) was subjected to de-diphenyl ethylesterification by treatment with trifluoroacetic acid-anisole to give 206.g (78.3 %) of the compound (51).
mp: 214 ° C
[a] D = + 6.9 ° (c = 0.5, DMF, 22 ° C)
IR (KBr) cm_1: 1753, 1708, 1657, 1560, 1413, 1343, 1280, 1241, 1175, 1095.
NMR (DMS0-d6): 9.02 (1H, d, J = 2.1 Hz), 8.46 (1H, d, J = 8.1 Hz), 7.78 (1H, s), 7.40 (1H, d, J = 8.4 Hz), 4.6-4.8 (2H, m), 4.18 (1H, d, J = 8.4 Hz), 3.25 (1H, dd, J = 4.2 and 15 Hz), 3.10 (1H, dd, J = 9.9 Hz and 15 Hz), 0.80 (3H, d, J = 6.6 Hz).
Elementary Analysis (C11H13N3O5S
Cale: C, 44.14; H, 4.38; N, 14.04; S, 10.71.
Found: C, 44.08; H, 4.39; N, 14.04; S, 10.71.
Example 58-process 5
Preparation of cis -L-5-met il-2-oxo-oxa-zol idin-4 -i-1 -carboni 1-3- (4-thiazolyl) -D-alanyl -2- (R) -methylpyrrolidine (1 -58)
In a manner similar to that described in the method of Example 57-process 5, compound (51) was condensed with p-toluenesulfonate of 2 (R) -met ilpyrrolidine in the presence of N-hydroxysuccinimide, DCC and triethylamine in DMF-THF to give the compound (1-58).
mp: 170-172 ° C
[a] D = -16.2 ° (c = 1.014, MeOH, 25 ° C)
IR (KBr) c "1: 1749, 1661, 1637, 1538, 1441, 1381, 1264.
NMR (CD3OD): 8.97 (1H, t, J = 2.1 Hz), 7.34 (1H, t, J = 2.1 Hz), 5.19 and 5.04 (1H total, each t, J = 7.5 Hz), 4.92 (1H, dq , J = 6.6 and 8.7 Hz), 4.36 and 4.35 (1H, d, J = 8.7 Hz), 4.07 and 3.92 (1H total, each m) 3.78 (1H, m) 3.42 (1H, m), 3.22 (2H, m), 1.5-2.0 (4H, m), 1.28 and 1.22 (3H, total, every d, J = 6.6 Hz), 1.21 and 1.02 (3H total, each d, J = 6.6 Hz).
Elemental Analysis (C? 6H22N404S H20)
Cale: C, 49.99; H, 6.29; N, 14.57; S, 8.34.
Found: C, 52.40; H, 5.98; N, 15.19; S, 8.77.
In a manner similar to that described in the above method, the following compounds could be capable of being synthesized.
Table 24 Example Example
No. And No. V
70 n-Hex 94 -CH2COOMe c-Hex 95 -CH-COOEt 71 72 -COOMe 96 -CH; CCO (n-Pr)
73 -. 73 -COOEt 97 -CH; CCO (i-? R) 1
74 -. 74 -COO (n-Pr) 98 -CH: COO (c-Pr)
75 -. 75 -COO (c-Pr) 99 -CH; CF 3 76 -COO (n-Bu) I 0 C -CH; CONH; | i
77 -. 77 -COO (c-Bu) 101 -CH2C (0) CH3
78 -. 78 -COO (c-? Er.) 102 -CH: C (0) Et
79 -. 79 -COO (c-Hex) 103 -CK; C (0) Pr | 1
80 -. 80 -COO (n-Dec) 104 -CH; Ph 1
81 -. 81 -COO (4-Me-? H) 105 -CH2 (4-Me-Ph) [1 1
82 -. 82 -COOPh 106 -CH2SK | I 1
Table 25
Table 26
Table 27
Table 2
Table 29
Table 30
Table 31
32
Table 33
Table 5
Table 35
Table 36
Table 37
Table 38
Table 39
Table 40
Table 41
Table 42
Reference Example
Preparation of cis-L-5-met il-2-oxo-oxazolidin-4 -carboni 1-L-hist idi 1-L-prolineamide (52)
In a manner similar to that described in the method of Example 1-3, N-hydroxysuccinimide cis-L-5-met il-2-oxo-oxazolidin-4-carboxylic acid ester was synthesized by the reaction of the cis-L-5-met il-2-oxo-oxazolidin-4-carboxylic acid (226 mg, 1.56 mmol), N-hydroxysuccinimide (179 mg, 1.56 mmol) and DCC (338 mg, 1.63 mmol) in N, N-dimetho-1-formamide (5 ml) was condensed with L-his-hydroxy-idyl-L-hydrobromide. prolineamide (870 mg, 1.56 mmol), which was synthesized according to the method described in Bull. Chem. Soc. Jpn. 44, 1689 (1971), in the presence of triethylamine (0.87 ml, 6.24 mmol) to give the reference compound (42) (223 mg, 38%).
The chemical formula was shown later.
[α] D = -49.9 ° (c = 0.505, MeOH, 24 ° C).
NMR (CD3OD): 7.60 (1H, s), 6.97 (1H, s), 4.90 (2H, m), 4.41 (1H, dd, J = 3.3, 8.5 Hz), 4.35 (1H, d, J = 8.4 Hz ), 3.85 (1H, m), 3.43 (1H, m), 3.13 (1H, dd, J = 6.6, 14.7 Hz), 2.98 (1H,), 2.29 (1H, m), 2.00 (3H, m), 1.22 and 1.29 (3H, total, d, J = 6.3 Hz).
Elemental analysis (C? 6H22N6? 5 2H20)
Cale C, 46.37; H, 6.32; N, 20.28.
Found: C, 46.30 6.27 N 20.54
Test example 1
Anti-recerpine action after oral administration of the test compounds.
Hypothermia of the mice induced by reserpine (ddY, male, body weight: 30 to 40 g) was prepared by subcutaneous administration of reserpine in the back of the rat (3 mg / kg) at 18 hours before the administration of the test compounds. Mice with their body temperature of approximately 25 C were used in the experiment. The test compounds were solubilized in saline and 0.2 ml (10 μmol / kg) thereof were administered by probe for oral administration. After rectal administration, the straight temperature was measured] at 30, 60, 120, 180, 240, 300 and 360 min. The area under the curve (AUC) of the body temperature-time profile was calculated by the general trapezoid method. In the control experiment, the vehicle (saline) was administered to the mice and the rectal temperature was measured by the same protocol. The effective dosage, which can increase the average of the body temperature to 1 C during 420 min in the hypothermia of the mice induced by the reserpine of the oral administration of the test compounds, is calculated by the following equation:
ad min dose orally administered Effective dose - A UC (test compounds) - AUC (vehicle) 1420
Effective dose: Dose that can increase average body temperatures to 1 ° C for 420 min in the hypothermia of mice induced by reserpine.
AUC (test compounds): The area under the curve (AUC) of the body temperature-time profile for 420 min after oral administration of the test compounds was calculated by the general trapezoid method.
AUC (vehicle): The area under the curve (AUC) of the body temperature-time profile for 420 min after the administration of saline was calculated by the general trapezoid method.
The results were shown in Table 43
Test example 2
The anti-i-recerpine action after intravenous administration and internal racerebrovent of the test compounds.
Reserpine-induced mouse hypothermia (ddY, male) was prepared by administration of reserpine (3 mg / kg) at 18 hours prior to administration of the test compounds. The test compounds were solubilized in saline and 0.1 ml (1 μmol / kg) of them were administered intravenously and 0.005 ml (0.21 μmol / kg) of them were administered intracerebroventricularly, respectively. After administration, the rectal temperature was measured at 30, 60, 120 and 180 min. The area under the curve (AUC) of the body temperature-time profile was calculated by the general trapezoid method. In the control experiment, the vehicle (saline) was administered to the mice int ravenously or intracerebroventricularly and the rectal temperature was measured by the same protocol. The effective dosage, which may increase the average body temperature at 1 ° C for 180 min in the hypothermia of the mice induced by the reserpine after intravenous or int racerebrovent administration of the test compounds, is calculated by the following equation
dose ad min orally administered Effective dose - A UC (test compounds) - A UC (vehicle)
ad min dose orally administered Effective dose - A UC (test compounds) - A UC (vehicle) 1180
Effective dose: A dose that can increase average body temperatures to 1 ° C for 180 min in the hypothermia of mice induced by reserpine.
AUC (test compounds): The area under the curve (AUC) of the body temperature-time profile for 180 min after the intravenous or int racerebrovent administration of the test compounds was calculated by the general trapezoid method.
AUC (vehicle): The area under the curve (AUC) of the body temperature-time profile during
180 min after the intravenous administration or int racerebrovent ricular of the saline solution was calculated by the general trapezoid method.
The results were shown in Table 44
Table 44
Test example 3
Effect on the release of acetylcholine
Male ister rats (body weight: 250 to 300 g) that were fasted overnight and anesthetized with urethane were placed in rat tereotaxic frames. After the skin of the scalp was incised and the skull was exposed, the cortex of the frontal lobe was perforated (A 3.7, L 3.0, H 4.0). The dialysis test used in the present experiment was I-shaped with a 3 mm long polycarbonate membrane tube shape (CMA-12, BAS Ce, LTD). The body temperature of the rats was maintained at 37 C by a warm blanket. Perfusion was performed at a constant rate of 2 μl / min with Ringer's solution containing 10 μ physostigmine. The perfusates were collected every 30 min. After perfusion for 2 hours, test compounds (24 μmol / kg) that were solubilized in saline were orally administered to rats and then perfusion was continued for 16 hours. Concentrations of acetylcholine in the perfusate were determined by HPLC / ECD. The level of acetylcholine before administration of the test compounds was defined as the baseline level average (100%). The data represents the increase in acetylcholine content of each fraction, expressed as a percentage compared to the level of the average baseline. The result was shown in Figure 1.
Test example 4
Change of blood glucose level after duodenal administration of the test compounds to rats.
Male Wister rats on an empty stomach (250-350 g) were anesthetized with urethane. Test compounds were solubilized in saline and administered int ravenously (50 μmol / kg). The body temperature of the rats was maintained at 37 ° C by a warm blanket. After administration, blood was collected from the jugular vein at 5, 15, 30, 60, 120, 180, 240, 300, 360, 420 and 480 min and levels. of blood glucose were measured (BM blood sugar test, Wako Chemical Indus.). The blood glucose levels at each sampling time in the rats treated with the vehicle (saline) were defined as the baseline level (100%). The results represent changes in blood glucose levels after duodenal administration of the test compounds to the rats, expressed as a percentage compared to the baseline level. The results were shown in Figure 2. The results were shown in Table 45.
Table 45
Formulation example
Formulation example 1
The are prepared using the following ingredients.
Ingredients The compound represented by the formula (I) 10 mg
Lactose 700 mg Corn starch 274 g HPC-L 16 mg
1000 mg
The compound represented by formula (I) and lactose were processed by passing through a 60 mesh screen. Corn starch was processed by passing through a 120 mesh screen. These were mixed by a double shell mixer. An aqueous solution of HPC-L
(low mucosity hydroxypropylcellulose) was added to the mixture and the resulting mixture was kneaded, granulated (by extrusion with pore size of 0.5 to 1 mm mesh), and dried.
The dried granules thus obtained were screened by a rolling screen (mesh
12/60) to produce the granules.
Formulation 2
Powders for filling the capsules are prepared using the following ingredients.
Ingredients The compound represented by the formula (I) 10 mg
Lactose 79 mg Corn starch 10 mg Magnesium stearate 1 mg
100 mg
The compound represented by formula (I) and lactose were processed by passing through a 60 mesh screen. Corn starch was processed by passing through a 120 mesh screen. These ingredients and magnesium stearate were mixed by a double shell mixer. 100 ma of the 10-fold crushing was filled into a No. 5 hard gelatin capsule.
Formulation 3
The granules for filling the capsules are prepared using the following ingredients.
Ingredients The compound represented by the formula (I) 15 mg
Lactose 90 mg Corn starch 42 mg HPC-L 3 mg
150 mg
The compound represented by the formula (I) and the lactose were processed by passing through a 60 mesh screen. The corn starch was processed by passing through a 120 mesh screen. Then they were mixed, an aqueous solution of HPC-L to the mixture and the resulting mixture was kneaded, granulated and dried. After the dried granules were lubricated, 150 mg of these were filled into a No. 4 hard gelatin capsule.
Formulation 4
Tablets are prepared using the following ingredients.
Ingredients The compound represented by the formula (I) 10 mg
Lactose 90 mg Microcrystalline cellulose - 30 mg CMC-Na 15 mg Magnesium stearate 5 mg
150 mg
The compound represented by formula (I), lactose, microcrystalline cellulose and CMC-Na (sodium carboxymethylcellulose salt) were passed through a 60 mesh screen and then mixed. The resulting mixture was mixed with magnesium stearate to obtain the powder mixture for the tablet formulation. The mixed powder was compressed to produce the 150 mg tablets.
Formulation example 5
The extended-release tablets are prepared using the following ingredients.
Ingredients The compound -represented by the formula (I) 15 mg
Lactose 20 mg Microcrystalline cellulose 100 mg Magnesium stearate 5 mg Bright wax 120H 110 mg
250 mg
The compound represented by formula (I), lactose and microcrystalline cellulose were passed through a 60 mesh screen and mixed. The mixed powders were heated and solubilized with 120H bright wax (Froint Inds.) And then granulated. The magnesium stearate was passed through a 60 mesh screen which was added to the granules obtained and the resulting granules were compressed to produce the prolonged-release tablets.
Formulation example 6
The extended release layer tablets are prepared using the following ingredient is.
Ingredients . Layer released immediately
The compound represented by the formula 15 mg
(I) Lactose 25 mg
100 mg microcrystalline cellulose
Methylcellulose 5 mg
Magnesium stearate 5 mg
150 mg
Extended layer
The compound represented by the formula 15 mg
Lactose 25 mg
Microcrystalline cellulose 90 mg
Stearic acid 10 mg
Methylcellulose 5 mg
Magnesium stearate 5 mg
150 mg
Immediate release layer: The compound represented by formula (I), lactose and microcrystalline cellulose were passed through a 60 mesh screen and mixed. A solution of methyl cellulose was added to the mixture and the resulting mixture was kneaded, granulated and dried to produce the granules.
Prolonged release layer: The compound represented by formula (I), lactose, and microcrystalline cellulose were passed through a 60 mesh screen and mixed. Stearic acid was added to the mixture and the resulting mixture was heated and dissolved. They were kneaded, granulated and dried to produce the granules.
Formation of the double layer tablet: Magnesium stearate was added to the granules of the immediate release layer and the resulting mixture was compressed. Subsequently, magnesium stearate was added to the granules of the immediate release layer and the resulting mixture was compressed to produce the extended release double-layer tablets.
Formulation example 7
The enteric coated granules are prepared using the following ingredients.
Ingredients The compound represented by the formula (I) 30 mg
Microcrystalline cellulose 125 mg Corn starch 50 mg CMC-Na 25 mg HPC or MC 10 mg
240 mg
(coating solution)
HP-55 10.5 mg
Ester of glycerin fatty acid 2.0 mg
Ethanol 41.0 mg
Dichloromethane 46.5 mg
Talc 4 mg
The active ingredient, microcrystalline cellulose, corn starch and CMC-Na were passed through a 20 mesh screen and mixed thoroughly. A solution of HPC (hydropropylcellulose) or MC (methylcellulose) was added to the mixture and the mass was passed through a 16 mesh screen. The obtained granules were dried at 50 to 60 ° C. The dried granules were spray coated with an "HP-55 (hydroxypropylmethylcellulose phthalate, Shinetsu Kagaku inc.) Solution in the fatty acid ester of glycerin, ethanol, dichloromethane and talc to produce the enteric coating granules.
Formulation 8
The enteric coated granules are prepared using the following ingredients.
Ingredients The compound represented by the formula (I) 30 mg
Microcrystalline cellulose 155 mg Corn starch 60 mg CMC-Na 25 mg HPC or MC 5 mg
275 mg
(coating solution)
Eudragit L30D-55 46.8 mg
Polysolvate 80 0.7 mg
PEG 6000 1.4 mg
Talc 4.2 mg
Purified water 46.8 mg
The granules that were prepared in a manner similar to that described in the method of Formulation Example 7 were coated with the coating solution comprising the solution of Eudragit L30D-55 (Rohm Pharman) in polysolvate 80 (polyoxyethylenesorbitan monooleate, Kao). inc.), PEG 6000, talc and purified water. After the obtained granules were dried, the resulting granules were passed through a 16 mesh screen to produce the enteric coating granules.
Formulation example 9
Sublingual tablets are prepared using the following ingredients.
Ingredients The compound represented by the formula (I) 10 mg
Lactose 70 mg Corn starch 12 mg Methylcellulose 5 mg Talc 2 mg Magnesium stearate 1 mg
100 mg
The compound represented by formula (I), lactose, and corn starch were passed through a mesh screen and mixed. The powder mixture was kneaded with methyl cellulose solution and granulated, dried, then the granules were lubricated.
Formulation example 10
The injections are prepared using the following ingredients.
Ingredients The compound represented by the formula (I) 1 mg
Glucose 2 mg Water for injection 997 mg
1000 mg
The above ingredients are filled in ampoule let as.
Formulation 11
Freeze-dried injections are prepared using the following ingredients.
Ingredients The compound represented by the formula (I) 1 mg
D-mannitol 200 mg Water for injection 779 mg
1000 mg
The above ingredients are filled into vials for freeze drying and the vials are dried by freezing to produce the injections dried by freezing.
Formulation 12
The suppositories are prepared using the following ingredients.
Ingredients The compound represented by the formula (I) 30 mg
Witepsol 1470 mg
1500 mg
The compound represented by the formula (I) was passed through a 60 mesh screen. The compound was dispersed in the solution of the molten witepsol (higher fatty acid triglyceride) of 50 to 60 ° C. The solution was cooled to 38 and at 40 ° C with agitation to produce the medical fluid. The medical fluid was filled into an aluminum foil container, sealed and then cooled to produce the suppositories.
Formulation example 13
The nasals are prepared using the following ingredients.
Ingredients The compound represented by the formula (I) 2 mg
Carboxyvinyl polymer 5 mg L-arginine 10 mg Sodium chloride 0.6 mg Purified water 84.2 mg
100 mg
Then the compound represented by the formula (I) was dissolved in the carboxyvinyl polymer, L-arginine and the sodium chloride was added to the solution. The pH of the solution was adjusted and the mucus was adjusted by adding purified water to produce the medical fluid of obj ective.
Formulation example 14
The endermatical formulation was prepared using the following ingredients.
Ingredients The compound represented by the formula (I) 10 mg
Isopropyl myristate 990 mg
1000 mg
Then the compound represented by the formula (I) was dispersed in isopropyl myristate, the mixture was mixed with the acrylic adhesive formulation and bound with gypsum to a support to produce the endermatical formulation.
Formulation example 15
The ointment was prepared using the following ingredients.
Ingredients The compound represented by the formula (I) 10 mg
Liquid paraffin 7.5 mg Glycerol 82.5 mg
100 mg
The compound represented by the formula (I) was dispersed in liquid paraffin and kneaded to produce the ointment.
Industrial Applicability
The new peptide derivatives having the 3- (4-thiazolyl or 5-thiazolyl) -alanine residue and having an activation effect of the central nervous system were provided.
It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.
Having described the invention as above, the content of the following is claimed as property.
Claims (14)
1. A peptide derivative of the formula (I characterized in that A is 4-thiazolyl or 5-thiazolyl wherein the nitrogen in the ring, of thiazolyl could be quaternary nitrogen-which is formed with optionally substituted alkyl or alkenyl, X is a bond, oxygen or sulfur, m is an integer of 0 to 4, Y is optionally substituted alkyl, optionally substituted carboxy, cyano or the substituent represented by the formula: g R 1 -CN R? wherein R1 and R2 are independently hydrogen or optionally substituted alkyl or R1 and R2 taken together could form a non-aromatic heterocyclic ring adjacent to the nitrogen which could contain oxygen, nitrogen or sulfur and could be substituted, Z is the substituent represented by the formula : wherein R is hydrogen, optionally substituted alkyl, optionally substituted carboxy or optionally substituted acyl, R4 and R5 are each independently hydrogen or optionally substituted alkyl and W is - (CH2) n- wherein n is 0, 1, 2 or 3, optionally substituted oxygen, sulfur or imine or the substituent represented by the formula: its pharmaceutically acceptable salt, or hydrate thereof.
2. A peptide derivative of the formula (II) characterized in that X, Y, Z and m are as defined antioriorment and the nitrogen in the thiazolyl ring could be quaternary nitrogen which is formed with optionally substituted alkyl or alkenyl, its pharmaceutically acceptable salt or hydrate thereof.
3. A peptide derivative of the formula (III) characterized in that X, Y, Z and m are as defined above and the nitrogen in the thiazolyl ring could be quaternary nitrogen which is formed with. optionally substituted alkyl or alkenyl, its pharmaceutically acceptable salt or hydrate thereof.
4. A peptide derivative of the formula (IV) characterized in that W, X, Y, m, R3, R4 and R5 are as defined above, their pharmaceutically acceptable salt or hydrate thereof.
5. A peptide derivative of the formula (V) characterized in that Y is as defined above, its pharmaceutically acceptable salt or hydrate thereof.
A peptide derivative of the formula (VI characterized in that Y is as defined above, its pharmaceutically acceptable salt or hydrate thereof.
7. A peptide derivative of any of claims 1 to 4, characterized in that m s 1 or 2, with the proviso that X is not a bond when m is 1, its pharmaceutically acceptable salt or hydrate thereof.
8. A peptide derivative of any one of claims 1 to 4, characterized in that m is 1 and Y is optionally substituted alkyl, optionally substituted carboxy or optionally substituted carbamoyl, its pharmaceutically acceptable salt or hydrate thereof.
9. A peptide derivative of any one of claims 1 to 4, characterized in that m is 2 or 3 and Y is optionally substituted alkyl, optionally substituted carboxy or optionally substituted carbamoyl, its pharmaceutically acceptable salt, or hydrate thereof.
10 A compound represented by the formula (VII) O O II H H II Z-C-N-C-C-OH (VII) .CH A " characterized in that A and Z are as defined above.
11. A compound represented by the formula (VIII characterized in that A, X, Y and m are as defined above.
12. A pharmaceutical composition, characterized in that it contains the compounds described in claims 1 to 9 as an active ingredient.
13. A composition for activating the central neryose system, characterized in that it contains the compounds described in claims 1 to 9 as an active ingredient.
14. A derivative of THR, characterized in that it has such an effect that the ratio represented by the blood glucose level of the administered active substance / blood glucose level of the saline group administered is from 0.7 to 1.3 °. n the rat to which an effective amount of this was administered intravenously for the display of the main activity.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP226386/96 | 1996-08-28 | ||
JP9/90529 | 1997-04-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA99001831A true MXPA99001831A (en) | 2000-06-05 |
Family
ID=
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