JPH0592948A - Propionic acid amide derivative and its medicine use - Google Patents
Propionic acid amide derivative and its medicine useInfo
- Publication number
- JPH0592948A JPH0592948A JP4056785A JP5678592A JPH0592948A JP H0592948 A JPH0592948 A JP H0592948A JP 4056785 A JP4056785 A JP 4056785A JP 5678592 A JP5678592 A JP 5678592A JP H0592948 A JPH0592948 A JP H0592948A
- Authority
- JP
- Japan
- Prior art keywords
- substituted
- aralkyl
- lower alkyl
- formula
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical class CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 239000003814 drug Substances 0.000 title abstract description 5
- -1 3-(2,2-dimethyl-3-mercaptopropionamido)benzoic acid Chemical compound 0.000 claims abstract description 99
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 65
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 59
- 125000001589 carboacyl group Chemical group 0.000 claims abstract description 29
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 17
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims abstract description 5
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 9
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 4
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 4
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 239000002792 enkephalinase inhibitor Substances 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 13
- 150000001875 compounds Chemical class 0.000 abstract description 122
- 108090000028 Neprilysin Proteins 0.000 abstract description 16
- 102000003729 Neprilysin Human genes 0.000 abstract description 16
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- 239000002253 acid Substances 0.000 abstract description 7
- 150000002148 esters Chemical group 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 238000002844 melting Methods 0.000 description 42
- 230000008018 melting Effects 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 23
- 239000000126 substance Substances 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 description 13
- 239000004471 Glycine Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 150000002431 hydrogen Chemical class 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000005457 ice water Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 102000002723 Atrial Natriuretic Factor Human genes 0.000 description 4
- 101800001288 Atrial natriuretic factor Proteins 0.000 description 4
- 101800001890 Atrial natriuretic peptide Proteins 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000002934 diuretic Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 208000001647 Renal Insufficiency Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- WJKJXKRHMUXQSL-UHFFFAOYSA-N benzyl glycinate 4-methylbenzenesulfonate salt Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.NCC(=O)OCC1=CC=CC=C1 WJKJXKRHMUXQSL-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- NSQLIUXCMFBZME-MPVJKSABSA-N carperitide Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 NSQLIUXCMFBZME-MPVJKSABSA-N 0.000 description 3
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 201000006370 kidney failure Diseases 0.000 description 3
- 229960003136 leucine Drugs 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- PZIYLFQOFHXDBM-UHFFFAOYSA-N 2-phenylethyl 2-aminoacetate Chemical compound NCC(=O)OCCC1=CC=CC=C1 PZIYLFQOFHXDBM-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- PINGORKRKGPVRO-UHFFFAOYSA-N CN(C)C(=O)COC(=O)CN Chemical compound CN(C)C(=O)COC(=O)CN PINGORKRKGPVRO-UHFFFAOYSA-N 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 229940122586 Enkephalinase inhibitor Drugs 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- 239000004395 L-leucine Substances 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 108010036928 Thiorphan Proteins 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000010779 crude oil Substances 0.000 description 2
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 2
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- ZQWPRMPSCMSAJU-UHFFFAOYSA-N methyl cyclohexanecarboxylate Chemical compound COC(=O)C1CCCCC1 ZQWPRMPSCMSAJU-UHFFFAOYSA-N 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 230000001452 natriuretic effect Effects 0.000 description 2
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 2
- 229960003104 ornithine Drugs 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 229960005190 phenylalanine Drugs 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
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- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 108700040249 racecadotril Proteins 0.000 description 1
- 229960002281 racecadotril Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000017619 regulation of gastric acid secretion Effects 0.000 description 1
- SITTWQPUINJZTD-UHFFFAOYSA-N s-(3-chloro-2,2-dimethyl-3-oxopropyl) ethanethioate Chemical compound CC(=O)SCC(C)(C)C(Cl)=O SITTWQPUINJZTD-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 description 1
- WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- ZMCBYSBVJIMENC-UHFFFAOYSA-N tricaine Chemical compound CCOC(=O)C1=CC=CC(N)=C1 ZMCBYSBVJIMENC-UHFFFAOYSA-N 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は中性エンドペプチダーゼ
阻害作用を有するプロピオン酸アミド誘導体およびその
医薬用途に関する。TECHNICAL FIELD The present invention relates to a propionic acid amide derivative having a neutral endopeptidase inhibitory activity and its pharmaceutical use.
【０００２】[0002]
【従来の技術】中性エンドぺプチターゼ（Ｅ．Ｃ．３．
４．２４．１１）は、エンケファリナーゼとも呼ばれ、
中枢神経系のオピオイドぺプチドの不活化酵素として知
られている。したがって、従来からこのエンケファリナ
ーゼ阻害剤を中枢性鎮痛剤として利用するため、チオル
ファン(Thiorphan) やアセトルファン(Acetorphan)など
が研究されている。また、特開平２−２０９８６１号公
報にはメルカプト基を有するある種のアミノ酸誘導体が
エンケファリナーゼ阻害作用を有し、種々の痛みを抑え
る鎮痛剤として有用であることが記載されている。さら
に、エンケファリナーゼ阻害剤としてヒドロキサム酸を
有したケラトルファン(Kelatorphan) なども知られてい
る。しかし、近年、中性エンドぺプチダーゼが強力なナ
トリウム***性、利尿性、血圧降下性のホルモンである
心房性ナトリウム利尿ぺプチド（Atrial Natri-uretic
Peptide:ANP）を不活化することが見出されて、本酵素
阻害剤を高血圧、心不全および腎不全のような種々の心
臓血管病の治療剤として利用する試みがなされている。
特開昭６３−１６５３５３号公報、特開平２−４２０４
７号公報、特開平２−１２４８６２号公報および特表平
２−５０３７９９号公報には、中性エンドぺプチダーゼ
阻害作用を有する一連のシクロアルキル置換またはスピ
ロ置換されたグルタルアミド誘導体が高血圧、心不全お
よび腎不全のような種々の心臓血管病の治療等に有用で
あることが記載されている。一方、ある種のメルカプト
基を有するシステイン関連化合物が肝障害抑制作用、免
疫調節作用を有することが特開平２−７７６号公報に記
載されているが、中性エンドペプチダーゼ阻害作用につ
いては記載されていない。2. Description of the Related Art Neutral endopeptidase (EC.3.
4.24.11) is also called enkephalinase,
It is known as an inactivating enzyme for opioid peptides in the central nervous system. Therefore, in order to utilize the enkephalinase inhibitor as a central analgesic, thiorphan (Acetorphan) and thiorphan have been studied. Further, JP-A-2-209861 describes that a certain kind of amino acid derivative having a mercapto group has an enkephalinase inhibitory action and is useful as an analgesic agent for suppressing various pains. Further, keratorphan having hydroxamic acid as an enkephalinase inhibitor is also known. However, in recent years, atrial natriuretic peptide (Atrial Natri-uretic peptide), which is a potent natriuretic, diuretic, and hypotensive hormone, is a neutral endopeptidase.
It has been found to inactivate Peptide: ANP), and attempts have been made to utilize this enzyme inhibitor as a therapeutic agent for various cardiovascular diseases such as hypertension, heart failure and renal failure.
JP-A-63-165353, JP-A-2-4204
No. 7, JP-A-2-124862 and JP-A No. 2-503799 disclose that a series of cycloalkyl- or spiro-substituted glutaramide derivatives having a neutral endopeptidase inhibitory effect are associated with hypertension, heart failure and It is described to be useful for treating various cardiovascular diseases such as renal failure. On the other hand, it is described in JP-A-2-776 that certain mercapto group-containing cysteine-related compounds have a liver damage inhibitory action and an immunomodulatory action, but a neutral endopeptidase inhibitory action is described. Absent.
【０００３】[0003]
【発明が解決しようとする課題】本発明は、中性エンド
ペプチダーゼ阻害作用を有し、医薬として有用な化合物
を見出すことを目的とする。DISCLOSURE OF THE INVENTION The object of the present invention is to find a compound having a neutral endopeptidase inhibitory action and useful as a medicine.
【０００４】[0004]
【課題を解決するための手段】本発明者らは鋭意研究を
かさねた結果、３位にメルカプト基またはヒドロキシカ
ルバモイル基を有し、かつ２位がジ置換されたプロピオ
ン酸アミド誘導体が、強力な中性エンドペプチダーゼ阻
害作用を有し、本酵素に起因する種々疾患の治療に有効
であることを見出して本発明を完成するに至った。Means for Solving the Problems As a result of extensive research conducted by the present inventors, a propionic acid amide derivative having a mercapto group or a hydroxycarbamoyl group at the 3-position and di-substituted at the 2-position has a strong effect. The present invention has been completed by finding that it has a neutral endopeptidase inhibitory effect and is effective in treating various diseases caused by this enzyme.
【０００５】すなわち、本発明は一般式That is, the present invention has the general formula
【化４】 〔式中、Ａは式Ｒ1 −Ｏ−Ｎ−（Ｒ2 ）−ＣＯ−（ここ
で、Ｒ1 ，Ｒ2 は同一または異なって水素、低級アルキ
ル、置換低級アルキル、アルカノイル、置換アルカノイ
ル、アラルキル、置換アラルキル、ベンゾイル、置換ベ
ンゾイルを示す。）または式Ｒ3 −Ｓ−（ここで、Ｒ3
は水素、低級アルキル、置換低級アルキル、アルカノイ
ル、置換アルカノイル、アラルキル、置換アラルキル、
ベンゾイル、置換ベンゾイル、ニトロソを示す。）を示
し、Ｒ4 ，Ｒ5は同一または異なって低級アルキル、置
換低級アルキル、アラルキル、置換アラルキルまたはＲ
4 ，Ｒ5 が一緒になって置換基を有していてもよい炭素
数２〜７個のアルキレン、置換基を有していてもよい少
なくとも１個の炭素−炭素不飽和結合を有してい炭素数
２〜７個のアルケニレンを示し、Ｒ6 は水素、低級アル
キル、置換低級アルキル、アラルキル、置換アラルキル
を示し、Ｒ7 はフェニル、置換フェニル、アラルキル、
置換アラルキル、ヘテロアリール、置換ヘテロアリー
ル、式−Ｘ−ＣＯＯＲ8 （ここで、Ｘは炭素数１〜１０
個の直鎖または分枝鎖状のアルキレン、シクロアルキレ
ン、低級アルキルシクロアルキレン、フェニレン、置換
フェニレン、式−ＣＨ（Ｒ9 ）−（ここで、Ｒ9 はアラ
ルキル、置換アラルキル、ヘテロアリール低級アルキ
ル、式−Ｑ−Ｚ−Ｒ10（ここでＱは低級アルキレンを示
し、Ｚは−Ｏ−，−Ｓ−，−Ｎ（Ｒ11）−を示し、Ｒ10
は水素、アルキル、置換アルキル、アルケニル、置換ア
ルケニル、アルキニル、置換アルキニル、アルカノイ
ル、置換アルカノイル、アリール、置換アリール、アラ
ルキル、置換アラルキルを示し、Ｒ11は水素、低級アル
キル、置換低級アルキル、アラルキル、置換アラルキル
を示す。）を示すか、Ｒ9 はＲ6 と一緒になってヘテロ
環を形成する基を示す。）を示し、Ｒ8 は水素、エステ
ル形成残基、アミド形成残基を示す。）但し、Ｒ4 ，Ｒ
5 が共に低級アルキルで、Ｒ7 がその定義中、式[Chemical 4] [In the formula, A is the formula R 1 -O-N- (R 2 ) -CO- (wherein R 1 and R 2 are the same or different and are hydrogen, lower alkyl, substituted lower alkyl, alkanoyl, substituted alkanoyl, aralkyl. , Substituted aralkyl, benzoyl, substituted benzoyl) or the formula R 3 —S— (wherein R 3
Is hydrogen, lower alkyl, substituted lower alkyl, alkanoyl, substituted alkanoyl, aralkyl, substituted aralkyl,
It shows benzoyl, substituted benzoyl and nitroso. ), R 4 and R 5 are the same or different and are lower alkyl, substituted lower alkyl, aralkyl, substituted aralkyl or R
4 , R 5 together have an alkylene having 2 to 7 carbon atoms which may have a substituent, and have at least one carbon-carbon unsaturated bond which may have a substituent. R 6 represents hydrogen, lower alkyl, substituted lower alkyl, aralkyl, substituted aralkyl, R 7 represents phenyl, substituted phenyl, aralkyl,
Substituted aralkyl, heteroaryl, substituted heteroaryl, formula —X—COOR 8 (where X represents 1 to 10 carbon atoms).
Number of straight or branched chain alkylene, cycloalkylene, lower alkyl cycloalkylene, phenylene, substituted phenylene, wherein -CH (R 9) - (wherein, R 9 is aralkyl, substituted aralkyl, heteroaryl-lower alkyl, formula -Q-Z-R 10 (wherein Q represents a lower alkylene, Z is -O -, - S -, - N (R 11) - indicates, R 10
Represents hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkanoyl, substituted alkanoyl, aryl, substituted aryl, aralkyl, substituted aralkyl, and R 11 represents hydrogen, lower alkyl, substituted lower alkyl, aralkyl, substituted Indicates aralkyl. Or R 9 represents a group which forms a heterocycle together with R 6 . And R 8 represents hydrogen, an ester-forming residue, or an amide-forming residue. ) However, R 4 , R
5 is lower alkyl, and R 7 is a compound of the formula
【化５】 （式中、Ｒ10' はＲ10の定義中、水素、低級アルキル、
アルカノイル、アラルキル、置換アラルキルであり、他
の記号は前記と同義である。）である場合は除く。〕に
より表わされるプロピオン酸アミド誘導体、その塩およ
び一般式（Ｉ）の化合物中、Ｒ4 ，Ｒ5 が共に低級アル
キルで、Ｒ7 がその定義中、式（ａ）（式中、Ｒ10' は
Ｒ10の定義中、水素、低級アルキル、アルカノイル、ア
ラルキル、置換アラルキルであり、他の記号は前記と同
義である。）である場合を含むプロピオン酸アミド誘導
体を含有することを特徴とする中性エンドぺプチダーゼ
阻害剤に関する。[Chemical 5] (In the formula, R 10 ′ is hydrogen, lower alkyl in the definition of R 10 ,
Alkanoyl, aralkyl, and substituted aralkyl, and other symbols have the same meanings as described above. ) Is excluded. ] In the propionic acid amide derivative represented by the formula], a salt thereof, and a compound of the general formula (I), R 4 and R 5 are both lower alkyl, and R 7 is in the definition thereof in the formula (a) (in the formula, R 10 ′ Is hydrogen, lower alkyl, alkanoyl, aralkyl, or substituted aralkyl in the definition of R 10 , and other symbols have the same meanings as defined above.) Sex endopeptidase inhibitors.
【０００６】上記各記号の定義中、低級アルキルとはメ
チル、エチル、プロピル、イソプロピル、ブチル、イソ
ブチル、第３級ブチル、ペンチル、ヘキシルなどの炭素
数１〜６個の直鎖または分枝鎖状のアルキルを、アルカ
ノイルとはアセチル、プロピオニル、ブチリル、２−メ
チルプロピオニル、ピバロイル、ヘキサノイル、オクタ
ノイル、ドデカノイル、オクタデカノイルなどの炭素数
２〜２２個のアルカノイルを、アラルキルとはベンジ
ル、フェニルエチル、フェニルプロピル、フェニルブチ
ルなどを、Ｒ4 ，Ｒ5 が一緒になって置換基を有してい
てもよい炭素数２〜７個のアルキレンとはエチレン、ト
リメチレン、テトラメチレン、ペンタメチレン、ヘキサ
メチレン、ヘプタメチレンなどを、Ｒ4 ，Ｒ5 が一緒に
なって置換基を有していてもよい少なくとも１個の炭素
−炭素不飽和結合を有する炭素数２〜７個のアルケニレ
ンとはビニレン、１−プロペニレン、２−プロぺニレ
ン、１−ブテニレン、２−ブテニレン、１，３−ブタジ
エニレン、１−ペンテニレン、２−ペンテニレン、１，
３−ベンタジエニレンなどを、また、これらのアルキレ
ン、アルケニレン、アルキニレンが有していてもよい置
換基とは塩素、臭素、ヨウ素、フッ素のハロゲン、メチ
ル、エチル、プロピル、イソプロピル、ブチル、イソブ
チル、第３級ブチルなどの炭素数１〜４個のアルキル、
メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブ
トキシ、イソブトキシ、第３級ブトキシなどの炭素数１
〜４個のアルコキシ、水酸基、ニトロ、アミノなどを、
ヘテロアリールとはピロリル、イミダゾリル、ピリジ
ル、ピラジニル、ピリミジニル、ピラゾロピリミジニ
ル、イミダゾピリミジニル、ピリダジニル、インドリ
ル、インダゾリル、チエニル、フリル、チアゾリル、オ
キサゾリルなどを、炭素数１〜１０個の直鎖または分枝
鎖状のアルキレンとはメチレン、エチレン、トリメチレ
ン、テトラメチレン、ペンタメチレン、ヘキサメチレ
ン、プロピレン、メチルメチレン、ジメチルメチレン、
エチルメチレン、イソプロピルメチレン、イソブチルメ
チレン、第２級ブチルメチレンなどを、低級アルキレン
とは炭素数１〜６個の直鎖または分枝鎖状のアルキレン
であって、メチレン、エチレン、トリメチレン、テトラ
メチレン、ペンタメチレン、ヘキサメチレン、プロピレ
ンなどを、シクロアルキレンとはシクロプロピレン、シ
クロブチレン、シクロペンチレン、シクロヘキシレン、
シクロヘプチレンなどの炭素数３〜７個のシクロアルキ
レンを、ヘテロアリール低級アルキルとはピロリルメチ
ル、イミダゾリルメチル、ピリジルメチル、ピラジニル
メチル、ピリミジニルメチル、ピラゾロピリミジニルメ
チル、イミダゾピリミジニルメチル、ピリダジニルメチ
ル、インドリルメチル、インダゾリルメチル、チエニル
メチル、フリルメチル、チアゾリルメチル、オキサゾリ
ルメチルなどを、アリールとはフェニル、ナフチルなど
を、アルケニルとはビニル、１−プロぺニル、２−プロ
ペニル、２−メチル−１−プロぺニル、１−ブテニル、
２−ブテニル、３−ブテニルなどを、アルキニルとはエ
チニル、１−プロピニル、２−プロピニル、１−ブチニ
ル、２−ブチニル、３−ブチニルなどを、Ｒ9 がＲ6 と
一緒になって形成されるヘテロ環とは環中にさらに硫
黄、酸素、窒素などのヘテロ原子を有していてもよく、
さらにそのヘテロ環が置換基として１〜３個のハロゲ
ン、低級アルキル、低級アルコキシ、水酸基、ニトロ、
アミノなどを有していてもよいベンゼン環と縮合してい
てもよいものであって、ピロリジン、ピペリジン、ホモ
ピぺリジン、チアゾリジン、オキサゾリジン、インドリ
ン、イソインドリン、１，２，３，４−テトラヒドロイ
ソキノリンなどをそれぞれ示す。In the above definition of each symbol, lower alkyl means straight chain or branched chain having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. Alkanoyl is an alkanoyl having 2 to 22 carbon atoms such as acetyl, propionyl, butyryl, 2-methylpropionyl, pivaloyl, hexanoyl, octanoyl, dodecanoyl, octadecanoyl, and aralkyl is benzyl, phenylethyl, phenylpropionyl. And phenylbutyl and the like, alkylene having 2 to 7 carbon atoms which may have a substituent together with R 4 and R 5 is ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, hepta. Methylene, etc., in which R 4 and R 5 together have a substituent Alkenylene having 2 to 7 carbon atoms having at least one carbon-carbon unsaturated bond may be vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 1,3-butadienylene. , 1-pentenylene, 2-pentenylene, 1,
3-Bentadienylene and the like, and these alkylene, alkenylene, and substituents which alkynylene may have include chlorine, bromine, iodine, halogen of fluorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and third group. Alkyl having 1 to 4 carbon atoms such as primary butyl,
1 carbon atom such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tertiary butoxy
~ 4 alkoxy, hydroxyl, nitro, amino, etc.
Heteroaryl is pyrrolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyridazinyl, indolyl, indazolyl, thienyl, furyl, thiazolyl, oxazolyl, etc., straight or branched chain having 1 to 10 carbon atoms. The form of alkylene is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, dimethylmethylene,
Ethylmethylene, isopropylmethylene, isobutylmethylene, secondary butylmethylene, etc., and lower alkylene is a linear or branched alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, Pentamethylene, hexamethylene, propylene, etc., and cycloalkylene are cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene,
A cycloalkylene having 3 to 7 carbon atoms such as cycloheptylene is defined as heteroaryl lower alkyl with pyrrolylmethyl, imidazolylmethyl, pyridylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyrazolopyrimidinylmethyl, imidazopyrimidinylmethyl, pyridazinylmethyl, indolyl. Methyl, indazolylmethyl, thienylmethyl, furylmethyl, thiazolylmethyl, oxazolylmethyl, etc., aryl with phenyl, naphthyl, etc., alkenyl with vinyl, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl,
2-butenyl, 3-butenyl, etc. are formed with alkynyl such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, R 9 together with R 6. The hetero ring may further have a hetero atom such as sulfur, oxygen or nitrogen in the ring,
Further, the hetero ring has 1 to 3 halogens as a substituent, lower alkyl, lower alkoxy, hydroxyl group, nitro,
It may be condensed with a benzene ring which may have amino and the like, and is pyrrolidine, piperidine, homopiperidine, thiazolidine, oxazolidine, indoline, isoindoline, 1,2,3,4-tetrahydroisoquinoline. Etc. are shown respectively.
【０００７】置換低級アルキルの置換基としては塩素、
臭素、ヨウ素、フッ素などのハロゲン、メトキシ、エト
キシ、プロポキシ、イソプロポキシ、ブトキシ、イソブ
トキシ、第３級ブトキシなどの炭素数１〜４個のアルコ
キシ、水酸基、ニトロ、アミノなどを、置換アルカノイ
ル、置換アラルキル、置換ベンゾイル、置換フェニル、
置換フェニレン、置換アルケニル、置換アルキニル、置
換アリール、置換ヘテロアリールの置換基とは塩素、臭
素、ヨウ素、フッ素などのハロゲン、メチル、エチル、
プロピル、イソプロピル、ブチル、イソブチル、第３級
ブチルなどの炭素数１〜４個のアルキル、メトキシ、エ
トキシ、プロポキシ、イソプロポキシ、ブトキシ、イソ
ブトキシ、第３級ブトキシなどの炭素数１〜４個のアル
コキシ、水酸基、ニトロ、アミノなどを示す。The substituent of the substituted lower alkyl is chlorine,
Halogen such as bromine, iodine, fluorine, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy and other alkoxy having 1 to 4 carbon atoms, hydroxyl group, nitro, amino, etc., substituted alkanoyl, substituted aralkyl , Substituted benzoyl, substituted phenyl,
Substituents of substituted phenylene, substituted alkenyl, substituted alkynyl, substituted aryl, substituted heteroaryl are chlorine, bromine, iodine, halogen such as fluorine, methyl, ethyl,
Alkyl having 1 to 4 carbon atoms such as propyl, isopropyl, butyl, isobutyl, and tertiary butyl, and alkoxy having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tertiary butoxy. , Hydroxyl group, nitro, amino, etc.
【０００８】Ｒ8 がエステル形成残基を示す場合のエス
テルとしてはアルキルエステル（メチルエステル、エチ
ルエステル、プロピルエステル、イソプロピルエステ
ル、ブチルエステル、第３級ブチルエステル、ヘキシル
エステル、オクチルエステル、ドデシルエステル、オク
タデシルエステルなど）、アラルキルエステル（ベンジ
ルエステル、フェネチルエステル、ベンズヒドリルエス
テル、トリチルエステル、ｐ−ニトロベンジルエステ
ル、ｐ−メチルベンジルエステルなど）または生体内で
加水分解されうるエステル化合物があげられる。生体内
で加水分解されうるエステル化合物を形成するエステル
残基とは、生体内で容易に分解して遊離のカルボン酸ま
たはその塩としうるものであって、ジメチルアミノエチ
ル、ジメチルアミノプロピル、ベンジルメチルアミノエ
チルなどのアミノアルキルエステル、アセトキシメチ
ル、ピバロイルオキシメチル、１−アセトキシエチル、
１−ピバロイルオキシエチルなどのアルカノイルオキシ
アルキルエステル、エトキシカルボニルオキシメチル、
１−エトキシカルボニルオキシエチルなどのアルコキシ
カルボニルオキシアルキルエステル、フタリジル、ジメ
トキシフタリジルなどのエステル、カルバモイルメチ
ル、カルバモイルエチル、Ｎ−メチルカルバモイルメチ
ル、Ｎ，Ｎ−ジメチルカルバモイルメチル、Ｎ，Ｎ−ジ
メチルカルバモイルエチル、Ｎ，Ｎ−ジエチルカルバモ
イルメチル、Ｎ，Ｎ−ジエチルカルバモイルエチルなど
のカルバモイルアルキルエステル、メトキシメチル、メ
トキシエチルなどのアルコキシアルキルエステルまたは
５−メチル−１，３−ジオキソレン−２−オン−４−イ
ルメチルエステルをあげることができる。When R 8 represents an ester-forming residue, alkyl ester (methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, tertiary butyl ester, hexyl ester, octyl ester, dodecyl ester, Octadecyl ester, etc.), aralkyl ester (benzyl ester, phenethyl ester, benzhydryl ester, trityl ester, p-nitrobenzyl ester, p-methylbenzyl ester, etc.) or ester compound which can be hydrolyzed in vivo. The ester residue that forms an ester compound that can be hydrolyzed in vivo is one that can be easily decomposed in vivo to give a free carboxylic acid or a salt thereof, such as dimethylaminoethyl, dimethylaminopropyl, and benzylmethyl. Aminoalkyl ester such as aminoethyl, acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl,
Alkanoyloxyalkyl esters such as 1-pivaloyloxyethyl, ethoxycarbonyloxymethyl,
Alkoxycarbonyloxyalkyl esters such as 1-ethoxycarbonyloxyethyl, esters such as phthalidyl and dimethoxyphthalidyl, carbamoylmethyl, carbamoylethyl, N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, N, N-dimethylcarbamoylethyl , N, N-diethylcarbamoylmethyl, carbamoylalkyl ester such as N, N-diethylcarbamoylethyl, alkoxyalkyl ester such as methoxymethyl, methoxyethyl or 5-methyl-1,3-dioxolen-2-on-4-yl Methyl ester can be mentioned.
【０００９】また、Ｒ8 がアミドを形成する場合のアミ
ド形成残基としてはアミノまたはメチルアミノ、エチル
アミノ、プロピルアミノ、ブチルアミノ、ジメチルアミ
ノ、ジエチルアミノ、ジプロピルアミノ、ジブチルアミ
ノなどのモノもしくはジアルキルアミノをあげることが
できる。When R 8 forms an amide, the amide-forming residue is amino or a mono- or dialkyl such as methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, dipropylamino or dibutylamino. Amino can be given.
【００１０】本発明の一般式（Ｉ）の化合物においてＲ
8 が水素である化合物の場合、その塩として、リチウム
塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネ
シウム塩、亜鉛塩、アルミニウム塩などの金属塩、トリ
エチルアミン、ジシクロヘキシルアミン、Ｎ−メチルモ
ルホリン、ピリジンなどの有機塩基との塩、リジン、ヒ
スチジン、オルニチン、アルギニンなどのアミノ酸との
塩、アンモニウム塩などをあげることができる。In the compound of the general formula (I) of the present invention, R
In the case of a compound in which 8 is hydrogen, as its salt, a metal salt such as lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, aluminum salt, triethylamine, dicyclohexylamine, N-methylmorpholine, pyridine, etc. Examples thereof include salts with organic bases, salts with amino acids such as lysine, histidine, ornithine and arginine, and ammonium salts.
【００１１】本発明化合物（Ｉ）が不斉炭素原子を有す
る場合にはラセミ体、ジアステレオ異性体および個々の
光学異性体が存在し得るが、本発明はそれらすべてを包
含する。また、シス体、トランス体の立体異性体もしく
はそれらの混合物も包含される。When the compound (I) of the present invention has an asymmetric carbon atom, racemates, diastereoisomers and individual optical isomers may exist, but the present invention includes all of them. In addition, cis and trans stereoisomers or a mixture thereof are also included.
【００１２】また、本発明化合物がその対応する水和物
または他の溶媒和物として存在する場合も本発明はそれ
らすべてを包含する。When the compound of the present invention exists as its corresponding hydrate or other solvate, the present invention also includes them.
【００１３】本発明によれば一般式（Ｉ）の化合物は、
以下の方法で製造することができる。According to the invention, the compounds of general formula (I) are
It can be manufactured by the following method.
【００１４】一般式General formula
【化６】 （式中、各記号は前記と同義である。）により表わされ
る酸化合物またはその反応性誘導体と一般式[Chemical 6] (Wherein each symbol has the same meaning as defined above) and an acid compound or a reactive derivative thereof represented by the general formula
【化７】 （式中、各記号は前記と同義である。）により表わされ
る化合物を反応させる方法。[Chemical 7] (Wherein each symbol has the same meaning as defined above).
【００１５】化合物（ＩＩ）が遊離のカルボン酸である
場合、反応は通常のアミド結合法を用いて行なわれる。
すなわち、縮合剤としてＮ，Ｎ' −ジシクロヘキシルカ
ルボジイミド、１−（３−ジメチルアミノプロピル）−
３−エチルカルボジイミドを用い、より好ましくは１−
ヒドロキシベンゾトリアゾールおよびＮ−メチルモルホ
リンのような有機塩基の存在下、冷却下から室温または
加温下にて行われる。When compound (II) is the free carboxylic acid, the reaction is carried out using the conventional amide coupling method.
Ie, N as a condensing agent, N '- dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -
3-ethylcarbodiimide is used, more preferably 1-
It is carried out under cooling to room temperature or under heating in the presence of an organic base such as hydroxybenzotriazole and N-methylmorpholine.
【００１６】また、化合物（ＩＩ）がカルボン酸の反応
性誘導体（酸ハロゲン化物、チオールエステル、酸無水
物、混合酸無水物、エステル、酸アジド、酸アミドな
ど）である場合、反応は通常、不活性溶媒下、トリエチ
ルアミン、ピリジン、ジイソプロピルエチルアミンなど
の３級塩基の存在下、冷却下から室温で行われる。縮合
反応で使用される不活性溶媒としてはメチレンクロライ
ド、クロロホルム、テトラヒドロフラン、ベンゼン、エ
ーテル、ジオキサン、トルエン、アセトン、メタノー
ル、エタノールなどまたはこれらの混合溶媒を適宜選択
して用いることができる。When the compound (II) is a reactive derivative of a carboxylic acid (acid halide, thiol ester, acid anhydride, mixed acid anhydride, ester, acid azide, acid amide, etc.), the reaction is usually The reaction is carried out in the presence of a tertiary base such as triethylamine, pyridine or diisopropylethylamine in an inert solvent, under cooling to room temperature. As the inert solvent used in the condensation reaction, methylene chloride, chloroform, tetrahydrofuran, benzene, ether, dioxane, toluene, acetone, methanol, ethanol or the like or a mixed solvent thereof can be appropriately selected and used.
【００１７】また、Ｒ1 ，Ｒ8 の置換基を除去する方法
としては、通常の酸あるいはアルカリによる加水分解ま
たは水素添加により、容易に行うことができる。The method of removing the substituents of R 1 and R 8 can be easily carried out by hydrolysis with an ordinary acid or alkali or hydrogenation.
【００１８】原料となる一般式（ＩＩ）の合成中間体
は、以下の合成法により製造することができる。The synthetic intermediate of the general formula (II) used as a raw material can be produced by the following synthetic method.
【００１９】（１）一般式（ＩＩ）のＡがＲ3 −Ｓ−で
ある化合物の製法 一般式（ＩＩ）のＡがＲ3 −Ｓ−で、Ｒ4 ，Ｒ5 がメチ
ルの化合物は公知化合物であって、たとえばJ.L.Greene
ら(J.Am.Chem.Soc.,第７７巻、３０１６頁、１９５５
年）、P.Blondeanら(Can.J.Chem., 第４９巻、３８６６
頁、１９７１年）の方法によって容易に合成できる。[0019] (1) A of the general formula (II) is A is R 3 -S- in the preparation of general formula compounds is R 3 -S- (II), R 4, R 5 are methyl compounds known A compound, for example JL Greene
(J. Am. Chem. Soc., 77, 3016, 1955).
Y.), P. Blondean et al. (Can. J. Chem., Vol. 49, 3866).
Page, 1971).
【００２０】また、一般式（ＩＩ）の化合物でＡがＲ3
−Ｓ−でＲ4 ，Ｒ5 がメチル以外の化合物は新規化合物
であり、以下の新規合成方法によっても製造することが
できる。In the compound of general formula (II), A is R 3
Compounds in which -S- and R 4 and R 5 are other than methyl are novel compounds, and can be produced by the following novel synthetic methods.
【００２１】まず、一般式First, the general formula
【化８】 （式中、Ｒは低級アルキル、アラルキルを示し、他の記
号は前記と同義である。）により表わされる化合物(J.C
asonら、J.Org.Chem.,第１４巻、１０３６頁、１９４９
年）を当モルの水酸化ナトリウム、水酸化カリウムなど
の水酸化アルカリで加水分解することによって一般式[Chemical 8] (In the formula, R represents lower alkyl or aralkyl, and other symbols have the same meanings as described above.) (JC
ason et al., J. Org. Chem., 14: 1036, 1949.
(Year) is hydrolyzed with an equimolar amount of sodium hydroxide, potassium hydroxide or another alkali hydroxide to give a general formula
【化９】 （式中、各記号は前記と同義である。）により表わされ
るハーフエステル化合物が得られる。[Chemical 9] (In the formula, each symbol has the same meaning as described above.) A half ester compound represented by the above is obtained.
【００２２】次いで、一般式（Ｖ）のハーフエステル化
合物をテトラヒドロフラン中、ジボランにて選択的に還
元すると一般式Then, the half-ester compound of the general formula (V) is selectively reduced with diborane in tetrahydrofuran to give the general formula
【化１０】 （式中、各記号は前記と同義である。）により表わされ
るアルコール化合物が得られ、また、化合物（Ｖ）のハ
ーフエステル化合物を第３級ブチルアルコール中、メタ
ノールを還元下滴下し、過剰の水素化ホウ素ナトリウム
にて還元すると、一般式[Chemical 10] (Wherein each symbol has the same meaning as defined above), and a half ester compound of the compound (V) is added dropwise in tertiary butyl alcohol under reduction of methanol to obtain an excess amount. When reduced with sodium borohydride, the general formula
【化１１】 （式中、各記号は前記と同義である。）により表わされ
るアルコール化合物が得られる。[Chemical 11] (In the formula, each symbol has the same meaning as described above.) An alcohol compound represented by the above is obtained.
【００２３】また、アルコール化合物（ＶＩＩ）につい
ては、公知の合成法(E.Testaら、J.Org.Chem.,第２４
巻、１９２８頁、１９５９年）によっても製造できる。Regarding the alcohol compound (VII), a known synthetic method (E. Testa et al., J. Org. Chem., No. 24) is used.
Vol., P. 1928, 1959).
【００２４】このようにして得られたアルコール化合物
（ＶＩ）および（ＶＩＩ）は、前述のJ.L.Greeneらおよ
びP.Blondeanらの方法に従って、化合物（ＩＩ）に導く
ことができる。The alcohol compounds (VI) and (VII) thus obtained can be converted into the compound (II) according to the method of JL Greene et al. And P. Blondean et al.
【００２５】すなわち、アルコール化合物（ＶＩ）およ
び（ＶＩＩ）（ここで、Ｒ4 ，Ｒ5 は前記と同義であ
り、カルボン酸は、また低級アルキル、ベンジルで置換
されていてもよい。）のヒドロキシメチルカルボン酸を
４７％臭化水素酸水、沃化カリウム−ポリリン酸、五塩
化リン、トリフェニルホスフィン−沃素、トリフェニル
ホスフィン−臭素、トリフェニルホスフィン−Ｎ−ブロ
ムコハク酸イミド、トリフェニルホスフィン−四塩化炭
素、トシルクロライド−ピリジン、メシルクロライド−
トリエチルアミン、三臭化リン、トリメチルシリルクロ
ライド−リチウムブロマイド等にて活性化すると一般式That is, the hydroxy of the alcohol compounds (VI) and (VII) (wherein R 4 and R 5 have the same meanings as described above, and the carboxylic acid may be substituted with lower alkyl or benzyl). Methyl carboxylic acid was added to 47% hydrobromic acid water, potassium iodide-polyphosphoric acid, phosphorus pentachloride, triphenylphosphine-iodine, triphenylphosphine-bromine, triphenylphosphine-N-bromosuccinimide, triphenylphosphine-4. Carbon chloride, tosyl chloride-pyridine, mesyl chloride-
When activated with triethylamine, phosphorus tribromide, trimethylsilyl chloride-lithium bromide, etc., the general formula
【化１２】 （式中、Ｘ2 は臭素、塩素、沃素などのハロゲン、トシ
ルオキシ、メシルオキシなどの活性エステルを示し、Ｒ
1 は水素、低級アルキル、アラルキルを示し、他の各記
号は前記と同義である。）により表わされるカルボン酸
誘導体が得られる。次いで、化合物（ＶＩＩＩ）をチオ
尿素と反応させ、Ｓ−アルキルイソチウロニウム塩と
し、これを水酸化アルカリ（水酸化ナトリウム、水酸化
カリウムなど）あるいはアンモニア水にて加水分解する
と、一般式[Chemical formula 12] (In the formula, X 2 represents halogen such as bromine, chlorine and iodine, active ester such as tosyloxy and mesyloxy, and R 2
1 represents hydrogen, lower alkyl or aralkyl, and other symbols are as defined above. A carboxylic acid derivative represented by Then, the compound (VIII) is reacted with thiourea to give an S-alkylisothiuronium salt, which is hydrolyzed with alkali hydroxide (sodium hydroxide, potassium hydroxide, etc.) or aqueous ammonia to give a compound of the general formula
【化１３】 （式中、各記号は前記と同義である。）により表わされ
るチオール化合物が得られる。[Chemical 13] A thiol compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained.
【００２６】また、一般式（ＩＩ）のＡがＨＳ−である
化合物は新実験化学講座第１４巻、「有機化合物の合成
と反応ＩＩＩ」、第８章に記載のａ）Bunte 塩を経由す
る方法、ｂ）ジチオカルバミン酸エステルを経由する方
法、ｃ）ジチオ炭酸エステルを経由する方法、ｄ）チオ
エーテルの開裂による方法、ｅ）チオ酢酸との反応によ
る方法などによっても合成することができる。Further, the compound of the general formula (II) in which A is HS-is routed through a) Bunte salt described in Chapter 8 of the New Experimental Chemistry Course, "Synthesis and Reaction III of Organic Compounds". It can also be synthesized by the method, b) via dithiocarbamate, c) via dithiocarbonate, d) by cleavage of thioether, or e) by reaction with thioacetic acid.
【００２７】こうして得られた一般式（ＩＩ）のうち、
Ｒ3 が低級アルカノイル、置換低級アルカノイル、ベン
ゾイル、置換ベンゾイルの化合物は、塩基の存在下、対
応する酸クロライド、酸無水物などによりアシル化する
ことができる。Of the general formula (II) thus obtained,
A compound in which R 3 is lower alkanoyl, substituted lower alkanoyl, benzoyl or substituted benzoyl can be acylated with a corresponding acid chloride, acid anhydride or the like in the presence of a base.
【００２８】また、一般式（ＩＩ）のＲ3 がニトロソの
化合物は、化合物（ＸＩ）を希塩酸あるいは酢酸中、低
温にて亜硝酸ナトリウムと反応させることにより得るこ
とができる。The compound of the general formula (II) in which R 3 is nitroso can be obtained by reacting the compound (XI) with sodium nitrite in dilute hydrochloric acid or acetic acid at low temperature.
【００２９】さらに、一般式（ＩＩ）のＲ3 が低級アル
キル、置換低級アルキル、アラルキル、置換アラルキル
である化合物は対応するハロゲン化アルキル、ハロゲン
化ベンジル等と反応させることによって得ることができ
る。Further, the compound of the general formula (II) in which R 3 is lower alkyl, substituted lower alkyl, aralkyl or substituted aralkyl can be obtained by reacting with a corresponding alkyl halide, benzyl halide or the like.
【００３０】（２）一般式（ＩＩ）のＡが式Ｒ1 −Ｏ−
Ｎ（Ｒ2 ）−ＣＯ−である化合物の製法 一般式（ＩＩ）のＡが式Ｒ1 −Ｏ−Ｎ（Ｒ2 ）−ＣＯ−
である化合物は新規化合物であり、一般式(2) A in the general formula (II) is represented by the formula R 1 --O--
N (R 2) A has the formula R 1 of formula general formula -CO-, compound (II) -O-N (R 2) -CO-
Is a novel compound of the general formula
【化１４】 （式中、各記号は前記と同義であり、一般式（Ｘ）の化
合物はE.Rothstein ら、J.Chem.Soc.,２０１１頁、１９
２６年に記載の方法により合成できる。）により表わさ
れる化合物と一般式 Ｒ1 −Ｏ−Ｎ（Ｒ2 ）−Ｈ （ＸＩ） （式中、各記号は前記と同義である。）により表わされ
る化合物とをテトラヒドロフラン、ジオキサン、クロロ
ホルム、塩化メチレンなどの溶媒中、塩基触媒（炭酸カ
リウム、炭酸ナトリウム、炭酸水素カリウム、炭酸水素
ナトリウム、トリエチルアミン、ピリジンなど）の存在
下または非存在下に、室温または冷却下、数時間反応す
ることによって得ることができる。[Chemical 14] (In the formula, each symbol has the same meaning as described above, and the compound of the general formula (X) is described in E. Rothstein et al., J. Chem. Soc., Page 2011, 19
It can be synthesized by the method described in 2014. ) And a compound represented by the general formula R 1 —O—N (R 2 ) —H (XI) (wherein each symbol has the same meaning as described above), tetrahydrofuran, dioxane, chloroform, chloride Obtained by reacting in a solvent such as methylene in the presence or absence of a base catalyst (potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, triethylamine, pyridine, etc.) at room temperature or under cooling for several hours. You can
【００３１】このようにして得られた一般式（Ｉ）の化
合物は再結晶、カラムクロマトグラフィーなどのそれ自
体公知の方法により、反応混合物から分離、精製するこ
とができる。Ｒ8 が水素である一般式（Ｉ）の化合物は
常法により無機塩基（水酸化ナトリウム、水酸化カリウ
ム、水酸化カルシウム、水酸化リチウム、水酸化マグネ
シウム、水酸化亜鉛、水酸化アルミニウムなど）、有機
塩基（トリエチルアミン、ジシクロヘキシルアミン、Ｎ
−メチルモルホリン、ピリジンなど）またはアミノ酸
（リジン、ヒスチジン、オルニチン、アルギニンな
ど）、アンモニアと処理することにより塩とすることが
できる。The compound of formula (I) thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization and column chromatography. The compound of the general formula (I) in which R 8 is hydrogen is an inorganic base (sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, etc.) Organic bases (triethylamine, dicyclohexylamine, N
-Methylmorpholine, pyridine, etc.) or an amino acid (lysine, histidine, ornithine, arginine, etc.), and ammonia to form a salt.
【００３２】本発明化合物（Ｉ）において、キラルな炭
素原子を有する場合には、通常ラセミ体またはジアステ
レオ異性体の混合物として得られる。ラセミ体は常法に
より光学異性体に分割することができる。そのような光
学異性体は光学活性な出発物質を使用することによって
も製造することができる。また、ジアステレオ異性体は
分別結晶またはクロマトグラフィーによって精製でき
る。さらにエナンチオ異性体も常法により合成・分離で
きる。また、立体異性体もそれ自体公知の方法に準じて
製造することができる。本発明の好ましい化合物を以下
の表１〜１２に例示する。When the compound (I) of the present invention has a chiral carbon atom, it is usually obtained as a mixture of racemates or diastereoisomers. The racemate can be resolved into optical isomers by a conventional method. Such optical isomers can also be produced by using optically active starting materials. Also, diastereoisomers can be purified by fractional crystallization or chromatography. Furthermore, enantiomers can be synthesized and separated by a conventional method. Also, stereoisomers can be produced according to a method known per se. Preferred compounds of the present invention are illustrated in Tables 1-12 below.
【００３３】[0033]
【表１】 [Table 1]
【００３４】[0034]
【表２】 [Table 2]
【００３５】[0035]
【表３】 [Table 3]
【００３６】[0036]
【表４】 [Table 4]
【００３７】[0037]
【表５】 [Table 5]
【００３８】[0038]
【表６】 [Table 6]
【００３９】[0039]
【表７】 [Table 7]
【００４０】[0040]
【表８】 [Table 8]
【００４１】[0041]
【表９】 [Table 9]
【００４２】[0042]
【表１０】 [Table 10]
【００４３】[0043]
【表１１】 [Table 11]
【００４４】[0044]
【表１２】 [Table 12]
【００４５】一般式（Ｉ）の化合物およびその医薬上許
容し得る塩を医薬として用いる場合、それ自体または製
薬上許容され得る担体、賦形剤、稀釈剤などと混合し、
粉末、顆粒、散剤、錠剤（フィルムコート錠、糖衣錠を
含む）、カプセル剤、注射剤、坐剤、軟膏剤、パップ
剤、経皮吸収剤、点鼻剤、点眼剤などの医薬組成物の形
態で経口または非経口的に治療を要する患者に投与する
ことができる。投与量は対象疾患、その症状、患者の年
齢または投与方法によって変わり得るが、経口投与の場
合、通常成人１日当たり１〜１０００ｍｇを１回または
数回に分けて投与される。When the compound of general formula (I) and a pharmaceutically acceptable salt thereof is used as a medicine, it is mixed with itself or a pharmaceutically acceptable carrier, excipient, diluent or the like,
Forms of pharmaceutical compositions such as powders, granules, powders, tablets (including film-coated tablets and sugar-coated tablets), capsules, injections, suppositories, ointments, poultices, transdermal agents, nasal drops, eye drops, etc. Can be administered orally or parenterally to a patient in need of treatment. The dose may vary depending on the target disease, its symptoms, the age of the patient or the method of administration, but in the case of oral administration, it is usually administered in an amount of 1 to 1000 mg per day for an adult, once or in several divided doses.
【００４６】[0046]
【実施例】以下、参考例および実施例により本発明を具
体的に説明するが、本発明はこれらにより何ら限定され
るものではない。EXAMPLES The present invention will now be described in detail with reference to reference examples and examples, but the present invention is not limited to these examples.
【００４７】参考例１ １−エトキシカルボニル−１−
シクロペンタンカルボン酸 １，１−シクロペンタンジカルボン酸ジエチルエステル
７９ｇをエタノール２５０ｍｌに溶解し、水冷下、８５
％水酸化カリウム２４ｇをエタノール２５０ｍｌに溶解
した溶液を徐々に加え、室温にて８時間攪拌する。溶媒
留去後、析出する結晶を濾取し、これを水に溶解させ、
希塩酸にて酸性とする。酢酸エチルエステルにて抽出
し、常法処理することによって標記化合物の粗油４４ｇ
を得る。1 H-NMR(CDCl3,ppm) δ:1.27(3H,t), 1.72(4H,br), 2.22
(4H,br), 4.22(2H,q),5.30(1H,brs)Reference Example 1 1-Ethoxycarbonyl-1-
Cyclopentanecarboxylic acid 1,1-cyclopentanedicarboxylic acid diethyl ester 79 g was dissolved in ethanol 250 ml, and water-cooled to 85
A solution of 24% potassium hydroxide (24 g) in ethanol (250 ml) is gradually added, and the mixture is stirred at room temperature for 8 hours. After distilling off the solvent, the precipitated crystals were collected by filtration, dissolved in water,
Acidify with dilute hydrochloric acid. 44 g of crude oil of the title compound was obtained by extraction with acetic acid ethyl ester and treatment by a conventional method.
To get 1 H-NMR (CDCl 3 , ppm) δ: 1.27 (3H, t), 1.72 (4H, br), 2.22
(4H, br), 4.22 (2H, q), 5.30 (1H, brs)
【００４８】参考例２ １−ヒドロキシメチル−１−シ
クロペンタンカルボン酸 １−エトキシカルボニル−１−シクロペンタンカルボン
酸３３ｇを第３級ブチルアルコール５００ｍｌに溶解
し、水素化ホウ素ナトリウム２０ｇを徐々に加える。反
応物を還流し、メタノール３０ｍｌを徐々に滴下する。
５時間還流後、溶媒留去し、水を加え、酢酸エチルエス
テルにて抽出し、１，１−シクロペンタンジメタノール
を除去する。水層を希塩酸にて酸性とし、酢酸エチルエ
ステルにて抽出し、常法処理後、得られた油をシリカゲ
ルカラムクロマト（展開溶媒；ヘキサン：酢酸エチル＝
１：１）にて精製することによって標記化合物６ｇを得
る。 融点９２〜９５℃1 H-NMR(CDCl3,ppm) δ:1.68(6H,brs), 2.08(2H,brs),
3.60(2H,s), 6.18(2H,br)Reference Example 2 1-Hydroxymethyl-1-cyclopentanecarboxylic acid 33 g of 1-ethoxycarbonyl-1-cyclopentanecarboxylic acid is dissolved in 500 ml of tertiary butyl alcohol, and 20 g of sodium borohydride is gradually added. The reaction mixture is refluxed and 30 ml of methanol is gradually added dropwise.
After refluxing for 5 hours, the solvent is distilled off, water is added, and the mixture is extracted with acetic acid ethyl ester to remove 1,1-cyclopentanedimethanol. The aqueous layer was acidified with diluted hydrochloric acid and extracted with acetic acid ethyl ester, and after the usual treatment, the resulting oil was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate =
Purification at 1: 1) gives 6 g of the title compound. Melting point 92-95 ° C 1 H-NMR (CDCl 3 , ppm) δ: 1.68 (6H, brs), 2.08 (2H, brs),
3.60 (2H, s), 6.18 (2H, br)
【００４９】参考例３ １−アセチルチオメチル−１−
シクロペンタンカルボン酸 １−ヒドロキシメチル−１−シクロペンタンカルボン酸
６ｇを４７％臭化水素酸水７０ｍｌに溶解し、２０時間
攪拌還流する。冷後エーテルにて不溶油を抽出し、炭酸
水素ナトリウム水にて２〜３回洗浄する。炭酸水素ナト
リウム水を希塩酸にて酸性とし、エーテルにて抽出する
と１−ブロモメチル−１−シクロペンタンカルボン酸の
粗油５ｇを得る。次いで、これをエタノール２０ｍｌに
溶解し、チオ尿素２ｇを加え、２０時間攪拌還流する。
これに窒素気流中、水酸化ナトリウム４ｇを水１６ｍｌ
に溶解した溶液を加え、３時間攪拌還流する。冷後硫化
ナトリウム９水和物２．８ｇを加え、エタノールを減圧
にて留去し、水層を希釈剤塩酸にて酸性とする。酢酸エ
チルエステルにて抽出し、常法にて処理後、得られた油
約３ｇを窒素気流中、５％炭酸水素ナトリウム水２０ｍ
ｌ、エーテル１０ｍｌに溶解し、無水酢酸３ｍｌを徐々
に加え、室温にて５時間攪拌する。エーテル層を水洗
し、無水硫酸ナトリウムにて乾燥する。溶媒留去後、得
られた油をシリカゲルカラムクロマト（展開溶媒；ヘキ
サン：酢酸エチル＝２：１）にて精製し、ヘキサン−酢
酸エチルから再結晶すると、融点６８〜７０℃の標記化
合物２．５ｇを得る。1 H-NMR(CDCl3,ppm) δ:1.60-1.85(6H,br), 2.00-2.20(2
H,br), 2.32(3H,s), 3.22(2H,s)Reference Example 3 1-Acetylthiomethyl-1-
Cyclopentanecarboxylic acid 1-Hydroxymethyl-1-cyclopentanecarboxylic acid 6 g is dissolved in 70 ml of 47% hydrobromic acid water, and the mixture is stirred and refluxed for 20 hours. After cooling, the insoluble oil is extracted with ether and washed with aqueous sodium hydrogen carbonate 2-3 times. Aqueous sodium hydrogen carbonate is acidified with diluted hydrochloric acid and extracted with ether to obtain 5 g of crude oil of 1-bromomethyl-1-cyclopentanecarboxylic acid. Then, this is dissolved in 20 ml of ethanol, 2 g of thiourea is added, and the mixture is stirred and refluxed for 20 hours.
In a nitrogen stream, add 4 g of sodium hydroxide to 16 ml of water.
The solution dissolved in is added and the mixture is refluxed with stirring for 3 hours. After cooling, 2.8 g of sodium sulfide nonahydrate is added, ethanol is distilled off under reduced pressure, and the aqueous layer is made acidic with a diluent hydrochloric acid. After extracting with ethyl acetate and treating with a conventional method, about 3 g of the obtained oil was treated with 5% sodium hydrogencarbonate water 20 m in a nitrogen stream.
l, dissolved in 10 ml of ether, 3 ml of acetic anhydride was gradually added, and the mixture was stirred at room temperature for 5 hours. The ether layer is washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the obtained oil was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 2: 1) and recrystallized from hexane-ethyl acetate to give the title compound having a melting point of 68 to 70 ° C. 5 g are obtained. 1 H-NMR (CDCl 3 , ppm) δ: 1.60-1.85 (6H, br), 2.00-2.20 (2
H, br), 2.32 (3H, s), 3.22 (2H, s)
【００５０】参考例４ １−ヒドロキシメチル−１−シ
クロヘキサンカルボン酸 シクロヘキサンカルボアルデヒド２８ｇ、３５％ホルム
アルデヒド水６８ｇ、エーテル５０ｍｌの混合物を室温
にて攪拌下、１０％炭酸カリウム水溶液５０ｍｌを徐々
に加え、室温にて１６時間攪拌する。反応物をエーテル
にて抽出し、溶媒留去し、減圧蒸留すると沸点４０〜６
０℃／５ｍｍＨｇの１−ヒドロキシメチル−１−シクロ
ヘキサンカルボアルデヒド１７ｇを得る。次いで、これ
に１０％水酸化ナトリウム水２５ｍｌを加え、４０〜５
０℃にて３時間加熱して不溶油を完全に溶かす。反応物
を酢酸エチルエステルにて抽出すると、１，１−シクロ
ヘキサンジメタノール５ｇが得られる。アルカリ層を希
塩酸にて酸性とし、酢酸エチルエステルにて抽出し、水
洗する。無水硫酸マグネシウムにて乾燥後、溶媒留去す
ることにより、融点９６〜９８℃の標記化合物３．５ｇ
を得る。Reference Example 4 1-Hydroxymethyl-1-cyclohexanecarboxylic acid A mixture of 28 g of cyclohexanecarbaldehyde, 68 g of 35% formaldehyde water and 50 ml of ether was stirred at room temperature, and 50 ml of 10% potassium carbonate aqueous solution was gradually added to the mixture at room temperature. Stir for 16 hours. The reaction product is extracted with ether, the solvent is distilled off, and the residue is distilled under reduced pressure to give a boiling point of 40 to 6
17 g of 1-hydroxymethyl-1-cyclohexanecarbaldehyde at 0 ° C./5 mmHg are obtained. Then, 25 ml of 10% aqueous sodium hydroxide was added to this, and 40 to 5
Heat at 0 ° C. for 3 hours to completely dissolve insoluble oil. When the reaction product is extracted with ethyl acetate, 5 g of 1,1-cyclohexanedimethanol is obtained. The alkaline layer is acidified with dilute hydrochloric acid, extracted with ethyl acetate and washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give 3.5 g of the title compound having a melting point of 96 to 98 ° C.
To get
【００５１】参考例５ １−アセチルチオメチル−１−
シクロヘキサンカルボン酸 １−ヒドロキシメチル−１−シクロヘキサンカルボン酸
３ｇを出発原料として、参考例４と同様に反応処理する
ことにより標記化合物１．２ｇを得る。1 H-NMR(CDCl3,ppm) δ:1.25-1.70(8H,br), 1.70-2.10(2
H,br), 2.33(3H,s), 3.15(2H,s)Reference Example 5 1-Acetylthiomethyl-1-
Cyclohexanecarboxylic acid 1-Hydroxymethyl-1-cyclohexanecarboxylic acid 3 g was used as a starting material, and the same reaction treatment as in Reference Example 4 was carried out to obtain 1.2 g of the title compound. 1 H-NMR (CDCl 3 , ppm) δ: 1.25-1.70 (8H, br), 1.70-2.10 (2
H, br), 2.33 (3H, s), 3.15 (2H, s)
【００５２】実施例１ ３−（２，２−ジメチル−３−
メルカプトプロピオンアミド）安息香酸（化合物No.1） ａ）３−アミノ安息香酸エチルエステルメタンスルホン
酸塩２．６ｇをメチレンクロライド５０ｍｌに溶解し、
トリエチルアミン３．３ｍｌを加え、氷冷する。これに
３−アセチルチオ−２，２−ジメチルプロピオニルクロ
ライド１．９４ｇを滴下し、室温にて２時間攪拌する。
反応液を氷冷中に注ぎ、クロロホルムにて抽出する。無
水硫酸マグネシウムにて乾燥後、溶媒留去し、得られた
残油をシリカゲルカラムクロマト（展開溶媒；酢酸エチ
ル：ヘキサン＝１：１）にて精製すると３−（３−アセ
チルチオ−２，２−ジメチルプロピオンアミド）安息香
酸エチルエステル３．１８ｇを油状物質として得る。 ｂ）上記エチルエステル３．１８ｇをメタノール５０ｍ
ｌに溶解し、窒素気流下、０℃にて１規定水酸化カリウ
ム水溶液３０ｍｌを徐々に滴下し、徐々に加温し、室温
にて３時間攪拌する。氷水にて冷却し、希塩酸にて弱酸
性にすると、結晶が析出する。結晶を濾取し、エタノー
ル−エーテルより再結晶すると標記化合物１．３８ｇを
得る。融点１６５〜１６６℃Example 1 3- (2,2-dimethyl-3-
Mercaptopropionamide) benzoic acid (Compound No. 1) a) 3-aminobenzoic acid ethyl ester 2.6 g of methanesulfonic acid salt is dissolved in 50 ml of methylene chloride,
Add 3.3 ml of triethylamine and cool with ice. To this, 1.94 g of 3-acetylthio-2,2-dimethylpropionyl chloride is added dropwise, and the mixture is stirred at room temperature for 2 hours.
The reaction solution is poured into ice cooling and extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residual oil was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 1) to give 3- (3-acetylthio-2,2-). 3.18 g of dimethylpropionamide) benzoic acid ethyl ester are obtained as an oil. b) 3.18 g of the above ethyl ester was added to 50 m of methanol
30 ml of a 1N aqueous potassium hydroxide solution was gradually added dropwise at 0 ° C. under a nitrogen stream, and the mixture was gradually heated and stirred at room temperature for 3 hours. When cooled with ice water and made weakly acidic with dilute hydrochloric acid, crystals are precipitated. The crystals are collected by filtration and recrystallized from ethanol-ether to obtain 1.38 g of the title compound. Melting point 165-166 ° C
【００５３】実施例２ シス−４−（３−アセチルチオ
−２，２−ジメチルプロピオンアミド）シクロヘキサン
カルボン酸ベンジルエステル（化合物No.2） シス−４−アミノシクロヘキサンカルボン酸ベンジルエ
ステルトシル酸塩３．７５ｇをメチレンクロライド７５
ｍｌに懸濁し、これにトリエチルアミン２．５ｍｌを加
え溶解し、氷冷する。これに３−アセチルチオ−２，２
−ジメチルプロピオニルクロライド１．５ｇを徐々に滴
下し、室温にて２時間攪拌する。氷水に注ぎ、クロロホ
ルムにて抽出する。無水硫酸マグネシウムにて乾燥後、
溶媒留去すると固化する。酢酸エチル−ヘキサンの混合
溶媒より再結晶すると、標記化合物２．４ｇを得る。融
点９０〜９２℃Example 2 cis-4- (3-acetylthio-2,2-dimethylpropionamide) cyclohexanecarboxylic acid benzyl ester (Compound No. 2) cis-4-aminocyclohexanecarboxylic acid benzyl ester tosylate salt 3.75 g Methylene chloride 75
2.5 ml of triethylamine is added and dissolved in the suspension, and the mixture is ice-cooled. 3-acetylthio-2,2
-1.5 g of dimethylpropionyl chloride is slowly added dropwise, and the mixture is stirred at room temperature for 2 hours. Pour into ice water and extract with chloroform. After drying over anhydrous magnesium sulfate,
It solidifies when the solvent is distilled off. Recrystallization from a mixed solvent of ethyl acetate-hexane gives 2.4 g of the title compound. Melting point 90-92 ° C
【００５４】実施例３ シス−４−（２，２−ジメチル
−３−メルカプトプロピオンアミド）シクロヘキサンカ
ルボン酸（化合物No.3） 実施例２で得られたシス−４−（３−アセチルチオ−
２，２−ジメチルプロピオンアミド）シクロヘキサンカ
ルボン酸ベンジルエステル１．６５ｇをメタノール２０
ｍｌに溶解し、窒素気流下、氷冷する。１規定の水酸化
カリウム水溶液１５ｍｌを徐々に加え、５〜１０℃で１
時間攪拌する。次いで、希塩酸にて弱酸性にすると結晶
が析出する。結晶を濾取し、メタノール−アセトンの混
合溶媒より再結晶すると、標記化合物６１３ｍｇを得
る。融点１８４〜１８８℃Example 3 cis-4- (2,2-dimethyl-3-mercaptopropionamide) cyclohexanecarboxylic acid (Compound No. 3) cis-4- (3-acetylthio-) obtained in Example 2
2,2-Dimethylpropionamido) cyclohexanecarboxylic acid benzyl ester (1.65 g) was added to methanol 20
Dissolve in ml and cool with ice under a stream of nitrogen. Gradually add 15 ml of 1N aqueous potassium hydroxide solution, and add 1 at 5-10 ° C.
Stir for hours. Then, when the solution is made weakly acidic with dilute hydrochloric acid, crystals are precipitated. The crystals are collected by filtration and recrystallized from a mixed solvent of methanol-acetone to obtain 613 mg of the title compound. Melting point 184-188 ° C
【００５５】実施例４ ３−（２，２−ジメチル−３−
メルカプトプロピオンアミド）プロピオン酸（化合物N
o.4） ａ）３−アミノプロピオン酸ベンジルエステルトシル酸
塩３．５ｇをメチレンクロライド５０ｍｌに懸濁し、１
−ヒドロキシベンゾトリアゾール１．２ｇ、３−アセチ
ルチオ−２，２−ジメチルプロピオン酸１．８ｇ、トリ
エチルアミン２ｇ、１−（３−ジメチルアミノプロピ
ル）−３−エチルカルボジイミド塩酸塩２．８ｇをそれ
ぞれ氷冷下に加え、室温にて１６時間攪拌する。反応物
を水中に注ぎ、クロロホルムにて抽出し、常法処理後、
得られた残油をシリカゲルカラムクロマト（展開溶媒；
ヘキサン：酢酸エチル＝２：１）にて精製すると３−
（３−アセチルチオ−２，２−ジメチルプロピオンアミ
ド）プロピオン酸ベンジルエステル３．０１ｇを油状物
質として得る。ｂ）上記ａ）により得られた化合物３ｇ
をメタノール１０ｍｌに溶解し、窒素通気下、氷冷下に
て１規定水酸化カリウム水溶液３０ｍｌを徐々に滴下す
る。室温にて３時間攪拌後、希塩酸にて酸性とし、クロ
ロホルムにて抽出し、常法処理することにより固化物を
得る。酢酸エチル−ヘキサンより再結晶すると、融点９
７〜９９℃の標記化合物１．５ｇを得る。Example 4 3- (2,2-dimethyl-3-
Mercaptopropionamide) propionic acid (Compound N
o.4) a) 3.5 g of 3-aminopropionic acid benzyl ester tosylate is suspended in 50 ml of methylene chloride, and
-Hydroxybenzotriazole 1.2 g, 3-acetylthio-2,2-dimethylpropionic acid 1.8 g, triethylamine 2 g, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 2.8 g were respectively cooled under ice cooling. In addition, the mixture is stirred at room temperature for 16 hours. The reaction product was poured into water and extracted with chloroform.
The obtained residual oil was subjected to silica gel column chromatography (developing solvent;
When purified with hexane: ethyl acetate = 2: 1), 3-
3.01 g of (3-acetylthio-2,2-dimethylpropionamide) propionic acid benzyl ester is obtained as an oily substance. b) 3 g of the compound obtained in a) above
Is dissolved in 10 ml of methanol, and 30 ml of a 1N potassium hydroxide aqueous solution is gradually added dropwise under ice cooling under aeration of nitrogen. After stirring at room temperature for 3 hours, the mixture is acidified with dilute hydrochloric acid, extracted with chloroform, and treated by a conventional method to obtain a solidified product. Recrystallized from ethyl acetate-hexane, melting point 9
1.5 g of the title compound are obtained at 7-99 ° C.
【００５６】実施例５ Ｎ−（１−アセチルチオメチル
−１−シクロヘキサンカルボニル）グリシンベンジルエ
ステル（化合物No.5） グリシンベンジルエステルトシル酸塩３．３ｇ、１−ア
セチルチオメチルシクロヘキサン−１−カルボン酸１．
８ｇ、１−ヒドロキシベンゾトリアゾール１ｇ、トリエ
チルアミン２ｇ、１−（３−ジチルアミノプロピル）−
３−エチルカルボジイミド２．４ｇをメチレンクロライ
ド５０ｍｌに溶解し、室温にて１６時間攪拌する。反応
物をクロロホルムにて抽出し、常法処理後、得られた残
油をシリカゲルカラムクロマト（展開溶媒；ヘキサン：
酢酸エチル＝２：１）にて精製することにより、融点６
３〜６５℃の標記化合物２．５ｇを得る。1 H-NMR(CDCl3,ppm) δ:1.25-1.70(8H,br), 1.75-2.10(2
H,br), 2.30(3H,s), 3.13(2H,s), 4.06(2H,d,J=6Hz),
5.18(2H,s), 6.30(1H,brs), 7,35(5H,s)Example 5 N- (1-acetylthiomethyl-1-cyclohexanecarbonyl) glycine benzyl ester (Compound No. 5) Glycine benzyl ester tosylate 3.3 g, 1-acetylthiomethylcyclohexane-1-carboxylic acid 1.
8 g, 1-hydroxybenzotriazole 1 g, triethylamine 2 g, 1- (3-ditylaminopropyl)-
2.4 g of 3-ethylcarbodiimide is dissolved in 50 ml of methylene chloride and stirred at room temperature for 16 hours. The reaction product was extracted with chloroform, and after the usual treatment, the obtained residual oil was subjected to silica gel column chromatography (developing solvent; hexane:
By refining with ethyl acetate = 2: 1), melting point 6
2.5 g of the title compound are obtained at 3-65 ° C. 1 H-NMR (CDCl 3 , ppm) δ: 1.25-1.70 (8H, br), 1.75-2.10 (2
H, br), 2.30 (3H, s), 3.13 (2H, s), 4.06 (2H, d, J = 6Hz),
5.18 (2H, s), 6.30 (1H, brs), 7,35 (5H, s)
【００５７】上記実施例１〜５と同様に反応処理するこ
とによって、以下の化合物を製造することができる。The following compounds can be produced by the same reaction treatment as in Examples 1 to 5 above.
【００５８】実施例６ Ｎ−（２，２−ジメチル−３−メルカプトプロピオニ
ル）グリシン（化合物No．６）、融点６７〜７０℃ 実施例７ Ｎ−（３−アセチルチオ−２，２−ジメチルプロピオニ
ル）グリシンエチルエステル（化合物No.7）1 H-NMR(CDCl3,ppm) δ:1.23(6H,s), 1.26(3H,t), 2.31
(3H,s), 3.14(2H,s), 3.97(2H,d,J=5Hz), 4.20(2H,q,J=
6H), 6.23(1H,brs) 実施例８ １−（３−アセチルチオ−２，２−ジメチルプロピオン
アミド）−１−シクロペンタンカルボン酸ベンジルエス
テル（化合物No.8）1 H-NMR(CDCl3,ppm) δ:1.19(6H,s), 1.65-2.10(8H,m),
2.26(3H,s), 3.08(2H,s), 5.13(2H,s), 6.20(1H,brs),
7.32(5H,s) 実施例９ １−（２，２−ジメチル−３−メルカプトプロピオンア
ミド）−１−シクロペンタンカルボン酸（化合物No.
9）、融点１６２〜１６４℃ 実施例１０ Ｎ−（３−アセチルチオ−２，２−ジメチルプロピオニ
ル）バリンメチルエステル（化合物No.10 ）1 H-NMR(CDCl3,ppm) δ:0.93(6H,d), 1.24(6H,s), 1.61
(3H,br), 2.33(3H,s),3.16(2H,s), 3.73(3H,s), 4.62(1
H,br), 6.10(1H,br)Example 6 N- (2,2-dimethyl-3-mercaptopropionyl) glycine (Compound No. 6), melting point 67-70 ° C. Example 7 N- (3-acetylthio-2,2-dimethylpropionyl) Glycine ethyl ester (Compound No. 7) 1 H-NMR (CDCl 3 , ppm) δ: 1.23 (6H, s), 1.26 (3H, t), 2.31
(3H, s), 3.14 (2H, s), 3.97 (2H, d, J = 5Hz), 4.20 (2H, q, J =
6H), 6.23 (1H, brs) Example 8 1- (3-Acetylthio-2,2-dimethylpropionamide) -1-cyclopentanecarboxylic acid benzyl ester (Compound No. 8) 1 H-NMR (CDCl 3 , ppm) δ: 1.19 (6H, s), 1.65-2.10 (8H, m),
2.26 (3H, s), 3.08 (2H, s), 5.13 (2H, s), 6.20 (1H, brs),
7.32 (5H, s) Example 9 1- (2,2-Dimethyl-3-mercaptopropionamide) -1-cyclopentanecarboxylic acid (Compound No.
9), melting point 162-164 ° C. Example 10 N- (3-acetylthio-2,2-dimethylpropionyl) valine methyl ester (Compound No. 10) 1 H-NMR (CDCl 3 , ppm) δ: 0.93 (6H, d), 1.24 (6H, s), 1.61
(3H, br), 2.33 (3H, s), 3.16 (2H, s), 3.73 (3H, s), 4.62 (1
H, br), 6.10 (1H, br)
【００５９】実施例１１ ２−（３−アセチルチオ−２，２−ジメチルプロピオン
アミド）−３−ベンジルオキシプロピオン酸メチルエス
テル（化合物No.11 ）1 H-NMR(CDCl3,ppm) δ:1.23(6H,s), 2.29(3H,s), 3.13
(2H,s), 3.72(3H,s), 3.78(2H,oct), 4.50(2H,s), 4.70
(1H,m), 6.50(1H,br), 7.29(5H,s) 実施例１２ ２−（２，２−ジメチル−３−メルカプトプロピオンア
ミド）−３−ベンジルオキシプロピオン酸（化合物No.1
2 ）1 H-NMR(CDCl3,ppm) δ:1.20(6H,s), 1.50(1H,t), 2.63
(2H,d), 3.80(2H,m), 4.50(2H,s), 4.75(1H,br), 6.15
(1H,br), 6.80(1H,br), 7.28(5H,s) 実施例１３ ４−（３−アセチルチオ−２，２−ジメチルプロピオン
アミド）酪酸ベンジルエステル（化合物No.13 ）1 H-NMR(CDCl3,ppm) δ:1.23(6H,s), 1.92(2H,q), 2.33
(3H,s), 2.45(2H,t),3.15(2H,s), 3.30(2H,q), 5.16(2
H,s), 6.10(1H,br), 7.33(5H,s) 実施例１４ ４−（２，２−ジメチル−３−メルカプトプロピオンア
ミド）酪酸（化合物No.14 ）1 H-NMR(CDCl3,ppm) δ:1.24(6H,s), 1.41(1H,t), 1.85
(2H,m), 2.43(2H,t), 2.69(2H,d), 3.33(2H,q), 6.40(1
H,br), 9.71(1H,br) 実施例１５ Ｎ−（１−アセチルチオメチル−１−シクロペンタンカ
ルボニル）グリシンベンジルエステル（化合物No.15 ）1 H-NMR(CDCl3,ppm) δ:1.50-1.90(6H,br), 1.90-2.20(2
H,br), 2.30(3H,s), 3.20(2H,s), 4.03(2H,d,J=6Hz),
5.16(2H,s), 6.23(1H,brs), 7.35(5H,s)Example 11 2- (3-Acetylthio-2,2-dimethylpropionamide) -3-benzyloxypropionic acid methyl ester (Compound No. 11) 1 H-NMR (CDCl 3 , ppm) δ: 1.23 ( 6H, s), 2.29 (3H, s), 3.13
(2H, s), 3.72 (3H, s), 3.78 (2H, oct), 4.50 (2H, s), 4.70
(1H, m), 6.50 (1H, br), 7.29 (5H, s) Example 12 2- (2,2-Dimethyl-3-mercaptopropionamide) -3-benzyloxypropionic acid (Compound No. 1
2) 1 H-NMR (CDCl 3 , ppm) δ: 1.20 (6H, s), 1.50 (1H, t), 2.63
(2H, d), 3.80 (2H, m), 4.50 (2H, s), 4.75 (1H, br), 6.15
(1H, br), 6.80 (1H, br), 7.28 (5H, s) Example 13 4- (3-acetylthio-2,2-dimethylpropionamide) butyric acid benzyl ester (Compound No. 13) 1 H-NMR (CDCl 3 , ppm) δ: 1.23 (6H, s), 1.92 (2H, q), 2.33
(3H, s), 2.45 (2H, t), 3.15 (2H, s), 3.30 (2H, q), 5.16 (2
H, s), 6.10 (1H, br), 7.33 (5H, s) Example 14 4- (2,2-dimethyl-3-mercaptopropionamide) butyric acid (Compound No. 14) 1 H-NMR (CDCl 3 , ppm) δ: 1.24 (6H, s), 1.41 (1H, t), 1.85
(2H, m), 2.43 (2H, t), 2.69 (2H, d), 3.33 (2H, q), 6.40 (1
H, br), 9.71 (1H, br) Example 15 N- (1-acetylthiomethyl-1-cyclopentanecarbonyl) glycine benzyl ester (Compound No. 15) 1 H-NMR (CDCl 3 , ppm) δ: 1.50-1.90 (6H, br), 1.90-2.20 (2
H, br), 2.30 (3H, s), 3.20 (2H, s), 4.03 (2H, d, J = 6Hz),
5.16 (2H, s), 6.23 (1H, brs), 7.35 (5H, s)
【００６０】実施例１６ Ｎ−（１−メルカプトメチル−１−シクロヘキサンカル
ボニル）グリシン（化合物No.16 ）1 H-NMR(CDCl3-CD3CD,ppm) δ:1.40-2.20(10H,br), 3.70
(2H,brs), 3.90(2H,brs), 7.3(1H,br) 実施例１７ Ｎ−（４−ピリジル）−３−アセチルチオ−２，２−ジ
メチルプロピオン酸アミド（化合物No.17 ）、融点１２
３〜１２４℃ 実施例１８ Ｎ−（４−ピリジル）−３−メルカプト−２，２−ジメ
チルプロピオン酸アミド（化合物No.18 ）、融点１３７
〜１３９℃Example 16 N- (1-Mercaptomethyl-1-cyclohexanecarbonyl) glycine (Compound No. 16) 1 H-NMR (CDCl 3 -CD 3 CD, ppm) δ: 1.40-2.20 (10H, br) , 3.70
(2H, brs), 3.90 (2H, brs), 7.3 (1H, br) Example 17 N- (4-pyridyl) -3-acetylthio-2,2-dimethylpropionic acid amide (Compound No. 17), melting point 12
3 to 124 ° C. Example 18 N- (4-pyridyl) -3-mercapto-2,2-dimethylpropionic acid amide (Compound No. 18), melting point 137
~ 139 ° C
【００６１】実施例１９ Ｎ−〔１−（Ｎ−ヒドロキシ
カルバモイルメチル）−１−シクロヘキサンカルボニ
ル〕グリシン（化合物No.60 ） ａ）ベンジルオキシアミン６．７７ｇをテトラヒドロフ
ラン３００ｍｌに溶解し、−２０℃冷却攪拌下、２−オ
キサスピロ〔４．５〕デカン−１，３−ジオンを加え、
約４５分かけて室温まで上昇させる。反応液を氷水にあ
け、稀塩酸を加えて酸性にした後、テトラヒドロフラン
を留去すると結晶が析出する。これをクロロホルムに溶
解し水洗、無水硫酸ナトリウムで乾燥後、溶媒を留去
し、ヘキサン−酢酸エチルより結晶を濾取すると、１−
（Ｎ−ベンジルオキシカルバモイルメチル）−１−シク
ロヘキサンカルボン酸（融点１１７〜１２０℃）８．４
７ｇを得る。母液を再びヘキサン−酢酸エチルより結晶
化して２番晶２．４５ｇを得る。 ｂ）１−（Ｎ−ベンジルオキシカルバモイルメチル）−
１−シクロヘキサンカルボン酸５．８３ｇをテトラヒド
ロフラン１４０ｍｌに溶解し、−２０℃に冷却攪拌下、
グリシンベンジルエステルトシル酸塩７．０９ｇ、１−
（３−ジメチルアミノプロピル）−３−エチルカルボジ
イミド塩酸塩４．０３ｇ、ジイソプロピルエチルアミン
１１．５ｍｌを順次加え、徐々に０℃まで上昇させ約３
時間攪拌する。さらに室温で２０分攪拌した後、氷水に
あけ、稀塩酸を加えて酸性にした後、酢酸エチルで抽出
し、水洗、無水硫酸ナトリウムで乾燥後、溶媒を留去
し、ヘキサン−酢酸エチルより結晶を濾取し、Ｎ−〔１
−（Ｎ−ベンジルオキシカルバモイルメチル）−１−シ
クロヘキサンカルボニル〕グリシンベンジルエステル
（融点１２１〜１２２℃）６．７６ｇを得る。 ｃ）Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチ
ル）−１−シクロヘキサンカルボニル〕グリシンベンジ
ルエステル６．７６ｇをエタノール１００ｍｌ、酢酸エ
チル５０ｍｌの混合溶媒に溶解し、１０％パラジウム炭
素を触媒として加え、水素雰囲気下、常温常圧で約６時
間激しく攪拌する。反応終了後、触媒を濾過し、濾液を
濃縮し、エタノールより結晶を濾取して１番晶３．６４
ｇ、２番晶０．３９ｇを得る。１番晶をさらにメタノー
ル−酢酸エチルの混合溶媒で再結晶し、Ｎ−〔１−（Ｎ
−ヒドロキシカルバモイルメチル）−１−シクロヘキサ
ンカルボニル〕グリシン（融点１６３〜１６７℃）２．
７１ｇを得る。Example 19 N- [1- (N-hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine (Compound No. 60) a) 6.77 g of benzyloxyamine was dissolved in 300 ml of tetrahydrofuran and cooled at -20 ° C. With stirring, 2-oxaspiro [4.5] decane-1,3-dione was added,
Allow to warm to room temperature over about 45 minutes. The reaction solution is poured into ice water, diluted hydrochloric acid is added to acidify it, and then tetrahydrofuran is distilled off to precipitate crystals. This was dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and crystals were collected by filtration from hexane-ethyl acetate to give 1-
(N-benzyloxycarbamoylmethyl) -1-cyclohexanecarboxylic acid (melting point 117 to 120 ° C.) 8.4
7 g are obtained. The mother liquor was recrystallized from hexane-ethyl acetate to obtain 2.45 g of second crystal. b) 1- (N-benzyloxycarbamoylmethyl)-
5.83 g of 1-cyclohexanecarboxylic acid was dissolved in 140 ml of tetrahydrofuran, and the mixture was cooled to −20 ° C. with stirring.
Glycine benzyl ester tosylate 7.09 g, 1-
(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.03 g) and diisopropylethylamine (11.5 ml) were sequentially added, and the temperature was gradually raised to 0 ° C to about 3
Stir for hours. After stirring at room temperature for 20 minutes, the mixture was poured into ice water, acidified by adding dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and crystallized from hexane-ethyl acetate. Was collected by filtration, and N- [1
6.76 g of-(N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine benzyl ester (mp 121-122 ° C) are obtained. c) N- [1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine benzyl ester (6.76 g) was dissolved in a mixed solvent of 100 ml of ethanol and 50 ml of ethyl acetate, and 10% palladium carbon was added as a catalyst. Stir vigorously under hydrogen atmosphere at room temperature and atmospheric pressure for about 6 hours. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated, and the crystals were collected from ethanol to give the No. 1 crystal 3.64.
g, second crystal 0.39 g is obtained. The No. 1 crystal was recrystallized from a mixed solvent of methanol-ethyl acetate to give N- [1- (N
-Hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine (melting point 163-167 ° C) 2.
71 g are obtained.
【００６２】実施例２０ Ｎ−〔３−（Ｎ−ヒドロキシ
カルバモイル）−２，２−ジエチルプロピオニル〕グリ
シン（化合物No.61 ） ａ）実施例１と同様にして得られる３−（Ｎ−ベンジル
オキシカルバモイル）−２，２−ジエチルプロピオン酸
１．３６ｇをテトラヒドロフラン１２ｍｌに溶解し、−
１０℃に冷却攪拌下、グリシンベンジルエステルトシル
酸塩１．６４ｇ、１−（３−ジメチルアミノプロピル）
−３−エチルカルボジイミド塩酸塩０．９３ｇ、ジイソ
プロピルエチルアミン２．７ｍｌを順次加え、徐々に０
℃まで上昇させ、約３時間攪拌する。反応液を氷水にあ
け、稀塩酸を加えて酸性にした後、酢酸エチルで抽出
し、水洗、無水硫酸ナトリウムで乾燥後、溶媒を留去
し、残査をシリカゲルカラムクロマトグラフィーで精製
（ヘキサン−酢酸エチルで流出させる）してＮ−〔１−
（Ｎ−ベンジルオキシカルバモイル）−２，２−ジエチ
ルプロピオニル〕グリシンベンジルエステル（融点１０
０〜１０２℃）１．２６ｇを得る。 ｂ）Ｎ−〔３−（Ｎ−ベンジルオキシカルバモイル）−
２，２−ジエチルプロピオニル〕グリシンベンジルエス
テル１．２０ｇをエタノール９０ｍｌに溶解し、１０％
パラジウム炭素０．６ｇを加え、水素雰囲気下、常温常
圧で約６時間激しく攪拌する。反応終了後、触媒を濾過
し、濾液を濃縮し残査をシリカゲルカラムクロマトグラ
フィーで精製（酢酸エチル−メタノールで溶出させ
る）、酢酸エチルより結晶化して、Ｎ−〔３−（Ｎ−ヒ
ドロキシカルバモイル）−２，２−ジエチルプロピオニ
ル〕グリシン（融点１７４〜１７９℃）０．７１ｇを得
る。Example 20 N- [3- (N-Hydroxycarbamoyl) -2,2-diethylpropionyl] glycine (Compound No. 61) a) 3- (N-benzyloxy) obtained in the same manner as in Example 1. 1.36 g of carbamoyl) -2,2-diethylpropionic acid was dissolved in 12 ml of tetrahydrofuran,
Glycine benzyl ester tosylate 1.64 g, 1- (3-dimethylaminopropyl) under cooling with stirring at 10 ° C.
0.93 g of 3-ethylcarbodiimide hydrochloride and 2.7 ml of diisopropylethylamine were sequentially added, and gradually added to 0
C. and stirred for about 3 hours. The reaction solution was poured into ice water, acidified with diluted hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane- Flow out with ethyl acetate) to give N- [1-
(N-benzyloxycarbamoyl) -2,2-diethylpropionyl] glycine benzyl ester (melting point 10
0-102 ° C.) 1.26 g. b) N- [3- (N-benzyloxycarbamoyl)-
Dissolve 1.20 g of 2,2-diethylpropionyl] glycine benzyl ester in 90 ml of ethanol, and add 10%.
0.6 g of palladium carbon is added, and the mixture is vigorously stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for about 6 hours. After completion of the reaction, the catalyst was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate-methanol) and crystallized from ethyl acetate to give N- [3- (N-hydroxycarbamoyl). 0.71 g of -2,2-diethylpropionyl] glycine (melting point 174-179 ° C) is obtained.
【００６３】上記実施例１９〜２０と同様に反応処理す
ることによって、以下の化合物を製造することができ
る。The following compounds can be produced by carrying out a reaction treatment in the same manner as in Examples 19 to 20 above.
【００６４】実施例２１ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロペンタンカルボニル〕グリシンベンジルエ
ステル（化合物No.62 ）、融点５８〜５９℃1 H-NMR(CDCl3,ppm) δ:1.52-2.22(8H,m), 2.45(2H,br
s), 3.97(2H,m), 4.88(2H,s), 5.18(2H,s), 7.37(10H,
s) 実施例２２ Ｎ−〔１−（Ｎ−ヒドロキシカルバモイルメチル）−１
−シクロペンタンカルボニル〕グリシン（化合物No.63
）、油状物1 H-NMR(DMSO-d,ppm)δ:1.40-1.80(6H,brs), 2.00(2H,
s), 2.35(2H,s), 3.72(2H,d-like), 8.05(1H,br) 実施例２３ Ｎ−〔１−（Ｎ−アセチル−Ｎ−ベンジルオキシカルバ
モイルメチル）−１−シクロヘキサンカルボニル〕グリ
シンベンジルエステル（化合物No.64 ）、油状物1 H-NMR(CDCl3,ppm) δ:1.30-2.00(8H,m), 2.32(3H,s),
3.04(2H,s), 4.09(1H,d,J=6Hz), 4.94(2H,s), 5.19(2H,
s), 6.48,(1H,t-like,J=6Hz), 7.35(5H,s), 7.40(5H,s) 実施例２４ ３−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロヘキサンカルボキサミド〕プロピオン酸ベ
ンジルエステル（化合物No.65 ）、融点１０３℃1 H-NMR(CDCl3,ppm) δ:1.20-1.80(10H,m), 2.35(2H,s),
2.56(2H,t,J=6Hz),3.50(2H,q,J=6Hz), 4.86(2H,s), 5.
14(2H,s), 6.62(1H,m), 7.36(10H,s), 8.80(1H,m) 実施例２５ ３−〔１−（Ｎ−ヒドロキシカルバモイルメチル）−１
−シクロヘキサンカルボキサミド〕プロピオン酸（化合
物No.66 ）、油状物1 H-NMR(CD3OD,ppm) δ:1.20-2.10(10H,m), 2.26(2H,s),
2.53(2H,t-like), 3.46(2H,m)Example 21 N- [1- (N-benzyloxycarbamoylmethyl)
-1-Cyclopentanecarbonyl] glycine benzyl ester (Compound No. 62), melting point 58-59 ° C 1 H-NMR (CDCl 3 , ppm) δ: 1.52-2.22 (8H, m), 2.45 (2H, br
s), 3.97 (2H, m), 4.88 (2H, s), 5.18 (2H, s), 7.37 (10H,
s) Example 22 N- [1- (N-hydroxycarbamoylmethyl) -1
-Cyclopentanecarbonyl] glycine (Compound No. 63
), Oil 1 H-NMR (DMSO-d, ppm) δ: 1.40-1.80 (6H, brs), 2.00 (2H,
s), 2.35 (2H, s), 3.72 (2H, d-like), 8.05 (1H, br) Example 23 N- [1- (N-acetyl-N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonyl ] Glycine benzyl ester (Compound No. 64), oily substance 1 H-NMR (CDCl 3 , ppm) δ: 1.30-2.00 (8H, m), 2.32 (3H, s),
3.04 (2H, s), 4.09 (1H, d, J = 6Hz), 4.94 (2H, s), 5.19 (2H,
s), 6.48, (1H, t-like, J = 6Hz), 7.35 (5H, s), 7.40 (5H, s) Example 24 3- [1- (N-benzyloxycarbamoylmethyl)
-1-Cyclohexanecarboxamide] propionic acid benzyl ester (Compound No. 65), melting point 103 ° C 1 H-NMR (CDCl 3 , ppm) δ: 1.20-1.80 (10H, m), 2.35 (2H, s),
2.56 (2H, t, J = 6Hz), 3.50 (2H, q, J = 6Hz), 4.86 (2H, s), 5.
14 (2H, s), 6.62 (1H, m), 7.36 (10H, s), 8.80 (1H, m) Example 25 3- [1- (N-hydroxycarbamoylmethyl) -1
-Cyclohexanecarboxamido] propionic acid (Compound No. 66), oily substance 1 H-NMR (CD 3 OD, ppm) δ: 1.20-2.10 (10H, m), 2.26 (2H, s),
2.53 (2H, t-like), 3.46 (2H, m)
【００６５】実施例２６ Ｎ−〔１−（Ｎ−ベンジルオ
キシカルバモイルメチル）−１−シクロペンタンカルボ
ニル〕−Ｌ−フェニルアラニンベンジルエステル（化合
物No.67 ） １−（Ｎ−ベンジルオキシカルバモイルメチル）−１−
シクロペンタンカルボン酸３．００ｇをテトラヒドロフ
ラン５０ｍｌに溶解し、氷冷下、Ｌ−フェニルアラニン
トシル酸塩５．０９ｇ、１−エチル−３−（３−ジメチ
ルアミノプロピル）カルボジイミド塩酸塩２．２８ｇ、
ジイソプロピルエチルアミン４．１ｍｌを順次加え、徐
々に室温まで上昇させ約３時間攪拌する。反応液を氷水
にあけ、希塩酸を加えて酢性にした後、酢酸エチルで抽
出し、水洗、無水硫酸ナトリウムで乾燥後、溶媒を留去
する。得られた残査０．６０ｇをシリカゲルカラムクロ
マトで精製（ヘキサン−酢酸エチルで溶出）し、ヘキサ
ン−酢酸エチルより結晶化して、Ｎ−〔１−（Ｎ−ベン
ジルオキシカルバモイルメチル）−１−シクロペンタン
カルボニル〕−Ｌ−フェニルアラニンベンジルエステル
（融点１０７〜１０８℃）０．４３ｇを得る。1 H-NMR(CDCl3,ppm) δ:1.40-2.00(6H,m), 2.40(2H,s),
3.12(2H,d,J=7Hz), 4.70-4.90(1H,m), 4.87(2H,s), 5.1
7(2H,s), 6.40(1H,m), 6.95-7.45(15H,m),8.85(1H,m)、
〔α〕D 25＝−２５．２°（ｃ＝０．６３、メタノー
ル） 実施例２７ Ｎ−〔１−（Ｎ−ヒドロキシカルバモイル
メチル）−１−シクロペンタンカルボニル〕−Ｌ−フェ
ニルアラニン（化合物No.68 ） Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロペンタンカルボニル〕−Ｌ−フェニルアラ
ニンベンジルエステル０．４１ｇをエタノール２５ｍｌ
に溶解し、１０％パラジウム炭素を触媒として加え、水
素雰囲気下、常温常圧で約２．５時間激しく攪拌する。
反応終了後、触媒を濾過し濾液を濃縮して、油状物のＮ
−〔１−（Ｎ−ヒドロキシルカルバモイルメチル）−１
−シクロペンタンカルボニル〕−Ｌ−フェニルアラニン
０．３２ｇを得る。1 H-NMR(CD3OD,ppm) δ:1.30-2.10(8H,m), 2.38(2H,s),
3.05-3.30(2H,m), 4.70(1H,m), 7.10-7.55(5H,m) 実施例２８ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモ
イルメチル）−１−シクロペンタンカルボニル〕−Ｌ−
イソロイシンベンジルエステル（化合物No.69 ） ａ）ベンジルオキシアミン１２．１ｇをテトラヒドロフ
ラン３００ｍｌに溶解し、−２０℃冷却攪拌下、２−オ
キサスピロ〔４．４〕ノナン−１，３−ジオン１５．４
ｇを加え、徐々に室温（１０℃）まで上昇させる。反応
液を低温で濃縮後、ヘキサンを加えて析出する結晶を濾
取する。これをもう一度クロロホルムに懸濁させ濾取し
て、１−（Ｎ−ベンジルオキシカルバモイルメチル）−
１−シクロぺンタンカルボン酸（融点１０５〜１１２
℃）２１．６ｇを得る。 ｂ）１−（Ｎ−ベンジルオキシカルバモイルメチル）−
１−シクロペンタンカルボン酸３．００ｇをテトラヒド
ロフラン５０ｍｌに溶解し、氷冷下、Ｌ−イソロイシン
トシル酸塩４．２５ｇ、１−エチル−３−（３−ジメチ
ルアミノプロピル）カルボジイミド塩酸塩２．２８ｇ、
ジイソプロピルエチルアミン４．１ｍｌを順次加え、徐
々に室温まで上昇させ約３時間攪拌する。反応液を氷水
にあけ、希塩酸を加えて酸性にした後、酢酸エチルで抽
出し、水洗、無水硫酸ナトリウムで乾燥後、溶媒を留去
し、ヘキサン−酢酸エチルより結晶を濾取して、Ｎ−
〔１−（Ｎ−ベンジルオキシカルバモイルメチル）−１
−シクロペンタンカルボニル〕−Ｌ−イソロイシンベン
ジルエステル（融点６７〜６８℃）０．２９ｇを得る。 実施例２９ Ｎ−〔１−（Ｎ−ヒドロキシカルバモイル
メチル）−１−シクロペンタンカルボニル〕−Ｌ−イソ
ロイシン（化合物No.70 ） Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロペンタンカルボニル〕−Ｌ−イソロイシン
ベンジルエステル０．２８ｇをエタノール１５ｍｌに溶
解し、１０％パラジウム炭素を触媒として加え、水素雰
囲気下、常温常圧で約５時間激しく攪拌する。反応終了
後、触媒を濾過し濾液を濃縮して、Ｎ−〔１−（Ｎ−ヒ
ドロキシカルバモイルメチル）−１−シクロペンタンカ
ルボニル〕−Ｌ−イソロイシン０．１５ｇを得る。1 H-NMR(CDCl3,ppm) δ:0.92(3H,t,J=7Hz), 0.96(3H,d,J
=7Hz), 1.30-2.30(9H,m), 2.46(2H,s), 4.38(1H,d,J=6H
z) 実施例３０ Ｎ−〔１−（Ｎ−ヒドロキシ−Ｎ−メチルカルバモイル
メチル）−１−シクロヘキサンカルボニル〕グリシン
（化合物No.111）、油状物1 H-NMR(CD3OD,ppm) δ:1.30-1.80(8H,br), 1.80-2.20(2
H,m), 2.78(2H,s), 3.20(3H,s), 3.93(2H,s)Example 26 N- [1- (N-benzyloxycarbamoylmethyl) -1-cyclopentanecarbonyl] -L-phenylalanine benzyl ester (Compound No. 67) 1- (N-benzyloxycarbamoylmethyl) -1 −
3.00 g of cyclopentanecarboxylic acid was dissolved in 50 ml of tetrahydrofuran, 5.09 g of L-phenylalanine tosylate, 2.28 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride under ice cooling.
Diisopropylethylamine (4.1 ml) was added successively, the temperature was gradually raised to room temperature, and the mixture was stirred for about 3 hours. The reaction mixture is poured into ice water, diluted with hydrochloric acid to make it acetylaceous, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and then the solvent is distilled off. The obtained residue (0.60 g) was purified by silica gel column chromatography (eluted with hexane-ethyl acetate) and crystallized from hexane-ethyl acetate to give N- [1- (N-benzyloxycarbamoylmethyl) -1-cyclo 0.43 g of pentanecarbonyl] -L-phenylalanine benzyl ester (mp 107-108 ° C) is obtained. 1 H-NMR (CDCl 3 , ppm) δ: 1.40-2.00 (6H, m), 2.40 (2H, s),
3.12 (2H, d, J = 7Hz), 4.70-4.90 (1H, m), 4.87 (2H, s), 5.1
7 (2H, s), 6.40 (1H, m), 6.95-7.45 (15H, m), 8.85 (1H, m),
[Α] D 25 = −25.2 ° (c = 0.63, methanol) Example 27 N- [1- (N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl] -L-phenylalanine (Compound No. 68) N- [1- (N-benzyloxycarbamoylmethyl)
-1-cyclopentanecarbonyl] -L-phenylalanine benzyl ester 0.41 g with ethanol 25 ml
And 10% palladium carbon is added as a catalyst, and the mixture is vigorously stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for about 2.5 hours.
After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to give N
-[1- (N-hydroxylcarbamoylmethyl) -1
0.32 g of -cyclopentanecarbonyl] -L-phenylalanine is obtained. 1 H-NMR (CD 3 OD, ppm) δ: 1.30-2.10 (8H, m), 2.38 (2H, s),
3.05-3.30 (2H, m), 4.70 (1H, m), 7.10-7.55 (5H, m) Example 28 N- [1- (N-benzyloxycarbamoylmethyl) -1-cyclopentanecarbonyl] -L-
Isoleucine benzyl ester (Compound No. 69) a) 12.1 g of benzyloxyamine was dissolved in 300 ml of tetrahydrofuran, and 2-oxaspiro [4.4] nonane-1,3-dione 15.4 was stirred under cooling and stirring at -20 ° C.
g and gradually increase to room temperature (10 ° C.). The reaction solution is concentrated at low temperature, hexane is added, and the precipitated crystals are collected by filtration. This was suspended again in chloroform and collected by filtration to give 1- (N-benzyloxycarbamoylmethyl)-
1-cyclopentanecarboxylic acid (melting point 105-112
C.) 21.6 g are obtained. b) 1- (N-benzyloxycarbamoylmethyl)-
3.00 g of 1-cyclopentanecarboxylic acid was dissolved in 50 ml of tetrahydrofuran, and under ice cooling, 4.25 g of L-isoleucine tosylate, 2.28 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride,
Diisopropylethylamine (4.1 ml) was added successively, the temperature was gradually raised to room temperature, and the mixture was stirred for about 3 hours. The reaction solution was poured into ice water, acidified by adding dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and crystals were collected from hexane-ethyl acetate by filtration to obtain N. −
[1- (N-benzyloxycarbamoylmethyl) -1
-Cyclopentanecarbonyl] -L-isoleucine benzyl ester (melting point 67-68 ° C) 0.29 g is obtained. Example 29 N- [1- (N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl] -L-isoleucine (Compound No. 70) N- [1- (N-benzyloxycarbamoylmethyl)
0.28 g of -1-cyclopentanecarbonyl] -L-isoleucine benzyl ester is dissolved in 15 ml of ethanol, 10% palladium carbon is added as a catalyst, and the mixture is vigorously stirred at room temperature and atmospheric pressure for about 5 hours. After completion of the reaction, the catalyst is filtered and the filtrate is concentrated to obtain 0.15 g of N- [1- (N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl] -L-isoleucine. 1 H-NMR (CDCl 3 , ppm) δ: 0.92 (3H, t, J = 7Hz), 0.96 (3H, d, J
= 7Hz), 1.30-2.30 (9H, m), 2.46 (2H, s), 4.38 (1H, d, J = 6H
z) Example 30 N- [1- (N-hydroxy-N-methylcarbamoylmethyl) -1-cyclohexanecarbonyl] glycine (Compound No. 111), oily substance 1 H-NMR (CD 3 OD, ppm) δ: 1.30-1.80 (8H, br), 1.80-2.20 (2
H, m), 2.78 (2H, s), 3.20 (3H, s), 3.93 (2H, s)
【００６６】実施例３１ Ｎ−〔１−（Ｎ−メトキシカルバモイルメチル）−１−
シクロぺンタンカルボニル〕グリシンベンジルエステル
（化合物No.112）、融点７３〜７７℃ 実施例３２ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロぺンタンカルボニル〕−Ｌ−ロイシンメチ
ルエステル（化合物No.113）、融点１２１〜１２４℃、
〔α〕D 25＝−２４．９°（ｃ＝０．７０、メタノー
ル） 実施例３３ Ｎ−〔１−（Ｎ−ヒドロキシカルバモイルメチル）−１
−シクロペンタンカルボニル〕−Ｌ−ロイシンメチルエ
ステル（化合物No.114）、融点１１９〜１２２℃、
〔α〕D 25＝−３４．７°（ｃ＝０．５１、メタノー
ル） 実施例３４ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロペンタンカルボニル〕−Ｌ−ロイシン（化
合物No.115）、融点１２２〜１２３℃、〔α〕D 25＝−
１４．６°（ｃ＝０．５７、メタノール）Example 31 N- [1- (N-methoxycarbamoylmethyl) -1-
Cyclopentanecarbonyl] glycine benzyl ester (Compound No. 112), melting point 73-77 ° C Example 32 N- [1- (N-benzyloxycarbamoylmethyl)
-1-Cyclopentanecarbonyl] -L-leucine methyl ester (Compound No. 113), melting point 121-124 ° C,
[Α] D 25 = -24.9 ° (c = 0.70, methanol) Example 33 N- [1- (N-hydroxycarbamoylmethyl) -1
-Cyclopentanecarbonyl] -L-leucine methyl ester (Compound No. 114), melting point 119 to 122 ° C,
[Α] D 25 = −34.7 ° (c = 0.51, methanol) Example 34 N- [1- (N-benzyloxycarbamoylmethyl)
-1-Cyclopentanecarbonyl] -L-leucine (Compound No. 115), melting point 122-123 ° C, [α] D 25 =-
14.6 ° (c = 0.57, methanol)
【００６７】実施例３５ シス−４−〔１−（Ｎ−ベンジルオキシカルバモイルメ
チル）−１−シクロヘキサンカルボキサミド〕シクロヘ
キサンカルボン酸メチルエステル（化合物No.116) 、融
点９８〜１０１℃ 実施例３６ Ｎ−〔１−（Ｎ−ヒドロキシカルバモイルメチル）−１
−シクロペンタンカルボニル〕−Ｌ−ロイシン（化合物
No.117) 、融点１３６〜１３８℃ 実施例３７ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロヘキサンカルボニル〕グリシンＮ，Ｎ−ジ
メチルカルバモイルメチルエステル（化合物No.118) 、
油状物1 H-NMR(CDCl3,ppm) δ:1.25-2.10(10H,m), 2.25-2.50(2
H,m), 2.93(6H,s), 4.09(2H,d,J=5Hz), 4.72(2H,s), 4.
96(2H,s), 6.92(1H,t-like,J=5Hz), 7.36(5H,s), 9.60
(1H,m) 実施例３８ Ｎ−〔１−（Ｎ−ヒドロキシカルバモイルメチル）−１
−シクロヘキサンカルボニル〕グリシンＮ，Ｎ−ジメチ
ルカルバモイルメチルエステル（化合物No.119) 、油状
物1 H-NMR(DMSO-d6,ppm) δ:1.10-1.70(8H,br), 1.92(2H,
m), 2.16(2H,m), 2.85(3H,s), 2.95(3H,s), 3.91(2H,d,
J=5Hz), 4.79(2H,s), 8.12(1H,t-like,J=5Hz),8.68(1H,
m) 実施例３９ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロヘプタンカルボニル〕グリシンベンジルエ
ステル（化合物No.120) 、融点９０〜９２℃Example 35 cis-4- [1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarboxamide] cyclohexanecarboxylic acid methyl ester (Compound No. 116), melting point 98-101 ° C. Example 36 N- [ 1- (N-hydroxycarbamoylmethyl) -1
-Cyclopentanecarbonyl] -L-leucine (compound
No. 117), melting point 136-138 [deg.] C. Example 37 N- [1- (N-benzyloxycarbamoylmethyl)
-1-Cyclohexanecarbonyl] glycine N, N-dimethylcarbamoylmethyl ester (Compound No. 118),
Oil 1 H-NMR (CDCl 3 , ppm) δ: 1.25-2.10 (10H, m), 2.25-2.50 (2
H, m), 2.93 (6H, s), 4.09 (2H, d, J = 5Hz), 4.72 (2H, s), 4.
96 (2H, s), 6.92 (1H, t-like, J = 5Hz), 7.36 (5H, s), 9.60
(1H, m) Example 38 N- [1- (N-hydroxycarbamoylmethyl) -1
-Cyclohexanecarbonyl] glycine N, N-dimethylcarbamoylmethyl ester (Compound No. 119), oily substance 1 H-NMR (DMSO-d6, ppm) δ: 1.10-1.70 (8H, br), 1.92 (2H,
m), 2.16 (2H, m), 2.85 (3H, s), 2.95 (3H, s), 3.91 (2H, d,
J = 5Hz), 4.79 (2H, s), 8.12 (1H, t-like, J = 5Hz), 8.68 (1H,
m) Example 39 N- [1- (N-benzyloxycarbamoylmethyl)
-1-Cycloheptanecarbonyl] glycine benzyl ester (Compound No. 120), melting point 90-92 ° C
【００６８】実施例４０ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロヘプタンカルボニル〕−Ｌ−ロイシンメチ
ルエステル（化合物No.121) 、融点１０３〜１０５℃、
〔α〕D 25＝−２２．９°（ｃ＝０．４７、メタノー
ル） 実施例４１ Ｎ−〔１−（Ｎ−ヒドロキシカルバモイルメチル）−１
−シクロヘプタンカルボニル〕グリシン（化合物No.12
2) 、融点１４０〜１４５℃ 実施例４２ Ｎ−〔１−（Ｎ−ヒドロキシカルバモイルメチル）−１
−シクロヘプタンカルボニル〕−Ｌ−ロイシンメチルエ
ステル（化合物No.123) 、油状物1 H-NMR(CDCl3,ppm) δ:0.93(6H,d,J=7Hz), 1.24(2H,t,J
=7Hz), 1.43(1H,m), 1.46-1.63(12H,m), 2.43(2H,s),
3.73(3H,s), 4.40-4.63(1H,br), 6.17-6.40(1H,br) 実施例４３ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロペンタンカルボニル〕−Ｌ−バリンエチル
エステル（化合物No.124) 、油状物、融点６０〜６３℃ 実施例４４ Ｎ−〔１−（Ｎ−ヒドロキシカルバモイルメチル）−１
−シクロペンタンカルボニル〕−Ｌ−バリンエチルエス
テル（化合物No.125) 、油状物1 H-NMR(CDCl3,ppm) δ:0.94(3H,d,J=7.5Hz), 0.95(3H,
d,J=7.5Hz), 1.30(3H,t,J=7.5Hz), 1.60-2.30(9H,m),
2.50(2H,s), 4.18(2H,q,J=7.5Hz), 4.45(1H,m),6.96(1
H,d,J=8Hz)Example 40 N- [1- (N-benzyloxycarbamoylmethyl)
-1-Cycloheptanecarbonyl] -L-leucine methyl ester (Compound No. 121), melting point 103-105 ° C,
[Α] D 25 = −22.9 ° (c = 0.47, methanol) Example 41 N- [1- (N-hydroxycarbamoylmethyl) -1
-Cycloheptanecarbonyl] glycine (Compound No. 12
2), melting point 140 to 145 ° C. Example 42 N- [1- (N-hydroxycarbamoylmethyl) -1
-Cycloheptanecarbonyl] -L-leucine methyl ester (Compound No. 123), oily substance 1 H-NMR (CDCl 3 , ppm) δ: 0.93 (6H, d, J = 7Hz), 1.24 (2H, t, J
= 7Hz), 1.43 (1H, m), 1.46-1.63 (12H, m), 2.43 (2H, s),
3.73 (3H, s), 4.40-4.63 (1H, br), 6.17-6.40 (1H, br) Example 43 N- [1- (N-benzyloxycarbamoylmethyl)
-1-Cyclopentanecarbonyl] -L-valine ethyl ester (Compound No. 124), oil, melting point 60-63 ° C. Example 44 N- [1- (N-hydroxycarbamoylmethyl) -1.
-Cyclopentanecarbonyl] -L-valine ethyl ester (Compound No. 125), oily substance 1 H-NMR (CDCl 3 , ppm) δ: 0.94 (3H, d, J = 7.5Hz), 0.95 (3H,
d, J = 7.5Hz), 1.30 (3H, t, J = 7.5Hz), 1.60-2.30 (9H, m),
2.50 (2H, s), 4.18 (2H, q, J = 7.5Hz), 4.45 (1H, m), 6.96 (1
(H, d, J = 8Hz)
【００６９】実施例４５ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロヘキサンカルボニル〕−Ｌ−トリプトファ
ンベンジルエステル（化合物No.126) 、油状物1 H-NMR(CDCl3,ppm) δ:1.10-1.80(10H,m), 2.22(2H,s),
3.27(2H,d-like,J=6Hz),4.76(2H,s), 4.83(1H,t,J=6H
z), 5.05(2H,s), 6.40-6.60(1H,br), 6.80-7.40(16H,
m), 8.40-8.50(1H,br) 実施例４６ Ｎ−〔１−（Ｎ−メトキシカルバモイルメチル）−１−
シクロヘキサンカルボニル〕グリシンベンジルエステル
（化合物No.127) 、融点１１３℃ 実施例４７ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロヘキサンカルボニル〕グリシン−ｔ−ブチ
ルエステル（化合物No.128) 、融点１２０〜１２５℃ 実施例４８ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロヘキサンカルボニル〕グリシン（化合物N
o.129) 、融点１２０℃ 実施例４９ Ｎ−〔１−（Ｎ−メトキシカルバモイルメチル）−１−
シクロヘキサンカルボニル〕グリシン（化合物No.130)
、融点１５３〜１５５℃Example 45 N- [1- (N-benzyloxycarbamoylmethyl)
-1-Cyclohexanecarbonyl] -L-tryptophan benzyl ester (Compound No. 126), oily substance 1 H-NMR (CDCl 3 , ppm) δ: 1.10-1.80 (10H, m), 2.22 (2H, s),
3.27 (2H, d-like, J = 6Hz), 4.76 (2H, s), 4.83 (1H, t, J = 6H
z), 5.05 (2H, s), 6.40-6.60 (1H, br), 6.80-7.40 (16H,
m), 8.40-8.50 (1H, br) Example 46 N- [1- (N-methoxycarbamoylmethyl) -1-
Cyclohexanecarbonyl] glycine benzyl ester (Compound No. 127), melting point 113 ° C. Example 47 N- [1- (N-benzyloxycarbamoylmethyl)
-1-Cyclohexanecarbonyl] glycine-t-butyl ester (Compound No. 128), melting point 120-125 ° C Example 48 N- [1- (N-benzyloxycarbamoylmethyl).
-1-Cyclohexanecarbonyl] glycine (Compound N
o.129), melting point 120 ° C. Example 49 N- [1- (N-methoxycarbamoylmethyl) -1-
Cyclohexanecarbonyl] glycine (Compound No. 130)
, Melting point 153-155 ° C
【００７０】実施例５０ Ｎ−〔１−（Ｎ−ヒドロキシカルバモイルメチル）−１
−シクロヘキサンカルボニル〕−Ｌ−ロイシンメチルエ
ステル（化合物No.131) 、油状物1 H-NMR(CDCl3,ppm) δ:0.96(6H,d,J=4.5Hz), 1.10-2.20
(13H,m), 2.44(2H,s),3.77(3H,s), 4.40-4.70(1H,br),
6.20-6.50(1H,br) 実施例５１ Ｎ−〔１−（Ｎ−ベンジルオキシ−Ｎ−（２，４−ジメ
トキシベンジル）カルバモイルメチル）−１−シクロヘ
キサンカルボニル〕グリシンベンジルエステル（化合物
No.132) 、油状物1 H-NMR(CDCl3,ppm) δ:1.30-1.70(10H,m), 1.80-2.10(2
H,m), 2.71(2H,s), 3.80(6H,s), 4.06(2H,d,J=6Hz), 4.
73(2H,s), 4.81(2H,s), 5.18(2H,s), 6.48(2H,m), 7.10
-7.40(12H,m) 実施例５２ Ｎ−〔１−（Ｎ−ベンジルオキシ−Ｎ−（２，４−ジメ
トキシベンジル）カルバモイルメチル）−１−シクロヘ
キサンカルボニル〕−Ｌ−プロリンベンジルエステル
（化合物No.133) 、油状物1 H-NMR(CDCl3,ppm) δ:1.25-2.35(16H,m), 2.70(2H,s),
3.78(3H,s), 3.80(3H,s), 4.5-4.8(1H,m), 4.74(2H,
s), 4.83(2H,s), 5.12(1H,d,J=12Hz), 5.15(1H,d,J=12H
z), 6.46(2H,m), 7.15-7.45(12H,m) 実施例５３ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロペンタンカルボニル〕−Ｌ−ロイシンベン
ジルエステル（化合物No.134) 、融点８７〜８９℃、
〔α〕D 24＝−２７．２°（ｃ＝０．７５、メタノー
ル） 実施例５４ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロペンタンカルボニル〕−Ｌ−バリンベンジ
ルエステル（化合物No.135) 、油状物1 H-NMR(CDCl3,ppm) δ:0.88(3H,d,J=7.5Hz), 0.92(3H,
d,J=7.5Hz), 1.20-1.90(9H,m), 2.45(2H,s), 4.50(1H,
m), 4.85(2H,s), 5.10(1H,d,J=12Hz), 5.20(1H,d,J=12H
z), 6.70(1H,br), 7.35(10H,s), 8.90(1H,br)Example 50 N- [1- (N-hydroxycarbamoylmethyl) -1
-Cyclohexanecarbonyl] -L-leucine methyl ester (Compound No. 131), oily substance 1 H-NMR (CDCl 3 , ppm) δ: 0.96 (6H, d, J = 4.5Hz), 1.10-2.20
(13H, m), 2.44 (2H, s), 3.77 (3H, s), 4.40-4.70 (1H, br),
6.20-6.50 (1H, br) Example 51 N- [1- (N-benzyloxy-N- (2,4-dimethoxybenzyl) carbamoylmethyl) -1-cyclohexanecarbonyl] glycine benzyl ester (compound
No.132), oil 1 H-NMR (CDCl 3 , ppm) δ: 1.30-1.70 (10H, m), 1.80-2.10 (2
H, m), 2.71 (2H, s), 3.80 (6H, s), 4.06 (2H, d, J = 6Hz), 4.
73 (2H, s), 4.81 (2H, s), 5.18 (2H, s), 6.48 (2H, m), 7.10
-7.40 (12H, m) Example 52 N- [1- (N-benzyloxy-N- (2,4-dimethoxybenzyl) carbamoylmethyl) -1-cyclohexanecarbonyl] -L-proline benzyl ester (Compound No. 133), oil 1 H-NMR (CDCl 3 , ppm) δ: 1.25-2.35 (16H, m), 2.70 (2H, s),
3.78 (3H, s), 3.80 (3H, s), 4.5-4.8 (1H, m), 4.74 (2H,
s), 4.83 (2H, s), 5.12 (1H, d, J = 12Hz), 5.15 (1H, d, J = 12H
z), 6.46 (2H, m), 7.15-7.45 (12H, m) Example 53 N- [1- (N-benzyloxycarbamoylmethyl)
-1-Cyclopentanecarbonyl] -L-leucine benzyl ester (Compound No. 134), melting point 87-89 ° C.
[Α] D 24 = -27.2 ° (c = 0.75, methanol) Example 54 N- [1- (N-benzyloxycarbamoylmethyl)
-1-Cyclopentanecarbonyl] -L-valine benzyl ester (Compound No. 135), oily substance 1 H-NMR (CDCl 3 , ppm) δ: 0.88 (3H, d, J = 7.5Hz), 0.92 (3H,
d, J = 7.5Hz), 1.20-1.90 (9H, m), 2.45 (2H, s), 4.50 (1H,
m), 4.85 (2H, s), 5.10 (1H, d, J = 12Hz), 5.20 (1H, d, J = 12H
z), 6.70 (1H, br), 7.35 (10H, s), 8.90 (1H, br)
【００７１】実施例５５ Ｎ−〔１−（Ｎ−ベンジルオキシ−Ｎ−ベンジルカルバ
モイルメチル）−１−シクロペンタンカルボニル〕グリ
シンベンジルエステル（化合物No.136)1 H-NMR(CDCl3,ppm) δ:1.35-1.78(8H,m), 2.20(2H,m),
2.82(2H,s), 4.03(2H,d,J=5Hz), 4.73(2H,s), 4.76(2H,
s), 5.15(2H,s), 7.32(15H,m) 実施例５６ Ｎ−〔１−（Ｎ−ベンジルオキシ−Ｎ−ベンジルカルバ
モイルメチル）−１−シクロペンタンカルボニル〕プロ
リンベンジルエステル（化合物No.137)、融点８０〜８
２℃、〔α〕D ＝−５２．１°（ｃ＝０．４７、メタノ
ール） 実施例５７ Ｎ−〔１−（Ｎ−ベンジル−Ｎ−ヒドロキシカルバモイ
ルメチル）−１−シクロペンタンカルボニル〕グリシン
（化合物No.138) 、融点９４〜９５℃ 実施例５８ Ｎ−〔１−（Ｎ−ベンジル−Ｎ−ヒドロキシカルバモイ
ルメチル）−１−シクロペンタンカルボニル〕プロリン
（化合物No.139)1 H-NMR(CD3OD,ppm) δ:1.50-2.38(12H,m), 2.86(1H,d,J
=14Hz), 3.03(1H,d,J=14Hz), 3.72(2H,m), 4.43(1H,m),
4.66(1H,d,J=16Hz), 4.85(1H,d,J=16Hz), 7.32(5H,s) 実施例５９ Ｎ−〔１−（Ｎ−ヒドロキシカルバモイルメチル）−１
−シクロペンタンカルボニル〕−Ｌ−バリン、油状物
（化合物No.144)1 H-NMR(CD3OD,ppm) δ:1.00(6H,d,J=8Hz), 1.50-1.80(9
H,m), 2.45(2H,s), 4.30(1H,d,J=6Hz)Example 55 N- [1- (N-benzyloxy-N-benzylcarbamoylmethyl) -1-cyclopentanecarbonyl] glycine benzyl ester (Compound No. 136) 1 H-NMR (CDCl 3 , ppm) δ : 1.35-1.78 (8H, m), 2.20 (2H, m),
2.82 (2H, s), 4.03 (2H, d, J = 5Hz), 4.73 (2H, s), 4.76 (2H,
s), 5.15 (2H, s), 7.32 (15H, m) Example 56 N- [1- (N-benzyloxy-N-benzylcarbamoylmethyl) -1-cyclopentanecarbonyl] proline benzyl ester (Compound No. 137), melting point 80-8
2 ° C., [α] D = −52.1 ° (c = 0.47, methanol) Example 57 N- [1- (N-benzyl-N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl] glycine ( Compound No. 138), melting point 94-95 ° C. Example 58 N- [1- (N-benzyl-N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl] proline (Compound No. 139) 1 H-NMR (CD 3 OD, ppm) δ: 1.50-2.38 (12H, m), 2.86 (1H, d, J
= 14Hz), 3.03 (1H, d, J = 14Hz), 3.72 (2H, m), 4.43 (1H, m),
4.66 (1H, d, J = 16Hz), 4.85 (1H, d, J = 16Hz), 7.32 (5H, s) Example 59 N- [1- (N-hydroxycarbamoylmethyl) -1
-Cyclopentanecarbonyl] -L-valine, oily substance (Compound No. 144) 1 H-NMR (CD 3 OD, ppm) δ: 1.00 (6H, d, J = 8Hz), 1.50-1.80 (9
H, m), 2.45 (2H, s), 4.30 (1H, d, J = 6Hz)
【００７２】実施例６０ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロヘキサンカルボニル〕グリシンエチルエス
テル（化合物No.145) 、融点８０〜８２℃ 実施例６１ Ｎ−〔１−（Ｎ−ヒドロキシカルバモイルメチル）−１
−シクロヘキサンカルボニル〕グリシンエチルエステル
（化合物No.146) 、融点１０６〜１０８℃ 実施例６２ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロヘキサンカルボニル〕グリシンフェネチル
エステル（化合物No.159) 、融点１１１〜１１４℃ 実施例６３ Ｎ−〔１−（Ｎ−ベンジルオキシカルバモイルメチル）
−１−シクロヘキサンカルボニル〕グリシンｎ−オクチ
ルエステル（化合物No.160) 、融点５４〜５６℃ 実施例６４ Ｎ−〔１−（Ｎ−ヒドロキシ−Ｎ−（２，４−ジメトキ
シフェニル）メチルカルバモイルメチル）−１−シクロ
ヘキサンカルボニル〕グリシン（化合物No.161）、油状
物1 H-NMR(CD3OD,ppm) δ:1.25-2.20(12H,m), 2.83(2H,s),
3.77(3H,s), 3.80(3H,s), 3.90(2H,s), 4.71(2H,s),
6.47(1H,d,J=9Hz), 6.52(1H,s), 7.12(1H,d,J=9Hz) 実施例６５ Ｎ−〔１−（Ｎ−ヒドロキシカルバモイルメチル）−１
−シクロヘキサンカルボニル〕グリシンフェネチルエス
テル（化合物No.157) 、融点１２０〜１２１．５℃Example 60 N- [1- (N-benzyloxycarbamoylmethyl)
-1-Cyclohexanecarbonyl] glycine ethyl ester (Compound No. 145), melting point 80-82 ° C. Example 61 N- [1- (N-hydroxycarbamoylmethyl) -1.
-Cyclohexanecarbonyl] glycine ethyl ester (Compound No. 146), melting point 106-108 ° C Example 62 N- [1- (N-benzyloxycarbamoylmethyl).
-1-Cyclohexanecarbonyl] glycine phenethyl ester (Compound No. 159), melting point 111-114 ° C Example 63 N- [1- (N-benzyloxycarbamoylmethyl).
-1-Cyclohexanecarbonyl] glycine n-octyl ester (Compound No. 160), melting point 54-56 ° C Example 64 N- [1- (N-hydroxy-N- (2,4-dimethoxyphenyl) methylcarbamoylmethyl) -1-Cyclohexanecarbonyl] glycine (Compound No. 161), oily substance 1 H-NMR (CD 3 OD, ppm) δ: 1.25-2.20 (12H, m), 2.83 (2H, s),
3.77 (3H, s), 3.80 (3H, s), 3.90 (2H, s), 4.71 (2H, s),
6.47 (1H, d, J = 9Hz), 6.52 (1H, s), 7.12 (1H, d, J = 9Hz) Example 65 N- [1- (N-hydroxycarbamoylmethyl) -1
-Cyclohexanecarbonyl] glycine phenethyl ester (Compound No. 157), melting point 120-121.5 ° C
【００７３】[0073]
【発明の効果】本発明の一般式（Ｉ）の化合物およびそ
の塩の中性エンドぺプチダーゼ阻害活性は、以下の試験
方法により確認される。The neutral endopeptidase inhibitory activity of the compounds of the general formula (I) and salts thereof of the present invention is confirmed by the following test methods.
【００７４】試験例１ 中性エンドぺプチダーゼ阻害活
性 試験方法は被検化合物のエタノールあるいは１０％エタ
ノール溶液（２または２０μｌ）、ラット中性エンドペ
プチダーゼ（ＮＥＰ）（蛋白量として１．１μｇ）およ
びロイシンアミノペプチダーゼをトリス緩衝液（５０ｍ
Ｍ、ｐＨ８．２）に混合する（総量１５０μｌ）。これ
に基質液（５ｍＭ、サクシニル−アラニル−アラニル−
アラニル−パラニトロアニリド）５０μｌを添加し、室
温で１５〜２０分間酵素反応を行い、次いで０．３規定
塩酸含有２０％エタノール５０μｌを加えて反応を停止
させる。遊離してくるパラニトロアニリン由来の４０５
ｎｍの吸光度（Ａ）を測定し、次式により阻害率を求め
た。 阻害率＝〔１−（Ａ−Ｂ）／（Ｔ−Ｂ）〕×１００ （Ｔ：被検液を添加しない場合の４０５ｎｍでの吸光
度、Ｂ：ＮＥＰを添加しない場合の４０５ｎｍでの吸光
度）その結果を表１３に示す。Test Example 1 Neutral Endopeptidase Inhibitory Activity The test method was as follows: test compound in ethanol or 10% ethanol solution (2 or 20 μl), rat neutral endopeptidase (NEP) (protein amount: 1.1 μg) and leucine. Aminopeptidase was added to Tris buffer (50m
M, pH 8.2) (150 μl total volume). Substrate solution (5 mM, succinyl-alanyl-alanyl-
50 μl of alanyl-paranitroanilide) is added, the enzyme reaction is performed at room temperature for 15 to 20 minutes, and then 50 μl of 20% ethanol containing 0.3 N hydrochloric acid is added to stop the reaction. 405 derived from para-nitroaniline released
The absorbance (A) at nm was measured, and the inhibition rate was calculated by the following formula. Inhibition rate = [1- (AB) / (TB)] × 100 (T: absorbance at 405 nm without addition of test solution, B: absorbance at 405 nm without addition of NEP) The results are shown in Table 13.
【００７５】[0075]
【表１３】 ─────────────────────────── 化合物No. ＮＥＰ阻害率 （ＩＣ50 ,ｎＭ） ─────────────────────────── ６０ ２．７ ６３ ５．６ ６６ ２．６ ６８ １．８ ７０ １．９ ───────────────────────────[Table 13] ─────────────────────────── Compound No. NEP inhibition rate (IC 50 , nM) ──────── ──────────────────── 60 2.7 63 5.6 66 66 2.6 68 1.8 70 1.9 ─────────── ─────────────────
【００７６】これらの試験およびその他の実験から、本
発明の一般式（Ｉ）の化合物およびその塩は、中性エン
ドぺプチダーゼ活性阻害作用を有し、強力なナトリウム
***性、利尿性、血圧降下性のホルモンである心房性ナ
トリウム利尿ペプチドの生物学的効果を強化することが
できる。したがって、本化合物は、高血圧、心不全、ア
ンギナ、腎不全、月経前症候群、周期性浮腫、メニエー
ル病、高アルドステロン症（一次および二次）肺水腫、
腹水および高カルシウム尿症を含む多くの循環器系疾患
の治療に有用である。また、本発明の化合物は緑内障の
治療や喘息、炎症、疼痛、てんかん、感情障害、痴呆お
よび老人性錯乱、肥満症および胃腸障害（特に下痢およ
び過敏性腸症候群）の治療、胃酸分泌の調節および高レ
ニン血症および白血病の治療を含む他の治療領域におい
ても有用である。From these tests and other experiments, the compound of the general formula (I) of the present invention and a salt thereof have a neutral endopeptidase activity inhibitory action, and have strong natriuretic, diuretic and hypotensive properties. The biological effects of the sex hormone, atrial natriuretic peptide, can be enhanced. Therefore, the compound is effective in treating hypertension, heart failure, angina, renal failure, premenstrual syndrome, periodic edema, Meniere's disease, hyperaldosteronism (primary and secondary) pulmonary edema,
It is useful in the treatment of many cardiovascular diseases, including ascites and hypercalciuria. The compounds of the present invention also treat glaucoma, asthma, inflammation, pain, epilepsy, affective disorders, dementia and senile confusion, obesity and gastrointestinal disorders (particularly diarrhea and irritable bowel syndrome), regulation of gastric acid secretion and It is also useful in other therapeutic areas, including the treatment of hyperreninemia and leukemia.
フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/215 ＡＣＸ 8413−4Ｃ 31/255 ＡＣＶ 8413−4Ｃ 31/40 7252−4Ｃ 31/44 ＡＢＮ 7252−4Ｃ Ｃ０７Ｃ 323/52 7419−4Ｈ 323/59 7419−4Ｈ 323/60 7419−4Ｈ 327/32 8619−4Ｈ Ｃ０７Ｄ 207/16 7019−4Ｃ 213/75 6701−4Ｃ 233/64 １０５ 7252−4Ｃ (72)発明者 和田 幸雄 埼玉県入間市小谷田３丁目７番25号 吉富 製薬株式会社東京研究所内 (72)発明者 細谷 真弘 埼玉県入間市小谷田３丁目７番25号 吉富 製薬株式会社東京研究所内Continuation of the front page (51) Int.Cl. 5 Identification code Office reference number FI Technical display location A61K 31/215 ACX 8413-4C 31/255 ACV 8413-4C 31/40 7252-4C 31/44 ABN 7252-4C C07C 323/52 7419-4H 323/59 7419-4H 323/60 7419-4H 327/32 8619-4H C07D 207/16 7019-4C 213/75 6701-4C 233/64 105 7252-4C (72) Inventor Yukio Wada 3-7-25 Oyada, Iruma City, Saitama Prefecture Yoshitomi Pharmaceutical Co., Ltd. Tokyo Research Laboratory (72) Inventor Masahiro Hosoya 3-7-25 Oyada, Iruma City, Saitama Prefecture Tokyo Research Laboratory, Yoshitomi Pharmaceutical Co., Ltd.
Claims (2)
で、Ｒ1 ，Ｒ2 は同一または異なって水素、低級アルキ
ル、置換低級アルキル、アルカノイル、置換アルカノイ
ル、アラルキル、置換アラルキル、ベンゾイル、置換ベ
ンゾイルを示す。）または式Ｒ3 −Ｓ−（ここで、Ｒ3
は水素、低級アルキル、置換低級アルキル、アルカノイ
ル、置換アルカノイル、アラルキル、置換アラルキル、
ベンゾイル、置換ベンゾイル、ニトロソを示す。）を示
し、 Ｒ4 ，Ｒ5 は同一または異なって低級アルキル、置換低
級アルキル、アラルキル、置換アラルキルまたはＲ4 ，
Ｒ5 が一緒になって置換基を有していてもよい炭素数２
〜７個のアルキレン、置換基を有していてもよい少なく
とも１個の炭素−炭素不飽和結合を有している炭素数２
〜７個のアルケニレンを示し、 Ｒ6 は水素、低級アルキル、置換低級アルキル、アラル
キル、置換アラルキルを示し、 Ｒ7 はフェニル、置換フェニル、アラルキル、置換アラ
ルキル、ヘテロアリール、置換ヘテロアリール、式−Ｘ
−ＣＯＯＲ8 （ここで、Ｘは炭素数１〜１０個の直鎖ま
たは分枝鎖状のアルキレン、シクロアルキレン、低級ア
ルキル置換シクロアルキレン、フェニレン、置換フェニ
レン、式−ＣＨ（Ｒ9 ）−（ここでＲ9 はアラルキル、
置換アラルキル、ヘテロアリール低級アルキル、式−Ｑ
−Ｚ−Ｒ10（ここでＱは低級アルキレンを示し、Ｚは−
Ｏ−，−Ｓ−，−Ｎ（Ｒ11）−を示し、Ｒ10は水素、ア
ルキル、置換アルキル、アルケニル、置換アルケニル、
アルキニル、置換アルキニル、アルカノイル、置換アル
カノイル、アリール、置換アリール、アラルキル、置換
アラルキルを示し、Ｒ11は水素、低級アルキル、置換低
級アルキル、アラルキル、置換アラルキルを示す。）を
示すか、Ｒ9 はＲ6 と一緒になってヘテロ環を形成する
基を示す。）を示し、Ｒ8 は水素、エステル形成残基、
アミド形成残基を示す。）を示す。但し、Ｒ4 ，Ｒ5 が
共に低級アルキルで、Ｒ7 がその定義中、式 【化２】 （式中、Ｒ10' はＲ10の定義中、水素、低級アルキル、
アルカノイル、アラルキル、置換アラルキルであり、他
の記号は前記と同義である。）である場合を除く。〕に
より表わされるプロピオン酸アミド誘導体およびその
塩。1. A general formula: [In the formula, A is a formula R 1 —O—N (R 2 ) —CO— (wherein R 1 and R 2 are the same or different and are hydrogen, lower alkyl, substituted lower alkyl, alkanoyl, substituted alkanoyl, aralkyl, Substituted aralkyl, benzoyl, substituted benzoyl) or the formula R 3 —S— (wherein R 3
Is hydrogen, lower alkyl, substituted lower alkyl, alkanoyl, substituted alkanoyl, aralkyl, substituted aralkyl,
It shows benzoyl, substituted benzoyl and nitroso. And R 4 and R 5 are the same or different and are lower alkyl, substituted lower alkyl, aralkyl, substituted aralkyl or R 4 ,
R 5 together has 2 carbon atoms which may have a substituent.
~ 7 alkylene, at least one carbon-carbon unsaturated bond optionally having 2 carbon atoms having a unsaturated bond
To 7 alkenylene, R 6 represents hydrogen, lower alkyl, substituted lower alkyl, aralkyl, substituted aralkyl, R 7 represents phenyl, substituted phenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, formula-X
—COOR 8 (where X is a linear or branched alkylene having 1 to 10 carbon atoms, cycloalkylene, lower alkyl-substituted cycloalkylene, phenylene, substituted phenylene, formula —CH (R 9 )-(here So R 9 is aralkyl,
Substituted aralkyl, heteroaryl lower alkyl, formula -Q
-Z-R 10 (wherein Q represents a lower alkylene, Z is -
O-, -S-, -N (R 11 )-is shown, and R 10 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
Alkynyl, substituted alkynyl, alkanoyl, substituted alkanoyl, aryl, substituted aryl, aralkyl and substituted aralkyl are shown, and R 11 is hydrogen, lower alkyl, substituted lower alkyl, aralkyl and substituted aralkyl. Or R 9 represents a group which forms a heterocycle together with R 6 . ), R 8 is hydrogen, an ester-forming residue,
The amide forming residues are shown. ) Is shown. Provided that R 4 and R 5 are both lower alkyl and R 7 is in the definition thereof. (In the formula, R 10 ′ is hydrogen, lower alkyl in the definition of R 10 ,
Alkanoyl, aralkyl, and substituted aralkyl, and other symbols have the same meanings as described above. ) Is excluded. ] The propionic acid amide derivative represented by these, and its salt.
で、Ｒ1 ，Ｒ2 は同一または異なって水素、低級アルキ
ル、置換低級アルキル、アルカノイル、置換アルカノイ
ル、アラルキル、置換アラルキル、ベンゾイル、置換ベ
ンゾイルを示す。）または式Ｒ3 −Ｓ−（ここで、Ｒ3
は水素、低級アルキル、置換低級アルキル、アルカノイ
ル、置換アルカノイル、アラルキル、置換アラルキル、
ベンゾイル、置換ベンゾイル、ニトロソを示す。）を示
し、 Ｒ4 ，Ｒ5 は同一または異なって低級アルキル、置換低
級アルキル、アラルキル、置換アラルキルまたはＲ4 ，
Ｒ5 が一緒になって置換基を有していてもよい炭素数２
〜７個のアルキレン、置換基を有していてもよい少なく
とも１個の炭素−炭素不飽和結合を有している炭素数２
〜７個のアルケニレンを示し、 Ｒ6 は水素、低級アルキル、置換低級アルキル、アラル
キル、置換アラルキルを示し、 Ｒ7 はフェニル、置換フェニル、アラルキル、置換アラ
ルキル、ヘテロアリール、置換ヘテロアリール、式−Ｘ
−ＣＯＯＲ8 （ここで、Ｘは炭素数１〜１０個の直鎖ま
たは分枝鎖状のアルキレン、シクロアルキレン、低級ア
ルキルシクロアルキレン、フェニレン、置換フェニレ
ン、式−ＣＨ（Ｒ9 ）−（ここでＲ9 はアラルキル、置
換アラルキル、ヘテロアリール低級アルキル、式−Ｑ−
Ｚ−Ｒ10（ここでＱは低級アルキレンを示し、Ｚは−Ｏ
−，−Ｓ−，−Ｎ（Ｒ11）−を示し、Ｒ10は水素、アル
キル、置換アルキル、アルケニル、置換アルケニル、ア
ルキニル、置換アルキニル、アルカノイル、置換アルカ
ノイル、アリール、置換アリール、アラルキル、置換ア
ラルキルを示し、Ｒ11は水素、低級アルキル、置換低級
アルキル、アラルキル、置換アラルキルを示す。）を示
すか、Ｒ9 はＲ6 と一緒になってヘテロ環を形成する基
を示す。）を示し、Ｒ8 は水素、エステル形成残基、ア
ミド形成残基を示す。）を示す。〕により表わされるプ
ロピオン酸アミド誘導体を含有することを特徴とする中
性エンドぺプチダーゼ阻害剤。2. A general formula: [In the formula, A is a formula R 1 —O—N (R 2 ) —CO— (wherein R 1 and R 2 are the same or different and are hydrogen, lower alkyl, substituted lower alkyl, alkanoyl, substituted alkanoyl, aralkyl, Substituted aralkyl, benzoyl, substituted benzoyl) or the formula R 3 —S— (wherein R 3
Is hydrogen, lower alkyl, substituted lower alkyl, alkanoyl, substituted alkanoyl, aralkyl, substituted aralkyl,
It shows benzoyl, substituted benzoyl and nitroso. And R 4 and R 5 are the same or different and are lower alkyl, substituted lower alkyl, aralkyl, substituted aralkyl or R 4 ,
R 5 together has 2 carbon atoms which may have a substituent.
~ 7 alkylene, 2 carbon atoms having at least one carbon-carbon unsaturated bond which may have a substituent
To 7 alkenylene, R 6 represents hydrogen, lower alkyl, substituted lower alkyl, aralkyl, substituted aralkyl, R 7 represents phenyl, substituted phenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, formula-X
—COOR 8 (where X is a linear or branched alkylene having 1 to 10 carbon atoms, cycloalkylene, lower alkylcycloalkylene, phenylene, substituted phenylene, formula —CH (R 9 ) — (wherein R 9 is aralkyl, substituted aralkyl, heteroaryl lower alkyl, formula -Q-
Z-R 10 (wherein Q represents a lower alkylene, Z is -O
-, - S -, - N (R 11) - indicates, R 10 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkanoyl, substituted alkanoyl, aryl, substituted aryl, aralkyl, substituted aralkyl And R 11 represents hydrogen, lower alkyl, substituted lower alkyl, aralkyl, or substituted aralkyl. Or R 9 represents a group which forms a heterocycle together with R 6 . And R 8 represents hydrogen, an ester-forming residue, or an amide-forming residue. ) Is shown. ] The neutral endopeptidase inhibitor containing the propionic acid amide derivative represented by these.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4056785A JPH0592948A (en) | 1991-02-06 | 1992-02-06 | Propionic acid amide derivative and its medicine use |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3811291 | 1991-02-06 | ||
| JP3-38112 | 1991-02-06 | ||
| JP4056785A JPH0592948A (en) | 1991-02-06 | 1992-02-06 | Propionic acid amide derivative and its medicine use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0592948A true JPH0592948A (en) | 1993-04-16 |
Family
ID=26377304
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4056785A Pending JPH0592948A (en) | 1991-02-06 | 1992-02-06 | Propionic acid amide derivative and its medicine use |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0592948A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998042662A1 (en) * | 1997-03-20 | 1998-10-01 | Novartis Ag | Certain cyclic thio substituted acylaminoacid amide derivatives |
| US6797820B2 (en) | 1999-12-17 | 2004-09-28 | Vicuron Pharmaceuticals Inc. | Succinate compounds, compositions and methods of use and preparation |
| JP2004535398A (en) * | 2001-05-11 | 2004-11-25 | ギルフォード ファーマシューティカルズ インコーポレーティッド | Hydroxamic acids and acylhydroxamines as NAALADase inhibitors |
| JP2006503053A (en) * | 2002-09-19 | 2006-01-26 | ノバルティス アクチエンゲゼルシャフト | Intermediate production method |
| US7045653B2 (en) | 2002-12-23 | 2006-05-16 | Pfizer, Inc. | Pharmaceuticals |
| WO2012065953A1 (en) * | 2010-11-16 | 2012-05-24 | Novartis Ag | Substituted carbamoylcycloalkyl acetic acid derivatives as nep inhibitors |
| JP2016150909A (en) * | 2015-02-17 | 2016-08-22 | 株式会社クラレ | Method for producing diol |
-
1992
- 1992-02-06 JP JP4056785A patent/JPH0592948A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998042662A1 (en) * | 1997-03-20 | 1998-10-01 | Novartis Ag | Certain cyclic thio substituted acylaminoacid amide derivatives |
| US6034136A (en) * | 1997-03-20 | 2000-03-07 | Novartis Ag | Certain cyclic thio substituted acylaminoacid amide derivatives |
| US6201133B1 (en) | 1997-03-20 | 2001-03-13 | Novartis Ag | Certain cyclic thio substituted acylaminoacid amide derivatives |
| US6797820B2 (en) | 1999-12-17 | 2004-09-28 | Vicuron Pharmaceuticals Inc. | Succinate compounds, compositions and methods of use and preparation |
| JP2004535398A (en) * | 2001-05-11 | 2004-11-25 | ギルフォード ファーマシューティカルズ インコーポレーティッド | Hydroxamic acids and acylhydroxamines as NAALADase inhibitors |
| JP2006503053A (en) * | 2002-09-19 | 2006-01-26 | ノバルティス アクチエンゲゼルシャフト | Intermediate production method |
| US7045653B2 (en) | 2002-12-23 | 2006-05-16 | Pfizer, Inc. | Pharmaceuticals |
| WO2012065953A1 (en) * | 2010-11-16 | 2012-05-24 | Novartis Ag | Substituted carbamoylcycloalkyl acetic acid derivatives as nep inhibitors |
| US8877815B2 (en) | 2010-11-16 | 2014-11-04 | Novartis Ag | Substituted carbamoylcycloalkyl acetic acid derivatives as NEP |
| JP2016150909A (en) * | 2015-02-17 | 2016-08-22 | 株式会社クラレ | Method for producing diol |
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