JPS6141512B2 - - Google Patents
Info
- Publication number
- JPS6141512B2 JPS6141512B2 JP1881279A JP1881279A JPS6141512B2 JP S6141512 B2 JPS6141512 B2 JP S6141512B2 JP 1881279 A JP1881279 A JP 1881279A JP 1881279 A JP1881279 A JP 1881279A JP S6141512 B2 JPS6141512 B2 JP S6141512B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- lower alkyl
- hydrogen atom
- alkyl group
- acyloxy
- 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.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- -1 acylmercapto group Chemical group 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 7
- 239000002220 antihypertensive agent Substances 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 5
- 125000004442 acylamino group Chemical class 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical class [H]OC(*)=O 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 1
- 239000002075 main ingredient Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 7
- 102000015427 Angiotensins Human genes 0.000 description 6
- 108010064733 Angiotensins Proteins 0.000 description 6
- 229940030600 antihypertensive agent Drugs 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- RLPBLYOMUDFEBW-PWSUYJOCSA-N (4r)-3-[(2s)-3-benzoylsulfanyl-2-methylpropanoyl]-1,3-thiazolidine-4-carboxylic acid Chemical compound C([C@@H](C)C(=O)N1[C@@H](CSC1)C(O)=O)SC(=O)C1=CC=CC=C1 RLPBLYOMUDFEBW-PWSUYJOCSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229940126062 Compound A Drugs 0.000 description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000036584 pressor response Effects 0.000 description 4
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 3
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 3
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 3
- 230000003276 anti-hypertensive effect Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- XNWRFHDIFVKSNS-UHFFFAOYSA-N 2-(2-acetyloxyphenyl)-3-(3-acetylsulfanylpropanoyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound CC(=O)OC1=CC=CC=C1C1N(C(=O)CCSC(C)=O)C(C(O)=O)CS1 XNWRFHDIFVKSNS-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000010171 animal model Methods 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
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- 230000005923 long-lasting effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229950001139 timonacic Drugs 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- VQEZDLXEVJCRMO-UHFFFAOYSA-N 1-chloroethyl 2,2-dimethylpropanoate Chemical compound CC(Cl)OC(=O)C(C)(C)C VQEZDLXEVJCRMO-UHFFFAOYSA-N 0.000 description 1
- GPBXPZUMIAJSMY-ZBFHGGJFSA-N 2,2-dimethylpropanoyloxymethyl (4r)-3-[(2s)-3-benzoylsulfanyl-2-methylpropanoyl]-1,3-thiazolidine-4-carboxylate Chemical compound C([C@@H](C)C(=O)N1[C@@H](CSC1)C(=O)OCOC(=O)C(C)(C)C)SC(=O)C1=CC=CC=C1 GPBXPZUMIAJSMY-ZBFHGGJFSA-N 0.000 description 1
- UUSLLECLCKTJQF-UHFFFAOYSA-N 2-(bromomethyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CBr)C(=O)C2=C1 UUSLLECLCKTJQF-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 206010005746 Blood pressure fluctuation Diseases 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000725101 Clea Species 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229960004064 bumetanide Drugs 0.000 description 1
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- ACGDKVXYNVEAGU-UHFFFAOYSA-N guanethidine Chemical compound NC(N)=NCCN1CCCCCCC1 ACGDKVXYNVEAGU-UHFFFAOYSA-N 0.000 description 1
- 229960003602 guanethidine Drugs 0.000 description 1
- 229960002474 hydralazine Drugs 0.000 description 1
- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 1
- 229960003313 hydroflumethiazide Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000005462 imide group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical group O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
【発明の詳細な説明】
本発明は一般式
〔式中、R1は水素原子、低級または高級アル
キル基、シクロアルキル基、アラルキル基、フエ
ニル基、フリル基、チエニル基、ピリジル基若し
くはナフチル基を示す。夫々の基は低級アルキル
基、ヒドロキシ基、メルカプト基、低級アルコキ
シ基、低級アルキレンジオキシ基、アシルオキシ
基、アシルメルカプト基、ハロゲン原子、ニトロ
基、アミノ基、低級アルキル置換アミノ基、アシ
ルアミノ基、カルボキシ基で置換されていてもよ
い。R2は水素原子、低級アルキル基、アラルキ
ル基またはR4CO―を示し、R4はR1に示す基のう
ち水素原子以外の基を示す。R3はアシロキシ低
級アルキル基またはイミド基と結合している低級
アルキル基を示す。Ａは１〜３個の炭素原子を有
する直鎖または分枝のアルキレンを示す。尚式
〔〕に示される化合物のR1における低級アルキ
ル基、高級アルキル基、シクロアルキル基、アラ
ルキル基、フエニル基、フリル基、チエニル基、
ピリジル基およびナフチル基の夫々の基はヒドロ
キシ低級アルキル基で置換されていてもよい。ま
た、R1はベンゾフリル基、ベンゾチエニル基、
イミダゾリル基およびインドリル基のいずれかで
あつてよく、夫々の基は低級アルキル基、ヒドロ
キシ基、ヒドロキシ低級アルキル基、メルカプト
基、低級アルコキシ基、低級アルキレンジオキシ
基、アシルオキシ基、アシルメルカプト基、ハロ
ゲン原子、ニトロ基、アミノ基、アルキル置換ア
ミノ基、アシルアミノ基、カルボキシ基で置換さ
れていてもよい。低級アルキル基またはアルキレ
ン基とは炭素原子１〜６個を有する飽和または不
飽和の直鎖若しくは分枝のものをいい、高級アル
キル基とは炭素原子７〜20個を有する飽和または
不飽和の直鎖若しくは分枝のものをいい、またア
シル基としては例えばアセチル基、ヒバロイル
基、非置換または置換ベンゾイル基、ベンジルオ
キシカルボニル基が挙げられ、アラルキル基とし
ては例えばベンジル基が挙げられ、イミド基とし
てはフタルイミド基、グルタルイミド基、サクシ
ニルイミド基が挙げられる。以下の説明において
はこれらの全ての基を含むものとする。以下同
じ。〕で表わされるチアゾリジン誘導体、ピロリ
ジン誘導体およびそれらの塩類、ならびにこれら
の化合物からなる血圧降下剤として有用なもので
ある。[Detailed Description of the Invention] The present invention relates to the general formula [In the formula, R 1 represents a hydrogen atom, a lower or higher alkyl group, a cycloalkyl group, an aralkyl group, a phenyl group, a furyl group, a thienyl group, a pyridyl group, or a naphthyl group. Each group is a lower alkyl group, hydroxy group, mercapto group, lower alkoxy group, lower alkylene dioxy group, acyloxy group, acylmercapto group, halogen atom, nitro group, amino group, lower alkyl-substituted amino group, acylamino group, carboxy It may be substituted with a group. R 2 represents a hydrogen atom, a lower alkyl group, an aralkyl group, or R 4 CO—, and R 4 represents a group other than a hydrogen atom among the groups represented by R 1 . R 3 represents an acyloxy lower alkyl group or a lower alkyl group bonded to an imido group. A represents straight-chain or branched alkylene having 1 to 3 carbon atoms. A lower alkyl group, a higher alkyl group, a cycloalkyl group, an aralkyl group, a phenyl group, a furyl group, a thienyl group in R 1 of the compound represented by the formula [],
Each of the pyridyl group and naphthyl group may be substituted with a hydroxy lower alkyl group. In addition, R 1 is a benzofuryl group, a benzothienyl group,
It may be either an imidazolyl group or an indolyl group, and each group may be a lower alkyl group, a hydroxy group, a hydroxy lower alkyl group, a mercapto group, a lower alkoxy group, a lower alkylene dioxy group, an acyloxy group, an acyl mercapto group, or a halogen group. It may be substituted with an atom, nitro group, amino group, alkyl-substituted amino group, acylamino group, or carboxy group. A lower alkyl group or an alkylene group refers to a saturated or unsaturated straight chain or branched group having 1 to 6 carbon atoms, and a higher alkyl group refers to a saturated or unsaturated straight chain group having 7 to 20 carbon atoms. It refers to a chain or branched group, and examples of the acyl group include an acetyl group, hivaloyl group, unsubstituted or substituted benzoyl group, and benzyloxycarbonyl group, examples of the aralkyl group include a benzyl group, and examples of the imide group include a benzyl group. Examples include a phthalimide group, a glutarimide group, and a succinylimide group. In the following description, all of these groups are included. same as below. The thiazolidine derivatives, pyrrolidine derivatives and salts thereof represented by the above formula are useful as antihypertensive agents comprising these compounds.
本発明化合物〔〕は、人または動物に投与さ
れたときに、酵素的およびまたは化学的に加水分
解され、高血圧症状に有効なアンジオテンシン変
換酵素阻害剤であるメルカプトアシルアミノ酸を
遊離するエステルである。このエステルは遊離酸
であるメルカプトアシルアミノ酸に比べて親油性
が増加することにより吸収特性を改善することが
でき、また持続時陥の延長を画ることもできる。 The compound of the present invention [ ] is an ester that is enzymatically and/or chemically hydrolyzed when administered to humans or animals to liberate mercaptoacylamino acid, which is an angiotensin-converting enzyme inhibitor effective in treating hypertension symptoms. This ester can improve absorption properties due to increased lipophilicity compared to the free acid mercaptoacylamino acid, and can also provide a longer duration.
本発明化合物は、例えば次のような方法で合成
される。一般式〔〕
で表わされる化合物と一般式〔〕
R3―Ｘ 〔〕
〔式中、Ｘはハロゲン原子を示す。〕で表わさ
れる化合物を反応させることにより本発明化合物
を得ることができる。 The compound of the present invention can be synthesized, for example, by the following method. General formula [] A compound represented by the general formula [] R 3 —X [] [wherein, X represents a halogen atom]. ] The compound of the present invention can be obtained by reacting the compound represented by the following.
尚本発明化合物〔〕は１個ないし複数の不整
炭素原子を有するので立体異性体が存在する。こ
れらはいずれも本発明化合物の範囲に包含され
る。以下に代表的な化合物について実施例を示す
が、本発明はこれらの実施例に限定されるもので
はなく血圧降下作用を有するすべてのメルカプト
アシルアミノ酸に適用されるものである。 Since the compound of the present invention [ ] has one or more asymmetric carbon atoms, stereoisomers exist. All of these are included within the scope of the compounds of the present invention. Examples of typical compounds are shown below, but the present invention is not limited to these examples and is applicable to all mercaptoacyl amino acids that have a blood pressure lowering effect.
実施例 １
（4R）―３―〔（2S）―Ｓ―ベンゾイル―３―
メルカプト―２―メチルプロパノイル〕―４―
チアゾリジンカルボン酸（１，３―ジヒドロ―
１，３―ジオキソ―2H―イソインドール―２
―イル）メチルエステルの製造
窒素雰囲気下、（4R）―３―〔（2S）―Ｓ―ベ
ンゾイル―３―メルカプト―２―メチルプロパノ
イル〕―４―チアゾリジンカルボン酸3.4ｇの無
水Ｎ，Ｎ―ジメチルホルムアミド11ml溶液に、ト
リエチルアミン1.4ml、Ｎ―プロモメチルフタル
イミド2.4ｇを加え、90℃で６時間撹拌する。反
応混合物を100mlの氷水の中に移し、エーテル抽
出する。有機層を飽和食塩水で洗浄後、硫酸マグ
ネシウムで脱水する。エーテルを減圧留去後、得
られた油状物をシリカゲルカラムクロマトで精製
し標記化合物4.5ｇ（収率90％）を得る。Example 1 (4R)-3-[(2S)-S-benzoyl-3-
Mercapto-2-methylpropanoyl]-4-
Thiazolidinecarboxylic acid (1,3-dihydro-
1,3-dioxo-2H-isoindole-2
Production of (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid 3.4 g of anhydrous N,N- under a nitrogen atmosphere Add 1.4 ml of triethylamine and 2.4 g of N-bromomethylphthalimide to 11 ml of dimethylformamide solution, and stir at 90°C for 6 hours. The reaction mixture is transferred into 100 ml of ice water and extracted with ether. The organic layer is washed with saturated brine and then dehydrated with magnesium sulfate. After distilling off the ether under reduced pressure, the resulting oil was purified by silica gel column chromatography to obtain 4.5 g (yield: 90%) of the title compound.
融点62〜64℃
〔α〕２５ Ｄ−89.7゜（ｃ＝0.7，メタノール）
IR（nujol，cm-1，以下特記なき限り同じ）
1784，1755，1725，1650，1456，1408，
1379，1205，915，728
NMR（クロロホルム―d1，δ，以下特記なき
限り同じ）
1.27（3H，ｄ，Ｊ＝６Hz），2.90（1H，
ｍ），3.16（2H，ｍ），3.18（2H，ｄ，Ｊ＝
5.3Hz），4.52，4.73（2H，ABq，Ｊ＝８
Hz），5.18（1H，ｔ，Ｊ＝5.3Hz），5.75
（2H，ｓ），7.30〜8.00（9H，ｍ）
実施例 ２
（4R）―３―〔（2S）―Ｓ―ベンゾイル―３―
メルカプト―２―メチルプロパノイル〕―４―
チアゾリジンカルボン酸２―（１，３―ジヒド
ロ―１，３―ジオキソ―2H―イソインドール
―２―イル）エチルエステルの製造
窒素雰囲気下、（4R）―３―〔（2S）―Ｓ―ベ
ンゾイル―３―メルカプト―２―メチルプロパノ
イル〕―４―チアゾリジンカルボン酸3.4ｍ無水
Ｎ，Ｎ―ジメチルホルムアミド11ml溶液に、トリ
エチルアミン1.4ml、Ｎ―（２―ブロモエチル）
フタルイミド2.6ｇを加え、90℃で６時間撹拌す
る。反応混合物を100mlの氷水の中に移し、エー
テル抽出する。有機層を飽和食塩水で洗浄後、硫
酸マグネシウムで脱水する。エーテルを減圧圧留
去し標記化合物4.7ｇ（収率92％）を得る。 Melting point 62-64℃ [α] 25 D −89.7゜ (c=0.7, methanol) IR (nujol, cm -1 , same below unless otherwise specified) 1784, 1755, 1725, 1650, 1456, 1408,
1379, 1205, 915, 728 NMR (Chloroform-d 1 , δ, the same below unless otherwise specified) 1.27 (3H, d, J = 6Hz), 2.90 (1H,
m), 3.16 (2H, m), 3.18 (2H, d, J=
5.3Hz), 4.52, 4.73 (2H, ABq, J=8
Hz), 5.18 (1H, t, J = 5.3Hz), 5.75
(2H, s), 7.30-8.00 (9H, m) Example 2 (4R)-3-[(2S)-S-benzoyl-3-
Mercapto-2-methylpropanoyl]-4-
Production of thiazolidinecarboxylic acid 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl ester Under nitrogen atmosphere, (4R)-3-[(2S)-S-benzoyl- To a solution of 3.4 m of 3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid in 11 ml of anhydrous N,N-dimethylformamide, 1.4 ml of triethylamine, N-(2-bromoethyl)
Add 2.6 g of phthalimide and stir at 90°C for 6 hours. The reaction mixture is transferred into 100 ml of ice water and extracted with ether. The organic layer is washed with saturated brine and then dehydrated with magnesium sulfate. The ether was distilled off under reduced pressure to obtain 4.7 g (yield 92%) of the title compound.
融点99〜100℃（エーテル）
〔α〕２５ Ｄ−131.6゜（ｃ＝0.9，メタノール）
IR 1772，1739，1707，1652，1628，1460，
1170，910，729
NMR 1.23（3H，ｄ，Ｊ＝６Hz），2.90（1H，
ｍ），3.17（ｍ，2H），3.20（2H，ｄ，Ｊ＝
5.3Hz），3.90（2H，ｔ，Ｊ＝5.2Hz），4.40
（2H，ｔ，Ｊ＝5.2Hz），4.47，4.70（2H，
ABq，Ｊ＝８Hz），5.03（1H，ｔ，Ｊ＝5.3
Hz），7.30〜8.00（9H，ｍ）
元素分析値C25H24N2O6S2として
計算値：Ｃ，58.58；Ｈ，4.72；Ｎ，5.47
実験値：Ｃ，58.70；Ｈ，4.64；Ｎ，5.41
実施例 ３
（4R）―３―〔（2S）―Ｓ―ベンゾイル―３―
メルカプト―２―メチルプロパノイル〕―４―
チアゾリジンカルボン酸（２，３―ジメチル―
１―オキソプロポキシ）メチルエステルの製造
窒素雰囲気下、（4R）―３―〔（2S）―Ｓ―ベ
ンゾイル―３―メルカプト―２―メチルプロパノ
イル〕―４―チアゾリジンカルボン酸3.4ｇの無
水Ｎ，Ｎ―ジメチルホルムアミド11ml溶液に、ト
リエチルアミン1.4ml、クロロメチルピバレート
1.5ｇを加え、90℃で６時間撹拌する。実施例１
と同様に操作し標記化合物4.1ｇ（収率91％）を
得る。 Melting point 99-100℃ (ether) [α] 25 D -131.6゜ (c=0.9, methanol) IR 1772, 1739, 1707, 1652, 1628, 1460,
1170, 910, 729 NMR 1.23 (3H, d, J = 6Hz), 2.90 (1H,
m), 3.17 (m, 2H), 3.20 (2H, d, J=
5.3Hz), 3.90 (2H, t, J = 5.2Hz), 4.40
(2H, t, J=5.2Hz), 4.47, 4.70 (2H,
ABq, J = 8Hz), 5.03 (1H, t, J = 5.3
Hz), 7.30~8.00 (9H, m) Elemental analysis value C 25 H 24 N 2 O 6 S 2 Calculated value: C, 58.58; H, 4.72; N, 5.47 Experimental value: C, 58.70; H, 4.64; N, 5.41 Example 3 (4R)-3- [(2S)-S-benzoyl-3-
Mercapto-2-methylpropanoyl]-4-
Thiazolidinecarboxylic acid (2,3-dimethyl-
Production of 1-oxopropoxy) methyl ester Under a nitrogen atmosphere, 3.4 g of (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid anhydrous N, 11 ml of N-dimethylformamide solution, 1.4 ml of triethylamine, chloromethyl pivalate
Add 1.5g and stir at 90°C for 6 hours. Example 1
Proceed in the same manner as above to obtain 4.1 g (yield 91%) of the title compound.
融点69〜69.5℃（ベンゼン―ｎ―ヘキサン）
〔α〕２５ Ｄ−153.8゜（ｃ＝1.0，メタノール）
IR 1770，1751，1655，1643，1457，1417，
1204，1102，990，912
NMR 1.18（9H，ｓ），1.30（3H，ｄ，Ｊ＝６
Hz），2.93（1H，ｍ），3.17（4H，ｍ），
4.50，4.77（2H，ABq，Ｊ＝８Hz），5.13
（1H，d.d，Ｊ＝5.6Hz），5.70，5.80（2H，
ABq，Ｊ＝６Hz），7.20〜8.07（5H，ｍ）
元素分析値C21H27NO6S2として
計算値：Ｃ，55.61；Ｈ，6.00；Ｎ，3.09
実験値：Ｃ，55.73；Ｈ，5.98；Ｎ，2.97
実施例 ４
（4R）―３―〔（2S）―Ｓ―ベンゾイル―３―
メルカプト―２―メチルプロパノイル〕―４―
チアゾリジンカルボン酸１―（２，２―ジメチ
ル―１―オキソプロポキシ）エチルエステルの
製造
窒素雰囲気下、（4R）―３―〔（2S）―Ｓ―ベ
ンゾイル―３―メルカプト―２―メチルプロパノ
イル〕―４―チアゾリジンカルボン酸3.4ｇの無
水Ｎ，Ｎ―ジメチルホルムアミド11ml溶液に、ト
リエチルアミン1.4ml、１―クロロエチルピバレ
ート1.7ｇを加え、90℃で６時間撹拌する。実施
例１と同様に操作し標記化合物4.1ｇ（収率88
％）を得る。 Melting point 69-69.5°C (benzene-n-hexane) [α] 25 D -153.8° (c=1.0, methanol) IR 1770, 1751, 1655, 1643, 1457, 1417,
1204, 1102, 990, 912 NMR 1.18 (9H, s), 1.30 (3H, d, J=6
Hz), 2.93 (1H, m), 3.17 (4H, m),
4.50, 4.77 (2H, ABq, J=8Hz), 5.13
(1H, dd, J=5.6Hz), 5.70, 5.80 (2H,
ABq, J=6Hz), 7.20~8.07 (5H, m) Elemental analysis value C 21 H 27 NO 6 S 2 Calculated value: C, 55.61; H, 6.00; N, 3.09 Experimental value: C, 55.73; H, 5.98; N, 2.97 Example 4 (4R)-3-[(2S)-S-benzoyl-3-
Mercapto-2-methylpropanoyl]-4-
Production of thiazolidinecarboxylic acid 1-(2,2-dimethyl-1-oxopropoxy)ethyl ester Under nitrogen atmosphere, (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl] To a solution of 3.4 g of -4-thiazolidinecarboxylic acid in 11 ml of anhydrous N,N-dimethylformamide, add 1.4 ml of triethylamine and 1.7 g of 1-chloroethyl pivalate, and stir at 90°C for 6 hours. The procedure was carried out in the same manner as in Example 1 to obtain 4.1 g of the title compound (yield: 88
%).
〔α〕２５ Ｄ−106.9゜（ｃ＝1.3，メタノール）
IR（neat，cm-1） 1757，1740，1662，1652，
1416，1207，1070，915
NMR 1.18（9H，ｓ），1.30，1.38（3H，共に
ｄ，Ｊ＝６Hz），1.47，1.50（3H，共にｄ，
Ｊ＝６Hz），3.00（1H，ｍ），3.23，3.25
（2H，共にｄ，Ｊ＝5.3Hz），3.28（2H，
ｍ），4.50，4.77，4.53，4.78（2H，共に
ABq，Ｊ＝８Hz），6.82（1H，ｑ，Ｊ＝６
Hz），7.20〜8.10（5H，ｍ）
実施例 ５
（4R）―２―（２―アセトキシフエニル）―３
―（Ｓ―アセチル―３―メルカプトプロパノイ
ル）―４―チアゾリジンカルボン酸（２，２―
ジメチル―１―オキソプロポキシ）メチルエス
テルの製造
窒素雰囲気下、（4R）―２―（２―アセトキシ
フエニル）―３―（Ｓ―アセチル―３―メルカプ
トプロパノイル）―４―チアゾリジンカルボン酸
4.0ｇの無水Ｎ，Ｎ―ジメチルホルムアミド13ml
溶液にトリエチルアミン1.4ml、クロロメチルピ
バレート1.5ｇを加え、90℃で６時間撹拌する。
実施例１と同様に操作し標記化合物4.2ｇ（収率
82％）を得る。 [α] 25 D −106.9° (c=1.3, methanol) IR (neat, cm -1 ) 1757, 1740, 1662, 1652,
1416, 1207, 1070, 915 NMR 1.18 (9H, s), 1.30, 1.38 (3H, both d, J = 6Hz), 1.47, 1.50 (3H, both d,
J=6Hz), 3.00 (1H, m), 3.23, 3.25
(2H, both d, J = 5.3Hz), 3.28 (2H,
m), 4.50, 4.77, 4.53, 4.78 (2H, both
ABq, J = 8Hz), 6.82 (1H, q, J = 6
Hz), 7.20 to 8.10 (5H, m) Example 5 (4R)-2-(2-acetoxyphenyl)-3
-(S-acetyl-3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid (2,2-
Production of dimethyl-1-oxopropoxy) methyl ester Under nitrogen atmosphere, (4R)-2-(2-acetoxyphenyl)-3-(S-acetyl-3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid
4.0g anhydrous N,N-dimethylformamide 13ml
Add 1.4 ml of triethylamine and 1.5 g of chloromethyl pivalate to the solution, and stir at 90°C for 6 hours.
The procedure was carried out in the same manner as in Example 1, yielding 4.2 g of the title compound (yield:
82%).
〔α〕２５ Ｄ＋83.0゜（ｃ＝0.7，メタノール）
IR（CHCl3，cm-1）1767，1680，1657，1404，
1172，1111，994
NMR 1.20（9H，ｓ），2.25（3H，ｓ），2.33
（3H，ｓ），2.47（2H，ｍ），3.13（4H，
ｍ），4.87（1H，ｄ，Ｊ＝6.9Hz），5.77，
5.93（2H，ABq，Ｊ＝９Hz），6.13（1H，
ｓ），7.20（3H，ｍ），8.00（1H，ｍ）
本発明化合物〔〕およびその塩類のうち代表
的な化合物について降圧剤として使用した場合の
薬理試験の結果を第１図に示す。第１図より明ら
かな如く本発明化合物は持続性ある有用な降圧作
用を示し安定性もすぐれていた。 [α] 25 D +83.0° (c=0.7, methanol) IR (CHCl 3 , cm -1 ) 1767, 1680, 1657, 1404,
1172, 1111, 994 NMR 1.20 (9H, s), 2.25 (3H, s), 2.33
(3H, s), 2.47 (2H, m), 3.13 (4H,
m), 4.87 (1H, d, J = 6.9Hz), 5.77,
5.93 (2H, ABq, J=9Hz), 6.13 (1H,
s), 7.20 (3H, m), 8.00 (1H, m) Figure 1 shows the results of pharmacological tests on representative compounds of the present invention and their salts when used as antihypertensive agents. As is clear from FIG. 1, the compound of the present invention exhibited a long-lasting and useful antihypertensive effect and had excellent stability.
薬理試験
アンジオテンシン変換酵素を阻害する化合物
は腎性高血圧のみならず、本態性高血圧の治療薬
となり得ることが最近明らかにされているので、
本発明化合物の血圧降下剤としての評価を下記の
如き方法で実施した。Pharmacological testing It has recently been revealed that compounds that inhibit angiotensin-converting enzyme can be used to treat not only renal hypertension but also essential hypertension.
The compounds of the present invention were evaluated as antihypertensive agents by the following method.
実験方法
動物は、ウイスター系雄性ラツト（体重200〜
300ｇ）を用いた。エーテル麻酔下で頚静脈にポ
リエチレンカニユーレを挿入し、頚静脈カニユー
レは電気血圧計に、頚静脈カニユーレは持続注入
装置に接続した。麻酔から完全に回復後、持続注
入装置を介してアンジオテンシン 300nｇ／
Kgを静脈内注入し、その時の血圧上昇変化をポリ
グラフ（日本光電、RM―150）にて記録した。
本発明化合物は0.5％トラガント液に懸濁し体重
100ｇ当り0.3mlの割合で経口投与してアンジオテ
ンシンを静脈内注入により生じる昇圧反応を経
時的に測定した。アンジオテンシン変換酵素阻
害活性はアンジオテンシン昇圧反応抑制率
（％）で表現した。Experimental method Animals were male Wistar rats (body weight 200~
300g) was used. A polyethylene cannula was inserted into the jugular vein under ether anesthesia, and the jugular cannula was connected to an electric blood pressure monitor and the jugular vein cannula to a continuous infusion device. After complete recovery from anesthesia, angiotensin 300ng/g was administered via a continuous infusion device.
Kg was injected intravenously, and the change in blood pressure at that time was recorded using a polygraph (Nihon Kohden, RM-150).
The compound of the present invention was suspended in 0.5% tragacanth solution and
Angiotensin was orally administered at a rate of 0.3 ml per 100 g, and the pressor response caused by intravenous infusion was measured over time. Angiotensin converting enzyme inhibitory activity was expressed as angiotensin pressor response inhibition rate (%).
実験結果
本発明化合物は公知の抗高血圧メルカプトアシ
ルアミノ酸と同様に無麻酔ラツトに経口投与する
ことによりアンジオテンシン昇圧反応を抑制し
たが、それはアンジオテンシン変換酵素を阻害す
る機序に由来するものである。本発明化合物はメ
ルカプトアシルアミノ酸の誘導体であり、これら
の化合物の等モル量を経口投与して、アンジオテ
ンシン昇圧反応抑制作用を比較した処、本発明
化合物は胃腸壁によく吸収され、徐々に開裂され
るため、より持続性を有し降圧剤としての利点が
認められた。Experimental Results Similar to known antihypertensive mercaptoacyl amino acids, the compound of the present invention suppressed angiotensin pressor response when orally administered to unanesthetized rats, and this was due to its mechanism of inhibiting angiotensin converting enzyme. The compounds of the present invention are derivatives of mercaptoacyl amino acids, and when equimolar amounts of these compounds were orally administered and their angiotensin pressor response inhibitory effects were compared, the compounds of the present invention were well absorbed into the gastrointestinal wall and were gradually cleaved. As a result, it has a longer-lasting effect and has an advantage as an antihypertensive agent.
安定性試験
メルカプトアシルアミノ酸とそのエステル化合
物のリン酸緩衝液（PH7.0）中での安定性を比較
した。Stability test The stability of mercaptoacyl amino acids and their ester compounds in phosphate buffer (PH7.0) was compared.
保存条件：室温、１ケ月
実験結果：エステル化合物はメルカプトアシル
アミノ酸に比し安定性が大であつた。 Storage conditions: room temperature, 1 month Experimental results: The ester compound was more stable than the mercaptoacylamino acid.
次に試験に使用した化合物を示す。 Next, the compounds used in the test are shown.
本発明化合物
化合物Ａ：（4R）―３―〔（2S）―Ｓ―ベンゾイ
ル―３―メルカプト―２―メチルプロパノイ
ル〕―４―チアゾリジンカルボン酸（２，２
―ジメチル―１―オキソプロポキシ）メチル
エステル
公知化合物
化合物Ｚ：（4R）―３―〔（2S）―Ｓ―ベンゾイ
ル―３―メルカプト―２―メチルプロパノイ
ル〕―４―チアゾリジンカルボン酸
毒性試験
本発明化合物Ａの急性毒性値LD50は約800mg／
Kgであり低毒性を示す。Compound A of the present invention: (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid (2,2
-Dimethyl-1-oxopropoxy)methyl ester known compound Compound Z: (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid toxicity test The present invention The acute toxicity value LD 50 of Compound A is approximately 800mg/
Kg and exhibits low toxicity.
実験動物
ddY―std.系（静岡実験動物育生）雄マウス
（４週令体重19〜21ｇ）を恒温恒湿（23±１℃，
55：５％）の飼育室で固型飼料（CE―２，日本
クレア製）および水を自由に与え１週間予備飼育
した中から順調な発育を示したものを使用した。Experimental animals ddY-std. strain (Shizuoka Laboratory Animal Breeding) male mice (4 weeks old, weight 19-21g) were kept at constant temperature and humidity (23±1℃,
The animals that showed good growth were used after being preliminarily reared for one week in a breeding room with a ratio of 55:5% (55:5%) and given free access to solid feed (CE-2, manufactured by CLEA Japan) and water.
投与法
試験薬物を0.5％トラガント溶液に４％の割合
で懸濁させ腹腔内投与した。Administration method The test drug was suspended in a 0.5% tragacanth solution at a ratio of 4% and administered intraperitoneally.
以上の薬理試験から明らかなように本発明化合
物〔〕は持続性を有する降圧剤として有用なも
のである。その場合、現在一般に行なわれている
ように、場合により利尿剤例えばヒドロフルメチ
アジド、フロセミドまたはブメタニドなどと組合
わせることができる。その投与形態としては経口
投与または非経口投与のいずれでもよく、錠剤、
カプセル剤、顆粒剤、散剤、坐剤、注射剤などが
治療用製剤として挙げられる。これらの製剤は、
特に高血圧の処置の際には通常の充てん剤のほか
に、更に抗高血圧剤たとえばレセルピン、α―メ
チルドーパ、グアネチジン、クロニジンまたはヒ
ドララジンなどを含有できる。また投与量は症
状、投与方法等により異なるが、通常１日１〜
5000mgであり好ましくは１日10〜1000mgを１回ま
たは数回に分けて投与することができる。 As is clear from the above pharmacological tests, the compound of the present invention [] is useful as a long-lasting antihypertensive agent. In that case, diuretics such as hydroflumethiazide, furosemide or bumetanide can optionally be combined, as is currently common practice. The dosage form may be oral or parenteral, and tablets,
Examples of therapeutic preparations include capsules, granules, powders, suppositories, and injections. These preparations are
Particularly in the treatment of hypertension, in addition to the usual fillers, antihypertensive agents such as reserpine, α-methyldopa, guanethidine, clonidine or hydralazine can also be included. The dosage varies depending on the symptoms, administration method, etc., but it is usually 1 to 1 day per day.
The dose is 5000 mg, preferably 10 to 1000 mg per day, which can be administered once or divided into several doses.
次に製剤についてその組成を例示する。 Next, the composition of the preparation will be illustrated.
(1) 内服用剤
錠剤
化合物Ａ 30mg
乳糖 150mg
結晶セルロース 50mg
カルボキシメチルセルロースカルシウム ７mg
ステアリン酸マグネシウム ３mg
計 240mg
本錠剤は通常行なわれているフイルムコーテイ
ングを行なつても差支えなく、更に糖衣を行なう
こともできる。(1) Oral tablet Compound A 30mg Lactose 150mg Crystalline cellulose 50mg Calcium carboxymethylcellulose 7mg Magnesium stearate 3mg Total 240mg This tablet can be coated with the usual film coating, and can also be coated with sugar. .
(2) 注射薬
化合物Ａ水溶液（PH6.5〜7.0）で１ml中に１〜
30mgを含む。(2) Injection: Compound A aqueous solution (PH6.5-7.0) at 1 to 1 mL
Contains 30mg.
第１図は本発明にかかる化合物および比較化合
物の時間の経過による降圧作用の変化を示すグラ
フである。図において縦軸の抑制率はアンジオテ
ンシンによる昇圧反応抑制率である。
FIG. 1 is a graph showing changes in the antihypertensive effects of the compounds according to the present invention and comparative compounds over time. In the figure, the inhibition rate on the vertical axis is the inhibition rate of the pressor reaction by angiotensin.
Claims (1)
キル基、シクロアルキル基、アラルキル基、フエ
ニル基、フリル基、チエニル基、ピリジン基若し
くはナフチル基を示す。夫々の基は低級アルキル
基、ヒドロキシ基、メルカプト基、低級アルコキ
シ基、低級アルキレンジオキシ基、アシルオキシ
基、アシルメルカプト基、ハロゲン原子、ニトロ
基、アミノ基、低級アルキル置換アミノ基、アシ
ルアミノ基、カルボキシ基で置換されていてもよ
い。R2は水素原子、低級アルキル基、アラルキ
ル基またはR4CO―を示し、R4はR1に示す基のう
ち水素原子以外の基を示す。R3はアシロキシ低
級アルキル基またはイミド基と結合している低級
アルキル基を示す。Ａは１〜３個の炭素原子を有
する直鎖または分枝のアルキレンを示す。〕 で表わされる化合物およびその塩類。 ２ 一般式 〔式中、R1は水素原子、低級または高級アル
キル基、シクロアルキル基、アラルキル基、フエ
ニル基、フリル基、チエニル基、ピリジル基若し
くはナフチル基を示す。夫々の基は低級アルキル
基、ヒドロキシ基、メルカプト基、低級アルコキ
シ基、低級アルキレンジオキシ基、アシルオキシ
基、アシルメルカプト基、ハロゲン原子、ニトロ
基、アミノ基、低級アルキル置換アミノ基、アシ
ルアミノ基、カルボキシ基で置換されていてもよ
い。R2は水素原子、低級アルキル基、アラルキ
ル基またはR4CO―を示し、R1はR4に示す基のう
ち水素原子以外の基を示す。R3はアシロキシ低
級アルキル基を示す。Ａは１〜３個の炭素原子を
有する直鎖または分枝のアルキレンを示す。〕で
表わされる化合物およびその塩類を主成分とする
血圧降下剤。[Claims] 1. General formula [In the formula, R 1 represents a hydrogen atom, a lower or higher alkyl group, a cycloalkyl group, an aralkyl group, a phenyl group, a furyl group, a thienyl group, a pyridine group, or a naphthyl group. Each group is a lower alkyl group, hydroxy group, mercapto group, lower alkoxy group, lower alkylene dioxy group, acyloxy group, acylmercapto group, halogen atom, nitro group, amino group, lower alkyl-substituted amino group, acylamino group, carboxy It may be substituted with a group. R 2 represents a hydrogen atom, a lower alkyl group, an aralkyl group, or R 4 CO—, and R 4 represents a group other than a hydrogen atom among the groups represented by R 1 . R 3 represents an acyloxy lower alkyl group or a lower alkyl group bonded to an imido group. A represents straight-chain or branched alkylene having 1 to 3 carbon atoms. ] Compounds represented by and salts thereof. 2 General formula [In the formula, R 1 represents a hydrogen atom, a lower or higher alkyl group, a cycloalkyl group, an aralkyl group, a phenyl group, a furyl group, a thienyl group, a pyridyl group, or a naphthyl group. Each group is a lower alkyl group, hydroxy group, mercapto group, lower alkoxy group, lower alkylene dioxy group, acyloxy group, acylmercapto group, halogen atom, nitro group, amino group, lower alkyl-substituted amino group, acylamino group, carboxy It may be substituted with a group. R 2 represents a hydrogen atom, a lower alkyl group, an aralkyl group, or R 4 CO—, and R 1 represents a group other than a hydrogen atom among the groups represented by R 4 . R 3 represents an acyloxy lower alkyl group. A represents straight-chain or branched alkylene having 1 to 3 carbon atoms. ] A hypotensive agent whose main ingredients are a compound represented by the following and its salts.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1881279A JPS55111481A (en) | 1979-02-19 | 1979-02-19 | Ester type hypotensive agent |
| US06/086,996 US4483861A (en) | 1978-10-31 | 1979-10-22 | Antihypertensive sulfur-containing compounds |
| GB7936988A GB2038800B (en) | 1978-10-31 | 1979-10-25 | Antihypertensive sulphurcontaining compounds |
| IT26923/79A IT1124841B (en) | 1978-10-31 | 1979-10-30 | COMPOUNDS CONTAINING SULFUR ANTI-HYPERTENSION |
| SE7908994A SE448541B (en) | 1978-10-31 | 1979-10-30 | NEW TIAZOLIDINE AND PYRROLIDINE DERIVATIVES AND A PHARMACEUTICAL PREPARATION THEREOF |
| CH977979A CH642351A5 (en) | 1978-10-31 | 1979-10-31 | Antihypertensive, SULPHUR CONTAINING COMPOUNDS, PROCESS FOR PRODUCING THE SAME AND CONTAINING THEM Pharmaceutical Compositions. |
| FR7926983A FR2440365A1 (en) | 1978-10-31 | 1979-10-31 | NOVEL MERCAPTO-AZOLIDINE-CARBOXYLIC ACID DERIVATIVES USEFUL AS HYPERTENSORS |
| DE19792944037 DE2944037A1 (en) | 1978-10-31 | 1979-10-31 | ANTI-HYPERTENSIVE SULFURING COMPOUNDS |
| US06/395,128 US4496578A (en) | 1978-10-31 | 1982-07-06 | Antihypertensive sulfur-containing compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1881279A JPS55111481A (en) | 1979-02-19 | 1979-02-19 | Ester type hypotensive agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55111481A JPS55111481A (en) | 1980-08-28 |
| JPS6141512B2 true JPS6141512B2 (en) | 1986-09-16 |
Family
ID=11981987
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1881279A Granted JPS55111481A (en) | 1978-10-31 | 1979-02-19 | Ester type hypotensive agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS55111481A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0331214U (en) * | 1989-08-07 | 1991-03-27 | ||
| US10845578B2 (en) | 2019-02-05 | 2020-11-24 | Panasonic Intellectual Property Management Co., Ltd. | Light source device and projection display apparatus |
-
1979
- 1979-02-19 JP JP1881279A patent/JPS55111481A/en active Granted
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0331214U (en) * | 1989-08-07 | 1991-03-27 | ||
| US10845578B2 (en) | 2019-02-05 | 2020-11-24 | Panasonic Intellectual Property Management Co., Ltd. | Light source device and projection display apparatus |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55111481A (en) | 1980-08-28 |
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