JPS6216943B2 - - Google Patents
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- Publication number
- JPS6216943B2 JPS6216943B2 JP53086683A JP8668378A JPS6216943B2 JP S6216943 B2 JPS6216943 B2 JP S6216943B2 JP 53086683 A JP53086683 A JP 53086683A JP 8668378 A JP8668378 A JP 8668378A JP S6216943 B2 JPS6216943 B2 JP S6216943B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- hydrogen
- compound according
- compound
- formula
- 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.)
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- 150000001875 compounds Chemical class 0.000 claims description 44
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 21
- -1 3-indolylmethyl Chemical group 0.000 claims description 15
- 125000001589 carboacyl group Chemical group 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000006301 indolyl methyl group Chemical group 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000000908 ammonium hydroxide Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- XGILAAMKEQUXLS-UHFFFAOYSA-N 3-(indol-3-yl)lactic acid Chemical compound C1=CC=C2C(CC(O)C(O)=O)=CNC2=C1 XGILAAMKEQUXLS-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 4
- UZEGMBFBQIDPHQ-UHFFFAOYSA-N (2-hydroxyacetyl) 3-acetylsulfanyl-2-methylpropanoate Chemical compound CC(=O)SCC(C)C(=O)OC(=O)CO UZEGMBFBQIDPHQ-UHFFFAOYSA-N 0.000 description 3
- PEOGPKAGXDGMIK-UHFFFAOYSA-N (2-hydroxyacetyl) 3-sulfanylpropanoate Chemical compound OCC(=O)OC(=O)CCS PEOGPKAGXDGMIK-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229940061720 alpha hydroxy acid Drugs 0.000 description 3
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 3
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VOXXWSYKYCBWHO-QMMMGPOBSA-N (S)-3-phenyllactic acid Chemical compound OC(=O)[C@@H](O)CC1=CC=CC=C1 VOXXWSYKYCBWHO-QMMMGPOBSA-N 0.000 description 2
- VFVHNRJEYQGRGE-UHFFFAOYSA-N 3-acetylsulfanyl-2-methylpropanoic acid Chemical compound OC(=O)C(C)CSC(C)=O VFVHNRJEYQGRGE-UHFFFAOYSA-N 0.000 description 2
- AYQXANXXZYKTDL-UHFFFAOYSA-N 3-acetylsulfanylpropanoic acid Chemical compound CC(=O)SCCC(O)=O AYQXANXXZYKTDL-UHFFFAOYSA-N 0.000 description 2
- VOXXWSYKYCBWHO-UHFFFAOYSA-N 3-phenyllactic acid Chemical compound OC(=O)C(O)CC1=CC=CC=C1 VOXXWSYKYCBWHO-UHFFFAOYSA-N 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 2
- 102000015427 Angiotensins Human genes 0.000 description 2
- 108010064733 Angiotensins Proteins 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- NWCHELUCVWSRRS-SECBINFHSA-N (2r)-2-hydroxy-2-phenylpropanoic acid Chemical compound OC(=O)[C@@](O)(C)C1=CC=CC=C1 NWCHELUCVWSRRS-SECBINFHSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 description 1
- XGILAAMKEQUXLS-JTQLQIEISA-N 3-(indol-3-yl) lactate Chemical compound C1=CC=C2C(C[C@H](O)C(O)=O)=CNC2=C1 XGILAAMKEQUXLS-JTQLQIEISA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 102000004881 Angiotensinogen Human genes 0.000 description 1
- 108090001067 Angiotensinogen Proteins 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- SZAWPEWXKVAYDZ-UHFFFAOYSA-N C(C)(=O)CCC(=S)OC(CO)=O Chemical compound C(C)(=O)CCC(=S)OC(CO)=O SZAWPEWXKVAYDZ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001419 dependent effect Effects 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
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000000295 fuel oil Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
- Medical Treatment And Welfare Office Work (AREA)
Description
【発明の詳細な説明】
本発明はメルカプトプロパン酸カルボキシメチ
ルエステル類ならびにその製法、更に詳しくは薬
理学的活性を有する新規メルカプトプロパン酸カ
ルボキシメチルエステル類およびその塩類ならび
にそれらの製法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to mercaptopropanoic acid carboxymethyl esters and processes for their production, and more particularly to novel mercaptopropanoic acid carboxymethyl esters and salts thereof having pharmacological activity, and processes for their production.
本発明のメルカプトプロパン酸カルボキシメチ
ルエステル類およびその塩類は血圧降下剤として
有用である。 The mercaptopropanoic acid carboxymethyl esters and salts thereof of the present invention are useful as antihypertensive agents.
本発明化合物はメルカプトプロパン酸カルボキ
シメチルエステル類およびその塩を包含する：
式〔〕中の各記号は本明細書を通じて下記の
意義を有する。 Compounds of the present invention include mercaptopropanoic acid carboxymethyl esters and salts thereof: Each symbol in formula [] has the following meaning throughout this specification.
Ｒは水素または低級アルカノイルを表わす。 R represents hydrogen or lower alkanoyl.
R1は水素または低級アルキルを表わす。 R 1 represents hydrogen or lower alkyl.
R2は水素、ベンジルまたはインドリルメチル
を表わす。 R 2 represents hydrogen, benzyl or indolylmethyl.
本明細書において、低級アルキルとは炭素数１
〜４の直鎖もしくは分枝状炭化水素基を意味し、
たとえばメチル、エチル、プロピル、イソプロピ
ル、ブチル、sec−ブチルを包含し、特にメチ
ル、エチルが好ましい。 In this specification, lower alkyl means carbon number 1.
~4 linear or branched hydrocarbon groups,
Examples include methyl, ethyl, propyl, isopropyl, butyl, and sec-butyl, with methyl and ethyl being particularly preferred.
低級アルカノイルとは炭素数２〜４のアシル基
を意味し、たとえばアセチル、プロピオニル、ブ
チリル、イソブチリルを包含し、特にアセチルが
好ましい。 Lower alkanoyl means an acyl group having 2 to 4 carbon atoms, and includes, for example, acetyl, propionyl, butyryl, and isobutyryl, with acetyl being particularly preferred.
本発明の化合物〔〕のうち、好ましいものは
Ｒが水素またはアセチル；R1が水素またはメチ
ル；R2が水素、ベンジルまたはインドリルメチ
ルである化合物である。 Among the compounds of the present invention, preferred are compounds in which R is hydrogen or acetyl; R 1 is hydrogen or methyl; and R 2 is hydrogen, benzyl or indolylmethyl.
本発明化合物〔〕は次の様にして製造するこ
とができる。すなわち常套のエステル化法に従つ
て式：
〔式中、R2は前記と同意義。〕
で示されるα−ヒドロキシ酸またはその反応性誘
導体を、式：
〔式中、ＲおよびR1は前記と同意義。〕
で示される酸でアシル化す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 produced as follows. That is, according to conventional esterification methods, the formula: [In the formula, R 2 has the same meaning as above. ] An α-hydroxy acid or a reactive derivative thereof represented by the formula: [In the formula, R and R 1 have the same meanings as above. ] The compound of the present invention [ ] can be obtained by acylation with the acid shown below.
この反応を好ましく行うには、酸〔〕とカル
ボジイミダゾールを反応させ式：
〔式中、ＲおよびR1は前記と同意義。〕
で示されるアシルイミダゾール中間体を形成せし
めることにより、酸〔〕を活性化する。この中
間体〔〕を単離することなく上記α−ヒドロキ
シ酸〔〕を作用させることにより本発明化合物
〔〕を得ることができる。また、Ｒが低級アル
カノイルである化合物〔〕を得た後、このアシ
ル誘導体〔〕をアンモニアまたは濃水酸化アン
モニウムと反応させることにより、Ｒが水素であ
る本発明化合物〔〕を得るのが好ましい。 To carry out this reaction preferably, acid [] and carbodiimidazole are reacted with the formula: [In the formula, R and R 1 have the same meanings as above. ] The acid [ ] is activated by forming an acylimidazole intermediate represented by the following. The compound of the present invention [] can be obtained by reacting with the above α-hydroxy acid [] without isolating this intermediate []. Further, after obtaining a compound [ ] in which R is lower alkanoyl, it is preferable to obtain a compound of the present invention [ ] in which R is hydrogen by reacting this acyl derivative [ ] with ammonia or concentrated ammonium hydroxide.
式〔〕中、星印を付した炭素原子は、R1お
よびR2が水素以外の場合に不斉炭素原子とな
る。不斉炭素原子を有する化合物〔〕はそのジ
アステレオマーまたはラセミ混合物として存在す
る。これら異性体も本発明の技術範囲に包含され
る。 In the formula [], the carbon atom marked with an asterisk becomes an asymmetric carbon atom when R 1 and R 2 are other than hydrogen. A compound [ ] having an asymmetric carbon atom exists as its diastereomer or racemic mixture. These isomers are also included within the technical scope of the present invention.
α−ヒドロキシ酸〔〕は周知であり、公知の
多くの方法で製造することができる。 α-Hydroxy acids [ ] are well known and can be produced by many known methods.
メルカプトプロパン酸〔〕は、米国特許第
4053651号（特許日：1977年10月11日）およびベ
ルギー国特許第851361号（特許日：1977年８月11
日）に開示された方法により製造することができ
る。たとえば、式：
R4−CO−SH 〔〕
〔式中、R4は低級アルキルを表わす。〕
で示されるチオ酸と式：
〔式中、R1は前記と同意義。〕
で示されるアクリル酸を反応させることにより、
Ｒがアルカノイルである化合物〔〕を得ること
ができる。 Mercaptopropanoic acid [ ] is disclosed in U.S. Patent No.
No. 4053651 (patent date: October 11, 1977) and Belgian patent No. 851361 (patent date: August 11, 1977)
It can be produced by the method disclosed in Japan. For example, the formula: R 4 -CO-SH [] [wherein R 4 represents lower alkyl]. ] Thioacid and formula: [In the formula, R 1 has the same meaning as above. ] By reacting acrylic acid shown by
Compounds [] in which R is alkanoyl can be obtained.
次いで上記化合物のR4−CO基を前述のように
アンモニアまたは濃水酸化アンモニウムで処理す
ることにより、Ｒが水素である化合物〔〕を得
ることができる。 Then, by treating the R 4 -CO group of the above compound with ammonia or concentrated ammonium hydroxide as described above, a compound [] in which R is hydrogen can be obtained.
上記R4−CO基を有する化合物（すなわちＲが
アルカノイルである化合物〔〕）と化合物
〔〕またはその反応性誘導体を反応させてＲが
アルカノイルである化合物〔〕を製し、これを
上記のようにアンモニアまたは濃水酸化アンモニ
ウムで処理してＲが水素である本発明化合物
〔〕を得ることもできる。 The above compound having an R 4 -CO group (i.e., the compound [] in which R is alkanoyl) is reacted with the compound [] or a reactive derivative thereof to produce a compound [] in which R is alkanoyl, and this is prepared as described above. The compound of the present invention in which R is hydrogen can also be obtained by treating with ammonia or concentrated ammonium hydroxide.
本発明化合物〔〕を無機酸または有機酸と反
応させて該カルボン酸の通常の（塩基性）塩を形
成させることができる。このような塩はアンモニ
ウム塩、アルカリ金属塩（たとえばナトリウム塩
およびカリウム塩）、アルカリ土類金属塩（たと
えばカルシウム塩およびマグネシウム塩）、有機
塩基との塩（たとえばジシクロヘキシルアミン
塩、ベンザチン塩、ヒドラバミン塩およびＮ−メ
チル−Ｄ−グルカミン塩）を包含する。本発明化
合物〔〕のうちあるものは、明確な融点を有す
る結晶性物質としては容易に得られないため、そ
の塩（必ずしも生理学的に受容される必要はな
い）として単離し、固定する。 The compound of the present invention [ ] can be reacted with an inorganic or organic acid to form a conventional (basic) salt of the carboxylic acid. Such salts include ammonium salts, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts), salts with organic bases (e.g. dicyclohexylamine salts, benzathine salts, hydrabamine salts). and N-methyl-D-glucamine salt). Some of the compounds of the present invention [] cannot be easily obtained as crystalline substances with a defined melting point, and therefore are isolated and fixed as salts thereof (which do not necessarily have to be physiologically acceptable).
本発明化合物〔〕はアンギオテンシン変換酵
素抑制剤であつて、血圧降下剤、特にレニン−ア
ンギオテンシン依存性高血圧を低下させるために
有用である。本発明のアンギオテンシン変換酵素
抑制剤〔〕またはその塩の１種もしくはそれ以
上の混合物から成る組成物を高血圧症の動物に投
与することにより、該活性化合物がレニン→アン
ギオテンシノーゲン→アンギオテンシン→アン
ギオテンシン変換系中に介在して高血圧症を軽
減ないし緩和する。 The compounds of the present invention [ ] are angiotensin-converting enzyme inhibitors and are useful as antihypertensive agents, particularly for reducing renin-angiotensin-dependent hypertension. By administering a composition comprising the angiotensin converting enzyme inhibitor of the present invention or a mixture of one or more salts thereof to a hypertensive animal, the active compound converts renin→angiotensinogen→angiotensin→angiotensin. It intervenes in the system and reduces or alleviates hypertension.
上昇した血圧を降下させるため、本発明の活性
化合物を約１〜1000mg／Kg／日、特に約10〜100
mg／Kg／日の投与基準に従つて製剤し、これを１
日１回、好ましくは２〜４回に分けて投与するの
が適当である。エンジエル（Engel）らが記載し
た動物モデル実験（プロシーデングス・オブ・
ザ・ソサエテイ・フオア・イクスペリメンタル・
バイオロジイ・アンド・メデイシン（Proc.Soc.
Exp.Biol.Med.）第143巻（1973年）483頁参照）
は有用な指針を与えるものである。 To lower elevated blood pressure, the active compounds of the invention may be administered at doses of about 1 to 1000 mg/Kg/day, especially about 10 to 100 mg/Kg/day.
It is formulated according to the dosage standards of mg/Kg/day, and
It is appropriate to administer once a day, preferably in 2 to 4 divided doses. Animal model experiments described by Engel et al.
The Society for Experimental
Biology and Medicine (Proc.Soc.
Exp. Biol. Med.) Volume 143 (1973) p. 483)
provides useful guidance.
本発明の活性化合物はこれを含有する組成物に
製剤して経口的に投与するのが好ましいが、皮
下、筋肉内、静脈内または腹腔内投与してもよ
い。活性化合物〔〕またはその塩もしくはこれ
らの混合物は経口投与のための錠剤、カプセル剤
またはエリキシル剤として製剤することができ
る。また活性化合物を非経口投与のための滅菌溶
液もしくは懸濁液として製剤してもよい。 The active compounds of the invention are preferably administered orally in compositions containing them, but may also be administered subcutaneously, intramuscularly, intravenously or intraperitoneally. The active compound or its salts or mixtures thereof can be formulated as tablets, capsules or elixirs for oral administration. The active compounds may also be formulated as sterile solutions or suspensions for parenteral administration.
本発明化合物〔〕またはその生理学的に許容
される塩もしくはこれらの混合物約20〜1000mg
を、生理学的に許容される媒体、担体、賦形剤、
結合剤、保存剤、安定剤、香味剤などに配合する
ことにより、薬剤学的に許容される通常の単位投
与剤型に製剤することができる。活性化合物の量
は前記投与基準の投与量を投与し得るように設計
しなければならない。 Approximately 20 to 1000 mg of the compound of the present invention [] or a physiologically acceptable salt thereof or a mixture thereof
a physiologically acceptable medium, carrier, excipient,
By incorporating binders, preservatives, stabilizers, flavoring agents, etc., it can be formulated into pharmaceutically acceptable conventional unit dosage forms. The amount of active compound must be designed so that the dosages specified above can be administered.
次に実施例を挙げて本発明の好ましい化合物の
製造法を具体的に詳述する。 Next, a method for producing a preferred compound of the present invention will be specifically described in detail with reference to Examples.
実施例 １
Ｏ−（３−アセチルチオプロパノイル）グリコ
ール酸の製造：−
乾燥テトラヒドロフラン20mlを室温で撹拌しな
がらこれに３−（アセチルチオ）プロパン酸2.96
ｇと１・1′−カルボニルジイミダゾール3.24ｇを
溶解する。20分後、グリコール酸1.52ｇとトリエ
チルアミン2.80mlの乾燥テトラヒドロフラン15ml
溶液を加え、混合物を室温で一夜放置する。減圧
下にテトラヒドロフランを留去し、粗残渣を酢酸
エチルに溶解し、IN酸塩で１回、水で３回洗浄
後、硫酸マグネシウムで乾燥し、生成物を減圧下
に濃縮乾涸してＯ−（３−アセチルチオプロパノ
イル）グリコール酸3.9ｇを得た。これをエーテ
ルに溶解し、ジシクロヘキシルアミンを加えて塩
を沈殿させ、ジシクロヘキシルアミン塩2.85ｇを
得た。融点150〜157℃。この塩を酢酸エチルに加
え、10％硫酸水素カリウム溶液を加えて処理し、
遊離酸1.5ｇを得た。Example 1 Preparation of O-(3-acetylthiopropanoyl)glycolic acid:- 2.96 mL of 3-(acetylthio)propanoic acid is added to 20 ml of dry tetrahydrofuran at room temperature with stirring.
g and 3.24 g of 1,1'-carbonyldiimidazole are dissolved. After 20 minutes, 15 ml of dry tetrahydrofuran with 1.52 g of glycolic acid and 2.80 ml of triethylamine.
Add the solution and leave the mixture at room temperature overnight. Tetrahydrofuran was distilled off under reduced pressure, the crude residue was dissolved in ethyl acetate, washed once with IN salt and three times with water, dried over magnesium sulfate, and the product was concentrated to dryness under reduced pressure to give O- 3.9 g of (3-acetylthiopropanoyl)glycolic acid was obtained. This was dissolved in ether and dicyclohexylamine was added to precipitate the salt to obtain 2.85 g of dicyclohexylamine salt. Melting point 150-157℃. This salt was added to ethyl acetate and treated with 10% potassium hydrogen sulfate solution,
1.5 g of free acid was obtained.
実施例 ２
Ｏ−（３−メルカプトプロパノイル）グリコー
ル酸の製造：−
アルゴン雰囲気下、Ｏ−（３−アセチルチオプ
ロパノイル）グリコール酸（実施例１の生成物）
を水７mlと濃水酸化アンモニウム７mlの冷溶液で
15分間処理する。これを冷やし、濃塩酸で酸性に
し、酢酸エチルで抽出し、Ｏ−（３−メルカプト
プロパノイル）グリコール酸1.2ｇを得た。
DEAEセフアデツクスA25（ポリデキストランア
ニオン交換樹脂）上、炭酸水素アンモニウムの直
線形向配液を溶離剤とし、生成物をクロマトグラ
フイ処理する。所望の分画（45〜70；254nｍに
おける紫外線吸収ピーク）を合して濃縮し、凍結
乾燥する。得られたＯ−（３−メルカプトプロパ
ノイル）グリコール酸アンモニウム塩を、ダウエ
ツクス50WX2カチオン交換樹脂で処理し、遊離
酸0.320ｇを得た。このＯ−（３−メルカプトプロ
パノイル）グリコール酸をエーテルに溶解し、ジ
シクロヘキシルアミンを添加して塩を沈殿させる
ことにより、そのジシクロヘキシルアミン塩を得
た。融点143〜144℃。Example 2 Preparation of O-(3-mercaptopropanoyl)glycolic acid: - O-(3-acetylthiopropanoyl)glycolic acid (product of Example 1) under argon atmosphere
in a cold solution of 7 ml of water and 7 ml of concentrated ammonium hydroxide.
Process for 15 minutes. This was cooled, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate to obtain 1.2 g of O-(3-mercaptopropanoyl)glycolic acid.
The product is chromatographed on DEAE Sephadex A25 (polydextran anion exchange resin) using a linearly directed solution of ammonium bicarbonate as eluent. The desired fractions (45-70; UV absorption peak at 254 nm) are combined, concentrated and lyophilized. The obtained O-(3-mercaptopropanoyl)glycolic acid ammonium salt was treated with Dowex 50WX2 cation exchange resin to obtain 0.320 g of free acid. The dicyclohexylamine salt was obtained by dissolving this O-(3-mercaptopropanoyl)glycolic acid in ether and adding dicyclohexylamine to precipitate the salt. Melting point 143-144℃.
実施例 ３
Ｏ−〔３−（アセチルチオ）−２−メチルプロパ
ノイル〕グリコール酸の製造：−
チオ酢酸50ｇとメタクリル酸40.7ｇの混合物を
蒸気浴上で１時間加熱した後、室温で18時間放置
する。メタクリル酸と完全に反応したことを
NMRスペクトル分析で確認した後、反応混合物
を減圧下に蒸留し、沸点128.5〜131℃（2.6mm
Hg）の分画を分離して所望の３−アセチルチオ
−２−メチルプロパン酸出発物質64ｇを得る。Example 3 Production of O-[3-(acetylthio)-2-methylpropanoyl]glycolic acid: - A mixture of 50 g of thioacetic acid and 40.7 g of methacrylic acid was heated on a steam bath for 1 hour and then left at room temperature for 18 hours. do. Completely reacted with methacrylic acid
After confirmation by NMR spectroscopy, the reaction mixture was distilled under reduced pressure with a boiling point of 128.5–131 °C (2.6 mm
Separation of the Hg) fraction yields 64 g of the desired 3-acetylthio-2-methylpropanoic acid starting material.
上記３−アセチルチオ−２−メチルプロパン酸
6.48ｇを乾燥テトラヒドロフラン40mlに溶解す
る。これに１・1′−カルボニルジイミダゾール
0.48ｇを加え、室温で30分間撹拌する。グリコー
ル酸6.08ｇとトリエチルアミン11.2mlおよび乾燥
テトラヒドロフラン60mlの混合物を加える。数分
後、溶液からグリコール酸イミダゾール塩が生成
し始める。室温で一夜放置してこの塩を生成せし
める。結晶性塩を過し、液を減圧下に濃縮乾
涸する。残渣を酢酸エチルに溶解し、1N塩酸で
１回、水で３回洗い、硫酸マグネシウムで乾燥
後、減圧下に濃縮乾涸する。この生成物をエーテ
ル／ヘキサンに溶解し、ジシクロヘキシルアミン
を添加することにより、生成物をそのジシクロヘ
キシルアミン塩に変換し、これをエーテルから再
結晶する。融点120〜122℃。次いでこの塩を酢酸
エチルに加え、10％硫酸水素カリウム溶液を添加
した後、エーテル／ヘキサンから結晶化してこの
塩を遊離酸に変換し、Ｏ−〔３−（アセチルチオ）
−２−メチルプロパノイル〕グリコール酸2.96ｇ
を得た。融点50〜51℃。 The above 3-acetylthio-2-methylpropanoic acid
Dissolve 6.48 g in 40 ml of dry tetrahydrofuran. In this, 1,1′-carbonyldiimidazole
Add 0.48g and stir at room temperature for 30 minutes. Add a mixture of 6.08 g glycolic acid, 11.2 ml triethylamine and 60 ml dry tetrahydrofuran. After a few minutes, the glycolic acid imidazole salt begins to form from the solution. This salt is allowed to form overnight at room temperature. The crystalline salts are filtered off and the liquid is concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, washed once with 1N hydrochloric acid and three times with water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The product is converted to its dicyclohexylamine salt by dissolving it in ether/hexane and adding dicyclohexylamine, which is recrystallized from ether. Melting point 120-122℃. This salt is then added to ethyl acetate and, after addition of 10% potassium hydrogen sulfate solution, the salt is converted to the free acid by crystallization from ether/hexane and O-[3-(acetylthio)
-2-methylpropanoyl]glycolic acid 2.96g
I got it. Melting point 50-51℃.
実施例 ４
Ｏ−（DL−３−メルカプト−２−メチルプロパ
ノイル）グリコール酸の製造：−
アルゴン雰囲気下、Ｏ−〔３−（アセチルチオ）
−２−メチルプロパノイル〕グリコール酸1.5ｇ
に、濃水酸化アンモニウム7.5mlと水7.5mlの冷溶
液を加え、混合物を室温で15分間放置する。これ
を濃塩酸で酸性にし、酢酸エチルで抽出して生成
物1.3ｇを得た。生成物をエーテ／ヘキサンに溶
解し、ジシクロヘキシルアミンを加えて生成物の
ジシクロヘキシルアミン塩（2.24ｇ）を沈殿させ
る。融点96〜98℃。この塩1.9ｇを酢酸エチルに
加え、10％硫酸水素カリウム溶液を加え、遊離Ｏ
−（DL−３−メルカプト−２−メチルプロパノイ
ル）グリコール酸0.9を得た。この重質油状生成
物をシリカゲル上、ベンゼン：酢酸（７：２）溶
離剤でクロマトグラフイ処理する。Ｒf＝0.49、
痕跡Ｒf＝0.22および0.57。Example 4 Production of O-(DL-3-mercapto-2-methylpropanoyl)glycolic acid: - Under argon atmosphere, O-[3-(acetylthio)
-2-methylpropanoyl]glycolic acid 1.5g
A cold solution of 7.5 ml of concentrated ammonium hydroxide and 7.5 ml of water is added to the mixture and the mixture is left at room temperature for 15 minutes. This was acidified with concentrated hydrochloric acid and extracted with ethyl acetate to obtain 1.3 g of product. The product is dissolved in ether/hexane and dicyclohexylamine is added to precipitate the dicyclohexylamine salt of the product (2.24 g). Melting point 96-98℃. Add 1.9 g of this salt to ethyl acetate and add 10% potassium hydrogen sulfate solution to release free O.
-(DL-3-mercapto-2-methylpropanoyl)glycolic acid 0.9 was obtained. The heavy oil product is chromatographed on silica gel with benzene:acetic acid (7:2) eluent. R f =0.49,
Trace R f =0.22 and 0.57.
実施例 ５
Ｏ−Ｌ−〔３−（アセチルチオ）プロパノイル〕
−３−フエニル乳酸の製造：−
乾燥テトラヒドロフラン10mlを撹拌しながらこ
れに３−（アセチルチオ）プロパン酸1.48ｇを加
える。これに１・1′−カルボニルジイミダゾール
1.62ｇを加え、混合物を室温で20分間撹拌する。
Ｌ−（−）−３−フエニル乳酸1.66ｇの乾燥テトラ
ヒドロフラン7.5mlとトリエチルアミン1.4ml溶液
を添加する。混合物を室温で一夜放置する。減圧
下にテトラヒドロフランを留去し、残渣を酢酸エ
チルに溶解し、IN塩酸で１回。水で３回洗浄
し、硫酸マグネシウム乾燥後、減圧下に濃縮乾涸
してＯ−Ｌ−〔３−（アセチルチオ）プロパノイ
ル〕−３−フエニル乳酸2.8ｇを得た。これをシリ
カゲルカラム上、ベンゼン：酢酸（７：１）で溶
離して精製し、生成物1.7ｇを得た。Example 5 O-L-[3-(acetylthio)propanoyl]
- Preparation of 3-phenyl lactic acid: - 1.48 g of 3-(acetylthio)propanoic acid is added to 10 ml of dry tetrahydrofuran with stirring. In this, 1,1′-carbonyldiimidazole
1.62 g are added and the mixture is stirred at room temperature for 20 minutes.
A solution of 1.66 g of L-(-)-3-phenyl lactic acid in 7.5 ml of dry tetrahydrofuran and 1.4 ml of triethylamine is added. Leave the mixture at room temperature overnight. Tetrahydrofuran was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and treated once with IN hydrochloric acid. The mixture was washed three times with water, dried with magnesium sulfate, and concentrated to dryness under reduced pressure to obtain 2.8 g of O-L-[3-(acetylthio)propanoyl]-3-phenyl lactic acid. This was purified on a silica gel column eluting with benzene:acetic acid (7:1) to yield 1.7 g of product.
実施例 ６
Ｏ−Ｌ−（３−メルカプトプロパノイル）−３−
フエニル乳酸の製造：−
アルゴン雰囲気下、Ｏ−Ｌ−〔３−（アセチルチ
オ）プロパノイル〕−３−フエニル乳酸1.5ｇに水
7.5mlと濃水酸化アンモニウム7.5mlの溶液を加え
る。15分後、反応混合物を冷やし、濃塩酸で酸性
にし、酢酸エチルで抽出して生成物1.1ｇを得
る。これをシリカゲルカラム上、ベンゼン：酢酸
（14：１）で溶離して精製し、Ｏ−Ｌ−（３−メル
カプトプロパノイル）−３−フエニル乳酸0.357ｇ
を得た。この半固状生成物の一部をエーテル／ヘ
キサンに溶解し、ジシクロヘキシルアミンで沈殿
を形成させることにより生成物のジシクロヘキシ
ルアミン塩を得た。融点100℃。Example 6 O-L-(3-mercaptopropanoyl)-3-
Production of phenyl lactic acid: - Under argon atmosphere, add water to 1.5 g of O-L-[3-(acetylthio)propanoyl]-3-phenyl lactic acid.
Add 7.5 ml and 7.5 ml of concentrated ammonium hydroxide solution. After 15 minutes, the reaction mixture is cooled, acidified with concentrated hydrochloric acid and extracted with ethyl acetate to yield 1.1 g of product. This was purified on a silica gel column, eluting with benzene:acetic acid (14:1), and 0.357 g of O-L-(3-mercaptopropanoyl)-3-phenyl lactic acid was purified.
I got it. The dicyclohexylamine salt of the product was obtained by dissolving a portion of this semi-solid product in ether/hexane and forming a precipitate with dicyclohexylamine. Melting point 100℃.
実施例 ７
Ｏ−DL−（３−アセチルチオプロパノイル）−
３−インドール乳酸の製造：−
実施例５の処理におけるＬ−β−フエニル乳酸
の代りにDL−３−インドール乳酸を用い、同様
に処理してＯ−DL−（３−アセチルチオプロパノ
イル）−３−インドール乳酸を得た。Example 7 O-DL-(3-acetylthiopropanoyl)-
Production of 3-indole lactic acid: - Using DL-3-indole lactic acid in place of L-β-phenyl lactic acid in the treatment of Example 5, the same treatment was performed to obtain O-DL-(3-acetylthiopropanoyl)- 3-indole lactic acid was obtained.
実施例 ８
Ｏ−DL−（３−メルカプトプロパノイル）−３
−インドール乳酸の製造：−
実施例６の処理におけるＯ−Ｌ−（３−アセチ
ルチオプロパノイル）−３−フエニル乳酸の代り
にＯ−DL−（３−アセチルチオプロパノイル）−
３−インドール乳酸を用い、同様に処理してＯ−
DL−（３−メルカプトプロパノイル）−３−イン
ドール乳酸をそのジシクロヘキシルアミン塩とし
て得た。融点151〜153℃。Example 8 O-DL-(3-mercaptopropanoyl)-3
- Production of indole lactic acid: - O-DL-(3-acetylthiopropanoyl)- instead of O-L-(3-acetylthiopropanoyl)-3-phenyl lactic acid in the treatment of Example 6
Using 3-indole lactic acid, O-
DL-(3-mercaptopropanoyl)-3-indole lactic acid was obtained as its dicyclohexylamine salt. Melting point 151-153℃.
Claims (1)
水素または低級アルキル；R2は水素、ベンジル
またはインドリルメチルを表わす］。 ２ Ｒが水素である特許請求の範囲第１項記載の
化合物。 ３ Ｒが低級アルカノイルである特許請求の範囲
第１項記載の化合物。 ４ Ｒがアセチルである特許請求の範囲第１項記
載の化合物。 ５ R1およびR2がそれぞれ水素である特許請求
の範囲第１項記載の化合物。 ６ Ｒが低級アルカノイル；R1が低級アルキ
ル；R2が水素である特許請求の範囲第１項記載
の化合物。 ７ 低級アルカノイルがアセチル；低級アルキル
がメチルである特許請求の範囲第６項記載の化合
物。 ８ ＲおよびR2がそれぞれ水素；R1がメチルで
ある特許請求の範囲第１項記載の化合物。 ９ ＲおよびR1がそれぞれ水素；R2がベンジル
である特許請求の範囲第１項記載の化合物。 １０ Ｌ−異性体形を有する特許請求の範囲第１
項記載の化合物。 １１ R2がインドリルメチルである特許請求の
範囲第１項記載の化合物。 １２ ＲおよびR1がそれぞれ水素；R2が３−イ
ンドリルメチルである特許請求の範囲第１項記載
の化合物。 １３ Ｒが水素；R1がメチル；R2が３−インド
リルメチルである特許請求の範囲第１項記載の化
合物。 １４ 式： で示される化合物またはその反応性誘導体と 式： で示される化合物もしくはその反応性誘導体を反
応させて 式： で示される化合物を得ることを特徴とするメルカ
プトプロパン酸カルボキシメチルエステル類およ
びその塩類の製法。 ［式中、Ｒは水素または低級アルカノイル；R1は
水素または低級アルキル；R2は水素、ベンジル
またはインドリルメチルを表わす］。[Claims] 1 Formula: Compounds represented by and their salts. [wherein R represents hydrogen or lower alkanoyl; R 1 represents hydrogen or lower alkyl; R 2 represents hydrogen, benzyl or indolylmethyl]. 2. The compound according to claim 1, wherein R is hydrogen. 3. The compound according to claim 1, wherein R is lower alkanoyl. 4. The compound according to claim 1, wherein R is acetyl. 5. The compound according to claim 1, wherein R 1 and R 2 are each hydrogen. 6. The compound according to claim 1, wherein R is lower alkanoyl; R 1 is lower alkyl; R 2 is hydrogen. 7. The compound according to claim 6, wherein the lower alkanoyl is acetyl; the lower alkyl is methyl. 8. The compound according to claim 1, wherein R and R 2 are each hydrogen; R 1 is methyl. 9. The compound according to claim 1, wherein R and R 1 are each hydrogen; R 2 is benzyl. 10 Claim 1 with L-isomeric form
Compounds described in Section. 11. The compound according to claim 1, wherein R 2 is indolylmethyl. 12. The compound according to claim 1, wherein R and R 1 are each hydrogen; R 2 is 3-indolylmethyl. 13. The compound according to claim 1, wherein R is hydrogen; R 1 is methyl; R 2 is 3-indolylmethyl. 14 Formula: A compound of the formula or its reactive derivative and the formula: By reacting a compound represented by the formula or a reactive derivative thereof, the formula: A method for producing mercaptopropanoic acid carboxymethyl esters and salts thereof, which is characterized by obtaining a compound represented by: [wherein R represents hydrogen or lower alkanoyl; R 1 represents hydrogen or lower alkyl; R 2 represents hydrogen, benzyl or indolylmethyl].
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81547277A | 1977-07-14 | 1977-07-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5419914A JPS5419914A (en) | 1979-02-15 |
| JPS6216943B2 true JPS6216943B2 (en) | 1987-04-15 |
Family
ID=25217891
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8668378A Granted JPS5419914A (en) | 1977-07-14 | 1978-07-14 | Mercaptopropanate carboxymethylesters and process for preparing same |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS5419914A (en) |
| AU (1) | AU522452B2 (en) |
| BE (1) | BE869014A (en) |
| CA (1) | CA1090354A (en) |
| CH (1) | CH632490A5 (en) |
| DE (1) | DE2830635A1 (en) |
| DK (1) | DK149770C (en) |
| FR (1) | FR2397401A1 (en) |
| GB (1) | GB2001963B (en) |
| HU (1) | HU177904B (en) |
| IE (1) | IE47423B1 (en) |
| IT (1) | IT1105098B (en) |
| NL (1) | NL7807492A (en) |
| NO (1) | NO146024C (en) |
| SE (1) | SE7807821L (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0535042T3 (en) * | 1990-06-22 | 1995-07-24 | Fisons Plc | Inhibitors of angiotensin converting enzyme |
| JPWO2006016517A1 (en) * | 2004-08-13 | 2008-05-01 | 株式会社カネカ | Process for producing optically active 2-substituted oxy-3- (4-substituted oxyphenyl) propionic acid derivative |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1527919A (en) * | 1967-03-23 | 1968-06-07 | New derivatives of salicylic acid | |
| BE793887A (en) * | 1972-01-12 | 1973-07-11 | Hoffmann La Roche | ACYLUS DERIVATIVES |
-
1978
- 1978-06-27 CA CA306,339A patent/CA1090354A/en not_active Expired
- 1978-06-28 IE IE1296/78A patent/IE47423B1/en not_active IP Right Cessation
- 1978-06-29 AU AU37588/78A patent/AU522452B2/en not_active Expired
- 1978-07-05 GB GB7828882A patent/GB2001963B/en not_active Expired
- 1978-07-10 IT IT50235/78A patent/IT1105098B/en active
- 1978-07-11 CH CH753578A patent/CH632490A5/en not_active IP Right Cessation
- 1978-07-12 HU HU78SU980A patent/HU177904B/en unknown
- 1978-07-12 NL NL7807492A patent/NL7807492A/en not_active Application Discontinuation
- 1978-07-12 DE DE19782830635 patent/DE2830635A1/en active Granted
- 1978-07-13 FR FR7821086A patent/FR2397401A1/en active Granted
- 1978-07-13 SE SE7807821A patent/SE7807821L/en unknown
- 1978-07-13 NO NO782429A patent/NO146024C/en unknown
- 1978-07-13 DK DK315378A patent/DK149770C/en not_active IP Right Cessation
- 1978-07-14 BE BE189300A patent/BE869014A/en not_active IP Right Cessation
- 1978-07-14 JP JP8668378A patent/JPS5419914A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| FR2397401A1 (en) | 1979-02-09 |
| GB2001963A (en) | 1979-02-14 |
| IE47423B1 (en) | 1984-03-07 |
| DK149770B (en) | 1986-09-29 |
| IT1105098B (en) | 1985-10-28 |
| DE2830635C2 (en) | 1988-06-23 |
| IT7850235A0 (en) | 1978-07-10 |
| IE781296L (en) | 1979-01-14 |
| FR2397401B1 (en) | 1983-06-17 |
| NO146024C (en) | 1982-07-14 |
| NO782429L (en) | 1979-01-16 |
| CH632490A5 (en) | 1982-10-15 |
| NO146024B (en) | 1982-04-05 |
| NL7807492A (en) | 1979-01-16 |
| DE2830635A1 (en) | 1979-02-01 |
| SE7807821L (en) | 1979-01-15 |
| AU522452B2 (en) | 1982-06-10 |
| GB2001963B (en) | 1982-02-24 |
| DK315378A (en) | 1979-01-15 |
| CA1090354A (en) | 1980-11-25 |
| AU3758878A (en) | 1980-01-03 |
| JPS5419914A (en) | 1979-02-15 |
| BE869014A (en) | 1979-01-15 |
| DK149770C (en) | 1987-03-09 |
| HU177904B (en) | 1982-01-28 |
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