IE47423B1 - Esters of mercaptorpropanoic acids - Google Patents

Esters of mercaptorpropanoic acids

Info

Publication number
IE47423B1
IE47423B1 IE1296/78A IE129678A IE47423B1 IE 47423 B1 IE47423 B1 IE 47423B1 IE 1296/78 A IE1296/78 A IE 1296/78A IE 129678 A IE129678 A IE 129678A IE 47423 B1 IE47423 B1 IE 47423B1
Authority
IE
Ireland
Prior art keywords
compound
hydrogen
acid
lower alkyl
formula
Prior art date
Application number
IE1296/78A
Other versions
IE781296L (en
Original Assignee
Squibb & Sons Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Squibb & Sons Inc filed Critical Squibb & Sons Inc
Publication of IE781296L publication Critical patent/IE781296L/en
Publication of IE47423B1 publication Critical patent/IE47423B1/en

Links

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)

Abstract

Carboxymethyl esters and salts thereof, have the formula wherein R is hydrogen or lower alkanoyl; R1 is hydrogen, or lower alkyl; and R2 is hydrogen, lower alkyl, phenyl, phenyl-lower alkyl, 4- hydroxyphenyl-lower alkyl or indolyl- lower alkyl. They may be used as hypotensive agents.

Description

This invention relates to carboxymethyl esters of mercaptopropanoic acids which have the formula R-S-CH -CH-CO-O-CH-COOH 2 * * and to salts thereof. . 5 In formula I and throughout this specification the symbols have the meanings described below.
R is hydrogen or lower alkanoyl.
R^ is hydrogen or lower alkyl.
R2 is hydrogen, lower alkyl, phenyl, phenyl-lower 10 alkyl, 4-hydroxyphenyl-lower alkyl or indolyl-lower alkyl.
The lower alkyl groups are straight or branched chain hydrocarbon radicals having up to seven carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, sec.butyl. The C^-C^ and especially C^-C^ alkyl groups are preferred. The phenyl-lower alkyl and indolyl lower alkyl groups include lower alkyl groups of the same type (with the same preferences expressed above.) The lower alkanoyl groups are the acyl radicals of the lower (C2-C7) fatty acids, e.g., acetyl, propionyl, butyryl, 20 isobutyryl. The conpounds mentioned, and especially acetyl, are preferred.
Preferred members of the invention are those compounds of formula I wherein R is hydrogen or lower alkanoyl, especially acetyl; R^ is hydrogen or lower alkyl, especially - 2 _ * 47423 methyl; and ϊ?2 is hydrogen, phenyl-lower alkyl or indolyl lower alkyl especially phenylmethyl.
The compounds of formula I are produced by acylation of an α-hydroxy acid having the formula (ID *2 HO-CH-COOH with an acid having the formula (III) I1 R-S-CH2-CH-COOH by conventional esterification procedures.
A preferred method comprises activating the acid of formula III with carbodiimidazole to form the acylimidazole intermediate having the formula (IV) *1 ,_ R-S-C^-CH-CO-N^^ N which is used without isolation. It is also preferred to form a product wherein R is lower alkanoyl, then treat the acyl derivative with ammonia or concentrated ammonium hydroxide to obtain the product wherein R is hydrogen.
The carbon atoms marked with an asterisk in formula I are asymmetric if R^.and R2 are other than hydrogen. Thus the compounds with the asymmetric carbon exist as diastereoisomers or in racemic mixtures thereof. All of these are within the scope of the invention.
The α-hydroxy acids of formula II are well known in the literature and can be produced by the many methods available.
The mercaptopropanoic acids of formula III can be produced as described in U.S. Patent No. 4,053,651 - 3 47423 issued October 11, 1977 and Belgian Patent No. 851,361 granted August 11, 1977 e.g., by reacting a thioacid of the formula (VI) R -CO-SH 4 wherein R^ is lower alkyl, with an acrylic acid having the formula (VII) *1 CH2=C-COOH The R^-CO group can be removed at this stage or later by treatment with ammonia or concentrated ammonium hydroxide as described above.
The compounds of formula I form the common (basic) salts of carboxylic acids, e.g., by reaction with inorganic or organic bases. Such salts include ammonium salts, alkali metal salts e.g. sodium and potassium salts, alkaline earth metal e.g. calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine, benzathine, hydrabamine and N-methyl-D-glucamine salts. Since some of the compounds of formula I are not readily obtainable as crystalline substances with well defined melting points, the salts (which are not necessarily physiologically acceptable) provide means to isolate and characterize the product.
Additional experimental details can be found in the illustrative examples below.
Compounds of this invention are angiotensin converting enzyme inhibitors and may be used as hypotensive agents, particularly for the reduction of renin-angiotensin dependent hypertension. By administering a composition containing one or a combination of angiotensin converting - 4 47423 enzyme inhibitors of this invention to a hypertensive mammal, it intervenes in the renin + angiotensinogen + angiotensin I + angiotensin II sequence and the hypertension is reduced or alleviated.
A single dose, or preferably two to four divided daily doses, provided on a basis of about i to 1000 mg. per kilogram per day and especially about iq to 100 mg. per kilogram per day is appropriate to bring about a reduction in elevated blood pressure. The animal model experiments described by Engel et al., Proc. Soc. Exp. Biol. Med. 143, 483 (1973) provide a valuable guide.
The composition is preferably administered orally, but it can also be administered subcutaneously, intramuscularly, intravenously or intraperitoneally. The compound or compounds of formula I can be formulated as tablets, capsules or elixirs for oral administration. Sterile solutions or suspensions e.g. aqueous injectable preparations can be used for parenteral use. Thus the invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutical carrier.
About 20 to lOOO mg. of a compound or compounds of formula I or physiologically acceptable salt thereof can be compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a conventional unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance is selected so as to provide a dosage in the range indicated.
The following examples are illustrative of the invention and represent preferred embodiments. All temperatures are in degrees Celsius. - 5 47423 Example 1 0-(3-Acetylthiopropanoyl)glycolic Acid 3-(Acetylthio)propanoic acid (2.96 g.) and l,l'-carbonyldiimidazole (3.24 g.) are dissolved in 20 ml. of dry tetrahydrofuran with stirring at room temperature. After twenty minutes,a solution of glycolic acid (1.52 g., and 2.80 ml. of triethylamine in 15 ml. of dry tetrahydrofuran are added. .The reaction mixture is stored overnight at room temperature. The tetrahydrofuran is removed in vacuo, the crude residue taken up into ethyl acetate, washed with IN hydrochloric acid and three times with water, dried over magnesium sulfate and the 0-(3-acetylthiopropanoyl)glycolic acid is concentrated to dryness in vacuo, yield 3.9 g.
This is dissolved in ether and dicyclohexylamine is added.
The dicyclohexylamine salt precipitates, yield 2.85 g.; m.p. 150-157°. The salt is converted to the free acid by adding to ethyl acetate and adding 10% potassium bisulfate solution, yield 1.5 g.
Example 2 0-(3-Mercaptopropanoyl)glycolic Acid O-(3-acetylthiopropanoyl)glycolic acid from Example 1 (1.3 g,), under a blanket of argon is treated for fifteen minutes with a cold solution of 7 ml. of water and 7 ml. of concentrated ammonium hydroxide. This is chilled, acidified with concentrated hydrochloric acid and extracted into ethyl acetate, yield: 1.2 g. This product 0-(3-mercaptopropanoyl)Registered glycolic acid is chromatographed on DEAE Sephadex (Trade Mark) A25 (Polidextrane anion exchange resin) with a linear gradient of ammonium bicarbonate. The desired fractions (45-70; u.V. peak at 254 nm.) are pooled, concentrated and lyophilized. - 6 47423 This ammonium salt of 0-(3-mercaptopropanoyl)glycolic acid is converted to the free acid by treatment with Dowex 50WX2 cation exchange resin, yield 320 mg. The 0-(3-mercaptopropanoyl) glycolic acid is converted to the dicyclohexylamine salt by dissolving in ether and precipitating by the addition of dicyclohexylamine, m.p. 143-144°.
Example 3 0-[3-(Acetylthio)-2-Methylpropanoyl]Glycolic Acid A mixture of thioacetic acid (50 g.) and methacrylic acid (40.7 g.) is heated on the steam bath for one hour and then stored at room temperature for 18 hours. After confirming by nmr spectroscopy that complete reaction of the methacrylic acid has been achieved, the reaction mixture is distilled in vacuo and the desired 3-acetylthio-2-methyIpropanoic . o acid is separated m the fraction with boiling point 128.5-131 (2.6 mmHg.), yield 64 g. 3-Acetylthio-2-methyIpropanoic acid (6.48 g.) is taken into 40 ml. of dry tetrahydrofuran. To this 1,1'-carbonyldiimidazole (0.48 g.) is added and stirred for 30 minutes at room temperature. Glycolic acid (6.08 g.) and 11.2 ml. of triethylamine in 60 ml of dry tetrahydrofuran are added. After several minutes, the imidazole salt of glycolic acid begins to come out of solution. The reaction is permitted to run overnight at room temperature. The crystalline salt is filtered and the filtrate concentrated to dryness in vacuo. The residue is taken up into ethyl acetate, washed with IN hydrochloric acid and three times with water, dried over magnesium sulfate and concentrated to dryness in vacuo.
This product is converted to its dicycloehxylamine salt by dissolving in ether/hexane and precipitating by the addition - 7 47423 . of dicyclohexylamine. The salt is recrystallized from ether, m.p. 120-122°. This salt is then converted to the free acid, 0-[3-(acetylthio)-2-methylpropanoyl]glycolic acid, by adding to ethyl acetate, adding 10% potassium bisulfate solution, then crystallizing from ethyl/hexane, yield 2.96 g., m.p. 50-51°.
Example 4 0-(PL-3-Mercapto-2-Methylpropanoyl)Glycolic Acid O-[3-(Acetylthio)-2-methylpropanoyl]glycolic acid (1.5 g.) is placed under a blanket of argon. To this a cold solution of 7.5 ml. of concentrated ammonium hydroxide and 7.5 ml. of water is added and the mixture is stored for 15 minutes at room temperature. This is then acidified with concentrated hydrochloric acid and extracted with ethyl acetate, yield 1.3 g. This product is dissolved in ether/hexane and dicyclohexylamine is added to precipitate the dicyclohexylamine salt, yield 2.24 g., m.p. 96-98°.
A 1.9 g. aliquot of the salt is converted to the free 0-(DL-3-mercapto-2-methylpropanoyl)glycolic acid by adding to ethyl acetate and adding 10% potassium bisulfate solution, yield 0.9 g. The product is a heavy oil which is chromatographed on silica gel (benzene 7:2 acetic acid), Rf=0.49, traces Rf=0.32 and 0.57.
Example 5 0-L-[3-(Acetylthio)propanoyl]-3-Phenyllactic Acid 3-(Acetylthio)propanoic acid (1.48 g.) is added to ml- of dry tetrahydrofuran with stirring. To this 1,1'-carbonyldiimidazole (1.62 g.) is added And the mixture stirred for twenty minutes at room temperature. L-(-)3-phenyllactic acid (1.66 g.) is added in a solution of - 8 47423 7.5 ml. of dry tetrahydrofuran and 1.4 ml. of triethylamine. The reaction mixture is stored overnight at room temperature. The tetrahydrofuran is removed in vacuo, the residue is taken up into ethyl acetate, washed with IN hydrochloric acid, three times with water, dried over magnesium sulfate and concentrated to dryness in vacuo, yield 2.8 g. The O-L-[3-(Acetylthio)propanoyl]-3-phenyllactic acid is purified on a silica gel column,eluting with benzene 7:1 acetic acid, yield 1.7 g.
Example 6 O-L-(3-Mercaptopropanoyl)-3-Phenyllactic Acid T° 1.5 g. of O-L-[3-(acetylthio)propanoyl]-3-phenyllactic acid a solution of 7.5 ml. of water and 7.5 ml. of concentrated ammonium hydroxide is added under an argon blanket. After fifteen minutes, the reaction mixture is chilled, acidified with concentrated hydrochloric acid and extracted into ethyl acetate, yield 1.1 g. The product, O-L-(3-mercaptopropanoyl )-3-phenyllactic acid is purified on a silica gel column, eluting with benzene 14:1 acetic acid, yield 357 mg.
A small portion of the semi-solid product is converted to its dicyclohexylamine salt by dissolving in ether/hexane and precipitating with dicyclohexylamine, m.p. 100°.
Example 7 O-DL-(3-Acetylthiopropanoyl)-3-Indolelactic Acid By substituting DL-3-indolelactic acid for the L-0phenyllactic acid in the procedure of Example 5, O-DL(3-acetylthiopropanoyl)-3-indolelactic acid is obtained.
Example 8 O-DL-(3-Mercaptopropanoyl)-3-lndolelactic Acid By substituting O-DL-(3-acetylthiopropanoyl)-3- 9 47423 indolelactic acid for the 0-L-(3-acetylthiopropanoyl)-3-phenyllactic acid in the procedure of Example 6, O-DL-(3-mercaptopropanoyl)-3-indolelactic acid is obtained, as the dicyclohexylamine salt, m.p. 151-153°C.
Example 9 O-DL-(3-Mercapto-2-Methylpropanoyl)-3-Indolelactic Acid By substituting 3-indolelactic acid for the glycolic acid in the procedure of Example 3 and then submitting the product to the procedure of Example 4, O-DL-[3-(acetylthio)-2-methylpropanoyl]10 3-indolelactic acid and O-DL-(3-mercapto-2-methylpropanoyl)-3indolelactic acid are obtained.
Example 10 O-L-(3-Mercaptopropanoyl)lactic Acid By substituting L-lactic acid for the glycolic acid in the 15 procedure of Example 1 and then submitting the product to the procedure of Example 2, 0-L-(3-acetylthiopropanoyl)lactic acid and 0-L-(3-mercaptopropanoyl)lactic acid are obtained.
Example 11 0-L-(3-Mercaptopropanoyl)-α-Hydroxyisocaproic Acid 20 By substituting L-a-hydroxyisocaproic acid [Winitz, et al., J, Am. Chem. Soc. 78, 2423 (1956)] for the glycolic acid in the procedure of Example 1 and then submitting the product to the procedure of Example 2, 0-L-(3-acetylthiopropanoyl)-a-hydroxyisocaproic acid and 0-L-(3-mercaptopropanoyl)-a-hydroxyisocaproic acid are obtained.
Example 12 0-L-(3-Acetylthiopropanoyl)-3-(p-tert-butoxyphenyl)lactic Acid By substituting 3-(p-tert-butoxyphenyl)lactic acid [obtained from O-tert-butyl-L-tyrosine by the procedure described by H.D. Dakin and H.W. Dudley ’in J. Biol. Chem., 18, 29 (1914) for the preparation of 3-L-phenyllactic acid) - 10 47423 for the 3-L-phenyllactic acid in the procedure of Example 5, 0-L-(3-acetylthiopropanoyl)-3-(p-tert-butoxyphenyl)lactic acid is obtained.
Example 13 0-L-(3-Mercaptopropanoyl)-3-p-Hydroxyphenyllactic Acid 0-L-(3-acetylthiopropanoyl)-3-(p-tert-butoxyphenyl)lactic acid (1.8 g.) is dissolved in trifluoroacetic acid (15 ml.) and the solution is stored at room temperature for one hour. After removing the trifluoroacetic acid in vacuo, the residue is dissolved in a mixture of water (7.5 ml.) and concentrated ammonium hydroxide (7.5 ml.) under an argon blanket. After fifteen minutes, the reaction mixture is chilled, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is con15 centrated in vacuo to yield 0-L-(3-mercaptopropanoyl)-3p-hydroxyphenyllactic acid.
Example 14 0-(3-Mercaptopropanoyl)mandelic Acid By substituting mandelic acid for the L-3-phenyllactic acid in the procedure of Example 5, and then submitting the product to the procedure of Example 6, 0-(3-acetylthiopropanoyl Jmandelic acid and 0-(3-mercaptopropanoyl)mandelic acid are obtained.

Claims (23)

1. A compound of the formula R R I 1 I 2 R- S-CH 2 ~CH-CO-O-CH-COOH wherein R is hydrogen or lower alkanoyl; R^ is hydrogen or lower alkyl; R 2 is hydrogen, lower alkyl, phenyl, pheny1-lower alkyl, 4-hydroxyphenyllower alkyl or indolyl-lower alkyl; or such a compound in salt form.
2. A compound as in Claim 1 wherein R is hydrogen or lower alkanoyl; R^ is hydrogen or lower alkyl: and R 2 is hydrogen or phenyl-lower alkyl.
3.
4. A compound A compound as in as in Claim 1 or 2 wherein R is hydrogen, lower Claim 1 or 2 wherein. R is alkanoyl.
5. A compound as in Claim 1 or 2 wherein R is acetyl.
6. A compound as in Claim 1 wherein R, and R 2 each is hydrogen.
7. A compound as in Claim 1 wherein R is lower alkanoyl; R^ is lower alkyl; and R 2 is hydrogen.
8. A compound as in Claim 7 wherein the lower alkanoyl group is acetyl and the lower alkyl group is methyl.
9. A compound as in Claim 1 wherein R and R^ each is hydrogen and R^ is methyl.
10. A compound as in Claim 1 wherein R and R^ each is hydrogen and R^ is phenyl-lower alkyl.
11. A compound as in Claim 10 wherein the phenyl-lower alkyl group is phenylmethyl.
12. The L-form of the compound of Claim 11. - 12 47423
13. A compound as in Claim 1 wherein is indolyImethyl.
14. A compound as in Claim 1 wherein R and Rj each is hydrogen and R 2 is 3-indolylmethyl.
15. A compound as in Claim 1 wherein R is hydrogen, Rj is methyl and R 2 is 3-indolylmethyl.
16. A process for preparing a compound as claimed in claim 1 which comprises reacting an alpha-hydroxy acid of the formula ?2 HO—CH—COOH with an acid having the formula R, R-S-CH 2 -CH-COOH
17. A process for preparing a mercaptopropanoic acid carboxymethyl ester, substantially as herein described with reference to the Examples.
18. A compound whenever prepared by a process according to claim 16 or claim 17.
19. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 15, 17 or 18 and a pharmaceutical carrier.
20. A composition as claimed in claim 19, in the form of a tablet, capsule, elixir or sterile aqueous injectable preparation.
21. A composition as claimed in claim 19 or 20 comprising a binder , preservative, stabilizer, or flavor.
22. A composition as claimed in any one of claims 19 to 21 in a dosage unit containing 20 to 100 mg of said compound.
23. A compound as claimed in any one of claims - 13 47423 1 to 15, 17 and 18 for use in the treatment of hypertension in mammals.
IE1296/78A 1977-07-14 1978-06-28 Esters of mercaptorpropanoic acids IE47423B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US81547277A 1977-07-14 1977-07-14

Publications (2)

Publication Number Publication Date
IE781296L IE781296L (en) 1979-01-14
IE47423B1 true IE47423B1 (en) 1984-03-07

Family

ID=25217891

Family Applications (1)

Application Number Title Priority Date Filing Date
IE1296/78A IE47423B1 (en) 1977-07-14 1978-06-28 Esters of mercaptorpropanoic acids

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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE120453T1 (en) * 1990-06-22 1995-04-15 Fisons Plc INHIBITORS FOR ANGIOTENSIN CONVERTING ENZYMES.
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)

* Cited by examiner, † Cited by third party
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

Also Published As

Publication number Publication date
AU522452B2 (en) 1982-06-10
JPS5419914A (en) 1979-02-15
CA1090354A (en) 1980-11-25
NO146024B (en) 1982-04-05
AU3758878A (en) 1980-01-03
HU177904B (en) 1982-01-28
DK149770C (en) 1987-03-09
IE781296L (en) 1979-01-14
CH632490A5 (en) 1982-10-15
IT7850235A0 (en) 1978-07-10
BE869014A (en) 1979-01-15
NO782429L (en) 1979-01-16
JPS6216943B2 (en) 1987-04-15
NO146024C (en) 1982-07-14
FR2397401A1 (en) 1979-02-09
GB2001963A (en) 1979-02-14
DK149770B (en) 1986-09-29
SE7807821L (en) 1979-01-15
DE2830635A1 (en) 1979-02-01
IT1105098B (en) 1985-10-28
NL7807492A (en) 1979-01-16
GB2001963B (en) 1982-02-24
DE2830635C2 (en) 1988-06-23
FR2397401B1 (en) 1983-06-17
DK315378A (en) 1979-01-15

Similar Documents

Publication Publication Date Title
US4108886A (en) Thiopropanoylamino acid derivatives
DE2801911C2 (en)
FI67369B (en) FRUIT PROCESSING FOR THERAPEUTIC ACTIVATION THERAPEUTIC ACTIVE DERIVATIVES OF 3,4-DEHYDROPROLINE
FI68221B (en) FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA DEIVAT AV PROLIN OCH PIPEKOLINSYRA
US4086338A (en) N-carboxyalkanoyl derivatives of azetidine-2-carboxylic acid
KR100225299B1 (en) Pentanoic acid derivatives
JPS6121226B2 (en)
US4154937A (en) Hydroxycarbamoylalkylacylpipecolic acid compounds
WO1998018803A1 (en) Novel (alpha-aminophosphino) peptide derivatives, method for making same and therapeutic applications thereof
EP0004494B1 (en) Derivatives of 1,3-dihydro-3-(1-(2-(2,3-dihydro-1,4-benzodioxin-2-yl)2-hydroxyethyl)piperidin-4-yl)2h-indol-2-on, process for their preparation, their use as medicaments and pharmaceutical compositions containing them
CA1090354A (en) Carboxymethyl esters of mercaptopropanoic acids
US4611002A (en) Carboxymethyl esters of mercaptopropanoic acids as enkephalinase inhibitors
US4325886A (en) Optical resolution of acylthiopropionic acid
US4242265A (en) Indolylalkyl esters of mercaptoalkanoic acids
CS199693B2 (en) Process for preparing derivatives of thiazolidin-,thiazan- and morpholincarboxylic acids
US4198509A (en) Mercaptoacylpiperazine carboxylic acid compounds
US5037987A (en) Production of optical isomers of certain 1,6-naphthyridine-3-carboxylate derivatives
EP0467599B1 (en) N-Alkyl thiazolidine derivatives
JP3250806B2 (en) N- (mercaptoacyl) amino acids, processes for their preparation, their use in therapy and pharmaceutical compositions containing them
CA1109475A (en) Thiopropanoylamino acid derivatives
IE47075B1 (en) N-acylated thiazolidine, thiazane and morpholine carboxylic acids and esters
KR810000540B1 (en) Method for preparing tricycle compound
KR810000464B1 (en) Process for preparing thiazolidine carboxylic acids and related acides and salts thereof
JPS60204799A (en) Carboxyalkyldipeptide derivatives and manufacture
EP0432204A1 (en) Derivatives and precursors of captopril and its analogues

Legal Events

Date Code Title Description
MM4A Patent lapsed