EP0000035B1 - Alpha-amino-acides, compositions et procédé pour la préparation de ces composés - Google Patents

Alpha-amino-acides, compositions et procédé pour la préparation de ces composés Download PDF

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Publication number
EP0000035B1
EP0000035B1 EP78100058A EP78100058A EP0000035B1 EP 0000035 B1 EP0000035 B1 EP 0000035B1 EP 78100058 A EP78100058 A EP 78100058A EP 78100058 A EP78100058 A EP 78100058A EP 0000035 B1 EP0000035 B1 EP 0000035B1
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EP
European Patent Office
Prior art keywords
compounds
formula
compound
hydrogen
alkyl
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
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EP78100058A
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German (de)
English (en)
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EP0000035A1 (fr
Inventor
Arthur Allan Patchett
David Taub
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Merck and Co Inc
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Merck and Co Inc
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Application filed by Merck and Co Inc filed Critical Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention is concerned with ⁇ -ethynyl- and ⁇ -vinyl-3,4-disubstituted phenylalanines and especially the 3,4-dihydroxyphenylalanine species.
  • a-Methyl-3,4-dihydroxyphenylalanine is a known antihypertensive agent.
  • U.S. 2,868,818; U.S. 3,344,023 French patent 1850M discloses ⁇ -C 2 and higher alkyl-3,4-OR-phenylalanines.
  • the a-ethyl derivative has antihypertensive activity.
  • Novel a-ethynyl- and a-vinyl-3,4-disubstituted phenylalanines have been discovered. These novel alanines have pharmaceutical activity including antihypertensive action.
  • the present invention is embodied in ⁇ -ethynyl or ⁇ -vinyl phenylalanine compounds having the formula wherein
  • the pharmaceutically acceptable salts of the formula I compounds are also included. These salts generally are acid addition salts of suitable organic or inorganic acids. Preferred salts are the hydrohalides such as the hydrobromides, the hydrochlorides, the hydrogen iodides. Most preferred salts are the hydrochlorides.
  • the compounds of formula I have a chiral center and may occur in optically active forms, i.e., as optical isomers. These isomers are conventionally designated as D and L, d and I, + and -, (S) and (R) or by a combination of these symbols. Where the compound name or formula does not specify the isomer form, all forms are included, i.e., the individual isomers, mixtures thereof and racemates.
  • R may be H or a C 1 -C 18 alkyl group.
  • suitable alkyl groups are octadecyl, 2-ethylhexyl, lauryl, undecyl, methyl, isopropyl, hexyl and the like.
  • Preferred R groups are H and C 1 -C 6 alkyl. Most preferred R groups are H and ethyl.
  • R i and R 2 include H and C 2 -C . alkanoyl groups. Examples of suitable alkanoyl groups are acetyl, pivaloyl, 2-methylpropanoyl, butanoyl and the like. The most preferred RJR 2 substituent is hydrogen.
  • a preferred class of compounds of the present invention is that having the formula Especially preferred are formula II compounds where R is hydrogen or C 1 -C 6 alkyl, preferably ethyl.
  • the L-isomer form of the formula II compound is also more preferred.
  • Another preferred class of compounds of the present invention is that having the formula Especially preferred are the formula III compounds where R is hydrogen or C 1 -C 6 alkyl, preferably ethyl.
  • the L-isomer form of the formula III compounds are also more preferred.
  • the compounds of the present invention have pharmaceutical activity especially as antihypertensive agents.
  • the present compounds are useful for treating hypertension in humans.
  • the present compounds may be administered to the hypertensive patient orally, parenterally or via any other suitable administration route.
  • Conventional dosage forms are used such as tablets; troches, capsules, liquid formulations, e.g., solutions, dispersions, emulsions, elixirs and the like.
  • Conventional compounding ingredients i.e., diluents, carriers, etc. and conventional preparation procedures are utilized.
  • the daily dosage of the present compounds may be varied as required.
  • a daily dosage range for the hypertensive patient is about 50 mg. to about 5000 mg.
  • a preferred daily dosage range is about 100 mg. to about 3500 mg.
  • a more preferred daily dosage range is about 250 to about 1500 mg.
  • Compounds of the present invention may be prepared by any convenient process.
  • the hydrolysis is carried out using conventional reagents and conditions, for example using an acid such as HCI, HBr, H 3 P0 4 , in a suitable solvent such as water, aqueous alkanols and the like.
  • the hydrolysis may be carried out at room temperature or at elevated temperatures up to about 140°C.
  • the reaction time will vary depending on other parameters such as temperature, etc.
  • R in formula I is an alkyl group
  • the compound is prepared by conventional esterification of the corresponding compound where R is H as illustrated by the following equation.
  • the pharmaceutically acceptable salts of the present compounds may be obtained directly from the hydrolysis reaction described above. Such salts may also be obtained by treatment of the formula I free base with an appropriate acid under suitable conditions.
  • the compounds of the present invention may be separated into the individual enantiomers by conventional resolution techniques. Such techniques commonly involve the formation of salts of the present racemic acids with optically active bases.
  • the resolution is preferably carried out on the O,O,N-triacyl derivatives of the racemic acid mixture. These acyl derivatives are prepared by treatment of the free acid mixture with a suitable acylating agent as illustrated by the following equation: The resolution procedure including hydrolysis of the resolved acylated acids is exemplified in U.S. 3,344,023.
  • the mass spectrum showed a large molecular ion peak at 501.
  • the HCI salt obtained in Example 1 H. may be conventionally neutralized or treated with an HCI scavenger such as propylene oxide to obtain the corresponding free amino acid.
  • the HCI salt obtained in Example 2 B may be conventionally neutralized or treated with an HCI scavenger such as propylene oxide to obtain the corresponding free amino acid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (15)

1. Comoosés réoondant à la formule
Figure imgb0026
dans laquelle
L représente ―C≡CH ou ―CH≡CH2,
R1 et R2 représentent chacun, independamment l'un de l'autre, un atome d'hydrogène ou un groupe alcanoyle en C2-C6 et
R représente un groupe alkyle en C1-C18 ou un atome d'hydrogène.
2. Les sels acceptables pour l'usage pharmaceutique des composés de la revendication 1.
3. Composés de la revendication 1 présentant la forme isomère L.
4. Composés de la revendication 1 dans lesquels R1 et R2 représentent tous deux des atomes d'hydrogène.
5. Composés de la revendication 4 dans lesquels R représente l'hydrogène.
6. Composé de la revendication 1, dans lequel L représente ―C≡CH, R représente le groupe éthyle et R1 et R2 représentent tous deux des atomes d'hydrogène.
7. Composé de la revendication 1, dans lequel L représente -C=CH, R1 et R2 représentent tous deux des atomes d'hydrogène et R représente un atome d'hydrogène, sous la forme isomère L.
8. Composés de la revendication 1, répondant à la formule.
Figure imgb0027
dans laquelle R, et R2 représentent tous deux des atomes d'hydrogène et R représente un atome d'hydrogène ou un groupe alkyle en C1-C6.
9. Composé de la revendication 8, dans lequel R représente un groupe éthyle.
10. Composé de la revendication 8, dans lequel R représente l'hydrogène, sous la forme isomère L.
11. Composition pharmaceutique contenant une quantité thérapeutique efficace d'un composé de la revendication 1, ou d'un sel acceptable pout l'usage pharmaceutique d'un tel composé.
12. Procédé de préparation d'un composé répondant à la formule.
Figure imgb0028
qui consiste à hydrolvser un composé répondant à la formule
Figure imgb0029
dans lequelle
L représente -C=CH ou -CH=CH2,
R représente un groupe alkyle en C1-C18 et
R3 et R4 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène, un groupe méthyle ou phényle.
13. Procédé selon la revendication 12, dans lequel R représente -CH3.
14. Procédé selon la revendication 13, dans lequel L représente ―C≡CH.
15. Procédé selon la revendication 13, dans lequel L représente -CH=CH2.
EP78100058A 1977-06-01 1978-06-01 Alpha-amino-acides, compositions et procédé pour la préparation de ces composés Expired EP0000035B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US802390 1977-06-01
US05/802,390 US4401676A (en) 1977-06-01 1977-06-01 Novel α-amino acids

Publications (2)

Publication Number Publication Date
EP0000035A1 EP0000035A1 (fr) 1978-12-20
EP0000035B1 true EP0000035B1 (fr) 1982-01-06

Family

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EP78100058A Expired EP0000035B1 (fr) 1977-06-01 1978-06-01 Alpha-amino-acides, compositions et procédé pour la préparation de ces composés

Country Status (7)

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US (1) US4401676A (fr)
EP (1) EP0000035B1 (fr)
JP (1) JPS543036A (fr)
DE (1) DE2861499D1 (fr)
DK (1) DK240778A (fr)
IE (1) IE47073B1 (fr)
IT (1) IT7849636A0 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE47082B1 (en) * 1977-07-01 1983-12-14 Merrell Toraude & Co -acetylenic amino acids
CA1157030A (fr) * 1977-07-01 1983-11-15 Brian W. Metcalf ACIDES AMINES .alpha.-VINYLIQUES
US4182891A (en) * 1977-07-01 1980-01-08 Merrell Toraude Et Compagnie α-Acetylenic derivatives of α-amino acids
DK309679A (da) * 1978-07-24 1980-02-22 Merck & Co Inc Fremgangsmaade til fremstilling af alfavinylaminosyrer og estere deraf
DK309579A (da) * 1978-07-24 1980-02-22 Merck & Co Inc Fremgangsmaade til fremstilling af alfaethynylaminosyrer og estere deraf
DK309379A (da) * 1978-07-24 1980-01-25 Merck & Co Inc Fremgangsmaade til fremstilling af aminosyrer og aminosyreestere
JPH02138A (ja) * 1987-09-18 1990-01-05 Banyu Pharmaceut Co Ltd Ｌ‐ドーパ誘導体
WO1995004530A1 (fr) * 1993-08-06 1995-02-16 Smithkline Beecham Corporation Antagonistes du recepteur d'endotheline
FR2724654B1 (fr) * 1994-09-16 1997-12-12 Roussel Uclaf Nouveaux derives de l'acide gallique, leur procede de preparation, les nouveaux intermediaires obtenus, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2868818A (en) * 1953-12-15 1959-01-13 Merck & Co Inc Alpha methyl phenylalanines
NL124121C (fr) * 1960-04-08
NL129419C (fr) * 1960-08-19
FR1850M (fr) * 1961-02-24 1963-06-10 Merck & Co Inc Dérivés de la phénylalanine.
CH441362A (de) * 1963-12-24 1967-08-15 Hoffmann La Roche Verfahren zur Herstellung von Phenylalaninderivaten
US3395176A (en) * 1964-03-06 1968-07-30 Merck & Co Inc Alpha-hydroxymethylphenylalanine compounds
US3488363A (en) * 1965-10-22 1970-01-06 Merck & Co Inc Preparation of alpha-methylphenyl alanines
CH475193A (de) * 1966-06-07 1969-07-15 Hoffmann La Roche Verfahren zur Herstellung von Phenylalaninderivaten
US3714241A (en) * 1969-10-29 1973-01-30 Merck & Co Inc PREPARATION OF alpha -METHYL-3,4-DISUBSTITUTED PHENYLALANINES
JPS5025465B1 (fr) * 1970-12-29 1975-08-23
US4022910A (en) * 1972-12-22 1977-05-10 Richardson-Merrell Inc. L-3-hydroxymethyltyrosine and salts thereof for lowering blood pressure
US3983138A (en) * 1973-09-25 1976-09-28 Merck & Co., Inc. Amino acid esters
US4051251A (en) * 1976-02-13 1977-09-27 Merck & Co., Inc. Novel anti-hypertensive compositions

Also Published As

Publication number Publication date
EP0000035A1 (fr) 1978-12-20
DK240778A (da) 1979-01-12
JPS543036A (en) 1979-01-11
IE781079L (en) 1978-12-01
DE2861499D1 (en) 1982-02-25
IE47073B1 (en) 1983-12-14
IT7849636A0 (it) 1978-05-31
US4401676A (en) 1983-08-30

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