Classifications

• • 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 a-ethynyl-and a-vinyl-3,4-disubstituted phenylalanines and especially the 3,4-dihydroxyphenyla- lanine species.
• a-Methyl-3,4-dihydroxyphenylalanine, particularly its L-isomer, is a known antihypertensive agent. (U.S. 2,868,818; U. S . 3,344,023).
• 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 a-ethynyl or a-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 1, + 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 an alkyl group, preferably 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 l -C 6 alkyl. Most preferred R groups are H and ethyl.
• R 1 and R 2 include H and C2-C6 alkanoyl groups.
• suitable alkanoyl groups are acetyl, octanoyl, pivaloyl, 2-methylpropanoyl, heptanoyl, butanoyl and the like.
• the most preferred R l/ R 2 substituent is hydrogen.
• a preferred class of compounds of the present invention is that having the formula
• 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
• R is hydrogen or C 3 -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, emulsiions, 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 HCl, HBr, H 3 PO 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 racemeic 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 reaction may be carried out in an acid medium, e.g., glacial acetic acid.
• an acid medium e.g., glacial acetic acid.
• An example illustrating such an acylation system is in U.S. 3,983,138.
• the mass spectrum showed a large molecular ion peak at 501.
• the HCl salt obtained in Example 1 H.) may be conventionally neutralized or treated with an HC1 scavenger such as propylene oxide to obtain the corresponding free amino acid.
• the HC1 salt obtained in Example 2 B may be conventionally neutralized or treated with an HC1 scavenger such as propylene oxide to obtain the corresponding free amino acid.

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• Chemical & Material Sciences (AREA)
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• Health & Medical Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
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• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
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• 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)

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• 1977
  • 1977-06-01 US US05/802,390 patent/US4401676A/en not_active Expired - Lifetime
• 1978
  • 1978-05-30 IE IE1079/78A patent/IE47073B1/en unknown
  • 1978-05-31 IT IT7849636A patent/IT7849636A0/it unknown
  • 1978-05-31 DK DK240778A patent/DK240778A/da not_active Application Discontinuation
  • 1978-06-01 DE DE7878100058T patent/DE2861499D1/de not_active Expired
  • 1978-06-01 JP JP6501778A patent/JPS543036A/ja active Pending
  • 1978-06-01 EP EP78100058A patent/EP0000035B1/fr not_active Expired

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