Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/72—Two oxygen atoms, e.g. hydantoin
  • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
  • C07D233/78—Radicals substituted by oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
  • C07C45/48—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation involving decarboxylation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
  • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups

Definitions

• the present invention is concerned with certain difluoro- or trifluoromethyl phenylethylamines.
• a-Methyl-3,4-dihydroxyphenylalanine, particularly its L-isomer, is a known antihypertensive agent. (U.S. 2,868,818; U.S. 3,344,023).
• a-Trifluoromethyloxyphenylalanines are known compounds which are specific in their physiological activity in vivo (U.S. 3,046,300). They reduce the norepinephrine to be found in the heart but have no effect on that to be found in the brain. Further, while they appear in vitro to be active as inhibitors of mammalian decarboxylase, they do not appear to have this activity in vivo. They can also be used as intermediates in the preparation of norepinephrine-like compounds by decarboxylation of the amino acid followed by hydroxylation of the A-carbon of the resulting amine.
• Novel a-difluoromethyl- or ⁇ -trifluoromethyl-3,4-di-OR-ethylamines have been discovered. These compounds have biological activity including decarboxylase inhibition.
• the pharmaceutically acceptable salts of the formula I ⁇ II 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 ⁇ II 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 alkanoyl groups
• the most preferred R substituent is hydrogen.
• a preferred compound is the trifluoromethyl compound having the formula The R-isomer of III is more preferred.
• Another preferred compound of the present invention is that having the formula The R-isomer form of the formula IV compound is also more preferred.
• the compounds of the present invention have 3,4-dihydroxyphenylalanine (DOPA) decarboxylase inhibiting activity. This activity was determined by conventional in-vitro assay procedures. This biological activity permits the present compounds to be used as diagnostic tools to determine the presence and importance of the corresponding decarboxylase in relation to diseases or to functioning of biological systems. Also the present, compounds may be used in combination with DOPA to improve DOPA's effectiveness in treating Parkinson's disease.
• DOPA 3,4-dihydroxyphenylalanine
• the compounds or their salts 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.
• Compounds of the present invention may be prepared by any convenient process.
• Homoveratric acid and its derivatives such as dialkyl amides, esters and thioesters may be transformed into an anionic species with such bases as metalated dialkyl amides (e.g., lithium diisopropylamide), metalated alkyls (e.g., butyl lithium), hydrides (NaH) or metal amides (KNH 2 ).
• bases such bases as metalated dialkyl amides (e.g., lithium diisopropylamide), metalated alkyls (e.g., butyl lithium), hydrides (NaH) or metal amides (KNH 2 ).
• Such anions may be condensed with activated forms of difluoroacetic acid such as its ester, or acid chlorides. Except in the case of homoveratric acid itself, these condensation products require hydrolysis to effect decarboxylation to the difluoromethyl veratryl ketone 1.
• a carbon nitrogen bond may be introduced at the ketonic position with the usual amine reagents such as NH 3 and hydroxylamine. However, this is most conveniently done by using methoxy amine to form the ketone O-methyl oxime, 2.
• This compound may be reduced to the amine 3 using metal catalysts and hydrogen, active metals (e.g., Zn) and most conveniently boranes such as BH 3 .
• the cleavage of the phenol ethers can be accomplished with reagents such as BBr 3 but is easily effected by heating with hydrohalic acids such as aq. HCI, aq. HBr and the like.
• Homoveratric acid and its derivatives such as dialkyl amides, esters and thio esters may be transformed into an anionic species with such bases as metalated dialkyl amides (e.g., lithium diisopropylamide), metalated alkyls (e.g., butyl lithium), hydrides (NaH) or metal amides (KNH 2 ).
• bases such bases as metalated dialkyl amides (e.g., lithium diisopropylamide), metalated alkyls (e.g., butyl lithium), hydrides (NaH) or metal amides (KNH 2 ).
• Such anions may be condensed with activated forms of trifluoroacetic acid such as its ester or acid chloride. Except in the case of homoveratric acid itself, these condensation products require hydrolysis to effect decarboxylation to the trifluoromethyl veratryl ketone 5.
• a carbon nitrogen bond may be introduced at the ketonic position with the usual amine reagents such as ammonia and hydroxylamine. However, this is most conveniently done by using methoxy amine (NH Z OCH 3 ) to form the ketone O-methyl oxime 6. This compound may be reduced to the amine 7 using metal catalysts and hydrogen, active metals and most conveniently boranes such as BH 3 .
• the cleavage of the phenol ethers can be accomplished with reagents such as BBr 3 but is easily effected by heating with hydrohalic acids such as aqueous HCI, aqueous HBr and the like.
• the pharmaceutically acceptable salts of the present compounds may be obtained directly from the acid hydrolysis steps described above. Such salts may also be obtained by treatment of the formula I ⁇ II 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 a salt of a present racemic amine with an optically active acid.
• THe following examples illustrate the preparation of compounds of the present invention. All temperatures are in °C. The melting points were obtained in open capillary and are uncorrected.
• a 1-liter three-neck flask, fitted with a magnetic stirrer, condenser, nitrogen inlet, and septum was charged with 23 ml of diisopropylamine (176 mmoles) and 50 ml of tetrahydrofuran (THF).
• the solution was cooled to 0°C followed by addition of 76 ml of 2.1M n-butyl lithium in hexane (159.6 mmoles) over a period of 15 min.
• the solution was then cooled to -78°C and to it was added 15.68 g of homoveratric acid (80 mmoles) in 80 ml of THF.
• the hemi naphthalene 1,5-disulfonate salt was prepared by treating 40 mg of 7 with 23 mg of naphthalene 1,5-disulfonic acid in 2-propanol and concentrating to dryness. The residue was twice redissolved and reconcentrated and then triturated with acetonitrile to give the crystalline hemi naphthalene disulfonate salt of 7, m.p. 265-268°C.). * Registered Trade Mark, at least in the United Kingdom.
• R,S-1-trifluoromethyl-2-(3',4'-dihydroxyphenyl)ethylamine is obtained by conventional neutralization of the disulfonate.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
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• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 1978
  • 1978-05-30 IE IE1077/78A patent/IE47542B1/en unknown
  • 1978-05-31 DK DK240678A patent/DK240678A/da not_active Application Discontinuation
  • 1978-05-31 IT IT7849635A patent/IT7849635A0/it unknown
  • 1978-06-01 DE DE7878100057T patent/DE2862407D1/de not_active Expired
  • 1978-06-01 EP EP78100057A patent/EP0000034B1/en not_active Expired
  • 1978-06-01 JP JP6501578A patent/JPS5416437A/ja active Pending

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