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
  • C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• • 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
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• • 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
  • 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
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
  • C07D209/16—Tryptamines

Definitions

• the present invention is concerned with novel 1-fluoromethyl substituted alkylamines.
• nonfluorinated substituted alkylamines such as histamine, 2-(3,'4-dihydroxyphenyl) ethylamine (dopamine), tyramine, amphetamine and hydroxyamphetamine. These compounds exhibit various physiological.activities and have various clinical utilities (See D. M. Aviado "Sympathomimetic Drugs", Charles C. Thomas, Publisher, 1970).
• 1-Fluoromethyl substituted alkyl amines have been discovered. These amines have decarboxylase inhibiting activity.
• An embodiment of the present invention is compounds having the formula wherein R is a substituted C l -C 4 alkyl group.
• the pharmaceutically acceptable acid addition salts of the formula I compounds are also included.
• the salts are those of the formula I base with a suitable organic or inorganic acid.
• Preferred inorganic acid salts are the hydrohalides e.g., hydrochlorides, hydro- iodides, hydrobromides; the sulfates, and the phosphates.
• the hydrohalides, and especially the hydrochlorides, are more preferred.
• the formula I compounds have a chiral center and may occur in optically active forms i.e., as optical isomers. These isomers are designated conventionally by the symbols L and D, + and -, 1 and d, S and R or combinations thereof. Where the compound name or formula has no isomer designation, the name or formula includes the individual isomers, mixtures thereof and racemates.
• the compounds having the S-isomer configuration are, in general, preferred.
• R is a substituted alkyl group exemplified by where R 1 is H or C 2 - C 6 alkanoyl e.g., CH 3 -Co, CH 3 (CH 2 ) 4 -CO, (C H 3 ) 3 C-CO and the like; preferably and
• Preferred compounds of formula I are those where R is
• Another particularly preferred compound has the formula
• Another preferred compound has the formula
• Another preferred compound has the formula
• Still another preferred compound has the formula
• the compounds of the present invention have potent decarboxylase inhibiting activity.
• Decarboxylases are enzymes which act on a-amino acid substrates, effecting decarboxylation to produce the corresponding amine. This action is illustrated by the following equation:
• a-fluoromethyl dopamine inhibits dopa decarboxylase and can be used in combination with dopa to potentiate the latter's usefulness in the treatment of Parkinson's disease.
• the present compounds also are substantially specific in their decarboxylase inhibition activity, that is an a-fluoromethyl alkylamine generally inhibits the decarboxylation of the corresponding non a-fluoromethyl-a amino acid.
• a-fluoromethyl dopamine inhibits the decarboxylation of dopa
• a-fluoromethyl histamine will inhibit the decarboxylation of histidine
• 4-FM-GABA (4-fluoromethyl-4-amino-butyric acid) inhibits glutamic acid decarboxylase
• the present compounds are also useful as diagnostic tools to determine the presence and importance of the corresponding decarboxylase in relation to diseases or to the functioning of biological systems.
• the role of catechol amines in certain CNS functions can be studied by inhibiting their biosynthesis with an appropriate a-fluoromethyl-alkylamine; a-fluoromethyl-tryptamine displays antihypertensive activity; and the study and treatment of ulcers can be advanced through modulation of histamine biosynthesis using a-fluoromethyl histamine.
• Representative compounds have been determined to have decarboxylase inhibiting activity using a conventional in-vitro assay.
• 4-FM-GABA displays CNS activities, including sedative and antidepressant indications.
• the compounds of the present invention may be prepared using any convenient method.
• One such useful process involves the reaction of an a-hydroxymethyl-alkyl amine with SF 4 in liquid HF, as illustrated by the following equation:
• the reaction is generally carried out at temperatures ranging from about -80°C to about 20°C.
• This general reaction is also referred to as fluorodehydroxylation and is described in the Journal of Organic Chemistry 40, 3809-10 (1975).
• An acid addition salt of a compound of the present invention may be prepared by conventional treatment of the a-fluoromethyl amine with a useful acid generally in a suitable solvent.
• a single enantiomer of the present compounds may be obtained by (1) resolving the fluoromethyl amine racemate using conventional resolution techniques or (2) resolving the precursor a-hydroxymethyl amine using conventional resolution techniques and then fluorodehydroxylating the precursor enantiomer.
• a conventional resolution technique may involve formation of a salt of the appropriate amine with an optically active acid and subsequently recovering the specific enantiomer from the salt.
• the product is located by the UV absorption monitor, which is connected with a chart recorder.
• the UV absorbing peak is released by the last solvent listed.
• the appropriate fractions are combined and evaporated to dryness in vacuo, to deliver the hydrochloride of R-a-hydroxymethyl-dopamine.
• For final purification this is recrystallized from isopropanol, to give crystalline product, m.p. 159-160°C. [a] D : 19.5 + 0.5° (c, 1 in 1M aq. HC1).
• SF 4 gas (1.5 ml, measured as liquid at -78°C) is passed in then under continuous cooling and stirring and the solution left standing overnight, while the reactor is being kept in the cooling bath, but without replenishing dry ice.
• the solvent is removed the next morning by passing through a stream of N 2 and the residue is redissolved in 2.5M aq. HC1 (25 ml), evaporated to dryness and the residue purified by elution chromatography on a column made of cation-exchange resin (190 ml of Dowex 50 AG50-X-8, 200/400 mesh). Elution with water, followed by 0.5M aq. HC1 with 5% methanol (2 1), followed by 0.6M aq. HC1 with 10% methanol (4 1).
• UV absorption of the effluent is followed by LKB UVICORD II recording UV monitor.
• the effluent fractions containing UV absorbing material are evaporated to dryness in vacuo to deliver R- ⁇ -fluoromethyl-dopamine.HCl.
• 0.6 g of this crude product is dissolved in isopropanol (4 ml), treated with DARCO G-60, then 26 ml of ethyl acetate is added.
• the crystalline product is refluxed once more in a similar manner, to give 0.545 g of pure HC1 salt , m.p. 152-3°C [ ⁇ ] D : 18.4 + 0 . 5 ( C, 1 in 1M aq. HCl).
• S-a-Fluoromethyl dopamine ⁇ HCl is synthesized in an entirely analogous manner as described in Example 1 for the R isomer; however to obtain the S isomer, the methyl ester of L-DOPA is employed as starting material.
• the intermediate S-hyaroxymethyl dopamine has a melting point of 159-60°C; [a] D : - 20.1 + 0.5° (C, 1 in 1M aq. HCl).
• D-histidinol is placed into a KEL-F reactor; the reactor is immersed into a dry-ice-acetone cooling bath and HF gas is passed in until a volume of 40 ml collects.
• SF4 gas is passed in (2.0 ml, measured as liquid, at -78°C) and the mixture kept at -78°C for 5 hours.
• the cooling bath is removed and the solvent evaporated by passing N 2 gas through it.
• the residue is dissolved in cc. aq. HC1 (15 ml), the solution is evaporated to dryness in vacuo to yield substantially pure R-a-fluoromethyl-histamine hydrochloride-hydrofluoride salt.
• this product is dissolved in water and charged onto a cation-exchange resin column Dowex 50-X-8 (ml resin, H + form). The column is washed first with H 2 0 until the effluent becomes neutral, then the product is eluted with 4M aq. H C1 (275 ml). This effluent is evaporated to dryness to deliver substantially pure R-a-fluoromethyl-histamine dihydrochloride. This is recrystallized by dissolving it in 40 ml of boiling ethanol 2BA, concentrating this solution by evaporation in vacuo to 15 ml volume and cooled (ice-bath) for 2 hours. The crystals formed are collected by filtration and dried in vacuo to give R-a-fluoromethyl-histamine dihydrochloride, m.p. 181-2°.
• the free amines are obtained from the hydrochloride salts by conventional neutralization.
• S(L)-Tryptophanol (0.7 g, 3.7 mmoles) was placed in a Kel-F reactor, cooled in a dry ice-acetone bath (-78°C) and approximately 20 ml of anhydrous HF was condensed with stirring at -78°C.
• Sulfur tetrafluoride (approx. 1.5 ml, 26 mmoles) was added with stirring at -78°C over a 15-minute period.
• the reaction mixture was stirred for 30 minutes at -78°C and then the HF was blown off with a fast stream of N 2 over a 2.5-hr. period at -78°C.
• (S)-a-fluoromethyl-tryptamine was contained in fractions No. 31-60 (12 ml each). They were combined and evaporated to dryness to yield S-a-fluoromethyl-tryptamine characterized as the tartarate salt, by 300 MH z H NM R, mass spectroscopy and microanalysis.
• HC1 is added and the solution refluxed for 16 hours, then evaporated to dryness in vacuo, redissolved in 100 ml of water and chromotographed on a column of cation-exchange resin. 3 1 of AG-50-X-8 (200-400 mesh) resin is employed in the H + form. Elution: 18 liters of water, followed by 0.4.N aq. HC1. The effluent is monitored by UVICORD Model III ultraviolet absorption monitor, filter 206 nm. 22 ml fractions are collected. Fractions 410-610 are combined and evaporated to dryness in vacuo to deliver 4-fluoromethyl-4-amino-butyric acid hydrochloride.
• the 4-FM-GABA ⁇ HCl is dissolved in water and passed through an AG-50-X-8 ion-exchange resin column (100 ml of resin). The column is first washed with water, then eluted with 2 N aq. NH 4 0H. Evaporation of the NH 4 OH solution in vacuo gives R,S-4-fluoromethyl-4-amino butyric acid. It is recrystallized from H 2 0/ isopropanol and charac- terized by C - H - N - F analysis and 1 H and 19 F NMR spectroscopy.

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Citations (3)

• 1978
  • 1978-05-30 IE IE1076/78A patent/IE46910B1/en unknown
  • 1978-05-31 IT IT49634/78A patent/IT1104712B/it active
  • 1978-05-31 DK DK240578A patent/DK240578A/da not_active Application Discontinuation
  • 1978-06-01 JP JP6501478A patent/JPS5416422A/ja active Granted
  • 1978-06-01 EP EP78100059A patent/EP0000036B1/fr not_active Expired
  • 1978-06-01 DE DE7878100059T patent/DE2861148D1/de not_active Expired

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