EP0000036B1 - Fluorinated alkylamines and process for preparing same - Google Patents

Fluorinated alkylamines and process for preparing same Download PDF

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Publication number
EP0000036B1
EP0000036B1 EP78100059A EP78100059A EP0000036B1 EP 0000036 B1 EP0000036 B1 EP 0000036B1 EP 78100059 A EP78100059 A EP 78100059A EP 78100059 A EP78100059 A EP 78100059A EP 0000036 B1 EP0000036 B1 EP 0000036B1
Authority
EP
European Patent Office
Prior art keywords
fluoromethyl
compounds
compound
hci
formula
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
Application number
EP78100059A
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German (de)
English (en)
French (fr)
Other versions
EP0000036A1 (en
Inventor
Janos Kollonitsch
Arthur Allan Patchett
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
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Merck and Co Inc
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Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0000036A1 publication Critical patent/EP0000036A1/en
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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).
  • G.B. 976,353 discloses 1-trifluoromethylphenylalkylamines having anorectic properties. No 1-monofluoromethylaralkylamines are suggested.
  • 3,839,170 discloses a-CH 2 F amines and amino acids and the process for direct replacement of a hydrogen atom with a F atom using fluoroxyperfluoroalkanes and fluoroxy- pentafluorosulfur in liquid or solid phase under specific reaction conditions. No 1-fluoromethylamines of the type disclosed in the present invention are suggested.
  • 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 C1-C4 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, hydroiodides, 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 -, I 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 C 1 -C 4 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, (CH 3 ) 3 C-CO and the like; preferably
  • 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 ⁇ -amino acid substrates, effecting decarboxylation to produce the corresponding amine. This action is illustrated by the following equation: L- alkyl or aralkyl group
  • ⁇ -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 ⁇ -fluoromethyl substituted alkylamine generally inhibits the decarboxylation of the corresponding non a-fluoromethyl-a amino acid.
  • ⁇ -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; etc.
  • 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.
  • CNS central nervous system
  • 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 substituted alkyl amine with SF 4 in liquid HF, as illustrated by the following equation:
  • the starting compounds as or can be obtained according to ENz et al., Helv. Chim. Acta 29, 1048-1060 (1946).
  • 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-substituted 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-substituted amine racemate using conventional resolution techniques or (2) resolving the precursor a-hydroxymethyl-substituted amine using conventional resolution techniques and then fluoro- dehydroxylating the precursor enantiomer.
  • a conventional resolution technique may involve formation of a salt of the appropriately substituted amine with an optically active acid and subsequent 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. [ ⁇ ] D : 19.5 ⁇ 0.5° (c, 1 in 1 M aq. HCI).
  • 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 2.5 M aq. HCI (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, (Registered Trade Mark) 200/400 mesh U.S. Bureau of Standards, Standard Screen Sieves 1919). Elution with water, followed by 0.5M aq.
  • S- ⁇ -Fluoromethyl dopamine.HCI 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-hydroxymethyl dopamine has a melting point of 159-60°C; [ ⁇ ] D : -20.1 ⁇ 0.5° (C, 1 in 1M aq. HCI).
  • 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.
  • SF 4 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. HCI (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 (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. HCI (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.
  • the desired product (S)-a-fluoromethyl-trypamine was contained in fractions No. 31-60 (12 ml each). They were combined and evaporated to dryness to yield S- ⁇ -fluoromethyl_ tryptamine characterized as the tartrate salt, by 300 MHz 1 H NMR, mass spectroscopy and microanalysis.
  • HCI is added and the solution refluxed for 16 hours, then evaporated to dryness in vacuo, redissolved in 100 ml of water and chromatographed on a column of cation-exchange resin. 3 l of AG-50-X-8 (200-400 mesh, U.S. Bureau of Standards, Standard Screen Sieves 1919) resin is employed in the H + form. Elution: 18 liters of water, followed by 0.4 N aq. HCI. The effluent is monitored by UVICORD Model III ultra-violet 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.HCI 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 0H solution in vacuo gives R,S - 4 - fluoromethyl - 4 - amino butyric acid. It is recrystallized from H 2 0/isopropanol and characterized by C-H-N-F analysis and 1 H and 19 F NMR spectroscopy.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Cardiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
EP78100059A 1977-06-01 1978-06-01 Fluorinated alkylamines and process for preparing same Expired EP0000036B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US80235077A 1977-06-01 1977-06-01
US802350 1977-06-01

Publications (2)

Publication Number Publication Date
EP0000036A1 EP0000036A1 (en) 1978-12-20
EP0000036B1 true EP0000036B1 (en) 1981-10-14

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EP78100059A Expired EP0000036B1 (en) 1977-06-01 1978-06-01 Fluorinated alkylamines and process for preparing same

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EP (1) EP0000036B1 (enrdf_load_stackoverflow)
JP (1) JPS5416422A (enrdf_load_stackoverflow)
DE (1) DE2861148D1 (enrdf_load_stackoverflow)
DK (1) DK240578A (enrdf_load_stackoverflow)
IE (1) IE46910B1 (enrdf_load_stackoverflow)
IT (1) IT1104712B (enrdf_load_stackoverflow)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3872678A (en) * 1977-09-01 1980-02-14 Merrell Toraude & Co Alpha-halomethyl amines
US4326071A (en) * 1977-09-28 1982-04-20 Merrell Toraude Et Compagnie Halomethyl derivatives of gamma-aminobutyric acid and related compounds
ZA785435B (en) * 1977-10-19 1979-09-26 Merrell Toraude & Co A-halomethyl derivatives of histamine and related compounds
NZ194348A (en) * 1979-07-26 1982-09-14 Merrell Toraude & Co Fluorinated methyl-beta-alanine derivatives and pharmaceutical compositions
US4542802A (en) * 1982-04-02 1985-09-24 Woodward Governor Company Engine and transmission control system for combines and the like
CA1302919C (en) * 1985-07-03 1992-06-09 Robert T. Buckler Histamine derivatives, immunogen conjugates and antibodies raised thereto

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR104F (enrdf_load_stackoverflow) * 1960-11-05
GB1218135A (en) * 1967-07-28 1971-01-06 Abbott Lab Substituted phenethylamine derivatives
US3839170A (en) * 1970-08-03 1974-10-01 Merck & Co Inc Process for the preparation of 3-fluoro-d-alanine

Also Published As

Publication number Publication date
IE781076L (en) 1978-12-01
IT7849634A0 (it) 1978-05-31
IT1104712B (it) 1985-10-28
DK240578A (da) 1978-12-02
IE46910B1 (en) 1983-11-02
JPS6123177B2 (enrdf_load_stackoverflow) 1986-06-04
JPS5416422A (en) 1979-02-07
DE2861148D1 (en) 1981-12-24
EP0000036A1 (en) 1978-12-20

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