IE842902L - (-)-1-(2-fluorophenyl)-2-tertiarybutylamino-1-ehtanol - Google Patents
(-)-1-(2-fluorophenyl)-2-tertiarybutylamino-1-ehtanolInfo
- Publication number
- IE842902L IE842902L IE842902A IE290284A IE842902L IE 842902 L IE842902 L IE 842902L IE 842902 A IE842902 A IE 842902A IE 290284 A IE290284 A IE 290284A IE 842902 L IE842902 L IE 842902L
- Authority
- IE
- Ireland
- Prior art keywords
- fluorophenyl
- crl
- ethanol
- tertiobutylamino
- addition salt
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Life Sciences & Earth Sciences (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)
Abstract
1. Claims for the contracting States BE, CH, DE, GB, IT, LI, LU, NL, SE Novel 1-(2-fluorophenyl)-2-alkylamino-1-ethanol derivative, characterized in that it is chosen from among the group constituted by (i) (-)-1-(2-fluorophenyl)-2-t-butylamino-1-ethanol ; and (ii) its addition salts. 1. Claim for the contracting State AT Process for the preparation of (-)-1-(2-fluorophenyl)-2-t-butylamino-1-ethanol and its addition salts, characterized in that it comprises the formation of the corresponding L-(+)-tartrate, the purification of said L-(+)-tartrate up to a constant rotatory power, the separation of the levorotatory free base and then, if appropriate, the transformation of said free base into an addition salt.
Description
This invention relates to (-)-l-(2-fluorophenyl)-2-tertiobutylamino-l-ethanol and its addition salts as new industrial products. It also relates to their use in therapy.
In EP-A-0 060 954 compounds belonging the N-fluorophenacyl-amines family of the formula F-CgH^-A-CI^-NHR (wherein A is CO or CHOH, and R is i-C^Hy or t-C^Hg) are disclosed, and their neuro-psychopharmacological properties are studied. In particular ( + )-l-(2-fluorophenyl)-2-tertiobutylamino-l-ethanol hydrochloride is proposed as a CNS antidepressant agent.
It has been found now that the free 1-base and its addition salts are therapeutically more interesting than the corresponding • racemic and d-isomers.
The new compounds according to this invention, which belong to the family of 1—(2—fluorophenyl)-2-alkylamino-l-ethanol derivatives are selected from (i) (—)—!—(2—fluorophenyl)-2-tertiobutylamino-l-ethanol, and (ii) its addition salts.
The expression "addition salts" is understood here as meaning firstly the acid addition salts obtained by reacting the free base of the 1-isomer with inorganic or organic acids, and secondly the ammonium salts. Hydrochloric, hydrobromic, acetic, formic, propionic, oxalic, fumaric, maleic, succinic, benzoic, cinnamic, mandelic,citric, malic, tartaric, aspartic, glutamic, methanesulfonic and p-toluene-sulfonic acids may be mentioned in particular among the acids which can be used to salify the free 1-base. Alkyl halides such as CH^I and CH^Cl may be mentioned in particular among the compounds making it possible to obtain ammonium salts. 3 10 The hydrochloride salt is the preferred acid addition salt according to the invention.
The free 1-base according to the invention can be prepared according to a method known per se by the application of classical reaction mechanisms. The method recommended here, which is examplified in Preparation I hereinafter, comprises forming the corresponding L-(+)-tartrate, purifying said L-(+)-tartrate up to a constant rotatory power, then separating the free 1-base.
The (-)-l-(2-fluorophenyl)-2-tertiobutylamino-l-ethanol and its addition salts, in particular the hydrochloride one, are therapeutically useful, in particular as antidepressive agents.
According to the invention a therapeutic composition is recommended, which comprises, in association with a physiologically acceptable excipient, at least a compound selected from (-)-1- (2- fluorophenyl)-2-tertiobutylamino-l-ethanol and its non-toxic addition salts, as active ingredient.
Of course, in a composition of this type, the active ingredient is present in a pharmaceutical^ effective amount. 90 Further advantages and characteristics of the invention will be understood more clearly on reading the following description of preparative examples and results of neuropsychopharmacological tests. These elements as a whole do not imply a limitation but are given by way of illustration. 25 PREPARATION I Obtention of (-)-l-(2-fluorophenyl)-2-tertiobutylamino-l-ethanol hydrochloride CHOH-CH 2-NH-C(CH3)3,HCl F 30 (Example 1 ; Code No : CRL 40 996) a) 84.4 g (0.4 mol) of racemic ( + )-l-(2-fluorophenyl)-2-tertiobu-tylamino-l-ethanol are dissolved in 1000 ml of isopropanol. The solution is heated up to about 50°C, and 30 g (0.2 mol) of L-(+)-tartaric acid are added. A precipitate is formed under stirring. 4 After cooling and isolating the precipitate by filtration, 56 g of a product containing the L-(+)-tartrate are obtained. b) The optical isomer is purified by returning to the base then precipitating the L-(+)-tartrate according to the modi operandi given 5 above, three times in a row.
Thus are isolated 12.5 g (0.0219 mol) of L-(+)-tartrate, the rotatory power of which does not envolve any longer. c) The 12.5 g of said L-(+)-tartrate are dissolved in 100 ml of water and the clear solution thus obtained is poured in 50 ml NaOH IN. 10 The precipitated base is filtered, washed with water and vacuum-dried in order to isolate 8.7 g (0.0412 mol) of pure base. d) The 8.7 g of said base are dissolved in 50 ml of isopropanol. The solution is made tepid, acidified with a HC1 gas stream, precipitated under stirring then cooled. The precipitate is filtered and vacuum- 15 dried in order to isolate 8.8 g (0.0355 mol ) of CRL 40 996, the rotatory power of it (in methanol) at a concentration of 10 g/l is the following one : — 9n°r L ° Results of assays which have been carried out the laevorotato-ry hydrochloride (Example 1 ; CRL 40 996), the dextrorotatory hydrochloride (CP 1 ; CRL 40 995) and the previously known racemic hy-drochloride (CP 2 ; CRL 40 827), are summed up hereinafter.
In these assays the products to be tested in solution in distilled water (pH 5) were administered intraperitoneally to male mice under a volume of 20 ml/kg and to male rats under a volume of 5 ml/kg.
I - TOXICITY 15 CRL 40 996 is less toxic than CRL 40 995 and CRL 40 827. If on the one hand the LD-0 (non-lethal maximal dosis) of the three compounds is higher than or equal to 64 mg/kg (I.P. ; mice), on the other hand the LD-60 of CRL 40 996 is of the order of 128 mg/kg (I.P. ; mice) while the LD-100 of CRL.40 995 and CRL 40 827 is lower 20 than or equal to 128 mg/kg (I.P. ; mice).
II - OVERALL BEHAVIOUR AND REACTIVITIES Groups of six animals are observed before then 0.25 hour, 0.50 hour, 1 hour, 2 hours, 3 hours and 24 hours after administration of the products to be tested. The following observations are made : 25 1°) CRL 40 996 induces a) in_mice at_a_dose of_32_mg/kg : - sedation for 0.5 h with a decrease in the reactivity to touch and muscular tonus for 0.25 h ; 30 - hypothermia ( - 2.0°C) for 1-2 h ; and, - suppression of the "spinna reflex" for 0.5 h ; - at_5_dose- of_8_mg/kg : - sedation for 0.5 h with a decrease in the reactivity to touch and muscular tonus for 0.25 h • - hypothermia (-1,8°C) for 0.25 h ; - at_doses_of_2_and_0J_5_mg/kg : - a behaviour and reactivities without noticeable modifi cations with respect to the control animals receiving only water ; b) in_rats - at a dose of 16 mg/kg : - sedation for 0.5 h ; and - disponea for 1 h ; - at_a_dose_of_4_mg/kg : - a fleeting sedation (0.25 h) ; - at_doses_of_l_and_0_125_mg/kg : - a behaviour and reactivities without noticeable modifi cations with respect to the control animals ; 2°) CRL 40 995 induces a) in_mice - at_doses_of_32_and_8_mg/kg : - a depressed respiration for 0.5 h ; - at doses of 2 and 0.5 mg/kg : - a behaviour and reactivities without noticeable modif cations with respect to the control animals. b) in_£ats - at doses of 16 mg/kg, 4 mg/kg, 1 mg/kg and 0.5 mg/kg : - a behaviour and reactivity without noticeable modi fications with respect to the control animals. Ill - INTERACTION WITH AP0M0RPHINE Groups of six mice receive each compound to be tested 0.5 h before the subcutaneous injection of 16 mg/kg of apomorphine.
It is observed that, at doses of 8 mg/kg and 32 mg/kg, CRL 40 995 opposes the hypothermia induced by apomorphine, without modifying the righting behaviour and the stereotypies.
On the other hand, as from the dose of 0.5 mg/kg, CRL 40 996 opposes the hypothermia induced by apomorphine without modifying the behavior of verticalisation and the stereotypies. 7 IV - INTERACTION WITH RESERPINE Four hours after the intraperitoneal injection of 2.5 mg/kg of reserpine, groups of 6 mice receive each compound to be tested.
It is noted that, at doses of 0.5 mg/kg, 2 mg/kg and 8 mg/kg, 5 CRL 40 995 oppose moderately the hypothermia induced by reserpine without modifying the ptosis. At a higher dose (32 mg/kg) this hypothermia antagonism is present in 5 out of 6 mice but is masked by the loss of the righting reflex (and the hypothermia resulting thereof) in 1 out of 6 mice. 10 CRL 40 996 exhibits a slightly different effect. From the dose of 0.5 mg/kg, it counteracts the hypothermia induced by reserpine without modifying the ptosis. This effect, which does not increase notably in intensity with the dose, appears with a latency of about 1 hour. 15 V - INTERACTION WITH 0X0TREM0RINE Each compound to be tested is administered to groups of 6 mice 0.5 hour before the intraperitoneal injection of 0.5 mg/kg of oxotremorine. 1 °) Action on.temperature 20 The hypothermic action of oxotremorine is opposed by CRL 40 996 and CRL 40 827 but is not modified by CRL 40 995. 2°) Action on trembling The trembling induced by oxotremorine is not modified by CRL 40 996 and CRL 40 827 ; however CRL 40 995 seems, at a dose of 25 32 mg/kg to cause potentation of this trembling. 3°) Action on peripheral cholinqerqic symptoms CRL 40 995 and CRL 40 827 do not modify the signs of cholinergic stimulation which appear after administration of oxotremorine. On the other hand CRL 40 996 seems to reduce defecation without 30 modifying salivation and lacrymation: VI - ACTION ON SPONTANEOUS MOTILITY 0.5 hour after they have received each compound to be tested, the mice (6 per dose, 12 control animals) are placed in an actimeter, where their motility is recorded for 30 minutes. It is observed that 35 the three compounds exhibit effects which are different : 8 - at doses of 8 mg/kg and 32 mg/kg, CRL 40 996 causes a very intense diminution of the spontaneous motility ; - at the doses of 8 mg/kg and 32 mg/kg, CRL 40 995 slightly decreases the spontaneous motility ; and, 5 - at the dose of 8 mg/kg, CRL 40 827 does not modify the spontaneous motility, and at the dose of 32 mg/kg that compound seems to diminish it moderately but not significantly.
VII - ACTION ON THE "BEHAVI OURAL DESPAIR" Half an hour after they have received the compounds to be 10 tested, groups of 6 mice are placed in a beaker filled with water to a height of 6 cm. The total period of immobility between the 2nd and 6th minutes following immersion is noted.
CRL 40 995 does not modify the period of immobility (of so-called despair). On the opposite, at doses of 8 mg/kg and 32 mg/kg, 15 CRL 40 996 reduces moderately the period of immobility.
VIII - CONCLUSION The results of the assay given above point out that CRL 40 996 is the optical isomer of CRL 40 827 which is active and which exhibits different and unexpected effects with respect to CRL 40 827 and 20 CRL 40 995.
In clinical trials, CRL 40 996 administered by oral route to human beings was shown to be a fair antidepressant agent in the treatment of depression. The recommended posology comprises administering 3 tablets or gelative capsules each containing from 3 to 4 mg 25 of CRL 40 996 per day.
Claims (7)
1. (-)-l-(2-Fluorophenyl)-2-tertiobutylamino-l-ethanolor an addition salt thereof.
2. (-)-l-(2-Fluorophenyl)-2-tertiobutylamino-l-ethanol hydrochloride.
3. A therapeutic composition comprising, in association with a physiologically acceptable excipient, a pharmaceutical^ effective amount of a compound selected from (—)—1—(2—fluorophenyl)-2— tertiobutylamino-1-ethanol or a non-toxic addition salt thereof.
4. An addition salt of (-)-1-(2-fluorophenyl)-2-tertiobutylamino-l-ethanol, which is any one of those specifically hereinbefore mentioned.
5. A therapeutic composition according to claim 3, substantially as hereinbefore described.
6. A process for the preparation of (-)-l-(2-fluorophenyl)2-tertiobutylamino-l-ethanol or an addition salt thereof, substantially as hereinbefore described with particular reference to Preparations I and II.
7. (-)-1-(2-Fluorophenyl)-2-tertiobutylamino-l-ethanol or an addition salt thereof, whenever prepared by a process claimed in claim 6. F.R. KELLY & CO., AGENTS FOR THE APPLICANTS.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8318140A FR2554811B2 (en) | 1979-12-14 | 1983-11-15 | (-) - 1- (2-FLUOROPHENYL) -2-TERTIOBUTYLAMINO-1-ETHANOL, THERAPEUTIC USE |
Publications (2)
Publication Number | Publication Date |
---|---|
IE842902L true IE842902L (en) | 1985-05-15 |
IE58085B1 IE58085B1 (en) | 1993-06-30 |
Family
ID=9294128
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE290284A IE58085B1 (en) | 1983-11-15 | 1984-11-12 | (-)-1-(2-fluorophenyl)-2-tertiobutylamino-1-ethanol, and its therapeutic application |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0146443B1 (en) |
JP (1) | JPS60126251A (en) |
AT (1) | ATE33824T1 (en) |
CA (1) | CA1227808A (en) |
DE (1) | DE3470735D1 (en) |
ES (1) | ES8600207A1 (en) |
FR (1) | FR2554811B2 (en) |
IE (1) | IE58085B1 (en) |
ZA (1) | ZA848864B (en) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1043510A (en) * | 1963-10-09 | 1966-09-21 | Bayer Ag | D-(--)-n-alkyl-1-phenyl-2-aminoethanols |
DE1493941A1 (en) * | 1964-12-04 | 1969-03-06 | Selvi & C Lab Bioterapico | Process for the production of the levorotatory form of 1- (4'-nitrophenyl) -2-isopropylamine-ethanol and its salts |
ATE8987T1 (en) * | 1981-03-23 | 1984-09-15 | Laboratoire L. Lafon Societe Anonyme Dite: | FLUORPHENACYL-AMINE DERIVATIVES AND THEIR THERAPEUTIC USE. |
JPS57169450A (en) * | 1981-04-13 | 1982-10-19 | Lafon Labor | Fluorophenacyl-amine derivative and application to remedy |
-
1983
- 1983-11-15 FR FR8318140A patent/FR2554811B2/en not_active Expired
-
1984
- 1984-11-12 IE IE290284A patent/IE58085B1/en not_active IP Right Cessation
- 1984-11-13 CA CA000467625A patent/CA1227808A/en not_active Expired
- 1984-11-14 AT AT84402313T patent/ATE33824T1/en not_active IP Right Cessation
- 1984-11-14 ZA ZA848864A patent/ZA848864B/en unknown
- 1984-11-14 DE DE8484402313T patent/DE3470735D1/en not_active Expired
- 1984-11-14 EP EP84402313A patent/EP0146443B1/en not_active Expired
- 1984-11-15 ES ES537944A patent/ES8600207A1/en not_active Expired
- 1984-11-15 JP JP59241550A patent/JPS60126251A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
ES537944A0 (en) | 1985-10-01 |
IE58085B1 (en) | 1993-06-30 |
CA1227808A (en) | 1987-10-06 |
JPS60126251A (en) | 1985-07-05 |
DE3470735D1 (en) | 1988-06-01 |
EP0146443B1 (en) | 1988-04-27 |
FR2554811B2 (en) | 1987-02-13 |
ATE33824T1 (en) | 1988-05-15 |
ES8600207A1 (en) | 1985-10-01 |
ZA848864B (en) | 1985-07-31 |
EP0146443A1 (en) | 1985-06-26 |
FR2554811A2 (en) | 1985-05-17 |
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Legal Events
Date | Code | Title | Description |
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MM4A | Patent lapsed |