Claims
- 1. A compound of the structural formula: ##STR5## when R is --NO.sub.2 or NH.sub.2, R.sub.1 is --CF.sub.3 and; when R is --CF.sub.3, R.sub.1 is --NO.sub.2 or NH.sub.2 ; and their salts with pharmacologically acceptable acids.
- 2. The compound according to claim 1:
- 2-nitro-5-trifluoromethyl-anilide of nicotinic acid.
- 3. The compound according to claim 1:
- 2-amino-5-trifluoromethyl-anilide of nicotinic acid and its pharmacologically acceptable salts.
- 4. The compound according to claim 1:
- 2-trifluoromethyl-5-nitroanilide of nicotinic acid.
- 5. The compound according to claim 1:
- 2-trifluoromethyl-5-aminoanilide of nicotinic acid and its pharmacologically acceptable salts.
- 6. A pharmaceutical composition comprising a compound according to claim 1 in an effective amount in unit dosage form in combination with a pharmaceutically acceptable vehicle.
- 7. The method of treating mammals in excited states which comprises administering to said mammals an effective amount in unit dosage form of a composition according to claim 6.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 52879 A/74 |
Sep 1974 |
ITX |
|
THE INVENTION
This application is a continuation-in-part of now abandoned application, U.S. Ser. No. 610,877 filed Sept. 5, 1975 claiming priority of Italy Pat. No. 52879-A/74 filed Sept. 5, 1974.
The object of the present invention is a series of physiologically and pharmacologically active novel fluorurated amides of nicotinic acid having the following structural formula: ##STR2## wherein when R is --NO.sub.2 or --NH.sub.2 then R.sub.1 is --CF.sub.3 and; when R is --CF.sub.3 then R.sub.1 is --NO.sub.2 or NH.sub.2.
In particular the compounds: ##STR3## are novel.
Compounds (I) and (III) above are intermediates for the preparation of pharmacologically active compounds (II) and (IV).
The present invention includes the process for the preparation of the aforesaid novel compounds and pharmaceutical compositions for the use of the pharmacologically active compounds.
Compounds II and IV also form salts with mineral acids, as for example hydrochloric acid, sulphuric acid, phosphoric acid, etc., or with mono- or pluricarboxylic aliphatic acids, e.g. formic, acetic, lactic, succinic, malonic, glutaric, adipic, tartaric, citric, maleic, fumaric acids, etc., or with aromatic acids, i.e. benzoic, salicylic, pamoic acids, etc., or with mandelic acid, diphenylacetic acid, benzylic acid, etc., or with sulphonic acids, i.e. metansulphonic, benzensulphonic, toluensulphonic, acids, etc., or with sulphamic acids, i.e. cyclamic acid, etc. The pharmaceutically acceptable salts are preferred when the compounds are administered for their pharmacological activity.
Compounds (II) and (IV) showed the following pharmacological activity and properties:
(1) reduction of spontaneous motor activity,
(2) motor decoordination,
(3) deconditioning effect,
(4) anticonvulsive effect, Max E. S and Cardiazol,
(5) amphetamine antagonizing effect,
(6) capability to increase barbiturate-induced hypnosis,
(7) hypothermal activity,
(8) analgesic activity,
(9) High therapeutic index.
In view of the low toxicity properties of compounds II and IV, they are useful as psychotropic drugs i.e. as tranquilizers and for the control of CNS excitement. The pharmacological properties are characteristic for these fluorated amides of nicotinic acid and differ generally from the properties of nicotinic acid per se. The compounds do not cause the characteristic peripheral vasodilation of nicotinic acid.
Further compounds II and IV do not cause toxic side effects after single daily consecutive repeated administration (40 days) of 150 mgm/Kg (per os) in rats.
Both compounds form a new class of psychotropic drugs and are useful in daily doses of between 25 - 300 mgm in control of CNS excitement states.
Compound II has an LD.sub.50 of 1200 mg kg.sup.-1 per os in mice and 850 mg kg.sup.-1 per os in rats;
Compound IV has an LD.sub.50 1200 mg kg.sup.-1 per os in mice and 800 mg kg.sup.-1 per os in rats.
LD.sub.50 and ED.sub.50 were calculated in accordance with:
(1) Reduction of spontaneous motor activity:
200 mg kg.sup.-1 per os reduced by 50% the spontaneous motor activity in rats. Movements were recorded by Animex apparatus (Farad-Coopenaghen).
The reduction of spontaneous motor activity was studied in accordance with the procedure of:
The ED.sub.50 of compounds II and IV were approximately 200 mgm/KG.
(2) Motor Decoordination:
200 mg kg.sup.-1 per os reduced the Rotarod performance (16 r.p.m.) in rats by the method of Janssen, P. A. et al.
"Effect of various drugs on isolation-induced fighting behaviour of male mice", J. Pharmacol. Exptl. Therap. 129, 471, (1960).
The ED.sub.50 for compounds II and IV were substantially 200 mgm/Kg.
(3) Deconditioning effect:
Compounds II and IV exhibited intense deconditioning activity in rats pretrained in seven previous consecutive sessions--50 trials per session--which had acquired an avoidance response in a Shuttle box (80% of avoidances); Deconditioning ED.sub.50 at 60 min after treatment was 150 mg kg.sup.-1 os (Litchfield and Wilcoxon).
End-point: No. of rats per group which reduced avoidances by 50% versus the previous trials.
The deconditioning effect was studied in accordance with:
The ED.sub.50 for compounds II and IV were substantially 150 mgm/KG.
(4) Anticonvulsive effect:
Compound II at the dose level of 260 mg kg.sup.-1 and compounds IV at the dose level of 65 mg kg.sup.-1 brought about death at 60 min after 100 mg kg.sup.-1 of pentylentetrazole was given to rats.
Against convulsions produced by electric shock the compounds exhibited a powerful protective effect ED.sub.50 in rats was respectively 32 mg kg.sup.-1 os for Compound II and 100 mg kg.sup.-1 os for compound IV (Litchfield and Wilcoxon).
End-point: no. of rats in each group which reduced the hind leg tonic extensor component.
The Anticonvulsive effect was studied in accordance with:
(5) Amphetamine-antagonising effect:
260 mg kg.sup.-1 os of compounds II and IV reduced by 50% the amphetamine-induced toxicity in grouped mice. i.e. ED.sub.50 = 260 mg/Kg.
200 mg kg.sup.-1 os of both compounds reduced the hypermotility which is induced in mice after administering 1-mg kg.sup.-1 i.p. of amphetamine. ED.sub.50 = substantially 200 mg/Kg.
The amphetamine antagonizing effect was studied in accordance with:
Reconsideration of the central nervous system pharmacology of amphetamine--Influence of pharmacologic agents on cumulative and total lethality in grouped and isolated mice. Toxicol. Appl. Pharmacol. 9, 536-554 (1966).
(6) Capability to increase barbiturate-induced hypnosis:
The duration of the absence of the righting reflex due to barbiturate (Evipan 75 mg kg.sup.-1 e.p.) in mice was increased (+ 50%) 1 hour after administering 13 mg kg.sup.-1 os of compound II and 45 mg kg.sup.-1 of compound IV respectively in accordance with:
The ED.sub.50 for compound II was substantially 13 mg/Kg and 45 mgm/Kg for compound IV.
(7) Hypothermal activity:
Both compounds II and IV, induced hypothermia 60 min after 130 mg kg.sup.-1 os was administered in rats.
Body-temperature decreases: At max -- 1.degree. C. by the method described in "Screening Methods In Pharmacology" by R. A. Turner, Academic Press--New York and London 1965 page 92.
(8) Analgesic activity:
Compounds II and IV are exhibited in a marked analgesic action.
Against intraarticular pain due to AgNO.sub.3 administration in rats: both compounds at the dose level of 130 mg kg.sup.-1 os reduced by 50% the response versus the previous trial. (ED.sub.50 = 130 mgm/Kg).
Against phenylquinone writhing test in mice: both compounds at the dose level of 130 mg kg.sup.-1 reduced by 50% the no. of spasms versus control group. (ED.sub.50 = 130 mgm/Kg).
Against the hot-plate test in mice: Compound II at the dose level of 130 mg kg.sup.-1 os, (ED.sub.50 = 130 mg/KG) and compound IV at the dose level of 100 mg kg.sup.-1 (ED.sub.50 = 100 mg/Kg) increased by 50% the reaction time (liking) versus the previous trial.
Analgesic testing in accordance with:
The method of preparation of these compounds comprises reacting an activated form of nicotinic acid such as the chloride or methylester, with either appropriate aniline; 2-nitro-5-trifluoromethyl-aniline and 2-trifluoromethyl-5-nitroaniline.
From the above reaction, compounds (I) and (III), which are novel intermediates, are reduced by a reducing agent such as hydrogen, using Ni/Raney as the catalyst, to form compounds (II) and (IV). ##STR4##
In both sequences (a.sub.1) and (b.sub.1) the reaction is effected by adding 2-nitro-5-trifluoromethyl-aniline or 2-trifluoromethyl-5-nitro-aniline to nicotinoyl chloride or to methylester of nicotinic acid in an inert solvent such as THF, or dioxan; compounds (I) and (III) are obtained.
When nicotinoylchloride is used it is advisable to employ an acceptor of the hydrochloric acid which is formed, as at least a portion of the solvent may include, trimethylamine, triethylamine, pyridine, morpholine, etc., for such a purpose.
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
| 3462532 |
Hardy |
Aug 1969 |
|
Continuation in Parts (1)
|
Number |
Date |
Country |
| Parent |
610877 |
Sep 1975 |
|
Patent Grant
4107316
