NO150483B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE THIENO (-3,2-C) AND THIENO (2,3-C) -PYRIDINES - Google Patents

Description

The present invention relates to an analogue method for the production of therapeutically active compounds of the formula:

1 2 in which R and R are hydrogen, (C₁-C₆)-alkyl, (C₂-C₃)-alkenyl or (C₂-C₂-alkynyl or R₂" is hydrogen and R₂ is phenyl optionally substituted with trifluoromethyl, phenyl-(C -^-C-,)-alkyl which in the phenyl group is optionally substituted with halogen or two (C1~C4)- alkoxy, pyridyl-(C1~C2)-alkyl, (C1~C4)-dialkylamino-(C2-C ) -alkyl or morpholino-(C2-C3)-alkyl or R<1> and R<2 >together with the nitrogen atom to which they are attached form pyrrolidine, piperidine, morpholine or piperazine which is substituted in the 4-position with (C1~C4 )-alkyl, benzyl or phenyl which may be substituted with halogen, (C^-C^)-alkyl or (C^-C^)-alkoxy, and pharmaceutically acceptable acid addition salts thereof. The analog method is characterized in that an amine of formula: in which R 1 and R 2 are as defined above, is reacted with a mixed anhydride of formula (III) or (IV):

wherein R is a C1-3-alkyl group.

The starting compounds of formula (III) and (IV) are in turn prepared by condensation, in the presence of triethylamine, of a thienopyridine of formula (V) or (VI):

with an alkyl chloroformate of the formula C1C00R in which R is as previously indicated. Both reactions are preferably carried out in sequence in the same container: mixed anhydrides of formula (III) and (IV) are first prepared at temperatures between -5 and +15° C in an inert solvent such as chloroform or methylene chloride; amine

, pure or dissolved in a solvent such as benzene,

toluene, chloroform or methylene chloride is then added at the same temperature, after which the mixture is allowed to stand at room temperature.

Thienopyridines of formula (V) and (VI) are prepared by reacting a compound of the formula:

with nitric acid, after which dehydration and removal of the nitroso group in the resulting compounds is carried out by reaction with an alkali metal hydroxide and subsequent neutralisation. The starting materials of formula (VII) or (VIII) can in turn be prepared by reacting a compound of formula

with an aqueous formaldehyde solution in the presence of a strong acid.

The following examples illustrate the invention.

Example 1

6-methylaminocarbonyl-thieno[3,2-c]pyridine

Formula (I): NR<1>!*<2> = NHCH3. Derivative No. 1

To a solution of 10 g (0.050 mol) 6-carboxy-thieno-[3,2-c]pyridine and 5.6 g (0.057 mol) triethylamine in 500 cm 3 of dry chloroform kept at 10° C was slowly added 6, 2 g (0.057 mol) of ethyl chloroformate with vigorous stirring. When the addition was complete, stirring was continued at room temperature for a further 40 minutes, after which a solution of 2 g (0.064 mol) methylamine in 50 cm 3 benzene was added dropwise. The reaction mixture was allowed to stand at room temperature for 4 hours, was evaporated to dryness, after which the residue was taken up in ether. The ether phase was washed with a saturated aqueous sodium carbonate solution, dried over sodium sulfate and evaporated to dryness.

The solid residue was recrystallized from benzene-diisopropyl ether. Pink crystals were obtained with m.p. 99° C. Yield: 79%.

Example 2

6- 3- dimethylaminoethylaminocarbonyl- thieno[ 3, 2- c] pyridine Formula (I): NR<1>R<2> = NH(CH2)2N(CH3)2. "Derivative No. 2

To a solution of 10 g (0.056 mol) of 6-carboxy-thieno-[3,2-c]pyridine and 5.6 g (0.057 mol) of triethylamine in 300 cm 3 of dry chloroform kept at 10° C was slowly added 6 .2 g (0.057 mol) of ethyl chloroformate under vigorous stirring. After the addition was complete, stirring was continued at room temperature for a further 40 minutes, after which 5.4 g (0.061 mol) of 3-dimethylaminoethylamine was added dropwise. The reaction mixture was allowed to stand at room temperature for 3.5 hours, and was then evaporated to dryness and the residue taken up in N-hydrochloric acid. The aqueous acid phase was washed with ether and then made alkaline with 6N sodium hydroxide and extracted with methylene chloride. The methylene chloride extracts were dried over dry sodium sulfate and evaporated to dryness. The oily residue was purified via its dihydrochloride. Beige crystals,

sm.p. = 170° C (isopropanol-methanol). Yield: 75%.

Example 3

5-(4-p-chlorophenyl-l-piperazinyl)carbonyl-thieno[2,3-c]pyridine

Formula (II):

Derivative No. 3

To a solution of 12 g (0.067 mol) 5-carboxy-thieno-[2,3-c]pyridine and 6.9 g (0.068 mol) triethylamine in 250 cm 3 of dry chloroform kept at 10° C, was slowly added 7 .3 g (0.068 mol) of ethyl chloroformate under vigorous stirring. Stirring was continued at room temperature for a further 50 minutes and 13.2 g (0.067 mol) of p-chlorophenylpiperazine dissolved in 50 cm 3 of chloroform was then added dropwise. The reaction mixture was allowed to stand at room temperature for 5 hours, after which it was evaporated to dryness and the residue was taken up in methylene chloride. The methylene chloride phase was washed with a saturated aqueous sodium bicarbonate solution, dried over dry sodium sulfate and evaporated to dryness. The resulting crystals were purified by column chromatography through silica (eluent: ethyl acetate). White crystals with m.p. = 170° C was obtained (isopropanol-diisopropyl ether). Yield: 41%.

Example 4 6-ethylaminocarbonyl-thieno[3,2-c]pyridine

Formula (I): NR<1>R<2> = NHC2H5. Derivative No. 4.

This compound was prepared according to the procedure

according to Example 1, from 6-carboxy-thieno[3,2-c]phridine and ethylamine. Beige crystals with m.p. 110° C. (diisopropyl ether) was obtained, yield equal to 87%.

Example 5

5-isopropylaminocarbonyl-thieno[2,3-c]pyridine

Formula (III): NR^-R<2> = NH C3H?. Derivative No. 5.

This compound was prepared according to Example 1 from 5-carboxy-thieno[2,3-c]pyridine and isopropylamine. Light brown crystals with melting point 102° C (diisopropyl ether) were obtained, yield equal to 80%.

Example 6

6-n-Butylaminocarbonyl-thieno[3,2-c]pyridine

Formula (I): NR<1>R<2> = NHC^Hg. Derivative No. 6

This compound was prepared as described in Example

2 from 6-carboxy-thieno[3,2—c]pyridine and n-butylamine. Hydrochloride: orange-yellow crystals of melting point 104° C. (acetonitrile) were obtained. Yield: 55%.

Example 7

6-octylaminocarbonyl-thieno[3,2-c]pyridine

Formula (I): NR^-R<2> = NHCgH^. Derivative No. 7.

This compound was prepared as described in Example

1 from 6-carboxy-thieno[3,2-c]pyridine and octylamine. White crystals with m.p. 63°C (diisopropyl ether) was obtained. Yield: 54%.

Example 8

6-dimethylaminocarbonyl-thieno[3,2-c]pyridine

Formula (-1): NR<1>R<2> = N(CH3)2. Derivative No. 8.

This compound was prepared as described in Example 1 from 6-carboxy-thieno[3,2-c]pyridine and dimethylamine. White kry^ stables with sm.p. 93°C (diisopropyl ether) was obtained. Dividend: 55%.. • - -

Example 9

6- diethylaminocarbonyl- thieno[ 3, 2- cj pyridine

Formula (I): NR<1>R<2> = N(C2H5)2. Derivative No. 9.

This compound was prepared as described in Example

1 from 6-carboxy-thieno[3,2-c]pyridine and diethylamine. Beige crystals with m.p. 110°C (diisopropyl ether) was obtained. Yield: 80%.

Example 10

6-(1-pyrrolidinyl)-carbonyl-thieno[3,2-c]pyridine

Formula (I):

derivative No. 10.

This compound was prepared as described in Example 1 from 6-carboxy-thieno[3,2-c]pyridine and pyrrolidine. Off-white crystals with m.p. 105°C (diisopropyl ether) was obtained. Yield: 52%.

Example 11

6-piperidinocarbonyl-thieno[3,2-c]pyridine

Formula (I):

Derivative No. 11.

This compound was prepared as described in Example 1 from 6-carboxy-thieno[3,2-c]pyridine and piperidine. Light brown powder with m.p. 145°C (diisopropyl ether) was obtained. Yield: 96%.

Example 12

6-morpholinocarbonyl-thieno[3,2-c]pyridine

Formula (I):

Derivative No. 12.

This compound was prepared as described in Example

1 from 6-carboxy-thieno[3,2-c]pyridine and morpholine. White crystals with m.p. 136° C (benzene-diisopropylether y was obtained. Yield: 79%.

Example 13

5-benzylaminocarbonyl-thieno[3,2-c]pyridine

Formula (III: NR 1R 2= NHCH2C5H5 Derivative no. 13

This compound was prepared as described in Example 1 from 5-carboxy-thieno[Zr 3 -clpyridine and benzylamine. Beige crystals with m.p. 113°C (isopropanol) was obtained. Yield: 75%.

Example 14

6-o-chlorobenzylaminocarbonyl-thieno[3,2-c]~ pyridine

Formula (X):

IN

Derivative No. 14.

This compound was prepared as described in Example 1 from 6-carboxy-thieno[3,2-c]pyridine and o-chlorobenzylamine. Beige-colored powder with m.p. 169°C (methanol) was obtained. yield: 58%.

IJUtOJ

Example 15

6-phenethylaminocarbonyl-thieno[3,2-c]pyridine

Formula (I): NR<1>!*<2> = NHCH2CH2C6H5. Derivative No. 15

This compound was prepared as described in Example 1 from 6-carbdoxy-thieno[3,2-c]pyridine and phenethylamine. Beige-colored crystals with m.p. 127° C (isopropanol-diisopropyl ether) is obtained. Yield: 66%.

Example 16

6- arylaminocarbonyl-thieno[3,2-c]pyridine

Formula (I): NR"<*>"R<2> = NHCH 2 -CH=CH 2 . Derivative No. 16

This compound was prepared as described in example 1 from 6-carboxy-thieno[3,2-c]pyridine and allylamine. Oxalate: white crystals with snot. 131° C (ethyl acetate), Yield: 54%.

Example 17

6-propargylaminocarbonyl- thieno [-3, 2- c j pyridine

Formula (I): NR<1>R<2> = NHCH2C=CH Derivative No. 17

This compound was prepared as described in Example 1 from 6-carboxy-thieno[3,2-c]pyridine and propargylamine.■ Pink

crystals with m.p. 134° Ct (isopropanol-diisopropyl ether) was obtained. Yield: 60%.

Example 18

6- 3- diethylaminoethylaminocarbonyl- thiecno[ 3, 2- c] pyridine Formula (I): NR<1>R<2> = NH(CH2)2N(C2H5)2 Derivative No. 18

This compound was prepared as described in example 2 from 6-carboxy-thieno[3,2-c]pyridine and Δ-diethylaminoethylamine.

Dihydrochloride: Beige crystals with m.p. 145° C (isopropanol-methanol) . Yield: 81%.

Example 19

6-p-morpholinoethylaminocarbonyl-thieno[,,3,2-c]pyridine

Formula (I):

Derivative No. 19

This compound was prepared as described in Example 2 from 6-carboxy-thieno[3,2-c]pyridine and N-(2-aminoethyl)-morpholine.

White crystals were obtained with m.p. 104° C (isopropanol-diisopropyl ether) . Yield: 71%.

Example 2 0

6-Y-dimethylamlnopropylaminocarbonyl-thieno[3,2-c]pyridine Formula (I):NR<1>!*<2> = NH (CH2) 3N (CH3) 2 . Derivative No. 20

This compound was prepared as described in Example 2 from 6-carboxy-thieno[3,2-c]pyridine and Y-dimethylaminopropylamine. Dihydrochloride: beige crystals with m.p. 146°C (ethanol). Out-exchange 77%

Example 21

5-(4-pyridiyl-methyl)aminocarbonyl-thieno[2,3-c]pyridine

Formula (II):

.Derivative No. 21

This compound was prepared as described in example 3 from 5-carboxy-thieno[2,3-c]pyridine and 4-raminomethyl-pyridine. Light brown crystals were obtained with m.p. 167° C (isopropanol-diisopropyl ether). yield: 78%.

Example 22

. 6"-(4-pyridyl-methyl)aminocarbonyl-thieno[3.,2-c]pyridine

FORumula (I):

Derivative No. 22

This compound was prepared as described in Example

3 from 6-carboxy-thieno-[3,2-c]pyridine and 4-aminomethyl-pyridine. j Orange crystals with a melting point of 146° C. (ethyl acetate) were obtained. Yield: 98%.

Example 2 3

5-( 3- pyridiyl- methyl) aminocarbonyl- thieno[ 3, 2-c] pyridine

in

The form (III):

Derivative No. 23 This compound was prepared as described in Example 3 from 5-carboxy-thieno[2,3-c]pyridine and 3-aminomethyl-pyridine. Beige crystals were obtained with m.p. 143° C (isopropanol-diisopropyl ether) . Yield: 73%. Example 2 4 6-(3-pyridiyl-methyl)aminocarbonyl-thieno[3,2-c]pyridine Formula (I): NR<1>R<2>=

Derivative No. 24.

This compound was prepared as described in Example 3 from 6-carboxy-thieno[3,2-c]pyridine and 3-aminomethyl-pyridine. Beige crystals were obtained with m.p. 137°C (ethyl acetate). Yield: 55%.

Example 25

6-(3-trifluoromethyl-phenyl)aminocarbonyl-thio[3,2-c]pyridine

Formula (I)r

This compound was prepared as described in Example 1 from 6-carboxy-thieno[3,2-c]pyridine and m-trifluoromethylaniline. White crystals with m.p. 151°C (isopropanol-diisopropyl ether) was obtained. Yield: 62%.

Example 2 6 6-(4-p-tolyl-l-piperazinyl)carbonyl-thieno[3,2-c~]pyridine

Formula (I)-:

This compound was prepared as described in Example 3 from 6-carboxy-thieno[3,2-c]pyridine and 1-p-tolyl-piperazine. Beige crystals were obtained with m.p. 150° C (isopropanol-diisopropyl ether). Yield: 82

Example 27

6-(4-o-chlorophenyl-l-piperazinyl)-carbonyl-thieno[3,2-c]pyridirr

Formula (I):

This compound was prepared as described in Example 3 from 6-carboxy-thieno[3,2-c]pyridine and 1-1-chlorophenyl-piperazine. Beige crystals with m.p. 140°C (isopropanol-diisopropyl ether) was obtained. Yield: 52%.

Example 28

6-(4-m-chlorophenyl-l-piperazinyl)carbonyl-thieno[3,2-c]pyridine

Formula (I):

This compound was prepared as described in Example 3 from 6-carboxy-thieno[3,2-c]pyridine and 1-m-chlorophenyl-piperazine. White crystals with m.p. 157°C (ethyl acetate) was obtained, yield: 52%.

Example 2 9

6-(4-p-Methoxyphenyl-1-piperazinyl)-thieno[3,2-c]pyridine

Formula (II):

Derivative No. 29

This compound was obtained as described in Example

3 from 6-carboxy-thieno[3,2-c]pyridine and 1-p-methoxyphenyl-piperazine. White crystals with m.p. 15^2°C (ethyl acetate-diisopropyl ether) was obtained. Yield: 7 2%.

Example 30

5-(4-o-Methoxyphenyl-l-piperazinyl)carbonyl-thieno[2,3-c]pyridine

Formula (II):

Derivative No. 3 0

This compound was prepared as described in Example

3 from 5-carboxy-thieno[2,3-c]pyridine and 1-o-methoxyphenyl-pipera-

zin. Beige-colored crystals were obtained with m.p. 171° C (isopropanol).. Yield: 62%.

Example 31

6-carbamoyl-thieno[3,2-c]pyridine

Formula -<I): NR<1>R<2> = NH2. Derivative No. 31

This compound was prepared as described in Example

1 from 6-carboxy-thieno[3,2-c]pyridine and ammonia. white crystal

laughing with sm.p. 172°C (acetonitrile) was obtained. Yield: 68%.

Example 32

5-carbamoyl-thieno[3,2-c]pyridine

Formula (II): NR<1>R<2> NH2• Derivative No. 32

This compound was prepared as described in Example 1 from 5-carboxy-thieno[2,3-c]pyridine and ammonia. white crystal

laughing with sm.p. 200°C (acetone thiril) was obtained. Yield: 76%.

Example 33

5-phenethylaminocarbonyl- thieno[ 2, 3- c j pyridine

Formula (II): NR<1>R<2> = NHCH2CH2CgH5. Derivative No. 3 3

This compound was prepared as described in Example

1 from 5-carbonyl-thieno[2,3-c]pyridine and phenethylamine. Beige-colored crystals with m.p. 130°C (isopropanol-diisopropyl ether) was obtained. Yield: 79%.

Example 34

6-(4-benzyl-l-piperazinyl)carbonyl-thieno[3,2-c]pyridine

Formula (I):

This compound was prepared as described in Example 3 from 6-carboxy-thieno[3,2-c]pyridine and 1-benzyl-piperazine. Dihydrochloride: white crystals with m.p. 187° C (isopropanol-ethanol). Yield: 4 9%.

Example 35

6-( 3, 4- dimethoxy-phenethyl)- aminocarbonyl- thieno[ 3, 2-c] pyridine

Formula (I) :

This compound was prepared as described in Example

. fel from: s6r-carboxy-thieno [3,2-c] pyr' ld"i'h:--pg..(3^.i4.?rdlméthoxy-f enethyl )-amine...White crystals with sm. at 125 C (isopropanol-diisopropyl-<■< ether) was retained. Yield: 77%."

'<■&■'■'■$'■■'■■ '■■ "'" . " '" ■'"; ' '•••s" ' '•■;'""!?<-■•.•>■ ■'. '■• •- ■■ ■

36.-

- tr5-( 3?;4- dimethoxy-phenethyl) aminocarbonyl- thieno [ 2 > 3- c] pyridine

..Formula, (II) :

This compound was prepared as described in Example 1 from 5-carboxy-thieno[2,3-c]pyridine and (3,4-dimethoxy-phenethyl)-amine. White crystals with m.p. 125°C (isopropanol-diisopropyl ether) was obtained. Yield: 73%.

Example 3 7

6-( 4- methyl- l- piperazinyl)- carbonyl- thieno[ 3, 2-c] pyridine

Formula (I):

This compound was prepared as described in Example 1 from 6-carboxy-thieno[3,2-c]pyridine and 1-methyl-piperazine. Maleate: brown powder with m.p. 168° C (isopropanol). Yield: 83%.

The pharmacological and toxicological data provided

in what follows shows the properties of the derivatives of formula (I)

and (II) both in terms of toxicity and tolerance, and in terms of their activities, typically their sedative, anti-convulsant and anti-inflammatory activities.

I - Toxicological examination

The compounds of formula (I) and (II) exhibit excellent tolerance and low toxicity.

Regarding acute toxicity, the LD^q/24 hours/kg body weight, determined according to the method described by Miller and Tainter, by oral administration is above 400 mg for all

derivatives in mice.

According to the same method, DLj.q/24 hours/kg body weight, be-

voted by intravenous administration 154 mg for derivative No. 1,

89 mg for derivative no. 2, 184 mg for derivative no. 10, 130 mg for derivative no. 11, 350 mg for derivative no. 12, 65 mg for derivative no.

18, 90 mg for derivative no. 22, 96 mg for derivative no. 24 and 105 mg for derivative no. 31. "<*>" • '?=> - '

In addition, tests ..performed with regard to-, to-.acute,

chronic, subchronic and delayedÆtoxicity- in difference^ge.;Myreé5^5t.. ■"<?>■><?>' species no local or systemic^ breaks ion, no-, disturbances" or deviations by biochemical, microscopic ^or Macroscopic-microscopic examinations carried out during the experiment. '-^fe^-;- ••- i;•

II - Pharmacological examination * "...

(I) Sedative effect *■ U*?-' ■ ~' ?- jMvt::

A). • Investigation of behaviour

This survey was carried out according to the method 'which is.

described by Samuel IRWIN (Ph. D. Animal and Clinical Pharma-

cology Techniques in Drug Evaluation). The derivatives of formula (I) and (II) were administered orally to mice at a dose of 100 mg/kg. The treated animals were observed for 4 hours after administration of the active compound. Their behavior was studied, and in addition various physiological parameters (temperature, heart rate and respiration rate) were determined. A marked reduction in moto-

increased activity and muscle tone, together with a reduction in oar alertness and reaction to noise and surroundings were noted for the treated animals.

B) Effect on hypnotic drugs

The compounds of formula (I) and (II) potentiate very markedly the effect of hypnotic drugs. When administered orally to different groups of mice, at a dose of 100 mg/kg, 30 minutes before intraperitoneal injection of an infra-hypnotic dose of sodium pentobarbital, these gave, compared to untreated reference animals, a marked potentiation of the effect of the barbiturate.

The number of sleeping mice, the average time to sleep and the duration of sleep are markedly increased in the treated group. The results obtained with the more active compounds are listed in the following table I.

(2) Anti-convulsant action

This effect was investigated with respect to electric shock. In rats, application of electrical stimulation over an electroconvulsive threshold will produce convulsions. The presence and duration of each convulsive phase and also the intensity of the total number were compared in reference animals and in treated animals.

Groups of 10 rats were used per test material, and each animal was orally administered 100 mg/kg of the test material.

An electrode was placed on each side of the root of the tail of each animal, and 30 minutes after treatment the animal, placed in a glass cage, was given 50 milliseconds of a sinus current of 50 periods/seconds at 120 volts.

Passage of the current induces a convulsive seizure if each phase (tonic, clonic, muscular relaxation) is appropriate. The intensity of the seizure is then graded according to a scale from 0 to 4, depending on the presence of each of the phases and their duration. The derivatives of formula (I) and (II) were tested together with phenobarbital which exhibits a marked anticonvulsant effect (the intensity of seizures is equal to 2), while in untreated reference animals a maximum intensity of 4 was obtained.

It was thus determined that all the compounds of formula (I) and (II) exhibit a significant protection against electric shock as the mean values for the intensity of the seizure in each group are 2.5 for derivative no. 5, 3 for derivative no. 4, 2.5 for derivative no. 5, 2.5 for derivative no. 9, 3 for derivative no. 13, 2.5 for derivative no. 19, 2.5 for derivative no. 25, 2.5 for derivative no. 30 and 2.5 for derivative no. 31.

(3) Anti-inflammatory action

a) Localized carrageenin-induced edema A 1% carrageenin solution (0.1 mol) was injected

at time 0 in the metatarsal flexor muscle in the right hind paw of rats. The animals in the treated group were further orally administered 100 mg/kg of the test material, respectively 1 hour before, simultaneously with, and then 1 hour and 2.5 hours after the injection of the phlogogenic agent. The percentage anti-inflammatory activity was determined as a function of time, relative to the reference group, by determinations made with a 'ROCH micrometer at time 0, 1 hour,

2 hours, 3 hours and 5 hours after the carrageenin administration.

The results obtained with the derivatives of formula (I) or (II) are indicated in the following table II.

b) Ovalbumin-induced systemic edema A simultaneous intraperitoneal injection of 1 ml ovalbumin

and 0.5 ml of 1% Evans blue solution was performed on rats. On the other hand, the animals in the treated group were orally administered 100 mg/kg of the test derivative 1 hour before and simultaneously with the ovalbumin administration. The intensity of the phenomenon thus induced was graded according to a scale from 1 to 5, depending on the course of the inflammatory syndrome. The mean edema intensity and the percentage reduction of the edema reaction, in relation to the control group, were thus determined as a function of time.

The percentage anti-inflammatory activity obtained 2 and 3 hours after ovalbumin injection is indicated in the following table III for certain derivatives of formula (I) or (II).

The results of the investigations show the low toxicity and good tolerance, and also the useful sedative, anti-convulsant and anti-inflammatory properties exhibited by the derivatives of formula (I) or (II) which make them valuable in human and veterinary medicine.

The compounds of formula (I) and (II) can be formulated for oral administration as tablets, coated tablets, capsules, drops and syrups. They can also be formulated for rectal administration as suppositories, and for parenteral administration as injectable solutions.

Each unit dose will preferably contain from 0.050 g to 0.500 g of active ingredient. Daily doses may vary from 0.050 g to 1.50 g of active ingredient, depending on the patient's age and condition.

Due to their sedative and anti-convulsive action, the derivatives of formula (I) or (II) will reduce personality and behavioral disorders and facilitate personal contact due to improved mental equilibrium. They are applicable to children and adults in cases of aggressiveness, irritability, instability, agitation and psychomotor agitation, and also in all manifestations of agitation.

Due to their anti-inflammatory action, these when administered in short or prolonged treatments act effectively on the inflammatory reaction to regulate edema, hypersecretion and sweating during the course of the various stages of inflammation. They are indicated in cases of chronic inflammatory rheumatism, degenerative rheumatism, ab-articular conditions, acute gout, in post-operative plastic surgery, in traumatology and in oto-rhino-laryngology.

Claims (1)

Analogous method for the preparation of therapeutically active compounds of formula: hevlolr in R (C1 ^o-Cg -^R -a2lkeyr nhyyl dreolgleenr , R1 (Ce^-r Chgy)-darolkgyen l, and (CR2-2 Ce3r )-afleknyenyl optionally substituted with trifluoromethyl, phenyl-(C^ -C2)-alkyl which in the phenyl group is optionally substituted with halogen or two (C1-C4)- alkoxy, pyridyl-(C^-C^)-alkyl, (C^-C^)-dialkylaminoc-(C2-C ) -alkyl or morpholino-(C2"C3)-alkyl or R<1> and R<2> together with the nitrogen atom to which they are attached, form pyrrolidine, piperidine, morpholine or piperazine which is substituted in the 4-position with (C1~C4)-alkyl, benzyl or phenyl which may be substituted with halogen, (C1~C4)-alkyl or (C 1 -C 4 )-Alkoxy, and pharmaceutically acceptable acid addition salts thereof, characterized in that an amine of formula: in which R 1 and R 2 are as defined above, is reacted with a mixed anhydride of formula (III) or (IV): wherein R is a C^_^ alkyl group.