CA1218374A - Derivatives of 3-pyrrolidinopropiophenone and a process for preparation thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The subject of the invention are valuable derivatives of 3-pyrrolidinopropiophenone of the formula:

wherein R is an ethyl-, propyl-, isopropyl-, butyl-, isobutyl-group or a cycloalkylgroup having 5 - 7 carbon atoms, and the pharmaceutically acceptable and addition salts thereof and a process for preparing such derivatives which involves the reaction of a derivative of propioPhenone of the formula:

where R is as above, with a formaldehyde or the equivalent and pyrrolidine or the salts thereof.

The compounds of this invention exhibit a potent activity on muscle relaxation.

Description

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PREPARATION THEREOF

FIELD OF THE INVENTION
This invention relates to novel derivatives of 3-pyrrolidinopropiophenone and the pharmaceutically acceptab-le acid addition salts thereof, which exibit a potent activity on muscle relaxation and t~ a process for preparati-on thereof.
More particularly, this invention relates to the derivatives of 3-pyrrolidinopropiophenone represented by formula(I) :

R ~ -CO-CH-CH2-N ~ (I), wherein R represents an ethyl-, propyl-, isopropyl-, butyl~
and isobutylgroup or a cycloalkylgroup having 5-7 carbon atoms and the pharmaceutically acceptable acid addition salts thereof, as well as to a process for preparation thereof.

DESCRIPTION OF THE PRIOR ART
Hitherto, as a medicine having an activity on muscle 37'~

relaxation, Tolperisone (generic name, MerCk Index, 9th Edition, 9219) represented by formula(II) :

3 ~ -CO-CH-CH2-N ~ (II), was on the market and been widely provided for clinical use in the treatment of muscular contractive and spastic paralysis.
Recently, for the purpose of improving the activity on muscle relaxation. of Tolperisone, Eperisone (WHO Chronicle, 36(2), roposed International Nonproprietary Names : List 47) represented by formula(II1) :

C2H5 ~ -co-cH-cH2-~ ~ (III), has been prepared and already clinically used.
Eperisone of formula(III) shows an improvement in muscle relaxation activity. However, Eperisone dose not show an improvement in toxicity and has just the same strong toxicity as Tolperisone. Further concerning the side effect, Fperisone causes hepatic and kidney function disorder, while Tolperisone possesses only the ~83~

hepatic functional disorder. Therefore, Eperisone is rather reyressive eompared to Tolperisone in respeet to the unwanted side effects.
Tolperisone and Eperisone, as medieines which are commercially available, are not yet satisfactory.

SUMMARY OF THE INVENTION
As a result of extensive investigation on new compounds having a potent aetivity on musele relaxation, it has been found that the eompounds of formula(I) have extremely weak toxieity and possess an effeetive aetivity on muscle relaxation as compared to those of formula(II) and (III), and thus this invention has been accomplished.

DETAILED DESCRIPTION OF THE INVENTION
In the foregoing formula(I), examples of cyeloalkyl-group shown by R are a eyclopentyl- cyclohexyl- and cyeloheptylgroup.
The eompounds represented by formula(I) can be eonverted into the corresponding pharmaceutically aeeeptable acid addition salts in a conventional manner and the base can be liberated from the so prepared acid addition salts, if neeessary.
Examples of the pharmaceutically acceptable acid ~Z~37~

addition salts of the compounds represented by formula(I?, are salts with a mineral acid, such as hydrochlorie acid, nitrie acid, sulfuric acid, hydrobromie acid, hydroiodic aeid, phosphoric acid and the like, and with an organic aeid, such as acetie aeid, maleie acid, fumaric acid, citric acid, oxalie aeid, tartaric acid and the like.
Aceording to this invention, the novel derivatives of 3-pyrrolidinopropiophenone represehted by formula(I) ean be prepared by reacting a derivative of propiophenone represented by formula(IV~ :

R ~ -CO-CH2-CH3 ~IVJ, wherein R is as defined above, with a formaldehyde and pyrrolidine represented by formula(V):

HN ~ (V), or a salt thereof in a solvent.
As a formaldehyde to be used for the preparation, formald-ehyde itself, linear or eyelie polymers of formaldehyde, sueh as paraformaldehyde, trioxane and the like, ean be employed.

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Pyrrolidine is used usually as a salt of a mineral acid such as hydrochloric acid, hydrobromic acid or nitric acid, whereas the pyrrolidine in the form of the free base is reacted in acid reaction medium by adding a sufficient amount of a mineral acid to the reaction mixtureA
The mole ratio of the reactants can be chosen freely.
However, 1 mol of pyrrolidine represented by formula(V) is reacted with at least 1 mol, preferably 1.1 moles, of a derivative of propiophenone represented by formula(IV) and at least 1 mol, preferably 1.5 moles, of formaldehyde, so that the pyrrolidine used can be eliminated from the reaction mi~ture, which should be submitted to an after treatment.
Solvent used in the process of this invention is an alcoholic solvent such as methanol, ethanol, propanol, is opropanol or the like, a nitroalkanic solvent, such as nitromethane, nitroethane or the like, or a lower alkyl ester of lower aliphatic acid, such as methyl acetate, ethyl acetate, ethyl propionate or the like. Preferably can be used a lower alkyl ester of a lower aliphatic acid.
The reaction can be carried out at a temperatu~re between room temperature and the boiling point of the solvent used, preferably at the boiling point of the solvent.
The derivatives of propiophenone represented by formula(IV), which can be used as the starting materials for .~

the process of this invention, are all known, and can be prepared in a manner as described, for example, in litera-ture, Pharmazie, 24, 735(1969), Journal of the American Chemical Society, 78, 5899(1953), Annalen der Chemie, Justus Liebigs, 5~6, 273(1941), DBP 2059618, etc.
The thus prepared derivatives of 3-pyrrolidino-propiophenone represented by formula(I) and pharmaceu-tically-acceptable acid addition salts thereof exibit an effective activity on muscle relaxation, inhibition of spinal reflex, nicotine-induced convulsion and oxotremorine-induced tremor and can be used extremely favorably as a medicine for treatment of spasmodic muscular contracture in diseases of kinesthetic origin such as low back pain, hernia of interver-tebral dice, and osteoarthritis of the spine.
The compounds of this invention exhibit strong muscle relaxant activity with minimized side effects.
The high order of these activities of the active agent of this invention is evidenced- by test in lower animals, representative of which are reported herein. A compound of this- invention can be administered pér os, e. g., in the form of pills or tablets, in which it may be present together with the usual pharmaceutical carriers, conventionally by compounding the compounds of this invention together with a custornary carrier or adjuvant, such as talc, magnesium ~Z1837~

stearate, starch, lactose, gelatin, any of numerous gums, and the like. Thus, in their most advantageous form, the compositions of this invention will contain a non-toxic pharmaceutical carrier in addition to the active ingredient of this invention. Exemplary solid carriers are lactose, magnesium stearate, calcium stearate, starch, terra alba, dicalcium acacia, or the like.
Representative liquid carr~ers are peanut oil, sesame oil, olive oil, water, or the like. The active agents of this invention can be conveniently administered in such composi-tions containing active ingredient so as to eventually be within the dosage range illustrated hereinafter. Thus, a wide variety of pharmaceutical forms suitable for many modes of administration and dosages may be employed.
For oral administration, the active ingredient and pharma-ceutical forms suitable for many modes of administration and dosages may be employed. For oral administration, the active ingredient and pharmaceutical carrier may, for example, take the form of a granule, pill, tablet, lozenge, elixir, syrup,or other liquid suspension or emulsion, whereas, for parenteral administration, the composition may be in the form of a sterile solution or suppository.
The method of using the compounds of this invention comprises internally or externally administering a 37~

compound of this invention, preferably orally or parente-rally and preferably admixed with the pharmaceutical carrier, for example, in the form of any of the above compositions, or filled into a capsule, to alleviate conditions to be treated and symptoms thereof in a living animal body. Illustratively, it may be used in an amount of about 1 to about 100 mg. per unit dose, preferably 30 to 80 mg. for an oral dose, while parenteral dosages are usually less and ordinarily about one-half of the oral dose. The unit dose is preferably given a suitable number of times daily, typically three times. The daily dose may vary depending upon the number of times given.
Naturally, a suitable clinical dose must be adjusted in accordance with the condition, age, and weight of the patient, and it goes without saying that the enhanced activities of the compounds of this invention, together with their reduced side effects, also make them suitable for wide variations, and the invention therefore should not be limited by the exact ranges stated. The exact dosage, both unit dosage and daily dosage, will of course have to be determined according to established medical principles.
The effective activity on muscle relaxation (rotating rod test), nicotine-induced convulsion and oxotremorine-induced tremor areshown in Fig.l, Table 1 and 2 respectively, examples representing the potentiating pharmacological i~837~

effect of the inventive compounds.
The acute toxicity has been determined as shown in Table 3, wherein as a reference compound, Eperisone, a marketed product, represented by formula~II) is used.
Test Compounds:
Compound of Invention 1 (Example 3) CH3(CH2)3 ~ -Co-c~i-ci~2-N ~ HCl Compound of Invention2(Example 6) CH3Cff~ CO-cl~-c1~2-N5 .HCl cll3 Reference Drug (Eperisone hydrochloride) CH3CH2 ~ -CO-CH-CH2-N ~ .HCl ~1~3 1. Activity on muscle relaxation (rotating rod test) ... ~, ~2~37~

Experiment:
Male ddY mice 5 weeks old were used with 10 animals in a group. The mice were tested previously by using a rotating rod of 3cm in diameter at the rate of lOr.p.m. and the mice which could stay on the rotating rod during more than 60 seconds were selected for the t~st. The compounds were administrated per os at a dose of 200 mg/kg and after 10, 20, 30 and 60 minutes of drug administration the mice were moved to the rotating rod. The times (seconds) of stayihg on the rod have been measured. It has been judged that the compound is effective, if the mice have fallen from the rod before staying 60 sec.
The results are shown in the Figure 1.

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2. Activity on nicotine-induced convulsion -Experiment:
Male ddY mice 5 weeks old were used with 5 animals in a group. The compounds were administrated per os at a dose of 25 mg/kg. After 15 minutes of drug administration, Nicotine tartarate was administered intravenously at an amount of 3mg/kg and the tonic convulsions and dead animals because of the convulsions have been measured. The effect of the compounds has been indicated by percentage of appearance of tonic convulsion and the mortaLity.
Results are shown in Table 1.

Table 1: Activity on nicotine-induced convulsion _ _ .
appearance of dru~s tonic convulsion mortality I

Compound 1 ~f this 20 40 invention _ . .
Compound 2 of this 40 Go invention Reference Drug 60 100 _ _ Control - 11 - 100 ~Z~837~

3. Effect on oxotremorine-induced tremor Experiment:
Male ddY mice 5 weeks old were usedwith 5 animals in a group. The compounds were administrated per os at a dose of lOOmg/kg and after 15 minutes oxotremorine was intraperitone-ally administered at dose of 1 mg/kg. The strength of the induced tremor was observed by the method of Suzuki ct al (Folia Pharmacologica Japonica, 83, 127(1983) and scored up with passage of time as rollows:

O = absent, 1 = very slight, 2 = slight, 3 - moderate,

4 = severe, 5 = lack of righting reflex.

.
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The results are shown in Table 2.

Table 2 : Effect on oxotremorine-induced tremor _ _ _ _ ~\ = Score time(min) 5 10 15 20 30 compound drugs\¦
_ _ Colnpound 1 Or 0 0.4 0.4 0.9 0.8 this invention _ _ _, _ . I
Compound 2 Or 0 4 0.3 0.4 0.4 this invention I .
Rererellce Drug 0 0.4 0.3 0.2 0 Control 3.23.2 3.1 2.7 2.4 4. Acute toxicity test ~ ale ddY mice 5 weeks old were usedwith 5 animals in a group. The compounds were administrated orally with each dosage. LD50 was determined by the Probit method from dead animals dying within 7 days.
Results are shown in Table 3.

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Table 3 Acute Toxicity . _ __ Compound LD50 (m~,/kg) . _ _ _ .
Compound 1 of 520 this invention _ . ._ _ Compound 2 Or 425 this invention ___ __ Reference 332 It is clear,ly seen from the results above that the compounds of this invention exhibit potent activity on muscle relaxation and excellent activity on nicotine-induced convul-sion as compared to the reference drug.
Further, the acute toxicity test shows that the compounds of the invention have a lower LD50 value as compared with Eperisone, Therefore, it is clear that the compounds of the invention are very useful as a medicine for clinical usage because of the superior pharmacological effects and of the lower toxicity.
This invention will be described in detail with reference to the examples below :

12~L8~374 Example 1 4'-Propyl-2-methyl-3-pvrrolidinopropiophenone ., .
To a solution of 5.00 g of 4'-Propylpropiophenone in 10 ml of isopropanol were added 3.00 g of pyrrolidine hydrochloride, 1.30 g of paraformaldehvde and 0.5 ml of 40% ethanolic hydro~en chloride, and the mixture was refluxed :for 4.~ hours and evaporated.
The residue was dissolved in aqueous hydrochloric acid and washed with ether. The aqueous layer was made alkaline with potassium carbonate and extracted with ether.
The extract was washed with water,Jdried and evaporated.
The residue was dissolved in ether and acidified with 40% ethanolic hvdro~en chloride. The precipitate was filtered, washed with a mixture of ethanol and ether, and recr~stallized from methyl ethyl ketone to give 1.50g of hydrochloride of the desired compound as colorless needles, mp 151-152.
Analysis for C17H25NO HCl Calculated % C, 69.02; H, 8.86; N, 4.73 Eound ~- C, 68.75; H, 9.23; N, 4.64 Example 2 4'-Isopropyl-2-methyl-3-pyrrolidinopropiophenone To a solution of 10.00 g of 4'-isopropylpropiophenone in 80 ml of ethyl acetate were added 2.00 g of pyrrolidine and 2.50 g of paraformaldehyde. The mixture was acidiied by the addition of gaseous hydrogen chloride and refluxed for 4 ~ours, 1~2183~'~

After cooling, the reac-tion mixture was extracted with water. The water layer was made alkaline with potassium car~onate and extracted with ethyl aceta-te.
The extract was washed with water, dried and evaporated.
The residue was dissolved in ethanol and acidified wi-th 15% ethanolic hydrogen chloride. The solution was evaporated and the residue was washed with a mixture of acetone and ether and then recrystallized from methyl ethyl ketone to give 3.58 g of hydrochloride of the desired compound as colorless needles, mp 131-133.
Analysis for C17 25 J
Calculated % C, 69.02; Il, 8.86; N, 4.73 Found ~ C, 68.62; H, 9.01; ~, 4.62 Example 3 4'-Butyl-2-methyl-3-pyrrolidinopropiophenone To a solution of 5.40 g of 4'-butylpropiophenone in 15 ml of ethyl acetate were added ~.00 g of pyrrolidine hydro-chloride, 1.30 g of paraformaldehyde and 0.5 ml of 22%
hydrogen chloride-ethyl acetate and the mixture was refluxed for 4.5 hours. After cooling, the reaction mixture was extracted with aqueous hydrochloric acid. The water layer was made alkaline with potassium carbonate and extracted with ether. The extract was washed with water, dried and evaporated. The residue was dissolved in ethanol and acidi~ied with 40% ethanolic hvdrogen chloride.
The solution was evaporated and the residue was washed with isopropyl ether and then recrystallized from methyl ethyl ketone to give 2.93 g of hydrochloride of the desired compound as colorless scales, mp 116-117.

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~nalysis for C18H27NO.HCl Calculated ~ C, 69.77; H, 9.11; N, 4.52 Found % C, 69.51; H, 9.25; N, 4.55 Example 4 4'-Isobutyl-2-methyl-3-pyrrolidinopropiophenone A solution of 5.40 g of 4' isobutylpropiophenone in 15 ml of ethyl acetate, 3.00 g of pyrrolidine hydrochloride, 1.30 g of paraformaldehyde and 0.5 ml of 22% hydrogen chloride-ethyl acetate were treated in the same manner as that described for Example 3 to give 3.53 g of hydrochloride of the desired compound which were recrystallized from methyl ethyl ketone as colorless scales, mp 127-128.

Analysis for C18H27NO- HCl Calculated % C, 69.77; H, 9.11; N, 4.52 Found % C, 70.13; H, 9.51; N, 4.66 ExamPle 5 -4'-Cyclohexyl-2-methyl-3-pyrrolidinopropiophenone A solution of 5.10 g of 4'-cyclohexylpropiophenone in 15 ml of ethvl acetate, 2.50 g of pyrrolidine hydrochloride, 1.30 5 of paraformaldehyde and 0.5 ml of 22% hydrogen chlorid~e-ethyl acetate were treated in the same manner as that described for Example 3 to give 3.65 g of hydrochloride of the desired compound, which were recrystallized from a mixture of ethanol and ether as colorless needles, mp 186-187.

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Analysis for C20H29NO HCl Calculated % C, 71.51; H, 9.00; N, 4.17 Found % C, 71.64; H, 8.86; N, 4.12 Example 6 4'-Ethyl-2-methyl-~-pyrrolidinopropiophenone J

To a solution of 6.80 g of 4'-ethylpropiophenone in 60 ml of ethyl acetate were added 1.50 g of pyrrolidine and 1.90 g of paraformaldehyde.
The mixture was acidified by the addition of gaseous hydrogen chloride and refluxed for 2 hours. After cooling, the re-action mixture was extracted with aqueous hydrochloric acid.
The water layer was made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was dissolved in ethanol and acidified with ethanolic hydrogen chloride.
The solution was evaporated and the residue was washed with ethyl acetate and then recrystallized from methyl ethyl ketone to give 3.00 og of hydrochloride of the desired compound as colorless needles, mp 152-153.

Analysis for C16H2~3NO.HCl 1/4H20 Calculated % C, 67.12; H, 8.62; N, 4.89 Found % C, 67.35; H, 8.65i N, 5.01

Claims (2)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparation of derivatives of 3-pyrrolidinopropiophenone represented by formula (I):

( I ) wherein R is an ethyl group, and the pharmaceutically accept-able acid addition salts thereof, which comprises selecting a process from the group of processes consisting of:

(a) reacting a derivate of propiophenone represented by formula (IV):

(IV) wherein R is as defined above, with a formaldehyde or paraformaldehyde and pyrrolidine or the salts thereof;

(b) converting a compound of formula (I) into the corresponding pharmaceutically acceptable salt;
and, (c) converting a salt of the formula (I) into the corresponding free base.

2. Derivatives of 3-pyrrolidinopropiophenone represented by formula (I):

( I ) wherein R is an ethyl group, and the pharmaceutically accept-able acid addition salts thereof, when prepared by the process of claim 1.