Novel pyrindines and their preparation, formulations and use.

The present invention relates to a process for the preparation of some ifr «s-4a-phenyls-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-IH-2-pyrindines, with the gene I gene:

rv · (I) / \ / \ /

N— R, wherein R, represents an alkyl group with i,, 8 cardboard atoms and R₃ represents an atm of hydroxy, a hydroxy or alkoxy group with ₂a

I ... 3 carbon atemi.

In recent years, the synthesis of analgesic drugs has been achieved, capable of removing the pain sensation. Many of the existing painkillers are limited to 25 cms, with regard to the use of lcr, due to different side effects, which frequently impede their continuous use.³⁰

Such side effects include allergy and habit. Examples of new analgesic drugs that have recently been discovered are decahydroisoquinolines (Patent, · Belgium, no. 802557). Zra "s-4a-Eenyl-2-substituted-octahydro-1H-2-pyridines, of general formula I, are somewhat structurally related to the above-mentioned isoquinoline derivatives.

Simple analogues of unsubstituted pyridine are known in the literature. For example, certain octahydro-2-pyridines have been prepared, none of which are substituted at position 4a (Volodina et al., Doc. Akad. Nauk, USSR, 173 (2), 342-345,

1967). Recently, cw-4a-aryl-2-substituted-octahydro-1H-2-pyridinc has been prepared, which are analgesic (Patent, Belgium, no. 860314).

A process for preparing unorcis -4a-phenyl-octahydro-1H-2- pyridipes similar to those of general formula I is known by treating unsubstituted pyridine; on nitrogen with an alkylating agent, namely, an alkyl chloride or bromide, which alkenylalkyl or tetrahydrochloride, in dimethylformamide medium, in the presence of an acid acceptor (Patent, RSR, No. 72900),

The process, according to the invention, extends the range of pyrenes with trans isomers of the formula, 75805. PRICE LEI 35.64 general II, by reducing a liexahydropyrindine, of general formula II:

0-_R, (Π) / \ / \ \ N ~ \ / W f - 7 wherein R_t and R, have the above meanings, with hydrogen in the presence of platinum oxide in clancl environment, at a temperature other than the reaction having a duration of about 4 hours and failing to give a pressure of about 4, Lei O⁶dyn / cm², after which it can be decrypted with glacial acetic acid and hydrobromic acid, at reflux temperature, for about Q5 h, for the conversion of the carbonyl into R_;is a methoxy group, in compounds wherein R₂is a hydroxy group, and if. it is desired to form a salt of the compounds I, in known manner, and the product is. separates by known methods.

S; I give below 3 examples of process analysis according to the invention.

Example 1. A solution of 5.0 g 4a-phenyl 2-methyl-3, 4, 4a, 5, 6, 7-hexahydro-2-pyrindine in 50 ml of ethanol, containing 500 mg of platinum oxide, was stirred at room temperature. for 4 h, under an atmosphere of hydrogen dc 4.13 X 10 * âynjcm. The mixture is then filtered and the solvent is removed from the filtrate by evaporation, resulting in an oil which is analyzed by NMR and high pressure liquid chromatography, admitting that it consists of about 40% ris-4-phenyl-2-methyl-2, 3, 4 , 4a, 5, 6, 7, 7a-octahydrid-2-pyrindine and about 60% of the corresponding trans isomer. The mixture was dissolved in 50 ml diethyl ether and acidified by the addition of a saturated solution of bromlihydric acid dissolved in diethyl ether. Concentration of the ethereal solution leads to crystallization. The mixture was filtered and the precipitate was recrystallized from 30 ml of isopropanol and 70 ml of diisopropyl ether to provide 2.6 g of bromide dc cfs-4a-phenyl-2-methyl-2, 3, 4, 4a, 5, 6, 7, 7a0ctahhydro -LH-2-pyrindine. The filtrate sc evaporates to dryness and the residue is dissolved in water. The aqueous solution sc is alkalized by the addition of sodium hydroxide dc In and then the aqueous alkaline solution is extracted with distillator. The ethereal extracts are combined, washed with water and dried. Removal of the solvent by evaporation under induction pressure yields 2.57 g of Zr 1 -is-4-phenyl-2-methyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine.

The fnws-pyrindine derivative was dissolved in 120 ml dc ethanol and reacted with 2.76 g picric acid to give 2.7 g picric dc / rriMS-4u-phenyl-2-nicyl-2, 3, 4, 4 a, 5, 6, 7, 7aoc.taliidrc-1H-2-p: rindium, with melting point 167., 168'C.

The analysis calculated for Cj, in%:

- theoretically: C '~ 56.75; FI = 5.44 · N 12.61;

- found: C = 56.99; H = 5.65; N, 12.46.

Example 2. Sc repeats the preparation described in example 1, except that the ΖΛ / ni-pyrindine derivative reacts with maleic acid and isolates the crI1-4a-f'myl-2 methyl-2, 3, 4 maleate. , 4a, 5, 6, 7, 7a-Cycahydro-I-2-pyridylines, with a melting point 113 ... 114%.

Analysis calculated for C_ofH_{? s}NO., Gave, in%:

- theoretically: C = CS, S6; II = 7, -60; N-r = = 4.23;

Found: C, 68.66; H = 7.82, N = 3.89. In acrylic mode, it prepares 4a- (3-hydroxybyl) derivative.

EXAMPLE 3. Following the procedure described in Example 1, 4a (3-methoxyphenyl) -2-methyl-3, 4, 4a, 5, 6, 7-hydroxy-2-pyrindine over platinum oxide is hydrogenated to give a 60: 40 mixture of trans -Aa.- (3-methoxyphenyl) -2-nicethyl-2,3,4,4,4a, 5,6,6,7,7a-octahydro-1H-2-pyrene and the corresponding cis isomer. The trans isomer crystallizes under the picrate farm. The trans isomer is isolated as a free base, namely trans-An, - (3-mctoxyphenyl) -2-mctil-2, 3, 4, 4a, 5, 6, 7, 7a- (etahydre-ΙΗ-2-pyrindtnf) , with melting point 40 ... 43%.

Analysis calculated for C _CH_2SNO is like ', in%:

- theoretically: C --- 78/52; II - 9.45 · N = = 3.71;

found: C, 78.26; H, 9.31; N, 5.61.

Working as in Example 1, the other compounds of general formula I.

For hydrolysis of the methoxy group, which is the substituent on the phenyl radical, st? thus yields: a solution of 3,5 g fre «.s-4a- (3-mtoxyphenyl) -2-methyl-2, 3, -4; 4a, 5, 6, 7, 7a octahydrc-lFl-2-pyrindine ml dc glacial acetic acid containing 35 ml dc 50% aqueous remodic acid , stirred and heated at reflux for 15 h. Then the reaction mixture was cooled. at room temperature and diluted with 100 nil of ice water. The aqueous acid solution is alkalized by the addition of concentrated sodium hydroxide up to a / dl of 9.8 and the aqueous alkaline solution is extracted several times with diethyl ether. The etheric extracts are combined, washed with water, and dried. By removing the solvent, by evaporation under reduced pressure, 1.8 g of the product as a solid is obtained. The solid thus formed is recrystallized from 150 ml of ethyl acetate to give l, 65, g fnms-4a- (3-lihydroxyphimyl) -2-methyl-2,3, -4,4a

75805'

5, 6, 7, 7a-cctahidiO-1H-2-pyrindine, with a melting point 192 ... 194 ^ 0.

The analysis calculated for C.rJI-qNO gave, in%:

- tecrelic: C = - 77.88; H = 9.15; ' N-6.05;

Found: C, 77.48; H, 8.71; N - 5.67.

Coir, p .: also with the general formula I, have two asymmetric centers, namely position 4a and position 7a. The present invention refers both to the separated isomers, as well as to their racemic mixtures of cystLeolate hatred, which are useful for use as agonist analgesics or antagonistic drugs. However, only the trans isomers of formula I are taken into account here, namely, those where the gupa 4a-aryl is; orient tc on the opposite side of the plane of the molecule from the hydrogen atom 7a. Thus, the present invention comprises, according to the above, the preparation of optically and pharmacologically active trans ismmerilcr and racemic mixture of trans isomeric. Such a racemic pair of // tfizs-octahydropyrindinclcr can be separated into its components by stereosamples well known in the art. If the entire useful pharmacological activity resides in a single stercoizcmer, i /, / - the racemate is useful in that it contains the pharmacologically active isomer as a constituent part.

The process for the preparation of 4a, 7a-trans isomerylcr of general formula I comprises the catalytic hydrogenation of 4a-phenylhexahydropyridine of general formula II, in a specific medium a pyrindine having a double bond to. position 1,7a. Such hydrogenation is generally carried out by reactivating a 4a-phenyl-2-alkyl-3, 4, 4a, 5, 6, 7-hexahydrrc-2-pyrindine in the presence of a catalyst, such as platinum oxide. Hydrogenation is typically carried out in a solvent, such as methanol or ethanol, and is usually completed 1 to 8 hours, when it is carried out at a temperature of about 25 hours.^ITC, under a hydrogen pressure of about 2.74 X 1G® up to about 5.48 X lOMyn / cubes Typically, hydrogenation results in a mixture of the 1, 7a-trans isomer and the i, 7a-Ji's isomer; however, in general, the trans isomer predominates. Isomer separation can be easily achieved by salt formation and crystallization. For example, the racemic mixture of octahydropyrindins may be converted to a suitable moiety, such as picrate or maleate, and the cis racemate normally crystallizes from solvents, such as diethyl ether and diisopropdeter, and may thus be separated from the trans by filtration. . The trans-racemates can be recovered by filtration and purified by recrystallization. ......

Preparation of their 4a-phenyloctahydropyrindins of general formula I requires materials:

bonuses, many of which have been celebrated until now unknown and not easy to obtain. Accordingly, the preferred method, described above, for the preparation of Zw-s-4α-phtnyl-2-substituted-cytahydro-1,2-pyrindines, requires 4α-ienyl-2-substituted 3, 4, 4a, 5, 6, Suitable 7-hcxahydrr-2-pyrindines, i.e. Δ 1, 7a-hcxahydrrpyridylines. Thus, the compounds may be prepared by condensation of phenyl lithium or phenyl lithium 3 substituted with 1-alkyl-4-piperidone to provide 1-alkyl-4-f (nyl- (or phenyl subs) -4-hydroxypipridine Dehydration of the 4-hydroxypiperidine derivative results in 1-alkyl-1aryl-1, 2, 3, 6-tctrahydropifidine. The tetrahydropyridine derivative further reacts with a propylene dihalcgenide such as 3-chlorpyr _of from 1-4 -alkyl-4- (2-halGpropyl) -J, 2, 3, 4-tetrahydrepyridine, which is then readily cycled by reaction with sodium iodide in acetonitrile to provide 4-phenyl-2-ylI3, 4, 4a-5, 6, 7-hcxahydrr-2-pyrindine.

The medium in which the preparation of the raw materials is indicated is shown in the cr.tiuurrc.

A.) A solution of 159 ml «-butylthio in ICO ml hexane containing 47.7 g 3-methoxyibrembenzene is stirred at -25^itC ', for 20 minutes and the water is heated to room temperature and stirred for one hour to obtain 3-nietoxifenIlithium. The reaction mixture was cooled to 10 ° C and stirred in a syrup, a 50 g l -methyl-4 piperide solution in ICO ml diethyl ether was added dropwise over 30 min. After the addition is complete, the reaction mixture is stirred for about 2 hours and then 50 ml of saturated aqueous sodium chloride solution is diluted. The solution is extracted several times with diethyl ether and the ethereal extracts are combined and concentrated to dryness to give 38 g of l-methyl-4-hydroxy-4- (3-mtoxyicnyl) -pipeihydride.

B.) To a solution under stirring, comprising

two hundred. ml and containing 50 g of phosphorus pentoxide in methanesulfonic acid are added in portions for 4 minutes 59 g l -Niethyl-4-hydroxy-4- (3-hydroxyphenyl) -piperidine. The reaction is exothermic and the temperature rises to 7G ° C. After the complete addition of the piperidine derivative, the reaction mixture was added to 200 g of ice and the aqueous mixture was alkalized by the addition of ammonium hydroxide. The alkaline mixture is extracted several times with diethyl ether and the etheric extracts are combined, washed with water, dried and the solvent removed by evaporation under reduced pressure, to give 4'4.7 g of the respective product under an oil farm, - ..- '···

The oil thus formed is dehydrated to give 1-methyl-4- (3-methoxyphenyl) -1,2

75005

7.

3, 6-tetrahydropyridine with boiling point dc

123...138³C at 0.1 mm Hg. Analysis calculated for C_l3H_L7U.S. n % :

- theoretically: C - 75.8 1; H, 8.43; N, 6.89;

- found; C, 76.52; H, 8.15; N, 6.67.

C. In a cold solution (temperature 5 to -10^:C), with stirring, 25 g of 1-methyl-4-phenyl-1,2,3-tetrahydricpyridine in 450 ml of tetrahydrofuran, 90 ml of 1.6 M of 1.6 M of hexane were added dropwise over 30 minutes. After the addition is complete, the solution is stirred for 10 minutes at -10^υ0 and then cooled to di-30^eC. The cold solution is added dropwise for 20 minutes to a stirred solution of 73.3 g of 3-chloropropyl bromide in 300 ml of diethyl ether cooled to -50.^{! i}C. After completion of the addition, the reaction mixture sc 'warms to -2043 and is diluted with 500 ml of saturated aqueous sodium chloride, which was cooled to 0 ° C. The organic layer was separated, washed with water and the product was extracted from it in 1200 ml of hydrochloric acid In. The aqueous acid layer was washed with diethyl ether and then basified by dropwise addition of concentrated aqueous sodium hydroxide. The alkaline solution is extracted several times with diethyl ether, and the ethereal extracts are combined, washed with water and dried. Evaporation of the solvent at 10 ° C gives an oil which is dissolved in 2,500 ml of acetonitrile containing 52.5 g of sodium iodide. The reaction mixture was heated to reflux and stirred for 24 hours, after which the solvent was removed by evaporation under reduced pressure. The crude product thus formed is dissolved in a mixture of 800 ml of sodium hydroxide In and 1 000 ml of diethyl ether and the mixture is stirred vigorously for 45 minutes. Then the ether layer is separated, washed with saturated aqueous sodium chloride and dried. Removal of the solvent by evaporation under reduced pressure gives the respective product as an oil, which after distillation gives 21.5 g 4a-phenyl-2-methyl-3, -; 4,._IT4a, 5/6,, 7-exabidrO2-piyindine. with boiling point 110 ... 112 ^ 0, at a pressure of 0.075 mmHg.

Analysis calculated for C₁₅H_IbN, gave, in%:

- theoretically; C, 84.46; H, 8.98; N, 6.57;

- found; C, 84.74; Η = 8.72; N, 6.28.

D.) Following the procedure shown in Example C, 1-methyl-4- (3-methoxyphenyl) -1, 2, 3, 6-tcrabrabyrrpyridine reacts with 3-chloropropyl bromide and sodium iodide to give 4a- ( 3-methoxyphenyl) -2-methyl-3,

4, 4a, 5, 6, 7-hexahydro-2-pyrene, with boiling point 132 ... 134 ^ 0, at a pressure of 0.1 mmHg.

'3

Analysis calculated for C_l4H «NO in%:

- theoretically; C, 73.97; 11 = 8.70 'N = = 5.75 mte, 213;

- found; 0 = 76.58; H, 8.28; N = = 5.36 rn /. ', 2 LL

A preferred group of compounds of general formula I is that wherein R, is hydroxy or methoxy. A group of preferred daily intermediate compounds, in particular, is that of compounds wherein R is hydrogen.

The term, C, - C- alkyl "refers both to the linear chains, as well as to branched chains with 8 carbon atoms or less. Examples of C 1-6 alkyl groups are: melyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl, 3-methylpentyl, I, 2-dimethyl, 2-methylbutyl, 3-ethylpentyl, -octyl, 2- iuctilheptyl, isobeptyl, 3-ethylhexyI, 1, 3, 3-trimethylpentyl, and related groups.

as compounds of general formula I, which are lightly produced by reducing the Δ bond of a 4a-phenyl-2-substituted-3, 4, 4a, 5, 6, 7-hexahydro-2-pyrindin of general formula II, in according to the method described above, the following can be cited:

- 4a-Eenyl-2, 3, 4, 4a, 5, 6, 7. 7a-octahydro-1H -2 - pi ri ndi na;

- 4a- (3-AIetoxyphenyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyrindine;

- 4a- (3-etc.xyphenyl) -2-methyl-2, 3, 4, 4a, 5. 6, 7, 7a-actahydro-ΙΗ-2-pyrindine;

- 4a-Phenyl-2-ethyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydrc-1H-2-pyrndine;

- 4a- (3-isopropoxyphenyl) -2-ber.zyl-2, 5,

4, 4a, 5, 6, 7, 7a-octahydro-1Η-2-pirmdine;

- 4a-fcnyl-2-isobutyl-2,3,3,4,4a, 5,6,6,7 / α-octahydrc-1-IL-1-pyrindine;

- 4- (3-methoxyphen 1) -2- (4-ethylhexyl) -2, 3,4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyrindine;

- 4a- (3-ethoxyphenyl) -2- (ebrbenzyl) -2, 3,

4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyrindle.

As mentioned above, very important intermediates for the preparation of all, the pyrin derivatives of formula I, are the 2-substituted pyrin derivatives, those in which I <! dm formula I is hydrogen. Such decomposed ones can easily be alkylated or acylated at position 2 to provide pharmaco.ogically active octahydropyrindh.e of formula I, or in the case of N-acylated derivatives, to provide intermediates which are readily converted into active analgesics of formula Γ. Therefore, Iaşea sr wants to prepare, 4a-phenyl-2-substituted-2, 3, 4, 4a, 5, 6, 7, 7a-0-tetrahydro-li-2-pyrene, in which the substituent di has position 2 it can be easily removed so as to produce corresponding, unsubstituted 2-substituted octahydropyrindine derivatives. The groups, N-methyl and -N-benzyl can be readily cleaved to give the corresponding unsubstituted 2-pyrene derivative. The 2-methyl derivatives of pyrindine may react with a haloformate, such as phenyl chlorofonnate or ethyl pentium ebroformate to produce the corresponding carlamate at p.section 2 of pyrindine. Such a carbamate is then treated with an aqueous base, such as, for example, sodium hydroxide, to cleave the 2-carbamate radical and thus give the 2-unsubstituted p'rindine derivative. (Abel-Monen and Portuguese, J. Med. Chem., 15.20-5, 1972).

Similarly, 4α-ienyl-2-benzyl-2,3,4,4,4a, 5,6,6,7,7a-octahydro-1,1-I-2-pyrindinclc, is transformed into pyrindine derivatives 2-. not properly replaced by a simple drawing^;LARC. Such debenzylation can be achieved by catalytic hydrogenation, using, for example, a catalyst, such as palladium 5% suspended on coal. These staining reactions are quite general in the preparation of secondary amines (Hartung and Simonoff, Org, Reacticns, 7,277, 1953 and Leonard and Fuji, J. Amcr. Chm. Scc. "85,3719, 1963).

As can easily be seen from the ones presented above, the following 2-unsubstituted pyrin derivatives are important intermediates for the preparation of pyrinines of formula I:

- 4a-phenyl-2, 3, 4, 4a, 5, 6, 7, 7a-octabidrc-1H-2-pyrindine;

- 4a- (3-Methoxyphenyl) -2, 3, 4, 4a, 5, 6, 7, 7a-cycthequinofro-II-2-pyrindine;

- 4a- (3-Ethoxyphenyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyrindine and - 4a- (3-Isopropoxyphenyl) -2, 3, 4, 4a, 5, '6, 7, 7a-octahydrc-1H-2-pyrene.

- 4a-Fcr the 2 nd and b: tituit-2, 3, 4, 4a, 5,

6, 7, 7a-octahydro-1H-2-pyrindines, thus prepared by being prepared by known methods to obtain pharmacologically active 2-substituted tertiary derivatives or may be used to obtain intermediates that are Do not turn into active analgesic drugs. For example, 4-phenyl-2, 3, 4, 4a, 5, 6, 7, 7_tt-octaiiiciro-1H-2-pyrindine, can be alkylated at position 2 by reaction with any reactive derivative of an alkyl group. Such alkylating agents are composed with the Rj - Z farm, where R_s it is defined as iui and Z is a cricca of the groups commonly called slightly dividable groups. These readily cleavable groups include hakgtnyl, ie I, chloro, b.cm or iodine, toluenesulfonyltosyl), funlsulfcnyl, nrctansulfonyl (mcsil), yl-Lrcinftnilsulfcnil (bronsyl) and azido. Iron as alkylating agents having the formula Ri - Z are compounds such as methyl bromate, ethyl bromide, 5-methylheptyltosilite, 1-bromide, 4-hexc-iodide. nil, 3-ctyl-4-ptilyl brosylate, cyclopropylmethyl chloride, cyclobutylmethyl yarn, cyclohexylmethyl mesylate, 2-tetrahydrefurylmethyl bromide, 2-thylazine, 2-phenylethylcorhide, aryl, benzo, 3-, 2- (2-Chlorophenylthio) -ethyl, 1-phenoxylmethyl bromide, 3-isopropylphenylenomethyl bromide, and related groups.

Thus, 4a-phenyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyrindine, can react with an alkylating agent to obtain 4-phenyl-2-substrate-2,3 , 4, 4a, 5, 6, 7, 7a-octahydrc-1H-2-pyrindine. Such an alkylation reaction is the general cbst reaction and may be accomplished by reacting the appropriate 4α-phenyloctahydro-1H-2-pyrindine with the corresponding alkylating agent, preferably in an inert organic solvent. The alkylating agent is typically used in excess amounts, from about 0.5 to about 2.0 molar excess of the pyrene derivative. Non-reactive organic solvents commonly used in the reaction comprise ethers, such as diethyl ether, dioxane, tetrahydrofuran, as well as solvents such as benzene, dichloromethane, dimethylformamide, dimethylsulfoxide, nitromethane and hexamethylphosphorphyriamine. A base is preferably introduced into the alkylation reaction medium to act as an acid cleavage agent, because the reaction of the pyrindine derivative with the alkylating agent is generally inhibited by the formation of an acid, such as hydrochloric acid or toluenesulfonic acid. , which can act in the salt binding of any unreacted 2-pyrene derivative. Bases commonly used as acids for removing acids in such a reaction include sodium bicarbonate, potassium carbonate, sodium hydroxide, triethylamine and pyridine. Typically, it is used around a basic, slow equivalent, however,_se p.jt also introduce excess quantities if desired. The alkylation reaction is normally carried out at a high temperature, varying from about 50 to 200¾ and at an asthl of temperature the reaction is completely completed in the range of about one hour to 10 hours, longer reaction times are not disadvantageous and can be used if a- is desired; what this. The product is recovered by simply adding water to the reaction mixture and then extracting the product from it in a water-immiscible organic solvent, such as benzene, diethyl acetate dichloromethane diethyl ether, chloroform, or related solvents. After removing the solvents from it. dc extracts, for example, by evaporation under reduced pressure, give 4a-phenyl-2-substituted-2, 3/4, 4a, 5, 6, 7, 7a-octahydro-1H-2 pyrindine, a compound that exists under the lithium oil or solid at room temperature. The product thus formed can be further purified, if desired, by standard processes comprising chromatography, crystallization, distillation, or alternatively, such a pyrindine product may be converted to a solid salt by addition by reaction. with An inorganic or organic acid · f υ

Such salts are typically crystalline solids and can be easily recrystallized to provide a high purity solid salt. If desired, such a salt can then be treated with a base, such as sodium hydroxide; they have potassium carlorate, thereby splitting the salt to obtain 4a-phenyl-2-substituted-2, 3, 4, 4a, 5, 6, 7, 7a-octahydrc-II'-2-pyrindine under a free base farm,

As previously indicated, 2-unsubstituted pyrindine derivatives, namely 4a-i-nii-cyctahiiiro- 1H-2-pyrindines, can be converted into a 2-substituted pyrindine derivative, which is either a pharmacologically useful agent. tsar sc, or one that can be easily transformed into a pharmacologically active agent. For example, by reacting 4-phenyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyrindine with an alkylating agent such as 2-henzoyl ethyl iodide, 4a-feh is obtained. Il-2- (2-benzylIthi) -2, 3, 4, 4a, (, 6, 7, 7a-octahydro-1H-2-pyrindine, active analgesic. If desired, such a compound could be reduced to the benzoylcarbonyl radical, dc, for example, by reaction with a reducing agent such as lithium aluminum hydride to obtain 4α-tert-2-phenyl-2- (3-hydroxy- 3-phenyl) -propyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pirmdine,. also a useful analgesic agent. In addition, a 2-unsubstituted pyrindine derivative may be acylated by any of the alkylating agents to provide a corresponding Nacylated pyrindine derivative.

Such N-acylated pyreneins, to reduce the carbonyl radical, produce. pyrindine derivatives - 2-substituted with formula I, which are active analgesics. Examples of^Jacylating agents commonly used in the medium, include acetyl chloride, pentonoyl chloride, 4-hexenoyl chloride, cyclobutiformyl bromide, 2- (tetrahydrofuryl) formyl chloride, benzoyl bromide, 3-phenoxyacetyl iodide, 4-dimethylphenylacetyl, 3- (2-fluorophenyl) -propionyl chloride, phenylipaceyl bromide, 4-phenyl-3-buteneyl chloride acetic anhydride and hexanoic anhydride, Acylation of the 2-unsubstituted pyrindine derivative, as an acylating agent It would be, The aforementioned clcl is carried out by reacting approximately equimolar amounts of the pyrindine derivative and the de-acylating agent, in an inert organic solvent, such as dichloromethane, ethanol or tetrahydrofuran. A base such as sodium bicarbonate, potassium carbonate or propylene oxide is commonly used to serve as an acid removal agent. The <sto reaction is best performed at a temperature of about -20 to about 30⁽C, and is generally complete within 1 to 8 hours. The product, for example, 4a-phenyl-2-acyl-2, 3, 4, 4a, 5, 6, 7, 7a12

-octahydrc-1H-2-pyrindine, is readily isolated. by simply removing the reaction solvent, by evapcrarc. The product a: tft 1 formed is not in the normal medium further purified, but is reduced immediately to give 4a.-phenyl-2-substitutes (omit-2, 3, 4, 4a, 5, 6, 7, 7a- < ctabidro-1H-2-pyrindine, with general forinula I.

Such a reduction of the N-acylcaronyl group can be accomplished by reacting the acylated pyrindine derivative with a reducing agent, such as lithium-aluminum hydride by catalytic hydrogenation or by recombination of the Ai, 7a bond with exidic platinum and hydrogen. It will further be noted that further modifications may be made to certain 4a-phenyl-2-substituted-2, 3, 4, 4a, 5/6, 7, 7a-octahydro-1H-2-pyrindines with formula I. For example, while a 4a-phenyl dc pyrindine derivative, wherein the fcn'l group is α 3-hydroxyphenyl group], can be prepared starting from taking a 2- {3-hydroxyphenyl} -2-croxycarbonylmethylcyclohexionion and modifying a ui. such compound in accordance with the various processes mentioned above, it might be preferable to prepare 4a- (3-methoxyphenyl) -2-substituted-2, 3, 4, 4a, 5, 6, 7, 7a₇octahhydro-IH-2-pyrindine and then convert the 3-nretoxy group of such a 4a-phenyl substituent into a hydroxy group. Such a conversion can easily be achieved by reacting a 4a- (3-methoxyphenyl) -pyrindino-derivative with hydrobromic acid to acetic acid, a reaction which is quite general for the conversion of the nretoxyphenyl group to a hydroxyphenyl group. The hydroxy group of such 4a- (3-hydroxyphenyl) -pyrindines can be supplemented, if desired, with the usual C 1 ... C 3 acyl acylation agents, for example, chloride. dc acetyl or propionic anhydride, thereby obtaining the corresponding derivatives of 4α- (3-alkanoyloxyphenyl) pyrindine.

As previously shown, the 4a-phenyl-2-substituted-ccfahydro-1H-2-pyrindin derivatives of general formula I may react with an organic or inorganic acid to form a crystalline salt which can be purified by crystallization and which then it can be converted back to the free pyrene base by treatment with a suitable base, such as sodium hydroxide. Thus, the acidic, toxic and pharmaceutically acceptable addition salts of the pyrindine bases described above are prepared. ,

Such acidic, non-toxic and pharmaceutically acceptable addition salts are prepared by reacting a 4a-phenyl-2-substituted-octahydro-1H-2-pyrindine, of general formula I, with an organic or inorganic acid. Acids commonly used to prepare acid salts; Pharmaceutically acceptable addition agents include anorgic acids, such as hydrochloric acid, hydrobromic acid, ionic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, phosphorous, nitrogen and related acids. Organic acids commonly used to prepare pharmaceutically acceptable acid addition salts of pyridium, of gn-area formula I, include acetic, propionic, toluenesulfonic, chloracetic, maleic, tartaric, succinic, oxalic, citric, lactic, palmitic, stearic acid , benzoic and related acids. The pharmaceutically acceptable acidic acid salts may be prepared in advantageous manner by simply dissolving 4a-phenyl-2-substituted-octahydro-1H-2-p: rindine in a suitable solvent, such as dictibter, acetate. ethyl, acetone or ethanol and adding to the solution, either an equivalent or an excess of a suitable acid. The salt thus formed which comes out of the solution by crystallization can be recovered by filtration and is suitable for use as a pharmacological agent, or it can be further purified by recrystallization from usual solvents such as acetone and methanol.

The following Zr.ins-4a-phenyl-2-substituted-2, 3, 4, 4a, 5, 6, 7, 7a-o; tachydro-1H-2-p: riadins are representative, for compounds of general formula I :

- 4a-Fcnyl-2- (3-ethylpentyl) -2, 3, 4, 4a, 3,

6, 7, 7a-octahydro-1H-2-pyrindine;

- 4a- (3-Methoxypheayl) -2- (n-octyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyrindinium bromide;

- 4a- (3-Hydroxyphenyl) - (2-propanyl) -2, 3, 4,4a, 5, 6, 7, 7a-octaihydrc-1H-2-pi; indine;

- 4a- (3-Propoxybnyl -2- (2,3-dime'dl-4-hexenyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H -2-pyrindine;

- 4a-Phenyl-2- (5-hc ptenyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octaludro-1H-2-pyrindinium acetate;

- 4a- (3-Hydroxyphtnyl) -2-cyclopentylmethyl-2,3,4,4,4a 5,6,6,7a-7-octahydrc-1Ty2-pyrindinium oxalate;

- 4a- (2-Ethoxyphenyl) -2- (2-tetrahydro-furylmethyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-ΙΗ-2-pyrindine;

- 4a-Fcnil-2- (2-fcnoxictil) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyrindine;

- 4a- (3-Hydroxyphenyl) -2- (2-methylphtimethyl) -2, 3, 4, 4a, 5, 6, 7, 7a-cyctahhydro-1H-2-pyrindinium succinate;

- 4a- (3-Mttoxyfcnyl) -2- (3, 5-dichlorobenzoylmethyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octalndro-1 Η-2-piiin. a;

- 4a- (3-Ethoxy <.nil) -2- [3- (3-mctiI-4-bromophenyl) - 3-hydroxy] - picpil -2, 3, 4, 4a, 5 6, 7, 7a-octahydrc -HH-2-pyrindinyl iodide;

- 4a-fcnyl-2- [3- (2-ethyl-6-methylfcnylthio) -pyrrole] -2, 3, 4, 4a, 5, 6, 7, 7a-cttcI.icrc-lH-2- pyrindinium;

- 4a- (3-Hydroxy <njJ) -2- [2- (3, 4-dibroinfenyl) - 2-hydroxy] -ethyl-2, 3, 4, 4a, 5, 6, 7₍H-7a-octahydro-2-pyrindine;

H - Citrate of 4a-phenyl-2- (3-phenylthio) -propyl-2, 3, 4, 4a, 5, 6, 7, 7a-octabhydro-1F-2-pyrindinium;

- 4a-phenyl-2- [3- (2-isopropylIphenyl) -p opium] -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyrindium maleate maleate;

- 4a- (3-ethoxyphenyl) -2- (2-phenyl-2-bidroxyethyl) phosphate -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1--2-pyrindinium;

- 4a-phenyl-2- (2- (4-chlorophenyl) -2-hydroxyethyl] -2,3,3,4,4a, 5,6,6,7,7a-oct3hydro-1α-2-pyrindinLU methanesulfonate;

- 4a- (3-Hydroxyphenyl) -2- [3- (2-ckr-2-bromphcnyl) -3-hydroxypropyl] -2, 3, 4, 4a, 3, 6, 7, 7a-octahydro-1H-2 -pirindina;

- 4a- (3-propoxyphenyl) -2- [(2-ethylbeazoyl) -ethyl] -2, 3, 4 chloride, ^za, 5, 6, 7, 7a-oct rhidrd-1 Η-2-pyrindinium;

- 4a- (3-Ethoxyphenyl) -2- [3- (2-chlorophenylthio) -propyl] -2, 3, 4, 4a 5, 6, 7, 7a-oetahydro-IH-2-pyrindine;

- 4 α-Phenyl-2- [3- (2-stiI-5-bromophenyl) -propyl] -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyrindine and - stearate of 4a- (3-hydroxyphenyl) -2- [2- (3,5-diethylphenoxy) -ethyl] -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1β-2-pyrindinium.

Some of the 4a-phenyl-substituted-octahydro-1H-2-pyrbidines in Formula I, are applied to the treatment of pain and so I can use it to achieve an analgesic effect in a subject suffering from pain and in need of treatment. In addition, the pyrin derivatives of formula I possess both agonobic and antagonistic analgesic properties and as such, are capable of producing analgesia in a mammal, and at the same time due to analgesic antagonistic activity, have a very low effect on the occurrence of the habit. in the case of treatment with these drugs. This ability of the aforementioned compounds to produce agonistic as well as antagonistic analgesic effects in mammals is what determines the decrease of the induction of the habit with a particular drug, a habit due to its analgesic action similar to that of opium-based drugs. For this reason, compounds are especially valuable, because they produce analgesia with only a minimal physical dependence. Some of the compounds discussed are useful, in addition, in combating the undesirable effects produced by opium drugs, such as morphine.

The analgesic activity presented by the compounds of the general formula I, was determined by. testing of these compounds at the standard experiments performed on animal PCs to tighten the analgesic action that can be attributed to the test compounds. Such experiences include tertiary driving. to severe pain applied to mice and the tail flutter in rats, also caused by pain shocks,

The experience of flying in mice is performed as follows: male mice from the Cox family, weighing 20, 22 g and starved overnight, are used in experiments. Fluttering, which. it is characterized by the contraction of the abdominal muscles, the extension of the back legs and the rotation of the trunk, is induced by an intraperitoneal administration of 55 mg / kg of acetic acid (0.55%). Each treatment group consists of 5 mice. The total number of strokes of the treatment group is determined by observation for 10 minutes, starting with 5 minutes after acetic acid administration. The control groups have totals of 200 ... 350 dc overturning during the observation period. The control and experimental groups are compared and a percentage inhibition is calculated as follows:

\ total witness f

The test compounds are administered at a concentration of 100 mg / kg by mouth, at 30; 90 and 180 minutes and subcutaneously by 30 minutes, before administration in critical acetic acid trap.

A second standard experience, regarding the analgesic activity, refers to the test of tail movement in rats, which is performed as follows: female Sprague-Davvley type female pups, weighing 70 ... 80 g, starving overnight and are used in the test

Following treatment, either with the administration substance or with the test compound, the animal is placed in a plexiglass tank.

A nickel-chromium resistance of the wire is positioned between two V-shaped copper tubes, it serves as a tail support. The tail of the mouse is placed on this support and the nickel-chrome wire is heated by passing an alternating current through it. After 6 ... 7 s, the radiant heat of the wire becomes annoying for a normal mouse and it tries to remove the heat source. The elapsed time from the return of the current in the wire until the body of the mouse is flipped is recorded as the reaction time of the tail flutter. The mean reaction time of the tail flutter of a group treated with the respective drugs is compared with the average reaction time of a group treated only with the carrier (control group). There are, in general, 5 animals per group to be treated, The average reaction time of a typical counter group is 6.85 ± 0.3 s.

in the¹ mouse rolling test, following ED_S, (doses mg / kg) that decrease the number of rolling observations by 50% 30 min after administration, compared to 16 conircl tests, were obtained for the compounds with the general forinula Ϊ and are presented in table 1. Also, in the rat tail tilt test, the following ED (effective effective dose in mg / kg) causing a 2 s increase during dc: reaction determined after 30 min,: - obtained for compounds of formula I and are also shown in table i.

<td rowspan="2">I ε s. &lt;u 3</td><td colspan="2">writhed (Mg / kg)</td><td colspan="2">Rats tail tail (seconds)</td>

<td>sc</td><td>oral</td><td>it</td><td>oral</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td>

<td> 1</td><td> 12,1</td><td> 25,5</td><td> 2,52'</td><td> 2,88’</td>

<td>e</td><td> 2,32</td><td> 4,6</td><td> —</td><td> —</td>

<td> 2</td><td> 0,94</td><td> 4,8</td><td> 2,80**</td><td> 2,20'*</td>

* = increase of the reaction time to 10 mg / kg (30 iui nutes) difference from the control;

** - Increased reaction time to 10 mg / kg (30 ml) difference from control.

4a-Fe-nyl-2-substituted-2, 3, 4, 4a, 5, 6, 7, 7a-cyctahydrc-1H-2-pyrinines, with I-terminus, are therefore useful in the production of analgesia in mammals, such as be, people. Thus, the mammals can be administered to a mammal either orally or parenterally. In general, it is preferred to use a pharmaceutically acceptable acid addition salt of the pyrindine derivative, when the diarrhea is performed orally. For example, one or more pharmacologically active compounds of formula I, either in free base form or as a pharmaceutically acceptable acid addition salt, are formulated for oral administration by mixing such compounds with any of the diluents, excipients or agents. carriers, commonly used. Examples of such diluents and excipients commonly used in pharmaceutical preparations include starch powder, sucrose, cellulose, magnesium stirrer, lactose, calcium sulphate, sodium benzoate and other similar diluents. Such compositions may be poured into tablets or enclosed in telescopic gelatin capsules for convenient administration. If desired, the active compounds of formula I, then: be additionally combined with one or more agents known as analgesics, such as caffeine, acetaminophen and propoxifene.

In addition, the active compounds of formula I may be formulated as sterile aqueous or non-aqueous solutions, suspensions and emulsions, for convenient parenteral administration. Agents. non-aqueous carriers commonly used in such formulations include propjlenglsccl, vegetable oils, such as

<img file="RO75805A_D0001.tif" />

(I) ts olives, rad and various organic esters such as ethyloleate. Aqueous solutions useful for oral and parenteral administration include isotonic saline.

The precise dcza of acliv ingredient, therefore ⁵the amount of one or more 4a-phenyl-2-substituted-octahydro-IH-2-pharmaceutically active pyrindines of formula I, administered to a mammal, such as d? For example, to a human, it can be varied over a relatively wide range, the formulations being required to constitute a proportion of one or more active ingredients, so as to obtain an adequate dosage. Such a convenient dose depends on the desired therapeutic dose, as-¹⁵the particular method of administration that is foksite and the duration of the treatment, as well as the precise conditions that are created. Typically, doses of active compounds of the formula. I ranges from about i, 0 to about 25 mg / kg²⁰animal body weight per day, conveniently divided for administration 1 to 4 times a day. Preferred oral doses generally range from about 2 to about 50 mg / kg. 25

The process, according to the invention, has the advantage that it extends the range of pyrindine derivatives with new compounds, trans isomers, which have analgesic properties. ₃θ