IE45901B1 - Cis-4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-1h-2-pyrindines and pharmaceutical compositions containing them - Google Patents

Abstract

A process for preparing novel 4a-phenyl and substituted phenyl cis-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindines having a 2-substituent, which is characterized by reacting the corresponding 2-unsubstituted compound with an acylating agent followed by reduction or with an alkylating agent, is disclosed herein. These novel compounds are useful as analgesic agents. [CA1100136A]

Description

This invention relates to pyridine derivatives.

In recent years, much effort has been devoted to the synthesis of drugs, capable of relieving the sensation of pain, i.e. analgesics. Several of the currently available analgesics are limited in their use due to various undesirable side effects which frequently accompany their continued use. Such side effects include addiction and allergy. Illustrative of new analgesic drugs which have recently been discovered are the decahydroisoquinolines, particularly the 4a-aryl-trans-decahydroisoquinolines which are described in Belgium Patent Specification No. 802,557.

The present invention relates particularlytto a group of cis4a-aryl-2-substituted-octahydro-lH-2-pyrindines. Such compounds are somewhat structurally related to the aforementioned isoquinoline derivatives; however, the compounds of formula (I) below have not heretofore been synthetically available. Only simple unsubstituted pyrindine analogs are known in the literature. Volodina et al., for example, prepared certain octahydro-2-pyrindine , none of which were substituted at the 4a-position; Dokl, Akad. Nauk USSR 173(2), 342-5(1967) cf. C.A. Vol. 67, 6034(1967). Similarly, Prochazka et al. prepared a trans-octahvdro-2-pvrindine lacking a 4a-substituenfc, Coll. Czech. Chem. Commun., 31(9), 3824-8(1966), Cf. C.A. Vol. 65, 13651(1966).

This invention provides cis-4a-phenyl and substituted phenyl 2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine not heretofore known or available. -24 59 01 This invention relates to new bicylic compounds characterized as being octahydro-lH-2-pyrindines, alternatively referred to as hexahydro-lH-cyclopenta[c]pyridines. Specifically, the invention provides cis-4a-aryl-2-substituted2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines of the general formula /*\ I »42 ,Lr (I) wherein: is hydrogen, C^-Οθ alkyl, or in which: R3 is C2-C7 alkenyl, c3_c6 cycloalkyl, furyl, or 20 tetrahydrofuryl; and Rg independently are hydrogen, C^-C^ alkyl, or halogen; n is 0, 1, 2, or 3; m is 0 or 1, except that when m is 0, n is other than 0; X is CO, CHOH, CH=CH, S, or 0, except that when n is Ο, X is other than S or 0; and R2 is hydrogen, hydroxy, C^-Cg alkoxy, or C-^-Cg alkanoyloxy; and -345901 the pharmaceutically acceptable acid addition salts thereof.

Some of the compounds of formula (I) wherein the 2-substituent is restricted may be prepared as indicated 5 below.

A process for preparing a cis-compound of the general formula in which R2, Rj, R^, n, m and X are as defined above, and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting a Compound of the general formula (III) wherein R2 is defined as before, and R^'1 is hydrogen, with an alkylating agent to obtain a compound of formula (II) in which R1' is C^-Cg alkyl or CH2R3 in which Rj is C2~C7 alkenyl, or with an acylating agent followed by reduction to obtain a compound of formula (II) in which R^‘ is CH2R3 in which R3 is C3~Cg cyeloalkyl, furyl, or tetrahydrofuryl. in which X, n, m, R^, and Rg are 'R defined as before, optionally de-etherifying when R2 is C^-C3 alkoxy to obtain a compound of formula (II) in which R2 is hydroxy, and optionally acylating a compound of formula (II) wherein R2 is hydroxy to obtain a compound of formula (II) wherein R2 is C^-Cg alkanoyloxy ; and optionally forming a pharmaceutically acceptable acid addition salt.

A compound of formula (I) wherein R^ is hydrogen may be prepared as indicated below.

A process for preparing a cis-compound of the general formula (Ilia) -54 5 9 01' wherein Rg1 is hydrogen, Cg-Οθ alkyl, or <CH2)n“iX)m- ' where x' n' m' R4' rs and R2 are as defined above, which comprises reacting a compound of the general formula ll (IV) wherein Rg’ and R2 are defined as before with a reducing agent, optionally cleaving the compounds of formula (Ilia) wherein Rg”' is Cg-Cg alkyl or - (CHg)^-(x)m-*^ s to obtain the compounds of formula (IHa) wherein Rg''· is hydrogen, and optionally de-etherifying the compounds of formula (Ilia) wherein R2 is Cg-Cg alkoxy to obtain the compounds of formula (ilia) wherein R2 is hydroxy.

A preferred group of compounds are those of formula (I) wherein Rg is Cg-Cg alkyl or CHgRg in whioh R3 is Cg-C? alkenyl or Cg-Cg cycloalkyl. A more preferred group of compounds within this latter preferred group are those of formula (I) wherein R2 is hydroxy or methoxy. -64Baoi As used throughout the present specification and in the appended claims, the term C^-Cg alkyl refers to both straight and branched chains of eight carbon atoms or less. Examples of typical C^-Cg alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl, 3-methylpentyl, 1,2-dimethylpentyl, 2-methyIbutyl, 3ethylpentyl, n-octyl, 2-methylheptyl, isoheptyl, 3-ethylhexyl and 1,3,3-trimethylpentyl.

The term in which Rg is c2-c7 alkenyl refers to both straight and branched alkenyl groups having eight or less carbon atoms, including groups such as allyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 2-methy1-2-butenyl, 3methyl-3-pentenyl, 3-isohexenyl, 2-ethyl-3-butenyl, 4hexenyl, 3-methy1-2-pentenyl, 3-octenyl, 2-isooctenyl, 2isopropyl-3-butenyl, 2,3-dimethyl-2-butenyl, 5-heptenyl, 6-octenyl and 2-methyl-3-heptenyl.

Additionally included within the definition of R^ in formula (I) is the group represented by CHgRg in which Rg is Cg-Cg cycloalkyl. Such groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

R^ can also represent groups such as 2-tetrahydrofurylmethyl, 3-tetrahydrofurylmethyl, and 3-furylmethyl.

Xn formula (I), R^ can also be a group of the ____ -R Z*—X 4 formula (CH2^n~^X^m · In this formula, the term C^-Cj alkyl includes methyl, ethyl and propyl.

Halogen refers to fluorine, chlorine, bromine and iodine. Examples of typical R^ groups represented by this formula include benzyl, 2-phenylethyl, 3-phenylpropyl, 3-methyl5 benzyl, 4-chlorobenzyl, 2,4-dibromobenzyl, 2-(2-methyl5-ethylphenyl)ethyl, 3-(4-isopropylphenyl)propyl, benzoylmethyl, benzoylethyl, 4-iodobenzoyImethyl, 2-methy14-chlorobenzoyImethyl, 2-pheny1-2-hydroxyethyl, 3-phenyl3-hydroxypropyl, 2-(4-fluorophenyl)-2-hydroxyethyl, phenoxy10 methyl, 3,5-diethylphenoxymethyl, 3-phenylthiopropyl, 2methylphenylthiomethyl, 3,5-dichlorophenylthiomethyl and 3chloro-5-bromophenylthiomethyl.

The foregoing pyrindine derivatives of formula (I) may be produced by first reacting an amine, specifically ammonia or a primary amine, with a cyclic anhydride, namely a 4a-aryl-tetrahydro-2,6-dioxocyclopenta[c]pyran, according to the following generalized reaction scheme: in which R^ and Rj have the above-defined meanings. The 1,3-dioxo-4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine , a cyclic imide, so produced is then reduced at the 1 and the -845301 3-oxo groups to provide a pyrindine derivative of formula (Ilia). In practice, it is preferred to utilize 4a-aryltetrahydro-2,6-dioxocyclopenta[c]pyrans in which the substituent on the aryl group, defined in the above formulas by I<2, is selected from hydrogen and C^-C3 alkoxy groups.

Among such C^-C3 alkoxy groups, the methoxy group is preferred since such group is readily de-methylated at a later stage to provide a hydroxyl moiety, as will be described hereinafter. In the reaction of an amine with the above-noted cyclic anhydride, it is similarly preferred to utilize amines such as ammonia, C]__C8 alkyl amines, especially methylamine, as well as aryl amines, particularly benzyl amine. The 2-methyl and 2-benzyl pyrindine derivatives so produced are readily converted to the corresponding 2unsubstituted pyrindine, which compound is easily derivatized by alkylation and acylation to produce other 2-substituted compounds of formula (I)· Such conversions will be elaborated upon hereinbelow.

In the preparation of the l,3-dioxo-4a-aryl2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines according to the above-noted reaction scheme, the 4-aryl-tetrahydro-2,6dioxo-cyclopenta[c]pyran and the amine are typically combined in approximately equimolar quantities, although an excess of either reactant can be used if desired. The reaction can be carried out in any of a number of commonly used unreactive organic solvents, including aromatic solvents such as benzene, toluene, xylene, methoxybenzene, and nitrobenzene, as well as non-aromatic solvents such as chloroform, dichloromethane, dimethyl sulfoxide, nitromethane, acetone, -9.» 45901 tetrahydrofuran, dimethylformamide, and dioxane. The reaction typically is conducted at an elevated temperature, for instance at a temperature ranging from about 50°C. to about 200°C., preferably at a temperature of about 80°C. to about 150°C. Since the reaction between the amine and the cyclic anhydride to form the corresponding cyclic imide is accompanied by the formation of water, it may be desirable to conduct the reaction -in such a way that water is removed from the reaction mixture as it is formed. Any of the commonly used techniques for maintaining a dry reaction mixture can be utilized, including the use of molecular seives, or alternatively a Dean Stark trap can be employed with reaction solvents such as benzene and toluene. The reaction between the amine and the cyclic anhydride normally is substantially complete within 24 to 72 hours; however, longer reaction times apparently are not detrimental to the product being formed and can be incorporated if desired.

The cyclic imide thus formed, namely the 4a-ary1-2,3,4,4a, 5,6,7,7a-octahydro-l,3-dioxo-lH-2-pyrindine , is readily isolated by removal of the reaction solvent, for instance by evaporation under reduced pressure, and the product can be further purified by standard procedures such as acid and base extraction, crystallization, and chromatography.

As hereinbefore stated, the 4-ary1-tetrahydro25 2,6-dioxocyclopenta[c]pyran can be reacted with ammonia to provide the corresponding 4a-aryl-2,3,4,4a,5,6,7,7aoctahydro-l,3-dioxo-lH-2-pyridine which is unsubstituted at the 2-position, or alternatively the pyran derivative can be reacted with a primary amine to provide directly a 4a-1045901 aryl-2-substituted-2,3,4,4a,5,6,7,7a-octahydro-l,3-dioxoΙΗ-2-pyrindine. It was further pointed out that when it is desired to react the pyran derivative with a primary amine so as to obtain a 2-substituted pyrindine derivative, it is preferred that such primary amine be methyl amine or benzyl amine. Such primary amines are preferred because they provide, when reacted with a 4-aryl-tetrahydro-2,6-dioxocyclopentatc]pyran, a 2-substituted 1,3-dioxo-pyrindine derivative which, when reduced, affords a 2-substituted pyrindine derivative in which the 2-substituent can be readily removed to afford a 2-unsubstituted pyrindine derivative. The 2-unsubstituted pyrindine derivative is an extremely important intermediate in the preparation of all other of the pyrindines of formula (I), as will be described hereinbelow. It should be noted, however, that while the preferred primary amines for reacting with the aforementioned pyran derivative are methyl amine and benzyl amine, essentially any primary amine can be reacted with the pyran derivative to provide the corresponding 4a-aryl-2-substituted20 2,3,4,4a,5,6,7,7a-octahydro-l,3-dioxo-lH-2-pyrindine. It will be further noted that since the latter named compound is a 1,3-dioxopyrindine derivative, that such compound must undergo a reduction of the 1- and the 3-oxo groups to provide the pharmacologically useful pyrindine of formula (I). It is preferred, therefore, that any group attached at the 2-position of such 4a-aryl-2-substituted-2,3,4,4a,5,6,7,7aoctahydro-1,3-dioxo-lH-2-pyrindine be a group which is substantially resistant to the reduction procedures utilized to reduce the 1- and the 3-oxo groups. For groups which are· -1145901 not so resistant to reduction, it is preferred to introduce such groups by alkylation, or acylation and susequent reduction, of the 2-unsubstituted pyrindine derivatives.

The following list presents representative 43ary 1-2 ,3,4,4a,5,6,7,7a-octahydro-l,3-dioxo-lH-2-pyrindines which are routinely prepared directly by reaction of an amine with a cyclic anhydride as hereinabove described and which are subsequently reduced to provide pharmacologically useful pyrindine derivatives as will be described in detail hereinbelow. 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-l,3dioxo-lH-2-pyrindine; 4a-phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro1,3-dioxo-lH-2-pyrindine; 4a-(3-methoxyphenyl)-2-n-pentyl-2,3,4,4a,5,6,7,7aootahydro-1,3-dioxo-lH-2-pyrindine; 4a-(3-ethoxyphenyl)-2-(3-phenylpropyl)-2,3,4,4a, ,6,7,7a-octahydro-l,3-dioxo-lH-2-pyrindine; 4a-phenyl-2-phenyImethyl-2,3,4,4a,5,6,7,7aootahydro-1,3-dioxo-lH-2-pyrindine; 4a-(3-propoxyphenyl)-2-n-propyl-2,3,4,4a,5,6,7,7aootahydro-1,3-dioxo-lH-2-pyrindine; 4a-(3-methoxyphenyl)-2-(2-tetrahydrofuryImethyl)2,3,4,4a,5,6,7,7a-ootahydro-l,3-dioxo-lH-2-pyrindine; 4a-phenyl-2-[2-(3-chlorophenyl)ethyl]-2,3,4,4a, ,6,7,7a-ootahydro-l,3-dioxo-lH-2-pyrindine; 4a-(3-methoxyphenyl)-2-cyclopropylmethyl-2,3,4,4a, 5,6,7,7a-ootahydro-l,3-dioxo-lH-2-pyrindine; -1245801 4a-(3-methoxyphenyl)-2-pheny Imethyl-2,3,4,4a, ,6,7,7a-octahydro-l,3-dioxo-lH-2-pyrindine; 4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro1.3- dioxo-ΙΗ-2-pyrindine; 4a-phenyl-2-(3,4-dimethylphenyl)methyl-2,3,4,4a, ,6,7,7a-octahydro-l,3-dioxo-lH-2-pyrindine; and 4a-(3-propoxyphenyl)-2-(4-phenylbutyl)-2,3,4,4a, ,6,7,7a-octahydro-l,3-dioxo-lH-2-pyrindine.

As has already been pointed out, the aforementioned 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-l,3-dioxo-lH-2-pyrindines, formula (IV), are converted to the 4a-aryl-2,3,4,4a,5,6,7,7aoctahydro-lH-2-pyrindines of formula (ilia) by reduction of the 1-oxo group and the 3-oxo group. Such reduction be be accomplished by any of a number of common reduction procedures familiar to those skilled in the art. For instance, the 1.3- dioxo-pyrindine derivative can be reacted with any of a number of alkali metal hydride reducing agents, including lithium aluminum hydride, sodium borohydride, lithium tritert.-butoxy aluminum hydride, and lithium trimethoxy aluminum hydride. Reducing agents such as zinc and acetic acid and catalytic hydrogenation can also be utilized if desired.

The preferred process for reducing a 4a-aryl-2,3,4,4a,5,6,7,7aoctahydro-l,3-dioxo-lH-2-pyrindine, formula (XV), involves the use of lithium aluminum hydride as the reducing agent. Typically a 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-l,3-dioxoΙΗ-2-pyrindine, such as 4a-phenyl-2-methyl-2,3,4,4a,5,6,7,7aoctahydro-1,3-dioxo-ΙΗ-2-pyrindine for instance, is reacted with about a two molar quantity of lithium aluminum hydride in an unreactive organic solvent. Unreactive organic solvents -13459 01 commonly used in the reaction include tetrahydrofuran, diethyl ether, dioxane and diglyme. The reaction normally is carried out at a temperature ranging from 20°C. to 100’C., and when carried out at such temperature, the reaction routinely is substantially complete after 4 to 20 hours. The product normally is recovered by first decomposing any unreacted reducing agent which may remain in the reaction mixture. Such decomposition is accomplished, in the case where lithium aluminum hydride is the reducing agent for instance, by adding to the reaction mixture an ester which readily reacts with any excess reducing agent. An ester such as ethyl acetate is commonly utilized for such purpose. Following the addition of the ester to the reaction mixture, an aqueous solution of ammonium chloride typically is added to the reaction mixture in order to coagulate any inorganic salts formed in the reaction, and then the product is extracted therefrom into a suitable organic solvent, such as ethyl acetate or tetrahydrofuran. The organic extracts are than combined and concentrated by evaporation of the solvent, thus providing the reduced product, namely a 4a-aryl-2,3,4,4a,5,6,7,7aoctahydro-ΙΗ-2-pyrindine, formula (III). Such product typically exists as an oil and is conveniently further purified if desired by methods such as distillation and chromatography, or alternatively such compound can be converted to an acid addition salt which can then be purified by crystallization. -1445901 Compounds of formula (I) [as indicated by formula (Ilia)] which are thus readily provided by reducing the 1-oxo and the 3-oxo groups of a 4a-aryl-2,3,4,4a,5,6,7,7aoctahydro-l,3-dioxo-lH-2-pyrindine according to the above5 described procedures include, among others: 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2pyrindine; 4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydroΙΗ-2-pyrindine; 4a-(3-ethoxyphenyl)-2-methy1-2,3,4,4a,5,6,7,7aoctahydro-lH-2-pyrindine; 4a-phenyl-2-ethyl-2,3,4,4a,5,6,7,7a-octahydroΙΗ-2-pyrindine; 4a-(3-isopropoxypheny1)-2-benzy1-2,3,4,4a,5,6,7,7a15 octahydro-ΙΗ-2-pyrindine; 4a-phenyl-2-isobutyl-2,3,4,4a,5,6,7,7a-octahydroΙΗ-2-pyrindine; 4a-(3-methoxyphenyl)-2-(4-ethylhexyl)-2,3,4,4a, ,6,7,7a-octahydro-lH-2-pyrindine; and 4a- (3-ethoxyphenyl)-2-(3-chlorobenzyl)-2,3,4,4a, ,6,7,7a-octahydro-lH-2-pyrindine.

As was hereinbefore noted, very important intermediates for preparing 2-substituted pyrindine derivatives of formula (I) are the 2-unsubstituted pyrindine derivatives of formula (III). Such compounds can be readily alkylated or acylated at the 2position to provide pharmacologically active octahydropyrindines of formula (I), or in the case of the N-acylated derivatives, to provide intermediates which are easily -1545901 converted to the active analgesics of formula (I). It is therefore often desirable to prepare, according to the above-described processes, 4a-aryl-2-substituted-2,3,4,4a, 5,6,7,7a-octahydro-lH-2-pyrindines in which the 2-substituent is readily removable so as to provide the corresponding 2-unsubstituted octahydropyrindine derivatives. As previously pointed out, N-methyl and N-benzyl groups are readily cleavable to afford the corresponding 2-unsubstituted pyrindine derivative. The 2-methyl pyrindine derivatives prepared as above described can be reacted with a haloformate ester such as phenyl chloroformate or ethyl chloroformate to afford the corresponding carbamate at the pyrindine 2-position. Such carbamate is then reacted with an agueous base such as sodium hydroxide to effect cleavage of the 2-carbamate moiety and thus provide the corresponding 2-unsubstituted pyrindine derivative. Such method for the cleavage of an N-methyl group is that of Abel-Monen and Portoghese as described in J. Med. Chem., 15, 208(1972).

Similarly, the aforementioned 4a-aryl-2-benzyl2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines are readily converted to the corresponding 2-unsubstituted pyrindine derivative by simple debenzylation. Such debenzylation may be achieved by catalytic hydrogention, utilizing for instance a catalyst such as five percent palladium suspended on carbon. Such debenzylation reactions are quite general for preparing secondary amines and are described in detail by Hartung and Simonoff, Org. Reactions, 7, 277(1953), and by Loenard and Fuji, J. Amer. Chem. Soc., 85, 3719 (1963). -1645901 As can readily be seen from the foregoing discussion, the following representative 2-unsubstituted pyrindine derivatives of formula (III) are also important intermediates for the preparation of 2-substituted pyrindines of formula (I). 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2pyrindine; 4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro1H-2-pyrindine; 4a-(3-ethoxy riienyl)-2,3,4,4a,5,6,7,7a-octahydro~ 1H-2-pyrindine; 4a-(3-isopropoxyphenyl)-2,3,4,4a,5,6,7,7aoc tahydro-1H-2-pyrindine; The 4a-aryl-2-unsubstituted-2,3,4,4a,5,6,7,7a15 octahydro-1H-2-pyrindines thsu prepared can be alkylated by normal procedures to provide pharmacologically active 2-substituted pyrindine derivatives, or can be acylated to provide intermediates which are readily converted to active analgesic drugs. For example, a 4a-aryl-2,3,4,4a,5,6,7,7a20 octahydro-1H-2-pyrindine can be alkylated at the 2-position <, 4 5901 by reaction with essentially any reactive derivative of an alkyl group. Such alkylating agents are compounds of the formula R^-Z in which R^ is as defined hereinabove and Z is any of a number of groups commonly referred to as good leaving groups. Groups most commonly known as good leaving groups include the halogens, particularly chlorine, bromine and iodine, para-toluenesulfonyl (tosyl), phenylsulfonyl, methanesulfonyl (mesyl), para-bromophenylsulfonyl (brosyl), and azido. It will be noted that when reference is made herein to an alkylating agent having the formula R^-Z, it is intended that the alkyl portion of such alkylating agent can be substituted for instance by unsaturated substituents, aryl substituents, and cyeloalkyl substituents. The term alkylating agent having the formula R^-Z thus includes compounds such as methyl chloride, ethyl bromide, 5-methylheptyltosylate, allyl bromide, 4-hexenyl iodide, 3-ethyl4-pentenyl brosylate, cyclopropylmethyl chloride, cyelobutylmethyl iodide, cyclohexylmethyl mesylate, 3-tetrahydrofurylmethyl bromide, 2-furylmethyl azide, 2-phenylethyl chloride, 3-benzoylpropyl bromide, 2-(3-chlorophenylthio)ethyl azide, phenoxymethyl bromide and 3-isopropylphenylthiomethyl bromide.

Thus, a 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-lH2-pyrindine can be reacted with an alkylating agent to provide the corresponding 4a-aryl-2-substituted-2,3,4,4a, ,6,7,7a-octahydro-lH-2-pyrindine. Such an alkylation reaction is quite general and can be accomplished by reacting the appropriate 4a-aryl-octahydro-lH-2-pyrindine with the appropriate alkylating agent, preferably in an unreactive organic -1845901 solvent. The alkylating agent typically is utilized in excess amounts, for instance from about 0.5 to about 2.0 molar excess relative to the pyrindine derivative. Unreactive organic solvents commonly utilized in the reaction include ethers such as diethyl ether, dioxane, tetrahydrofuran, as well as solvents such as benzene, diehloromethane, dimethylformamide, dimethyl sulfoxide, nitromethane, and hexamethylphosphor triamide. A base is preferably incorporated in the alkylation reaction to act as an acid scavenger since the reaction of the pyrindine derivative and the alkylating agent generally is accompanied by the formation of an acid such as hydrochloric acid or para-toluenesulfonic acid which may act to tie up any unreacted 2-pyrindine derivative as a salt. Bases commonly utilized as acid scavengers in such reaction include sodium bicarbonate, potassium carbonate, sodium hydroxide, triethylamine, and pyridine. Typically, about one equivalent amount of base is employed; however, excessive amounts can be incorporated if desired. The alkylation reaction normally is carried out at an elevated temperature ranging from about 50°C. to 200°C., and at such temperature, the reaction normally is substantially complete within about 1 to 10 hours; however, longer reaction times are not detrimental and can be used if desired. The product typically is recovered by simply adding water to the reaction mixture and then extracting the product therefrom into a water-immiscible organic solvent such as benzene, ethyl acetate, diehloromethane, diethyl ether, chloroform, or related solvents. Upon removal of the solvent from such extracts, for instance by evaporation under reduced pressure, -194S00 1 there is obtained the product 4a-aryl-2-substituted-2,3,4,4a, 5,6,7,7a-octahydro-lH-2-pyrindine, which compound exists either as an oil or as a solid at room temperature. The product so formed can be further purified if desired by standard procedures including chromatography, crystallization, distillation, or alternatively such pyrindine product oan be converted to an acid addition salt by reaction with an inorganic or organic acid. Such salts routinely are highly crystalline solids and are readily recrystallized to provide a solid salt of high purity. If desired such salt can then be treated with a base such as sodium hydroxide or potassium carbonate, thereby cleaving the salt to provide the purified 4a-aryl-2-substituted-2,3,4,4a,5,6,7,7a-octatiydro-lH-2pyrindine as a free base.

As herebefore indicated, the 2-unsubstituted pyrindine derivatives, namely the 4a-aryl-octahydro-lH-2pyrindines, can be converted to a 2-substituted pyrindine derivative whioh is either a pharmacologically useful agent per se, or one whioh can be readily converted to a pharmacologically useful agent. For example, reaction of a 4aaryl-2,3,4,4a,5,6,7,7a-OCtahydro-lH-2-pyrindine with an alkylating agent such as 2-benzoylethyl iodide provides the corresponding 4a-aryl-2-(2-benzoylethyl)octahydro-2,3,4,4a, 5,6,7,7a-2-pyrindine, an active analgesic. If desired, such compound can be reduced at the benzoyl carbonyl moiety, for instance by reaction with a reducing agent such as lithium aluminum hydride, to afford the corresponding 4a-aryl-2-(3hydroxy-3-phenyl) propyl-2,3,4,4a,5,6,7,7a-ootahydro-lH-2-2048801 pyrindine, also a useful analgesic agent. Additionally, a 2-unsubstituted pyrindine derivative can be acylated with any of a number of acylating agents to provide an N-acylated pyrindine derivative, a compound of formula (I) wherein is C-C1-C? alkyl, C-R3, or C- (CH2)n_j- (X)t s Such N-acylated pyrindines, upon reduction of the carbonyl moiety, provide 2-substituted pyrindine derivatives of formula (I) which are active analgesics. For example, a 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine can be acylated with any common acylating agent such as an acid halide or acid anhydride. Examples of commonly used acylating agents include acetyl chloride, pentanoylchloride, 4-hexenoyl chloride, cyclobutyIcarbonyl bromide, 2-(tetrahydrofuryl (carbonyl 'chloride, benzoyl bromide, phenoxyacetyl iodide, 3,4-dimethylphenylacetyl chloride, 3-(2-fluorophenyl)propionyl chloride, phenylthioaoetyl bromide, 4phenyl-3-butenoyl chloride, acetic anhydride, and hexanoic anhydride. The acylation of the 2-unsubstituted pyrindine derivative with an acylating agent such as the aforementioned is carried out by reacting approximately equimolar quantities of the pyrindine derivative and the acylating agent in an unreactive organic solvent such as dichloromethane, ethanol, or tetrahydrofuran. The reaction typically utilizes a base such as sodium bicarbonate, potassium carbonate, or propylene oxide to serve as an acid scavenger. The reaction is best carried out at a temperature of -20°C. to 30eC., and generally is complete within 1 to 8 hours. The product, for example a 4a-aryl-2-acylated-214 5 9 31 2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine, is readily isolated by simply removing the reaction solvent by evaporation. The product so formed normally is not purified further, but rather is reduced immediately to provide a 4a-aryl-2-substituted-2,3,4,4a,5,6,7,7a-octahydro1H-2-pyrindine of formula (I). Such reduction of the N-acyl carbonyl group can be accomplished by reaction of the acylated pyrindine derivative with a reducing agent such as lithium aluminum hydride or by catalytic hydrogenation.

It will additionally be recognized that still other modifications can be made on certain of the 4a-aryl2-substituted-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindines of formula (I). For example, a 4a-(3-methoxyphenyl)-2substituted-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine may be prepared and.then the 3-methoxy group of such 4a-aryl substituent converted to a hydroxy group. Such conversion is readily accomplished by reacting a 4a-(3-methoxyphenyl)pyrindine derivative with hydrobromic acid in acetic acid.

Such a reaction is quite general for the conversion of a methoxyphenyl group to a hydroxyphenyl group. The hydroxy group of such 4a-(3-hydroxyphenyl,pyrindines can, if desired, be acylated with common Cj-C3 alkanoyl acylating agents, for instance acetyl chloride or propionyl anhydride, thereby providing the corresponding 4a-(3-alkanoyloxyphenyl) pyrindine derivatives.

As hereinbefore pointed out, the 4a-aryloctahydro-lH-2-pyrindine derivatives of formula (I) can be reacted with an organic or inorganic acid so as to provide a crystalline salt which can be purified by crystallization, and which then can be converted back to the pyrindine free basfe by treatment with a suitable base such as sodium hydroxide. Certain of the acid addition salts are encompassed within the scope of the invention. Specifically, there are included herein the pharmaceutically acceptable acid addition salts of the pyrindine bases which are described hereinabove. Such pharmaceutically acceptable acid addition salts are prepared by reacting a 4a-aryl-octahydro-lII-2-pyrindine of formula (I) with an organic or an inorganic acid. Acids commonly used to prepare the pharmaceutically acceptable acid addition salts of formula (X) include the hydrogen halide acids such as hydrogen chloride, hydrogen bromide, and hydrogen iodide, as well as acids such as sulfuric, phosphoric, nitric, perchloric, phosphorous and nitrous. Organic acids commonly used to prepare pharmaceutically acceptable acid addition salts of the pyrindines of formula (I) include acetic, propionic, paratoluenesulfonic, chloroacetic, maleic, tartaric, succinic, oxalic, citric, lactic, palmitic, stearic and benzoic.

The pharmaceutically acceptable acid addition salts of formula (I) can be conveniently prepared by simply dissolving a 4a-aryl-octahydro-lH-2-pyrindine in a suitable solvent such as diethyl ether, ethyl acetate, acetone, or ethanol, and adding to such solution either an 23equivalent amount or an excess of a suitable acid. The salt so formed normally crystallizes out of solution and can be recovered by filtration, and is accordingly ready for use as a pharmacological agent, or can be further purified by recrystallization from common solvents such as acetone and methanol.

The following list of cis-4a-aryl-2-sub3tituted2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines is representative of the compounds falling within the scope of formula (I). 4a-phenyl-2-(3-ethylpentyl)-2,3,4,4a,5,6,7,7aoctahydro-lH-2-pyrindine; 4a-(3-methoxyphenyl)-2-(n-octyl)-2,3,4,4a,5,6,7,7aoctahydro-lH-2-pyrindinium bromide; 4a-(3-hydroxyphenyl)-2-(2-propenyl)-2,3,4,4a, ,6,7,7a-octahydro-lH-2-pyrindine; 4a-(3-propoxyphenyl)-2-(2,3-dimethyl-4-hexenyl)2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine; 4a-pheny1-2-(5-heptenyl)-2,3,4,4a,5,6,7,7aoctahydro-lH-2-pyrindiniura acetate; 4a-(3-hydroxyphenyl)-2-cyclopentylmethyl-2,3,4,4a, ,6,7,7a-octahydro-IH-2-pyrindinium oxalate; 4a-(3-ethoxyphenyl)-2-(2-tetrahydrofuryImethyl)2,3,4,4a,5,6,7,7a-octahydro-ΙΗ-2-pyrindine; 4a-pheny1-2-(2-phenoxyethyl)-2,3,4,4a,5,6,7,7a25 octahydro-ΙΗ-2-pyrindine; 4a- (3-hydroxyphenyl)-2-(2-methylphenoxymethyl)2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium succinate; 4a- (3-methoxyphenyl) -2- (3,5-dichlorobenzoyimethyl)2,3,4,4a,5,6,7,7a-octahydro-lll-2-pyrindine; -2445901 4a-(3-ethoxyphenyl)-2-[3-(3-methy1-4-bromophenyl)3-hydroxy1 propyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium iodide; 4a-phenyl-2-[3-(2-ethyl-6-methylphenylthio)propyl]2,3,4,4a,5,6,7,7a-octahydro-lh-2-pyrindinium perchlorate; 4a-(3-hydroxyphenyl)-2-[2-(3,4-dibromophenyl)-2hydroxy]ethyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine; 4a-phenyl-2-(3-phenylthio)propyl-2,3,4,4a,5,6,7,7aoctahydro-lH-2-pyrindinium citrate; 4a-phenyl-2-[3-(2-isopropylphenyl)propyl-2,3,4,4a, ,6,7,7a-octahydro-lH-2-pyrindinium maleate; 4a- (3-ethoxyphenyl)-2-(2-phenyl-2-hydroxyethyl)2,3,4,4a,5,6,7,7a-octahydro-lh-2-pyrindinium phosphate; 4a-phenyl-2-[2-(4-chlorophenyl)-2-hydroxyethyl]2,3,4,4a,5,6,7,7a-octahydro-lIl-2-pyrindinium methanesulfonate; 4a-(3-hydroxyphenyl)-2-[3-(2-chloro-3-bromophenyl)3-hydroxypropyl]-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine; 4a-(3-propoxyphenyl)-2-(2-ethylbenzoylethyl)2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium chloride; 4a-(3-ethoxyphenyl)-2-[3-(2-chlorophenylthio)propyl]-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine; 4a-phenyl-2-[3-(2-ethyl-5-bromophenyl)propyl]2,3,4,4a,5,6,7,7a-octahydro-lii-2-pyrindine; and 4a- (3-hydroxyphenyl)-2-[2-(3,5-diethylphenoxy)ethy1]-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium stearate.

It will be noted that the compounds of formula (I) have two asymmetric centers, namely the 4a position and the 7a position. This invention comprehends both separated -254390)· isomers and racemic mixtures of such isomers which are useful pharmacologically as analgesic agonist or antogonist drugs. However, only the cis-isomers of formula (I) are intended thereby, namely, such that the 4a-aryl group is ι 5 oriented on the same side of the plane of the molecule I from the 7a-hydrogen atom. This invention accordingly comprehends the pharmacologically active individual optically-active cis isomers, in addition to the racemic mixture of cis isomers. Such racemic pair of cis-octaV- : Ϊ10; -: hydropyrindines can be separated into its component stereoisomers by procedures well known in the art. Ini the event that all useful pharmacologic activirty~resides in one stereoisomer, the;dl-facemate is still useful in that it ; ί ; contains, as a constituent part7 The preparation of the 4a-aryl-octahydropyrindines of formula·. (I) requires starting materials, many of which are hitherto unknown and not readily available. The pyrindines of formula (I) may utilize 4a-aryl-tetrahydro-2,620 dioxocyclopentale]pyrans as starting materials. Such starting materials may be prepared fran 2-arylcyclchexananes such as 2-phenyloyclohexanone and 2-(3-methoxyphenyl)cyclohexanone. For the preparation of the dioxocyclopentapyran derivatives, the 2-arylcyclohexanone may be alkylated at the 2-position by reaction with an alkyl haloacetate such as ethyl chloroacetate, in the presence of a base such as sodium hydride, thereby providing the corresponding 2aryl-2-alkoxyoarbonylmethylcyclohexanone. Similarly, in the preparation of 2-ary1-2-alkenyl-l-aminomethylcyolopentanes, -2645901 a 2-arylcyclohexanone may first be alkylated at the 2-position by reaction with an alkenyl halide, such as allyl iodide or 2-butenyl bromide, in the presence of a base such as sodium hydride, to provide the corresponding 2-ary1-2-alkenylcyclohexanone. Both the 2-ary1-2-alkoxycarbonylmethylcyclohexanones and the 2-ary1-2-alkenylcyclohexanones may be formylated at the 6 position by reaction with an alkyl formate such as ethyl formate in the presence of metallic sodium or potassium. The formyl cyclohexanone derivatives may be reacted with para-toluene sulfonyl azide, thus effecting displacement of the 6-formyl moiety with a diazo group to provide, respectively, 2-ary1-2-alkoxycarbony1methyl-6-diazocyclohexanones and 2-ary1-2-alkeny1-6-diazocyclohexanones. Such diazocyclohexanone derivatives may be photolyzed with a light having a wavelength of about 3000 angstroms in an alcoholic solvent such as methanol to effect ring contraction with concommittant expulsion of nitrogen gas to provide, respectively, 2-ary1-2-alkoxycarbonylmethyl-l-methoxycarbonylcyclopentanes and 2-aryl-2alkenyl-l-methoxycarbonylcyclopentanes. Such compounds may be de-esterified, i.e. hydrolyzed, by reaction with aqueous alkali to provide the corresponding diacid and mono-acid. Specifically, hydrolysis of a 2-aryl-2-alkoxycarbonylmethyl-l-methoxycarbonylcyclopentane provides the corresponding 2-ary1-2-hydroxycarbonylmethyl-l-hydroxycarbonylcyclopentane. Similarly, hydrolysis of a 2-ary1-2-alkenyl1- methoxycarbonylcyclopentane affords the corresponding 2- ary1-2-alkenyl-l-hydroxycarbonylcyclopentane. The diacid, namely the 2-aryl-2-hydroxycarbonylmethy1-1-hydroxycar-2743901 bonylcyclopentane, may be cyclized by reaction with an acid halide such as acetyl chloride to provide the corresponding anhydride, a 4a-aryl-tetrahydro-2,6-dioxocyclopenta[c]pyran. These pyrans are the starting materials for the preparation of the pyrindines of formula (I) Certain of the 4a-aryl-2-substituted octahydroΙΗ-2-pyrindines of formula (I) have found utility in the treatment of pain, and accordingly can be used to effect analgesia in a subject suffering from pain and in need of treatment. Additionally, the pyrindine derivatives of formula (I) have been found to possess both analgesic agonist and analgesic antagonist properties, and as such are capable of producing analgesia in a mammal while at the same time, because of the analgesic antagonist activity, having a greatly decreased incidence of addiction liability. Such ability of the compounds disclosed herein to cause analgesic agonist as well as analgesic antagonist effects in mammals is thus responsible for a decrease in any addictive properties of a particular drug caused by its opiate-like analgesic action. The compounds are thus particularly valuable since they produce analgesia with only minimal physical dependance liability. Certain of the compounds are additionally useful in combating the undesirable effects produced by opiates such as morphine.

The analgesic activity possessed by the compounds of formula (I) has been determined by testing such compounds in standard animal assays routinely used to measure analgesic action attributable to test compounds. Such assays include the mouse-writhing test and the rat tail jerk assay. -2845901 As indicated hereinbefore, the compounds of formula (I) have demonstrated analgesic activity when tested in the standard mouse writhing assay. In this procedure, writhing is induced in mice by the intraperitoneal injection of acetic acid. The degree of analgesic activity possessed by a drug is then determined by observing the inhibition of such writhing when the drug is administered prior to the administration of the acetic acid. When 4a-(3-methoxyphenyl) -2-methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine, as the hydrochloride salt, is administered subcutaneously at the rate of 20 mg./kg. of body weight to a mouse in which writhing has been induced, there is observed a 100 percent reduction in such writhing. A subcutaneous dose of 10 mg./kg. produces a 96 percent inhibition of writhing. Similarly, an oral dose of the above-named compound produces a 100 percent inhibition of writhing at a dose of 20 mg./kg., and a 98 percent inhibition at a dose of 10 mg./kg. Additionally, naloxone was found to totally prevent the inhibitory action of the compound at an subcutaneous dose of 5 mg./kg., thus indicating that the compound is an opiate-type analgesic. When tested in the rat tail jerk assay, the above-named compound produced a significant increase in reaction time at dose levels of 80 mg./kg., both subcutaneously and orally, and produced the same effect at oral doses as low as 20 mg./kg., all measurements being made at 1/2 hour and 2 hours following dosing.

Similarly tested was 4a-(3-hydroxyphenyl)-2methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine. At a -2945901 subcutaneous dose of 0.5 mg./kg., the compound caused a 75 percent inhibition of writhing in a test animal. With an oral dose of 10 mg./kg. of such compound, a 98 percent inhibition of writhing was observed after 1/2 hour following dosing. Naloxone totally prevented the inhibitory action of the compound at a 0.5 mg/kg subcutaneous dose. The rat tail jerk assay revealed that the compound caused a significant increase in reaction time at subcutaneous and oral doses of 20 mg./kg. 4a-Pheny1-2-methyl-2,3,4,4a,5,6,7,7 a-octahydrolH-2-pyrindinium bromide, another compound of formula (I), effected a 70 percent inhibition of writhing in a group of test animals at a dose of 100 mg./kg., 1/2 hour following dosing; At an oral dose of 20 mg./kg., the compound caused a 58 percent inhibition after 1 1/2 hours following dosing, which effect was completely prevented in the presence of naloxone. The rat tail assay indicated that the compound caused only a moderate increase in reaction time at dose levels of 80 mg./kg.

In the mouse writhing assay and the rat tail jerk assay, the following E.D.5Q,s (dose which decreases the number of writhing observations by 50 percent compared to controls) were obtained for the compounds of formula (I) as follows: -3043901 Table Example No. Salt Writhing e.d.5O Hat Tail e.d.5O 12 HC1 5 <<80 13 — 0.4 0.2 14 HBr 1.0 1.0 15 HC1 >20 >80 16 HBr 1.0 0.5 17 — 20 >80 18 HBr 50 >80 19 HBr 20 — 20 HBr 20 >80 21 HBr 1.0 «80 The 4a-aryl-2· -substituted-2 ,3, 4/43/5/6/7/73™ octahydro-IH- 2-pyrindines of formula (I) are thus useful producing analgesia in mammals such as humans. Such compounds can be administered to a mammal by either the oral or the parenteral route. It generally is preferred to utilize a pharmaceutically acceptable acid addition salt of the pyrindine derivative when the dosage is by the oral route, since such salts are easily formulated for convenient oral administration. For example, one or more pharmacologically active compounds of formula (I), either as the free base or as a pharmaceutically acceptable acid addition salt, will be formulated for oral administration by admixing such compounds with any of a number of commonly used diluents, excipients, or carriers. Examples of such diluents and excipients commonly employed in pharmaceutical preparations include -314390 1 starch powder, sucrose, cellulose, magnesium stearate, lactose, calcium sulfate and sodium benzoate. Such compositions can be molded into tablets or enclosed in telescoping gelatin capsules for convenient administration. If desired, the active compounds of formula (I) can additionally be combined with one or more other agents known to effect analgesia, such as caffeine, acetaminophen, and propoxyphene.

The active compounds of formula (I) can addition10 ally be formulated as sterile aqueous or non-aqueous solutions, suspensions, and emulsions for convenient parenteral administration. Non-aqueous vehicles commonly utilized in such formulations include propylene glycol, vegetable oils such as olive oil, as well as various organic esters such as ethyl oleate. Useful aqueous solutions for oral and parenteral administration include isotonic saline solution.

The precise dosage of active ingredient, that is the amount of one or more of the pharmacologically active compounds of formula (I) administered to a mammal, such as a human subject for example, may be varied over a relatively wide range, it being necessary that the formulations should constitute a proportion of one or more of the active ingredients of formula (I) such that a suitable dosage will be obtained. Such suitable dosage will depend on the particular therapeutic effect desired, on the particular route of administration being utilized, and on the duration of treatment, as well as the precise condition being treated. Typically the dosages of the active compounds of formula (I) will range from -3245901 1.0 to about 25 mg./kg. of animal body weight per day, appropriately divided for administration from 1 to 4 times per day. Preferred oral dosages will generally range from about 2 to about 50 mg./kg.

In order to demonstrate more fully the scope of the compounds of formula (I) and their starting materials, the following examples are provided by way of illustration.

STARTING MATERIALS Example A A solution of 130 g. of 2-phenyl-2-ethoxycarbonylmethylcyclohexanone in 2000 ml. of diethyl ether containing 56 g. of ethyl formate and 11.5 g. of metallic sodium was stirred at 25°C. for forty-eight hours. The reaction mixture was then added to 1000 ml. of ice-water, and the ethereal layer was removed. The aqueous layer was acidified to pH 6.5 by the addition of IN hydrochloric acid, and further extracted with fresh diethyl ether. The ethereal extracts were combined, washed with water, and dried. Evaporation of the solvent under reduced pressure provided 98 g. of 2-phenyl-2-ethoxycarbonylmethyl-6-formylcyclohexanone as an oil. B.P. 158-175°C. at 0.5 torr.

Analysis Calc, for C17H20°4 Theory: C, 70.81; H, 6.99.

Found: C, 70.85; H, 6.77.

Example B Following the procedure set forth in Example A, 2-(3-methoxyphenyl)-2-ethoxycarbonylmethylcyclohexanone was reacted with ethyl formate in the presence of metallic -3345901 sodium to provide 2-(3-methoxyphenyl)-2-ethoxycarbonylmethyl-6-formyicyclohexanone.

Example C A solution of 87.0 g. of 2-phenylcyclohexanone in 100 ml. of benzene was added dropwise over 1 hour to a stirred refluxing solution of 28.0 g. of sodium amide in 400 ml. of benzene. The reaction mixture was heated at reflux for an additional 2.5 hours, and then cooled to 0°C. in an ice bath. To the cold reaction mixture was added in one portion a solution of 83.5 g. of allyl iodide in 100 ml. of benzene. The reaction mixture was heated at reflux for 1/2 hour, and then cooled to 25°C. and poured onto 400 g. of ice. The organic benzene layer was separated, washed with water and dried. Evaporation of the solvent afforded 50 g. of 2-pheny1-2-(2-propenyl)cyclohexanone. B.P. 114-120°C. at 0.1 torr.

Example D A solution of 30 g. of 2-phenyl-2-(2-propenyl) cyclohexenone in 600 ml. of diethyl ether containing 3.4 g. of sodium metal and 11.8 g. of ethyl formate was stirred at 25°C. for forty-eight hours. The reaction mixture was then added to water, and the organic layer was separated and set aside. The aqueous layer was acidified to pH 2.5 by the addition of aquoeus hydrochloric acid. The aqueous acid layer Was extracted with fresh diethyl ether. The ethereal extracts were combined, washed with water, dried, and the solvent was removed thereform by evaporation under reduced pressure to provide the product as an oil. The oil so -344ΰί)ΰι formed was distilled to afford 14.6 g. of 2-phenyl-2-(2propenyl)-6-formylcyclohexanone. B.P. 125-130°C. at 0.1 torr.

Example E A solution of 50.0 g. of 2-phenyl-2-ethoxycarbonylmethyl-6-formylcyclohexanone in 500 ml. of diethyl ether was stirred at 25°C. while a solution of 24.8 g. of diethylamine in 100 ml. of diethyl ether was added dropwise over thirty minutes. After stirring the reaction mixture for two hours at 25°C., the solution was cooled to 5°C., and then a solution of 33.5 g. of g-toluenesulfonylazide in 50 ml. of diethyl ether was added dropwise over fifteen minutes. The reaotion mixture was allowed to warm to room temperature, and was stirred for an additional five hours. The reaotion mixture was then washed with water and dried. Evaporation of the solvent under reduced pressure afforded 43.0 g. of 2-phenyl-2-ethoxyoarbonylmethyl-6-diazocyclohexanone as an oil. IR (neat) 2080 cm-1 diazo group.

Examples F-G Following the procedure set forth in Example E, 2-(3-methoxyphenyl)-2-ethoxycarbonylmethyl-6-formyIcyclohexanone was converted to 2-(3-methoxyphenyl)-2-ethoxycarbonylmethyl-6-diazooyclohexanone, and 2-phenyl-2-(2propenyl)-6-formylcyclohexanone was converted to 2-phenyl2-(2-propenyl,-6-diazocyclohexanone.

Example H A solution of 57 g. of 2-phenyl-2-ethoxycarbonylmethyl-6-diazooyclohexanone in 500 ml. of anhydrous methanol was stirred at 25°C. while nitrogen gas was bubbled through -3545001 the reaction mixture. The solution was photolyzed for o forty hours with a quartz lamp having wavelength of 3000 A.

The solvent was then removed under reduced pressure to provide the product as a crude oil, which was dissolved in 500 ml. of diethyl ether. The ethereal solution was washed with aqueous sodium bicarbonate solution, with water, and dried. Removal of the solvent under reduced pressure afforded 27.4 g. of methyl 2-phenyl-2-ethoxycarbonyImethyl-· 1-cyclopentaneearboxylate as an oil. The oil was further purified by distillation. B.P. 160-190°C. at 0.02 torr.

Analysis Calc, for cx7H22°4 Theory: C, 70.32; H, 7.64.

Found: C, 70.30; H, 7.36.

Examples I-J Following the procedure set forth in Example H, 2-(3-methoxyphenyl)-2-ethoxycarbonylmethyl-6-diazocycloo hexanone was photolyzed at 3000 A to provide nethyl 2-(3-nethaxyphenyl)-2-ethoxycarbonylmethyl-l-cyclopentane earboxylate.

B.P. 190°-210°C.

Analysis Calc, for Theory: C, 67.48; II, 7.55.

Found: C, 67.61; H, 7.37.

Similarly, 2-pheny1-2-(2-propenyl)-6-diazocyclo0 hexanone was irradiated with ultraviolet light at 3000 A from a quartz lamp in the presence of methanol to provide methyl 2-pheny1-2-(2-propenyl)-1-cyclopentane earboxylate B.P. 113-115°C. at O.l torr. -3645901 Analysis Calc, forC16U20°2 Theory: C, 78.65; H, Found ·· C, 78.80; H, Analysis Calc, forC19H25°5 Theory: C, 68.24; H, Found: C, 68.15; H, Example K A solution of methyl 2- (3-methoxyphenyl)-2-ethoxycarbonylmethyl-1- cyclopentane carboxylate in 650 ml. of 1,4-dioxane containing 500 ml. of 5 percent aqueous potassium hydroxide was stirred and heated at reflux for twelve hours. After cooling the reaction mixture to room temperature, 500 ml. of water was added. The reaction mixture was made acidic by the addition of 2N hydrochloric acid, and the aqueous acidic mixture was extracted several times with equal volumes of diethyl ether. The ethereal extracts were Combined, washed with water, and dried. Evaporation of the solvent under reduced pressure provided 38 g. of 2-(3methoxypheny1)-2-carboxymethyl-l-cyclopentane carboxylic acid as a crystalline solid. M.P. 175-180°C.

Examples L-M Following the procedure set forth in Example K, methyl 2--phenyl-2-ethoxycarbonylmethyl-l~cyclopentane carboxylate was hydrolyzed to provide 2-phenyl-2-carboxymethyl1-cyclopentane carboxylic acid. M.P. 205-208°C.

Analysis Calc, for C14H16°4 Theory: C, 67.73; H, 6.50.

Found: C, 67.70; H, 6.32. -3745901 Methyl 2-pheny1-2-(2-propenyl)-1-cyclopentane carboxylate was hydrolyzed by reaction with aqueous potassium hydroxide to provide 2-phenyl-2-(2-propenyl)-1-cyclopentane carboxylic acid.

Example N A solution of 25 g. of 2-pheny 1-2- carboxymethyl- 1- cyclopentane carboxylic acid in 150 ml. of acetyl chloride was stirred and heated at reflux for four hours.

After cooling the reaction mixture to room temperature, the excess solvent was removed by evaporation under reduced pressure, providing 26 g. of tetrahydro-4-phenyl-2,6dioxocyclopenta [ cj’pyran as an oil. The product was further purified by distillation. B.P. 205-207°C at 0.25 torr.

Analysis Calc, for C14H15°3 Theory: C, 73.03; H, 6.13.

Pound: C, 73.30; H, 6.37.

Example 0 Following -the procedure set forth in Example N, 2- (3-methoxyphenyl)-2- carboxymethyl-l-cyclopentane carboxy20 lie acid was dehydrated and cyclized by reaction with acetyl chloride to provide tetrahydro-4-(3-methoxyphenyl)2,6-dioxocyclopenta[c]pyran. B.P. 200-220’C.

Example P To a stirred solution of 6.2 g. of 2-phenyl25 2-(2-propenyl)-1-cyclopentane carboxylic acid in 100 ml. of chloroform was added dropwise over thirty minutes 30 g. of thionyl chloride. The reaction mixture was then heated at reflux and stirred for fifteen hours. After cooling the -3845901 reaction mixture, the solvent was removed therefrom byevaporation under reduced pressure to afford 7.4 g. of 2phenyl-2-(2-propenyl)-1-cyclopentane-carbonyl.chloride.

Example Q A solution of 10.7 g. of benzylamine in 100 ml. of toluene was stirred at 25°C. while a solution of tetrahydro-4-(3-methoxyphenyl)-2,6-dioxocyclopenta[c] pyran in 300 ml. of toluene was added dropwise over one hour. Following complete addition of the pyran derivative, the reaction mixture was stirred and heated at reflux for three days in a flask equipped with a Dean-Stark trap for water removal. Following the reflux period, the reaction mixture was cooled to room temperature and the solvent was removed by evaporation under reduced pressure, thus providing the product as a crude oil. The oil was dissolved in 400 ml. of IN sodium hydroxide solution and the alkaline reaotion mixture was heated to 50°C. for fifteen minutes. The aqueous alkaline mixture was then extracted with diethyl ether, and the ethereal extracts were combined, washed with water, dried, and the solvent was evaporated therefrom under reduced pressure to provide the product as a solid residue. Recrystallization of the solid from diethyl ether afforded 4a-(3-methoxyphenyl)-2-benzy1-2,3,4,4a,5,6,7,7a-oetahydrol,3-dioxo-lH-2-pyrindine. M.P. 75-77’C.

Analysis Calc, for C22H23NO3 Theory: C, 75.62; H, 6.63; N, 4.01.

Found: C, 75.40; H, 6.58; N, 3.78. -3945901 Example R Tetrahydro-4-phenyl-2,6-dioxocyclopenta[c]pyran was reacted with benzylamine according to the procedure of Example Q to provide 4a-phenyl-2-benzyl-2,3,4,4a,5,6,7,7aoctahydro-1,3-dioxo~lH-2-pyrindine. M.P. 77-79°C.

Analysis Calc, for C2iH21NO2 Theory: C, 78.97,- H, 6.63; N, 4.39.

Found: C, 78.73; II, 6.65; N, 4.26.

FINAL PRODUCTS Example 1 A solution of 18 g. of 4a-phenyl-2-benzyl2,3,4,4a,5,6,7,7a-octahydro-l,3-dioxo-lH-2-pyrindine dissolved in 200 ml. of tetrahydrofuran was added dropwise over ninety minutes to a stirred suspension of 5.8 g. of lithium aluminum hydride in 150 ml. of tetrahydrofuran. After the addition was complete, the reaction mixture was heated at reflux for ten hours. While maintaining the temperature of the reaction mixture below 50°C., 50 ml. of ethyl acetate was added dropwise over fifteen minutes, followed by the addition of 100 ml. of aqueous ammonium chloride. Additional tetrahydrofuran was then added to the aqueous reaction mixture to effect separation of the organic layer from the aqueous layer. The organic layer was decanted and concentrated under reduced pressure to provide the product as an oil.

The oil thus prepared was dissolved in 500 ml. of diethyl ether. The ethereal solution was Washed with water, dried, and the solvent was removed by evaporation under reduced -4045901 pressure to provide 15 g. of 4a-phenyl-2-benzyl-2,3,4,4a, ,6,7,7a-octahydro-lH-2-pyrindine. M+/e 291 (parent peak), 213 (-77, phenyl), and 200 (-91, benzyl).

Example 2 Following the procedure set forth in Example 1, 4a-(3-methoxyphenyl)-2-benzyl-2,3,4,4a,5,6,7,7a-octahydro1,3-dioxo-lH-2-pyrindine was reduced by reaction with lithium aluminum hydride to provide 4a-(3-methoxyphenyl)2-benzyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine.

Example 3 A solution of 21 g. of 4a-phenyl-2-benzyl2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine in 172 ml. of ethanol was stirred while 7 g. of 5 percent palladium suspended on carbon was added in one portion. The reaction mixture was stirred under a hydrogen gas atmosphere at 4.13 fi 2 x 10 dynes/cm. and heated at 60°C. for three hours. The reaction mixture was cooled to room temperature, filtered, and the solvent was removed by evaporation under reduced pressure to provide 13.3 g. of the product as an oil. The oil was distilled to afford 4a-phenyl-2,3,4,4a,5,6,7,7aoctahydro-lH-2-pyrindine.

Example 4 4a-(3-Methoxypheny1)-2-benzy1-2,3,4,4a,5,6,7,7aoctahydro-lH-2-pyrindine was hydrogenated in the presence of palladium suspended on charcoal according to the procedure set forth in Example 3 to provide 4a-(3-methoxyphenyl)2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine. B.P. 145-160°C., 0.05 torr. -41459 01 Example 5 A solution of 8.4 g. of 4a-(3-methoxyphenyl)2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine dissolved in 60 ml. of glacial acetic acid and 60 ml. of 48 percent aqueous hydrobromine and was stirred and heated at reflux for fifteen hours. After cooling the reaction mixture to room temperature, the reaction mixture was added to 100 g. of ice, and the pH of the resulting aqueous solution was adjusted to 10.2 by the addition of concentrated aqueous sodium hydroxide solution. The alkaline reaction mixture was then extracted with 400 ml. of a mixture of 3 parts n-butanol and 1 part benzene. The extract was separated, washed several times with water, dried, and the solvent was removed by evaporation under reduced pressure to provide the product as a crude solid. The solid so formed was crystallized from ethyl acetate to afford 4.2 g. of 4a-(3-hydroxyphenyl) -2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine. M.P. 180-181°C.

Analysis Calc, for Cg^HggNO Theory: C, 77.38; H, 8.81; N, 6.45.

Found: C, 77.56; H, 8.84; N, 6.24.

Example 6 A solution of 2 g. of 4a-phenyl-2,3,4,4a,5,6,7,7aoctahydro-lH-2-pyrindine in 30 ml. of N,N-dimethylformamide containing 1.23 g. of sodium bicarbonate was stirred at °C. while 1.23 g. of 2-propenyl bromide was added in one portion. The reaction mixture was stirred and heated at reflux for four hours. After being cooled to room temperature, the reaction mixture was filtered and concentrated -42to an oil under reduced pressure. The residual oil was dissolved in 300 ml. of diethyl ether. The ethereal solution was washed with water, dried, and the solvent was then removed by evaporation under reduced pressure, thus providing 4a-phenyl-2-(2-propenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH2-pyrindine as an oil. The oil so formed was dissolved in 150 ml. of fresh diethyl ether, and hydrogen bromide gas was bubbled through the ethereal solution. The precipitated salt was collected by filtration and recrystallized from diisopropyl ether and isopropanol to afford 1.3 g. of 4aphenyl-2-(2-propenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2pyrindinium bromide. M.P. 185-187°C.

Analysis Calc, for C17H24BrN Theory: C, 63.36; H, 7.51; N, 4.35.

Found: C, 63.63; H, 7.24; N, 4.24.

Examples 7-8 Following the procedure set forth in Example 6, the following 1-alkyl pyrindine derivatives were prepared by reaction of 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-lH2-pyrindine with an appropriate alkylating agent. 4a-Phenyl-2-n-propyl-2,3,4,4a,5,6,7,7a-octahydroΙΗ-2-pyrindinium bromide. M.P. 245-247°C.

Analysis Calc, for C^l^gBrN Theory: C, 62.96; H, 8.08; N, 4.32.

Found: C, 62.74? H, 8.22; N, 4.23. 4a-Phenyl-2-n-pentyl-2,3,4,4a,5,6,7,7a-octahydroΙΗ-2-pyrindinium bromide. M.P. 240-243°C.

Analysis Calc, for C^H^BrN -43Theory: C, 64.77; H, 8.58; N, 3.98.

Found: C, 65.04,- H, 8.70; N, 3.87.

Example 9 A solution of 3.0 g. of 4a-phenyl-2,3,4,4a,5,6,7,7aoctahydro-lH-2-pyrindine in 10 ml. of 88% formic acid was stirred at 20°C. while 10 ml. of 38% formaldehyde was added dropwise over fifteen minutes. The reaction mixture was then heated at 95°C. for eight hours. After cooling the reaction mixture to 25°C. 100 ml. of 4 N hydrochloric acid was added dropwise over thirty minutes. The aqueous acidic reaction mixture was concentrated under reduced pressure to provide an oily residue. The oil was then dissolved in 100 ml. of water, and the aqueous solution was made.basic by the addition of 50 percent aqueous sodium hydroxide solution.

The product precipitated out of the aqueous alkaline solution, and was extracted into diethyl ether. The ethereal extracts were combined, washed with water, dried, and the solvent was evaporated under reduced pressure to provide 4a-phenyl-2methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine as an oil. The oil so formed was dissolved in 150 ml. of diethyl ether. The ethereal solution was stirred at 25°C. while a solution of 10 ml. of 48 percent hydrobromic acid in 10 ml. of ethanol was added dropwise over ten minutes. The product precipitated out of solution and was recovered by filtration. The solid precipitate was recrystallized from diisopropyl ether and isopropanol to afford 2.7 g. of 4a-phenyl-2-methyl2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium bromide. M.P. 209-210°C. -4443901 Analysis Calc, for C15H22BrN Theory: C, 60.81; H, 7.49; N, 4.73.

Found: C, 60.55; H, 7.49; N, 4.57.

Example 10 To a cold solution (0-5°C.) of 3.0 g. of 4aphenyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2~pyrindine in 47 ml. of methanol containing 14 ml. of water and 2.6 g. of potassium carbonate was added 2.6 g. of phenylacetyl chloride in one portion. The reaction mixture was stirred at 0-5°C. for thirty minutes and then was warmed to 25°C., at which it was stirred for an additional one hour. The reaction mixture was concentrated under reduced pressure, leaving an oily residue. The oil was then dissolved in 500 ml. of diethyl ether and washed with dilute aqueous sodium bicarbonate solution and with water. After drying the ethereal solution, the solvent was evaporated under reduced pressure to afford 4a-phenyl-2-phenylacetyl-2,3,4,4a,5,6,7,7a-octahydro-lH2-pyrindine formed in the above acylation reaction as an oil.

The oil so formed was dissolved in 25 ml. of tetrahydrofuran and added dropwise over thirty minutes to a stirred suspension of 3.0 g. of lithium aluminum hydride in 150 ml. of tetrahydrofuran. After the addition was complete, the reaction mixture was stirred and heated at reflux for four hours. After the reaction mixture was cooled to 30°C., 60 ml. of ethyl acetate was added, followed by the addition to the reaction mixture of 100 ml. of saturated aqueous ammonium tartrate solution. The organic layer was separated by decanting, and the aqueous layer was extracted with -4545901 diethyl ether. The organic solvents were combined and concentrated under reduced pressure to provide the product as a crude oil. The oil was then dissolved in 400 ml. of diethyl ether, washed with water, and Iried. Removal of the solvent by evaporation under reduced pressure provided 4a-phenyl-2-(2-phenylethyl)-2,3,4,4a,5,6,7,7a-octahydro1H-2-pyrindine as an oil. The oil was then dissolved in 150 ml. of diethyl ether and added to a solution of 10 ml. of 48 percent hydrobromic acid in 10 ml. of 3thanol. The hydrobromide salt of the above-named pyrindine precipitated out of solution and was recrystallized fron diisopropyl ether and isopropanol to provide 2.4 g. of 4a-pheny1-2-(2-phenylethyl )-2,3,4,4a,5,6,7,7a-octahydro-IH-2-pyrindinium bromide. M.P. 269-270°C.

Analysis Calc, for C22H28BrN Theory: C, 68.39; H, 7.30; N, 3.63.

Found: C, 68.61; H, 7.57; N, 3.69.

Example 11 Following the procedure outlined in Example 10, 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine was acylated with cyclopropanecarboxylic acid chloride to provide 4 a-phenyl-2-cyclopropanecarbonyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine. Reduction of th’ acylated pyrindine intermediate by reaction with lithium iluminium hydride afforded the corresponding 2-alkyl pyrindine, which when reacted with hydrobromic acid provided 4a-phenyl-2cyclopropylmethyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium bromide. M.P. 240-241°C. -4645001 Analysis Calc, for C^gf^gBrN Theory: C, 64.28; H, 7.79; N, 4.16.

Found: C, 64.54; H, 7.51; N, 4.13.

Example 12 A solution of 75 ml. of toluene containing 1.76 ml. of liquid methylamine was cooled to -70°C. in a dry ice/acetone bath and stirred while a solution of 10.4 g. of tetrahydro-4-(3-methoxyphenyl)-2,6-dioxocyclopenta[cIpyran in 125 ml. of toluene was’ added dropwise over thirty minutes. The reaction mixture was warmed to room temperature and then heated at reflux for twenty-two hours. The reaction mixture was again cooled to room temperature and concentrated under reduced pressure to an oil. The oil so formed was dissolved in 152 ml. of 1 N sodium hydroxide solution and was heated with stirring to 50°C. for fifteen minutes. The product was extracted from the aqueous alkaline reaction mixture into diethyl ether. The ethereal extracts were combined, washed with water, and dried. Evaporation of the solvent under reduced pressure provided 8.3 g. of 4a-(3-methoxyphenyl)2-methyl-2,3,4,4a,5,6,7,7a-octahydro-l,3-dioxo-lH-2-pyridine.

Reduction of 8.2 g. of 4a-(3-methoxyphenyl)-2methyl-2,3,4,4a,5,6,7,7a-octahydro-l,3-dioxo-lH-2-pyrindine by reaction with lithium aluminum hydride according to the procedure set forth in Example 1 provided 4.6 g. of 4a-(3methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-lH2-pyrindine. B.P. 133-138°C. at 0.25 torr.

Analysis Calc, for C^gH23NO Theory: C, 78.32; H, 9.45; N, 5.71.

Found: C, 78.13; H, 9.30; N, 5.68. -47A solution-of 4a-(3-methoxypnenyl)-2-methyl2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine in 100 ml. of diethyl ether was stirred while hydrogen chloride gas was bubbled through the solution. The reaction mixture was stirred for thirty minutes and then filtered. The solid product was recrystallized from diisopropyl ether and isopropanol to provide 4a-(3-methoxyphenyl)-2-methyl2,3,4,4a,5/6,7,7a-octahydro-lH-2-pyrindinium chloride.

M.P. 175-177°C.

Analysis Cale, for cx6H24H0C1 Theory: C, 68.19; H, 8.58; N, 4.97.

Found: C, 68.00; H, 8.22; N, 4.68.

Example 13 A solution of 1.6 g. of 4a-(3-methoxyphenyl)-2methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine in 12 ml. of acetic acid containing 12 ml. of 48 percent aqueous hydrobromic acid was stirred and heated at reflux for fifteen hours. The acidic reaction mixture was cooled to about 10°C. and the pH was adjusted to 10.2 by the addition of 50 percent aqueous sodium hydroxide solution. The product was insoluble in the aqueous alkaline solution and was extracted therefrom into a solution of 90 ml. of n-butanol and 30 ml. of benzene. The organic solution was then separated, washed with water and dried. Evaporation of the excess solvent under reduced pressure provided the de-methylated product as an oil, which was then crystallized from diethyl ether and ethyl acetate to provide 4a-(3-hydroxyphenyl)-2-methyl2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrirdine. M.P. 151-153’C. -4845901 Analysis Calc, for C^-H^NO Theory: C, 77.88; H, 9.15; N, 6.05.

Found: C, 77.60; H, 8.88; N, 5.76.

Example 14 A solution of 2.17 g. of 4a-(3-hydroxyphenyl)2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine prepared as described in Example 5 in 50 ml. of Ν,Ν-dimethylformamide containing 3.95 g. of triethylamine was stirred at room temperature while 3.87 g. of phenylacetyl chloride was added dropwise over 15 minutes. Following complete addition, the reaction mixture was heated at 70“C for two hours, and then poured into 200 ml. of water. The aqueous reaction mixture was extracted several times with diethyl ether, and the ethereal extracts were combined, washed with saturated aqueous sodium chloride solution and with water, and dried. Removal of the solvent by evaporation under reduced pressure afforded 4a-(3-hydroxyphenyl)-2-(2-phenylacetyl)-2,3,4,4a, ,6,7,7a-octahydro-lH-2-pyrindine. Such product was dissolved in 50 ml. of tetrahydrofuran and stirred while a solution of 4.0 g. of lithium aluminum hydride in 150 ml. of tetrahydrofuran was added dropwise over thirty minutes. The reaction mixture was then heated at reflux for four hours, and then cooled to about 25°C. While the reaction mixture was stirred, 25 ml. of ethyl acetate was added, followed by the addition of a saturated aqueous solution of ammonium tartrate. The reaction mixture then was filtered and the filtrate was concentrated by evaporation of the solvent under reduced pressure. The product thus formed was dissolved in diethyl ether and washed with water and dried. Removal 49< 45301 of the solvent then provided 4a-(3-hydroxyphenyl)-2-(2phenylethyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine as an oil. The oil was dissolved in 150 ml. of diethyl ether and stirred while a fifty percent solution of 48% hydrobromic acid in ethanol was added. The hydrobromide salt of the above-named product crystallized and was collected by filtration, affording, after recrystallization from ethyl acetate, 1.3 g. of 4a-(3-hydroxyphenyl)-2-(2-phenylethyl) -2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium bromide.

M.P. 135-137°C.

Analysis Calc, for C22H28NBrO Theory: C, 65.67; H, 7.01; N, 3.48.

Found: C, 65.41; H, 7.12; N, 3.66.

Example 15 Following the procedure set forth in Example 14, 4a-(3-hydroxyphenyl)-2,3,4,4a,5,6,7,7a-ootahydro-lH-2pyrindine was reacted with cyclopropylcarboxylic acid chloride in the presence of potassium carbonate to provide 4a-(3-hydroxyphenyl)-2-(cyclopropylcarbonyl)-2,3,4,4a, ,6,7,7a-octahydro-lH-2-pyrindine. This latter named compound was reduced by reaction with lithium aluminum hydride to provide 4a-(3-hydroxyphenyl)-2-cyclopropylmethyl2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine, whioh was converted to the hydrochloride salt by reaction with hydrogen chloride gas in diethyl ether. M.P. 256-258°C.

Analysis Calc, for CggH^NOCl Theory: C, 70.22; H, 8.51; N, 4.55; Cl, 11.52. Found: C, 69.93; H, 8.25; N, 4.72'; Cl, 11.52. -50459 01 Example 16 A solution of 1.5 g. of 4a-(3-hydroxyphenyl)~ 2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine in 15 ml. of Ν,Ν-dimethylformamide containing 1.0 g. of sodium bicarbonate and 0.95 g. of 2-tetrahydrofurylmethyl bromide was heated at reflux for four hours. After cooling the reaction mixture to about 25°C., the mixture was extracted several times with diethyl ether. The ethereal extracts were combined, washed with water, and dried. Removal of the solvent by evaporation under reduced pressure provided 4a-(3-hydroxyphenyl)-2-(2-tetrahydrofurylmethyl)-2,3,4,4a, 5,6,7,7a-octahydro-lH-2-pyrindine as an oil. The oil so formed was dissolved in diethyl ether and added to a solution of hydrogen bromide gas in diethyl ether. The product crystallized out of solution and was collected by filtration to provide 1.0 g. of 4a-(3-hydroxyphenyl)-2-(2-tetrahydrofurylmethy1)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium bromide. M.P. 190-192°C.

Analysis Calc, for cigH28NO2Br Theory: C, 59.69; H, 7.38; N, 3.66.

Found: C, 59.89; H, 7.40; N, 3.78.

Examples 17-19 Following the procedure set forth in Example 16, 4a-(3-hydroxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH2-pyrindine was reacted with allyl iodide in the presence of sodium bicarbonate to provide 4a-(3-hydroxyphenyl)-2(2-propenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine.

M.P. 106-108°C. -5143301 Analysis.Calo. for C^H^NO Theory: C, 79.33,- H, 9.01; N, 5.44.

Found: C, 79.29; H, 8.92; N, 5.44.

Similarly, 4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7aoctahydro-ΙΗ-2-pyrindine from Example 4 was reacted with 1- iodopropane in-the presence of sodium bicarbonate to provide 4a-(3-methoxyphenyl)-2-n-propyl-2,3,4,4a,5,6,7,7aoctahydro-lH-2-pyrindine, which was then converted to the hydrobromide salt by reaction with hydrogen bromide gas in diethyl ether. M.P. 197-199°C.

Analysis Calc, for C18H28NOBr Theory: C, 61.02; H, 7.97; N, 3.95.

Found: C, 60.65; H, 7.52; N, 4.07.

Similarly, 4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a( octahydro-ΙΗ-2-pyrindine was reacted with 1-bromopentane in the presence of sodium bicarbonate to provide 4a-(3methoxyphenyl)-2-n-pentyl-2,3,4,4a,5,6,7,7a-oetahydro-lH2- pyrindine. Such compound was treated with hydrogen bromide gas in diethyl ether to provide 4a-(3-methoxyphenyl, -2-n-pentyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2pyrindinium bromide as a crystalline solid. M.P. 179-181°C. Analysis Calc, for C2Q H32N°Br Theory: C, 62.82; H, 8.44; N, 4.18.

Found: C, 62.87; H, 7.98; N, 4.02.

Example 20 A solution of 2.0 g. of 4a-(3-methoxyphenyl)-2n-propy1-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine, prepared as described in Example 18, dissolved in 20 ml. of glacial acetic acid and 20 ml. of 48 percent aqueous hydrobromic -524S901 acid was stirred and heated at reflux for twelve hours. The reaction mixture was then cooled and poured over 100 g. of ice, and the resulting aqueous solution was made alkaline by the addition of aqueous sodium hydroxide to pH 10.2. The aqueous alkaline mixture was extracted with 200 ml. of a mixture of 3 parts n-butanol and 1 part benzene. The extracts were combined, washed with water and dried.

Removal of the solvent by evaporation under reduced pressure provided 1.3 g. of 4a~(3-hydroxyphenyl)-2-n-propyl-2,3,4, 4a,5,6,7,7a-octahydro-lH-2-pyrindine is an oil. The oil was dissolved in diethyl ether and added to a solution of hydrogen bromide gas in diethyl ether. The hydrobromide salt of the above-named compound crystallized and was recovered by filtration to give 1.1 g. of 4a-(3-hydroxyphenyl) -2-n-propyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2pyrindinium bromide. M.P. 235-236°C.

Analysis Calc, for C^jH^gNOBr Theory: C, 60.00; Η, 7.70; N, 4.12.

Found: C, 59.98; H, 7.50; N, 3.98.

Example 21 Following the procedure set forth in Example 20, 4a-(3-methoxyphenyl)-2-n-pentyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine was reacted with aqueous hydrobromic acid in glacial acetic acid to afford 4a-(3-hydroxyphenyl)2-n-penty1-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine, which was then converted to the corresponding hydrogen bromide salt. M.P. 171-173°C.

Analysis Calc, for CggH^gNOBr Theory: C, 61.95; Η, 8.21; N, 3.80.

Found: C, 61.65; H, 7.93; N, 3.54.

Claims (26)

1. A cis-compound of the general formula wherein: is hydrpgen, C^-Cg alkyl, CH 2 R 3 , or /== R s in which: R 3 is C 2 ~C 7 alkenyl, C 3 -C g oycloalkyl, furyl, or tetrahydrofuryl; R 4 and Rg independently are hydrogen, C-^-Cj alkyl, or halogen; n is 0, 1, 2, or 3; m is 0 or 1, except that when m is 0, n is other than 0; X is CO, CHOH, CH=CH, S, or 0, except that when n is Ο, X is other than S or 0; R 2 is hydrogen, hydroxy, C^-C 3 alkoxy, or C^-C 3 alkanoyloxy; and the non-toxio pharmaceutically acceptable acid addition salts thereof.

2. The oompound of claim 1 wherein R^ is C^-Cg alkyl or CH 2 R 3 in which R 3 is C 2 -C 7 alkenyl or Cg-Cg oycloalkyl. -54459 01

3. The compound of claim 2 wherein R 2 is hydroxy or methoxy.

4. The compound of claim 1 wherein R 2 is hydroxy.

5. The compound of claim 1 wherein R^ is hydrogen.

6. 4a-(3-Methoxyphenyl)-2-benzyl-2,3,4,4a,5,6,7,7aoctahydro-lH-2-pyrindine.

7. 4a-Phenyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2pyrindine.

8. 4a-(3-Methoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine.

9. 4a-(3-Hydroxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine.

10. 4a-(3-Methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7aoctahydro-lH-pyrindine.

11. 4a-(3-Hydroxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7aoc tahydrο-IH-2-pyrindine.

12. 4a-(3-Hydroxyphenyl)-2-(2-phenylethyl)2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine.

13. 4a-(3-Hydroxyphenyl)-2-cyclopropylmethyl2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine.

14. 4a-(3-Hydroxyphenyl)-2-(2-tetrahydrofurylmethyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine.

15. 4 a-(3-Hydroxypheny1)-2-(2-propenyl) -2,3,4,4 a, 5,6,7,7 a-octahydro-ΙΗ-2-pyrindine.

16. 4 a-(3-Me thoxypheny1) -2-n-propyl-2,3,4,4a,5,6, 7,7a-octahydro-lH-2-pyrindine.

17. 4a-(3-Methoxyphenyl)-2-n-pentyl-2,3,4,4a,5,6, 7,7a-octahydro-lH-2-pyrindine.

18. 4a-(3-Hydroxyphenyl)-2-n-propyl-2,3,4,4a,5,6, 7,7a-octahydro-lH-2-pyrindine. 5545901 V

19. 4a-(3-Hydroxyphenyl)-2-n-pentyl2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine

20. A process for preparing a cis-compound of the general formula wherein: R 2 is as defined in claim 1 and R^' is Cj-Cg alkyl, CH 2 R 3 , or -< CH 2>n in which -(X) R 3 , R^, Rg, m, n and X are as defined in Claim 1, and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting a 15 compound of the general formula 4as οι (III) wherein Rg is defined as before, and Rg 1 ' is hydrogen, with an alkylating agent to obtain a oompound of formula (II) in which Rg' is Cg-Cg alkyl or CHgRg in whioh Rg is Cg-C? alkenyl, or with an acylating agent followed by reduction to obtain a compound of formula (II) in which Rg* is CHgRg in which Rg is Cg-Cg cycloalkyl, furyl, or tetrahydrofuryl, or -< εΗ 2>η-< χ ννΧ in which n, m, R^ and Rg are 15 defined as before, optionally de-etherifying when R 2 is Cg-Cg alkoxy to obtain a compound of formula (II) in which R 2 is hydroxy, optionally acylating a compound of formula (II) wherein Rg is hydroxy to obtain a compound of formula (II) wherein Rg is Cg-Cg alkanoyloxy: and optionally forming a 20 pharmaceutically acceptable acid addition salt.

21. A process for preparing a cis-compound of the general formula (Ilia) -5745901 wherein R 1 ’is hydrogen, C-^-Cg alkyl, or /'=% R “ -( CH 2 ) n~ (x >m~\ /wherein χ, n, m, R 4 , Eg and R 2 % are as defined in claim J. which comprises reacting a compound of the general formula (IV) wherein ''·and R 2 are defined as before with a reducing agent, optionally cleaving the compounds of formula (Ilia) F >7 * wherein ^'is C^-Cg alk yl or - ( CH 2’n - ^ X ^m”% R to obtain the compounds of formula (Ilia) wherein R^'^is hydrogen, and optionally de-etherifying the compounds of formula (Ilia) wherein R 2 is C^-Cg alkoxy to obtain the compounds of formula (Ilia) wherein R 2 is hydroxy.

22. A pharmaceutical composition comprising a cis compound of formula (I) as defined in any one of claims 1 to 19 in association with a pharmaceutically-acceptable carrier therefor.

23. A method of preparing a pharmaceutical composition 25 which comprises bringing' a cis-compound of formula (I) as defined in any one of Claims 1 to 19 into association with a pharmaceutically-acceptable carrier therefor. -5843901

24. A compound as claimed in claim 1 substantially as hereinbefore described with particular reference to any one of the examples.

25. A process as claimed in claim 20 or 21 sub5 stantially as hereinbefore described with particular reference to any one of the examples.

26. A composition as claimed in claim 22 substantially as hereinbefore described.