CA1100136A - 4a-aryl octahydro-1h-2-pyrindines - Google Patents

Abstract

Abstract of the Disclosure 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 use-ful as analgesic agents.

Description

3~

4a-ARYL-OCTAHYDRO-lH-2-PYRINDINES
In recent years, much effort has been devoted to the synthesis of drugs, l.e. analgesics, capable of relieving the sensation of pain. Several of the currently available analgesics are limited in their usa due to various undesi~-able 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 d cahydroisoquinolines, particularly the 4a-aryl~trans-decahydroisoquinolines which are described in Belgium Patent iNo. 802,557.
The present invention rela~es to a process for preparing a group of cls-4a-aryl-2-substituted-octahydro~

lH-2~pyrindines. Such compounds are somewhat structurally related to the aforementioned isoquinoline derivatives, however, the compounds of formula (I) belo~ have not hereto-fore been synthetically available. Only simple u~substituted pyrindine analogs are known in the literature. Volodina et al., for example, prepared certain octahydro-2- pyrindines, none of which were substituted at the 4~-position; Dokl, Akad. Nauk USSR 173(2), 342-5(1967) cf. C.A. Vol. 67, 6034(1967). Similarly, Prochazka et al. prepared a trans-octahydro-2-pyrindine lacking a 4a-substituent, Coll.
Czech. Chem. Commun., 31(9), 3824-8(1966), Cf. C.A. Vol. 65, 13651(1966).
This invention provides a process for preparing ClS 4a-phenyl and substituted phenyl 2,3,4,4a,5,6,7,7a-octahydr~-lH-2- pyrindines not heretofore known or available, and interm~diates useful in their preparation.

X-~466 2-.~,/ , .....

f ~. ~
3~

This invention rela~es ~o a process for preparing new bicylic compounds characterized as b0ing octahydro-lH-

2-pyrindines, alternatively referred ~o as hexahydro-lH-cyclopenta[c~p~ridines. Speci~ically, the invention, in one aspect, provides a proce~s for preparing cis-~a-aryl-2-substituted-2,3,4,4a,5,6,7,7a-octa~ydro-lH-2-pyridines of th~
general formula .. . ... . . ..
/~
Il I - R2 \~;
~4a \3t wherein:
~== ~ R4 R is C -C alkyl, CH2R3, ox (C~2)n (X)m ~ ~ R

in which:
2a R3 is C2~C7 alkenyl~ C3-C6 cycloalkyl, furyl, or tetrahydrofuryl;
R4 and R5 independently are hydxo~en, Cl-C3 alkyl~ or halogen;
n is 0, 1, 2, or 3t ~ m is O or 1, except that when m i5 O, n is other ; than 0:

X-4466 . -3 - :

x is Co, CHOH, CH=CH, S, or O, except that wh~n n is O, X is other than S or Oi R2 is hydrogen, hydroxy, or Cl-C3 alkoxy; and the non-toxie pharmaceutieally acceptable acid addition salts thereof, which comprises reacting a eompound of the general formula ~ r . ~ ,~
/ \ ~,~
\ ~/ ~ R1' (II) wherein R2 is defined as before, and Rl' is hydrogen, with an alkylating agent to obtain a eompound of formula (I) in X-4466 ~4~
' ,

3~

which Rl is Cl c8 alkyl or C~2R3 i~ which R3 is C2-C7 alkenyl, or with an acylating agent followed by reduction to obtain a compound of formula (I) in which Rl is CH2Ps3 in which R3 is C3 C6 cycloalkyl~ furyl, or tetrahydrofuryl, o~ R4 or ~(~2)n (X)m ~ ~ in which n, m, R4, and R5 are defined as before, and optionally de-etherifying when R2 is 1 3 xy to obtain a co=pound of formula (I) in which.
R2 i5 hydroxy, and where desired, ~or~ing a non-toxic, pharma-ceutically accepta~le acid addition salt of said compound of :~oxmula (I).
. A compound of formula (II~ wherein Rll is hydrogen is prepared as indicated ~elow. In ano~her a~pect, the invention pro~ides a process for preparing a cis-compound o the ~eneral ormula 0 R~
\~

:
,.

.

~ , .

31~i wherein R1' is hydrogen, Cl-C8 alk.yl, or ~__ ~ R4 ~__3~ , nd R2 is hydrogen, hydr Cl-C3 alkoxy, which comprises reacting a compound of the general formula ~, DI

~ ~ ~ , (III) O

wherein Rl' and R2 are defined as before with a reducing agent t optionally cleaving the compounds of formula (II) wherein R1' is Cl-C8 alkyl or (CH2)n-(X)m-~

to obtain the compounds of formula (II) wherein Rl' ishydrogen, and optionally de-etheri~ying the compounds of formula (II) wherein R2 is Cl-C3 alkoxy to obtain the compounds of formula (II) whereln R2 is hydroxy, A preferred group of compounds are those of formula (I) wherein R1 is Cl-C8 alkyl or CH2R3 in which R3 is C2-C7 alkenyl or C3-C6 cycloalkyl. A more preferred group of compounas within this latter preferred group are those of formula ~I) wherein R2 is hydroxy or methoxy.

An especially preferred group of intermediate compounds are those of formula (II) wherein R1' is hydrogen.

::
:

X-4466 ~6-` -As us~d throughout the present specification and in the appended claims, the term "Cl-C8 alkyl" refers to both straight and branched chains of eight car~on atoms or less. Examples o~ typical Cl-C8 alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, iso~utyl, pentyl, 3-methylpentyl, 1,2-dimethylpentyl, 2-methylbutyl, 3-ethylpentyl, n-octyl, 2-methylheptyl, isoheptyl, 3-ethyl-hexyl, 1,3,3-trimethylpentyl, and related groups.
2 3~ in which R3 is C -C alke 1"
10 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-methyl-2-butenyl, 3-methyl-3-pentenyl, 3-isohexenyl, 2-ethyl-3-butenyl, 4-hexenyl, 3-methyl-2-pentenyl, 3-octenyl, 2-isooctenyl, 2-isopropyl-3-butenyl, 2,3-dimethyl-2-butenyl, S-heptenyl, ; 6-octenyl, 2-methyl-3-heptenyl, and related alkenyl groups.
Additionally included within the clefinition of Rl in formula (I) is the group represented by CH2R3 in which R3 is C3-C6 cycloalkyl. Such groups include cyclopropylmethyl, 20 cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
Rl can also represent groups such as 2-tetrahydrofuryl-methyl, 3-tetrahydrofurylmethyl, and 3-furylmethyl. J
In formula (I~, Rl can al50 be a group of ~he ~_ ~ R
2 n m ~2-- ~ R
3, m is 0 or 1, except that whcn m is O, n is other than 0; X is CO, CHOH, CH=CH, S or~O, cxcept that when n is O, X
is othcr than S or Oi and R4 and R5 indepcndently are 30 hydrogen, Cl-C3 alkyl, or halo~en. In such formula, the L3~

term "Cl-c3 alkyl" includes methyl, ethyl and propyl~
"Halogen" refers to fluorine, chlorine, bromine and iodine.
Examples of typical Rl yroups represented by foxmula (I) include benzyl, 2-phenylethyl, 3-phenylpropyl, 3-methyl-benzyl, 4-chlorobenzyl, 2,4-dibromobenzyl, 2-(2-methyl-5-ethylphenyl)ethyl, 3-(4-isopropylF,henyl)propyl, benzoyl-methyl, benzoylethyl, 4-iodobenzoylmethyl r 2-methyl-

4-chlorobenzoylmethyl, 2-phenyl~2-hydroxyethyl, 3-phenyl-~-hydroxypropyl, 2-(4-fluorophenyl)-2-hydroxyethyl, phenoxy-methyl, 3,5-diethylphenoxymethyl, 3-phenylthiopropyl, 2-methylphenylthiomethyl, 3,5-dichlorophenylthiomethyl, 3-chloro-5-bro~ophenylthiomethyl, and related groups~
The ~oregoi~g pyrindine derivatives of formula (I) are produced by ~ixst 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:

20 ~ ~f ~ R~

+ H ~R, 11 ~ 11 0 ~V) 0 (IV) , in which Rl and R2 have the above-defined meanings. The 1,3-dioxo-4a-aryl~2,3,4,4a,5,6,7,7a-oc~ahydro-lH-Z-PY
a cyclic imide, so produced is then reduced at the 1 and the , ~-4466 -8-,~,, ..,,, .. ; ~

3-oxo groups to provide a pyrindine derivative of formula (II). In practice, it is preferred to utilize 4a-aryl-tetrahydro-2,6-dioxocyclopenta[c]pyrans in which the sub~
stituent on the a~yl group, defined in ~he above formulas by R2, is selected from hydroqen and Cl-c3 alkoxy groups.
Among such Cl-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 here-inafter. In the reaction of an amine with the above-noted cyclic anhydride, it is similarly preferred to utilize amines such as ammonia, Cl-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 2-unsubstituted pyrindine, which compound is easily derivatized by alkylation and acylation to produce other 2-subs~ituted compounds of formula (I~. Such conversions will be elaborated upon hereinbelow.
In the preparation of the 1,3-dioxo-4a-aryl-20 2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines according to the above-noted reaction scheme, the 4-aryl-tetrahydro-2,6-dioxo-cyclopenta~cJpyran 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 unreactlvc organic solvents, including aromatic solvents such as benzene, toluene, xylene, methoxybenzene, and nitrobenzene, as well as non-aromatic ~olvents ~uch as chloroform, di-chloromethane, dimethyl sulfoxide, nitromethane~ acetone tetrahydrofura~, dimethylfarmamide, and diox~ne~ The reaction typically is co~ducted at a~ ele~at~d temperature, for inst~nce at a temperature ranging from about 50c. to abou~ 200C., preferably at a tempera~urP of abau~ 80C. ~o about 150C. Since the reaction between the amine and the cyclic anhydride to form the corxesponding cyclic imide is accompanied by the ~ormation of watex, it may b~ desirable ~o condu~t the reaction în 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 bQ utilized, including the use of molecular sieves, or alternatively a Dean S~ark trap can be employed with reaction solvents such as benzene and tolue~e. ~he reac~ion between the amine a~d the cyclic a~hydride normally is subs~antially comple~e within 24 to 7Z hours; however, longer reaction time~ apparently are no~ detrimental ~o the product being form~d and can be incorporated if desired.
The cyclic imide thu~ formed, namely the 4a~axyl-2,3,4,4a, .5,6,7,7a-octahydro-1,3-dioxo-1~-2-.pyrindine, is readily isolated by removal of the reaction solvent, for instance by evaporation under reduced pressure, and the product can be fur~h~r puri~ied by standard proc~dur~s ~uch as zcid and base ex~raction, cry~tallization, and chromatography.
- As hereinbefore stated, the 4-a~yl-tetrahydro- : ~ -2~6-dioxocyclopentalcjpyran can be ~eacted with ammonia to provide the correspondi~g 4a-aryl-2,3,4,4a,5,6,7,7a-.. .. .. . __. . . . ., , .. _ _ . _ . ,,_ . .. . , . -- . _ .
~ octahydro-1,3-dioxo-lH-2 pyrindine which is unsubstituted at .....
the 2-position, or alternaki~ely the pyran derivative can be reacted with a primary amine to provide directly a 4a-X-4466 ~10-. ~ .
.

3~i aryl-2-substituted-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-lH-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-dioxo-cyclopenta[c]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-substituted-2,3,4,4a,5,6,7,7a-octahydro-1,3-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 g~oup attached at the 2-position of such 4a-aryl-2-substituted 2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo lH-2-pyrindine be a group which is substantially resistant to the reduction procedures utilized to reducP the 1- and the 3-oxo groups. For groups which are X~4466 not so resistant to reduction, it is pre~erred to introduce such groups by alkylation, or acylation and subsequent reduction, , . ... . . . . _ _ _, , _ _ , _ ,, ,, , _ of ~he 2-unsubstituted pyrindine derivatives.
The following list presents representati~e 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-lH-2 pyrindines which are routi~ely prepared directly by reaction of an amine with a cyclic anhydride as hereinabove described and which are subsequently reduced to provide pharmacologically use~ul pyrindine derivatives as will be described in detail hereinbelow.
4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine;
4a-phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine;
4a-(3-methoxyphenyl)-2-n-pentyl-2,3,4,4a,5,6,7,7a-octahydro-1,3 dioxo-lH-2-pyrindine;
4a-(3-ethoxyphenyl)-2-(3-phenylpropyl)-2,3,4,4a,

5,6,7~7a-octahydro-1,3-dioxo-lH 2-pyrindine;
4a-ph~nyl-2-phenylmethyl-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine;
4a-(3-propoxyphenyl)-2-n-propyl-2,3,4,4a,5,6,7,7a~
octahydro-1,3-dioxo-lH-2-pyrinaine;
4a-(3-m~thoxyphenyl)-2-(2-tetrahydrofurylmethyl)-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-1~-2-pyrindine;
4a-phenyl-2-[2-(3-chlorophenyl)ethyl~-2,3,4,4a, 5,6,7~7a-octahydro-1,3-dioxo-lH-2-pyrindine;
4a-(3 methoxyphenyl)-2-cyclopropylmethyl-2,3,4,4a, : 5,6~7,7a-octahydro 1,3-dioxo-lH-2-pyrindine;

.
X-446~ -12-3~36 4a-(3-methoxyphenyl)-2-phenylmethyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine;
4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a~octahydro-1,3-dioxo-lH-2-pyrindine;

4a-phenyl-2-(3,4-dlmethylphenyl)methyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine; and 4a-(3-propoxyphenyl)-2-(4-phenylbutyl)-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine.

As has already been pointed out, the aforementioned 4a-aryl-2,3~4,4a,5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindines, formula (III), are convexted to the 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines of formula (II) by r~duction of the l-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 tri-tert~ butoxy aluminum hydride, and lithium trimethoxy aluminum 20hydride. 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,5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine, formula (III), involves the use of lithium aluminum hydride as the reducing agent.
Typlcally a 4a-aryl-2,3,4,4a,5,6,7j7a-octahydro-1,3-dioxo-lH~2 pyrindine, such as 4a~phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-lH~2 pyrindine for instance, is reacted with about a two molar quantity of lithium aluminum hydride in an unreactive organic solvent. Unreactive organic solvents 3~

commonly used in the reaction include tetrahydrofuran, diethyl ether, dioxane, diglyme, and related solvents. Tne reaction normally is carried out at a temperature ranqing from about 20C. to about 100C., and when carried out at such temperature, the reaction routinely is substantially complete after about 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 re-ducing agent. An ester such as ethyl acetate is commonly utilized for such purpose. Following the addition of the ester to the reaction mixture, an a~ueous solution o~
ammonium ~hloride 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 orqanic solvent, such as ethyl acetate or tetra-hydrouran. 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,5,6~7,7a-octahydro-lEI-2-pyrindine, formula ~II). Such product typically exists as an oil and is convenlently ~urther puri~ied i~ desired by methods ~uch as distillation and chromatography, or alternatively such compound can be con-verted to an acid addition salt which can then be puri~ied by crystallization. -~-~466 -14-.

L3~
Compounds of formula (I) [as indicated by formula ~II)] which are thus readily provided by reducing the l-oxo and the 3-oxo groups of a 4a-aryl-2,3,4,4a,$,6,7,7a~
octahydro-1,3-dioxo lH-2-pyrindine according to the above-described procedures include, amony others:
4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH 2-pyrindine;
4a-(3-ethoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-phenyl-2-ethyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-(3-isopropoxyphenyl)-2-benzyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrlndine;
4a-phenyl~2-isobutyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-(3-methoxyphenyl)-2-(4-ethylhexyl)-2,3,4,4a, 5,6,7,7a-octahydro-lH-2-pyrindine; and 4a-(3-ethoxyphenyl)~2-(3-chlorobenzyl~-2,3~4,4a, 5,6,7,7a-octahydro-lH-2-pyrindine~
~ As was hereinbefore noted~ very important inter-mediates for preparing all of the pyrindine derivatives of formula (I) a~e the 2-unsubstituted pyrindine derivatives, those in which Rl' in formula (II) is hydrogen. Such com-pounds can be readily alkylated or acylated at the 2-position to provide pharmacologically active octahydro-pyrindines of ~ormula (I), or in the case of the N-acylated derlvatives, to provide intermediates which are easily ~-4466 -15-13~

converted to the active analgesics of formula (I ) . I t 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-1~-2-pyrindines in which the 2-substituent is readily removable so as to provide the corresponding 2-unsubstituted octahyd~opyrindine derivatives. As previously pointed out, N-methyl and l~-benzyl group~ are readily cleavable to afford the corresponding 2-unsubstituted pyrindine derivativ~. The 2-methyl pyrindine derivatives prepared as above described can be reacted with a haloformate ester such as phenyl chloroformate or ethyl chloroformàte to afford the corresponding carbamate at the pyrindine 2-position. Such carbamate is then reacted with an aqueous 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 JO Med. Chem., 15, 208(1972).
Similarly, ~he aforementioned 4a-aryl-2-benzyl 2,3,4,4a,5,6,7,7a-octahydro-lEI-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 ~u~pended on carbon. Such debenzylation reaction~ are quite general for preparlng secondary amines and are des~ribed in detail by ~lartung and Simonoff, O~ caction~, 7, 277(1953), and by Loenard and Fuji, J. Amer. Chem. Soc., 85, 3719 (1963).

.. ..

3~

As can readily be seen from the foregoing dis-cussion, the following xepresentative 2-unsubstituted pyrindine derivatives formula (II) where Rl' is hydrogen are also important intermediates for the preparation of the pyrindines of formula (I~.
4a-phe~yl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-(3-ethoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-(3-isopropoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a~phenyl 2-methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-phenyl-2-ethyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
~ 4a-(3-methoxyphenyl)-2-n-pen~yl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine, and 4a-(3-methoxyphenyl)-2-isopropyl-2,3,4,4a,5,6,7,7a-octahydro-1~-2-pyrindine.
:~ ~ Th~ 4a-aryl-2-unsubstituted-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines thus prepared can be alkylated by ~normal procedures to provide pharmacologically active 2-substltuted 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,5,6,7,7a-octahydro-lH-2-pyrindine can be alkylated at the 2-position : ~ :
. .

. . . . .
: : . ,.. : . , 3~;

by reaction with essentially any reactive derivative of an alkyl group. Such alkylating agents axe compounds of the formula Rl-Z in which Rl is as defined hereinabove and Z i9 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, ~ara-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 Rl-Z, it is intended that the alkyl portion of such alkylating agent can be derivatized, for instance b~ unsaturated substituents, aryl substituents, and cycloalkyl substituents. The term "alkyiating agent having the formula Rl-Z" thus includes compounds such as methyl chloride, ethyl bromide, 5-methyl-heptyl~osylate, allyl bromide, 4-hexenyl iodide, 3-ethyl-4-pentenyl broqylate, cyclopropylmethyl chloride, cyclo~
butylmethyl iodide, cyclohexylmethyl mesylate, 3-ketra-hydrofurylmethyl bromide, 2-furylmethyl azide, 2-phenyleth~l -chloride, 3-benzoylpropyl bromide, 2-(3-chlorophenylthio)-ethyl azide, phenoxymethyl bromide, 3-isopropylphenylthio-methyl bromide, and related groups.
Thus,:a 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine can be reacted wi~h an alkylating agent to provide the correspondiny 4a-aryl-2-substituted-2,3,4,4a, 5 r 6,7,7a-octahydro-lH~2-pyrindiIle. Such alkylation reackion i9 quite general and can be accomplished by reacting the appropriate 4a~aryl-octahydro-11~-2-pyrindine with th~ appro-priate alkylating agent, preferably in an unreactive organic ~-4466 -18-.
.

"
~ 3~ ~ ~

solvent. The alkylating agent typically i5 utilized in excess amounts, for instance from about 0.5 to about 2.0 molar excess relative to the pyrindine derivative. Unreactive organic solvents cornmonly utilized in the reaction include ethers such as diethyl ether, dioxane, tetrahydrofuran, as well as solvents such as benzene, dichloromekhane, dimethyl-formamide~ dimethyl sulfoxide, ni~romethane, and hexamethyl-phosphortriamide. 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 ac:id 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 temperatur2 ranging from about 50C. 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 waker to the reaction mixture and then extracting the product therefrom into a water-immiscible organic solvent such as benzene, ethyl acetate, dichlorornethane, diethyl ether, chloroform, or related solvents. Upon removal o~ the solvent from such extracts, for instance by evaporation under reduced pressure, ~-4466 -19 3~
i there is obtaincd 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 can 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 o 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 pxovide the purified 4a-aryl-2-substituted-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine as a free base.
As herebefore indicated, the 2-unswbstituted pyrindine derivatives, namely the 4a-aryl-octahydro-lH-2-pyrindines, can be converted to a 2-~ubstituted pyrindine derivative which is either a pharmacologically useful agent per se, or one which can be readily converted to a pharma-cologically useful agent. For example, reaction of a 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine ~ith an alkylating agent such as 2-benzoylethyl iodide provides the ~orresponding 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 af~ord the corresponding 4a-aryl-2-~3-hydroxy-3 phenyl)propyl~2,3,4,4a,5,6,7,7a-octahydro-lH-2-3~

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 O /~ 4 R is C-Cl-C7 alkyl, C-R3, and C-(CH2)n-1~(X)m ~

Such N-acylated pyrindines, upon reduction of the aarbonyl moiety, provide 2-substituted pyrindine derivatives of formula (I) which are active analgesics. For example, a 4a-aryl-3-alkyl-2,3,4,4a,5,6,7,7a-octahydro-lH-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, cyclobutylformyl bromide, 2~(tetra-hydrofuryl)formyl chloride, benzoyl bromide, phenoxyacetyl iodide, 3,4-dimethylphenylacetyl chloride, 3-(2-fluoro-phenyl)propionyl chloride, phenylthioacetyl bromide, 4-phenyl-3-butenoyl chloride, acetic anhydride, and hexanoic anhydride~ The acylation of the 2-unsub~tituted pyrindine derivative with an acylating agent such as the aforemen-tloned is carried out by reacting approximately equimolar quantitiés of the pyrindine derivative and the acylating agent in an unreactive organic solvent such as dichloro-methane, ethanol, or tetrahydrofuran. The reaction typically -utillzes 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 about -20C. to about 30C., and generally is complete within 1 to 8 hours. The product, for example a 4a-aryl-2-acylated-. .

X-4~66 -21-3~

2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine, is readily isolated by simply removi~g ~he reaction solvent by evapora-tion. The product so formed normally is not purified further, but xather is reduced immediately to provide a 4a-aryl-2-substituted-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine of formula (I). Such reduction of the N-acyl carbonyl group can be accomplishcd by reaction of the acyla*ed pyrindine derivative with a reducing agent such as lithium aluminum hydride or by catalytic hydrogenation.
It will additionally be recognized that ~till other modiflcations can be made on certain of the 4a-aryl-2-sub~tituted-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines of formula (I). For example, while a 4a-aryl pyrindine deriva-tive wherein the aryl group is a 3-hydroxyphenyl moiety can be prepared by starting with a 2-(3-hydroxyphenyl)-2-ethoxycarbonylmethyl-cyclohexanone and modifying such : compound according to the various processes discussed he~einabove, it might be pre~erable to prepare a 4a-(3-methoxyphenyl)-2-substituted-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine, and then convert the 3-methoxy group of such 4a-aryl 5ubstituent to a hydroxy group. Such conversion is readily accomplished by reacting a 4a-(3-methoxyphenyl)-pyrindine derivative with hydrobromic acid in acetic acid.
Suah reaction is quit~ g~neral ~or the conversion of a methoxyphenyl group to a hydroxyphenyl group.

AS hereinbefore pointed ou~_, the 4a-aryl- 2 - 5 ub-stituted-octahydro-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 crystal-lization, and which then can be conver~ed back to ~he pyrindine free base by treatmenk with a suitable base such as sodium hydroxide~ Certain of the acid addition salts are encompassed within the scope of formula (I). Specifically, there are included herein the non-toxic pharmaceutically acceptable acid addition salts of the pyrindine bases which are described hereinabove. Such non-toxic pharmaceutically acceptable acid addition salts are prepared by reacting a 4a-aryl-2-substituted-octahydro-lH-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 (I) include the hydrogen halide acids such as hydrogen chloride, hydrogen bromide, and hydrogen iodide, as well as acids such as sulfuric, phosphoric, nitric, perchloric, phosphorcus, nitrous, and related acids. Organic acids commonly used to prepare pharmaceutically acceptahle acid addition salts of the pyrindine~ of ~ormula ~I) include acetic, propionic, para-toluenesulfonic, chloroacetic, maleic, tartaric, succinic, oxalic, citric, lacti~, palmitic9 stearic, benzoic, and related acids. The pharmaceutically acceptable acid addition salts Qf formula (I) can be conveniently prepared by simply dissolving a 4a-aryl-2 substituted-octahydro-lE~-2wpyrindine in a suitable solvent such as diethyl ether, ethyl acetate, acetone, or ethanol, and adding to such solution either an X~4~66 -23-3~

equivalent amount or an excess of a suitable acid. The salt so ~ormed 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 cls-4a-aryl-2-substituted-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines is representative : of the compounds falling within the SCOp2 of formula (I).
4a-phenyl 2-(3-ethylpentyl)-2,3,4,4a,5,6,7,7a-octahydro-1~-2-pyrindinei 4a-(3-methoxyphenyl)-2-(n-octyl)-2,3,4,4a,5,6~7,7a-octahydro-lH-2-pyrindinium bromide;
4a-(3-hydroxyphenyl~-2~(2-propenyl)-2,3,4,4a, 5,6,7,7a-octahydro-1~-2-pyrindine;
4a-(3-propoxyphenyl)-2-(2,3-dimethyl-4-hexenyl)- ~:
2,3,4,4a,5,6~7,7a-octahydro~ ~2-pyrindine;
4a-phenyl-2-(5-heptenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium acetate;
4a-(3-hydroxyphenyl)-2-cyclopentylmethyl 2,3,4,4a, 5,6/7,7a-octahydro~lH-2-pyrindinium oxalate;
4a-(3-ethoxyphenyl)-2-(2-tetrahydrofurylmethyl~-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
; 4a-phenyl-2-(2-phenoxyethyl)-2,3,4,4a,5,6,7,7a~
octahydxo-lH-2-pyrindine;
4a-(3-hydroxyphenyl)-2-(2-methylphenoxymethyl)-2 t 3,4,4a,5,6,7,7a-octahydro-11~-2-pyrindinium succinate;
4a-(3 methoxyphenyl)~2-(3,5-dichlorobenzoylmethyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;

3~i 4a-(3-ethoxyphenyl)-2-[3-(3-methyl-4-bromophenyl)-3-hydroxy]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) 2-hydroxy]ethyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-phenyl-2-(3-phenylthio)propyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium citrate;
4a-phenyl-2-[3-~Z-iRopropylphenyl)propyl-2,3,4,4a, 5,6,7,7a-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-lH-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-pyrindlne;
4a-(3-propoxyphenyl)-2-(2-ethylbenzoylethyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium chloridei 4a-(3-ethoxyphenyl~-2-[3-(2-chlorophenylthio)-propyl]-2,3,4,4ag5,6,7,7a-octahydro-lH-2-pyrindine;
4a-phenyl-2-13-(2-ethyl-5-bromophenyl)propyl~-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine; and 4a-(3-hydroxypheny~)-2-[2-(3,5-diethylphenoxy)-ethyll-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 L3~

isomers and racemic mixtures of such isomers which are useful pharmacologically as analgesic agonist or antagonist drugs. However/ only the cl5-isomers of formula (X) are intended thereby, namely, such that the 4a-aryl group is oriented on the same side of the plane of the molecule from the 7a-hydrogen atom. This invention accordlnqly comprehends the pharmacologically active individual optically-active cls isomers, in addition to ~he racemic mix~ure of cis isomers. Such xacemic pair of cis-octa~
hydropyxindines can be separated into its component stereo-isomer~ by procedures well known in the art. In the even~ -: that all useful pharmacologic activity resides in one stereoisomer, the dl-racemate is 5till useful in ~hat it contains, as a constituent part, the pharmacologically active isomer.
The prepaxation of the 4a-axyl-octahydxopyrindines of formula (I) requires starting materials, many of which are hitherto unknown a~d not readily available~ The pyrindines of formula (I) utilize 4a-aryl~tetrahydro 2,6-dioxocyclopenta[c]pyrans as starting materials. Suchstarting materials are prepared from ~-arylcyclohexanones such as 2-phenylcyclohexanone and 2-(3-methoxyphenyl)cyclo-hexanone. For the preparation of the dioxocyclopentapyran derivatives, the 2-arylcyclohexanone is alkylated at the 2-position by reaction with an alkyl haloacetate such as ethyl chloroacetate, in the presence of a base such as sodiwm hydride, ~hereby providin~ the corresponding 2 aryl-2-alkoxycarbonylmethylcyclohexanone. Similarly, in th~
preparation of 2-aryl-2-alkenyl-1-aminomethylcyclopentanes, ~-4466 -26-.., . ~:,~, a 2-arylcyclohexanone is first alkylated at the 2~position by reaction with an alkenyl halide, such as allyl iodide or 2-butenyl bromide, ln the presence of a base such as sodium hydride, to provide the corresponding 2-aryl-2-alkenylcyclo-hexanone. Both the 2-aryl-2-alkoxycarbonylmethylcyclo-hexanones and the 2-aryl-2-alkenylcyclohexanones are next for~ylated at the 6 posi~ion by reaction with an alkyl formate such as ethyl formate in the presence of metallic sodium or potassium~ The formyl cyclohexanone derivatives are ne~t reacted with para-toluene sulfonyl azide, thus effecting displacement o the 6-fvrmyl moiety with a diazo group to provide, respectively, 2-aryl-2 alkoxycarbonyl-methyl-6-diazocyclohexanones and 2-aryl-2-alkenyl-6-di-azocyclohexanones. Such diazocyclohexanone derivatives are next photolyzed with a light having a wavelength of about 3000 angstroms in an alcoholic solvent such as methanol to effect ring contraction with concomitant expulsion of nitrogen gas t~ provide, respèctively, 2-aryl 2-alkoxycar-bonylmethyl-l-methoxycarbonylcyclopentanes and 2-aryl-2-alkenyl~l-methoxycarbonylcyclopentanes. Such compounds are next de-esterified, lOe. hydrolyzed, by reaction with aqueous alkali to provide the coxresponding diacid and mono-acid.
Specifically, hydrolysis of a 2-aryl-2-alkoxycarbonyl-methyl-l-methoxycarbonylcyclopentane provides the corre-~ponding 2-aryl-2-hydroxycarbonylmethyl-1-hydroxycarbonyl-cyclopentane. Similarly, hydrolysis of a 2-aryl~2-alkenyl-l-methoxycarbonylcyclopentane affords the corre~ponding 2-aryl-2-alkenyl-1-hydroxycarbonylcyclopentane. The diacid, namely the 2~aryl-2-hydroxycarbonylmethyl-1-hydroxycar-, .?~
'''''' , , .' , ' ' : .

bonylcyclopentane, is next cyclized by reaction wi~h an acid halide such as acetyl chloride to provide the corresponding anhydride, a 4a-aryl-tetrahydro-2,6-dioxocyclopenta[c3pyxan.
These pyrans are the starting materials for the preparation of the pyrindines of formula (I).
Certain of the 4a-aryl-2-substitutea octahydro-lH-2-pyrindines o formula (I) have ~ound 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 lia~ility. Such ability of the compounds disclosed herein to cause ana~gesic ago~ist as well as analgesic antagonist ef~ects in mammals is thus responsible for a decrease in any addictive properties of a par~ticular drug caused by its opiate-like analgesic action. The ~ompounds are thus particularly valuable since they produce analgesia with only minimal physical dependance liability. Certain of the compounds are additionally useul in combating the undesirable effects pxoduced by opiates such as moxphine~
The anal~esia activity pos~essed by the compounds o~ formula ~I) has been determined by testing such compounds in standard animal as~ays routinely used to measurP analgesic action attribiltable to te~t compound.s. Such assays include the mouse-writhing test and the rat tail jerk assay.

3~
As indicated hereinbefore, the compounds of formula (I) have demonstrated analgesic acti~i~y 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 dxug is administered prior to the administration of the acetic acid. When 4a-(3-methoxy-phenyl)-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. Addition-ally, naloxone was found to ~otally prevent the inhibitory action of the compound at an subcutaneous dose of 5 mg-/kg- r thus indicating that the compound is an opiate-type analgesicO
When tested in the rat tail jerk assay, the above-named compound produced a significant increase in reaction time at dose level~ 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 ~ollowing dosing.
Similarly tested was 4a-(3-hydroxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1~-2-pyrindine. At a X-4~6 ~29-P~3~

subcutaneous dose of 0.5 mg./ky., 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 mq./kg.
4a-Phenyl-2 methyl-2,-3,4,4a,5,6,7,7a-octahydro-lH-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 ollowing 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 o naloxone. The rat tail assay indicated that the compound caused only a moderate increase in reac ion time at dose levels of 80 mg./kg.
In the mouse writhing assay and the rat tail jerk -~
assay, the ollowing E.D.50,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:

X-446~ -30-3~

~rable Example Writhing~at Tail No. Salt ~-D-50 ~-D-50 12 HCl 5 <~80 13 --- 0.4 0.2 14 HBr 1.0 l.0 HCl >20 >80 16 HBr 1.0 0.5 17 --- 20 >80 18 HBr 50 >80 l9 HBr 20 --HBr 20 >80 21 HBr l.0 80 The 4a-aryl-2-substituted 2,3,4,4a,5,6,7,7a-octahydro~ 2-pyrindines o~ formula (I) are thus useul in 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 utllize 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 o formula (I), either as the free base or as a pharmaceutically acceptable acid addition salt, will be ~ formulated or oral administration by admixing such compounds - with~any o a number o commonly used diluents, excipients, or carriers. Bxamples of such diluents and excipients commonly employed in pharmaceutical preparations include ~: .

starch powder, sucrose, cellulose, maynesium stearate, lactose, calcium sulfate, sodium benzoate and related diluents. 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, acet-aminophen, and propoxyphene.
The active compounds of formula (I) can addition-ally be formulated as sterile aqueous or non-aqueous solu-tions, 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 ~or oral and parenteral administration include isotonic saline solution.
The precise dosage of active ingredient, that is the amount of one ox more o the pharmacologically active 4a-aryl-2-substituted-octahydro-lH-2-pyrindines of formula (I) administered to a mammal, such as a human subje~t for example~ may be varied over a relatively wid~ range, it being necessary that the formulations should constitute a proportion of one or more of the active ingredient5 oE formula (I) such that a suitable dosage will be obtained. Such suitable dosage will depend on the parkicular therapeutic effect desired, on the particular route of administration being utilized, and on the duration o~ treatment, as well as the precise condition being treate~. Typically the dosages ~ of the active compounds o~ formula (I) will range from about X-4~6~ -32-3~

l.0 to about 25 mg./kg. of animal body weight per day, appropriately divided for administration from l to 4 times per day. Preferred oral dosages will yenerally 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-ethoxycarbonyl-methylcyclohexanone in 2000 ml. of diethyl ether containing 56 g. of ethyl formate and 11.5 g. of metallic sodium was s~irred at 25C. for forty-eight hours. The reaction mixture was then added to lO00 ml. of ice-water, and the ethereal layer was removed. The aqueous layer was acidiied to pH 6.5 by the addition of lN hydrochloric acid, and further extracted with fresh diethyl ether. The ethereal extracts were combined~ washed with water, and dried. -~
Evaporation of the solvent under xeduced pressure provided 98 g. of 2-phenyl-2-ethoxycarbonylmethyl-6-form hexanone as an oil. B.P. 158-175C. at 0.5 torr.
Analysis Calc. for Cl7~20O4 Theory: C, 70.81; H, 6.99.
Found: C, 70.85; H, 6.77.
Example B
Eollowing the procedure set ~orth in Example A, 2-(3-methoxyphenyl)-2-ethoxycarbonylmethylcyclohexanone was reacted with ethyl formate in the prcsence of metallic X-~66 -33- ^

3~
sodium to pro~ide 2-~3-methoxyphenyl)-2-ethoxycarbonyl-methyl-6-formylcyclohexanone .
ExamE~e C
A solution of 87.0 g. o~ 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. ~he reaction mixtuxe was heated at reflux for an additional 2.5 hours, and then cooled to 0C.
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 25C. and poured onto 400 g. of ice~ The organic benzene layer was separa~ed, washed with watex and dried. Evaporation of the solvent afforded 50 g.
of 2-phenyl-2~2-propenyl)cyclohexanone. B.P. 114-120C. at 0.1 torr.
Example D
- A ~olution of 30 g. of 2-phenyl 2-(2-propenyl) cyclohexanone in 600 ml. of diethyl ether containing 3.4 g.
of sodium metal and 11.8 g. of ethyl ormate was stirred at 25C. 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 acidi~ied to pH 2.5 by the - addition of aqueou~ hydrochloric acid. The aqueou~ 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. ~he oll so X-4466 ~34-L, ,,~

3~;

formed was distilled to afford 14.6 g. of 2 phenyl 2~(2-propenyl)-6-formylcyclohexanoneO B.P. 125-130C. at 0.1 torr.
Example E
A solution of 50.0 g. of 2-phenyl-2-ethoxycar-bonylme~hyl~6-formylcyclohexanone in 500 ml. of diethyl e~her was stirred at 25C. while a solution of 24.8 gO of diethylamine in 100 ml. of die~hyl ether was added dropwise over thirty minutes. After stirring the reactlon mixture for two hours at 25C., the solution was cooled to 5C., and then a solution of 33.5 g. of ~-toluenesulfonylazide in 50 ml. of diethyl e~her was added dropwise over fiftPen minutes.
The reaction mixture was allowed to warm to room ~emp~rature, and was stirred for an additional five hours. The reaction ; mixture was then washed with water and dried. Evaporation of the solvent under reduced pressure afforded 43.0 g. of 2-phenyl-2-ethoxycarbonylmethyl-6-diazocyclohexanone as an oil. IR tneet) 2080 cm 1 diazo group.
Examples F-G
Following the procedure s~t forth in Example E, 2-(3-methoxyphenyl)-2-ethoxycarbonylmethyl-6-formylcyclo- -hexanone was converted to 2-(3-methoxyphenyl)-2-ethoxy~
carbonylmethyl 5-dia~ocyclohexanone, and 2~phenyl-2-(2-propenylj 6-formylcyclohexanone was converted to 2-phenyl-2-(2-propenyl)-6-diazocyclohexanone.
EX_ e~
A solution of 57 g. of 2-phenyl-2-ethoxycarbonyl-methyl-6-diazocyclohexanone in S00 ml. of anhydrous methanol was stirred at 25C. while nitrogen gas was bubbled through ~7 ~,~

.' '' ' ' .. . . .,' ' ' .

the reaction mixture. The solution was photolyzed for 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 2-phenyl-2-ethoxycarbonylmethyl-1-methoxycar-bonylcyclopentane as an oil. The oil was further purified by distillation. B.P. 160-190C. at 0.02 torr.
Analysis Calc. for C17H22O4 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-diazocyclo-hexanone was photolyzed at 3000 A to provide 2-(3-methoxy-phenyl)-2-ethoxycarbonylmethyl-1-methoxycarbonylcyclopentane.
B.P. 190-210C.
Analysis Calc. for C18H24O5 Theory: C, 67.48; ~l, 7.55.
Found: C, 67.61; H, 7.37.
Similarly, 2-phenyl-2-(2-prope~yl)-6-diazocyclo-hexanone was irradiated with ultraviolet light at 3000 A
from a quartz lamp in the presence o~ methanol to provide 2-phenyl-2-(2-propenyl~-1-methoxycarbonylcyclopentane. B.P.
113-115C. at 0.1 torr.

:

. . . .

L3~
Analysis Calc~ for C16~20O2 Theory: C, 78.65; H, 8.25.
Found: C, 78.80; H, 7.99.
Analysis Calc. for ClgH25O5 Theory: C, 68.24; H, 7.84.
Found: C, 68.15; H, 7.57.
Example K
A solution of 2-(3-methoxyphenyl)-2-ethoxycar-bonylmethyl-l-methoxycarbonylcyclopentane in 650 ml. of 1,4-dioxane containing 500 ml. of 5 percent aqueous potas-sium hydroxide was stirred and heated at reflux for twelve hours. After cooling the reaction mixture to room tem-perature, 500 ml. of water wa~ added. The reaction mixture was made acidic by the addition of 2N hydrochloric acid, and the aqueous acidic mixture was extrzct~d 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-(3-methoxyphenyl)-2-hydroxycarbonylmethyl-1-hydroxycarbonyl-cyclopentane as a crystalline solid. M.P. 175-180C.
Examples L-M
Following the procedure set ~orth in Example K, 2-phenyl-2-ethoxycarbon~lmethyl-1-methoxycarbonylcyclo-pentane was hydrolyzed to provide 2-phenyl~2-hydroxycar-bonylmethyl-l-hydroxycarbonylcyclopentane. M.P. 205-208C~
Analysis Calc. ~or C14H16O4 Theory: C, 67.73; H, 6.50.
Found: C, 67.70; H~ 6.32.

.

2~Phenyl-2-(2-propen~1)-1-methoxycarbonylcyclo-pentane was hydrolyzed by reaction with aqueous potassium hydroxide to provide 2-phenyl-2-(2-propenyl~-1-hydroxy-carbonylcyclopentane.
Example N
A solution of 25 g. of 2-phenyl-2-hydroxycarbonyl-methyl-l-hydroxycarbonylcyclopentane in 150 ml. o~ 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~2,6-dioxocyclopenta[c]pyran as an oil. The product was urther purified by distillation. B.P. 205-207C at 0.25 torr.
Analysis Calc. for C14H15O3 Theory: C, 73.03; H, 6 13.
Found: C, 73.30; H, 6.37.
Example O
Following the procedure set forth in Example N, 2-(3-methoxyphenyl)-2-hydroxycarbonyl-1-hydxoxycarbonyl-cyclopentane was dehydrated and cyclized by reaction withacetyl chloride to provide tetrahydro-4-(3-methoxyphenyl)-2,6-dioxocyclopentaLc]pyran. B.P. 200-220C.
Example P
To a stirred solution of 6.2 g. of 2-phenyl~
2-(2-propenyl)-1-hydroxycarbonylcyclopentane in 100 ml. of chloroorm 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 . . . .

3~

reaction mixture, the solvent was removed therefrom by evaporation under reduced pressure to afford 7.4 g. of 2-; phenyl-2-(2-propenyl)-1-chlorocarbonylcyclopentane.
Example Q
A solution of 10.7 g. of benzylamine in 100 ml. of toluene was stixred at 25C. while a solutio~ of tetra-hydro-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 day~ in 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 lN sodium hydroxide solution and the alkaline reaction mixture was heated to 50C. 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. Re~
crystallization of the solid from diethyl ether afforded 4a (3-methoxyphenyl)-2-benzyl-2,3,4,4a,5,6,7,7a-octahydro~
1,3-dioxo-lH-2-pyrindlne. M.P. 75 i70C.
Analysis Calc, for C22H23N03 Theory: C, 75.62; H, 6.63; ~, ~.01.
FoundO C, 75.40; H, 6.58; N, 3.78.
' X-4~66 ~39-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,5,6,7,7a-octahydro-1,3-dioxo-1~-2-pyrindine. M.P. 77-79C.
Analysis Calc. for C21H21NO2 Theory: C, 78.97i H, 6.63; N, 4.39.
Found: C, 78.73; H, 5.65; N, 4.26.
FINAL PRODUCTS
Example 1 A solution of 18 g. of 4a-phenyl-2-benzyl-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine dissolved ; in 200 ml. of tetrahydrofuran was added dropwise over ninety minutes to a stixred 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 50C., 50 ml. of ethyl acetate was added dropwise over fifteen minutes, followed by the addition of 100 ml. of aqueous ammonium chloride. Additional tetra-hydrofuran 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 pressurb 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 X-4466 ~40-.

pressure to provide 15 g. of 4a-phenyl-2-benzyl-2,3,4,4a, 5,6,7,7a-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-octahydro-1,3 dioxo-lH-2-pyrindine was reduced by reaction with iithium 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-benzyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine in 172 ml. of ethanol was stirred while 7 g. of 5 percent palladium suspended on aarbon was added in one portion. The reaction mixture was stirred under a hydrogen gas atmosphere at 4.13 x 106 dynes/cmO2 and heated at 60C. 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 dlstilled to a~ford 4a-phenyl-2,3,4,4a,5,6,797a-octahydro-lH-2~pyrindine.
~ le 4 4a-(3-Methoxyphenyl)-2-benzyl 2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine was hydrogenated in the presence o palladlum suspended on charcoal according to the procedure set orth in Example 3 to provide 4a-(3-methoxyphenyl)~
2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine. B.P. 145-160C., 0.05 torr.
, .
X-~466 -41-13~;

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 hydrobromic acid and was stirred and heated at reflux for fi~teen hours. After cooling the reaction mixture to room temperature, the reaction mixture was added to 100 g. of ice, and the pH of the r~sulting 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 pressuxe to provide the product as a crude solid. The solid so form~d was cry~tal-lized from ethyl acetate to afford 4.2 g. of 4a-~3-hydroxy-phenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine. M.P.
180-181C~
AnalySis Calc- for C14HlgNO
20~heory: C, 77.38; H, 8.81; N, 6.45.
Found; C, 77.55; ~, 8.84; N, 6.24.

A solution of 2 g. of 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine in 30 ml. of N,N-dimethyl~ormamide conkaining 1.23 gO of sodium bicarbonate was stirred at 25~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 tem-perature t the xeaction mixture was filtered and concentrated 3~

to 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 pressurel thus providing 4a-phenyl-2-(2-propenyl)-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 fresh diethyl ethar, and hydrogen bromide gas was bubbled through the ethereal solution. The precipitated salt was collected by ~iltration and recrystallized ~rom diisopropyl ether and isopropanol to afford lo 3 g~ Of 4a-phenyl-2-(2-propenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium bromide. M.P. 185-187C.
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 6l the following l-alkyl pyrindine derivatives were prepared by reaction of 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-lH~
2-pyrindine with an appropriate alkylating agent.
4a-Phenyl-2-n-propyl~2,3,4,4a,5,6,7,7a-octahydro-lH~2-pyrind in i am bromide. M.P. 245-247C.
Analysis Calc. for C17H26BrN
Theory: C, 62.96; H, 8.08; N, 4.32.
Found: C, 62.74; ~, 8.22; N, 4.23.
4a-Phenyl-2-n-pentyl~2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium bromide. M.P. 240-243C.
Analysis Calc. for ClgH30~rN

X-4466 ~43~

Theor~: C, 64.77; H, 8.58; N, 3.98.
Found: C, 65004; H, 8~70; N, 3.87.
Example 9 A solution o~ 3.0 g. o~ 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine in 10 ml. o 88~ Eormic acid was stirr~d at 20~C. while 10 ml. o~ 38% Pormaldehyde was added dropwise over fifteen minutes. The reaction mixtu~e was then heated at 95C. for eight hours. After cooling the reaction mixture to 25C. 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 lO0 ml. o~ water, and the aqueous solution was made basic by the addition of 50 percent aqueous sodium hydroxide solution.
The product precipitated out of the agueous alkaline solution, and was extracted into diethyl etherO The ethereal extracts were combined, washed with water, dried, and the solvent was evaporated under reduced pressure to provide 4a-phenyl-2-methyl-2,3,4,4a,5,G,7,7a~octahydro-lH-2-pyrindine as an oil.
The oil so foxmed was dissolved in 150 ml. of diethyl ethex.
The ethereal solution was stirred at 25C. while a solution o 10 ml. of 4 a percent hydrobromic acid in 10 ml. of ethanol was added dropwise over ten minutes. The product precipi~ated ouk o solution and was recovered by iltrakion.
The solid precipitate was recrystallized from diisopropyl ether and isopropanol to aford 2.7 g. o~ 4a-phenyl-2-methyl-2,3,4,4a,5,6,707a~octahydro-lH~2-pyrindinium bromide. M.P.
209-~10C.

X ~466 ~44~

Anal~sis Calc. or Cl5H22srN
Th~ory: C, 60.81; H, 7 4g; N, 4.73.
Found: C, 60.55; H, 7.49; N, 4.57.
~1 To a cold solution (0-5C.3 of 3.0 g. of 4a-phenyl-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 potas-sium carbonate was added 2.6 g of phenylacetyl chloride in one portion. Th~ reaction mixture was stirred at 0-5C.
for thirty minutes and then was warmed to 25C., 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 Ater drying the ethereal solution, the solvent was e~aporated under reduced pressure to af~ord 4a-phenyl-2-phenylacetyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrlndine formed in the above acylation raaction as an Oil~.
The oil ~o formed was dissolved in 25 ml. of tetrahydrouran and added dropwise ove~ thirty minutes to a stirred suspension of 3.0 g. of lithiu~ aluminum hydride in 150~ ml. o tetrahydro~uran. APter the addition was complete, ; ~ the reaction mixtu~e w~as stirred and heated at reflux ~or four ~hours. After the reac~ion mix~ure wa~ cooled to 30C., 60 ml of ethyl acetate was added,-Pollowed by the addition to the reaction mixture of 100 ml. o~ saturated aqueous ammonium tartrate solution. The organic layer was ~eparated by decan~ing, and the aqueous layer was extracted with .

die~hyl ether. The organic solvents were combined and concentrated under reduced pressure ~o provide the product as a crude oil. The oil was then dissolved in 400 ml. of diethyl ether, washed with water, and dried. Removal of the solvent by evaporation under reduced pressure provided 4a-phenyl-2-(2-phenylethyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine as an oil. The oil was then dissolved in 150 ml. of diethyl ether and added to a solution of 10 ml. o 48 percent hydrobromic acid in 10 ml. of ethanol. The hydro-bromide salt of the above-named pyrindine precipitated out of solution and was recrystallized from diisopropyl ether and isopropanol to provide 2.4 g. of 4a-phenyl-2-(2-phenyl-ethyl) 2j3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium bromide.
M.P. 269-27GC.
Analysis Calc. for C22H28BrN
Theory: C, 68.39; H, 7.30; N, 3.63.
Found: C, 68.61; H, 7.57; N, 3.69.
E~ e 11 Following the procedure outlined in Example 10, 20 4a-phenyl-2,3,4,4a,5,6,7,7a-ostahydro-lH-2-pyrindine was acylated with cyclopropanecarboxylic acid chloride to provide 4a-phenyl-2-cyclopropanecarbonyl-2,3,4,4a,5,6,7,7a-octa-hydro-lH-2-pyrindine. Reduction of the acylated pyrindine intermediate by reactlon with lithium aluminium hydride afforded ~he corresponding 2-alkyl pyrindine, which when reacted with hydrobromic acid provided 4a-phenyl-2-cyclopropylmethyl-2,3,4,4a,5,6,7,7a-octahydro-lH~2~pyrindinium bromide. M.P. 240-241C.

Analysis Calc. for Cl8H26BrN
Theory: C, 64.28; H, 7.79; N~ 4.16.
Found: C, 64.54; H, 7.51; N, 4~13.
Exampl~ 12 A solution of 75 ml. of toluene containing 1.76 ml. of liquid methylamine was cooled to -70C~ 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 mlO of toluene was added dropwise over ~hirty minutes.
The reaction mixture was warmed to room ~emperature and then heated at reflux for twenty-two hours. The reaction mixture was again cooled to room temperature and concentrated under reduced pre~sure to an oil. The oil so ~ormed was di~sol~ed in 152 ml. of 1 N sodium hydroxide solution ~nd was heated with stirring to 50C. for fifteen minutes. ~he produc~ 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 xeduced pressure provided 8.3 g. of 4a-(3~methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a octahydro-1,3-diGxo-lH-2-pyrlndine.
Reduction of 8.2 g. of 4a-~3-methoxyphenyl)-2-methyl-2, 3,4,4a,5,6,7,7a-octahydro-1,3~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- ~3 methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine. B.P. 133-138C. at 0.25 torr.
Analysis Calc. for Cl6H23N0 Theory: C, 78.32; H, 9.45; N, 5.71.
Found: C, 78.13; H, 3.30; N, 5.68.

X-4466 -4~-.~, .

3~;

A solution o~ 4a-~3-methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine in 100 ml. of diethyl ether was stirred while hydrogen chloride ~as 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-methyl-2,3,4,4a,5~6,7,7a-octahydro-lH-2-pyrindinium chloride~
M.P. 175-177C.
Analysis Calc. for C16H24HOCl Theory: C, 68.19; H, 8.58; N, 4.97.
Found: C, 68.00; H, 8.2~; N, 4.68.
E ~
A solution of 1.6 g. of 4a-(3-methoxyphenyl)-2-methyl-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 10C~ and the pH was adjusted to 10.2 by the addition of 50 percent aqueous sodium hydroxide solution. The product was in~oluble 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-m~thyl-2,3,4,4a,5,6,7,7a-octahydro-lH~2~pyrindine. M.P. 151-153C.

Analysis Calc. for C15H21NO
Theory: c, 77.88; H, 9.15; N, 6.05.
Found: C, 77.60; H, 8.88; N, 5.76.

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 ~xample 5 in 50 ml. of N,N-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. F~llowing complete addition, the reaction mixture was heated at 70C 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, 5,6,7,7a-octahydro-lH-2-pyrindine. Such product was dis-solved in 50 ml. of tetrahydxofuran and stirred while a 20 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 our hours, and then cooled to about 25C. While the reaction mixture was s~tirred, 25 ml. of ethyl aae~ate 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 X-4466 -~9-3~

of the solvent then provided 4a-(3-hydroxyphenyl)-2-(2-phenylethyl)-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 fil-tration, affording, after recrystallization from ethyl acetate, 1.3 g. of 4a-(3-hydroxyphenyl)-2-(2-phenyl-ethyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium hromide.
M.P. 135-137C.
~nalysis Calc. for C22H2~NBrO
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-octahydro-lH-2-pyrindine was reacted with cyclopropylcarboxylic acid chloride in the presence of potassium carbonate to provide 4a-(3-hydroxyphenyl)-2-(cyclopropylcarbonyl)-2,3,4,4a, ~0 5,6,7,7a-octahydro-lH-2-pyrindine. This latter named compound was reduced by reaction with lithium aluminum hydride to provide 4a-(3-hydroxyphenyl)-2-cyclopropylmethyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine, which was converted to the hydrochloride salt by reaction with hydrogen chloride gas in diethyl ether. M.P. 256~258C.
Analysis Calc. for C18H26NOCl Theory: C, 70.22; El, 8.51; N, 4.55; Cl, 11.52.
Found: C, 69.93; H, 8~25; N, 4.72; Cl, 11.52.

xample 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 N,N-dimethylformamide containing 1.0 g. of sodium bicar-bonate and 0.95 g. o~ 2-tetrahydrofurylmethyl bromide was heated at reflux for our hours. After cooling the reaction mixture to about 25C., the mixture was extrac~ed 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 ~ormed was dissolved in diethyl ether and added to a solution of hydrogen bromide gas in diethyl ether. The product srystallized out of solution and was collected by filtration to provide 1.0 g. o 4a-(3-hydroxyphenyl)-2-(2-tetrahydro-furylmethyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium bromide. M.P~ 190-192C.
Analysis Calc. for ClgH2~NO2~r ~ Theory: C, 59.69; Hr 7.38; N, 3.66.
Found: C, 59.89; H, 7.40; N, 3.78.
xamp~es 17-19 Following the procedure set forth in Example 16, 4a-(3-hydroxyphenyl)~2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrinaine ~as reacted wlth allyl iodide in the presence of sodium biaarbonate to provide 4a-(3-hydroxyphenyl)-2-(2-propenyl)-2,3,4,4a,5,6,7,7a-octahydro-1~-2-pyrindine.
M.P. 106-108C.

X-~46~ -51-Analysis Calc. for C17H23NO
Theory: C, 79.33; ~, 9.01; N, 5.44.
Found: C, 79.29; H, 8.92; N, 5.44.
Similarly, 4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine from Example 4 was reacted with l-iodopropane in the presence o~ sodium bicarbonate to provide 4a-(3-methoxyphenyl)-2-n-propyl-2,3,4,4a,5,6,7,7a~
octahydro-lH-2-pyrindine, which was then converted to the hydrobromide salt by reaction with hydrogen bromide gas in diethyl ether. M.P. 197-199C.
Analysis Calc. for C18H28NOBr Theory: C, 61.02; H, 7.97; N, 3.95.
Found: C, 60.65; H, 7.52; N, 4~07O
i Similarly, 4a-~3-methoxyphenyl)-2,3,4,4ay5,6,i,7a-octahydro-lH-2-pyrindine was reacted with l-bromopentane in the presence of s~dium bicarbonate to provide 4a-(3-methoxyphenyl)-2-n-pentyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine. Such compound was treated with hydrogen bromide ~as in diethyl ether to provide 4a-(3-methoxy-phenyl)-2-n-pentyl-2,3,4,4a~5,6,7,7a-octahydro-lH-2-pyrindinium bromide as a crystalline solid. M.P. 179-181C.
Analysis Calc. for C20H32NOBr Theory: C, 62.82; H, 8.44; N, 4~18D
Found: C, 62.87; ~, 7.98; N, 4.02.

A solution o~ 2.0 g. of 4a-(3-me~hoxyphenyl)-2-n-propyl-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 acid was stirred and hea~ed at reflu~ for twelve hours. The reaction mixture was then csol2d and poured over 100 g. of i~e, and the resulting aqueous solu~ion was made alkaline by the addition of aqueous sodium hydro~ide ~o pH 10.2. The aqueous alkaline mixture was extrac~ed 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 re~uced pressure provided 1.3 g. of 4a-(3-hydroxyphenyl)-2-n-propyl-2,3,4, 4a,5,6,7,7a-octahydro-lH~2-pyrindine as an oilO The oil was dissolved in diethyl ether and added to a solution Gf hydro~en 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-hydroxy-phenyl~-2-n-propyl~2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium bromide. M.P. 235-23ÇCC.
~nalysi~ Calc. for C15H26NOBr Theory: C, 60.00; H, 7.70, N, 4.12.
Found: C, 59.98; H, 7.50; N, 3.98.
ExamEæ~
Following the procedure set forth in Example 20, 4a-(3-methoxyphenyl)-2-n-pentyl-2,3,4,4a,5,6,7~7a-octa-hydro-lH-2 pyrindine was reacted with aqueous hydrobromic acid in glacial acetic acid ~o aford 4a-(3-hydroxyphenyl~-2-n-pentyl-2,3,4,4a,5,6,7,7a octahydro-lH-2-pyrindine, which was then converted to the corresponding hydrogen bromide salt. M.P. 171-173C.
Analysis Calc. fvr C20H30NOBr Theory: C, 61.95; H, 8.21; W, 3~80.
30Found: C, 61.65; H, 7.93; N, 3.54.
X-4466 ~53

Claims (26)

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

1. A process for preparing a cis-compound of the general formula (I) wherein:
R1 is C1-C8 alkyl, CH2R3, or ;
in which:
R3 iS C2-C7 alkenyl, C3-C6 cycloalkyl, furyl, or tetrahydrofuryl;
R4 and R5 independently are hydrogen, C1-C3 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 O, except that when n is O, X is other than S or O;
R2 is hydrogen, hydroxy, or C1-C3 alkoxy; and the non-toxic pharmaceutically acceptable acid addition salts thereof, which comprises reacting a compound of the general formula (II) wherein R2 is defined as before, and R1' is hydrogen, with an alkylating agent to obtain a compound of formula (I) in which R1 is C1-C8 alkyl or CH2R3 in which R3 is C2-C7 alkenyl, or with an acylating agent followed by reduction to obtain a compound of formula (I) in which R1 is CH2R3 in which R3 is C3-C6 cycloalkyl, furyl, or tetrahydrofuryl, or in which n, m, R4, and R5 are defined as before, and optionally de-etherifying when R2 is C1-C3 alkoxy to obtain a compound of formula (I) in which R2 is hydroxy; and where desired, forming a non-toxic, pharmaceutically acceptable acid addition salt of said compound of formula (I).

2. A cis-compound of the general formula (I) wherein:
R1 is C1-C8 alkyl, CH2R3, or ;
in which:

R3 is C2-C7 alkenyl, C3-C6 cycloalkyl, furyl, or tetrahydrofuryl;
R4 and R5 independently are hydrogen, C1-C3 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 o, except that when n is O, X is other than S or O;
R2 is hydrogen, hydroxy, or C1-C3 alkoxy; and the non-toxic pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process of claim 1 or by any obvious chemical equivalent thereof.

3. The process of claim 1 wherein R1 is C1-C8 alkyl or CH2R3 in which R3 is C2-C7 alkenyl or C3-C6 cycloalkyl.

4. The compound of claim 2 wherein R1 is C1-C8 alkyl or CH2R3 in which R2 is C2-C7 alkenyl or C3-C6 cycloalkyl, whenever prepared by the process of claim 3 or an obvious chemical equivalent thereof.

5. The process of claim 3 wherein R2 is hydroxy or methoxy.

6. The compound of claim 2 wherein R1 is C1-C8 alkyl or CH2R3 in which R3 is C2-C7 alkenyl or C3-C6 cycloalkyl and R2 is hydroxy or methoxy, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

7. The process of claim 1 wherein R2 is hydroxy.

8. The process of claim 1 wherein R2 is hydrogen.

9. The compound of claim 2 wherein R2 is hydroxy, whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

10. The compound of claim 2 wherein R1 is hydrogen whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.

11. The process of claim 1 for preparing 4a-(3-hydroxyphenyl)-2-(2-phenylethyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyridine which comprises acylating 4a-(3-hydroxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyridine with phenylacetyl chloride, followed by reducing with lithium aluminum hydride.

12. 4a-(3-Hydroxyphenyl)-2-(2-phenylethyl)-2,3,4,4a,5,6,7,7a octahydro-1H-2-pyrindine, whenever pre-pared by the process of claim 11 or by an obvious chemical eguivalent thereof.

13. The process of claim 1 for preparing 4a-(3-hydroxyphenyl)-2-cyclopropylmethyl-2,3,4,4a,5,6,7,7a-octa-hydro-1H-2-pyrindine which comprises acylating 4a-(3-hydroxy-phenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine with cyclopropylcarboxylic acid, followed by reducing with lithium aluminum hydride.

14. 4a-(3-Hydroxyphenyl)-2 cyclopropylmethyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine, whenever pre-pared by the process of claim 13 or by an obvious chemical equivalent thereof.

15. The process of claim 1 for preparing 4a-(3-hydroxypheny)-2-(2-tetrahydrofurylmethyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine which comprises alkylating 4a-(3-hydroxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine with 2-tetrahydrofurylmethyl bromide.

16. 4a-(3-Hydroxyphenyl)-2-(2-tetrahydrofuryl-methyl)-2,3,4,4a,5,6,7,7a-octahydxo-1H-2-pyrindine, whenever prepared by the process of ciaim 15 or by an obvious chemical equivalent thereof.

17. The process of claim 1 for preparing 4a-(3-hydroxyphenyl)-2-(2-propenyl)-2,3,4,4a,5,6,7,7a-octahydro 1H-2-pyrindine which comprises alkylating 4a-(3-hydroxy-phenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine with allyl iodide.

18. 4a-(3-Hydroxyphenyl)-2-(2-propenyl)-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.

19. The process for preparing 4a-(3-methoxyphenyl)-2-n-propyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine which comprises alkylating 4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine wikh 1-iodo-propane.

20. 4a-(3-Methoxyphenyl)-2-n-propyl-2,3,4,4a,5,6, 7,7a-octahydro-1H-2-pyrindine, whenever prepared by the process of claim 19 or by an obvlous chemical equivalent thereof.

21. The process for preparing 4a-(3-methoxyphenyl)-2-n-pentyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine which comprises alkylating 4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine with 1-bromo-pentane.

22. 4a-(3-Methoxyphenyl)-2-n-pentyl-2,3,4,4a,5,6, 7,7a-octahydro-1H-2-pyrindine, whenever prepared by the process of claim 21 or by an obvious chemical equivalent thereof.

23. The process of claim 19 for preparing 4a-(3-hydroxyphenyl)-2-n-propyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine which comprises de-etherifying 4a-(3-methoxy-phenyl)-2-n-propyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine with aqueous hydrobromic acid and glacial acetic acid.

24. 4a-(3-Hydroxyphenyl)-2-n-propyl-2,3,4,4a,5,6, 7,7a-octahydro-1H-2-pyrindine, whenever prepared by the process of claim 23 or by an obvious chemical equivalent thereof.

25. The process of claim 21 for preparing 4a-(3-hydroxyphenyl)-2-n-pentyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine which comprises de-etherifying 4a-(3-methoxy-phenyl)-2-n-pentyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine with aqueous hydrobromic acid and glacial acetic acid.

26. 4a-(3-Hydroxyphenyl)-2-n-pentyl-2,3,4,4a,5,6, 7,7a-octahydro-1H-2-pyrindine, whenever prepared by the process of claim 25 or by an obvious chemical equivalent thereof.