CA1119175A - 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. Also provided by this invention are intermediates having the general formula

Description

4a-ARYL-~CTAHYDRO-lH-2-PYRI~DINES
In recent years, muc~ e~fort has been devoted to the synthesls of drugs, 1.e. analgesics, capable of reLieving the sensation of pain. Several o~ the currently available analgesics are l~mited in thei~ use due to various un~esi~-able side efrects which freauently accompa~y their continued use. Such side erfects include addiction and aller~y.
lllustrative of new analgesic drugs which have recently been discovered are the decahydroisoquinolines, particularly the 4a-aryl-trans-decahydroi50quinolines which are described i~
Belgium Patent i~o. 802,557.
The present i~vention relates 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 isoauinoline derivatives;
however, the comp~unds of formula (I) below have not hereto- -fore been synthetically available. Only simple unsubstituted pyrindine analogs are known in the literature. Volodina et al., for example, prepared certain octahydro-2- pyrindines, none ~ which were substituted at the 4a-position, Dokl, Ak . Nau~ USSR 173~2), 342-5(1967) cf. C.A. Vol. 67, 6034(1967). Similarly, Prochazka e~ al. prepared a t~ans-octahydro-2-pyrindine lac~ing a 4a-substituent, Coll.
Czcch. Chem. Commun., 31(9), 3824-8(1966), Cf. C.A. Vol. 65, 13651(1966).
This in~ention provides a procass for preparing cis-4a-phenyl znd substituted phenyl 2,3,4,4a,5,6,7,~a-octahydro-lH-2- pyrindines not heretofore known or available, .... ..
and intermediates use~ul in theijr preparation.

~-4466 -2-11~9:~75 This invention relates to a process for preparing new bicylic compounds characterized as being octahydro~

2-pyrindines, alternatively referred to as hexahydro-l~-cyclopenta[c~pyridines. Specifically~ the in~ention, in one aspect, pro~ides a process for preparing c -4a-aryl-2-substit~ted-2,3,4,4a,5,6,7,7a-octa~ydro-lH-2-pyridines of the general formula ~
~5\ /4\

~ / ~ ~ Rl (I) wherein~

R is Cl-C8 alkyl, CH2R3, or (C~2)n ( m ~ ~ ,~

Rs in which:
R3 is C2-C7 alkenyl, C3-C6 cycloalkyl, furyl, or tetrahydrofuryl;
R4 and R5 ir.dependently are hydro~en, Cl-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;

11~9175 X is CO, CXOH, C~=C~, S, or O, except that when n is O, X is other than S or O;
R2 is hydrogen, hydroxy, or C~-C3 alkoxy; and the non-toxic pharmaceutically acceptable acid addition salts thereof, which comprises reacting a compound of the general formula /~
rR2 \~ ~

~ \t\ ~ R ' (IT) wherein R2 is defined as before, and Rl' is hydrogen, with an alkylating agent to obtain a compound o~ ~ormula (I) in , which Rl is Cl-C8 alkyl or CH2R3 in which R3 is C2-C7 alkenyl, or with an acylating agent followed by ~eduction to obtain a compound of formula (I) in which Rl is C~2R3 in which R3 is C3-C6 cycloalkyl, furyl, or tetrahydrofuryl, r (C~2)n (X)m ~ _ ~ in which n, m, 4, and R5 are defined as before, and optionally de-etherifying when Rz is Cl-C3 alkoxy to obtain a compound of formul (I) in whick R2 is hydroxy, and wh~re desired, ~or~ing a non-toxlc, pharma-ceutically accepta~le acid addition salt of said compound of formula (I).
A compound of formula (II~ wherein Rl' is hydrogen is prepared as indicated ~elow. In another aspect, the invention provides a process-for preparing a c -compound of the general .. . .. . . . . . . . . . .
ormula / ~

/\~/\' , ~
\ ~ ~ ~ R ' (II) , ~-4466 5 wherein Rl' is hydrogen, Cl-C8 alkyl, or 5~ 4 (CH2)n (X)m ~ ~ , and R2 is hydrogen, hydroxy, or Cl-C3 alkoxy, which comprises reacting a compound of the ge;neral formula /-~

\ ~ .,,. ~;.
lo , ~ ,~f \ / \ ~ R~' (III) O

wherein Rl' and R2 are defined as before with a reducing gent, optionally cleaving the compounds of formula (II) ~_ ~ R4 wherein Rl' is Cl-C8 alkyl or -(C~2)n-(X)m--~

to obtain the compounds of formula (II) wherein Rl' is ~;~
hydrogen, and optionally de-etherifying the compounds ; 20 of formula (II) wherein R2 is Cl-C3 alkoxy-to obtain the compounds of formula (II) wherein R2 is hydroxy.
A preferred group of compounds are those of formula (I) wherein Rl is Cl-C8 alkyl or CH2R3 in which R3 is C2-C7 alkenyl or C3-C6 cycloalkyl. A more preferred group of compounds within this latter preferred group are tho~e of formula (I) wherein R2 is hydroxy or methoxy.

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

As used throughout the present specification and in the appended claims, the term "Cl-C8 alkyl" refers to both straight and branched chains of eight carbon atoms or less. Examples of typical Cl-C8 alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl,

3-methylpentyl, 1,2-dimethylpentyl, 2-methylbutyl, 3-ethylpentyl, n-octyl, 2-methylheptyl, isoheptyl, 3-ethyl-hexyl, 1,3,3-trimethylpentyl, and related qroups.
The term "CH2R3, in which R3 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-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-~utenyl, 5-heptenyl, 6-octenyl, 2-methyL-3-heptenyl, and related alkenyl groups.
Additionally included within the definition of R
- in formula (I) is the group represented by CH2R3 in which R3 is C3-C6 cycloalkyl. Such groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
Rl Can also represent groups such as 2-tetrahydrofuryl-methyl, 3-tetrahydrofurylmethyl, and 3-furylmethyl.
In formula (I), Rl can also be a group or the ~ ~2)n (X)m ~ ~ in which 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; and R4 and R5 lndependently are hydrogen, Cl-C3 alkyl, or halogen. In such formula, the ...., ~
I, term "Cl-C3 al.kyl" includes methyl, ethyl and propyl.
"Halogen" refers to fluorine, chlorine, bromine and iodine.
~xamples of typical R~ qro~ps repr~sented by ror~ula (I) include benzyl, 2-phenylethyL, 3-phenylpropyl, 3-methyl-benzy~, 4-chlorobenzyl, 2,4-di~romobenzyl, 2-(2-methyl-S-ethylphenyl)ethyl, 3-(4-isopropylphenyl)propyl, benzoyl-. methyl, benzoylethyl, 4-iodobenzoylmethyl, 2-methyl-

4-chlorobenzoyL~ethyl, 2-phenyl-2-hydroxyethyl, 3-~nenyl- :
3-hydroxypropyl, 2-(4-~luorophenyl)-2-hydroxyethyl, phenoxy- :
methyl, 3,5-diethylphenoxymethyl, 3-phenylthiopropyl, 2-methylphenylthiomethyl, 3,5-dichlorophenyl~hiomethyl, 3-chloro-S-bromophenylthiomethyl, and rela~ed.groups.
The foregoing pyrindine derivatives o~ rormula (I) are produced by first reacting an amine, specirically ammonia or a primary amine, with a cyclic anhydride, namely a 4a-aryl-tetrahydro-2,6-dioxocyclopenta~c]pyran, accordins to the following generalized reaction scheme:

20 ~\ f ~

H~ / <

o (V) ~ (IV) in which R~ and R2 have the above-derined meaninss. The 1,3-dioxo-4a-aryl-2,3,4,4a,;,6,7,7a-octahydro-lX-2-Y
a cyclic imide, so produced is then reduced at the 1 and the 11~917S

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 aryl group, defined in the above formulas by R2, is selected from hydrogen and C~-C3 alkoxy groups.
Amonq such Cl-C3 alkoxy groups, the methoxy group is preferred sinc2 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 deri~atives so produced are readily converted to the corresponding ~-unsubstituted 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 1,3-dioxo-4a-aryl-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[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, di-chloromethane, dimethyl sulfoxide, nitromethane, acetone, X-4466 ~9~

~1~75 tetrahydrofuran, dimethylformamide, and dioxane. The reaction typically is conducted at an elevated temperature, for instance.at a temperature ranginq from about 50C. to a~out 200C., preferably at a temperature o ab~ut 80C.. to ..
about 150C. Since the reaction bet~een the amine and the cyclic anhydride to for~ the corresponding cyclic lmide is .:
accompanied by the formation of water, it may be desirable to conduct the reaction in such a way that water is removed fr~m the reaction mixture as it is formed. Any o~ the ..
10 commonly used techniques for maintaining a dry reac~ion mixture can be utilized, including the use or^ molecular , _ ,, _ _ _ .. ..
sieves-, or alternativeIy a Dean Star~ trap can be employed with reaction solvents such as benzene and. toluene. The reaction between the amine and the cyclic anhydride normally is 3ubstantially complete within.24 to 72 hours; however, longe~-reaction times apparently are not detrimental to the ; ~-product.being formed and can be incorporated if desired.
m e cyclic imide thus for~ed, namely the 4a-aryl-2,3,4,4a,

5,:6,.7,7a-octahydro-1,3-dioxo-1~-2-pyrindine, is readily -. .
i~olated by removal of the reactio~ salvent, or ins~ance by ~vaporation under reduced pressure, and the product can be further purified by standard procedures such as acid and bas2 extraction, crystallization, and chromatography.
As hereinbefore stated, the 4-aryl-tetrahydro-2,6-dioxocyclopentafc~pyran can be reacted with ammonia to .
provide the corresponding 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-1~-2-Pyrindine which is unsu~stituted at the 2-position, or alternatively the pyran derivative can De reacted with a primary amine to provide directly a 4a-. , .

- . :

11~9~7~

aryl-2-substituted-2,3,4,4a,5,6,7,7a-octahydro-i,3-dioxo-1~-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-substitllted pyrindine derivative, it is preferred that such primary amine be methyl a~.ine 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 i5 preferred, therefore, that any group attached at the 2-position of such 4a-aryl-2-substituted-~,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 reduce the 1- and the 3-oxo groups. For groups which are -: 1119175 not so resistant to reduction, it is prefcrred to introduce such groups by alXylation, or acylation and subsequent reduction, of the 2-unsubstituted pyrindine derivatives.
The following list presents representative 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-1,3-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 ?harmacologically useful 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,;,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-phenyl-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,i,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine;
4a-(3-methoxyphenyl)-2-(2-tetrahydrofurylmethyl)-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine;
4a-phenyl-2-E2-(3-chlorophenyl)ethyl]-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine;
4a-(3-methoxyphenyl)-2-cyclopropylmethyl-2,3,4,42, 5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine;

_ , ' :
.

11~9~75 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,5,6,1,7a-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-2,3,4p4a,5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindines, formula (III), are converted to the 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines of formula (II) by reduction 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. ~or 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 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,5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine, formula (III), involves the use of lithium aluminum hydride as the reducing agent.
Typically a 4a-aryl-2,3,4,4a,5,6,7,7a-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-1~-2-pyrindine for instance, is reacted with about a two molar quantity of lithium aluminum hydride in an unreactive organic solvent. Unreactlve organic solvents 111~175 commonly used in the reaction include tetrahydrofuran, diethyl ether, dioxane, diglyme, and related solvents. The reaction normally is carried out at a temperature ranging from about 20C. to about 100C., and when carried out at such temperature, the reaction routinely i~ substantially complete after ab~ut 4 to 20 hours. The product ~ormally 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 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 tetra-hydrofuran~ ~he 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-lH-2-pyrindine, formula (II). Such product typically exists as an oil and is conveniently further puriied if desired by methods such as distillation and chromatography, or alternatively such compound can be con-verted to an acid addition salt which can then be purified by crystallization.

:-- 1119175 Compounds of formula (I) [as indicated by formula (II)] which are thus readily provided by reducing the l-oxo and the 3-oxo groups o~ a 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-1,3-dloxo-lH-2-pyrindine according to the above-described procedures include, among others:
4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-(3-methoxyphenyl)-2,3,4,4a,5,6,1,7a-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-pyrindine;
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) are the 2-unsubstituted pyrindine derivatives, those in which Rll 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 formula (I), or in the case of the N-acylated derivatives, to provide intermediates which are easily 11~9175 converted to the activc 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-1~-2-pyrindines in which the 2-substituent is readily removable so as to provide ~he 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 2S
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 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 J. Med. Chem., 15, 208(1972).
Similarly, the aforementioned 4a-aryl-2-benzyl-2,3,4,4a,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 Uartung and Simonoff, Ora. Reactions, 7, 277(1953), and by Loenard and Fuji, J. Amer. Chem. Soc., 85, 3719 (1963).

1~19175 As can readily be seen from the fore~oing dis-cussion, the following representative 2-unsubstituted pyrindine derivatives formula (II) where Rl' is hydrogen are als~ important intermediates for the preparation of the pyrindines o~ ~ormula (I).
4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,1a-octahydro-lH-2-pyrindine;
4a-(3-ethoxyphenyl)-2,3,~,4a,5,6,7,7a-octahydro-2-pyrindine;
4a-(3-isopropoxyphenyl)-2,3,4,4a,5,6,7,7a-oct~hydro-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-pentyl-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-lH-2-pyrindine.
The 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-substituted pyrindine derivatives, or can be acylated to provide intermediates which are readily converted to active analgesic drugs. ~or example, a 4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine can be alkylated at the 2-position ;

; '' '; --` ! :

.

by reaction with essentially any reactive derivative of an alkyl group. Such aLkylating agents are 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, ~ -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 ~l-Z~ it is intended that the alXyl portion of such alkylating agent .
can be derivatized, for instance by unsaturated substituents, aryl substituents, and cycioalkyl substituents. The term "alkyiating a~ent.having~the formula Rl-Z" thus includes compounds such as methyl chloride, ethyl bromide, 5-methyl- : :
heptyltosylate, allyl bromide, 4-hexenyl iodide, 3-ethyl~
4-pentenyl brosylate, cyclopropylmethyl chloride, cyclo- .
butylmethyl iodide r cyclohexylmethyi mesylate, 3-tetra-. , .
hydrofurylmethyl bromide, 2-furylmethyl azide, 2-phenylethyl 20 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 corresponding 4a-aryl-2-substituted-2,3,4,4a, 5,6,7,7a-octahydro-1~-2-pyrindine. Such alkylation reaction .
is quite general and can be accomplished by reacting the appropriate 4a-aryl-octahydro-lH-2-pyrindine with the appro-priate alkylating agent, preferably in an unreactive organic ,- . - , . -: . -. , : .

111~175 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, dichloromethane, dimethyl-formamide, dimethyl sulfoxide, nitromethane, and hexamethyl-phosphortriamide. A base is preferably incorporated in the alXylation 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, ~odium 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 50C. to 200C., 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 typLcally is recovered by simply adding water to the reaction mixture and then extracting the product thererom into a water-immiscible organic solvent such as benzene, ethyl acetate, dichloromethane, diethyl ether, chloroform, or related solvents. Upon removal of the solvent from such extracts, for instance by evaporation under reduced pressure, ,~

.. ' th~r~ i~ 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, crystalliza~ion, distillation, or alternatively such pyrindir.e 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 of high purity. If desired such salt can then be treated with a base such as sodium hydroxide or potassium car~onate, thereby cleaving the salt to provide the purified 4a-àryl-2-substituted-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine as a free base.
As herebefore indicated, the 2-unsubstituted ... . ... . ... . ... . _ . . . . .
pyrindine derivatives, namely the 4a-aryl-octahydro-lH-2-pyrindines, can be converted to a 2-substituted 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 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-(3-hydroxy-3-phenyl)propyl-2,3,4,4a,5,6,7,7a-octahydro-1~-2-, pyrindine, also a useful analgesic agent. Additionally, a - 2-unsubstituted pyrindine derivative can be acylated with any o~ a number of acylating agents to provide an N-acylated pyrindine derivative, a compound of formula (I) wherein O O O ~=~R
Rl is C-Cl-C7 alkyl, C-R3, and C-(C~2)n l-(X)m~

Such N-acylated pyrindines, upon reduction of the carbonyl moiety, provide 2-substituted pyrindine deri~ati~es of ormula (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 acylati~g~a~ent such as an acid halide or acid anhydride. Examples of commonly used acylating agents include acetyl chloride, pentanoylchloride, 4-hexenoyI 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-unsubstituted pyrindine derivative with an acylating agent such as the aforemen-tioned is carried out by reacting approximately equimolar quantities of the pyrindine derivative and the acylating agent in an unreactive organic solvent such as dichloro-metha~e, 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 about -20C. to about 30C., and generally is complete within 1 to 8 hours. The product, for example a 4a-aryl-2-acylated-- , -1119~75 2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine, is readily isolated by simply removing the reaction solvent by evapora-tion.. 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-octahydro-1~-2-pyrindine of formula (I). Such reduction of the N-acyl car~onyl group can be accomplished by-reaction of the acylated pyrindine derivative with a reducing agent such as lithium alllminum hydride or by catalytic hydrogenation.
It will additionally be recognized that still other. modifications can be made on certain of the 4a-aryl-2-substituted-2,3,4,4a,5,6,7,1a-octahydro-1~-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 - hereinabove, it.might be preferable 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 substituent to a hydroxy group. Such conversion is readily accomplished by reacting a 4a-(3-methoxyphenyl)-pyrindine derivative with hydrobromic acid in acetic acid.
Such reaction i~ guite general for the conversion of a methoxyphenyl group to a hydroxyphenyl group.
' .

, 111~175 As hereinbefore pointed ou~:, the 4a-aryl-2-sub-stituted-octahydro-lH-2-pyrind'ne derivatives of formula (I) can be reacted with an organic or inorganic acid so as to pro~ide a crystalline salt which can be purified ~y crystal-lization, and which then can be converted bac~ to the pyrindine free base by treatment 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-Z-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, i! phosphoric, nitric, perchloric, phosphorous, nitrous, and "
~elated acids. Organic acids commonly used to prepare pharmaceutically acceptable acid addition salts of the pyrindines of formula (I) include acetic, propionic, para-toluenesulfonic, chloroacetic, maleic, tartaric, succinic, oxalic, citric, lactic, palmitic, stearic, benzoic, and ; related acids. The pharmaceutically acceptable acid addition salts of formula (I) can be conveniently prepared by simply dissolving a 4a-aryl-2-substituted-octahydro-lH-2-pyrindine in a suitable solvent such as diethyl ether, ethyl acetate, acetone, or ethanol, and adding to such solution either an -e~uivalent amount or an excess o a suitable acid. Thc saLt 50 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 ~urther purified by recrystallization from common solvents such as acetone and methanol..
The following list of cis-4a-aryl-2-substituted-2,3,4,4a,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,?a-octahydro-1~-2-pyrindi~e;
4a-(3-methoxyphenyl)-2-(n-octyl)-2,3,4,4a,5,6,7,7a-; octahydro-1~-2-pyrindinium bromide; ...
4a-(3-hydroxyphenyl)-2-(2-propenyl)-2,3,4,4a, S,6,7,7a-octahydro-lH-2-pyrindine; ~ :;
4a.-(3-propoxyphenyl)-2-~2,3-dimethyl-4-hexenyl)-~ :
2,3 t 4,4a,5,6,7,7a-octahydro-lH-2-pyrindine, -~
4a-phenyl-2-(S-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- :
octahydro-lH-2-pyrindine;
- 4a-(3-hydroxyphenyl)-2-(2-methylphenoxymethyl)-2,3,4,4a,5,6,7,7a-octahydro-1~-2-pyrindinium succinate;
4a-(3-methoxyphenyl)-2-(3,5-dichlorobenzoylmethyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine;
.
X-4.466 -24-.. . . . .

4a-(3-ethoxyphenyl)-2-~3-(3-methyl-4-bromophenyl)-3-hydroxylpropyl-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-phenylthlo)propyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium citrate;
4a-phenyl-2-[3-(2-isopropylphenyl)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-1~-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)propyll-2,3,4,4a,5,6,7,7a-octahydro-1~-2-pyrindine; and 4a-(3-hydroxyphenyl)-2-[2-(3,5-diethylphenoxy)-ethyl]-2,3,4,4a,5,6,7,7a-octahydro-1~-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 X-4466 . -25-isomers and racemic mixtures of such isomers which are useful pharmacologically as anal~esic a~onist or antagonist drugs~ ~owever, only the c -isomers o~ formula (I) are intended.thereby, name}y, such ~hat. the 4a-aryl group is ,,~
orient~d on the 3ame side of the plane of the molecul~
from.the, 7a-hydrogen atom.. This i~vention accordingly ' comprehenas the phar~acologically active indi~idual optically-active c~s isomers, in addition to the racemic ~ ;
~ixture of c~ isomers. Such racamic pair of cis-qcta-hydropyrindines can be separated into its component stereo-i~omers by procedures well.known in the art... In~the event :
that all.useful pharmacologic activity resides in one stereoisomer, the dl-racemate is. still useful in -~hat it contains, as a constituent part, the pharmacologically ,:
acti~e isomer. , "
. . .
The ~rep7ration of the 4a-aryl-octahydropyrindines o~ formula (Ij r-s~ res starting materials, many of which are hitherto unknown and not readily available. The , pysin~ines of formula ~I) utilize 4a-aryl-tetrahydro-2,6-dioxocyclopenta~c]pyrans as starting materials. Such ~tarting materials are prepared from 2-arylcyclohexanones such as 2-phenylcyclohexanone and 2-(3-methoxy~henyl)cyclo-haxanone. For the preparation of the dioxocyclopentapyran ;derivatives, the 2-arylcyclohexanone.is alXylated at the 2-position by reaction with an alkyl haloacetate such as ethyl chloroacetate, in the presence of a ~ase such as sodium hydride, thereby providing ~he corresponding 2-aryl-2-alXoxyca~onylmethylcyclohexanone. Similarly, in the preparation o~ 2-aryl-2-alkenyl-1-aminomethylcyclopentanes, .

1~19~75 a 2-arylcyclohexanone is first alXylated at the 2-position by raaction with an aLcenyl halide, such as allyl iodide or 2-butanyl bromide, in the presence of a base such as sodium hydride, to provide the corresponding 2-aryl-2-a~ke~ylcyclo-hexanone. Both the 2-aryl-2-alXoxycarbonylmethylcyclo-hexanones and the ~-aryl-2-alkenylcyclohexar.ones are next formylated at the 6 position by reaction with an alXyl formate such as ethyl formate in the presence of metallic sodium or potassium. The rormyl cyclohexanone derivatives L0 are next reacted with para-toluene ~ulfonyl azide, thus e~fqcting displ~c ment of the 6-formyl moiety with a dlazo - group to provide, respectively, 2-aryl-2-alkoxycarbonyl-methyl-6-diazocyclohexanones and 2-aryl-2-alX2nyl-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 me~hanol to ?i :`:
effect ring contract~on with concomltant ex~ulsion of ... . _ _ .. _ . . _ . . . .. _ . . ...
nit~ogen gas to provide, respectively, 2-aryl-2-alkoxycar-bonylmethyl-l-methoxycarbonylcyclopentanes znd 2-aryl-2-alkenyl-l-methoxycarbonylcyclopentanes. Such compounds are next de-esteri~ied, l.e. hydrolyzed, ~y reaction with a~ueous alXali to provide the corresponding diacid and mono-acid.
Speci~ically, hydrolysis of a 2-aryl-2-aL~oxycarbonyl-methyl-l-methoxycarbonylcyclopentane provides the corre-sponding 2-aryl-2-hydroxycarbonylmethyl-1-hydroxycarbonyl-cyclopentane. Similarly, hydrolysis OL a 2-aryl-2-aLkenyl-l-methoxycarbonylcyclopentane af~ords the correspGndi~g 2-aryl-2-alXenyl-l-~ydroxycarbonylcyclopent2ne. ~he diacid, namely the 2-aryl-2-hydroxycarbonylmethyl-1-hydroxycar-X-446~ -2~-1~19175 bonylcyclopentane, is next 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 octahydro-1~-2-pyrindines of formula (I~ have found utility in the treatment of pain, and accordingly can be used to ef'ect analgesia in a subject sufering 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 compGunds disclosed herein to cause analgesic agonist as well as analgesic antagonist effects in mammals .i9 thus responsible for a decrease in any addLctive properties o a particular dru~ caused by its opiate-like analgesic 20 action~ The compounds are thus particularly valuable since they produce analgesia with only minimal physical dependance liability. Certa;n 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 ormula (I) has been determined by testing such compounds in ~tandard animal assays routinely used to measure analgesic action attributable to test compounds. Such assays include the mouse-writhing test and the rat tail jer~ assay.

.
.~ ' .

1~1917S

AS indicated hereinbe~ore, 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 obser~ing the inhibition of - such writhing when the drug 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 o~ 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 totally prevent the inhibitory action o the compound at an subcutaneous dose of 5 mg./kg., ~hus indicating that the compound is an opiate-type analgesic.
When ~ested in the rat tail jer~ assay, the above-named compound produced a significant increase in reaction time at dose levels of 80 mg./kg., ~oth 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 42- ~3-hydroxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1~-2-pyrindine. At a 1119~7S

¦ 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 compo~nd caused a si~nificant increase in reaction time at subcutaneous and oral doses of 20 mg./Xg.
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 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.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:

-~ -~19175 Table Example Writ~ingRat Tail ~o. Salt E.D.50 E.D.50 12 ~Cl ~ ~80 1 13 --- 0.4 0.2 ¦ 14 HBr 1.0 1.0 ¦ 15 HCl >20 ~80 16 HBr 1.0 0.5 17 --- 20 >80 18 HBr 50 >80 19 HBr 20 --HBr 20 >80 21 ~Br 1.0 c<80 The 4a-aryl-2-substituted-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindines of formula (I) are thus useful 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 utilize a pharmaceutically acceptable acid addition salt of the pyrindine derivative when the dosage is by the oral route, since ~uch 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 a~mixing such compounds with any of a number of commonly used diluents, excipients, or carriers. ~xamples of such diluents and excipients commonly employed in pharmaceutical preparations include " .

1~19175 starch powder, sucrose, cellulose, magnesium stearata, 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-a~ueous 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. Useul 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 4a-aryl-2-substituted-octahydro-lH-2-pyrindines of formula ~I) administered to a mammal, such as a human subject for example, ma~ 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 efect desired, on the particular route of administration being utilized, and on the du.atlon of treatment, as well as the precise condition being treated. Typically the dosages o the active compounds of formula (I) will range from about ~19175 l.0 to about 25 mg./kg. of animal body weight per day, appropriately divided for a&ministration from 1 to 4 times ¦ per-day. Preferred oral doszges 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 startin~ materials, the following examples are provided by way of illustration.
STARTING ~ATE~IALS
Example A
A solution of 130 g. of 2-phenyl-2-ethoxycar~onyl-methylcyclohexanone in 2000 ml. of diethyl ether containing 56 g. of ethyl formate and 11.5 g. of metallic sodium was stirred at 25C. for forty-eght hours. The reaction mixture was then added to 1000 ml. of ice-water, and the ethereal layer was removed. The a~ueous layer was acidified 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.
~vaporation of the solvent under reduced pressure provided 98 g~ of 2-phenyl-2-ethoxycarbonylmethyl-6-formylcyclo-hexanone as an oil. B.P. 158-175C. at 0.5 torr.
Analysis Calc. for C17~2004 Theory: C, 70.81; H, 6.99.
Found: C, 70.85; H, 6.77.
Example B
Following the procedure set forth n Example A, 2-(3-methoxyphenyl)-2-ethoxycar~onylmethylcyclohexanone was reacted with ethyl formate in the presence of metallic X-4466 ~33~

, " .~ ,. , sodium to provide 2-t3-me~hoxyphenyl)-2-ethoxyca~onyl-me~hyl-6-formyicyclohexanone.
ExamD 1 e C
A solution of 87.0 q~ of 2-phenylcyclohexanone in 100 ml. of ~enzene was added dropwise over 1 hour to a stirred re~luxi~g solution ot 28.0 g. of sodium amide in 400 ml. of benz~ne. The reaction mixtuxa was neated at reflux _or an additional 2.5 hours, a~d then cooled to 0C.
in an ice bath. To the cold reaction mixture was added in one portion a solution of 83.~ g. of allyl iodlde in 100 ml.
or benzene. T~e reaction mixture was heated at reflux ror I/2 hour, and then cool~d to 25C. and poured onto 400 g. of ice. The org&nic benzene layer was separated, washed with water and dried. Evaporation of the solvent afforded 50 g.
of 2-phenyl-2-(2-propenyl)cyclohexanone. 3.P. 114-120C. at 0.~ torr.
-- Example D
A solution or 30 g. of 2-phenyl-2-(2-propenyl) cyclohexanone in 600 ml. of diethyl ether containing 3.4 g.
o~ sodium metal and 11.8 g. of ethyl formate was stirred at 25~C. for ~orty-eiqht hours. The reaction mixture was then added to water, and the organic layer was separated and set aside. The a~ueous layer was acidiried to p~ 2.5 by the addition of aqueous hydrochloric acid. The aqueous acid .. ,,, .. ,,,, . _, , _ _, ., ., . _ _ , . . .
layer was extracted with fresh diethyl ether. The ethereal extracts were combi~ed, washed with water, dried, and he solvent was removed thereform by e~a~orat on under reduced pr2ssure to provide the product as an oll. The oil so X-446~ -34-formed was distiLled to ~fford 14.6 g. of 2-~henyl-2-(Z-propenyl)-6-formylcyclohexanone. B.P. 125-130C. at 0.1 torr. ' '~
Exam~le E
- A solution of 50.0 g~ of 2-phenyl-2-ethoxycar-bony1~ethyl-6-for~ylcyclohexanone in 500 ml. of diethyL
ethe~ was stir~ed at 25C. while a solution of 24.8 g. o~
diethylamine in lG0 ml. of diethyl ether was added dro~wise over thirty ~i~utes. After stirring the reactior mixture for two hours at 25C., the solution was cooled to 5~C., and then a solution of 33.5 g. of ~-toluenesulfonylazide ln 50 ml,, of diethyl ether was added dropwise over fifteen minutes.
The reaction ~ixture was allowed to warm to room temperature, and was stirred for, an additional rive hours. The reaction mixture was then washed with,water and dried. Evaporation o~ the solvent under reduced pressure arorded 43.0 g. o 2-phenyl-2-ethoxycar~onylmethyl-6-diazocyclohexanone as an oil. IR ~neet) 2080 cm 1 diazo group.
Examples F-G
' Following the procedure set forth in 3xample E, 2-~3-~ethoxyphenyl)-2-ethoxycarbonylmethyl-6-rormylcyclo-hexanone was converted to 2-(3-methoxyphenyl)-2-ethoxy-carbonylmethyl-~-diazocyclohexanone, and 2-~henyl-2-(2-propenyl)-6-formylcyclohexanone was converted to 2-phenyl-2-(2-propenyl)-6-diazocyclohexanone.
Exam~le ~
A solution of 57 g. of 2-phenyl-2-e~hcxyc2r~onyl-~e~hyl-6-diazocyclohexanone in 500 ml. of anhydrous methanol was stirred at 25C. while nitrogen gas was bubbled ~hrough P17$

the reaction mixture. ~he solution was photoly~ed for forty hours with a quartz lamp having wavelength of 3000 A.
The solvent was ~hen removed un~er reduced pressure to provide the product as a crude oil, which was dissolved in 500 ml. of diethyl ether. T'ne ethereal solution was washed with a~ueous sodium bicarbonate solution, with water, and dried. Removal of the solvent under reduced pressure afforded 27.4 g. of 2-phenyl-2-ethoxycar~onylmethyl-1-methoxycar-bonylcyclopentane as an oil. The oil was further purified }o by distillation. B.~. 160-190C. at 0.02 torr.
Analysis Calc. for C17H22O4 Theory: C, 70.32; H, 7.64.
Found: C, 70.30i H, 7.36.
Examples I-J
Following the procedure set forth in Example H, 2-~3-methoxyphenyl)-2-ethoxycarbonylmethyl-6-diazocyclo-I hexanone was photolyzed at 3000 A to provide 2-(3-methoxy-I phenyl)-2-ethoxycarbonylmethyl-1-methoxycarbonylcyclopentane.
B.~. 190-210C.
Analysis Calc. for C18H24O5 Theory: C, 67.48; H, 7.55.
Found: C, 67.61; H, 7.37.
Similarly, 2-phenyl-2-(2-propenyl)-6-diazocyclo-hexanone was irradiated with ultraviolet light at 3000 A
from a quartz lamp in the presence of methanol to provide 2-phenyl-2-(2-propenyl)-1-methoxycarbonylcyclopen~ane. B.P.
113-115C. at 0.1 torr.

-: f Analysis Calc. for Cl6~202 Theory: C, 78.65; H, 8.25.
Pound: C, 78.80; H, 7.99.
Analysis Calc. for ClgH25O5 Thecry; C, 68.24; H, 7.84.
Found: C, 68.15; ~, 7.57.
Example K - -A solution of 2-(3-methoxyphenyl)-2-ethcxycar-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-peraturer 500 ml. of water was added. The reaction mixture was ~ade acidic by the addition of 2N hydrochloric acid, and the aqueous acidic mixture was extrz~cted several times with-, . . :
equal volumes of diethyI 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 forth in Example K, 2-phenyl-2-ethoxycarbonylmethyl-l-methoxycarbonylcyclo-pentane was hydrolyzed to provide 2-phenyl-2-hydroxycar~
bonylmethyl-l-hydroxycar~onylcyclopentane. M.P. 205-208C.
Analysis Calc. for C14H16O4 Theory: C, 67.73; H, 6.50.
~ound: C, 67.70; H, 6.32.

: , . . . .

~9175 2-Phenyl-2- (2-propenyl) -l-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. 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-2,6-dioxocyclopenta[c~pyran as an oil. The product was further purified by distillation. B.P. 205-207~C 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-hydroxycar~onyl-cyclopentane was dehydrated and cyclized by reaction withacetyl chloride to provide tetrahydro-4-(3-methoxyphenyl)-2,6-dioxocyclopenta~c]pyran. B.P. 200-220C.
Examp7e P
To a stirred solution of 6.2 g. of 2-phenyl-2-~2-propenyl)-1-hydroxycarbonylcyclopentane in 100 ml. of chloroform was added dropwise over thirty minutes 30 g. of thionyl chloride. The reaction mixture was then heated a' r~flux and stirred for flfteen hours. After cooling the 11~9~75 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.
Exam~le Q
A solution of lO.7 g. of be~zylamine in 100 ml. of toluene was stirred at 25C. while a solution 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 rerlux for three days in a flas~ equipped with a Dean-Star~ trap ~r water removal.
Following the reflux period, the reaction mixture was cooled to room temperature and the solvent was removed by evaporation . .
undex 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. ~e-crystallization of the solid from diethyl ether af orded 4a-(3-methoxyphenyl)-2-benzyl-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine. M.P. 75-i70C.
Analysis Calc. for C22H23N03 Theory: C, 75.62i H, 6.63; N, 4.01.
Found: C, 75.40; H, 6.58; N, 3.78.

X-4466 ~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-berzyl-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine. M.P. 77-79C.
Analysis Calc. for C2l~21NO2 Theory: C, 78.97; ~, 6.63; N, 4.39.
Found: C, 78.73; H, 6.65; N, 4.26.
FINAL PRODUCTS
Example 1 A salution 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 stirred suspension of S.8 g. of lithium aluminum hydride in l5a ml. of tetrahydrofuran. After the addition was complete, the reaction mixture was heated at ref~ux for ten hours. W~ile 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 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 X-~466 -40-11191~7S

pressure to provide 15 g. of 4a-phenyl-2-ben2yl-2,3,4,4a, 5,6,7,7a-octahydro-lH-2-pyrindine. M /e 291 (parent peak), 213 (-77, phenyl), and 200 ~-91, ~enzyl).
Example 2 Following the procedure set forth in Example 1, 4a-(3-methoxyphenyl)-2-~enzyl-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-lH-2-pyrindine was reduced by reaction with lithium aluminum hydride to provide 4a-(3-methoxyphenyl)-2-~enzyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine.
Exam~le 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 carbon was added in one portion. The reaction ;~
mixture was stirred under a hydrogen gas atmosphere at 4.13 x 106 dynes/cm.2 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 distilled to a~ford 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine.
Example 4 4a-~3-Msthoxyphenyl)-2-~enzyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine was hydrogenated in the presence of 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.

i .. .~ . . , ~ '' ' ~.

1~19175 Exam~le 5 A solution of 8.4 g. of 4a-(3-methoxy?henyl~-2,~,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine dissoLved in 60 ml. o~ glacial acetic acid and 60 ml. of 48 percent aqueous hydrobromic acid and was stirred and 'neated at reflux for . . _ _ . . _ _ . .
fifteen hours. After coolin~ 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 o~ concentrated aqueous sodium hydroxide solution. The alkaline reaction mixture was then extract~d with 400 ml. of a mixture o 3 parts n-butanol and 1 part benzene. ~he extract was separated, washed several times with wat2r, dried, and the solvent was removed by evaporation under reduced pressure to provide the product as a crude solid. The solid so formed was crystal-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.

lsa-lsloc. -~
Analysis CaLc~ for C14HlgNO --Theory: C, 77.38; ~, 8.81; N, 6.45.
Found: C, 77.56; H, 8.84; N, 6.24.
Exam~le 6 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-dimethylformamide ~ containing 1.23 g. of sodium bicarbonate was stirred at ;~ 25C. while 1.23 g. of 2-propenyl bromide was added in one ii portion. The reaction mixture was stirred and heated at ~ reflux for four hours. After bein~ cooled to room tem-.~ ~ perature, the reaction miYture was filt2red and concentrated 11J~91'7S

to an oil under reduced pressure. The residual oll was dissolved in 300 ml. of diethyl ether. The ethereal soluti on was washe~ 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-lH-2-pyrindine as an oil. The oil so formea was dissolved in 150 ml. of fresh diethyl ether, and hydrogen bromide gas ~as bubbled through the ethereal solution. The precipitated salt was collected by eiltration and recrystallized ~rom diisopropyl ether and isopropanol to afford 1.3 g. o~ 4a-pheny1-2-(2-propenyl)-2,3,4,4a,5,6,7,1a-octahydro-lH-2-pyrindinium bromide. M.P. 185-187C.
Analysis Calc. for Cl7H24BrN
Theory: C, 63.36; H, 7.51; N, 4.3S.
Found: C, 63.63; H, 7.24; N, 4.24.
Examples 7-8 Following the procedure set forth in Example 6, 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-pyrindinium bromide. M.P. 245-247C.
Analysis Calc. ~or C17H26BrN
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-octahydro-lH-2-pyrindinium bromide. M.P. 240-243C.
Analysis Calc. for C19~30srN

X-4466 ~43~

.

~191~75 Theor~: C, 6~.77; H, 8.58i N, 3.98.
Found: C, 65.04; H, 8.70; N, 3.87.
Example 9 A solution of 3.0 g. o~ 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine in 10 ml. of 88% formic acid was stirred at 20C. while 10 ml. of 38~ formaldehyde was added dropwise over fifteen minutes. The reaction mixture 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 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 I evaporated under reduced pressure to provide 4a-phenyl-2-¦ methyl-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 25C. while a solution o~ 10 ml. of 48 percent hydrobromic acid in 10 ml. of ethanol was added dropwise over ten minutes. ~he 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-methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium bromide. M.P.
209-210C.
.

X-4466 , 44 .

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 ~0-5C.) of 3.0 q. of 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine in 47 ml.
of methanol containinq 14 ml. of water and 2.6 g. of potas-sium 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 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 a~ueous 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-1~-2-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 30C., 60 ml~ of ethyl acetate was added, followed by the addition to the reaction mixture of 100 ml. of saturated aaueous ammonium tartrate solution. The organic layer was separated by decanting, and the aqueous layer was extracted with . __ . . .... . _ _ . .... .. .. . .. .. . .. . .. . .

1119~75 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, a~d dried. Removal of the s~lvent 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. of 48 percent hydrobromic acid in 10 ml. of ethanol. ~he 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)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium ~romide.
M.P. 269-270C.
Analysis Calc, for C ~ BrN
Theory: C, 68.39; H, 7.30; N, 3.63.
Fo~nd: C, 68.61; H, 7.57; N, 3.69.
Example 11 Following the procedure outlined in Example 10, 4a-phenyl-2~3t4~4a~5~6~7~7a-octahydro-lH-2-pyrindine was acylated with cyclopropanecarboxylic acid chloride to provide 4a-phenyl-2-cyclopropanecar~onyl-2,3,4,4a,5,6,7,7a-octa-hydro-1~-2-pyrindine. Reduction of the acylated pyrindine intermediate by reaction with lithium aluminium hydride afforded the 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 C18H26~rN
Theory: C, 64.28; ~, 7.79; N, 4.16.
Found: C, 64.54; ~, 7.51; N, 4.13.
ExamDle 12 A solution of 75 ml. or toluene containing 1.76 ml. of li~uid methylamine was cooled to -70C. in a dry ice~ac~one bath and stirred while a solution of 10.4 g. of te~ahydro-4-(3-methoxyphenyl)-2,6-dioxocyclopenta[c]pyran in 125 ml. of toluene was added dropwise over thirty minutes.
The reaction mixture was warmed to r~om temperzture and then heated at reflux for twenty-two hours. The reac~ion mixture was-again cooled to room temperature and concentrated under '-reduced pressure to an oi}. The oil so rormed was dissolved in 152 ml. of 1 N sodium hydroxide solution and was heated with stirring to 50C. for fifteen minutes. The product was extracted from the aqueous alkaline reaction mixture into diethyl ether. The ethereal extracts were co~'oined, washed -with water, and dried. Evaporation o~ 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-~yrindine.
Reduction of 8.2 g. of 4a-(3-methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-1~-2-~yrindine by reaction with lithium aluminum hydride according to the procedure set ~orth in ~xample 1 provided 4.6 g. o' 4a-~3-methoxyphenyl)-2-meth~1-2,3,4,4a,5,6,7,7a-octahydro-1~-2-pyrindine. 3.P. 133-138C. at 0.25 torr.
Analysis Calc. for C16;i23NO
Theory: C, 78.32; '~, 9.45; N, 5.71.
Found: C, 78.13; 'd, 9.30; N, 5.68.

A solution o~ 4a-(3-methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine in iO0 ml. of diethyl ether was stirred while hydrogen chloride ~as was bubbled through the solution. ~he reaction mixture was stirred for thirty minutes and then ~iltered. 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.
~.P. 175-177C.
Analysis Calc. for C16H24HCCl Theory: C, 68.19; H, 8.58; N, 4.97.
Found: C, 68.00; ~, 8.2a; N, 4.68.
Exam~le 13 A solution of 1.6 g. or 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 re~lux for fifteen hours. The acidic reaction mixture was cooled to about 10C. and the p~ 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 30 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-hydroxyphenvl)-2~methvl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine. M.P. 151-153C.

X-4466 4~

111~175 Analysis Calc. for Cl5~2lNO
Theory: C, 77.88; ~, 9.1;; N, 6.05.
Found: C, 77.6Q; H, 8.88; N, 5.76.
Example 14 A solution of 2.17 g. of 4a-~3-hydrox~phenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindir.e prepared as described in Example S in 50 ml. of N,N-dim~thylformamide containing 3.95 ~. 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 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-t2-phenylacetyl)-2,3,4,4a, 5,6,7,7a-octahydro-1~-2-pyrindine. Such product was dis-solved 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, ~ollowed 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 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-~-phenyl-ethyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindinium bromide.
M.P. 135-137C.
Analysis Calc. for C22H2gNBr -~
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, 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; H, 8.51; N, 4.55; Cl, 11.52.
Found: C, 69.93; H, 8.25; N, 4.72; Cl, 11.52.

X-4466 ~50-. :

- 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 N,N-dimethylformamide containing 1.0 g. of sodium bicar-bonate and 0.95 g. of 2-tetrahydrofurylmethyl bromide was heated at reflux for four hours. After cooling the reaction mixture to about 25C., 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 diethyI ether. The product crystallized ou~ of solution and was collected by filtration , . .. . . ... . .
to provide 1.0 g. of 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 ClgH28NO2Br Theory: C, 59.69; H, 7.38; N, 3.66.
Found: C, 59.89; H, 7.40; N, 3.78.
Examples 17-19 Pollowing the procedure set forth in Example 16, 4a-(3-hydroxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine was reacted with allyl iodide in the presence of sodium bicarbonate to provide 4a-(3-hydroxyphenyl)-2-(2-propenyl)-2,3,4,4ar5,6,7,7a-octahydro-lH-2-pyrindine.
- M.P. 106-108C.

Analysis Calc. for C17H23NO
Theory: C, 79.33; H, 9.01; N, S.44.
Found: C, 79.29; H, 8.92; N, 5.44.
Slmilarly, 4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine from Example 4 was rèacted with L-Lodopropane in the presence of 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 ~y 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, 4.07.
Similarly, 4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine was reacted with l-bromopentane in the presence of sodium bicarbonate to provi~e 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 gas in diethyl ether to provide 4a-(3-methoxy-phenyl)-2-n-pentyl-2,3,4,4a,5,6,7-,7a-octahydro-1~-2-pyrindinium bromide as a crystalline solid. M.P. 179-181C.
Analysis Calc. for C20H32NOBr ~ Theory: C, 62.82; H, 8.44; N, 4.18.
j Found: C, 62.87; H, 7.98; N, 4.02.
¦ Example 20 A solution of 2.0 g. of 4a-(3-methoxyphenyl)-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 `:

: . ,- ..

i~L19~7~

acid was stirred and heated at reflux for twelve hours. The reaction mixture was then cooled and poured over 100 q or ice, and the resultinq aqueous solution was made al.~aline by the addition of aqueous sodium hydro:~ide to pH 10.2. The aqueous alkaline mixture was extracted with 200 ml. of a I mixtn e of 3 parts n-~utanol and 1 part benzene. ~he extracts were combi~ed, washed with water and dried.
¦ Removal of ~he s~lvent by evaporation under reduced pressure pro~ided 1.3 g. of 4a-(3-hydroxyphenyl)-2-n-propyl-2,3,4, 4a,5,6,7,7a-octahydro~ 2-pyrindine as an oil. The oil was dissolved in diethyl ether and added to a solution of hydrogen bromide gas i~ die~hyl ether. The hydrobromide salt of the a~ove-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-1~-2-pyr m dinium bromide. M.P. 235-236C.
Analysis Calc~ for C15H26NOBr Theory: C, 60.00; H, 7.70; N, 4.12.
Found C, Sg.98; H, 7.S0; N, 3.98.
Example 21 Following the procedure set forth in Example 20, 4a-~3-~ethoxyphenyl)-2-n-pentyl-2,3,4,4a,5,6,7,7a-octa-hydro~l~-2-pyrindine was reacted with a~ueous nydrobromic acid in glacial acetic acid to afford 4a-(3-hydroxypheryl)-2-_-pentyl-2,3,4,4a,5,6,7,7a-octahydro-lH-2-pyrindine, which was then con~erted to the corresponding hydrogen bromide ~alt. M.P. 171-173C.
~nalysis Calc. for C20~3oNosr I The~ry: C, 61.95; H, 8.21; N, 3.80.
¦ 30 Found: C, 61.65; ~, 7.93; N, 3.54.
I X-4466 ~53~

Claims (2)

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 (IIa) wherein R2 is hydrogen, hydroxy, or C1-C3 alkoxy, which comprises reacting a compound of the general formula (IIIa) wherein R2 is as defined above, with a reducing agent, and optionally de-etherifying the compounds of formula (IIa) wherein R2 is C1-C3 alkoxy to obtain the compounds of formula (IIa) wherein R2 is hydroxy.

2. As a novel intermediate a cis-compound of the general formula IIa wherein R2 is hydrogen, hydroxy, or C1-C3 alkoxy, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.