Amine intermediates for analgesic compounds

1,2-Cycloaliphatic diamines and protected diamines of the formulas II and IIa ##STR1## and ##STR2## wherein the wavy line bonds, p, n, R, R.sub.1, R.sub.2, Z, m and Q are as defined in the specification, e.g., (.+-.)-(5.xi.,6.alpha.,7.beta.)-1-[6-methylamino-1-oxaspiro[4.5]dec-7-yl]p yrrolidine, are disclosed and claimed herein. These diamines and protected diamines are useful as intermediates for preparing mono-oxa, and thiaspirocyclic-benzene acetamide and benzamide analgesic compounds.

INTRODUCTION 
This invention relates to 1-oxa-, thia- and 
aza-spirocyclicbenzene-acetamide and -benzamide compounds. More 
particularly, this invention provides some new 1-oxa-, thia- and 
aza-spirocyclic-phenylacetamide and -benzamide compounds which have useful 
analgesic activity, low physical dependence and abuse liability 
properties, and little if any dysphoria inducing properties, or which 
compounds are useful as chemical intermediates to such useful compounds. 
Processes for their preparation are disclosed. Pharmaceutical compositions 
and methods of use are also disclosed. 
BACKGROUND OF THE INVENTION 
Szmuszkovicz U.S. Pat. No. 4,145,435 discloses some cis- and 
trans-N-(2-aminocycloaliphatic)-2-arylacetamide derivative compounds, 
e.g., N-[(N',N'-dimethylamino)cyclohexyl]-N-methyl-2-(4-bromophenyl)acetam 
ide and 
trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-2-(3,4-dichlorophenyl)acet 
amide, which have potent analgesic activity; the preferred compounds 
thereof have, in addition, only low to moderate apparent physical 
dependence liability compared to morphine and methadone. That Szmuszkovicz 
U.S. Pat. No. 4,145,435 also describes some prior art patent and 
publication background that may be of interest herein also. 
Also, Szmuszkovicz U.S. Pat. No. 4,098,904 discloses some cis- and 
trans-N-(2-aminocycloaliphatic)benzamide compounds, e.g., 
N-methyl-N-(2-aminocycloaliphatic)benzamide compounds, e.g., 
N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichlorobenzamide which have 
potent analgesic activity, making them useful for relieving pain in warm 
blooded animals. That U.S. Pat. No. 4,098,904 also discloses background 
patents and publications which may be of interest herein. 
Lednicer U.S. Pat. No. 4,212,878, discloses some N-[(1-amino-4-(mono- or 
di-oxygen-group-substituted)cyclohexyl)methyl]benzeneacetamide 
derivatives, e.g., 
2-(3,4-dichlorophenyl)-N[[8-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl]m 
ethyl]acetamide, which also have analgesic drug properties with lower 
physical dependence liability characteristics than morphine or methadone. 
That Lednicer patent also refers to what is now Lednicer U.S. Pat. No. 
4,065,573 which discloses some 4-amino-4-phenylcyclohexanoneketal 
compounds, e.g., 4-(m-hydroxyphenyl)-4-(dimethylamino)-cyclohexanone 
ethylene ketal and 4-(m-hydroxyphenyl)-4-(m-butylmethylamino)cyclohexanone 
ethylene ketal, which are useful for relieving pain in animals, some of 
which compounds exhibit narcotic antagonist activity. 
A recently filed U.S. application, Ser. No. 06/252,535, filed Apr. 9, 1981, 
now U.S. Pat. No. 4,360,531 discloses some 
N-[2-amino-(oxy-group-substituted cycloaliphatic)]phenylacetamide and 
-benzamide compounds, e.g., 
trans-3,4-dichloro-N-methyl-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]-dec-8- 
yl]benzamide, and salts thereof, as analgesic compounds having low apparent 
physical dependence liability properties. 
Also, recently filed U.S. application Ser. No. 06/252,536, filed Apr. 9, 
1981, now U.S. Pat. No. 4,359,476, discloses some 
N-2-amino-adjacently-oxy-substituted-cycloaliphatic-phenylacetamide and 
-benzamide compounds, e.g., cis- and 
trans-4-bromo-N-[3-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzamide 
, and cis- and 
trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]-dec- 
6-yl]benzamide, and salts thereof, as analgesic compounds having low 
apparent physical dependence liability properties. 
Representative compounds of some of the above types have been or are being 
studied in advanced animal drug studies. Some concern has been expressed 
about possible dysphoric side effects of such compounds when used as 
analgesic drugs. Those skilled in the art continue to search for new and 
more potent and otherwise advantageous analgesic compounds. 
OBJECTS OF THE INVENTION 
It is an object of this invention to provide some new spiromono-oxy, thia- 
and aza ring-2-aminocyclohexylbenzeneacetamide and -benzamide compounds 
which are useful as analgesic compounds or as chemical intermediates to 
analgesic compounds. 
It is a further object of this invention to provide new compounds of the 
above type which have more potent analgesic properties when administered 
by either the oral, subcutaneous or other parenteral route, only low to 
moderate physical dependence liability, and hopefully also, less dysphoria 
inducing properties than prior known analgesic compounds. 
Other objects, aspects and advantages of this invention will become 
apparent from reading the remaining specification and claims which follow. 
SUMMARY OF THE INVENTION 
Briefly, this invention provides some new, more potent spiromono-oxy-, 
thia- and -aza ring-2-aminocyclohexyl benzeneacetamide and benzamide 
compounds, e.g., 
(.+-.)-5.alpha.,7.alpha.,8.beta.-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidiny 
l)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide, and salts thereof, which have 
been found to have useful ranges of analgesic properties for use in 
valuable warm blooded animals, including humans, while also having low 
apparent physical dependence liability, reduced sedative and/or dysphoria 
inducing properties, and better analgesic activities when administered by 
either the oral or parenteral routes to the warm blooded animal or human 
patient in need of pain relieving treatment. 
This invention also includes compounds of the above general type which may 
exhibit some analgesic activity of their own, but which are of some 
importance as chemical intermediates for the preparation of more 
advantageous analgesic drug compounds included herein. This invention also 
includes pharmaceutical compositions containing these compounds as an 
active analgesic component and the method of inducing analgesic activity 
in the animal patient, including humans, by administering one of these new 
compounds in an amount effective and sufficient to induce analgesic 
activity, regardless of origin of the pain, e.g., traumatic pain, bone 
pain, cancer pain, post-surgical pain, homotropic pain, menstrual pain, 
headache, and the like. This invention also relates to the use of these 
new compounds in pharmaceutical dosage unit forms, to be used, hopefully 
more advantageously, by the oral or parenteral administration route, for 
the relief of pain in valuable animals and human patients suffering pain. 
With more potent analgesic compounds, it should be possible to administer 
less of the compound to obtain a desired degree of relief from pain in the 
patient. 
DETAILED DESCRIPTION OF THE INVENTION 
More particularly, this invention provides some new N-(2-amino-substituted 
cyclohexyl)benzeneacetamide and -benzamide compounds having a new chemical 
structure I (See General Chemical Structure sheets) featuring a new 
asymmetric carbon atom and a (spiro mono-oxa-, thia- or aza-ring structure 
substituted)-2-amino cyclohexylbenzeneacetamide or -benzamide structure, 
which are more analgesically potent, more active administered by the oral 
route, and otherwise more advantageous than prior known compounds. 
In the compounds of formula I, the wavy line bonds indicate a cis or trans 
relationship of the two nitrogen-containing groups at positions 1 and 2 of 
the cycloaliphatic ring, p is a whole number integer 0, 1 or 2, and n is a 
whole number integer 1, 2, or 3, so that the resulting cycloaliphatic ring 
containing them has six (6) carbon atoms; 
m is 3 or 4; 
A is a single chemical bond (--), --(CH.sub.2).sub.q -- where q is a whole 
number integer 1 to 4 or --CH(CH.sub.3)--; 
X and Y are independently selected from the group consisting of hydrogen, a 
halogen having an atomic number of from 9 to 35, trifluoromethyl, nitro, 
methoxy, hydroxy, azido, C.sub.1 to C.sub.3 -alkyl, phenyl, 
methanesulfonyl, cyano, amino, C.sub.1 to C.sub.3 -alkoxycarbonyl, C.sub.1 
to C.sub.3 -alkanoyloxy, C.sub.1 to C.sub.3 -carboxyacylamino 
(--NHC(.dbd.O)R.sub.4 wherein R.sub.4 is hydrogen or C.sub.1 to C.sub.2 
-alkyl); 
R is hydrogen or C.sub.1 to C.sub.3 -alkyl; 
R.sub.1 and R.sub.2, taken separately, are each hydrogen, C.sub.1 to 
C.sub.3 -alkyl or allyl; 
R.sub.1 and R.sub.2, taken together with the nitrogen to which they are 
bonded complete a ring selected from the group consisting of azetidinyl, 
pyrrolidinyl and piperidinyl; 
E is oxygen or sulfur; 
Z is selected fom the group consisting of oxygen (--O--), --NR.sub.3 --, 
bivalent sulfur (--S--), sulfinyl (--S(O)--) and sulfonyl (--S(O).sub.2 
--); 
R.sub.3 is hydrogen, C.sub.1 to C.sub.3 -alkyl, benzoyl, X and Y-ring 
substituted benzoyl 
##STR3## 
C.sub.2 to C.sub.4 -alkanoyl (--C(O)--C.sub.1 to C.sub.3 -alkyl); provided 
that when p is 2, n is 1, m is 3, A is (--CH.sub.2).sub.q -- where q is 1, 
R is methyl, R.sub.1 and R.sub.2 are taken together with the nitrogen to 
which they are bonded to complete a pyrrolidinyl ring, E is oxygen, Z is 
oxygen, and the relative stereochemistry is (5a, 7a, 8b), when X and Y 
taken together on the phenyl ring cannot be chlorine on the 2- and 
4-positions of the phenyl ring. 
Pharmacologically acceptable salts of such Formula I compounds are also 
part of this invention. 
The compound excluded by the above proviso is (5a, 
7a,8b)-2,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl 
]benzeneacetamide, and the pharmacologically acceptable salts thereof. 
Thus, these new compounds contain a mono-oxy-, thia-, or aza-ring structure 
attached to the 4- or 5-position of the cyclohexyl ring and an asymmetric 
carbon atom at such position 4- or 5- which are not found in prior art 
compounds of which we are aware. 
The compounds of Formula I or their acid addition salts in their 
crystalline state may sometimes be isolated from their reaction mixtures 
as solvates, i.e., with a discrete quantity of solvent, e.g., water, ethyl 
acetate, methanol, and the like, associated physically, and thus not 
affecting the chemical entity per se. 
It will be recognized by those in the organic chemical art that the carbon 
atoms at positions 1 and 2 of the cyclohexyl ring of structure (I) to 
which nitrogens are bonded are asymmetrically substituted. Likewise, the 
cyclohexyl ring carbon atom to which the Z-ring is bonded is also 
asymmetrically substituted. Each of these three cyclohexyl carbon atoms 
can independently possess an R or S-configuration and thus a compound of 
the formula (I) may have as many as 2.sup.3 or 8 stereoisomers which 
comprise four pairs of enantiomers; each enantiomeric pair is termed a 
racemate. See, for example, J. B. Henderickson, D. J. Cram, and G. S. 
Hammond, Organic Chemistry, Third Edition, McGraw-Hill Book Company, New 
York, N.Y., 1970, pages 198-230, particularly pages 207, 208, 213, 215. Of 
the four racemates, two will have the nitrogen-containing groups at 
positions 1 and 2 of structure (I) in a trans orientation: that is, the 
groups will be on opposite sides of the plane of the cycloaliphatic ring; 
such compounds will be generally referred to in this specification as 
trans compounds and are meant to include both possible configurations of 
the third substituted ring carbon. The other two racemates will have the 
nitrogen-containing groups at positions 1 and 2 of structure (I) in a cis 
orientation: that is, the groups will be the on the same side of the 
cycloaliphatic ring; such compounds will be generally referred to in this 
specification as cis compounds and are meant to include both possible 
configurations of the third substituted ring carbon atom. The four 
racemates of structure (I) compounds each exist as a mixture of the two 
enantiomers or each enantiomer of each pair can be separated by 
conventional methods. This invention includes within its scope all 
enantiomeric and diastereomeric forms of the formula I compounds either in 
pure form or as mixtures of enantiomers or diastereomers. In General 
Chemical Structure Chart A and Schemes I through IX below, when a 
particular enantiomer or diastereomer or set of enantiomers or 
diastereomers is illustrated, the intent is only to convey relative 
stereochemistry. When it is desired to specify for a formula (I) compound 
the configuration of the other asymmetric centers relative to that of 
position 1, this is done according to the Chemical Abstracts Serive 
publication, "Naming and Indexing of Chemical Substances for Chemical 
Abstracts during the Ninth Collective Period (1972-1976)," a reprint of 
Section IV (Selection of Index Names for Chemical Substances) from the 
Chemical Abstracts Volume 76 Index Guide. Accordingly, the relative 
stereochemistry of three asymmetric carbon atoms in the cycloaliphatic 
ring of formula I compounds is indicated by: (1) the arbitrary designation 
of 1.alpha. for the orientation of the substituent on (asymmetric) carbon 
atom number one; (2) the designation 2.alpha. or 2.beta. when the 
substituent on (asymmetric) carbon atom number two is on the same or 
opposite side of the plane of the cycloaliphatic ring, respectively, 
relative to said C.sub.1 substituent; and (3) the designation x.alpha. or 
x.beta. when the substituent on (asymmetric) carbon atoms number x is on 
the same or opposite side of the plane of the cycloaliphatic ring, 
respectively, relative to said C.sub.1 substituent. 
When the stereochemistry at carbon atom number x is unknown, the 
designation x.xi. (x Xi) is used to denote either a single epimer or a 
mixture of epimers at carbon atom x. 
Two isomers which differ only in the stereochemistry at one asymmetric 
carbon atom of the cycloaliphatic ring are sometimes herein referred to as 
epimers. 
If desired the formula I compounds of this invention can be resolved into 
their respective d- and l-optical isomers by methods known in the art. In 
this case, the optical resolution can be done by at least two different 
routes. The resolving agents by either route are any of the known 
resolving agents such as optically active camphorsulfonic acid, 
bis-o-toluyltartaric acid, tartaric acid, and diacetyl tartaric acid which 
are commercially available and which are commonly used for resolution of 
amines (bases), as for example in Organic Synthesis, Coll. Vol. V., p. 932 
(1973), resolution of R-(+) and S-(-)-.alpha.-phenylethylamine with 
(-)-tartaric acid. 
By the first method for resolving the compounds of this invention, for 
example, one of the aminoamide compounds can be converted into its 
optically active diastereomeric salts by reaction with an optically active 
acid--examples mentioned above--in a manner standard in the isomer 
resolution art. These diastereomeric salts can then be separated by 
conventional means such as differential crystallization. Diastereomeric 
salts have different crystallization properties, which are taken advantage 
of in this separation. On neutralization of each diastereomeric salt with 
aqueous base the corresponding optically active enantiomers of the free 
amino amide can be obtained, each of which can subsequently and separately 
be converted as hereinafter described in the examples to the desired acid 
addition salt. 
By the second method, which in the case of some of these compounds is 
preferred, the formula I compounds can be made into their respective d- 
and l-isomers, by first resolving each cis- or trans-1,2-cycloaliphatic 
unsymmetrically substituted amino-alcohol or diamine into its respective 
d- or l-isomers by treatment with the resolving agent, crystallization, 
separation and regeneration of the respective trans-d-diamine, 
trans-l-diamine, or the cis-d-diamine and cis-l-diamine, and then reacting 
the respective resolved diamine starting material with the desired aracyl 
imidazole (III) or the acyl halide (IV) to form the respective cis or 
trans- d- or l-compound of Formula I, which can then be converted to any 
desired pharmaceutically acceptable acid addition salt by procedures 
exemplified hereinafter. 
In the Formula I compounds, the halogens having atomic numbers of from 9 to 
35 are fluorine, chlorine and bromine, the term "C.sub.1 to C.sub.3 
-alkyl" means methyl, ethyl, n-propyl and isopropyl. 
A most significant subgroup of these Formula I compounds are those of 
formula Ia wherein p is 2, n is 1, m is 3, A is --(CH.sub.2).sub.q -- 
wherein q is 1, X and Y are each hydrogen or a halogen having an atomic 
number of from 9 to 35 in the 3-, 4-, or 2- or 3- and 4-positions, R is 
C.sub.1 to C.sub.3 -alkyl, R.sub.1 and R.sub.2 are taken together with the 
nitrogen to which they are bonded to complete a ring selected from the 
group consisting of azetidinyl, pyrrolidinyl and piperidinyl, E is oxygen, 
and the pharmacologically acceptable salts thereof. Examples of this group 
of compounds include the cis- and trans-isomers of: 
3,4-difluoro-N-methyl-N-[7-(1-azetidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneac 
etamide 
4-bromo-N-ethyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetam 
ide 
3-bromo-N-(n-propyl)-N-[7-(1-piperidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneac 
etamide 
3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzene 
acetamide, and the like, and the pharmacologically acceptable salts 
thereof. 
In preliminary standard laboratory animal tests used to determine various 
properties associated with analgesia, a representative example of these 
new compounds has been shown to have a better analgesic potency than 
2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]acetamide, 
described and claimed in Szmuszkovicz, U.S. Pat. No. 4,145,435, referred 
to as the '435 patent compound herein. The lead compound of this invention 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidi 
nyl)-1-oxaspiro-[4.5]dec-8-yl]benzeneacetamide, referred to as the Example 
1 compound herein has a better oral potency than the above '435 patent 
compound in standard laboratory animal tests. The ratio of sedative to 
analgesic activity of the Example 1 compound is about the same as that of 
the above '435 patent compound. 
Thus, the compound of Example 1 is an analgesic drug compound lead of 
considerable importance. It is 2 to 4 times more potent than morphine by 
the subcutaneous route in standard laboratory animals and has good oral 
route activity. It is a member of this new group of 1,2-diamine derivative 
analgesic series of compounds which lack the typical physical dependence 
liability of morphine-like properties in mice, rats and monkeys. For 
example, chronic intravenous infusion of large doses of the Example 1 
compound produces at most a low level of physical dependence. Because of 
these properties, the Example 1 compound was tested in rats at doses 
ranging from 0.032 to 0.32 mg/kg injection by self-administration methods 
to determine whether the compound caused any reinforcing properties 
compared to known analgesic drugs such as butorphanol, morphine, 
pentazocine and propoxyphene. In contrast to these known opiate compounds 
with agonist properties (which were actively self-administered by the rat 
test animals), the compound of Example 1 was not active at inducing the 
reinforcing side effect at the doses tested. 
Examples of other compounds within the scope of this invention include: 
(a) those wherein Z is --S--, --S(O)--, or --S(O).sub.2, such as: 
3,4-dichloro-N-methyl-N-[7-(1-azetidinyl)-1-thiaspiro[4.5]dec-8-yl]benzenea 
cetamide, 
4-bromo-N-ethyl-N-[7-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-8-yl]benzeneaceta 
mide, 1-oxide, 
3-[3,4-difluoro-N-methyl-N-[8-(1-pyrrolidinyl)-1-thiaspiro-[5.5]undec-9-yl] 
benzene]propionamide, 1,1-dioxide and the like. 
(b) those wherein --Z-- is --NR.sub.3 --, such as: 
4-trifluoromethyl-1,N-dimethyl-N-[7-(1-pyrrolidinyl)-1-azaspiro[4.5]dec-8-y 
l]benzamide, 
4-chloro-3-methoxy-N-ethyl-N-[8-(1-azetidinyl)-1-azaspiro-[5.5]undec-9-yl]b 
enzeneacetamide, 
4-azido-N-methyl-N-[1-acetyl-7-(1-piperidinyl)-1-azaspiro[4.5]dec-8-yl]benz 
eneacetamide, and the like, and the pharmacologically acceptable salts of 
all of such compounds. 
Some further more specifically structurally identified compounds of the 
above type included within this invention include: 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-[7-(1-pyrrolidinyl 
)-1-azaspiro[4.5]dec-8-yl]benzeneacetamide, 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-1,N-dimethyl-N-[7-(1-pyrrol 
idinyl)-1-azaspiro[4.5]dec-8-yl]benzeneacetamide, 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1 
-azaspiro-[4.5]dec-8-yl]benzamide, 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin 
yl)-1-thiaspiro[4.5]dec-8-yl]benzamide, 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin 
yl)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide, 1-oxide, 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin 
yl)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide, 1,1-dioxide, and the 
pharmaceutically acceptable salts thereof. 
In general, the new compounds of formula I can be prepared by reacting the 
selected 1,2-cycloaliphatic diamine of formula II, wherein the wavy line 
bonds, p, n, R, R.sub.1, R.sub.2, Z and m are as defined above with a 
suitable acyl source such as: 
(1) the appropriate aracyl imidazole of formula III wherein q, E, X and Y 
are as defined above; 
(2) an acyl halide of formula IV wherein M is chloride or bromide and q, E, 
X and Y are as defined above, in the presence of an acid scavenger such as 
triethylamine; or 
(3) the carboxylic acid of formula V where q, E, X and Y are as defined 
above, in the presence of a condensing agent, in an organic solvent for 
the reactants, preferably in an ether solvent such as diethyl ether or a 
cyclic ether solvent such as tetrahydrofuran (THF) or dioxane, or the 
like, until the compound of the invention is produced. Carbodiimides such 
as dicyclohexylcarbodiimide or diisopropylcarbodiimide can be used as 
condensing agents. 
The reactants (II) and (III) or (II) and (IV) or (II) and (V) can be mixed 
in substantially equimolar proportions to effect formation of the desired 
product (I), but if one of the reactants (II), (III), (IV) and (V) is more 
expensive than the other, it is sometimes preferred to use a 
stoichiometric excess of the less expensive reactant to insure that 
substantially all of the more expensive reactant is consumed in the 
reactions. The reaction will proceed at ambient temperature for most 
combinations of reactants, but for some combinations of reactants, 
variations from the initial to final reaction conditions may vary between 
-25.degree. C. and reflux temperature of the mixture depending on the 
reactivity of the reactants, the desired reaction time, the solvent being 
used, the molar proportions, and similar factors of concern to the chemist 
operating the process. When the new compound of this invention is to be 
one of formula (I) in which one or both of R.sub.1 and R.sub.2 are to be 
hydrogen, the amino-hydrogens in the R.sub.1 and/or R.sub.2 positions must 
first be protected by procedures known in the art, then the N-protected 
diamine reactant (IIa) wherein the wavy line bonds, R, Z, m, n and p are 
as defined for formula II and each "--H--Q" denotes that if present, an 
amino hydrogen has been protected from reaction, is reacted with the 
selected aracyl imidazole (III) or with the acyl halide (IV) or with the 
carboxylic acid (V) in the presence of a condensing agent to form the 
N-[2-(N-protected-amino)oxa or thia- or aza-group substituted 
cycloaliphatic]benzamide or -phenylacetamide, which is then treated to 
remove the N-protecting group to leave as product the desired 
N-[2-(amino)oxa, thia- or aza-group-substituted-cycloaliphatic]benzamide 
or -phenylacetamide. 
Procedures for preparing the aracyl imidazoles (III) and acyl halide (IV) 
reactants used to form compounds of this invention are known in the art. 
See, for example, R. B. Wagner and H. D. Zook, Synthetic Organic 
Chemistry, 1953, John Wiley and Sons, Chapter 17, p. 546 et seq. The 
aracyl imidazole can be prepared in situ by reacting carbonyldiimidazole 
with the acid of the formula (V) in an organic solvent. Carboxylic acids 
of the formula (V) are known in the art or are prepared by known methods. 
Acid addition salts can be prepared by reacting a Formula I free base with 
a stoichiometric amount of an acid, such as hydrogen chloride, hydrogen 
bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, 
lactic acid, citric acid, succinic acid, benzoic acid, salicylic acid, 
pamoic acid, cyclohexanesulfamic acid, methanesulfonic, 
naphthalenesulfonic, p-toluenesulfonic, maleic, fumaric, oxalic acids and 
the like. The reaction can be carried out in aqueous or organic liquid 
solvent, non-aqueous media such as diethyl ether, ethyl acetate, and the 
like. Non-aqueous media are preferred. Also, whereas oxalic acid and other 
equivalent acids can be used to produce the aminoamide product in a more 
easily handled solid form, e.g., in plant manufacturing isolation 
procedures, it would preferably not be used as a pharmaceutically 
acceptable salt form of the amino-amide product. 
As indicated generally above, the amide bond of the compounds of formula I 
will be formed by the condensation of the selected diamine (II) with a 
carboxylic acid or acid derivative utilizing known methods. Preferred 
methods for this transformation are summarized in the following sets of 
conditions: 
1. Diamine, 
##STR4## 
(where Ar denotes the 
##STR5## 
moiety), tertiary amine or equivalent amine, tetrahydrofuran (THF) or 
diethyl ether (Et.sub.2 O) and 0.degree. to reflux of the mixture. 
2. Diamine, 
##STR6## 
N,N'-carbonyldiimidazole, THF or Et.sub.2 O and 0.degree. to reflux. 
3. Diamine, 
##STR7## 
dicyclohexylcarbodiimide, THF or Et.sub.2 O and 0.degree. to reflux. 
4. Diamine, 
##STR8## 
THF, or Et.sub.2 O and 0.degree. to reflux. 
5. Diamine, 
##STR9## 
tertiary amine, THF or Et.sub.2 O and 0.degree. to reflux. 
These methods require that all acidic hydrogens, which are not bonded to 
the nitrogen atom to be acylated, i.e., the phenolic or amino hydrogens, 
in the starting diamine and acid reactants be protected with a suitable 
protecting group. 
Under certain circumstances it may be necessary to protect two (or more) 
different nitrogens with different protecting goups such that one such 
protecting group can be selectively removed while leaving the second 
protecting group in place. For example, the trityl and benzyl protecting 
groups can be used in this way, the trityl group being removable in the 
presence of the benzyl group under acidic conditions. 
The requirements for protecting groups in Schemes I to IX are generally 
well recognized by one skilled in the art of organic chemical synthesis. 
It is recognized that conditions for introduction and removal of 
protecting groups should not undesirably alter any other groups in the 
molecule. In Schemes I to IX, m is 3 or 4; P is a suitable protecting 
group; r is 1 or 2; R.sub.11 is R, R.sub.1, or a suitable nitrogen 
protecting group; R.sub.12 is R.sub.2 or a suitable protecting group; 
R.sub.13 is R, R.sub.1, or a suitable nitrogen protecting group; R.sub.14 
is R.sub.2 or a suitable nitrogen protecting group; with the proviso that 
when R.sub.11 is R.sub.1, then R.sub.12 is R.sub.2, R.sub.13 is not 
R.sub.1, and R.sub.14 is not R.sub.2 ; when R.sub.13 is R.sub.1, then 
R.sub.14 is R.sub.2, R.sub.11 is not R.sub.1, and R.sub.12 is not R.sub.2 
; when R.sub.12 is R.sub.2, then R.sub.11 is R.sub.1 ; when R.sub.14 is 
R.sub.2, then R.sub.13 is R.sub.1 ; when one of R.sub.11 and R.sub.13 is R 
the other of R.sub.11 and R.sub.13 is not R. In this way R.sub.11, 
R.sub.12, R.sub.13, and R.sub.14 are defined so that Scheme I shows that 
either the ultimate amide nitrogen atom or the ultimate NR.sub.1 R.sub.2 
nitrogen atom can be introduced first (Scheme I, step 10) followed by the 
introduction of the other (Scheme I, step 11). 
Examples of suitable nitrogen protecting groups are: 
(1) benzyl (C.sub.6 H.sub.5 --CH.sub.2 --); 
(2) triphenylmethyl(trityl, C.sub.6 H.sub.5).sub.3 C); 
(3) para-toluenesulfonyl (p--CH.sub.3 --C.sub.6 H.sub.4 --SO.sub.2 --); and 
(4) trialkylsilyl, for example, trimethylsilyl ((CH.sub.3).sub.3 Si--) or 
tertiary butyldimethylsilyl ((CH.sub.3).sub.3 Si(CH.sub.3).sub.2 --) and 
the like. 
(5) tert-butoxycarbonyl (t-BOC), 
(6) benzyloxycarbonyl, 
(7) trifluoroalkanoyl, e.g., trifluoroacetyl, trifluoropropionyl, 
(8) diphenyl(methyl)silyl, 
(9) methanesulfonyl, and the like. 
Introduction and removal of such nitrogen protecting groups are well known 
in the art or organic chemistry: See, for example, 
(1) J. F. W. McOmie, Advances in Organic Chemistry, Vol. 3, pages 191-281 
(1963); 
(2) R. A. Boissonas, Advances in Organic Chemistry, Vol. 3, pages 159-190 
(1963); 
(3) "Protective Groups in Organic Chemistry", J. F. W. McOmie, Ed., Plenum 
Press, New York, 1973, pg 74, and 
(4) Protective Groups in Organic Synthesis, Theodora W. Greene, John Wiley 
and Sons, New York, 1981. 
Syntheses of the requisite material compounds are outlined in Schemes I to 
IX. 
SCHEME I 
In the Scheme I reaction, wherein Z is oxygen, the following comments are 
offered on the respective chemical step reactions. 
1. The reaction between the bromoalkanol and the ethyl vinyl ether is 
conducted in the presence of dichloroacetic acid at about 23.degree. to 
50.degree. C. to form the bromoalkyl ethoxyethyl ether shown at the 
beginning of step 2. 
2. The bromoalkyl ethoxyethyl ether is reacted in step (a) with metallic 
lithium in diethyl ether or THF as solvent at about -20.degree. to 
0.degree. C. Lithium containing about 0.6 to 1% sodium is preferred. In 
step (b) the monoethylene ketal of cyclohexane-1,4-dione is added dropwise 
in diethyl ether or THF to the organolithium solution formed in step (a) 
to form the .beta.-ethoxyethoxyalkyl-1,4-dioxaspiro[4.5]decan-8-ol shown 
at the beginning of step 3. 
3. A mild selective acidic hydrolysis of the acetal-ether is accomplished 
by treatment of the above cyclohexan-1-ol derivative with (a) an acidic 
ion exchange resin (Dowex-50 W-X8) in methanol at about 23.degree. C. for 
one to 6 hours, (b) with an ethanol/water/hydrochloric acid (57.6/38.6/3.8 
v/v) mixture at about 23.degree. C. for 0.25 to 4 hours, to remove the 
ethyl acetal group and form the dihydroxy compound shown at the beginning 
of step 4. 
4. The dihydroxy compound from step 3 is cyclized by treatment with 
methanesulfonyl chloride and two equivalents of triethylamine in methylene 
chloride at about 0.degree. to 41.degree. C. 
5. The cyclized mono-oxy ketal is then subjected to acid hydrolysis (a) 
with 3 to 7% v/v aqueous perchloric acid (HClO.sub.4) in THF at 40.degree. 
to 80.degree. C., or (b) with 1 to 4N aqueous hydrochloric acid in acetone 
at about 23.degree. to 60.degree. C. to convert the ketal ring to the keto 
(--C(O)--) group compound shown at the beginning of step 6. 
6. The ketone product from step 5 is treated (a) with lithium aluminum 
hydride in diethyl ether or THF at about 23.degree. to reflux or (b) with 
sodium borohydride in methanol or ethanol at about 23.degree. to 
80.degree. C., to form the spiro alkanol shown at the beginning of step 7. 
7. The cyclohexanol derivative from step 6 is treated with 
p-toluenesulfonyl chloride in the presence of pyridine at about 31.degree. 
C. to 0.degree. C. for about 18 to 72 hours to form the 
p-toluenesulfonyl-(tosyl) structure shown at the beginning of step 8. 
8. The tosyl group on the structure shown at the beginning of step 8 is 
eliminated by treatment with either (a) 
1,8-diazabicyclo-[5.4.0]undecene-5(DBU) at 80.degree. to 120.degree. C. or 
(b) with 1,5-diazabicyclo-[4.3.0]nonene-5(DBN) at 80.degree. to 
120.degree. C., to form the unsaturated ring compound (olefin) shown at 
the beginning of step 9. 
9. The olefin from step 8 is epoxidized preferably by treatment with 
m-chloroperoxybenzoic acid in methylene dichloride at about -20.degree. to 
23.degree. C. Other solvents such as hexane, carbon tetrachloride, 
benzene, chloroform, ethyl acetate and diethyl ether may be used in place 
of methylene chloride, or in admixture therewith, above their freezing 
points. Other peroxy acids, e.g., peroxyacetic, peroxybenzoic, 
p-nitroperoxybenzoic, monoperoxyphthalic, peroxylauric, 
peroxytrifluoroacetic and peroxyforic acids may be used in place of 
m-chloroperoxybenzoic acid in appropriate solvents therefor. 
Alternatively, the olefin may be epoxidized with vanadyl acetyl acetonate 
[VO(AcAc)HD 2], tert-butyl hydroperoxide in benzene at about 23.degree. 
C., or with molybdenum hexacarbonyl [Mo(CO).sub.6 ], 
tert-butylhydroperoxide in benzene at 23.degree. C. to reflux to form the 
epoxide shown at the beginning of step 10. 
10. The epoxide from step 9 is then opened with a secondary amine by any of 
various procedures to form the hydroxy-amine compound shown at the 
beginning of step 11. 
(a) The epoxide can be treated with the secondary amine, e.g., with an 
HNR.sub.11 R.sub.12 amine with no solvent at about 23.degree. to 
150.degree. C., 
(b) The epoxide can be treated with the secondary amine, HNR.sub.11 
R.sub.12 in water at about 23.degree. to 100.degree. C., 
(c) The epoxide can be treated with the secondary amine, HNR.sub.11 
R.sub.12 in a mixture of N,N-dimethylformamide (DMF), dimethylsulfoxide 
(DMSO) and ethanol at from 23.degree.-reflux temperature of the mixture, 
or 
(d) The epoxide can be opened with the secondary amine, HNR.sub.11 R.sub.12 
on an aluminum oxide carrier, to form the hydroxyamine structure shown at 
the beginning of step 11. 
Depending upon the reaction conditions and the selected reagents, this 
epoxide opening reaction can give rise to up to 4 isomers which may, if 
convenient, be separated at this stage by chromatography or carried 
further in this reaction sequence as a mixture through the next step. 
Depending on the structure of the final target molecule, it may be 
advantageous at this stage to utilize a secondary amine such as 
methyl(benzyl)amine, ethyl(benzyl)amine, propyl(benzyl)amine or 
dibenzylamine. The N-benzyl-protecting group would be removed at a later 
stage in the process. (See step 12 below) 
11. (a) The hydroxy-amine from step 10 is treated with methanesulfonyl 
chloride and triethylamine in methylene chloride at about 0.degree. C. to 
form the intermediate methanesulfonate (mesylate) bicyclic amine, 
(b) The crude amine-mesylate from step 11(a) is treated with ammonia, a 
primary amine (HNR.sub.13 R.sub.14) or secondary amine (HNR.sub.13 
R.sub.14). The treatment can be conducted (11b1) using the selected 
nitrogen compound (ammonia, primary or secondary amine), no solvent at 
from about 23.degree. C. to reflux temperature or in a sealed reaction 
bomb up to about 150.degree. C., or (11b2) using the amine, as above, in 
water at about 23.degree. C. to reflux temperature. 
If isomerically pure amino-alcohols are used in Step 11 as starting 
materials, two regioisomeric diamine products are possible. If a mixture 
of amino-alcohols is used a total of four isomeric diamine products are 
possible. Chromatographic separation of the diamine isomers may be 
performed at this stage. 
12. Amine protection and deprotection. 
A suitable diamine precursor (II and IIa) for the final acylation must have 
only one of the two amino nitrogens from step 11 bearing a 
nitrogen-hydrogen bond. Depending upon the desired structure of the final 
target molecule (Ia) several situations may be considered at this point. 
(a) One of the amino substituents R.sub.11, R.sub.12, R.sub.13, R.sub.14 
(Step 12) is a benzyl group while the remaining three are non-removable 
R.sub.1 and R.sub.2 defined groups. 
1. Catalytic hydrogenolysis of the diamine using 10% palladium on carbon as 
catalyst in ethanol or methanol as a solvent with or without an acidic 
catalyst, e.g., perchloric acid or hydrochloric acid. 
2. Subjecting the benzyl-substituted diamine to dissolving metal reduction 
using lithium metal in liquid ammonia. 
(b) The diamine nitrogen to be acylated can bear an N-alkyl and N-benzyl 
group or two N-benzyl groups and the other amino nitrogen bears one or two 
hydrogens; 
1. The primary or secondary amine must first be protected before acylation. 
Suitable protecting groups are (a) tertbutoxycarbonyl (BOC), (b) 
benzyloxycarbonyl, or (c) trifluoroacetyl. 
2. The N-benzyl group is cleaved as in step 12a, supra. 
(c) The diamine (protected or non-protected as necessary) is acylated, as 
described above, and 
(d) The amino nitrogen protecting groups are removed, by known procedures, 
which do not undesirably alter the other parts of the molecule. 
For preparing compounds according to Scheme II, wherein Z is NR.sub.3 --, 
and R.sub.3 is shown as an N-benzoyl group, as an example, it should be 
noted that the starting cyclic cyclohexanol derivative where r is 1 is 
known. See. R. A. Johnson, et a., J. Org. Chem. 35, 622 (1970). For 
compounds were r is 2, the starting materials would be prepared as 
outlined in Scheme III. 
SCHEME II 
1. In Scheme II, Step 1, the hydroxy group of the starting material is 
protected by (a) treatment with dihydropyran (P) in the presence of an 
acid, e.g., p-toluenesulfonic acid or hydrochloric acid, or by treatment 
with tert-butyl(dimethyl)silyl chloride or diphenyl(methyl)-silyl chloride 
in the presence of imidazole and DMF, or the like. 
2. Protected alcohol compound manipulation. Several possibilities exist: 
A. If R.sub.3 is not hydrogen: 
1. The protected alcohol can be subjected to metal hydride reduction on the 
N-benzoyl group to convert it to the N-benzyl 
(a) by treatment with lithium aluminum hydride in diethyl ether or THF at 
about 0.degree. to reflux. 
(b) by treatment with diborane (B.sub.2 H.sub.6) in diethyl ether or THF at 
0.degree. to reflux, or 
(c) by treatment with sodium dihydrobis(methoxyethoxy)aluminate in diethyl 
ether or THF at about 0.degree. to reflux. 
2. The resultant N-benzyl group can be subjected to reductive cleavage to 
form the N-H ring protected alcohol by catalytic hydrogenolysis using 10% 
palladium on carbon as a catalyst in ethanol or methanol with or without 
an acid catalyst, e.g., acetic acid, perchloric acid, or the like, 
3. If it is desired to form one or the other --NR.sub.3 -- ring compounds, 
the N-H protected alcohol can be N-alkylated or N-acylated: 
(a) by treatment with a methyl, ethyl or propyl chloride or bromide to form 
the respective N-C.sub.1 to C.sub.3 -alkyl ring protected alcohol, in the 
presence of a base such as sodium hydride, potassium hydride or 
butyllithium in DMF, THF, or DMSO, 
(b) by reductive alkylation using formaldehyde, acetaldehyde or 
propionaldehyde in methanol in the presence of excess sodium 
cyanoborohydride, or 
(c) by an N-acylation procedure using procedures outlined hereinabove. 
B. If R.sub.3 is hydrogen: 
1. Following reduction and cleavage steps 1 and 2 in Scheme II, Section 2A, 
hereinabove, 
2. Protect the resultant secondary amine nitrogen using, for example, 
(a) methanesulfonyl chloride, or 
(b) benzyloxycarbonyl chloride. 
3. Deprotect the ring hydroxyl group (remove the P group) with acid, e.g., 
with hydrochloric acid or p-toluenesulfonic acid, or with 
tetra(n-butyl)ammonium fluoride, and then 
4. Proceed with the tosylation, elimination, epoxidation, epoxide opening, 
mesylate formation, diamine formation and amine protection and acylation 
steps as set forth in Scheme I, steps 7 to 12, hereinabove. 
SCHEME III 
Scheme III outlines a procedure for making a 1-azaspiro[5.5]-undecan-9-ol. 
1. The 1-azaspiro[5.5]undecane starting material can be prepared by the 
method described by H. Hodjat, et al., in J. Heterocyclic Chem., 9, 1081 
(1972). This starting material is treated with benzoyl chloride in 
pyridine to form the N-benzoyl-1-azaspiro-[5.5]undecane, shown at the 
beginning of step 2. 
2. The N-benzoyl compound from step 1 is subjected to hydroxylation by the 
microorganism, Sporotrichium sulfurescens V. Begma (ATCC 7159) by a 
microbiological oxidation procedure carried out as described by R. A. 
Johnson, et al., in J. Org. Chem., 35, 622 (1970). 
SCHEME IV 
The procedure of Scheme IV can be used to prepare compounds where Z is to 
be bivalent sulfur (--S--), sulfinyl (--S(O)--) or sulfonyl (--S(O).sub.2 
--). 
1. The bromoalkylthio starting material is protected (P) by either (a) 
treatment with dihydropyran and acid, e.g., p-toluenesulfonic acid or 
hydrochloric acid, or (b) ethyl vinyl ether and acid, e.g., dichloroacetic 
acid, to give the protected bromoalkylthiol at the beginning of step 2. 
2. The protected bromoalkylthiol is then 
(a) metalated by either: 
1. Treatment with lithium metal in diethyl ether or THF at about 
-20.degree. to 0.degree. C. (Lithium wire containing 0.6% to 1% sodium is 
preferred), or 
2. Treatment with metallic magnesium in diethyl ether or THF as solvent at 
about -20.degree. C. to reflux and then 
(b) the organometallic protected thiol is treated by the dropwise addition 
thereto of the monoethylene ketal of cyclohexane-1,4-dione in diethyl 
ether or THF at about 0.degree. to reflux to form the ketal addition 
product shown at the beginning of step 3. 
3. The ketal addition product from step 2 is treated, e.g., with acid to 
effect an acid catalyzed cleavage of the ketal or acetal and deprotection 
of the sulfur, accompanied by the dehydrative spirocyclization to form the 
thio-ring-cyclohexanone shown at the beginning of step 4, e.g., by: 
(a) treatment with p-toluenesulfonic acid in a solvent such as THF, 
acetone, methanol, ethanol, or water at 0.degree. to 100.degree. C., or 
(b) by treatment with hydrochloric acid in THF, acetone, methanol or 
ethanol or water at about 0.degree. to 100.degree. C., or 
(c) by use of other mineral acids in place of those indicated above. 
4. The ketone product from step 3 is reduced to the alcohol by either: 
(a) treatment with lithium aluminum hydride in diethyl ether or THF at 
about 23.degree. to reflux, or 
(b) treatment with sodium borohydride in methanol or ethanol at 23.degree. 
to 80.degree. C. 
5. The alcohol from step 4 is tosylated by treatment with p-toluenesulfonyl 
chloride in pyridine at about 0.degree. to 20.degree. C. 
6. The tosylated product from step 5 is treated to eliminate the tosyl 
group, e.g., 
(a) by treatment with 1,8-diazabicyclo[5.4.0]undecene-5(DBU) at about 
80.degree. to 120.degree. C., or 
(b) by treatment with 1,5-diazabicyclo[4.3.0]nonene-5(DBN) at about 
80.degree. to 120.degree. C. to form the cyclic olefin shown at the 
beginning of step 7. 
7. In the cyclic olefin from step 6 the ring sulfur is oxidized to the 
corresponding sulfoxide or sulfone, if desired, and the double bond is 
epoxidized by: 
(a) treatment of the cyclic olefin with m-chloroperoxybenzoic acid (or 
other peracid, as indicated above) in methylene chloride at about 
-20.degree. to 23.degree. C. Other solvents such as hexane, carbon 
tetrachloride, benzene, chloroform, ethyl acetate, and diethyl ether may 
be used at temperatures above their freezing points. Other peroxy acids, 
e.g., peroxyacetic, peroxybenzoic, p-nitroperoxybenzoic, 
monoperoxyphthalic, peroxylauric, peroxytrifluoroacetic in appropriate 
solvents therefor can be used. 
(b) treatment with aqueous sodium metaperiodate followed by 
meta-chloroperoxybenzoic acid treatment as in part (a) above. 
8. The synthesis of the target compounds Ia where Z is --S--, --S(O)-- or 
--S(O).sub.2 -- can be completed by following the epoxide opening, 
mesylation, diamine formation and amine protection and acylation 
procedures of steps 10 to 12 of Scheme I. The oxidation state of sulfur 
(thioether, sulfoxide, or sulfone) can be adjusted by known methods just 
prior to final acylation. See "Organic Chemistry of Sulfur" by S. Oae 
Plenum Press, N.Y. and London (1977). 
SCHEME V 
1. Procedures according to Scheme V are preferred to prepare intermediates 
to compounds of this invention wherein Z is NR.sub.3. In Scheme V, Step 1, 
the benzene ring of the starting amine is converted to the non-conjugated 
diene by reduction with sodium or lithium in refluxing liquid ammonia in 
the presence of ethanol and an ether cosolvent. 
2. The diene-amine is converted to the sulfonamide by treatment with 
methanesulfonyl chloride in the presence of triethylamine at 0.degree. to 
23.degree. C. in methylene chloride. 
3. The sulfonamide is cyclized by treatment with an acid in a suitable 
solvent, e.g., (a) treatment with trifluoromethanesulfonic acid in 
benzene, diethyl ether, or methylene chloride at 0.degree. to 23.degree. 
C. 
It may be advantageous to remove the methanesulfonyl group at this stage of 
the synthesis (see step 4 immediately below) or it may be beneficial to 
retain the methanesulfonyl group as a nitrogen protecting group and 
proceed with epoxidation, epoxide opening, mesylate formation, and diamine 
formation as in Scheme I, steps 9-11. At this point the methanesulfonyl 
group of the sulfonamido-diamine with any diamine N-H bonds suitably 
protected, is removed (see step 4 immediately below) and if necessary the 
resulting N-H bond is suitably protected, e.g., with a 
tert-butyloxycarbonyl group. The diamine nitrogen to be acylated is then 
deprotected, e.g., by hydrogenation over a palladium on carbon catalyst in 
ethanol if the benzyl protecting group was utilized, followed by acylation 
as described above. If R.sub.3 is to be other than hydrogen, R.sub.3 is 
introduced at this point by N-alkylation or N-acylation as described 
hereinabove for Scheme II. Finally any necessary nitrogen deprotection is 
effected to produce a 1-azaspiro-amino-amide of this invention. 
4. Removal of the methanesulfonyl group in either case recited in step 3 
immediately above is accomplished by reaction with sodium 
dihydrobis(2-methoxyethoxy)aluminate in benzene, toluene, or xylene 
solvent at 23.degree. to reflux. 
The process of Scheme VI is a preferred method for making certain 
1-thiaspiro-olefin intermediates, and the steps are described as follows. 
SCHEME VI 
1. Reduction to the unconjugated diene using lithium or sodium metal in 
liquid ammonia in the presence of ethanol with or without an ether 
(diethyl ether or THF) cosolvent at -78.degree. to reflux. 
2. Spirocyclization by heating with an acid catalyst such as hydrochloric, 
p-toluenesulfonic or trifluoromethanesulfonic acid or the like, with or 
without a solvent such as DMF, THF, N,N-dimethylsulfoxide (DMSO), or 
benzene. 
SCHEME VII 
The process of Scheme VII is used to prepare 1-oxaspiro-olefin 
intermediates to make compounds of this invention wherein Z=0, p is zero, 
and n=3, and the steps are described as follows. 
1a. The protected bromoalkanol is metalated 
(a) lithium wire at -20.degree. to 23.degree. C. in diethyl ether (Et.sub.2 
O) or THF, or 
(b) with tertiary butyllithium at -78.degree. in Et.sub.2 O or THF. 
1b. To the lithium reagent prepared in step 1a is added 2-cyclohexene-1-ol 
in Et.sub.2 O or THF at -78.degree. to reflux. 
2. The acetal protecting group is removed by mild acid hydrolysis with: 
(a) an ion exchange resin (Dowex-50-WX8) in methanol at about 23.degree. 
C., or 
(b) with ethanol/water/hydrochloric acid (57.6/38.6/3.8, v/v/v) at about 
23.degree. C. 
3. Spirocyclization using an acid catalyst such as p-toluene-sulfonic, 
hydrochloric or trifluoromethanesulfonic acid, etc., without solvent at 
23.degree. to 120.degree. or with solvent such as DMF, THF, benzene or 
DMSO at 23.degree. to reflux. 
SCHEME VIII 
The process of Scheme VIII is used to prepare 1-azaspiro-olefin 
intermediates to make compounds of this invention wherein Z=NR.sub.3, p is 
zero, and n=3, and the steps are described as follows. 
1a. The protected bromoalkanol is metalated 
(a) lithium wire at -20.degree. to 23.degree. C. in diethyl ether (Et.sub.2 
O) or THF, or 
(b) with tertiary butyllithium at -78.degree. in Et.sub.2 O or THF. 
1b. To the lithium reagent prepared in step 1a is added 2-cyclohexene-1-ol 
in Et.sub.2 O or THF at -78.degree. to reflux. 
2. Acid catalyzed azaspirocyclization using acids such as 
p-toluenesulfonic, hydrobromic or trifluoromethanesulfonic acid, etc., 
with or without a solvent such as methanol, ethanol, THF, or benzene. 
3. Reductive cleavage of methanesulfonyl at the desired stage as in steps 3 
and 4, Scheme V. 
SCHEME IX 
The process of Scheme IX is used to prepare 1-thiaspiro-olefin 
intermediates to make compounds of this invention wherein Z=S, SO, or 
SO.sub.2, p is zero, and n=3, and the steps are described as follows. 
1a. The protected bromoalkanol is metalated 
(a) lithium wire at -20.degree. to 23.degree. C. in diethyl ether (Et.sub.2 
O) or THF, or 
(b) with tertiary butyllithium at -78.degree. in Et.sub.2 O or THF. 
1b. To the lithium reagent prepared in step 1a is added 2-cyclohexene-1-ol 
in Et.sub.2 O or THF at -78.degree. to reflux. 
2. The protecting group is cleaved by: 
(a) stirring in methanol solution in the presence of an acidic resin such 
as Dowex-50-WX8 resin or other acid catalyst such as hydrochloric, 
p-toluenesulfonic or hydrobromic in acetic acid, methanol or ethanol, or 
(b) treating with boron trifluoride etherate in acetic acid. 
3. Spirothiacyclization using acids such as p-toluenesulfonic, 
hydrochloric, trifluoromethanesulfonic with or without solvents such as 
methanol, ethanol, THF or DMF. 
The cyclized olefins produced by the processes of Charts V to IX are 
further reacted by epoxidation, epoxide opening, mesylate formation, 
diamine formation and amine protection and acylation steps as set forth in 
Scheme I, steps 9-12 and Scheme IV, steps 7 and 8, hereinabove. 
The compounds having the nitrogen containing groups at positions 1 and 2 of 
structure (I) in a cis orientation are prepared by using (1) methodology 
herein described to construct the Z-containing ring, (2) methodology 
described in the Ser. No. 06/252,535 and Ser. No. 06/252,536 applications 
described hereinabove to construct the cis diamine orientation, and (3) 
methodology described herein for the acylation of the cis diamines. The 
cis-compounds are included within the general structure I, wherein the m, 
n, p, A, E, R, R.sub.1, R.sub.2, X, Y and Z are as defined hereinabove. 
The compounds of formula I wherein E is to be bivalent sulfur are made by 
methodology disclosed in applications Ser. Nos. 06/252,535 and 06/256,536, 
referred to hereinabove. 
The term "dosage unit form" as used in this specification and in the claims 
refers to physically discrete units suitable as unitary dosages for 
mammalian subjects, each unit containing as the essential active 
ingredient a predetermined quantity of a compound of this invention with 
the required pharmaceutical means which adapt said ingredient for systemic 
administration. The specification for the novel dosage unit forms of this 
invention are dictated by and directly dependent on the physical 
characteristics of the essential active ingredient and the particular 
effect to be achieved in view of the limitations inherent in the art of 
compounding such an essential active material for beneficial effects in 
humans and animals as disclosed in detail in this specification under 
preferred embodiments, those being features of the present invention. 
Examples of suitable dosage unit forms in accordance with this invention 
are tablets, capsules, orally administered liquid preparations in suitable 
liquid vehicles, sterile preparations in suitable liquid vehicles for 
intramuscular and intravenous administration, suppositories, and sterile 
dry preparations for the extemporaneous preparation of sterile injectable 
preparations in a suitable liquid vehicle. Suitable solid diluents or 
carriers for the solid oral pharmaceutical dosage unit forms are selected 
from the group consisting of lipids, carbohydrates, proteins and mineral 
solids, for example, starch, sucrose, lactose, kaolin, dicalcium 
phosphate, gelatin, acacia, corn syrup, corn starch, talc and the like. 
Capsules, both hard and soft, are filled with compositions of these 
amino-amide active ingredients in combination with suitable diluents and 
excipients, for example, edible oils, talc, calcium carbonate and the like 
and also calcium stearate. Liquid preparations for oral administration are 
prepared in water or aqueous vehicles which advantageously contain 
suspending agents, for example, methylcellulose, acacia, 
polyvinylpyrrolidone, polyvinyl alcohol and the like. In the case of 
injectable forms, the injectable formulation must sterile and must be 
fluid to the extent that easy syringeabil-ity exists. Such preparations 
must be stable under the conditions of manufacture and storage, and 
ordinarily contain in addition to the principal solvent or suspending 
liquid, preservatives in the nature of bacteriostatic and fungistatic 
agents, for example, parabens, chlorobutanol, benzyl alcohol, phenol, 
thimerosal, and the like. In many cases, it is preferable to include 
osmotically active agents, for example, sugars or sodium chloride in 
isotonic concentrations. Carriers and vehicles include vegetable oils, 
ethanol, polyols, for example, glycerol, propylene glycol, liquid 
polyethylene glycol, and the like. Any solid preparations for subsequent 
extemporaneous preparation of sterile injectable preparations are 
sterilized, preferably by exposure to a sterilizing gas, for example, 
ethylene oxide. The aforesaid carriers, vehicles, diluents, excipients, 
preservative, isotonic agents and the like constitute the pharmaceutical 
means which adapt the preparations for systemic administration. 
The pharmaceutical dosage unit forms of the compounds of this invention are 
prepared in accordance with the preceding general description to provdie 
from about 0.5 to about 350 mg of the essential active ingredient per 
dosage unit form, which as aforesaid may be in the form of a semi-solid or 
solid, topical, oral or rectal preparation, a liquid oral preparation, an 
injectable preparation including liquid preparations and solid dry 
preparations for extemporaneous reconstitution to a liquid injectable 
preparation. The amount of the essential active ingredient provided in the 
pharmaceutical dosage unit forms is that amount sufficient to obtain 
analgesic effects within the aforesaid effective non-toxic range. 
Expressed otherwise, when used systemically, an amount of the essential 
active ingredient is provided to a recipient within a range from about 
0.01 mg/kg to about 5 mg/kg of body weight of the recipient. 
Preferred dosages for most applications are 0.05 to 2.0 mg/kg of body 
weight. In a topical semi-solid ointment formulation the concentration of 
the active ingredient may be 0.2-10%, preferably 0.5-5% in a carrier, such 
as a pharmaceutical cream base. 
The useful pharmaceutical dosage unit forms of these compounds in 
pharmaceutical formulations are preferably adapted for systemic 
administration to obtain analgesic effects comprising an effective, 
nontoxic amount of a compound according to Formula I or as its 
pharmacologically acceptable salt. 
Further, the invention relates to methods of obtaining analgesic effects in 
mammals, for example, humans and valuable warm-blooded animals such as 
dogs, cats, horses and other commercially valuable animals, by 
administering systemically to the mammals the aforesaid pharmaceutical 
dosage unit forms supplying an effective, non-toxic amount for analgesic 
effets. These preferred compounds have an advantage, to a greater extent, 
depending upon the particular compound, of having lower physical 
dependence liability than known analgesic compounds such as morphine and 
methadone, as shown by evaluation of representative compounds and those 
standard analgesic drug compounds in various pharmacological test 
procedures which measure analgesia and the physical dependence liability 
of the test compounds in standard laboratory test animals. 
Representative examples of these Formula I compounds have ED.sub.50 values 
of less than about 75 mg/kg s.c. (subcutaneous administration) in standard 
laboratory animal analgesic tests such as the tail flick, pinch, and 
hydrochloric acid or air writhing tests, and the more potent of them have 
ED.sub.50 values of less than 10 mg/kg (s.c.) in these tests, while at the 
same time giving quite high values (greater than 250 mg/kg s.c.) in the 
naloxone jumping test thus possessing low apparent physical dependence 
liability as compared to commercial analgesics used as standards. The 
procedures used to determine these properties of these new compounds were 
essentially those of Way et al., (Way, E. L. et al., "Simultaneous 
Quantitative Assessment of Morphine Tolerance and Physical Dependence", J. 
Pharmacol. Exp. Ther., 167, pp. 1-8 (1969)) and Saelens et al., (Saelens, 
J. K. et al., The Mouse Jumping Test--A Simple Screening Method to 
Estimate the Physical Dependence Capacity of Analgesics", Arch. Int. 
Pharmacodyn., 190, pp. 213-218 (1971)). Statistical effective doses 
(ED.sub.50 values) and 95% confidence limits were calculated by the method 
of Spearman and Karber (Finney, D. J., "Statistical Methods in Biological 
Assay", Hafner Publ. (1952)). 
For example, representative preferred compounds of Formula I give low 
analgesic ED.sub.50 values (less than about 10 mg of test compound/kg of 
animal body weight, subcutaneous administration route) in standard 
laboratory animal tests while at the same time possessing quite high 
ED.sub.50 values (greater than 250 mg/kg s.c.) in the naxolone jumping 
test, evidencing substantial freedom from apparent physical dependence 
liability. In contrast, known analgesic drugs such as morphine and 
methadone exhibit analgesic ED.sub.50 values of les than 2 mg/kg s.c., 
respectively, in these standard analgesic tail flick, pinch and writhing 
tests, but are known to have high apparent physical dependence liability 
effects, and this is confirmed by their (morphine and methodone) having 
relatively low naloxone jumping ED.sub.50 values ranging form 12 to 30 
mg/kg s.c. Other representative compounds of this invention have analgesic 
potencies somewhat less than the preferred compounds (analgesic activity 
ED.sub.50 values up to about 75 mg/kg s.c., in these standard tests), and 
some such compounds still are characterized by having only low to moderate 
apparent physical dependence liability. 
This invention is further exemplified by the following detailed examples, 
the procedures of which can be used to prepare compounds of this 
invention, but these examples are not intended to limit the scope of the 
invention. All temperatures are in degrees centigrades unless otherwise 
noted. For brevity, Hg means mercury, bp means boiling point, CH.sub.2 
Cl.sub.2 means methylene chloride solvent, K.sub.2 CO.sub.3, MgSO.sub.4 or 
Na.sub.2 SO.sub.4 means the organic layer was dried over anhydrous forms 
of these salts, mp means melting point, NMR means a nuclear magnetic 
resonance spectrum, and DBN means 1,5-diazobicyclo[4.3.0]non-5-ene; h 
means hour(s), N.sub.2 means nitrogen, tlc means thin layer chromatography 
procedures, Na.sub.2 SO.sub.3 means sodium sulfite, NaHCO.sub.3 means 
sodium bicarbonate, DMSO is dimethylsulfoxide, Skellysolve B (or Skelly B) 
is a tradename for a solvent of esentially n-hexane, bp 
60.degree.-68.degree. C. (Merck Index, Ninth Edition (1976) page 1106), 
Et.sub.2 O means diethyl ether, MeOH means methanol, THF means 
tetrahydrofuran, H.sub.2 O means water, CHCl.sub.3 means chloroform, brine 
is saturated aqueous sodium chloride solution, DMF means 
N,N-dimethylformamide, Et.sub.3 N is triethylamine, HRMS means high 
resolution mass spectrum, EtOAc means ethyl acetate, GC (or g.c.) means 
gas chromatography, GLPC means gas liquid phase chromatography.

EXAMPLE 1 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin 
yl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide 
Step A. 8-[3-(1-ethoxyethoxy)propyl]-1,4-dioxaspiro[4.5]decan-8-ol 
To an oven-dried two liter three-necked round bottom flask equipped with an 
addition funnel, low temperature thermometer, magnetic stir bar, positive 
nitrogen pressure inlet and a serum cup, there was placed 12.03 g (1.79 g 
atoms) of lithium [1/8 inch lithium wire containing 0.6% sodium--Lithium 
Corporation of America--cut into approximately 1 inch pieces under a flow 
of nitrogen] in one liter of dry diethyl ether. (Fresh cans of anhydrous 
ethyl ether were used without further drying). Then 161 g (0.76 mol) of 
ethyl 3-bromopropyl acetaldehyde acetal (J. Org. Chem, 37, 1947 (1972), P. 
E. Eaton, et al.) was added as follows. An approximately 25 ml portion of 
the bromide (neat) was added and the temperature of the reaction mixture 
was monitored. When the temperature reached 28.degree. C. the reaction 
flask was immersed in a dry ice/carbon tetrachloride cooling bath (about 
-20.degree. C.) and the rate of addition of the remaining bromide reactant 
was controlled to maintain a reaction temperature of about -5.degree. to 
0.degree. C. After the addition of the bromide was completed the reaction 
mixture was stirred at about -20.degree. C. for one hour and then 
transferred via a canula (syringe and needle) to an oven dried 
three-necked three liter round bottom flask equipped with an addition 
funnel, a magnetic stir bar, a positive nitrogen inlet and cooled 
externally by an ice-water bath, to obtain and maintain the 
ethoxyethoxypropyl lithium intermediate. 
To the above lithiated intermediate there was added dropwise a solution of 
85.8 g (0.55 mol) of 8-oxo-1,4-dioxaspiro[4.5]decane in one liter of dry 
diethyl ether (fresh cans, as above) over a period of about 2.5 hr. The 
resulting reaction mixture was allowed to warm slowly to room temperature 
and then poured into two liters of ice cold half saturated ammonium 
chloride in water solution. The phases were separated and the aqueous 
phase was extracted with one liter of diethyl ether. The ether layers were 
combined and washed with brine solution, dried over sodium sulfate, and 
then the ether solvent was removed under reduced pressure to leave, after 
drying to 45.degree. C. (0.25 mm.Hg) for 14 hours, 142.15 g of a light 
yellow oil, the above named decan-8-ol acetal intermediate, which was of 
sufficient purity to use in the next step. A small sample of the named oil 
was distilled at reduced pressure to obtain a purer material bp 
135.degree.-140.degree. C. (0.01 mmHg). The nuclear magnetic resonance 
spectrum (using CDCl.sub.3 solvent), was consistent with the above named 
decan-8-ol acetal compound. 
Step B. 1,4,9-Trioxadispiro[4.2.4.2]tetradecane 
To a solution of 142 g (0.52 mol) of the crude decan-8-ol acetal from Step 
A in one liter of methanol there was added 50 g of an acid resin 
(Dowex.RTM. 50W-X8 (200-400 mesh) and the mixture was stirred at room 
temperature for 2.5 hr. The reaction mixture was filtered through a filter 
aid pad (Celite) and the filtrate was evaporated to leave, after drying at 
55.degree. C. (0.25 mmHg) for 16 hr, 108.1 g (96% yield) of a crude diol 
intermediate which was of sufficient purity for the next transformation. 
The NMR was consistent with the expected intermediate product. 
To a solution of 108 g (0.5 mol) of the above crude diol mixed with 116.3 g 
(1.15 mol) of triethylamine in 2 liters of methylene chloride, cooled to 
0.degree. C. in an ice bath there was added dropwise over 2 hr a solution 
of 65.8 g (0.575 mol) of methanesulfonyl chloride in 500 ml of ethylene 
chloride. After the addition was completed the reaction mixture was 
stirred for 16 hr (ice not replenished) and then washed once with water, 
dried over magnesium sulfate and the solvent was removed in vacuo. 
The crude product residue was distilled at reduced pressure to give 77.6 g 
(78% yield) of a water white liquid which crystallized upon standing at 
room temperature, bp 84.degree.-87.degree. C. (0.7 mmHg), mp 
48.degree.-50.degree. C. The NMR was consistent with the above named 
tetradecane ketal compound. 
Step C. 1-Oxaspiro[4.5]decan-8-one 
To a solution of 75.5 g (0.38 mol) of the ketal tetradecane from Step B 
above in 400 ml of tetrahydrofuran (THF) there was added 300 ml of 5% 
aqueous perchloric acid and the mixture was heated to 70.degree. C. for 18 
hr. The resulting reaction mixture was cooled to room temperature and this 
distributed between 1.5 liters of saturated aqueous sodium bicarbonate 
solution and one liter of diethyl ether. The liquid phases were separated 
and the aqueous phase was extracted once with diethyl ether. The ether 
phases were combined, washed with brine solution, dried over magnesium 
sulfate and the solvent was removed in vacuo to leave as residue 53.9 g 
(92% yield) of a colorless liquid, which gas chromatography (GC) showed to 
contain 9% of the starting ketal. The NMR was consistent with the named 
decan-8-one compound, but showed the ketal impurity shoulder at 3.93 ppm. 
This named crude ketone/ketal was used for further transformation without 
additional purification. 
An aliquot of this crude ketone/ketal was distilled at reduced pressure, bp 
77.degree.-84.degree. C./0.8 mmHg. 
Step D. 1-Oxaspiro[4.5]decan-8-ol, 4-methylbenzenesulfonate 
To a suspension of 4.7 g (0.116 mol) of lithium aluminum hydride in 600 ml 
of dry diethyl ether there was added dropwise at a rate to maintain gentle 
reflux a solution of 53.9 g (0.35 mol) of 1-oxaspiro[4.5]decan-8-one, from 
Step C above, in 225 ml of dry ethyl ether. After the addition was 
completed the resulting reaction mixture was stirred at room temperature 
for 0.5 hr and quenched by dropwise addition of 10 ml of ethyl acetate, 
followed in succession by 4.7 ml of water, 4.7 ml of 15% aqueous sodium 
hydroxide and 14.1 ml of water. The resultant mixture was filtered, the 
filter cake was washed with diethyl ether and the solvent was removed in 
vacuo leaving 52.3 g of a light yellow liquid (of reduced ketone; crude 
alcohol) which was used without further purification. The NMR was 
consistent with the reduced ketone structure. 
To a solution of 51.3 g (0.32 mol) of the crude alcohol reduction product 
from above in 700 ml of dry pyridine cooled to -17.degree. C. there was 
added a solution of 69 g (0.36 mol) of p-toluenesulfonyl chloride in 400 
ml of dry pyridine (solution cooled to 0.degree. C.), and the resultant 
mixture was stored at -17.degree. C. for 110 hr. The bulk of the pyridine 
was removed in vacuo and the residue was distributed between ethyl ether 
and water. The aqueous phase was extracted twice with ethyl ether, the 
combined ethyl ether liquid phases were extracted twice with ice cold 5% 
aqueous hydrochloric acid, once with saturated aqueous sodium bicarbonate, 
dried over magnesium sulfate and the solvent was removed in vacuo leaving 
79 g (80% yield) of the titled 4-methylbenzenesulfonate as a white solid. 
A small sample of the above sulfonate solid was recrystallized twice from 
diethyl ether; mp 82.degree.-84.degree. C. The NMR of the solid was 
consistent with the title named 4-methylbenzenesulfonate compound. 
Anal. Calcd. for C.sub.16 H.sub.22 O.sub.4 S: C, 61.91; H, 7.14; S, 10.33 
Found %: C, 61.64; H, 7.35; S, 10.24. 
Step E. 1-Oxaspiro[4.5]dec-7-ene 
A mixture of 79.0 g (0.27 mol) of 1-oxaspiro[4.5]decan-8-ol, 4-methyl 
benzenesulfonate (tosylate) from Step D above, and 50 g (0.33 mol) of 
1,8-diazabicyclo[5.4.0]undecene-5(DBU) was heated at 100.degree. C. for 8 
hr. The resulting reaction mixture was cooled to room temperature and 
distributed between 600 ml of water and 200 ml of diethyl ether. The 
liquid phases were separated, the aqueous phase was extracted twice with 
200 ml portions of ethyl ether, the ethereal phases were combined, washed 
twice with 10% aqueous hydrochloric acid, once with saturated aqueous 
sodium bicarbonate, once with brine solution, dried over sodium sulfate 
and the solvent was removed on a steam bath at atmospheric pressure 
through a 12 in. Vigreux column. 
The crude product thus obtained was distilled at reduced pressure to give 
23.8 g (64% yield) of the sub-titled dec-7-ene compound: bp 
62.degree.-63.degree. C. (3.25 mmHg). The NMR was consistent with the 
sub-titled compound. 
Anal. Calcd for C.sub.9 H.sub.14 O: C, 78.21; H, 10.21 Found, %: C, 77.80; 
H, 10.21. 
Step F. 
(.+-.)-(1'.alpha.,3'.beta.,6'.alpha.)-dihydrospiro[furan-2(3H),3'-[7]-oxab 
icyclo-[4.1.0]heptane-(Isomer B, cis), and 
(.+-.)-(1'.alpha.,3'.alpha.,6'.alpha.)-dihydrospiro[furan-2(3H),3'-[7]oxab 
icyclo[4.1.0]heptane-(Isomer A, trans) 
To a solution of 20.0 g (0.145 mol) of 1-oxaspiro[4.5]dec-7-ene in 200 ml 
of dichloromethane there was added dropwise over a period of about 2.5 hr 
a solution of 32.3 g (about 0.16 mol) of m-chloro-peroxybenzoic acid 
(80-90%, Aldrich) in 600 ml of dichloromethane. The resulting reaction 
mixture was stirred at ambient temperature for one hr and then 100 ml of 
10% aqueous sodium bisulfate was added. After stirring the resulting 
reaction mixture for one hr the mixture gave a negative starch iodine 
test. The reaction mixture was washed twice with one liter portions of 
half saturated aqueous sodium bicarbonate solution, dried over sodium 
sulfate and sodium carbonate and the solvent was then removed in vacuo at 
ambient temperature leaving 21.0 g of a light yellow liquid. Analysis of 
this liquid mixture by gas liquid phase chromatography (GLPC) showed it to 
be a 45:55 w/w mixture of Isomer A and Isomer B named above. The GLPC 
analysis was done using a 3% SE-30 column. Isomer A was assigned the trans 
epoxide and Isomer B was assigned the cis epoxide configuration on the 
basis of chemical conversion to a product of known stereochemistry. 
A 1.0 g aliquot of the liquid mixture was removed and the remainder used in 
further chemical reactions without further purification. 
The 1.0 g aliquot from above was chromatographed on 170 g of 40-63 micron 
(u) silica gel (Merck) eluting with 20% ethyl acetate/benzene mixture to 
give 170 mg of pure Isomer A above and 220 mg of pure Isomer B along with 
still mixed fractions. 
For Isomer A: The NMR was consistent for the named Isomer A. 
Anal. Calcd. for C.sub.9 H.sub.14 O.sub.2 : Mol. Wt. 154.0994. Found: 
154.0985. 
For Isomer B. The NMR was consistent for the named Isomer B. 
Anal. Calcd. for C.sub.9 H.sub.4 O.sub.2 : Mol. Wt. 154.0994. Found: 
154.0988. 
Step G. 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-1-[8-[{ethyl(phenylmethyl)amino]-1-oxas 
piro-[4.5]dec-7-yl]pyrolidine (Isomer A), 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-1-[7-[methyl(phenylmethyl)amino]-1-oxas 
piro-[4.5]-dec-8-yl]pyrrolidone (Isomer C). 
A solution consisting of 10.0 g (about 65 mmol) of a mixture of the cis- 
and trans-1-oxaspiro[4.5]decan-7-ene oxides, from Step F above, 17.42 
(0.14 mol) of benzyl(methyl)amine and 6 ml of water was heated at 
90.degree. C. for 18 hr. The resulting reaction mixture was allowed to 
cool to room temperature and distributed between 10% aqueous sodium 
hydroxide solution and dichloromethane. The phases were separated, the 
aqueous layer was extracted once with dichloromethane, the organic liquid 
layers were combined, dried over magnesium sulfate and the solvent was 
removed in vacuo. The crude product liquid residue thus obtained was 
distilled at reduced pressure to give 9.5 g of a mixture of amino-alcohols 
as a water white viscous oil, bp 150.degree.-160.degree. C. (0.005 mmHg). 
To a solution of 9.0 g (34 mmol) of the amino-alcohol mixture, from above, 
and 4.1 g (37.3 mmol) of triethylamine in 125 ml of dichloromethane cooled 
to 0.degree. C. there was added dropwise a solution of 4.3 g (37.3 mmol) 
of methanesulfonyl chloride in 50 ml of dichloromethane. After the 
addition was completed the resulting mixture was stirred at 0.degree. C. 
for one hr and then transferred to a separatory funnel. The resulting 
mixture was washed once with water, dried over magnesium sulfate and the 
solvent was removed in vacuo at ambient temperature leaving 13.8 g of 
crude methanesulfonate (mesylate) intermediate. 
The crude mesylate intermediate, from above, was treated with 31.5 g (0.44 
mol) of pyrrolidine and 13 ml of water and the resulting mixture was 
heated under a reflux condenser at 65.degree. C. for 16 hr. The bulk of 
the excess pyrrolidine was removed from the resulting reaction mixture on 
a rotary evaporator and the residue was distributed between 10% aqueous 
sodium hydroxide and dichloromethane. The aqueous layer was extracted once 
with dichloromethane, the organic layers were combined, dried over 
magnesium sulfate and the solvent was removed in vacuo leaving 9.8 g of a 
yellow oil. A thin layer chromatography (tlc) analysis of the crude 
product suggested a mixture of at least three diamine isomers. 
The crude product was chromatographed on 1 kg. of 40-63 micron size silica 
gel (Merck) eluting with an ammonia/methanol/ethanol (0.8/7.2/92 v/v) 
mixture. Fractions containing pure isomers were combined to to give 2.1 g 
of Isomer A, 2.5 g of isomer C, and 1.5 g of a mixture of isomer A, B, and 
C. 
Isomer A: The NMR was consistent with the named Isomer A. 
Mass Spectral Analysis: (m/e) 328 (M.sup.+), 244 (M.sup.+ CH.sub.2 
.dbd.CCH.sub.2 CH.sub.2 CH.sub.2 O), 166 (CH.sub.2 (CH.sub.2).sub.3 
N.dbd.CHCH.dbd.C(CH.sub.2).sub.3 O), 160 (CH.sub.2 
.dbd.CHCH.dbd.N(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5). 
Isomer C: The NMR was consistent with the named Isomer C. 
Mass spectral analyses: (m/e) 328 (M.sup.+), 216 (C.sub.6 H.sub.5 CH.sub.2 
N(CH.sub.3).dbd.CHCH.dbd.C(CH.sub.2).sub.3 O, and 10 (CH.sub.2 
.dbd.CHCH.dbd.N(CH.sub.2).sub.3 CH.sub.2). 
Step H. 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidi 
nyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide. 
To a solution of 2.0 g (6.1 mmol) of Isomer A from step G above in 100 ml 
of absolute ethanol there was added 2.0 g of 10% palladium on carbon and 
the mixture was shaken on a Parr apparatus under 35 psig of hydrogen 
pressure, to remove the N-benzyl protecting group. Once the uptake of 
hydrogen had ceased the reaction mixture was filtered through a filter aid 
pad (Celite), the pad was washed with several portions of ethanol and the 
filtrate was evaporated in vacuo leaving, after high vacumn drying, 1.3 g 
of the de-benzylated amine intermediate product 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-7-(1-pyrrolidinyl)-1-oxaspiro[ 
4.5]decan-8-amine, as a colorless oil. 
To a solution of 0.75 g (362 mmol) of 3,4-dichlorophenylacetic acid in 25 
ml of dry tetrahydrofuran there was added (in a single batch) 0.59 g (3.62 
mmol) of 1,1-carbonyldiimidazole and the resultant mixture was stirred at 
ambient temperature for one hour. A solution of 0.75 g (3.15 mmol) of the 
de-benzylated diamine, obtained hereinabove, in 20 ml of dry THF was added 
dropwise and the resultant mixture was stirred at ambient temperature for 
18 hours. The bulk of the THF was removed on a rotary evaporator and the 
residue was distributed between ethyl ether and water. The liquid phases 
were separated and the ethereal liquid phase was washed once with water, 
once with brine solution, dried over magnesium sulfate and the solvent was 
removed in vacuo leaving 1.25 g of a white, waxy solid. 
This crude amino-amide solid was crystallized twice from acetonitrile to 
give 0.8 g (54% yield) of the titled compound, mp 
105.5.degree.-106.5.degree. C. The NMR and infrared spectrum (IR) were 
consistent with the named compound. It analyzed as follows: 
Anal. Calcd. for C.sub.22 H.sub.30 Cl.sub.2 N.sub.2 O.sub.2 : C, 62.11, H, 
7.11; Cl, 16.67; N, 6.59%. Found: C, 62.06, H, 7.19; Cl, 16.58; N, 6.39%. 
An X-ray crystal structure determination on the titled compound confirms 
the regio- and stereochemical assignment. 
The monohydrobromide of the titled compound was prepared by adding diethyl 
ether-hydrobromic acid to the free base in diethy ether. The resultant 
precipitate was collected and recrystallized from a methanol/diethyl ether 
mixture to give white microcrystals, mp 209-210/C, of the monohydrobromide 
of the titled compound. 
Anal. Calcd. for C.sub.22 H.sub.31 N.sub.2 O.sub.2 Cl.sub.2 Br: C, 52.18; 
H, 6.17; N, 5.53; Cl, 14.00; Br, 15.78. Found: C, 51.91; H, 6.20; N, 5.51; 
Cl, 13.92; Br, 15.69. 
A preferred process for preparing the titled compound of Example 1, Part H, 
is the following. The epoxidation of 1-oxaspiro[4.5]-dec-7-ene is carried 
out using m-chloroperoxybenzoic acid in diethyl ether solvent to give a 
mixture of epoxides enriched in the (1'.alpha.,3'.beta.,6'.alpha.) isomer. 
This mixture of epoxides is reacted with pyrrolidine according to step 10 
of Scheme I to produce a pyrrolidinyl-alcohol. This intermediate, 
according to stepp 11 of Scheme I, is converted to the mesylate, which is 
then rected with benzyl(methyl)amine. The resulting diamine mixture is 
debenzylated according to step 12a or 12b of Scheme I and acylated as 
described hereinabove, and the product titled in Example 1, Part H, is 
purified by recrystallization from acetonitrile. 
EXAMPLE 2 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1 
-oxaspiro[4.5]dec-8-yl]benzamide 
To a solution of 0.54 g (2.28 mmol) of the de-benzylated diamine, from Step 
H of Example 1, and 0.28 g of triethylamine in 35 ml of dry diethyl ether 
there was added dropwise a solution of 0.55 g (2.5 mmol) of 4-bromobenzoyl 
chloride in 25 ml of dry diethyl ether. After the addition was complete 
the resulting reaction mixture was stirred at ambient temperature for 3 
hr. and then distributed between water and ethyl acetate. The phases were 
separated and the organic liquid phase was washed once with water, once 
with brine solution, dried over magnesium sulfate and the solvent removed 
in vacuo leaving 1.0 g of a white powder which was recrystallized twice 
from acetonitrile to give 0.7 g (74% yield) of the titled amino-amide as 
white crystals: mp 181.degree.-185.degree. C. (dec). The NMR, IR and mass 
spectral analyses were consistent with the named product. The elemental 
analysis was as follows: 
Anal. Calcd. for C.sub.21 H.sub.29 BrN.sub.2 O.sub.2 : C, 59.85; H, 6.94; 
N, 6.65; Br, 18.96%. Found: C, 59.77; H, 7.00; N, 6.69; Br, 19.10%. 
EXAMPLE 3 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidin 
yl)-1-oxaspiro[4.5]dec-7-yl]benzeneacetamide, and its 
monohydrochloride-methanol solvate 
To a solution of 2.4 g (7.31 mmol) of the diamine, Isomer C, Step G of 
Example 1, in 100 ml of absolute ethanol there was added 2.4 g of 10% 
palladium on carbon and the resulting mixture was shaken on a Parr 
apparatus under 35 psig of hydrogen to de-benzylate the amine. After the 
uptake of hydrogen had ceased the resulting reaction mixture was filtered, 
the filter cake was washed thoroughly with absolute ethanol and the 
filtrate was evaporated in vacuo leaving 1.6 g of the debenzylated Isomer 
A amine as a colorless oil. 
To a solution of 0.8 g (3.86 mmol) of 3,4-dichlorophenylacetic acid in dry 
THF there was added 0.63 g (3.86 mmol) of 1',1'-carbonyldiimidazole and 
the resulting mixture was stirred at ambient temperature for one hr. A 
solution of 0.8 g (3.36 mmol) of the de-benzylated Isomer A diamine, from 
above, in 20 ml of dry THF was added dropwise and the resultant solution 
was stirred at ambient temperature for 18 l hr, to ensure complete 
reaction. The bulk of the THF was removed on a rotary evaporator and the 
residue was distributed between ethyl ether and water. The liquid phases 
were separated and the ethereal phasewas concentrated in vacuo leaving 1.3 
g of crude, titled product as an oil. 
An ethereal solution of the crude product thus obtained was treated with 
ethereal hydrochloric acid and the resultant hydrochloride salt of the 
titled amino-amide precipitate was collected and recrystallized twice from 
a methanol/ethyl acetate (50/50 v/v) mixture to give 0.6 g of the titled 
amino-amide hydrochloride salt-solvate, mp 203.degree.-210.degree. C. The 
elemental analysis was as follows: 
Anal. Calcd. for C.sub.22 H.sub.30 Cl.sub.2 N.sub.2 O.sub.2.HCl.0.5CH.sub.3 
OH: Calcd: C, 56.61; H, 6.86; N, 5.87; Cl, 22.28%. Found: C, 56.42; H, 
6.91; N, 5.96; Cl, 22.99%. 
EXAMPLE 4 
(.+-.)-(5.xi.,6.alpha.,7.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl) 
-1-oxaspiro[4.5]dec-6-yl)benzeneacetamide 
A. Preparation of 1-[3-(1-ethoxyethoxy)propyl]cyclohex-2-en-1-ol 
In an oven dried 250 ml, 3 neck, round bottom flask fitted with magnetic 
stir bar, low temperature thermometer, septum and pressure equalizing 
addition funnel connected to a source of nitrogen there was placed 2.0 g 
(0.3 mol) of 1/8 in diameter lithium wire (containing 0.6% sodium) cut 
into 1/2 in pieces under a stream of nitrogen, and 125 ml of anhydrous 
diethyl ether. About 3 ml of ethyl 3-bromopropylacetaldehyde acetal was 
added dropwise with stirring under nitrogen. When the reaction temperature 
of the mixture had risen to 30.degree. C. and the lithium wire began to 
turn shiny the reaction mixture was cooled to -5.degree. C. in a dry 
ice/carbon tetrachloride mixture bath. The temperature of the mixture was 
maintained between 5.degree. C. and 0.degree. C. by the dropwise addition 
of the remainder of the 30.2 g (0.14 mol) of ethyl 
3-bromopropylacetaldehyde acetal. After complete addition, the resultant 
mixture was stirred at dry ice/carbon tetrachloride cooling temperature 
(about -78.degree. C.) for two hr, at which time the surface of the 
residual lithium wire had tarnished. 
The organo-lithium intermediate compound formed in this above reaction 
mixture was transferred via a cannulus apparatus to a 250 ml oven dried, 
round bottom flask fitted with magnetic stir bar, septum, pressure 
equalizing additional funnel connected to a source of nitrogen and cooled 
to 0.degree. C. in an ice/water bath. The addition funnel had been charged 
with 9.95 g (0.10 mol) of 2-cyclohexen-1-one and 100 ml of anhydrous ethyl 
ether. The cyclohexenone solution was added dropwise to the cold, stirred 
organolithium intermediate compound under nitrogen over a 1.5 hr period. 
The resultant mixture was stirred at 0.degree. C. for one hr and then 
allowed to slowly warm to room temperature by stirring for 18 hr without 
replenishing the ice in the bath. The reaction mixture was poured into 250 
ml of ice cold, 1/2 saturated ammonium chloride aqueous solution. The 
liquid phases were separated and the aqueous phase was extracted twice 
with 200 ml portions of diethyl ether. The combined ethereal liquid phases 
were washed with brine solution, dried over sodium sulfate and 
concentrated in vacuo to leave 21.4 g (93% yield) of the above named 
-cyclohex-2-ene-1-ol intermediate as a colorless oil which was used as 
such in the next step. The NMR of this intermediate was consistent with 
the above named intermediate compound. 
B. Preparation of 1-Oxaspiro[4.5]dec-6-ene 
A mixture of 21 g (0.10 mol) of the acetal, prepared as in part A 
hereinabove, 10 g of a cation exchange resin (Dowex.RTM. 50W-X8) (200 to 
400 mesh) and 200 ml of methanol was stirred at room temperature for four 
hr to ensure complete reaction, and then filtered through a filter pad 
(Celite.RTM.). The filter pad was washed twice with 50 ml portions of 
methanol. The solvent from the combined filtrate and washings was removed 
from the mixture in vacuo to leave as residue 7.2 g (60% yield) of the 
sub-titled -dec-6-ene after distillation (bp 90.degree.-96.degree. C. at 
25 mmHg). The NMR was consistent with the sub-titled -dec-6-ene. The mass 
spectrum analysis showed an m/e of 138(M.sup.+). 
C. Preparation of 
(.+-.)-(1'.alpha.,2'.beta.,6'.alpha.)-Dihydrospiro[furan-2(3H),2'-[7]oxabi 
cyclo[4.1.0]heptane] and 
(.+-.)-(1'.alpha.,2'.alpha.,6'.alpha.)-dihydrospiro[furan-2(5H),2'-[7]-oxa 
bicyclo[4.1.0]heptane] (Isomer A is faster moving and Isomer B is slower 
moving as described below). 
To a stirred portion of 36 g (0.094 mol) of 1-oxaspiro[4.5]dec-6-ene, 
prepared as described hereinabove, 150 ml of ethylene chloride there was 
added dropwise 23 g of 80-90% m-chloroperbenzoic acid in 500 ml of 
methylene chloride over a 2 hr period. The reaction mixture was stirred 
for 18 hr at room temperature. To the resulting solution there was added 
180 ml of 10% (W/V) aqueous sodium bisulfite solution and the resulting 
two liquid phase system was stirred rapidly for one hr (until a negative 
starch/iodide test result was obtained). Then, about 5 g of sodium 
bicarbonate was slowly added to the mixture in several batches with 
stirring. The resulting mixture was washed twice with 1/2 saturated sodium 
bicarbonate solution, once with saturated sodium chloride solution and 
dried over sodium sulfate/potassium carbonate. The solvent was removed and 
the residue was chromatographed on silica gel eluting with a 1:1 v/v 
hexane-ethyl acetate mixture to yield 9.5 g of the faster moving epoxide, 
isomer A above, and 4.64 g of the slower moving epoxide, Isomer B above. 
The NMR spectra of each isomer A and B were consistent with the respective 
above named intermediate compounds, but the relative stereochemistry was 
undetermined. The mass spectrum of each isomer A and B showed an 
m/e=154(M.sup.+). 
D. Preparation of 
(.+-.)-(5.xi.,6.alpha.,7.beta.)-1-[6-[methyl(phenylmethyl)-amino]-1-oxaspi 
ro[4.5]dec-7-yl]pyrrolidine 
A mixture of 3.65 g (0.024 mol) of 5,6-epoxy-1-oxaspiro[4.5]-decane, 
(Isomer A, hereinabove), 4.37 g (0.036 mol) of benzyl(methyl)amine and 2 
ml of water was heated at 90.degree. C. for 18 hr until the reaction was 
complete by thin layer chromatography (tlc) analysis. The reaction mixture 
was cooled in an ice bath to 0.degree. C. and then 4 ml of 25% sodium 
hydroxide solution was added with stirring. The resulting basic mixture 
was extracted twice with 100 ml of methylene chloride. The combined 
organic liquid phase was dried over magnesium sulfate and removal of the 
solvent in vacuo left 4.9 g of an intermediate amino alcohol (See Scheme 
I, step 10) 
(.+-.)-(5.epsilon.,6.alpha.,7.beta.)-7-[methyl(phenyl-methyl)amino]-1-oxas 
piro[4.5]decan-6-ol. The NMR and mass spectral analyses were consistent. 
The above amino-alcohol intemediate thus formed, 1.98 g (0.018 mol) of 
triethylamine and 60 ml of methylene chloride were placed in an oven dried 
250 ml round bottom flask equipped with a magnetic stir bar and pressure 
equalizing addition funnel connected to a source of nitrogen. The additon 
funnel was charged with 2.02 g (0.018 mol) of methylene chloride. The 
system was purged with nitrogen and cooled to 0.degree. C. in an ice bath. 
The methanesulfonyl chloride (mesyl chloride) solution was added dropwise 
over a one hr period to the stirred amino alcohol reactant mixture. The 
resulting mixture was stirred for an additional one hr at 0.degree. C. 
after complete addition to ensure complete reaction. The reaction mixture 
was washed once with 100 ml of water. The organic liquid phase was 
seprated, dried over magnesium sulfate and the solvent was removed in 
vacuo to leave a residue 5.6 g of the crude mesylate intermediate. 
To the above crude mesylate thus formed there was added 20 ml of 
pyrrolidine and 6 ml of water. The mixture was heated with stirring at 
90.degree. C. for 18 hr to ensure complete reaction. The excess 
pyrrolidine was removed in vacuo and the resulting crude residue was 
distributed between 100 ml of methylene chloride and 100 ml of 10% sodium 
hydroxide aqueous solution. The aqueous phase was extracted once with 50 
ml of methylene chloride. The combined organic liquid phases were dried 
over magnesium sulfate and the solvent was removed in vacuo to leave 5.6 g 
(95% yield) of the above sub-titled pyrrolidine diamine derivative, after 
pumping at high vacuum (e.g. 0.1 mmHg) for 20 hr. The diamine derivative 
was used as such in the next step. The NMR and mass spectral analyses were 
consistent with the sub-titled diamine derivatives. 
E. Preparation of 
(.+-.)-(5.xi.,6.alpha.,7.beta.)-1-[6-methylamino-1-oxaspiro[4.5]dec-7-yl]p 
yrrolidine 
A mixture of 5.3 g (0.016 mol) of 
6-benzyl(methyl)-amino-7-pyrrolidinyl-1-oxaspiro[4.5]-decane, from step D 
hereinabove, 5 g of 10% palladium on carbon and 150 ml of absolute ethanol 
was hydrogenated at about 40 psig for 4 days on a Parr apparatus to ensure 
complete reaction. 
The hydrogenated mixture was filtered through a filter pad (Celite.RTM.) 
and the filter cake was washed twice with 50 ml portions of absolute 
ethanol. Removal of the solvent in vacuo left 3.11 g (82% yield) of the 
sub-titled pyrrolidinyl diamine intermediate as a colorless oil which was 
used as such in the next step. The NMR and mass spectral analyses of 
samples of this diamine oil were consistent with the sub-titled compounds. 
F. 
(.+-.)-(5.xi.,6.alpha.,7.beta.)-3,4-Dichloro-N-methyl-N-[7-(1-pyrrolidinyl 
)-1-oxaspiro[4.5]dec-6-yl]benzeneacetamide 
In a 50 ml oven dried round bottom flask fitted with a magnetic stir bar 
and a pressure equalizing addition funnel connected to a source of 
nitrogen there was placed 1.44 g (7.0 mmol) of 3,4-dichloroophenylacetic 
acid and 15 ml of THF (dried over 3A molecular sieves). To the stirred 
mixture there was added in three batches, as a solid, 1.13 g (7.0 mmol) of 
1,1-carbonyldiimidazole over a 15 min period. The apparatus was flushed 
with nitrogen and the resultant mixture was stirred at room temperature 
for one hr. 
To the thus activated 3,4-dichlorophenylacetic acid solution there was 
added dropwise a solution of 1.5 g (6.35 mmol) of 
6-methylamino-7-(1-pyrrolidinyl)-1-oxaspiro[4.5]decane, prepared in part E 
above, in 10 ml of dry THF over a 20 min period. After complete addition 
the reaction mixture was stirred for 3 hr at room temperature to ensure 
complete reaction. The THF was removed in vacuo and the residue was 
distributed between 100 ml of diethyl ether and 100 ml of water. The ether 
phase was washed with 50 ml of brine solution, dried over magnesium 
sulfate and the solvent removed in vacuo. Chromatography of the residue on 
silica gel, eluting with 2.5% methanol (containing 10% ammonia/ethyl 
acetate) afforded 2.1 g (78% yield) of the above titled product. An 
ethereal solution of the free base product thus obtained was treated with 
a diethyl ether solution of hydrogen chloride. The resulting titled 
-amine.hydrochloride salt precipitate was recrystalized from a 1:1 v/v 
methanol:diethyl ether mixture to give the above titled amine product as 
the hydrochloride salt, mp 248.degree.-251.degree. C. The NMR and mass 
spectral analyses were consistent with this named titled product. The 
elemental analysis was as follows: 
Anal. Calcd. for C.sub.22 H.sub.31 N.sub.2 O.sub.2.HCl.0.5H.sub.2 O; C, 
56.12; H, 6.85; N, 5.95, Cl, 22.59%. Found: C, 56.30; H, 6.85; N, 6.15, 
Cl, 22.20%. 
The titled compound produced by the procedure of this example is a single 
epimer of unknown stereochemistry at C.sub.5. The other C.sub.5 epimer has 
mp 135.degree.-137.degree. C. and is named hereinbelow in Example 14. 
EXAMPLE 5 
Resolution of the dextro(+) and leavo(-) enantiomers of detailed Example 1 
compounds 
Preparation of 
(+)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl 
)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide and 
(-)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl 
)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide 
To a solution of 10.0 g (23.5 mmol) of the 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidi 
nyl)-1-oxaspiro[4.5]dec-8-yl]ben-zeneacetamide, prepared as described in 
Example 1 hereinabove, in 250 ml of methanol there was added 9.1 g (23.5 
mmol) of di-p-toluoyl-d-tartaric acid and the resultant mixture was 
evaporated to dryness in vacuo. The resultant white solid was dissolved in 
a minimum volume of boiling methanol and enough diethyl ether was added to 
cause a slight clouding of the mixture. The slightly cloudy solution was 
allowed to stand at room temperature for 18 hr and the resultant crystals 
were collected to give 9.8 g of a white crystalline product. The 
crystalline product thus obtained was recrystallized twice from a 1:1 v/v 
mixture of methanol:diethyl ether to give 5.0 g of salt. This 
dextro-tartrate salt product was distributed between diethyl ether and 10% 
sodium hydroxide aqueous solution, the resulting liquid phases were 
separated, the ethereal phase was washed with brine, dried over magnesium 
sulfate and the solvent removed leaving 3.0 g of a white solid which was 
recrystallized from a diethyl ether/hexane (1:1 v/v) mixture to give 2.3 g 
of the essentially pure levo(-) isomer, mp 106.degree.-107.5.degree. C., 
[.alpha.].sub.25.sup.D -6.13, [.alpha.].sub.436.sup.D -14.38 
(C=1.13,ethylacetate). The NMR spectrum was consistent. 
Anal. Calcd. for C.sub.22 H.sub.20 Cl.sub.2 N.sub.2 O.sub.2 : C, 62.11; H, 
7.11; N, 6.59; Cl, 16.67%. Found: C, 61.92; H, 7.16; N, 6.42; Cl, 16.83%. 
The mother liquors from the above original crystallization was evaporated 
to dryness in vacuo and the residue was distributed between 10% sodium 
hydroxide aqueous solution and diethyl ether. The liquid phases were 
separated and the ethereal phase was washed with brine solution, dried 
over magnesium sulfate and the solvent removed in vacuo to leave 4.1 g of 
the above titled (.+-.) free base as a white solid. The white free base 
(.+-.) isomer mixture thus obtained was dissolved in 150 ml of methanol to 
which was added 3.9 g (9.6 mmol) of di-p-toluoyl-l-tartaric acid and the 
resultant solution was evaporated to dryness in vacuo. The resultant solid 
residue was recrystallized three times from a methanol/diethyl ether (1:1 
v/v) mixture to give 3.2 g of salt. Treatment of this levo-tartrate salt 
as described above for the dextro-tartrate salt gave 2.0 g of the 
above-titled free levo(-) base which was recrystallized from diethyl 
ether/hexane (1:1 v/v) to give 1.55 g of the titled levo(-) isomer free 
base, mp 106.5.degree.-107.5.degree. C.; [.alpha. ].sub.25.sup.D +6.18, 
[.alpha.].sub.436.sup.546 +14.51. The NMR spectrum was identical to that 
for the dextro(+) isomer above. 
Anal. Calcd. for C.sub.22 H.sub.20 Cl.sub.2 N.sub.2 O.sub.2 : C, 62.11; H, 
7.11; N, 6.59; Cl, 16.67%. Found: C, 62.02; H, 7.17; N, 6.64; Cl, 16.60%. 
EXAMPLE 6 
General Procedure for the Acylation of 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-7-(1-pyrrolidinyl)-1-oxaspiro[ 
4.5]decan-8-amine. 
Preparation of 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspi 
ro[4.5]dec-8-yl]benezeneacetamide. 
This example illustrates a general procedure for acylating the titled 
decan-8-amine to make compounds of this invention and, specifically, the 
production of 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspi 
ro[4.5]dec-8-yl]benzeneacetamide. 
In a dried vessel containing stirring apparatus and pressure equalizing 
addition funnel equipment connected to de-aerating gas source such as 
nitrogen there is placed about 0.48 g (3.5 mmols) of the phenylacetic acid 
(or its equivalent of the selected ring-substituted phenylacetic acid or 
benzoic acid or phenylalkanoic acid and 5 ml of THF (dried with 3A 
molecular sieves). To this stirred mixture is added, as a solid, 0.56 g 
(3.5 mmol) of 1,1'-carbonyldiimidazole in two batches. The mixture is 
stirred at room temperature for 45 min. To the resulting stirred activated 
acid mixture there is added dropwise 0.75 g (3.15 mmol) of the selected 
diamine, e.g., 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-7-(1-pyrrolidinyl)-1-oxaspiro[ 
4.5]decan-8-amine (Example 1, Step H) in 10 ml of dry THF over a 10 min 
period. The resultant mixture is stirred at room temperature for 18 hr to 
ensure complete reaction. The THF is removed in vacuo and the residue is 
distributed between 30 ml of ethyl acetate and 20 ml of water. The 
organic liquid phase is separated, dried over magnesium sulfate and the 
solvent removed in vacuo to leave the acylated product of this invention, 
e.g., 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-[7-(1-pyrrolidinyl)-1-oxaspiro 
[4.5]dec-8-yl]benzeneacetamide, as a powdered product which is 
recrystallized, e.g., from acetonitrile to give the desired 
benzeneacetamide or benzamide product, e.g., 800 mg (71% yield) of the 
titled amino-amide, mp 123.degree.-125.degree. C. 
EXAMPLE 7 
1-Oxaspiro[4.5]dec-7-ene 
This example illustrates a preferred procedure for preparing the compound 
of step E in Example 1 hereinabove. 
In an oven dried 5 liter 3-neck round bottom flask equipped with two Dewar 
condensers, a glass covered magnetic stir bar and a positive nitrogen 
inlet there was condensed 1.75 liters of anhydrous ammonia (flask was 
immersed in a dry ice/isopropanol bath during ammonia condensation). A 
solution of 136.19 g (1 mol) of 3-phenylpropanol (well known in the art) 
in 200 ml of dry diethyl ether (cooled to -78.degree. C.) was added 
followed by a solution of 107.3 g (2.33 mol) of absolute ethanol in 200 ml 
of diethyl ether (cooled to -78.degree. C.). To this solution there was 
added in small pieces, over a two hr period, 69.0 g (3 gram-atoms) of 
sodium metal (freed from mineral oil by washing with pentane). The first 
pieces caused vigorous exotherms and the rate of addition had to be 
carefully monitored. After the addition was complete, the reaction mixture 
(deep blue) was stirred for 18 hr without replenishing the coolant in the 
condenser. 
The flask containing a white solid was cooled in an ice/water bath and 800 
ml of ice cold water was added followed by 800 ml of diethyl ether. After 
all of the solid had dissolved the reaction mixture was transferred to a 
separatory funnel, the phases were separated and the ethereal phase was 
washed three times with 800 ml portions of water, once with brine 
solution, dried over magnesium sulfate and the solvent was removed leaving 
143 g of crude 3-(1,4-cyclohexadienyl)propan-1-ol. 
This crude 3-(1,4-cyclohexadienyl)propan-1-ol thus obtained was divided 
into two batches. Each batch was treated separately with 2.5 g of 
p-toluenesulfonic acid. The pressure was lowered to 12 mmHg and the pot 
immersed in an oil bath heated to 115.degree. C. After about 0.3 hr 
distillation through a short vacuum jacketed vigreaux column at reduced 
pressure began and continued at a steady rate as cyclization proceeded. A 
total of 105.4 g (76% yield) of the 1-oxaspiro[4.5]dec-7-ene was obtained 
as a water white liquid, bp 79.degree.-81.degree. C. (12 mmHg). The NMR 
spectrum was identical to that for the same compound described in Example 
1 above, step E. 
EXAMPLE 8 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-4-chloro-N-methyl-N-[7-(1-pyrrolidinyl)- 
1-oxaspiro[4.5]dec-8-yl]benzeneacetamide 
Employing the general procedure of Example 6, but using instead 
4-chlorophenylacetic acid, there is produced in 89% yield the titled 
amino-amide, mp 109.degree.-110.degree. C., with the following elemental 
analysis. 
Calcd for C.sub.22 H.sub.31 ClN.sub.2 O.sub.2 : C, 67.59; H, 7.99; N, 7.17; 
Cl, 9.07%. Found: C, 67.48; H, 7.98; N, 7.05; Cl, 9.11%. 
EXAMPLE 9 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1 
-oxaspiro[4.5]dec-8-yl]benzeneacetamide 
Employing the general procedure of Example 6, but using instead 
4-bromophenylacetic acid, there is produced in 93% yield the titled 
amino-amide, mp 120.degree.-122.degree. C., with the following elemental 
analysis. 
Calcd for C.sub.22 H.sub.31 BrN.sub.2 O.sub.2 : C, 60.69; H, 7.18; N, 6.43; 
Br, 18.35. Found: C, 60.71; H, 7.16; N, 6.35; Br, 18.31. 
EXAMPLE 10 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-4-methoxy-N-methyl-N-[7-(1-pyrrolidinyl) 
-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide 
Employing the general procedure of Example 6, but using instead 
5-methoxyphenylacetic acid, there is produced in 73% yield the titled 
amino-amide, mp 110.degree.-111.degree. C., with the following elemental 
analysis. 
Calcd for C.sub.23 H.sub.34 N.sub.2 O.sub.3 : C, 71.47; H, 8.87; N, 7.25. 
Found: C, 71.26; H, 8.97; N, 7.17. 
EXAMPLE 11 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-N,4-dimethyl-N-[7-(1-pyrrolidinyl)-1-oxa 
spiro[4.5]dec-8-yl]benzeneacetamide 
Employing the general procedure of Example 6, but using instead 
4-methylphenylacetic acid there is produced in 74% yield the titled 
amino-amide, mp 95.degree.-97.degree. C., with the following elemental 
analysis. 
Calcd for C.sub.23 H.sub.34 N.sub.2 O.sub.2 : C, 74.55; H, 9.25; N, 7.56. 
Found: C, 74.66; H, 9.22; N, 7.68. 
EXAMPLE 12 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-3-chloro-N-methyl-N-[7-(1-pyrrolidinyl)- 
1-oxaspiro[4.5]dec-8-yl]benzeneacetamide 
Employing the general procedure of Example 6, but using instead 
3-chloroacetic acid there is produced in 70% yield the titled amino-amide, 
mp 91.degree.-92.degree. C., with the following elemental analysis. 
Calcd for C.sub.22 H.sub.31 N.sub.2 O.sub.2 Cl: C, 67.59; H, 7.99; N, 7.17; 
Cl, 9.07. Found: C, 67.11; H, 7.98; N, 7.07; Cl, 8.98. 
EXAMPLE 13 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-4-nitro-N-[7-(1-pyrrolidinyl)-1 
-oxaspiro[4.5]dec-8-yl]benzeneacetamide 
Employing the general procedure of Example 6, but using instead 
4-nitrophenylacetic acid there is produced in 71% yield the titled 
amino-amide as the monohydrochloride, hydrate, mp 156.degree.-158.degree. 
C., with the following elemental analysis. 
Calcd for C.sub.22 H.sub.31 N.sub.3 O.sub.4.HCl.H.sub.2 O: C, 60.33; H, 
7.36; N, 9.60; Cl, 8.06. Found: C, 59/86; H, 7.27; N, 9.61; Cl, 8.10. 
EXAMPLE 14 
(.+-.)-(5.xi.,6.alpha.,7.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl) 
-1-oxaspiro[4.5]dec-6-yl]benzeneacetamide 
Reacting 6,7-epoxy-1-oxaspiro[4.5]decane Isomer B from Example 4, Part C, 
as described for Isomer A in Example 4, Parts D, E, and F, there is 
produced the titled compound, mp 135.degree.-137.degree. C., which is the 
spiro epimer of the compound produced by the procedure of Example 4, Part 
F. 
Calcd for C.sub.22 H.sub.30 N.sub.2 Cl.sub.2 O.sub.2 : C, 62.11; H, 7.11; 
N, 6.59; Cl, 16.67. Found: C, 62.06; H, 7.16; N, 6.54; Cl, 16.60. 
EXAMPLE 15 
(.+-.)-(5.alpha.,7.beta.,8.alpha.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidin 
yl-1-oxaspiro[4.5]dec-7-yl]benzeneacetamide and its monohydrobromide, 
chloroform solvate 
A. 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-1-[7-(methylamino)-1-oxaspiro[4.5]dec-8 
-yl]pyrrolidine (Isomer A) and 
(.+-.)-(5.alpha.,7.beta.,8.alpha.)-1-[7-(methylamino)-1-oxaspiro[4.5]dec-8 
-yl]pyrrolidine (Isomer B) 
In a 25 ml round bottom flask, fitted with reflux condenser and magnetic 
stir bar, was placed 3.4 g (22.0 mmol) of epoxide Isomer A from Example 1, 
Part F, 1.72 g (24.0 mmol) pyrrolidine and 1 ml water. The mixture was 
heated with stirring under nitrogen at 70.degree. C. for 2 hr. The 
reaction mixture was cooled to 0.degree. in an ice water bath, 3.5 ml of 
25% NaOH was added and the basic mixture was stirred in the cold for 15 
min. The excess pyrrolidine was removed in vacuo. The aqueous residue was 
extracted two times with 50 ml methylene chloride. The combined organics 
were washed with 100 ml brine and dried (MgSO.sub.4). The solvent was 
removed in vacuo and the residue distilled through a short path at reduced 
pressure to yield 4.3 g (87%, bp 100.degree.-102.degree. (0.05 mm), of 
amino-alcohol intermediate. 
In an oven dried 100 ml r.b. flask, fitted with pressure equalizing 
addition funnel and magnetic stir bar, was placed 4.3 g of the above amino 
alcohol, 2.43 g (24.0 mmol) triethylamine and 25 ml of methylene chloride, 
and the mixture was cooled to 0.degree. in an ice/water bath. To the 
stirred mixture was added 2.7 g (24.0 mmol) of methanesulfonyl chloride in 
20 ml of methylene chloride dropwise over a 30 min period. The mixture was 
stirred in the cold another 30 min. The reaction mixture was washed with 
50 ml water. The organic phase was dried (MgSO.sub.4) and the solvent 
removed in vacuo to leave 6.0 g of crude mesylate product which was 
carried on without further purification. 
The crude mesylate product from above was placed in a 100 ml round bottom 
flask, fitted with reflux condenser and magnetic stir bar, and 40 ml of 
40% aqueous methyl amine. The mixture was heated at 70.degree. for 2 hr. 
The excess methyl amine was removed in vacuo and the residue distributed 
between 150 ml of 10% sodium hydroxide and 150 ml methylene chloride. The 
aqueous phase was extracted with 150 ml of methylene chloride. The 
combined organics were dried (MgSO.sub.4) and the solvent removed in vacuo 
to leave 4.3 g of crude product. Gas chromatography indicated a 2:1 
mixture of the titled Isomers A and B respectively. Chromatography of half 
of the crude on R.P.-2 silica gel, eluting with 2% NH.sub.4 OH (50% 
aqueous), 10% water, 88% CH.sub.3 CN (v:v:v) gave 1.6 g of Isomer A and 
0.63 g of Isomer B (95%, based on crude product recover). 
The HNMR of Isomer A was consistent with the named compound. 
The HNMR of Isomer B was consistent with the above named Isomer B. The mass 
spec of Isomer B: m/3=238 (M+24.7%), 194 (78.5%), 126 (15.2%), 110 (100%), 
97 (61.9%). 
B. 
(.+-.)-(5.alpha.,7.beta.,8.alpha.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidi 
nyl)-1-oxaspiro[4.5]-dec-7-yl]benzeneacetamide and its monohydrobromide 
In an oven dried 50 ml round bottom flask, fitted with pressure equalizing 
addition funnel and magnetic stir bar, was placed 0.59 g (2.9 mmol) 
1,1'-carbonyldiimidazole. The resulting mixture was stirred at room 
temperature for 1 hr at which time 0.63 g (2.6 mmol) of diamine Isomer B 
from Part A above in 5 ml of THF was added dropwise over a 15 min period. 
The reaction mixture was stirred for 18 hr. The THF was removed in vacuo 
and the residue distributed between 30 ml. ethyl ether and 30 ml. of 
water, the ethereal phase was washed 2 times with 30 ml. of water, 1 time 
30 ml. brine, dried (MgSO.sub.4) and the solvent removed in vacuo. 
Chromatography on silica gel, eluting with 3% methanol (containing 10% 
ammonia)/97% ethyl acetate gave 0.8 g (75%) of the titled amino amide. The 
product was dissolved in ethyl ether and treated with an ethereal hydrogen 
bromide solution. The resultant precipitate was recrystallized from 
chloroform/hexane to yield the hydrobromide salt (mp 
212.degree.-215.degree.). 
High resolution mass spec: Calcd: 424.1692; Found: 424.1684. 
Anal. Calc'd for C.sub.22 H.sub.30 N.sub.2 O.sub.2 Cl.sub.2.HBr.0.5H.sub.2 
O.0.034CHCl.sub.3 : C, 50.95; H, 6.22; N, 5.39; Cl, 14.37; Br, 15.40. 
Found: C, 50.94; H, 6.13; N, 5.45; Cl, 14.37; Br, 16.20. 
The HNMR (80 MHz, CDCl.sub.3, free base) was consistent with the titled 
amino-amide. IR (Nujol): C=O 1640 cm.sup.-1. Mass spec: M+ m/e 424, 426 
(7.5 5.1%); 314, 316 (14.2, 9.3%), 207 (30.7%), 110 (100%), 97 (55.5%). 
EXAMPLE 16 
(.+-.)-(5.xi.,6.alpha.,7.beta.)-3,4-dichloro-N-[7-(dimethylamino)-1-oxaspir 
o[4.5]dec-6-yl]-N-methylbenzeneacetamide 
A. (.+-.)-(5.xi.,6.alpha.,7.beta.)-N.sup.6 
-(phenylmethyl-N.sup.6,N.sup.7,N.sup.7 
-trimethyl-1-oxaspiro[4.5]decan-6,7-diamine 
In a 100 ml round bottom flask, fitted with condenser and magnetic stir 
bar, was placed 3.8 g (25 mmol) of 5,6-epoxy-1-oxaspiro-[4.5]decane 
(Isomer B from Example 4 Part C), 4.5 g (37.5 mmol) benzyl(methyl)amine 
and 3 ml water. The mixture was heated with stirring at 90.degree. for 3 
days. The reaction mixture was cooled to 0.degree. in an ice/water bath. 
To the cold mixture was added 4 ml of 25% sodium hydroxide solution. The 
basic mixture was extracted 2 times with 75 ml methylene chloride. The 
combined organics were dried (MgSO.sub.4) and the siolvent removed in 
vacuo. The excess benzyl(methyl)amine was removed by heating at 40.degree. 
at high vacuo to leave 6.32 g (92%) of crude amino alcohol product that 
was used wthout further purification. The NMR spectrum was consistent with 
this amino alcohol intermediate. 
In a 250 ml round bottom flask, fitted with pressure equalizing addition 
funnel, magnetic stir bar and positive nitrogen inlet, was placed 4.0 g 
(14.5 mmol) of the amino alcohol from above, 1.76 g (16.0 mmol) 
triethylamine and 40 ml methylene chloride. The mixture was cooled to 
0.degree. in an ice/water bath and 1.83 g (16.0 mol) of 
methanesulfonylchloride in 30 ml of methylene chloride was added dropwise 
over a 30 min period. The reaction mixture was stirred in the cold another 
30 min. The solution was washed with 70 ml water, dried (MgSO.sub.4) and 
the solvent removed in vacuo to leave 5.4 g of crude mesylate 
intermediate. 
The crude mesylate was placed in a 100 ml round bottom flask, fitted with 
magnetic stir bar and condenser, along with 40 ml of 25% aqueous 
dimethylamine. The mixture was heated at 90.degree. with stirring for 2 
days. The mixture was cooled to 0.degree. in an ice/water bath and treated 
with 2 ml 25% sodium hydroxide solution. The basic mixture was extracted 2 
times with 50 ml methylene chloride. The combined organics were dried 
(MgSO.sub.4) and the solvent removed in vacuo. Chromatography on silica 
gel eluting with 3% methanol (containing 10% NH.sub.3)/97% ethylacetate 
yielded 2.4 g (55%) of the subtitled diamine. The HNMR (80 MHz, 
CDCl.sub.3) and mass spectral analyses were consistent with the subtitled 
diamine. 
B. (.+-.)-(5.xi.,6.alpha.,7.beta.)-N.sup.6,N.sup.7,N.sup.7 
-trimethyl-1-oxaspiro[4.5]-6,7-diamine 
A mixture of 2.4 g (7.95 mmol) of the diamine from part A above, 2.4 g of 
20% palladium on carbon and 100 ml of absolute ethanol was hydrogenated on 
a Parr apparatus at 40 psi for 4 hr. The reaction mixture was filtered 
through a filter aid. Celite.RTM.. The filtered cake was thoroughly washed 
with ethanol and the combined filtrate and wash were concentrated in vacuo 
to leave 1.38 g (82%) of the subtitled diamine, which was used without 
further purification. 
C. 
(.+-.)-(5.xi.,6.alpha.,7.beta.)-3,4-dichloro-N-[7-(dimethylamino)-1-oxaspi 
ro[4.5]dec-6-yl]-N-methylbenzeneacetamide 
In an oven-dried 100 ml round bottom flask, fitted with pressure equalizing 
addition funnel, magnetic stir bar and positive nitrogen inlet, was placed 
800 mg (3.88 mmol) 3,4-dichlorophenylacetic acid and 5 ml THF (dried over 
3A molecular sieves). To the mixture was added in two batches 630 mg (3.88 
mmol) of 1,1'-carbonyldiimidazole and the mixture was stirred at room 
temperature for 1 hr. The system was purged with nitrogen and 750 mg (3.53 
mmol) of the diamine from part B above in 5 ml THF was added dropwise over 
a 15 min period. The resultant mixture was stirred at room temperature for 
18 hr. The THF was removed in vacuo, the residue was distributed between 
30 ml ethyl acetate and 20 ml water. The organic phase was dried 
(MgSO.sub.4) and the solvent removed in vacuo to leave a solid which was 
recrystallized from ethyl acetate to yield 1.15 g (82%) of the titled 
amino-amide, mp 131.degree.- 133.degree.. HNMR (80 MHg, CDCl.sub.3) 
.delta.=1.2-1.95 (m, 10H); 209 (s, 6H), 2.89 (s, 3H), 3.55-4.0 (m, 4H), 
4.75 (d, 2H), 7.0-7.35 (m, 3H). IR (Nujol): C=O, 1634 cm.sup.-1. Mass 
spec: m/e 398,400 (5.5, 3.6%, M+); 181 (33%); 168 (21%), 98 (18%); 84 
(100%). 
Anal. Calcd for C.sub.20 H.sub.28 Cl.sub.2 N.sub.2 O.sub.2 : C, 60.15; H, 
7.07; N, 7.01; Cl, 17.76. Found: C, 59.92; H, 7.08; N, 6.93; Cl, 17.77. 
The titled amino-amide thus produced is the C.sub.5 -epimer of the compound 
produced by the procedure of Example 17, Parts A-C. 
EXAMPLE 17 
(.+-.)-(5.xi.,6.alpha.,7.beta.)-3,4-dichloro-N-[7-(dimethylamino)-1-oxaspir 
o[4.5]dec-6-yl]-N-methylbenzeneacetamide, and its monohydrochloride, 
hydrate 
A. (.+-.)-(5.xi.,6.alpha.,7.beta.)-N.sup.6 
-(phenylmethyl-N.sup.6,N.sup.7,N.sup.7 
-trimethyl-1-oxaspiro[4.5]decan-6,7-diamine 
In a 250 ml round bottom flask, fitted with condenser and magnetic stir 
bar, was placed 9.8 g (64 mmol) 5,6-epoxy-1-oxaspiro-[4.5]decan (Isomer A 
from Example 4, Part C), 11.57 g (95 mmol) benzyl(methyl)amine and 6 ml 
water. The mixture was heated, with stirring, at 70.degree. for 18 hr. The 
reaction mixture was cooled to 0.degree. in an ice/water bath. To the 
cold, stirred mixture was added, all at once, 6 ml of 25% sodium hydroxide 
solution. The basic mixture was extracted 2 times with 100 ml methylene 
chloride. The combined organic phases were dried (MgSO.sub.4) and the 
solvent removed in vacuo. The excess benzyl(methyl)amine was removed by 
heating at 40.degree. with high vacuum. The product was distilled through 
a short path at reduced pressure to give 15.7 g. (90%) of the amino 
alcohol intermediate product, bp 145.degree.-150.degree. (0.02 mm), as a 
liquid which crystallized at room temperature, mp 63.degree.-65.degree.. 
Anal. Calcd. for C.sub.17 H.sub.25 N.sub.2 O.sub.2 : C, 74.14; H, 9.15; N, 
4.09. Found: C, 74.34; H, 9.03; N, 5.09. 
The NMR and Mass Spectral analyses were consistent with this amino-alcohol 
intermediate. 
In a 100 ml oven dried round bottom flask, fitted with magnetic stir bar 
and pressure equalizing addition funnel, was placed 3.0 g (10.9 mmol) the 
amino alcohol from above, 1.32 g (12.0 mmol) triethylamine and 40 ml 
methylene chloride. The flask was cooled to 0.degree. in an ice bath under 
nitrogen. To the cold, stirred solution was added dropwise over a 15 min 
period 1.38 g (12.0 mmol) methanesulfonyl chloride in 20 ml methylene 
chloride. The reaction mixture was stirred for another 30 min in the cold 
and washed with 50 ml water. The organic phase was separated, dried 
(MgSO.sub.4) and the solvent removed in vacuo to leave 4.2 g of crude 
mesylate intermediate. 
To half of the crude mesylate thus formed was added 15 ml of 25% aqueous 
dimethylamine and the mixture was heated and stirred in a sealed, 
stainless steel bomb at 110.degree. for 24 hr. The reaction mixture was 
cooled to room temperature and treaed with 1.5 ml 25% sodium hydroxide 
solution. The basic material was extracted two times with 50 ml methylene 
chloride. The combined organics were dried (MgSO.sub.4) and the solvent 
removed in vacuo. The remaining mesylate was treated in like manner to 
give a combined yield of 3.3 g of crude product. The combined materials 
were chromatographed on silica gel, eluting with 1.5% methanol (containing 
10% NH.sub.3)/98.5% ethyl acetate to give 1.35 g (41%) of the subtitled 
diamine. The NMR spectrum was consistent with this benzylated diamine 
intermediate. 
B. (.+-.)-(5.xi.,6.alpha.,7.beta.)-N.sup.6,N.sup.7,N.sup.7 
-trimethyl-1-oxaspiro[4.5]decan-6,7-diamine 
A mixture of 1.35 g (4.5 mmol) of the diamine from part A above, 1.35 g of 
10% palladium on carbon and 100 ml absolute ethanol was hydrogenated at ca 
40 psi for 18 hr. The reaction mixture was filtered through filter aid 
(Celite.RTM.) and the filter cake was washed thoroughly with ethanol. The 
combined filtrate and washings were concentrated in vacuo to leave 1 g 
(100% of debenzylated diamine product which was used without further 
purification. 
(C. 
(.+-.)-(5.xi.,6.alpha.,7.beta.)-3,4-dichloro-N-[7-(dimethylamino)-1-oxaspi 
ro[4.5]dec-6-yl]-N-methylbenzeneacetamide and its monohydrochloride, 
hydrate 
In a 50 ml oven dried flask, fitted magnetic stir bar and pressure 
equalizing adition funnel, was placed 0.53 g (2.6 mmol) 
3,4-dichlorophenylacetic acid and 5 ml of THF (dried over 3A molecular 
sieves). To the stirred mixture was added in two batches, as a solid, 0.42 
g (2.6 mmol) 1,1'-carbonyldiimidizole. The apparatus was flushed with 
nitrogen and stirred at room temperature for 45 min at which time 0.5 g 
(2.4 mmol) of the diamine from part B above in 5 ml THF was added dropwise 
over a 15 min period. The reaction mixture was stirred at room temperature 
for 4 hr. The THF was removed in vacuo and the residue distributed between 
30 ml ethyl acetate and 20 ml water. The organic phase was dried 
(MgSO.sub.4) and solvent in vacuo. Silica gel chromatography of the 
material, eluting with 2% methanol (containing 10% NH.sub.3), 98% ethyl 
acetate gave 0.6 g (63 %) of the titled free base as a colorless oil. The 
product was dissolved in ether and treated with an ethereal solution of 
HCl. The precipitate was collected and recrystallized from methanol/ether 
to yield the titled HCl salt, mp 190.degree.-194.degree.. HNMR (80 MHz, 
CDCl.sub.3, free base) .delta.=1.2-1.90 (m, 10H), 2.18 (s, 6H), 2.98 (s, 
3H), 3.55-3.75 (m, 4H), 4.5 ((d, 2H), 7.0-7.4 (m, 3H). 
Anal. Calcd for C.sub.20 H.sub.28 Cl.sub.2 N.sub.2 O.sub.2.HCl.0.5H.sub.2 
O: C, 54.00; H, 6.46; N, 6.29; Cl, 23.91. Found: C, 54.16; H, 6.69; H, 
6.39; Cl, 24.00. 
IR: C=O 1645 cm.sup.-1. Mass spec.: m/e-398,400 (M+, 24.16%); 181 (81%); 
168 (42%); 84 (100%). 
The titled amino-amide thus produced is the C.sub.5 -epimer of the compound 
produced by the procedure of Example 16, Parts A-C. 
EXAMPLE 18 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-4-bromo-3-methoxy-N-methyl-N-[7-(1-pyrro 
lidinyl)-1-oxaspiro[4.5]dec-8-yl]benzamide 
The debenzylated diamine of Example 1, Step H is acylated with 
3-bromo-4-methoxy benzoic acid by the general acylation procedure of 
Example 6 to produce in 60% yield the titled amino-amide, mp 
156.degree.-158.degree. C., with the following elemental analysis. 
Calcd for C.sub.22 H.sub.31 N.sub.2 O.sub.3 Br: C, 58.67; H, 6.71; N, 6.22; 
Br, 17.44. Found: C, 58.49; H, 6.71; N, 6.22; Br, 17.38. 
EXAMPLE 19 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-3-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1 
-oxaspiro[4.5]dec-8-yl]benzeneacetamide 
Employing the general procedure of Example 6 but using instead 
3-bromophenylacetic acid there is produced the titled amino-amide, mp 
93.5.degree.-97.degree. C., with the following elemental analysis. 
Calcd for C.sub.22 H.sub.31 BrN.sub.2 O.sub.2 : C, 60.69; H, 7.18; N, 6.43; 
Br, 18.35. Found: C, 60.48; H, 7.33; N, 6.30; Br, 18.10. 
EXAMPLE 20 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspir 
o[4.5]dec-8-yl]-3-(trifluoromethyl)benzeneacetamide 
Employing the general procedure of Example 6 but using instead 
3-(trifluoromethyl)phenylacetic acid there is produced the titled 
amino-amide, which is isolated as the monohydrobromide, hemihydrate, mp 
198.degree.-201.degree. C., with the following elemental analysis. 
Calcd. for C.sub.23 H.sub.31 N.sub.2 O.sub.2 F.sub.3 HBr0.5H.sub.2 O: C, 
53.70; H, 6.47; N, 5.45; Br, 15.53. Found: C, 53.70; H, 6.33; N, 5.28; Br, 
15.77. 
EXAMPLE 21 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-2-nitro-N-[7-(1-pyrrolidinyl)-1 
-oxaspiro[4.5]dec-8-yl]benzeneacetamide 
Employing the general procedure of Example 6 but using instead 
2-nitrophenylacetic acid there is produced in 63% yield the titled 
amino-amide, mp 124.degree.-127.degree. C. (from ethyl acetate), with the 
following elemental analysis. 
Calc'd for C.sub.22 H.sub.31 N.sub.3 O.sub.4 : C, 65.81; H, 7.78; N, 10.47. 
Found: C, 65.52; H, 7.82; N, 10.40. 
EXAMPLE 22 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-3-nitro-N-[7-(1-pyrrolidinyl)-1 
-oxaspiro[4.5]dec-8-yl]benzeneacetamide 
Employing the general procedure of Example 6 but using instead 
3-nitrophenylacetic acid there is produced the titled amino-amide, which 
is isolated as the monohydrochloride, hemihydrate, mp 
186.degree.-189.degree. C., with the following elemental analysis. 
Calc'd for C.sub.22 H.sub.31 N.sub.3 O.sub.4 HCl0.5H.sub.2 O: C, 59.12; H, 
7.44; N, 9.40; Cl, 8.16. Found: C, 59.17; H, 7.39; N, 9.23; Cl, 8.07. 
EXAMPLE 23 
(35)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-4-nitro-N-[7-(1-pyrrolidinyl)-1-o 
xaspiro[4.5]dec-8-yl]benzeneacetamide and its monohydrochloride 
Employing the general procedure of Example 6 but using instead 
4-nitrophenylacetic acid there is produced the titled amino-amide, mp 
168.degree.-171.degree. C. (from diethyl ether-methanol), with the 
following element analysis. 
Calcd for C.sub.22 H.sub.31 N.sub.3 O.sub.4 HCl: C, 60.32; H, 7.36; N, 
9.60; Cl, 8.10 Found: C, 59.86; H, 7.27; N, 9.61; Cl, 8.06. 
EXAMPLE 24 
1-methanesulfonyl-1-azaspiro[4.5]dec-7-ene 
In an oven dried 2 liter round bottom, three-neck flask, fitted with pyrex 
magnetic stir bar and Dewar condenser charged with dry ice/acetone, 
nitrogen inlet and cooled at -78.degree. in a dry ice/acetone bath, was 
condensed 600 ml of anhydrous ammonia. A solution of 100 ml dry ethyl 
ether, 56.26 g (1.22 mol) absolute ethanol and 50 g (0.37 mol) 
3-phenyl-1-propylamine (Aldrich Chemical Co.)(cooled to -78.degree.) was 
added and the dry ice/acetone bath removed. To this solution was added, in 
small pieces, over a 2 hr period 25.5 g (1.11 mol) of sodium metal (freed 
from mineral oil by washing in pentane) at a rate to maintain a gentle 
reflux of the ammonia. After complete addition the deep blue reaction 
mixture was stirred for 18 hr without replenishing the dry ice in the 
condenser. 
The reaction flask, containing a white solid, was cooled with an ice/water 
bath and 500 ml of ice cold water was added followed by 600 ml of ether. 
After all the solids had dissolved the mixture was transferred to a 
separatory funnel and 150 ml of a saturated aqueous solution of ammonium 
chloride was added. The phases were mixed and separated. The aqueous was 
extracted with 400 ml ether. The combined ethereals were washed with 
brine, dried (MgSO.sub.4) and the solvent removed in vacuo to leave 51 g 
of crude diene intermediate. 
The crude product thus formed was placed in an oven dried 1 liter round 
bottom flask, fitted with magnetic stir bar, pressure equalizing additoin 
funnel and nitrogen inlet, along with 41.2 g (0.41 mol) triethylamine and 
250 ml methylene chloride. The flask was cooled in an ice/water bath and 
46.6 g (0.41 mol) methanesulfonylchloride in 150 ml methylene chloride was 
added dropwise over a 1 hr period to the stirred solution. The reaction 
mixture was stirred in the cold for another 45 min. The mixture was washed 
in 300 ml of water and dried (MgSO.sub.4). 
The mixture thus formed was diluted to 700 ml with methylene chloride and 6 
ml of trifluoromethane sulfonic acid was added dropwise via syringe over a 
10 min period and then stirred for 1 hr at room temperature. The mixture 
was washed 2 times with half saturated sodium bicarbonate solution, dried 
(MgSO.sub.4) and the solvent removed in vacuo to leave 73 g of crude 
product. Silica gel chromatography, eluting with 40% ethylacetate/60% 
hexane, of 8 g of the crude afforded 6 g of the titled product as a white 
crystalline solid. The remaining crude was distilled through a short path 
at reduced pressure to yield 27.4 g (bp 126.degree.-130.degree. at 0.01 
mm) of a colorless oil which crystallized upon standing at room 
temperature. The combined materials were recrystallized from 
hexane/ethylacetate to yield 33.4 g (42%) of the titled azacyclic olefin, 
mp 57.degree.-59.5.degree.. The NMR spectrum was consistent with the 
sub-titled product. 
Anal calcd for C.sub.10 H.sub.17 NO.sub.2 S: C, 55.78; H, 7.96; N, 6.51; S, 
14.89. Found: C, 55.46; H, 7.94; N, 6.46; S, 14.69. 
The mass spectrum analysis was also consistent with the sub-titled product. 
EXAMPLE 25 
1-thiaspiro[4.5]dec-7-ene 
In an oven dried 2 liter round bottom three neck flask, fitted with pyrex 
magnetic stir bar and Dewar condenser charged with dry ice/acetone 
nitrogen inlet and cooled to -78.degree. in a dry ice/acetone bath was 
condensed 500 ml anhydrous ammonia. A solution of 100 ml dry ethyl ether, 
27.5 g (86.0 mmol) absolute ethanol and 40 g (26.0 mmol) 
3-phenylpropylmercaptan (Aldrich Chemical Co.)(cooled to -78.degree.) was 
added and the cooling bath was removed. To the stirred solution was added, 
in small pieces, over a 3 hr period, 23 g (1.05 mol) of sodium metal 
(freed from mineral oil by pentane wash) at a rate to maintain a gentle 
reflux of the ammonia. After complete addition the deep blue reaction 
mixture was stirred for 18 hr without replenishing the dry ice in the 
condenser. 
The reaction flask, containing a white solid, was cooled with an ice/water 
bath and 500 ml of ice cold water was added followed by 500 ml Et.sub.2 O. 
After all the solids had dissolved the mixture was transferred to a 
separatory funnel, 200 ml of saturated NH.sub.4 Cl was added and the 
phases were mixed. The aqueous was extracted with 400 ml ether, the 
combined ethereals were washed with brine, dried (MgSO.sub.4) and the 
solvent removed in vacuo to leave 40 g of a water white liquid. Gas 
chromatographic analysis showed the material to be a 4:1 mixture of 
product diene intermediate to starting material. The mixture was used 
without purification. 
The crude material thus formed was treated with 2.5 g of p-toluenesulfonic 
acid and the pressure was lowered to 20 mm and the reaction flask was 
heated in an oil bath at 150.degree.. After a short period distillation 
began through a vacuum jacketed vigreux column and continued as the 
cyclization proceeded, to give 28 g of material, 
bp=105.degree.-109.degree. (20 ml) which by G.C. analysis consisted of an 
11:2:1 mixture of the titled cyclized olefin. This fraction was 
redistilled though a vacuum jacketed vigreux column at reduced pressure to 
collect 15 g (38%) of 1-thiaspiro[4.5]dec-7-ene as a colorless liquid, bp 
118.degree.-125.degree. (32 mm). The NMR was consistent. 
Other representative examples of compounds within the scope of this 
invention which can be prepared by procedures described in this 
specification are the cis and trans isomers of: 
a. 
N-methyl-N-[7-(1-pyrrolidinyl)-1-azospiro[4.5]dec-8-yl]-4-trifluoromethylb 
enzeneacetamide 
b. 
N-methyl-N[8-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-7-yl]-3-trifluoromethylb 
enzeneacetamide 
c. 
4-chloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-[N-ethylazaspiro[4.5]dec-8-yl]be 
nzamide 
d. 
4-fluoro-N-methyl-N-[7-(1-pyrrolidinyl)-1-benzoylazaspiro[4.5]dec-8-yl]ben 
zamide 
e. 
4-bromo-N-methyl-N-[7-(1-piperidinyl)-1-(3,4-dichlorobenzoyl)-1-azaspiro[4 
.5]undec-8-yl]benzeneacetamide 
f. 
N-[8-(1-azetidinyl)-1-acetyl-1-azaspiro[4.5]dec-7-yl]-N-methyl-4-nitrobenz 
amide 
g. 
N-[8-amino-1-(1-propionyl)-1-azaspiro[4.5]dec-7-yl]-N-methyl-2-chlorobenze 
neacetamide 
h. 
3-amino-N-methyl-N-[8-(1-pyrrolidinyl)-1-butanoyl-1-azaspiro[4.5]dec-7-yl] 
benzeneacetamide 
i. N-[8-(ethylamino)-1-thiaspiro[4.5]dec-7-yl]-4-methoxy-N-methylbenzamide, 
1,1-dioxide 
j. 
3-hydroxy-N-[7-(isopropylamino)-1-thiaspiro[4.5]dec-8-yl]N-methylbenzeneac 
etamide, 1-oxide 
k. 
N-[7-(diethylamino)-1-thiaspiro[4.5]dec-8-yl]-N,2-dimethylbenzeneacetamide 
l. 
N-[8-(1-azetidinyl)-1-oxaspiro[4.5]dec-7-yl]-N-methyl-[1,1'-biphenyl]-3-ac 
etamide 
m. 
N-[8-(dimethylamino)-1-azospiro[4.5]dec-7-yl]-3-methanesulfonyl-N-methylbe 
nzamide 
n. 
3-ethoxycarbonyl-N-methyl-N-[7-(1-piperidinyl)-1-propyl-1-azaspiro[4.5]dec 
-8-yl]benzamide 
o. 
3,4-dichloro-N-ethyl-N-[8-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-7-yl]benzene 
ethanethioamide 
p. 
4-bromo-N-methyl-N-[8-(1-pyrrolidinyl)-1-[N-(4-methylbenzoyl)-1-azaspiro[4 
.4]non-7-yl]benzenecarbothioamide 
q. 
3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-N-(4-methoxybenzoyl)-azaspir 
o[4.5]dec-8-yl]benzeneethanethioamide 
r. 
4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1-N-(4-hydroxybenzoyl)-azaspiro[4.5 
]dec-8-yl]benzenecarbothioamide 
s. 
3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-7-yl]benze 
neethanethioamide, 1,1-dioxide 
t. 
4-ethoxycarbonyl-N-methyl-N-[8-(1-pyrrolidinyl)-1-N-methylazaspiro[4.5]dec 
-7-yl]benzenecarbothioamide 
u. 
4-methanesulfonyl-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]b 
enzeneethanethioamide 
v. 
4-azida-N-(1-n-propyl)-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benze 
neethanethioamide 
w. 
4-phenyl-N-methyl-N-[8-(1-pyrrolidinyl)-1-thiaspiro[4.5]-dec-7-yl]benzenee 
thanethioamide 
x. 
4-cyano-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzenecarb 
othioamide 
y. 
4-amino-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzenecarb 
othioamide 
z. 
4-acetoxy-N-ethyl-N-[8-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-7-yl]benzenecar 
bothioamide 
aa. 
4-acetamido-N-ethyl-N-[7-(N,N-dimethylamino)-1-oxaspiro[4.5]dec-8-yl]benza 
mide 
bb. 
3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1-oxaspiro[5.5]undec-9-yl]benz 
eneacetamide 
cc. 
3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1-aza[5.5]-undec-9-yl]benzenea 
cetamide 
dd. 
3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1-thia[5.5]undec-9-yl]benzenea 
cetamide and its 1-oxides and 1,1-dioxides 
ee. 
3,4-dichloro-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamid 
e. 
ff. 4-bromo-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide 
gg. 3-chloro-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide 
EXAMPLE 26 
(5.alpha.,7.alpha.,8.beta.)-(.+-.)-3,4-Dichloro-N-methyl-N-[7-(1-pyrrolidin 
yl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide, methanesulfonate 
For reasons relating to various chemical and physical properties, as they 
may affect pharmaceutical drug formulation compounding, such as ease of 
being able to obtain profile drug (i.e., good elemental analyses, low 
solvent content, etc., melting point, water solubility properties, 
hygroscopic properties, chemical stability, and the like), the 
methanesulfonate salt form of the compound of detailed Example 1 above, 
has been selected for more advanced testing. The following description 
sets forth two methods for preparing the above-named methanesulfonate 
salt. 
Method A: 
To a solution of 5.0 g (11.7 millimoles) of 
(5.alpha.,7.alpha.,8.beta.)-(.+-.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidi 
nyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide in 100 ml of dry methanol 
cooled in an ice-water bath there was added dropwise 11.7 ml (11.7 
millimoles) of a 1.0M solution of methanesulfonic acid in methanol. After 
the addition was complete the solvent was removed in vacuo leaving a white 
foam. The crude product was recrystallized from methanol/diethyl ether to 
give 5.1 g (83 percent yield) of white crystals of the titled salt, m.p. 
210.degree.-214.degree. C. 
Anal. Calcd. for C.sub.23 H.sub.34 Cl.sub.2 N.sub.2 O.sub.5 S: C, 52.97; H, 
6.57; N, 5.37; C, 13.60; S, 6.15. Found: C, 52.62; H, 6.62; N, 5.41; C, 
13.64; S, 6.08. 
Method B: 
A 1130 g (2.66 mole) batch of 
(5.alpha.,7.alpha.,8.beta.)-(.+-.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidi 
nyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide was dissolved in 5 liters of 
methylene chloride and filtered into a clean, dry 12 liter reaction vessel 
equipped with a mechanical stirrer nitrogen inlet, thermometer, and a 1 
liter dropping funnel. (Footnote 1) 
The solution was cooled to about 15.degree. C. in an ice-water bath and a 
solution of 256 g (173 ml, 2.66M) of methanesulfonic acid in 500 ml of 
methylene chloride was added over about 1 hour and stirred for about 30 
minutes (Footnote 2). 
The addition funnel was replaced with vacuum distillation apparatus and 
most of the methylene chloride was removed under vacuum pressure at about 
40.degree. C. (Footnote 3). 
Then 600 ml of methanol was added to the residue and sufficient time was 
allowed, with stirring, for solution to become complete. 
The resulting solution was cooled to 20.degree. C. and diluted by the slow 
addition of 6 liters of diethyl ether over 2 hours. 
The resulting mixture was stirred overnight at room temperature under 
nitrogen (Footnote 4). 
The resulting mixture was filtered and the solids were washed with 2 liters 
of diethyl ether. The filtered crystals of the titled methanesulfonate 
salt were air-dried for 3 hours and then dried in vacuo at 50.degree. C. 
for 20 hours (Footnote 5). 
Footnotes: 
FNT (1)The 
(5.alpha.,7.alpha.,8.beta.)-(.+-.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidi 
nyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide free base was contaminated 
with an inorganic solid. Actually, 1230 g of material was used of which 
1130 g was the desired free base. The inorganic solid was filtered away 
and apparently caused no difficulty with the subsequent methanesulfonate 
salt formation. 
FNT (2)The pH is helpful to determine if enough methanesulfonic acid has been 
added. When addition is complete a pH of 5 to 7 should be observed on 
moist pH litmus paper. If a large excess of methanesulfonic acid has been 
added, decomposition in the concentration step may be a problem. 
FNT (3)A final volume of about 2 liters of residual material, with some 
crystallization, was obtained. 
FNT (4)The methanesulfonate salt of the titled amino-amide crystallizes slowly 
and best yields are obtained with overnight stirring. 
FNT (5)If methylene chloride is present in the final solids (as determined by 
NMR analysis), a recrystallization from methanol/diethyl ether may be 
required. 
FNT (a) Dissolve the crystalline material in 3 to 4 ml/g of methanol, 
FNT (b) Dilute the resulting solution with 25 ml/g of diethyl ether, 
FNT (c) Stir the mixture for several hours, filter, and dry as described 
above. 
Compounds of formula (I) where the cycloalkyl ring (the ring that contains 
the --(CH.sub.2).sub..rho. - and --(CH.sub.2).sub.n -moieties) contains 5 
or 7 ring carbon atoms are also included within the scope of this 
invention. Such 5 or 7 ring carbon atom cycloalkyl ring compounds are 
those wherein p+n+3 equals 5 or 7. In the process Schemes X to XII, 
provided herewith, r is 1 or 2, and p+n+3 carbon atoms equals 5 or 7 when 
j+k equals 2 or 4. 
With respect to chemical formula Schemes X to XII, the following comments 
are offered: 
SCHEME X 
The process of Scheme X can be used to prepare the 1-oxaspiroolefin 
intermediate compounds which ring olefin compounds are used to prepare 
compounds of this invention wherein Z (in the generic compound per se 
Formula I) is oxygen and p+n+3 is equal to 5 or 7, so that the 
cycloaliphatic ring containing p and n is a five- or seven-membered carbon 
ring. In Scheme X, j+k is equal to 2 or 4, and the chemical process steps 
are described as follows: 
1a. The protected bromoalkanol (shown as an acetal) is metalated (i) with 
lithium wire at -20.degree. to 23.degree. C. in diethyl ether (Et.sub.2 O) 
or THF, or (ii) with tertiary butyllithium at -78.degree. C. in Et.sub.2 O 
or THF. 
1b. To the resulting lithium reagent from step 1(a) is added the selected 
C.sub.5 or C.sub.7 cycloalkenone in Et.sub.2 O or THF at -78.degree. C. to 
reflux, to form the cyclic compound shown at the beginning of Step 2. 
2. The acetal protecting group is removed by mild acid hydrolysis with: 
(a) an ion exchange resin (e.g., Dowex-50-WX8) in methanol at about 
23.degree. C. (room temperature), or 
(b) with an ethanol/water/hydrochloric acid (57.6/38.6/3.8 v/v/v) mixture 
at about 23.degree. C., to form the di-hydroxy (--OH) compound shown at 
the beginning of Step 3. 
3. The di-hydroxy compound from Step 2 is subjected to spirocyclization: 
(i) for all values of j and k by treatment with methanesulfonyl chloride 
and two equivalents of triethylamine in methylene chloride at about 
0.degree. to 41.degree. C., or (ii) when one of j and k is zero using 
acids such as p-toluenesulfonic, hydrochloric, or trifluoromethanesulfonic 
acid with or without solvents such as methanol, ethanol, THF or DMF. 
SCHEME XI 
The chemical process of Scheme XI is used to prepare the 1-oxaspiro olefin 
intermediate compound used to prepare compounds of this invention where Z 
(in the generic compound per se Formula I) is NR.sub.3 and p+n+3 is equal 
to 5 or 7, so that the cycloaliphatic ring, containing p and n, is a five- 
or seven-membered carbon ring. In Scheme XI, j+k is equal to 2 or 4, and 
the chemical process steps are described as follows: 
1a. The sulfonyl-protected bromo-amine is metalated (i) with lithium wire 
at -20.degree. to 23.degree. C. in Et.sub.2 O or THF, or (ii) with 
tertiary butyllithium at -78.degree. C. in Et.sub.2 O or THF. 
1b. To the resulting lithium reagent, from Step 1a, there is added the 
appropriate C.sub.5 or C.sub.7 -cycloalkenone in Et.sub.2 O or THF at 
-78.degree. C. to reflux, to form the cyclic compound shown at the 
beginning of Step 2. 
2. The resulting hydroxy-olefinic compound from Step 1 is subjected (i) to 
acid catalyzed azaspirocyclization when one of j and k is zero using acids 
such as p-toluenesulfonic, hydrobromic or trifluoromethanesulfonic acid or 
the like, with or without a solvent such as methanol, ethanol, THF or 
benzene, or (ii) for all values of j and k to treatment with 
methanesulfonyl chloride and two equivalents of triethylamine in methylene 
chloride at about 0.degree. to 41.degree. C., to form the sulfonyl 
protected aza-spiro-bicyclic olefin shown at the beginning of Step 3. 
3. The N-protected-aza-spiro bicyclic olefin, is subjected to reductive 
cleavage of the methanesulfonyl-protecting group at the desired stage in 
the synthesis, as described in Steps 3 and 4 of Scheme V, hereinabove. 
SCHEME XII 
The process of Scheme XII can be used to prepare the 1-thiaspiroolefin 
intermediate compounds used to make the compounds of this invention of 
Formula I wherein Z is S, SO or SO.sub.2 and p+n+3 is equal to 5 or 7, so 
that the resulting cycloaliphatic ring containing p and n is a five- or 
seven-membered carbon ring. In Scheme XII j+k is equal to 2 or 4, and the 
steps shown are described as follows: 
1a. The protected bromothiol is metalated (i) with lithium wire at 
-20.degree. to 23.degree. C. in Et.sub.2 O or THF, or (ii) with tertiary 
butyllithium at -78.degree. C. in Et.sub.2 O or THF. 
1b. To the resulting lithium reagent prepared in Step 1a, there is added 
the appropriate C.sub.5 or C.sub.7 -cycloalkenone in Et.sub.2 O or THF at 
-78.degree. C. to reflux, to form the cyclic compound shown at the 
beginning of Step 2. 
2. The mono-thio acetal protecting group is cleaved by (a) stirring the 
sulfur-protected cyclic compound in methanol solution in the presence of 
an acidic resin such as Dowex-50-WX8 resin or other acid catalyst such as 
hydrochloric, p-toluenesulfonic or hydrobromic acid in acetic acid, 
methanol or ethanol, or (b) treating the sulfur-protected cyclic compound 
with boron trifluoride etherate in acetic acid, to form the cyclic 
olefinic hydroxy thiol compound shown at the beginning of Step 3. 
3. The cyclic olefinic hydroxy thiol compound is subjected (i) to acid 
catalyzed spirothiacyclization when one of j and k is zero using acids 
such as p-toluenesulfonic, hydrochloric or trifluoromethanesulfonic acid 
with or without solvents such as methanol, ethanol, THF or DMF, or (ii) 
for all values of j and k to treatment with methanesulfonyl chloride and 
two equivalents of triethylamine in methylene chloride at about 0.degree. 
to 41.degree. C. 
The cyclized olefins produced by the processes of Schemes X to XII are 
further reacted by epoxidation, epoxide opening, mesylate formation, 
diamine formation, amine protection, amine-acylation, and optional sulfur 
oxidation steps as set forth in Scheme I, Steps 9 to 12, and Scheme IV, 
Steps 7 and 8, hereinabove. 
The cycloalkenone compounds used in the various process scheme outlines 
shown hereinabove are commercially available or at least known compounds. 
Thus, 3-cyclopentenone, a compound where j is 1 and k is 1, is described 
in the J. Org. Chem., 32, 3148 (1967). 
The 2-cyclopentenone, a compound where j is 0 and k is 2, is commercially 
available. 
2-Cycloheptenone, where j is 0 and k is 4, is commercially available. 
3-Cycloheptenone, where j is 1 and k is 3, is disclosed in Tetrahedron, 
Suppl. 8, Part 1, p. 105 (1966). 
4-Cycloheptenone where j is 2 and k is 2, is described in J. Am. Chem. Soc, 
94, (1972), p. 6026. 
Thus, this invention includes compounds of Formula I, having expanded 
definitions of the variables set forth hereinabove, for the compounds of 
Formula I wherein the wavy line bonds between the nitrogens and the 
cycloaliphatic ring carbon atoms indicate a cis or trans relationship of 
the two nitrogen-containing groups at positions 1 and 2 of the 
cycloaliphatic ring, 
p is a whole number integer 0, 1, 2, 3, 4 and n is a whole number integer 
0, 1, 2, 3, or 4 so that the resulting cycloaliphatic ring containing p 
and n has 5, 6 or 7 carbons; 
m is 3 or 4; 
A is a single chemical bond (--), --(CH.sub.2).sub.q -- where q is a whole 
number integer 1 to 4 or --CH(CH.sub.3)--; 
X and Y are independently selected from the group consisting of hydrogen, a 
halogen having an atomic number of from 9 to 35, trifluoromethyl, nitro, 
methoxy, hydroxy, azido, C.sub.1 to C.sub.3 -alkyl, phenyl, 
methanesulfonyl, cyano, amino, C.sub.1 to C.sub.3 -alkoxycarbonyl, C.sub.1 
to C.sub.3 -alkanoyloxy, C.sub.1 to C.sub.3 -carboxyacylamino 
(--NHC(O)R.sub.4 wherein R.sub.4 is hydrogen or C.sub.1 to C.sub.2 
-alkyl); 
R is hydrogen or C.sub.1 to C.sub.3 -alkyl; 
R.sub.1 and R.sub.2, taken separately, are each hydrogen, C.sub.1 to 
C.sub.3 -alkyl or allyl; 
R.sub.1 and R.sub.2, taken together with the nitrogen to which they are 
bonded, complete a ring selected from the group consisting of azetidinyl, 
pyrrolidinyl, piperidinyl, pyrrolyl, 3-pyrrolin-1-yl 
##STR10## 
3-azabicyclo[3.1.0]hexan-3-yl 
##STR11## 
and 3-azabicyclo[3.2.0]heptan-3-yl 
##STR12## 
E is oxygen or sulfur, 
Z is selected from the group consisting of oxygen (--O--), --NR.sub.3 --, 
bivalent sulfur (--S--), sulfinyl (--S(O)--) and sulfonyl (--S(O).sub.2 
--); 
R.sub.3 is hydrogen, C.sub.1 to C.sub.3 -alkyl, benzoyl, X- and Y-ring 
substituted benzoyl, C.sub.2 to C.sub.4 -alkanoyl (--C(O)--C.sub.1 to 
C.sub.3 -alkyl); 
provided that when p is 2, n is 1, m is 3, A is (CH.sub.2).sub.q where q is 
1, R.sub.1 is methyl, R.sub.1 and R.sub.2 are taken together with the 
nitrogen to which they are bonded to complete a pyrrolidinyl ring, E is 
oxygen, Z is oxygen, and the relative stereochemistry is 
(5.alpha.,7.alpha.,8.beta.), then X and Y taken together on the phenyl 
ring cannot be chlorine on the 2- and 4-positions on the phenyl ring. 
Pharmacologically acceptable salts of such compounds of Formula I are also 
part of this invention. 
This expanded definition of the group of compounds thus includes all of the 
C.sub.5 to C.sub.7 -cycloaliphatic ring compounds, (p+n+3=5 or 7), and an 
expanded list of --NR.sub.1 R.sub.2 amino groups. 
All of the compounds of Formula I are characterized by their containing the 
new mono-oxy, thia- or aza-ring structure attached to the C.sub.5 to 
C.sub.7 -cycloaliphatic ring and an asymmetric carbon atom of the 
cycloaliphatic ring which features are not found in prior art compounds of 
which we are aware. 
The compounds of Formula I or their acid addition salts in their 
crystalline state may sometimes be isolated from their reaction mixtures 
as solvates, as indicated above. Also, as with the cyclohexyl compounds 
described above, the cyclopentyl and cycloheptyl ring compounds contain at 
least three asymmetric carbon atoms, each of which possess R- and 
S-configurations, and possess the same possible cis and trans orientation 
considerations as is indicated above for the cyclohexyl compounds. 
After preparing the required C.sub.5 or C.sub.7 -cycloaliphatic ring 
containing olefin intermediates, and the respective diamine therefrom, the 
new Formula Ia compounds are prepared by acylation procedures described 
hereinabove. If desired, the respective d- and L-optical isomers can be 
prepared or separated by methods described above. 
Using the procedures described above, the following compounds are prepared: 
hh. 
(.+-.)-(5.xi.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl 
)-1-azaspiro[4.5]dec-8-yl]benzeneacetamide, mp 94.degree.-96.degree. C., 
ii. 
(.+-.)-(5.xi.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl 
)-1-azaspiro[4.5]dec-8-yl]benzeneacetamide, the 5-epimer of the compound 
named immediately above, fumarate, mp 125.degree.-131.degree. C., 
jj. 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspi 
ro[4.5]dec-8-yl]benzenepropanamide, mp 116.degree.-118.degree. C., 
kk. 
(.+-.)-(5.xi.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl 
)-1-azaspiro[4.5]dec-7-yl]benzeneacetamide, mp 97.degree.-99.degree. C., 
ll. 
(.+-.)-(5.xi.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl 
)-1-azaspiro[4.5]dec-7-yl]benzeneacetamide, 5-epimer of the compound named 
immediately above, mp 83.degree.-85.degree. C., 
mm. 
(.+-.)-(5.xi.,7.alpha.,8.beta.)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1-a 
zaspiro[4.5]dec-8-yl]benzamide, mp 124.degree.-125.5.degree. C., 
nn. 
(.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspi 
ro[4.5]-dec-8-yl]benzenebutanamide, mp 74.5.degree.-77.degree. C., 
oo. 
(.+-.)-(5.xi.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl 
)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide, 1,1-dioxide, mp 
130.degree.-132.degree. C., 
pp. 
(.+-.)-(5.xi.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl 
)-1-thiaspiro[4.5]dec-7-yl]benzeneacetamide, 1,1-dioxide, mp 
147.degree.-148.degree. C., 
qq. 
(.+-.)-(5.xi.,7.alpha.,8.beta.)-4-bromo-N-methyl-N-[8-(1-pyrrolidinyl)-1-a 
zaspiro[4.5]dec-7-yl]benzamide, mp 118.degree.-121.degree. C., 
rr. 
(.+-.)-(5.xi.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl 
)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide, mp 118.5.degree.-120.degree. 
C., 
ss. 
(.+-.)-(5.xi.,7.alpha.,8.beta.)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1-t 
hiaspiro[4.5]dec-8-yl]benzamide, mp 136.degree.-137.degree. C., 
tt. 
(.+-.)-(5.xi.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl 
)-1-thiaspiro[4.5]dec-7-yl]benzeneacetamide, mp 104.degree.-106.degree. C., 
uu. 
(.+-.)-(5.xi.,7.alpha.,8.beta.)-4-bromo-N-methyl-N-[8-(1-pyrrolidinyl)-1-t 
hiaspiro[4.5]dec-7-yl]benzamide, mp 136.degree.-140.degree. C., 
vv. 
3,4-dichloro-N-methyl-N-[7-(1-pyrrolyl)-1-oxaspiro[4.5]dec-8-yl]benzeneace 
tamide, 
ww. 
4-bromo-N-methyl-N-[7-(1-piperidinyl)-1-oxaspiro-[4.5]dec-8-yl]benzamide, 
xx. 
3-chloro-4-methoxy-N-methyl-N-[7-(3-pyrrolin-1-yl)-1-oxaspiro[4.5]dec-8-yl 
]benzeneacetamide, 
yy. 
4-trifluoromethyl-N-methyl-N-[7-(3-azabicyclo-[3.1.0]hexan-3-yl)-1-oxaspir 
o[4.5]dec-8-yl]benzenepropanamide, 
zz. 
3,4-dichloro-N-methyl-N-[7-(3-azabicyclo-[3.2.0]-heptan-3-yl]-1-oxaspiro[4 
.5]dec-8-yl]benzeneacetamide, 
aaa. 
3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.6]undec-6-yl]benz 
eneacetamide, 
bbb. 
3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1-oxaspiro[4.6]undec-7-yl]benz 
eneacetamide, 
ccc. 
3,4-dichloro-N-methyl-N-[9-(1-pyrrolidinyl)-1-oxaspiro[4.6]undec-8-yl]benz 
eneacetamide, 
ddd. 
3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.6]undec-8-yl]benz 
eneacetamide, 
eee. 
3,4-dichloro-N-methyl-N-[6-(1-pyrrolidinyl)-1-oxaspiro[4.6]undec-7-yl]benz 
eneacetamide, 
fff. 
3,4-dichloro-N-methyl-N-[6-(1-pyrrolidinyl)-1-oxaspiro[4.4]non-7-yl]benzen 
eacetamide, 
ggg. 
3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.4]non-8-yl]benzen 
eacetamide, 
hhh. 
3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.4]non-6-yl]benzen 
eacetamide, 
iii. 
(.+-.)-(5.xi.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl 
)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide, mp 129.degree.-132.degree. C., 
and the like. 
The expanded group of compounds of Formula I are useful for the same uses 
set forth above for the previous, above Formula I compounds. The compound 
of Example 1, as its methanesulfonate salt, has been selected for advanced 
analgesic testing. 
##STR13##