9-Hydroxyhexahydrodibenzo[b,d]pyrans, 1-substituted-9-hydroxyhexahydrodibenzo[b,d]pyrans wherein the substituent is hydrogen, methyl, hydroxymethyl, formyl, carboxy, carbamyl, amino, mono- and di-alkylamino, alkanoylamino, phenalkylsulfonamido or alkylsulfonamido, and the corresponding 9-ketones, all of which are useful as CNS agents, especially as analgesics and tranquilizers, intermediates therefor the processes for their preparation.

BACKGROUND OF THE INVENTION 
1. Field of Invention 
This invention relates to certain novel dibenzopyrans and, more 
particularly, to 9-hydroxyhexahydrodibenzo[b,d]pyrans, 
1-substituted-9-hydroxyhexahydrodibenzo[b,d]pyrans wherein the substituent 
is hydrogenn, methyl, hydroxymethyl, formyl, carboxy, carbamyl, amino, 
mono- or dialkylamino, alkanoylamino, phenalkylsulfonamido or 
alkylsulfonamido, and the corresponding 9-ketones having at the 3-position 
an alkyl, aralkyl or pyridylalkyl, in each of which an oxygen atom can be 
present at some point in the alkyl moiety, or phenoxy or pyridyloxy, the 
use of such compounds as CNS agents, especially as tranquilizers and 
analgesics in mammals, including man, intermediates therefor, and 
processes for preparation of such compounds. 
2. Description of the Prior Art 
Despite the current availability of a number of analgesic agents, the 
search for new and improved agents continues, thus pointing to the lack of 
an agent useful for the control of broad levels of pain and accompanied by 
a minimum of side-effects. Aspirin, the most commonly used agent, is of no 
practical value for the control of severe pain and is known to exhibit 
various undesirable side-effects. Other, more potent analgesic agents such 
as d-propoxyphene, codeine and morphine, possess addictive liability. The 
need for improved and potent analgesic agents is, therefore, evident. 
The preparation and analgesic properties of tetrahydro- and 
hexahydro-1-amino-3-alkyl-6H-dibenzo[b,d]pyrans having at the 9-position a 
hydrogen or a methyl group are described in U.S. Pat. No. 3,886,184, 
issued May 27, 1975. 
Mechoulam et al., Chem. Revs., 76, 75-112 (1976) discuss several 
derivatives of .DELTA..sup.1 -and .DELTA..sup.6 -tetrahydrocannabinols 
which have at the 9-position a hydrogen, methyl, hydroxymethyl, formyl or 
carboxyl group. No references to the preparation and properties of 
saturated A-ring cannabinol-like compounds having such substituents at the 
1-position are known. 
U.S. Pat. No. 3,901,926, issued Aug. 26, 1975, describes 
1-hydroxy-3-aralkyl-6,6-di(lower alkyl)-hexahydrodibenzo[b,d]pyrans having 
hydrogen or methyl at the 9-position which are useful as analgesic agents. 
U.S. Pat. Nos. 3,507,885 and 3,636,058, issued Apr. 21, 1970 and Jan. 18, 
1972, respectively, describe various 
1-hydroxy-3-alkyl-6H-dibenzo[b,d]pyrans having at the 9-position 
substituents such as oxo, hydrocarbyl and hydrocarbylidene useful as 
psychotropic and analgesic agents, and intermediates therefor. 
Mechoulam et al., pages 129-130 in "Marijuana, Chemistry, Pharmacology and 
Clinical Effects", Academic Press, New York, N. Y. 1973, summarize 
structure-activity relationships in the cannabinoids. With respect to the 
1-position, the implication is that an aromatic hydroxyl group is 
essential for activity. Blocking of the hydroxyl group at the 1-position 
as an ether group inactivates the molecule. Additionally, it is noted that 
introduction of a hydroxyl group on the methyl group at the 9-position 
retains activity. No studies appear to have been made as to the effect of 
substitution of groups other than hydroxyl, methyl ether or acetoxy at the 
1-position. 
SUMMARY OF THE INVENTION 
It has now been found that certain dibenzo[b,d]pyrans; namely, 
9-hydroxyhexahydro-3-substituted-6H-dibenzo[b,d]pyrans and the 
corresponding 9-ketone derivatives thereof (formulae I and II, 
respectively) are effective as CNS agents, especially as analgesics and 
tranquilizers, in mammals, including humans. Also included in this 
invention are various derivatives of said compounds which are useful as 
dosage forms of said compounds, and intermediates for said compounds. The 
compounds have the formulae: 
##STR1## 
wherein R.sub.0 is selected from the group consisting of oxo and 
alkylenedioxy having from two to four carbon atoms; 
Or is selected from the group consisting of hydroxy and alkanoyloxy having 
from one to five carbon atoms; 
R.sub.1 is selected from the group consisting of hydrogen, methyl, 
hydroxymethyl, formyl, carboxy, carbamyl, alkylsulfonamido having from one 
to six carbon atoms, phenalkylsulfonamido having from one to four carbon 
atoms in the alkyl moiety, and NR.sub.4 R.sub.5 wherein R.sub.4 is 
selected from the group consisting of hydrogen and alkyl having from one 
to four carbon atoms, and R.sub.5 is selected from the group consisting of 
R.sub.4 and alkanoyl having from one to four carbon atoms, with the 
proviso that when R.sub.5 is alkanoyl, R.sub.4 is hydrogen; 
each of R.sub.2 and R.sub.3 is selected from the group consisting of 
hydrogen and methyl; 
Z is selected from the group consisting of 
(a) alkylene having from one to 10 carbon atoms; 
(b) --(alk.sub.1).sub.m --O--(alk.sub.2).sub.n -- wherein each of 
(alk.sub.1) and (alk.sub.2) is alkylene having from one to ten carbon 
atoms, with the proviso that the summation of carbon atoms in (alk.sub.1) 
plus (alk.sub.2) is not greater then 10; each of m and n is 0 or 1; and 
W is selected from the group consisting of hydrogen, pyridyl, 
##STR2## 
wherein W.sub.1 is selected from the group consisting of hydrogen, fluoro 
and chloro; 
and the pharmaceutically acceptable acid addition salts of those compounds 
wherein R.sub.1 is NR.sub.4 R.sub.5 and/or W is pyridyl. 
For convenience, the above formulae depict the racemic compounds. However, 
the above formulae are considered to be generic to and embracive of the 
racemic modifications of the compounds of this invention, the 
diastereomeric mixtures, the pure enantiomers and diastereomers thereof. 
The utility of the racemic mixtures, the diastereomeric mixtures as well 
as of the pure enantiomers and diastereomers is determined by the 
biological evaluations described below. 
Further, various intermediates useful in the preparation of compounds 
having the above formulae are also included in this invention. The 
intermediates have the formulae: 
##STR3## 
wherein each of R.sub.0, R.sub.1, R.sub.2, R.sub.3, Z and W are as defined 
above; R.sub.1 ' is hydrogen, methyl or hydroxymethyl; and R.sub.6 is 
hydrogen or formyl. 
Also included in this invention are pharmaceutically-acceptable acid 
addition salts of those compounds described herein which contain a basic 
group; i.e., those compounds wherein R.sub.1 is NR.sub.4 R.sub.5 and/or W 
is pyridyl, especially those compounds of formulae I and II having such 
values of R.sub.1 and/or W. Representative of such salts are mineral acid 
salts as the hydrochloride, hydrobromide, sulfate, nitrate, phosphate; 
organic acid salts such as the citrate, acetate, sulfosalicylate, 
tartrate, glycolate, malonate, maleate, fumarate, malate, 
2-hydroxy-3-naphthoate, pamoate, salicylate, stearate, phthalate, 
succinate, gluconate, mandelate, lactate and methanesulfonate. 
Compounds having the formulae I, II and III above contain asymmetric 
centers at the 6a- and/or 10a-positions. There may be additional 
asymmetric centers in the 3-position substituent (-Z-W), and 6- and 
9-positions. Diastereomers with the 9.beta.-configuration are generally 
favored over the 9.alpha.-isomers because of greater (quantitatively) 
biological activity. For the same reason, the trans(6a,10a)diastereomers 
of compounds of formula I are generally favored over the 
cis(6a,10a)diastereomers. Among the enantiomers of a given compound one 
will generally be favored over the other and the racemic because of its 
greater activity. The enantiomer favored is determined by the procedures 
described herein. For convenience, the above formulae depict the racemic 
compounds. However, the above formulae are considered to be generic to and 
embracive of the racemic modifications of the compounds of this invention, 
the diastereomeric mixtures, the pure enantiomers and diastereomers 
thereof. The utility of the racemic mixtures, the diastereomeric mixtures 
as well as of the pure enantiomers and diastereomers is determined by the 
biological evaluations described below. 
Asymmetric centers may exist in intermediates IV-VIII at the 2-position and 
in the 7-position substituent (-Z-W). The 2- and 7-positions in formulae 
IV-VIII correspond to the 6- and the 3-positions, respectively, of 
compounds having formulae I, II and III. 
Favored because of their greater biological activity relative to that of 
other compounds described herein are compounds of formulae I and II 
wherein OR and R.sub.0 are as defined above; R.sub.1 is hydrogen, methyl, 
hydroxymethyl or NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as 
defined above; R.sub.2 is methyl; R.sub.3 is hydrogen or methyl, and group 
-Z-W has the values shown below. 
TABLE I 
______________________________________ 
Z W m n 
______________________________________ 
alkylene having from 5-9 carbon atoms 
H -- -- 
alkylene having from 2-5 carbon atoms 
phenyl or -- -- 
4-pyridyl -- -- 
(alk.sub.1).sub.m --O--(alk.sub.2).sub.n 
H, phenyl 1 1 
H, phenyl 0 1 
H, phenyl 1 0 
______________________________________ 
Preferred compounds are those favored compounds designated above 
wherein OR is hydroxy; 
R.sub.0 is oxo; 
R.sub.1 is hydrogen, methyl, hydroxymethyl or amino; 
R.sub.2 is methyl; 
R.sub.3 is methyl; 
and Z and W have the values shown below: 
______________________________________ 
Z W m n 
______________________________________ 
alkylene having 2-5 carbon atoms 
phenyl or -- -- 
4-pyridyl -- -- 
alkylene having 5-9 carbon atoms 
H -- -- 
(alk.sub.1).sub.m --O--(alk.sub.2).sub.n where (alk.sub.2) 
H, phenyl 0 1 
alkylene having 5-9 carbon atoms 
______________________________________ 
Additionally, the favored and preferred classes of intermediates of 
formulae III-VIII are those compounds which serve as intermediates for the 
favored and preferred compounds of formulae I and II. 
DETAILED DESCRIPTION OF THE INVENTION 
Compounds of this invention of formulae I and II wherein R.sub.1 is other 
than hydrogen or methyl are prepared by the following sequence (Scheme A): 
##STR4## 
In what can be considered as one of the simpler exemplifications of the 
above sequence, --Z--W in the starting material represents --OH. The 
3,5-dihydroxystilbene is converted to the 4-chromanone derivative of 
formula VII by reaction with an acrylic acid derivative of the formula 
R.sub.2 R.sub.3 --C.dbd.CH--COOH in the presence of boron trifluoride 
etherate at from about 20.degree. C. to about 125.degree. C. In addition 
to the 4-chromanone of formula VII a second product, isomeric to formula 
VII (7-R.sub.1 '-2,2-R.sub.2 R.sub.3 -5-Z-W-4-chromanone), is also 
produced. 
When the group -Z-W represents an ether group having the formula --O-- 
(alk.sub.2).sub.n -W it is convenient to convert the 7-hydroxy (Z--W) 
group at this stage of the sequence. Typical procedures for ether 
formation comprise reaction of the 2,2-R.sub.2 R.sub.3 
-7-hydroxy-5-(2-phenylethenyl)-4-chromanone with the mesylate or tosylate 
of the appropriate alcohol having the formula HO--(alk.sub.2).sub.n --W in 
a reaction-inert solvent in the presence of a base such as an alkali metal 
carbonate. A suitable solvent for the reaction is N,N-dimethylformamide. 
The reaction is generally conducted at a somewhat elevated temperature 
such as, for example, at about 50.degree. C. to about 85.degree. C. An 
alternative procedure for preparing such ethers is the Williamson 
Synthesis which comprises reacting the 4-chromanone of formula VII in 
N,N-dimethylformamide with an alkali metal hydroxide, e.g. potassium 
hydroxide, to form the potassium salt thereof which is subsequently 
reacted with the appropriate bromide having the formula Br--Z--W at an 
elevated temperature such as, for example, fromm about 75.degree. C. to 
about 125.degree. C. 
The compound having formula VII is then subjected to oxidation by means of 
sodium periodate and osmium tetroxide in a reaction-inert solvent at 
ambient temperatures to produce the 4-chromanone-5-carboxaldehyde having 
formula VI-A. The aldehyde group of formula VI-A is then converted to a 
hydroxymethyl group (formula VI-B) by reduction with potassium or lithium 
trisec-butylborohydride. Conversion of the aldehyde function to the 
hydroxymethyl group provides a convenient means for protecting the 
aldehyde function and, additionally, provides compounds having formulae I 
and II wherein R.sub.1 is hydroxymethyl which are in themselves active as 
CNS agents. The 4-chromanones of formula VI-B are then converted to 
hydroxymethylene derivatives of formula V by reaction with methyl or ethyl 
formate and sodium hydride. Compounds having formula III-A are prepared by 
ring annelation of the appropriate 3-hydroxymethylene compounds of formula 
V with methyl vinyl ketone in the presence of a base; for example, an 
alkali metal hydroxide or alkoxide or a tertiary organic base, such as 
triethylamine, to effect Michael addition, followed by treatment with a 
base, e.g an alkali metal hydroxide or alkoxide (sodium or potassium 
hydroxide, ethoxide or methoxide), to complete the cyclization. 
The thus-produced 6a,7-dihydro-1-hydroxymethyl-6,6-R.sub.2 R.sub.3 
-3-(Z-W)-6H-dibenzo[b,d]pyran-9(8H)-one (III-A) is then converted via 
Birch reduction to a mixture of the corresponding 
6a,.beta.,7,10,10a.alpha.-tetrahydrodibenzo[b,d]pyran-9(8H)-one and the 
isomeric 6a.beta.,10a.beta.-isomer (formula II-A). The reduction is 
conveniently carried out using lithium as the metal. However, sodium or 
potassium can also be used. The reaction is generally conducted at a 
temperature of from about -35.degree. C. to about -80.degree. C. Other 
methods of reduction can, of course, be used. However, the Birch reduction 
is favored because it offers stereo-selectivity resulting in formation of 
the trans-ketone of formula II-A as the major product. 
Treatment of compounds of formulae II and III wherein R.sub.O is oxo with 
the appropriate alkylene glycol having from two to four carbon atoms in 
the presence of a dehydrating agent such as p-toluenesulfonic acid, or 
other acid used in ketalization (oxalic, adipic), affords the 
corresponding ketals. 
Reduction of the 9-oxo groups of formulae II and III compounds (R.sub.O = 
oxo) via metal hydride reduction affords compounds of formula I (R = H). 
Representative of the metal hydrides useful for such conversion are 
lithium aluminum hydride, lithium borohydride and sodium borohydride. 
Sodium borohydride is favored as reducing agent in this step since it not 
only affords satisfactory yields of desired product, but reacts slowly 
enough with hydroxylic solvents (methanol, ethanol, water) to permit their 
use as solvents. A temperature of from about 0.degree. C. to 30.degree. C. 
is generally used. Lower temperatures, even down to about -70.degree. C., 
can be used to increase selectivity of the reduction. Higher temperatures 
cause reaction of the sodium borohydride with the hydroxylic solvent. If 
higher temperatures are desired or required for a given reduction, 
isopropyl alcohol or the dimethyl ether of diethylene glycol are used as 
solvents. Agents such as lithium borohydride or lithium aluminum hydride 
require anhydrous conditions and non-hydroxylic solvents 
(1,2-dimethoxyethane, tetrahydrofuran, ether, dimethyl ether of diethylene 
glycol). The isomeric 9.alpha.- and 9.beta.-hydroxy compounds are produced 
in this step. 
When the value of the R.sub.1 variable as hydroxymethyl is desired, direct 
conversion of formula II-A compounds to formula I compounds is achieved as 
described above. When, however, R.sub.1 is to be other than hydroxymethyl, 
compounds having formula II-A are converted to corresponding 
carboxaldehydes having formula II-B by oxidation with the stable reagent 
pyridinium chloro chromate according to the procedure described in 
Tetrahedron Letters, 2647 (1975). Oxidation of the carboxaldehyde group by 
means of potassium permanganate affords the corresponding carboxylic acid 
compound of formula II-C. Treatment of the carboxylic acid compound with 
oxalyl chloride in the presence of a base such as sodium hydroxide 
followed by treatment of the thus-produced acid chloride with ammonia 
affords the corresponding carboxamide derivatives having formula II-D. A 
variety of halogenating agents other than oxalyl chloride can, of course, 
be used in this process to produce the acid chloride. Representative of 
such agents are thionyl chloride, phosphorous pentachloride or phosphorous 
oxychloride. The carboxamide derivatives are then converted, by treatment 
with sodium hypobromite, to the corresponding amino compounds which, when 
treated with acid, are deketalized to give compounds having formula II-E 
wherein R.sub.1 is amino. Reduction of the 9-oxo groups by sodium 
borohyride, as previously described, produces the corresponding 9-hydroxy 
derivatives having formula I. The isomeric 9.alpha.- and 9.beta.-hydroxy 
compounds are produced. 
It is evident from the above reaction sequence that compounds of formula I 
having the various values previously ascribed to it can be produced by 
reduction of the 9-oxo group of the appropriate formula II compound having 
the desired R.sub.1 value. 
Compounds of formula II-B are deformylated by treatment with 
tris-triphenylphosphine rhodium chloride, thus providing a convenient 
route to compounds of formulae I and II wherein R.sub.1 is hydrogen. The 
procedure comprises refluxing the formyl compound of formula II-B with 
tris-triphenylphosphine rhodium chloride in a reaction-inert solvent such 
as toluene or other hydrocarbon having a boiling point above 75.degree. C. 
for several hours until reaction is complete. 
An alternative procedure to production of formula VI-A compounds comprises 
the reaction of 3,3',5,5'-tetrahydroxystilbene with the appropriate 
3,3-R.sub.2 R.sub.3 -substituted acrylic acid in boron trifluoride 
etherate to produce the corresponding bis-(2,2-R.sub.2 R.sub.3 
-7-hydroxy-5-methylidene-4-chromanone). This compound is then converted to 
ethers in the manner described above for preparation of ethers of 
compounds having formula VII. Oxidation of the 
bis-(5-methylene-4-chromanone) compound by means of sodium periodate and 
osmium tetroxide produces compounds having formula VI-A. This reaction 
sequence is outlined in Scheme B below. 
##STR5## 
A still further procedure for producing compounds having formulae I and II 
wherein R.sub.1 is amino comprises the reaction sequence illustrated in 
Scheme C. 
##STR6## 
This sequence comprises reaction of the appropriate 
6a,7,10,10a-tetrahydro-1-hydroxy-3-(Z-W)-6,6-R.sub.2 R.sub.3 
-6H-dibenzo[b,d]pyran-9(8H)-one ethylene ketal with a coupling agent such 
as diethylchlorophosphate, bis(dimethylamino)phosphorochloridate or 
trifluoromethanesulfonyl imidazole in the presence of a suitable base as 
acid acceptor. The diethyl phosphoryl or other derivative thus produced is 
then reacted with sodium or potassium in the presence of ferric nitrate 
and with ammonia to produce the corresponding amino derivative. The 
phosphorous containing couplers produce, in addition to the desired amino 
derivative, the dehydroxylated compound. 
The necessary starting materials for the reaction sequence of Scheme C are 
known compounds described by Fahrenholtz, U.S. Pat. No. 3,636,058, issued 
Jan. 18, 1972; Archer, U.S. Pat. No. 3,928,598, issued Dec. 23, 1975 and 
in Netherlands specification No. 7,612,174, published May 5, 1977. 
Compounds of this invention wherein R.sub.1 is hydrogen, methyl or 
hydroxymethyl are prepared by the sequence of Scheme A but beginning, of 
course, with the appropriate 3-R.sub.1 -5-Z-W phenol. The required 
starting materials are prepared according to reaction Scheme D (R.sub.1 " 
= H, CH.sub.3, 2-phenylethenyl). 
##STR7## 
The starting 3-hydroxy-5-R.sub.1 " benzoic acid (IX) is converted to a 
compound of formula X wherein Y.sub.2 represents an alkoxy group, 
desirably methoxy or ethoxy for ease of preparation, or an amino group; 
and Y.sub.1 is a hydroxy protecting group, by methods described in the 
literature. 
When Z is alkylene, Y.sub.1 is desirably alkyl having from one to four 
carbon atoms or benzyl. The function of group Y.sub.1 is to protect the 
hydroxy groups during subsequent reactions. It is its ability to perform a 
specific function; i.e. protection of the hydroxy groups, rather than its 
structure which is important. The selection and identification of 
appropriate protecting groups can easily and readily be made by one 
skilled in the art. The suitability and effectiveness of a group as a 
hydroxy protecting group are determined by employing such a group in the 
above-illustrated reaction sequence. It should, therefore, be a group 
which is easily removed to permit restoration of the hydroxy groups. 
Methyl is favored as a protecting alkyl group since it is easily removed 
by treatment with pyridine hydrochloride. The benzyl group, if used as a 
protecting group, is removed by catalytic hydrogenolysis or acid 
hydrolysis. 
When Z is --(alk.sub.1).sub.m --O--(alk.sub.2).sub.n --, Y.sub.1 is 
preferably benzyl or a substituted benzyl group since it can subsequently 
be removed without detriment to the Z group. 
The protected benzoic acid derivative (X) is then converted to a compound 
of formula XXI by known technology. In one procedure, X is hydrolyzed to 
the corresponding acid (Y.sub.2 = OH), or lithium salt, and reacted with 
the appropriate alkyl lithium to produce a substituted phenyl ketone 
(Y.sub.2 = alkyl). When methyl lithium is used, the resulting acetophenone 
derivative is treated with a Grignard Reagent (W--Z'--MgBr) where Z' = Z 
less one CH.sub.2 group. The intermediate adduct is hydrolyzed to the 
corresponding alcohol which is then hydrogenolyzed to replace the hydroxy 
group with hydrogen. This procedure is especially useful for those 
compounds wherein Z is alkylene. 
The ether group (or groups) are deblocked by suitable means: treatment with 
pyridine hydrochloride (Y.sub.1 = methyl) or catalytic hydrogenolysis 
(Y.sub.1 = benzyl), or by treatment with an acid such as trifluoroacetic 
acid, hydrochloric, hydrobromic or sulfuric acids, or pyridine 
hydrochloride. 
A further method for converting compounds of formula X to those of formula 
XI comprises reaction of a ketone of formula X (Y.sub.2 = alkyl) with the 
appropriate triphenyl phosphonium bromide derivative [(C.sub.6 
H.sub.5).sub.3 p.sup.+--Z--W]Br.sup.- in the presence of a base (e.g. 
sodium hydride). The reaction proceeds via an alkene which is subsequently 
catalytically hydrogenated to the corresponding alkane (Z--W) and 
deblocked to provide compound XII. Of course, when --Z-- is 
(alk.sub.1).sub.m -- O--(alk.sub.2).sub.n and Y.sub.1 is benzyl, the 
catalytic hydrogenation also results in cleavage of the benzyl ethers. 
Alternatively, conversion of formula X compounds to those of structure XII 
can be achieved by the sequence X .fwdarw. XI .fwdarw. XII. In this 
sequence, the diprotected benzamide (formula X, Y.sub.2 = NH.sub.2) is 
converted to the ketone (XI, Z' = Z less one CH.sub.2 group) by reaction 
with the appropriate Grignard reagent (BrMg-Z'-W) followed by reaction 
with methyl- or ethyl-magnesium halide to form the corresponding carbinol. 
Dehydration of the carbinol, e.g. with p-toluenesulfonic acid, affords the 
corresponding alkene which is then catalytically hyrogenated (Pd/C) to the 
alkane (XII). Any ether groups present are deblocked (converted to 
hydroxy) as described above. 
The conversion of XII to the 4-chromanone VI is achieved by the reaction of 
XII with an acrylic acid of the formula R.sub.2 R.sub.3 --C.dbd.CH--COOH 
as is described above. 
Compounds of formula XII wherein --Z--W is --alkylene--W or 
--(alk.sub.1)--O-- (alk.sub.2).sub.n --W wherein (alk.sub.1), (alk.sub.2), 
W, R.sub.1 " and n are as defined above are obtained by the Scheme E: 
##STR8## 
The first step in the above sequence (the Wittig reaction) provides 
opportunity, by choice of appropriate reactants, to produce compounds 
having straight or branched alkylene groups. In the given illustration, 
the value of R' as methyl or ethyl permits formation of a compound having 
alkyl substitution on the carbon atom (.alpha.) adjacent to the phenyl 
group. Substitution of a methyl or ethyl group at other sites, e.g. the 
.beta.-carbon atom of the alkylene group, is achieved by choice of the 
appropriate carbalkoxy alkylidene triphenylphosphorane, e.g. (C.sub.6 
H.sub.5).sub.3 P.dbd.C(R')--COOC.sub.2 H.sub.5. The unsaturated ester thus 
produced is reduced to the corresponding saturated alcohol by reaction 
with lithium aluminum hydride. 
Alternatively, when Y.sub.1 is other than benzyl (e.g. methyl), the alcohol 
is produced by catalytic reduction of the unsaturated ester using 
palladium-carbon, followed by treatment of the saturated ester thus 
produced withe lithium aluminum hydride. Conversion of the alcohol to the 
corresponding tosylate or mesylate followed by alkylation of the tosylate 
or mesylate with an alkali metal salt of the appropriate HO--(alk.sub.2)-W 
reactant, and finally removal of the protecting group (Y.sub.1) affords 
the desired resorcinol. 
A variation of the above sequence comprises bromination of the alcohol 
rather than converting it to a tosylate or metylate. Phosphorous 
tribromide is a convenient brominating agent. The bromo derivative is then 
reacted with the appropriate HO--(alk.sub.2)--W in the presence of a 
suitable base (Williamson synthesis). 
The bromo compounds also serve as valuable intermediates for increasing the 
chain length of the alkylene moiety in the above sequence to give 
compounds wherein Z is --alkylene--W. The process comprises treating the 
bromo derivative with triphenyl phosphine to produce the corresponding 
triphenylphosphonium bromide. Reaction of the triphenylphosphonium bromide 
with the appropriate aldehyde or ketone in the presence of a base such as 
sodium hydride or n-butyl lithium affords an unsaturated derivative which 
is then catalytically hydrogenated to the corresponding saturated 
compound. 
In this variation, the value of the protecting group (Y.sub.1) selected 
depends upon the particular sequence followed. When the vertical sequence 
on the right is used, benzyl is the preferred protecting group by reason 
of the catalytic hydrogenation step. Methyl is the peferred protecting 
group when the left vertical sequence is followed, since it is 
conveniently removed by treatment with acid as described herein. 
A further method for making compounds of formula XII wherein Z--W is 
(alk.sub.1)--O--(alk.sub.2)--W comprises reaction of the appropriate 
3-(protected hydroxy)5-R.sub.1 '-styrene oxide with an alcohol 
[HO--(alk.sub.2)--W] as its alkali metal (preferably sodium or potassium) 
salt. Benzyl is a favored protecting group because of its ease of removal. 
The resulting ether compound (formula XII-A) is converted to the 
corresponding alkyl ether (formula XIII-B) by treatment with phosphorous 
oxychloride. The thus-produced olefinic mixture is reduced with hydrogen 
over palladium. Removal of the protecting groups as described above 
affords the desired compound. The reaction sequence is presented below 
(Y.sub.1 = benzyl, alkyl having one to four carbon atoms; R' = H, 
CH.sub.3, C.sub.2 H.sub.5 and may be alike or different); R.sub.1 " is H, 
CH.sub.3 or 2-phenylethenyl. 
##STR9## 
Similarly, 1-Z-W-5methoxy-3-stilbene derivatives are prepared from the 
appropriate 5-methoxy-3-stilbene carboxylic acid methyl ester. Removal of 
the protective methyl group is achieved by treatment with pyridine 
hydrochloride. The thus produced 5-hydroxy-3-stilbene derivative is then 
converted to the corresponding 4-chromanone by the above described 
procedures. 
Esters of formula I compounds in which the OR group is esterified are 
prepared by acylation with the appropriate alkanoic acid in the presence 
of a condensing agent such as dicyclohexylcarbodiimide or by reaction with 
the appropriate alkanoic acid chloride or anhydride, e.g. acetyl chloride 
or acetic anhydride, in the presence of a base such as pyridine. Formula I 
compounds wherein R.sub.1 is amino in which only the 1-amino group is 
acylated are obtained by borohydride reduction of the corresponding 
formula II ketone acylated at the 1-position. The thus-produced formula I 
compounds bearing 1-acylamido-9-hydroxy substitution can then be acylated 
further with a different acylating agent to produce a diacylated compound 
of formula I in which the acyl groups at the 1- and the 9-positions are 
different. Acylation of formula I compounds wherein R.sub.1 is amino and 
OR is OH according to the above-described procedures affords diacyl 
derivatives wherein the acyl groups on the 1-amino and 9-hydroxy groups 
are alike. 
Compounds of formula II-E in their ketalized form serve as valuable 
intermediates for preparation of compounds wherein R.sub.1 is --NR.sub.4 
'R.sub.5, wherein R.sub.4 ' is alkyl and R.sub.5 is as previously defined, 
by reductive alkylation according to known procedures, e.g. using the 
appropriate aldehyde and sodium cyanoborohydride; and for compounds 
wherein R.sub.1 is alkylsulfonamido or phenalkylsulfonamido by 
chlorosulfonamidation according to known methods; i.e., in a 
reaction-inert solvent in the presence of an acid acceptor at from 
-20.degree. C. to 50.degree. C. 
Additionally, the amino group can be converted by known procedures to the 
diazonium group which in turn can be replaced with or converted to a 
variety of groups via known methodology, e.g. chloro, fluoro, cyano, 
bromo, iodo and mercapto. The said derivatives have the same utility as 
the compounds of formulae I and II described herein and are used in the 
same manner. 
The analgesic properties of the compounds of this invention are determined 
by tests using nociceptive stimuli. 
Tests Using Thermal Nociceptive Stimuli 
a. Mouse Hot Plate Analgesic Testing (HP) 
The method used is modified after Woolfe and MacDonald, J. Pharmacol. Exp. 
Ther., 80, 300-307 (1944). A controlled heat stimulus is applied to the 
feet of mice on a 1/8 inch thick aluminum plate. A 250 watt reflector 
infrared heat lamp is placed under the bottom of the aluminum plate. A 
thermal regulator, connected to thermistors on the plate surface, programs 
the heat lamp to maintain a constant temperature of 57.degree. C. Each 
mouse is dropped into a glass cylinder (61/2 inch diameter) resting on the 
hot plate, and timing is begun when the animal's feet touch the plate. The 
mouse is observed at 0.5 and 2 hours after treatment with the test 
compound for the first "flicking" movements of one or both hind feet, or 
until 10 seconds elapse without such movements. Morphine has an MPE.sub.50 
= 4-5.6 mg./kg. (s.c.). 
b. Mouse Tail Flick Analgesic Testing (TF) 
Tail flick testing in mice is modified after D'Amour and Smith, J. 
Pharmacol. Exp. Ther., 72, 74-79 (1941), using controlled high intensity 
heat applied to the tail. Each mouse is placed in a snug-fitting metal 
cylinder, with the tail protruding through one end. This cylinder is 
arranged so that the tail lies flat over a concealed heat lamp. At the 
onset of testing, an aluminum flag over the lamp is drawn back, allowing 
the light beam to pass through the slit and focus onto the end of the 
tail. A timer is simultaneously activated. The latency of a sudden flick 
of the tail is ascertained. Untreated mice usually react within 3-4 
seconds after exposure to the lamp. The end point for protection is 10 
seconds. Each mouse is tested at 0.5 and 2 hours after treatment with 
morphine and the test compound. Morphine has an MPE.sub.50 of 3.2-5.6 
mg./kg. (s.c.). 
c. Tail Immersion Procedure (TI) 
The method is a modification of the receptacle procedure developed by 
Benbasset, et al., Arch. int. Pharmacodyn., 122, 434 (1959). Male albino 
mice (19-21 g.) of the Charles River CD-1 strain are weighed and marked 
for identification. Five animals are normally used in each drug treatment 
group with each animal serving as its own control. For general screening 
purposes, new test agents are first administered at a dose of 56 mg./kg. 
intraperitoneally or subcutaneously, delivered in a volume of 10 ml./kg. 
Preceding drug treatment and at 0.5 and 2 hours post drug, each animal is 
placed in the cylinder. Each cylinder is provided with holes to allow for 
adequate ventilation and is closed by a round nylon plug through which the 
animal's tail protrudes. The cylinder is held in an upright position and 
the tail is completely immersed in the constant temperature waterbath 
(56.degree. C.). The endpoint for each trial is an energetic jerk or 
twitch of the tail coupled with a motor response. In some cases, the 
endpoint may be less vigorous post drug. To prevent undue tissue damage, 
the trial is terminated and the tail removed from the waterbath within 10 
seconds. The response latency is recorded in seconds to the nearest 0.5 
second. A vehicle control and a standard of known potency are tested 
concurrently with screening candidates. If the activity of a test agent 
has not returned to baseline values at the 2-hour testing point, response 
latencies are determined at 4 and 6 hours. A final measurement is made at 
24 hours if activity is still observed at the end of the test day. 
Test Using Chemical Nociceptive Stimuli 
Suppression of Phenylbenzoquinone Irritant-Induced Writhing (PBQ) 
Groups of 5 Carworth Farms CF-1 mice are pretreated subcutaneously (SC) or 
orally (PO) with saline, morphine, codeine or the test compound. Twenty 
minutes (if treated subcutaneously) or 50 minutes (if treated orally) 
later, each group is treated with intraperitoneal injection of 
phenylbenzoquinone, an irritant known to produce abdominal contractions. 
The mice are observed for 5 minutes for the presence or absence of 
writhing starting 5 minutes after the injection of the irritant. ED.sub.50 
's or MPE.sub.50 's of the drug pretreatments in blocking writhing are 
ascertained. 
Tests Using Pressure Nociceptive Stimuli 
Effect on the Haffner Tail Pinch Procedure (Rat Tail Clamp, RTC) 
A modification of the procedure of Haffner, Experimentelle Prufung 
Schmerzstillender. Mittel Deutch Med. Wschr., 55, 731-732 (1929) is used 
to ascertain the effects of the test compound on aggressive attacking 
responses elicited by a stimulus pinching the tail. Male albino rats 
(50-60 g.) of the Charles River (Sprague-Dawley) CD strain are used. Prior 
to drug treatment, and again at 0.5, 1, 2 and 3 hours after treatment, a 
Johns Hopkins 2.5-inch "buildog" clamp is clamped onto the root of the 
rat's tail. The endpoint at each trial is clear attacking and biting 
behavior directed toward the offending stimulus, with the latency for 
attack recorded in seconds. The clamp is removed in 30 seconds if 
attacking has not yet occurred, and the latency of response is recorded as 
30 seconds. Morphine is active at 17.8 mg./kg. (i.p.). 
Tests Using Electrical Nociceptive Stimuli 
The "Flinch-Jump" Test (FJ) 
A modification of the flinch-jump procedure of Tenen, Psychopharmacologia, 
12, 278-285 (1968) is used for determining pain thresholds. Male albino 
rats (175-200 g.) of the Charles River (Sprague-Dawley) CD strain are 
used. Prior to receiving the drug, the feet of each rat are dipped into a 
20% glycerol/saline solution. The animals are then placed in a chamber and 
presented with a series of 1-second shocks to the feet which are delivered 
in increasing intensity at 30-second intervals. These intensities are 
0.26, 0.39, 0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04 
mA. Each animal's behavior is rated for the presence of (a) flinch, (b) 
squeak and (c) jump or rapid forward movement at shock onset. Since upward 
series of shock intensities are presented to each rat just prior to, and 
at 0.5, 2, 4 and 24 hours subsequent to drug treatment. 
Results of the above tests are recorded as the effective dose which 
protects 50% of the animals tested (ED.sub.50) against the nociceptive 
stimuli during the test period or as percent maximum possible effect (% 
MPE). The % MPE of each group is statistically compared to the % MPE of 
the standard and the predrug control values. The % MPE is calculated as 
follows: 
##EQU1## 
The compounds of the present invention are active analgesics via oral and 
parenteral administration and are conveniently administered in composition 
form. Such compositions include a pharmaceutical carrier selected on the 
basis of the chosen route of administration and standard pharmaceutical 
practice. For example, they may be administered in the form of tablets, 
pills, powders or granules containing such excipients as starch, milk 
sugar, certain types of clay, etc. They may be administered in capsules, 
in admixtures with the same or equivalent excipients. They may also be 
administered in the form of oral suspensions, solutions, emulsions, syrups 
and elixirs which may contain flavoring and coloring agents. For oral 
administration of the therapeutic agents of this invention, tablets or 
capsules containing from about 0.01 to about 100 mg. are suitable for most 
applications. 
The physician will determine the dosage which will be most suitable for an 
individual patient and it will vary with the age, weight and response of 
the particular patient and the route of administration. Generally, 
however, the initial analgesic dosage in adults may range from 0.01 to 500 
mg. per day in single or divided doses. In many instances, it is not 
necessary to exceed 100 mg. daily. The favored oral dosage range is from 
about 0.01 to about 300 mg./day; the preferred range is from about 0.10 to 
about 100 mg./day. The favored parenteral dose is from about 0.01 to about 
100 mg./day; the preferred range from about 0.01 to about 50 mg./day.