U.S. patent number 3,862,239 [Application Number 05/193,200] was granted by the patent office on 1975-01-21 for aryl substituted cyclohexenecarbinols.
This patent grant is currently assigned to Ortho Pharmaceutical Corporation. Invention is credited to George Karmas.
United States Patent |
3,862,239 |
Karmas |
January 21, 1975 |
**Please see images for:
( Certificate of Correction ) ** |
ARYL SUBSTITUTED CYCLOHEXENECARBINOLS
Abstract
Compounds of the formula: ##SPC1## Wherein R is carboxy, lower
carbalkoxy, methylol, carboxamide or carboxylic alkali metal salts,
R' is lower alkyl and Ar is substituted aryl are active agents for
the suppression of animal reproduction.
Inventors: |
Karmas; George (Bound Brook,
NJ) |
Assignee: |
Ortho Pharmaceutical
Corporation (Raritan, NJ)
|
Family
ID: |
27497980 |
Appl.
No.: |
05/193,200 |
Filed: |
October 27, 1971 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
747075 |
Jul 24, 1968 |
|
|
|
|
662311 |
Aug 22, 1967 |
|
|
|
|
Current U.S.
Class: |
568/644; 549/284;
549/286; 549/447; 560/42; 560/59; 560/141; 562/426; 562/469;
568/743; 568/808; 549/285; 558/57; 560/56; 560/102; 562/85;
562/457; 562/490; 568/807 |
Current CPC
Class: |
C07D
317/60 (20130101); C07C 39/23 (20130101); C07C
2601/16 (20170501) |
Current International
Class: |
C07C
39/00 (20060101); C07C 39/23 (20060101); C07D
317/00 (20060101); C07D 317/60 (20060101); C07c
043/20 () |
Field of
Search: |
;260/619D,619R,613R |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Nathan et al., Jour. Amer. Chem. Soc., Vol. 78 (1956)
6163-6166..
|
Primary Examiner: Helfin; Bernard
Attorney, Agent or Firm: Lambert; Benjamin F.
Parent Case Text
This application is a continuation-in-part of copending application
Ser. No. 747,075 filed July 24, 1968, which is in turn a
continuation-in-part of U.S. Pat. application Ser. No. 662,311
filed Aug. 22, 1967 and both now abandoned.
Claims
What is claimed is:
1. A compound selected from the group consisting of ##SPC8##
wherein R.sub.1 is ethyl, R.sub.2 is methyl, and R.sub.3 is
hydroxyl or methoxy.
2. A compound of the formula of claim 1 having the chemical name
[2-methyl-3-ethyl-4-(p-hydroxyphenyl)-3-cyclohexenyl-1]methanol.
3. A compound of the formula of claim 1 having the chemical name
[2-methyl-3-ethyl-4-(p-hydroxyphenyl)-4-cyclohexenyl-1]methanol.
4. A compound of the formula of claim 1 having the chemical name
[4-(p-anisyl)-3-ethyl-2-methyl-3-cyclohexenyl-1]methanol.
5. A compound of the formula of claim 1 having the chemical name
[4-(p-anisyl)-3-ethyl-2-methyl-4-cyclohexenyl-1]methanol.
Description
The compounds of the present invention are of the formula:
##SPC2##
Wherein R is carboxy, lower carbalkoxy, methylol, carboxamide or
carboxylic alkali metal salts, R' is lower alkyl of up to 6 carbon
atoms and Ar is 3,4-methylenedioxyphenyl, .alpha.-naphthyl,
.beta.-naphthyl or ##SPC3##
Wherein R.sub.1 is hydrogen, hydroxy, lower alkoxy of up to 4
carbon atoms, lower acyloxy of up to 5 carbon atoms, or
tetrahydropyranyl-2-oxy, R.sub.2 is hydrogen, hydroxy, lower alkyl
of up to 4 carbon atoms, lower alkoxy of up to 4 carbon atoms,
lower acyloxy of up to 5 carbon atoms, tetrahydropyranyl-2-oxy,
chlorine or trifluoromethyl, and R.sub.3 is hydrogen, hydroxy,
lower alkyl of up to 4 carbon atoms, lower acyloxy of up to 5
carbon atoms, diethylaminoethoxy, thiomethyl, trifluoromethyl,
dimethylamino, or tetrahydropyranyl-2-oxy, and wherein at least one
and not more than two of R.sub.1, R.sub.2 and R.sub.3 is
hydrogen.
The compounds of the present invention which are preferred are
[2-methyl-3-ethyl-4-(p-hydroxyphenyl)-3-cyclohexenyl-1]methanol,
[2-methyl-3-ethyl-4-(p-hydroxyphenyl-4-cyclohexenyl-1]methanol,
[4-(p-anisyl)-3-ethyl-2-methyl-3-cyclohexenyl-1]methanol and
[4-(p-anisyl)-3-ethyl-2-methyl-4-cyclohexenyl-1]methanol. They
possess improved estrogenicity and anti-littering properties.
The following reaction scheme illustrates the preparation of
precursor compounds of the present invention: ##SPC4##
In the above illustrated reaction scheme, an aryl Grignard reagent
is used. Any highly active arylmetallic reagent such as
aryllithium, arylsodium or arylpotassium reagents may be used
equally well to prepare the lactone (I). The acid used in the
dehydration of the hydroxy acid (II) is an acid of the type which
produces a carbonium ion from the tertiary alcohol portion of the
hydroxy acid and may be any strong organic or inorganic acid. While
almost any Lewis acid may be used, p-toluenesulfonic acid, sulfuric
acid, phosphoric acid, perchloric acid, iodine, boron trifluoride,
perhalocarboxylic acids, and halides of boron, aluminum, tin and
antimony are particularly useful. The solvent in which the
dehydration is performed is generally acetic acid, but other
organic solvents, such as hydrocarbons, ethers, esters, ketones,
alcohols, etc., may be used. The dehydration of the hydroxy acid
may lead to the production of certain dehydrated acid isomers in
addition to those of Formula III a. and III b. Chemical
purification as well as chromatography and recrystallization are
therefore useful in isolating the desired products.
Generally, the .DELTA..sup.4 -isomer (Formula III a.) is the
predominant product. Prolonged heating of the dehydration mixture
will cause isomerization of .DELTA..sup.4 to the .DELTA..sup.3
-isomer and recrystallization affords the 3-cyclohexenecarboxylic
acid.
The hydroxy acids of Formula II may also be prepared by the
reaction of an aryl Grignard reagent with a 2-lower alkyl-3-lower
alkyl-4-ketocyclohexanecarboxylic acid.
The hydroxyacids of Formula II may be converted to the
corresponding hydroxyesters, which upon dehydration yield the
unsaturated esters. The unsaturated esters, upon saponification,
yield a mixture of the isomers of Formulae III a. and III b. The
dehydration may be accomplished with any of the strong acids
mentioned above, as well as with phosphorus halides and sulfur
halides in the presence of such bases as pyridines, quinolines,
trialkylamines, dialkylanilines, etc., in any solvent which is not
reactive with the halides. The saponification is performed with an
alkali or alkaline earth hydroxide or carbonate in the presence of
an alkali-stable solvent.
The dehydrated acids of Formulae III a. and III b. may also be
prepared by a Diels-Alder type of synthesis, as follows:
##SPC5##
The o-acetoxyphenyl-hydroxy acids of Formula II undergo spontaneous
decomposition at room temperature as follows: ##SPC6##
As exemplified hereinafter, the esters, amides and methylols may be
prepared by methods generally known in the art.
The following examples illustrate the preparation of the compounds
of the invention:
REACTION OF HYDROXYACIDS WITH BORON TRIFLUORIDE
EXAMPLE I
2-methyl-3-ethyl-4-(p-thioanisyl)-4-cyclohexenecarboxylic acid
A suspension of 4.0 g. of
2-methyl-3-ethyl-4-hydroxy-4-(p-thioanisyl) cyclohexanecarboxylic
acid in 75 ml. of ether is stirred and 6 ml. of boron trifluoride
etherate is added. The mixture is stirred at 25.degree.C. for 5
hours. Ice is added and the ether solution is extracted three times
with 7% aqueous potassium carbonate to separate the acids from the
neutral products. The combined carbonate extract is acidified with
dilute hydrochloric acid and extracted with ether. The ether
extract is dried over anhydrous sodium sulfate and evaporated to
give a residue. The residue is recrystallized from ether to afford
2-methyl-3-ethyl-4-(p-thioanisyl)-4-cyclohexenecarboxylic acid,
m.p. 149.degree.-150.degree.C.
Calcd. for C.sub.17 H.sub.22 O.sub.2 S: C, 70.37; H, 7.63
Found: C, 70.39; H, 7.70
.lambda..lambda.max: 5.90, 7.78, 9.11, 11.71, 12.15, 12.48,
13.80.mu.(KBr.)
Nmr(cdcl.sub.3): shows vinyl H at 5.62 p.p.m.
EXAMPLE II
2-methyl-3-ethyl-4-(o-methoxy-p-hydroxyphenyl)-4-cyclohexenecarboxylic
acid
Following the procedure of Example I, but starting with
2-methyl-3-ethyl-4-hydroxy-4-(o-methoxy-p-hydroxyphenyl)cyclohexanecarboxy
lic acid and carrying out the reaction for 10 minutes, there is
afforded, upon recrystallization from nitromethane,
2-methyl-3-ethyl-4-(o-methoxy-p-hydroxyphenyl)-4-cyclohexenecarboxylic
acid, m.p. 156.degree.-158.degree.C.
Calcd. for C.sub.17 H.sub.22 O.sub.4 : C, 70.32; H, 7.64
Found: C, 70.13; H, 7.46
.lambda..lambda.max: 5.90, 8.35, 8.62, 9.65, 10.45, 12.00, 12.11,
12.50.mu.. (KBr)
Nmr (pyr.): shows alkyl pattern of .DELTA..sup.4.
EXAMPLE III
2-methyl-3-ethyl-4-(o,p-dihydroxyphenyl)-4-cyclohexenecarboxylic
acid
Following the procedure of Example I, but starting with
2-methyl-3-ethyl-4-hydroxy-4-(o,p-dihydroxyphenyl)
cyclohexanecarboxylic acid and carrying out the reaction for 10
minutes, there is afforded upon recrystallization from methylene
chloride and carbon tetrachloride,
2-methyl-3-ethyl-4-(o,p-dihydroxyphenyl)-4-cyclohexenecarboxylic
acid, m.p. 75.degree.-85.degree.C.
.lambda..lambda.max: 2.90-3.10, 5.87, 7.37, 8.60, 8.99, 10.28,
11.75-11.90.mu.. (KBr.)
Nmr (cdcl.sub.3 +CD.sub.3 CO.sub.2 D): shows vinyl H at 5.69
p.p.m.
REACTION OF HYDROXY ACIDS WITH AN ACID CATALYST
EXAMPLE IV
2-methyl-3-ethyl-4-(m-hydroxyphenyl)-4-cyclohexenecarboxylic
acid
To a gently boiling solution of 1.5 g. of
2-methyl-3-ethyl-4-hydroxy-4-(m-hydroxyphenyl)
cyclohexanecarboxylic acid in 50 ml. of acetic acid is added 0.15
g. of p-toluenesulfonic acid monohydrate. This mixture is refluxed
for 5 minutes and then to it is added 0.15 g. of sodium acetate.
After evaporation of the acetic acid solution, a pasty residue is
obtained. The residue is shaken with ether and water and the layers
are then separated. The ether layer is extracted three times with
7% aqueous potassium carbonate to separate acidic from neutral
products. The combined carbonate extract is acidified with dilute
hydrochloric acid and is extracted with ether. The ether solution
is dried over anhydrous magnesium sulfate and is evaporated to
dryness. The residue is recrystallized from acetone to afford
2-methyl-3-ethyl-4-(m-hydroxyphenyl)-4-cyclohexenecarboxylic acid,
m.p. 165.degree.-168.degree.C.
Calcd. for C.sub.16 H.sub.20 O.sub.3 : C, 73.82; H, 7.74
Found: C, 72.74; H, 7.85
.lambda..lambda.max: 3.02, 5.88, 7.80, 8.02, 11.50, 11.95, 12.72,
13.73 14.21.mu.. (KBr.)
Nmr (pyr.): shows alkyl pattern of .DELTA..sup.4.
EXAMPLE V
2-methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-4-cyclohexenecarboxylic
acid
Following the procedure of Example IV, but starting with
2-methyl-3-ethyl-4-hydroxy-4-(3,4-methylenedioxyphenyl)-cyclohexanecarboxy
lic acid, there is afforded
2-methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-4-cyclohexenecarboxylic
acid, m.p. 173.degree.-174.degree.C.
Calcd. for C.sub.17 H.sub.24 O.sub.4 : C, 70.81; H, 6.99
Found: C, 70.59; H, 6.93
.lambda..lambda.max: 5.91, 8.06, 9.57, 10.58, 12.22, 13.89, 14.50
.mu.. (KBr.)
Nmr (cdcl.sub.3): shows vinyl H at 5.59 p.p.m.
EXAMPLE VI
2-methyl-3-ethyl-4-(m-tolyl)-3(and 4)-cyclohexenecarboxylic
acid
Following the procedure of Example IV, but starting with
2-methyl-3-ethyl-4-hydroxy-4-(m-tolyl)cyclohexanecarboxylic acid,
there is afforded a mixture of 2-methyl-3-ethyl-4-(m-tolyl)-3(and
4)-cyclohexenecarboxylic acids. By fractional crystallization from
nitromethane and from hexane, there is afforded
2-methyl-3-ethyl-4-(m-tolyl)-4-cyclohexenecarboxylic acid, m.p.
93.degree.-95.degree.C.
Calcd. for C.sub.17 H.sub.22 O.sub.2 : C, 79.03; H, 8.58
Found: C, 79.21; H, 8.55
.lambda..lambda.max: 5.90, 7.99, 11.83, 12.49, 12.76, 13.29, 13.74,
14.20 .mu.. (KBr)
Nmr (cdcl.sub.3): shows vinyl H at 5.60 p.p.m. and
2-methyl-3-ethyl-4-(m-tolyl)-3-cyclohexenecarboxylic acid, m.p.
100.degree.-102.degree.C.
Calcd. for C.sub.17 H.sub.22 O.sub.2 : C, 79.03; H, 8.58
Found: C, 79.29; H, 8.41
.lambda..lambda.max: 5.89, 7.99, 11.30, 12.72, 13.41, 14.11 .mu..
(KBr)
Nmr (cdcl.sub.3): shows no vinyl H.
EXAMPLE VII
2-methyl-3-ethyl-4-(p-diethylaminoethoxyphenyl)-4-cyclohexenecarboxylic
acid p-toluenesulfonate
Following the procedure of Example IV but starting with
2-methyl-3-ethyl-4-hydroxy-4-(p-diethylaminoethoxyphenyl)-cyclohexanecarbo
xylic acid and using 1.0 g. of p-toluenesulfonic acid and no sodium
acetate, the residue from low-temperature evaporation of the acetic
acid solution is recrystallized from acetone to afford
2-methyl-3-ethyl-4-(p-diethylaminoethoxyphenyl)-4-cyclohexenecarboxylic
acid p-toluenesulfonate, m.p. 150.degree.-160.degree.C.
.lambda..lambda.max: 5.80, 8.08, 8.50, 8.64, 8.88, 9.62, 9.87,
12.00, 12.27 .mu.. (KBr.)
Nmr (cd.sub.3 co.sub.2 d): shows vinyl H at 5.59 p.p.m.
In some cases, the product formed contains .DELTA..sup.3 and
.DELTA..sup.4 -isomers which cannot be separated by fractional
crystallization. Chromatography is used to effect the separation.
The crude acid mixture is developed on a silicic acid column, which
is then eluted with gradually increasing amounts (0.1-2.0%) of
ethyl acetate in benzene. The .DELTA..sup.4 -isomer is the first
eluted acid, and eluate residues with similar infrared spectra are
combined and recrystallized several times from ether or
nitromethane to afford the 4-cyclohexenecarboxylic acid. Middle
fractions from the chromatograph are a mixture of .DELTA..sup.3
-and .DELTA..sup.4 -acids and can only be rechromatographed. The
late fractions are rich in .DELTA..sup.3 -isomers and are combined
and recrystallized from ether, acetone, hexane, nitromethane or
methylene chloride to afford the 3-cyclohexenecarboxylic acid.
EXAMPLE VIII
2-methyl-3-ethyl-4-(o-anisyl)-3-(and 4)-cyclohexenecarboxylic
acid
Following the procedure of Example IV, but starting with
2-methyl-3-ethyl-4-hydroxy-4-(o-anisyl) cyclohexanecarboxylic acid,
there is afforded, after purification by chromatography, as shown
in Example VII,
2-methyl-3-ethyl-4-(o-anisyl)-4-cyclohexenecarboxylic acid, m.p.
148.degree.-149.degree.C.
Calcd. for C.sub.17 H.sub.22 O.sub.3 : C, 74.42: H, 8.09
Found: C, 74.47; H, 8.27
.lambda..lambda.max: 5.87, 8.02, 9.68, 11.67, 13.22, 13.52,
13.90.mu.. (KBr.)
Nmr (cdcl.sub.3): shows vinyl H at 5.58 p.p.m., and
2-methyl-3-ethyl-4-(o-anisyl)-3-cyclohexenecarboxylic acid, m.p.
160.degree.-162.degree.C.
Calcd. for C.sub.17 H.sub.22 O.sub.3 : C, 74.42; H, 8.09
Found: C, 74.53; H, 8.34
.lambda..lambda.max: 5.88, 8.02, 8.12, 9.48, 9.67, 12.69,
13.17.mu.(KBr.)
Nmr (cdcl.sub.3): shows no vinyl H.
EXAMPLE IX
2-methyl-3-ethyl-4-(p-tolyl)-3-(and 4)cyclohexenecarboxylic
acid
Following the procedure of Example IV, but starting with
2-methyl-3-ethyl-4-hydroxy-4-(p-tolyl)cyclohexanecarboxylic acid,
there is afforded, after purification by chromatography, as shown
in Example VII.
2-methyl-3-ethyl-4-(p-tolyl)-4-cyclohexenecarboxylic acid, m.p.
173.degree.-175.degree.C.
Calcd. for C.sub.17 H.sub.22 O.sub.2 : C, 79.03; H, 8.58
Found: C, 78.96; H, 8.63
.lambda..lambda.max: 5.90, 8.07, 11.78, 12.16, 12.41, 13.20,
13.84.mu.(KBr.)
Nmr (cdcl.sub.3): shows vinyl H at 5.61 p.p.m., and
2-methyl-3-ethyl-4-(p-tolyl)-3-cyclohexenecarboxylic acid, m.p.
187.degree.-188.degree.C.
Calcd. for C.sub.17 H.sub.22 O.sub.2 : C, 79.03; H, 8.58
Found: C, 78.59; H, 8.74
.lambda..lambda.max: 5.89, 7.99, 11.47, 12.23, 13.38, 14.59.mu.
(KBr.)
Nmr (cdcl.sub.3): shows no vinyl H.
EXAMPLE X
2-methyl-3-ethyl-4-(p-diethylaminoethoxyphenyl)-3-cyclohexenecarboxylic
acid p-toluenesulfonate
A mixture of 3.5 g. of
2-methyl-3-ethyl-4-hydroxy-4-(p-diethylaminoethoxyphenyl)cyclohexanecarbox
ylic acid and 2.7 g. of p-toluenesulfonic acid monohydrate in 100
ml. of acetic acid is refluxed for 5 hours and is then evaporated
to remove acetic acid. The pasty residue is recrystallized twice
from acetone to afford
2-methyl-3-ethyl-4-(p-diethylaminoethoxyphenyl)-3-cyclohexanecarboxylic
acid p-toluenesulfonate, m.p. 172.degree.-173.degree.C.
Calcd. for C.sub.29 H.sub.41 O.sub.6 NS: C, 65.59; H, 7.77
Found: C, 65.45; H, 7.72
.lambda..lambda.max: 5.80, 8.10-8.20, 8.50-8.70, 8.88, 9.62, 9.87,
12.21, 13.57, 14.62 .mu.. (KBr)
Nmr (cd.sub.3 co.sub.2 d): shows no vinyl H.
EXAMPLE XI
2-methyl-3-ethyl-4-(p-diethylaminoethoxyphenyl)-3-cyclohexenecarboxylic
acid
A mixture of 0.2 g. of
2-methyl-3-ethyl-4-(p-diethylaminoethoxyphenyl)-3-cyclohexenecarboxylic
acid p-toluenesulfonate (as prepared according to Example X), 15
ml. of ether, 3 ml. of water, and 0.9 ml. of a solution of 1.6 g.
sodium hydroxide in 100 ml. of water is stirred at 25.degree.C. for
20 minutes. The layers are permitted to separate and the ether
layer is removed, dried over anhydrous magnesium sulfate and
evaporated to a viscous residue. The residue is recrystallized from
nitromethane to afford 0.1 g. of
2-methyl-3-ethyl-4-(p-diethylaminoethoxyphenyl)-3-cyclohexenecarboxylic
acid, m.p. 130.degree.-138.degree.C.
Calcd. for C.sub.22 H.sub.33 O.sub.3 N: C, 73.50; H, 9.25
Found: C, 73.72; H, 9.19
.lambda..lambda.max: 5.90, 8.07, 8.52, 9.52, 12.07, 13.80-13.90
.mu.. (KBr)
Nmr (cd.sub.3 co.sub.2 d): shows no vinyl H.
EXAMPLE XII
2-methyl-3-ethyl-4-(p-thioanisyl)-3-cyclohexenecarboxylic acid
A mixture of 3.5 g. of
2methyl-3-ethyl-4-hydroxy-4-(p-thioanisyl)cyclohexanecarboxylic
acid and 0.6 g. of p-toluenesulfonic acid monohydrate in 100 ml. of
acetic acid is refluxed for a period of 5 hours and then to this is
added 0.6 g. of sodium acetate and the mixture is evaporated to
remove acetic acid. The pasty residue is shaken with ether and
water and the ether phase is extracted three times with 7% aqueous
potassium carbonate. The combined carbonate solution is acidified
with dilute hydrochloric acid and extracted with ether. After
drying over anhydrous magnesium carbonate and evaporation of the
ether, the residue is recrystallized from methylene chloridehexane
to afford 2-methyl-3-ethyl-4-(p-thioanisyl)-3-cyclohexenecarboxylic
acid, double m.p. 145.degree.-147.degree., then
151.degree.-152.degree.C.
Calcd. for C.sub.17 H.sub.22 O.sub.2 S: C, 70.37; H, 7.63
Found: C, 70.58; H, 7.71
.lambda..lambda.max: 5.88, 8.00, 9.11, 11.47, 12.18, 13.26,
14.50.mu.. (KBr.)
Nmr (cdcl.sub.3): shows no vinyl H.
EXAMPLE XIII
2-methyl-3-ethyl-4-(m-chlorophenyl)-3-(and 4)-cyclohexenecarboxylic
acid
Following the procedure of Example XII, but starting with 2
-methyl-3-ethyl-4-hydroxy-4-(m-chlorophenyl)cyclohexanecarboxylic
acid, there is afforded upon fractional recrystallization from
nitromethane,
2-methyl-3-ethyl-4-(m-chlorophenyl)-4-cyclohexenecarboxylic acid,
m.p. 100.degree.-103.degree.C.
Calcd. for C.sub.16 H.sub.19 O.sub.2 Cl: C, 68.92; H, 6.87
Found: C, 69.12; H, 6.70
.lambda..lambda.max: 5.90, 7.97, 11.89, 12.72, 13.08, 13.60,
14.33.mu.. (KBr.)
Nmr (cdcl.sub.3): shows vinyl H at 5.65 p.p.m., and
2-methyl-3-ethyl-4-(m-chlorophenyl)-3-cyclohexenecarboxylic acid,
m.p. 99.degree.-101.degree.C.
Calcd. for C.sub.16 H.sub.19 O.sub.2 Cl: C, 68.92; H, 6.87
Found: C, 68.78; H, 6.70
.lambda..lambda.max: 5.88, 8.00, 12.78, 13.07, 13.70, 14.30 .mu.
(KBr.)
Nmr (cdcl.sub.3): shows only a trace of vinyl H.
Following the procedure of Example XII, but starting with the
appropriate 4-hydroxy acid there are prepared: ##SPC7##
EXAMPLE XXII
2-methyl-3-ethyl-4-(m-anisyl)-4(and 3)-cyclohexenecarboxylic
acid
A mixture of 6.0 g. of
2-methyl-3-ethyl-4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid
and 0.9 g. of p-toluenesulfonic acid monohydrate in 150 ml. of
acetic acid is refluxed for three hours and is then evaporated to a
pasty residue. The residue is shaken with ether and water, the
layers are separated and the ether phase is extracted three times
with 7% aqueous potassium carbonate. The combined carbonate extract
is acidified with dilute hydrochloric acid and is extracted with
ether. The extract is chromatographed as in Example VII on a
silicic acid column and the eluates afford, upon recrystallization
from chloroform,
2-methyl-3-ethyl-4-(m-anisyl)-4-cyclohexenecarboxylic acid, m.p.
110.degree.-111.degree.C.
Calcd. for C.sub.17 H.sub.22 O.sub.3 : C, 74.42; H, 8.09
Found: C, 74.61; H, 8.08
.lambda..lambda.max: 5.86, 8.26, 8.49, 9.47, 11.13, 12.81, 13.22,
13.84.mu.. (KBr.)
Nmr (cdcl.sub.3): shows vinyl H at 5.68 p.p.m. and
2-methyl-3-ethyl-4-(m-anisyl)-3-cyclohexenecarboxylic acid, m.p.
126.degree.-127.degree.C.
Calcd. for C.sub.17 H.sub.22 O.sub.3 : C, 74.42; H, 8.09
Found: C, 74.27; H, 8.09
Nmr (cdcl.sub.3): shows no vinyl H.
EXAMPLE XXIII
2-methyl-3-ethyl-4-(o,p-diacetoxyphenyl)-4-cyclohexenecarboxylic
acid
To a solution of 1.0 g. of
2-methyl-3-ethyl-4-(o,p-dihydroxyphenyl)-4-cyclohexenecarboxylic
acid (as prepared according to Example III) in 20 ml. of pyridine
is added, with stirring, 2 ml. of acetic anhydride. The solution is
maintained at 25.degree.C. for 4 hours and it is then hydrolyzed
with ice and water and the mixture is acidified with hydrochloric
acid and extracted with ether. The ether solution is washed with
cold hydrochloric acid and it is then rapidly extracted three times
with cold 5% aqueous potassium carbonate, with each carbonate
extract being immediately acidified to avoid hydrolysis of acetoxy
groups. The acidified extracts are combined and are extracted with
ether. The ether solution is dried over anhydrous magnesium sulfate
and is evaporated to a residue. The residue is recrystallized from
nitromethane to afford
2-methyl-3-ethyl-4-(o,p-diacetoxyphenyl)-4-cyclohexenecarboxylic
acid, m.p. 170.degree.-172.degree.C.
Calcd. for C.sub.20 H.sub.24 O.sub.6 : C, 66.65; H, 6.71
Found: C, 66.59; H, 6.68
.lambda..lambda.max: 5.68, 5.90, 8.20-8.40, 8.73, 9.83, 11.12,
12.12 .mu.. (KBr.)
EXAMPLE XXIV
2-methyl-3-ethyl-4-(o-hydroxy-p-acetoxyphenyl)-4-(and
3)-cyclohexenecarboxylic acid
One gram of
2-methyl-3-ethyl-4-hydroxy-4-(o,p-diacetoxyphenyl)cyclohexanecarboxylic
acid is held at 25.degree.C for 3 weeks. The decomposition products
are fractionally crystallized from nitromethane to afford 0.2 g. of
2-methyl-3-ethyl-4-(o-hydroxy-p-acetoxyphenyl)-4-cyclohexenecarboxylic
acid, m.p. 151.degree.-155.degree.C.
Calcd. for C.sub.18 H.sub.22 O.sub.5 : C, 67.91; H, 6.97
Found: C, 68.04; H, 6.93
.lambda..lambda.max: 2.91, 5.75, 5.87, 8.10, 8.75, 9.80, 10.16,
10.26, 11.00, 11.78, 13.81 .mu.. (KBr.)
Nmr (cdcl.sub.3): shows vinyl H at 5.72 p.p.m. and, from carbon
tetrachloride, 0.3 of
2-methyl-3-ethyl-4-(o-hydroxy-p-acetoxyphenyl)-3-cyclohexenecarboxylic
acid, m.p. 137.degree.-139.degree.C.
Calcd. for C.sub.18 H.sub.22 O.sub.5 : C, 67.91; H, 6.97
Found: C, 67.87; H, 6.86
.lambda..lambda.max: 2.90, 5.72, 5.86, 8.10, 8.73, 9.12, 9.79,
10.22, 10.98 11.58 .mu.. (KBr.)
Nmr (cdcl.sub.3): shows no vinyl H.
The esters of the compounds of the present invention may be
prepared by any one of a number of methods. For example, the
carboxylic acid prepared in accordance with any of the preceding
Examples may be converted to its alkali metal or alkaline earth
metal salt, which in turn is reacted with an alkyl or aralkyl
halide, sulfate, or sulfonate in an alkali-stable medium such as
dimethylformamide, formamide, dimethylsulfoxide, hydrocarbons,
ethers, etc. Likewise, an acyl halide prepared by the reaction of
the appropriate carboxylic acid with a sulfur halide or a
phosphorus halide may be reacted with an alcohol or phenol in an
acid-resistant solvent such as hydrocarbons, ethers, esters,
tertiary bases, chlorinated hydrocarbons, etc.; or an acid halide
may be reacted with the metal (alkoxide) derivative of almost any
alcohol or phenol in an acid-resistant solvent.
Other methods for preparing esters are:
1. the reaction of the appropriate carboxylic acid with diazoalkane
in an inert solvent,
2. the reaction of the appropriate carboxylic acid with an alcohol
in the presence of strong organic or inorganic acid catalysts, and
by
3. ester interchange by heating one ester in a large excess of
another ester in the presence of acidic or basic catalysts.
EXAMPLE XXV
Butyl 2-methyl-3-ethyl-4-(p-tolyl)-3-cyclohexenecarboxylate
A solution of 0.6 g. of
2-methyl-3-ethyl-4-(p-tolyl)-3-cyclohexenecarboxylic acid in 5 ml.
of 10% methanolic sodium hydroxide is diluted with 65 ml. of
dimethylformamide. The solution is evaporated to a volume of 35 ml.
and the resulting suspension is cooled to 10.degree.C., stirred and
treated with 1.0 ml. of dibutyl sulfate. After 1 hour at
25.degree.C., this mixture is evaporated and the residue is shaken
with ether and water. The ether phase is washed with dilute alkali,
dried and evaporated, and the residue is distilled to afford butyl
2-methyl-3-ethyl-4-(p-tolyl)-3-cyclohexenecarboxylic, an oil of
b.p. 115.degree.-117.degree.C. at 0.005 mm.
Anal. Calcd. for C.sub.21 H.sub.30 O.sub.2 : C, 80.21; H, 9.62.
Found: C, 80.14; H, 9.80.
.lambda..lambda.max: 5.78, 8.61, 9.78, 12.28 .mu..
Nmr (cdcl.sub.3): 0.75, 0.87, 0.99, 1.06 ppm.
EXAMPLE XXVI
Hexyl
2-Methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-3-cyclohexenecarboxylate
A mixture of 0.3 g. of
2-methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-3-cyclohexenecarboxylic
acid and 3 ml. of thionyl chloride is refluxed for 15 minutes and
then it is evaporated and the residue is distilled to afford 0.3 g
of the acid chloride. a viscous orange oil of b.p.
130.degree.-140.degree. at 0.02 mm. The distilled acid chloride is
dissolved in 4 ml. of n-hexyl alcohol and to this is added 4 ml. of
pyridine. The mixture is heated at 90.degree. for 30 minutes and
then five drops of water are added and the heating is continued for
5 minutes. The reaction mixture is diluted with ether and then it
is washed with dilute acid, water, and dilute alkali. The final
ether solution is dried and evaporated, and the residue is
distilled to afford 0.3 g. of hexyl
2-methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-3-cyclohexenecarboxylate,
an oil of b.p. 150.degree.-160.degree. at 0.001 mm.
Anal. Calcd. for C.sub.23 H.sub.32 O.sub.4 : C, 74.16; H, 8.66
Found: C 74.10; H, 8.75
.lambda..lambda.max: 5.78, 8.10, 8.60, 9.57, 10.62, 11.60,
12.31.mu..
Nmr (cdcl.sub.3): 0.76, 0.88, 0.92, 1.00, 1.03 ppm.
Typical esters which are prepared are:
Methyl
2-methyl-3-ethyl-4-(o-methoxy-p-hydroxyphenyl)-4-cyclohexenecarboxylate,
Methyl
2-methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-4-cyclohexenecarboxylate,
Methyl 2-methyl-3-ethyl-4-(m-tolyl)-4-cyclohexenecarboxylate,
Methyl 2-methyl-3-ethyl-4(m-tolyl)-3-cyclohexenecarboxylate,
Propyl 2-ethyl-3-propyl-4-(m-tolyl)-3-cyclohexenecarboxylate,
Butyl 2-methyl-3-ethyl-4-(p-tolyl)-4-cyclohexenecarboxylate,
Hexyl
2-methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-4-cyclohexenecarboxylate,
Octyl
2,3-dimethyl-4-(p-diethylaminoethoxyphenyl)-4-cyclohexenecarboxylate,
Octyl 2,3-dibutyl-4-(m-hydroxyphenyl)-3-cyclohexenecarboxylate,
and
Octyl
2-ethyl-3-propyl-4-(.alpha.-naphthyl)-4-cyclohexenecarboxylate.
EXAMPLE XXVII
2-methyl-3-ethyl-4-(p-trifluoromethylphenyl)-3-cyclohexenecarboxylic
acid
A solution of 9.0 g. of p-toluenesulfonic acid monohydrate in 45
ml. of acetic anhydride is evaporated under vacuum to a syrupy
residue of anhydrous sulfonic acid. The syrup is dissolved in 100
ml. of acetic acid and this solution is again evaporated to a
syrupy residue to which is added 9.0 g. of methyl
2-methyl-3-ethyl-4-hydroxy-4-(p-trifluoromethylphenyl)cyclohexanecarboxyla
te and 450 ml. of acetic acid. The mixture is stirred, rapidly
heated, and boiled for 15 minutes. This dehydration solution is
cooled to 70.degree.C. and 7.0 g. of sodium acetate is added. The
mixture is evaporated under vacuum to a pasty residue which is
shaken with ether and water. The ether phase is washed twice with
aqueous potassium bicarbonate, dried over anhydrous magnesium
sulfate and evaporated to an oil which is a mixture of the
.DELTA..sup.3 and .DELTA..sup.4 -isomers of methyl
2-methyl-3-ethyl-4-(p-trifluoromethylphenyl)cyclohexenecarboxylate.
The mixture of dehydrated esters is refluxed with stirring for two
hours in 90 ml. of methanol and 90 ml. of water containing 9.0 g.
of sodium hydroxide. The resulting clear solution is diluted with a
large volume of water and is acidified with hydrochloric acid to
precipitate the dehydrated acid. The precipitate is filtered off
and dried in air. The dry precipitate is chromatographed on silicic
acid, eluting with ethyl acetate-benzene. Eluates rich in the
.DELTA..sup.4 -isomer are first obtained from the column, and these
are followed by mixed .DELTA..sup.3 and .DELTA..sup.4 and then by
the .DELTA..sup.3 -rich fractions. These changes are followed by
infrared spectroscopy. The portions which are largely .DELTA..sup.3
-isomer are combined and recrystallized several times from 25%
aqueous methanol to afford 1.3 g. of white prisms of
2-methyl-3-ethyl-4-(p-trifluoromethylphenyl)-3-cyclohexenecarboxylic
acid, m.p. 174.degree.-176.degree.C.
Calcd. for C.sub.17 H.sub.19 O.sub.2 F.sub.3 : C, 65.40; H,
6.13
Found: C, 64.83; H, 5.97
.lambda..lambda.max: 5.88, 7.53, 8.57, 8.85, 9.32, 11.72, 12.00,
14.58.mu.. (KBr)
.lambda.max: 247 m.mu.. (.epsilon. 5820, methanol)
EXAMPLE XXVIII
2-methyl-3-ethyl-4-(p-trifluoromethylphenyl)-4-cyclohexenecarboxylic
acid
The residues from early chromatographic elutions, described in
Example XXVII, are recrystallized several times from ether-hexane
to afford 1.5 g. of
2-methyl-3-ethyl-4-(p-trifluoromethylphenyl)-4-cyclohexenecarboxylic
acid, m.p. 181.degree.-183.degree.C.
Calcd. for C.sub.17 H.sub.19 O.sub.2 F.sub.3 : C, 65.40; H,
6.13
Found: C, 65.67; H, 6.26
.lambda..lambda.max: 5.90, 7.55, 8.53, 8.80, 9.34, 11.65, 11.95
.mu.. (KBr.)
.lambda.max: 244 m.mu.. (.epsilon.9060, methanol)
Nmr (cdcl.sub.3): shows vinyl H at 5.70 p.p.m.
The alkali metal salts of the hexenyl acids of the invention are
prepared by mixing equivalent amounts of the appropriate hexenyl
acid and an alkali metal carbonate, bicarbonate or hydroxide in a
solvent such as water or methanol until the neutralization reaction
is complete. The reaction mixture is then evaporated to dryness to
afford the alkali metal salts of the acid.
Methylols may be prepared by the reduction of a carboxylic acid,
carboxylic ester or carbonyl halide with lithium aluminum hydride.
The reductions may be performed in any inert solvent, but ethers
are most favored because they dissolve lithium aluminum
hydride.
EXAMPLE XXIX
[2-methyl-3-ethyl-4-(m-tolyl)-4-cyclohexenyl-1] methanol
To a stirred solution of 0.15 g. of
2-methyl-3-ethyl-(m-tolyl)-4-cyclohexenecarboxylic acid in 10 ml.
of tetrahydrofuran is added 0.4 g. of lithium aluminum hydride. The
mixture is stirred at 25.degree. for 20 hours and then it is poured
into ice and water. The hydrolysis mixture is acidified with
hydrochloric acid and filtered, the filter cake being washed
thoroughly with ether. After separation of the filtrate layers, the
ether solution is washed with dilute aqueous sodium hydroxide,
dried, and evaporated to a residue which is distilled to afford
0.12 g. of
[2-methyl-3-ethyl-4-(m-tolyl)-4-cyclohexenyl-11]-methanol, a
viscous oil, b.p. 105.degree.-110.degree. at 0.001 mm.
Anal. Calcd. for C.sub.17 H.sub.24 O: C, 83.55; H, 9.90
Found: C, 83.30; H, 9.76
.lambda..lambda.max: 3.00, 9.65, 9.91, 11.80, 12.53, 12.81, 14.14
.mu..
Nmr (cdcl.sub.3): 0.70, 0.82, 0.94; 0.82, 0.93; 5.63 ppm.
Following the procedure of Example XXIX, the appropriate
cyclohexenyl acid affords
[2-Methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-3-cyclohexenyl-1]
methanol; viscous oil of b.p. 125.degree.-130.degree. at 0.001
mm.
Anal. Calcd. for C.sub.17 H.sub.22 O.sub.3 : C, 74.42; H, 8.08
Found: C, 74.11; H, 8.20
.lambda..lambda.max: 3.00, 8.03, 8.20, 9.59, 10.63, 11.58,
12.31.mu..
Nmr (cdcl.sub.3): 0.73, 0.86, 0.99,; 0.89, 1.00 ppm.
Utilizing 2-methyl-3-ethyl-4-(p-anisyl)-4-cyclohexene carboxylic
acid and following the procedure of Example XXIX,
[2-methyl-3-ethyl-4-(p-anisyl)-4-cyclohexenyl-1] methanol is
prepared as a colorless oil of b.p. 135.degree.-140.degree.C/ 0.03
mm which is recrystallized from pentane to yield white granules of
m.p. 71.degree.-72.degree.C.
Anal. Calcd. for C.sub.17 H.sub.24 O.sub.2 : C, 78.42; H, 9.29
Found: C, 78.51; H, 9.30
.lambda..lambda.max: 3.00, 7.93, 8.48, 9.63, 11.90,
12.33.mu.(KBr)
Nmr (cdcl.sub.3): 0.69, 0.79, 0.87, 0.90, 0.97, 1.02
from the corresponding .DELTA..sup.3 acid,
[2-methyl-3-ethyl-4-(p-anisyl)-3-cyclohexenyl-1] methanol is
similarly prepared as a colorless viscous oil of b.p.
129.degree.-132.degree.C/ .001 mm.
Anal. Found: C, 78.25 H, 9.29
.lambda..lambda.max: 2.99, 8.02, 8.47, 8.71, 9.62, 11.23,
12.03.mu.(neat)
Nmr (cdcl.sub.3): 0.72, 0.84, 0.96, 0.89, 1.00
again following generally the procedure of Example XXIX, and
starting with
2-methyl-3-ethyl-4-(p-hydroxyphenyl)-4-cyclohexenecarboxylic acid,
[2-methyl-3-ethyl-4-(p-hydroxyphenyl)-4-cyclohexenyl-1] methanol is
prepared as white prisms of m.p. 166.degree.-167.degree.C.
Anal. Calcd. for C.sub.16 H.sub.22 O.sub.2 : C, 78.01; H, 9.00
Found: C, 78.01; H, 9.06
.lambda..lambda.max: 2.92, 6.61, 8.00, 8.17, 9.97, 11.76,
12.10.mu.. (KBr)
From the corresponding .DELTA..sup.3 acid,
[2-methyl-3-ethyl-4-(p-hydroxyphenyl)-3-cyclohexenyl-1] methanol is
similarly prepared as white prisms which melt at
102.degree.-103.degree. C.
Anal. Found: C, 77.33; H, 9.61
.lambda..lambda.max: 2.96, 3.10, 6.61, 8.02, 9.77, 9.83, 11.21,
12.09.mu. (KBr.)
In like manner there are prepared:
[2-methyl-3-ethyl-4-(m-tolyl)-3-cyclohexenyl-1] methanol,
[2-methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-4-cyclohexenyl-1]-methanol,
[2-methyl-3-ethyl-4-(o-methoxy-p-hydroxyphenyl)-4-cyclohexenyl-1]-methanol,
[2-ethyl-3-propyl-4-(m-tolyl)-3-cyclohexenyl-1] methanol,
[2-methyl-3-ethyl-4-(p-tolyl)-3-cyclohexenyl-1] methanol,
[2-methyl-3-ethyl-4-(p-tolyl)-4-cyclohexenyl-1] methanol,
[2,3-dimethyl-4-(p-diethylaminoethoxyphenyl)-4-cyclohexenyl-1]-methanol,
[2,3-dibutyl-4-(m-hydroxyphenyl)-3-cyclohexenyl-1] methanol,
[2-ethyl-3-propyl-4-(.alpha.-naphthyl)-4-cyclohexenyl-1]
methanol,
[2-methyl-3-ethyl-4(o,p-dihydroxyphenyl)-4-cyclohexenyl-1]
methanol,
[2-methyl-3-ethyl-4-(m-anisyl)-4-cyclohexenyl-1] methanol, and
[2-methyl-3-ethyl-4-(m-anisyl)-3-cyclohexenyl-1] methanol.
Amides may be prepared by reacting the acid chloride of the
appropriate cyclohexenyl carboxylic acid in dioxane with
concentrated aqueous ammonium hydroxide, with propylamine, or with
a secondary amine. Alternatively, the amide may be prepared by
heating the carboxylic acid in the presence or absence of a high
boiling inert solvent, with ammonia or a primary or secondary
amine, or by heating a carboxylic ester, in the presence or absence
of an inert solvent, with ammonia or a primary or secondary
amine.
EXAMPLE XXX
1-carbamyl-2-methyl-3-ethyl-4-(p-tolyl)-3-cyclohexene
A mixture of 0.5 g. of
2-methyl-3-ethyl-4-(p-tolyl)-4-cyclohexenecarboxylic acid and 5 ml.
of thionyl chloride is refluxed for 15 minutes and then it is
evaporated and the residue is distilled to afford 0.5 g. of the
acid chloride, a mobile oil of b.p. 100.degree.-110.degree. at
0.002 mm. The distilled acid chloride is dissolved in 7 ml. of
dioxane and 2 ml. of 28% aqueous ammonium hydroxide is added with
stirring. The solution is then heated at 80.degree. for 5 minutes,
diluted with 100 ml. of water, and evaporated to remove most of the
dioxane. The insoluble amide is extracted from the residual
suspension with ether, and the ether solution is washed with dilute
sodium hydroxide, dried, and evaporated. Recrystallization of the
residue from aqueous methanol affords 0.4 g. of
1-carbamyl-2-methyl-3-ethyl-4-(p-tolyl)-3-cyclohexene, m.p.
166.degree.-168.degree..
Anal. Calcd. for C.sub.17 H.sub.23 ON: C, 79.33; H, 9.01
Found: C, 79.34: H, 9.10
.lambda..lambda.max: 2.94, 3.12, 6.06, 12.29.mu.. (KBr)
Nmr (cdcl.sub.3): 0.77, 0.88, 1.00; 1.03, 1.14; 5.97, 6.44 ppm.
Following the above general procedure, and reacting the acid
chloride of the appropriate cyclohexenyl acid in dioxane with
concentrated aqueous ammonia, with propylamine, or with a secondary
amine (25% dimethylamine in water), the following amides are
prepared:
1-(N,N-Dimethylcarbamyl)-2-methyl-3-ethyl-4-(m-anisyl)-3-cyclohexene;
viscous oil of b.p. 150.degree.-155.degree. at 0.005 mm.
Anal. Calcd. for C.sub.19 H.sub.27 O.sub.2 N: C, 75.71; H,
9.03.
Found: C, 74.02; H, 8.97.
.lambda..lambda.max: 6.10, 7.77, 8.89, 9.50, 11.41, 12.70, 13.69,
14.21.mu..
Nmr (cdcl.sub.3): 0.77, 0.89, 1.01; 0.96, 1.07; 2.99, 3.13 ppm.
1-(N,N-dimethylcarbamyl)-2-methyl-3-ethyl-4-(m-tolyl)-4-cyclohexene;
viscous oil of b.p. 130.degree.-135.degree. at 0.005 mm.
Anal. Calcd. for C.sub.19 H.sub.27 ON: C, 79.95; H, 9.54.
Found: C, 79.63; H, 9.58.
.lambda..lambda.max: 6.10, 8.80, 11.90, 12.70, 13.27,
14.15.mu..
Nmr (cdcl.sub.3): 0.81, 0.88, 0.92; 5.71 ppm.
1-(N-Propylcarbamyl)-2-methyl-3-ethyl-4-(m-tolyl)-4-cyclohexene;
viscous oil of b.p. 160.degree.-165.degree. at 0.01 mm.
Anal. Calcd. for C.sub.20 H.sub.29 ON: C, 80.22; H, 9.76.
Found: C, 80.38; H, 10.05.
.lambda..lambda.max: 3.02, 6.09, 11.32, 11.90, 12.74,
14.18.mu..
Nmr (cdcl.sub.3): 0.82, 0.92, 0.95, 1.06, 5.67, 6.09 ppm.
In like manner there may be prepared:
1-carbamyl-2-methyl-3-ethyl-4-(p-tolyl)-4-cyclohexene,
1-(N,N-dimethylcarbamyl)-2-methyl-3-ethyl-4-(m-anisyl)-4-cyclohexene,
1-(N,N-dimethylcarbamyl)-2-methyl-3-ethyl-4-(m-tolyl)-3-cyclohexene,
1-(N-propylcarbamyl)-2-methyl-3-ethyl-4-(m-tolyl)-3-cyclohexene,
1-carbamyl-2,3-dibutyl-4-(m-hydroxyphenyl)-3-cyclohexene,
1-carbamyl-2-ethyl-3-propyl-4-(.alpha.-naphthyl)-4-cyclohexene,
1-(N,N-dimethylcarbamyl)-2-methyl-3-ethyl-4-(o,p-diacetoxyphenyl)-4-cyclohe
xene,
1-carbamyl-2-methyl-3-ethyl-4-(o-methoxy-p-hydroxyphenyl)-4-cyclohexene,
and
1-(N-propylcarbamyl)-2-methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-4-cycloh
exene.
The compounds of the present invention are active agents for the
suppression of animal reproduction.
One method of determining the ability of a chemical compound to
suppress reproduction is to determine its effect upon the littering
of animals.
The antilittering effect of a compound is determined by
administering a compound to adult rats according to the following
sequence:
1. The compound to be evaluated is administered in the diet for 7
days with the sexes segregated.
2. The treatment is continued with the sexes cohabitant over a
period of 15 days.
3. The sexes are segregated and observed for 21 days with no
administration of the compound.
A control group is similarly treated except that no compound is
administered.
Table I tabulates the minimum effective dosage of each of the
compounds tested in completely suppressing littering.
TABLE I
__________________________________________________________________________
ANTILITTERING M.E.D. (per Kg. COMPOUND TESTED body
__________________________________________________________________________
wt/day) 2-methyl-3-ethyl-4-(o-anisyl)-4-cyclohexenecarboxylic acid
50 .mu.g. 2-methyl-3-ethyl-4-(o-anisyl)-3-cyclohexenecarboxylic
acid 250 .mu.g.
2-methyl-3-ethyl-4-(m-anisyl)-3-cyclohexenecarboxylic acid 500
.mu.g.
2-methyl-3-ethyl-4-(p-diethylaminoethoxyphenyl)-3-cyclohexenecarboxylic
acid 2.5 mg.
2-methyl-3-ethyl-4-(p-diethylaminoethoxyphenyl)-3-cyclohexenecarboxylic
acid p-toluenesulfonate 10.0 mg.
2-methyl-3-ethyl-4-(p-thioanisyl)-3-cyclohexenecarboxylic 10.0 mg.
2-methyl-3-ethyl-4-(p-tolyl)-4-cyclohexenecarboxylic acid 10.0 mg.
2-methyl-3-ethyl-4-(p-tolyl)-3-cyclohexenecarboxylic acid 5.0 mg.
2-methyl-3-ethyl-4-(m-tolyl)-4-cyclohexenecarboxylic acid 10 .mu.g.
2-methyl-3-ethyl-4-(m-tolyl)-3-cyclohexenecarboxylic acid 25 .mu.g.
2-methyl-3-ethyl-4-(m-chlorophenyl)-4-cyclohexenecarboxylic 10 mg.
2-methyl-3-ethyl-4-(p-dimethylaminophenyl)-4-cyclohexenecarboxylic
10 mg. 2-methyl-3-ethyl-4-(m-hydroxyphenyl)-3-cyclohexenecarboxylic
250 .mu.g.
2-methyl-3-ethyl-4-(o-hydroxyphenyl)-3-cyclohexenecarboxylic 50
.mu.g.
2-methyl-3-ethyl-4-(o-methoxy-p-hydroxyphenyl)-4-cyclohexenecarboxylic
acid 500 .mu.g.
2-methyl-3-ethyl-4-(o,p-diacetoxyphenyl)-3-cyclohexenecarboxylic
500 .mu.g.
2-methyl-3-ethyl-4-(o,p-diacetoxyphenyl)-4-cyclohexenecarboxylic
100 .mu.g.
2-methyl-3-ethyl-4-(o-hydroxy-p-acetoxyphenyl)-3-cyclohexenecarboxylic
acid 200 .mu.g.
2-methyl-3-ethyl-4-(o-hydroxy-p-acetoxyphenyl)-4-cyclohexenecarboxylic
acid 100 .mu.g.
2-methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-3-cyclohexenecarboxylic
acid 500 .mu.g.
2-methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-4-cyclohexenecarboxylic
acid 1000 .mu.g.
2-methyl-3-ethyl-4-(.alpha.-naphthyl)-4-cyclohexenecarboxylic 5.0
mg. Carbinols
[2-methyl-3-ethyl-4-(p-hydroxyphenyl)-3-cyclohexenyl-1]methanol 2.5
.mu.g.
[2-methyl-3-ethyl-4-(p-hydroxyphenyl)-4-cyclohexenyl-1]methanol 5.0
.mu.g. [2-methyl-3-ethyl-4-(p-anisyl)-3-cyclohexenyl-1]methanol 2.5
.mu.g. [2-methyl-3-ethyl-4-(p-anisyl)-4-cyclohexenyl-1]methanol 5.0
.mu.g. (2-methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methanol* 10.0
__________________________________________________________________________
.mu.g. *Compound of Example V of U.S. Patent No. 3,344,147
As can be seen from the foregoing results, the substituted phenyl
cyclohexenyl carbinol compounds of the present invention are at
least twice as active in preventing the formation of litters as the
corresponding unsubstituted phenyl compounds. In addition, the
compounds of the invention posses higher estrogenic activity than
does the unsubstituted phenyl compound.
While the determination of the antilittering effect of a compound
is important in that it shows whether or not a compound will
suppress reproduction, it does not pinpoint the precise manner in
which reproduction is suppressed. It has been determined that the
compounds of the invention are active antizygotic agents. A zygote
is the fertilized ovum, and an antizygotic agent is one which
destroys the zygote prior to implantation in the uterus. One
specific form of zygote destruction is the lysing of the
zygote.
In order to determine whether or not a compound is antizygotic,
adult male and female rats are cohabited until sperm is found in
the vagina. Following the presence of sperm, the female rats are
dosed on two successive days with the compound, and on the ninth
day after the presence of sperm is noted, the rats are autopsied
and the uteri are examined for the presence of conceptuses. Lack of
conceptuses indicates antizygotic effect. A control group of rats
is similarly treated except that there is no dosing with the
compound under test.
Table II tabulates the minimum effective dosage of the compounds
needed to obtain an antizygotic effect.
TABLE II
__________________________________________________________________________
ANTIZYGOTIC M.E.D. (ug/kg Compound Tested body wt/day)
__________________________________________________________________________
7 2-methyl-3-ethyl-4-(m-anisyl)-4-cyclohexenecarboxylic acid 1000
2-methyl-3-ethyl-4-(m-anisyl)-3-cyclohexenecarboxylic acid 1000
2-methyl-3-ethyl-4-(o-anisyl)-4-cyclohexenecarboxylic acid 200
2-methyl-3-ethyl-4-(o-anisyl)-3-cyclohexenecarboxylic acid 500
2-methyl-3-ethyl-4-(p-diethylaminoethoxyphenyl)-3-cyclohexenecarboxylic
acid p-toluenesulfonate 10,000
2-methyl-3-ethyl-4-(p-thioanisyl)-3-cyclohexenecarboxylic 1,000
2-methyl-3-ethyl-4-(m-tolyl)-4-cyclohexenecarboxylic acid 50
2-methyl-3-ethyl-4-(m-tolyl)-3-cyclohexenecarboxylic acid 50
2-methyl-3-ethyl-4-(p-trifluoromethylphenyl)-4-cyclohexenecarboxylic
10,000
2-methyl-3-ethyl-4-(p-trifluoromethylphenyl)-3-cyclohexenecarboxylic
10,000 2-methyl-3-ethyl-4-(m-chlorophenyl)-4-cyclohexenecarboxylic
1,000 2-methyl-3-ethyl-4-(m-hydroxyphenyl)-3-cyclohexenecarboxylic
2,000 2-methyl-3-ethyl-4-(o-hydroxyphenyl)-3-cyclohexenecarboxylic
200d
2-methyl-3-ethyl-4-(o-methoxy-p-hydroxyphenyl)-4-cyclohexenecarboxylic
acid 1,000
2-methyl-3-ethyl-4-(o,p-diacetoxyphenyl)-4-cyclohexenecarboxylic
500d
2-methyl-3-ethyl-4-(o-hydroxy-p-acetoxyphenyl)-4-cyclohexenecarboxylic
acid 500
2-methyl-3-ethyl-4-(o-hydroxy-p-acetoxyphenyl)-3-cyclohexenecarboxylic
acid 1,000
2-methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-4-cyclohexenecarboxylic
acid 5,000
2-methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-3-cyclohexenecarboxylic
acid 1,000
2-methyl-3-ethyl-4-(.alpha.-naphthyl)-4-cyclohexenecarboxylic
10,000 2-methyl-3-ethyl-4-(.beta.-naphthyl)-4-cyclohexenecarboxylic
500d 2-methyl-3-propyl-4-(p-anisyl)-3-cyclohexenecarboxylic acid 25
__________________________________________________________________________
* * * * *