US3825576A

US3825576A - Alkyl esters of 2-(lower alkyl)-3-(lower alkyl)-4-aryl-3-or 4-cyclohexene-carbinols

Info

Publication number: US3825576A
Application number: US00072220A
Authority: US
Inventors: G Karmas
Original assignee: Ortho Pharmaceutical Corp
Current assignee: Ortho Pharmaceutical Corp
Priority date: 1968-05-14
Filing date: 1970-09-14
Publication date: 1974-07-23
Anticipated expiration: 1991-07-23

Abstract

ARE DISCLOSED WHEREIN -R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HYDROXY, LOWER ALKOXY OF UP TO 8 CARBON ATOMS, LOWER ALKYL OF UP TO 8 CARBON ATOMS; -R'' IS S,: LOWER ALKYL ANILINO OF UP TO 4 CARBON ATOMS; -R'' IS SELECTED FROM THE GROUP CONSISTING OF ALKYL AND ALKENYL OF UP TO 20 CARBON ATOMS, CYCLOALKYL LOWER ALKYL OF UP TO 3 CARBON ATOMS IN THE ALKYL PORTION, ADAMANTYL, PYRIDYL, FURYL, LOWER ALKYL CARBOXYLIC ACIDS AND THEIR ALKALI METAL SALTS, ESTERS AND CARBAMATES; AND R" AND R"'' ARE SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL OF UP TO 3 CARBON ATOMS. THESE COMPOUNDS EXHIBIT ESTROGENIC PROPERTIES AND WHEN GIVEN IN A SINGLE SUBCUTANEOUS DOSE HAVE LONG ACTING EFFECTS IN THE SUPPRESSION OF ANIMAL REPRODUCTION.

ENE

1-(R''-CO-O-CH2-),2-R",3-R"'',4-(R-PHENYL)-CYCLOHEX-3 OR 4-

COMPOUNDS OF THE GENERAL FORMULA

Description

United States Patent Ofiice Patented July 23, 1974 ABSTRACT OF THE DISCLOSURE Compounds of the general formula R!!! I l/I are disclosed wherein R is selected from the group consisting of hydrogen, hydroxy, lower alkoxy of up to 8 carbon atoms, lower alkyl of up to 8 carbon atoms, and lower alkyl anilino of up to 4 carbon atoms; -R' is selected from the group consisting of alkyl and alkenyl of up to 20 carbon atoms, cycloalkyl lower alkyl of up to 3 carbon atoms in the alkyl portion, adamantyl, pyridyl, fury], lower alkyl carboxylic acids and their alkali metal salts, esters and carbamates; and R" and R' are selected from the group consisting of lower alkyl of up to 3 carbon atoms. These compounds exhibit estrogenic properties and when given in a single subcutaneous dose have long acting effects in the suppression of animal reproduction.

This is a division of application Ser. No. 728,900, filed May 14, 1968, now US. Pat. No. 3,557,129.

The present invention relates to compounds of the general formula wherein -R is selected from the group consisting of hydrogen, hydroxy, lower alkoxy of up to 8 carbon atoms, lower alkyl of up to 8 carbon atoms, and lower alkyl anilino of up to 4 carbon atoms; R' is selected from the group consisting of alkyl and alkenyl of up to 20 carbon atoms, cycloalkyl lower alkyl of up to 3 carbon atoms in the alkyl portion, adamantyl, pyridyl, furyl, lower alkyl carboxylic acids and their alkali metal salts, esters and carbamates; and R" and R' are selected from the group consisting of lower alkyl of up to 3 carbon atoms.

The compounds of the present invention are related to the compounds disclosed in U.S. Pat. 3,344,147 and in my copending patent applications, Ser. Nos. 662,310, now U.S. Pat. 3,591,624; 662,311, now abandoned; 662,295, now U.S. Pat. No. 3,567,770; and 560,116, now abandoned. The compounds of the patent and of my copending patent applications are known to possess activity as agents for the suppression of reproduction when fed orally to animals. The compounds of the present invention are active as suppressants of reproduction not only upon oral administration but also when given parenterally and some of the compounds of the present invention can suppress reproduction over a long period of time when given in only one subcutaneous injection.

These compounds are all esters of 2-(lower alkyl)-3- (lower alkyl)-4-phenylcyclohexenecarbinol and analogs of the same and therefore may be prepared generally by the esterification of the appropriate carbinol with acids (RCOOH), acid halides (R'COCl), acid anhydrides (R'COOOCR') and ketenes In addition, the compounds may be prepared by the monoacetylation of the primary-tertiary diol with subsequent dehydration according to the following reaction scheme:

R R OH -omorr @lOomooorv CHQOH The following examples illustrate the preparation of some of the compounds of the invention. While only one method of preparation is disclosed for each compound, it is to be understood that any of the other methods noted above can also be utilized.

ALKYL ESTERS (l) R=Hydrogen or Lower Alkyl The' starting material for Examples I through V1 is (Z-methyl-3-ethyl-4-phenyl-4- or 3-cyclohexenyl-1)methanol which is suitably prepared as described in U.S. Pat. 3,344,147.

Example I.-(2-methyl-3-ethyl-4-phenyl- 3-cyclohexenyl-l methyl acetate A mixture of 0.35 g. of (2-methyl-3-ethyl-4-phenyl-3- cyclohexenyl-1)methanol and 50 mg. of p-toluene-sulfonic acid in 10 ml. of acetic acid is refluxed for 15 minutes and then diluted with water and extracted with hexane. The hexane solution is washed twice with dilute potassium carbonate, dried and evaporated. The oily residue is distilled to afford 0.30 g. of the acetate, a colorless oil which boils at 90 C. at .001 mm.

Calcd. for C H O C, 79.37; H, 8.88. Found: C, 79.14; H, 8.64.

M 5.75, 8.09, 9.71, 13.17, 14.26 1 (neat).

Example II.(2-methyl-3-ethyl-4-phenyl- 3-cyclohexeny1-1)methyl caproate A solution of 4 g. of the M-cyclohexenylcarbinol in 15 ml. of dry pyridine is stirred at 05 C. while 1 /2 molecular equivalents of caproyl chloride is added. The resulting pasty mixture is stirred at 25 C. for 15 minutes, heated at -95 C. for 15 minutes, and then cooled. Five ml. of water is added and the mixture stirred vigorously for 2 hours. After dilution with ml. of ether, the

Example IH.2(-methyl-3-ethyl-4-phenyl- 4-cyclohexenyl- 1 methyl octano ate This compound is prepared following the procedure of Example II and using octanoyl chloride. The compound is an oil which boils at ISO-155 C. at .001 mm.

Calcd. for C H O C, 80.85; H, 10.18. Found: C, 80.66; H, 10.28.

M 5.74, 8.56, 9.01, 11.79, 13.14, 14.25 2 (neat).

Example 1V.(2-methyl-3-ethyl-4-phenyl- 4-cyclohexenyl-1 methyl eiscosanoate Using eicosanoyl chloride and again following the procedure of Example 11 and recrystallizing the crude solid ester from hexane (2-methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methy1 eicosanoate is prepared in the form of white flakes having a melting point of 47-48 C.

Calcd. for C H O C, 82.38; H, 11.52. Found: C, 82.25; H, 11.38.

M 5.74, 8.62, 11.88, 13.21, 13.90, 14.22 (KBr).

Example V.-(2-methyl-3-ethyl-4-phenyl-4- cyclohexenyl-l )methyl 2-ethylhexanoate A mixture of 2.0 g. of (Z-methyl-3-ethyl-4-phenyl-4- cyclohexenyl-1)methanol and 6.3 ml. of a 20% solution of butylethyl ketene in toluene is held for one hour at 25 C. and then for one hour at 100 C. After the addition of methanol to destroy excess ketene, the toluene solution is evaporated and the oily residue is chromatographed on alumina (benzene-hexane elution) to isolate the crude ester. The ester is then further purified by two distillations to yield 1.7 g. of a colorless mobile oil which boils at ISO-154 C. at .001 mm.

Calcd. for C H C, 81.76; H, 10.29. Found: C, 81.16; H, 10.24.

M 5.77, 8.52, 8.71, 10.00, 11.80, 13.17, 14.28;. (neat).

Any alkyl alkyl ester of the basic carbinol can be prepared by selecting the proper acid, acid chloride, acid anhydride or ketene. The A or A analog is prepared by utilizing the appropriate carbinol.

Example VI.-(2-methyl-3-ethyl-4-phenyl- 4-cyclohexenyl-1)methyl benzoate This compound is prepared using benzoyl chloride in the procedure of Example II. It is a colorless viscous oil which boils at 180-185 C. at .001 mm.

Calcd. for C23H2602: C, 82.59; H, 7.84. Found: C, 82.38; H, 7.71.

M 5.81, 7.85, 9.00, 9.32, 9.72, 11.81, 13.18, 14.0, (neat).

Example VII.-[2-methyl-3-ethyl-4-(m-toly1)- 4-cyclohexenyl-1 methyl octanoate This compound is formed from [2-methyl-3-ethyl-4- (m-tolyl)-4-cyclohexenyl-l]methanol and octanoyl chloride following the procedure of Example II. The carbinol starting material is prepared in the manner described in my copending application Ser. No. 662,311.

The compound is a pale yellow oil which boils at 15 5- 165 C. at .001 mm.

Calcd. for C H O C, 81.03; H, 10.34. Found: C, 81.05; H, 10.36.

M 5.77, 8.58, 9.03, 11.81, 12.83, 1419 2 (neat).

Esters having other lower alkyl substitution in the meta position in the phenyl ring may be prepared following the same procedure of Example 11 from the appropriate carbinol. The ortho and para analogs also may be prepared following this same procedure. The starting carbinols for the latter are prepared as described in the above-noted copending application and my copending application Ser. No. 662,310.

2) R=Lower Alkoxy Example V'II I.[2-methyl-3-ethyl-4-(o-anisyl)-'4-cyclohexanyl-lJmethyl hexanoate To a stirred solution of 3.1 g. of 2-methyl-3-ethyl-4- hyd-roxy-44(o-'anisyl) cyclohexanecanboxylic acid (the preparation of which is disclosed in my copending application Ser. No. 662,295) in ml. of tetrahydrofuran is added cautiously 4.0 g. of lithium aluminum hydride. The reaction mixture is refluxed with stirring for one hour and then hydrolyzed in a large volume of ice and water. After acidification with dilute hydrochloric acid, the mixture is filtered, the filter cake being washed well with ether and Water. Organic products in the filtrate are separated by extracting twice with ether; and the combined ether solution is then washed with dilute sodium hydroxide, dried and evaporated. The ether residue is distilled to afford 3.0 g. of a pale yellow glass having a boiling point of -145 C. at .001 mm. This is the 1,4- diol: 2-met-hyl-3-e thyl-4-hydroxy-4 (o anisyl) cyclohexanyl- 1 methanol.

'Calcd: C, 73.84; *H, 9.41. Found: C, 73.20; H, 953.

M 2.92, 8110, 9.70, 11.00, 12,5 1, -13.24,u. (KBr).

A solution of 2.6 g. of the 1,4-diol, described above, and 6 ml. of hexanoic anhydride in 20 ml. of pyridine is heated at 85 C. for 1% hours, 2 ml. of water added and heating continued at 85 C. for /2 hour more. The solution is diluted with hexane and the hexane solution is washed with water, twice with dilute hydrochloric acid, and twice with dilute potassium carbonate. After drying and evaporation of the hexane solution, the oily residue is distilled to afford 3.0 g. of a yellow oil having a boiling point of l60-165 'C. at .001 mm. This is the ester-monoalcohol: [2-methyl-3-ethyl-4-hydroxy-4-(o-anisyl) cyclohexanyl l]methyl hexanoate.

Calcd: C, 73.36; H, 9.64. Found: C, 74.32; H, 9.76.

M 283, 5.78, 8.10, 8:50, 9.70, 12.51, 113.232 (neat).

A solution of -1.0 g. of the ester-monoalcohol and 4 ml. of boron tri-fluoride etherate in 20 ml. of ether is held at 20-25 C. for 5 hours and then further diluted with ether and Washed twice with aqueous potassium carbonate. The ether solution is dried and evaporated and the oily residue is distilled to afford 0.8 g. of [2-methyl-3-ethyl 4- (o anisyl)-4-cyclohexenyl-1]methyl hexanoate, a yellow oil which boils at 140-045" C. at .001 mm.

Calcd: C, 77.05; H, 9.56. Found: C, 76.86; H, 9.39.

M 5.75, 8.02, 8.50, 11.82, 13.28, (neat).

Other esters of the o-anisyl series can be prepared by selecting the proper acid anhydride. iIn forming the psubstituted esters the starting canbinol is suitably formed according to the procedures disclosed in my copending application Ser. No. 560,116.

'(3) R=-Hydroxyl and Acyloxy Example -IX. [Q-methyl-3-ethyl-4- (p-acetoxyphenyl) -4- cyclohexenyl-ll methyl acetate To a stirred solution of 4.0 g. of 2-methyl-3-ethyl-4- (p-hydroxyphenyl) 4 cyclohexenecar-boxylic acid (prepared as described in my copending application Ser. No.

560,116) in 250 ml. of tetrahydrofuran is added cautiously 7.0 g. of lithium aluminum hydride. The thick mixture is stirred at 202 5 C. for 20 hours and then it is hydrolyzed in a large volume of ice and water. After the mixture has been acidified with dilute hydrochloric acid, it is filtered and the rfilter cake is washed thoroughly with ether and water. The organic products in the filtrate are separated by two extractions with ether and then the combined ether solution is washed twice with aqueous potassium bicarbonate, dried, and evaporated 'to a solid residue. The latter is recrystallized from ether to afford 2.5 g. of white prisms which melt at 16'6-167 C. This is the carbinol, [2-methyl-3-ethyl-4-(p hydroxyphenyl) 4- cyclohexenyll ]methanol.

Calcd. for C H O C, 78.01; -H, 9.00. Found: C, 78.01; H, 9.06.

M 2.92, 6.61, 8.00, 8117, 9.97, 11.76, 12. (KBr).

A solution of 1.5 g. of the carbinol and 7.0 ml. of acetic anhydride in ml. of pyridine is heated at 70 C. for /2 hour and then it is hydrolyzed in ice plus water. The hydrolysis mixture is extracted twice with ether and the combined ether solution is washed twice with dilute hydrochloric acid and then with aqueous potassium bicarbonate. After drying and evaporation of the ether solution, the oily residue is distilled to afford 1.6 g. of [2-methyl-3-ethyl-4-(p-acetoxyphenyl) 4 cyclohexenyl- 1]methyl acetate, a colorless oil which boils at 135 140 C. at .001 mm.

Calcd. for C H O C, 72.70; H, 7.93. Found: C, 72.44; H, 8.00.

M 5.68, 5.74, 7.30, 8.33, 9.68, 9.80, 10.97, 1183a (neat).

Other di-esters of the para-hydroxy phenyl carbinols may be prepared by selecting the proper acid chloride.

Example X. 2-methyl-3-ethyl-4- (p-hydroxyphenyl) 4-cyclohexenyl-l methyl acetate This and other hydroxy derivatives are obtained from the appropriate di-esters which are in turn prepared as described in Example IX.

A mixture of 1.0 g. of the diacetate, 0.8 g. of potassium bicarbonate, 10 ml. of water, and 17 ml. of methanol is refluxed for five minutes and then diluted with cold water. The organic material is extracted with an ether-hexane mixture which is dried and evaporated to an oily residue which slowly crystallizes. This crude monoacetate is recrystallized from hexane containing 5% ether to afford 0.5 g. of [2 methyl-3-ethyl-4-(p-hydroxyphenyl)-4-cyclohexenyl-1]methyl acetate in the form of white prisms which melt at 67-72" C.

Calcd. for C H O C, 74.97; H, 8.39. Found: C, 75.74; H, 8.68.

M 2.89, 5.81, 6.61, 7.90, 9.68, 11,76, 11.91 (KBr).

Example XI.[2-methyl-3-ethyl-4-(p-isobutyryloxyphenyl -4-cyclohexenyl-1 1 methyl acetate Where the acyloxy group is different from the ester group, the compound is produced from the p-hydroxyphenyl mono ester obtained as described in Example X.

A solution of 0.35 g. of the phenolic monoacetate and 2.5 ml. of isobutyric anhydride in 15 ml. of pyridine is held at 25 C. for 3 hours and then hydrolyzed by stirring with water for one hour. The product is extracted with hexane and the hexane solution is washed with dilute hydrochloric acid and with potassium carbonate. After drying and evaporation of the hexane solution, the residue is distilled to afford 0.35 g. of [2-methyl-3-ethyl- 4-(p-isobutyryloxyphenyl) 4 cyclohexenyl-11methyl acetate, a colorless oil which boils at 145-150 C. at .001 mm.

Calcd. for C H O C, 73.71; H, 8.44. Found: C, 73.58; H, 8.48.

6 M 5.70, 5.75, 8.10, 8.31, 8.57, 8.81, 9.69, 10.90, 11.48, 11.80; (neat).

(4) R=Anilino Example XII.[2-methy1-3-ethyl-4-(p-dimethylanilino)- 3 and 4-cyclohexenyl-11methyl valerate This compound is prepared from 2-methyl-3-ethyl-4- (p-dimethylanilino)-3 and 4-cyclohexenecarboxylic acid which is prepared as described in my copending patent application 662,311.

To a stirred solution of 3.0 g. of the inseparable mixture of 2-methyl-3-ethyl-4-(p-dimethylanilino) 3 and 4- cyclohexenecarboxylic acids in ml. of tetrahydrofuran is added cautiously 3.0 g. of lithium aluminum hydride. The mixture is stirred at 25 C. for 20 hours and then it is hydrolyzed in a large volume of ice and water. This hydrolysis mixture is filtered and the filter cake is washed thoroughly with ether. The product is isolated by two extractions of the filtrate with ether and the combined ether solution is dried and evaporated. The oily ether residue is distilled to afford 2.5 g. of a very viscous yellow oil which boils at -145" C. at .001 mm. This is carbinol mixture, [2-methyl-3-ethyl-4- (p-dimethylanilino)-3 and 4-cyclohexenyl-1 methanol.

Calcd. for CmHgqONZ C, 79.07; H, 9.95. Found: C, 79.08; H, 9.91.

"1229a (neat).

A solution of 1.0 g. of the mixed carbinol described above and 20 ml. of pyridine is stirred and cooled in an ice bath while 3 ml. of valeryl chloride is added. The dark mixture is held at 20 for 3 hours and then it is hy drolyzed by stirring with water and hexane for one hour. The hexane layer is separated and is washed twice with dilute sodium hydroxide, dried, and evaporated. The oily residue is developed onto a chromatographic column of neutral alumina, and elution with ether affords the crude ester. Distillation of the ester gives the mixture of [2- methyl 3 ethyl-4-(p-dimethylanilino)-3 and 4-cyclohexenyl-1]methyl valerate as a yellow oil which boils at 165 C. at .001 mm.

Calcd. for C H O N: C, 77.26; H, 9.07. Found: C, 77.82; H, 9.95.

M 5.77, 6.20, 6.59, 7.41, 8.57, 10.56, 12.28, (neat).

ADAMANTOATE ESTERS Example XIII.-(2-methyl-3-ethyl-4-penyl-3-cyclohexenyl-l )methyl l-adamantoate This compound is prepared from (2-methyl-3-ethyl-4- phenyl-3-cyclohexenyl-1)methanol and adamantoic acid chloride following the procedure of Example II.

Calcd. for C H O C, 82.60; H, 9.24. Found: C, 82.37; H, 9.41.

kk t 5.80, 8.07, 8.45, 9.25, 13.19, 14.28, 14.7414 (KBr).

M.P. 7576 C.

Example XIV. [2-methyl-3-ethyl-4- p-anisyl) -4- cyclohexenyl-l methyl l-adamantoate This compound is prepared from [2-methyl-3-ethyl- 4-(p-anisyl)-4-cyclohexenyl-1]methanol and adamantoic acid chloride following the procedure of Example II. It is a viscous oil which boils at 200-220" C. at .002 mm.

Calcd. for C H O C, 79.58; H, 9.06. Found: C, 79.23; H, 9.09.

M 5.80, 8.01-8.12, 8.42, 9.02, 9.24, 9.60, 11.93, 13.50 (neat).

CYCLOALKYL LOWER ALKYL ESTERS Example XV 2-methyl-3-ethyl-4- p-anisyl -3- cyclohexenyl- 1 methyl fl-cyclopentylpropionate This compound is formed from cyclopentylpropionic acid chloride and [2-methyl-3-ethyl-4-(p-anisyl)-3-cyclohexenyl-1]methanol according to the procedure of Example II. The compound is an oil which boils at 160- 170 C. at .001 mm.

Calcd. for C H O C, 78.08; H, 9.44. Found: C, 78.04; H, 9.49.

M 5.75, 8.01, 8.49, 9.61, 12.04 (neat).

NMR (CDCl;.): 0.73, 0.84, 0.96, 0.90, 1.01.

FUROATES ANDD NICOTINATES Example XVI.( 2-rnethyl-3 -ethyl-4-phenyl-4- cyclohexenyl-l )methyl nicotinate This compound is prepared using nicotinoyl chloride following the procedure of Example II but omitting the HCl washing. It is a yellow oil which boils at 175-480 C. at .001 mm.

Calcd. for C H O N: C, 78.77; H, 7.51. Found: C, 78.54; H, 7.57.

M 5.79, 7.78, 8.81, 8.95, 9.73, 11.80, 13.15, 13.50, 14.27, (neat).

Example XVII.-(Z-methyl-3-ethyl-4-phenyl-4- cyclohexenyl-l )methyl Z-furoate This compound is prepared generally following the procedures of Example II and using Z-furoyl chloride to afford white granules which melt at 7072 C.

Calcd. for C H O C, 77.75; H, 7.46. Found: C, 77.81; H, 7.54.

M 5.86, 7.70, 8.56, 9.00, 11.83, 12.92, 13.17, 14.30;. (KBr).

OTHER MISCELLANEOUS ESTERS OF THE CAR- BINOLS INCLUDING ESTERS WITH DIBASIC ACIDS, UNSATURATED ACIDS, ETC.

Example XVIII.--(Z-methyl-3-ethyl-4-phenyl-4- cyclohexenyl-l )methyl hemisuccinate A solution of 3.1 g. of the carbinol and 9.0 g. of succinic anhydride in 60 ml. of pyridine is heated at 90-95 C. for one hour, then 9 ml. of water is added and heating is continued for minutes longer. The mixture is diluted with hexane and the hexane solution washed four times with water to remove succinic acid, dried and evaporated. Distillation of the oily residue affords 3.4 g. of the hemisuccinate, a viscous colorless oil which boils at 180-190 C. at .001 mm.

Calcd. for C H O C, 72.70; H, 7.93. Found: C, 72.61; H, 8.05.

M 5.77, 5.83, 8.57, 10.03, 11.82, 13.17, 14.28 (neat).

Example XIX.(2-methyl-3-ethyl-4-phenyl-4- cyclohexenyl-l methyl succinamate 1.0 g. of the compound of Example XVIII and 8 ml. of thionyl chloride is refluxed for minutes, diluted with 20 ml. of toluene, and evaporated to afford an oily residue of the ester acid chloride. The latter is dissolved in 20 ml. of cold dioxane and this solution is treated with 4 ml. of 28% aqueous ammonia. After a period of 1% hours at 20 C. this reaction mixture is diluted with water and extracted with ether. The ether solution is washed with water, dried and evaporated. The residue is recrystallized from ether to afford 0.68 g. of the ester amide, white prisms which melt at 9091 C.

Calcd. for C H O N: C, 72.92; H, 8.26. Found: C, 72.77; H, 8.44.

M 2.95, 3.11, 5.78, 5.97, 7.42, 8.49, 10.12, 11.88, 13.20, 14.23 1. (KBr).

Example XX.(2-methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl ethyl succinate The compound of Example XVIII and thionyl chloride are reacted as described in Example XIX to obtain the acid chloride. The latter is dissolved in 10 ml. of pyridine containing 3 ml. of ethanol. The product is isolated, as described in earlier examples, as a pale yellow oil which boils at 145-150 C. at .001 mm.

8 Calcd. for C H O C, 73.71; H, 8.44. Found: C, 74.23; H, 8.54.

M 5.77, 8.60, 9.72, 11.70, 11.80, 13.16, 14.27 1 (neat).

Example XXI.(2-methyl-3-ethyl-4-phenyl-3- cyclohexenyl- 1 methyl succinate This compound is prepared utilizing succinyl chloride and following the procedure of Example II. The product is purified by chromatography on alumina to yield a yellow oil.

Calcd. for C H O C, 79.66; H, 8.54. Found: C, 80.61; H, 9.06.

)ix g 5.75, 8.60, 9.96, 10.13, 13.17, l4.27,u. (neat).

Example XXII.(2-methyl-3-ethyl-4-phenyl-3-cyclohexenyl-l )methyl 10-undecenoate This compound is prepared using undecenoyl chloride and following the general procedure of Example II to yield a colorless oil which boils at 175-180 C. at .001

Calcd. for C H O C, 81.76; H, 10.17. Found: C, 81.68; H, 10.23.

M 5.75, 8.52, 10.00, 11.00, 13.18, 14.27,. (neat).

While the preparation of only some of the compounds of this invention has been specifically described, one skilled in the art should be able to prepare the remainder of the compounds following the general techniques set forth.

As mentioned previously, the compounds of this invention exhibit anti-littering effects when given orally or parenterally and are estrogenic agents to varying degrees.

Estrogenic effects are measured against the estrogenic effects of estradiol as a standard. In carrying out the test, female rats of a Wistar-derived strain are bilaterally ovariectomized under light ether anesthesia. About a week following surgery all animals are given a priming dose of 2-10 ,ug. estradiol-175' by subcutaneous injection and vaginal smears are taken on each of the next two days. Animals which do not show vaginal cornification are rested a week and reprimed. Rats which respond positively to the priming injection are rested a week and then given a single subcutaneous injection of the test material in sesame oil. Vaginal smears are taken daily to assess the duration of estrogenic response (vaginal cornification) in each animal as opposed to the vaginal cornification induced by the priming. The results, tabulated in Table I, for certain of the compounds prepared according to the examples hereinbefore set out show that the compounds of this invention have substantial estrogenic activity.

The parenteral anti-littering properties of the compounds are measured by administering to adult female rats of Wistar-derived strain a single subcutaneous injection of the test material in sesame oil. Controls receive sesame oil vehicle only. Ordinarily twenty animals are assigned to each group.

Both groups are cohabitated with adult male rats in the ratio of 3 males per 5 females starting on the day of treatment. Rats are examined twice weekly for gross signs of pregnancy. Gravid animals are removed and allowed to deliver so that a count of young and their condition may be recorded. The mean interval between drug administration (and cohabitation) and conception is calculated for each group using an average gestation length of 21 days.

Cohabitation is continued for 90 days or until of the females become pregnant, whichever occurs sooner.

The minimum dosage in mg./ kg. body weight required to prevent littering in the rats for various compounds, the preparation of which was specifically described in the examples, is set out in Table I. The actual effect of some of the compounds on littering at various dosage levels is set out in Table II.

"11 12 9. [Z-methyl 3 ethyl 4 (m-tolyl)-4-cyclohexenyl- References Cited 1]methyl octanoate of Claim 1.

10. [Z-methyl 3 ethyl 4-(o-anisyl)-4-cyclohexeny1-. UNITED STATES PATENTS 1]methyl hexanoate of Claim 1. 3,344,147 9/ 1967 Mebane 260-3265 11. [2-methyl-3-ethyl 4 (p-acetoxyphenyl)-4-cy 1 3,702,853 11/1972 Edwards et a1. 260-3433 5 3,591,624 7/1971 Karmas et a1. 260473 hexenyl-1]methyl acetate of Claim 1.

12. [2-methyl 3 ethyl-4-(p-hydroxyphenyl)-4-cyclohexenyl-11methyl acetate of Claim 1. LEWIS GOTTS Pnmary Examiner 13. [Z-methyl 3 ethyl-4-(p-isobutyryloxyphenyl)-4- RIVERS, Assistant Examiner cyc1ohexenyl-1]methyl acetate of Claim 1. 10

14. [2-methyl 3 ethyl-4-(p-dimethylanilino)-3- and 4-cyclohexenyl-l]methyl valerate of Claim 1. 260-404, 479 R, 488 CD; 424312 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,825,576 r I Dated July 23,197 1 Inventor(s) George Karmas It is certified that error appears in the above-identified patent and that said Letters Patent are hereby, corrected as shown below:

In Column 1, 1ine +3, In the formula:

should be In Column 3, line 1 In the heading of Example 111: 2(-methyl should read (2-methyl -,e. In Column 3, line 25, "ei scosanoate" should read eicosanoate In Column 3, line 52, "Any alkyl alkyl eater" should read Any alkyl ester In Column 1, line 36, "12,51" should read 12.51

In Column 5, line 5 1, "11,76" should read 11.76

In Column 6, line 22, "This is carbinol mixture" should read This is the carbinol mixture In Column 7, line 8, In the title: "FURoATEs ANDD NICOTINATES" should read FUROATES AND NICOTINATES Table 1, In line XV under Column Anti-littering parental, mg'. 2 1" should read--- Z l ---.v

Signed and sealed this 3rd day of December 1974.

(SEAL) Attest McCOY M. GIBSON JR. I Y I I C. MARSHALL DANN Attesting Officer Commissioner of Patents