US3557129A - Certain pyridoyl and furoyl esters of 2-(lower alkyl) - 3 - (lower alkayl)-4-aryl-3 or 4-cyclohexene carbinols - Google Patents

Certain pyridoyl and furoyl esters of 2-(lower alkyl) - 3 - (lower alkayl)-4-aryl-3 or 4-cyclohexene carbinols Download PDF

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US3557129A
US3557129A US728900A US3557129DA US3557129A US 3557129 A US3557129 A US 3557129A US 728900 A US728900 A US 728900A US 3557129D A US3557129D A US 3557129DA US 3557129 A US3557129 A US 3557129A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • 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;
  • 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 substaneous injection.
  • the compounds may be prepared by the mono-acetylation of the primary-tertiary diol with subsequent dehydration according to the following reaction scheme:
  • ALKYL ESTERS (1) R- hydrogen or lower alkyl
  • R- hydrogen or lower alkyl
  • the starting material for Examples I through VI is (2-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-ethy1-4-phenyl-3-cyc1ohexenyl 1)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 ml. of acetic acid is refluxed for 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 8590 C. at .001 mm.
  • Example II-(Z-methyl-3-ethyl-4-phenyl-3-cyclohexenyl-1)methyl caproate A solution of 4 g. of the A -cyclohexenylcarbinol in 15 ml. of dry pyridine is stirred at 0-5 C. while 1% molecular equivalents of caproyl chloride is added. The resulting pasty mixture is stirred at 25 C. for 15 minutes, heated at 9095 C. for 15 minutes, and then cooled. Five ml. of water is added and the mixture stirred vigorously for 2 hours. After dilution with 150 ml.
  • the ether phase is washed twice with cold 5% hydrochloric acid to remove pyridine, and then twice with cold 5% sodium hydroxide.
  • the ether solution is then dried and evaporated.
  • the residual oil is developed on a column of alumina (neutral, WI) prepared in benzene-hexane. Elution with benzene and ether affords the ester free of alcohol and carboxylic acid.
  • the oily ester is distilled under high vacuum to afford the purified product, an oil which boils at 138140 C. at .002 mm.
  • Example III (2-methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl octanoate. This compound is prepared following the procedure of Example II and using octanoyl chloride. The compound is an oil which boils at 150- 1500 C. at .001 mm.
  • Example IV (2-methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl eicosanoate.-Using eicosanoyl chloride and again following the procedure of Example II and recrystallizing the crude solid ester from hexane (2-methyl-3- ethyl 4 phenyl 4-cyclohexenyl-1)methyl eicosanoate is prepared in the form of white flakes having a melting point of 47-48 C.
  • Example V (2-methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl 2-ethylhexanoate.--A mixture of 2.0 g. of (2 methyl 3 ethyl 4 phenyl-4-cyclohexenyl-1)methanol and 6.3 ml. of a solution of butylethyl ketene in toluene is held for one hour at 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 (benzenehexane 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 150-154 C. at .001 mm.
  • Any 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 I1. It is a colorless viscous oil which boils at 180-185" C. at .001 mm.
  • Example VII [2 methyl-3-ethyl-4-(m-tolyl)-4-cyclohexenyl-l]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 155- 165 C. at .001 mm.
  • Esters having other lower alkyl substitution in the meta position in the phenyl ring may be prepared following the same procedure of Example II 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.
  • esters of the o-anisyl series can be prepared by selecting the proper acid anhydride.
  • the starting carbinol is suitably formed according to the procedures disclosed in my copending application Ser. No. 560,116.
  • diesters 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-1]methyl acetate.This and other hydroxy derivatives are obtained from the appropriate diesters which are in turn prepared as described in Example IX.
  • Example XI [2-methyl 3 ethyl-4-(p-isobutyryloxyphenyl)-4-cyclohexenyl-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.
  • ADAMANTOATE ESTERS Example XIII(2-methy1 3 ethyl-4-phenyl-3-cyclohexenyl-l )methyl-1-adamantoate.-This compound is prepared from '2-methy1-3-ethyl-4-phenyl-3-cyclohexenyl-1) methanol and adamantoic acid chloride following the procedure of Example II.
  • Example XIV [2-methyl 3 ethyl-4-(p-anisyl)-4-cyclohexenyl-1]methyl 1-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 200220 C. at .002 mm.
  • Example XVII-(2 methyl 3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl 2-furoate This compound is prepared generally following the procedures of Example II and using Z-furoyl chloride to afford white granules which melt at 70-72 C.
  • Example XVIII(2-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 wtih 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 180190 C. at .001 mm.
  • Example XIX(2 methyl 3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl succinamate.l.0 g. of the compound of Example XVIII and 8 ml. of thionyl chloride is refiuxed for 20 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.
  • Example XX-(2 methyl 3-ethyl-4-phenyl-4-cyclohexenyl-l )methyl ethyl succinate The compound of EX- ample XVIII and thionyl chloride are reacted as described in Example XIX to obtain the acid chloride.
  • the latter 8 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 -150 at .001 mm.
  • Example XXII (2 methyl-3-ethyl-4-phenyl-3-cycloheXenyl-l)methyl IO-undecenoate. This compound is prepared using undecenoyl chloride and following the general procedure of Example II to yield a colorless oil which boils at -l80 C. at .001 mm.
  • 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.
  • female rats of a Wistar-derived strain are bilaterally ovariectomized under light ether anesthesia.
  • a priming dose 210 g. estradiol-17B 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-litering 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 80% of the females become pregnant, whichever occurs sooner.
  • R is pyridyl. 488, 515, 518, 520, 999
  • Invontoth 1: a certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

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Abstract

COMPOUNDS OF THE GENERAL FORMULA

1-(R''-COO-CH2-),2-R",3-R"'',4-(R-PHENYL)CYCLOHEX-3 OR 4-ENE

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 PORTIONS, 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 EXHIBITS ESTROGENIC PROPERTIES AND WHEN GIVEN IN A SINGLE SUBCUTANEOUS DOSE HAVE LONG ACTING EFFECTS IN THE SUPPRESSION OF ANIMAL REPRODUCTION.

Description

United States Patent Oflice 3,557,129 Patented Jan. 19, 1971 U.S. Cl. 260-2955 Claims ABSTRACT OF THE DISCLOSURE Com ounds of the general formula 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, 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 estrogenie properties and when given in a single subcutaneous dose have long acting effects in the suppression of animal reproduction.
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;
662,311; 662,295; and 560,116. 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 substaneous 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 esteri-fication of the appropriate carbinol with acids (R'COOH), acid halides ('RCOCl), acid anhydrides (RCOOOCR') and ketenes (O=C=CR) In addition, the compounds may be prepared by the mono-acetylation of the primary-tertiary diol with subsequent dehydration according to the following reaction scheme:
l RI! 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 (1) R-=hydrogen or lower alkyl The starting material for Examples I through VI is (2-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-ethy1-4-phenyl-3-cyc1ohexenyl 1)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 ml. of acetic acid is refluxed for 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 8590 C. at .001 mm.
Calcd. for C H O (percent): C, 79.37; H, 8.88. Found (percent): C, 79.14; H, 8.64.
M 5.75, 8.09, 9.71, 13.17, 14.26; (neat).
Example II-(Z-methyl-3-ethyl-4-phenyl-3-cyclohexenyl-1)methyl caproate.A solution of 4 g. of the A -cyclohexenylcarbinol in 15 ml. of dry pyridine is stirred at 0-5 C. while 1% molecular equivalents of caproyl chloride is added. The resulting pasty mixture is stirred at 25 C. for 15 minutes, heated at 9095 C. for 15 minutes, and then cooled. Five ml. of water is added and the mixture stirred vigorously for 2 hours. After dilution with 150 ml. of ether, the ether phase is washed twice with cold 5% hydrochloric acid to remove pyridine, and then twice with cold 5% sodium hydroxide. The ether solution is then dried and evaporated. The residual oil is developed on a column of alumina (neutral, WI) prepared in benzene-hexane. Elution with benzene and ether affords the ester free of alcohol and carboxylic acid. The oily ester is distilled under high vacuum to afford the purified product, an oil which boils at 138140 C. at .002 mm.
Calcd. for C H O (percent): C, 80.44; H, 9.83. Found (percent): C, 80.25; H, 9.81.
M 5.76, 8.01, 8.51, 9.07, 9.92, 13.14, 1422 (neat).
Example III(2-methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl octanoate.This compound is prepared following the procedure of Example II and using octanoyl chloride. The compound is an oil which boils at 150- 1500 C. at .001 mm.
Calcd. for C H O (percent): C, 80.85; H, 10.18. Found (percent): C, 80.66; H, 10.28.
M 5.74, 8.56, 9.01, 11.79, 13.14, 1425 (neat).
Example IV(2-methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl eicosanoate.-Using eicosanoyl chloride and again following the procedure of Example II and recrystallizing the crude solid ester from hexane (2-methyl-3- ethyl 4 phenyl 4-cyclohexenyl-1)methyl eicosanoate is prepared in the form of white flakes having a melting point of 47-48 C.
Calcd. for C H O (percent): C, 82.38; H, 11.52. Found (percent): C, 82.25; H, 11.38.
M 5.74, 8.62, 11.88, 13.21, 13.90, 1422p. (KBr).
Example V(2-methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl 2-ethylhexanoate.--A mixture of 2.0 g. of (2 methyl 3 ethyl 4 phenyl-4-cyclohexenyl-1)methanol and 6.3 ml. of a solution of butylethyl ketene in toluene is held for one hour at 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 (benzenehexane 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 150-154 C. at .001 mm.
Calcd. for C H O (percent): C, 81.76; H, 10.29. Found (percent): C, 81.16; H, 10.24.
M 5.77, 8.52, 8.71, 10.00, 11.80, 13.17, 14.28,u (neat).
Any 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 I1. It is a colorless viscous oil which boils at 180-185" C. at .001 mm.
Calcd. for C H O (percent): C, 82.59; H, 7.84. Found (percent): C, 82.38; H, 7.71.
xx,,,,,,: 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-tolyl)-4-cyclohexenyl-l]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 155- 165 C. at .001 mm.
Calcd. for C H O (percent): C, 81.03; H, 10.34. Found (percent): C, 81.05; H, 10.36.
M z 5.77, 8.58, 9.03, 11.81, 12.83, 14.19 1 (neat).
Esters having other lower alkyl substitution in the meta position in the phenyl ring may be prepared following the same procedure of Example II 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 VIII[2-methyl 3 ethyl 4 (o-anisyl)-4- cyclohexenyl-]methyl hexanoate.-To a stirred solution of 3.1 g. of 2-methyl-3-ethyl 4 hydroxy-4-(o-anisyl) cyclohexanecarboxylic acid (the preparation of which is disclosed in my copending application Ser. No. 662,295) in 100 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 at 140-145 C. at .001 mm. This is the 1,4-diol: [2-methyl-3-ethyl-4-hydoxy-4-(o-anisyl) cyclohexanyl-1methanol.
Calcd. (percent): C, 73.34; H, 9.41. Found (percent): C, 73.20; H, 9.53.
M 2.92, 8.10, 9.70, 11.00, 12.51, 13.24,:1 (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 160-165 C. at .001 mm. This is the ester-monoalcohol: [Z-methyl 3 ethyl-4-hydroxy-4- (o-anisyl) cyclohexanyl-lJmethyl hexanoate.
Calcd. (percent): C, 73.36; H, 9.64. Found (percent): C, 74.32; H, 9.76.
M 2.83, 5.78, 8.10, 8.50, 9.70, 123.51, 13.23 (neat).
A solution of 1.0 g. of the ester-monoalcohol and 4 m1. of boron trifluoride etherate in 20 ml. of ether is held at 2025 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-l]methyl hexanoate, a yellow oil which boils at 140-145 C. at .001 mm.
Calcd. (percent): C, 77.05; H, 9.56. Found (percent): 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. In forming the p-substituted esters the starting carbinol is suitably formed according to the procedures disclosed in my copending application Ser. No. 560,116.
(3) R=hydroxy1 and acyloxy Example 'IX-[2 methyl 3 ethyl 4-(p-acetoxyphenyl) 4 cyclohexenyl 1]methyl acetate.To a stirred solution of 4.0 g. of 2-methy1-3-ethyl-4-(p-hydroxyphenyl)-4-cyclohexenecarboxylic 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 2025 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 filter 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 afiord 2.5 g. of white prisms which melt at 166167 C. This is the carbinol, [2 methyl 3 ethyl-4-(p-hydroxyphenyl)-4- cyclohexenyl-l methanol Calcd. for C H (percent): C, 78.01; H, 9.00. Found (percent): C, 78.01; H, 9.06.
M 2.92, 6.61, 8.00, 8.17, 9.97, 11.76, 12.10u (KBr).
A solution of 1.5 g. of the carbinol and 7.0 ml. of acetic anhydride in 20 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 alford 1.6 g. of [2 methyl 3 ethyl 4-(p-acetoxyphenyl)-4-cyclohexenyl-l] methyl acetate, a colorless oil which boils at 135-140 C. at .001 mm.
Calcd. for C H O (percent): C, 72.70; H, 7.93. Found (percent): C, 72.44; H, 8.00.
M 5.68, 5.74, 7.30, 8.33, 9.68, 9.80, 11.83 1 (neat).
Other diesters 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-1]methyl acetate.This and other hydroxy derivatives are obtained from the appropriate diesters 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 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 6772 C.
Calcd. for C H O (percent): C, 74.97; H, 8.39. Found (percent): 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]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-1]methyl acetate, a colorless oil which boils at 145-150" C. at .001 mm.
Calcd. for C H O (percent): C, 73.71; H, 8.44. Found (percent): C, 73.58; H, 8.48.
M 5.70, 5.75, 8.10, 8.31, 8.57, 8.81, 9.69, 10.90, 11.48, 11.8011. (neat).
(4) R=anilino Example XII-[2-methyl 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 other 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 the carbinol mixture, [2-methyl-3-ethyl-4-(p-dimethylanilino)-3 and 4-cyclohexenyl-1 methanol.
Calcd. for C18H27ON (percent): C, 79.07; H, 9.95. Found (percent): C, 79.08; H, 9.91,
M 2.99, 6.20, 6.59, 7.40, 9.42, 9.70, 9.91, 10.58, 12.29 1 (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 hydrolyzed 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 afiords 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 (percent): C, 77.26; H, 9.07. Found (percent): C, 77.82; H, 9.95.
M 5.77, 6.20, 6.59, 7.41, 8.57, 10.56, 12.28 1 (neat).
ADAMANTOATE ESTERS Example XIII(2-methy1 3 ethyl-4-phenyl-3-cyclohexenyl-l )methyl-1-adamantoate.-This compound is prepared from '2-methy1-3-ethyl-4-phenyl-3-cyclohexenyl-1) methanol and adamantoic acid chloride following the procedure of Example II.
Calcd. for C H O (percent): C, 82.60; H, 9.24. Found (percent): C, 82.37; H, 9.41.
m z 5.80, 8.07, 8.45, 9.25, 13.19, 14.28. 14.74,:1 (KBr).
M.P., 75-76 C.
Example XIV[2-methyl 3 ethyl-4-(p-anisyl)-4-cyclohexenyl-1]methyl 1-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 200220 C. at .002 mm.
Calcd. for C H O (percent): C, 79.58; H, 9.06. Found (percent): 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 4 (neat).
7 CYCLOALKYL LOWER ALKYL ESTERS Example XV[2 methyl-3-ethyl-4-(p-anisyl)-3-cyclohexenyl 1]methyl ,B-cyclopentylpropionate.-This compound is formed from cyclopentylpropionic acid chloride and [2 methyl 3 ethyl-4-(p-anisyl)-3-cyclohexenyl-l] methanol according to the procedure of Example II. The compound is an oil which boils at 160l70 C. at .001 mm.
Calcd. for C H O (percent): C, 73.71; H, 8.4. Found (percent): C, 74.23; H, 8.54.
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 AND NICOTINATES Example XVI-(2 methyl 3-ethyl-4-phenyl-4-cyclohexenyl 1)rnethyl 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 l75l80 C. at .001 mm.
Calcd. for C H O N (percent): C, 78.77; H, 7.51. Found (percent): 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 1. (neat).
Example XVII-(2 methyl 3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl 2-furoate.This compound is prepared generally following the procedures of Example II and using Z-furoyl chloride to afford white granules which melt at 70-72 C.
Calcd. for C H O (percent): C, 77.75; H, 7.46. Found (percent): 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(2-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 wtih 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 180190 C. at .001 mm.
Calcd. for C H O (percent): C, 72.70; H, 7.93. Found (percent): C, 72.61; H, 8.05.
M 5.77, 5.83, 8.57, 10.03, 11.82, 13.17, 14.28 4 (neat).
Example XIX(2 methyl 3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl succinamate.l.0 g. of the compound of Example XVIII and 8 ml. of thionyl chloride is refiuxed for 20 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 (percent): C, 72.92; H, 8.26. Found (percent): 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-l )methyl ethyl succinate.The compound of EX- ample XVIII and thionyl chloride are reacted as described in Example XIX to obtain the acid chloride. The latter 8 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 -150 at .001 mm.
Calcd. for C H O (percent): C, 73.71; H, 8.44. Found (percent): C, 74.23; H, 8 .54.
M 5.77, 8.60, 9.72, 11.70, 11.80, 13.16, 14.27, (neat).
Example XXI( 2 methyl 3-ethyl-4-phenyl-3-cyclohexenyl-1)methyl succinate.'Ihis 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 (percent): C, 79.66; H, 8.54. Found (percent): C, 80.61; H, 9.06.
M 5.75, 8.60, 9.96, 10.13, 13.17, 14.27 (neat).
Example XXII(2 methyl-3-ethyl-4-phenyl-3-cycloheXenyl-l)methyl IO-undecenoate. This compound is prepared using undecenoyl chloride and following the general procedure of Example II to yield a colorless oil which boils at -l80 C. at .001 mm.
Calcd. for C H O (percent): C, 81.76; H, 10.17. Found (percent): C, 81.68; H, 10.23.
M 5.75, 8.52, 10.00, 11.00, 13.18, 1427,11 (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 210 g. estradiol-17B 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-litering 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 80% of the females become pregnant, whichever occurs sooner.
The minimum dosage in mg./kg. body weight required to prevent littering the rats for various compounds, the preparation of which was specifically described in the examples, is set out in Table I. The actual effects of some of the compounds on littering at various dosage levels is set out in Table II.
TABLE I CH; C211 Pharmacological activity Estrogenic Anti- (times littering estrogenic parenteral, Example R R A eiiect) mg.
X p-OH XL. p-OOICH(CI'I3)g XII p-N(CII;) CJ'I0 3-4 0. 001 XIII H Adamantyl-l 3 1. 2 1 XIIIA... H 4 2/3 1 2 5 XIV pO CH 4 4/3 1 XV p-O OH; 3 2 21 XVI II 4 XVII 4 XIX 4 XXII II 4 1 (290 days) TABLE II Number litters] Mean value day number rats pregnancy occurred Days Dose Experi Expericohabi- Compound of Example mgJkg. Control mental Control mental tatcd III 0. 1 10/10 9/10 10. 3 7. 3 27 1. 0 10/10 5/10 10. 3 50. 5 90 XIIIA O. 5 16/20 15/20 4 7 7. 9 33-34 1. 0 16/20 16/20 4 7 7. 0 33-62 2. 5 10/20 3/20 5 9 15. 0 90 5. 0 10/10 0/10 15 XIII 0. 5 10 8/10 6. 2 6. 8 27 1. 0 16/20 10/20 5. 6 12. 7 27-90 2. 5 1 90 XIV 0. 1 10/10 10/10 10. 3 8. 9 27 1.0 10/10 3/10 10.3 33. 7 90 What is claimed is: 5. (2 methyl 3 ethyl-4-phenyl-4-cyc1ohexenyl-1)- 1. A compound of the formula methyl nicotinate of claim 4.
References Cited UNITED STATES PATENTS l l, 2,582,253 1/1952 Hoggetal 260520 R R 3,344,147 9/1967 Mebane 260-326.5 3,449,373 6/1969 Mebane 260-345.9 wherein R is hydrogen; --R is piridyl and furyl and R" and R are lower alkyl of up to 3 carbon atoms. ALAN ROTMAN Pnmary Exammer 2. A compound of claim 1 wherein R is furyl. U S C1 X R 3. (2 methyl 3 ethyl-4-phenyl-4-cyclohexenyl-1)- methyl 2-furoatc of claim 2. 260-295, 347.5, 410.5, 468, 469, 479, 482, 485, 486,
4. A compound of claim 1 wherein R is pyridyl. 488, 515, 518, 520, 999
wag?" UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Potent No- 3,557, 9 Dated January 19, 197
Invontoth) 1: a certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
In Column 3, line 35, "1500" should read --l55--. In Column h, line 2?, insert --1-- after "cyclohexenyl-" Same Column, line &3, insert -il-- after "cyclohexanyl-". In Column 7, lines 8-9 should read: Calcd. for C H 03: (1,753.08; H,9. t Found: C,78.0 H,9. #9.-
In Column 8, line 3, insert --C-- after the degrees sign. Same Column, line 52, anti-littering" is misspelled. In Table I, under R, -CH should read -C H In Table II, under "Experimental" "7.0" should read --7.l--. In Claim I, that portion of the formula reading -3- should read -J- Same Claim, "pyridyl" is misspe Signed and sealed this 11th day of May 1971.
(SEAL) Attest:
EDWARD M.FIETCHER, JR. Attesting Officer WILLIAM E. SCHUYLER, Comissioner of Peter
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Cited By (4)

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Publication number Priority date Publication date Assignee Title
US3876648A (en) * 1972-04-10 1975-04-08 Ciba Geigy Corp Certain pyridine carboxylic acid esters
US3897437A (en) * 1972-08-16 1975-07-29 Ciba Geigy Corp Certain substituted anilino-phenylacetic-acid-(2,3 or 4-pyridyl)-methyl esters and derivatives
US3928363A (en) * 1972-08-16 1975-12-23 Ciba Geigy Corp Alpha-{8 p-(1-cyclolower alkenyl)-phenyl{9 lower fatty acid-pyridyl-lower alkyl esters and derivatives
US3973024A (en) * 1972-08-16 1976-08-03 Ciba-Geigy Corporation Analgesic and anti-inflammatory anilino-phenylacetic acid-(2,3 or 4 pyridyl)-methyl esters and derivatives

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US3344147A (en) * 1966-03-08 1967-09-26 Ortho Pharma Corp 2-(lower alkyl)-3-(lower alkyl)-4-phenyl-3-or-4-cyclohexenecarboxylic acids and derivatives thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3876648A (en) * 1972-04-10 1975-04-08 Ciba Geigy Corp Certain pyridine carboxylic acid esters
US3897437A (en) * 1972-08-16 1975-07-29 Ciba Geigy Corp Certain substituted anilino-phenylacetic-acid-(2,3 or 4-pyridyl)-methyl esters and derivatives
US3928363A (en) * 1972-08-16 1975-12-23 Ciba Geigy Corp Alpha-{8 p-(1-cyclolower alkenyl)-phenyl{9 lower fatty acid-pyridyl-lower alkyl esters and derivatives
US3973024A (en) * 1972-08-16 1976-08-03 Ciba-Geigy Corporation Analgesic and anti-inflammatory anilino-phenylacetic acid-(2,3 or 4 pyridyl)-methyl esters and derivatives

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