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

Info

Publication number
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
Authority
US
United States
Prior art keywords
methyl
percent
lower alkyl
ethyl
carbon atoms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US728900A
Other languages
English (en)
Inventor
George Karmas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ortho Pharmaceutical Corp
Original Assignee
Ortho Pharmaceutical Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ortho Pharmaceutical Corp filed Critical Ortho Pharmaceutical Corp
Application granted granted Critical
Publication of US3557129A publication Critical patent/US3557129A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US728900A 1968-05-14 1968-05-14 Certain pyridoyl and furoyl esters of 2-(lower alkyl) - 3 - (lower alkayl)-4-aryl-3 or 4-cyclohexene carbinols Expired - Lifetime US3557129A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US72890068A 1968-05-14 1968-05-14

Publications (1)

Publication Number Publication Date
US3557129A true US3557129A (en) 1971-01-19

Family

ID=24928724

Family Applications (1)

Application Number Title Priority Date Filing Date
US728900A Expired - Lifetime US3557129A (en) 1968-05-14 1968-05-14 Certain pyridoyl and furoyl esters of 2-(lower alkyl) - 3 - (lower alkayl)-4-aryl-3 or 4-cyclohexene carbinols

Country Status (10)

Country Link
US (1) US3557129A (de)
AT (2) AT291230B (de)
BE (1) BE732961A (de)
BR (1) BR6908702D0 (de)
DE (1) DE1920865A1 (de)
FR (1) FR2008458A1 (de)
GB (1) GB1210340A (de)
IL (1) IL32216A0 (de)
NL (1) NL6907448A (de)
SU (1) SU368741A3 (de)

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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Also Published As

Publication number Publication date
IL32216A0 (en) 1969-07-30
AT291230B (de) 1971-07-12
BR6908702D0 (pt) 1973-02-22
DE1920865A1 (de) 1969-11-27
AT296272B (de) 1972-02-10
FR2008458A1 (de) 1970-01-23
BE732961A (de) 1969-11-13
GB1210340A (en) 1970-10-28
SU368741A3 (de) 1973-01-26
NL6907448A (de) 1969-11-18

Similar Documents

Publication Publication Date Title
US3931257A (en) Polyene compounds
DE2437607A1 (de) Polyenverbindungen
CH420117A (de) Verfahren zur Herstellung von Farnesylessigsäureestern
DE2416193C2 (de) Prostaglandin-Analoge, Verfahren zu ihrer Herstellung sowie ihre Verwendung als cytoprotektives Mittel
US3629269A (en) Derivatives of the 2-(lower alkyl)-3-(lower alkyl)-4-phenyl-3- or 4-cyclohexenecarboxylic acids
DE1768856A1 (de) Tricyclische Verbindungen
US3707566A (en) Aryloxypentane compounds
DE1693019A1 (de) a-Naphthylessigsaeuren und Verfahren zu deren Herstellung
US3825576A (en) Alkyl esters of 2-(lower alkyl)-3-(lower alkyl)-4-aryl-3-or 4-cyclohexene-carbinols
DE1005973B (de) Verfahren zur Herstellung von neuen spasmolytisch wirksamen basischen Estern
DE2108649C3 (de) 2-Methyl-2-hepten-6-on-l-al und seine Acetale
US3816507A (en) Derivatives of the 2-(lower alkyl)-3-(lower alkyl)-4-aryl-3-or 4-cyclo-hexenecarbinols
US3793363A (en) Benzoates of the 2-(lower alkyl)-3-(lower alkyl)-4-aryl-3or4-cyclohexen-carbinols
US3678102A (en) {60 ,{60 ,{60 {40 ,{60 {40 -tetrasubstituted carboxylic diacids and process for their preparation
US3758552A (en) Derivatives of the 2-(lower alkyl)-3-(lower alkyl)-4-aryl-3- or 4-cyc lohexenecarbinola
CH622760A5 (de)
US2582253A (en) Synthetic estrogens
US3719693A (en) Alkenyl esters of 2(lower alkyl)-3-(lower alkyl)-4-acyl 3-or-4 cyclohexencarbinols
DE1793264B2 (de) Substituierte phenylessigsaeuren
DE2656750C2 (de) In 5-Stellung substituierte 2-Indancarbonsäuren, Verfahren zu deren LIPHA-Herstellung und sie enthaltende Arzneimittel
Bergmann et al. Synthesis of 2-Indenylacetic Acid
Lauer et al. The Rearrangement of Phenyl Allyl Ethers. VI. The Isomeric Ethyl p-(α-and γ-Ethylallyloxy)-benzoates
DE2150146B2 (de) Verfahren zur Herstellung von Flavon-7-oxyessigsäureäthylester
US3567770A (en) Aryl substituted - hydroxy substituted cyclohexanecarboxylic acids and esters
Klein et al. The Stereochemistry of Bromination of o-Substituted Cyclohexanecarboxylic Acids1