Alkyl, alkoxy and thioalkoxy substituted diphenyl acetylenes having retinoid like activity

BACKGROUND
This invention relates to novel compounds having retinoid like activity. More specifically, the invention relates to acetylenes linked to an alkyl, alkoxy or thioalkoxy substituted phenyl group and to another phenyl group which may be unsubstituted, but which preferably bears an esterified or free carboxylic acid group.
RELATED ART
Carboxylic acid derivatives useful for inhibiting the degeneration of cartilage of the general formula 4-(2-(4,4-dimethyl-6-X)-2-methylvinyl)benzoic acid where X is tetrahydroquinolinyl, chromanyl or thiochromanyl are disclosed in European Patent Application 0133795 published Jan. 9, 1985. See also European Patent Application 176034A published Apr. 2, 1986 where tetrahydronaphthalene compounds having an ethynylbenzoic acid group are disclosed, and U.S. Pat. No. 4,739,098 where three olefinic units from the acid-containing moiety of retinoic acid are replaced by an ethynylphenyl functionality.
SUMMARY OF THE INVENTION
This invention covers compounds of Formula 1 ##STR2## wherein R.sub.1 -R.sub.4 independently are hydrogen, lower alkyl, cycloalkyl or lower alkenyl, A and B independently are hydrogen, lower alkyl, cycloalkyl, lower alkenyl, SR* or OR* where R* is lower alkyl, cycloalkyl or lower alkenyl;
Y is lower alkenyl, lower alkynyl, lower cycloalkyl, lower branched chain alkyl, or (CH.sub.2).sub.n where n is 0-6; and Z is H, --COOH or a pharmaceutically acceptable salt, ester or amide thereof, --CH.sub.2 OH or an ether or ester derivative, or --CHO or an acetal derivative, or --COR' or a ketal derivative where R' is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons.
In a second aspect, this invention relates to the use of the compounds of Formula 1 for treating dermatoses, such as acne, Darier's disease, psoriasis, icthyosis, eczema, atopic dermatitis and epithelial cancers. These compounds are also useful in the treatment of arthritic diseases and other immunological disorders (e.g. lupus erythematosus), in promoting wound healing, in treating dry eye syndrome and in delaying sun damage or reversing the effects of sun damage to skin. The compounds are further useful for treating disorders of gut epithelial differentiation, such as ileitis colitis and Krohn's disease.
This invention also relates to a pharmaceutical formulation comprising a compound of Formula 1 in admixture with a pharmaceutically acceptable excipient.
In another aspect, this invention relates to the process for making a compound of Formula 1 which process comprises reacting a compound of Formula 2 with a compound of Formula 3 in the presence of cuprous iodide and Pd(PQ.sub.3).sub.2 Cl.sub.2 (Q is phenyl) or a similar complex ##STR3## where R.sub.1 -R.sub.4 are the same as described above, X is a halogen, preferably iodine; A, B, and Y are the same as defined above; and Z is H, or an ester or an amide, or a protected or unprotected acid, alcohol, aldehyde or ketone, giving the corresponding compound of Formula 1; or to the process of making a compound of Formula 1 which consists of reacting a zinc salt of a compound shown in Formula 2 with a compound of Formula 3 in the presence of Pd(PQ.sub.3).sub.4 (Q is phenyl) or a similar complex.
In still another aspect, the present invention also relates to preparation of compounds of Formula 1 by conversion of compounds having the structure of Formula 4. ##STR4##
In Formula 4 the symbols A, B, R.sub.1 -R.sub.4, and Y are defined as above in connection with Formula 1, and Z' symbolizes such precursors of the group Z which can be readily converted by reactions well known to organic chemists, into the desired Z group. Thus, the present invention also relates to the above-noted processes involvings steps such as:
converting an acid of Formula 4 to a salt; or
forming an acid addition salt;
converting an acid of Formula 4 to an ester; or
converting an acid or ester of Formula 4 to an amide; or
reducing an acid or ester of Formula 4 to an alcohol or aldehyde; or
converting an alcohol of Formula 4 to an ether or ester; or
oxidizing an alcohol of Formula 4 to an aldehyde; or
converting an aldehyde of Formula 4 to an acetal; or
converting a ketone of Formula 4 to a ketal,
extending by homologation the length of the alkyl chain of a compound of Formula 4.
GENERAL EMBODIMENTS
Definitions
The term "ester" as used here refers to and covers any compound falling within the definition of that term as classically used in organic chemistry. Where Z (of Formula 1) is --COOH, this term covers the products derived from treatment of this function with alcohols. Where the ester is derived from compounds where Z is --CH.sub.2 OH, this term covers compounds of the formula --CH.sub.2 OOCR' where R' is any substituted or unsubstituted aliphatic, aromatic or aliphatic-aromatic group.
Preferred esters are derived from the saturated aliphatic alcohols or acids of ten or fewer carbon atoms or the cyclic or saturated aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms. Particularly preferred aliphatic esters are those derived from lower alkyl acids or alcohols. Here, and where ever else used, lower alkyl means having 1-8 carbon atoms and includes straight, branched chained and cycloalkyl groups as well. Also preferred are the phenyl or lower alkylphenyl esters.
Amide has the meaning classically accorded that term in organic chemistry. In this instance it includes the unsubstituted amides and all aliphatic and aromatic mono- and di-substituted amides. Preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms or the cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon atoms. Particularly preferred amides are those derived from lower alkyl amines. Also preferred are mono- and di-substituted amides derived from the phenyl or lower alkylphenyl amines. Unsubstituted amides are also preferred.
Acetals and ketals include the radicals of the formula --CK where K is (--OR').sub.2. Here, R' is lower alkyl. Also, K may be --OR'O-- where R' is lower alkyl of 2-5 carbon atoms, straight chain or branched.
A pharmaceutically acceptable salt may be prepared for any compound of this invention having a functionality capable of forming such salt, for example an acid or an amine functionality. A pharmaceutically acceptable salt may be any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
Such a salt may be derived from any organic or inorganic acid or base. The salt may be a mono or polyvalent ion. Of particular interest where the acid function is concerned are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic amine salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide. Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri-acid may also be used.
The preferred compounds of this invention are those where the ethynyl group and the Z group are attached in the 1,4 (para) positions of the phenyl ring; n is 0; and Z is --COOH, an alkali metal salt or organic amine salt, or a lower alkyl ester, or --CH.sub.2 OH and the lower alkyl esters and ethers thereof, or --CHO and acetal derivaives thereof. Further preferred are those compounds where R.sub.1 -R.sub.4 are hydrogen, and where one of the A and B groups is branch chained alkyl, branch chained alkenyl, or thio alkoxy, or thio alkenoxy. The most preferred compounds shown in Formula 5 are:
ethyl 4-(3-tert-butylphenyl)-ethynyl benzoate (Compound 1, A =(CH.sub.3).sub.3 C, B=H, R*=CH.sub.2 --CH.sub.3);
4-(3-tert-butylphenyl)-ethynyl benzoic acid (Compound 2, A=(CH.sub.3).sub.3 C, B=H, R*=H;
ethyl 4-(4-tert-butylphenyl)-ethynyl benzoate (Compound 3, A =H, B=(CH.sub.3).sub.3 C, R*=CH.sub.2 --CH.sub.3);
4-(4-tert-butylphenyl)-ethynyl benzoic acid (Compound 4, A=H, B=(CH.sub.3).sub.3 C, R*=H);
ethyl 4-[4-(4-methylpentyl)phenyl-ethynyl] benzoate (Compound 5, A=H, B=(CH.sub.3).sub.2 CH--(CH.sub.2).sub.3, R*=CH.sub.2 --CH.sub.3);
4-[4-(4 -methylpentyl)phenyl-ethynyl] benzoic acid (Compound 6, A=H, B=(CH.sub.3).sub.2 CH--(CH.sub.2).sub.3, R*=H.
ethyl 4-[4-(1,1,4-trimethylpentyl)phenyl] ethynyl benzoate (Compound 7, A=H, B=(CH.sub.3).sub.2 CH--(CH.sub.2).sub.2 --C(CH.sub.3).sub.2, R*=CH.sub.2 --CH.sub.3);
4-[4-(1,1,4-trimethylpentyl)phenyl] ethynyl benzoic acid (Compound 8, A=H, B=(CH.sub.3).sub.2 --CH--(CH.sub.2).sub.2 --C(CH.sub.3).sub.2, R*=H);
ethyl 4-(3-thio-tert-butoxyphenyl)-ethynyl benzoate (Compound 9, A=(CH.sub.3).sub.3 CS, B=H, R*=CH.sub.2 --CH.sub.3);
4-(3-thio-tert-butoxyphenyl)-ethynyl benzoic acid (Compound 10, A=(CH.sub.3).sub.3 CS, B=H, R*=H);
ethyl 4-(4-thio-tert-butoxyphenyl)-ethynyl benzoate (Compound 11, A=H, B=(CH.sub.3).sub.3 CS, R*=CH.sub.2 --CH.sub.3);
4-(4-thio-tert-butoxyphenyl)-ethynyl benzoic acid (Compound 12, A=H, B=(CH.sub.3).sub.3 CS, R*=H);
ethyl 4-[4-(3-methyl-thio-2-buteneoxyphenyl)]-ethynyl benzoate (Compound 13, A=H, B=(CH.sub.3).sub.2 C.dbd.CH--CH.sub.2 --S--, R*=CH.sub.2 --CH.sub.3);
4-[4-(3-methyl-thio-2-buteneoxyphenyl)]-ethynyl benzoic acid (Compound 14, A=H, B=(CH.sub.3).sub.2 C.dbd.CH--CH.sub.2 --S--, R*=H; ##STR5##
The compounds of this invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and similar considerations.
In the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases such as treatment of severe cystic acne, oral administration may also be used. Any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may be used. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pa. For topical application, these compounds could also be administered as a powder or spray, particularly in aerosol form.
If the drug is to be administered systemically, it may be confected as a powder, pill, tablet or the like, or as a syrup or elixir for oral administration. For intravenous or intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as an extended release formulation for deposit under the skin or intermuscular injection.
Other medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness, providing protection against light; other medications for treating dermatoses, preventing infection, reducing irritation, inflammation and the like.
Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds will be effected by administration of the therapeutically effective dose of one or more compounds of the instant invention. A therapeutic concentration will be that concentration which effects reduction of the particular condition, or retards its expansion. In certain instances, the drug potentially could be used in a prophylactic manner to prevent onset of a particular condition. A given therapeutic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, a given therapeutic concentration will be best determined at the time and place through routine experimentation. However, it is anticipated that in the treatment of, for example, acne, or other such dermatoses, that a formulation containing between 0.001 and 5 percent by weight, preferably about 0.01 to 1% will usually constitute a therapeutically effective concentration. If administered systemically, an amount between 0.01 and 100 mg per kg body weight per day, but preferably about 0.1 to 10 mg/kg, will effect a therapeutic result in most instances.
The retionic acid like activity of these compounds was confirmed through the classic measure of retionic acid activity involving the effects of retionic acid on ornithine decarboxylase. The original work on the correlation between retinoic acid and decrease in cell proliferation was done by Verma & Boutwell, Cancer Research, 1977, 37, 2196-2201. That reference discloses that ornithine decarboxylase (ODC) activity increased precedent to polyamine biosynthesis. It has been established elsewhere that increases in polyamine synthesis can be correlated or associated with cellular proliferation. Thus, if ODC activity could be inhibited, cell hyperproliferation could be modulated. Although all causes for ODC activity increase are unknown, it is known that 12-0-tetradecanoyl-phorbol-13-acetate (TPA) induces ODC activity. Retinoic acid inhibits this induction of ODC activity by TPA. The compounds of this invention also inhibit TPA induction of ODC as demonstrated by an assay essentially following the procedure set out in Cancer Res., 35: 1662-1670, 1975.
By way of example of retinoic acid-like activity it is noted that in the assay conducted essentially in accordance with the method of Verma & Boutwell, ibid, the following examples of the preferred compounds of the present invention (Compounds 1, 3 and 7) attained an 80% inhibition of TPA induced ODC activity at the following concentrations (IC.sub.80):
______________________________________Compound IC.sub.80 conc (nmols)______________________________________1 3.02 2.13 3.04 13.55 -300.07 21.09 9.611 7.813 28.614 28.3______________________________________
SPECIFIC EMBODIMENTS
The compounds of this invention can be made by a number of different synthetic chemical pathways. To illustrate this invention, there is here outlined a series of steps which have been proven to provide the compounds of Formula 1 when such synthesis is followed in fact and in spirit. The synthetic chemist will readily appreciate that the conditions set out here are specific embodiments which can be generalized to any and all of the compounds represented by Formula 1. Furthermore, the synthetic chemist will readily appreciate that the herein described synthetic steps may be varied and or adjusted by those skilled in the art without departing from the scope and spirit of the invention.
Referring now specifically to Reaction Scheme 1, the compounds of the invention can be synthesized by coupling of a suitable substituted phenylethyne compound (shown and defined in connection with Formula 2) with a suitable phenyl compound (shown and defined in connection with Formula 3) which has a leaving group (X in Formula 3). In other words, the phenyl substituent is coupled to the substituted phenylethyne compound (Formula 2) by reacting the latter with a halogen substituted phenyl compound (Formula 3) in which the the halogen substituted phenyl nucleus either has the desired substituent Y--Z or wherein the actual substituent Y--Z' can be readily converted to the desired substituent by means of organic reactions well known in the art. ##STR6##
Coupling of the substituted phenylethyne compound (Formula 2) with the reagent X--Ph--Y--Z (Formula 3, Ph=benzene ring) or with the reagent X--Ph--Y--Z' (where Z' is defined as above in connection with Formula 4) is affected directly in the presence of cuprous iodide, a suitable catalyst, typically of the formula Pd(PQ.sub.3).sub.2 Cl.sub.2 and an acid acceptor, such as triethylamine, by heating in a sealed tube under an inert gas (argon) atmosphere.
The resulting disubstituted acetylene compounds may be the target compounds made in accordance with the invention (Formula 1), or maybe compounds described by Formula 4 which can be readily converted into the target compounds by such steps as salt formation, esterification, deesterification, homologation, amide formation and the like. These steps are further discussed below.
The disubstituted acetylene compounds of the invention (Formula 1) may also be obtained by first converting the substituted phenylethyne compounds of Formula 2 into the corresponding metal salts, such as a zinc salt (Compound 15) and thereafter coupling the salt 15 with the reagent X--Ph--Y--Z (Formula 3) or with the reagent X--Ph--Y--Z' (Z' defined as above) in the presence of a catalyst having the formula Pd(PQ.sub.3).sub.4 (Q is phenyl), or similar complex.
Derivatization of the compounds of Formula 3 (or of compounds of Formula 4) is indicated in Reaction Scheme 1 as conversion to "Homologs and Derivatives" (Compounds 16).
More specifically with respect to either derivatization or deblocking of protected functionalities in compounds corresponding to Formula 1 or Formula 4, or with respect to the preparation of phenyl compounds of the formula X--Ph--Y--Z or of the formula X--Ph--Y--Z' (that is intermediates which after coupling either directly yield the compounds of the invention, or yield the compounds of Formula 4) the following is noted.
Where a protected phenyl compound is needed to couple with the compounds of Formula 2 such may be prepared from their corresponding acids, alcohols, ketones or aldehydes. These starting materials, the protected acids, alcohols, aldehydes or ketones, are all available from chemical manufacturers or can be prepared by published methods. Carboxylic acids are typically esterified by refluxing the acid in a solution of the appropriate alcohol in the presence of an acid catalyst such as hydrogen chloride or thionyl chloride. Alternatively, the carboxylic acid can be condensed with the appropriate alcohol in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine. The ester is recovered and purified by conventional means. Acetals and ketals are readily made by the method described in March, "Advanced Organic Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810). Alcohols, aldehydes and ketones all may be protected by forming respectively, ethers and esters, acetals or ketals by known methods such as those described in McOmie, Plenum Publishing Press, 1973 and Protecting Groups, Ed. Greene, John Wiley & Sons, 1981.
To increase the value of n before effecting a coupling reaction, where such compounds are not available from a commercial source, the phenyl compounds where Z is --COOH are subjected to homologation by successive treatment under Arndt-Eistert conditions or other homologation procedures. Alternatively, phenyl compounds where Z is different from COOH, may also be homologated by appropriate procedures. The homologated acids can then be esterified by the general procedure outlined in the preceding paragraph.
An alternative means for making compounds where n is 0-6 is to subject the compounds of Formula 1, where Z is an acid or other function, to homologation, using the Arndt-Eistert method referred to above, or other homologation procedures.
The acids and salts derived from Formula 1 are readily obtainable from the corresponding esters. Basic saponification with an alkali metal base will provide the acid. For example, an ester of Formula 1 may be dissolved in a polar solvent such as an alkanol, preferably under an inert atmosphere at room temperature, with about a three molar excess of base, for example, potassium hydroxide. The solution is stirred for an extended period of time, between 15 and 20 hours, cooled, acidified and the hydrolysate recovered by conventional means.
The amide may be formed by any appropriate amidation means known in the art from the corresponding esters or carboxylic acids. One way to prepare such compounds is to convert an acid to an acid chloride and then treat that compound with ammonium hydroxide or an appropriate amine. For example, the acid is treated with an alcoholic base solution such as ethanolic KOH (in approximately a 10% molar excess) at room temperature for about 30 minutes. The solvent is removed and the residue taken up in an organic solvent such as diethyl ether, treated with a dialkyl formamide and then a 10-fold excess of oxalyl chloride. This is all effected at a moderately reduced temperature between about -10 degrees and +10 degrees C. The last mentioned solution is then stirred at the reduced temperature for 1-4 hours, preferably 2 hours. Solvent removal provides a residue which is taken up in an inert inorganic solvent such as benzene, cooled to about 0 degrees C. and treated with concentrated ammonium hydroxide. The resulting mixture is stirred at a reduced temperature for 1-4 hours. The product is recovered by conventional means.
Alcohols are made by converting the corresponding acids to the acid chloride with thionyl chloride or other means (J. March, "Advanced Organic Chemistry", 2nd Edition, McGraw-Hill Book Company), then reducing the acid chloride with sodium borohydride (March, Ibid, pg. 1124), which gives the corresponding alcohols. Alternatively, esters may be reduced with lithium aluminum hydride at reduced temperatures. Alkylating these alcohols with appropriate alky halides under Williamson reaction conditions (March, Ibid, pg. 357) gives the corresponding ethers. These alcohols can be converted to esters by reacting them with appropriate acids in the presence of acid catalysts or dicyclohexlcarbodiimide and dimethlaminopyridine.
Aldehydes can be prepared from the corresponding primary alcohols using mild oxidizing agents such as pyridinium dichromate in methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethyl sulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D., Tetrahedron, 1978, 34, 1651).
Ketones can be prepared from an appropriate aldehyde by treating the aldehyde with an alkyl Grignard reagent or similar reagent followed by oxidation.
Acetals or ketals can be prepared from the corresponding aldehyde or ketone by the method described in March, Ibid, p 810.
Compounds where Z is H can be prepared from the corresponding halo-benzene entity, preferably where the halogen is iodine.
The intermediate substituted phenylethynes (compounds of Formula 2) can be prepared from substituted phenyl compounds in accordance with the reactions described below.
Alkyl, cycloalkyl or alkenyl substituted phenylethynes (compounds shown in Formula 2 where R.sub.1 -R.sub.3 as well as A and B independently are hydrogen, lower alkyl, cycloalkyl, or lower alkenyl) can be synthesized in accordance with Reaction Scheme 2, starting from a halogen (preferably bromo or iodo) substituted phenyl compound (Compound 17). Compound 17 is reacted with trimethylsilylacetylene Compound 18 in the presence of cuprous iodide and a suitable catalyst, typically having the formula Pd(PQ.sub.3).sub.2 Cl.sub.2 (Q is phenyl). The reaction is typically conducted in the presence of bis(triphenylphosphine) palladium (II) chloride catalyst, an acid acceptor (such as triethylamine) under an inert gas (argon) atmosphere, by heating in a sealed tube. The resulting alkyl or alkenyl substituted trimethylsilylethynylbenzene is shown as Compound 19 in Reaction Scheme 2. ##STR7##
As is shown on Reaction Scheme 2, the trimethylsilyl moiety is removed from the trimethylsilylethynylbenzene 19 in the next synthetic step, to provide the alkyl or alkenyl substituted ethynylbenzene derivative (Compound 20). The latter reaction is conducted under basic conditions, preferably under an inert gas atmosphere.
Reaction Scheme 3 discloses a specific synthetic route to 4-tert-butylphenyl ethyne (Compound 21) starting with 4-bromo t-butylbenzene (Compound 22) which is either available commercially or is readily synthesized in accordance with known prior art. Thus, 4-bromo t-butylbenzene 22 is heated with trimethylsilylacetylene 18 in the presence of cuprous iodide, bis(triphenylphosphine) palladium (II) chloride catalyst and triethylamine under an inert gas atmosphere. The resulting trimethylsilyl-(4-tert-butyl)phenylethyne (Compound 23) is reacted with aqueous KOH in isopropanol to yield 4-tert-butylphenylethyne 21. ##STR8##
Reaction Scheme 4 discloses a specific synthetic route to 3-tert-butylphenylethyne (Compound 24) starting with meta bromobenzoic acid (Compound 25), which is treated with trimethylaluminum in hexane to yield 3-tert-butyl bromobenzene (Compound 26). 3-Tert-butyl bromobenzene 26 is thereafter converted into the ethyne derivative 24 through the trimethylsilyl ethyne intermediate 27 in steps similar to the steps described in connection with Reaction Scheme 3.
Reaction Scheme 5 discloses a specific synthetic route to 4-(4-methylpentyl)-phenylethyne (Compound 28). In accordance with this scheme, bromobenzene (Compound 29) is reacted under Friedel Crafts conditions (AlCl.sub.3) with the acid chloride (Compound 30) prepared in situ from 4-methyl valeric acid, to yield 4-(1-oxo-4-methyl-pentyl) bromobenzene (Compound 31). Compound 31 is reduced under Wolff-Kishner conditions (KOH, NH.sub.2 NH.sub.2) to yield 4-(4-methylpentyl) bromobenzene (Compound 32). The bromobenzene derivative 32 is converted to the ethyne derivative 28 through the intermediate trimethylsilyl ethyne derivative 33 in a manner similar to the conversion described in connection with Reaction Scheme 3. ##STR9##
Reaction Scheme 6 discloses specific synthetic steps leading to 4-(1,1,4-trimethylpentyl)phenylethyne (Compound 34). In this synthetic route 4-(1-oxo-4-methyl-pentyl) bromobenzene (Compound 31, obtained for example as shown in Reaction Scheme 5) is reacted under a protective nitrogen atmosphere with trimethylaluminum in hexane to yield 4-(1,1,4-trimethyl-pentyl)bromobenzene (Compound 35). The bromobenzene derivative 35 is converted through the corresponding trimethylsilylethyne derivative 36 into the target intermediate 34 by treatment with trimethylsilyl ethyne and subsequently with KOH in isopropanol, as described above. ##STR10##
Specific examples of coupling the above-noted phelylethynes with reagents of the General Formula 3 are disclosed below under the heading "Specific Examples".
Alkylthio, alkyloxy, cycloalkylthio, cycloalkyloxy, alkenylthio, and alkenyloxy substituted phenylethynes which may or may not be additionally substituted with alkyl, cycloalkyl or alkenyl groups, in other words, compounds shown in Formula 2 where R.sub.1 -R.sub.3 independently are hydrogen, lower alkyl, cycloalkyl, or lower alkenyl and where at least one of A and B alkylthio, alkyloxy, cycloalkylthio, cycloalkyloxy, alkenylthio, or alkenyloxy, can be synthesized in accordance with the steps outlined in Reaction Scheme 7.
Thus, in accordance with Reaction Scheme 7 a halogen substituted phenol, preferably an iodophenol or bromophenol, or a corresponding thiophenol (Compound 37) which may or may not be additionally substituted with an alkyl, alkenyl or cycloalkyl group (in Compound 37, X' is halogen, Y' is sulphur or oxygen and R.sub.1 -R.sub.3 are defined as in connection with Formula 1) is alkylated with a reagent R*--X" where X" is a leaving group such as a halogen, and R* is defined as in connection with Formula 1. Alternatively, the R* group can also be formed by reacting the halogen substituted thiophenol (Compound 37) with an appropriate alkene. The resulting alkoxy, thio-alkoxy , alkenoxy or thio-alkenoxy halobenzene (Compound 38) is reacted with trimethylsilylacetylene (Compound 18) in the presence of cuprous iodide and a suitable catalyst, such as Pd(PQ.sub.3).sub.2 Cl.sub.2, where Q is phenyl. As is noted in connection with the analogous reaction disclosed in Reaction Scheme 2, the reaction is typically conducted in the presence of bis(triphenylphosphine) palladium (II) chloride catalyst, and an acid acceptor, such as triethylamine, under an inert gas (argon) atmosphere. The resulting alkoxy, thio-alkoxy, alkenyloxy or thio-alkenyloxy trimethylsilylethynylbenzene derivatives are shown as Compound 39 in Reaction Scheme 7. ##STR11##
The trimethylsilyl moiety is removed from the trimethylsilylethynylbenzene 39 in the next synthetic step, to provide the alkoxy, thio-alkoxy, alkenoxy or thio-alkenoxy substituted ethynylbenzene derivative (Compound 40). ##STR12##
Reaction Scheme 8 discloses a specific series of synthetic steps which lead to 4-thio-tert-butoxyphenyl ethyne (Compound 41). Thus, 4-bromo-thiophenol (Compound 42) is reacted with isobutylene gas to yield 4-bromophenyl-tert-butyl-sulfide (Compound 43). Compound 43 is thereafter reacted under the conditions described above, with trimethylsilylacetylene (Compound 18) and the resulting trimethylsilyl phenylethyne derivative 44 is thereafter hydrolyzed to yield Compound 41. The corresponding 3-thio-tert-butoxyphenyl ethyne (Compound 45) can be synthesized from 3-bromo-thiophenol under substantially similar conditions. ##STR13##
Reaction Scheme 9 discloses synthetic steps which lead to 4(3-methyl-thio-2-butenoxy)phenyl ethyne (Compound 46). 4-Bromothiophenol (Compound 42) is heated with 4-bromo-2-methyl-2-butene (Compound 47) in a suitable solvent (such as acetone) in the presence of strong base (NaOH) to yield 4-bromophenyl-3-methyl-2-butenyl-sulfide (Compound 48). Compound 48 is converted to the ethyne derivative 46 through the trimethylsilyl ethyne compound 49 by the reactions which are described above. ##STR14##
Reaction Scheme 10 illustrates specific synthetic steps which can be utilized to obtain 4-(3-methyl-thiobutoxy)-phenyl ethyne (Compound 50). In this synthetic procedure 4-bromothiophenol (Compound 42) is heated with 1-bromo-3-methylbutane (Compound 51) in a suitable solvent in the presence of strong base (refluxing acetone and NaOH) to yield 4-bromophenyl-3-methylbutyl-sulfide (Compound 52). Compound 52 is transformed to the desired ethyne derivative 50 through the intermediate trimethylsilylethyne 53. ##STR15##
An alternative general route for introducing the ethyne (acetylenic) function into a phenyl or substituted phenyl derivative so as to obtain the intermediates of Formula 2, is disclosed in Reaction Scheme 11. In accordance with this general procedure, a suitably substituted benzene derivative (Compound 54) is acetylated under Friedel Crafts conditions to provide the acetophenone derivative 55. The acetylation is preferably conducted in the presence of AlCl.sub.3 and in a solvent such as nitromethane. The acetylenic (triple) bond is introduced into the molecule by converting the acetyl moiety of the acetophenone derivative 55 to an acetylene moiety. This is accomplished, preferably, by treatment with lithium diisopropylamide (at low temperature, such as -78 degrees C.) which causes enolization of the acetyl group. The intermediate enol compound (not shown in Reaction Scheme 11) is esterified by treatment with diethylchlorophosphate (or the like) and is again reacted at reduced temperature (e.g. -78 degrees C.) with lithium diisopropylamide, to form the triple bond (presumably by an elimination reaction) followed by aqueous work-up to yield the compounds of Formula 2. If instead of aqueous work-up a carbon dioxide quench of the intermediate lithium salt is used, the corresponding propargylic acid is obtained.
It is noted at this point that the present invention is not intended to be limited or bound by the above-mentioned and other theories of reaction mechanisms. Brief description of the theory of reaction mechanism of the above-noted reaction is given to further enable and facilitate the work of a skilled artisan in the field to modify and adjust the synthetic conditions to fit particular specific intermediates and to make the several compounds of the invention, without departing from the scope and spirit of the invention.

The following examples of specific compounds of the invention, and specific examples of the synthetic steps in which the compounds and certain intermediates are made, are set out to illustrate the invention, not to limit its scope.
SPECIFIC EXAMPLES
Ethyl-4-iodobenzoate (Compound 56)
To a suspension of 10 g (40.32 mmol) of 4-iodobenzoic acid in 100 ml absolute ethanol was added 2 ml thionyl chloride and the mixture was then heated at reflux for 3 hours. Solvent was removed in vacuo and the residue was dissolved in 100 ml ether. The ether solution was washed with saturated NaHCO.sub.3 and saturated NaCl solutions and dried (MgSO.sub.4). Solvent was then removed in vacuo and the residue kugelrohr distilled (100 degrees C.; 0.55 mm) to give the title compound as a colorless oil, PMR (CDCl.sub.3): .delta.1.42 (3H, t, J.about.7 Hz), 4,4 (2H, q, J.about.7 Hz), 7.8 (4H).
In the same manner, but substituting for 4-iodobenzoic acid the appropriate acid, the following examples of compounds can be prepared:
ethyl 4-iodophenylacetate;
ethyl 3-(4-iodophenyl)propionate;
ethyl 4-(4-iodophenyl)butanoate; and
ethyl 5-(4-iodophenyl)pentanoate.
The just mentioned esters (including ethyl-4-iodobenzoate, Compound 56) can serve, for example, as the reagents, X--Ph--Y--Z for coupling with the correspoding ethynyl compounds (such as Compounds 21, 24, 28, 34, 41, 46, and 50, or their zinc salts) to provide the target compounds of the invention.
3-Tert-butyl bromobenzene (Compound 26 )
A suspension of 4.02 g (20 mmol) of m-bromobenzoic acid (Compound 25) in 10 ml hexane was cooled in an ice-bath under nitrogen and then treated slowly with 40 ml of 2M (80 mmol) trimethylaluminum in hexane. The hexane was removed by distillation under nitrogen and the apparatus modified for reflux. The reaction mixture was then heated in an oil bath at 140-150 degrees C. for 3 hours. The oil bath was then replaced by an ice-water bath and the reaction mixture quenched by the slow dropwise addition of water. The mixture was acidified with dilute HCl and mixture heated at reflux until the aluminum salts were dissolved. The reaction mixture was allowed to cool and extracted with 3.times.8 ml ether. The ether extracts were combined, washed with dil. HCl, water and saturated NaCl and then dried (MgSO.sub.4). The solvent was removed in-vacuo and the residue distilled to give a mixture of the title compound and 3-(1-methyl-ethenyl) bromobenzene as a colorless oil. A small portion (200 mg) of this mixture was dissolved in 1 ml of methylene chloride and then treated with a solution of 200 mg of m-chloroperbenzoic acid in 4 ml of methylene chloride. The mixture was stirred at room temperature for 1 hour and the methylene chloride removed in-vacuo. The residue was dissolved in hexane and filtered through a short silica column and the filtrate concentrated in-vacuo to give pure title compound as a colorless oil. PMR (CDCl.sub.3): .delta.1.30 (9H, s), 7.25 (1H, m), 7.41 (2H, m), 7.65 (H, t, J.about.2.1 Hz).
4-(1-oxo-4-methyl-pentyl) bromobenzene (Compound 31)
A mixture of 25 g (0.215 mol) of 4-methyl valeric acid and 29.35 g (0.247 mol) of thionyl chloride was heated at reflux for 1.5 hour. The excess thionyl chloride was removed under reduced pressure using a cryogenic trap. The residue was taken up with 120 g (0.764 mol) of bromobenzene (Compound 29) and the mixture was cooled in an ice-bath and then treated with 23 g (0.172 mol) of anhydrous aluminum chloride through a powder addition funnel. The mixture was stirred at room temperature for 82 h and then quenched by the addition of 50 ml of an ice/water mixture, followed by 30 ml of conc. HCl. The organic layer was separated and the aqueous layer extracted with 2.times.50 ml of ether. The organic extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO.sub.4). The solvent was then removed in-vacuo and the residue purified by distillation (.about.80 degrees C./0.01 mm) to give the title compound as a colorless solid. PMR (CDCl.sub.3): .delta.0.94 (6H, d, J.about.6.0 Hz), 1.53-1.68 (3H, m), 2.85-2.97 (2H, m), 7.60 (2H, d, J.about.8.4 Hz), 7.83 (2H, d, J.about.8.4 Hz).
4-(4-methylpentyl) bromobenzene (Compound 32)
A mixture of 6.45 g (115 mmol) of potassium hydroxide and 42 ml of triethylene glycol was heated at around 100 degrees C. until the potassium hydroxide was dissolved. The mixture was allowed to cool and then treated with 10 g (39 mmol) of 4-(1-oxo-4-methylpentyl) bromobenzene (Compound 31) followed by 3 g (94 mmol) of hydrazine hydrate. The mixture was slowly brought to reflux and heated at reflux for 1 hour. The apparatus was modified for distillation and the mixture heated until approximately 7 ml of liquid had distilled over and the flask temperature had reached 220 degrees C. The apparatus was again modified for reflux and the mixture was heated at reflux for 5 hours and then stirred at room temperature for 8.5 hours. The mixture was then heated to 100 degrees C. and poured into 40 ml of water and the flask rinsed with an additional 25 ml of water. This diluted mixture was acidified to pH=2 with conc. HCl and extracted with ether. The ether extract was washed successively with water and saturated NaCl and then dried (MgSO.sub.4). The solvent was removed in vacuo and the residue subjected to kugelrohr distillation (70 degrees C., 0.05 mm) to give the title compound as a colorless oil. PMR (CDCl.sub.3): .delta.0.88 (6H, d, J.about.6 Hz), 1.12-1.26 (2H, m), 1.48-1.66 (3H, m), 2.54 (2H, t, J.about.7.7 Hz) 7.06 (2H, d, J.about.8.3 Hz), 7.39 (2H, d, J.about.8.3 Hz).
4-(1,1,4-Trimethyl-pentyl) bromobenzene (Compound 35)
To a cooled (ice bath) solution of 5.35 g (20.9 mmol) of 4-(1-oxo-4-methylpentyl) bromobenzene (Compound 31) and 200 microliters of water in 8 ml of chlorobenzene was added slowly, under nitrogen, 20.9 ml of 2M (41.8 mmol) trimethylaluminum in hexane. The hexane was removed by distillation under nitrogen and the residue heated at reflux for 80 hours. The reaction mixture was then cooled in an ice bath and quenched by the slow addition of water. The mixture was then treated with 24 ml of 2N HCl and heated until the aluminum salts were dissolved. The mixture was cooled and extracted with 3.times.20 ml of ether. The ether extracts were combined and washed successively with water and saturated NaCl and then dried (MgSO.sub.4). The solvent was removed in-vacuo and the residue distilled (90-100 degrees C./0.16 mm) to give a crude product which appeared to be a mixture of the desired title compound, starting bromoketone and some olefinic material. This product was then dissolved in 20 ml of methylene chloride, treated with 2 g of m-chloroperbenzoic acid and stirred at room temperature for 12 hours. The solvent was then removed in-vacuo and the residue purified by flash chromatography (silica, hexane) to give the title compound as a colorless oil PMR (CDCl.sub.3): .delta.0.82 (6H, d, J.about.6.9 Hz), 0.85-0.97 (2H, m), 1.27 (6H, s), 1.32-1.49 (1H, m), 1.53-1.62 (2H, m), 7.20 (2H, d, J.about.8.7 Hz), 7.42 (2H, d, J.about.8.7 Hz).
Trimethylsilyl (4-tert-butyl) phenylethyne (Compound 23)
A stirred mixture of 3.05 g (14.31 mmol) of 4-tert-butylbromobenzene (Compound 22), 1.41 g (14.39 mmol) of trimethylsilylacetylene (Compound 18), 139 mg (0.13 mmol) of cuprous iodide, 293 mg (0.42 mmol) of bis(triphenyophosphine) palladium (II) chloride and 3 ml of triethylamine was flushed with nitrogen and then heated under nitrogen at 65-70 degrees C. for 20 hours. The reaction mixture was stirred at room temperature for a further 4 hours and the triethylamine then removed under vacuum. The residue was purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDCl.sub.3): .delta.0.26 (9H, s), 1.31 (9H, s), 7.32 (2H, d, J.about.8.2 Hz), 7.42 (2H, d, J.about.8.2 Hz).
Trimethylsilyl (3-tert-butyl) phenylethyne (Compound 27)
Using the same general procedure as described for Compound 23, but using 3-tert-butyl-bromobenzene, (Compound 26) the title compound was synthesized as a colorless oil. PMR (CDCl.sub.3): .delta.0.36 (9H, s), 1.40 (9H, s), 7.32 (1H, m), 7.37-7.47 (2H, m), 7.61 (1H, m).
Trimethylsilyl [4-(4-methylpentyl)] phenylethyne (Compound 33)
Using the same general procedure as described for Compound 23, but using instead 4-(4-methylpentyl) bromobenzene (Compound 32), the title copound was synthesized as a colorless oil. PMR (CDCl.sub.3): .delta.0.32 (9H, s), 0.93 (6H, d, J.about.6.6 Hz), 1.18-1.29 (2H, m), 1.52-1.70 (3H, m), 2.58 (2H, t, J.about.7.7 Hz), 7.12 (2H, d, J.about.8.1 Hz), 7.43 (2H, d, J.about.8.1 Hz).
Trimethylsilyl [4-(1,1,4-trimethylpentyl)] phenylethyne (Compound 36)
Using the same general procedure as described for Compound 23, but using instead 4-(1,1,4-trimethylpentyl) bromobenzene (Compound 35), the title compound was synthesized as a colorless oil. PMR (CDCl.sub.3): .delta.0.26 (9H, s), 0.81 (6H, d, J.about.6.6 Hz), 0.85-0.97 (2H, m), 1.29 (6H, s), 1.33-1.46 (1H, m), 1.54-2.65 (2H, m), 7.27 (2H, d, J.about.8.1 Hz), 7.42 (2H, d, J.about.8.1 Hz).
4-tert-butylphenyl ethyne (Compound 21)
To a stirred solution of 1.44 g (6.23 mmol) of trimethylsilyl (4-tert-butyl) phenylethyne (Compound 23) in 5 ml of isopropanol was added 10 ml of 1N aqueous KOH and the mixture then stirred at room temperature for 6.5 hours. The isopropanol was removed under vacuum and the residue extracted with ether. The ether extract was washed with dilute HCl until the washings were acidic. The ether solution was then successively washed with water, saturated NaCl and NaHCO.sub.3 solutions and then dried (MgSO.sub.4). Solvent was then removed in-vacuo to give the title compound as a colorless oil. PMR (CDCl.sub.3): .delta.1.34 (9H, s), 3.05 (1H, s), 7.37 (2H, d, J.about.8.2 Hz), 7.46 (2H, d, J.about.8.2 Hz).
3-tert-butylphenyl ethyne (Compound 24)
Using the same general procedure as described for Compound 21), but using instead trimethylsilyl (3-tert-butyl) phenylethyne (Compound 27) and aqueous KOH in methanol, the title compound was synthesized as a colorless oil. PMR (CDCl.sub.3): .delta.1.29 (9H, s), 3.03 (1H, s), 7.22 (1H, t, J.about.7.5 Hz), 7.30 (1H, dt, J.about.7.5 Hz, 1.5 Hz), 7.36 (1H, dt, J.about.7.5 Hz, 1.5 Hz), 7.53 (1H, t, J.about.1.5 Hz).
4-(4-methylpentyl)-phenylethyne (Compound 28)
Using the same general procedure as described for Compound 21), but using instead trimethylsilyl [4-(4-methylpentyl)]phenylethyne (Compound 33), the title compound was synthesized as a colorless oil. PMR (CDCl.sub.3): .delta.0.94 (6H, d, J.about.6.6 Hz), 1.20-1.32 (2H, m), 1.56-1.62 (3H, m), 2.64 (2H, t, J.about.7.8 Hz), 3.08 (1H, s), 7.18 (2H, d, J.about.8.1 Hz), 7.47 (2H, d, J.about.8.1 Hz).
4-(1,1,4-trimethylpentyl)-phenylethyne (Compound 34)
Using the same general procedure as described for Compound 21, but using instead trimethylsilyl [4-(1,1,4-trimethylpentyl)]phenylethyne (Compound 36), the title compound was synthesized as a colorless oil. PMR (CDCl.sub.3): .delta.0.81 (6H, d, J.about.6.6 Hz), 0.85-0.96 (2H, m), 1.29 (6H, s), 1.32-1.48 (1H, m). 1.55-1.66 (2H, m), 3.04 (1H, s), 7.29 (2H, d, J.about.8.4 Hz), 7.44 (2H, d, J.about.8.4 Hz).
4-Bromophenyl-tert-butyl-sulfide (Compound 43)
A constant flow of isobutylene was bubbled through a solution of 4 g (21.16 mmol) of 4-bromo-thiophenol (Compound 42) in 250 ml of methylene chloride under a nitrogen atmosphere and the mixture treated slowly with 0.6 ml of conc. H.sub.2 SO.sub.4. Isolutylene was bubbled through the reaction mixture at room temperature for 2.5 hours and the mixture then stirred for a further 12 hours. The mixture was then washed successively with saturated NaHCO.sub.3, water, 1N HCl, water and saturated NaCl and then dried (MgSO.sub.4). The solvent was then removed in-vacuo and the residue purified by flash chromatography (silica; 3% ethyl acetate in hexanes) to give the title compound as a colorless oil. PMR (CDCl.sub.3): .delta.1.28 (9H, s), 7.39 (2H, d, J.about.8.4 Hz), 7.47 (2H, d, J.about.8.4 Hz).
3-Bromophenyl tert-butyl sulfide (Compound 57)
Isobutylene was bubbled through 75% H.sub.2 SO.sub.4 solution at -5 degrees C. until 2.65 g (47.2 mmol) of isobutylene had been absorbed. The mixture was treated with 3.8 g (20.1 mmol) of 3-bromothiophenol and then allowed to warm to room temperature and stirred for 72 hours. The reaction mixture was then poured into 40 ml of an ice/water mixture and then extracted with ether. The ether extracts were combined and washed successively with 5% NaOH, water and saturated NaCl solution and then dried (MgSO.sub.4). The solvent was removed in-vacuo and the residue distilled (69-75 degrees C., 0.6 mm) to give the title compound as a pale yellow oil. PMR (CDCl.sub.3): .delta.1.30 (9H, s), 7.23 (1H, t, J.about.8.0 Hz), 7.45-7.54 (2H, m), 7.72 (1H, t, J.about.1.8 Hz).
4-Bromophenyl 3-methyl-2-butenyl sulfide (Compound 48)
A mixture of 12.8 g (67.7 mmol) of 4-bromothiophenol (Compound 42) and 2.7 g (67.7 mmol) of sodium hydroxide in 50 ml acetone was heated at reflux under argon for 2.5 hours. The refluxing mixture was then treated dropwise with a solution of 10.0 g (67.1 mmol) of 4-bromo-2-methyl-2-butene (Compound 47) in 10 ml acetone and the mixture heated at reflux for a further 24 hours. The mixture was then cooled and solvent removed in-vacuo. The residue was treated with 50 ml water and extracted with 3.times.75 ml ether. The ether extracts were combined and washed successively with 3.times.30 ml of 5% NaOH, 50 ml of water and 50 ml of saturated NaCl and then dried (MgSO.sub.4). Solvent was then removed in-vacuo and the residual oil purified by kugelrohr distillation (70 degrees C., 0.1 mm) to give the title compound as a colourless oil. PMR (CDCl.sub.3): .delta.1.58 (3H, s), 1.70 (3H, s) 3.5 (2H, d, J.about.7.0 Hz), 5.27 (1H, t, J.about.7.0 Hz), 7.17 (2H, d, J.about.8.3 Hz), 7.36 (2H, d, J.about.8.3 Hz).
4-Bromophenyl 3-methylbutyl sulfide (Compound 52)
A mixture of 15 g (79 mmol) of 4-bromo-thiophenol (Compound 42), 3.16 g (79 mmol) of powdered sodium hydroxide and 150 ml of acetone was heated at reflux for 15 minutes. The refluxing mixture was then treated dropwise with a solution of 12 g (79 mmol) of 1-bromo-3-methylbutane (Compound 51) in 25 ml of acetone and then refluxed for a further 18 hours. The mixture was allowed to cool and the solvent removed in-vacuo. The residue was taken up in 25 ml of water and the mixture basified with 2N NaOH solution. The mixture was extracted with ether and the combined ether extracts washed successively with 1N NaOH, water and saturated NaCl and then dried (MgSO.sub.4). The solvent was removed in-vacuo and the residue distilled (113-117 degrees C., 0.2 mm) to give the title compound as a colourless oil. PMR (CDCl.sub.3): .delta.0.93 (6H, d, J.about.6.6 Hz), 1.47-1.58 (2H, m), 1.65-1.80 (1H, m), 2.90 (2H, t, J.about.7.8 Hz), 7.18 (2H, d, J.about.8.6 Hz), 7.39 (2H, d, J.about.8.6 Hz).
Trimethylsilyl (4-thio-tert-butoxyphenyl) ethyne (Compound 44)
A mixture of 1.25 g (5.1 mmol) of 4-bromophenyl tert-butyl sulfide, (Compound 43) 500 mg (5.1 mmol) of trimethylsilyl acetylene (Compound 18), 100 mg (0.53 mmol) of cuprous iodide, 200 mg (0.28 mmol) of bis (triphenylphosphine) palladium (II) chloride and 1 ml of triethylamine was degassed and then heated under argon at 55 degrees C. for 160 hours. The triethylamine was then removed under vacuum and the residue purified by flash chromatography (silica; hexanes) to give the title compound as a colourless oil. PMR (CDCl.sub.3): .delta.0.20 (9H, s), 1.22 (9H, s), 7.32-7.42 (4H, AB quartet)
Trimethylsilyl (3-thio-tert-butoxyphenyl) ethyne (Compound 58)
Using the same general procedure as described for Compound 44, but fusing instead 3-bromophenyl tert-butyl sulfide (Compound 57), the title compound was synthesized as a pale yellow oil. PMR (CDCl.sub.3): .delta.0.25 (9H, s), 1.25 (9H, s), 7.22 (1H, t, J.about.8.0 Hz), 7.39-7.46 (2H, m), 7.62 (1H, s).
Trimethylsilyl 4-(3-methyl-thio-2-butenoxyphenyl) ethyne (Compound 49)
Using the same general procedure as described for Compound 44, but using instead 4-bromophenyl 3-methyl-2-butenyl sulfide (Compound 48), the title compound was synthesized as a pale yellow oil. PMR (CDCl.sub.3): .delta.0.25 (9H, s), 1.62 (3H, s), 1.71 (3H, s), 3.55 (2H, d, J.about.7.5 Hz), 5.28 (1H, t, J.about.7.5 Hz), 7.21 (2H, d, J.about.8.1 Hz), 7.36 (2H, d, J.about.8.1 Hz).
Trimethylsilyl 4-(3-methyl-thiobutoxyphenyl) ethyne (Compound 53)
Using the same general procedure, as described for Compound 44, but using instead 4-bromophenyl 3-methyl-butyl sulfide (Compound 52), the title compound was synthesized as a colourless oil. PMR (CDCl.sub.3): .delta.0.25 (9H, s), 0.92 (6H, d, J.about.6.6 Hz), 1.48-1.58 (2H, m), 1.65-1.79 (1H, m), 2.92 (2H, t, J.about.7.8 Hz), 7.20 (2H, d, J.about.8.4 Hz), 7.37 (2H, d, J.about.8.4 Hz).
4-Thio-tert-butoxyphenyl ethyne (Compound 41)
To a solution of 850 mg (3.24 mmol) of trimethylsilyl 4-thio-tert-butoxyphenyl ethyne (Compound 44) in 3 ml of isopropanol was added 5 ml of 1N KOH solution and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with ether and the combined ether extracts were washed successively with dilute HCl, water, saturated NaHCO.sub.3 and NaCl solutions and then dried (MgSO.sub.4). The solvent was removed in-vacuo to give the title compound as a pale yellow oil. PMR (CDCl.sub.3): .delta.1.29 (9H, s), 3.16 (1H, s), 7.42-7.52 (4H, AB quartet).
3-Thio-tert-butoxyphenyl ethyne (Compound 45)
Using the same general procedure as described for Compound 41, but using instead trimethylsilyl 3-thio-tert-butoxyphenyl ethyne (Compound 58), the title compound was synthesized as a colorless oil. PMR (CDCl.sub.3): .delta.1.30 (9H, s), 3.11 (1H, s), 7.31 (1H, t, J.about.7.7 Hz), 7.48-7.56 (2H,m), 7.69 (1H, t, J.about.1.7 Hz).
4-(3-Methyl-thio-2-butenoxylphenyl) ethyne (Compound 46)
Using the same general procedure as described for Compound 41), but using instead trimethylsilyl 4-(3-methyl-thio-2butenoxyphenyl) ethyne (Compound 49), the title compound was synthesized as a pale yellow oil. PMR (CDCl.sub.3): .delta.1.63 (3H, s), 1.72 (3H, s), 3.08 (1H, s), 3.56 (2H, d, J.about.7.5 Hz), 5.29 (1H, t, J.about.7.5 Hz), 7.23 (2H, d, J.about.8.4 Hz), 7.38 (2H, d, J.about.8.4 Hz).
4-(3-methyl-thiobutoxyphenyl) ethyne (Compound 50)
Using the same general procedure as described for Compound 41, but using instead trimethylsilyl 4-(3-methylthiobutoxyphenyl) ethyne (Compound 53) the title compound was synthesized as a colourless oil. PMR (CDCl.sub.3): .delta.0.93 (6H, d, J.about.6.7 Hz), 1.49-1.60 (2H, m), 1.65-1.80 (1H, m), 2.93 (2H, t, J.about.7.8 Hz), 7.22 (2H, d, J.about.8.5 Hz), 7.39 (2H, d, J.about.8.5 Hz).
Ethyl-4-[4-tert-butylphenyl]ethynyl benzoate (Compound 3)
A mixture of 309 mg (1.96 mmol) of 4-tert-butylphenylethyne, (Compound 2) 521.5 mg (1.89 mmol) of ethyl-4-iodobenzoate, (Compound 56) 17.7 mg (0.09 mmol) of cuprous iodide, 40.6 mg (0.06 mmol) of bis(triphenylphosphine) palladium (II) chloride and 2 ml of triethylamine was flushed with nitrogen and then stirred under nitrogen for 40 hours. The triethylamine was removed under vacuum and the residue was taken up in water and extracted with ether. The ether extracts were combined and washed with saturated NaHCO.sub.3 and NaCl solutions and then dried (MgSO.sub.4). The solvent was then removed in-vacuo and the residue purified by flash chromatography (silica; 2 percent ethyl acetate in hexanes) to give the title compound as a pale yellow solid. PMR (CDCl.sub.3): .delta.1.34 (9H, s), 1.41 (3H, t, J.about.7.2 Hz), 4.40 (2H, q, 7.2 Hz), 7.39 (2H, d, J.about.8.3 Hz), 7.50 (2H, d, J.about.8.3 Hz), 7.59 (2H, d, J.about.8.1 Hz), 8.03 (2H, d, J.about.8.1 Hz).
Ethyl-4-[3-tert-butylphenyl]ethynyl benzoate (Compound 1)
Using the same general procedure, but using instead (3-tert-butyl)phenylethyne (Compound 24), the title compound was synthesized as a white solid. PMR (CDCl.sub.3): .delta.1.35 (9H, s), 1.41 (3H, t, J.about.7.2 Hz), 4.40 (2H, q, J.about.7.2 Hz), 7.31 (1H, t, J.about.7.8 Hz), 7.36-7.44 (2H, m), 7.57-7.65 (3H, m), 8.04 (2H, d, J.about.7.8 Hz).
Ethyl-4-[4-(4-methylpentyl)phenyl] ethynyl benzoate (Compound 5)
Using the same general procedure, but using instead 4-(4-methylpentyl) phenylethyne (Compound 28), the title compound was synthesized as a pale yellow oil. PMR (CDCl.sub.3): .delta.0.88 (6H, d, J.about.6.3 Hz), 1.15-1.30 (2H, m), 1.39 (3H, t, J.about.7.0 Hz), 1.50-1.70 (3H, m), 2.59 (2H, t, J.about.7.8 Hz), 4.38 (2H, q, J.about.7.0 Hz), 7.17 (2H, d, J.about.8.0 Hz), 7.47 (2H, d, J.about.8.0 Hz), 7.57 (2H, d, J.about.8.1 Hz), 8.02 (2H, d, J.about.8.1 Hz).
Ethyl-4-[4-(1,1,4-trimethylpentyl) phenyl] ethynyl benzoate (Compound 7 )
Using the same general procedure but using instead 4-(1,1,4-trimethylpentyl)-phenyl ethyne (Compound 34), the title compound was synthesized as a pale yellow solid. PMR (CDCl.sub.3): .delta.0.70 (6H, d, J.about.6.6 Hz), 0.72-0.88 (2H, m), 1.17 (6H, s), 1.22-1.37 (4H, m), 1.43-1.53 (2H, m), 4.26 (2H, q, J.about.7.2 Hz), 7.20 (2H, d, J.about.8.6 Hz), 7.38 (2H, d, J.about.8.6 Hz), 7.46 (2H, d, J.about.8.3 Hz), 7.91 (2H, d, J.about.8.3 Hz).
4-[4-Tert-butylphenyl]ethynyl benzoic acid (Compound 4)
To a solution of 66.4 mg (0.217 mmol) of ethyl 4-[4-tert-butylphenyl] ethynyl benzoate (Compound 3) in 7 ml of ethanol was added 0.25 ml of an aqueous ethanolic KOH solution. The mixture was stirred at room temperature for 144 hours and then concentrated in-vacuo. The residue was then taken up in ether and water and the aqueous layer was separated. The aqueous layer was acidified with 10 percent HCl and extracted with ether. The ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO.sub.4). The solution was filtered and the filtrate was concentrated in-vacuo to give the title compound as a white solid. PMR (CDCl.sub.3): .delta.1.32 (9H, s), 7.39 (2H, d, J.about.8.4 Hz), 7.48 (2H, d, J.about.8.4 Hz), 7.57 (2H, d, J.about.8.3 Hz), 8.02 (2H, d, J.about.8.3 Hz).
4-[3-Tert-butylphenyl] ethynyl benzoic acid (Compound 2)
Using the same general procedure, but using instead ethyl 4-[3-tert-butylphenyl] ethynyl benzoate (Compound 1), the title compound was synthesized as a white solid. PMR (CDCl.sub.3): .delta.1.36 (9H, s), 7.30-7.47 (3H, m), 7.57-7.65 (3H, m), 8.06 (2H, d, J.about. 8.4 Hz).
Ethyl-4-(3-thio-tert-butoxyphenyl) ethynyl benzoate (Compound 9)
A mixture of 190.5 mg (1.003 mmol) of 3-thio-tert-butoxyphenyl ethyne (Compound 45), 290.5 mg (1.053 mmol) of ethyl 4-iodobenzoate (Compound 56), 20 mg (0.105 mmol) of cuprous iodide, 40 mg (0.057 mmol) of bis(triphenylphosphine) palladium (II) chloride and 1.5 ml of triethylamine was degassed under argon and heated at 55 degrees C. for 80 hours. The triethylamine was then removed under vacuum and the residue purified by flash chromatography (silica, 3 percent ethyl acetate in hexanes) to give the title compound as a pale yellow solid. PMR (CDCl.sub.3): .delta.1.31 (9H, s), 1.41 (3H, t, J.about.7.1 Hz), 4.40 (2H, q, J.about.7.1 Hz), 7.34 (1H, t, J.about.7.7 Hz), 7.52-7.58 (2H, m), 7.61 (2H, d, J.about.8.4 Hz), 7.74 (1H, t, J.about.1.8 Hz), 8.05 (2H, d, J.about.8.4 Hz).
Ethyl-4-(thio-tert-butoxyphenyl) ethynyl benzoate (Compound 11)
Using the same general procedure, but using instead 4-thio-tert-butoxyphenyl ethyne (Compound 41), the title compound was synthesized as a pale yellow solid. PMR (CDCl.sub.3): .delta.1.32 (9H, s), 1.42 (3H, t, J.about.7.1 Hz), 4.40 (2H, q, J.about.7.1 Hz), 7.48-7.57 (4H, AB quartet), 7.60 (2H, d, J.about.8.3 Hz), 8.05 (2H, d, J.about.8.3 Hz).
Ethyl-4-[4-(3 -methyl-thiobutoxyphenyl)]ethynyl benzoate (Compound 59)
Using the same general procedure, but using instead 4-(3-methyl-thiobutoxy) phenyl ethyne (Compound 50), the title compound was synthesized as a pale brown solid. PMR (CDCl.sub.3): .delta.0.94 (6H, d, J.about.6.7 Hz), 1.41 (3H, t, J.about.7.2 Hz), 1.52-1.61 (2H, m), 1.66-1.81 (1H, m), 2.92-3.00 (2H, m), 7.27 (2H, d, J.about.8.4 Hz), 7.45 (2H, d, J.about.8.4 Hz), 7.58 (2H, d, J.about.8.4 Hz), 8.03 (2H, d, J.about.8.4 Hz)
Ethyl-4-[4-(3-methyl-thio-2-butenoxyphenyl)]ethynyl benzoate (Compound 13)
Using the same general procedure, but using instead 4-(3-methyl-thio-2-butenoxyphenyl) ethyne (Compound 46), the title compound was synthesized as a pale yellow solid. PHR (CDCl.sub.3): .delta.1.32 (3H, t, J.about.7.1 Hz), 1.56 (3H, s), 1.65 (3H, s), 3.50 (2H, d, J.about.7.5 Hz), 4.30 (2H, q, J.about.7.1 Hz), 5.22 (1H, t, J.about.7.5 Hz), 7.19 (2H, d, J.about.8.4 Hz), 7.36 (2H, d, J.about.8.4 Hz), 7.49 (2H, d, J.about.8.4 Hz), 7.94 (2H, d, J.about.8.4 Hz).
4-[4-(3-methyl-thio-2-butenoxyphenyl)]ethynyl benzoic acid (Compound 14)
To a solution of 75.2 mg (0.214 mmol) of ethyl 4-[4-(3-methyl-thio-2-butenoxyphenyl]ethynyl benzoate (Compound 13) in 1 ml of ethanol was added 0.23 ml of an aqueous ethanolic KOH solution. The reaction mixture was stirred under nitrogen at room temperature for 72 hours. The mixture was poured into iced water and washed with ether. The aqueous solution was acidified with 10 percent HCl solution and then extracted with 3.times.25 ml ether. The ether extracts were combined and washed successively with 2.times.25 ml of water and 1.times.25 ml of saturated NaCl solution and then dried (MgSO.sub.4). The solution was filtered and the filtrate was concentrated in-vacuo to give the title compound as a white solid. PMR (CDCl.sub.3): .delta.1.65 (3H, s), 1.74 (3H, s), 3.59 (2H, d, J.about.7.4 Hz), 5.30 (1H, t, J.about.7.4 Hz), 7.28 (2H, d, J.about.8.4 Hz), 7.44 (2H, d, J.about.8.4 Hz), 7.57 (2H, d, J.about.8.3 Hz), 8.04 (2H, d, J.about.8.3 Hz).
Using the method described for the preparation of ethyl 4-(4-tert butylphenyl)-ethynyl benzoate (Compound 3) or of ethyl 4-(3-thio-tert-butoxyphenyl)-ethynyl benzoate (Compound 9) but using other examples of reagents corresponding to General Formula 2 and General Formula 3, respectively, numerous specific examples of compounds of the invention can be prepared. Still further, as examples, the ethyne compounds (General Formula 2) which were specifically described above, i.e.
4-tert-butylphenyl ethyne (Compound 21);
3-tert-butylphenyl ethyne (Compound 24);
4-(4-methylpentyl)-phenylethyne (Compound 28);
4-(1,1,4-trimethylpentyl)phenylethyne (Compound 34);
4-thio-tert-butoxyphenyl ethyne (Compound 41);
3-thio-tert-butoxyphenyl ethyne (Compound 45)
4-(3-methyl-thio-2-butenoxy)phenyl ethyne (Compound 46);
4-(3-methyl-thiobutoxy)-phenyl ethyne (Compound 50)
can be coupled with the reagents (General Formula 3) noted above, i.e. with
ethyl 4-iodophenylacetate;
ethyl 3-(4-iodophenyl)propionate;
ethyl 4-(4-iodophenyl)butanoate; and
ethyl 5-(4-iodophenyl)pentanoate.
to provide a large number of further examples of compounds of the invention.
Ethyl trans-4-(3-tert-butylphenyl)ethynyl cinnamate (Compound 60)
A solution of 225 mg (1.424 mmol) of 3-tert-butylphenyl ethyne (Compound 24) in 2 ml of triethylamine was added to a mixture of 363 mg (1.424 mmol) of ethyl trans-4-bromo-cinnamate, 30 mg (0.043 mmol) of bis(triphenylphosphine) palladium (II) chloride and 20 mg (0.105 mmol) of cuprous iodide placed in a heavy-walled tube. The mixture was degassed under argon and the tube was then sealed. The mixture was heated at 60 degrees C. for 72 hours and then cooled to room temperature. The mixture was diluted with ether and filtered through celite. The filtrate was concentrated in-vacuo and the resultant crude product was purified by flash chromatography (silica; 5 percent ethyl acetate in hexanes) to give the title compound as a yellow oil. PMR (CDCl.sub.3): .delta.1.30-1.38 (12H, m), 4.27 (2H, q, J.about.7.2 Hz), 6.45 (1H, d, J.about.16.1 Hz), 7.26-7.41 (2H, m), 7.44- 7.60 (6H, m), 7.67 (1H, d, J.about.16.1 Hz).
4-(3-Tert-butylphenyl)ethynyl acetophenone (Compound 61)
A solution of 439.4 mg (2.785 mmol) of 3-tert-butylphenyl ethyne (Compound 24) in 2 ml of triethylamine was added to a mixture of 556 mg (2.793 mmol) of 4-bromo-acetophenone, 50 mg (0.071 mmol) of bis(triphenylphosphine) palladium (II) chloride and 25 mg (0.131 mmol) of cuprous iodide placed in a heavy-walled tube. The mixture was degassed under argon and the tube was sealed. The reaction mixture was heated at 60 degrees C. for 72 hours and then cooled to room temperature. The mixture was diluted with ether and filtered through celite. The filtrate was concentrated and the residue was purified by flash chromatography (silica; 5 percent ethyl acetate in hexanes) to give the title compound as a yellow solid. PMR (CDCl.sub.3): .delta.1.36 (9H, s), 2.63 (3H, s), 7.28-7.45 (3H, m), 7.60 (1H, t, J.about.1.7 Hz), 7.64 (2H, d, J.about.8.4 Hz), 7.96 (2H, d, J.about.8.4 Hz). Compound 61 can be converted to 4-3(tert-butylphenyl)-ethynylphenylpropinoic acid through sequential treatment with lithium diisopropylamide, diethyl chlorophosphate, lithium diisopropylamide and quenching with carbon dioxide, followed by aqueous work-up.
Examples of Formulation for Topical Administration
Preferably the compounds of the invention may be administered topically using various formulations. Such formulations may be as follows:
______________________________________Ingredient Weight/Percent______________________________________SolutionRetinoid (active ingredient) 0.1BHT 0.1Alcohol USP 58.0Polyethylene Glycol 400 NF 41.8GelRetinoid (active ingredient) 0.1BHT 0.1Alcohol USP 97.8Hydroxypropyl Cellulose 2.0______________________________________

Number	Name	Date
3957871	Remy	May 1976
4096341	Frazer	Jun 1978
4326055	Loeliger	Apr 1982
4391731	Boller et al.	Jul 1983
4695649	Magami et al.	Sep 1987
4723028	Shudo	Feb 1988
4730032	Rossi	Mar 1988
4739098	Chandraratna	Apr 1988
4740519	Shroot et al.	Apr 1988
4810804	Chandraratna	Mar 1989
4826969	Maignan et al.	May 1989
4855320	Chatterjee et al.	Aug 1989
4895868	Chandraratna	Jan 1990
4980369	Chandraratna	Dec 1990
4992468	Chandraratna	Feb 1991
5006550	Chandraratna	Apr 1991
5013744	Chandraratna	May 1991
5015658	Chandraratna	May 1991
5023341	Chandraratna	Jun 1991
5037825	Klaus et al.	Aug 1991
5045551	Chandraratna	Sep 1991
5053523	Chandraratna	Oct 1991
5068252	Chandraratna	Nov 1991
5089509	Chandraratna	Feb 1992
5130335	Chandraratna	Jul 1992
5134159	Chandraratna	Jul 1992
5162546	Chandraratna	Nov 1992
5175185	Chandraratna	Dec 1992
5183827	Chandraratna	Feb 1993
5202471	Chandraratna	Apr 1993

Number	Date	Country
0130795	Jan 1985	EPX
176034A	Apr 1986	EPX
0284288	Sep 1988	EPX
0318860	Jul 1989	EPX
0350846	Jul 1989	EPX
3708060	Sep 1987	DEX

Alkyl, alkoxy and thioalkoxy substituted diphenyl acetylenes having retinoid like activity

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Abstract

Description

Claims

CROSS-REFERENCE TO RELATED APPLICATION

US Referenced Citations (30)

Foreign Referenced Citations (6)

Non-Patent Literature Citations (10)

Continuations (1)

Entry
A General Synthesis of Terminal and Internal Arylalkynes by the Palladium-Catalyzed Reaction of Alkynylzinc Reagents with Aryl Halides by Anthony O. King and Ei-ichi Negishi, J. Org. Chem. 43 No. 2, 1978 p. 358.
Conversion of Methyl Ketones into Terminal Acetylenes and (E)-Tri-substituted Olefins of Terpenoid Origin by Ei-ichi, Anthony O. King, and William L. Klima, J. Org. Chem. 45 No. 12, 1980 p. 2526.
Sporn et al. in J. Amer. Acad. Derm. 15:756-764 (1986).
A Convenient Synthesis of Ethynylarenes and Diethynylarenes by S. Takahashi, Y. Kuroyama, K. Soogashira, N. Hagihara, Synthesis 1980 pp. 627-630.
Shudo et al. in Chem. Phar. Bull. 33:404-407 (1985).
Kagechika et al., in J. Med. Chem. 31:2182-2192 (1988).
Chemistry and Biology of Synthetic Retinoids by Marcia I. Dawson and William H. Okamura, published by CRC Press Inc., 1990, pp. 334-335, 354 Synthesis of 2,2'-Diacyl-1,1'-biaryls. Regiocontrolled Protection of . . . by Mervic, et al., J. Org. Chem., No. 45, pp. 4720-4725, 1980.
A Dopamine Receptor Model and Its Application in the Design of a New Class of Rigid Pyrrolo[2,3-g]isoquinoline Antipsychotics, Gary L. Olson, et al. American Chemical Society, 1981, vol. 24, No. 9, pp. 1026-1031.
6.2.3 Conformational Restriction, Williams, et al., Drug Discovery and Development, 1987 The Humana Press, pp. 54-55.
Davis et al. J. Organomettalic Chem 387 (1990) 381-390.