EP0555235A1 - Acetylenes disubstitues par un groupe heteroaromatique et un groupe chromanyl a substitution en position 2, thiochromanyl ou 1,2,3,4-tetrahydroquinolinyl presentant une activite de type retinoide - Google Patents

Acetylenes disubstitues par un groupe heteroaromatique et un groupe chromanyl a substitution en position 2, thiochromanyl ou 1,2,3,4-tetrahydroquinolinyl presentant une activite de type retinoide

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Publication number
EP0555235A1
EP0555235A1 EP91917319A EP91917319A EP0555235A1 EP 0555235 A1 EP0555235 A1 EP 0555235A1 EP 91917319 A EP91917319 A EP 91917319A EP 91917319 A EP91917319 A EP 91917319A EP 0555235 A1 EP0555235 A1 EP 0555235A1
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EP
European Patent Office
Prior art keywords
compound
formula
ethyl
hydrogen
ethynyl
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.)
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Application number
EP91917319A
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German (de)
English (en)
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EP0555235A4 (en
Inventor
Roshantha A. S. Chandraratna
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Allergan Inc
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Allergan Inc
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Publication of EP0555235A1 publication Critical patent/EP0555235A1/fr
Publication of EP0555235A4 publication Critical patent/EP0555235A4/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to novel compounds having retinoid-like activity. More specifically, the invention relates to compounds having an ethynylheteroaromatic acid portion and a second portion which is a 2-substituted tetrahydroquinolinyl, thiochromanyl, or chromanyl group.
  • the acid function may also be converted to an alcohol, aldehyde or ketone or derivatives thereof, or may be reduced to -CH 3 .
  • 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 January 9, 1985. See also European Patent Application 176034A published April 2, 1986 where tetrahydronaphtha- lene compounds having an ethynylbenzoic acid group are disclosed, and United States Patent No. 4,739,098 where three olefinic units from the acid-containing moiety of retinoic acid are replaced by an ethynylphenyl functional ⁇ ity. Summary of the Invention This invention covers compounds of Formula 1
  • R1-R3 are hydrogen or lower alkyl
  • R 4 and R 5 are hydrogen or lower alkyl with the proviso that R 4 and R 5 cannot both be hydrogen
  • A is pyridinyl, thie ⁇ nyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl
  • n is 0-5
  • B is H, -COOH or a pharmaceuti ⁇ cally acceptable salt, ester or amide thereof, -CH OH or an ether or ester derivative, or -CHO or an acetal deriva ⁇ tive, or -COR- ⁇ or a ketal derivative where R- j ⁇ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons.
  • this invention in a second aspect, 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.
  • dermatoses such as acne, Darier's disease, psoriasis, icthyosis, eczema, atopic dermatitis and epithelial cancers.
  • arthritic diseases and other immunological disorders e.g. lupus erythematosus
  • This invention also relates to a pharmaceutical formulation comprising a compound of Formula 1 in admix ⁇ ture with a pharmaceutically acceptable excipient.
  • 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 III in the presence of cuprous iodide and Pd(PQ 3 ) 2 Cl 2 (Q is phenyl) or a similar complex
  • Formula 2 where R1-R5 are the same as described above, X' is a halogen, preferably I; n, and A are the same as defined above; and B is H, or a protected acid, alcohol, aldehyde or ketone, giving the corresponding compound of Formula 1; or to the process of making a compound of Formula l which consists of reacting a zinc salt of Formula 4 with a compound of Formula 3 in the presence of Pd(PQ 3 ) (Q is phenyl) or a similar complex.
  • X' is a halogen, preferably I
  • n, and A are the same as defined above
  • B is H, or a protected acid, alcohol, aldehyde or ketone, giving the corresponding compound of Formula 1; or to the process of making a compound of Formula l which consists of reacting a zinc salt of Formula 4 with a compound of Formula 3 in the presence of Pd(PQ 3 ) (Q is phenyl) or a similar complex.
  • 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.
  • lower alkyl means having 1-6 carbon atoms.
  • the phenyl or lower alkylphenyl esters are also preferred.
  • .Amide has the meaning classically accorded that term in organic chemistry. In this instance it includes the unsubstituted amides and all aliphatic and aromatic ono- 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 pre ⁇ ferred.
  • Acetals and ketals include the radicals of the formu ⁇ la -CK where K is (-OR) 2 .
  • R is lower alkyl.
  • 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 inor- 5 ganic acid or base.
  • the salt may be a mono or polyvalent ion.
  • the inorganic ions sodium, potassium, calcium, and magnesium.
  • Organic amine salts may be made with amines, particularly ammonium salts such as mono-, 0 di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar mole ⁇ cules. 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 5 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 B group are attached to the 2 and 5 positions respectively of a pyridine ring (the 6 and 3 positions in the nicotinic acid nomenclature being equivalent to the 2/5 designation in the pyridine nomen- 5 clature) or the 5 and 2 positions respectively of a thio- phene group respectively; n is 0; and B is -COOH, an alkali metal salt or organic amine salt, or a lower alkyl ester, or -CH 2 OH and the lower alkyl esters and ethers thereof, or -CHO and acetal derivaives thereof.
  • the compounds of this invention may be administered systemically or topically, depending on such considera ⁇ tions as the condition to be treated, need for site-spe ⁇ cific treatment, quantity of drug to be administered, and similar considerations.
  • 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, Pennsylvania. For topical application, these compounds could also be administered as a powder or spray, particularly in aerosol form.
  • the drug may be confected as a powder, pill, tablet or the like, or as a syrup or elixir for oral 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.
  • medicaments can be added to such topical formu ⁇ lation for such secondary purposes as treating skin dry ⁇ ness, providing protection against light; other edica- tions 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 adminis ⁇ tration 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.
  • 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 treat ⁇ ment. Accordingly, a given therapeutic concentration will be best determined at the time and place through routine experimentation.
  • a formulation containing between 0.001 and 5 percent by weight, preferably about 0.01 to 1% will usually con ⁇ stitute 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 in ⁇ stances.
  • retionic acid like activity of these compounds was confirmed through the classic measure of retionic acid activity involving the effects of retionic acid on orni- thine decarboxylase.
  • the original work on the correlation between retionic acid and decrease in cell proliferation was done by Verma & Boutwell, Cancer Research. 1977. 37. 2196-2201. That reference discloses that ornithine decar- boxylase (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.
  • ODC ornithine decar- boxylase
  • TPA 12-0-tetradecanoyl- phorbol-13-acetate
  • 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.
  • 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.
  • R -R 3 are hydrogen or a lower alkyl group
  • A is as defined above in connection with Formula 1
  • n is 0-5 and B is H, or a protected acid, alcohol, aldehyde or ketone.
  • X' is Cl, Br or I when n is O but preferably be Br or I when n is 1-5.
  • Reaction Scheme 2 the definitions of R ⁇ Rg, n, A, B and X' are the same as in Reaction Scheme 1.
  • a general description of the synthetic steps outlined in Reaction Schemes 1 and 2 is as follows.
  • the 4-bromo-thio-phenol (Com ⁇ pound 9) is acylated with an acylating agent, such as an acid chloride (Compound 10) derived from an appropriately substituted acrylic acid.
  • the acylation is conducted in an inert solvent (such as tetrahydrofuran) in the presence of strong base (for example sodium hydrdride) .
  • the re ⁇ sulting thioester (Compound 11) which contains the olefin- i ⁇ bond of the acrylic acid moiety is ring closed in the presence of a Fridel Crafts type catalyst (such as alumi ⁇ num chloride) by stirring in a suitable solvent such as methylene chloride.
  • a Fridel Crafts type catalyst such as alumi ⁇ num chloride
  • R 4 and/or R 5 substituents are intro-ucked by treating the 2-oxo-6-bromo-thiochroman (Compound 1)
  • the substituted 6-bromothiochroman 14 is reacted with trimethylsilylacetylene in the presence of cuprous iodide and a suitable catalyst, typically having the formula Pd(PQ 3 ) Cl (Q is phenyl).
  • a suitable catalyst typically having the formula Pd(PQ 3 ) Cl (Q is phenyl).
  • the reaction is typi ⁇ cally 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 6-trimethylsi- lylethynylthiochroman is shown as Compound 15 in Reaction Scheme 1.
  • the trimethylsilyl moiety is removed from the 6-trimethylsilylethynyl-thio- chroman 15 in the next synthetic step, to provide the ring substituted 6-ethynyl-thiochroman derivative (Compound 16) .
  • the latter reaction is conducted under basic condi ⁇ tions, preferably under an inert gas atmosphere.
  • compound 16 5 is coupled with the reagent X'-A-(CH 2 ) n -B (Formula 3) where the symbols X 1 , A and B have the same meaning as defined in connection with Formula 3.
  • the heteroaryl substituent is introduced into the 6-thiochro- manylethyne 16 by reacting the latter with a halogen 0 substituted heteroaromatic compound (Formula 3) in which the heteroaramatic nucleus (A) either has the desired substituent [(CH 2 ) n -B] or wherein the actual substituent (CH 2 ) n -B can be readily converted to the desired substitu ⁇ ent by means of organic reactions well known in the art.
  • Coupling of the 6-thiochromanylethyne 16 with the reagent X'-A-(CH 2 ) n -B is affected directly in the presence of cuprous iodide, a suitable catalyst, typically of the formula Pd(PQ 3 ) Cl 2 and an acid acceptor, such as triethy- lamine, by heating in a sealed tube under an inert gas o (argon) atmosphere.
  • a suitable catalyst typically of the formula Pd(PQ 3 ) Cl 2 and an acid acceptor, such as triethy- lamine
  • the resulting disubstituted acetylene compound may be the target compound made in accord ⁇ ance with the invention, or maybe readily converted into the target compound by such steps as salt formation, 5 esterification, deesterification, ho ologation, amide formation and the like. These steps are further discussed below.
  • Compound 18 may also be obtained by first converting the 6-thiochromanylethyne derivative 16 into the corre- 0 sponding metal salt, such as a zinc salt, (Compound 17) and thereafter coupling the salt 17 with the reagent X'-A- (CH 2 ) n -B (Formula 3) in the presence of a catalyst having the formula Pd(PQ 3 ) 4 ( is phenyl), or similar complex. Derivatization of Compound 18 is indicated in Reac ⁇ tion Scheme 1 as conversion to "ho ologs and derivatives", Compounds 19.
  • the corre- 0 sponding metal salt such as a zinc salt
  • a protected heteroaromatic compound is needed to couple with the compounds of Formula 2 (Compounds 16 in Reaction Scheme 1) , such may be prepared from their corre ⁇ sponding acids, alcohols, ketones or aldehydes. These starting materials, the protected acids, alcohols, alde ⁇ hydes or ketones, are all available from chemical manufac ⁇ turers or can be prepared by published methods.
  • Carboxyl ⁇ ic 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.
  • 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 de ⁇ scribed in March, "Advanced Organic Chemistry," 2nd Edi ⁇ tion, McGraw-Hill Book Company, p 810). Alcohols, alde ⁇ hydes and ketones all may be protected by forming respec ⁇ tively, ethers and esters, acetals or ketals by known methods such as those described in McOmie, Plenum Publish ⁇ ing Press, 1973 and Protecting Groups. Ed. Greene, John Wiley & Sons, 1981.
  • heteroaromatics where B is -COOH are subjected to homologation by successive treat ⁇ ment under Arndt-Eistert conditions or other homologation procedures.
  • heteroaromatics where B is a different from COOH may also be homologated by appropri ⁇ ate procedures.
  • the homologated acids can then be esteri- fied by the general procedure outlined in the preceding paragraph.
  • An alternative means for making compounds where n is 1 - 5 is to subject the compounds of Formula 1, where B is an acid or other function, to homologation, using the Arndt-Eistert method referred to above, or other homologa ⁇ tion procedures.
  • the acids and salts derived from Formula 1 are readi ⁇ ly obtainable from the corresponding esters.
  • Basic sapon- ification with an alkali metal base will provide the acid.
  • 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 hydro- lysate 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.
  • 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 forma ide and then a 10-fold excess of oxalyl chloride.
  • Alcohols are made by converting the corresponding acids to the acid chloride with thionyl chloride or other means (J. March, "Advanced Organic Chemistry", 2nd Edi ⁇ tion, McGraw-Hill Book Company) , then reducing the acid chloride with sodium borohydride (March, Ibid, pg. 1124) , which gives the corresponding alcohols.
  • esters may be reduced with lithium aluminum hydride at reduced temperatures. Alkylating these alcohols with appropriate alky halides under Williamson reaction condi ⁇ tions (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 dimethlami- nopyridine.
  • 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 sulfox ⁇ ide/oxalyl chloride in methylene chloride (Omura, K. , Swern, D., Tetrahedron. 1978. 34. 1651).
  • mild oxidizing agents such as pyridinium dichromate in methylene chloride (Corey, E. J., Schmidt, G. , Tet. Lett.. 399, 1979) . or dimethyl sulfox ⁇ ide/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 corre ⁇ sponding aldehyde or ketone by the method described in March, Ibid, p 810.
  • Compounds where B is H can be prepared from the corresponding halo-heterocyclic entity, preferably where the halogen is I.
  • phenol, or a phenol substituted in the 3 (meta) position by an alkyl substituent (R 3 ) (Compound 20) is acylated with an acylat- ing agent, such as an acid chloride (Compound 10) derived from an appropriately substituted acrylic acid.
  • an acylat- ing agent such as an acid chloride (Compound 10) derived from an appropriately substituted acrylic acid.
  • the R 1 and R 2 substituents of the target compounds are introduced through this acrylic acid derivative 10.
  • the acylation with the acid chloride 10 is preferably conducted in the presence of a strong base (e.g. sodium hydride) in an inert solvent (such as tetrahydrofuran) .
  • a strong base e.g. sodium hydride
  • an inert solvent such as tetrahydrofuran
  • the substituted phenyl-acrylate 21 is ring closed under Friedel Crafts type reaction conditions (A1C1 3 catalyst, in an inert solvent, such as methylene chloride) to provide the 2-oxo-chroman compound (Compound 22) which bears, in the 4-position, the R ⁇ and R 2 substituents and in the 6-position the R 3 substituent (as applicable) .
  • the 2-oxo-chroman 22 of Reaction Scheme 2 is treated with a Grignard reagent to introduce the R 4 and R 5 substituents.
  • R 4 and R 5 both cannot be hydrogen.
  • the Grig ⁇ nard reagent is preferably methylmagnesium chloride (dissolved in tetrahydrofuran, THF) .
  • THF tetrahydrofuran
  • a solution of com ⁇ pound 22 in a suitable solvent, for example in dry diethy- lether is added to this Grignard reagent.
  • the resulting phenol containing a tertiary alcohol side chain, (that is a molecule in which the chroman ring had been opened) is shown in Reaction Scheme 2 as Compound 23.
  • Compound 23 which already has the desired R lf R , R 3 , R 4 and R 5 substituents, is ring closed under acidic condi ⁇ tions, (e.g. by heating in aqueous sulfuric acid) to provide the chromane derivative (Compound 24) .
  • acidic condi ⁇ tions e.g. by heating in aqueous sulfuric acid
  • chromane derivative Compound 24
  • Similar or analogous steps are involved for making both the thiochro- man (Reaction Scheme 1) and chroman derivatives (Reaction Scheme 2) , the only difference being that in Reaction Scheme 2 the starting phenol derivative does not have a halogen (such as a bromo) substituent.
  • reaction Scheme 2 For introducing the acetylene (ethyne) group into the 6-position of the chro ⁇ man moiety are different from the steps utilized for introducing the acetylene moiety into the analogous thio ⁇ chroman (Reaction Scheme 1) .
  • an acetyl group is intro ⁇ pokerd into the 6-position of the chroman derivative 24 under Friedel Crafts type conditions.
  • This acetylation is preferably conducted with acetyl chloride, in nitromethane solvent, in the presence of aluminum chloride.
  • the re ⁇ sulting 6-acetyl-chroman derivative is Compound 25.
  • the acetylenic (triple) bond is introduced into the molecule by converting the 6-acetyl moiety of chroman 25 to an acetylene moiety. This is accomplished, preferably, by treatment with lithium diisopropylamide (at low temper ⁇ ature, such as - 78 degrees C) which causes enolization of the acetyl group.
  • the intermediate enol compound (not shown in Reaction scheme 2) 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 (presum- ably by an elimination reaction) and to yield the 6-ethy- nyl-chroman derivative (Compound 26) .
  • the 6- ethynyl-chroman derivative 26 may be converted into the target compounds of the invention in synthetic steps which are analogous to the conversion of 6-ethynyl-thiochromans (Compound 16) into the corresponding target thiochroman derivatives (See Reaction Scheme 1) .
  • Compound 26 is preferably heated with a reagent X'-A-(CH ) n -B (Formula 3) in the presence of cuprous iodide, a suitable catalyst, typically of the formula Pd(PQ 3 ) 2 Cl (Q is phenyl or the like) and an acid acceptor, such as triethylamine.
  • the 6-ethynyl-chroman compounds 26 may first be converted to the corresponding metal (zinc) salt (Compound 27) and thereafter coupled with the reagent X'-A-(CH 2 ) n -B (Formula 3) under conditions which are similar to the conditions described in Reaction Scheme l for coupling of Compounds 18 with the same reagent.
  • substituted 6- bromothiochroman 14 where one of the R 4 or R 5 substituent is alkyl and the other is hydrogen can be made by treating the 2- oxo-6-bromo-thiochroman (Compound 12) with Grignard reagent as in Reaction Scheme 1.
  • the 2-oxo-thio chroman 12 is treated with excess Grignard reagent bearing the necessary alkyl substituent R 4 , such as methyl magnesium bromide when R 4 or R 5 is methyl.
  • the reaction is kept at a con ⁇ stant relatively low temperature (approximately 14 degrees C) for a relatively short time (approximately 0.5 hours) whereupon the hemiacetal derivative (Compound 55) is formed, as shown in Reaction Scheme 3.
  • the hemiacetal 55 is then subjected to acidic conditions, preferably by 5 heating it with aqueous sulfuric acid, to give the 6-bromo thio olefine derivative (Compound 56) .
  • the 6-bromo thio olefin is reduced, by hydrogenation in the presence of palladium sulfide catalyst, at moderate pressure (approxi ⁇ mately 30 psi) .
  • Ring closure of the tertiary alco ⁇ hol which bears the desired R ⁇ , R 2 , R 3 , R and R 5 substit ⁇ uents is affected, as before, by heating in acidic condi ⁇ tions, preferably by heating Compound 13 with aqueous sulfuric acid.
  • the resulting 6-bromothiochroman which contains the desired alkyl and hydrogen substituents at R ⁇ , R 2 , R 3 , R 4 and R 5 is shown as Compound 14.
  • the olefin 58 can then be reduced using the same conditions as described for the reduction of Compound 56 in Reaction Scheme 3, or by a more general reducing procedure avail ⁇ able in the art.
  • the resulting chroman derivative is shown as Compound 24 in Reaction Scheme 5. It should be noted that up to this point in the synthetic sequence (which is preferably but not necessarily exclusively used for making the compounds of the invention) similar or analogous steps are involved for making both the thio ⁇ chroman (Reaction Scheme 3) and the chroman derivatives (Reaction Scheme 5) the major difference being that in Reaction Scheme 5 the starting lactone does not have a halogen (such as a bromo substituent) .
  • a halogen such as a bromo substituent
  • esters including ethyl-6-chloronicotinate, Compound 29
  • reagents X 1 -A-(CH 2 ) n -B for coupling with the correspoding ethynyl compounds (such as Compounds 16 and 26, or their zinc salts 17 and 27) to provide the target compounds of the invention.
  • the mixture was heated at 100 degrees C for 24 h, allowed to cool to room tempera ⁇ ture and then treated with a further 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride.
  • the mixture was then degassed, placed under argon and then heated in the sealed tube at 100 degrees C for 96 h.
  • the mixture was cooled to room temperature and extracted with 3 x 10 ml of ether.
  • the reaction mixture was allowed to warm to room tempera ⁇ ture and transferred by double-ended needle into a solu ⁇ tion of lithium diisopropylamide in THF at -78 degrees C [prepared as described above from 1.04 g (10.34 mmol) of diisopropylamine and 6.46 ml of 1.6 M (10.34 mmol) n-butyl lithium in hexane] .
  • the cooling bath was removed and the mixture was stirred at room temperature for 16 h.
  • the mixture was then treated with 10 ml of ice water and acidified to a pH of 2 with 10% HCl.
  • the organic layer was separated and the aqueous layer was extracted with 3x30 ml of pentane.
  • the mixture was allowed to warm to room tem ⁇ perature and then transferred by a double-ended needle into a solution of lithium diisopropyl amide in 10 ml dry THF at -78 degrees C which was prepared as described above using 910 mg (9.0 mmol) of diisopropylamine and 6 ml of 1.5 M (9.0 mmol) n-BuLi in hexane.
  • the mixture was stirred at room temperature fur 15 h and then poured into 10 ml of iced water.
  • the organic layer was separated and the aqueous layer extracted with pentane.
  • the pressure tube was then sealed and the reaction mixture heated at 60 degrees C for 72 h.
  • the mixture was cooled to room tem ⁇ perature and the triethylamine removed under vacuum.
  • the residue was purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid.
  • a 250 ml 3-necked flask is fitted with a stirrer, a dropping funnel, a nitrogen inlet and a thermometer.
  • a solution of 379.5 mg (10 mmol) of lithium aluminum hydride in 30 ml of dry diethyl ether is placed in the flask.
  • the solution is cooled to -65 degrees C under nitrogen and a solution of 3.632 g (10 mmol) of ethyl 6-[(2,2,4,4- tetramethylchroman-6-yl)ethynyl]-nicotinate (Compound 43) in 15 ml of dry ether is added dropwise at a rate such that the temperature does not exceed -60 degrees C.
  • any of the other aldehydes of this invention can be converted to the corresponding secondary alcohols.
  • Such secondary alcohols may be converted to their corresponding ketones using the procedure described for the preparation of Compound 52 or other oxidation proce ⁇ dures.
  • 2-r 2 .2.4.4-tetramethylchroman-6-yl)ethynyl]-5- dimethoxymethylpyridine (Compound 54)
  • a round-bottomed flask is fitted with a Dean-Stark apparatus under a reflux condenser protected by a drying tube.
  • a mixture of 3.58 g (12 mmol) of 2-[2,2,4,4-tetra- methyl-chroman-6-yl)-ethynyl]-pyridine-5-carboxaldehyde (Compound 52) 4.80 mg (15 mmol) of anhydrous methanol, 2 mg of p-toluenesulfonic acid monohydrate and 10 ml of anhydrous benzene is placed in the flask and the mixture heated at reflux under nitrogen until close to the theo ⁇ retical amount of water is collected in the Dean-Stark trap.
  • reaction mixture is cooled to room temperature and extracted successively with 5 ml of 10% sodium hydrox- ide solution and two 5 ml portions of water and then dried (MgS0 4 ) .
  • the solution is then filtered and the solvent removed in vacuo.
  • the residue is purified by chromatogra ⁇ phy and then recrystallization to give the title compound.
  • any aldehyde or ketone of this invention may be converted to an acetal or a ketal.
  • the reaction mixture was placed under argon and the tube was sealed. The mixture was heated at 55 degrees C for 72 hours. The mixture was cooled to room temperature and filtered through celite and the residue was washed with CH 2 C1 2 . The filtrate was concentrated in- vacuo and the residue was purified by flash chromatography (silica; hexanes) to give the title compound as a yellow oil.
  • Ethvl 6rf2.4.4-Trimethvl- 6-thiochromanvll-ethvnvn Nicot ⁇ inate (Compound 62) A solution of 55 mg (0.26 mmol) of 2,4,4-trimethyl-6- ethynyl-thiochroman (Compound 61) and 47 mg (0.26 mmol) of ethyl-6-chloro-nicotinate (Compound 29) in 2 ml of dis ⁇ tilled triethylamine was placed in a heavy walled tube. Argon was bubbled through the mixture for 20 minutes under slightly reduced pressure.
  • the compounds of the invention may be administered topically using various formulations.
  • Such formulations may be as follows:

Abstract

Une activité de type rétinoïde est présentée par des composés de formule (I) dans laquelle X représente S, O ou NR'; R' représente hydrogène ou un alkyle inférieur; R1, R2 et R3 représentent hydrogène ou un alkyle inférieur; R4 et R5 représentent hydrogène ou un alkyle inférieur, à condition que R4 et R5 ne puissent pas représenter tous deux hydrogène, A représente pyridyl, thiényl, furyl, pyridazinyl, pirimidinyl, pyrazinyl, thiazolyl ou oxazolyl; n est 0 - 5, et B représente H, -COOH ou un sel, un ester ou une amine pharmaceutiquement acceptable de ces substances, -CH2OH ou un dérivé d'éther ou d'ester, ou -CHO ou un dérivé d'acétal, ou -COR1 ou un dérivé de cétal où R1 représente -CH2)mCH3, où m est 0 - 4, ou un sel pharmaceutiquement acceptable de ces substances.
EP19910917319 1990-10-09 1991-09-24 Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity Withdrawn EP0555235A4 (en)

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US59512890A 1990-10-09 1990-10-09
US595128 1990-10-09

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EP (1) EP0555235A4 (fr)
JP (1) JPH06501684A (fr)
AU (1) AU657100B2 (fr)
CA (1) CA2091763A1 (fr)
FI (1) FI931624A (fr)
HU (1) HUT63412A (fr)
IE (1) IE913568A1 (fr)
IL (1) IL99618A0 (fr)
NZ (1) NZ240059A (fr)
PL (1) PL168075B1 (fr)
PT (1) PT99189A (fr)
WO (1) WO1992006092A1 (fr)
ZA (1) ZA918025B (fr)

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US8618132B2 (en) 2002-10-31 2013-12-31 Boehringer Ingelheim Pharma Gmbh & Co. Kg Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds

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US5602130A (en) * 1987-03-20 1997-02-11 Allergan Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity
CN107176945B (zh) 2016-03-11 2021-06-08 中国科学院上海有机化学研究所 一种视黄酸类化合物、其制备方法、中间体及应用

Citations (3)

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EP0284288A1 (fr) * 1987-03-20 1988-09-28 Allergan, Inc Acétylènes disubstitués ayant des groupes hétéro-aromatiques et hétérocycliques à activité du type rétinoide
EP0419132A2 (fr) * 1989-09-19 1991-03-27 Allergan, Inc. Procédé et intermédiaires pour préparer des composés ayant une partie acétylénique disubstituée et une activité biologique analogue à l'acide rétinoique
EP0419130A2 (fr) * 1989-09-19 1991-03-27 Allergan, Inc. Acétylènes disubstitués avec un groupe hétéroaromatique et un groupe chromanyle, thiochromanyle ou 1,2,3,4-tétrahydroquinolinyle substitué en position 2 ayant une activité analogue de rétinoide

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US3816466A (en) * 1971-12-22 1974-06-11 Warner Lambert Co Flavanoid ring systems
US3868379A (en) * 1972-04-28 1975-02-25 Warner Lambert Co Heterocyclic amides of 4-hydroxy-2H-1-benzothiopyran-3-carboxylic acid 1,1-dioxide

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EP0284288A1 (fr) * 1987-03-20 1988-09-28 Allergan, Inc Acétylènes disubstitués ayant des groupes hétéro-aromatiques et hétérocycliques à activité du type rétinoide
EP0419132A2 (fr) * 1989-09-19 1991-03-27 Allergan, Inc. Procédé et intermédiaires pour préparer des composés ayant une partie acétylénique disubstituée et une activité biologique analogue à l'acide rétinoique
EP0419130A2 (fr) * 1989-09-19 1991-03-27 Allergan, Inc. Acétylènes disubstitués avec un groupe hétéroaromatique et un groupe chromanyle, thiochromanyle ou 1,2,3,4-tétrahydroquinolinyle substitué en position 2 ayant une activité analogue de rétinoide

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8618132B2 (en) 2002-10-31 2013-12-31 Boehringer Ingelheim Pharma Gmbh & Co. Kg Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds

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CA2091763A1 (fr) 1992-04-10
EP0555235A4 (en) 1993-11-10
PT99189A (pt) 1992-09-30
IE913568A1 (en) 1992-04-22
FI931624A0 (fi) 1993-04-08
JPH06501684A (ja) 1994-02-24
HUT63412A (en) 1993-08-30
WO1992006092A1 (fr) 1992-04-16
AU8614991A (en) 1992-04-28
PL168075B1 (pl) 1995-12-30
AU657100B2 (en) 1995-03-02
HU9301031D0 (en) 1993-07-28
ZA918025B (en) 1992-06-24
NZ240059A (en) 1993-10-26
IL99618A0 (en) 1992-08-18
FI931624A (fi) 1993-04-08

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