IE48754B1 - Derivatives of 4,5-dihydro-4-oxofuran-2-carboxylic acid,especially for use as hypolipidemic agents,processes for their preparation and pharmaceutical compositions comprising them - Google Patents

Description

This invention relates to novel derivatives of 4,5dihydro-4-oxofuran-2-carboxylic acid, to therapeutically acceptable salts thereof, to processes for their preparation, to methods for using the derivatives and to pharmaceutical compositions containing the derivatives.

Mere specifically, the present invention relates to novel derivatives of 4,5-dihydro-4-oxofuran-2-carboxylic acid having tuo substituents at position 5 and in addition being optionally further substituted at position 3 with a louer alkyl group as uell as esters thereof. These derivatives are useful as hypolipidemic agents in a mammal at dosages uhich do not elicit undesirable side effects. 4,5-Dihydro-4-oxofuran derivatives are extensively described in the literature. Additionally, derivatives of 4,5-dihydro-4-oxofuran-carboxylic acids have also bean disclosed. For, example, 4,5-dihydro-2-methyl-4-oxofuran3-carboxylib acid and its ethyl ester are described by R.E.Rosenkranz et al., Halv, Chim. Acta., 46, 1259(1963) and references cited therein. In addition, this reference discloses the structure of 4,5-dihydro-5-methyl-4-oxofuran -2-carboxylic acid as a hypothetical intermediate during the decarboxylation of 4-methoxy-5-methylfuren-2-carboxylic acid. The presence of 4,5-dihydrD-5-mBthyl-4-oxofuran-2carboxylic acid uas not confirmed by isolation or other means.

Recently a feu furan derivatives uere reported to be hypolipidemic agents. More specifically, some derivatives of 2,3,4,5-tstrahydro-3-oxo-4-hydroxy-iminofurans, 2,5dihydrofurans and 2,3,4,5-tetrahydrofurans are described to have ueak to moderate hypolipidemic activity by G.B. Bennett et al., 3. Fted. Chem., 19. 709 (1976). Houever, the latter report also states that the furan derivatives, disclosed therein, are devoid of a desirable level of hypolipidemic activity. - 3 The 4,5-dihydro-4-oxofuran-2-carboxylic acid derivatives of this invention are novel compounds having hypolipidemic activity uithout affecting liver weight.

Accordingly this invention provides compounds of (I) cycloalkyl, mono- or halo, nitro louer alkoxy(louer)alkylena, phenyl or phenyl disubstituted with lower alkyl, lower alkoxy, 2 or trifluoromethyl; or R and R together form a -(CH„) -X-(CH„) - chain wherein m and π each is an 2 m 2 n integer from one to four end X is methylene, oxa or thia; 2 or R and R together with the carbon atom to which they are joined form a spiro[l,2,3,4-tetrahydronaphthalene]-1 or spiro[indan]-1 radical; R5 is hydrogen or louer alkyl; and R4 is hydrogen, lower alkyl, lower eyeloalkyi, phenyl(lower)alkylens, amino(louer)alkylene, lower alkylamino(lower)alkylena, di(lowar alkyl)amino(louer)alkylene or 3-pyridinyl(louer)alkylane, or a therapeutically acceptable addition salt thereof.

A preferred group of compounds of formula I are those in which R is louer alkyl, phenyl or phenyl monosubsti2 12 tuted uith halo; R is lower alkyl; or R and R together uith the carbon atom to which they are joined form a spiro[l,2,3,4-tetrahydronaphthalene]-1 radical; 4 R is hydrogen; and R is hydrogen, louer alkyl or 3pyridinyl(louar)alkylanB, or a therapeutically acceptable addition salt thereof.

A most preferred group of compounds of formula I are those in which R is lower alkyl, phenyl or 4-chlorophenyl; 7 12 R is lower alkyl; or R and R together uith the carbon atom to which they are joined form a spiro[1,2,3,4-tetrahydronaphthalenej-1 radical; R5 is hydrogen; and R4 is - 4 hydrogen, lower alkyl or 3-pyridinyl methyl, or a therapeutically acceptable addition salt thereof. 3 The compounds of formula I in which R , R and R are as defined herein and R4 is hydrogen can be prepared by a process, which comprises: cyclizing a compound of formula X f2 R1-C-C0-CH(R3)-C0-C00H (X) I OH 3 in which R , R and R are as defined herein under acidic conditions.

Compounds of formula I uherein R is lower alkyl, lower cycloalkyl, phenyl(louer)alkylene, amino(louer)alkylene, lower alkylamino(louer)alkylene, di(lower alkyl) amino(louer)alkylene or 3-pyridinyl(louer)alkylBne can be prepared by esterifying a compound of formula I wherein R4 is hydrogen. More specifically, the compounds of 12 3 4 formula I in which R , R , R and R are as defined herein can be prepared by a process, which comprises: reacting a compound of formula II R21 3 R -C-CO-CH,RJ (II) I 2 OH 3 in which R , R and R are as defined herein with a di(louer alkyl)oxalate in the presence of a strong inorganic proton acceptor under anhydrous conditions, hydrolyzing the mixture uith water at pH 10 to 12, to give a compound of formula X and allowing the latter jc mixture to stand under acidic conditions to obtain the 12 corresponding compound of formula I in which R , R and 4 R are as defined herein and R is hydrogen; and if desired esterifying the latter compound of formula I - 5 to obtain the corresponding compound of formula I in 3 4 which R , R and R are as defined herein and R is lower alkyl, lower cycloalkyl, phenyl(lower)alkylene, amino(lower)alkylene, lower alkylamino(lower)alkylene, di(lower alkyl)amino(lower)alkylene, or 3-pyridinyl(lower) -alkylene. • 4 The compound of formula I wherein R is hydrogen may also be prepared by hydrolysing a compound of formula 3 wherein R , R and R are as defined above, under aqueous alkaline conditions at pH 10 to 12, e.g. using KOH or NaOH, and the acidifying to pH 0.5 to 3.

Certain novel compounds of formula XI and processes for preparing them are claimed in our copending Patent Application Νο.4-875ί The compounds of formula I, or a therapeutically acceptable addition salt thereof, lower lipid levels in a mammal when administered to said mammal in an effective hypolipidemic amount.

A convenient form for administering the compounds involves a pharmaceutical composition comprising a compound of formula I or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The term lower alkyl as used herein means straight chain alkyl radicals containing from one to six carbon atoms and branched chain alkyl radicals containing three or four carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and n-hexyl.

The term lower alkoxy as used herein means straight chain alkoxy radicals containing from one to six carbon atoms and branched chain alkoxy radicals containing three or four carbon atoms and includes methoxy, ethoxy. - 6 isopropoxy, n-butoxy and n-hexyloxy.

The term lower alkylene as used herein means a divalent organic radical derived from either straight or branched chain aliphatic hydrocarbons containing from one to six carbon atoms by removal of two hydrogen atoms and includes methylene, ethylene, 1-methylpropylene, 2-methylpropylene, 2-ethyIpropylene and 2-butylethylene.

The term lower cycloalkyl as used herein means saturated cyclic hydrocarbon radicals containing from three to six carbon atoms, i.e., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term lower alkanol as used herein means both straight and branched chain alkanols containing from one to four carbon atoms and includes methanol, ethanol, isopropanol and butanol.

The term strong inorganic proton acceptor as used herein means the inorganic bases or corresponding alkoxides, preferably the alkali metals, the alkali metal hydrides, amides, hydroxides and alkoxides, for example, sodium, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide and sodium hydride.

The term organic proton acceptor as used herein means the organic bases, or amines for instance, triethyiamine, pyridine, N-ethylmorpholine and l,5-dia2a25 bicyclo[4.3.0]non-5-ene.

The term therapeutically acceptable addition salt as used herein includes the therapeutically acceptable acid addition salts of the compound of formula I in which R is amino(lower)alkylene, lower alkylamino(lower)30 alkylene, di(lower alkyllamino(lower)alkylene or 3pyridinyKlower)alkylene. The acid addition salts are prepared by reacting the base form of the appropriate - 7 compound of formula I uith one or more equivalents, preferably uith an excess, of the appropriate aoid in an organic solvent, for example, diethyl ether or an ethanoldiethyl ether mixture. These salts, uhen administered to a mammal, possess the same pharmacologic activities as the corresponding bases. For many purposes it is preferable to administer the salts rather than the base compounds. Suitable acids to form these salts include the common mineral acids, for instance hydrohalio, sulfuric or phosphoric acid; as uell as the organic acids, for instance, formic, acetic, maleic, malic, ascorbic, succinic, fumaric, citric, or tartaric acid; or acids uhich are sparingly soluble in body fluids and uhich impart slourelease properties to their respective salts such as pamoic or tannic acid or carboxymethyl cellulose.

The addition salts thus obtained ere the functional equivalent of the parent base compound in respect of their therapeutic use. Hence, these addition salts are included uithin the scope of this invention and are limited only by the requirement that the acids employed in forming the salts be therapeutically acceptable.

Furthermore, the term therapeutically acceptable addition salt as used herein also includes the therapeutically inorganic or organic basB addition salts of the conpounds of formula I in uhich R^ is hydrogen, i.e. compounds of formula I uhich are acids. These derived salts possess the same activity as the parent acid and are included uithin the scope of this invention. The acid is transformed in excellent yield into the corresponding therapeutically acceptable salt by neutralisation of said acid uith the appropriate inorganic or organic base. The salts are administered in the same manner as the parent acid compounds. Suitable inorganic bases to form these salts include, for example, the hydroxides, carbonates, bicarbcnates or alkoxides of the alkali metals or alkaline earth metals, for example, sodium, potassium, magnesium and calcium. Suitable organic bases 48734 - 8 include the following amines; louer mono-, di- and trialkylaminBs, the alkyl radicals of uhich contain up to three carbon atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, di- and triethylamine and N-inethyl5 M-ethylamine; mono-, di and trialkanolamines, the alkanol radicals of uhich contain up to three carbon atoms, for example, mono-, di- and triethanolamine; alkylens-diaminBs uhich contain up to six carbon atoms, such as hexamethylsnediamine; phenylalkylamines, for example, benzylamine, phenylethylamine and N-methylphenylethylamins; cyclic saturated or unsaturated bases containing up to six carbon atoms, such as pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl and N-hydroxyalkyl derivatives, such as N-methyl-morphdline and N-(2-hydroxyethyl)-piperidine, as uell as pyridine. Furthermore, there may be mentioned the corresponding quaternary salts, such as the tetraalkyl (for example tetramethyl), alkyl-alkanol (for example methyltrimethanol and trimethyl-monoBthanol) and cyclic ammonium salts, for example the N-methylpyridinium, N-methyl-N(2-hydroxyethyl)-morpholiniumJ N,N-dimsthylmorpbolinium, N-methyl-N-(2-hydroxyethyl)-morpholinium, N,N-dimethylpiperidinium salts, uhich are characterized by having good uater-solubility. In principle, houever, there can be used all the ammonium salts uhich are physiologically compatible.

The transformations to the salts oan be carried out by a variety of methods knoun in the art. For example, in the case of the inorganic salts, it is preferred to dissolve the acid of formula I in water containing at least one equivalent amount of hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. Advantageously, ths reaction is performed in a uatermiscible, inert organic solvent, for example, methanol, ethanol or dioxane in the presence of water. - 9 For example, such use of sodium hydroxide, sodium carbonate or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the solution or addition of a uater miscible solvent of a more moderate polarity, for example, a louer alkanol, for instance, butanol, or a louer alkanone, for instance, ethyl methyl ketone, gives the solid inorganic salt if that form is desired.

To produce an amine salt, the acidic compound of formula I is dissolved in a suitable solvent of either moderate or louer polarity, for example, ethanol, methanol, ethyl acetate, diethyl ether end benzene. At least an equivalent amount of the amine corresponding to the desired cation ie then added to that solution. If thB resulting salt does not precipitate, it can usually be obtained in solid form by addition of a miscible diluent of lou polarity, for example, benzene or petroleum ether, or by evaporation. If the amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use substantially equivalent amounts of the less volatile amines.

Salts uherein the cation is quaternary ammonium are produced by mixing the acid of formula I uith an equivalent amount of the corresponding quaternary ammonium hydroxide in uater solution, followed by evaporation of the uater.

Also included in this invention are the stereochemical isomers of the compounds of formula I uhich result from asymmetric centres, contained therein.

It is to be understood that all isomers and mixtures thereof arising from such asymmetry are included within the scope of this invention. Uhen tuo asymmetric centres are present diastereomers are obtainable in substantially pure form by classical separation techniques and by statically controlled synthesis.

Individual enantiomers are included. ThBse can be separated by fractional crystallization of the diastereomeric salts thereof. - 10 The compounds of formula I, or a therapeutically acceptable salt thereof, are useful hypolipidemic agents in a mammal upon oral or parenteral administration.

Their hypolipidemic properties are readily demonstrated by the following method: male albino rats (eight rats per group), weighing 140- 170g are given a single daily oral dose of the test compound by gauage as a suspension in 2% Tween-80 in water (1.0 ml). (TUEEN is a ., Trade Mark). In the same manner, controls are given only 2% Tween-80 in water (l.O ml) daily. After one week of treatment, animals are decapitated and the blood is collected. The serum is separated by centrifugation and serum cholesterol levels are measured by the method of A. Zlatkis et al., 0.Lab.Clin. Med., 41, 486 (1953), as modified for the autoanalyser (Method Np-24). Serum phospholipids are determined by the semi-automated technique of M.Kraml, Clin. Chim. Acta., 13. 442 (1966) and sarum triglycerides are measured by the semiautomated method of M.Kraml and L.Cosyns, Clin. Biochem., 2, 373 (1959). The activity of a test compound is assessed by comparing serumcnolesterol, phospholipid and/or triglyceride levels in rats treated uith the test compound and control rats and the data are analysed for significance by the Student's t-test. The following results demonstrat25 ing hypotriglyceridemic activity are calculated by subtracting the serum triglyceride level in treated rats from the control serum triglyceride level, and expressing the difference as a percentage of the control .level. The « [ following compounds of formula I at a dose of 1.0 mmole per kilogram of body weight per day louer triglyceride levels by the indicated percentage: 4,5-dihydro-5-methyl4-oxo-5-phenylfuran-2-carboxylic acid (42%, described in Example 4), 4,5-dihydro-5(l-methylethyl)-4-oxo-5-phenylfuran-5-carboxylic acid (53%, described in Example 4), 4,5-dihydro-5,5-dimethyl-4-oxofuran-2-carboxylic acid (37%, described in Example 4), sprio[furan-5(4H),1'(2'H)naphthalena]-3',4'-dihydro-4-oxo-2-carboxylic acid (43%, 487S4 - 11 described in Example 4>, 4,5-dihydro-5-methyl-4-oxo-5phenylfuran-2-carboxylic acid methyl ester (53%, described in Example 5) and 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran -2-carboxylic acid 3-pyridinylmethyl aster (61%, described in Example 6).

The compounds of formula I, or a therapeutically acceptable salt thereof, can be used also in combination uith knoun hypolipidemic agents, for example, clofibrate? for reduction of elevated lipids in a mammal. Uhen used in this combination, the oaqpawta of formula I can be administered sequentially or simultaneously in combination uith an affective amount of the knoun hypolipidemic agent. Suitable methods o’ administration, compositions and dosages of clofibrate (flTROMID-S) is described by Charles E. Baker, Or. Physician's Desk Reference,Medical Economics Company, Oradell, N.3. 1977, pp 593-594, for example, 0.5 to 2.0 g per patient per day in divided dosages. The compounds of formula I, or a therapeutically acceptable salt thereof, in combination uith a knoun hypolipidemic agent, are used in the same manner as described herein for their use as hypolipidemic agents.

Uhen the compounds of formula I of this invention are used as hypolipidemic agents in a mammal, e.g. rats and dogs, they are used alone or in combination uith pharma25 cologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice. For example, they are administered orally in solid form, e.g. capsule or tablet. They are also administered orally in the form of suspension or solutions, or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, far example, enough saline or glucose to make the solution isotonic.

The tablet compositions for oral administrations contain the active ingredient in admixture uith non-toxic *cte?ibrt»k is rtIgL pharmaceutical excipients known to be suitable in the manufacture of tablets. Suitable pharmaceutical excipients are, for example, starch, milk sugar and certain types of clay. The tablets can be uncoated or they can be coated oy knoun techniques so as to delay disintegration and absorption in the gastroinestinal tract and thereby provide a sustained action.

The aqueous suspensions for oral use of the compounds of the invention contain the active ingredient in admixture uith one or more non-toxic pharmaceutical excipients, for instance, emulsifyirlg and suspending agents, knoun to.be suitable in the manufacture of aqueous suspensions.

Suitable excipients are, for example, methyl-cellulose, sodium alginate, gum acacia and lecithin. The aqueous suspensions can also contain one or more preservatives, one or more colouring agents and/or one or more sueetening agents.

Non-aqueous suspensions for oral use can be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil, or coconut oil; or in mineral oil. The suspension can contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. These compositions can also contain a sueetening agent, flavouring agent and antioxidant.

For parenteral administration, uhich includes intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention can be used in the form of a sterile solution, uherein the pH should be suitably adjusted and buffered. The solution can contain other pharmaceutical excipients, for example, enough saline or glucose to make the solution isotonic.

The dosage of a compound of formula I of this invention as a hypolipidemic agent will vary with the form of administration and the particular host as well as the age and condition of the host under treatment. Generally, treatment is initiated uith small dosages substantially less than the optimal dose of the compound. Thereafter, 48784 - 13 the dosage is increased by small increments until the optimal effect under the circumstances is reached. In general, a compound of this invention is most desirably administered at a ccncentraticn that will generally afford effective results without causing any harmful or deleterious side effects. The effective hypolipidemic amount of the compound usually ranges from 1.0 mg to 500 mg per kilogram of body weight per day, although as aforementioned variations will occur. However, a dosagB level that is in the range of from 5 mg to 300 mg per kilogram of body weight, -per· day is employed most desirably in order to achieve effective results. for the preparation of the 4,5-dihydro-4-oxofuran-2~ carboxylic acid derivatives of formula I the preferred starting materials sr= tne α-hydroxyketones of formula II R1 2 R1.i;-CO-CH2R3 (II) in in which R and R each is lower alkyl, lower cycloalkyl lower alkoxy(louer)alkylene, phenyl or phenyl mono- or disubstituted uith lower alkyl, lower alkyl, lower alkoxy, 2 halo, nitro or trifluoromethyl; or R and R together form a chain uharein m and n each is an integer from one to four and X is methylene, oxa or thia; 2 or R and R together uith the carbon atom to which they are joined form a spiro[l,2,3,4-tetrahydronaphthalenej-1 or spiro[indanj-1 radical; and R3 is hydrogen or lower alkyl.

The starting materials of formula II in which R and 3 R are as defined herein and R is hydrogen are either knoun’or they can be prepared as is illustrated in reaction scheme 1. - 14 R1-CO-R2 HC=CH Reaction Scheme 1 R2 Na or Li $ R '-C-CSCH HgO I OH H2sD4J R1-C-CO-CH, i OH (III) (IV) (II) in which R-5 is hydrogen With reference to reaction scheme 1, a number of acetylenic carbinols of formula IV arB known and commercially available. Alternatively, acetylenic carbinols are readily available from addition of a metallic 1 2 acetylide to the ketone of formula III in uhich R and R are as defined herein using the method described by A. U.Johnson, Acetylenic Compounds, Vol. 1, The Acetylenic Alcohols, E. Arnold C·:·., London, 1946; R.A.Raphael, Acetylenic Compounds in Organic Synthesis, London, Butteruorth’s Sci. Publ., 1955; P.A.Robins and J.Ualker, J. Cham. Soc., 177 (1957); and E.D,Bergmann at al..

J.Appl. Chem. 5, 39(1953). In the preferred method a mixture of the compound of formula III and lithium or sodium in a solution of anhydrous liquid ammonia saturated uith gaseous acetylene is allowed to react for nine hours and the corresponding compound of formula IV is isolated.

The acetylenic carbinols of formula IV are converted 2o to the corresponding α-hydroxyketones of formula II, by hydration of the acetylenic carbinol in a mixture of mercuric oxida (rad form) or mercuric sulfate, aqueous tetrahydrofuran and sulfuric acid at 60-65°C for one to six hours, according to the procedure described by A.U.

Johnson, cited above pp 102-105; E.D.Bergmann and D.F. Herman, J. Appl. Chem., 2» 42(1953)) G.F.Hennian and B. R.Fleck, J. Amar. Cham. Soc., 77, 3253 (1955); and G.F.Hennian and E.J.Uatson, J. Org. Cham., 23.656(1958). 75 4 - 15 The starting materials of formula II in uhich R1 and 3 R are as defined herein and R is louer alkyl are either knoun or they can be prepared as is illustrated in reaction scheme 2.

Reaction Scheme 2 R2 R2 R1-CH2C0-CH2-R3-} R1-CH-CO-CH2-R3-^-R1-i-CO-CH2-R3 :r (V) (VI) 1 (VII) 9 W Rz I _ -COBr + R1-C0-R2 _. R -C-C0-CHo-R3 in 2 (VIII) (III) (II) in uhich R is louer alkyl Uith reference to reaction scheme 2, an organometallic derivative of the compound of formula VIII is condensed uith the ketone of formula III to obtain the corresponding α-hydroxyketone of formula II in uhich R is louer alkyl according to the conditions described by I.I.Lapkin and T.N.Povarnitsyna, Zh. Obshch. Khim., 38.99(1968). cf.

Chem. Abstr., 69, 19233z.

The alternative route starting from the compound of formula V is especially suitable for preparing the cc-keto 1 2 alcohols of formula II in uhich R or R ia phenyl or phenyl mono- or disubstituted uith louer elkyl, lower alkoxy, halo, nitro or trifluoromethyl. Alkylation of the compound of formula V, using the method of K.Binovic and S. Vrancea, Chem. Ther., 313(1968), gives the corresponding compound of formula VI. The latter compound is brominated, according to the conditions described by 3.R.Catch et al.. 3. Chem. Soc. 272(1948), to obtain the corresponding bromo-ketone of formula VII. Conversion of the latter bromoketone to the corresponding α-hydroxyketone of formula II is described by 3.G.Aston and R.B.Greenberg, - 16 J.Amer. Chem. Soc., 62, 2590(1940); J. Kapron and 0. Uiemann, Bull. Soc. Chim. France, 12, 945(1945); and Y.L. Pascal, Ann. Chim. (Paris), 245(1968).

In addition to the above described preparations, a-hydroxyketones of formula II can be prepared by methods described by Y.L.Pascal, cited above and P. Kaufmann, 3. Amer. Chem. Soc., 26, 5794(1954).

Reaction scheme 3 illustrates the conversion of the α-hydroxyketone of formula II to the corresponding 12 3 compound of formula I in uhich R , R and R are as defined herein.

Reaction Scheme 3 R1-p-C0-CH2R3 -> OH I..

CH(R3)-C0-C00Alk . . 4 (I) in uhich R is hydrogen (IX) ?2 R1-C-CO-CH(R3)-CO-COOH 4h (X) As illustrated by reaction scheme 3, the compound of formula I in uhich R^ is hydrogen is prepared from the compound of formula II via the route II-> IX->X-^I.

Although the intermediates of formula IX and X oan be isolated and further reacted in separate steps, the compound of formula II can be converted to the corresponding compound of formula I via intermediates IX and X in a single reaction vessel without isolating the latter intermediates. - 17 The first step in the conversion of the «-hydroxyketone of formula II is the condensation of substantially equimolar amounts of the α-hydroxyketone and a di(lower alkyl)oxalate, preferably dimethyl or diethyl oxalate, in the presence of one to four molar equivalents of a strong inorganic proton acceptor, preferably sodium hydride, in an anhydrous inert organic solvent. Preferred inert organic solvents can be selected from the di(lower alkyl)ethers or cyclic ethers, for example, diethyl ether, dioxane and tetrahydrofuran. The reaction mixture is maintained at 30 to 70°C, preferably 50 to 60°C, for 10 to 30 hours. The resultant enolate salt ia filtered as rapidly as possible, dissolved in water, acidified uith e diluted inorganic acid, and the corresponding compound of formula IX is extracted uith an inert water immiscible organic solvent, preferably diethyl ether.

Hydrolysis of the latter compound is readily achieved under alkaline conditions, for example uith a solution of one to three molar equivalents of potassium or sodium hydroxide in an aqueous solution of a uater miscible organic solvent, preferably methanol, ethanol, tetrahydrofuran or dioxane, at 15 to 30°C for 15 to 40 hours. The aqueous solution is washed uith a uater immiscible organic solvent, preferably diethyl ether, benzene, chloroform or, dichlororeethane. The pH of the aqueous solution is adjusted to 3 to 5 uith e strong acid, e.g. hydrochloric or sulfuric acid. Thereafter, the corresponding compound of formula X is obtained by extraction of the aqueous solution uith a uater immiscible organic solvent, for example one of the previously noted organic solvents.

The latter compound can be cyclizad under acidic conditions to obtain the corresponding compound of formula 12 3 4 I in uhich R , R and R are as defined herein and R is hydrogen. In one method of achieving this cyclization, a solution of the compound of formula X and 0.1 to 10 molar equivalents, preferably 0.1 to 0.4 molar equivalents, of - 18 an acid catalyst, for example, hydrogen chloride, hydrogen bromide, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably ρ-toluenesulfonic acid or hydrogen chloride, in an inert organic solvent, preferably benzene or toluene, is maintained at 20 to 100°C for two to 50 hours. In another method, the compound of formula X is cyclizsd in an aqueous solution containing the acid catalyst at 10 to 50°C for 10 to 5D hours. Preferred acid catalysts for use in the aqueous solutions can be selected from hydrochloric acid, sulfuric acid, hydrobromic acid and phosphoric acid. The aqueous solution usually requires sufficient acid catalyst so that the solution is maintained at pH 0.5 to 3.0 preferably 1.0 to 2.0.

In a modification of the conversion of the compound of formula II to the corresponding compound of formula I, the above individual steps of condensation, alkaline hydrolysis dnd cyclization are combined in a process wherein the intermediates of formula IX and X ars not isolated.

In this modification, the α-hydroxyketone of formula II is condensed uith a di(lower alkyl) oxalate in thB same manner as described above. However, the reaction mixture is not filtered but instead is mixed uith about an equal volume of water. The resulting aqueous alkaline solution is, if required, adjusted to pH 10 to 12 uith, for example, sodium hydroxide and maintained at pH TO to 12 and at 15 to 30°C for 10 to 40 hours and washed uith a water immiscible organic solvent, preferably diethyl ether or benzene. An acid catalyst, preferably hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, is added to the aqueous solution until the solution reaches pH 0.5 to 3.0, preferably 1.0 to 2.0. The acidic solution is maintained at 10 to 50°C, preferably 20 to 30°, for 0.5 to 10 hours and extracted uith a water immiscible organic solvent,35 for example, ethyl acetate, diethyl ether, benzene, toluene, chloroform, or dichloromethane. The organic extract is evaporated and, if required, purified to obtain - 19 the corresponding compound of formula I in uhich R4 is hydrogen.

If the aqueous alkaline solution in the latter preparation is maintained at pH 8 to 9 instead of pH 10 to 12, a corresponding intermediate of formula XI R 3 in uhich R , R and R are as defined herein can be isolated after acidification of the aqueous alkaline solution. Flore specifically, the α-hydroxyketone of formula II is condensed uith a diflouer alkyl)oxalate in the same manner as described above. The reaction mixture is not filtered but instead is mixed uith about an equal volume of uater and if necessary the resulting aqueous solution is adjusted to pH 8 to 9, for example, uith dilute hydrochloric acid or sodium hydroxide. The resulting aqueous solution is preferably maintained at pH 8 to 9 and at 15 to 30°C for one to five hours and uashed uith a uater immiscible organic solvent, in the same manner as described above. The mixture is acidified, maintained at 10 to 50°C, preferably 20 to 30°C, for one to 30 minutes and extracted, in the same manner as described above for II-tH, to obtain the corresponding intermediate of formula XI.

Reaction of the intermediate of formula XI under aqueous alkaline conditions at pH 10 to 12 gives the corresponding compound of formula I in uhich R4 is hydrogen. For this reaction, a solution of the compound of formula II in aqueous potassium or sodium hydroxide is maintained at pH 10 to 12 and at 15 to 30°C for 10 to 40 hours and uashed uith a uater immiscible organic solvent, in the same manner as described above. Subsequently, acidification, of the aqueous solution, maintenance of the acidic solution and extraction, in the same manner as described above for II—>1, 487 5 4 gives the corresponding compound of formula I in which 4 R is hydrogen.

The acidic compound of formula I in which R is hydrogen is esterified to obtain the corresponding ester of formula I in which R is lower alkyl, lower cycloalkyl, phenyl(lower) alkylene, amino(lower)alkylene, lower alkylamino(lower) alkylene, di(lower alkyl)amino(lower)alkylene or 3-pyridinyl (lower)alkylene. A number of esterification methods can be used, for example, mixed anhydride; dehydrative coupling reagents, for instance, dicyclohexyl-carbodiimide; acid catalysts; diazoalkanes; and acid chloride.

A preferred method of esterification employs an acid catalyst, preferably 0.1 to 1.0 molar equivalents of anhydrous sulfuric acid or hydrogen chloride, and 2 to 50 equivalents of an alcohol selected from a lower alkyl-,lower cycloalkyl-, phenyl(lower)alkyl-,amino(lower)alkyl-, lower alkylamino(lower)alkyl-, di(lower alkyl)amino(lower)alkyl-, or 3pyridinyl(lower)alkyl-alcohol at 50 to 100°C for one to ten hours. It should be noted that when amino(lower)alkyl-, lower alkylamino(lower)alkyl-, di(lower alkyl)amino(lower)alkyl-, or 3-pyridinyl (lower) alkyl-alcohol is used, then a corresponding additional molar mount of the acid catalyst should be present in the reaction vessel. If the reactants are mutually soluble, a solvent for the esterification can be omxt25 ted. Otherwise, any anhydrous inert organic solvent can be used, for example, dimethylformamide, benzene, toluene or chloroform.

Another preferred method of esterification proceeds through the acid chloride. In this method, a solution of the acidic compound of formula I in which R4 is hydrogen and 5 to 50 molar equivalents of thionyl chloride is heated - 21 at 50 to 80°C for one to ten hours and evaporated to obtain the corresponding acid chloride. A solution of the latter acid chloride, one to ten molar equivalents of the above noted alcohols and an organic proton acceptor, for example, pyridine or triethylamine, in an inert organic solvent, for example, acetone, benzene, dichloromethane, toluene, chloroform or dimethylformamide, preferably acetone, is maintained at 0 to 50°C for two to ten hours. Evaporation and purification affords the compound of formula I in which H1, R2 and H3 are as defined herein and R4 is lower alkyl, lower cycloalkyl, phenyl(lower)alkylene, amino(lower)alkylene, lower alkylamino(lower)alkylene, di(lower alkyl)amino (lower) alkylene or 3-pyridinyl(lower) alkylene.

The following Examples numbered 4,5,6,8 and 9 illustrate the preparation of compounds of formula I. Example 7 is a reference example which illustrates the general procedure for the process of preparing compounds of formula XI. Examples 1 to 3 illustrate the preparation of starting materials.

EXAMPLE 1 3-Hydroxy-4-mathyl-3-phanyl-1-pantyne (IV:R2 =CH(CH3)g and R1 = Ph) A reaction flask, equipped uith a dry-ice reflux 5 condenser, is charged uith 700 ml of freshly condensed liquid ammonia. The ammonia gas is passed through a touer of potassium hydroxide pellets. Upon stirring, a rapid stream of acetylene gas (dried in a sulfuric acid uash bottle) is introduced into the ammonia for 10 min, then the rate of passage of the acetylene is reduced and a continuous flou of acetylene through the reaction mixture is maintained during the following operations (approx. 9 hr.). Small pieces of sodium (9.2 g.) are inserted, and 2 hr later, 2-methyl-1-phanyl-1-propanone (50 g) is added dropwise. The stirring is continued for 6 hr at -33°C then, the stream of acetylene is shut off, and the ammonia is allowed to evaporate in the hood (overnight). After adding cautiously ice-water, the resultant solution is acidified with diluted sulfuric acid, and extracted uith diethyl ether. The combined extracts are washed uith saturated brine, dried over magnesium sulfate, filtered, and evaporated to yield 45.5 g of the title compound, ir (CHCl^) 3600, 3310, 1450, and 1010 cm and nmr (CDCl3)S0.85 and 1.07 (d), 2.10(heptuplat), 2.35(s), 2.65(s), 7.27(m) and 7.55(m).

EXAMPLE 2 3-Hydroxy-4-methyl-3-phenyl-2-pantanone (II: R2 = CH(CH3)g R1 = Ph To a refluxing mixture of tetrahydrofuran (70 ml), water (5 ml), and cone, sulfuric acid (1.5 g) is added 1 g of red mercuric oxide and the reflux is continued for 5 min. Then,the insidB temperature is adjusted to 60-62°C and 10 g of 3-hydroxy-4-methyl-3-phenyl-1-pentyne - 23 (described in Example 1) is added. The reaction is exothermic (spontaneous mild reflux) and there is a noticeable clearing of the mixture. Another 1 g of mercuric oxide ie added, and the solution is refluxed for 30 min. The reaction mixture is stirred at 60°C for an additional 3 hr, during which time the precipitation of a mercury sludge occurred. After cooling, the slurry is diluted uith 100 ml of diethyl ether and filtered through diatomaceous earth. The filter cake is washed uith 200 ml of diethyl ether, and the combined filtrates are washed repeatedly uith water, dried over magnesium sulfate, filtered, and evaporated to give 10.6 g of the titlB product, ir (COClg) 3470 and 1715-1710 cm1 and nmr (CDClg)S0.91(d), 2.15(e), 2.79(heptuplet), 4.39(s) and 7.20-7.65(m).

EXAMPLE 3 3-Hydroxy-3-phenyl-2-butanone(II:R2 = Me, R^ = Ph and R3 = H).

The title compound is prepared by using a modified method of G.f.Hennion and B.R.fleck, 0.Amer.Chem.Soc., 77. 3258(1955). To a mixture of methanol (5 ml), water (0.2 ml), sulfuric acid (100 mg), and mercuric sulfate (100 mg) is added at 55°C a solution of 3-hydroxy-3phenyl-1-butyne (2 g) in 90% aqueous methanol (5 ml) over a period of 90 min. The reaction is slightly exothermic, and the inside temperature is maintained at 55-57°C. During the reaction time, 50 mg of mercuric sulfate is added. Uhen addition of the acetylenic component is complete, another portion (50 mg) of mercuric sulfate is added, and the mixture is stirred at 55·°0 for 1 hour. During this time 1 ml of water is added. After cooling, the reaction mixture is poured into ice-water and extracted uith diethyl ether. The combined extracts are washed uith water, dried over magnesium sulfate, filtered and evaporated. The resultant oil is chromatographed on silica gel using - 24 benzene. The appropriate eluates are evaporated to give 0.5g of tha title compound, ir(CHCl3)3450 and 1751 cm-1 and nmr(CDClj)S 1.75(s), 2.08(s), 4.50(s) and 7.40(m) In the same manner but replacing 3-phenyl-3-hydroxy5 1-butyne uith an equivalent amount of 3-hydroxy-3(4-chlorophenyl)-1-butyne, 3-hydroxy-3-methyl-1-butyne, 1- ethynyl-1,2,3,4-tetrahydronaphthalane, 3-athyl-3hydroxy-1-heptyne, 3-hydroxy-3, 3-diphenyl-1-propyna, 3-cyclohexyl-3-hydroxy-1-hexyne, 4-ethoxy-3-(3-methoxy10 phenyl)-3-hydroxy-1-butyne, 3-(3,4-diethylphenyl)-3hydroxy-3-(4-nitrophenyl)-1-propyne, 3-ethynyl-3-hydroxytetrahydrofuran, 1-ethynyl-1-hydroxycyolohexana, 1ethynyl-1-hydroxyindane or 3-oyclopentyl-5-ethoxy-3hydroxy-1-pentyne, the following compounds of formula II are obtained, respectively: 3-hydroxy-3-(4-chlorophenyl)2- butanone, ir (CHC13)344O and 1710 cm , 3-hydroxy-3methyl-2-butanone, 1-acetyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene ir(film) 3450 and 1710 cm” , 3-ethyl-3hydroxy-2-heptanone, 3-hydroxy-3,3-diphenyl-2-propanona, 3-cyclohexyl-3-hydroxy-2-hexanone, 4-ethoxy-3-(3methoxyphenyl)-3-hydroxy-2-butanone, 3-(3,4-diethylphenyl) 3- hydroxy-3-(4-nitrophenyl)-2-propanone, 3-acetyl-3hydroxytetrahydrofuran, 1-acetyl-1-hydroxycyclohexane, 1-acatyl-1-hydroxyindane and 3-cyclopentyl-5-ethoxy-325 hydroxy-2-pentanonB.

EXAMPLE 4 4,5-0ihydro-5-methyl-4-oxo-5-phanylfuran-2-carboxylic acid(l:R2 = Me, R1 = Ph, and R3 and R4 = H) (a) To a stirred suspension of sodium hydride (10.5 g, 54% in mineral oil) in dry tetrahydrofuran (400 ml) is added dropwise a solution of diethyl oxalate (16 g) and 3-hydroxy-3-phenyl-2-butanone (15.4 g described in Example 3) in tetrahydrofuran (50 ml). The solution temperature ia maintained at 55-60°C, and the solution is maintained at this temperature for 18 hr after the - 25 addition ia complete. The cold reaction mixture is poured into water, the mixture is adjusted to pH 11 uith sodium hydroxide and allowed to stand for 24 hours, and uashed uith diethyl ether. Upon addition of 6N hydrochloric acid, the aqueous solution is adjusted to pH 1. The acidic mixture is kept at 20 to 30°C for 2 hours and extracted uith diethyl ether. The ether extract is dried and slouly evaporated to obtain crystals (20 g) of the title compound, mp 174-176°C.

ANAL: Calculated fftr C, 66.06; H, 4.62% Bound: C, 66.41; H, 4.69%. (b) A solution of the title ccmccund in diethyl ether and a solution of an equimolar amount of benzylamine in diethyl ether are nixed at O°C. The precipitate is collected by filtration and crystallized from isopropanol to obtain the benzylamine salt of the title compound, m.p. 192-193°C. (c) In the same manner but replacing 3-hydroxy-3-phenyl2-butanone uith an equivalent amount of another compound of formula II described in Examples2 and 3, the fcllouing compounds of formula I are obtained, respectively; 4,5-20 dihydro-5-(1-methylethyl)-4-oxo-5-phenylfuran-2-carboxylic acid, mp 151-153°C; 5-(4-chloro-ph.enyl)-4,5-dihydro-5-methyl4-oxofuran-2-carboxylic acid, mp 169°C and nmr (CDClg)S 1.75(s), 6.25(s) and 7.45(m); 4,5-dihydro-5,5-dimethyl-4-oxofuran-2carboxylic acid, mp 18O-181°C and ir (Nujol Registered Trade Mark) 2800 (broad), 1737, 1670 and 1600 era-1; spiro ^furan -5 (4H) , 1' (2’H)-naiiithalene_7-3' ,4 '-dihydro-4-oxo-2-carboxylic acid, mp 152-154°C and nmr (MeOH-d4)J 2.07(m), 2.84(t), 6.29(s) and 6.8-7.4(m); 5-butyl-5-ethyl-4,5-ditiydro-4-oxofuran-2carboxylic acid;4,5-d±hydro-4-oxo-5,5-diphenylfuran-2-carboxylic acid; 5-cyclohexy1-4, 5rdihydro-4-oxo-5-propylfuran-2rcarboxylic acid; 4,5-dihydro-5-ethoxymethyl-5-{3-methoxyphenyl)-4-oxofuran -2-carboxylic acid; 4,5-dihydro-5-(3,4-diethylphenyl)-5-(4nitrophenyl)-4-oxofuran-2-carboxylic acid; - 26 1,7-dioxaspiro[4,4]non-2-ene-4-oxo-2-carboxylic acid; 1oxaspiro[4,5]dec-2-ene-4-oxo-2-carboxylic acid; spiro[furan-5(4H), 11-indan]-4-oxo-2-carboxylic acid; and 5cyelopenty1-4,5-dihydro-5-(3-ethoxypropyl)-4-oxofuran-25 carboxylic acid.

EXAMPLE 5 4.5- Dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic Acid Methyl Ester (I:R2 and R4 = Me, R1 = Ph and R3 = H) (a) A mixture of 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran10 2-carboxylic acid (0.4 g, described in Example 4), absolute methanol (50 ml), and sulfuric acid (3 drops) is refluxed overnight and evaporated. The residue is diluted uith 50 ml of diethyl ether, and the solution is uashed quickly uith saturated sodium bicarbonate and uater, dried over magnesium sulfate, filtered, and evaporated. The residue is crystallized from diethyl ether to obtain the title compound (0.32 g) mp 60-62°C and nmr (CDC13)S 1.81(s), 3.99(s), 6.25(s) and 7.42(m). (b) In the same manner but replacing methanol uith an equivalent amount of ethanol, propanol or butanol, the Following compounds of formula I are obtained, respectively: 4.5- dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid ethyl ester, 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2carboxylic acid propyl ester and 4,5-dihydro-5-methyl-425 oxo-5-phenylfuran-2-carboxylic acid butyl ester.

Similarly, but replacing 4,5-dihydro-5-methyl-4-oxo5-phenylfuran-2-carboxylic acid with an equivalent amount of another compound of formula I described in Example 4, the following compounds of formula I are obtained, resp30 ectively: 4,5-dihydro-5-(1-methylethyl)-4-oxo-5-phenylfuran-2-carboxylic acid methyl ester; 5-(4-chlorophenyl)4.5- dihydro-5-methyl-4-oxofuran-2-carboxylic acid methyl ester; 4,5-dihydro-5,5-dimethyl-4-oxofuran-2-carboxylic acid methyl ester, mp 65°C, ir(CHClj)l720, 1695 and 1575 cm~\ spiro[furan-5(4H), 11(2'H)-naphthalene]-3',4'48754 - 27 dihydro-4-oxo-2-carboxylic acid methyl ester; 5-butyl-5ethyl-4,5-dihydro-4-oxofuran-2-carboxylic acid methyl ester; 4,5-dihydro-4-oxo-5,5-diphenylfuran-2-carboxylic acid methyl ester; 5-cyclohexyl-4,5-dihydro-4-oxo-55 propylfuran-2-carboxylic acid methyl aster; 4,5-dihydro5-ethoxymethyl-5-(3-methoxyphanyl)-4-oxofuran-2-carboxylie acid methyl ester; 4,5-dihydro-5-(3,4-diethylphanyl)-5(4-nitrophenyl)-4-oxofuran-2-carboxylic acid methyl aster; 1,7-dioxaspiro[4,4]non-2-ene-4-oxo-2-carboxylic acid methyl ester; 1-oxaspiro[4,5]dec-2-ene«4-oxo-carboxylic acid acid methyl ester; spiro[furan-5-(4H), 1'-indanJ-4-oxo-2carboxylic acid methyl ester; and 5-cyclopentyl-4,5dihydro-5-(3-ethoxypropyl)-4-oxofuran-2-oarboxylic acid methyl ester.

EXAMPLE 6 4,5-Dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic Acid 3-Pyridinylmethyl Ester (I:R2 = Me, R1 = Ph, R3 = H and R4 = 3-pyridinyImethyl). (a) A mixture of 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran20 2-carboxylic acid (8.75 g, described in Example 4) and thionyl chloride (90 ml) is refluxed for 3 hr and evaporated. The residue is dissolved in benzene (100 ml) and evaporated (tuice.) The infrared spectrum of the residue is indicative of a quantitative conversion of tha carboxylic acid into the carbonyl chloride, ir (CHClj) 1820 and 1795, 1755 and 1715 cm-1. This material is dissolved in 50 ml of dry acetone and added to a mixture of 3-pyridinemethanol (4.8 g), pyridine (3.1 g), and acetone (100 ml) at 0°C.

The reaction mixture is stirred at 20 to 30°C temperature for 4 hr and evaporated under reduced pressure. ThB residue ie partitioned bBtueen chloroform and saturated sodium bicarbonate. The organic phase is collected, dried and evaporated to give 8.8 g of the title compound, ir (CHClj) 1753, 1742, 1715(broad), 1595 and 1100 cm1 and nmr (CDClg)& 1.78(e), 5.45(s), 6.29(e), ?.42(m), 7.84 (doublet of triplets) and 8.60(m). - 28 (b) The title compound (18 g) is dissolved in acetone (20 ml) and a solution of hydrogen chloride in diethyl ether is added until precipitation is complete. The solvent is decanted and the residue is triturated uith diethyl ether. The residue is crystallized from acetone to obtain the hydrochloride salt (15 g) of the title compound, mp 124-125°C. ANAL: Calculated for C18H15NO4'HC1: c’52·52; h« 4.66; N> 4.05%; Found: 0,62.30; H, 4.53; N, 3.94%. (c) A solution of the title compound in diethyl ether and a solution of a half molar of (E)-2-butenedioic acid in isopropanol are combined at -10°C. The resulting precipitate is filtered and crystallized from acetonitrile to obtain the hemi-(E)-2-butenedioate salt, mp 128-130°C, of the title compound. (d) In the same manner but replacing 4,5-dihydro-5methyl-4-oxo-5-phenylfuran-2-carboxylic acid uith an equivalent amount of another compound of formula X described in Example 4, the following compounds of formula I are obtained, respectively: 4.5- dihydro-5-(1-methylethyl)-4-oxo-5-phenylfuran-2carboxylic acid 3-pyridinylmethyl aster; 5-(4-chlorophenyl)4.5- dihydro-5-methyl-4-oxofuran-2-carboxylic acid 3pyridinylmethyl ester, nmr(CDC13) 1.77(s), 5.46(s), 6.29(s), 7.42(m), 7.86(m) and 8.70(m); 4,5-dihydro-5,5-dimethyl-4oxafuran-2-carboxylic acid 3-pyridinylmethyl ester, mp 109-110°C; spiro[furan-5(4H),-1'(2'H)-naphthalene]-3',4'dihydro-4-oxo-2-carboxylic acid 3-pyridinylmethyl ester; -butyl-5-ethyl-4,5-dihydro-4-oxofuran-2-carboxylic acid 3-pyridinylmethyl ester; 4,5-dihydro-4-oxo-5,5-diphenylfuran-2-carboxylic acid 3-pyridinylmethyl ester; 5cyclohexyl-4,5-dihydro-4-oxo-5-propylfuran-2-carboxylic acid 3-pyridinylmethyl ester; 4,5-dihydro-5-ethoxymethyl5-(3-methoxyphenyl)-4-oxofuran-2-carboxylic acid 335 pyridinylmethyl ester; 4,5-dihydro-5-(3,4-diethylphenyl)5-(4-nitrophenyl)-4-oxofuran-2-carboxylic aoid 3-pyridinyl48754 - 29 methyl ester; 1,7-dioxaspiro[4,4]non-2-sne-4-oxo-2carboxylic acid 3-pyridinylmethyl ester; 1-oxaspiro[4,5]dec-2-ene-4-oxo-2-carboxylic acid 3-pyridinylmethyl ester; spiro[furan-5(4H), 1'-indan]-4-oxo-2-carboxylic acid 35 pyridinylmethyl ester; and 5-cyclopentyl-4,5-dihydro-5(3-ethoxypropyl)-4-oxofuran-2-oarboxylic acid 3-pyridinylmethyl ester.

EXAMPLE 7 ft 6-Methyl-6-phBnyltetrahydropyran-2,3,5-trione (XI:R = Me, R1 = Ph and R3 a H) To a stirred suspension of sodium hydride (10.5 g 54% in mineral oil) in dry tetrahydrofuran (400 ml) is added dropwise a solution of diethyl oxalate (16 g) and 3-hydroxy-3-phenyl-2-butanone (16.4 g described in Example 3) in tetrahydrofuran (50 ml). The solution temperature is maintained at 55-60°C, and the solution is maintained at this temperature for 18 hr after the addition is completed. The cold reaction mixture is poured into water and the mixture is adjusted to pH 8 to 9 uith sodium hydroxide or hydrochloric acid. This mixture at pH 8 to 9 is allowed to stand for 24 hr and extracted uith diethyl ether. The ether extract is dried, evaporated and crystallized from diethyl ether to obtain the title compound: mp 142-144°C; ir(Nujol) 3130, 1718 and 1640 cm-'; uv (MaOH) X)J)ax268nm(i = 8830) and nmr (MeOH-dj) 1.89 (s), 5.92 (s) and 7.34 (s).

Anal. Calculated for C^HgO^: C, 66.05; H, 4.62% Found: C, 66.14; H, 4.83%.

EXAMPLE 8 3θ 4,5-Dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid (l:R2 = Ma, R1 = Ph, and R3 and R4 » H) A mixture of 6-methyl-6-phenyltetrahydropyran-2,3,5triona (2.18 g, described in Example 7) in aqueous 487 54 - 30 sodium hydroxide (15 ml) at pH 11 is stirred for 24 hr and washed uith diethyl ether. Hydrochloric acid (6N) is added until ths solution becomes acidic at pH 1 to 4. The precipitate is collected and crystallized from diethyl ether to obtain the title compound (2.0 g), mp 174-176°C.

EXAMPLE 9 Optical Resolution of 4,5-Dihydro-5-methyl-4-oxo-5phenylfuran-2-carboxylic acid.

A solution of (+)-a-methyl benzylamine (3.63 g) in diethyl ether ( 50 ml) is added to a solution of 4,5dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid (6.54 g, described in Example 4) in 200 ml of 10% isopropyl alcohol in diethyl ether. The mixture is cooled and the crystals (5.5 g)are collected while saving the mother liquor. The crystals are recrystallized three times from methanol to obtain 5.0 g of the benzylamine salt having a constant rotation of [5= +110° (C=2, methanol) and mp 194-196°C. The latter salt (5.0 g) is stirred into water (100 ml) and diethyl ether (100 ml), and then 6N hydrochloric acid ie addBd until the solution is acidic (pH 1). The Bthsr phase is collected, washed uith water until the washings are neutral, dried, evaporated and recrystallized from diethyl ether to give (+)-4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid (2.7 g): mp 87-89°C; [α]θ5= +146.4 (C=2, methanol); ir (Nujol) 3440, 3320, 2540, 2440, 1720 and 1669 cm''; and Anal Calcd. for C^H^gO^.HgO: C, 61.01%, H, 5.12%,water, 7.62% and found: C, 61.19%, h, 5.07%,water, 7.85%.

The mother liquors, obtained from the above benzylamine salt, are evaporated. The residue (4.3 g) is dissolved in a solution of water (50 ml) and diethyl ether (50 ml) and 6N hydrochloric acid is added dropwise until the water layer is acidic (pH 1). The ether layer - 31 is collected, uashsd uith uater until the uaahings are neutral, dried over magnesium sulfate and evaporated.

The residue (2.7 g) is dissolved in 70 ml of 10% isopropyl alcohol- diethyl ether solution and a solution of (-)-a-msthyl benzylamine in diethyl ether is added.

The solution is cooled and the crystals (3.9 g) are collected and recryatallized three times from methanol to obtain 2.4 g of the benzylamine salt having a constant rotation of [α]^5« -108° (C«=2, mBthanol) and mp 198-199°C.

The latter salt (2.4 g) is stirred into water ( 70 ml) and diethyl ether (70 ml), and 6N hydrochloric acid is added until the uater phase is acidic (pH 1). Tha ether phase is separated, uashed uith uater until the uashings are neutral and evaporated to give 1.6 g of residue. The residue is recrystallized from diBthyl ether to give 1.2 g of (-)-4,5-dihydro-5-methyl-4-oxo-5~ phanylfuran-2-carboxylic acid: mp 87-89°C; [α]θ3 = -144.1° (C=2,methanol); ir (Nujol) 3440, 3320, 2540, 1720 and 1669 cm-1; Anal.Calcd. for C12H1O°4'H2O: C, 61.01% H, 5.12%,uater, 7.62% and Found: C, 61.14%, H, 5.05%, uater, 5.82%.

Claims (12)

CLAIMS A compound of general formula I 1 2 in uhich R and R each is louer alkyl, louer cycloalkyl, 5 louer alkoxy(louer)alkylene, phenyl or phenyl mono- or disubstituted uith louer alkyl, louer alkoxy, halo, 1 2 nitro or trifluoromethyl; or R and R together form a -(CH2) m -X-(CH2) n -ohain uherein m and n each is an integer from one to four and X is methylene, oxa or 1 2 10 thia; or R and R together uith the carbon atom to uhich they are joined form a spiro[1,2,3,4-tetrahydronaphthalene]-1 or spiro[indan]-1 radical; R 3 is z hydrogen or louer alkyl; and R is hydrogen, lower alkyl, louer cycloalkyl, phenyl(louer)alkylene, 15 amino(louer)alkylene, lower alkylamino(louer)alkylene, di(louer alkyl)amino(louer)alkylene or 3-pyridinyl(louer)alkylene, or a therapeutically acceptable addition salt thereof, the term louer used in relation to an alkyl or alkoxy group denoting that such 20 a group contains 1 tc 6 carbon atoms uhen a straight chain and 3 or 4 carbon atoms uhen a branched chain; the term louer alkylene. denoting a straight or branched chain divalent organic radical derived from aliphatic hydrocarbons containing from 1 to 6 carbon 25 atoms.--and the term louer cycloalkyl denoting a saturated cyclic hydrocarbon radical of 3 to 6 carbon atoms. - 33 2. A compound of general formula I as claimed in Ί
1. Claim 1, in which R is lower alkyl, phenyl or phenyl 2 mono-substituted with halo; R is lower alkyl; 1 2 or R and R together uith the carbon atom to which 5 they are joined form a spiro[l,2,3,4-tetrahydroτ 3 4 naphthalenej-1 radical; R is hydrogen; and R is hydrogen, lower alkyl or 3-pyridinyl(lower)alkylsne, or a therapeutically acceptable addition salt thereof. 3. A compound of general formula 1 as claimed in Claim 1, <1 10 in which R is lower alkyl, phenyl or 4-chlorophenyl;
2. 2. 12 R is lower alkyl; or R and R together with the carbon atom to which they are joined form a spiro[l, 2,3,4-tatrahydronaphthalene]-1 radical; R 3 is hydrogen; and R is hydrogen, lower alkyl or 15 3-pyridinylmethyl, or a therapeutically acceptable addition salt thereof. 4. A compound of formula 1 as claimed in Claim 1 which is 4.5- dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid; 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-220 carboxylic acid, benzylamine salt; 5-(4-chlorophenyl) -4,5-dihydro-5-msthyl-4-oxofuran-2-carboxylio acid; 4.5- dihydro-5-(1-mathylathyl)-4-oxo-5-phenylfuran-2carboxylic acid; apiro[furan-5(4H),1’(2'H)-naphthalsna]-3',4’-dihydro-4-oxo-2-oarboxylic acid; 25 4,5-dihydro-5,5-dimethyl-4-oxofuran-2-carboxylic acid methyl eater; 4,5-dihydro-5-methyl-4-oxo-5-phanylfuran-2-earboxylic acid methyl ester; 4,5- dihydro-5methyl-4-oxo-5-phenylfuran-2-carboxylic acid
3. 3. -pyridinylmethyl ester hemi-(E)-2-butanedioate 30 salt; 4,5-dihydro-5,5-dimathyl-4-oxofuran-2-carboxylic acid 3-pyridinylmethyl ester; „48754 or 5-(4-chlcrophenyl)-4,5-dihydro-5-mathyl-4-oxofuran2-carboxylic acid 3- pyridinylmethyl ester. 5. A compound cf formula I uhich is (+)-4,5-dihydro-5mathyl-4-oxo-5-phanylfuran-2-carboxylic acid; (-)-4, 5 5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid; 4,5-dihydro-5-methyl-4-cxo-5-phenylfuran-2carboxylic acid, 3-pyridinylmethyl ester or the hydrochloride salt thereof; or 4,5-dihydro-5,5dimBthyl-4-oxofuran-2-carboxylic acid. 6.lo A process for preparing a compound uithin formula I as claimed in Claim 1 uhich comprises one of the following; (a) cyclizing a compound.of formula X R 2 ,l R -C-CO-CH(R J )-CO-COOH | (X) OH 12 3 15 in uhich R , R and R are as defined in Claim 1 under acidic conditions tc obtain the corresponding 12 3 compound of formula I in uhich R , R and R are 4 as defined herein and R is hydrogen, or (b) esterifying a compound of formula I in uhich R , 2 3 4 20 R and R are as defined herein and R is hydrogen to obtain the corresponding compound of formula I in 12 3 4 uhich R , R and R are as defined herein and R is lcuer alkyl, louar cycloalkyl, phanyl(louer)alkylene, amino(louer)alkylana, louer alkylamino(louer)alk 25 ylene, di(louar alkyl)amino(loua^alkylsna or 3pyridinyl-(louer)alkylene; or (c) neutralizing a compound of formula I uherain
4. 4. 12 3 R is hydrogen and R , R and R are as defined herein uith a therapeutically acceptable organic or inorganic 30 base to obtain the corresponding therapeutically - 35 acceptable organic or inorganic base addition salt; or (d) reacting a compound of formula I uherein R 4 is amino(louer)alkylane, louer alkylamino(louer)alkylene, 5 di(louer alkyl)amino(louer)alkylene or 3-pyridinyl(louer)alkylens with a therapeutically acceptable acid to obtain the corresponding therapeutically acceptable acid addition salt; or (e) hydrolyzing a compound of formula aqueoue alkaline conditions at pH 10 to pH 12, and then acidifying to pH 0.5 to 3 to obtain a 4 compound of formula I uherein R is hydrogen; or 15 (f) reacting a compound of formula II R 1 -C-C0-CH,R 3 I 2 OH (II) 12 3 in uhich R , R and R are as defined herein uith a di(louer alkyl)oxalate in the presence of a strong inorganic proton acceptor under anhydrous conditions 20 in an anhydrous inert organic solvent, hydrolyzing ths mixture uith uater at pH 10 to pH 12 and allowing the mixture to stand under acidic conditions to give a compound of formula I uhere R is hydrogen; ths term strong inorganic proton acceptordenoting 25 an inorganic base or a corresponding alkoxide; 487 54 - 36 and if desired separating a stereoisomeric mixture of compounds of formula I. 7. A process (a) or (f) as claimed in Claim 6, uherein said acidic conditions are selected From an inert
5. 5. Organic solvent cr aqueous solution containing hydrogen chloride, hydrogen bromide, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid cr polyphosphoric acid. lo 8. A- process (f) as claimed in
6. Claim 6 or
7. Claim 7 uherein the strong inorganic proton acceptor is sodium hydride. 6. 9. A process (f) as claimed in any one of Claims 6, 7 and Θ uherein the di(louer)alkyl oxalate is dimethyl 15 oxalate or diethyl oxalate. 7. 10. A process as claimed in any one of Claims 6 to 9 •i uherein, in the final product, R is louer alkyl, phenyl or phenyl monoaubstituted uith halogen, R 1 2 is louer alkyl or R and R together uith the carbon 2o atom to uhich they are joined form a spiro[l,2,3,4tetrahydronaphthalene]-1 radical; R^ is hydrogen, and R 4 is hydrogen, louer alkyl or 3-pyridinyl(lcuer)alkylene. ;
8. 8. 11. A pharmaceutical composition comprising a compound of 25 formula I or a therapeutically acceptable salt thereof, as claimed in any ons of Claims 1 to 5 and a pharmaceutically acceptable carrier.
9. 9. 12. A pharmaceutical composition as claimed in Claim 11 also comprising clofibrate. 487S4 - 37
10. 10. 13. A pharmaceutical composition as claimed in
11. Claim 11 or
12. Claim 12 uherein said compound of formula I is 4,5-dihydro-5-methyl-4-oxo-5-phBnylfuran-2-carboxylic acid 3-pyridinylmethyl ester, or the hydrochloric acid addition salt thereof, or the hemi-(E)-2butenedioate salt thereof. 11. 14. A compound of formula I or a therapeutically acceptable addition salt thereof as claimed in any one of Claims 1 to 5 for use as a hypolipidemic agent.