Claims
- 1. A 11.alpha.,15(S)-bis(lower dialkyl' lower alkoxy' methyloxy)-9-oxo-5-cis,13-trans-prostadienoic acid wherein the lower alkyl group is from 1 to 8 carbon atoms and the lower alkoxy is from 1 to 8 carbon atoms.
- 2. The compound 11 .alpha.,15(S)-bis(dimethyl', isoproxy',-methyloxy)-9-oxo-5-cis,13-trans-prostadienoic acid.
BACKGROUND OF THE INVENTION
This is a continuation of application Ser. No. 117,166, filed Feb. 19, 1971, now abandoned.
This invention relates to mono or di-substituted lower alkyl diether prostaglandins of Formula 1 as follows: ##STR4## wherein: R.sub.1 is hydrogen or lower alkyl;
The term lower alkyl appearing above and elsewhere in the specification and claims denotes the straight and branched chain lower alkyl hydrocarbon groups of 1 to 8 carbon atoms inclusive, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, pentyl, neopentyl, n-hexyl, isohexyl, heptyl and the like.
The term lower alkoxy appearing in the instant specification denotes straight and branched chain lower alkoxy hydrocarbon groups of 1 to 8 carbon atoms inclusive, such as methoxy, ethoxy, n-propoxy, butoxy, sec-butoxy, amoxy, iso-amoxy, hexyoxy, iso-butoxy, iso-propoxy, and the like.
The phrases pharmaceutically acceptable and non-toxic salts as embraced by the above Formulae and elsewhere in the disclosure and the accompanying claims includes the non-toxic alkali metal and the non-toxic alkaline earth metal bases such as sodium, potassium, copper, magnesium and the like, the hydroxides and carbonates thereof, the ammonium salts and substituted ammonium salts, for example, the non-toxic salts of trialkylamines such as triethylamine, trimethylamine and tri-isopropylamine, and other amines such as morpholine, diethylamine, dimethylamine, methylcyclohexylamine, glucosamine, procaine, dibenzylamine, triethanolamine, N-benzyl-.beta.-phenylethylamine, ethyldimethylamine, benzylamine,N-(lower) alkyl piperidines, such as N-ethylpiperidine, N-methylpiperidine and other pharmaceutically acceptable amines. Also, non-toxic salts with monoalkyl and dialkylamines, and aralkylamines salts formed with compounds of Formula 1 (R.sub.1 .dbd.H) and tetra-alkylammonium hydroxides. The latter are generally called therapeutically acceptable quaternary ammonium salts, for example, tetramethylammonium, tetrapropylammonium, tetra-ethylammonium, phenyltriethylammonium, benzyltri-isopropylammonium salts, and the like.
The term "lower alkyl diether" as used herein denotes a lower alkyl substituted ether group of the formula ##STR10## as covalently bonded to the prostaglandin backbone. The lower alkyl diether group is attached to the prostaglandin through an ether-carbon structure ##STR11## that may be conveniently named "methyloxy". The methyloxy group has bonded thereto the groups R'.sub.9, R'.sub.10 and R'.sub.11. The group R'.sub.9 is a hydrogen or lower alkyl group and R'.sub.10 and R'.sub.11 are lower alkyl groups. When R'.sub.9, R'.sub.10 and R'.sub.11 are lower alkyl groups they may be the same or they may be different lower alkyl groups of the straight or branched chain hydrocarbon type of 1 to 8 carbon atoms inclusive, as defined above. The group R'.sub.11 as bonded through the oxygen atom to the carbon atom may also be viewed as a lower alkoxy group. The lower alkoxy group, also an ether, is a straight or branched alkoxy group of 1 to 8 carbon atoms inclusive, as set forth above. Representative of diethers suitable for the present purpose are thus mono or lower dialkyl, lower alkoxy methyloxy groups such as (methyl' methoxy' methyloxy); (methyl' ethyl' methoxy' methyloxy); (ethyl' methyl' propoxy' methyloxy); (diethyl' methoxy' methyloxy); (ethyl' propyl' ethoxy' methyloxy); (dipropyl' ethoxy' methyloxy); (ethyl' iso-propyl' ethoxy' methyloxy) and the like.
The numbering system and the stereochemical nomenclature used for the novel prostaglandin ethers of the invention is the art accepted numbering and nomenclature. That is, the cyclopentane ring of the prostanoic acid is numbered 8 through 12 inclusive, the carboxyl side chain attached to the cyclopentane ring at its 8 position and the alkyl side chain attached to the cyclopentane ring at its 8 position and the alkyl side chain attached to the cyclopentane at its 12 position. When longer or shorter side chains are used, the carboxyl position is numbered as 1 and the numbers increased or decreased throughout the compound to correspond to the length of the chains and the ring inclusive. The stereochemistry of the substituents on the 5-membered cyclopentane ring may be .alpha.-oriented or .beta.-oriented as indicated by a wavy line; the dashed line indicates an .alpha.-orientation and the solid wedged line indicates a .beta.-orientation. Alpha-substituents are oriented on the opposite side of the cyclopentane ring as the .omega.-terminal chain, and .beta.-substituents are oriented in the opposite sense; that is, on the same side as the alkyl side chain. Also, in the formulae as illustrated herein the substituents at positions R.sub.3, R.sub.4, R.sub.5, and the like, as graphically depicted by ##STR12## and the like, indicate that both groups, for example, hydrogen and hydroxyl, are bonded to the carbon atoms of the cyclopentane ring. The substituents attached to the alkyl side chain may have a sinister (S) or rectus (R) configuration which for these compounds in the projection shown, is the equivalent nomenclature of .alpha. and .beta. respectively. The diether prostaglandins depicted in the specification and accompanying claims thus includes the analogues and all the diastereomers thereof, and in addition, the enantiomeric forms and such mixtures as are designated racemates. The numbering system and the stereochemistry nomenclature is disclosed and described in Progress In The Chemistry of Fats and Other Lipids, Vol. IX, Part 2, pages 233 to 236, 1968, Pergamon Press, New York, and in J. Lipid Research, Vol. 10, pages 316 to 319, 1969.
The novel lower alkyl diethers of prostaglandins of Formula 1 can be prepared from the corresponding prostaglandins, natural or synthetic, or from prostaglandin intermediates by separately converting them to the appropriate prostaglandin diether by chemical means. The corresponding starting prostaglandins can be represented by Formula 2 or from the starting prostaglandin intermediates represented by Formula 3: ##STR13## wherein Formula 2:
The starting prostaglandin materials of Formulae 2 and 3 used to synthesize the novel diether prostaglandins of Formula 1 are well known to the art and they are prepared by art known biosynthetic or chemical synthetic ways, or they are obtained from commercial sources. The starting materials of Formula 2 are prepared by the biosynthetic method of isolating the prostaglandin from natural sources, for example, the vesicular glands of sheep, or by the enzymatic conversion from fatty acid substrates, such as arachidonic acid, and, depending on the substituent desired, routinely chemically transforming double bonds to single bonds by hdyrogenation, converting keto groups to hydroxymethylene groups by reduction, by dehydrating to introduce double bonds, by forming carbinol derivatives by treating carbo (lower) alkoxy groups with an alkali metal alumino hydride reducing agent such as lithium aluminum hydride and the like. The prior art methods that describe the procedures for providing all of the naturally derived starting compounds embraced by Formula 2 are found in Science, Vol. 158, pages 382 to 391, 1967; Recueil, Vol 85, pages 1233 to 1250, 1966; Biochem, Biophysic, Acta., Vol 106, pages 215 to 217, 1965; Agnew. Chem. Inter. Ed., Vol 4, pages 410 to 416, 1965; Experientia, Vol 21, pages 113 to 176, 1965; Recueil, Vol 85, pages 1251 to 1253; and in other art recorded procedures.
The starting prostaglandin reactants and the starting intermediate prostaglandin reactants of Formula 2 and 3 can be chemically synthesized by well known procedures. For example, the prostaglandins can be synthesized from a common chemical intermediate 11,15-bis(tetrahydropyranyl)ether of 9.alpha.,11.alpha.,15(S)-trihydroxy-5-cis,13-trans-prostadienoic acid according to the procedure reported in J. Am. Chem. Soc., Vol 92, pages 2586 to 2587, 1970, and references cited therein, to give the starting prostaglandins. The starting prostaglandins can also be prepared by the reduction of 2-oxa-3-oxo-6-exo-(trans-3-(S)-hydroxy-hept-1-enyl)-endo-7-acetoxy-cis-bicyclo(3.3.0)octane followed by reduction and treatment with Wittig reagent to give the corresponding prostaglandins as set forth in J. Am. Chem. Soc., Vol 91, pages 5675 to 5677, 1969; by the total synthesis of prostaglandins via a tricarbocyclic intermediate as reported in Tetrahedron Letters, Vol 4, pages 307 to 310, 1970; by the total synthesis of prostaglandins from 2-oxabicyclo(3.3.0)oct-6-en-3-one, ibid, pages 310 to 311, 1970; and other reported chemical synthesis embracing the prostaglandin materials within Formulae 2 and 3 such as the J. Am. Chem. Soc., Vol 90, pages 3245 to 3247, 1968; ibid, Vol 91, pages 535 to 536, 1969; ibid, Vol 92, pages 397 to 398, 1970; and in The Proceedings of the Robert A. Welch Foundation Conference on Chemical Research, Vol XII, pages 51 to 79, 1969. The intermediate prostaglandin starting materials as embraced by Formula 3 can also be prepared by the chemical synthetic route described in J. Am. Chem. Soc., Vol 90, pages 3245 to 3247, 1968; and ibid, pages 3247 to 3248, 1968; ibid, Vol 91, pages 535 to 536, 1969.
The novel diether prostaglandins of Formula 1 are prepared from the starting reactants represented by Formulae 2 and 3 by contacting and reacting the reactants of Formulae 2 and 3 generally under anhydrous conditions with an excess of an aliphatic enol ether; for example, with from about 1 to about 30 or more molecular equivalents of the aliphatic enol ether for each etherifiable hydroxyl group present in Formulae 2 and 3 to be etherified in the starting prostaglandin material. The reaction is carried out in an inert organic solvent and generally in the presence of a small amount of an acid catalyst. The reaction is usually carried out at a temperature of about 0.degree. C to about 80.degree. C, usually at ambient temperature of about 25.degree. C. The starting materials begin to react on contact but it is generally preferable to carry out the reaction for about 10 minutes to about 90 hours to produce from the starting reactants the corresponding ether compound of Formula 1.
The starting aliphatic enol ethers used for etherification of the various alcohol groups of the prostaglandin starting materials of Formula 2 and 3 to form the novel, improved alkali resistant, acid labile ethers prostaglandins of Formula 1 are obtained from commercial sources or they are readily prepared by the thermal decarboxylation of alkoxy unsaturated acids to yield the corresponding alkoxy enol ether according to J. Org. Chem., Vol 27, pages 3875 to 3878, 1962; and by the Claisen type reaction in Ber., Vol 31, pages 1019 to 1024, 1898. Exemplary of alkoxy enol ethers containing an olefinic group suitable for the purpose of the invention is methoxyisopropenyl ether, ethoxyisopropenyl ether, isopropoxyisopropenyl ether, n-butoxyisopropenyl ether, hexoxyisopropenyl ether, isobutoxy-isopropenyl ether and the like.
Exemplary of suitable inert, organic solvents for performing the etherification include anhydrous halogenated solvents such as methylene chloride, chloroform, carbon tetrachloride, ethylene chloride; anhydrous ether solvents such as diethylether, dimethylether; and other solvents such as anhydrous tetrahydrofuran, dioxane, n-hexane, cyclooctane, benzene, mixtures thereof, and the like. Representative of acid catalysts suitable for performing the reactions according to the spirit of the invention are p-toluenesulfonic acid, hydrochloric acid, anhydrous hydrobromic acid, Lewis acids such as boron trifluoride, boron trichloride etherate, stannic oxychloride, phosphorus oxychloride, phosphorus pentachloride, zinc chloride, mixtures thereof, and the like.
The novel diethers of prostaglandins can be chemically transformed to their non-toxic, pharmaceutically acceptable salt by neutralizing the prostaglandin diether with an equivalent or an excess amount of the corresponding non-toxic salt forming organic or inorganic base. The pharmaceutical salts are prepared by procedures known to the art, for example, equivalent or stoichiometric quantities of the prostaglandin and the organic base are dissolved in an inert organic solvent at room temperature or in a warmed solvent with a gentle mixing of the reactants, the prostaglandin diether and the base, until all the reactants are in solution. The product, or salt, is obtained by chilling the resulting mixture to precipitate the powder or crystals, or the product can be isolated by the addition of a miscible diluent of low polarity, or by the use of standard evaporation techniques. The inorganic prostaglandin diether salts are synthesized by procedures known to the art; for example, the prostaglandin diether is dissolved or dispersed in a mutual solvent containing stoichiometric amounts or an excess amount of a non-toxic salt forming inorganic compound. The synthesis can be carried out in the presence of an inert organic solvent and the product is obtained by procedures such as the evaporation of the reaction solvent, or by the addition of miscible solvents of low polarity, or by chilling the mixture to precipitate the product.
The lower alkyl esters of the prostaglandin diethers are obtained by known procedures, such as, the treatment of the diether of prostaglandin acid with a solution containing di(lower) azoalkanes to produce the corresponding diether prostaglandin ester. Esterification of the starting diether prostaglandin acid is performed by reacting the acid with the diazoalkane, for example, diazomethane, diazoethane, diazopropane, diazobutane, etc., in an inert organic solvent, for example, lower alkanols, symmetrical and unsymmetrical ethers, halogenated solvents, and other solvents such as tetrahydrofuran, acetone, dioxane, etc., or with mixtures thereof. The esterification reaction is usually performed at a temperature of 0.degree. to 75.degree. C, usually at ambient temperature and atmospheric pressure, with the ester recovered by evaporation of the solvent and by the like techniques. Esterification reactions are described in Organic Chemistry, by Fieser and Fieser, pages 180 to 181, 1944.
The following examples are set forth as representative methods illustrative of the spirit of the present invention. These examples are not to be construed as limiting the scope of the invention as other functionally equivalent means will be readily apparent to those skilled in the subject art in the light of the present specification and accompanying claims.
US Referenced Citations (3)
Non-Patent Literature Citations (1)
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| Corey et al., JACS 91, 5675 (1969). |
Continuations (1)
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117166 |
Feb 1971 |
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Patent Grant
4055593
