JPS6252745B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 15-deoxy-16-hydroxy-16-substituted prostanoic acids and processes for their preparation. The novel compound of the present invention includes all optical antipodes, racemic mixtures, and diastereomer mixtures corresponding to the following general formula, and its absolute configuration is that of natural mammalian prostaglandins. . Compounds of the invention can be represented by the following general formula and its enantiomers as well as their pharmaceutically acceptable salts when R ₁ is hydrogen. In the formula, W is and R ₁ is selected from the group consisting of hydrogen and an alkyl group having 1 to 12 carbon atoms;
R ₂ may be optionally substituted with 1 or 2 alkyl groups having up to 3 carbon atoms 2
selected from the group consisting of alkyl groups having ~7 carbon atoms; R ₃ is a hydroxyl group; T is a divalent group [Formula] or [Formula], where R ₅ is a vinyl group. and component _C13 - _C14 is a trans-vinylene group; Z is _-CH2- CH=CH-( _CH2 ) _o- , and n is an integer from 3 to 5. Useful pharmaceutically acceptable salts of the above formula in which R ₁ is hydrogen are salts with pharmaceutically acceptable metal cations, ammonium, amine cations or quaternary ammonium cations. Preferred metal cations are those derived from alkali metals such as lithium, sodium and potassium and from alkaline earth metals such as magnesium and calcium, although cationic forms of other metals such as aluminum, zinc and iron are contemplated. It is within the scope of the invention. Pharmaceutically acceptable amine cations include mono-, di- or trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, mono- or dibenzylamine, α or β-phenylethylamine,
Ethylenediamine, diethylenetriamine, and aryliphatic amines containing up to about 18 carbon atoms, and heterocyclic amines such as piperidine, morpholine, pyrrolidine, piperazine, and their lower alkyl derivatives, such as 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-
Primary, secondary or tertiary amines such as methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine etc. and amines containing water solubilizing or hydrophilic groups such as mono-, di- or triethanolamine, ethyl Diethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris(hydroxymethyl)aminomethane , N-phenylethanolamine, N-(p
-tert-amyl phenyl) diethanolamine,
It is derived from galactamine, N-methylglucamine, N-methylglucosamine, efuedrine, phenylephrine, epinephrine, procaine, and the like. Suitable pharmacologically acceptable quaternary ammonium cations include tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like. Next, the present invention will be explained in detail. Compounds of the invention may be used for a variety of purposes, including intravenous, intravenous,
It is administered in a variety of ways: intramuscularly, subcutaneously, orally, intravaginally, rectally, bucally, sublingually, topically, and for permanent action in the form of a sterile implant. Sterile isotonic aqueous solutions are preferred for intravenous injection or infusion. For that purpose, it is preferred that R ₁ is hydrogen or a pharmacologically acceptable cation for high water solubility. Sterile solutions or suspensions of the acid, salt or ester form in aqueous or non-aqueous media are used for subcutaneous or intramuscular injections. Tablets, capsules, and liquid preparations such as syrups, elixirs and simple solutions are used for oral or sublingual administration with conventional pharmaceutical carriers. For rectal or vaginal administration, suppositories are used, manufactured as is well known in the art. Sterile tablets or silicone rubber capsules or other objects containing or impregnated with the substance are used for tissue transplantation. In some cases it may be advantageous to administer the compounds of the invention as clathrates with substances such as alpha-cyclodextrin. Prostaglandins are a group of closely related compounds obtained from various animal tissues that stimulate smooth muscle, lower arterial blood pressure, and antagonize epinephrine-induced free fatty acid mobilization. , also has other pharmacological and autopharmacological effects in mammals [Bergstom et al., J. Biol.
Chem. 238 , 3555 (1963) and Horton,
Experientia, 21 , 113 (1965) and the literature cited therein], so-called natural prostaglandins are all derivatives of prostanoic acid. The hydrogen atoms bonded to C-8 and C-12 are in the trans configuration. Natural prostaglandins exhibit only one possible optical isomer.
The compounds of the present invention include all possible optical isomers and racemic mixtures. The configuration of the substituent on the prostaglandin molecule is α if it is below the plane of the molecule as shown above.
- is shown to be in the configuration and is shown by a 〓〓 bond.
As mentioned above, substituents above the plane of the molecule are β
It is shown by 〓〓connection. The novel compounds of the present invention can be prepared by a novel 1,4-conjugate addition procedure in which ether-capped cyclopentenone (15) is prepared using a lithiocubrate reagent such as (13) as illustrated in Flowsheet A. processing is included. Its R ₂ ,
R ₃ , R ₅ , W and n are as previously indicated.
R ₁ ' is a lower alkyl (C ₁ -C ₁₂ ) group, a tri-lower alkylsilyl group, or a tetrahydropyran-2-yl group, and R ₃ ' is hydrogen, a tri-lower alkylsilyloxy group, or a tetrahydropyran-2-yl group. It is an yloxy group. Following the procedure outlined in Flow Sheet A, aldehyde (1) is treated with propargyl magnesium halide to produce homopropargyl alcohol.
(2) is formed and converted to its trimethylsilyl ether by conventional methods. The silylated derivative is then prepared in situ from dicyamylborane (2-methyl-2-butene, sodium borohydride and an ethereal solution of boron trifluoride in tetrahydrofuran solution at ice bath temperature). It is then treated with anhydrous trimethylamine oxide. The resulting solution and the iodine solution in tetrahydrofuran are then simultaneously added to an aqueous sodium hydroxide solution to yield 1-iodo-4-trimethylsilyloxy-trans-
1-alkene (3) is obtained. Removal of the trimethylsilyl protecting group with a mild acid and oxidation of the resulting vinyl iodide alcohol with pyridinium chlorochromate yields 1-iodo-4-oxo-trans-1-alkene (4), which is purified using Grignard reagent (R ₅ MgX ) to give 1-iodo-4-hydroxy-trans-1-alkene, which is then silylated by a conventional method to give silyl ether (8a). A more preferred method of making vinyllithium intermediate (9) is also shown in Flow Sheet A. Treatment of the required carboxylic acid (5 or 5a) with the appropriate organolithium reagent (R ₂ Li or R ₅ Li, respectively) yields the corresponding ketone (6), which upon treatment with propargyl magnesium halide yields homopropargyl alcohol. (7) is obtained, which is trans- Converted to vinylstannyl derivatives. Treatment of vinylstannyl reagent (8b) with n-butyllithium at temperatures between -10°C and -78°C yields vinyllithium reagent (9). Treatment of (8a) with an alkyllithium such as n-butyllithium or t-butyllithium (2 eq.) in an inert solvent such as hexane, ether or toluene at low temperature, preferably from -30°C to -78°C, results in trans- 1-Alkenyllithium reagent (9)
is obtained. In the case of vinylstanine (8b), n-butyllithium is preferred for producing the vinyllithium reagent. Copper()-1- in anhydrous tributylphosphine or HMPTA, preferably 1 to 5 molar equivalents of ether, for the preparation of asymmetric lithioquuprates (12), etc.
Alkynes, preferably copper()-1-pentyne 1
A molar equivalent of the solution is added to one molar equivalent of the vinyllithium solution cooled to about -78°C. After about 1 hour at this temperature, 1 molar equivalent of the required cyclopentenone (15) is added. After several hours at -30°C to -70°C, the reaction mixture is quenched with an aqueous solution of ammonium chloride and the shielded product (16) is isolated in the conventional manner. Also, asymmetric lithioquiuprate (14) derived from vinyllithium (9) and cuprous thiophenoxide
It is also possible to perform a conjugate 1,4-addition with .
A drug prepared by mixing a solution of vinyllithium (9) in ether with equimolar amounts of cuprous thiophenoxide and copper() iodide tributylphosphonium complex in ether at temperatures between 0°C and -78°C. React with equimolar amounts at -78°C. After about 30 minutes at this temperature, the lithioquuprate (14) is treated with the required cyclopentenone (15) as described above for conjugate addition with the 1-alkynyl lithioquuprate (12). For the preparation of symmetric lithioquuprate (13), one molar equivalent of copper()iodidetributylphosphine complex dissolved in anhydrous ether was heated to -78°C at about -78°C.
The vinyl iodide (9) in hexane cooled to °C.
Add 2 molar equivalents of solution. After about 1 hour at this temperature, the lithioquuprate (13) is treated with the required cyclopentenone (15) as described for the conjugate addition with 1-alkynyl lithioquuprate (12). Conjugate addition procedures involving organocopper reagents are well known in the art. For example, CJSih et al., J.
See Amer. Chem. Soc. 97 , 865 (1975). In the case of R ₁ ′ = trimethylsilyloxy in cyclopentenone (15), the conjugate addition occurs between −78°C and −
It is carried out at 40℃. The reaction is quenched by the addition of an ethereal solution of acetic acid. Removal of the shielding group is then carried out as described in the above reference;
The product (16a) is obtained in which R ₁ , R ₂ are as shown above and R ₃ ″ is hydrogen or a hydroxyl group. We have come to believe that the _-CH═CH- function in the product (16) occupies the trans position to _the 11-oxy function. The conclusion is reached that the chains are in trans with respect to each other.However, since it is obtained directly from the Cuiprate method,
The inventors have not confirmed this configurational relationship in the product. These products may have side chains in a trans or cis configuration, or may be a mixture containing both trans and cis isomers. This is shown by the display of compounds contained in those indicated by 8〓. (16) Subjecting these compounds to conditions known in the _literature to ensure the trans relationship in can. These conditions include treatment with potassium acetate in aqueous methanol for about 96 hours at room temperature. Tri-lower alkylsilyloxy-substituted lithiokuuprate reagents of type (12) and their iodo and trialkylstannyl precursors are new and useful compounds and are also encompassed by the present invention.
They can be represented by the general formulas (A) and (B). In the formula, W is iodine or tri-n-butylstannyl, R ₃ and R ₅ are as shown above, R ₆ is hydrogen or a tri-lower alkylsilyl group, and T is a thiophenoxide group, a substituted thiophenoxide group,
Alkynes or similar vinyl components. The 13-dihydro derivative is prepared by treating a cycloalkenone of formula (15) with a Grignard reagent such as (10) in the presence of a catalyst such as tributylphosphine-cuprous iodide complex in a conventional manner as shown in Flow Sheet A. It can be manufactured by The trimethylsilyl and other shielding groups are then removed in a conventional manner as described above. According to flow sheet B, it is included in (17)
When 11-hydroxyl derivatives (R ₁ = hydroxy) or 11-oxy derivatives are treated with dilute acids or bases, those groups are removed and the corresponding △ ¹⁰ of type A is obtained.
Derivatives (18) can form prostaglandins. The preferred procedure is about 70 hours at ambient temperature in a tetrahydrofuran:water (2:1) solvent.
with 0.5N HCl or methanol at ambient temperature.
Treatment with 0.2M potassium carbonate in aqueous medium (1:5) for 16 hours is included. Under acidic conditions, tetrahydropyranyl or trialkylsilyl esters undergo hydrolysis. In Flow Sheet B, R ₁ , Z and C ₁₃ -C ₁₄ are as defined above, and R ₈ is the component [Formula] or [Formula] (R ₂ and R ₅ are as defined above). ). The 11-oxy-9-keto derivatives of the present invention can be converted to the corresponding 9-hydroxy derivatives as shown in Flow Sheet C. If this conversion is carried out with sodium borohydride, the products are a mixture of 9α- and 9β-hydroxy derivatives, (19) and (20), respectively, as shown in the reaction scheme below. During the ceremony
R ₁ , R ₃ , Z and C ₁₃ -C ₁₄ are as previously defined, and R ₈ is the component [Formula] or [Formula] (R ₂ and R ₅ are as previously defined .) The reaction is carried out using lithium perhydro-9b-borafenyl hydride [HCBrown and WCDickason
J. Amer. Chem. Soc., 92 , 709 (1970)] or lithium tris-(t-butyl)-borohydride [H.
C.Brown and S.Krishnamurthy, ibid., 94 7159
(1972)], the product is at least mostly 9
α-Hydroxy derivatives, the 9-hydroxy group is present in the side chain attached to _C8 and 11-
It is cis to the oxy functional group. According to accepted convention, the .alpha.-substituents at the 8, 9, 11 or 12 positions are behind the page, while the .beta.-substituents at those positions are at the front of the page. This is usually the α substituent...
A bond is indicated by a 〓〓 bond for a β substituent, or by a 〓〓 bond when both are shown. Flow sheet D [in the formula, R ₉ is hydrogen or a lower alkyl (C ₁ to C ₉ ) group, and Z, R ₈ and C ₁₃ to C ₁₄
is as defined earlier. Treatment of PGFα analogs with an oxidizing agent such as John's reagent or pyridinium chlorochromate results in selective oxidation of the 11α-hydroxyl, yielding compounds with PGD structures such as (22). The carboxylic acids of this invention can be converted to the various alkyl esters of this invention by treatment with the appropriate diazoalkane in a conventional manner. The production of diazoalkanes by various procedures is well described in the art. For example, CD Gutsche, Organic
See Reactions, 389 (1954). Some of the esters of the invention can also be obtained directly by use of suitable cyclopentenone esters. Various esters can also be used as acid chlorides (pre-shielding the free alcohol group with a suitable shielding group such as trialkylsilyl, tetrahydropyranyl, etc.)
Alternatively, they can be prepared by any of several procedures well known in the art for treating these intermediates with appropriate alcohols via mixed acid anhydrides. Mixed acid anhydrides are prepared by preparing prostaglandic acid in a solvent such as dioxane with a molar equivalent of a trialkylamine, preferably triethylamine, tributylamine, etc., followed by a molar equivalent of isobutyl chlorocarbonate, etc. at a temperature ranging from 0 to 15°C. It can be obtained by processing with The resulting mixed acid anhydride is then treated with a suitable alcohol to obtain the derivatized product.
See Prostaglandins, 4 , 738 (1973). Another method involves treating the prostaglandic acid with a molar equivalent of a trialkylamine in excess of a suitable alcohol in an anhydrous solvent such as methylene chloride, followed by addition of a molar equivalent of p-toluenesulfonyl chloride (adding more if necessary). molar equivalents may be added) and working up the product in a conventional manner after stirring at ambient temperature for about 15 minutes to 1 hour.
(For a suitable analogous document, reference is made to US Pat. No. 3,821,279.) A third method involves the use of dicyclohexylcarbodiimide in a conventional manner; for a suitable analogous document, reference is made to DE 2365205
Publication, Chemical Abstracts, 81 , 120098g
(1974). The esterified alcohol derivatives of this invention are also conventionally prepared from the appropriate alkanoic anhydride or acid chloride by procedures well known in the art. The compounds of this invention are prepared from racemic starting compounds to yield two racemates. If appropriate, these racemates are separated from each other by careful use of conventional chromatographic procedures. In more difficult cases it may be necessary to apply high pressure liquid chromatography, including recirculation methods. [G.Fallick, American
Laboratory, 19-27 (August 1973) and its references for additional information regarding high performance liquid chromatography and the equipment necessary for its application.
Waters Associate Inc., Maple Street,
Available from Milford, Mass. ] In the following equation, Z is as defined above. 4-Hydroxycyclopentenone racemic compounds can be synthesized into their component enantiomers by derivatizing the ketone functionality with reagents containing optically active centers (23)
and (24) (where Z is as shown above). The resulting diathreomeric mixture can then be separated by fractional crystallization or by chromatography or by high performance liquid chromatography, including recycle methods if necessary. Useful optically active ketone derivatizing agents include 1-α-aminoxy-β-methylpentanoic acid hydrochloride [(25)(R)
-2-amineoxy-3,3-dimethylbutyric acid hydrochloride] and 4-α-methylbenzyl semicarbazide. After separation of the diastereomeric derivatives, reconstitution of the keto functionality yields the individual 4-hydroxycyclopentenone enantiomers (23) and (24).
is obtained. A procedure useful for the resolution of 4-hydroxycyclopentenone racemates via oximes such as (25) has been demonstrated in the art [R.
Pappo, P.Collins and C.Jung, Tetrahedron
Letters., 943, (1973)]. The resolution of hydroxycyclopentenone where Z is [formula] is described by Bruhn et al.
Described in Tetrahedron Letters, 235, (1976). Another method for preparing 4(R)-hydroxycyclopentenone enantiomers such as (23) includes a key step in which the trione (26) is selectively converted to 4(R)-hydroxycyclopentanedione (27). Includes microbial reduction or chemical reduction. A wide variety of microorganisms can perform asymmetric reduction, and one of the most useful is Dipodascus unincleatus. Enol ether or enol ester (28) of hydroxycyclopentanedione (27), [E=
alkyl, preferably isopropyl; aroyl such as benzoyl; or arylsulfonyl such as 2-mesitylenesulfonyl], for example with isopropyl iodide and a base such as potassium carbonate in refluxing acetone for 15 to 20 hours; or This is accomplished by treatment with a base such as triethylamine and 0.95 equivalents of benzoyl chloride or a slight excess of 2-mesitylenesulfonyl chloride in an aproton-transferring solvent at a temperature of about -10°C to -15°C. (28) was reduced with excess sodium bis(2-methoxyethoxy)aluminum hydride in a solvent such as tetrahydrofuran or toluene at a low temperature such as −60°C to −78°C, followed by 1
Mild acid hydrolysis (typical conditions, oxalic acid, sodium oxalate in dilute aqueous hydrochloric acid PH 2.5 or chloroform) for ~3 hours produces the 4(R)-hydroxycyclopentenone ester (29). The ester (29) can be subjected to a conjugate addition reaction after blocking the hydroxy functionality as previously shown and also as previously shown. Upon unmasking of the 11- and 15-hydroxy groups, the conjugate addition product is a methyl ester which is hydrated to the corresponding carboxylic acid by enzymatic or microbial procedures, e.g. by baker's yeast or by exposure to Rhijopus oryjae. Can be disassembled. A technical description of these steps can be found in CJSih
et al., JACS, 95 , 1676 (1973); JBHeather
et al., Tetrahedron Letters, 2213 (1973); R.
Pappo and PWCollins, Tetrahedron
Letters, 2627 (1972); R. Pappo, P. Collins
and C.Jung, Ann.NYAcad.Sci, 180 , 64
(1971); CJSih et al., JACS, 97 , 865
(1975). For a description of the baker's yeast procedure, see CJSih et al., JACS, 94 , 3643 (1972). The procedure for producing the required cyclopentantrione (26) is technically well established and is generally ω
Treatment of the -1 oxo long chain ester (30) with methyl or ethyl oxalate and a base such as sodium methoxide in methanol followed by treatment with dilute hydrochloric acid in aqueous methanol leads to dealkoxalylation of the intermediate (31). It includes causing. Kutube and Matsui, Agr.Biol.Chem., 33 , 1078
(1969); P.Collins, CJJung and R.Pappo,
Israel Journal of Chemistry, 6 , 839
(1968); R.Pappo, P.Collins and C.Jung,
Ann.NYAcad.Sci., 180 , 64 (1971); CJSih
et al., JACS, 95 , 1676 (1973) (see cited document 7); and JB Heather et al., Tetrahedron.
Letters, 2313 (1973) is referenced as appropriate background literature. The intermediate ketoester (30) can be prepared by various methods known in the art. One useful procedure is outlined below, in which the sodium salt of ethyl acetoacetate (32) is prepared in a conventional manner using a suitable side chain precursor (33), X = Cl, Br, I, preferably Br.
or I], followed by decarbetoxylation and re-esterification, all in conventional manner. It is also possible to resolve the racemic compound of 4-hydroxycyclopentenone (36) by microbial methods. Therefore, suitable microorganisms, preferably Saccharomyces sp.
1375-143, and 4-O-alkanoyl or aroyl derivatives (37) of cerami compounds (36), [R ₁₂ =aryl or alkyl group] (preferably 4-O-acetyl and 4-O- treatment of propionyl derivative) results in preferential de-O-acylation of the 4(R)-enantiomer to yield (23),
It is then separated from the unreacted 4(S)-O-acyl enantiomer (38) by chromatographic procedures. After separation, the 4(S) derivative (38) is subjected to mild hydrolysis to produce 4(S)-hydroxycyclopentenone (24). [N.J.Marsheck and M.
Miyano, Biochimica et Biophysica Acta ,
316 , 363 (1973) are referred to for similar examples. ]. It is also possible to directly prepare the individual 4-hydroxycyclopentenones (23) and (24) by selective microbial hydroxylation of the corresponding 4-unsubstituted cyclopentenone (39). For example, Aspergillus niger
(39) Selective 4(R)-hydroxylation of [Z=( _CH2 ) ₆ ] by ATCC9142 has been reported. Examples of literature include S. Kurozumi, T. Tora and
S. Ishimoto), Tetrahydron Letters , 4959
(1973) referenced. Other microorganisms can also perform this hydroxylation. Another resolution procedure involves derivatization of the alcohol function of racemic hydroxycyclopentenone.
R ₃ ″ is hydrogen or an alkyl group, and n′ is 0 or 2
and where Z is as previously shown (40). Such derivatives can be obtained from the corresponding free hydroxycyclopentenone by treatment with oxalyl chloride, succinyl chloride, succinic anhydride, etc. in a conventional manner. The resulting acid or diacid (R ₃ ″=hydrogen) is treated with an optically active amine such as l-(-)-α-methylbenzylamine, d-(+)-α-methylbenzylamine, brucine, dehydroabiethylamine, Treatment with strychnine, quinine, cinchonine, quinidine, efuedrin, (+)-α-amino-1-butanol, etc., fractional crystallization of the resulting diastereomeric mixture, and subsequent crystallization of each of the individually isolated diastereomers. -cleavage of the oxyester functionality yields individual 4-(S)- and 4-(R)-hydroxycyclopentenone enantiomers (23) and (24)
or their respective esters are prepared. Cleavage of hydrogen oxalate (40, n'=0) can be carried out by treatment with lead tetraacetate in pyridine solution. Examples of similar uses of hydrogen oxalate include JGMolotkovsky and L.D. Bergelson;
Reference is made to Tetrahedron Letters, 4791 (No. 50 1971), and examples of the use of hydrogen succinate include B.
Goffinet, German Official Publication No. 2263880,
See Chemical Abstracts, 79 , 78215z (1973). Additional procedures, well understood in the literature, for the resolution of the racemic prostenotic acids and esters of the present invention are described next. In these procedures 9-oxo-11α,16
(S)-16-vinyl-dihydroxy-5-cis, 13
-trans-prostadienoic acid and its 9α-hydroxy derivatives are used for illustration; however, the procedure is general and can also be used for other products of the invention, in particular substituted in the 11-position with an oxy function. It should be understood that other derivatives not mentioned above are also applicable. The conversion of the 9α-hydroxy racemate (the component enantiomers are exemplified by (41) and (42) below) is carried out as follows. _C11 and _C16 hydroxy functions are preferentially shielded as tetrahydropyranyl or trialkylsilyl ethers, and diacids (e.g.
43) optically active amines (e.g. l-(-)-α-methylbenzylamine, D-(+)-α-methylbenzylamine, brucine, dehydroabiethylamine, strychnine, quinine, cinchonine, cinchonidine, quinidine, efuedrine, Deoxyephedrine, amphetamine, (+)-2-amino-
1-butanol, (-)-2-amino-1-butanol, etc.) to bis salts (e.g. 44), the resulting diastereomers are then separated by fractional crystallization, and the individual components are acidified and saponified. were converted into 9α-hydroxy enantiomers ( ₄₁ ) and ( ₄₂ ) with individual optical activity by Oxidation gives the corresponding individual 9-oxo enantiomers (45) and (46) [Appropriate literature procedures include EW
Yankee, CHLin and J.Fried, Journ.Chem.
See Soc, 1972 , 1120. ] Other procedures include the 9α-hydroxy racemate (as a prostenate ester and also for C ₁₁ and C ₁₆
(preferentially shielding the alcohol functional group as a tetrahydropyranyl or trialkylsilyl ether) with an optically active isocyanate, e.g. (+)-
1-phenylethyl isocyanate or (-)-
Conversion to the diastereomeric carbamate with 1-phenylethyl isocyanate followed by deblocking is included. Diastereomers, e.g. (47)
The separation of and (48) can be carried out by fractional crystallization or conventional chromatographic procedures, or if necessary, by high performance liquid chromatography, including recirculation methods if necessary. Base treatment of individual diastereomeric carbamates provides individual diastereomeric alcohols, such as (41) and (42). Alternatively, after prior preferential blocking of the C ₁₁ and C ₁₆ hydroxy functions as tetrahydropyranyl or trialkylsilyl ethers, the 9α-hydroxy functions are esterified via their acid chlorides with an optically active acid and then the C ₁₁ and Resolution of the 9α-hydroxy racemate, preferably the prostenoic acid ester, can be achieved by unmasking the C ₁₆ alcohol group. Suitable optically active acids include ω-cynoacid, menthoxyacetic acid, 3α-acetoxyacetic acid, △ ⁵
-ethianic acid, (-)-α-methoxy-α-trifluoromethylphenylacetic acid and (+)-α-methoxy-α-trifluoromethylphenylacetic acid. The resulting diastereomeric esters are then separated by fractional crystallization or, if necessary, chromatographic methods including the use of high performance liquid chromatography. Saponification of the individual diastereomers then yields 9α-hydroxyprostenic acid enantiomers (49) and (50). Although less useful than the previously described methods based on 9α-hydroxy derivatives, the 11
- Other fractionation procedures that are particularly applicable to unsubstituted compounds include the ketone function of the racemic 9-oxoprostenoic acid or ester, exemplified by (51) and (52), which contains a conventional optically active center. Derivatization with a derivatizing agent is included. The resulting mixture of diastereomeric derivatives can then be separated by fractional crystallization or by chromatography or, if necessary, high performance liquid chromatography. The individual diastereomeric keto derivatives, such as (51) and (52), can then be converted to the individual 9-oxo enantiomers (45) and (46) by any conventional cleavage method. However, these techniques must be mild enough not to disturb the sensitive 11-hydroxy-9 keto system. (The points mentioned below are
There is no problem with 11-unsubstituted derivatives. ) Ketone reduction of the 9-oxo enantiomer as shown above gives the corresponding 9α-hydroxy or 9β-hydroxy enantiomer. Optically active reagents useful for ketone derivatization include 1-α-aminoxy-α-methylpentanoic acid hydrochloride [E. Testa et al., Helv. Chimica Acta;
47 , (3), 766 (1973)], methylhydrazine, and 4-α-methylbenzyl semicarbazide.
A useful procedure for the cleavage of oximes such as (51) and (52) involves treating the oxime in 1:2 water-tetrahydrofuran buffered with ammonium acetate and containing titanium trichloride at 60 °C for approximately 4 hours. is included. Other useful ketone derivatizing reagents include optically active 1,2-glycols such as D(-)-2,3-
Butanediol or 1,2-dithiols such as L(+)-2,3-butanediol. These are used to convert 9-oxy derivatives to 9,9-alkylene dioxa or 9,9-alkylene dithia derivatives, followed by separation of the diastereomers by chromatographic procedures followed by individual 9
-Regeneration of oxodiastereomers by ketal cleavage can be carried out by procedures well known in the art. Both ketalization and deketalization should be carried out by procedures that do not disrupt the 11-oxo-9-keto system, which of course is not a problem in the 11-unsubstituted series. The novel compounds of the present invention are antihypertensive agents, antiulcer agents, agents for the treatment of extrafluid hyperplasia and gastric ulcers,
Agents that provide protection against ulcer induction and other complications associated with the use of various non-steroidal anti-inflammatory drugs (e.g. indomethacin, aspirin and phenylbutazone), bronchodilators, anti-inflammatory agents, abortifacients,
Drugs for inducing childbirth, drugs for inducing menstruation, drugs for controlling fertility,
It has potential utility as an estrus regulator and central nervous system regulator for use in cattle and other domestic animal husbandry. Certain of the novel compounds of this invention are useful as intermediates for making other novel compounds of this invention. This is a novel compound of the present invention, the PGE type, and will be explained in conjunction with the PGFα type, etc. shown below. The novel compounds of the present invention have the pharmacological activities described below in relation to the appropriate prostaglandin type of alkene. Known PGE, PGFα, PGFβ, PGA and PGB
All compounds are potent in producing many biological reactions even at low doses. For example, PGE ₁ and PGE ₂ are highly potent in producing vasomotor inhibition and smooth muscle stimulation, and are also effective as antilipolytic agents. Furthermore, for many applications, the short duration of biological activity of these known prostaglandins is inconvenient. In sharp contrast, the novel prostaglandin analogs of the present invention are shown to possess substantially the ability to produce prostaglandin-like biological reactions and/or have a substantially longer duration of biological activity. . Thus, each of these novel prostaglandin analogs is significantly and surprisingly more useful than one of the corresponding known prostaglandins for at least one of the pharmacological purposes described below for the known prostaglandins. This is because it has a different and narrower spectrum of biological activity than the known prostaglandins, and therefore its activity is more specific and the resulting undesirable side effects are less compared to the known prostaglandins. Either because they are smaller and fewer, or because their activity is longer, it is often possible to use fewer and smaller amounts of new prostaglandin analogs to reach the desired effect. The 11-deoxy PGE, PGFα and PGFβ compounds are even more selective since most of them are relatively very weak stimulants of smooth muscle.
11-Deoxy PGE compounds have another advantage in that they are more stable and have a longer "shelf life" than the corresponding 11-hydroxy derivatives, as shown in more detail below. Another advantage of the novel compounds of the present invention compared to known prostaglandins is that these novel compounds can be injected or injected intravenously, intramuscularly or subcutaneously using conventional known prostaglandins. In addition, it can be effectively administered orally, sublingually, intravaginally, buccally, or rectally. These properties make it easier to maintain uniform levels of these compounds with fewer, shorter or smaller doses, and they also facilitate self-administration by patients. Because it makes it possible. Compounds such as PGE ₁ , PGE ₂ , PGE ₃ and dihydro-PGE ₁ and the corresponding PGFα, PGFβ and PGA, their esters and pharmacologically acceptable salts are highly potent in producing various biological reactions. . These compounds are therefore useful for pharmacological purposes. For example, Bergstrom et al., pharmacol.
Reference is made to Rev. 20 , 1 (1968) and the references cited therein. Some of these biological responses are, for example, PGE measured in anesthetized (phenobarbital sodium) and pentolinium-treated aortic and right heart cannulated rats, systemic arterial blood pressure reduction in the case of PGFβ and PGA compounds, and PGFα similarly measured. Hypertensive activity of the compound; stimulation of smooth muscle, as demonstrated by testing of small pieces of guinea pig ileum, rabbit duodenum, or gerbil colon, for example; synergism with other smooth muscle stimulants; antagonism of epinephrine-induced free fatty acid mobilization. or antilipolytic activity shown by inhibition of the spontaneous release of glycerin from liberated rat adipose tissue masses; suppression of foreign fluid secretion in the case of PGE and PGA compounds shown in dogs whose secretion was stimulated by food or histamine injection; Activity on the central nervous system; reduction of platelet adhesion of PGE as shown by platelet adhesion to glass and various physical stimuli such as arterial damage and various biochemical stimuli such as ADP, ATP, serotonin, thrombin and collagen. inhibition of platelet aggregation and thrombus formation induced by
In the case of PGE compounds, stimulation of epidermal proliferation and stratum corneum proliferation is shown when applied to culture on fetal chick and rat skin sections. Because of these biological reactions, these known prostaglandins are present in a wide variety of species in birds, mammals including humans, domestic animals, pets and zoological specimens, as well as in laboratory animals such as mice, rats, rabbits and monkeys. It is useful in the study, prevention, control or alleviation of a variety of diseases and undesirable physiological conditions. For example, these compounds, particularly PGE compounds, are useful in mammals, including humans, as nasal decongestants. For this purpose, the compounds are used for topical application in a dosage range of about 10 μg to about 10 mg per ml of a pharmacologically suitable liquid vehicle or as an aerosol spray. PGE and PGA compounds are used to reduce and control excessive foreign fluid secretion and thereby reduce or avoid foreign sores or gastrointestinal ulcer formation, as well as to facilitate the healing of such ulcers already present in the gastrointestinal tract. It is useful for humans and certain useful animals, such as mammals, including dogs and pigs. For this purpose, these compounds may be administered in the injection dosage range of about 0.1 μg/kg body weight per minute to about 500 μg/kg body weight per day, or about 0.1 mg/kg body weight per day.
It may be injected or injected intravenously, subcutaneously, or intramuscularly in total daily doses ranging from about 20 mg to about 20 mg, the exact dosage depending on the age of the patient or animal,
It depends on body weight and condition, and frequency and route of administration. These compounds are also used in conjunction with various non-steroidal anti-inflammatory drugs such as aspirin, phenylbutazone, indomethacin, etc. to minimize the well-known ulcerogenic effects of the latter. PGE ₁ and PGD ₂ compounds are useful whenever inhibition of platelet aggregation, reduction of the sticky properties of platelets, and elimination or prevention of thrombus formation in mammals, including humans, rabbits, and rats, is desired. For example, these compounds are useful in treating and preventing myocardial infarction and in treating and preventing post-operative thrombosis. For these purposes, these compounds are administered systematically, for example intravenously, subcutaneously, intramuscularly, and for long-term action in the form of sterile implants. For rapid response, the intravenous route of administration is preferred, especially in urgent cases. Approximately per kg of body weight per day
Doses ranging from 0.005 mg to about 20 mg are used, with the exact amount depending on the age, weight and condition of the patient or animal, and the frequency and route of administration. 11-α-Hydroxy-PGE compounds are significantly more potent in producing smooth muscle stimulation than other known smooth muscle stimulants, such as various ergots, including labor-promoting agents such as oxytocin, and derivatives and analogs thereof. Its synergistic effect on alkaloids is very active. Therefore, PGE ₂ can be used, for example, instead of or in combination with sub-normal doses of these known smooth muscle stimulators.
For example, it is useful for overcoming symptoms of paralytic ileus, for controlling or preventing uterine bleeding after miscarriage or delivery, for promoting delivery of the placenta, and during the puerperal period. For the latter purpose, the PGE compound may be administered at a dosage of about 0.01 μg to about 50 μg per kg body weight per minute until the desired effect is achieved.
It is administered by intravenous infusion immediately after miscarriage or delivery in a range of doses. Subsequent doses will be based on body weight per day.
intravenously during the puerperium in the range of 0.01 mg to 2 mg per kg;
It is given by subcutaneous or intramuscular injection or infusion, and the exact dosage depends on the age, weight, and condition of the patient or animal. PGE, PGFβ and PGA compounds are useful as antihypertensive agents in lowering blood pressure in mammals including humans. For this purpose, those compounds weigh in kg of body weight per minute.
at a rate of about 0.01 μg to 50 μg per
It is administered by intravenous infusion in single or multiple doses of about 25 μg to 2500 μg per kg of total body weight per day. PGE, PGFα and PGFβ compounds are used in humans, cattle,
It is used in place of oxytocin to induce parturition in pregnant female animals, including sheep and pigs, at or near the due date, or in pregnant animals whose fetus has died in utero from about 20 weeks to the due date. For this purpose, the compound is added at 0.01 kg body weight per minute until or near the end of the second stage of labor, i.e. expulsion of the fetus.
It is injected intravenously in doses ranging from μg to 50 μg. These compounds are particularly useful when the female has been overripe for a week or more and has not yet begun natural parturition, or when the female has not yet begun natural parturition 12 to 60 hours after membrane rupture. PGE, PGFα, and PGFβ compounds are useful in controlling the reproductive cycle of ovulation in female mammals, including humans and other animals. For this purpose, e.g.
PGF ₂ α is administered systematically at dosage levels ranging from about 0.01 to about 20 mg/kg body weight, advantageously during a short period from about the onset of ovulation to about the end of menstruation, or just before menstruation. Furthermore, the embryo or fetus is delivered during the first third or third trimester of normal mammalian gestation.
This is accomplished by similarly administering the compound for 2/3 periods. They are therefore useful as abortifacients. They are also useful in inducing menstruation during approximately the first two weeks of the stopped menstrual period and are therefore useful as fertility inhibitors for contraception. PGA compounds and their derivatives and salts increase blood flow in the kidneys of mammals, thereby increasing urine volume and electrolyte content. Therefore,
PGA compounds are useful in the management of renal dysfunction, particularly in cases of severely impaired renal blood flow, such as liver-kidney syndromes and early kidney transplant rejection. The diuretic effect of these compounds is even greater in case of excessive or inappropriate ADH antidiuretic hormone vasopressin secretion. The vasopressin action of these compounds is particularly useful under anesthesia. For this reason, these compounds can be used to treat burns, e.g.
It is useful in expediting the healing of damaged skin due to trauma and epidermal detachment and after surgery. These compounds may also be used to accelerate the attachment and growth of skin autografts, especially small deep (Devis) grafts, intended to cover dermal areas by initial rather than subsequent surface growth, as well as allogeneic tissue grafts. Useful to prevent section rejection. For these purposes, these compounds are preferably applied topically at or near the locations where cell growth and keratinization are desired, advantageously as an aerosol solution or micronized powder spray, or as an isotonic aqueous solution in the case of a wet dressing. , or lotion,
It is administered as a cream or ointment with conventional pharmaceutically acceptable diluents. In some cases, when there is significant depletion of body fluids, for example in the case of extensive burns or skin loss from other causes, it may be necessary to administer the treatment separately or in conjunction with regular injections of blood, blood, or their substitutes. It is advantageous to administer the combination systematically, for example by intravenous injection or infusion. Other routes of administration include subcutaneously or intramuscularly near the location, orally;
Sublingual, buccal, rectal, or intravaginal. The exact dosage will depend on the route of administration and on such factors as the age, weight, and condition of the patient. Skin area 5-25cm ² of 2
An example of a moist dressing applied topically to first and/or third degree burns is 2-2000 μg/ml of PGE compound.
This may advantageously include the use of isotonic aqueous solutions containing. Particularly for topical use, these prostaglandins are combined with antibiotics such as gentamicin, neomycin, polymyxin B, bacitracin, spectinomycin and oxytetracycline and other antibacterial agents such as mafenide hydrochloride,
Combinations of sulfadiazine, furazolium chloride and nitrofurazone and corticoid steroids such as hydrocortisone, prednisolone, methylprednisolone and fluoroprednisolone are useful, used in combination at conventional concentrations suitable for each individual use. The novel compounds of the present invention induce biological responses as indicated above in association with their particular prostaglandin type. These new compounds can therefore be used for the corresponding purposes mentioned above. The novel PGE, PGFβ and PGA compounds of the present invention are also useful as bronchodilators in the treatment of asthma and chronic bronchitis. They may therefore be conveniently administered by inhalation of an aerosol spray prepared in a dosage range of about 10 μg to about 10 mg per ml of a pharmacologically suitable liquid vehicle. Compared to natural prostaglandins, PGE compounds in particular have the important advantage of inducing long-term effects. The invention is further illustrated by the following specific examples. Reference Example 1 Production of 4-trimethylsiloxy-1-octyne 4-hydroxy-1-octyne in dimethylformamine 1 [Prostaglandins 10 , 289
(1975)] and 240 g of imidazole are added dropwise to a cold solution of 202 g of chlorotrimethylsilane. The mixture is left at room temperature for 2-3 days. Partition the mixture between water and hexane. Wash the hexane layer with prine, dry over magnesium sulfate and concentrate. Distillation of the residue yields a colorless liquid with a boiling point of 38° (0.2
mm), is obtained. Reference Example 2 Production of 1-iodo-4-trimethylsiloxy-trans-1-octene A solution of 0.20 mol of freshly produced bis-(3-methyl-2-butyl)borane in 300 ml of tetrahydrofuran was stirred at 0 to 5°C. A solution of 19.8 g of 4-trimethylsiloxy-1-octyne in 30 ml of tetrahydrofuran is added dropwise to the solution. The resulting mixture is stirred at ambient temperature for several hours, cooled in an ice bath and treated with 53 g of trimethylamine oxide.
The mixture is stirred for several hours at 25-40°C and then poured into 15% sodium hydroxide solution 2. The resulting mixture is immediately treated with a solution of 140 g of iodine in 300 ml of tetrahydrofuran. After 0.5 hours the organic phase is separated and the aqueous phase is extracted with ether. The combined organic phases were washed with water, sodium thiosulfate solution, and brine;
Dry over magnesium sulfate and concentrate to give an oil. pmr spectrum (CDCL ₃ ): 6.2 (d.IC H
= ) and 6.7 (quintet = C H −). Reference example 3 4-hydroxy-1-iodo-trans-1-
Preparation of octene 23 g of 1-iodo-4-trimethylsiloxy-trans-1-octene are dissolved in a mixture of 200 ml of glacial acetic acid, 100 ml of tetrahydrofuran and 50 ml of water. After a solution has formed, toluene is added and the mixture is evaporated. The resulting oil is chromatographed on silica gel using increasingly concentrated hexane in benzene and then acetone to give 16 g of oil.
PMR spectrum ( _CDCl3 ): 3.69 (mC H OH) and 2.3 (sO H ). Reference Example 4 Production of 4-oxo-1-iodotrans-1-octene Pyridinium chlorochromate in 20 ml of methylene chloride (Tetrahedron Letters, 1975, 2647) 6.15
Add 450 mg of sodium acetate to the stirred suspension of g. After 5 minutes hydroxyl in 15 ml of methylene chloride
A solution of 3.64 g of 1-iodo-trans-1-octene is added all at once. The dark mixture is stirred at room temperature for 75 minutes, diluted with 50 ml of ether and decanted. The solid sludge is washed and decanted repeatedly with ether. The solutions are combined and leached through Florisil. Concentrate the solution to obtain an orange liquid.
pmr spectrum ( _CDCl3 ): 3.2.0 (d, j=
7 cps, ₌ CHC H2CO ). Reference Example 5 Preparation of 4-hydroxy-4-vinyl-1-iodo-trans-1-octene A stirred solution of 7.8 ml of vinylmagnesium chloride (2.3 M in tetrahydrofuran) was dissolved in 4-oxo-4-vinyl-1-iodo-trans-1-octene in 20 ml of tetrahydrofuran at -25°C. 1-Iodine-
A solution of 3.55 g of trans-1-octene is added for 15 minutes. After addition, the solution is stirred at -20°C to -15°C for 30 minutes. Quench the reaction with a mixture of hexane and ice. Separate the aqueous phase and extract with additional hexane.
Combine the hexane extracts and wash sequentially with water and brine. The solution is dried over magnesium sulfate and concentrated. The residue is subjected to dry column chromatography on silica gel using benzene as the developing solvent to obtain a liquid. pmr spectrum ( _CDCl3 ): 5.2 (m, terminal C H2 ₎ , 5.83 (q, C
H = CH ₂ ), 6.13 (d, IC H =) and 6.52 (m,
ICH=CH). Reference Example 6 Production of 4-trimethylsiloxy-4-vinyl-1-iodo-trans-1-octene 456 mg of 4-hydroxy-4-vinyl-1-iodo-trans-1-octene and 320 mg of imidazole in 1.0 ml of dimethylformamide Add 0.23 ml of chlorotrimethylsilane to the stirred solution for 3 minutes.
The mixture is stirred at room temperature for 22 hours and partitioned with a cold mixture of hexane and water. The hexane layer is washed repeatedly with water and then with brine, dried over magnesium sulfate, and concentrated to an oil. PMR spectrum (CDCl ₃ ): 0.13 (s.trimethylsiloxy group) and
2.32 (d.= _CHC H2 ). Reference Example 7 Preparation of 9-oxo-11α,16-dihydroxy 16-vinyl-13-trans-prostenic acid 4-trimethylsiloxy-4 in 2 ml of ether
-vinyl-1-iodo-trans-1-octene
A solution of t-butyllithium (1.6M) in pentane is added to 555 mg of the stirred solution at -78°C for 10 minutes.
The solution is stirred at -78°C for 1.5 hours and at -50°C for 30 minutes to yield the 1-lithio-trans-alkene. 1-Copper()-1-pentyne in a separate flask
0.21g, hexamethylphosphorustriamide 0.70
ml and 2 ml of ether are stirred until a clear solution is obtained. This solution is added over a period of 10 minutes to a stirred solution of 1-lithio-trans-alkene at -78°C. The solution was stirred at -78°C for 2 hours and then 4-(trimethylsiloxy)-2-(6
-carbotrimethylsiloxyhexyl)cyclopent-2-en-1-one (580 mg) for 10 minutes. After 10 minutes at -78°C, the solution is stirred at -40°C to -50°C for 1 hour and at -35°C to -30°C for 1 hour. The solution is cooled to −50° C., poured into 100 ml of saturated ammonium chloride solution and diluted with ether.
The organic phase is separated, washed successively with water, dilute hydrochloric acid and filtered through diatomaceous earth. The solution is washed successively with water and brine and dried over magnesium sulfate. Evaporation of the solution gives crude bis-trimethylsilyl ether as an oil. Add this oil to 10 ml of glacial acetic acid and 5 ml of tetrahydrofuran.
and 2.5 ml of water. The mixture is stirred at room temperature for 30 minutes and diluted with 50 ml of toluene. After concentration in vacuo at 33°C, the residue was dissolved in ethyl acetate 1
Chromatography on silica gel with % acetic acid gives an oil. pmr( _CDCl3 ): 4.08
(q, 11β- H ) _, 5.1 (m, terminal CH2 ), 5.57
(m, trans-C H =C H ) and 5.89 (m, C
Reference Example 8 Preparation of 4-cyclopropyl-4-hydroxy-1-octyne Stirred and refluxed suspension of an amalgam made from 6.2 g _of magnesium and 50 mg of mercuric chloride suspended in 60 ml of ether . A solution of a mixture of 30.4 g of n-butylcyclopropyl ketone and 29.8 g of propargyl bromide in 65 ml of ether is added to the solution over a period of 60 minutes. After reacting for a further 30 minutes at reflux temperature, the mixture is cooled to 0° C. and treated with 35 ml of saturated ammonium chloride. The mixture was diluted with ether and passed through Celite.
Wash the solution with brine, dry over potassium carbonate and concentrate. Distillation of the residue yields a liquid.
Boiling point 93-94℃ (12mm), PMR spectrum ( _CDCl3 ): δ0.43 (cyclopropyl hydrogen), 2.07
(Triple line, H C≡C) and 2.44 (Double line, C≡CC
H2 ₎ . Reference Example 9 Production of 4-cyclopropyl-4-trimethylsiloxy-1-octyne 27.8 g of 4-cyclopropyl-4-hydroxy-1-octyne (Reference Example 8) and 33.3 g of imidazole in 130 ml of dimethylformamide at 5°C. Add 24 ml of chlorotrimethylsilane to the stirred solution over 5 minutes. The solution is stirred at ambient temperature for 17 hours and then partitioned between 600 ml hexane and 250 ml ice water. Separate the hexane phase and wash sequentially with water and brine. The solution is dried over magnesium sulfate and evaporated to give a liquid. PMR spectrum ( _CDCl3 ): δ0.12
(singlet, trimethylsiloxy group), 2.02 (triplet, H C≡C), and 2.45 (double line, C≡C H
₂ ). Reference Example 10 Production of 4-cyclopropylol-4-trimethylsiloxy-1-(tri-n-butylstannyl), trans-1-octene 4-Cyclopropyl-4-trimethylsiloxy-1-octyne (Reference Example 9 ), 28 ml of tri-n-butyltin hydride and 50 mg of azobisisobutyrolanitrile, stirred under nitrogen and heated to 85°C. After the resulting exothermic reaction has subsided, the mixture is
Stir at 130°C for 1 hour. Evaporative distillation of the crude product yields a liquid. PMR spectrum ( _CDCl3 ): δ0.10 (trimethylsiloxy group), 2.33
(Doublet, =CHC H2 ) and _6.02 (vinyl hydrogen). Reference examples 11-14 Technically well-known procedures [JCFloyd,
Tetrahedron Letters, 2877 (1974)], the vinyl ketones shown in Table 1 are prepared by reaction of vinyllithium with the required carboxylic acids shown in the table. [Table]
[Table]
14 n〓heptanoic acid n〓hexyl vinyl ke
ton
Reference Examples 14a to 16 The following 4-substituted-1 was prepared by reacting propalmagnesium bromide with the ketone shown in Table 2 using the method of Reference Example 8.
-Producing an alkyl-4-ol. [Table] Reference Examples 17 to 19 The 4-substituted-1-alkyne-4-ols in Table 3 are converted to their corresponding trimethylsilyl ethers by the method of Reference Example 9. [Table] Reference Examples 20 to 22 The following 1-(tri-n-butylstannyl)- A 4-substituted-4-trimethylsiloxy-trans-1-alkene is produced. [Table] Trimethylsiloxy
Trans〓1〓Desen
Reference Example 23 Production of 9-oxo-11α,16-dihydroxy-16-cyclopropyl-5-cis,13-trans-prostadienoic acid 4-cyclopropyl-4-trimethylsiloxy-1-(tri- n-
To a stirred solution of 11.54 g of (butylstannyl)-trans-1-octene (Reference Example 10) at -78 DEG C., 9.1 ml of 2.4Mn-butyllithium in hexane are added over a period of 10 minutes. The resulting solution was incubated at −70°C for 10 min at −40°C.
Stir for 1 hour at <0>C and 40 minutes at -40<0>C to -30<0>C. Add copper pentyne to the solution stirred at −78°C.
A solution made from 2.84 g, 10.8 ml of tri-n-butylphosphine, and 25 ml of ether is added. The resulting solution was stirred at -78°C for 2 hours and then diluted with 20 ml of ether.
2-(6-trimethylsiloxycarbonyl-
Treat for 10 minutes with a solution of 6.03 g of 2-cis-hexenyl)-4-trimethylsiloxycyclopent-2-en-1-one (Table 5, Reference A). After 10 minutes, the solution is stirred at -50°C to -40°C for 1 hour and then at 40°C to -30°C for 50 minutes. Cool the solution again to −50°C and add 600 ml of saturated ammonium chloride and 300 ml of ether.
Add to the stirred mixture with ml. Separate the organic phase;
Wash sequentially with dilute hydrochloric acid, water, and brine. The residue obtained after solvent evaporation was mixed with 120 ml of glacial acetic acid,
Treat with 60 ml of tetrahydrofuran and 30 ml of water, stir the mixture for 30 minutes at room temperature, dilute with 150 ml of toluene and concentrate. The residue is purified by dry column chromatography on silica gel using 1% acetic acid in ethyl acetate to give an oil. PMR spectrum (acetone- _d6 ): δ0.26 (multiplet, cyclopropyl hydrogen) and 4.12 (quartet, C H OH) Reference Examples 24 to 26, Examples 1 to 4 The product 9-oxo-11α,16-dihydroxy-prostadienoic acid or prostenoic acid of No. 5 is obtained. Following the method described, the starting compounds 1-(tri-n
-butylstannyl)-4-trimethylsiloxy-trans-1-alkene with n-butyllithium gives the corresponding trans-1-alkenyllithium derivative, which is converted into a copperpentyne-tri-n-butylphosphine complex. Treatment with gives the corresponding trans-1-alkenyl cuuprate, which is then treated with the 4-oxycyclopent-2-en-1-one shown in the table. arise 9
-Oxo-11α,16-bis(trimethylsiloxy)-prostadienoic acid or prostenic acid trimethylsilyl ester is hydrolyzed to the products shown in the table when treated with acetic acid-tetrahydrofuran-water. [Table] [Table] Example 5 The prostadiene residue shown in Table 6 is treated with the diazoalkane shown in the table as follows to obtain the product prostadienoic acid ester. An ethereal solution containing a molar excess of diazoalkane is added to a solution of the carboxylic acid in ether or etheracetone. After 10-30 minutes, the solution is carefully evaporated and the remaining ester purified by chromatography on silica gel in the usual manner. [Table] Nsu〓Prostar
Ethyl dienoate reference examples 27-30 When carboxy-cyclopentenone or carbomethoxycyclopenterone in Table 7 is treated according to the procedure described in U.S. Patent No. 3,873,607 (Example 958), bistrimethylsilyl ether ester or trimethylsilyl in Table 7 Ether methyl ester is produced. [Table] [Table] Examples 6 to 13 When the prostadienoic acids shown in Table 8 are treated with the diazo alkanes shown in the table as follows, the products prostadienoic acid esters shown in the table are obtained. An ethereal solution containing a molar excess of diazoalkane is added to a solution of the carboxylic acid in ether or etheracetone. After 10-30 minutes, the solution is carefully evaporated and the remaining ester purified by chromatography on silica gel in the usual manner. [Table] Examples 14-17 The product 9- of Table 9 was prepared by the procedure described in Reference Example 23.
Oxo-11α,16-dihydroxy-prostadienoic acid is obtained. Following the described method, the starting compounds 1-(tri-n-butylstannyl)-4-trimethylsiloxy-trans-1 listed in Table 9
Treatment of alkenes with n-butyllithium gives the corresponding trans-1-alkenyllithium derivatives, which are treated with copperpentyne-tri-n-butylphosphine complexes to give the corresponding trans-1-alkenyllithium derivatives.
The 1-alkenyl cuuprate is obtained, which is then treated with the 4-oxycyclopent-2-en-1-one shown in the table. The resulting 9-oxo-11
When α,16-bis(trimethylsiloxy)-prostadienoic acid trimethylsilyl ester is treated with acetic acid-tetrahydrofuran-water, it is hydrolyzed to the products shown in the table. Table Examples 18-25 16-Hydroxy epiisomers are separated by HPLC as described in the specification (EtOAc, heptane
HOAc) and the 16α-hydroxy and 16β-hydroxy isomers shown in Table 10 are obtained. TABLE TABLE Compounds of the present invention are useful as bronchodilators in the treatment of asthma and chronic bronchitis. Bronchodilator activity in guinea pigs, Konzett
[J. Lulling, P.
Lievens.F.El Sayed and J.Prinot et al.
See Arzneimittel-Forschung 18 , 955 (1968)]. Table 11 shows the bronchodilatory activity of representative compounds of the invention against one or more of three proconvulsant drugs as ED ₅₀ determined from results obtained with 3 logarithemic cummulative intravenous administration. It can be done. In this assay, the compounds of the invention provide a longer lasting effect than natural _-PGE1 or _-PGE2 . [Table] [Table]

Claims (1)

[Claims] 1 Formula: An optically active 15-deoxy-16-hydroxy-16-substituted prostanoic acid represented by: and its racemic mixture or enantiomer thereof. where R ₁ in the above formula is selected from the group consisting of hydrogen and an alkyl group having from 1 to 12 carbon atoms; R ₂ is optionally one or two alkyl groups having up to 3 carbon atoms; selected from the group consisting of alkyl groups having 2 to 7 carbon atoms optionally substituted with; n is an integer of 3 to 5; 2 formula: However, in the above formula; R ₃ ″ is a tri-lower alkylsilyloxy group or a tetrahydropyranyloxy group; R ₁ is selected from the group consisting of hydrogen and an alkyl group having 1 to 12 carbon atoms; n is 3 An integer from 5 to 5, a compound of the formula: However, in the above formula; R ₂ is selected from the group consisting of alkyl groups having 2 to 7 carbon atoms optionally substituted with 1 or 2 alkyl groups having up to 3 carbon atoms; V is a thiophenoxide group, a substituted thiophenoxide group, an alkyne group or a vinyl group. However, in the above formula; R ₁ , R ₃ ″ and R ₂ have the above meanings, and then the ether group is descreened with a mild acid to form a compound of the formula: However, in the above formula, R ₁ and R ₂ have the above meanings. Optically active 15-deoxy-16-hydroxy-16-substituted prostanoic acids and racemic mixtures thereof or mirror images thereof How the body is made. 3. The method of claim 2, wherein _R2 is selected from the group consisting of lower alkyl groups having 3 to 7 carbon atoms. 4 [Formula] is The manufacturing method according to claim 2.