Abstract:
Enlarged-hetero-ring prostacyclin analogs having a Δ 2  feature are disclosed, for example ##STR1## said analogs having pharmacological activity. Processes for preparing them and the appropriate intermediates are disclosed.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation-in-part of copending application Ser. No. 819,856, filed July 28, 1977, issued as U.S. Pat. No. 4,123,441, which was a continuation-in-part of then copending application Ser. No. 725,546, filed Sept. 22, 1976 since abandoned which was a continuation-in-part of then copending application Ser. No. 716,960, filed Aug. 23, 1976, since abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     This invention relates to certain heterocyclic organic compounds, namely prostacyclin analogs and to processes for preparing them. 
     Prostacyclin and prostacyclin-type compounds are well-known organic compounds. Prostacyclin (PGI 2 ) is represented by the formula ##STR2## for which see R. A. Johnson et al., J. Am. Chem. Soc. 99, 4182 (1977). Other prostacyclin-type compounds are disclosed by R. A. Johnson et al., Prostaglandins 15, No. 5, 737-740 (1978) and in Belg. Patents No. 851,122, 855,224, 859,057, and 860,278. See, respectively, Derwent Farmdoc Abstract Nos. 57511Y, 86540Y, 25186A, and 32096A. 
     Detailed background for this application will be found in U.S. patent application Ser. No. 819,856, filed July 28, 1977 issued as U.S. Pat. No. 4,123,441 which is incorporated herewith by reference in its entirety under the provisions of M.P.E.P. 608.01(p). Therein is also a statement of the utility of these compounds, alternate processes of synthesis, and complete description of starting materials useful herein. 
     SUMMARY OF THE INVENTION 
     It is the purpose of this invention to provide novel products having pharmacological activity. It is a further purpose to provide processes for preparing those products and their intermediates. More specifically, there are provided Δ 2  enlarged-hetero-ring prostacyclin analogs. 
     Accordingly there are provided (4Z) compounds of the formula ##STR3## wherein the terms Q, R 1 , etc. are defined herein in the TABLE of Definition of Terms for Formulas. 
     TABLE 
     DEFINITION OF TERMS FOR FORMULAS 
     Q is ##STR4## wherein R 8  is hydrogen or alkyl of one to 4 carbon atoms, inclusive. 
     Q 3  is ##STR5## wherein R 8  is hydrogen or alkyl of one to 4 carbon atoms, inclusive. 
     Q 4  is ##STR6## wherein R 8  is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and R 24  is (a) tetrahydropyranyl, (b) tetrahydrofuranyl, or (c) a group of the formula ##STR7## wherein R 14  is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R 15  and R 16  are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, or, when R 15  and R 16  are taken together, --(CH 2 ) a  -- or --(CH 2 ) b  --O--(CH 2 ) c  -- wherein a is 3, 4, 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4, and wherein R 17   is hydrogen or phenyl. 
     R 1  is 
     (1) --COOR 3   
     (2) --CH 2  OH 
     (3) --CH 2  N(R 9 )(R 18 ) ##STR8## wherein R 3  is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR9## wherein R 10  is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wherein R 11  is hydrogen or benzoyl, or 
     (n) a pharmacologically acceptable cation, wherein R 9  is hydrogen, methyl, or ethyl, and R 18  is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive. 
     R 4  is ##STR10## wherein C g  H 2g  is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR 5  R 6  -- and terminal methyl, wherein R 5  and R 6  are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R 5  and R 6  is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R 5  nor R 6  is fluoro when Z is oxa (--O--); wherein Z represents an oxo atom (--O--) or C j  H 2j  is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR 5  R 6  - and the phenyl ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or -OR 7  - wherein R 7  is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2 or 3, with the proviso that not more than two T&#39;s are other than alkyl and when s is 2 or 3 the T&#39;s are either the same or different. 
     R 12  is alkyl of one to 4 carbon atoms, inclusive. 
     R 19  is chloro, bromo, or iodo. ##STR11## wherein R 24  is (a) tetrahydropyranyl, (b) tetrahydrofuranyl, or (c) a group of the formula ##STR12## wherein R 14  is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R 15  and R 16  are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, or, when R 15  and R 16  are taken together, --(CH 2 ) a  -- or --(CH 2 ) b  --O--(CH 2 ) c  -- wherein a is 3, 4, 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4, and wherein R 17  is hydrogen or phenyl. 
     R 24  is as defined immediately above. 
     X is 
     (1) trans--CH═CH-- 
     (2) cis--CH═CH-- 
     (3) --C.tbd.C-- or 
     (4) --CH 2  CH 2  --. 
     The symbol ˜ (wavy line) indicates attachment in alpha or beta configuration. 
     END OF TABLE 
     There are also provided (4E) compounds of the formula ##STR13## As to &#34;Z&#34; and &#34;E&#34; nomenclature see J. E. Blackwood et al., J. Am. Chem. Soc. 90, 509 (1968). 
     Chart E shows a preferred process for preparing Δ 2  -prostacyclin analogs XXXVIII with the scope of formula XL. All terms such as Q 3 , R 4 , etc. are as defined in the TABLE included herein. The starting materials of formula XXXIII are available by methods disclosed in the predecessor application and are within the scope of 4-halo compounds of formula III described therein. 
     In step (a), compounds XXXIV are formed by blocking C-11 and C-15 hydroxyls of the formula XXXIII compounds. When the blocking group, R 24  is tetrahydropyranyl or tetrahydrofuranyl, the appropriate reagent, e.g., 2,3-dihydropyran or 2,3-dihydrofuran, is used in an inert solvent such as dichloromethane, in the presence of an acid condensing agent such as p-toluene solfonic acid or pyridine hydrochloride. The reagent is used in slight excess, preferably 1.0 to 1.2 times theory. The reaction is carried out at about 20°-50° C. 
     When the blocking group is of the formula ##STR14## CHR 16  R 17 , the appropriate reagent is a vinyl ether, e.g., ethyl vinyl ether, isobutyl vinyl ether or any vinyl ether of the formula R 14  --O--C(R 15 )═CR 16  R 17  wherein R 14 , R 15 , R 16 , and R 17  ##STR15## are as defined herein; or an unsaturated cyclic or heterocyclic compound, e.g., 1-cyclohex-1-yl methyl ether ##STR16## or 5,6-dihydro-4-methoxy-2H-pyran ##STR17## In step (b), the formula-XXXV selenide derivatives are prepared. For background on preparing Δ 2  -prostaglandin analogs by an analogous method, see for example U.S. Pat. No. 4,024,174. The compounds of formula XXXIV are transformed first to 2-lithium derivatives, for example by reaction with a lithium amide formed from a secondary amine such as N-isopropylcyclohexylamine. It is preferred that that reaction be done at a low temperature, as in a Dry Ice bath. Thereafter the formula-XXXV compounds are obtained by reaction with diphenyldiselenide or benzeneselenyl bromide using about 3 equivalents for each molecular equivalent of the C-2 lithium derivative. Here again the preferred temperature is about -78° C. 
     In step (c) the formula-XXXVI Δ 2  intermediates are formed by oxidative elimination. Hydrogen peroxide or sodium periodate are useful. 
     In step (d) the R 24  blocking groups are replaced, as by mild acid hydrolysis, to yield the XXXVII intermediates. 
     Finally in step (e) the formula-XXXVIII enol ethers, i.e. Δ 2  prostacyclin analogs, are obtained by dehydrohalogenation using any of the reagents and conditions known in the art for the prostacyclins, as fully described in the predecessor application. For example, the formula-XXXVII 4-halo compound is treated with a tertiary amine such as 1,5-diazabicyclo[4.3.0]non-5-ene (&#34;DBN&#34;) at about 40° C. In a solvent. 
     Salts such as the preferred alkali metal salts, including sodium, potassium or lithium salts, are obtained simply by saponification of any of these R 12  lower alkyl esters, such as the methyl ester, under mild conditions. 
     Other compounds within the scope of formula XL are obtained by transformations known in the art. For example, other esters are obtained by transesterification or by selection of suitable starting materials or intermediates with the desired ester groups. Amides within the scope of R 1  are obtained by replacing the formula-XXXIII starting material with corresponding 4-halo amides. Compounds wherein  R 20     is other than  R 22    are obtained by known transformations. Thus, the intermediates of formula XXXVI or XXXVII may be converted to Δ 10  compounds, or to 11-hydroxymethyl compounds, or to 11-methylene compounds and finally to the desired formula-XL compound by transformations shown herein or in the predecessor referenced application, or known in the art. Likewise, other forms of Q are obtained by transforming these intermediates or final products. Various forms of R 4  or X are obtained by using the appropriate formula-XXX 4-halo starting materials which are derived from the corresponding PGF 2 α  analogs. 
     The amides are also conveniently prepared by reaction of ammonia or an amine with a mixed anhydride obtained from the sodium salts. The anhydride may be prepared by the reaction of isobutylchloroformate in the presence of a tertiary amine. 
     The (4E) compounds are obtained by replacing the starting materials of Chart E with 4-halo compounds derived from the corresponding trans-Δ 4  -PGF 2 α  compounds. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The invention is further illustrated by, but not limited to, the following examples. 
     All temperatures are in degrees centigrade. 
     &#34;Brine,&#34; herein, refers to an aqueous saturated sodium chloride solution. 
     Chromatography, as used herein, is understood to be chromatography on a silica gel column, and to include elution, collection of fractions, and combinations of those fractions shown by TLC (thin layer chromatography) to contain the desired product free of starting material and impurities. 
     &#34;Drying&#34;, as used herein, refers to contacting a compound, in solution, with an anhydrous agent such as sodium sulfate or magnesium sulfate to remove water, followed by filtering to remove solids. 
     &#34;Concentrating&#34; as used herein, refers to concentration under reduced pressure, preferably at less than 50 mm. and at temperatures below 35° C. 
     Examples 1-33 are in U.S. Pat. No. 4,123,441, incorporated here by reference. 
     EXAMPLE 34 
     (4Z)-9-Deoxy-5,9α-epoxy-Δ 4  -trans-66  2  -PGF 1 , Methyl Ester. (Formula XXXVIII) 
     I. Refer to Chart E. There is first prepared XXXIV, the 11,15-bis(tetrahydropyran-2-yl ether) of the formula-XXXIII iodo compound. The (4R,5R)-4-iodo-9-deoxy-5,9α-epoxy-PGF 1 , methyl ester of Example 6 of the parent application is reacted with excess dihydropyran in methylene chloride in the presence of pyridine hydrochloride at about 25° C. for 6 hr. The reaction mixture is washed with aqueous potassium bicarbonate solution, dried, and concentrated. 
     II. The formula-XXXV selenide derivative is next prepared. To a solution of n-isopropylcyclohexylamine (8.27 mmol) in 30 ml of tetrahydrofuran at -78°, under nitrogen, is added n-butyllithium (4.7 ml, 7.52 mmol, 1.6 in hexane) via syringe. The mixture is stirred for 15 min. and to it is added the product of step I above (3.76 mmol) in 10 ml. of tetrahydrofuran and stirring is continued at -78° C. for an additional 30 min. Diphenyl diselenide (5.64 mmol) in 15 ml. of tetrahydrofuran is then added to the reaction mixture. After stirring at -78° for an additional hour, the Dry Ice bath is removed and the reaction mixture allowed to warm up to 0°. The resulting mixture is poured into 150 ml of saturated aqueous ammonium chloride and 150 ml. of ether. The ether layer is separated and the aqueous layer extracted with ether (800 ml total). The combined ether extracts are washed successively with  40 ml of ice water and 30 ml. of saturated brine. The organic extract is dried over Na 2  SO 4  and concentrated in vacuo to yield crude 2-phenyl-selenide derivative. 
     III. The formula-XXXVI Δ 2  compound is next prepared. A solution of the selenide derivative of part II above (2.88 mmol) in 65 ml. of methylene chloride is treated at about 25° C. with hydrogen peroxide (29 mmol) as a 10% aqueous solution and stirred for one hr. The organic phase is separated, washed with 5% sodium bicarbonate, saturated sodium bicarbonate, and brine, dried, and concentrated. The residue is chromatographed to yield the Δ 2  compound. 
     IV. The THP blocking groups are next removed. The product of Part III is treated at 40° C. with methanol-tetrahydrofuran-water-acetic acid (42:35:21:2) for 4 hr. The mixture is concentrated and again concentrated using benzene as an azeotropic agent. The resulting oily residue is chromatographed to yield the formula-XXXVII compound. 
     V. The title compound is obtained by dehydrohalogenation. The formula-XXXVII iodo ether of Part IV above (1.20 mmol) is dissolved in 33 ml. of benzene and treated with 1.2 ml. of 1,5-diazo-bicyclo[4.3.0]non-5-ene at 40° C. for 1.75 hr. The mixture is cooled to about 25° C., washed with ice water and dried to yield the title compound. 
     EXAMPLE 35 
     (4Z)-9-Deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  PGF 1 , Sodium Salt. 
     A solution of the methyl ester (Example 34), (0.41 mmole) in 5 ml. of methanol is treated with aqueous 0.05 N. sodium hydroxide (9.0 ml., 0.45 mmole). The mixture is stirred at about 25° C. for 48 hr. The mixture is concentrated to remove methanol. The remaining aqueous solution is freeze-dried to yield the title compound. 
     Following the procedures of Examples 34 and 35, but replacing the formula-XXXIII starting material with the appropriate compound, there are prepared for the following compounds, which are methyl esters and sodium salts of the respective prostacyclin analogs: 
     (4Z)-9-deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  -15(S)-15-methyl-PGF 1 , methyl ester and sodium salt 
     (4Z)-9-deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  -16,16-dimethyl-PGF 1 , methyl ester and sodium salt 
     (4Z)-9-deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  -13,14-dihydro-PGF 1 , methyl ester and sodium salt 
     (4Z)-9-deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  -17-phenyl-18,19,20-trinor-PGF 1 , methyl ester and sodium salt 
     (4Z)-9-deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  -16-phenoxy-17,18,19,20-tetranor-PGF 1 , methyl ester and sodium salt 
     (4Z)-9-deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  -16-(m-chlorophenoxy)-17,18,19,20-tetranor-PGF 1 , methyl ester and sodium salt 
     (4Z)-9-deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  -16-(α,α,α-trifluoro-p-tolyloxy)-17,18,19,20-tetranor-PGF 1 , methyl ester and sodium salt 
     (4Z)-9-deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  -13,14-dihydro-16-phenoxy-17,18,19,20-tetranor-PGF 1 , methyl ester and sodium salt 
     (4E)-9-deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  -PGF 1 , methyl ester and sodium salt 
     EXAMPLE 36 
     (4Z)-9-deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  -PGF 1 , Amide (Formula XL) 
     The mixed anhydride is prepared by treating a suspension of the corresponding sodium salt (Example 35) in methylene chloride with a slight excess of isobutylchloroformate in the presence of triethylamine at about 0° C. and continuing the reaction at about 25° C. until the anhydride is formed. Thereafter the mixture is cooled to 0° C. and treated with gaseous ammonia. The mixture is then warmed to 25° C. and filtered. The filtrate is concentrated, then taken up in ethyl acetate and water. The organic phase is washed with water, dried, and concentrated to give the title compound. 
     Following the procedures of Example 36 but replacing that sodium salt with the appropriate sodium salt, the following amides are prepared: 
     4(Z)-9-deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  -PGF 1 , amide 
     4(Z)-9-deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  -13,14-dihydro-16-phenoxy-17,18,19,20-tetranor-PGF 1 , amide 
     4(E)-9-deoxy-5,9α-epoxy-Δ 4  -trans-Δ 2  -PGF 1 , amide.