Tetraenyl prostanoic acid derivatives as prodrugs for the treatment of peptic ulcer disease
This is a division of application Ser. No. 07/546,218, filed Jun. 28, 1990, now U.S. Pat. No. 5,089,524. 
    
    
     BACKGROUND OF THE INVENTION 
     This invention relates to a novel class of prostanoic acid derivatives, to a method of treating peptic ulcer disease, and to pharmaceutical compositions containing these derivatives. 
     It is known that certain prostaglandins have been found to be useful in the treatment of peptic ulcer disease. It is further known that a specific class of these prostaglandins, namely tetraenyl, 16-hydroxy prostaglandins which are represented by the following structural formula ##STR2## wherein R represents hydrogen or lower alkyl having 1 to 6 carbon atoms; R 1  represents vinyl, or lower alkyl having 1 to 4 carbon atoms and the wavy line represents R or S stereochemistry; R 2 , R 3  and R 4  are hydrogen or lower alkyl having 1 to 4 carbon atoms or R 2  and R 3  together with carbon Y form a cycloalkenyl having 4 to 6 carbon atoms or R 3  and R 4  together with carbons X and Y form a cycloalkenyl having 4 to 6 carbons have potent gastric antisecretory and cytoprotective properties which makes them effective in the treatment of peptic ulcer disease. These compounds are described further in U.S. Pat. No. 4,683,328. 
     Applicants have discovered that certain 16-alkyl tetraenyl prostanoic acid derivatives which are represented by formula I function as in vivo precursors or pro drugs of the aforementioned 16-hydroxy tetraenyl prostanoic acid derivatives which are represented by formula IV (Scheme A). In order for the compounds of formula I to exert their antisecretory and cytoprotective properties they must be &#34;transformed&#34; into the active species which are represented by formula IV. This &#34;transformation&#34; takes place in an acidic medium. Thus the pro drugs must be administered by a method that would allow for exposure to said condition. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The specific prodrugs of this invention are the compounds represented by the following structural formula ##STR3## or a pharmaceutically acceptable base addition salt when R is hydrogen thereof: wherein 
     R is hydrogen or alkyl having 1 to 6 carbon atoms; 
     R 1  is alkyl having 1 to 6 carbon atoms; 
     R 2 , R 3  and R 4  are each independently hydrogen or alkyl having 1 to 4 carbon atoms or R 3  and R 4  together with carbons X and Y form a cycloalkyl having 4 to 6 carbon atoms or a cycloalkenyl having 4 to 6 carbon atoms with the proviso that the cycloalkenyl group is only present when A is present; 
     A is an optionally present alkoxy group having 1 to 6 carbon atoms with the proviso that when A is present the double bond at carbon 16 and carbon 18 of formula I shifts to carbon 17 and carbon 19, respectively; 
     B is an optionally present group represented by the following formula 
     
         OR.sub.5 
    
      wherein 
     R 5  is hydrogen, alkyl having 1 to 4 carbon atoms or acyl which is represented by the following formula ##STR4##  wherein R 6  is alkyl having 1 to 6 carbon atoms with the proviso that B is present when A is not present. 
     A preferred embodiment of the present invention are compounds of the formula ##STR5## wherein R is alkyl having 1 to 6 carbon atoms; 
     R 1  is alkyl having 1 to 6 carbon atoms; 
     R 2  is hydrogen; 
     R 3  and R 4  together with carbon X and Y form a cycloalkyl having 4 to 6 carbon atoms; 
     R 5  is hydrogen, alkyl having 1 to 4 carbon atoms or acyl which is represented by the following formula ##STR6##  wherein R 6  is alkyl having 1 to 6 carbon atoms. 
     Exemplifying this embodiment are the following compounds 
     (±)-methyl 7-[3α-hydroxy-2β-[6-(2-hydroxy-Z-cyclopentylidine)-4-methyl-1E,4E-hexadienyl]-5-oxo-1α-cyclopentyl]-4Z-heptenoate 
     and 
     (±)-methyl 7-[2β-(6-(2-(acetyloxy)-Z-cyclopentylidine]-4-methyl-1E,4E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4-Z-heptenoate. 
     Another preferred embodiment of the present invention are compounds of the formula ##STR7## wherein R is alkyl having 1 to 6 carbon atoms; 
     R 1  is alkyl having 1 to 6 carbon atoms; 
     R 2 , R 3  and R 4  are each independently hydrogen or alkyl having 1 to 4 carbon atoms; and 
     R 5  is hydrogen, alkyl having 1 to 4 carbon atoms or acyl which is represented by the following formula ##STR8##  wherein R 6  is alkyl having 1 to 6 carbon atoms. 
     Exemplifying this embodiment are the following compounds 
     (±)-methyl 7-[3α-hydroxy-2β-(8-hydroxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate 
     and 
     (±)-methyl 7-[3α-hydroxy-2β-(8-methoxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate. 
     A further preferred embodiment of the present invention are compounds of the formula ##STR9## wherein R is alkyl having 1 to 6 carbon atoms; 
     R 1  is alkyl having 1 to 6 carbon atoms; 
     R 2 , R 3  and R 4  are each independently hydrogen or alkyl having 1 to 4 carbon atoms; and 
     R 7  is alkyl having 1 to 6 carbon atoms. 
     Exemplifying this embodiment is the following compound 
     (±)-methyl 7-[2β-(4,8-dimethyl-4-methoxy-1E,5E,7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate. 
     As used herein the term &#34;alkyl having 1 to 6 carbon atoms&#34; refers to straight chain or branched chain hydrocarbon groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl and isohexyl. 
     As used herein the term &#34;cycloalkyl having from 4 to 6 carbon atoms&#34; included cycloalkyl groups having from four to six carbon atoms. Illustrative of such cycloalkyl groups are cyclobutyl, cyclopentyl and cyclohexyl. 
     As used herein the term &#34;cycloalkenyl having 4 to 6 carbon atoms&#34; included cycloalkenyl groups having from four to six carbon atoms. Illustrative of such cycloalkenyl groups are cyclobutenyl, cyclopentenyl and cyclohexenyl. 
     As used herein the term &#34;alkoxy wherein the alkyl is 1 to 6 carbon atoms&#34; refers to straight or branched chain ethers. Illustrative of such groups are methoxy, ethoxy, propoxy, butoxy, isopropoxy and the like. 
     Compounds of general Formula I can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or diastereoisomeric mixtures thereof. The optical isomers and mixtures thereof can be obtained by processes described in U.S. Pat. Nos. 4,683,328 and 4,863,961, by formation and chromatographic separation of diastereoisomeric derivatives and then regeneration of the resolved product. 
     Within this class of prostaglandin, compounds and derivatives of the invention are the pharmaceutically-acceptable salts of the compounds of Formula I when R═H. The term &#34;pharmaceutically-acceptable salts&#34; embraces salts commonly used to form alkali metal salts. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include alkali metal salts, e.g., salts of sodium and potassium, and ammonium salts and amine salts. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate base with the compound of Formula I. 
     The compounds of formula (I) may be prepared in accordance with the following procedures. ##STR10## wherein R, R 1 , R 2 , R 3 , R 4  and R 5  are defined as before. This general reaction as well as specific preparations of compounds encompassed by Formula IV are described in U.S. Pat. No. 4,683,328. Compounds of formula IV will undergo acid catalyzed allylic rearrangement to give the compounds of formula II. ##STR11## wherein R, R;, R 2 , R 3 , R 4 , R 5  and R 7  are defined as before. Scheme B follows the Scheme A synthetic route to the preparation of the di-silylated precursors of Formula IV, Scheme A. The di-silylated intermediates are then treated with pyridinium p-toluenesulfonate to give the compounds of Formula II and Formula III which are separated by chromatographic methods. 
     This invention also relates to a method of treatment for subjects suffering from peptic ulcer disease, and more specifically, a method of treatment involving the administration of compounds which are represented by formula I as the active ingredient. The compounds of the present invention must be administered by an oral route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds of the present invention required to prevent or arrest the progress of the medical condition are readily ascertained by one of ordinary skill in the art. 
     Accordingly, the invention provides a class of novel pharmaceutical compositions comprising one or more compounds of the present invention in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as &#34;carrier&#34; materials) and if desired other active ingredients. 
     For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit contained in a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. These may with advantage contain an amount of active ingredient from about 1 to 500 μg, preferably from about 5 to 200 μg. A suitable daily dose for a subject may vary widely depending on the condition of the patient and other factors. However, a dose of from about 0.01 to 1000 ug/kg body weight, particularly from about 0.1 to 100 ug/kg body weight may be appropriate. 
     For therapeutic purposes, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. For per os administration, the compounds may be admixed with lactose, sucrose, starch power, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and thus tableted or encapsulated for convenient administration. 
     Alternatively, the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants are well and widely known in the pharmaceutical art. Appropriate dosages, in any given instance, of course depend upon the nature and severity of the condition treated and the species of mammal involved, including its size and any individual idiosyncrasies. 
     Representative carriers, diluents and adjuvants include for example, water, lactose, gelatin, starches, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical compositions may be made up in a solid form such as granules or powders or in a liquid form such as solutions, suspensions or emulsions. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. 
     The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated. For example, a formulation intended for the oral administration of subjects may contain from 1 μg to 500 μg of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 μg to about 500 μg of active ingredient. 
     It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. 
     The following Examples are intended to further illustrate the present invention and not to limit the invention in spirit or scope. 
     EXAMPLE 1 
     Preparation of (±)-methyl 7-[3α-hydroxy-2β-(6-(2-hydroxy-Z-cyclopentylidine)-4-methyl-1E,4E-hexadienyl]-5-oxo-1α-cyclopentyl]-4Z-heptenoate ##STR12## 
     The di-silylated intermediate (±)-methyl 7-[2β-(6-(1-cyclopenten-1-yl)-4-methyl-4-[trimethylsilyl)oxy]-1E,5E-hexadienyl]-5-oxo-3α-[(triethylsilyl)-1α-cyclopentyl]-4Z-heptenoate (830 mg) was dissolved in a mixture of 18 ml of acetone and 2 ml H 2  O and 26 mg of pyridinium p-toluenesulfonate (PPTS) was added. The solution was allowed to stand at room temperature for about 24 hours. The solution was reduced in volume on a rotary evaporator and the resulting mixture was diluted with ether and washed with water and then saturated sodium chloride solution. The organic layer was dried over sodium sulfate (Na 2  SO 4 ) and evaporated on a rotary evaporator. The residue was chromatographed on silica gel with 70% ethyl acetate/30% hexane as eluent to give 15 mg of the title compound and 120 mg of a mixture of deprotected starting material. 
     NMR data for title compound: 
       1  H (CDCl 3 ) δ 1.77 (s,C-16 CH 3 ); 2.24, 2.75 (multiplets C-10 H&#39;s); 2.86 (d C-15 H&#39;s); 4.49 (broad, s,C-20 H); 6.37 (d, C-17 H); 5.92 (d, C-18 H). This compound is a mixture of eight isomers at C-16 (E &amp; Z), C-18 (E &amp; Z) and C-20 (R &amp; S). 
     EXAMPLE 2 
     Preparation of (±)-methyl 7-[3α-hydroxy-2β-(6-(2-hydroxy-Z-cyclopentylidine)-4-methyl-1E, 4E-hexadienyl]-5-oxo-1α-cyclopentyl]-4Z-heptenoate ##STR13## 
     Alternate Method 
     (±)-methyl 7-[2β-(6-(1-cyclopenten-1-yl)-4S-hydroxy-4-methyl-1E,5E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate (100 mg) dissolved in 2 ml THF was added in one portion to 15 ml of fresh dog gastric juice (pH˜1) with stirring. The turbid mixture was stirred for 1 hour at room temperature. The mixture was extracted with ether and then twice with ethyl acetate. The organic extracts were combined, washed with H 2  O and then saturated sodium chloride solution, dried (Na 2  SO 4 ) and evaporated. The residue was chromatographed on silica gel using 55% ethyl acetate/45% hexane as eluent to give 3.4 mg of the title compound and a mixture of (±)-methyl 7-[2β-(6-(1-cyclopenten-1-yl)-4R-hydroxy-4-methyl-1E, 5E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate and (±)-methyl 7-[2β-(6-(1-cyclopenten-1-yl)-4S-hydroxy-4-methyl-1E,5E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate. 
     NMR data for title compound: 
       1  H (CDCl 3 ) δ 1.77 (s,C-16 CH 3 ); 2.24, 2.75 (multiplets C-10 H&#39;s); 2.86 (d C-15 H&#39;s); 4.49 (broad, s,C-20 H); 6.37 (d, C-17 H); 5.92 (d, C-18 H). This compound is a mixture of eight isomers at C-16 (E &amp; Z), C-18 (E &amp; Z) and C-20 (R &amp; S). 
     EXAMPLE 3 
     Preparation of (±)-methyl 7-[3α-hydroxy-2β-(8-methoxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate ##STR14## 
     and (±)-methyl 7-[2β-(4,8-dimethyl-4-methoxy-1E,5E-7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate ##STR15## 
     A solution of 92 mg of the disilylated prostaglandin in 4 ml of methanol and several crystals of pyridinium p-toluenesulfonate was allowed to stand at room temperature for 3 hours. The solution was reduced in volume on a rotary evaporator, diluted with ether and washed twice with H 2  O, once with saturated NaCl solution, dried (Na 2  SO 4 ) and evaporated. Chromatography of the residue on silica gel with 50% ethyl acetate/50% hexane as eluent gave 13 mg of (±)-methyl 7-[3α-hydroxy-2β-(8-methoxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate. 
     NMR:  1  H (CDCl 3 ) δ 1.21 (s,C-20 CH 3 ); 3.18 (s,C-20 OCH 3 ); 2.24, 2.76 (m,C-10 H&#39;s); 1.79 (s,C-16 CH 3 ); 5.89 (d, C-17 H); 6.37 (dd, C-18 H); 5.59 (d, C-19 H). 
     This compound is an approximate 3:2 mixture of E and Z isomers at C-16 and 9.1 mg of (±)-methyl 7-[2β-(4,8-dimethyl-4-methoxy-1E,5E,7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate. 
     NMR:  1  H (CDCl 3 ) δ 1.28 (s,C-16 CH 3 ); 1.78, 1.79 (s,C-20 CH 3 ); 3.17 (s,C-16 OCH 3 ); 5.45, 5.46 (m,C-17 H); 5.84 (d,C-19 H); 6.34, 6.35 (m,C-18 H). 
     EXAMPLE 4 
     Preparation of (±)-methyl 7-[3α-hydroxy-2β-(8-hydroxy-4,8-dimethyl-1E,4,6-nonatrienyl)-5-oxo-1α-cyclopentyl]-4Z-heptenoate ##STR16## 
     A mixture of (±)-methyl 7-[2β-(4,8-dimethyl-4R-hydroxy-1E,5E, 7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate and (±)-methyl 7-[2β-(4,8-dimethyl-4S-hydroxy-1E,5E,7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate (90 mg) was dissolved in a mixture of 6 ml of acetone and 2 drops of 0.5N HCl and allowed to stand at room temperature for 3 hours. The solution was diluted with ether and washed successively with dilute NaHCO 3  solution and saturated NaCl solution and evaporated. The residue was chromatographed with 65% ethyl acetate/35% hexane as eluent to give 17 mg of the title compound. 
     NMR:  1  H(CDCl 3 ) δ 1.35 (s,C-20 CH 3 ); 1.77 (s,C-16 CH 3 ); 5.77 (m,C-19 H); 5.86 (m,C-17 H); 5.95 (m,C-18 H). 
     EXAMPLE 5 
     Preparation of (±)-methyl 7-[2β-(6-(2-(acetyloxy)-Z-cyclopentylidine]-4-methyl-1E,4E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate ##STR17## 
     (±)-methyl 7-[2β-(6-(1-cyclopenten-1-yl)-4S-hydroxy-4-methyl-1E,5E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate (0.13 g) was mixed with 3 ml glacial acetic acid at room temperature and stirred under N 2  for 24 hours. The reaction was quenched by addition to 50 ml saturated NaHCO 3  solution and was extracted with 2 portions of ethyl ether. The combined ether extracts were washed with brine, and dried (Na 2  SO 4 ) Chromatography on silica (45% Ethyl acetate/55% Hexane) gave 52 mg of the title compound. 
     NMR:  1  H (CDCl 3 ) δ 2.06 (s,acetyl CH 3 ); 1.77 (s,C-16 CH 3 ); 5.49, 5.53 (m,C-20 H); 5.90, 5.94 (d,C-18 H); 6.41, 6.47 (d,C-17 H). 
     This compound is an approximate 4:1 mixture of isomers, probably C-20 R and S diastereomers. 
     EXAMPLE 6 
     In vitro regeneration of 16-hydroxy compounds A and B from corresponding prodrug. 
     (±)-methyl 7-[2β-(4,8-dimethyl-4R-hydroxy-1E,5E,7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate (Compound A) ##STR18## and (±)-methyl 7-[2β-(4,8-dimethyl-4S-hydroxy-1E,5E,7E-nonatrienyl)-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate (Compound B) ##STR19## 
     5 mg of the product of Example 4 was dissolved in 1 ml of a 3:1:1 mixture of acetic acid, THF (tetrahydrofuran) and H 2  O and allowed to stand about 1 hour at room temperature. Thin layer monitoring with standards of Compounds A and B indicated the generation of the title compounds and the diminishment of starting material. 
     EXAMPLE 7 
     (±)-Methyl 7-[3α-hydroxy-2β-[6-(2-hydroxy-Z-cyclopentylidine)-4-methyl-1E,4E-hexadienyl]-5-oxo-1α-cyclopentyl]-4Z-heptenoate 
     Compound of Example 1 
     (±)-methyl 7-[3α-hydroxy-2β-(8-hydroxy-4,8-dimethyl-1E,4,6-nonatrienyl-5-oxo-1α-cyclopentyl]-4Z-heptenoate (Compound of Example 4) and 
     (±)-methyl 7-[2β-[6-(2-(acetyloxy)-Z-cyclopentylidine)-4-methyl-1E,4E-hexadienyl]-3α-hydroxy-5-oxo-1α-cyclopentyl]-4Z-heptenoate (Compound of Example 5) were tested for gastric antisecretory activity in the Pavlov Pouch Dog Test. The procedure for this test is described as follows. 
     Adult female beagles (6-11 kg), with innervated (Pavlov) gastric pouches, were food deprived with access to water 24 h prior to experiments. Following a 30 min basal collection period, the prostaglandin in a buffer/ethanol vehicle was administered into the pouch through a Thomas cannula followed by either a saline or 0.1N HCl flush. Thirty minutes later the gastric pouch was emptied and gastric secretion was stimulated by feeding 10-12 oz of canned dog food (Evanger&#39;s Dog and Cat Food Co., Inc., Wheeling, Ill.). Gastric juice samples were collected over a 4 h period at 30 min intervals. Total acid output (mequiv/30 min) was determined for each collection period by multiplying the volume of secretion (mL/30 min) and the acidity (mequiv/L). Percent reduction of total acid output from control was calculated over each 4 h experiment. 
     The compounds of Example 1, 4 and 5, have the following results: 
     
         ______________________________________                                    
                                 % Decrease in 4 hr                       
Compound of                                                               
         n     Flush     Dose    Total Acid Output                        
______________________________________                                    
Example 1                                                                 
         4     saline    0.3 μg/kg                                     
                                 31                                       
         2     0.1 NHCl  0.3 μg/kg                                     
                                 87                                       
Example 4                                                                 
         2     saline    0.3 μg/kg                                     
                                 28                                       
         2     0.1 NHCl  0.3 μg/kg                                     
                                 76                                       
Example 5                                                                 
         2     saline    0.3 μg/kg                                     
                                 88                                       
         2     0.1 NHCl  0.3 μg/kg                                     
                                 73                                       
______________________________________