7-[5-Oxo-3-hydroxy-2-(3-substituted)-3-hydroxypropyl)-1- cyclopentene]-heptanoic acids and derivatives thereof

7-[5-oxo-3-hydroxy-2-(3-substituted)-3-hydroxypropyl)-1-cyclopentene]-hepta noic acids having the following general formula ##STR1## wherein X is oxygen or hydroxyl, R.sub.1 and R.sub.3 are independently hydrogen or methyl, and R.sub.2 is --(CH.sub.2)n-Y where n is an integer from 0 through 4 inclusive, and Y is phenyl, or a cycloalkyl group having 4 to 6 carbon atoms. Said acids as well as certain derivatives thereof are useful as nasal decongestants, inhibitors of gastric secretion, inhibitors of platelet aggregation, blood additives, smooth muscle stimulators, hypotensive agents, labor inducers, and in controlling ovulation.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to novel 11,15-dihydroprostenoic acid 
derivatives and the pharmacologically acceptable salts thereof which are 
useful as inhibitors of gastric secretion. 
2. Description of the Prior Art 
U.S. Pat. No. 3,812,172 describes 15-methyl dihydroprostoglandin E 
(dihydro-PGE), derivatives which are disclosed to be useful as nasal 
decongestants, inhibitors of gastric secretion, inhibitors of platelet 
aggregation, blood additives, smooth muscle stimulators, hypotensive 
agents, labor inducers, and in controlling ovulation. 
The compounds of the present invention differ from the compound disclosed 
in U.S. Pat. No. 3,812,172 in that they are unsaturated between C.sub.8 
and C.sub.12 and they have a phenyl or cycloalkyl group attached to C-15 
through an alkylene linkage. The compounds of the present invention also 
differ from prior art compounds in that they do not exhibit the 
undesirable side effect of smooth muscle stimulation. 
SUMMARY OF THE INVENTION 
The present invention provides novel 8(12)-prostenoic acid derivatives 
represented by formula I 
##STR2## 
wherein X is oxygen, alpha-hydroxyl or beta-hydroxyl; R.sub.1 and R.sub.3 
may be alike or different and are hydrogen or an alkyl having 1 to 4 
carbon atoms; R.sub.2 is --(CH.sub.2).sub.n --Y wherein n is an integer 
from 0 to 4 inclusive, and Y is phenyl or a cycloalkyl having 4 to 6 
carbon atoms; solvates thereof and pharmacologically acceptable salts 
thereof. When X is oxygen, it is bonded to a carbon atom on the main ring 
by a double bond, and when X is hydroxyl there is a single bond. The bond 
between the second and third carbon atoms on the lower side chain may be a 
single or a double bond. 
Compounds of the present invention are useful as anti-secretory agents when 
administered intravenously in dosages of from 10 .mu.g to 1 mg/kg daily; 
preferred dosage is from 50 to 100 .mu.g/kg. Preferably the compounds are 
administered in divided dosages, i.e. 3 to 4 times daily. The compounds 
can also be administered in such oral unit dosage forms such as tablets, 
capsules, pills, powders, or granules. 
Surprisingly the compounds of this invention are substantially devoid of 
the undesirable side effect of smooth muscle stimulation. 
Each of the novel prostanoic acid derivatives of this invention is 
encompassed by one of the following formulas or by the combination of that 
formula and its mirror image: 
##STR3## 
wherein X, R.sub.1, R.sub.2 and R.sub.3 are as defined in formula I. 
The terms "alpha-hydroxyl" and "beta-hydroxyl" refer, respectively to the 
following configurations: 
##STR4## 
In formula II the configuration of the hydroxyl at C.sub.15 is S and in 
formula II the hydroxyl at C.sub.15 is in the unnatural R configuration. 
See J. Chem. Education, 41:116 (1964) for a discussion of S and R 
configuration. 
The present invention includes within its scope solvates in which 
pharmacologicaly insignificant amounts of solvent are present and 
pharmacologically acceptable salts. Also included within the scope of the 
invention are intermediates in the preparation of the 8(12)-prostenoic 
acid derivatives of this invention. Said intermediate compounds include 
(.+-.)-9,15-dioxo-11-hydroxy-17-phenyl-18,19,20-trisnor-prosta-8(12)-enoic 
acid methyl ester and 
(.+-.)-9,15-dioxo-11-hydroxy-17-cyclohexyl-18,19,20-trisnorprosta-8(12), 
13 (14)-dien-1-oic acid, and have the following general formula: 
##STR5## 
wherein R.sub.4 is hydrogen or methyl, R.sub.5 is --(CH.sub.2)-Y wherein n 
is an integer from 0 to 4 inclusive, and Y is a cycloalkyl having 4 to 6 
carbon atoms. The solvates and salts of said intermediate compounds are 
also within the scope of the present invention. 
Generally speaking, the compounds of the present invention are conveniently 
prepared by reacting the appropriate 2-formyl-3-hydroxy-5-substituted 
cyclopentene-1-heptanoic acid or ester, the preparation of which is 
described in U.S. Pat. No. 3,932,467, with a substituted carbonylmethylene 
triphenylphosphorane to give the 
15-oxo-11-hydroxy-9-substituted-prosta-8(12),13-dienoic acid or ester. 
This compound or its silyl ether is reacted with a Grignard reagent to 
give the corresponding 15-hydroxy-15-alkyl compound which may be reduced 
to remove the unsaturation at C.sub.13 -C.sub.14. The preparation is 
summarized by the following reaction scheme wherein X, R.sub.1, R.sub.2 
and R.sub.3 are defined as above. 
##STR6## 
The anti-secretory activity of the compounds of this invention was 
initially established in the Heidenhain pouch dog assay which evaluates 
inhibition of gastric secretion stimulated by secretogogues such as 
histamine and pentogastrin. The specific assay useds to detect gastric 
antisecretory activity is conducted as follows: 
Adult female mongrel dogs weighing 13-20 kg are prepared with denervated 
fundic Heidenhain pouches. After a recovery period of at least 4 weeks 
following surgery, the animals are fasted for approximately 20 hours, then 
are placed in Pavlov stands and infused intravenously with saline 
solution. The pouched secretions are collected every 15 minutes and 
measured for volume and total acidity by titration with 0.1 N sodium 
hydroxide in pH 7.0. Following a 30 minute basal secretion the dogs are 
infused with a saline solution of histamine dihydrochloride at a dose of 
1.0 mg/hr. The volume of the diffusion is kept at approximately 13 ml/hr. 
A steady state plateau of gastric secretion is obtained approximately 1 
hour following the start of histamine infusion, at the end of which time 
the test compound dissolved in an ethanolic iso-osmotic phosphate buffer 
solution is administered by a single intravenous injection. The duration 
of the anti-secretory effects is determined and the side-effects, if any, 
recorded. The compound is rated active if statistically significant 
inhibition of secretory parameters occur following compound treatment.

The following examples further illustrate the present invention. These 
examples are given by way of illustration only and are not to be construed 
as limiting the invention either in spirit or in scope as many 
modifications both in materials and in methods will be apparent from this 
disclosure to those skilled in the art. In these examples, temperatures 
are given in degrees Centigrade (C.degree.) and quantities of materials in 
parts by weight unless parts by volume is indicated. The relationship 
between parts by weight and parts by volume is the same as that existing 
between grams and milliliters. 
EXAMPLE 1 
Preparation of (.+-.)-9-oxo-11,15-dihydroxy-17-phenyl-18,19,20-trisnor 
prost-8(12)-en-1-oic acid methyl ester. 
A solution of 475 mg (1.15 mmole) of 
(.+-.)-9-oxo-11,15-dihydroxy-17-phenyl-18,19,20-trisnor-prosta-8(12),13(14 
)-dienoic acid methyl ester in 25 ml of dioxane was hydrogenated in the 
presence of Raney Nickle at atmospheric pressure and room temperature for 
a period of six hours. The catalyst was removed by filtration and washed 
with dioxane. The filtrate was concentrated under reduced pressure to give 
an oil. Low pressure chromatography of the oil on Woelm silica provided 
(.+-.)-9-oxo-11,15-dihydroxy-17-phenyl-18,19,20-trisnor-prost-8(12)-enoic 
acid methyl ether which exhibits the following nuclear magnetic resonance 
spectras: NMR (CDCl.sub.3): .delta. 7.22 (S,5); 4.75 (m,1); 3.70 (m,1); 
3.67 (S,3) and is represented by the formula 
##STR7## 
EXAMPLE 2 
Preparation of 
(.+-.)-9-oxo-11,15-dihydroxy-15-methyl-17-phenyl-18,19,20-trisnor-prosta-8 
(12),-13(14)-dienoic acid. A solution of 4.4 g of 
(.+-.)9,15-dioxo-11-hydroxy-17-phenyl-prost-8(12),13(14)-dien-1-oic acid 
in 230 ml of tetrahydrofuran was cooled to -70.degree. C. under a nitrogen 
atmosphere. A solution of 30 ml of 2.74 M methyl magnesium chloride in 
tetrahydrofuran was added dropwise with stirring while maintaining the 
temperature in about -70.degree. C. Stirring was continued at -70.degree. 
C. for two hours then the mixture was poured onto ice and aqueous citric 
acid. A small amount of sodium chloride was added and the mixture was 
extracted twice with ethyl acetate. The combined organic extracts were 
washed twice with cold, dilute aqueous sodium chloride, dried over 
anhydrous sodium sulfate, and concentrated under reduced pressure. The 
residue was purified by low pressure liquid chromatography on silica gel 
(Silic AR CC-4) using mixtures of methylene chloride-ethyl acetate as 
eluate to give an oil which was an epimeric mixture of 
(.+-.)-9-oxo-11,15-dihydroxy-15-methyl-17-phenyl-18,19,20-trisnor-prosta-8 
(12),13(14)-dienoic acid. This product exhibits the following nuclear 
magnetic resonance spectra: NMR(CDCl.sub.3): .delta. 7.20(S,5); 6.67(S,2); 
6.22(broad S,2); 5.04(m,1); 1.40(S,3) and is represented by the formula 
##STR8## 
EXAMPLE 3 
Preparation of 
(.+-.)-9,11,15-trihydroxy-15-methyl-17-phenyl-18,19,20-trisnor-prosta-8(12 
),13(14)-dienoic acid. 
A solution of 495 mg (1.2 mmole) of 
(.+-.)-9-oxo-11,15-dihydroxy-15-methyl-17-phenyl-18,19,20-trisnor-prosta-8 
(12),13(14)-dien-1-oic acid in 25 parts by volume of tetrahydrofuran is 
stirred and cooled to -70.degree. C. under a nitrogen atmosphere. A 
solution of 12 ml of 0.5 M lithium perhydroborophenalyl borohydride in 
tetrahydrofuran is added dropwise while maintaining a temperature of about 
-70.degree. C. The solution is held at -70.degree. C. and stirred for 45 
minutes then carefully poured into ice water. The mixture is washed twice 
with ether to remove any neutral material. The aqueous phase is acidified 
with citric acid and extracted three times with ethyl acetate. The organic 
solutions are combined, washed 3 times with cold water, dried over 
anhydrous sodium sulfate, then concentrated under reduced pressure to give 
an oil. Low pressure liquid chromatography of the oil on Silic AR CC-4 
gives 
(.+-.)-9,11,15-trihydroxy-15-methyl-17-phenyl-18,19,20-trisnor-prosta-8(12 
),13(14)-dienoic which exhibits the following nuclear magnetic resonance 
spectra: NMR(CHCl.sub.3) .delta. 7.22(S,5); 6.28(m2); 4.8-4.2(complex,4); 
1.40(S,3) and is represented by the formula 
##STR9## 
EXAMPLE 4 
Preparation of 
(--)-9,15-dioxo-11-hydroxy-17-cyclohexyl-18,19,20-trisnor-prosta-8(12),13( 
14)-dienoic acid. 
About 25 g of crude 
(.+-.)-2-formyl-3-hydroxy-5-oxo-1-cyclopentene-1-heptanoic acid is 
dissolved in 250 ml of tetrahydrofuran acid reacted with 35 g of 
3-cyclohexyl-propionyl-methylene(triphenyl)phosphorane. After standing at 
room temperature for seven days in a stoppered flask the reaction mixture 
is concentrated under vacuum and the residue is azeotroped with toluene to 
remove the last traces of tetrahydrofuran. The residue is twice subjected 
to low pressure chromatography on Silic AR CC-4 silica gel to give 
(.+-.)-9,15-dioxo-11-hydroxy-17-cyclohexyl-18,19,20-trisnor-prosta-8(12),1 
3(14)-dienoic acid an almost colorless oil exhibiting the following nuclear 
magnetic resonance spectra: NMR (CHCl.sub.3) .delta. 7.50(d,1); 7.20(d,1); 
5.11(m,1) and represented by the formula 
##STR10## 
EXAMPLE 5 
Preparation of 
(.+-.)-9-oxo-11,15-dihydroxy-15-methyl-17-cyclohexyl-18,19,20 trisnor-pros 
ta-8(12),13(14)-dien-1-oic acid. 
A solution of 3 g of 
(.+-.)-9,15-dioxo-11-hydroxy-17-cyclohexyl-8(12),13(14)-dien-1-oic acid in 
300 ml of tetrahydrofuran is cooled to -70.degree. C. under a nitrogen 
atmosphere. A solution of 30 ml of 2.5 M methylmagnesium chloride in 
tetrahydrofuran is added dropwise at -70.degree. C. The reaction mixture 
is stirred for 90 minutes at -70.degree. C. then poured into ice and 
aqueous citric acid. The mixture is extracted twice with ethyl acetate. 
The combined organic solutions are washed with cold, dilute aqueous sodium 
chloride, dried over anhydrous sodium sulfate, then concantrated to an oil 
under reduced pressure. This crude product is purified by low pressure 
liquid chromatography on Silic AR CC-4 silica gel using mixtures of 
toluene and ethyl acetate as eluant to give an epimeric mixture obtained 
as an oil which exhibits the following nuclear magnetic resonance spectra: 
NMR (CDCl.sub.3) .delta. 6.68(broad S,2); 5.42(broad m,3); 5.10(m,1); 
1.38(S,3) and is represented by the formula 
##STR11##