# Patent

## Title
Esters of p-carbonylphenoxy-isobutyric acids

## Abstract

This is a continuation, of application Ser. No. 531,991, filed Dec. 12, 1974. Now abandoned, which is a division of Ser. No. 431,598, filed Jan. 8, 1974, now U.S. Pat. No. 3,931,281.

## Background
This invention relates to novel ester derivatives of prostaglandin A.sub.2 (hereinafter identified as "PGA.sub.2 "), 15-alkyl-PGA.sub.2, 15(R)-15-alkyl-PGA.sub.2, and their racemic forms, and to processes for producing them.

PGA.sub.2 is represented by the formula: ##STR1## A systematic name for PGA.sub.2 is 7-}2.beta.-[(3S)-3-hydroxy-trans-1-octenyl]-5-oxo-1.alpha.-cyclo-3-penteny l]-cis-5-heptenoic acid. PGA.sub.2 is known to be useful for a variety of pharmacological and medical purposes, for example to reduce and control excessive gastric secretion, to increase the flow of blood in the mammalian kidney as in cases of renal dysfunction, to control spasm and facilitate breathing in asthmatic conditions, and as a hypotensive agent to reduce blood pressure in mammals, including humans. See Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and references cited therein. As to racemic PGA.sub.2, see for example J. Martel et al., Tetrahedron Lett. 1491 (1972).

The 15-alkyl-PGA.sub.2 analog and its 15(R) epimer are represented by the formula: ##STR2## wherein Y' is ##STR3## following the usual convention wherein broken line attachment of hydroxy to the side chain at carbon 15 indicates the natural of "S" configuration and solid line attachment of hydroxy indicates the epi or "R" configuration. See for example Nugteren et al., Nature 212, 38 (1966) and Cahn, J. Chem. Ed. 41, 116 (1964). The 15-alkyl-and 15(R)-15-alkyl-PGA.sub.2 analogs in their optically active and racemic forms are known. See for example Belg. Patent No. 772,584, Derwent Farmdoc No. 19694T. These analogs are also useful for the above-described pharmacological purposes.

Esters of the above compounds are known, wherein the hydrogen atom of the carboxyl group is replaced by a hydrocarbyl or substituted hydrocarbyl group. Among these is the methyl ester of PGA.sub.2 (J.P. Lee et al., Biochem. J. 105, 1251 (1967)).

It is a purpose of this invention to provide novel ester derivatives of prostaglandin PGA.sub.2, 15-alkyl-PGA.sub.2, 15(R)-15-alkyl-PGA.sub.2, and their racemic forms. It is a further purpose to provide such esters derived from substituted phenols and naphthols. It is a further purpose to provide such esters in a free-flowing crystalline form. It is still a further purpose to provide novel processes for preparing these esters.

The presently described esters include compounds represented by the generic formula: ##STR4## wherein Z is the substituted phenyl or naphthyl group as defined immediately below, and Y is ##STR5## i.e. esters of PGA.sub.2, 15-methyl-PGA.sub.2, and 15(R)-15-methyl-PGA.sub.2, 15-ethylPGA.sub.2, and 15(R)-15-ethyl-PGA.sub.2 ; and also the racemic compounds represented by each respective formula and the mirrow image thereof; Z being represented by ##STR6##

For example, PGA.sub.2, p-acetamidophenyl ester, is represented by formula III when Y is ##STR7## and Z is A, i.e. ##STR8## and is conveniently identified herein as the PGA.sub.2 ester of formula III-A. Racemic compounds are designated by the prefix "racemic" or "dl"; when the prefix is absent, the intent is to designate an optically active compound. Racemic 15-methyl-PGA.sub.2, p-benzamidophenyl ester, corresponds to formula III wherein Y is ##STR9## and Z is B, i.e. ##STR10## including or course not only the optically active isomer represented by formula III but also its mirror image.

The novel formula-III compounds and corresponding racemic compounds of this invention are each useful for the same purposes as described above for PGA.sub.2 and are used for those purposes in the same manner known in the art, including oral, sublingual, buccal, rectal, intravaginal, intrauterine, or topical administration.

For many applications these novel prostaglandin esters which I have obtained from certain specified phenols and naphthols have advantages over the corresponding known prostaglandin compounds. Thus, these substituted phenyl and naphthyl esters are surprisingly stable compounds having outstanding shelf-life and thermal stability. In contrast to the acid form of these prostaglandins, these esters are not subject to decomposition either by elimination of water, epimerization, or isomerization. Thus these compounds have improved stability either in solid, liquid, or solution form. In oral administration these esters have shown surprisingly greater efficacy than the corresponding free acids or lower alkyl esters, whether because of longer duration of biological activity or because of improved lipophilicity and absorption is not certain. These esters offer a further advantage in that they have low solubility in water and the body fluids and are therefore retained longer at the site of administration.

A particularly outstanding advantage of many of these substituted phenyl and naphthyl esters is that they are obtained in free-flowing crystalline form, generally of moderately high melting point, in the range 90.degree.-180.degree. C. This form is especially desirable for ease of handling, administering, and purifying. These crystals are highly stable, for example showing practically no decomposition at accelerated storage tests at 65.degree. C., in comparison with liquid alkyl esters or the free acids. This quality is advantageous because the compound does not lose its potency and does not become contaminated with decomposition products.

These crystalline esters also provide a means of purifying PGA.sub.2, 15-methyl-PGA.sub.2, 15(R)-methyl-PGA.sub.2, 15-ethyl-PGA.sub.2, or 15(R)-15-ethyl-PGA.sub.2, which are first converted to one of these esters, recrystallized until pure, and then recovered as the free acid. One method of recovering the free acid is by enzymatic hydrolysis of the ester, for example with a lipase. See German Patent No. 2,242,792, Derwent Farmdoc No. 23047U.

To obtain the optimum combination of stability, duration of biological activity, lipophilicity, solubility, and crystallinity, certain compounds within the scope of formula III are preferred.

One preference is that Z is limited to either ##STR11##

Another preference is that Z is further limited to ##STR12## wherein R.sub.1 is ##STR13## wherein R.sub.2 is ##STR14## Another preference is that Z is limited to ##STR15## Another preference is that Z is limited to ##STR16## wherein R.sub.3 is ##STR17## wherein R.sub.4 is ##STR18##

Especially preferred are those compounds which are in free-flowing crystalline form, for example:

The substituted phenyl and naphthyl esters of PGA.sub.2, 15-alkyl-PGA.sub.2, and 15(R)-15-alkyl-PGA.sub.2 encompassed by formula III wherein Z is defined by ester groups A through Y are produced by the reactions and procedures described and exemplified hereinafter. For convenience, the above prostaglandin or prostaglandin analog is referred to as "the PG compound". The term "phenol" is used in a generic sense, including both phenols and naphthols.

Various methods are available for preparing these esters, differing as to yield and purity of product. Thus, by one method, the PG compound is converted to a tertiary amine salt, reacted with pivaloyl halide to give the mixed acid anhydride and then reacted with the phenol. Alternately, instead of pivaloyl halide, an alkyl or phenylsulfonyl halide is used, such as p-toluenesulfonyl chloride. See for example Belgian patents Nos. 775,106 and 776,294, Derwent Farmdoc Nos. 33705T and 39011T.

Still another method is by the use of the coupling reagent, dicyclohexylcarbodiimide. See Fieser et al., "Reagents for Organic Synthesis", pp. 231-236, John Wiley and Sons, Inc., New York (1967). The PG compound is contacted with one to ten molar equivalents of the phenol in the presence of 2-10 molar equivalents of dicyclohexylcarbodiimide in pyridine as a solvent.

The preferred novel process for the preparation of these esters, however, comprises the steps (1) forming a mixed anhydride with the PG compound and isobutylchloroformate in the presence of a tertiary amine and (2) reacting the anhydride with an appropriate phenol or naphthol.

The mixed anhydride is represented by the formula: ##STR19## for the optically active PG compounds, Y having the same definition as above.

The anhydride is formed readily at temperatures in the range -40.degree. to +60.degree. C., preferably at -10.degree. to +10.degree. C. so that the rate is reasonably fast and yet side reactions are minimized. The isobutylchloroformate reagent is preferably used in excess, for example 1.2 molar equivalents up to 4.0 per mole of the PG compound. The reaction is preferably done in a solvent and for this purpose acetone is preferred, although other relatively non-polar solvents are used such as acetonitrile, dichloromethane, and chloroform. The reaction is run in the presence of a tertiary amine, for example triethylamine, and the co-formed amine hydrochloride usually crystallizes out, but need not be removed for the next step.

The anhydride is usually not isolated but is reacted directly in solution with the phenol, preferably in the presence of a tertiary amine such as pyridine.

The phenol is preferably used in equivalent amounts or in excess to insure that all of the mixed anhydride is converted to ester. Excess phenol is separated from the product by methods described herein or known in the art, for example by crystallization. The tertiary amine is not only a basic catalyst for the esterification but also a convenient solvent. Other examples of tertiary amines useful for this purpose include N-methylmorpholine, triethylamine, diisopropylethylamine, and dimethylaniline. Although they may be used, 2-methylpyridine and quinoline result in a slow reaction. A highly hindered amine such as 2,6-dimethyllutidine is not useful because of the slowness of the reaction.

The reaction with the anhydride proceeds smoothly at room temperature (about 20.degree. to 30.degree. C.) and can be followed in the conventional manner with thin layer chromatography (TLC), usually being found complete within 1-4 hours.

The reaction mixture is worked up to yield the ester following methods known in the art, and the product is purified, for example by silica gel chromatography.

Solid esters are converted to a free-flowing crystalline form on crystallization from a variety of solvents, including ethyl acetate, tetrahydrofuran, methanol, and acetone, by cooling or evaporating a saturated solution of the ester in the solvent or by adding a miscible non-solvent such as diethyl ether, hexane, or water. The crystals are then collected by conventional techniques, e.g. filtration or centrifugation, washed with a small amount of solvent, and dried under reduced pressure. They may be dried in a current of warm nitrogen or argon, or by warming to about 75.degree. C. Although the crystals are normally pure enough for many applications, they may be recrystallized by the same general techniques to achieve improved purity after each recrystallization.

The invention can be more fully understood by the following examples.

All temperatures are in degrees centigrade.

Silica gel chromatography, as used herein, is understood to include chromatography on a column packed with silica gel, elution, collection of fractions, and combination of these fractions shown by thin layer chromatography (TLC) to contain the desired product free of starting material and impurities. "TLC", herein, refers to thin layer chromatography.

A solution of p-hydroxyaniline (20 g.) in 200 ml. pyridine is treated with benzoic anhydride (20 g.). After 4 hr. at about 25.degree. C., the mixture is concentrated under reduced pressure and the residue is taken up in 200 ml. of hot methanol and reprecipitated with 300 ml. of water. The product is recrystallized from hot acetonitrile as white crystals, 8.5 g., m.p. 218.0.degree.-218.5.degree. C.

A solution of p-acetamidobenzoic acid (12.5 g.) in 250 ml. of tetrahydrofuran is treated with triethylamine (11.1 ml.). The mixture is then treated with isobutylchloroformate (10.4 ml.) and, after 5 min. at about 25.degree. C., with p-aminophenol (13.3 g.) in 80 ml. of dry pyridine. After 40 min. the crude product is obtained by addition of 2 liters of water. The product is recrystallized from 500 ml. of hot methanol by dilution with 300 ml. of water as white crystals, 5.9 g., m.p. 275.0.degree.-277.0.degree. C.

A solution of PGA.sub.2 (0.310 g.) and triethylamine (0.244 ml.) in 20 ml. of acetone is treated at -10.degree. C. with isobutylchloroformate (0.236 ml.) whereupon triethylamine hydrochloride is precipitated. After 5 min. the mixture is treated with p-benzamidophenol (0.558 g.) in 5 ml. of pyridine for 0.25 hr. at about 25.degree. C. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate and washed with aqueous citric acid (2%) and water. The organic phase is dried over sodium sulfate, concentrated, and subjected to silica gel chromatography, eluting with acetonitrile-chloroform (1:4). The residue obtained by concentration of selected fractions, a solid on chilling, is the title compound, 0.293 g., having R.sub.f 0.6 (TLC on silica gel in acetonitrile-chloroform (1:4)). It is recrystallized from ethyl acetate-hexane as white free-flowing crystals, m.p. 56.5.degree.-57.5.degree. C.

Following the procedure of Example 1 but using 0.308 g. of PGA.sub.2, 0.244 ml. of triethylamine, 0.236 ml. of isobutylchloroformate, and 0.714 g. of p-[(p-acetamidophenyl)carbamoyl]phenol (Preparation 2), there is obtained a crude solid residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate. The residue obtained by concentration of selected fractions, 0.260 g., is chromatographed again on silica gel, eluting with acetonitrile-chloroform (1:1) to yield 0.047 g. which is recrystallized from ethyl acetate-methanol-hexane (97:3:10) as the title compound, 0.044 g., white freeflowing crystals, m.p. 159.5.degree.-160.0.degree. C., having R.sub.f 0.42 (TLC on silica gel in ethyl acetate).

Following the procedure of Example 1 but using 0.561 g. of PGA.sub.2, 0.302 ml. of triethylamine, 0.286 ml. of isobutylchloroformate, and 0.570 g. of p-phenylphenol, there is obtained a crude oily residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-hexane (2:3) saturated with water. The residue obtained by concentration of selected fractions, 0.381 g., an oil, is the title compound, having R.sub.f 0.5 (TLC on silica gel in ethyl acetate-hexane (2:3).

Following the procedure of Example 1 but using 0.310 g. of PGA.sub.2, 0.244 ml. of triethylamine, 0.236 ml. of isobutylchloroformate, and 0.470 g. of p-hydroxybenzaldehyde semicarbazone, there is obtained a crude solid residue. This residue is subjected to silica gel chromatography, eluting with tetrahydrofuran-ethyl acetate (3:2). The residue obtained by concentration of selected fractions, 0.600 g., is crystallized from acetone-water (1:2) as the title compound, 0.376 g., as white free-flowing crystals. An analytical sample recrystallized from acetonitrile has m.p. 128.3.degree.-129.0.degree. C. and R.sub.f 0.5 (TLC on silica gel in ethyl acetate-methanol (95:5)).

Following the procedures of Examples 1-4 but employing the racemic forms of the PG compounds, there are obtained the corresponding esters of racemic PG compounds.

The substituted phenyl and naphthyl esters of PGA.sub.2, 15-methyl-PGA.sub.2, and 15(R)-15-methyl-PGA.sub.2 of Tables I-III below are obtained following the procedures of Example 1, wherein the prostaglandin compound is reacted in the presence of triethylamine and isobutylchloroformate with the appropriate hydroxy phenyl or naphthyl compound, listed in the Table. These phenols or naphthols are readily available or prepared by methods described herein or known in the art. The crude products, obtained by concentration under reduced pressure, are purified by means described herein or known in the art, including partitioning, solvent extraction, washing, silica gel chromatography, trituration, or crystallization.

Following the procedures of Examples 5-75 but employing the racemic forms of the PG compounds, there are obtained the corresponding esters of the racemic PG compounds. ______________________________________ Esters of PGA.sub.2 Hydroxy Phenyl or      Product PGA.sub.2 Ex. Naphthyl Compound      Ester of formula: ______________________________________ 5   p-acetamidophenol      111-A 6   p-[(p-benzami-dophenyl)carbamoyl]- 111-D phenol 7   p-hydroxyphenylurea    111-E 8   p-hydroxy-1,3-diphenylurea 111-F 9   p-tritylphenol         111-H 10  N-acetyl-L-tyrosinamide 111-1 11  N-benzoyl-L-tyrosinamide 111-J 12  p-hydroxyacetophenone  111-L 13  p-hydroxybenzophenone  111-M 14  p-hydroxybenzamide     111-N 15  o-hydroxybenzamide     111-O 16  N-(p-tritylphenyl)-p-hydroxybenzamide 111-P 17  p-hydroxybenzoic acid, methyl ester 111-Q 18  hydroquinone benzoate  111-R 19  hydroquinone, p-acetamidobenzoic 111-S acid ester 20  2,4-diacetamidophenol  111-T 21  1-acetamido-4-hydroxynaphthalene 111-U 22  1-benzamido-4-hydroxynaphthalene 111-V 23  1-hydroxy-4-ureidonaphthalene 111-W 24  2-naphthol             111-X 25  1-hydroxy-5-naphthalenesulfonamide 111-Y ______________________________________ ______________________________________ Esters of 15-Methyl-PGA.sub.2 Product Hydroxy Phenyl or      15-Methyl-PGA.sub.2 Ex. Naphthyl Compound      Ester of formula: ______________________________________ 26  p-acetamidophenol      111-A 27  p-benzamidophenol      111-B 28  p-[(p-acetamidophenyl)carbamoyl]-phenol 111-C 29  p-[(p-benzamidophenyl)carbamoyl]-phenol 111-D 30  p-hydroxyphenylurea    111-E 31  p-hydroxy-1,3-diphenylurea 111-F 32  p-phenylphenol         111-G 33  p-tritylphenol         111-H 34  N-acetyl-L-tyrosinamide 111-1 35  N-benzoyl-L-tyrosinamide 111-J 36  p-hydroxybenzaldehyde semicarbazone 111-K 37  p-hydroxyacetophenone  111-L 38  p-hydroxybenzophenone  111-M 39  p-hydroxybenzamide     111-N 40  o-hydroxybenzamide     111-O 41  N-(p-tritylphenyl)-p-hydroxybenzamide 111-P 42  p-hydroxybenzoic acid, methyl ester 111-Q 43  hydroquinone benzoate  111-R 44  hydroquinone, p-acetamidobenzoic 111-S acid ester 45  2,4-diacetamidophenol  111-T 46  1-acetamido-4-hydroxynaphthalene 111-U 47  1-benzamido-4-hydroxynaphthalene 111-V 48  1-hydroxy-4-ureidonaphthalene 111-W 49  2-naphthol             111-X 50  1-hydroxy-5-naphthalenesulfonamide 111-Y ______________________________________ ______________________________________ Esters of 15(R)-15-Methyl-PGA.sub.2 Product 15(R)- Hydroxy Phenyl or      15-Methyl-PGA.sub. 2 Ex. Naphthyl Compound      Ester of formula: ______________________________________ 51  p-acetamidophenol      111-A 52  p-benzamidophenol      111-B 53  p-[(p-acetamidophenyl)carbamoyl] -phenol 111-C 54  p-[(p-benzamidophenyl)carbamoyl] -phenol 111-D 55  p-hydroxyphenylurea    111-E 56  p-hydroxy-1,3-diphenylurea 111-F 57  p-phenylphenol         111-G 58  p-tritylphenol         111-H 59  N-acetyl-L-tyrosinamide 111-I 60  N-benzoyl-L-tyrosinamide 111-J 61  p-hydroxybenzaldehyde semicarbazone 111-K 62  p-hydroxyacetophenone  111-L 63  p-hydroxybenzophenone  111-M 64  p-hydroxybenzamide     111-N 65  o-hydroxybenzamide     111-O 66  N-(p-tritylphenyl)-p-hydroxybenzamide 111-P 67  p-hydroxybenzoic acid, methyl ester 111-Q 68  hydroquinone benzoate  111-R 69  hydroquinone, p-acetamidobenzoic acid 111-S ester 70  2,4-diacetamidophenol  111-T 71  1-acetamido-4-hydroxynaphthalene 111-U 72  1-benzamido-4-hydroxynaphthalene 111-V 73  1-hydroxy-4-ureidonaphthalene 111-W 74  2-naphthol             111-X 75  1-hydroxy-5-naphthalenesulfonamide 111-Y ______________________________________

## Claims

1. An optically active compound of the formula: ##STR20## or a racemic compound of that formula and the mirror image thereof, wherein Y is ##STR21##

2. An optically active compound according to claim 1 wherein Y is ##STR22##

3. An optically active compound according to claim 1 wherein Y is ##STR23##

4. An optically active compound according to claim 1 wherein Y is ##STR24##

5. An optically active compound of the formula: ##STR25## or a racemic compound of that formula and the mirror image thereof, wherein Y is ##STR26##

6. An optically active compound according to claim 5 wherein Y is ##STR27##

7. An optically active compound according to claim 5 wherein Y is ##STR28##

8. An optically active compound according to claim 5 wherein Y is ##STR29##