IE47075B1 - N-acylated thiazolidine, thiazane and morpholine carboxylic acids and esters - Google Patents

Abstract

New substituted derivatives of thiazolidine-, thiazaneand related carboxylic acids which have the general formula are useful as angiotensin converting enzyme inhibitors.

Description

This invention provides new thiazolidine-, thiazaneand related carboxylic acids which have the general formula (I) R__ s—— (CH2)- and such compounds in the form of a salt with a base, wherein R is hydroxy or lower alkoxy; R^ R2 Rg and Rg each is hydrogen or lower alkyl with the proviso that either both and Rg or both R2 and Rg must be lower alkyl; Rg is hydrogen, lower alkyl or mercapto-lower alkylene; R^ is hydrogen, lower alkanoyl, benzoyl or -S-(CH,)-CH— CO—N-CH—CO-R (in which formula the variables are identical to those in formula I) with the provisos that when R^ is mercapto-lower alkylene, R4 is hydrogen and when R4 is hydrogen R is hydroxy; X is 0, S', SO or SO, ; m is 1, 2 or 3; n is 0, 1 or 2; and m + n is 2 or 3 with the proviso that when X is 0, m is 2, and n is 1; p is 0 or 1. The asterisks denote centers of asymmetry.

The invention also includes pharmaceutical compositions comprising such compounds and a pharmaceutical carrier.

The compounds of this invention are characterised by an unsubstituted or lower alkyl substituted 5- or 6-membered heterocyclic carboxylic acid having one nitrogen atom and one sulfur or oxygen atom in the ring, the remaining members of the ring being carbon, preferably thiazolidine-, thiazaneand morpholine carboxylic acids. The ring, as indicated, - 2 4 7 0 7s contains a hetero atom in addition to the nitrogen, which is oxygen or sulfur and the sulfur can be oxidized to the sulfinyl The side chain, attached to the nitrogen of the heterocyclic ring, is an unsubstituted or substituted mercapto-alkanoyl group. The compound can also be a dimer wherein the sulfur containing substituted is a similar unit.

The lower alkyl groups represented by any of the variables are straight and branched chain hydrocarbon radicals from methyl to heptyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and isopentyl. The lower alkylene groups are similar divalent groups also having 1 to 7 carbons. Similarly the iower alkoxy groups are lower alkyl groups with a link to oxygen, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and t-butcxy. iue c,members, especially and members, of all types are preferred. The lower alkanoyl groups are the acyl radicals of the lower (up to 7 carbons) saturated fatty acids, e.g., acetyl, propionyl and butyryl, acetyl being preferred.

The symbols have the foregoing meanings throughout this specification.

Certain preferred combinations of variables are hereinafter set out in the claims.

The products of formula I can be produced by various methods of synthesis.

According to a preferred method, the acid of the formula CH-CO-R wherein R is hydroxy and the other symbols have the same meaning as above, is acylated with an acid of the formula ΐ3 — R^-S-(CH2) --CH-COOH iii by one of the known procedures in which the acid III maybe activated, prior to reaction with the acid II, involving formation of a mixed anhydride, symmetrical anhydride, acid chloride, active ester. Woodward reagent Κ, Ν,Ν1-carbony1bisimidazole or EEDQ (N-ethoxycarbony1-2-ethoxy-1,2-dihvdroguinoline). when R is lower alkoxy, this method or other known methods for coupling such moieties can be used, [For review of these methods, see Methoden der Organischen 1° Chemie (Houben-Weyl) Vol. XV, parts 1 and 2 (1974).

The acid of formula II can, of course, be acylated stagewise. For example, a fragment of the acylating agent III can be first attached to the acid of formula II, e.g., by reacting that acid with a haloacyl halide of the formula f3 hal—(CH,)—CH—CO—hal p wherein hal represents a halogen, preferably chlorine or bromine, 3-bromopropanoyl chloride for instance. This yields a product of the formula hal-(CH2) -CH CO— N-CH— CO— R The reaction of this intermediate with a thiol R^-SH then yields the desired product of formula I. This stepwise Application acylation is illustrated in Example 1 of parent Patent / No. 2397/77 CSpecification No. 46169 Ί. 4-7 0 75 When the product obtained is an ester, e.g., R is lower alkoxy, the ester can be converted to the free carboxy group by alkaline hydrolysis, or by treatment with trifluoroacetic acid and anisole. Conversely the free acid can be estefified by conventional procedures.

The disulfides, i.e., when R^ is -S-(CH2 hg-CH CO— N CH-CO-R are obtained by oxidation of a compound of the formula HS-(CH,)2 i ZR, .X Rt-'\ (5) 41,-0 ra i» ι m :h—co—N(C-R.I -CH — CO—P. e.g., with an alcoholic solution of iodine.

Products of formula I have at least one or may have up to 4 asymmetric carbon atoms. These carbon atoms are indicated by an asterisk in formula I. The compounds accordingly exist in diastereoisomeric forms or in racemic mixtures thereof.

All of these are within the scope of the invention. The above described syntheses can utilize the racemate or one of the enantiomers as starting material. When the racemic starting material is used in the synthetic procedure, the stereoisomers obtained in the product can be separated by conventional chromatographic or fractional crystallization methods. In general, the L-isomer with respect to the carbon of the amino acid constitutes the preferred isomeric form. az u ( a The compounds of this invention form salts with various inorganic and organic bases which are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as arginine and lysine.

The non-toxic, phvsiologicallv acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product as in the case of the dicyclohexylamine salt. The salts are formed in conventional manner by reacting the free acid form of the product with one or more equivalents of the appropriate base providing the desired cation in a solvent or medium in which the salt is insoluble and filtering, or in water and removing the water by freeze drying. By neutralizing the salt with an insoluble acid such as a cation exchange resin in the hydrogen form [e.g., polystyrene sulfonic acid resin - DOwex (Trade Mark) 50 (Mikes, Laboratory Handbook of Chromatographic Methods, Van Nostrand', 1961) page 256] or with an aqueous acid and extraction with an organic solvent, e.g., ethyl acetate or diehloromethane, the free acid form can be obtained, and, if desired, another salt formed.

Additional experimental details are found in the examples which are preferred embodiments and also serve as models for the preparation of other members of the group.

The compounds of this invention inhibit the conversion of the decapeptide angiotensin I to angiotensin II and therefore may be used in reducing or relievinq anuiotensin 7 0 7 5 related hypertension. The action of the enzyme renin on angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II. The latter is an active pressor substance present which has been implicated as the causative agent in various forms of hypertension in various mammalian species, e.g., rats and dogs. ' The compounds of this invention intervene in the angiotensinogen—^ angiotensin 1-^ angiotensin II sequence by ingibiting angiotensin converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin II.

The inhibition of the angiotensin converting enzyme by compounds of formula I can be measured in vitro with isolated angiotensin converting enzyme from rabbit lungs following the procedure described by Cushman and Cheung [Biochem. Pharmacol., 20, 1637 (1971], and with an excised smooth muscle assay [E. O'Keefe, et al., Federation Proc. 31, 511 (1972)) in which these compounds have been shown to be powerful inhibitors of the contractile activity of angiotensin I and potentiators of the contractile activity of bradykinin.

The administration of a composition containing one or a combination of compounds of formula I or physiologically acceptable salt thereof to the species of hypertensive mammal alleviates or reduces angiotensin dependent hypertension. A single dose, or preferably two to four divided daily doses, provided on a basis of 5 to 1000 mg. per kilogram per day, preferably 10 to 500 mg. per kilogram per day is appropriate to reduce blood pressure. The animal model experiments described by S.L. Engel, T.R. Schaeffer, M.H. Waugh 07 5 and B. Rubin, Proc. Soc. Exp. Biol. Med. 143, 483 (1973) serve as a useful guide.

The substance is preferably administered orally, but parenteral routes such as subcutaneously, intramuscularly, intravenously or intraperitoneally can also be employed.

The compounds of this invention can be utilized to achieve the reduction of blood pressure by formulating in compositions such as tablets, capsules or elixirs for oral administration or in sterile solution or suspensions for parenteral administation. For example, 10 to 500 mg. of a compound or mixture of compounds of formula X or physiologically acceptable salt may be compounded with a Dhvsioloaically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer and/or flavor, in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.

The following Examples (except Example 14) are illustrative of the invention and constitute preferred embodiments. All temDeratures are in degrees Celsius.

EXAMPLE 1 3-(3-Acetylthiopropanoyl)-2,2-dimethyl-4-L-thiazolidinecarboxylic acid. 2,2-Dimethylthia2oli'dine-4-carboxylic acid (5.74 g) is dissolved in 58 ml of anhydrous pyridine with heating. The solution is chilled in an ice bath with stirring and 3acetylthiopropanoyl chloride (4.814 g) is added dropwise.

The bath is removed and the reaction mixture is kept overnight at room temperature. The precipitate is filtered and the - 8 1 7 0 7 5 filtrate is concentrated to dryness in vacuo. The residue is taken up into ethyl acetate and washed with 10% potassium bisulfate and water. The ethyl acetate extract is dried over magnesium sulfate and concentrated to dryness in vacuo. This residue is triturated with ether, filtered and the filtrate is concentrated to dryness, then crystallized from acetonitrile to yield 2.63 g of 3-(3-acetylthiopropanoyl)2,2-dimethyl-4-L-thiazolidinecarboxylic acid, m.p. 126-127®.

EXAMPLE ?. 3-(3-Mercaptopropanoyl)-2,2-d1methyJ-4-L-th1azolidinecarboxylic acid. 3-(Acetyl thiopropanoyl)-2,2-dimethyl-4-L-thiazolidi necarboxylic acid (5.82 g) is dissolved in a cold solution of 15 ml of water and 15 ml of concentrated ammonium hydroxide under argon and kept for thirty minutes at room temperature.

The reaction mixture is chilled and acidified with concentrated hydrochloric acid. The crystals are chilled, filtered and washed with water, yield 4.79 g, m.p. 132-136° (haze). This is taken up in hot acetonitrile and the haze filtered. The filtrate yields 3.4 g of 3-(3-mercaptopropanoyl)2,2-dimethyl-4-L-thiazolidinecarboxylic acid, m.p. 135-136°.

EXAMPLE 3 3-(3-Acetylthlo-2-methylpropanoyl)-2,2-dimethyl-4-L-thiazolidinecarboxylic acid, isomer A. 2,2-Dimethyl-4-thiazolidinecarboxylic acid hydrochloride (19.8 g) is dissolved in 200 ml of anhydrous pyridine with stirring in an ice bath. To this 3-acetylthio-2-methylpropanoyl chloride (18.0 g) is added dropwise. The reaction'mixture is stirred overnight at room temperature. The precipitate is filtered and the filtrate concentrated to dryness in vacuo.

The residue is dissolved in ethyl acetate, washed with 10% potassium bisulfate, water, dried over magnesium sulfate and concentrated to dryness in vacuo to obtain 31 g of crude 3-(3-acetylthio-2-methylpropanoyl)-2,2-dimethyl-4-L-thiazolidinecarboxylic acid, isomer A. The dicyclohexylamine salt is obtained by adding the free 'acid and dicyclohexylamine to acetonitrile, yield 24 g. The salt is recrystallized from 700 ml of acetonitrile to yield 18.2 g, m.p. 197-198°.

The salt is converted back to the free acid by dissolving in ethyl acetate and 10% potassium bisulfate then crystallizing from 100 ml of acetonitrile to yield 8.9 g. m.p., 171-172°.

EXAMPLE 4 3-(3-Acetylthio-2-methylpropanoyl)-2,2-dimethyl-4-L-thiazolidinecarboxylic acid, isomer B.

The mother liquors from the preparation of the dicyclohexylamine salt obtained in Example 3 are concentrated to dryness in vacuo. The residue is added to ethyl acetate and 10% potassium bisulfate, then crystallized from 80 ml of acetonitrile to obtain 7.5. g of 3-(3-acetylthio-2-methylpropanoyl)-2,2-dimethyl-4-L-thiazolidinecarboxylic acid, isomer B, m.p. 156-157°.

EXAMPLE 5 3-(3-Mercapto-2-methylpropanoyl)-2,2-dimethyl-4-L-thiazolidinecarboxylic acid, isomer A. 3-(3-Acetylthio-2-methylpropanoyl)-2,2-dimethyl-4-Lthiazolidinecarboxylic acid, isomer A (5 g) is dissolved in a cold solution of 15 ml of water and 15 ml of concentrated ammonium hydroxide while under a blanket of argon. After thirty minutes, it is chilled and acidified with concentrated hydrochloric acid. The crystalline precipitate is filtered and washed with water. The product; 3-(3-mercapto-2-methylpropanoyl)-2,2-dimethyl-4-L-thiazolidinecarboxylic acid, isomer A, is recrystallized from 40 ml of acetonitrile (haze filtered), yield 4.2 g, m.p. 174-175°.

EXAMPLE 6 3-(3-Mercapto-2-methylpropanoyl)-2,2-dimethyl-4-L-thiazolldinecarboxylic acid, isomer B. 3-(3-Acetylthio-2-methylpropanoyl)-2,2-dimethyl-4-Lthiazolidinecarboxylic acid, isomer B (4 g) is dissolved in a cold solution of 6 ml of water and 6 ml of concentrated ammonium hydroxide under an argon blanket. After thirty minutes at room temperature, it is chilled or acidified with concentrated hydrochloric acid. The crystalline precipitate, is filtered and washed with water. The product, 3-(3-mercapto2- methylpropanoyl)-2,2-dimethyl-4-L-thiazolidinecarboxylic acid, isomer B, is recrystallized from acetonitrile (insoluble filtered), yield 3.7 g, m.p. 197-198°.

EXAMPLE 7 3- (3-Acetylthiopropanoyl)-5,5-dimethyl-4-DL-thiazolidinecarboxylic acid.

A) 5,5-Dimethyl-4-thiazolidinecarboxylic acid D,L-Penicillamine (20 g, 134 mmol) is dissolved in 134 ml of IN hydrochloric acid at room temperature, and 40 ml (492 mmol) of 37% aqueous formaldehyde are added. After thirty minutes, sodium acetate (11 g 134 mmol) is added, and the reaction mixture is stirred at room temperature overnight.

After filtering, the solid is washed with ice cold 50% aqueous ethanol, and dried in vacuo to yield 14.4 g of the product, 5,5-dimethyl-4-thiazolidinecarboxylic acid, m.p. 209-210°.

After concentrating in vacuo, the mother liquor is triturated 4 7 0 7 5 with 95% ethanol to afford an additional 1.4 g of product, m.p. 212-213°; total yield; 15.8 g (73%).

B) 3-(3-Acetylthiopropanoyl)-5,5-dimethyl-4-DL-thiazolidinecarboxylic acid.

The product of part A (6 g, 37.2 mmol) is dissolved in a mixture of 3.5 g (41.4 mmol) of sodium bicarbonate in 42 ml of tetrahydrofuran and 41 ml of water. 3- Acetylthiopropanoyl chloride (5.5 ml, 41.1 mmol) in 5.5 ml of ether is added dropwise, followed by titration with 2Nsodium hydroxide, keeping the pH between 6 and 7. The reaction is stirred for thrity minutes after completion of the addition, then quenched with 100 ml of hydrochloric acid. The mixture is extracted with 2 X 250 ml of ether acetate and the organic extracts are washed with 100 ml portions of water and brine, dried with sodium sulfate, and stripped to dryness in vacuo. The resulting oil solidifies upon standing at room temperature to yield 11.0 g of crude 3-(3-acetylthiopropanoyl)-5,5dimethyl-4-DL-thiazolidinecarboxylic acid. Recrystallization from ether petroleum ether gives 7.9 g (73%) of product, m.p. 99-100.5°.

EXAMPLE 8 3-(3-Mercaptopropanoyl)-5,5-dimethyl-4-DL-thiazolidinecarboxylic acid.

A suspension of 2.91’g (10 mmol) of 3-(3-acetylthio25 propanoyl)-5,5-dimethy1-4-thiazolidinecarboxylic acid in 8 ml of water is stirred rapidly at room temperature under a blanket of argon. The stirred suspension is treated with 8 ml of ca. 58% aqueous ammonium hydroxide, added dropwise over a period of about one minute. The non-homogeneous solution is stirred under argon for thirty minutes, then chilled and - 12 acidified with concentrated hydrochloric acid. The aqueous solution is extracted with 40 ml and 30 ml portions of ethyl acetate. The combined organic solutions are washed with 5 ml of water, 10 ml of brine, dried (Na^SO^, and concentrated in vacuo to 2.74 g of crude oil. When the oil is treated with ca. 50 ml of (4:6), ethyl acetate/hexanes, rapid crystallization induced by scratching yields 1.88 g of a light, white solid 3-(3-Mercaptopropanoyl)-5,5-dimethyl4-DL-thiazolidinecarboxylic acid (75%), m.p. 100-101.5° Tic, Rf=0.46 (silica gel; 60:20:6:11, EtOAczpyridine:MeOH:HjO) .

EXAMPLE 9 DL-3-(3-Mercapto-2-methylpropanoyl)-2,2,5,5-tetramethyl-4DL-thiazolidine carboxylic acid.

By substituting 2,2,5,5-tetramethyl-4-thiazoledinecarboxylic acid for the 2,2-dimethyl-4-thiazolidinecarboxylic acid hydrochloride in the procedure of Example 3 and then submitting the product to the procedure of Example 5 3-(3(acetylthio)-2-methylpropanoyl]-2,2,5,5-tetramethyl-4-DLthiazolidinecarboxylic acid and 3-(3-mercapto-2-methylpropanoyl)2,2,5,5-tetramethyl-4-DL-thiazolidinecarboxylic acid are obtained.

EXAMPLE 10 3-(3-Mercapto-2-methylpropanoyl)-2-ethyl-2-methyl-4-Lthiazolidinecarboxylic acid.

By substituting 2-ethyl-2-methyl~4~L-thiazolldinecar— boxylic acid for the 2,2-dimethyl-4-L-thiazolidinecarboxylic acid hydrochloride in the procedure of Example 3 and then submitting the product to the procedure of Example 5, 3-(3(acetylthio)-2-methylpropanoyl]-2-ethyl-2-methyl-4-L-thiazolidine carboxylic acid and 3- (3 - mercapto - 2 - methylpropanoyl) 2- ethyl - 2 - methyl - 4 -L - thiazolidineearboxylic acid are obtained. 4 7 0 7 5 EXAMPLE 11 3-(3-Mercaptopropanoyl)-2-ethyl-5,5-dimethyl-4-DL-thiazolidine carboxylic acid By substituting 2-ethyl-5,5-dimethyl-4-0L-thiazolidine carboxylic acid for the 5,5-dimethy1-4-thiazolidinecarboxylic acid in the procedure of Example 7 and then submitting the product to the procedure of Example 8,3-^3- (acetylthio)propanoy^ 2-ethyl-5,5-dimethyl-4-DL-thiazolidinecarboxylic acid and 3-£ (3-mercaptopropanoyl5j-2-ethyl-5,5-dimethy1-4-DLthiazolidinecarboxylic acid are obtained.

EXAMPLE 12 3-[2-(Mercaptomethyl)-3-mercaptopropanoyl3-5,5-dimethyl-4DLthiazolidlnecarboxylic acid By substituting 5,5-dimethy1-4-DL-thiazoliilinecarboxylic acid hydrochloride for 2,2-dimethyl-4-L-thiazolidinecarboxylic acid hydrochloride and 3-acetylthio-2-acetylthiomethy1propanoyl chloride for 3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 3 and then submitting the product to the procedure of Example 5, 3-[2-(acetylthiomethyl)-3acetylthiopropanoylj -5,5-dimethyl-4-DL-thiazolidinecarboxylic acid and 3-[2-(mercaptomethyl)-3-mercaptopropanoylJ-5,5dimethyl-4-DL-thiazolidinecarboxylic acid are obtained.

EXAMPLE 13 4-(3-Mercapto-2-methylpropanoyl)-5,5-dimethyl-l,4-I.-thiazane3-carboxylic acid By substituting 5,5-dimethyl-l,4-L-thiazane-3carboxylic acid for the 2,2-dimethyl-4-L-thiazolidinecarboxylic acid hydrochloride in the procedure of Example 3 and then submitting the product to the procedure of Example 5, 4-^3(acetylthio)-2-methylpropanoylJ-5^ 5-dimethyl-l,4-L-thiazane3-carboxylic acid and 4- (3-mercapto-2-methylpropanoyl)-5,530 dimethyl-1,4-L-thiazane-3-carboxylic acid are obtained.

EXAMPLE 14 Ethyl-2,2-d imethyl-1,4-DL-thlazane-3-carboxylate A mixture of DL-penicillamine ethyl ester hydrochloride (1.133 mole) and triethylamine (0.4 mole) in chloroform (200 ml) is added to a solution of ethylene dibromide (0.133 mole) in chloroform:benzene (3:5; 170 ml). The mixture is refluxed for one hour and then stirred at room temperiiture for sixteen hours. The precipitate is filtered off, and the filtrate is concentrated in vacuo and then distilled to give ethyl 2,2dimethyl-1,4-DL-thiazane-3-carboxylate.

EXAMPLE 15 4- (3-Mercapto-2-methylpropanoyl)-2,2-dlmethy1-1,4-DL-thiazane3- carboxylic acid By substituting ethyl 2,2-dimethyl~l,4-DL-thiazane-3carboxylate for the 2,2-diinethy 1-4-th j.azol idinecarboxy lie acid hydrochloride in the procedure of Example 3, and then submitting the product to the procedure of Example 5, ethyl-4-J^3(acetylthio)-2-metbylpropanoylJ -2,2-dimethyl-1,4-DL-thiazane20 3-carboxylate and 4-(3-mercapto-2-methylpropanoyl)-2,2-dimethyl -1,4-DL-thiazane-3-carboxylic acid are obtained.

EXAMPLE 16 3,3'-fDithlobls- (3-propanoylJ -bis-(2,2-dimethyl)-L-thiazolidine4- carboxylic acid By substituting 3-(3-mercaptopropanoy1)-2,2-dimethyl-Lthiazolidine-4-carboxylic acid for the 3-(3-mercapt.opropanoyl) -L-thiazolidine-4-carboxylic acid in the procedure of Example 25 of parent Patent Application No. 2397/77 ( Specification No. 46169 ), 3,3'-[oithiobis- (3-propanoy l.)J-bis- (2,230 dimethyl)-L-thiazolidine-4-carboxylic acid is obtained. 7 0 7 5 EXAMPLE 17 l-Oxo-4-(3-mercapto-2-methylpropanoyl)-5,5-dimethy1-1,4-Lthiazane-3-carboxylic acid.

By substituting l-oxo-5,5-dimethyl-l,4-L-thiazane-35 carboxylic acid for the 2,2-dimethyl-4-L-thiazolidinecarboxylic acid in the procedure of Example 3 and then submitting the product to the procedure of Example 5, 1oxo-4-(3-acetylthio-2-methylpropanoyl)-5,5-dimethyl-l ,-4-Lthiazane-3-carboxylic acid and l-oxo-4-{3-mercapto-2-methyl10 ' propanoyl)-5,5-dimethyl-l,4-L-thiazane-3-carboxylic acid are obtained.

Claims (28)

CLAIMS:

1. A compound of the formula <5 / V s ) R, -C) (C-R/ 13 2 ι m . ± π H—CO-N--~Ci H-C0'4 “ 2'p wherein R is hydroxy or lower alkoxy; R is hydrogen or lower alkyl with the proviso that either both R hydrogen, lower alkyl or mercapto-lower alkylene; R^ is hydrogen, lower alkanoyl, benzoyl or , R_ R r and R, each 1, 2, j ύ and Rg or both Rg and Rg must be lower alkyl; Rg is (in which formula the variables are identical to those in formula I) with the provisos that when Rg is mercapto-lower alkylene, is hydrogen and when R^ is hydrogen, R is hydroxy; X is 0, S, SO or SO.?; m is 1, 2 or 3; n is 0, 1 or 2 and m+n is 2 or 3 with the proviso that when X is 0, m is 2 and η is 1,- p is 0 or 1; or such a compound in the form of a salt with a base.

2. A compound as in claim 1 wherein R^ is hydrogen, lower alkanoyl or benzoyl; X is sulfur or oxygen; m is 1 or 2; and n is 1 (subject to the proviso given in claim 1).

3. A compound as in claim 1 wherein R is hydroxy, methoxy, or ethoxy; R. R o and R„ each is hydrogen, methyl or ethyl; is hydrogen, acetyl or benzoyl; X is sulfur; m is 1 or 2; n is 1; and p is 0 or 1. 4. 7 U 7 5

4. A compound

5. A compound

6. A compound

7. A compound as in claim as in claim as in claim as in claim 1 wherein R. 1 wherein R. 1 wherein R. 1 wherein R. is hydrogen, is acetyl, is benzoyl, is

8. A compound as in claim 1 wherein R is hydroxy.

9. A compound as in claim 1 wherein p is 1.

10. A compound as in claim 1 wherein X is oxygen.

11. A compound as in claim 1 wherein X is sulfur.

12. A compound as in claim 11 wherein R is hydroxy; R 2 and Rj each is hydrogen; R^ is benzoyl; m and n each is 1; and p is 1.

13. A compound as in claim 11 wherein R is hydroxy; R^, R 2> Rj and R^ each is hydrogen; m and n each is 1; and p is 1 15

14. A compound as in claim 11 wherein R is hydroxy; Rj, R 2 and each is hydrogen; Rj is methyl; m and n each is 1; and p is 1.

15. A compound as in claim 11 wherein R is hydroxy; R^, R 2 and Rj each is hydrogen; R^ is acetyl; m is 2; n is 1; and 20 p is 1.

16. A compound as in claim 11 wherein R is hydroxy; Rj, R 2 , Rj and each is hydrogen; m is 2; π is 1; and p is 1.

17. A compound as in claim 11 wherein R^ and Rg each is hydrogen; R 2 and R g each is methyl; and m, n and p each is 1. 25

18. A compound as in claim 11 wherein and Rg each is methyl; R 2 and R g each is hydrogen; and m, n and p each is 1. - 18 4 ? υ 7 5

19. A compound as in claim 17 wherein R is hydroxy and is hydrogen.

20. A compound as in claim 18 wherein R is hydroxy and is hydrogen.

21. A compound as in claim 17 wherein R is hydroxy and Rg and each is hydrogen.

22. A compound as in claim 17 wherein R is hydroxy, is hydrogen and Rg is methyl.

23. A compound as in claim 1, as named in any of the Examples.

24. A pharmaceutical composition comprising a compound according to any preceding claim and a pharmaceutical carrier.

25. A composition according to claim 24, in the form of a tablet, capsule, elixir or sterile injectable preparation.

26. A composition according to claim 24 or 25, including an excipient, hinder, preservative, stabilizer or flavour.

27. A process for producing a compound as claimed in Claim 1, substantially as herein described with reference to the Examples.

28. The product of a process as claimed in Claim 27.