CA1102812A

CA1102812A - Derivatives of thiazolidinecarboxylic acids and related acids

Info

Publication number: CA1102812A
Application number: CA304,036A
Authority: CA
Inventors: Miguel A. Ondetti
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1978-05-22
Filing date: 1978-05-25
Publication date: 1981-06-09
Also published as: HU179780B; IE47075B1; SU816400A3; ZA783013B; AU3660278A; BE867776R; FR2426685B2; DE2823352A1; NZ187390A; AU521516B2; DK242378A; IT1156791B; PH14405A; CH633782A5; YU131478A; FR2426685A2; SU730303A3; IT7849660A0; PL207332A3; IE781098L

Abstract

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

Description

28~ HA142b-f This invention relates to new thiazolidine-, thiazane-and related carboxylic acids which have the general formula /x (I) ( 6 * / ~ */ 5) ~3 2~ )m l-Rl n R4 S - (CH2)p CH CO N CH CO R

and salts thereof, wherein R is hydroxy or lower alkoxy; R
h yC~ro~ o and R2 each is hydrogen or lower alkyl; R5 and R6 are ~ro~on or lower alkyl with the proviso that R5 and R6 cannot both be hydrogen; R3 is hydrogen, lower alkyl or mercapto-lower alkylene; R4 is hydrogen, lower alkanoyl, benzoyl or R3 ~ 2-CI)m ~ Cl Rl n -S (CH2)p- CH - CO - N CH - CO - R

X is O, S, SO or SO2; when X is O, m is 2 and n is 1; m is 1,

2 or 3; n is O, 1 or 2; and m + n is 2 or 3; p is O or 1.
The asterisks denote centers of asymmetry.

The invention in its broad aspects includes derivatives of thiazolidine-, thiazane- and related carboxylic acids having formula I above.
The compounds of this invention are characterized 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-, thiazane-and morpholine carboxylic acids. The ring, as indicated, contains a hetero atom in addition to the nitrogen, which i~

~ z ~ ~ HA142b-f oxygen or sulfur and the sulfur can be oxidized to the sulfinyl (-~-) or sulfonyl ( ~S~ ) state. 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 R4 is a similar unit.
The lower alkyl groups represented by any of the variables include straight and branched chain hydrocarbon radicals from methyl to heptyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl and the like. The lower alkylene groups are of the same kind also having 1 to 7 carbons. Similarly the lower alkoxy groups are of the same kind with a link to oxygen, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and the like.
The Cl-C4 members, especially Cl and C2 members, of all types are preferred. The lower alkanoyl groups are the acyl radicals of the lower (up to 7 carbons) fatty acids, e.g., acetyl, propionyl, butyryl and the like, acetyl being preferred.
The symbols have the foregoing meanings throughout this specification.
The products of formula I can be produced by various methods of synthesis.
According to a preferred method, the acid of the formula X ~ R ~

HN CH - CO R

wherein R is hdyroxy and the other symbols have the same meaning as above, is acylated with an acid of the formula ~ ~ Z~ ~ HA142b-f ~R3 R4 S (CH2)p CH COOH

by one of the known procedures in which the acid III is activated, prior to reaction with the acid II, involving formation of a mixed anhydride, symmetrical anhydride, acid chloride, active ester, Woodward reagent K, N,N'-carbonyl-bisimidazole, EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydro-quinoline) or the like. 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 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 hal - (CH2)p- CH- CO -hal wherein hal represents a halogen, preferably chlorine or bromine, 3-bromopropanoyl chloride for instance. This yields a product of the formula (R~ / ~ R5) IR3 R2-CI)m ( -Rl n hal (CH2)p- CH CO - N CH - CO - R

The reaction of this intermediate with a thiol R4-SH then yields the desired product of formula I. This stepwise acylation is illustrated in Example 1.

~ Z8~ HA142b -f 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 esterified by conventional procedures.
The disulfides, i.e., when R4 is (R~ X R ) -S (CH2)p CH---CO - N CH CO R

are obtained by oxidation of a compound of the formula R (R~ C / ~ / ) HS (CH2)p CH- CO N CH - CO - R

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.

~Z8~2 HA142b-f The compounds of this invention form basic 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., dicyclohexyl-amine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like. The non-toxic, physiologically 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 like a cation exchange resin in the hydrogen form [e.g., polystyrene sulfonic acid resin - Dowex 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, dichloromethane or the like, 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 are useful in reducing or relieving angiotensin * Trade Mark ~ Z~ ~ HA142b-f related hypertension. The action of the enzyme renin on angiotensinogen, a pseudoglobulin ln 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, dogs, etc. The compounds of this invention intervene in the angiotensinogen-~angiotensin I-~ 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 about 5 to 1000 mg. per kilogram per day, preferably about 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 ~1~2~ HA142~f 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. About 10 to 500 mg. of a compound or mixture of compounds of formula I or physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions ore preparation is such that a suitable dosage in the range indicated is obtained.
The following examples are illustrative of the invention and constitute preferred embodiments. All temperatures are in degrees celsius.

3-(3-Acetylthiopropanoyl?-2~2-dimethyl-4-L-thiazolidine carboxylic acid.
2,2-Dimethylthiazolidine-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 3-acetylthiopropanoyl 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 ~ 2~ HA142b-f filtrate is concentrated to dryness in vacuo. The residue is taken up into ethyl acetate and washéd with 10~ potassium bisulfate and water. The ethyl acetate extract is dried over magnesium sulfate and concentrated to dryness 1n 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.

3-~3-Mercaptopropanoyl)-l-oxopropyl-2,2-dimethyl-4-L-thia-zolidinecarboxylic acid.
3-~Acetylpropanoyl)-2,2-dimethyl-4-L-thiazolidine-carboxylic acid (5.82 g) is diqsolved 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)-1-oxopropyl-2,2-dimethyl-4-L-thiazolidinecarboxylic acid, m.p. 135-136.

3-(3-Acetylthio-2-methylpropanoyl)-2,2-dimethyl-4-L-thia-zolidinecarboxylic 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 dyrness ln vacuo.

~ * ~ HA142b-f The residue is dissolved in ethyl acetate, washed with 10%
potassium bisulfate, water, dried over magnesium sulfate and concentrated to dryness _ vacuo to obtain 31 g of crude 3-(3-acetylthio-2-methylpropanoyl)-2,2-dimethyl-4-L-thia-zolidinecarboxylic acid, isomer A. The dicyclohexylamine salt is obtained by adding the free acid and dicyclohexyl-amine 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.

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

3-(3-Mercapto-2-methylpropanoyl)-2~2-dimethyl-4-L-thia zolidinecarboxylic acid, isomer A.
3-(3-Acetylthio-2-methylpropanoyl)-2,2-dimethyl-4-L-thiazolidinecarboxylic 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 _g _ ~1~28 ~æ HA142b-f and washed with water. The product, 3-(3-mercapto-2-methyl-propanoyl)-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.

3-t3-Mercapto-2-methylpropanoyl)-2,2-dimethyl-4-L-thia-zolidinecarboxylic acid, isomer B.
3-(3-Acetylthio-2-methylpropanoyl)-2,2-dimethyl-4-L-thiazolidinecarboxylic 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-mercapto-2-methylpropanoyl)-2,2-dimethyl-4-L-thiazolidinecarboxylic acid, isomer ~, is recrystallized from acetonitrile (insoluble filtered), yield 3.7 g, m.p. 197-198.

3-(3-Acetylthiopropanoyl)-5,5-dimethyl-4-DL-thiazolidine-carboxylic acid.

A) 5,5-Dimethyl-4-thiazolidinecarboxylic acid D,L-Penicillamine (20 g, 134 mmol) is dissolved in 134 ml of lN 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 i5 triturated ~z~
HAl42b-f 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-thia-zolidinecarboxylic 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 ln vacuo. The resulting oil solidifies upon standing at room temperature to yield 11.0 g of crude 3-(3-acetylthiopropanoyl)-5,5-dimethyl-4-DL-thiazolidinecarboxylic acid. RecrystallizatiOn from ether petroleum ether gives 7.9 g (73%) of product, m.p. 99-100.5.

3-(3-Mercaptopropanoyl)-5,5-dimethyl-4-DL-thiazolidinecarboxylic acid.
A suspension of 2.91 g (10 mmol) of 3-(3-acetylthio-propanoyl)-5,5-dimethyl-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 ~11 -;~lS~28~
HA142b-f acidified with concentrated hydrochloric acid. The aqueous solution is extracted with 40 ml and 30 ml portions of ethyl acetate. ~he combined organic solutions are washed with 5 ml of water, 10 ml of brine, dried (Na2S04) 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-dimethyl-

4-DL-thiazolidinecarboxylic acid (75%), m.p. 100-101.5 Tlc, Rf=0.46 (silica gel; 60:20:6:11, EtOAc:pyridine:MeOH:H20).

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

3-(3-Mercapto-2-methylpropanoyl)-2-ethyl-2-methyl-4-L-thiazolidinecarboxylic acid.
By substituting 2-ethyl-2-methyl-4-L-thiazolidinecarO
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-thiazoli-~l~Z~ HA142b-f dinecarboxylic acid and 3-(3-mercapto-2-methylpropanoyl)-2-ethyl-2-methyl-4-L-thiazolidinecarboxylic acld are obtained.

3-t3-Mercaptopropanoyl)-2-ethyl-5,5-dimethyl-4-DL-thiazolidine carboxylic acid.
By substituting 2-ethyl-5,5-dimethyl-4-DL-thiazolidine carboxylic acid for the 5,5-dimethyl-4-thiazolidinecarboxylic acid in the procedure of Example 7 and then submitting the product to the procedure of Example 8, 3-[3-(acetylthio) propanoyl]-2-ethyl-5,5-dimethyl-4-DL-thiazolidinecarboxylic acid and -3-(3-mercaptopropanoyl)-2-ethyl-5,5-dimethyl-4-DL-thiazolidinecarboxylic acid are obtained.

3-[2-(Mercaptomethyl)-3-mercaptopropanoyl]-5,5-dimethyl-4-DL-thiazolidinecarboxylic acid.
By substituting 5,5-dimethyl-4-DL-thiazolidinecarboxylic acid for the 4-L-thiazolidinecarboxylic acid in the procedure of Example 9 and then submitting the product to the procedure of Example lO, 3-[2-(acetylthiomethyl)-3-acetylthiopropanoyl]-

5,5-dimethyl-4-DL-thiazolidinecarboxylic acid and 3-[2-(mercaptomethyl)-3~mercaptopropanoyl]-5,5-dimethyl-4-DL-thia-zolidinecarboxylic acid are obtained.

4-(3-Mercapto-2-methylpropanoyl)-5,5-dimethyl-1,4-L-thiazane-3-carboxylic acid.
By substituting 5,5-dimethyl-1,4-L-thiazane-3-carboxylic 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-methylpropanoyl]-5,5-dimethyl-1,4-L-thiazane-3-carboxylic ~ HA142b-f acid and 4-(3-mercapto-2-methylpropanoyl)-5,5-diemthyl-1, 4-L-thiazane-3-carboxylic acid are obtained.

Ethyl-2,2-dimethyl-1,4-DL-thiazane-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 ~olution of ethylene dibromide (0.133 mole) in chloroform:benzene (3:5; 120 ml). The mixture if refluxed for one hour and then stirred at room temperature for sixteen hours. The precipitate is filtered off, and the filtrate is concentrated in vacuo and then distilled to give ethyl 2,2-dimethyl-1,4-DL-thiazane-3-carboxylate.

4-(3-Mercapto-2-methylpropanoyl)-2,2-dimethyl-1,4-DL-thiazane-3-carboxylic acid.
By substituting ethyl 2,2-dimethyl-1,4-DL-thiazane-3-carboxylate for the 2-thiazolidinecarboxylic acid methyl ester in the procedure of Example 4, and then submitting the product to the procedure of Example 5, ethy~4-[3-(acetylthio)-2-methylpropanoyll-2,2-dimethyl-1,4-DL-thiazane-3-carboxylate and 4-(3-mercapto-2-methylpropanoyl)-2,2-dimethyl-1,4-DL-thiazane-3-carboxylic acid are obtained.

3,3'-[Dithiobis-(3-propanoyl)]-bis-(2,2-dimethyl)-L-thiazolidine-4-carboxylic acid.
By sub~tituting 3-(3-mercaptopropanoyl)-2,2-dimethyl-L-thiazolidine-4-carboxylic acid for the 3-(3-mercaptopropanoyl)-L-thiazolidine-4-carboxylic acid in the procedure of Example 25, 3,3'-[Dithiobis-~3-propanoyl)]-bis-(2,2-dimethyl)-L-thia-zolidine-4-carboxylic acid is obtained.

~2~Z HA142~ -f l-Oxo-4-(3-mercapto-2-methylpropanoyl)-5,5-dimethyl-1,4-L-thiazane-3-carboxylic acid.
By substituting l-oxo-5,5-dimethyl-1,4-L-thiazane-3-carboxylic acid for the 2,2-dimethyl-4-L-thiazolidine-carboxylic acid in the procedure of Example 3 and then submitting the product to the procedure of Example 5, 1-oxo-4-(3-acetylthio-2-methylpropanoyl)-5,5-dimethyl-1,4-L-thiazane-3-carboxylic acid and 1-oxo-4-(3-mercapto-2-methyl-propanoyl)-5,5-dimethyl-1,4-L-thiazane-3-carboxylic acid are obtained.

.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the formula wherein R is hydroxy or lower alkoxy; R1, R2, R5 and R6 each are hydrogen or lower alkyl; at least two of said groups being lower alkyl and both are attached to the same carbon atom; R3 is hydrogen or lower alkyl; R4 is hydrogen, lower alkanoyl or benzoyl; p is 0 or 1, characterized by acylating a compound of the formula with an acid of the formula or a reactive equivalent thereof to form a product and treating said product wherein R4 is lower alkanoyl or benzoyl with ammonium hydroxide to form a product wherein R4 is hydrogen.

2. A process according to claim 1 wherein R is hydroxy.

3. A process according to claim 1 wherein R is hydroxy and R3 is lower alkyl.

4. A process according to claim 1 wherein R is hydroxy, R3 is lower alkyl and R4 is hydrogen.

5. A process according to claim 1 wherein R is hydroxy, R3 is lower alkyl, R4 is hydrogen and p is 1.

6. A process according to claim 1 wherein R is hydroxy, R4 is hydrogen and R2 and R6 are lower alkyl.

7. A process according to claim 1 wherein R is hydroxy, R4 is hydrogen and R1 and R5 are lower alkyl.

8. A process according to claim 1 wherein R4 is lower alkanoyl.

9. A process according to claim 1 wherein R4 is benzyl.

10. A process according to claim 1 wherein R4 is lower alkanoyl and R is hydroxy.

11. A process according to claim 1 wherein R4 is benzoyl and R is hydroxy.

12. A compound of the formula wherein R is hydroxy or lower alkoxy; R1, R2, R5 and R6 each are hydrogen or lower alkyl; at least two of said groups being lower alkyl and both are attached to the same carbon atom; R3 is hydrogen or lower alkyl; R4 is hydrogen, lower alkanoyl or benzoyl; p is 0 or 1, whenenever prepared by the process of claim 1.

13. A compound according to claim 12 wherein R is hydroxy, whenever prepared by the process of claim 2.

14. A compound according to claim 12 wherein R is hydroxy and R3 is lower alkyl, whenever prepared by the process of claim 3.

15. A compound according to claim 12 wherein R is hydroxy, R3 is lower alkyl and R4 is hydrogen, whenever prepared by the process of claim 4.

16. A compound according to claim 12 wherein R is hydroxy, R3 is lower alkyl, R4 is hydrogen and p is 1, whenever prepared by the process of claim 5.

17. A compound according to claim 12 wherein R is hydroxy, R4 is hydrogen and R2 and R6 are lower alkyl, whenever prepared by the process of claim 6.

18. A compound according to claim 12 wherein R is hydroxy, R4 is hydrogen and R1 and R5 are lower alkyl, whenever prepared by the process of claim 7.

19. A compound according to claim 12 wherein R4 is lower alkanoyl, whenever prepared by the process of claim 8.

20. A compound according to claim 12 wherein R4 is benzyl, whenever prepared by the process of claim 9.

21. A compound according to claim 12 wherein R4 is lower alkanoyl and R is hydroxy, whenever prepared by the process of claim 10.

22. A compound according to claim 12 wherein R4 is benzoyl and R is hydroxy, whenever prepared by the process of claim 11.