DE1768169A1 - New glycerol esters, processes for their preparation and pharmaceutical compositions containing these esters - Google Patents

Description

Cologne, Deichmannhaus _ _

Scherico Ltd., Lucerne (Switzerland)

New glycerol esters, ^/ learn about their preparation and pharmaceutical compositions containing these esters

The invention relates to new derivatives of salicylic acid with valuable pharmacological properties, procedures too their preparation and pharmaceuticals containing these esters Compositions.

The analgesic and antipyretic effects of salicylic acid has long been known; however, lead large and common Doses of the same almost always cause nausea, often spasms and vomiting, and in some cases even coma. These undesirable phenomena can be significantly affected by use Acetylsalicylic acid, which - as is well known - is a powerful analgesic and Represents antipyreticum. In some cases, however, it already resolves a normal dose of acetylsalicylic acid severe gastric upset the end; and in cases of illness in which the administration large doses, especially over long periods of time, is necessary, as may be the case in certain cases of rheumatic diseases serious ulcers of the gastrointestinal tract result.

109845/1872

Derivatives of acetylsalicylic acid with a methyl group as a core substituent and / or an acyl group larger than that Acetyl groups can generally be used in those cases where salicylic acid therapy is effective, however, side effects similar to those of the administration of n ^ occur.

It has now been found that the c ^ -Glycerolester of acetylsalicylic acid and their derivatives having a methyl group as a core substituent and an acyl group larger than that Acetyl group are generally better tolerated by the gastrointestinal tract than the corresponding free acids. Cyclic acetals and ketals of these glycerol esters, which are used in particular as starting materials for the o (-Glyeerinester

even
serve, have themselves / favorable pharmacological properties.

The invention thus relates to compounds of the general formula I:

^^ \. COO. CH ₂ . CHOH. CH ₂ OH

(CH, LUI "' _a y .. f

³ "" ^ V. J O.CO.CH R ^a R ^b

away
in which R and R, which can be the same or different, denote alkyl groups or hydrogen atoms, the total

a b number of carbon atoms in R and R is not more than 3, and η is 0 or 1, and their pharmaceutically acceptable cyclic acetals and ketals, e.g. ... the compounds of general formula II:

00. CH,

CH-

-CIt

O.CO.CH R ^a R ^b 0,

109845/1872 _η / \ ₂

R ¹ R

12th
in which R and R, which can be identical or different, denote hydrogen atoms or alkyl, aryl or aralkyl groups or together represent a polymethylene group, and n, R and R have the meanings given above.

Because of its excellent pharmacological properties is the £ X-glycerol acetyl salicylate according to the Invention particularly preferred.

If a cyclic acetal or ketal of a compound of the general formula I is used in therapy, Λ comes

preferably a compound in question in which R is a water.

2 is a material atom or a lower alkyl group and R is a lower alkyl group (the term "lower alkyl group" is understood to mean an alkyl group with up to k carbon atoms). Preferred cyclic acetals and ketals of this type are derived from cc-glycerol acetyl salicylate; it is therefore a matter of connections in which

η = 0;

away' *

R = R = a hydrogen atom,

R = a hydrogen atom or a lower alkyl group '

2
and R = a lower alkyl group.

A particularly preferred compound of this type is β, V -Isopropylidene-dioxypropyl-acetylsalicylate.

Because the ß-Kohleristpffatom of the glycerol component in the glycerol esters itself and their cyclic acetals and ketals is asymmetrically substituted, the inventive method

109845/187 2

^ indications in stereoisomeric forms. All stereoisomers Forms, both the pure forms and the mixtures or racemates, are encompassed by the present invention.

The compounds according to the invention can by known methods of esterification, including indirect methods, e.g. transesterification. For the preparation of a compound of the general formula IA:

in which X denotes a qc, ß-dihydroxyethyl group or a cyclic acetal or ketal of such a group and n, R and R ^b have the meaning given for formula I, a compound of the general formula

Y.CH ₂ .X ¹

according to known esterification methods with a compound of the general formula

Z.CO.CR ^a R ^b .A
are condensed, in which X is the group X or defined above

attyl _a b

represents a vinyl or epoxy vittyig group and R and R represent have the meaning given for formula I, and

either Y and Z are reactive groups capable of condensation during the esterification, one of the groups Y and Z being the grouping

CO ■ ■ ■

ο _ 1 0 9 8 Λ 5/1872

- 5 - ■. ■ - ■

a,

in which η is 0 or 1, and A is a hydrogen atom, or Y the group

Oh

represents, in which η is 0 or 1, and Z and A together are one represent another carbon-carbon bond, and, in the event that X is a vinyl or Ep oxy vittyi group means the product obtained by known methods of oxidation and / or hydrolysis into a β, Y -dihydroxypropyl ester is convicted.

The term "known methods" includes those in the chemical literature described or the relevant Methods known to those skilled in the art understood.

The ones listed for the production of a ß, γ * dihydroxypropyl ester Oxidation and / or hydrolysis can be carried out in one or more stages. For example, when X is a vinyl group represents the conversion of the intermediate product into a β, γ-dihydroxypropyl ester in a single stage by oxidation by means of osraium tetroxide (essentially in the absence of others Oxidizing agent) or in more than one stage by epoxidation of the double bond with an organic peracid and hydrolysis of the epoxy. Further reagents that can be used for the oxidation are, for example, potassium permanganate, Silver chlorate and osmium tetroxide, hydrogen peroxide and

109845/1872 - 6 -

Osmiumtetroxydj hydrogen peroxide and selenium dioxide as well Silver iododibenzoate (followed by an ilodrolysis step).

V
If X denotes an epoxy group, the hydrolysis can be carried out in a single stage, but it is generally carried out in two stages, e.g. by opening the epoxy ring by reaction with an acid, e.g. p-nitrobenzoic acid, followed by a hydrolysis stage.

The grouping

(in which η stands for O or 1) the part of one of the reactive Forming groups Y and Z remains inert during the condensation reaction, although the reaction takes place at their free valences.

Suitable pairs of the reactive groups Y and Z are known to those skilled in the art common; however, some examples are given below. . . ,

In the molecules of the cC-glycerol esters of the general formula I and their cyclic ketals and acetals are two ester linkages

the
present, of which / one is formed in the condensation reaction according to the invention, while the other is already present.

If the ester bond becomes the glycerol component or its ketal or acetal in a condensation reaction according to the invention

109845/1872 ₇ _

176 «169

formed, is preferably a compound of the general Formula III:

link LT ¹ Shape IV: (in) with a the general. calmly. T ² .Q (IV) react

In the above formulas, L means the grouping

O.CO, CH R ^a R ^b

away
in which n, R and R have the meaning given for formula I, Q stands for one of the following groups VA, VB and VC:

CH .CHOH.CH ₂ OH
or their cyclic ketal or acetal, ■

CH ₀ . CH CH_ (vbV

and CH CH: CH ( ^vc )

12 ·

and T and T represent reactive groups which can be eliminated during the reaction to form an oxygen atom connecting the groups L and Q; then, if Q represents the radical VB or VC, the product is oxidized and / or hydrolyzed to a β, ■ / -dihydroxypropyl ester as required, for example in the manner described above.

10 9 8 4 5/1872

The following sections 1-6 are preferred pairs of the Reaction components of the general formulas III and IV

described:

ο
1. If T in the compound of the general formula IV is a hydroxyl group, the compound of the general formula III can expediently be an acid halide, preferably the chloride (T denotes halogen, preferably chlorine), or an anhydride, preferably the symmetrical anhydride of the acid general formula IHA:

(gh ,;

O, CO.CHR R

(in which n, R and R have the meaning given for formula I), or a mixed anhydride, formed with a sterically hindered acid, such as, for example, pivalic acid

(e.g., T ¹ - (CH ₃ )

₃ ) _n

₀ .CO.CH R ^a R ^b

"away
in which η, R and R have the meaning given for formula I.

have, or

), C.CO.O).

The symmetrical anhydride of the acid of formula IIIA can from the acid itself and a carbodiimide, e.g. the dicyolohexylcarbodiimide, be won. The anhydride is preferably combined with the compound of the general formula IV (in the T means the OH group) at elevated temperature in opposite

109845/1872

■. . - 9 -r

waiting for a catalyst, e.g. zinc chloride, and in the presence an inert organic solvent implemented.

2. If T in the compound of the general formula IV is a hydroxyl group, the compound of the general formula IV can also be condensed directly with the acid of the general formula IIIA in the presence of a dehydrating agent. Preferred dehydrating agents are carbodiimides, in particular dicyclohexylcarbodiimides; & -Alkynylamines are also useful as dehydrating agents. It should be pointed out, however, that numerous carbodiimides react with the epoxy group of epoxy * t * yl alcohol, that glycerol itself readily forms a cyclic adduct with many carbodiimides and that allyl alcohol can be converted into ether with the aid of garbodiimides; therefore, in this reaction, a cyclic ketal or acetal of glycerol is the preferred reaction component of the general formula IV.

3 · According to a variant of that described in the previous paragraph The process management is the dehydrating agent '- e.g. carbodiimide or οζ-alkynylamine, preferably Dicyclohexyl carbodiimide. - either with the acid of the general formula IIIA or with a compound of the formula HO.Q (in which Q has the meaning given above) reacted and the resulting product of the general formula III or IV with a compound of the general formula IV, in

ο
the T denotes the hydroxyl group, or with the acid the

general formula IIIA allowed to react. Will the connection

109845/1872 -.-.

- ίο -

dung HO.Q with a dehydrating agent such as a Carbodiimide, implemented, comes as the compound HO.Q from the im For reasons given in the previous paragraph, a cyclic acetal or ketal of glycerol is preferably used.

The reaction of the compound HO.Q with a carbodiimide is Usually in the presence of a catalyst. Preferably a copper salt, e.g. cupro chloride or cuprie chloride. The resulting addition product is then with the Acid.der general formula IIIA in the presence of a inert organic solvent, e.g. dioxane, preferably at temperatures between room temperature and 150 ° C, implemented.

The reaction of the acid of the general formula IIIA with a carbodiimide is usually carried out in a basic solvent such as pyridine. The reaction product can with the compound of the general formula HO.Q under transesterification conditions (Trans-esterification) are condensed.

A, A particularly preferred method for the preparation of compounds of the general formula I and their cyclic acetals and ketals consists in the transesterification of a reactive ester of an acid of the general formula IIIA with a compound of the general formula HO.Q, in which Q is the one given above Has meaning. The reactive ester of the acid

the
/ general formula IIIA preferably has the structure of general formula VI:

109845/1872 - η -

- li -

CO.0.CH ₂ B

in which B is a cyano-, carbamoyl- (e.g. Ν, Ν-dimethylcarbamoyl-), Alkoxycarbonyl (e.g. ethoxy carbonyl or methoxy carbonyl) or acyl (e.g. alkanoyl or aroyl, especially acetyl

a b or benzoyl-) group and n, R and R the for Formula I have given meaning. This transesterification is preferably carried out in the presence of a basic catalyst, e.g. anhydrous potassium carbonate. An excess of alcohol HO.Q is usually used as the solvent, since the transesterification is reversible. The reaction is conveniently carried out at temperatures in the range of 80 to 250 ° C, for example at the reflux temperature of the reaction mixture carried out.

The reactive ester of the general formula VI is preferably prepared by reacting the acid of the general formula IIIA with a compound of the general formula Cl.CH .B (B has the meaning given above) in the presence of a tertiary base, for example triethylamine. The preferred compound of the formula Cl.CH ₀ .B is chloroacetonitrile.

5 ·. A compound of the general formula.

in which M is an equivalent of a metal ion, preferably silver . 109845/1872 - 12 -

or an alkali metal, e.g., sodium, and n, R

and R have the meaning given for formula I, can with a compound of the general formula

W.Q r.

in which Q has the above meaning and ¥ the remainder of a reactive Ester, preferably a halogen atom or a sulfonate ester group, is to be implemented.

6. An acid of the general formula II can be used with a ref binding the general formula:

D- CJH-, '> - OQ

in which D is a secondary amino group, e.g. a dimethylamino group, means and Q has the above meaning, be condensed.

According to the invention, the ester bond, including the Acetoxy group are formed, the process according to the invention comprises the acylation of a compound of the general fc formula

(CH ₃ )

CO. OQ

OH
in which Q has the above meaning and n. is 0 or 1.

An anhydride (including ketenes) or a halide, preferably chloride, of the acid R ^a R CH-COOH (where R ^a and R ^{b have} the above meanings) can be used as acylating agent.

Because of the difficulties encountered in the selective acylation * of the phenolic hydroxyl group in the presence of two aliphatic ^II y ^drox y _i ¹ g ^r ₃ ^u | ^ _/ Y | ^ ₂ , the group Q is at

of this process variant, preferably a cyclic ketal or acetal of the group of the general formula VA or a group "of the general formula VB or VC. If Q stands for a Group of the general formula VB or VC, the product obtained becomes, depending on the requirement, the β, / -dihydrodroxypropyl ester oxidized and / or hydrolyzed ..

In the aforementioned procedures, Q preferably sets cyclic ketal or acetal of a group of the formula VA, in particular a group of the formula

• '- CH ₀ .CH- CHo

² I ι ²

LJ

R- ¹ • R ²

1 2
in which R and R have the meaning given above. The preferred reaction component of the formula HO.Q is 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane.

If the end product of the aforementioned procedure is a Ct-glycerol ester and a cyclic ketal or acetal (dioxolane) thereof is desired, the oC-glycerol ester can be reacted with the corresponding aldehyde or ketone in the presence of a condensing agent. Conversely, if a cyclic ketal or acetal (dioxolane) of the ct-glycerol ester is obtained as the process product and the ct-glycerol ester itself is desired, the ketal or acetal group can be selectively removed by known methods.This removal can be carried out by selective hydrolysis, preferably under weakly acidic conditions, e.g. with the help of aqueous acetic acid or p-toluene

109845/1872

- Ik -

'! 7 K H 1 6 9

sulfonic acid hydrate in a low-boiling solvent such as tetrahydrofuran or dioxane; or leave that Dioxolane react with boron trichloride at low temperatures, preferably at about -80 C, expediently in the presence an inert organic solvent such as methylene chloride and then hydrolyzes the resulting borate Complex compound. You can also use certain dioxolanes, namely those with aromatic aldehydes (R = a hydrogen atom, R = an aromatic group), split into the iX-glycerol ester by hydrogenation, for example using of palladium on charcoal or potassium carbonate as a catalyst. For hydrogenolysis, benzaldehyde (R = a Hydrogen atom, R = the phenyl group) formed dioxolanes are particularly preferred.

In particular, cyclic ketals and acetals of ci-glycerol salicylate to the corresponding cyclic ketals or acetals des ά-glycerol acetylsalicylates (e.g. those of the above given general formula II, in which η stands for 0 and R and R a hydrogen atom, in particular the ß, j ~~ -Isopropylidenedioxypropyl-acetylsalicylate) are acetylated. oC-Glycerin-acetylsalicylat can then from its cyclic Acetals or ketals through selective hydrolysis of the dioxolane ring, preferably under weakly acidic conditions.

If a glycerol ester or its cyclic acetal or ketal with a certain stereochemical structure in the glycerol component is to be obtained, the esterification of the

109845/1872 " ¹⁵ "

ORIGINAL INSPECTED

Acid of the general formula IIIA or a reactive derivative the same carried out with a dissolved enantiomeric compound of a cyclic ketal or acetal of glycerol.

The following examples illustrate the process for preparing the compounds according to the invention.

Example 1: A. Cyanomethyl salicylate:

A mixture of 48 g of salicylic acid, 200 ml of acetone, 51 g of triethylamine and 38 g of chloroacetonitrile are heated with stirring and reflux for 3 hours. The excess of acetone and triethylarain is evaporated, the residue treated with ice water and the mixture filtered. The cyanomethyl salicylate obtained "has a melting point of 68 to 70 ° C (from benzene petroleum ether).

B. ß, £ -Isopropylidenedioxypropyl salicylate:

Eijie mixture of 30 g of cyanomethyl salicylate, 135 g of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane and 1 g of anhydrous potassium carbonate is heated with stirring on the steam bath for 2 hours. The reaction mixture is poured onto ice water and the ß, γ-Isopropylidenedioxypropyl salicylat filtered off.

C. ß, "γ -Isopropyiidenedioxypropyl-o-acetoxybenzoate:

8 g of acetyl chloride are added to a suspension of 27.4 g of the sodium salt of ß, Y -isopropylidenedioxypropyl salicylate in 500 ml of anhydrous ether with stirring and cooling. The mixture is stirred for 3 hours at room temperature, the sodium chloride is filtered off and the ether filtrate is concentrated to dryness.

10 9-845 / 187 2 -16-

D. ß, γ-Dihydroxypropyl-o-acetoxybenzoate: The crude ketal of stage C, the ß, ji -isopropylidenedioxypropylo-acetoxybenzoate, is dissolved in 250 ml of tetrahydrofuran containing 10 g of p-toluenesulfonic acid hydrate and the mixture for 2 hours heated under reflux. The excess tetrahydrofuran is removed in vacuo, ice water is added and the product is extracted with ether; the ether solution is dried and concentrated to obtain the ß, ^ -dihydroxypropyl-o-acetoxybenzoate ( Cf -glycerol acetylsalicylate).

Example 2: A. Ö- (ß, V-IsopropylidenedioxypropylJ-NjN'-dicyclohexyl-isourea: A mixture of 33 g of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, 51.5 g of dicyclohexylcarbodiimide and 50 mg Cuprous chloride is stirred at room temperature for 24 hours. That The resulting mixture is dissolved in 500 ml of petroleum ether, the The resulting solution was slurried with aluminum oxide, filtered and the filtrate was concentrated to dryness.

B. ß, ^ -Isopropylidenedioxypropyl-o-acetoxybenzoate: 33.9 g of 0- (ß, \ j -IsopropylidenedioxypropylJ-NjN'-nicyclohexyl-

¹ in

Isourea and 18 g of acetylsalicylic acid / 500 ml of dioxane are introduced and the mixture is stirred at 50-100 ° C. for k hours. The resulting mixture is filtered, the filtrates concentrated to dryness and the desired β, γ -isopropylindendioxypropylo-acetoxybenzoate is recrystallized from isopropyl ether, melting point 34 ° -35 ° C.

- 17 -. 109845/18 72

C. β, ^ -dihydroxypropyl-o-acetoxybenzoate: 30 g of Q, J -isopropylidenedioxypropyl-o-acetoxybenzoate and 10 g of p-toluenesulfonic acid hydrate are dissolved in 250 ml of dioxane and the mixture is refluxed for 2 hours. The excess of dioxane is evaporated off in vacuo, ice water is added and the product is extracted with ether. To obtain the ß, I [-e-dihydroxypropyl-o-acetoxybenzoate ( A- glycerol acetylsalicylate), the ether extract is dried and concentrated to dryness.

Example 3: β, \ -Isopropylidenedioxypropyl-acetylsalicylate; 17.2 g of dicyclohexylcarbodiimide and then 15 g of acetylsalicylic acid are added to a stirred, cooled (0 ° C.) solution of 50 ml of dry pyridine and 22 g of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane. The reaction mixture is kept at 0 ° C. for 18 hours, diluted with 300 ml of ether and the dicyclohexylurea is filtered off. The ether solution is washed with 5% acetic acid, water and dilute sodium bicarbonate solution, dried and concentrated. The residue is fractionally distilled and the product which passes over at 156-162 ° C./0.45 mm is collected. Recrystallization from isopropyl ether yields the desired colorless product with a melting point of 3 ^ _f 5 - 35t5 ° C

Example k: ß, y -dihydroxypropyl-o-acetoxybenzoate (# -glycerol acetylsalicylate) *. A solution of 2 g of B, | Isopropylidenedioxypropyl acetyl salicylate in 10 ml of 75% acetic acid is heated on a steam bath for 10 minutes. The solution is in

- 18 109845/1872

Poured water, neutralized with dilute sodium bicarbonate solution and extracted with ether. The ether extracts are dried, concentrated and the residue is recrystallized.

Example 5: glycerol 2-valeryloxy-3-methyl-benzoate; Allyl 2-valeryloxy-3-methyl-benzoate is produced by transesterification of cyanomethyl-2-valeryloxy-3-methyl-benzoate with allyl alcohol according to Example 1, stage B prepared.

A solution of 0.25 mol of this allyl ester in 300 ml of pyridine is cooled to 5 ° C and treated with a solution of 69.9 g (0.27 ** mol) of osmium tetroxide in 400 ml of pyridine. The rea-. tion mixture is stirred at room temperature for 24 hours, diluted with water and ether and saturated with hydrogen sulfide, The osmium dioxide is filtered off and the desired cA-glycerin * ester isolated in the usual way.

from Example 6: Production / Glycerin - ^ - isobutyryloxy - ^ - methyl benzoate *. A solution of 2.2 g of 2-phenyl-1,3-dioxolan-4-ylmethyl-2-isobutyryloxy-4-methyl-benzoate in 40 ml of ethanol is with 1 g of palladium black and hydrogen (under a pressure of 1 l / 2 atmospheres) at room temperature until 2 moles of hydrogen are absorbed. The catalyst is filtered off and the filtrate concentrated to a residue. To obtain the crystalline glycerol 2-isobutyryloxy-4-methyl-benzoate, the residue is dissolved in methanol and Added water.

- 19 -109845/1872

Example 7ϊ Preparation of glycerol ^ -propionoxy-S-methylbenzoate; 2.22 g of 2-phenyl-1,3-dioxolan-4-yl-methyl-2-propionoxy-5-methyl-benzoate are dissolved in methylene chloride and an excess of boron trichloride in methylene chloride to -80 ° C (Acetone carbonated snow bath) added. The temperature is left Raise the mixture to room temperature, concentrate (in vacuo) and treat the resulting residue with methanol and then with water and, after filtration, the crystalline glycerol 2-propionoxy-5-methylbenzoate is obtained.

The 2-phenyl-l, 3-dioxolan - ^ - yl-methyl ester used as starting material in Examples 6 and 7 can be obtained by transesterification the corresponding cyanomethyl ester with 2-phenyl-1,3-dioxolan-4-yl-methanol, according to example 1, stage B, are obtained.

The active compounds according to the invention can be administered in the form of pharmaceutical compositions consisting of at least one of the active compounds exist together with a pharmaceutical carrier substance or a binding agent. These compositions can be administered to any-. be formed in a suitable way in one of the usual ways, e.g. for administration by the oral, rectal, enteral, external and transcutaneous routes.

Pharmaceutical compositions can, for example, in solid or liquid form, expediently in the form of dosage units, are present, each dose unit containing a certain amount of active ingredient, preferably 20-500 mg. Examples of dose units are

109845/1872

- 20 -

I / b 'ö "! Tablets, coated tablets, capsules, lozenges and suppositories.

The compositions can also be formulated as powders, granules, suspensions, elixirs, lotions and ointments will.

Depending on the particulars of the case, it is generally advisable a total daily dose of about 2 to .40 mg per kg of body weight.

Topical compositions can be used in the treatment of localized inflammation and / or irritation will. Compositions intended for internal use can be used in the treatment of pain and Inflammations, such as those associated with rheumatic and osteoporous joint diseases, collagen diseases, Bursitis, gouty arthritis and spondylitis related can be used.

In the following Examples AE, pharmaceutical compositions according to the invention are explained in more detail; the Compositions are made according to standard methods. Any compound according to the invention, preferably ^ -glycerol acetyl salicylate.

Example A: Enterally acting, coated tablets:

Composition of the tablet core mg / core

Active substance, finely divided 100.0 r

Citric acid 1.0

Lactose, USP 33.5

Dicalciuraphosphate 70.0

Pluronic F-6S '30.0'

Sodium Lauryl Sulphate 15.0

Polyvinyl pyrrolidone 15.0

Carbowax 150O * u5

Carbowax 600O ^ 5.0

Corn starch 30.0

Sodium Lauryl Sulphate 3.O

Magnesium stearate 3.0

109845/1872 350.0

ORIGINAL INSPECTED _O1

17 68

The tablet cores (manufactured according to the usual methods) are provided with an enteral lacquer coating, colored and polished.

Pluronic F-68 is a non-ionic surfactant Means made by adding ethylene oxide to a polypropylene glycol with a molecular weight of 1750 is obtained.

Example B: Capsules of active substance finely divided Citric Acid Pluronic F-68 Sodium Lauryl Sulphate Lactose

Magnesium stearate

mg / capsule 100.0

1.0

40.0 20.0

238.0 101.0 400.0

The individual ingredients are put into two-part gelatin capsules of a suitable size.

Example C: Oral suspension active substance finely divided Veegum, Vanderbilt standard granulated sugar, USP sorbitol solution, USP sodium saccharin, NF sodium benzoate, USP ethanol, USP
Menthol, USP
Flavors qs Pure Water, USP on

mg / 5 ml 100.0 50.0

2500.0 1250.0 50.0

5.0

0.025 ml 1.0

5.0 ml

109 8 45/1 872

ORIGINAL INSPECTED

- 22 - y 7 h 8 1 6

Example D: Suppositories' mg / suppository Active substance finely divided 100 * 0

Theobroma oil, pharmaceutical quality to 2.0 g

Example E: Ointment, externally mg / g active substance finely divided 20.0

Methyl paraben, USP 0.5

Propyl paraben, USP 0.1

Petrolatum, USP on 1.0 g

- 23 -

1093 * 4 57 1 Ö f 2

i r

^ i-ECTEO

Claims (1)

Claims a ■ b
in which R and R, which can be the same or different, denote alkyl groups or hydrogen atoms, the total number of carbon atoms in R and R not being more than 3, and η being 0 or 1,
and their pharmaceutically acceptable cyclic acetals and ketals. 2. Compounds of the general formula II: COO. CH ₂ - CH CH ₂ O.CO.CffiTR "C _? (II \ 1 2
in which R and R, which can be identical or different, hydrogen atoms or alkyl, aryl or aralkyl groups or a b together denote a polymethylene group and n, R and R have the meaning given in claim 1. 3. Compounds according to claim 2, of the general formula II, in 1 2 where R is a hydrogen atom, a lower alkyl group and R is a lower alkyl group. - 2k - 109845/1872 - 2k - 1 7 G H Ί Β 9 k. Compounds according to claim 3, in which η is O and R and R are hydrogen + atoms. 5. OL glycerol acetyl salicylate. 6. β, γ-Isopropylidenedioxypropyl acetyl salicylate. 7. Process for the preparation of a compound of the general formula IA: 0.OCHgX .CO.CHR ^a R ^b in which X is an (X, ß-dihydroxyethyl group or a cyclic Acetal or ketal of such a group and n, R and R have the meaning given in claim 1, thereby characterized in that a compound of the general formula Y.CH ₂ .X ¹ according to known methods with a compound of the general formula Z.C0.R ^a R ^b .A is condensed, where in these formulas X is the group X defined above or a vinyl or epoxy vinyl group and away
R and R have the meaning given in claim 1, and either Y and Z represent reactive groups capable of condensation during the esterification, one of the groups Y and Z being the grouping .CO- (CHJ. 10984 5/1 87 2 -UN ORIGINAL i? CPECTED i 7 6 H 1 6 in which η is 0 or 1, and A is a hydrogen atom means, or Y the group CO. Ow represents, in which η stands for 0 or 1, and Z and A together represent another carbon-carbon bond, and, in the event that X is a vinyl or epoxy-vinyl group means the product obtained by known methods of oxidation and / or hydrolysis into a β, f -dihydroxypropyl ester is convicted. 8. A method for producing a compound according to claim 1, characterized in that a compound of the general formula III: LT ¹ , (III) with a compound of the general formula IV: T ² .Q, (IV) is implemented, where L is the grouping CO O.CO.CHR ^a R ^b away
means in which n, R and R are those indicated in claim 1 Have meaning, Q is one of the following groups: _o . CHOH. CII ₀ OH VA, 109845/1872 ORIGINAL t · K ^ lCTED i 7 ß 8 I b or a cyclic ketal or acetal thereof, CH ₂ -CH - CH ₂ and CH ₂ .CIItCH ₂ VC, '12
and T and T are reactive groups which can be eliminated during the reaction with the formation of an oxygen atom connecting the groups L and Q, V and, if Q represents the radical of the formula VB or pC, the product is oxidized and / or hydrolyzed to a β, V-dihydroxypropyl ester, as required. 9 · The method according to claim 8, characterized in that Compounds are used in which T is a halogen O
atom and T represent a hydroxyl group. 10. The method according to claim 8, characterized in that Compounds are used in which T is a hydroxyl group and T is a chlorine atom or one of the groups CO.0 O.CO.CHR ^a R ^b away
in which n, R and R have the meaning given in claim 1, and (CH -) - C.CO.O. mean. 11. The method according to claim 8, characterized in that an acid of the general formula IIIA: 109845/1872 - 27 ORIGINAL INSPECTED i 7 6 β Ί b (CH ₃ ) _n O.CO.CHR ^a R ^b in which η, R ^a and R have the meaning given in claim 1, condensation is carried out with glycerol or one of its cyclic ketals or acetals, allyl alcohol or epoxy alcohol in the presence of a dehydrating agent. 12. The method according to claim 11, characterized in that a carbodiimide or a dehydrating agent oC-alkynylamine is used. 13. The method according to claim 12, characterized in that dicyclohexylcarbodiimide is used as the carbodiimide. Ik. Process according to claim 8, characterized in that an acid of the general formula IIIA according to claim 11 is reacted with a carbodiimide or an ÖC-alkynylamine and the resulting addition product with a compound of the general formula HO.Q, in which Q is the one in claim 8 has given meaning, is implemented. 15. The method according to claim 8, characterized in that a compound of the general formula HO.Q, in which Q the has the meaning given in claim 8, reacted with a carbodiimide or a tf-alkynylamine and the resulting addition product is reacted with an acid of the general formula IIIA given in claim 11 will. 109 84.5 / 1872 - 2b - ORIGINAL INSPECTED . ' 1 7 β Η 1 6 16. The method according to claim Ik or 15, characterized in that dicyclohexylcarbodiimide is used as the carbodiimide. 17. The method according to claim 8, characterized in that a reactive ester indicated in claim 11 general Formula IIIA with a compound of the general formula HO.Q, in which Q has the meaning given in claim 8, is transesterified. 18. The method according to claim 17, characterized in that the reactive ester is an ester of the general formula VI: (CH ,; CO.OCH .B (VI) in which B is a cyano, carbamoyl, alkoxycarbonyl or acyl group and n, R and R have the meaning given in claim 1, is used. ™ 19. The method according to claim 18, characterized in that a Ester of the general formula VI, in which B is an alkanoyl or aroyl group is used. 20. The method according to claim 18, characterized in that an ester of the general formula VI, in which B is an ethoxycarbonyl, Methoxycarbonyl, acetyl or benzoyl group is used. - 29 - 1 0 9 8 A 5/1 8 7 2 ORIGINAL INSPECTED t / 68169 21. The method according to claim 8, characterized in that an ester of the general formula VI in which B is an N, N-dimethyloarbamoyl group means is used. 22. The method according to any one of claims 17 to 21, characterized in that that the transesterification is carried out in the presence of a basic catalyst. 23. The method according to claim 22, characterized in that the basic catalyst is anhydrous potassium carbonate is used. 2k, method according to claim 8, characterized in that a compound of the general formula: CO »OM O.CO.CHR ^ in which M is an equivalent of a metal ion and n, away
R and R have the meaning given in claim 1, with a compound of the general formula in which ¥ is a reactive ester radical and Q has the meaning given in claim, is implemented. 25 · The method according to claim 24, characterized in that one Compound is used in which M stands for an alkali metal. 109845/1872 _ ^ n _ ORIGINAL IN6PECTED ■ i 7 h H 1 6 26. The method according to claim 2k, characterized in that a compound is used in which M stands for silver or sodium. 27. The method according to any one of claims 2k to 26, characterized in that a compound is used in which V is a halogen atom or a sulfonate ester group. 28. The method according to claim 8, characterized in that an acid of the general formula IIIA given in claim 11 with a compound of the general formula D - in which D is a secondary amino group and Q has the meaning given in claim 8, condensation is carried out. 29. The method according to claim 28, characterized in that a compound is used in which the secondary Amino group D is a dimethylamino group. 30. A method for producing a compound according to claim 1, characterized in that a compound of the general formula CO.OQ ¹ in which η stands for 0 or 1 and Q is a cyolic ketal or acetal of the group of the general formula VA or a group of the general formula VB or VC specified in claim 8 109845/1872 ORIGINAL INSPECTED 17 88169 means, is acylated, and, if Q, the one in claim 8 given general formula VB or VC means the product obtained to a ß, | * - Dihydroxypropylester each is oxidized and / or hydrolyzed as required. 31. The method according to any one of claims 8 to 30, characterized in that that compounds are used in which Q or Q is a cyclic ketal or acetal of the group of general formula VA mean. 32. The method according to claim 31, characterized in that connections are used in which Q or Q mean tion the general Formula: - CH ₀
I. ·; CI J ₂ -CH- I. I. R ² R ¹ 1 2 in which R and R ^, which can be the same or different, are hydrogen atoms or alkyl-r, aryl or aralkyl group or together represent a polymethylene group. ™ 33. The method according to claim 32, characterized in that connections are used in which Q or Q is a ß, yIsopropylidenedioxypropylgruppe mean. "bk. A method according to any one of claims 8 to 33, characterized in that when Q or Q has the meaning as defined in claim 8 Formula VB, the hydrolysis of the Epoxydringes performed by ring opening with p-nitrobenzoic acid and hydrolysis of the resulting p-nitrobenzoate ester will. 109845/1872 1 7 6 H 1 6 35 · Method according to one of Claims 8 to 33, characterized in that if Q or Q has the meaning of the in Claim 8 given general formula VB has, the oxidation by means of osmium tetroxide is carried out essentially in the absence of other oxidizing agents. 36. The method according to any one of claims 8 to 33, characterized in that if Q or Q is the meaning of the in Claim 8 given general formula VC has, the oxidation by means of potassium permanganate or by means of silver chlorate and osmium tetroxide or by means of hydrogen peroxide and osmium tetroxide or by means of hydrogen peroxide and selenium dioxide or by means of silver iododibenzoate and hydrolysis or by means of an organic peracid, and then the conversion of the resulting epoxide takes place in the dihydroxypropyl ester. 37. The method according to claim 36, characterized in that the Conversion of the epoxide is carried out by reacting it with p-nitrobenzoic acid and subsequent hydrolysis. 38. The method according to any one of claims 8 to 37, characterized in that when a cyclic ketal or acetal one Glycerol ester of the general formula I given in claim 1 is desired and the product of the ot-glycerol ester is, this ester is reacted with the corresponding aldehyde or ketone in the presence of a condensing agent will. - 33 - 109845/1 872 ORIGINAL INSPECTED 39. The method according to any one of claims 8 to 33, characterized in that that when the ÖC-glycerol ester in claim 1 given general formula I is desired and the product whose cyclic ketal or acetal is the acetal or ketal is converted to the # -glycerol ester by known methods. 40. The method according to any one of claims 8 to 33, characterized in that that when the cC-glycerol ester is in claim 1 given general formula I is desired and the product whose cyclic ketal or acetal is the ketal or acetal is selectively hydrolyzed to the C 1-4 glycerol ester. 41. The method according to claim 40, characterized in that the Hydrolysis is carried out under weakly acidic conditions. 42. The method according to any one of claims 8 to 33, characterized in that that when the {Ä.-glycerol ester of claim 1 given general formula I desired and the product whose cyclic acetal or ketal is the acetal or Ketal to the C-glycerol ester by reaction with boron trichloride is cleaved at reduced temperature and subsequent hydrolysis of the borate complex formed. 43 · Method according to one of Claims 8 to 33, characterized in that that when the tfC glycerol ester is the one in claim 1 given general formula I is desired and the product is its cyclic acetal or ketal (dioxolane) .is, the dioxolane, the ring of which can be split by hydrogenation, is split into the desired δC-glycerol ester by hydrogenation will. 109845/1872 "I 7 b a 1 6 d4. Method according to claim 43, characterized in that a dioxolane is used that with an aldehyde of the general formula R ¹ ^ CHO, in which R is an aromatic group, is formed. 45 · The method according to claim 44, characterized in that a Aldehyde is used in which R is a phenyl group. 46. Process for the preparation of cyclic ketals and acetals of an oc-glycerol acetyl salicylate, characterized in that that corresponding ketal or acetal desöC-glycerol salicylates is acetylated. 47 · The method according to claim 46, characterized in that a Ketal or acetal desöC-Glycerinacetylsalicylates with the general formula CO.0 CHg-CH v ° O.CO.CHj> ^ JC R ² 1 ο
in which R and R have the meaning given in claim 2 , is used. 48. Process for the preparation of ß, ^ -Isopropylidenedioxypropyl acetyl salicylate, characterized in that ß, | -Isopropylidenedioxypropyl salicylate is aoetylated. 109845/1872 -35- ORlGlNAL INSPECTED 49. Process for the preparation of ^ -Glycerol acetylsalicylate, characterized in that a cyclic ketal or acetal of (/ -glycerol salicylate acetylates and the resulting Product is selectively hydrolyzed. 50. The method according to claim 49 »characterized in that the hydrolysis is carried out under weakly acidic conditions. 51. Process for the preparation of cX-glycerol esters of in Claim 1 given general formula I and its W cyclic acetals and ketals as described. 52. 0 <T-glycerol ester of the general given in claim 1 Formula I and their cyclic acetals and ketals, produced by a process according to one of Claims 7 to 51. 53 Pharmaceutical compositions, characterized in that that they have at least one of theΛ-glycerol ester as an active ingredient of the general formula I indicated in claim 1 and its ™ contain pharmaceutically acceptable cyclic acetals and ketals. 54. Compositions according to claim 53 «characterized in that that they are in the form of dosage units. 55. Compositions according to claim 54, characterized in that that they have the form of tablets, capsules, coated tablets, suppositories or lozenges. - 36 - 109845/1872 1 7 υ 8 16 9 56. Compositions according to claim 54 or 55 »characterized in that they contain 20-500 mg of active ingredient. 57. Compositions according to claim 53, characterized in that that they are in the form of ointments, suspensions, or elixirs. 58. Compositions according to one of claims 53 to 57, characterized characterized as having as active ingredients C-glycerol acetyl salicylate contain. 59 * Compositions according to any one of claims 53 to 57, characterized characterized in that they contain 6, J- isopropylidenedioxypropy1-acetylsalicylate as active ingredient. 60. All described new compounds, compositions, Procedures and methods. 109 845/1872 ORIGINAL INSPECTED