NL8602767A - ORGANIC ACID ANHYDRIDE, AND A PHARMACEUTICAL PREPARATION BASED ON A PRODRUG. - Google Patents

Description

t * NL 33862-dJ / cs

Organic acid anhydride, as well as a pharmaceutical preparation based on a prodrug.

The present invention relates to novel organic acid anhydrides, as well as to a pharmaceutical preparation based on a prodrug.

Prodrugs are compounds which in themselves do not have a pharmacological effect, but which, once absorbed into the body, release the active substance so that it can fulfill its medicinal function. Such prodrugs are especially important on the one hand to prevent the free active substance from undergoing a chemical change before it has reached its destination in the body, as a result of which its effect is lost, and on the other hand to prevent the physical chemical properties of the drug so as to provide adequate and timely absorption into the body and appropriate and timely release of the drug there.

Numerous existing medicines contain an organic acid function. This acid function generally creates drug absorption problems, which can be attributed to the polarity and acidity of such drugs.

Many proposals are known for solving these problems, mainly using prodrugs in the form of an ester or amide of the pharmacologically active organic acid. In addition, the active organic acid must be released into the body by hydrolysis of the ester or amide group.

A drawback of these known ester and amide prodrugs is that their hydrolysis to the active free acid in vivo takes place only slowly, so that the drug is not immediately available after absorption of its prodrug. The cause of this slow hydrolysis lies in the fact that the hydrolysis of these ester and amide prodrugs requires the action of enzymes, the esterases.

The present invention now aims to provide new organic acid anhydrides, which can function as prodrug, and whose hydrolysis to the free active organic acid is not dependent on the action of enzymes.

To this end, the invention provides a new organic acid anhydride, characterized in that it is a mixed acid anhydride of formula 1 of the formula sheet, wherein 1 R is the residue of an organic acid with anti-inflammatory, anti-epileptic, ACE- inhibitory, biocidal, cytostatic, antidiuretic, antidiarrhoeic or cerebrotonic action, or of a steroid acid, and wherein 2 1 R is different from R and represents either a group of formula 2, wherein R, R and R are are not the same and hydrogen, C 1-20 alkyl or alkenyl, cycloalkyl or alkenyl, aryl, alkaryl, aralkyl, which groups are optionally substituted by alkyl, aryl, alkoxy, aryloxy, alkoxycarbonyl or aryloxycarbonyl and optionally contain one or more hetero atoms; either a steroid fragment; either an amino acid or peptide moiety; or a pharmaceutically acceptable salt thereof.

These mixed acid anhydrides of formula 1 of the formula sheet have the particularly advantageous property for prodrugs that the hydrolysis of the mixed acid anhydride to the pharmacologically active compound is independent of enzyme activity, so that the degree of hydrolysability in vivo can be adjusted by adjusting for a given R group to choose an appropriate R group. Inherent in the anhydride form in which the drug is introduced is reduced polarity and acidity and increased lipophilicity. On the one hand, this reduces the irritation of the gastrointestinal system upon oral ingestion and, on the other hand, increases the ability to be absorbed through the skin, such as in transdermal and transmucosal absorption of the mixed acid anhydride.

As mentioned above, by a suitable choice of the mixed anhydride, a prodrug can be obtained which, once absorbed into the body and hydrolysed to the pharmacologically active organic acid, exhibits the desired pharmacological activity, while the physicochemical properties such as the degree of hydrolysability in water and in body fluids, lipophilicity, taste, odor 8602767 - 3 - 4 · * and color, miscibility with additives and processability, of the prodrug depending on the nature of the drug, the mode of administration and the objective can be systematically adjusted. This entails important advantages in pharmaceutical practice.

The degree of hydrolysability can be adjusted by choosing one or more of the R, R and R groups of hydrogen atoms in formula 2 of the formula sheet. When R, R and R represent all hydrogen, the hydrolysis proceeds quickly. As more hydrogen atoms are substituted, the hydrolysis rate decreases.

The degree of lipophility can be adjusted by suitably selecting the chain length of one or more of the groups R, R and R. The lipophility then increases with increasing chain length.

2

By choosing a steroid fragment or an amino acid or peptide fragment for R, very specific properties can be obtained. The R group can then, for example, fulfill a carrier function in order to transport the active organic acid 20 through cell membranes.

In formula 1 of the formula sheet, as mentioned, R may be the remainder of an organic acid with an anti-inflammatory, anti-epileptic, ACE-inhibiting, biocidal, cytostatic, anti-diuretic, anti-diarrheic or cerebrotonic action. , or of a steroid acid.

Examples of residues R of free organic acids with anti-inflammatory effect are: residues of tolmetin, summer pirac, tiaprofenic acid, sulindac, niflumic acid, ibuprofen, mefenamic acid, ketoprofen, indometacin, flurbiprofen, pheno-30 profen, fenclofenac, naproxen, fenbufen etodolac, cinmetacin, acetylsalicylic acid and penicillamine. However, this list is not exhaustive, and other non-steroidal anti-inflammatory organic acid residues can also be used. As R, the radicals of ibuprofen, ketoprofen, flurbiprofen, diclofenac, naproxen, etodolac, sulindac and indometacin are particularly preferred.

Examples of residues of anti-epileptic organic acids are given by general formula 3 of the formula sheet, wherein R and R may or may not be the same as 8602767-4 i and represent an aliphatic group. Preferably R is the valproic acid residue, wherein R and R in formula 3 are both n-propyl.

The term "ACE inhibitory activity" used in this specification and claims stands for "angiotensin converting enzyme inhibitory activity". This action resides in inhibiting the renin-angiotensin system and more particularly the enzyme that converts angiotensin. Substances exhibiting such ACE inhibitory activity have anti-hypertensive properties.

Examples of residues of organic acids with ACE inhibitory activity are described by general formula 4 or

Q

5 of the formula sheet, wherein R is hydrogen, alkyl or arylcarbonyl, R is hydrogen, alkyl or aminoalkyl, R alkyl or 15 is an optionally alkyl or aryl substituted C 6 -cycloalkyl, 11 10 11 R alkyl or aryl is whether R and R together represent an optionally alkyl or aryl substituted C 3-8 alkylene or alkenylene, which may be part of a saturated or unsaturated 12 quinoline or isoquinoline group, R is a hydrogen atom or 20 alkyl, R 1 is hydrogen, alkyl or R 1 -C (O) -, and R ** is alkyl or aralkyl.

A favorable representative of this is the rest

O

of formula 4 of the formula sheet, wherein R tert-butylcar-

- Q IQ Λ A

bonyl, R is methyl, R and R together form a propylene group 12 and R is hydrogen. This residue is the captopl residue of which the hydrogen atom of the thiol function has been replaced by a tert-butylcarbonyl protecting group.

Another preferred radical R has formula 4 of the 8 formula sheet, wherein R is tert-butylcarbonyl, R is methyl, 10 1112 is 30 R cyclopentyl, R and R are hydrogen. This residue is the pivopril residue, the hydrogen of the thiol function of which has been replaced by a tert-butylcarbonyl protecting group.

Λ

Further particularly favorable radicals R have formula g 35 of the formula sheet, wherein R is methyl or 4-amino-butyl, 1011 12 R and R together form a propylene group, R is hydrogen 13 2 14, RR is -C (O) - and R is phenylethyl. Such anhydrides, where R has the meaning of R -C (O) - can be considered as the dianhydrides of enalapril 8502767-5 and lysinopril, respectively. Conversely, enalapril and lysinopril residues have an ethyl group such as R. There is then an ester function, which must be hydrolysed in vivo, which entails the aforementioned drawbacks. These drawbacks can be avoided by replacing the ester function with an anhydride function, in which case both anhydride functions of the mixed dianhydride may or may not be the same.

As examples of residues of organic acids with biocidal activity, the residues of pipemidic acid, oxo-linic acid, flumequin, nalidixic acid and cinoxacin can be mentioned, with the residues of oxolic acid, flumequin and cinoxacin being preferred.

Examples of R residues of organic acids with cytostatic action are the residues of chlorambucil and of the free acid of vinblastin, the former being preferred,

Examples of residues of organic acids with anti-diuretic activity include residues of decililic acid, etacrynic acid and furosemid, while the latter residue is preferred.

As examples of residues of organic acids with antidiarrhoeic action are mentioned the residues of the free acid of loperamide and of the free acid of diphenoxylate. The remainder of the free acid of loperamide is particularly suitable in the intended mixed acid anhydrides.

As representatives of residues of organic acids with cerebral activity, the residues of the free acid of piracetam and of the free acid of vincamine can be mentioned, the former mentioned being preferred.

Finally, examples of steroid acid residues are the residues of chenodiol, ursodeoxycholic acid and canrenoic acid. The remainder of ursodeoxycholic acid is especially preferred.

A particular form of the mixed anhydride 1 2 35 is obtained when both the R and R groups represent a residue of a pharmacologically active organic acid. Hydrolysis in vivo of the mixed acid anhydride then releases two active substances, whereby the effects of two drugs can be combined. This offers several advantages over the conventional combination preparations, which contain two separate active substances, whether or not in the form of a prodrug.

The preparation of the mixed acid anhydrides according to the invention is effected in a manner known per se for analogous compounds. However, problems may arise if, in addition to the anhydride function, free amine, alcohol or thiol functions also occur in the mixed anhydride. Such free amine, alcohol and thiol functions often do not tolerate anhydride functions and must therefore be masked using protective groups. Such protecting groups should be readily removable in vivo. For primary and secondary amines, the protection can be by salt formation, and preferably hydrochloride salt formation, or by substitution of the or the hydrogen atoms of the amine group with an appropriate protecting group. The protection of alcohols can be achieved by converting the alcohol function into an appropriate protecting group. Likewise, protection of the thiol function is achieved by substituting the thiol hydrogen atom with an alkyl or aryl carbonyl.

The mixed acid anhydrides of the invention can contain asymmetric carbon atoms in both the R and 2 nd R groups. The mixed acid anhydrides can accordingly exist in one particular diastereomeric form or as a mixture of different diastereomeric forms. Racemates or diastereomers can be used as starting materials for the preparation of the compounds according to the invention. The products of the desired diastereomeric form can be prepared via a specific asymmetric synthesis. On the other hand, when a mixture of diasteromeric products is formed, they can be separated by the usual methods, such as chromatography, fractional crystallization.

The amino acid portions present in the mixed acid anhydrides are preferably in the S configuration.

In another aspect, the invention relates to pharmaceutical preparations based on a prodrug, characterized in that they contain as prodrug a mixed anhydride or a pharmaceutically acceptable salt thereof according to the present invention, as well as a pharmaceutically acceptable carrier.

Such pharmaceutical preparations exhibit the advantages previously mentioned for the mixed acid anhydride of the invention. In addition, such preparations can be applied topically where it is needed, since the extent and mode of absorption can be influenced by choosing a suitable R group for a particular R 'group. Since the absorption of the prodrug and the release of the pharmacologically active organic acid take place in a more effective manner, there is a more efficient use of the drug present as prodrug, in acid anhydride form, as a result of which the preparation can contain a smaller amount of prodrug, which reduces at the cost of such a composition and may result in a reduction in the volume of the composition.

In addition to the prodrug or its pharmaceutically acceptable salt, the compositions of the invention may also contain physiologically acceptable carriers, vehicles, excipients, binders, preservatives, stabilizers, flavors, penetration enhancers, and the like.

The pharmaceutical preparations can be administered orally, anally, sublingually, parenterally. They can be formulated as tablets, dragees, capsules, capsules, suppositories, aerosol preparations with an inert carrier gas, ointments. Especially the forms suitable for transdermal, transbuccal and oral administration are preferred. In this context, the compositions of the invention may contain penetration enhancers such as isopropyl myristate, lauracapram and the like. Technical aids, such as adhesive plasters and subcutaneous or cutaneous pastilles, are also recommended. Using such aids, a time-controlled and more uniform release of the drug into the bloodstream can be obtained.

The invention will be explained in more detail below with reference to some non-limiting examples.

8602767 - 8 -

EXAMPLE I

Anhydride of ibuprofen and propionic acid 20 g (97 mmol) ibuprofen (2- (4-isobutylphenyl) propionic acid) was dissolved in 160 ml of tetrahydrofuran. To this, 13.5 ml of triethylamine was added dropwise at 0 ° C. 8.44 ml of propionyl chloride was dissolved in 100 ml of ether and added to the ibuprofen solution over a period of 60 min at 0 ° C. After complete addition, the mixture was further stirred at ambient temperature for 30-60 min. The resulting reaction mixture was poured into an ice-cold 10% sodium carbonate solution and the organic solution was washed three times with this. After washing with cold distilled water to neutrality, the solution was dried and evaporated under reduced pressure.

After column chromatography with SiC> 2 and chloroform as eluent, 17.4 g of the mixed anhydride was obtained as a light yellow oil.

Thin layer chromatography, infrared and mass spectroscopy indicate the title compound.

TLC (SiO2): Rf (CHCl3) = 0.60; Rf (ether) = 0.69

Infrared spectrum: IR (NaCl): 3040, 3020, 3010, 2950, 2875, 1820, 1750, 1520, 1460, 1040 (wide), 850, 800 cm 1

Mass spectrum MS (FAB, pos): m / z = 264, 263, 262, 252, 219, 25 205, 202, 161, 145, 132, 131, 129, 105, 91, 77.

EXAMPLE II

Anhydride of ibuprofen and lauric acid

Analogous to the method described in Example I, 20 g of ibuprofen was reacted with lauroyl chloride, obtained from 19.5 g of lauric acid and thionyl chloride, to form 30 g of an anhydride of ibuprofen and lauric acid. This anhydride was purified by column chromatography on SiO2 and with chloroform as eluent.

Thin layer chromatography: TLC (SiO2): Rf (CHCl3) = 0.60;

Rf (ether) = 0.76

Infrared spectrum: IR (NaCl): 3100, 3050, 3020, 2950, 2925, 2850, 1820, 1750, 1460, 1040 cm "1 860 27 6 7 - 9 -

Mass spectrum MS (FAB, pos): m / z = 284, 256, 161, 145, 131, 119, 118, 117, 105, 102, 91, 77, 71, 69

EXAMPLE III

Anhydride of ibuprofen and cis-9-octadecenoic acid (oleic acid) 5 Analogous to the procedure described in example I, 20 g of ibuprofen was reacted with oleolyl chloride, obtained from 27.5 g of oleic acid and thionyl chloride, to form 38 g of an anhydride of ibuprofen and oleic acid. This anhydride was purified by column chromatography over SiO2 and using chloro-10 form as eluent.

Thin layer chromatography: TLC (SiO2): Rf (CHCl2) = 0.69;

Rf (ether) = 0.76

Infrared spectrum: IR (NaCl): 3050, 3000, 2920, 2850, 1820, 1750, 1460, 1040 citf1 15 Mass spectrum: MS (FAB, pos): m / z = 338, 321, 310, 280, 265, 263, 247 , 233, 219, 206, 205, 161, 145, 128, 119, 118, 117, 105, 97, 91, 78

EXAMPLE IV

Anhydride of ibuprofen and benzenecarboxylic acid. Analogous to the procedure described in Example I, 20 g of ibuprofen was reacted with 11.3 ml of benzoyl chloride to form 19 g of anhydride of ibuprofen and benzenecarboxylic acid. This mixed anhydride was purified by column chromatography over SiO2 using chloroform as the eluent.

Thin layer chromatography: TLC (SiO2): Rf (CHCl3) = 0.53;

Rf (ether) = 0.67

Infrared spectrum: IR (NaCl): 3050, 3020, 2950, 2925, 2820, 1800, 1730, 1600, 1450, 1210, 1040, 1020, 1000, 700 cm "1 30 Mass spectrum: MS (FAB, pos): m / z = 229, 217, 205, 188, 162, 161, 145, 131, 128, 119, 118, 117, 105, 91, 78, 77, 63

EXAMPLE V

Anhydride of diclofenac and propionic acid 50 mg (0.18 mmol) diclofenac ([2- (2,6-dichloroanilino) phenyl acetic acid) was dissolved in 2 ml dry tetrahydrofuran. To this, 25 µl of triethylamine was added dropwise at -15 ° C. 8602767-10. After about 5 min, 16 µl of propionyl chloride was added dropwise, producing a white precipitate immediately. The reaction flask was then brought to ambient temperature and stirred for an additional 30 minutes. The solution was filtered and evaporated. Thus, 60 mg of the anhydride of diclofenac and propionic acid was obtained as a pale yellow liquid that quickly solidified.

Infrared spectrum: IR (NaCl): 3330, 3050, 3020, 2970, 2930, 1805, 1730, 1450, 1040, 780, 750 cm "1 10 Mass spectrum: MS (FAB, pos): 280, 278, 244, 214, 180 , 102, 91, 77, 57

Nuclear magnetic resonance spectrum: H.NMR (CDClg): 7.7-6.3 (7H, m), 5.30 (2H, s), 3.80 (1H), 2.40 (2H, m), 1, 16 (3H, t)

EXAMPLE VI

Anhydride of enalapril (N- [1- (S) -ethoxycarbonyl-3-phenyl-propyl] -L-alanyl-L-proline) and valproleic acid (2-propyl-pentanoic acid)

To a solution of 1.5 g (5.4 mmol) [s- (R *, R *)] - 20-ethyl-α- [O-carboxyethyl) amino] benzenebutanoate prepared according to the procedure of J.S. KALTENBRONN, D. DE JOHN, U. KROLLS, Org. Prep. Proc. Int. (1983), 1.55, 35-40, and 2.85 g (26.8 mmol) of benzaldehyde in 30 ml of absolute methanol, 4 g of pulverized 4A molecular sieves were added. After cooling 25 to 0 ° C, 0.34 g (5.5 mmol) sodium cyanoborohydride was added in small portions. The solution was further stirred and slowly brought to ambient temperature. After a reaction time of 16 hours, the methanol was evaporated under reduced pressure, after which the residue was taken up in methylene chloride and filtered. After evaporation, a practically colorless oil was obtained. This was further purified by column chromatography (SiCl 2) by elution with ethyl acetate. The [s- (R *, R *)] ethyl-α-benzyl (1-carboxyethyl) amino] benzenobutanoate was thus obtained.

0.32g (0.86mmol) of the above-obtained [s- (R *, R *) 3 -ethyl-a- [benzyl (1-carboxyethyl) amino] benzenebutanoate were dissolved in 5ml of dry dimethylformamide. To this was added 0.33 g of 1-hydroxybenzotriazole. Under ice cooling Awerd Dropwise slowly 0.20 g of dicyclohexylcarbodiimide, dissolved 860 Z / o 7-11, dissolved in 2 ml of dry dimethylformamide. After stirring for 1 hour, also under ice-cooling, 0.20 g (0.95 mmol) of L-proline tert-butyl ester hydrochloride in 2 ml of dry dimethyl formamide, adding 130 µl of triethylamine, was added dropwise. The whole was stirred at ambient temperature for 16 hours. The dimethylformamide was then evaporated under reduced pressure and ethyl acetate was added. The precipitate was filtered off and the organic solution was washed successively with a 1% citric acid solution, a 10% sodium bicarbonate solution and water. After drying over magnesium sulfate, the solution was evaporated. The residue was taken up in 25 ml of dry dioxane and an HCl gas stream was bubbled through the solution for 15 min under ice cooling. The solution was then evaporated several times after addition of methylene chloride. The hydrochloride salt was then taken up in 4 ml of dry tetrahydrofuran, with 239 µl of triethylamine being added dropwise with cooling (-15 ° C). After stirring for 30 min, 0.15 g (0.9 mmol) of 2-propylpentanoyl chloride dissolved in 2 ml of dry tetrahydrofuran was added. After stirring for 1 hour, the solution was poured into a cold 10% sodium carbonate solution and washed three times with it. After drying over magnesium sulfate, the solution, after addition of 50 mg palladium on carbon, was hydrogenated for 2 hours under a hydrogen pressure of 25 atm. After filtering off the catalyst, the solution was evaporated and the residue was purified by column chromatography. The anhydride of enalapril and valproic acid was thus obtained.

Infrared spectrum: IR (NaCl): characteristic are the anhydride bands at 1810 and 1750 (also _ 1 COOEt) and 1060 cm and the amide band at 1680 cm -1.

Mass spectrum: MS (FAB, pos): 357, 347, 329, 321, 275, 234, 185, 118, 116, 102, 91, 86, 70, 57

EXAMPLE VII

Anhydride of enalapril and propionic acid

The anhydride of enalapril and propionic acid 8602767-12 was obtained in an analogous manner as in Example 6, where propionyl chloride was added instead of 2-propylpentanoyl chloride.

Infrared spectrum: IR (NaCl): 3480, 3020, 2970, 2930, 1810, 1740, 1660, 1480, 1400, 1060, 1050, 1000 cm "1 5 Mass spectrum: MS (FAB, pos): 405, 389, 377, 359 , 222, 189, 166, 154, 146, 128, 102, 93, 75, 62, 57.

8602767

Claims (15)

1. Organic acid anhydride, characterized in that it is a mixed acid anhydride of formula 1 of the formula sheet, wherein "IR is the remainder of an organic acid with anti-inflammatory, anti-epileptic, ACE-inhibiting, biocidal, cytostatic, antidiuretic, antidiarrhoeic or cerebrotonic action, or of a sterolic acid, and wherein R is different from R and represents: either a group of formula 2, wherein R 4, R 4 and R 4 are the same or different and hydrogen, C 2 20-alkyl or -alkenyl, cycloalkyl or -alkenyl, aryl, alkaryl, aralkyl, which groups are optionally substituted by alkyl, aryl, alkoxy, aryloxy, alkoxycarbonyl or aryloxycarbonyl and optionally contain one or more heteroatoms, either a steroid -15 ment, either an amino acid or peptide moiety, or a pharmaceutically acceptable salt thereof. Organic anhydride according to claim 1, characterized in that R is the remainder of the organic acids with anti-inflammatory activity ibuprofen, diclofenac, naproxen, etodolac, sulindac, ketoprofen, indometacin or flurbiprofen. Organic acid anhydride according to claim 1, characterized in that R is the remainder of an organic acid with anti-eptileptic activity of general formula 3 of the cn formula sheet, in which R and R are different or represent an aliphatic group . Organic anhydride according to claim 3, characterized in that R has formula 3, wherein R and R both represent n-propyl. Organic acid anhydride according to claim 1, characterized in that R is the remainder of an organic acid with ACE-inhibiting action of general formula 4 or 5 of the O formula sheet, wherein R is hydrogen, alkyl or aryl carbonyl. R is hydrogen, alkyl or aminoalkyl, R is alkyl or an optionally alkyl or aryl substituted C 1 -C 18 cycloalkyl, R 10 is 11 alkyl or aryl, or R and R together are an optionally alkyl or aryl substituted C 1 β-alkylene or alkenylene, which may be part of a saturated or unsaturated β 50 2 7 6 7 - 14 - Sj- C 12 quinoline or isoquinoline group, R is hydrogen or alkyl, hydrogen, alkyl or R 2 - C (O) -, and R 1 is alkyl or aralkyl. Organic anhydride according to claim 5, characterized in that R has formula 4 of the formula Q Q "IQ sheet, wherein R is tert-butylcarbonyl, R is methyl, R and R together form a propylene group and R is hydrogen. Organic acid anhydride according to claim 5, characterized in that R has formula 4 of the formula sheet O Q 1 Q 10, wherein R is tert-butylcarbonyl, R is methyl, R 11 is cyclopentyl, R and R are hydrogen. Organic acid anhydride according to claim 5, characterized in that R has formula 5 of formula sheet 9 10 11, wherein R is methyl or 4-aminobutyl, R and R together form 12 13 2 15, R is hydrogen and RR -C (0) -14 and R is phenylethyl. Organic acid anhydride according to claim 1, characterized in that R is the remainder of the organic acids with biocidal action oxolic acid, flumequin or cinoxacin. 20 Organic acid anhydride according to claim 1, characterized in that R is the remainder of the organic acid with cytostatic action chlorambucil. Organic anhydride according to claim 1, characterized in that R is the remainder of the organic acid with antidiuretic action furosemide. Organic anhydride according to claim 1, characterized in that R is the remainder of the free acid of loperamide, which has an antidiarrhoeic effect. Organic anhydride according to claim 1, characterized in that R is the remainder of the free acid of piracetam, which has a cerebrotonic effect. Organic anhydride according to claim 1, characterized in that R is the remainder of the steroidal ursodeoxycholic acid. Pharmaceutical preparation based on a prodrug, characterized in that it contains as prodrug a mixed acid anhydride according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier. 8602767