FI98911C - A process for the preparation of pharmaceutically useful pilocarpine derivatives - Google Patents

Description

98911

This invention relates to a process for the preparation of novel pilocarpine prodrug compounds useful in the treatment of glaucoma.

(+) - Pilocarpine, (3S-cis) -3-ethyldihydro-4 - [(1-methyl-1H-imidazol-5-yl) methyl] -2 (3H) -furanone, is a drug used in the treatment of glaucoma to reduce intraocular pressure 10 by accelerating the outflow of ventricular fluid from the eye. The antihypertensive effect of pilocarpine is based on the narrowing effect of the drug on the radius of the eye, which widens the angle of the anterior chamber, which is important for the outflow of ventricular fluid, and facilitates the outflow of fluid.

15

However, the decrease in intraocular pressure is not the only effect of pilocarpine in the eye. When the drug concentration is high enough, the excitatory effect of pilocarpine on the radius muscle is intensified and causes the lens of the eye to adapt for close viewing. In this case, it is difficult for the patient to adjust his eyes to look further away, which is inconvenient for the po-patient. Pilocarpine also causes the iris of the eye to shrink, or iris, causing a significant reduction in eye blackness. In addition to these undesirable and embarrassing ocular effects for the patient, pilocarpine can cause side effects outside the eye. These effects include increased salivation • · · • · · * · '' and low heart rate (bradycardia).

Pilocarpine is most commonly administered by glaucoma patients. locally as eye drops. Thus administered pilocarpine. However, only about 1% of the dose is absorbed into the eye and about 70% into the bloodstream. Low absorption of pilocarpine i: ....

y in the eye is due to three main factors: 35:, 1) rapid flushing of the drop from the surface of the eye 2) rapid absorption of pilocarpine through the conjunctiva of the inner surface of the eyelids into the bloodstream 2 98911 3) poor ability of pilocarpine to penetrate the cornea of the eye.

Pilocarpine is absorbed through the cornea of the eye. In the corneal-5 membrane, it is first absorbed into a dense epithelial layer rich in cell membrane lipids (fats) on the surface of the eye. However, pilocarpine is not very fat-soluble, which is why it penetrates relatively little into the corneal epithelium. At the same time, the corneal epithelium acts as a membrane and reservoir limiting the absorption of pilocarpine, which further releases pilocarpine through the aqueous corneal stroma and endothelium into the anterior chamber fluid. From the ventricular fluid, pilocarpine easily reaches its site of action in the beam muscle. The duration of action of pilocarpine in the eye is significantly shortened by its partial conversion to ineffective pilocarpic acid and the rapid elimination of pilocarpine from the eye through the ventricular fluid circulation and iris circulation.

20 The low absorption of pilocarpine administered to the eye v the interior of the eye and its short duration of action cause difficulties in drug treatment. In order to improve the efficacy of the drug and prolong its duration of action, pilocarpine must be used in relatively high doses.

25 This results in high concentrations of pilocarpine in the ventricular fluid, iris and radius of the eye, which cause severe blackheads. , contraction and adaptation of the eye to close range. In addition, increasing the dose of pilocarpine is a fairly ineffective way of prolonging the effect of the drug with such a rapidly excreted drug, and pilocarpine drops • · · are administered 3-8 times a day, depending on the patient's case. The administration of eye drops so often is difficult for the patient, especially as the ocular side effects ‘•• 35 always follow the administration of the drops. The use of high doses of pilocarpine also increases the amount of pilocarpine absorbed into the bloodstream, and thus the risk of other side effects 3,98911.

Attempts have been made to overcome the above-mentioned disadvantages due to poor absorption of pilocarpine by better absorption of pilocarpine prodrugs into the corneal epithelium. Such derivatives must be more fat-soluble than pilocarpine in order to improve absorption. In addition, they must be cleaved as completely as possible in the corneal epithelium to release 10 medically effective pilocarpine and ineffective prose. The amount of cleavage in the cornea depends on the residence time of the derivative in the corneal epithelium and its rate of cleavage there. The residence time of the derivative in the epithelium increases as its fat solubility increases and its diffusion coefficient decreases.

To date, two different types of pilocarpine prodrug derivatives have been developed. In U.S. Patent 4,061,722, Bodor describes pilo-20 carpine prodrugs based on quaternary ammonium compounds. Bundgaard et al. has described in EP patent application 0 106 541 diesters of pilocarpic acid which have achieved better ocular absorption than pilocarpine. In Int. J. Pharm. 79; 233-242 and ibid. 243-250, 1992 describe monoesters of bispilocarpic acid and 25 Int. J. Pharm. 75; 249-258, 1991 and Pharm.

·; ·. Res. 1991, 8 (12) 1539-42 describe S · · diesters of bispilocarpic acid. Bundgaard pilocarpine diesters. However, there are some disadvantages, such as incomplete cleavage in the cornea, as a result of which intact prodru- • · V'30 gia is transported into the ventricular fluid, which reduces the benefit of the prodrug. In addition, diesters • «· ,,, r. breaks down a large number of unfavorable by-products relative to • · · the actual active substance, pilocarpine.

The present invention relates to novel bispilocarpic acid esters, i.e. bispilocarpates, with which the above-mentioned disadvantages can be largely avoided or at least minimized.

4,98911

Thus, the prodrug derivatives of the invention cleave to pilocarpine and pro-moiety at least as rapidly compared to the corresponding fat-soluble prodrugs of Bundgaard et al. And promote at least as much transmembrane permeability of pilocarpine. In addition, bispilocarpate derivatives carry one pro-moiety per two pilocarpine molecules to the cornea, whereas derivatives according to Bundgaard et al. Carry one pro-moiety for each pilocarpine molecule. The diffusion coefficient of the bispilocar-10 patate derivatives in the corneal epithelium is lower than that of the Bundgaard compounds, due to which the as yet uncleaved bispilocarpate derivatives linger longer in the corneal epithelium. This gives the prodrug more time to break down completely. In addition, the compounds of the invention are more soluble and thus better suited for the preparation of pharmaceutical formulations.

The diesters of the invention are more stable in aqueous solution than the monoesters because the degradation of the diesters only begins with enzymatic hydrolysis in the eye. Thus, known monoesters are less useful in aqueous solution, e.g. as eye drops. The diesters of the invention undergo a two-step degradation process, whereby the rate of degradation of pilocarpine can be adjusted in two different release phases, giving wider ranges of release rate of pilocarpine compared to monoesters.

• '• · • ·; The intermediate released from the diesters of the invention is water soluble and more readily migrates from the lipophilic epithelium of the cornea to the aqueous stroma than before. intermediate products described above. The rapid migration of the intermediate from the corneal epithelium to the stroma reduces the storage of the prodrug in the corneal epithelium and thus reduces the eye irritation caused by the high prodrug content of the epithelium.

5 98911 By varying the length of the straight-chain hydrocarbon chain of the intermediate, the rate of release of pilocarpine can also be easily controlled.

The invention thus allows a sustained, slow release of the drug from the cornea into the interior of the eye, which can effectively prolong the duration of action of pilocarpine and also reduce peak concentrations of pilocarpine in the eye, which is important to reduce the aforementioned side effects.

The novel prodrug derivatives of pilocarpine according to the invention, in particular the bispilocarpic acid esters or bispilocarpates, have the general formula I ch3ch2 V_ ^ Nn / CH3 3) 0 0 o R = o 20 / :: "2 (I) \ o" il ö CHjCHj, 'CH3 • 1 «· wherein • is R 1 is C 1 -C 4 alkyl, • B is a direct bond, a methylene group or an ethylene group, and • · · Acid addition salts of said compounds.

In the context of the above general formula I, C 1 -C 4 alkyl is straight-chain or branched, preferably methyl, ethyl, propyl, butyl. In particular, it is straight-chain or branched ethyl, propyl or butyl, such as n-, i-propyl, n-, i- or t-butyl.

B is preferably a direct bond or methylene.

5

Preferred compounds of the invention are: 0,0'-succinyl (diethyl) bispilocarpate 0,0'-succinyl (diisopropyl) bispilocarpate 0,0'-succinyl (di-t-butyl) bispilocarpate 0,0'-glutaroyl ( diisopropyl) bi spilocarpate 0,0'-glutaroyl (di-t-butyl) bispilocarpate.

Acid addition salts of the compounds of formula I include, in particular, pharmaceutically acceptable addition salts with non-toxic inorganic or organic acids. Examples of suitable acids are hydrochloric, hydrobromic, sulfuric, nitrogen, phosphoric, etc., and as organic acids, for example, acetic, propionic, stearic, oxalic, malonic, succinic, glutaric, adipic-20-nitric, maleic, fumaric, malic, tartaric, citric, ascorbic, benzoic, pamoic or sulfonic acid, such as mesyl or tosylic acid.

25:::

According to the process of the invention, the compound,, of the formula • · «« «« · • * · "30 c«, I ~ w-b is obtained

0 = \ '-0H

Where R is the same as above, to react with dicarboxylic acid having the formula 0 0 teaspoons tl,

HO-C-CH2-CH2-B-C-OH

5 or a bifunctional acid derivative thereof, wherein B is as defined above, and optionally converting the obtained compound to its acid addition salt.

The compound used as a starting material above is prepared by preparing pilocarpic acid having the formula “v

'' '' 'I

0 = / '-on

OH

Is reacted with a compound of formula RX, wherein X represents hydroxy, or a leaving group such as halogen, acyloxy, or alkyl or arylsulfonyl solutions, and R is as defined above.

25 The above reactions use a function of acids. as thionic derivatives are preferably halides, anhydrides, alkyl or aryl sulfonates. The reaction intermediate used is preferably inert solvents such as hydrocarbons, halogenated hydrocarbons, ethers, ketones, etc. Preferred hydrocarbons are aromatic hydrocarbons such as benzene and alkylbenzene. "': fungi such as toluene and xylene. Suitable halogenated hydrocarbons are, for example, dichloromethane.

«I

Denmark, chloroform and chlorobenzene. Examples of ketones are acetone, ethyl methyl ketone and isobutyl methyl ketone, and ethers include diethyl ether, diisopropyl ether, dibutyl ether and 1,4-dioxane. Other suitable solvents include dimethyl sulfoxide, dimethylformaride and acetonitrile.

The reaction temperature is not critical but may range from, for example, -10 ° C to the boiling point of the solvent. Room temperature is suitably used. The reaction time can vary within wide limits and is usually 12 to 72 hours, usually about 24 hours. It is preferable to use acid-binding excipients such as alkali and alkaline earth metal carbonates or organic bases in the reactions. Suitable metal carbonates include sodium carbonate and potassium carbonate and, as organic bases, pyridine and its homologues, 4- (dimethylamino) pyridine, quinoline and its homologues, Ν, Ν-dimethylaniline and tri-alkylamines, preferably triethylamine. The above reactions can take place either in a homogeneous solution or in a heterogeneous system, such as under PTC conditions.

Ester bonds of the compounds of the invention may also be formed using known water cleavage reagents such as carbodiimides. In some cases, known acid-catalyzed inhibition reactions may also be considered.

25

»M

♦ · · 9 · · «« 4 m t 9 · »•« ·

Ml V '30 • f The pharmaceutical preparations are prepared in a manner known per se using M * #. * · · · »Carriers and other excipients known in the art. The carriers can be, for example, liquids, suspensions or emulsions, or

• 1 I

',,. 35 ointments and creams. The preparation may also be formulated as a solid ophthalmic dosage form. A suitable dosage form is, for example, an eye drop solution containing 9,98911 of a compound of the invention in a suitable concentration, such as 0.1-4%, in a sterile aqueous solution buffered to a suitable pH or adjusted to a suitable pH with an acid or base, and preferably used in water-soluble acid addition salt form. This eye drop solution of the desired concentration is administered to the eye, depending on the condition of the patient, preferably 1 to 3 times a day.

10 PERFORMANCE OF TESTS

The compounds of the invention have been tested in the following experiments.

15 1) Stability of compounds

The ability of bispilocarpic acid monoesters released from bispilocarpic acid diester to release pilocarpine under physiological conditions was tested by buffer hydrolysis (pH 7.4) at 37 ° C. The results show that the compounds are chemically hydrolyzed in aqueous solution to release ..pilocarpine and that the rate of hydrolysis can be controlled by changing the chemical group attached to the pilocarpic acid.

25 • *: 2) Lipophilic

The lipophilicity of the compounds was determined by measuring the partition coefficients (P) of the compounds at pH 7.40 and 5.00.

30: ** Assays were performed with 1-octanol-phosphate buffer. In this case, by measuring the concentration of the test compound in the buffer phase • · '' .. .. before and after the distribution. Based on the results, all the compounds according to the invention are more fat-soluble than • / • pilocarpine (log P = 0.01) and derivative 35: “the fat solubility of these can be controlled by changing the substituents to be attached to pilocarpic acid.

10 98911 3) Entsvvmihvdrolvvsi

The enzyme hydrolysis half-lives of the bispilocarpates according to the invention were determined in plasma / buffer mixture 5 and / or in rabbit corneal homogenate.

A. In plasma / buffer mixture

Enzyme hydrolysis half-lives of bispilocarpic acid diesters were determined in plasma / phosphate buffer pH 7.40 10 (80% -20%) at 37 ° C. The logarithm of the remaining diester was plotted as a function of time, and the half-life T, A was determined from the graph thus obtained, which are shown in connection with the examples.

It can be seen from the results that in buffer solutions the stable diester is degraded by plasma esterases to monopilo-carpate intermediates which are chemically degraded at physiological pH to active pilocarpine. The rate of degradation of the prodrug can be controlled by changing the substituents to be attached to the pilocarpic acid.

20 j '; B. In corneal homogenate, the half-lives of enzymatic hydrolysis of bispilocarpic acid diesters were determined in rabbit corneal homogenate at pH 7.40 at 37 ° C. Corneal homogenate 25! ! was prepared in 0.05 M Tris buffer. The logarithm of the amount of diester remaining I, 'was plotted as a function of time, and the half-life T * determined from the examples was determined from the graph thus obtained.

• · It can be seen from the results that the rabbit corneal barrier phrases hydrolyze diis of bispilocarpic acid to mono-: '-.pilocarpate intermediates, which are chemically degraded at physiological pH to active pilocarpine.

• # ‘I’ The rate of degradation of the Prodrug derivative can be controlled:. ’: By substituting the substituents-35 to be attached to pilocarpic acid; ,:and.

11 98911 4) Corneal penetration

Corneal penetration of the novel bispilocarpates according to the invention was studied in a diffusion chamber, in which the migration of 5 compounds from the donor phase (epithelial side) through the cornea to the recipient side of the diffusion chamber (endothelial side) was monitored. The cornea of the rabbit eye was used in the study. The permeability coefficients (Papp) calculated from the permeability rate are shown in connection with the examples.

The results show that the new compounds can improve the corneal permeability of pilocarpine (Pw = 2.77 cm / s x 10-6). The results also show that the compounds of the invention hydrolyze in the cornea to form pilocarpine and that the groups attached to pilocarpic acid can regulate the corneal penetration of the prodrug and the rate of pilocarpine formation. It should be noted that the permeability coefficient is lower for derivatives which release pilocarpine slowly due to the suitably slow chemical hydrolysis of the intermediate released from the derivative, e.g., for derivatives which release pilocarpine rapidly.

! The following table shows the comparative values of kek-25; The compounds obtained by the invention and the Bundgaard EP; / between compounds known from patent application 0 106 541. From the results, it can be seen that the compounds of the invention, in addition to the above-mentioned advantageous properties, are at least as good as Bundgaard compounds in all aspects, and some; \ Compounds are better.

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13 98911

Summary

The fat solubility of the compounds of the invention, enzymatic hydrolysis, corneal penetration, chemical hydrolysis of the intermediate and thus the formation of active pilocarpine in the eye can be easily controlled by changing the chemical groups attached to the pilocarpic acid. Bispilo-carcic acid diesters are enzymatically hydrolyzed to monoesters of 10 pilocarpic acid, which are chemically (spontaneously) hydrolyzed to pilocarpine.

The bispilocarpic acid diesters of the invention carry one pro moiety to the cornea per two piles of pilocarpine molecule, thereby minimizing the amount of release pro moieties. By minimizing the amount of loose pro-parts, the aim is to reduce the eye irritation and stinging caused by the drug.

The bispilocarpic acid diesters of the invention, as fat-soluble compounds, are efficiently absorbed into the corneal epithelium by the release of corneal esterases. to move from the epithelium to the stroma and from there to the interior of the eye towards its site of action, releasing pilocarpine throughout the transition. In this case, no excess prodrug lead is stored in the corneal epithelium, • », which could cause eye irritation.

30::; The compounds of the invention can be used to largely eliminate the disadvantages (poor bioavailability, systemic and ocular side effects, frequent dosing and consequent poor patient compliance) of pilocarpine. Due to the improved corneal permeability, the compounds of the invention can be administered at significantly lower doses and dosing rates / day can be reduced, thereby reducing side effects, improving patient compliance, and enhancing drug therapy in glaucoma patients.

The following examples illustrate the invention without limiting it in any way.

EQUIPMENT USED

10 Melting point determination: Reichert Thermovar equipment

Determination of refractive index: Atago Illuminator equipment Determination of pKa value: by titration of the derivative in a water-ethanol mixture (50% -50%)

Mass spectrometer: VG 70-250SE

15 Measurement conditions in electron bombardment ionization: electron energy: 70 eV (unless otherwise stated) ionization current: 500 μΑ ionization chamber temperature: 150 ° C sample applicator temperature 30 ° C => 500 ° C 2-5 in 20 minutes: 'i': resolution: 10 000 .- Thermospray mass spectrometer: VG thermospray / plasma spray! VG Trio-2 quadropol 25 l I Beckmann 112 pump: · .: ...

Measurement conditions in thermospray ionization J · · · ’* optimized daily NMR spectrometer: Bruker AC 250 / Aspect 3000 • · ·. · * 1H / 13C 5 mm dual probe 30 :: CDjOD 20 mg / ml: * ·. δ ppm (tetramethylsilane = 0) • · · • · · · • ·:: 15 98911

Example 1 0.01-Succinyl (diethyl) bispilocarpate (R = ethyl, B direct bond) 5

To a solution of 9.80 mmol (2432 mg) of the sodium salt of pilocarpic acid in 60 ml of dimethyl sulfoxide was added dropwise 9.80 mmol of ethyl bromide (1068 mg) over about an hour. The solution was stirred at room temperature for 48-72 hours and poured into 100 ml of distilled water. The mixture was extracted with two 150 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with 150 ml of distilled water, 150 ml of 2% sodium bicarbonate solution and 150 ml of distilled water. The ethyl acetate extracts were dried over calcium sulfate (30 min) and the ethyl acetate was evaporated under reduced pressure, and the resulting ethyl ester of pilocarpic acid was crystallized from chloroform / petroleum ether to give 448 mg (1.76 mmol) of the ester.

20 Sul.p. = 104-107 ° C

pKt = 6.60; HR-MS spectrum: m / e (relative intensity):. NMR: δ; Log P = 25 = 315 min (in phosphate buffer, pH 7.40, 37 ° C).

To a mixture of 401 mg of pilocarpic acid ethyl ester and 873 mg (6.32 mmol) of potassium carbonate in toluene (50 μm) was added dropwise succinyl chloride (98 mg; 0.63 • · · 30v: mmol). within about 24 hours. The solution was stirred at room temperature for about 48 hours. To the reaction mixture was added 2% sodium bicarbonate solution (50 ml), and the mixture was stirred at room temperature for 3 hours. The layers were separated and the toluene phase was washed twice with distilled water (2 x 100), dried over calcium sulfate (30 min) and evaporated under reduced pressure to give 0,0'-succinyl (diethyl) bispilocarpate (192 mg; 32 98911 16 mmol). pK = HR-MS spectrum: m / e (relative intensity): δ NMR: δ 7.50 2H bs, 6.75 2H bs, 4.16 4H m, 4.12 4H m, 3.61 6H s, 2.68 4H m, 2.62 4H m, 2.46 2H m, 2.29 2H m, 1.67 4H m, 1.28 6H t, 0.91 6H t LogP = 0.46 (pH 5, 0) T.Ä = 10 The starting material, the sodium salt of pilocarpic acid, can be prepared as follows:

Pilocarpine hydrochloride (3.92 g; 16.00 mmol) was dissolved in distilled water (4 mL) and the solution was cooled to about 0 ° C. To the solution was added 18 mL of ice-cold 2M NaOH in four portions. The solution was allowed to stand at about 0 ° C for one hour. After neutralization of the excess NaOH with 5 ml of 1M HCl, the solution was evaporated under reduced pressure. The residue was dissolved in 60 ml of absolute ethanol and stirred for 10 minutes at 60 ° C. After cooling: to 4 ° C, insoluble NaCl was removed by filtration. The filtrate was evaporated under reduced pressure to give 13.93 g of sodium pilocarpate as a white, highly hygro-25. as an isopic substance.

In the same manner as described above, 0,0'-glutaroyl (diethyl) bispilocarpate can be prepared.

• · • · · • «• · · · 4 · • · · · · · · · · · · · · 4::

Claims (2)

17 98911 A process for the preparation of pharmaceutically usable pilocarpine derivatives of the formula 5 A) O 9 o io ry = o? H2 (I) B ch2 R \ = 0 15, ° o ^ ti A CH3CH2 '' CHj 20 in the formula <; R is C 1 -C 4 alkyl,, B is a direct bond, a methylene group or an ethylene group, and for the preparation of acid addition salts of said compounds, characterized in that the compound has the formula • · c "; 0 = 1'-OH * \ i * ': 0R 35 / In the run R means the same as above, is reacted with a dicarboxylic acid of the formula 9891Ί 18 OO π "HO-C-CH2-B-CH2-C-OH (IV ) or a bifunctional acid derivative thereof, wherein in formula B has the same meaning as above, and optionally converting the obtained compound into its acid addition salt. Process according to Claim 1, characterized in that 0,0'-succinyl (diethyl) bispilo-10 carpate is prepared. 15 1. For the manufacture of a pharmaceutical product containing a mixture of CH3qH2 'CH3 20 R 0 - - O:; : ch2 (i). i b: ·: R N = o 25:: ° o 'H tl. JX CH3CH2 '' CH3 • «·, · ji vilken formula * ·· 30 · 1: * tR is C1-C4-alkyl, • · ♦ t! .1B is a ring bond, a methyl group or an ethyl group, • 1 , 'samt syraadditonssalt av nämnda föreningar, kännetecknat •) därav, att en förening med formeln 35.: 19 98911 c \; 0 == \ '-OH OR is selected from the group consisting of dicarboxylic acid in the form of 10 o O tt II HO-C-CH2-B-CH2-C-OH (IV) or a bifunctional syrading compound, i vilken formulael B betecknar decemberamam som ovan, och eventuellt 15 överför nämnda förening till sitt syraadditionssalt. A preferred embodiment according to claim 1, which comprises the O-O'-succinyldiethyl] bispilocarp. IJ 4 »41 • · aa» * • · · • t »·» · * * · · • I «* • ·« I »« · ft • • ft ·% · ft • «I • ft ft • • · • · ft • · · * * ft · «4 · ft ft • * • # ft» «f ·