FI98910C - A process for the preparation of pharmaceutically useful pilocarpine derivatives - Google Patents

Description

98910

This invention relates to a process for the preparation of novel pilocarpine prodrug compounds, in particular bispilocarpic acid esters, 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 by accelerating the outflow of ventricular fluid from the eye. The antihypertensive effect of pilocarpine is based on the contractile effect of the drug on the radius muscle of the eye, which widens the anterior chamber angle important for ventricular fluid outflow and facilitates fluid outflow.

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 intensifies 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 patient. Pilocarpine also causes the iris of the eye to shrink, causing the eye black to shrink ... considerably. In addition to these unnecessary and embarrassing ocular effects on the patient, pilocarpine can cause side effects outside the eye. Lella. These effects include increased salivation • • v ’and low heart rate (bradycardia).

♦ · · • 4 ·, · Most often, patients with glaucoma administer pilocarpine • · * · * topically as eye drops. However, when administered as such, only about 1% of the pilocarpine dose is absorbed into the eye and about 70% into the bloodstream. The low absorption of pilocarpine in the eye is due to three main factors:. 98910 2 1) rapid rinsing 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 3) poor ability of pilocarpine to penetrate the cornea of the eye.

Pilocarpine is absorbed through the cornea of the eye. In the cornea, it is first absorbed into a dense epithelial layer of cell membranes rich in 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 store that restricts the absorption of pilocarpine, which further releases pilocarpine through the aqueous corneal stroma and endothelium into the anterior chamber fluid. From ventricular fluid, pilocarpine easily reaches its site of action in the radial 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.

The low absorption of pilocarpine administered to the eye into 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.

; , This results in that in the ventricular fluid of the eye, the color is <i * 'y. High concentrations of pilocarpine are achieved in the m and torso muscle, which cause a strong blackhead «M * contraction and the adaptation of the eye to the close range to the intermittent. In addition, increasing the dose of pilocarpine is a rather ineffective way to prolong the effect of the drug with such a rapidly excreted drug from the eye, and pilocarpine drops are administered 3-8 times a day, depending on the patient's case. The dosing of eye drops so often is difficult for the patient, especially since the side effects of the eyes always follow the dosing of the drops. The use of large pilocarpine lifts also increases the amount of pilocarpine absorbed into the bloodstream, and thus the risk of other side effects.

Attempts have been made to overcome the above-mentioned disadvantages due to poor absorption of pilocarpine by prodrug derivatives of pilocarpine which are better absorbed 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 the medically effective pilocarpine and the ineffective pro-moiety. 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 pilot-carpine prodrugs based on quaternary ammonium compounds. Bundgaard et al. has described in EP patent application 0 106 541 diesters of pilocarpic acid.

In Int. J. Pharm. 79; 233-242 and ibid. 243-250, 1992 describe monoesters of bispilocarpic acid and * · *: Int. J. Pharm. 75; 249-258, 1991 and Pharm.

0

Res. 1991, 8 (12) 1539-42 describe diesters of bispilocarpic acid. Bundgaard diesters have achieved better eye absorption than pilo- carpine. However, these pilocarpine diesters have some drawbacks, such as; \ Incomplete cleavage of the cornea by l. ·

As a result, the intact prodrug is transported into the ventricular fluid, which reduces the benefit of the prodrug. In addition, diesters break down a large number of unfavorable by-products relative to the actual active ingredient, pilocarpine.

98910 4 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. 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 good corneal 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 bispilocarpate derivatives in the corneal epithelium is lower than that of Bundgaard compounds, due to which the as yet undigested 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.

Y; Compared to known monoesters, the diesters according to the invention are more stable in aqueous solution because the decomposition of the diesters only begins by enzymatic hydrolysis in the eye. Monoesters are thus less useful in aqueous solution, e.g. as eye drops. The compounds of the invention are also better absorbed into the cornea of the eye because they are more fat-soluble than monoesters.

• · · .:; The monoesters release pilocarpine as a result of chemical hydrolysis, while the diesters according to the invention leave. undergo a two-stage decomposition process, in which the rate of decomposition of the pilocar • ♦ · * 11 / silicon can be adjusted in two different release phases. This gives wider ranges for the release rate of pilocarpine compared to monoesters.

Compared to known diesters, the diesters of the invention have used a straight chain to combine pilocarpic acid molecules instead of xylylene, with the monoester released from the compounds of the invention being more water soluble than the corresponding xylene monoester and more readily transitioning from fat soluble to chemically soluble epithelium. The rapid migration of the monoester from the corneal epithelium to the stroma reduces the storage of the prodrug in the epithelium and thus reduces the eye irritation caused by the high prodrug content of the epithelium. The direct hydrocarbon chains used in the compounds of the invention achieve rapid chemical degradation of the intermediate, whereby the rate of release of pilocarpine can be controlled more extensively than when using a xylylene chain. The relatively short hydrocarbon chains used in the compounds of the invention bring the pilocarpine molecules very close together, opening up the spatial structure of the prodrug molecule and making the ester bonds more accessible to esterase enzymes. This also allows the rate of enzyme hydrolysis to be controlled.

The invention thus allows a long-term, slow release of the drug from the cornea into the inner parts of the eye, which can effectively prolong the duration of action of pilocarpine and also reduce the peak concentrations of pilocarpine in the eye, which is important in the above-mentioned manner. to reduce the side effects.

The novel pilodarpine prodrug derivatives according to the invention, in particular the bispilocarpine esters, i.e. the bispilocarpates, have the general formula I »o · • V <•« »» • · • «· • · · • · · · · · 98910 6 CH3CH2 ^ ^ \ __ n'CH3 A) 0? o

CHj Y

A

I (!)

CH, Y

'il jLi

'' "'^ V CH

CH3CH2 "3

where in the formula O

II

Y is -C-R, wherein R is C 1 -C 4 alkyl, tax C 3 -C 6 cycloalkyl, A is a direct bond or a methylene group, and acid addition salts of said compounds.

In connection with the above-mentioned 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 propyl or butyl, such as n-, i-propyl, n-, i- or t-butyl.

R · «R is preferably cycloalkyl having 3 to 6 ring carbon atoms, which may also be substituted by a methyl group such as V; cyclopropyl or cyclobutyl.

«· C •« · «· ·« j ···. 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, ma. -leic, fumaric, malic, tartaric, citric, ascorbic, benzoic, pamoic or sulfonic acid, such as mesyl or tosylic acid.

A particularly preferred group of compounds of formula I is that wherein R is unsubstituted cycloalkyl, such as cyclobutyl.

Preferred individual compounds are: 0,0'-dicyclopropylcarbonyl (1,2-ethylene) bispilocarpate 0,0'-dicyclobutylcarbonyl (1,2-ethylene) bispilocarpate 0,0'-dicyclopropylcarbonyl (1,3-propylene) bispilocarpate 0, O'-dicyclobutylcarbonyl (1,3-propylene) bispilocarpate 0,0'-dipropionyl (1,3-propylene) bispilocarpate 0,0'-dipivaloyl (1,2-ethylene) bispilocarpate 0,01-dipivaloyl (1,3- propylene) bispilocarpate 0,0'-di (1-methylcyclopropylcarbonyl) (1,2-ethylene) - ·; ·· bispilocarpate O, O'-dicyclopentylcarbonyl (1,2-ethylene) bispilocarpate 0,0'-dipropionyl (1, 2-ethylene) bispilocarpate 0,0'-diisobutyroyl (1,2-ethylene) bispilocarpate i:: * 0,0'-dicyclohexylcarbonyl (1,2-ethylene) bispilocarpate • · • · · "·" 0.0 '-dicyclopentylcarbonyl (1,3-propylene) bispilo-V: carpate • 0,0'-dicyclohexylcarbonyl (1,3-propylene) bispilocarbo- • · # «, ···. boat.

• ·

According to the process of the invention, a compound of formula 989108 with the formula ch3ch2 ch> A) X>? o

p H

A

CH. H (II) ii xx CU3CH2 'chj wherein A is as defined above, to react with an acid of formula RCO2H, or a functional derivative thereof, and optionally converting the obtained compound into an acid addition salt.

4 I 4 I I I

The compound used as a starting material is prepared in such a way that pilocarpic acid of the formula:

\ 'OH

* · * «· • · · • · t, * · *. is reacted with a compound of formula X-CH 2 -A-CH 2 -X 'wherein X and X' are independently hydroxy, or a leaving group such as halogen, acyloxy, alkyl or arylsulfonyloxy, and A is as defined above.

98910 9

In the above-mentioned reactions, their halides, anhydrides, alkyl or aryl sulfonates are preferably used as functional derivatives of the acids. As the reaction medium, inert solvents such as hydrocarbons, halogenated hydrocarbons, ethers, ketones, etc. are preferably used. Preferred hydrocarbons are aromatic hydrocarbons such as benzene and alkylbenzenes such as toluene and xylene. Suitable halogenated hydrocarbons include, for example, dichloromethane, chloroform and chlorobenzene. Ketones include 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, dimethylformaroid and acetonitrile.

The reaction temperature is not critical but may range, for example, from -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 preferred 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 trialkylamines, preferably triethylamine. The above reactions • *. can occur 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.

98910 10

The pharmaceutical preparations are prepared in a manner known per se using carriers and other excipients known in the art. Carriers can be, for example, liquids, suspensions or emulsions, or 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 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 the compound is 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.

, ·: PERFORMANCE OF TESTS

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

i »· • ·· t:: '1) The stability of the compounds • • · · - The ability of bispilocarpic monoesters released from bispilocarpic acid diester to release pilocarpine under physiological conditions was tested by buffer hydrolysis (pH • · <<· ··· value 7.4) at 37 ° C. The results are presented in the context of • examples (eg l). 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.

98910 11 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. Assays were performed in 1-octanol-phosphate buffer mixture by measuring the concentration of test compound in the buffer phase before and after partitioning. The log P values of the test compounds are shown in connection with the examples. It can be seen from the results that all the compounds of the invention are more fat-soluble than pilocarpine (log P = 0.01) and the fat solubility of the derivatives can be controlled by changing the substituents to be attached to the pilocarpic acid.

3) Entsvvmihvdrolvvsi

The enzyme hydrolysis half-lives of the bispilocarpates according to the invention were determined in plasma / buffer mixture and / or 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 (80% -20%) at 37 ° C. The logarithm of the remaining diester was plotted as a function of time and thus ♦. *! from the obtained graph, the half-life Tw, which 1 «« is shown in the examples, was determined.

, i It can be seen from the results that in buffer solutions stable • · · ;; · The diester is degraded by plasma esterases to 0.0'- * · * divethybispilocarpate intermediate, which is chemically • degraded at physiological pH to active pilocar • * · · t ***. piiniksi. The rate of degradation of the prodrug can be controlled by changing the substituents to be attached to the pilocarpic acid.

B. In corneal homogenate

The half-lives of the enzymatic hydrolysis of bispilocarpic acid diesters were determined in rabbit corneal homogenate at pH 7.40 at 37 ° C. Corneal homogenate was prepared in 0.05 M Tris buffer. The logarithm of the remaining diester was plotted as a function of time, and the half-life T 1 determined from the examples was determined from the graph thus obtained.

It can be seen from the results that rabbit corneal esterases hydrolyze diis of bispilocarpic acid to the 0,0'-dihydybispilocarpate intermediate, which is chemically degraded at physiological pH to active pilocarpine. The rate of degradation of the prodrug can be controlled by changing the substituents attached to the pilocarpic acid.

4) Corneal penetration

Corneal penetration of the novel bispilocarpates according to the invention was studied in a diffusion chamber, in which the migration of the compound from the donor taasis (epithelial side) through the cornea to the recipient side of the diffusion chamber was monitored: : (endothelial side). The cornea of the rabbit eye was used in the study. 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 (P, pp = 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 be adjusted; corneal penetration of the prodrug and pilots · **. carcinogen formation rate. It should be noted that the permeability coefficient is lower for derivatives which release pilocarpine slowly due to, for example, a suitably slow chemical hydrolysis of the intermediate released from the derivative than for derivatives which release pilocarpine rapidly.

98910 13

The following table shows the comparative values between the compounds obtained by the invention and the compounds known from Bundgaard EP patent application 0 106 541. From the results, it can be seen that the compounds according to the invention, in addition to the advantageous properties mentioned above, are at least as good as the Bundgaard compounds in all respects, and are superior for some compounds.

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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. Bispilocarpic acid diesters are enzymatically hydrolyzed to esters of bispilocarpic acid, which are chemically (spontaneously) hydrolyzed to pilocarpine.

The bispilocarpic acid diesters of the invention deliver one pro moiety to the cornea per two pilocarpine molecules, 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.

20. . The bispilocarpic acid diesters of the invention, as fat-soluble compounds, are efficiently absorbed into the corneal epithelium, where the corneal esterases release ': a rapidly suitable water-soluble intermediate (e.g., 0.0'- '25 divety (1,2-ethylene) bispilocoate), which . * · As a compound is able to migrate from the epithelium to the stroma and • ψ r! #I · from there to the interior of the eye towards its site of action, releasing pilocarpine throughout the transition. In this case, sar-:. . no excess prodrugjoh-, v30 dosta is stored in the bovine epithelium, which could cause eye irritation.

The compounds according to the invention can largely eliminate the disadvantages of poor pharmacological use of pilocarpine (poor bioavailability, systemic and ocular side effects, and the consequent poor patient-care efficacy). 98910 16 can be administered at significantly lower doses and the number of doses / day can be reduced, thereby reducing side effects, improving patient compliance, and enhancing drug therapy in glaucoma patients.

5

The following examples illustrate the invention.

EQUIPMENT USED

10

Melting point determination: Reichert Thermovar apparatus Determination of refractive index: Atago Illuminator apparatus Determination of pKa value: by titration of the derivative in a water-ethanol mixture (50% -50%)

Mass spectrometers: VG 70-250SE

Measurement conditions in electron bombardment ionization: electron energy: 70 eV (unless otherwise stated) ionization current: 500 μΑ ionization chamber temperature: 150 ° C 20 sample applicator temperature 30 ° C => 500 ° C in 2-5 minutes resolution: 10,000 • Thermospray mass spectrometer: VG thermospray / plasma spray .25 VG Trio-2 quadropol • *

Beckmann 112 pump • · · i / Measurement conditions in thermospray ionization optimized daily NMR spectrometer: Bruker AC 250 / Aspect 3000 •>. · ”3.0 1 H / ^ C 5 mm dual probe CD30D 20 mg / ml • · δ ppm (tetramethylsilane = 0) f · 98910 17

Example 1 0,0'-dihydrogen (1,2-ethylene) bispilocarpate (Y = hydrogen, A = direct bond) 5

The monoester was prepared by adding dropwise 247 mg (1.31 mmol) of 1,2-dibromoethane to a solution of 1302 mg (5.25 mmol) of the sodium salt of pilocarpic acid in 60 ml of dimethyl sulfoxide. The solution was stirred at room temperature for 72 hours, and poured into 100 ml of distilled water. The mixture was extracted with two 100 ml portions of chloroform. The combined chloroform extracts were washed with 100 ml of distilled water, 100 ml of 2% sodium bicarbonate solution and 100 ml of distilled water. The chloroform-15 extracts were dried over calcium sulfate (30 min) and the chloroform was evaporated under reduced pressure, and the resulting bispilocarpate was crystallized from ethyl acetate / ether to give 332 mg (0.69 mmol) of the title compound.

20

Mp = 111-115 ° C pK. = 6.30 HR-MS spectrum: m / e (relative intensity): 209 l (8%), 208 (19%), 96 (30%), 95 (100%).

· 25 NMR: δ 7.49 2H bs, 6.74 2H bs, 4.30 4H m, 3.60 6H s, 3.54 4H m, 2.73 2H m, 2.56 2H m, 2 .51 2H m, 2.02 2H m, 1.68 4H m, 0.89 6H t.

Log P = 0.50 (pH 7.40):: T * = 10 min (in buffer, pH 7.40, 37 ° C).

. The starting material, the sodium salt of pilocarpic acid, can be * ". * As follows: t *" *

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 98910 at 18 ° 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 3.93 g of sodium pilocarpate as a white, highly hygroscopic substance.

In a similar manner, 0,0'-dihydro (1,3-propylene) bispilocarpate can be prepared from the sodium salt of pilocarpic acid (1021 mg; 4.11 mmol) and 1,3-dibromopropane (208 mg; 1.03 mmol). Yield 330 mg (0.70 mmol).

In a similar manner, 0,0'-dihydrogen (2-hydroxy-1,3-propylene) bispilocarpate can be prepared from the sodium salt of pilocarpic acid (1674 mg; 6.75 mmol) and 1,3-dibromo-2-hydroxypropane (341 mg; 1, 69 mmol). The 0,0'-dihydrogen (2-hydroxy-1,3-propylene) bispilocarpate 20 can also be prepared from the sodium salt of pilocarpic acid and epichlorohydrin (2: 1).

Example 2 0,0'-Dicyclopropylcarbonyl (1,2-ethylene) bispilo-1 '*: carpate · (Y = cyclopropylcarbonyl; A = direct bond): The compound was prepared so that a mixture of • · ·; '' Ο, Ο'-divety (1,2-ethylene) bispilocarpate (540 mg; 1.13. * Mmol) (cf. Example 1) and 1866 mg of potassium carbonate (13, 5 mmol) in toluene (150 mL), 945 mg (9.64 mmol) of cyclopropanecarbonyl chloride was added dropwise over about 24 hours. The mixture was stirred for 24-72 • 35 hours. To the reaction mixture was added 2% sodium bicarbonate solution (150 ml) and the mixture was stirred at room temperature for 3 hours. The layers were separated and the toluene phase was washed twice with water (2 x 150 ml), dried calcium sulfate (30 min) and evaporated under reduced pressure to give 0.01-dicyclopropylcarbonyl (1,2-ethylene) bispilocarpate in a yield of 304 mg 5 (0.49 mmol).

nd20 = PK. = 5.70 HR-MS spectrum: m / e (relative intensity): 614 [M +] 10 (1%), 408 (11%), 393 (10%), 321 (7%), 320 (29%) ), 307 (9%), 291 (16%), 209 (18%), 208 (11%), 207 (78%), 163 (29%), 162 (14%), 121 (47%), 113 (52%), 96 (38%), 95 (100%).

HR-MS: molecular weight = 614.3299260 (observed) 614.3315650 (calculated).

NMR: δ 7.56 2H bs, 6.78 2H bs, 4.35 4H m, 4.08 4H m, 3.63 6H s, 2.69 4H m, 2.50 2H m, 2.33 2H m , 1.69 4H m, 1.61 2H m, 1.10 6H t, 0.92 6H t, 0.90 8H m.

20 P P = - 0.58 (pH 5.0) 2.83 (pH 7.4) ..... = 24 min (corneal homogenate)

Pw = 2.60 x 10-6 cm / s.

! 25 Example 3 l · ..

• · • * · * · '* 0,0'-dipropionyl (1,2-ethylene) bispilocarpate (Y = propionyl, A = direct bond) • · • · • · • · The compound was prepared from Ο, Ο'- dihydrogen (1,2-ethylene) bispilo-; '·. carpate (300 mg; 0.63 mmol) (cf. Example 1) and propionyl chloride (464 mg; 5.02 mmol) according to the procedure described in Example 2. The yield was 243 mg (0.41 mmol).

; Δ 3 nd 2 O = pK, = 6.00 98910 20 HR-MS spectrum: m / e (relative intensity): 591 (5%), 590 [M +] (5%), 503 (7%), 397 (19%), 396 (85%), 395 (8), 382 (20%), 381 (95%), 309 (11%), 209 (18%), 195 (45%), 121 (18%) ), 96 (78%), 95 (100%).

HR-MS: molecular weight = 590.3363040 (observed) 590.3315650 (calculated).

NMR: δ 7.61 2H bs, 6.78 2H bs, 4.33 4H m, 4.08 4H m, 3.62 6H s, 2.68 4H m, 2.49 2H m, 2.32 2H q , 1.68 4H m, 1.10 6H t, 0.90 6H t.

10 P P = - 0.77 (pH 5.0) 2.57 (pH 7.4)

Tw = 9 min (corneal homogenate)

Pipp = 1.67 x 10 "6 cm / s.

Example 4 0,0'-Dicyclobutylcarbonyl (1,2-ethylene) bispilocarbate (Y = cyclobutylcarbonyl, A direct bond; fumarate)

The compound was prepared from θ, θ'-dihydrogen (1,2-ethylene) bispilocarpate (470 mg; 0.98 mmol) (cf. Example 1) and cyclobutanecarbonyl chloride (931 mg; 7.86 mmol) according to the procedure described in Example 2. The compound; 25 was crystallized from 2-propanol / toluene / petroleum ether. The yield was 810 mg (0.82 mmol).

Γ! "

Mp = 49-51 ° C (fum.); nd - 30 pK, =, HR-MS spectrum: ra / e (relative intensity): 642 [M +] (4%), 529 (6%), 436 (10%), 423 (22%), 422 ( 100%), 421 (13%), 408 (18%), 407 (85%), 335 (10%), 221 (52%), 209 (12%), 121 (13%), 96 (86%) ), 95 (50%).

: 35 HR-MS: molecular weight = 642.3648680 (observed) 642.3628651 (calculated).

NMR: δ 8.50 2H bs, 7.23 2H bs, 6.73 s (fum.), 4.36 4H m, 98910 δ 4.11 4H m, 3.79 6H s, 3.16 2H m, 2.77 4H m, 2.54 2H m, 2.40 2H m, 2.22 4H m, 2.01 4H m, 1.89 4H m, 1.71 4H m, 0.93 6H t.

Log P = 0.30 (pH 5.0) δ 3.76 (pH 7.4)

Ta = 4 min (corneal homogenate) = 7 min (in 80% plasma)

Papp = 10.46 x 10 ^ cm / s.

Example 5 0,0'-Dipropionyl (1,3-propylene) bispilocarpate (Y = propionyl, A = methylene) The compound was prepared from 0,0'-divety (1,3-propylene) bispilo-carpate (500 mg; 1 .02 mmol) (cf. Example 1) and propionyl chloride (751 mg; 8.12 mmol) according to the procedure described in Example 2. The yield was 467 mg (0.77 mmol).

20 n <2 ° = pK, = 5.95 HR-MS spectrum: m / e (relative intensity): 604 [M +] (6%), 517 (7%), 411 (13%), 410 (57 %), 396 (16%), 395: 25 (71%), 339 (36%), 209 (15%), 208 (6%), 195 (48%), 121 * · *: (20%) .96 (56%), 95 (100%).

V · HR-MS: molecular weight = 604.3491210 (observed) 604.3472151 (calculated).

1 H NMR: δ 7.56 2H bs, 6.76 2H bs, 4.18 4H m, 4.08 4H m, 3.62

: ': *? 0 6H S, 2.69 4H m, 2.49 2H m, 2.33 2H m, 2.31 4H q, 2.01 4H

9. qv, 1.68 4H m, 1.10 6H t, 0.91 6H t.

Log P = - 0.61 (pH 5.0) '; 2.93 (pH 7.4) T% = 7 min (corneal homogenate): "3; 5 Papp = 3.19 x 10-6 cm / s.

98910 22

Example 6 0,0'-Dicyclopropylcarbonyl (1,3-propylene) bispilo-carpate 5 (Y = cyclopropylcarbonyl, A = methylene)

The compound was prepared from Ο, Ο'-dihydrogen (1,3-propylene) bispilo-carpate (422 mg; 0.86 mmol) (cf. Example 1) and cyclopropylcarbonyl chloride (719 mg; 6.88 mmol) according to the procedure described in Example 2. . The yield was 297 mg (0.47 mmol).

nd 2 O = pK, - 6.05 HR-MS spectrum: m / e (relative intensity): 629 (4%), 628 [M +] (7%), 423 (19%), 422 (76%), 408 (16%), 407 (73%), 352 (10%), 351 (40%), 335 (9%), 334 (9%), 209 (19%), 208 (11%), 207 ( 73%), 121 (32%), 96 (55%), 95 (100%).

HR-MS: molecular weight = 628.3428340 (found) 628.3472151 (calculated).

NMR: δ 7.51 2H bs, 6.73 2H bs, 4.19 4H m, 4.07 4H m, 3.61 6H s, 2.68 4H m, 2.49 2H m, 2.33 2H m , 2.02 2H qv, 1.68 / 4H m, 0.91 6H t, 0.90 8H m.

25 Log P = - 0.30 (pH 5.0) '*. * “· 3.43 (pH 7.4) • ♦ · V * T% = 11 min (corneal homogenate)

Pw = 4.26 x 10 ^ cm / s.

* · • · • ··: ':' 50 Example 7 • · • <· 0,0 · -dicyclobutylcarbonyl (1,3-propylene) bispilot * carpate (Y = cyclobutylcarbonyl, A = methylene)

The compound was prepared from 0,0'-dihydrogen (1,3-propylene) bispilo-carpate (705 mg; 1.43 mmol) (cf. Example 1) and 35,989,103 cyclobutylcarbonyl chloride (1357 mg; 11.45 mmol) as described in Example 2. according to the method. The yield was 960 mg (0.96 mmol).

Mp = 33-35 ° C (fum.) Nd 2 O = pK. = HR-MS spectrum: m / e (relative intensity): 657 (4%), 656 [M +] (6%), 543 (9%), 437 (23%), 436 (100%), 422 (22%), 421 (86%), 366 (10%), 365 (46%), 222 (9%), 221 (58%), 209 (14%), 121 (15%), 96 (68%) %), 95 (78%).

HR-MS: molecular weight = 656.3743290 (observed) 656.3785152 (calculated).

NMR: δ 8.50 2H bs, 7.23 2H bs, 6.73 s (fum.), 4.21 4H m, 3.80 6H s, 3.16 2H m, 2.78 4H m, 2 .53 2H m, 2.40 2H m, 2.22 4H m, 2.03 2H mq, 2.01 4H m, 1.89 4H m, 1.71 4H m, 0.92 6H t.

Log P = 0.60 (pH 5.0) = 4 min (corneal homogenate) 20 5 min (in 80% plasma)

Pw = 12.86 x 10-6 cm / s.

In a similar manner, 0,0'-dipropionyl (2-hydroxy-1,3-propylene) - 'can be prepared according to Example 2. 25 bispilocarpate starting from 0.01-dihydro (2-hydroxy-1,3-i · · ((((, propylene) bispilocarpate (544 mg; 1.07 mmol)) i: ....

• (cf. Example 1) and propionyl clone (785 mg; 8.49 mmol).

• *

• · V

• · ♦ · • · · i · · «t · •« «♦ • ·

«· K

·· »r ·

Claims (7)

A process for the preparation of pharmaceutically useful compounds of formula e) 0 k V In CH, Y Ίί yj CH3CV "" CH3 in which formula o Y is -CR, wherein R is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl and A is a straight bond or a methylene group, and of the acid addition salt of said compounds, characterized in that a compound of formula *: ./ ch3ch2 \ CH> l 9o • · · * \ • M · / ~ L1 XH; ϊ -30 | / :. ϊ :. In which A is the same as above, it is reacted with an acid of the formula RCO2H, or a functional derivative thereof, in which R represents the same as above, and optionally transfers the obtained compound to its acid addition salt. Process according to Claim 1, characterized in that 0,0'-dicyclopropylcarbonyl (1,2-ethyl) bispilocarpate is prepared. 10 Process according to Claim 1, characterized in that Ο, Ο'-dicyclobutylcarbonyl (1,2-ethyl) bispilocarpate is prepared. 15 Process according to claim 1, characterized in that 0,0'-dicyclopropylcarbonyl (1,3-propylene) bispilocarpate is prepared. Process according to claim 1, characterized in that 0,0'-dicyclobutylcarbonyl (1,3-propylene) bispilocarpate is prepared. Process according to claim 1, characterized in that 0,0'-dipropionyl (1,3-propylene) bis-pilocarpate is prepared. 7. A process according to claim 1, characterized in that 0,0'-dipropionyl (1,2-ethylene) bis-pillo-carpate is prepared. 30 • · • • • •