LV10257B - Novel pilocarpine derivatives and process for their preparation - Google Patents

Description

LV 10257

Novel piļocarpine deriVatives and process for their preparation 5 The present invention relates to novel piļocarpine prodrug compounds useful for the treatment of glaucoma, and specifically to bispilocarpic acid esters, processes for the preparation of the said novel compounds, pharmaceuti-cal compositions containing the novel compounds and their 10 use. (+)-piļocarpine, (3S-cis)-3-ethyldihydro-4-[(l-methyl-lH-imidazol-5-yl)methyl]-2(3H)-furanone, is a drug which is used for the treatment of glaucoma, which lowers the ocular 15 pressure by increasing the flow of chamber fluid from the eye. The intraocular pressure reducing effect of pilocar-' pine is based on the ciliary muscle contracting effect of the drug widening the angle of the anterior chamber which is important from the viewpoint of the outflow of the 20 chamber fluid and the outflow of the fluid is facilitated.

The reduction of the intraocular pressure is, however, not the only effect of piļocarpine in the eye. When the drug concentration is sufficiently high, the contracting effect 25 of piļocarpine on the ciliary muscle is increased, resul-ting in the adaptation of the ocular lēns for seeing at close distance. It is then difficult for the patient to accommodate the eye for seeing at a greater distance, which is inconvenient for the patient. Piļocarpine also causes 30 the iris of the eye to contract, the pupil of the eye decreasing· considerably. Besides these effects on the eye which are unnecessary from a medical point of view and unpleasant for the patient, piļocarpine may cause side effects outside the eye. Such effects are i.a. increased salivation and bradycardia.

Conventionally glaucoma patients administer piļocarpine locally as eyedrops. Administered in such a manner, 35 2 however, only about 1 % of the pilocarpine dose is absor-bed by the eye and about 70 % in the blood stream. The low absorption rāte of pilocarpine in the eye is due to three major factors: 1) the drop is quickly flushed away from the surface of the eye 2) the rapid absorption of pilocarpine into the blood stream through the conjunctiva of the inner surface of the eyelid 3) the poor corneal penetration capability of pilocarpine.

Pilocarpine is absorbed into the eye through the cornea. In the cornea it is first absorbed in the dense epitheliura layer on the eye surface containing celi membrane lipids (fats) in abundance. However, pilocarpine is not very fat soluble wherefore it penetrates relatively little into the corneal epithelium. The corneal epithelium functions simultaneously as a film restricting the absorption of pilocarpine, and as a storage, which delivers pilocarpine through the aqueous stroma and endothelium of the cornea into the fluid of the anterior chamber. From the chamber fluid pilocarpine has easy access to its action site, the ciliary muscle. The duration of the effect of pilocarpine in the eye is substantially reduced by its partial conver-sion to inactive pilocarpic acid and the rapid departure of pilocarpine from the eye through the ch.amber fluid circula-tion and the blood circulation of the iris.

The low absorption into the inner parts of the eye and the short duration of action of pilocarpine administered into the eye cause difficulties in drug treatment. In order to improve the action of the drug and increase its duration of action, pilocarpine must be used in relatively big doses. From this follows that high pilocarpine Ievels are obtained in the chamber fluid, in the iris and the ciliary muscle 3 LV 10257 which lead to a strong contraction of the pupil and adapta-tion of the eye to seeing at close distance. Increasing the dose of pilocarpine is, in addition, a relatively ineffec-tive way of prolonging the action of the drug, the drug 5 being of the type that is rapidly excreted from the eye, and thus pilocarpine eyedrops are administered 3 to 8 times daily depending on the patient. Administration of eyedrops so frequently is inconvenient from the point of view of the patient, especially when the administration of the drops is 10 always followed by side effects in the eye. The use of big doses also increases the amount of pilocarpine absorbed in the blood circulation and thus also the risk for other side effects. 15 Efforts have been aimed at solving the afore said disad- vantages relating to the poor absorption of pilocarpine by using pilocarpine prodrug derivatives which absorb better into the corneal epithelium. Such derivatives have to be more fat soluble than pilocarpine in order to improve 20 absorption. In addition, they have to degrade as complete-ly as possible in the corneal epithelium to liberate the pharmaceutically effective pilocarpine and the ineffective pro-moiety. The degree of degradation in the cornea is dependant on the residence time of the derivative in the 25 corneal epithelium and its degradation rāte therein. The residence time of the derivative in the epithelium is increased with increased lipophilicity and decreased diffusion coefficient. 30 Up to now two kinds of prodrug derivatives of pilocarpine have been developed. Bodor discloses in the US-patent 4,061,722 pilocarpine prodrugs based on quaternary am-monium compounds. Bundgaard et al. have disclosed in EP-patent application 0 106 541 pilocarpic acid diesters, by 35 means of which improved ocular absorption has been reach-ed. The said pilocarpic diesters are, however, associated with certain disadvantages, such as poor aqueous solubility 4 and eye irritation. Also, a great number of undesirable side products are released from the diesters as compared to 5 the active aģent itself, pilocarpine.

The present invention relates to novel bispilocarpic acid esters, i.e. bispilocarpates, by means of which the aforementioned disadvantages may largely be eliminated or 10 at least minimized. Thus the prodrug.derivatives according to the invention degrade at least as rapidly to pilocarpine and the pro-moiety when compared to the prodrugs of Bundgaard et al. of corresponding lipophilicity/ and they also promote at least to the same degree the penetration of 15 pilocarpine through the cornea. In addition, the bispilo-carpate derivatives carry into the cornea one pro-moiety for every two pilocarpine molecules, whereas the derivatives of Bundgaard et al. carry one pro-moiety for every pilocarpine molecule. The diffusion coefficient of the 20 bispilocarpate derivatives in the corneal epithelium is smaller than that of the Bundgaard compounds, wherefore stili undegraded bispilocarpate derivatives remain in the corneal epithelium longer. Thus there will be more time left for the prodrug to break down completely. In addition, 25 the novel compounds of the invention have a better solubi-lity/ and are thus better suited for the preparation of drug formulations.

Thus the invention allows for extended slow drug release 30 from the cornea into the inner parts of the eye, by means of which it is possible to effectively prolong the dura-tion of action of pilocarpine and also reduce the peaks of high pilocarpine concentration in the eye, which is of importance from the view of reducing the afore mentioned 35 side effects.

The novel pilocarpine prodrug-derivatives of the inventi- 5 LV 10257

on, specifically bispilocarpic acid esters, i.e. bispilo-carpates, have the general formula I \ 5 10

(I) wherein A) Y is -C(=0)-R, wherein R is Cj-C4-alkyl, C3-C6~cy-cloalkyl or phenyl, and W is the group 15

20 25 wherein Y has the meaning given above, and A is a direct bond or a methylene group, which can be substituted with hydroxy, the group Υ-0- wherein Y has the meaning given, or 30 with one or two methyl groups, or B) W has the meaning of R' which is Ο^^-β^γΙ or C3*-C6-cycloalkyl, and Y has the meaning of 35 6

wherein B has the meaning of a direct bond, methylene or ethylene, and R' has the meaning given above, with the proviso that when both the R and R' groups in the compound 15 (I) are ethyl, A and B are different from a direct bond and A in addition is different from OH-substituted methylene group, as well as the acid additibn salts of the said compounds. 20 A preferred subgroup of the compounds of the formula (I) is thus formed by the compounds having-the formula (IA)

A 25 (IA)

I CH,

30

ch3ch2 wherein Y and A have the meanings indicated above, with the proviso that when both R groups are ethyl, A is different from a direct bond or OH-substituted methylene. 35 7 LV 10257

In the formula (IA) R is preferably C3-C6-cycloalkyl or a straight or branched propyl or butyl, whereby A advantageously is a direct bond, unsubstituted methylene or methylene substituted with hydroxy or with one or two 5 methyl groups, especially a direct ‘bond or unsubstituted methylene.

According to a further embodiment, A has the meaning of a unsubstituted methylene or methylene substituted with one 10 or two methyl groups, and R has the meaning indicated, especially Cj-C4-alkyl or C3-C6-cycloalkyl. A second advantageous subgroup according to the invention is formed by compounds having the formula (IB)

I CH-, 15 20 (IB)

25 wherein R' and B have the meanings indicated, with the proviso that when both R' groups are ēthyl, B is different from a direct bond. 30

In the formula (IB) R' is preferably C3-C6-cycloalkyl or straight or branched propyl or butyl, whereby B advantageously has the meaning of a direct bond, or unsubstituted methylene or ethylene, especially a direct 35 bond or unsubstituted methylene. A further subgroup of compounds of the formula (IB) is 8 formed by compounds, wherein B has the meaning of unsubstituted methylene or ethylene and R' has the meaning indicated in connection with formula (IB). 5 In connection with the afore mentioned general formula I, C1-C4-alJcyl is straight or branched, advantageously metini, ethyl, propyl, butyl. It is preferably straight or branched propyl or butyl, such as n-, i-propyl/ n-, i- or t-butyl. 10

Cycloalkyl R or R' has 3-6 ring carbon atoms, which may also be substituted with a methyl group, such as cyclopro-pyl or cyclobutyl. 15 In the compounds, preferably both the groups R and R' are equal.

The acid addition salts of . the compounds according to formula I are preferably pharmaceutically acceptable 20 addition salts with non-toxic inorganic or organic acids. As examples of suitable acids hydrochloric, hydrobromic, sulphuric, nitric, phosphoric acid etc., and as organic acids for example acetic, propionic, stearic, oxalic, malonic, succinic, glutaric, adipic, maleic, fumaric, 25 malic, tartaric, citric, ascorbic, benzoic, pamoic or sulphonic acid, such as mesyl or tosyl acid, may be mentioned.

Preferred individual compounds of the formula (IA) are: 30 0,0/-dicyclopropylcarbonyl (1,2-ethylene) bispilocarpate O,0/-dicyclobutylcarbonyl (1,2-ethylene) bispilocarpate O,o/-dicyclopropylcarbonyl (1,3-propylene) bispilocarpate O,0'-dicyclobutylcarbonyl (1,3-propylene) bispilocarpate O,0'-dicyclopropylcarbonyl (2-methyl-l,3-propylene) bispi- 35 locarpate O,O'-dicyclopropylcarbonyl (2,2-dimethyl-l,3-propylene) bispilocarpate 9 LV 10257 0,0'-dipropionyl (1,3-propylene) bispilocarpate O,0'-dicyclopropylcarbonyl(2-hydroxy-l,3-propylene) bispilocarpate 0,0'-dicyclopropylcarbonyl (2-cyclopropylcarbonyloxy-l, 3-5 propylene) bispilocarpate 0,0'-dipivalyl (1,2-ethylene) bispilocarpate 0/0,-dipivalyl (l,3-propylene) bispilocarpate O,0'-di(l-methylcyclopropylcarbonyl) (1,2-ethylene) bispilocarpate 10 O,0'-dicyclopentylcarbonyl (l,2-ethylene) bispilocarpate 0,0'-diisobutyryl (l,2-ethylene) bispilocarpate O,0'-dicyclohexylcarbonyl (1,2-ethylene) bispilocarpate O,0'-diCyclopentylcarbonyl (1,3-propylene) bispilocarpate O,0'-dicyclohexylcarbonyl (1,3-propylene) bispilocarpate 15 O,0'-dibenzoyl (l,2-ethylene) bispilocarpate 0,0'-dibenzoyl (1,2-propylene) bispilocarpate.

Preferred compounds of the formula (IB) are: 0,0'-succinyl (diisopropyl) bispilocarpate 20 0,0'-succinyl (di-t-butyl) bispilocarpate 0,0'-succinyl (dicyclopropyl) bispilocarpate 0,0'-succinyl (dicyclobutyl) bispilocarpate 0,0'-glutaryl (diisopropyl) bispilocarpate 0,0'-glutaryl (di-t-butyl) bispilocarpate 25 0,0/-glutaryl (dicyclopropyl) bispilocarpate 0,0/-glutaryl (dicyclobutyl) bispilocarpate.

The invention relates also to a process for the prepa-ration of the compounds according to the formula I. 30

According to the process of the invention, a) for the preparation of a compound having the formula 35 5 10

wherein A and Y have the meaningš indicated above in connection with the formula (I) , a compound having the 15 formula

A

20 25 wherein A has the same meaning as above, is reacted with an acid of the formula RC02H, or a functional derivative thereof, wherein R has the meaning indicated above, or 35 b) for the preparation of a compound of the formula 11 LV 10257 5 10

(IB) wherein B and R' have the meanings given in in connection with the formula (I), a compound of the formula 15

wherein R' has the same meaning as above, is reacted with 25 a dicarboxylic acid of the formula O 0 ii ii ho-c-ch2-b-ch2-c-oh or a bifunctional acid derivative thereof, wherein B has the same meaning as above, and optionally the compound 30 obtained is converted to its acid addition salt.

For the preparation of the compound used above as starting material in the process a) , pilocarpic acid of the formula 35 12

is reacted with a coinpound of the formula X-CH2-A-CH2-X', wherein X and X', indepedently, have the meaning of hydroxy, or a leaving group, such as halogen, acyloxy, 15 alkyl- or aryl sulfonyloxy/ and A has the same meaning as above.

For the preparation of the compound used above as starting material in the process b) , pilocarpic acid as defined 20 above, is reacted with a compound of the formula R'X, wherein X has the meaning of hydroxy, or a leaving group, such as halogen, acyloxy, or alkyl- or aryl sulfonyloxy, and R' has the same meaning as above. 25 In the above mentioned reactions, as the functional acid derivatives, preferably the halogenides, anhydrides, alkyl or aryl sulfonates thereof are used. As the reaction medium, solvents such as hydrocarbons, halogenated hydro-carbons, ethers, ketones etc. are used, which are inert to 30 the reaģents. Suitable hydrocarbons are the aromatic hydrocarbons, such as benzene and alkyl benzenes, such as toluene and xylene. Suitable halogenated hydrocarbons are for example dichloromethane, chloroform and chlorobenzene. As ketones acetone, ethyl methyl ketone and isobutyl methyl 35 ketone may be mentioned, and as ethers diethyl ether, di-isopropyl ether, dibutyl ether and l,4-dioxane may be mentioned. Other suitable solvents include dimethyl 13 LV 10257 sulfoxide, dimethylformamide and acetonitril.

The reaction temperature is not critical but may vary for example from -10°C to the boiling point of the solvent. 5 Suitably room temperature is used. The reaction time may vary within broad limits and is conventionally 12-72 hours, usually about 24 hours. It is advantageous to use acid binding aģents in the reactions, such as alkali mētai and alkaline earth mētai carbonates or organic bases. Suitable 10 mētai carbonates include sodium carbonate and potassium carbonate and as organic bases pyridine and its homologues, 4-(dimethylamino)pyridine, guinoline and its homologues, N,N-dimethylaniline and trialkylamines/ preferably triethylamine. The said reactions may take place either in 15 a homogenous solution or in a heterogenie system, such as under PTC-conditiorts.

The ester bonds of the compounds according to the inven-tion may be formed also by using known water cleaving 20 reaģents, such as carbodiimides. In some cases also the known acid catalyzed esterification reactions may come into question.

The invention relates also to the pharmaceutical composi-25 tions containing the corapound of the invention as the active aģent together with pharmaceutically acceptable adjuvants and carriers.

The pharmaceutical compositions according to the inventi-30 on are prepared in a known manner by using carriers and other adjuvants known in the art. The carriers may, for example, be liquids, suspensions or emulsions, or creams and ointments. The composition raay also be formed into a solid pharmaceutical form to be inserted in the eye. A 35 suitable form of administration is for example an eyedrop solution which contains the compound according to the invention at a suitable concentration, for example 0.1- 14 4 %, in a sterile aqueous solution buffered to a suitable pH or adjusted to a suitable pH with an acid or a base, the compound preferably being used in its water soluble acid addition salt form. An eyedrop solution with the said 5 desired concentration is administered into the eye, depending on the condition of the patient, preferably 1 to 3 times a day.

TĒST METHODS 10

The compounds of the invention have been tested in the following tests. 1) Lipophilicitv 15

The lipophilicity of the compounds was determined by measuring the partition coefficients (P) of the compounds at pH-values 7.40 and 5.00. The measurements were made in a 1-octanol-phosphate buffer mixture by determining the 20 concentration of the compound to be studied in the buffer phase before and after partitioning. From the results it can be seen that ali the compounds of the invention are more fat soluble than pilocarpine (log P = 0.01, pH 7.40 and -1.74, pH 5.0), and the fat solubility of the 25 derivatives can be regulated by changing the substituents attached to pilocarpic acid. 2) Enzvme hvdrolvsis 30

The half-lives of enzyme hydrolysis of the bispilocarpates according to the invention were determined in a plasma/buf-fer mixture and/or rabbit corneal homogenate. 35 A. In a plasma/buffer mixture

The half-lives of enzyme hydrolysis of bispilocarpic acid 15 LV 10257

diesters were determined in a plasma/phosphate buffer pH 7.40 -mixture (80%-20%)) at 37°C. The logarithm of re-maining diester was presented as a function of time and from the plot obtained was determined the half-life T^. 5

From the results it may be seen that in buffer Solutions the stable diester degradēs under the influence of plasma esterases to 0,0'-dihydrogen bispilocarpate and monopilocarpate intermediates, which are chemically 10 degraded to active pilocarpine at physiological pH-value. The degradation rāte of the prodrug derivative can be regulated by changing the substituents attached to pilocarpic acid. 15 B. In corneal homogenate

The half-lives of enzyme hydrolysis of bispilocarpic acid diesters were determined in rabbit corneal homogenate pH

7.40 at 37°C. The corneal homogenate was prepared in 0.05 M 20 Tris buffer. The logarithm of remaining diester was presented as a function of time and from the plot obtained the half-life T^ was determined.

From the results it can be seen that the esterases of 25 rabbit eye cornea hydrolyze bispilocarpic acid diesters to a 0,0'-dihydrogen bispilocarpate and monopilocarpate intermediates, which chemically degrade to active pilocarpine at physiological pH-value.· The degradation rāte of the prodrug derivative can be regulated by changing the 30 substituents to be attached to pilocarpic acid. 3) Corneal penetration

The corneal penetration of the novel bispilocarpates 35 according to the invention was studied in a diffusion chamber, wherein the migration of the compound was follo-wed from the delivering phase (epithelium side) through the 16 cornea to the acceptor side (endothelium side) of the diffusion chamber. In the study, rabbit eye cornea was used. The permeability coefficients (P ) were calculated **lrr from the permeability rāte.

From the results it is seen that with the novel compounds it is possible to improve the corneal permeability of pilocarpine (Papp = 2.77 cm/s x 10-6). LV 10257

18

The results show that the compounds of the invention are hydrolyzed in the cornea forming pilocarpine and that with the groups attached to pilocarpic acid it is possible to regulate the corneal penetration of the prodrug and the rāte of formation of pilocarpine. It is worth mentioning that the permeability coefficient is smaller for derivati-ves which release pilocarpine only at a slow rāte, due to e.g. the appropriately slow Chemical hydrolysis of the intermediate liberated from the derivative, than for derivatives, from which pilocarpine is released rapidly.

Conclusion

The fat solubility, enzymatic hydrolysis, corneal penetration and the Chemical hydrolysis of the intermediate of the compounds according to the invention and thus the formation of active pilocarpine in the eye can be easily regulated according to purpose by changing the Chemical groups attached to the pilocarpic acid. Bispilocarpic acid diesters are enzymatically hydrolyzed to bispilocarpic acid esters and pilocarpic acid monoesters respectively, which are chemically (spontaneously) hydrolyzed to pilocarpine.

The bispilocarpic acid diesters according to the invention transfer to the cornea one pro-moiety for every two pilocarpine molecules, whereby the amount of pro-moieties released is minimized. The minimization of the amount of released pro-moieties is aimed at reducing drug related irritation and smarting of the eye.

As fat soluble compounds the bispilocarpic acid diesters of the invention are effectively absorbed into the corneal epithelium, where the corneal esterases rapidly release a suitable water soluble intermediate (e.g. 0,0'-dihydrogen (1,2-ethylene) bispilocarpate (from IA) or 0-hydrogen (ethyl) bispilocarpate, (from IB) , resp. , which as a water soluble compound is capable to migrate from the epithelium 19 LV 10257 to the stroma and from there into the iriner parts of the eye towards its action site releasing pilocarpine continuously during migration. Thus there is no excessive accumulation of prodrug-derivative nor pilocarpine in the 5 corneal epithelium, which might cause irritation of the eye.

By means of the compounds of the invention it is possible to eliminate to a large extent the disadvantages relating 10 to drug treatment with pilocarpine (poor biological availability, system and eye side effects, frequent ad-ministration and thus poor patient compliance). Due to the better corneal permeability, the compounds of the invention may be administered in considerably smaller doses and the 15 number of doses/day may be reduced, whereby the side effects are reduced, patient compliance is improved and the drug treatment of the glaucoma patients is made more effective. 20 The following examples illustrate the invention without limiting the same in any way. 20

EOUIPMENT USED

Melting point determination: Reichert Thermovar apparatus Determination of refraction index: Atago Illuminator apparatus pKa-value determination: titrating the derivative in a

water-ethanol mixture (50%-50%) Mass spectrometer: VG 70-250SE Tēst conditions in the electron bomb ionisator: electron energy: 70 eV (unless otherwise mentioned) ionisation current: 500 μΑ

ionisation chamber temperature: 150°C sample holder temperature 30°C => 500°C in 2-5 minūtes resolution: 10.000

Thermospray-mass spectrometer: VG thermospray/plasmaspray VG Trio~2 quadropole Beckmann 112 pump Tēst conditions in the thermospray-ionisation optimized daily NMR-spectrometer: Bruker AC 250/Aspect 3000 1H/13C 5 mm dual probe CD30D 20 mg/ml δ ppm (tetramethylsilane = 0) 5 21 LV 10257

Example 1 O,0'-Dihydrogen (l,2-ethylene) bispilocarpate (Y = hydrogen, A = direct bond)

The monoester was prepared by adding 247 mg (1.31 mmoles) of 1,2-dibromoethane dropwise to a solution containing 1302 mg (5.25 mmoles) pilocarpic acid sodium salt in 60 ml of dimethyl sulfoxide. The solution was mixed at room 10 temperature for 72 hours and poured into 100 ml of dis-tilled water. The mixture was extracted with two portions of each 100 ml of chloroform. The combined chloroform extracts were washed with 100 ml of distilled water, with 100 ml of 2 % sodium bicarbonate solution and with 100 ml 15 of distilled water. The chloroform extracts were dried on calcium sulfate (30 min) and the chloroform evaporated under reduced pressure, and the bispilocarpate obtained was crystallized from a ethyl acetate/ether mixture, whereby 332 mg (0.69 mmoles) of the title compound were obtained. 20 M.p. = 111-115 °C pKa =6.30 HR-MS-spectrum: m/e (relative intensity): 209 (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.

The starting material, the sodium salt of pilocarpic acid, 30 can be prepared as follows:

Pilocarpine hydrochloride (3.92 g; ,16.00 mmoles) was dissolved in distilled water (4 ml) and the solution was cooled to about 0°C. To the solution 18 ml of ice cold 35 2M NaOH were added in four.portions. The solution was left standing at about 0°C for one hour. After neutralizing excess NaOH with 5 ml of 1M HCl, the solution was evapo- 22 rated under reduced pressure. The residue was dissolved in 60 ml of absolute ethanol and mixed for 10 minūtes at 60°C. After cooling to 4°C undissolved NaCl was removed by filtration. The filtrate was evaporated under reduced pressure, whereby 3.93 g of sodium pilocarpate were obtained as a white, extremely hygroscopic substance.

Correspondingly, 0,0/-dihydrogen (1,3-propylene) bispilocarpate was prepared from the sodium salt of pilocarpic acid (1021 mg; 4.11 mmoles) and 1,S-^dibromopropane (208 mg; 1.03 mmoles). The yield is 330 mg (0.70 mmoles).

Correspondingly, 0,0'-dihydrogen (2-hydroxy-l,3-propylene) bispilocarpate can be prepared from the sodium salt of pilocarpic acid (1674 mg; 6.75 mmoles) and 1,3-dibromo-2-hydroxy propane (341 mg; 1.69 mmoles). 0,0/-dihydrogen (2-hydroxy-l,3-propylene) bispilocarpate can also be prepared from the sodium salt of pilocarpic acid and epichlorohydrine (2:1).

Example 2 O,0/-Dicyclopropylcarbonyl (1,2-ethylene) bispilocarpate (Y = cyclopropylcarbonyl; A = direct bond)

The compound was prepared by adding 945 mg (9.64 mmoles) of cyclopropylcarbonyl chloride dropwise during ca. 24 hours to a mixture containing 0,0'-dihydrogen (l,2-ethyle-ne) bispilocarpate (540 mg; 1.13 mmoles) (see Example 1) and 1866 mg potassium carbonate (13.5 mmoles) in toluene (150 ml). The mixture was stirred for 24-72 hours. To the reaction mixture a 2 % sodium bicarbonate solution (150 ml) was added and the mixture was stirred at room temperature for 3 hours. The layers were separated and the toluene phase washed twice with water (2 x 150 ml), was dried on calcium sulfate (30 min) and evaporated under reduced pressure, whereby 0,0/-dicyclopropylčarbonyl (l,2-ethyle- 23 LV 10257 ne) bispilocarpate was obtained. The yield was 304 mg (0.49 mmoles). pKa = 5.70 5 HR-MS-spectrum: m/e (relative intensity): 614 [M+'] (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 (measured) 10 614.3315650 (calculated). NMR: S 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. 15 Example 3 O,0'-Dicyclobutylcarbonyl (l,2-ethylene) bispilocarpate (Y = cyclobutylcarbonyl, A direct bond; fumarate) 20 The compound was prepared from 0,0/-dihydrogen (1,2- ethylene) bispilocarpate (470 mg; 0.98 mmoles) (see Example 1) and cyclobutylcarbonyl chloride (931 mg; 7.86 mmoles) according to the method described in Example 2. The fumarate salt was made by dissolving the compound in 25 toluene, adding fumaric acid in 2-propanol and precipitating with Petroleum ether. The yield was 810 mg (0.82 mmoles). M.p. = 49-51°C (fum.) 30 HR-MS-spectrum: m/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%). HR-MS: molecular weight = 642.3648680 (measured) 642.3628651 (calculated) NMR: S 8.50 2H bs, 7.23 2H bs, 6.73 s (fum.), 4.36 4H m, 4.11 4H m, 3.79 6H S, 3.16 2H m, 2.77 4H m, 2*54 2H m, 2.40 35 24 2Η m, 2.22 4H m, 2.01 4H m, 1.89. 4H m, 1.71 4H m, 0.93 6H t.

Example 4 5 O,0'-Dipropionyl (1,3-propylene) bispilocarpate (Y = propionyl, A = methylene)

The compound was prepared from 0,0'-dihydrogen (1,3-10 propylene) bispilocarpate (500 mg; 1.02 mmoles) (see Example 1) and propionyl chloride (751 mg; 8.12 mmoles) according to the method described in the Example 2. The yield was 467 mg (0.77 mmoles). 15 pKa =5.95 HR-MS-spectrum: m/e (relative intensity): 604 [M+*] (6%), 517 (7%), 411 (13%), 410 (57%), 396 (16%), 395 (71%), 339 (36%), 209 (15%), 208 (6%), 195 (48%), 121 (20%), 96 (56%), 95 (100%). 20 HR-MS: molecular weight = 604.3491210 (measured) 604.3472151 (calculated). NMR: S 7.56 2H bs, 6.76 2H bs, 4.18 4H m, 4.08 4H m, 3.62 6H s, 2.69 4H TO, 2.49 2H m, 2.33 2H m, 2.31 4H q, 2.01 4H qv, 1.68 4H m, 1.10 6H t, 0.91 6H t. 25

Example 5 O,0'-Dicyclopropylcarbonyl (1,3-propy.lene) bispilocarpate (Y = cyclopropylcarbonyl, A = methylene) 30

The compound was prepared from 0,0'-dihydrogen (1,3-propylene) bispilocarpate (422 mg; 0.86 mmoles) (see Example 1) and cyclopropylcarbonyl chloride (719 mg; 6.88 mmoles) according to the method described in Example 2. The 35 yield was 297 mg (0.47 mmoles). pKa = 6.05 25 LV 10257 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%). 5 HR-MS: molecular weight = 628.3428340 (measured) 628.3472151 (calculated). NMR: δ 7.51 2H bs, 6.73 2H bs, 4.19 4H m, 4.07 4H Itl, 3.61 6H s, 2.68 4H m, 2.49 2H xu, 2.33 2H m, 2.02 2H qv, 1.68 4H m, 0.91 6H t, 0.90 8H m. 10

Example 6 O,0'-Dicyclobutylcarbonyl (1,3-propylene) bispilocarpate (Y = cyclobutylcarbonyl, A = methylene, fumarate) 15

The compound was prepared from Ο,O'-dihydrogen (1,3-propylene) bispilocarpate (705 mg; 1.43 itunoles) (see Example 1) and cyclobutylcarbonyl chloride (1357 mg; 11.45 mmoles) according to the method described in Example 2. The 20 fumarate salt was crystallized according to Example 3. The yield was 960 mg (0.96 mmoles). M.p. = 33-35°c (fum.) HR-MS-spectrum: m/e (relative intensity): 657 (4%), 656 25 (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· (measured) 656.3785152 (calculated). 30 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 qv, 2.01 4H m, 1.89 4H m, 1.71 4H m, 0.92 6H t. 35 5 26

Example 7 O,0'-Dipivalyl (1,2-ethylene) bispilocarpate (Y = pivalyl, A = direct bond, fumarate)

The compound was prepared from 0/0,-dihydrogen (1,2-ethylene) bispilocarpate (384 mg; 0,80 mmoles; see Example 1) and pivalyl chloride (772 mg; 6.41 mmoles) according to the method disclosed in Example 2. The fumarate salt was 10 crystallized according to Example 3 from a 2- propanol/toluene/petroleum ether mixture. Yield 293 mg (0.29 mmoles). M.P, =61-65 °C (fum.) HR-MS-spectrum: m/e (relative intensity): 647 (5%), 646 15 [M+*] (7%), 645 (3%), 631 (6%), 531 (6%), 425 (24%), 424 (91%)/ 410 (17%)/ 409 (67%), 337 (9%), 293 (7%), 223 (34%), 209 (9%), 163 (9%), 123 (10%), 122 (5%), 121 (29%), 96 (84%), 95 (100%). HR-MS: molecular weight = 646.39318800 (measured) 20 646.39416531 (calculated). NMR: δ 8.51 2H bs, 7.23 2H bs, 6.73 S (fum.), 4.37 4H m, 4.10 4H m, 3.80 6H s, 2.78 4H m, 2.55 2H m, 2.39 2H m, 1.71 4H m, 1.20 18H S, 0.93 6H t. 25 Example 8 O,0/-Dicyclopentylcarbonyl (1,3-propylene) bispilocarpate (Y = cyclopentylcarbonyl, A = methylene, fumarate) 30 The compound was prepared from 0,0'-dihydrogen (1,3- propylene) bispilocarpate (401 mg; 0.81 mmoles; see Example 1) and cyclopentylcarbonyl chloride (859 mg; 6.48 mmoles) according to the method disclosed in Example 2. The compound was crystallized from a 2- propanol /toluene/ 35 Petroleum ether mixture. Yield 501 mg (0.48 mmoles). M.P. = The compound is hygroscopic 27 LV 10257 HR-MS-spectrum: m/e (relative intensity): 685 (4%), 684 [M+ ‘ ] (6%), 683 (2%), 451 (11%), 450 (48%), 436 (7%), 435 (25%), 379 (15%), 235 (29%), 209 (12%), 163 (12%), 121 (31%), 96 (47%), 95 (100%). 5 HR-MS: molecular weight = 684.4060820 (measured) 684.4098154 (calculated). NMR: S 8.57 2H bs, 7.27 2H bs, 6.72 s (fum.), 4.21 4H t, 4.10 4H d, 3.81 6H s, 2.80 4H m, 2.75 2H m, 2.54 2H m, 2.40 2H m, 2.03 2H qv, 1.88 4H Itl, 1.74 4H m, 1.71 4H m, 1.62 8H 10 m, 0.92 6H t.

Example 9 O,0'-Dicyclohexylcarbonyl (1,3-propylene) bispilocarpate 15 (Y = cyclohexylcarbonyl, A = methylene, fumarate)

The compound was prepared frora O,0'-dihydrogen (1,3-propylene) bispilocarpate (424 mg; 0.86 itmioles; see Example 1) and cyclohexylcarbonyl chloride (1009 mg; 6.88 mmoles) 20 according to the method disclosed in Exaraple 2. The compound was crystallized frora a 2- propanol /toluene/ Petroleum ether mixture. Yield 722 mg (0.68 mmoles).

M.P. =50-53 °C 25 HR-MS-spectrum: m/e (relative intensity): 713 (2%), 712 [M+‘] (6%), 711 (3%), 465 (16%), 464 (54%), 450 (9%), 449 (31%), 394 (5%), 393 (18%), 250 (6%), 249 (33%), 209 (12%), 163 (12%), 121 (32%), 96 (56%), 95 (100%). HR-MS: molecular weight = 712.4428410 (measured) 30 712.4411156 (calculated). NMR: S 8.55 2H bs, 7.26 2H bs, 6.71 s (fum.), 4.20 4H t, 4.09 4H-d, 3.81 6H s, 2.79 4H m, 2.54 2H m, 2.39 2H m, 2.32 2H m, 2.03 2H qv, 1.87 4H m, 1.74 4H m, 1.72 4H m, 1.70 4H m, 1.38 8H m, 0.92 6H t. 35 5 28

Example 10 0,0'-Glutaryl (diethyl) bispilocarpate (R' = ethyl, B = methylene) 9.80 mmoles of ethylbromide (1068 mg) were added dropwise within about an hour to a solution containing 9.80 mmoles (2432 mg) of pilocarpic acid sodium salt in 60 ml of di-methyl sulfoxide. The solution was stirred at room tempe-10 rature for 48-72 hours and poured into 100 ml of distilled water. The mixture was extracted with two portions of each 150 ml of ethyl acetate. The combined ethyl acetate ext-racts were washed with 150 ml of distilled water, with 150 ml of 2 % sodium bicarbonate solution and with 150 ml of 15 distilled water. The ethyl acetate extracts were dried on calcium sulfate (30 min) and the ethyl acetate evaporated under reduced pressure, and the pilocarpic acid ethyl ester obtained was crystallized from a chloroform/petroleum ether mixture, whereby 448 mg (1.76 mmoles) of the ester were 20 obtained. M.p. = 104-107°C pKa =6.60 HR-MS-spectrum: m/e (relative intensity): 254 [M+] (17%), 25 236 (18%), 223 (11%), 209 (24%), 207 (11%), 163 (14%), 139 (46%), 121 (31%), 96 (53%), 95 (100%). HR-MS: molecular weight = 254.1620180 (measured) 254.1630428'(calculated) NMR: S 7.49-1H bs, 6.74 1H bs, 4.13 2H m, 3.61 3H s, 3.55 30 2H m, 2.73 1H m, 2.53 1H m, 2.50 1H m, 2.03 2H m, 1.68 2H m, 1.27 3H t, 0.90 3H t.

The starting material, the sodium salt of pilocarpic acid, may be prepared according to Example 1.

Glutaryl chloride (157 mg; 0.93 mmoles) was added dropwise within about 24 hours to a mixture containing 589 mg of 35 29 LV 10257 pilocarpic acid ethyl ester and 1282 mg (9.27 mmoles) cal-cium carbonate in toluene (65 ml). The solution was stir-red at room temperature for ca. 48 hours. To the reaction mixture 2 % sodium bicarbonate solution (60 ml) was added 5 and the mixture was stirred at room temperature for 3 hours. The layers were separated and the toluene phase washed twice with distilled water (2 x 100), was dried on calcium sulfate (30 min) and evaporated under reduced pressure, whereby 0,0,-glutaryl (diethyl) bispilocarpate 10 (152 mg; 0.25 mmoles) was obtained. HRMMS*spectrum· m/e (relative xntensity)* 604 [M+] (7%), 559 (11%), 490 (21%), 489 (75%), 237 (9%), 223 (6%), 209 (8%), 163 (10%), 123 (6%), 122 (10%), 121 (100%), 96 (26%), 15 95 (61%). HR-MS; molecular weight = 604.3478240 (measured) 604.3472151 (calculated) NMR: 8 7.53 2H bs, 6.74 2H bs, 4.13 4H m, 4.08 4H m, 3.61

6H s, 2.67 4H m, 2.45 2H m, 2.39 4H m, 2.30 2H m, 1.89 2H 20 m, 1.67 4H m, 1.26 6H t, 0.90 6H t

Example 11 0,0'-Adipoyl (diethyl) bispilocarpate 25 (R' = ethyl, B = ethylene)

The compound was prepared from the ethyl ester of pilocarpine (609 mg; 2.40 mmoles) and adipoyl chloride (176 mg; 0.96 mmoles) according to Example 10. Yield 259 mg 30 (0.42 mmoles). HR-MS-spectrum: m/e (relative intensity): 618 [M+] (10%), 573 (9%), 504 (20%), 503 (67%), 489 (10%), 368 (10%), 365 (17%), 295 (9%), 249 (29%), 237 (11%), 236 (24%), 223 35 (15%), 209 (18%), 207 (2.0%), 163 (21%), 123 (9%), 122 (12%), 121 (100%), 96 (51%). HR-MS: molecular weight = 618.3625030 (measured) 30 618.3628652 (calculated) NMR: S 7.53 2H bs, 6.73 2H bs, 4.13 4H m, 4.08 4H m, 3.61 6H s, 2.67 4H m, 2.47 2H m, 2.34 4H m, 2.30 2H m, 1.68 4H m, 1.63 4H m, 1.26 6H t, 0.90 6H t 5 5 31LV 10257

Claims 1. Bispilocarpic acid ester derivatives. of the general formula 10 ch3 \

(I) vrtierein 15 A) Y is -C(=0)-R, wherein R is Cj-C4-alkyl, C3-C6-cy-cloalkyl or phenyl, and W is the group 20 25 i ch2

(la) wherein Y has the meaning given above, and A is a direct 30 bond or a methylene group, which can be substituted with hydroxy, the group Υ-0- wherein Y has the meaning given, or with one or two methyl groups, or B) W has the meaning of R' which is C1-c4-alkyl or C3-C6-cycloalkyl, and Y has the meaning of 35 32 32

(Ib) vrtierein B has the meaning of a direct bond, methylene or ethylene, and R' has the meaning given above, with the proviso that when both the R and R' groups in the compound (I) are ethyl, A and B are different from a direct bond and A in addition is different from OH-substituted methylene group, as well as the acid addition salts of the said compounds. 2. Bispilocarpic acid ester derivatives according to formula (I) of claim 1A, vherein R is C3-C6-cycloalkyl. 3. Bispilocarpic acid ester derivatives according to formula (I) of claim 1A, wherein R is straight or branched propyl or butyl. 4. Bispilocarpic acid ester derivatives according to formula (I) of claim 1A, wherein R is C3-C6-cycloalkyl or straight or branched propyl or butyl, and A has the meaning of a direct bond, unsubstituted methylene or methylene substituted with hydroxy, -0-Υ or with one or two roethyl groups, especially a direct bond or unsubstituted methylene. 5. Bispilocarpic acid ester derivatives according to 33 formula (I) of claim 1A, vherein R has the meaning indica-ted in claim 1A, especially Cļ-C4-alkyl or C3-C6-cycloal-kyl, and A has the meaning of a unsubstituted methylene or methylene substituted with one or two methyl groups. 5 6. Bispilocarpic acid ester derivatives according to formula (I) of claim 1B, vherein R' is C3-C6-cycloalkyl, 7. Bispilocarpic acid ester derivatives according to 10 formula (I) of claim 1B, vherein R' is straight or bran- ched propyl or butyl. 8. Bispilocarpic acid ester derivatives according to formula (I) of claim 1B, wherein R' is c3-C6-cycloalkyl or 15 straight or branched propyl or butyl, and B has the meaning of a direct bond, unsubstituted methylene or ethylene, especially a direct bond or unsubstituted methylene. 9. Bispilocarpic acid ester. derivatives according to 20 formula (I) of claim 1B, wherein R' has the meaning indicated in claim 1B, and B has the meaning of unsubstituted methylene or ethylene. 10. Bispilocarpic acid ester derivative according to claim 25 1A) which is O,0'-dicyclopropylcarbonyl (l,2-ethylene) bispilocarpate 0,0'-dicyclobutylcarbonyl (l,2-ethylene) bispilocarpate 0,0'-dicyclopropylcarbonyl (l,3-propylene) bispilocarpate 0,0'-dicyclobutylcarbonyl (1,3-propylene) bispilocarpate 30 O,0'-dicyclopropylcarbonyl (2-methyl-l,3-propylene) bispilocarpate O,0/-dicyclopropylcarbonyl (2,2-dimethyl-l,3-propylene) bispilocarpate 0,0'-dipropionyl (1,3-propylene) bispilocarpate 35 0,0'-dicyclopropylcarbonyl (2-hydroxy-l,3-propylene) bispilocarpate 0,O'-dicyclopropylcarbonyl (2-cyclopropylcarbonyloxy-l,3- 34 LV 10257 propylene) bispilocarpate 0,0'-dipivalyl (l,2-ethylene) bispilocarpate 0,0'-dipivalyl (l,3-propylene) bispilocarpate Ο,Ο'-di(l-methylcyclopropylcarbonyl) (l/2-ethylene) bispi-5 locarpate O,0'-dicyclopentylcarbonyl (1,2-ethylene) bispilocarpate 0,0'-diisobutyryl (l,2-ethylene) bispilocarpate O,0/-dicyclohexylcarbonyl (1,2-ethylene) bispilocarpate O,0'-dicyclopentylcarbonyl (1,3-propylene) bispilocarpate 10 O,0'-dicyclohexylcarbonyl (1,3-propylene) bispilocarpate 0,0'-dibenzoyl (1,2-ethylene) bispilocarpate 0,0'-dibenzoyl (1,2-propylene) bispilocarpate. 11. Bispilocarpic acid ester derivative according to claim 15 1B, which is 0,0'-succinyl (diisopropyl) bispilocarpate 0,0'-succinyl (di-t-butyl) bispilocarpate 0,0'-succinyl (dicyclopropyl) bispilocarpate 0,0'-succinyl (dicyclobutyl) bispilocarpate 20 0,0'-glutaryl (diisopropyl) bispilocarpate 0,0'-glutaryl (di-t-butyl) bispilocarpate 0,0'-glutaryl (dicyclopropyl) bispilocarpate 0,0'-glutaryl (dicyclobutyl) bispilocarpate. 25 12. Process for the preparation of a compound according to any one of the previous claims, characterized in that for the preparation of a compound according to claim 1A having the formula

30 (IA)

A

ch3ch2 ch3 35 35 LV 10257 a wherein A and Y have the meanings indicated in claim 1A, compound having the formula 5

10 15

(”) wherein A has the same meaning as in the claim 1, is reacted with an acid of the formula RC02H, or a functional derivative thereof, wherein R has the same meaning as in the claim 1A, or 20

b) for the preparation of a compound according to claim 1B ch. of the formula 25

CHj I \ R 0 o' = 0 > (IB) 30

ch3ch2 wherein B and R' have the meanings given in claim 1B, a compound of the formula 35 36 36 ch3 \

(III)

wherein R' has the same meaning as in the 'claim 1B, is reacted with a dicarboxylic acid of the formula 0 O ho-c-ch2-b-ch2-c-oh or a bifunctional acid derivative thereof, wherein B has the same meaning as in the claim 1B, and optionally the compound obtained is converted to its acid addition salt. 13. Pharmaceutical preparation, which contains as an active aģent a compound according to any one of the claims 1 to 11 together with a pharmaceutically acceptable vehicle.

Claims (13)

5LV 10257 NEW PILOKARPINAS DERIVATIVES AND THEIR METHOD OF OBTAINING PATENT FORMULA 10 1. Derivatives of bispilocarpine acid esters with the common formula where A) Y is -C (= O) -R, where R is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or phenyl, and W is a group 30 35 2 where Y is with the above meaning and A is a direct bond or a methyl group which may be substituted by a hydroxyl group, the group Υ-0-, where Y has the meaning given, or by one or two methyl groups, B 5) W is with R ', which is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, and Y represents a group Derivatives of bispilocarpinic acid esters according to formula (I), (I), wherein R is C 3 -C 6 cycloalkyl. 3. Derivatives of bispilocarpic acid esters according to 1A. wherein R is straight or branched propyl or butyl. 4. Derivatives of bispilocarpine acid esters according to 1A. wherein R is C 3 -C 6 cycloalkyl or straight or branched 35 propyl or butyl and A represents a direct bond, an unsubstituted methyl group or a methyl group substituted with a hydroxyl group, LV 10257 3 groups -0-Υ or one or two methyl groups, in particular a direct bond or an unsubstituted methylene group. 5. Derivatives of bispilocarpic acid esters according to 1A. wherein R is 1A. , especially C1-C4-alkyl or C3-C6 * cycloalkyl, and A represents an unsubstituted methyl group or a methyl group substituted with one or two methyl groups. 10 6 Derivatives of bispilocarpine acid esters according to 1B. wherein R 1 is C 3 -C 6 cycloalkyl. 7. Derivatives of bispilocarpine acid esters according to claim 1B. wherein R 1 is straight or branched propyl or butyl. 15 8. Bispilocarpinic acid ester derivatives according to claim 1B. wherein R 'is C3-C (, - cycloalkyl or straight or branched propyl or butyl and B represents a direct bond, unsubstituted methylene or ethylene group, especially <; this link or unsubstituted-methylgroup. 9. Derivatives of bispilocarpine acid esters according to claim 1B. wherein R 'is 1B. and B represents an unsubstituted methylene or ethylene group. A derivative of bispilocarpine acid according to claim 1A. 0,0 '- dicyclopropylcarbonyl (1,2-ethylene) bispilocarpate 0,0' - dicyclobutylcarbonyl 0, 2-ethylene) bispiloacetate 0,0 '- dicyclopropylcarbonyl fl, 3-propylen) bispilocarpate 30 0,0' - dicyclobutylcarbonyl (1, 3-propylene) bispilocarpate 0.0 '' - dicyclopropylcarbonyl (2-methyl-1,3-prppylen) bispilocarpate, 0.0 '- dicyclopropylcarbonyl (2,2-dimethyl-1,3-propylen) bispilocarpate 0,0'-dipropionyl (1,3-propiten) bispilocarpate 0.0 '- dicyclopropylcarbonyl (2-hydroxy-1,3-propylen) bispilocarpate 35 0.0' - dicyclopropylcarbonyl (2-cyclopropylcarbonyloxy-1,3-propylene) bispilocarpate 0,0 '- dipivalyl (1,2-ethylene) bispilocarpate 5 4 0,0' - dipivalyl (1,3-propylen) bispilocarpate 0,0 '- di (1-methylcyclopropylcarbonyl) (1,2-ethylene) bispilocarpate 0,0'-Dicyclopentylcarbonyl (1,2-ethylene) bispilocarpate 0,0 '- diisobutyryl (1,2-ethylene) bispilocarpate 0,0' - dicyclohexylcarbonyl (1,2-ethylene) bispilocarpate 0,0 '- dicyclopentylcarbonyl (1 , 3-propi len) bispilocarpate 0.0 '- dicyclohexylcarbonyl (1,3-propylen) bispilocarpate 0.0' - dibenzoyl (1,2-ethylene) bispilocarpate 0.0 '- dibenzoyl (1,2-propylen) bispilocarpate. 10 10 15 20 where B denotes a direct bond, a methylene or ethyl group and R 'is as defined above, provided that when both R and R' compounds (I) are ethyl, then A and B are not of direct linkage and, additionally, there is also no OH group substituted with methylgroup, as well as salts of suitable acids of said compounds. 11. An ester derivative of bispilocarpine acid according to claim 1B. 15 '- 0,0' - succinyl (diisopropyl) bispilocarpate 0,0 '- succinyl (di-t-butyl) bispilocarpate 0,0' - succinyl (dicyclopropyl) bispilocarpate 0,0 '- succinyl (dicyclobutyl) bispilocarpate 0,0 '- glutaryl (diisopropyl) bispilocarpate 0,0' - glutaryl (di-t-butyl) bispilocarpate 0,0 '- glutaryl (dicyclopropyl) bispilocarpate 0,0' - glutaryl (dicyclobutyl) bispilocarpate. A method for obtaining a compound according to any one of the preceding claims, characterized in that to obtain 1A. 30 of the compound of formula 25 Where A and Y are with 1A. of the formulas, the connection with the formula 10 15 wherein A has the same meanings as in paragraph 1, reacts with an acid of formula RCO2H or a functional derivative thereof, wherein R has the same meanings as 1A. or 20 (b) for the purpose of obtaining 1B. point to the formula where B and R 'are 1B. for the purposes of formula 35 where R 'has the same meanings as 1B. requires the reaction of the dicarboxylic acid with the formula ΗΟ- · ΟΗ2-Β-ΟΗ2 - ^ - ΟΗ or its bifunctional acid derivative and optionally converting the resulting compound with a suitable acid into its salt. 13. A pharmaceutical preparation comprising as an active agent for any one of claims 1-11. with a pharmaceutically acceptable carrier.