LT3081B - Novel pilocarpine derivatives and process for their preparation - Google Patents

Abstract

The invention relates to pharmaceutically utilizable compounds of the formula <IMAGE> in which formula Y is <IMAGE>, in which R is C1-C4-alkyl, C3-C6-cycloalkyl or phenyl, A is a direct linkage or a methylene group which can be substituted by hydroxyl, the group Y-O- in which Y denotes the same as above, or by one or two methyl groups and to acid addition salts of the said compounds.

Description

The present invention provides novel pilocarpine-type / pharmaceutical compounds for use in the treatment of glaucoma; speaking. more particularly, the present invention describes bispilocarpic acid esters, processes for their preparation and / or novel compounds, pharmaceutical compositions containing the novel compounds and their use.

(+) - Pilocarpine, (3S-cis) -3-ethylhydride-4 - [(1-methyl-1H-imidazol-5-yl) methyl] -2- (3 H) -furanone is a drug used in glaucoma treatment that lowers intraocular pressure by increasing fluid outflow from the eye. The IOP-lowering effect of pilocarpine is based on this effect of the drug; shrinkage of the drum muscle, which increases the angle of the anterior chamber, leading to chamber fluid leakage, and facilitates fluid drainage.

Unfortunately, IOP is not the only one. pilocarpine effects on the eye. At sufficiently high concentrations, pilocarpine potentiates the contraction of the ciliary muscle, and the lens of the eye adjusts to see near objects. It is difficult for the patient to adjust to seeing further objects and this causes discomfort. Pilocarpine also causes the iris to shrink and significantly reduces the pupil in the eye. In addition to these events, which are medically undesirable and uncomfortable for the patient, .pilocarpine can cause other side effects not related to the eyes. For example, it can increase salivation with cause bradycardia.

Patients with glaucoma usually take pilocarpine topically for eye drops. forms. Then only about 1% of the pilocarpine dose is absorbed by the eye, about 70% / dose into the blood. This poor ocular absorption of pilocarpine is due to three factors:

1) The drop is quickly washed away from the surface of the eye

2) rapid absorption of pilocarpine into the conjunctiva of the inner surface of the eye

3) low penetration of pilocarpine through the cornea.

abundant cells poorly soluble

Pilocarpine is absorbed into the eye via the cornea. When it enters the cornea, it is primarily absorbed into the dense epithelium layer of the surface of the eye, where the membranes are lipid. However, pilocarpine in fat, so only small. part of it penetrates the corneal epithelium. The corneal epithelium simultaneously plays the role of a film limiting the absorption of pilocarpine. and a depot that supplies pilocarpine via aqueous stroma and corneal epithelium to the anterior chamber fluids. When piled into the chamber fluids, pilocarpine easily reaches its site of action, the ciliary muscle. The duration of ocular action of pilocarpine is greatly reduced by its partial conversion to inactive pilocarpic acid and the rapid elimination of pilocarpine from the eye by the circulation of chamber fluids and by the circulation of blood in the iris.

Poor absorption into the inner part of the eye and short-term exposure to pilocarpine for ocular administration cause difficulties in the treatment with this product. Pilocarpine should be used in relatively high doses to improve and prolong the effect of the drug. This results in high concentrations of pilocarpine in the chamber fluids, iris and ciliary muscle, which causes a slight contraction of the puppet and adapts the eyes to seeing near objects. In addition, doses of pilocarpine. augmentation is a rather ineffective way of prolonging the effect of the drug, as this type of drug is rapidly removed from the eye, which is why pilocarpine eye drops are given 3-8 times per day depending on

1.13081 B

Y patient condition. Such frequent use of eye drops is also • uncomfortable for the patient, since the administration of drops is always associated with side effects to the eye. High doses increase the risk of pilocarpine absorption, absorption into the blood and other side effects.

Efforts have been made to develop pilocarpine - type drug precursors in order to overcome the above disadvantages of poor absorption of pilocarpine. which are better absorbed by the corneal epithelium. These derivatives should be more fat soluble to improve absorption. In addition, as much of them as possible should break down in the corneal epithelium and release the pharmaceutically active pilocarpine and inactive structural part. The degree of degradation in the cornea depends on the residence time of the derivative and its rate of degradation in the corneal epithelium. The residence time of the derivative in the epithelium · increases with increasing lipophilicity and decreasing the diffusion coefficient,

To date, two types of pilocarpine precursors for pharmaceutical use have been described. 4,061,722 Bodor describes pilocarpine derivatives - - drug precursors based on quaternary ammonium compounds.-Bundgaard et al. EP patent application no. 0 '106 541 describes '25 pilocarpic acid diesters which provide better ocular absorption. The aforementioned pilocarpic acid diesters have some drawbacks, such as poor water solubility and irritation to the eyes. In addition, diesters give rise to many undesirable by-products compared to pilocarpine itself.

The present invention describes novel bispilocarpic acid esters, i. y. bispilocarpates, which by their use can avoid or at least significantly reduce the aforementioned drawbacks. · Such drug precursors of the present invention are degraded as rapidly as pilocarpine and have a structural lipophilicity consistent with Bundgaard et al. etc.

/ 1Τ3081Β

/. ./ _; '// - //> // 4 /:.

// The compounds described / are ingested into the stomach and the piocarpine penetration through the cornea is not reduced. In addition, bispilocarpate derivatives deliver a single structural moiety to the cornea. corresponding to two polycarpine molecules, while R in the invention.5 Bundga'ard et al. 'one structural moiety corresponds to one piocarpine molecule. The diffusion coefficient of bispilocarpates in the corneal epithelium is lower than that of the Bundgaard compounds, and the o-unfragmented bispilocarpate derivatives remain longer in the corneal epithelium. Therefore, the 'complete drug precursor breakdown .--. 'more time. Furthermore, the novel compounds of the present invention have a better solubility and, therefore, are better suited for the preparation of pharmaceutical formulations.

'Φ. · ...... '·. . · .. · · // R? R ': j-'. </ IR> R: .'R / R; R - /? 'R.:?R. R; / r ',. / ^; RR / R: // /; :.; · / + - + / R / · / + · r'r'.R '''.' / '/' + / · + .. · '.' / + R.

Thus, the invention allows for slow, sustained release of drugs from the cornea to the inner parts of the eye and can significantly prolong the action of piocarpine and reduce the peak levels of piocarpine in the eye, which is important given the side effects mentioned above.

The novel piocarpine drug precursors of the present invention, in particular the bispilocarpic acid esters, e.g. bispilocarpates, have the general formula I

wherein / H3 ^; 5 '''' --- R ^ ////+-R/.+//++R/RR- '++ /' ·

A) Y is -C (= O) -R where R is C ₆ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl / or phenyl, and W is radical (Ia) R.

(la) when Y has the values defined above and A is. simply a bond or a methylene group which may be substituted by a hydroxy radical, Y-O- when Y has the meanings defined above, or substituted by one or two methyl groups, or

B) W has the values of R ', i.e. C ₂ -C ₆ -alkyl or C ₃ -C ₆ cycloalkyl, and Y represents / = ° CH, t ^£

B

I

CH ₃ CH ₂ '

(Ib) when B is simply a bond, methylene or ethylene, R 'has the meanings defined above, except that both R and R' in (I) are ethyls ^ A and B cannot be a bond, ' , A cannot be an OH-substituted methylene group, or salts of the above compounds with acids.

A more appropriate subset; (yf _; (IA) compounds of formula (I) from compounds of formula

wherein Y and A are as defined above, except when both R and R 'in the compound (I)' are ethyl, A cannot be a direct bond or an OH substituted methylene group.

In the formula (IA> more preferably R is C ₃ -C ₆ cycloalkyl or straight or branched propyl or butyl, more preferably A is simply a bond, unsubstituted methylene or methyl substituted by hydroxy or one or two methyl groups, more preferably is simply a bond or unsubstituted, methylene.

As defined below, A is unsubstituted methylene or methyl substituted with one or two methyl groups, the R values are as defined above, with C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl being particularly suitable.

³⁵

Another more preferred subgroup of compounds of the present invention are compounds of formula (IB)

wherein R 'and B are as defined above except. in the case where both radicals R 'are ethyl, B cannot simply be a bond.

In formula (IB), a more preferred radical R 'is C ₃ -C ₆ cycloalkyl or straight-branched propyl or butyl, more preferably B is simply a bond, unsubstituted methylene or ethylene, a more suitable substituent is simply a bond or unsubstituted methylene.

Another subset of the compounds of formula (IB) is composed of compounds wherein B is unsubstituted methylene or ethylene, and the R 'values are indicated next to formula (IB). .

According to the above general formula I, C 1 -C 4 alkyl is straight or branched, more preferably methyl, 'ethyl, propyl, butyl. Most preferred is straight or branched propyl or butyl such as n-, i-propyl, n-,

1-, or tert-butyl.

Cycloalkyl R or R 'has from 3 to 6 carbon atoms which may be substituted by methyl, such as' cilopropyl or cyclobutyl.

Compounds in which R and R 'are the same are more suitable.

More preferred salts of the compounds of formula (I) formed with an acid are pharmaceutically acceptable salts with non-toxic inorganic or organic acids. Suitable acids are, for example, the aforementioned hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, etc. and organic acids such as acetic, propionic, · stearic, oxalic, malonic, succinic, glutaric, adipic, maleic, fumaric, malic, tartaric, citric, ascorbic, benzoic, pamo or sulfonic acids such as mesylic or tosylic acid.

More preferred individual compounds of the formula · (IA) are as follows:.

O, O'-Dicyclopropylcarbonyl (1,2-ethylene) bispilocarpate

0,0 '-dicyclobuccylcarbonyl (1,2' -ethylene) bispilocarpate

0,0'-Dicyclopropylcarbonyl (1,3-propylene) bispilocarpate

0,0 '-dicyclobutylcarbonyl (1,3-propile'n) bispilocarpate

0,0 ^r -dicyclopropylcarbonyl (1-methyl-1,3-propylene) bispilocarpate

0,0'-Dicyclopropylcarbonyl (2,2-methyl-1,3-propylene) bispilocarpate

0,0'-dipropionyl (1,3-propylene) bispilocarpate \ · _? 0,0'-Dicyclopropylcarbonyl (2-hydroxy-1,3-propylene) bispilocarpate

0,0'-Dicyclopropylcarbonyl (2-cyclopropycarbonyl-oxy-1,3-propylene) bispilocarpate /

0,0'-dipivalil (1,2-ethylene) bispilocarpate

0,0 '- d i p i v a 1 i 1 (1,3 -or op ii en) b i s p i 1 o'k a r p a t s

0.01-di (1-methylcyclopropylcarbonyl (1,2-ethylene) bis-pilocarpate

0,0 '-dicyclopentylcarbonyl (1,2-ethylene) bispilocarpate

0,0 '-diisobutyril (1,2-ethylene) bispilocarpate

0,0'-Dicyclohexylcarbonyl (1,2-ethylene) bispilocarpate

0,0'-Dicyclopentylcarbonyl (1,3-propylene) bispilocarpate

0,0'-Dicyclohexycarbonyl (1,3-propylene) bispilocarpate

0,0'-dibenzoyl (1,2-ethylene) bispilocarpate

0,0'-dibenzoyl (1,2-propylene) bispilocarpate

More preferred compounds of formula (IB) are y. such:

0,0'-Succinyl (diisopropyl) bispilocarpate

0,0'-Succinyl (di-t-butyl) 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 ¹ -glutaril (dicikiobutii) bispilocarpate

The invention also relates to a process for the preparation of compounds of formula (I).

According to the method described in the invention, for

(IA) wherein A and Y are as defined above as a compound of formula (I) having the formula

where A is as defined above, is reacted with an acid of formula RC ₂ OH or a functional derivative thereof where R is as defined above, or

(b) preparing a compound of the formula

(IB) wherein B and R 'are as defined above for Formula (I), a compound of Formula'

3.0 (III)>

wherein R * values as defined above are treated with a dicarboxylic acid of formula

0

II II ho-c-ch ₂ -b-ch ₂ -c-oh or a bifunctional derivative thereof, where B is as defined above, and the resulting compound can be converted into the salt by treatment with an acid. , i

To produce the above used: / as starting material in process a), pilofarpin / acid; · Whose formula is

ve to a residue of formula X-CH ₂ -ACH ₂ -X '' / wherein X and / X 'independently of one another are' / hydroxy. /, for example,, -halogen, acyloxy, alkyl or arylsulfonyloxy, the values of A are defined above.

7, 13.

In order to produce the compound used above as starting material in process b), the pilocarpic acid as defined above is treated with a compound of formula R'X when X is a hydroxy radical or a leaving group such as halogen, acyloxy-radical, alkyl or arylsulfonyloxy, R 'values as defined above.

The functional acid derivatives used in the above reactions, more preferably, are halides, anhydrides, alkyl or arylsulfonates. Solvents such as carbons are used as reaction media. .. ... · R ··· .. ···. ··· '·' denyls, ethers, ketones, etc., which are inert to reagents. Suitable hydrocarbons include, for example, aromatic hydrocarbons such as benzene and alkylated benzenes such as toluene and xylene. Suitable halogenated hydrocarbons include, for example, dichloromethane, chloroform and chlorobenzene. Ketones include acetone, ethylmethylketone and isobutylmethylketone, and ethers include diethyl ether, diisopropyl ether, dibutyl ether and 1,4'-dioxane. · Among other suitable ones. solvents include dimethylsulfoxide, dimethylformamide and acetonitrile.

The reaction temperature is not a critical parameter, but can vary, for example, from -10 ° C to the boiling point of the solvent. Typically, room temperature is used ... Reaction times can vary over a wide range and are usually from 12 to 72 hours, more often about 24 hours. Reactions can use 'acid-binding agents such as alkali metals and alkaline earth carbonates or organic'. bases. Suitable metal carbonates. are sodium carbonate and potassium carbonate, and suitable bases are pyridine and its homologs, N, N-dimethylaniline and. trialkylamines, more preferably triethylamine. These may be carried out in a homogeneous solution or system, such as PTC.

reactions can heterogeneously <14

In the compounds of the present invention, the ester linkage may be formed using known water. cleaving reagents such as carbodiimides. In some cases, acid-catalyzed reactions of known esterification are suitable.

In the invention · also; describes pharmaceutical compositions containing the compounds ^{of the} present invention as an active ingredient ^; together with pharmaceutically acceptable carriers and adjuvants.

The pharmaceutical compositions of the present invention are prepared in a known manner using standard carriers and other adjuvants. Carriers may include, for example, liquids, · emulsions or · suspensions, * creams, and ointments. The composition can be as follows. also formulated as a pharmaceutical dosage form for administration to the eye. A suitable form of administration is, for example, the eye. drops solution containing the appropriate concentrations of the present invention. compound, for example, in 0.1-4% sterile aqueous buffer solution having an 'appropriate pH' or a solution adjusted with acid or alkali. ' The water-soluble acid salt of this compound is more suitable. An eye drops solution containing the above concentration is administered to the eye depending on the condition of the patient, and it is preferable to administer the drops 1 to 3 times daily.

METHODS OF ANALYSIS

The compounds of the present invention are analyzed. according to the tests below.

• 1} Lipophilicity

The lipophilicity of the compounds was determined by measuring the partition coefficient (P) of the compounds at pH

Y; ...,.

for values of 7.40 and 5.00. Measure in a mixture of 1-octanol and phosphate buffer to determine the concentration of the test compound in the buffer phase before and after distribution. The measurement results show that all of the compounds of the invention are more fat soluble than pilocarpine (log P '= 0.01, pH 7.40 and -1.74, pH 5.0, respectively), and fat solubility can be regulated by altering pilocarpic acid substitutions.

2) Enzymatic hydrolysis

The half-life of enzymatic hydrolysis of the bispilocarpates of the present invention was determined in a plasma-buffer mixture and / or in rabbit corneal homogenate.

A. Measurement in plasma / buffer mixture.

The enzymatic hydrolysis half-life of bispilocarpic acid diesters was measured in plasma / phosphate buffer, pH 7.40 (80% / 20%) at 37 ° C. The logarithm of the residual diester concentration is plotted as a function of time and obtained from the resulting graph is a _half-life 'T _1/2 .

The results show that the stable diester in buffer solutions is degraded by the plasma esterases to the 0.0 dihydro-bispilocarpate and monopilocarpate compounds, which are chemically degraded to the active pilocarpine under physiological conditions. The rate of drug degradation can be controlled by conditions of precursor exchange of acid.

alternations connected to pilocarpine. 16 'a; B. Measurement of corneal homogenate.

The half-life of enzymatic hydrolysis of bispilocarpic acid diesters was measured in the rabbit cornea

.. homogenate (pH 7 * .40) at 37 ° C. Rabbit corneal homogenate was prepared in 0.05 M Tris buffer.

The logarithm of the residual diester concentration is plotted as a function of time and the resulting _{half-life is} determined by T _1/2 .

'. '

The results indicate that in buffer solutions, the stable diester, when exposed to rabbit corneal diesters, is degraded to 0,0 * -dihydro-bispilocarpate and monopilocarpate intermediates, which under physiological conditions are chemically degraded to active pilocarpine.

The degradation rate of the drug precursor can be regulated by altering the substituents attached to pilocarpic acid.

3) Penetration through the gene

The corneal permeability of the novel bispilocarpates of the present invention was investigated in a diffuse chamber by following the migration of the compound from the presentation phase (epithelial side) through the corneal to the diffuse chamber receiving end (endothelial side). The rabbit eye cornea was used for testing. From the permeation rate, the permeability coefficient (P _app ) was determined 30 The results show that the new compounds can improve the corneal permeability of pilocarpine (P _app = 2.77 cm / s χ 10 ⁶ ).

Examples Log P  P.-.r.n ' corneas hcmogenizate min plasma ( min pH 5.0 pH 7.4 ΧΙΟ ⁶ cm / s 2 · 26th ((('7'33' - '77. -0.58 ((( ^; 2-7'83 (- ((' 2.60 3 to (77 '(4 ^: 7 (7 (: /.0(7(6 {77 (0 7-00.3: 0 (( '{3 (7.6/7 10.46 4 (777 5.- (0 / (( ((> '-' 0 '(.: 6U (.:. ((((2.93- (0 ( 3.19 5 (- (j . · '; ·., «»; 'to'. -0.30 .3.43 . 4.26 6th 77 {7-0 {4 {7 {(7. {.. 0 77 (7 (5. (((( 0.60 '' - (((( 12.86 7th 97 '/ (0 ·' - '0 / - (:(: - C '' {: '7,777 6.55 · 8th - 1.71 - 10.77 10th • 39 - -0.27 11th 14th - -0.02  -, /

The results show that the compounds of the invention are hydrolyzed in the cornea to form pilocarpine; and that it is possible to control the permeability of the drug precursor through the cornea and the rate of pilocarpine formation by attaching the substituents to the pilocarpic acid. It is worth noting that the permeation coefficient · is lower for those compounds that slow the release of pilocarpine (for example, due to the slow chemical degradation reaction of the intermediate in question) compared to those that rapidly ¹ release pilocarpine.

Conclusion

Fat solubility, enzymatic hydrolysis, corneal permeability, and chemical hydrolysis of the intermediates formed by the compounds of this invention, as well as the formation of active pilocarpine in the eye, are readily controlled by altering pilocarpic acid derivatives as required.

Bispilocarpic acid diester '· //. Enzymes are enzymatically hydrolyzed to (bi-pilocarpic acid esters and, respectively, to pilocarpic acid m-esters, which undergo chemical (spontaneous) hydrolysis to pilocarpine).

The bispilocarpic acid diesters of the present invention are in the ////) //. 5 7./'(777:7/::I/77::/;:(7'777//)/:(7/7'77-77 ' ^?, ) 7'77:) /' // /7'!*(7',77'.7 ^! 777: 777117.7-17) //77////77(^/--77)7/-/.-./- ///// - :) / 7 / 7-7 (/ (7.7 /// 7 (// · // /, / ^K - transports through the cornea, one. Structural element, respectively, two pilocarpine. Molecules, thus reducing the... Release structure. . '- The amount of structural elements to be relaxed should be reduced to reduce eye irritation and

7 (/ (777 / 7- (7 ^ / - 77 (777/7) 7777/77 /: 777 - {/ {7 (/ 7 /// - / 7 // 77/77 //: 7 ^{/7/7-/7///7.77/7/7:7)7(/7777?;} 7 ^'; 7-777 / 7 /// ((' - '(' (7 /. \ 7) 7 / 7 '- //) / (7' //// 7 (-77: / 7 - //. 7 (/ 7) pain associated with the use of the Drug.

/77777^-1^(.^//(/-//77777:777,(7)/7777/://-7/77^777(//7/)//(7)7:7- 7 //) / (/ 7 // - ^ () / 7 // 7777/7 // - / - / 7 / - {^: 7 (7 ·; / //>//.//--/ 7 </./·· '/ 77 /// / 7 // 77 77 / ·' ·· - - 77-./:./ // Because bispilocarpic acid diesters are fat soluble, they are effectively absorbed by the corneal epithelium, containing - corneal esterases fast

1.5 · discloses a suitable water-soluble intermediate '(e.g., 0.0 ^r -dihydro (1,2-ethylene) bis-spirocarpate' (from

IA) - or -, respectively, .CHhydro (ethyl) foispilocarpate (from

IB), which, when dissolved, can migrate from the epithelium to the Stroma and from there to. the inner part of the eye to the site of action,

20. releasing all the pilocarpine in migration. Therefore, the corneal epithelium does not accumulate excess drug precursor or pilocarpine, which could cause eye irritation- ...

The use of the compounds of the present invention avoids most of the disadvantages associated with pilocarpine treatment (poor bioavailability, systemic side effects and ocular side effects, frequent use, which are difficult to lift by patients). For improved corneal permeability, the compounds of the present invention may be administered. significantly lower doses and reduced side effects, improved patient tolerance and more effective treatment of glaucoma patients.

The following examples illustrate the present invention, but do not limit its scope.

, '' '' ''::, .'- {..

USED EQUIPMENT

Melting point determination: Reichert Thermovar apparatus.

Determination of refractive index: determination of Atago Illuminator pK _a ; is titrated with water / ethanol in a mixture (50% / 50%) '·' · - '·''i. ·. ··. ·. · i ·.:' = '·

Mass Spectrometer: VG 70-250SE

Test conditions for electron bombardment ionizer:

electron energy: 70 eV (unless otherwise stated) ionization current; 500 micro ampere ionization chamber temperature: 150 ° C sample holder temperature 30 ° C to 150 ° C in 2-5 minutes resolution: 10,000

Thermal Injection Mass Spectrometer: VG Thermal Injection / Plasma Injection

VG T.rio-2 Quadropolis

Reckmann 112 pump

Test conditions for ionization by thermal injection:

optimized daily

FB20 - // '®3F ·. NMR Spectrometer: Bruker AC 250 / Aspect 3000

1H / 13C '5mm Dual Sample

CB3OD 20 mg / mL chemical, displacement m.d. (t'etramethylsilane = 0)

Example 1 «'

OQ ^T -dihydro (1,2-ethylene) bispilocarpate (Y = hydrogen; A = just bond)

3-- '' .3 '. Β; 3'ΒΒ'Β · 3β / · 3 /3Β/63®.·7''··3'y®®;® / </ _; 'BfBB ^; 3Bf7f37 »36 ®.? · ®. / · .® · ^; · '? ®3' / B3y3. ' / f'®®? · /; 3-'3 / 73? / '7/3 · B® · /? : /.-- 77 37.; '/ ·' ·

Manchester Synthesized by Dropping 247 mg {1.31 mmol)

1,2-Bromoethane into a solution of 1302 mg (5.25 'mmol) of the sodium salt of pilocarpic acid and 60 / ml of dimethylsulfoxide. The solution is stirred at room temperature for 72 hours and poured into 100 ml of distilled water. The mixture was extracted with chloroform (2 x 100 mL). The combined chloroform extracts are washed

100 ml distilled water, * 100 ml 2% sodium bicarbonate solution and 100 'ml distilled water. The chloroform extracts were dried over calcium sulfate (30 min) and the chloroform was evaporated under reduced pressure to give the bispilocarpate crystallized from ethyl. acetate / ether to give 332 mg (0.69 mmol) of the title compound.

Lt = 111-115 ° C pK _a = 6.30

HR-MS spectrum: m / e (relative intensity): 209 (8%), 208 (19%), 96 (30%), 95 (100%).

. 21 ',

R y / B ^: // to; 7i49 _; 2H / bs ^ '6 ·' ^{74ί 2Η} bs ^,, 4.30 4Η .m, 3.60 6Η s, ./,7 // 3 ./54 4Η m, 2.73 2H m, 2ί56 2H m, 2/51 2H m, 2.02 2Hm,

7, / 1 /. 4. H // 68 / ^IRI: /0.89 6H t /.

Starting material, pilocarpine. sodium salt of acid, may be prepared as follows:

Dissolve pilocarpine hydrochloride (3.92 'g; · 16.00 mmol) in distilled water (4 mL) and cool to about 0 ° C. Solution 1 is added four times in 18 mL of chilled 2M NaOH. The solution is left to stand for one hour at a temperature close to 0 ° C. Neutralizing excess sodium.alcohol.with 5 //////.77/-ymi././!/'lM// /:.HČl/////háfpalas//./,/hugąrąna/mas/7 // Dissolve // under reduced pressure // // Remain // £ mill / B0 // ml // Alcohol and stir for 10 minutes at 60 ° C. Cool to 4 ° C and filter the insoluble NaCl. The filtrate was evaporated under reduced pressure to give 3.93 g of pilocarpate sodium as a white, highly hygroscopic material.

The 0.0'-dihydro (1,3-propylene) bispil carpate was synthesized from pilocarpic acid sodium salt (1021 mg; 4.11 mmol) and 1,3-dibromopropane (208 mg, 1.03 mmol), respectively. Yield: 330 mg (0.70 mmol).

.

The 0, 0 '-dihydro (2-hydroxy-1,3-propylene) bispilocarpate can be synthesized from pilocarpic acid sodium salt (1674 mg, 6.75 mmol) and 1,3-dibromo-2-hydroxypropane (341 mg, 1.69 mmol), respectively.

·

The 0.0'-dihydro (2-hydroxy-1,3-propylene) bispilocarpate may also be synthesized from pilocarpic acid sodium salt and epichlorohydride (2: 1). 35

Example 2

0,0 '-dicyclopropylcarbonyl (1,2-ethylene) bis, pilocarpate (Y = cyclopropylcarbonyl; A = just bond)

The compound was synthesized by instillation; 945 mg (9.64 mmol) of eicopropylcarbonyl chloride over a period of 24 hours into a mixture of 0.0 * -dihydro (1,2-ethylene) bispilocarpate (540 mg; 1.13 mmol) (see Figure 1>, 1866 mg) potassium carbonate *

(13.5 mmol) and 150 mL of toluene. The mixture is stirred for 24-72 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 are separated and the toluene phase is washed with water (2x150 mL),

- dried over calcium sulfate (30 minutes) and evaporated under reduced pressure. Obtained 0,0 '-dicyclocarbonyl (inl, 2? Ή;?;. 7 ή ??'; Z / 7 ΐΖ-'7/7), Χ /;:?.?:? · /.' 7? -. <· ..? <7 '' ·.? · /. 'Z ^; ''-'7 / · '·? // -' 7 --.- 7 /., 7 /, 77> 7-.7 / 777-77 / 77 -.- 7--. - //: 7-7,? -? -? - 777 / / 7 ethylene) bispilocarpate, yield 304 mg (0.49 mmol). : I. _P K _a = 5.70 '

HR-MS spectrum: m / e (relative intensity) ·: 614 [M ⁺ .I (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 mass = 614.3299260 (measured)

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, 2.96 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. ' . Example 3

Ό, Ο'-Dicyclobutylcarbonyl (η, 2-ethylene) bispilocarpate

λ; / 23, .. /''/7//</:+.++?//;'////;

(Y = Cyclobutylcarbonyl; A = Just J; Fumarate)

The compound was synthesized from 0,0'-dihydro (1,2-ethylene) bis 5. pilocarpate (470 mg; 0.98 mmol) (see Example 1) and cyclobutylcarbonyl chloride (931 mg; 7.86 mmol) according to the procedure in Fig. 2. The fumarate salt is prepared by dissolving the compound in toluene, adding fumaric acid in 2 'propanol and precipitating with petroleum ether. Yield 810 mg (0.82 mmol).

L.t. 49-51 ° C (fumarate)

HR-MS spectrum: m / e (relative intensity): - 642 15 [M / a] (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 mass = 642.3648680 (measured)

642.3628651 (calculated).

NMR : 5 8.50 2H bs, 7th 23rd 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 2H m, 2.22 4H m, 2.01 4Hm, 1.8'9 4H m, 1.71 4H 25th m, 0.93 6H t.

Example 4

0,0'-dipropionyl (1,3-propylene) bispilocarpate 30 (Y = propionyl; A = methylene)

The compound was synthesized from 0.0'-dihydro (1,3-propylene) bispilocarpate (500 mg; 1.02 mmol) (see Figure 1) and propionyl chloride (751 mg; 8.12 mmol) according to the procedure set forth in FIG. 2. Yield 467 mg (0.77 mmol).

///'•./I'pWhat = 5.95 7.////··'·'''/

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%).

....... HR-MS: Molecular Weight = 604.3491210 (measured)

604.3472151 (calculated).

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

3.62 6H s, 2.69 4H m, 2.49 2H m, 2.33 2H m, 2.31 4H q,, 2.01 4H m, 1.68 4H m, 1.10 6H t, 0.91 6H t.

Example 5

- 0,0 * -dicyclopropylcarbonyl (1,3-propylene) bispilocarpate.

'(Y = cyclopropylcarbonyl; A = methylene)

The compound was synthesized from 0.0 * -dihydro (1,3-propylene) bispilocarpate (422 mg; 0.86 mmol) (see Figure 1, 'and cyclopropylcarbonyl chloride (71Y mg; 6.88 mmol)) according to the procedure in Figure 2. Yield: 297 mg (0.47 mmol).

pK _a = 6.05

..... HR-MS spectrum: m / e (relative intensity) 629 (4%), 628 [M ⁴ -] (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 (Measured) • 628.3472151 (Calculated). .

. BMR: δ 7.51 2H bs, 6.73 2H bs, 4/19 4H m, 4.07 4H m, 35 3.61 6H s, 2.68 4H m, 2.49 2H m, 2.33 2H m, 2.02 2 H g v, 1.68 4H m, 0.91 6H t, 0.90 8H m.

/ EN 3081 B '

EXAMPLE 67

O, 0'-dicyclobutylcarbonyl (1,3-propylene) bispilocarpate (Y = cyclobutylcarbonyl; A = methylene, fumarate) g + g / g- + g // + gg '-g', // - '+++ g '/// 7 +7.7> compound / prepared from 0,0'-dihydrogen (1,3-propylene) bigpįi _o] é _or p _a t _o (7Q5 _mg in .43 mmol) (see. Fig. 1) and cyclobutylcarbdnyl chloride + (1357 mg; 11.45 mmol) according to the procedure in Fig. ¹ > Fig. + 7/27 /. Fumarato. salt. crystallization: according to the / procedure given in fig. 3. Yield

960 mg (0.96 mmol). / :.

L.t. 33-35 ° C (fumarate) 7 ''

HR-MS: 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 (5%), 96 (68%), - 95 (78%).

HR-MS 'Molecular Weight - 656.3743290 (measured)

656.3785152 (calculated).

NMR: δ 8750 2H bs, 7.23 2H bs, 6. 73 s (fumarate), 4.21 4H m, 37 80 6H s, 3.16 2H m. 2.78 4H m, '2.53 2H m, 2.40 25th 2H m,; 2.22 4H m, 2.03 2Hqv, 2.01 4H m, 1.89 4H m, 1.71 4H-m, ( K 92 6H t. / + :: + V ///+:+.:7:,///+ _e :

Example 7 - / + /. ^? '+:' /// .//../://

0,0'-dipivalyl (1,2-ethylene) bispilocarpate (Y = pivalyl; A = simply fumarate)

The compound was prepared 0,0 ¹ -dihydro IS7 (1,2-ethylene) bispilocarpate (384 mg; 0.80 mmol) (see. Fig. 1), and + pivalilo chloride (772 mg, 6:41 mmol) according to the method described in Fig. 2. The fumarate salt is crystallized according to

refer to the methodology in Fig. 3. from 2-propanol, toluene and. petroleum ether mixture. Yield: 293 mg (0.29 mmol).

L.t. 61-65 ° C (fumarate)

HR-MS spectrum: m / e, (relative intensity): 647 (5%), € 46 [M7J (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 mass = 646.39318800 (measured)

646.39416531 (calculated).

. · BMR:. δ 8.51 2H bs, 7.23 2H bs, 6'.73 s (fumarate), 4.37. '.. S.' ·. · 7-7'7 7? 77> 7 · ''7;%? ^ 777 /> 77 ·. 777 ·; 7 _{: ι} .. ’‘ 7 ^: · .7 ^{; ::} ''^7;'' ·? · 7 77 '·' · -. -: /:. 7-: · .'7 · '. '· To ·' Λα · '' 4Η m, 4.10 4Η m, 3.80 6Η s, 2.78 4Η m, 2.55 2H m, -2.39

2H m, 1.71 4H m, 1.20 18H s, 0.93 6.H t.

Example 8 ¹

0,0 ¹ -dicyclopentylcarbonyl (1,3-propylene) bis-pilocarpate (Y = cyclopentylcarbonyl; A = methylene, fumarate)

The compound was synthesized from 0.0'-dihydro (1,3-propylene) 25 bispilocarpate (401 mg; 0.81 mmol) (see Figure 1) and cyclopentylcarbonyl chloride (859 mg; 6.48 mmol) according to the procedure described in Figure 2. . The compound is crystallized from a mixture of 2-propanol, toluene and petroleum ether. Yield: 501 mg (0.48 mmol).

L.t. = compound hygroscopic

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%).

LT

HR-MS: molecular mass =,

684.4060820 (measured) 684.4098154 (ap number o ta)

NMR: δ. 8.57 , 2'H bs , 7.2 ^-7 2H bs, 6. 72 s (fumarate), 4.21 4H m, 4.10 4H h, 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 / 4Hm, 1.74 4Hm, 1.71 4H m, 1.62 8H m, 0.92 6H t. 7./:,/7- / '57 /. Example 9 , λ "

0, 0 ' -di-ci clohe x 1 with carbon 1 (1,3 -prop i 1 yen) b w i t h (Y = cyclohexylcarbonyl; A = methylene, fumarate).

The compound was synthesized from O, O'-dihydro (1,3-propileh) bi-salt (424 mg, 0.86 mmol) (see Figure 1) and eiclohexycarbonyl chloride (1009 mg, 6.88 mmol) according to the procedure described above. Refer to Fig. 2. The compound is crystallized from a mixture of 2-propanol, toluene and petroleum ether. Yield: 722 mg (0.68 mmol).

7b / t /;

50-53 ° C: HR-MS calcd. 5.7571: 5 m / e (relative intensity): 713 (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) </ 7:

712.4411156 (calculated).

NMR: δ 8.55 2H bs, 7.26 2H bs, '6.71 s (fumarate), 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.

Example 10.

0, 0'-glutaryl (diethyl) bispilocarpate (R * = ethyl; B = methylene) / 004000100 / -70 / 0 / 7- ^ 4 .- /: / 00 //// 4. / 0 // 0/0 /; 0 / '// 4/0/4;

To a solution of 9.80 mmol (2432 mg) of pilocarpic acid sodium salt and 60 ml of dimethylsulfoxide is added dropwise over a period of about one hour 9.80 mmol (1068 mg) of ethyl bromide. . The solution is stirred at room temperature for 48-72 hours and poured into 100 ml of distilled -water. The mixture was extracted with ethyl acetate (2 x 150 mL). Combined ethyl acetate extracts washed * 150 ml distilled water, 150 ml 2% sodium bicarbonate solution and 150 ml distilled water.

The ethyl acetate extracts were dried over calcium sulfate (30 min) and the ethyl acetate was evaporated under reduced pressure. The resulting 'pilocarpic acid ethyl ester: -.// 4 / 4/4. /'4//.0// · /: / '; ./ 4, ///// - / y / · 47 // 4 //.,·0/404··: / .. · </ 4 / 4-4- '/ -4 ·. '<. · // i- .. 4 ·.'. - / ..- // 447 '4'7 · / 7' / ^: ·; >'. · · / - // -: 4 - //' recrystallized from a mixture of chloroform and petroleum ether to give 448 mg (1.76 mmol) of the ester.

Lt = 104-107 ° C '// 7' · / 0 // 0004 /// '' · 00 H ///// ·. ·· '' · '7000', /-./0/1 / . '· · 44- ^1. , / - / 0 - //''4' · / /.-7-. .4-40 7/4 -, ./. 0-- 0./.,/ '.00.7. ^: ,. · 4. · · V ......, - .. ···· - ·. ·· pK _a = 6.60

HR-MS spectrum: m / e (relative intensity) 254 [M ⁺ ] (17%), 236 (18%), 223 (11%), 209. (24%), 207 (11%), 163. (14%), 139 (46%), 121 (31%), 96 (53%), 95 '(100%)'.

HR-MS: molecular mass = 254.16201804 (measured)

254.1630428 (calculated).

BMR: • δ 7.49 IH bs, 6.74 IH bs, 4.13 2H m, 3.61 3H * s, 3.55 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, pilocarpic acid sodium, can be synthesized according to the procedure described in fig. 1.

Glutaryl chloride (157 mg, 0.93 mmol) was added dropwise over 24 hours to a mixture of -589 mg of pilocarpic acid ethyl ester and 1282 mg (9.27 mmol) of calcium carbonate in toluene (65 mL). The solution was stirred at room temperature for about 48 hours. To the reaction mixture was added 2% sodium bicarbonate solution (60 mL) and the mixture was stirred at room temperature for 3 hours. The layers were separated and the toluene phase was washed with water (2 x 100 mL) and dried over calcium sulfate (30 min) and the solvent was evaporated under reduced pressure 152 mg (0.25 mmol) of O, O'-glutaryl (diethyl) bispilocarpate.

HR-MS spectra: m / e (relative intensity): 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%), 95 (61%).

HR-MS: molecular mass = 604.3478240 (measured)

604.3472151 (calculated).

BMR: δ 7.53 2H bs, 6.74 2H bs, 4. 13th 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 m, 1.67 4H m, 1.26 6H t, 0. 90 6H t.

Example 11

0,0'-adipoyl (diethyl) bispilocarpate (R '= ethyl; B = ethylene)

The compound was synthesized from pilocarpic acid ethyl. of the ester (609 mg; 2.40 mmol) and adipoyl chloride (176 mg; 0.96 mmol) according to the procedure described in p'av. 10. Yield 259 mg (0.42 mmol).

.. 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 (15%), 209 (18%), 207 (20 %), 163 (21%), 123 (9%), 122 (12%), 121 (100%), 96 (51%).

HR-MS: Molecular Weight = 618.3625030 (Measured) »618.3628652 (Calculated).

BMR: Δ 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.

Claims (13)

DEFINITION OF INVENTION Derivatives of bispilocarpic acid esters of the general formula (I) in which 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 radical CHj A (Ia) wherein Y has the meanings defined above and A is simply a bond or a methylene group which may be substituted with hydroxy radical, Y-O- when Y has the meanings defined above or substituted with one or two methyl groups, or B) W has the values of R ', i.e. C ₁ -C ₄ alkyl or' C ₃ -C ₆ cycloalkyl, and Y represents (Ib), where B is a direct bond. methylene or ethylene, R ^r has the meanings defined above, except in the case '. ·, · ·>.' ·? when both the radicals R and R 'in the compound (I) are ethyl, A and B cannot be direct bonds, moreover A cannot be an OH substituted methylene group, as well as salts of said compounds with acids. 2.. Derivatives of bispilocarpic acid esters according to claim 1A, formula (I), characterized in that ® / ® 'Ή' / './;? i ./Vi/·®3®.® -i '·' ® · '.® / 3 -. ,, 8 ///:./. /// / - ·. ·. · ®y ^; ®®i.'®8 · / ®® / //Z:.· _: / '/ · i: / * -' / that R is C ₃ -C ₆ -cycloalkyl. , ',. '88 · · 6 ..... ·. . / -7 ® / .8®. / Γ®Ζ · 8: ® / ®®, Z® ®®®®8 ^: 8 Z / ./ ^; y®3 /// Z /; Z - // - /.-8. // ®®Z '' ·. · <&''®'Z/; . · · '8, ® /// 3 / ®3-' · i®? ® z ' 3. Derivatives of bispilocarpic acid esters according to claim 1A, formula (I), wherein R is straight or branched propyl or butyl. 4. Derivatives of bispilocarpic acid esters according to claim 1A, formula (I), wherein R is C ₃ -C 1 -, cycloalkyl or straight or branched propyl or butyl, - O is simply a bond unsubstituted with methylene hydroxy radical, -OY , or methylene substituted with either one or two methyl ...... 8 / · ·· / '/: ·> in particular, straight-chain or unsubstituted methylene is particularly suitable. 35 '5. Derivatives of bispilocarpic acid esters according to Claim 1A, Formula (I), characterized in that the R values are as defined in Claim 1A, especially C 1 -C ₄ alkyl or C ₃ -C ₆ cycloalkyl and A is unsubstituted. 'methylene or methylene substituted with one or two methyl groups. / 4 ^; 4 · / · 4 ·. '/ · / 5 6. Bispilocarpic acid ester derivatives according to claim 1B, wherein R 'is C ₃ -C ₆ -cycloalkyl. '' 7. Derivatives of bispilocarpic acid esters according to claim 1B 10, wherein R 'is straight or branched propyl or butyl. * 8. Derivatives of bispilocarpic acid esters according to claim 1B, formula (I), Wherein R 'is C ₃ -C ₆ -cycloalkyl or straight or branched propyl or butyl, and B is a direct bond, unsubstituted methylene or ethylene, especially a bond or unsubstituted methylene. 20th Derivatives of bispilocarpic acid esters according to claim 1B, formula (I), characterized in that the R 'values are as defined in claim 1B and B is unsubstituted methylene or ethylene. 10. Derivatives of bispilocarpic acid esters according to claim IA: 0.0 ¹ -diciklopropilkarbonil (1,2-ethylene) bispilocarpate 30th · · 0,0'-Dicyclobutylcarbonyl (1,2-ethylene) bispilocarpate 0,0 '-dicyclopropylcarbonyl (Γ, 3-propylene) eispilo ~ .35 Carpathian ·' ³⁴ 0,0'-Dicyclobutylcarbonyl (1,3-propylene) bispilocarpate 0,0'-Dicyclopropylcarbonyl (2-methyl-1,3-propylene) 5 .. bispilocarpate 0,0 * -Dicyclopropylcarbonyl (2 *, 2-methyl-1,3-propylene) bispilocarpate 10 '0,0'-dipropionyl <1,3-propylene) bispilocarpate 0,0'-Dicyclopropylcarbonyl (2-hydroxy-1,3-propylene) bispilocarpate 0,0'-Dicyclopropylcarbonyl (2-eicopropylcarbonyl xyl-1,3-propylene) bispilocarpate 0,0'-dipivalil (1,2-ethylene) bispilocarpate 0,0 '-dipivalil (1,3-propylene) bispilocarpate 0,0 '-di (1-methylcyclopropylcarbonyl (1-, 2-ethylene) bispilocarpate 0.0'-Dicyclopentylcarbonyl (1 2-ethylene) bispilocarpate 0,0 '-diisobutyryl (1,2-ethylene) bispilocarpate 30Q, 0'-dicyclohexylcarbonyl (1,2-ethylene) bispilocarpate, 0,0'-Dicyclopentylcarbonyl (1,3-propylene) -bisoilocarpate 0,0 '-dicyclohexylcarbonyl (1,3-propylene) bispilocarpate' '/' '' - to ./ 35 O, O'-dibenzoyl (1,2-ethylene) bispilocarpate / / 0,0'-dibenzoyl (1,2-propylene) bispilocarpate. 5 11. Bispilocarpic acid ester derivatives according to claim IB: 0,0'-Succinyl (diisopropyl) bispilocarpate 0,0'-succinyl (di-t-butyl) bispilocarpate <0,0'-succinyl (dicyclopropyl) bispiloc acid 0,0'-Succinyl (dicyclobutyl) bispilocarpate 0,0'-glutaryl (diisopropyl) bispilocarpate 0,0'-glutaryl (di-t-butyl) bispilocarpate 0,0'-Glutaryl (dicyclopropyl) bispilocarpate Ο, Ο'-glutaryl (dicyclobutyl) bispilocarpate. Process for the preparation of bispilocarpic acid ester derivatives according to any one of the preceding claims, characterized in that. for the preparation of a compound according to claim IA of formula CHgCH ₂ (IA) wherein A and Y are as defined in claim 1A above, a compound of formula Ctt ₃ CK _? ch ₃ ck ₂ where A has the same meanings as' and in claim 1, is reacted with an acid of formula RCO ₂ H or a functional derivative thereof where R has the same meanings as in claim 1A, or (b) for the preparation of a compound, the content of the formula> • the compound _z ck ₃ (ΓΒ) given in 1B, when B and R 'have the values (III), where R' has the same meanings as in 1B, 15 acts on a dicarboxylic acid of formula O O II II. HO-C-CH ₂ ~ B-CH ₂ -C-OH or a bifunctional derivative of the B have the same meanings as above and 1B, -gauna and a compound which can be salified with an acid. Pharmaceutical composition, characterized in that the active ingredient is a compound according to any one of claims 1 to 11 together with a pharmaceutically acceptable carrier.