NO863944L - L-DOPA DERIVATIVES, THE PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL MIXTURE CONTAINING THESE DERIVATIVES. - Google Patents

Description

The invention relates to hitherto unknown derivatives of L-dopa or L-3,4-dihydroxyphenylalanine with improved properties

in relation to the properties of L-dopa itself, as well as methods for its production and pharmaceutical preparations containing such compounds, and it also covers their use, particularly in human medicine. L-dopa is commonly used in the treatment of the most disabling symptoms of Parkinson's disease (tremors, stiffness, bradykinesia). Although the treatment may be effective for several years,

this treatment nevertheless suffers from significant disadvantages due to the extremely short biological half-life of L-dopa and its rapid degradation to dopamine, which leads to significant and rapid fluctuations in blood concentration and occurrence of side effects due to circulating dopamine, and these phenomena are responsible for serious and unwanted effects such as dyskinesia, gastrointestinal and cardio-vascular disturbances. The condition of this case is due to a very high degree to a very strong first-pass effect at the level of the liver, but especially at the gastrointestinal level.

The purpose of the present invention is essentially

to obtain new compounds and pharmaceutical compounds containing these compounds which make it possible to avoid the above-mentioned disadvantages.

The strategy chosen to overcome these problems consisted in synthesizing an L-dopa derivative by coupling L-dopa to a glycerol derivative forming an ester bond with a hydroxyl group in the glycerol, while at least one of the remaining hydroxyl positions was esterified with an acyl chain and the other remaining hydroxyl position was similarly esterified; either with an acyl chain which is identical to or different from the first chain/ or with an esterification agent which has a different character but is pharmacologically acceptable.

Incorporation of L-dopa into a glyceride structure enhances the therapeutic value of L-dopa in several ways:

- by reducing the intestinal and hepatic first-pass effect and thus the side effects associated with the formation of certain metabolic products (especially dopamine), - by ensuring blood concentrations that are more evenly distributed over a period of time, thereby eliminating excessive fluctuations in blood concentrations observed with L-dopa, - by short-circuiting the active transport system that ensures intestinal resorption of L-dopa, which is at least partially responsible for the therapeutic reaction.

Preferred compounds according to the invention can be expressed

by the general formula

where R i is a glycerol residue and R 2 and R 3 which may be identical or different, each denotes an acyl group with 4-22 carbon atoms or the residue of a pharmacologically acceptable acid, at least one of these two symbols denotes an acyl group with 4-22 carbon atoms.

Compounds of the general formula II are preferred:

2 3

and to a very particular extent those compounds where R and R each denote an acyl group with 4-22 carbon atoms.

The compounds where R 2 and R 3 denote identical groups are particularly preferred.

Provided that one of the symbols R 2 and R 3 denotes an acyl group with 4-22 carbon atoms, the other symbol may however denote another group and may e.g. in particular be a phosphoric acid residue.

The invention also includes compounds analogous to

those stated above, where the acyl group in L-dopa is bound to position 1 or 3 in glycerol instead of to position 2.

The above-mentioned compounds can be used as active principle in the treatment of Parkinson's disease, or they can serve as intermediates for the characterization, purification or synthesis of such active products, in particular by transesterification.

As an example of a compound within the scope of the invention,

which has been subjected to special investigations, the compound with formula III must be mentioned:

Derivatives of L-dopa, in particular dipeptides or tripeptides, are already known, which, however, do not have the same advantages as the compounds according to the present invention, namely enabling resorption via the lymphatic system while avoiding significant destruction of the compound in the intestinal tract or the liver . The supply of large amounts of L-dopa to patients, which is currently necessary to ensure the availability of dopamine in sufficient quantity to the brain after passage through the blood/brain barrier, is thereby avoided. As a result, there is also a reduction in harmful side effects due to peripheral dopamine, which is particularly responsible for nausea and the like.

Compounds according to the invention are preferably administered orally

in the form of pharmaceutical preparations prepared in the usual way by well-known galenic techniques by adding the usual adjuvants, excipients and carriers. The preparations can be in the form of emulsions, suspensions, gelatin capsules or especially juice.

It is worth noting that, as the substitutions on the glycerol radical in the above-mentioned molecules lead to a carbon atom becoming asymmetric, the invention encompasses the racemic mixture and the various diastereoisomeric forms that derive from the coupling of the asymmetric carbon atom in L-dopa- part to the asymmetric carbon atom in the glyceride part.

It is noted that the compounds according to the invention make it possible to achieve the same pharmacological effects as those achieved with L-dopa and with improving pharmacokinetic properties, in particular an effect with regard to slow release, as will be shown in the following examples.

The dose and dosage range for the pharmaceutical preparations according to the invention depend on the selected compounds. Professionals in the field can easily adapt the doses and dosage ranges, taking into account in particular the extent to which the patient suffers from the identified "attacks" and the patient's general condition. Doses and dosage ranges are selected theoretically so that they are sufficient to produce values for cerebral availability of dopamine from the compounds according to the invention, which correspond to the values currently recommended for the use of L-dopa, taking into account that it is generally accepted that only one percent of the orally administered L-dopa is converted into active dopamine at the level of the central nervous system. It is worth noting that the significant reduction of side effects resulting from improved utilization of the active principle, which is made possible with the compounds according to the invention, allows increased doses of these compounds to be given if desired.

It is also within the scope of the invention to combine the compounds according to the invention with inhibitors of peripheral dopadecarboxylase such as benserazide or carbidopa, which as is known makes it possible to increase the availability of dopamine in the brain.

Combination of the compounds according to the invention with other active compounds is also within the scope of the invention.

Summary of the state of the art

It should be noted that different molecules are described in the literature which have a certain structural similarity to the compounds according to the invention. The following documents should be particularly mentioned: US-A-4 360 533 (A. A. Patchett), US-A-4 134 991 (J. J. Baldwin et al.) which corresponds to FR-A-2 365 341 (Synthelabo), US-A- 4,254,273 (B.F. Powell et al.) which corresponds to FR-A-2,313,922 (Merck) and EP-A-0,030,734 (Merck).

Among these documents, only US-A-4 134 991 (J. J. Baldwin et al.) mentions use for the treatment of Parkinson's disease.

It has not been possible from any of these documents to predict that the mentioned products would effect an improvement in the therapeutic value for the treatment of Parkinson's disease, such as the products according to the invention.

Synthesis processes

Different synthesis routes are possible for the preparation of the compounds according to the invention. Certain synthesis routes are elucidated in more detail in the following examples which relate to a particular compound according to the invention, that of formula III, and the syntheses are shown schematically in figure 1 of the drawing.

Example 1 (method A in Fig. 1)

( L)- N, 0, 0'- tricarbobenzoxidopa- 1, 3- dipaimitine ester ( 3)

To a solution of 28.4 g (50 mmol) 1,2,3-trihydroxypropane dipalmitate (1 , 3-dipalmitin) (2) and 30.1 g (50 mmol) (L)-N,0,0' -tricarbobenzoxidopa (1) in 250 ml of dichloromethane, magnetically stirred and cooled to 0°C in an ice bath, 10.3 g (50 mmol) of dicyclohexylcarbodiimide and 100 mg of 4-pyrrolidinopyridine are added there in a single portion. After 1 hour, the ice bath is removed. The reaction mixture is then stirred for 25 hours at room temperature. The precipitate of dicyclohexylurea is filtered off and the filtrate is washed with 100 ml of water, 100 ml of 5% w/v sodium bicarbonate and then 100 ml of 0.05 M hydrochloric acid. The organic solution is dried over magnesium sulphate, filtered and evaporated to dryness. The residue is chromatographed on silica gel and the desired compound (3) is eluted using a mixture of n-hexane/diethyl ether 70:30 (calculated by volume). After evaporation to dryness of the fractions containing compound 3, the residue is recrystallized from methanol. Dividend 38%. The product is characterized by its melting point of 75 o C and its optical rotation [ct]D 25 pao

-3.14 (c = 3 in methanol).

L- dopa- 1, 3- dipalmitine esters

A solution of 10.0 g of compound 3 in 150 ml of tetrahydrofuran is hydrogenolysed in the presence of 1.0 g of palladium on charcoal under an initial pressure of 250 kPa for 18 hours. The suspension is then filtered, and the filtrate is evaporated to dryness. The residue is purified by chromatography under the same conditions as for compound 3. Recrystallization in ethanol gives a product with m.p. 78°C and an optical rotation [a]^of -6.23° (c = 3.2

in DMF).

Calculated for C^H-^NOg: C 70, 64 H 10.37 0 17.1 1 N 1.87

Found: C 70.61 H 10.25 0 16.94 N 2.20% Mass spectrum, (m/e): 747 (M<+>), 477, 256, 239.

Example 2 (method B in Fig. 1)

The same compound (III) can be synthesized via route B on

fig. 1. However, the yields, which require further optimization, are lower.

Example 3 (method C in Fig. 1)

It is also possible to recover the compound of formula III by method C. The same comments as in example 2 apply here.

Example 4

Pharmacological and pharmacokinetic assessment

The derivative obtained according to example 1 was evaluated with consideration

to its activity against Parkinson's disease using two classic tests: the oxotremorine test and the reserpine test, followed by the general protocol described by Horst et al. (see Europ. J. Pharmacol. 21, 337-342, 1973).

In the reserpine test, the effectiveness is measured in the inhibition of ptosis and catatonia, and in the oxotremorine test in the inhibition of tremors and hypothermia, the calculation of the ED^Q values being carried out according to Litchfield and Wilcoxon's classic method (J. Pharmacol. Exptl. Therap., 96, 69 ... (1949)).

The working protocol that is followed for these two tests is described below.

A) The reserpine test

1. Reserpine is given i.p. in a dose of 5 mg/kg.

2. 4 hours later, the compounds to be tested, namely L-dopa and its glyceride derivative, are given p.o. in different doses,

this happens with five mice per dose.

3. The changes in the effects induced by reserpine, namely catatonia and ptosis, are followed at different time points: 15, 30, 60, 90, 120 min.

B) The oxotremorine test

1. The compounds to be tested, namely L-dopa and its glyceride derivative, are given p.o. at different doses, and this

done with five mice per dose.

2. Oxotremorine (0.5 mg/kg i.p.) is given to the pretreated mice after different periods of time: 15, 45, 90, 120 min.

3. The animals' reaction to the effects of oxotremorine, namely hypothermia and tremors, are measured respectively 15 and 30 min after they have been given the cholinergic agent.

For these two tests, male mice of the strain NMRI were used with a weight of between 22 and 25 g. L-dopa and its glyceride derivative are given by probe in the form of suspensions in a 5% solution of gum arabic.

The observed effects are shown graphically in fig. 2-5.

It can be seen from these two samples that the glyceride derivative III has an effect against Parkinson's disease, which is essentially of the same order of magnitude as L-dopa, but its effect lasts for periods of approx. twice as long as those observed for L-dopa.

From a pharmacokinetic standpoint, fig. 6 and 7 dramatically the lymphotropic effect produced by grafting 1,3-dipalmitin onto L-dopa. Indeed, it turns out that after oral administration of a dose corresponding to 0.5 mmol/kg of either L-dopa or the glyceride derivative of L-dopa (III) one achieves lymphatic levels which, in the case of compound III, are more than 40 times higher than that which is achieved with L-dopa, and in addition, the latter predominantly manifests itself in the form of the metabolite dopamine.

Claims (10)

1. Derivative of L-dopa, characterized in that L-dopa is linked to a glycerol derivative by forming an ester bond with a hydroxyl group in the glycerol, with at least one of the remaining hydroxyl groups being esterified with an acyl chain and the other of the remaining hydroxyl groups are also esterified either with an acyl chain which is identical to or different from the first-mentioned chain, or with an esterification agent which is of a different character, but pharmacologically acceptable. 2. L-dopa derivative as stated in claim 1, characterized in that it has the formula 1 2 3 where R denotes a glycerol radical and R and R , which may be the same or different, each denotes an acyl group with 10-20 carbon atoms or the remainder of a pharmacologically acceptable acid, at least one of these two groups being an acyl group with 4- 22 carbon atoms. 3. L-dopa derivative as stated in claim 1, characterized in that it has the formula where R 2 and R 3 each denote an acyl group with 4-22 carbon atoms. 4. L-dopa derivative as stated in claim 3, characterized in that it has the formula 5. L-dopa derivative as stated in claim 2, character- 2 3 in that one of the symbols R and R denotes an acyl group with 4-22 carbon atoms and the other the residue of an acid which is of a different nature but pharmacologically acceptable. 6. L-dopa derivative as stated in claim 1, characterized in that the acyl group in L-dopa is bound to position 1 of the glycerol molecule. 7. Process for the production of L-dopa derivative as stated in any one of claims 1-6, characterized in that a glycerol derivative is connected to an L-dopa derivative by forming an ester bond with a hydroxyl group in the glycerol, with at least one of the remaining hydroxyl groups is esterified with an acyl chain and the other of the remaining hydroxyl groups is also esterified, either with an acyl chain that is identical to or different from the first-mentioned chain or with an esterification agent that has a different nature but is pharmacologically acceptable . 8. Use of the derivatives specified in any of claims 1-6, or a derivative obtained by the method according to claim 7, as an active principle in the treatment of Parkinson's disease or as intermediates for the characterization, purification or synthesis of such active products , especially in the case of transesterification. 9. Pharmaceutical preparation, particularly intended to be given orally, characterized in that it contains at least one derivative as specified in any of claims 1-6 or obtained according to claim 7, in admixture with conventional adjuvants , excipients and carriers in the form of an emulsion, suspension, gelatin capsule or juice. 10.' Pharmaceutical preparation as stated in claim 9, characterized in that it also contains an inhibitor of peripheral dopa decarboxylase such as benserazide or carbidopa.