JPS63501498A - Novel derivative of L-dopa, its production method and pharmaceutical composition containing it - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Novel derivative of L-dopa, its production method and pharmaceutical composition containing it The present invention has improved properties with respect to L-dopa itself and monodopa A novel derivative of L-3,4-dihydroxyphenylalanine, its production method, and With regard to pharmaceutical formulations containing compounds such as, this particularly includes applications in human medicine.

Shi-Dopa can be used to cure most of the incapacitation symptoms of Parkinson's disease (shaking, rigidity, bradykinesia). commonly used to treat ost-disaNing symptoms) .

Nevertheless, although treatment may be effective for several years, the biological half of L-dopa It has an extremely short shelf life and is rapidly broken down to dopamine, making it a prominent presence in blood levels. , causing side effects due to rapid fluctuations (waves) and circulation of dopamine, This can lead to complications and harmful side effects such as gastrointestinal and cardiovascular problems. treatment has substantial drawbacks. This situation occurs at the liver level, but especially at the gastrointestinal level. very much depends on the rapid excretion effect which is very evident in the

An object directed to this invention is an essentially new compound, and a compound containing this compound. The object is to provide a pharmaceutical composition that makes it possible to avoid the above-mentioned disadvantages.

The strategy adopted to overcome these problems is to sterkly bond L-dopa and At least one of the remaining hydroxyl positions of glycerin is esterified with an acyl chain. , the other remaining hydroxyl positions are also the same as the first chain or a different acyl chain or the fact that Although it has a hole in the upper part, it is esterified with a pharmacologically acceptable esterifying agent. The process consisted of synthesizing a derivative of phosphorus.

Therapeutic enhancement of L-dopa by incorporation into the glycerin ester structure of L-dopa Values will be revised in various aspects as described below.

It reduces the rapid excretion effect of the intestine and fl. This reduces the side effects associated with the formation of

The blood concentration seen with L-dopa is Significantly large fluctuations (waves) at medium levels are removed.

Intestinal reabsorption of monodopa accounts for at least part of the variability in treatment response. short-circuiting the active ingredient transport system.

Preferred compounds of this invention can be represented by formula (I>).

However, the mark ★ indicates one body.

In the formula, R+ is a glycerin group, R2 and R3 may be the same or different, and 4 to 22 an acyl group or a pharmacologically acceptable acid group containing carbon atoms of At least one of them is an acyl group containing 4 to 22 carbon atoms.

Reference is made to compounds of formula <Ir).

However, the mark ★ indicates one body.

and especially those in which R2 and R8 are acyl groups containing 4 to 22 carbon atoms. affect

Most preferred are compounds in which R2 and R3 are the same group.

Either one of R2 and R3 represents an acyl group containing 4 to 22 carbon atoms. If so, the other males may be different, especially for example the phosphate group.

This invention also provides that the acyl group of monodopa is not at the 2-position of glycerin but at the 1- or 3-position. includes compounds similar to those listed above, which are attached to the

The above-mentioned compounds can be used as active ingredients in the treatment of Parkinson's disease and in particular Identification of such active ingredients by transesterification, II production or intermediates for synthesis can be useful as.

As an example of a compound that has been the subject of particular research into this invention, the formula (I[l ) can be mentioned.

However, the mark ★ indicates one body.

-dopa derivatives, especially dipeptides or tripeptides, are known; Advantages of compounds of the invention i.e. substantial distribution of compounds in the intestinal system or by the liver It does not have the advantage of allowing reabsorption via the lymphatic system while avoiding decomposition. L- to the patient Large doses of dopa, which are currently used to release dopamine into the brain after its passage through the blood-brain barrier. This is necessary to ensure that there are sufficient personnel for the project, but this can be avoided. Furthermore, this conclusion As a result, there is a positive effect caused by the presence of dopamine in peripheral nerves, which causes nausea, etc. There is a decrease in unwanted side effects.

The compounds of this invention can be prepared using well-known formulation techniques by adding conventional adjuvants, excipients and carriers. Preferably, it is administered orally in the form of a preparation obtained by conventional surgical methods. Especially It can be provided in the form of a emulsion, suspension, gelatin capsule or syrup.

In the above-mentioned molecule, the carbon atom becomes asymmetric due to the substitution on the glycerin group, so this The invention relates to the asymmetric carbon of the racemate and the L-dopa moiety and the asymmetric carbon of the glycerin ester moiety. to include other diastereoisomeric forms formed as a result of bonding with carbon; I would like to note that.

The compounds of the present invention have particularly strong pharmacological properties such as sustained release, as will be seen in the Examples below. With improved chemical properties, it is possible to obtain pharmacological effects similar to L-dopa. It is observed that the

The dosage and method of administration of the pharmaceutical compositions of this invention will depend on the compound selected. mature in this field Practitioners are particularly concerned with the extent to which the patient is at ease with the observed symptoms and the patient's level of complacency. It is easy to select the dosage and administration method depending on the general condition. Dosage and method of administration Theoretically, this would be sufficient to provide the brain effect of dopamine in the case of the compounds of the present invention. The amount should be selected to be similar to the current recommendation when using L-dopa. be. The recommended value is that monodopa is the active dose at the level of the central nervous system when taken orally. Since it is generally accepted that only 1% of the amount is converted to pamin, is being given. The availability of active substances made possible by means of the compounds of this invention is improved. If desired, these drugs may be used, as the side effects resulting from the The dosage of the compound can be increased.

This inventive compound is known to increase the availability of dopamine to the brain. Inhibition of peripheral dopa decarboxylase such as ceramide or carbidopa It is also within the scope of this invention to combine with agents.

Combinations of the compounds of this invention with other active compounds are also within the scope of the invention.

(Margin below, continued on next page) (Summary of technology status) Please note that various molecules with similar structures to this invention compound have been described in the literature. I want to write it down. In particular, the following documents can be found.

U.S. Patent No. 4,360,533 (A.A. patchett) ), No. 4,134,991 (J, J, Baldwin, etc.) (This is French Patent No. 2,365,341@(SYNTHELABO) U.S. Patent No. 4,254.273 @ (B, F, Bowe) (Powell, etc.) (This is Lt7 Lance Patent No. 2,313,922 (Mell. Lylerck) and Yo-O-7 Patent No. 0.030.734 (Med. (equivalent to fvlerck)) Of these documents, U.S. Pat. No. 4,134.9'lI (J. etc.) only mention its application in the treatment of Parkinson's disease.

The products in question have improved therapeutic value, like this inventive product in the treatment of Parkinson's disease. There is no literature that suggests that this is the case.

(synthesis method) There are various synthetic routes by which the compounds of this invention can be obtained.

These synthetic routes are schematically shown in Figure 1 for specific compounds of the invention of formula (I[[). The explanation will be given with reference to the examples shown in the figure.

Example 1 (Method A in Figure 1) K2Ns! 22 Hiuusu V Shitsue' Rijo Niga 1 Upper 2 Ha Fire Mutual Chinester (3) 1.2.3-Trihydroxypropane shibalmitate (1,3-shibalumi f> ) (2) 28,4a (SO+e mol) (L) -N, 0. O'- 2501 with MJ carbobenzooxidopa (1) 30.1g (5-axis mol) The dichloromethane solution of was kept under magnetic stirring and cooled to 0 °C in a water bath. However, dishik I] hexylcarbodiimide io,: +g (50 i mol) and 100 mg of 4-Bio'J dinohyridine were added once.

After 1 hour, the water bath was removed. The reaction mixture was stirred at ambient temperature for 25 hours.

The precipitate of zinc 0 hexyl urea was removed, and the filtrate was diluted with water (10 (lyf), 5% (w) /v) 11M sodium hydrogen (100if), then 0.05M hydrochloric acid ( 1001! ). The organic solution was dried over magnesium sulfate, filtered and evaporated to dryness. Hardened. The residue was subjected to silica gel chromatography to obtain the desired compound (3). was obtained by elution with a mixture of n-hexane/diethyl needles (70:30 by volume). . The fractions containing 3 were evaporated to dryness and the residue was recrystallized from ethanol.

The yield was -38%. The product was identified as follows.

Melting point = 75℃ Specific optical rotation (α)′″’ 3.14°C3, methanol) ρ (shi-dopa 1,3-cibalmitin ester) compound (3) 10. Oo　’( 7) Rahit O75 Fan (150xf) Presence of palladium catalyst on wood Hydrocracking was carried out for 18 hours at an initial pressure of 250 kpa. Filter the suspension The Sl solution was evaporated to dryness. The residue was treated under the same conditions as compound (3) to give zero adhesion. It was purified by adding The product of (C3,2, DMF) was obtained.

Elemental analysis (C44H77Not) kun vl(lt[actual measurement candy C70, 64% 70.01 )1, 10.37 10.25 0 17.11 16.94 N 1.87 2,20.

Mass spectrum (II 10): 747 (M number), 417.256. 239° Example 2 (Method B in Figure 1) The same compound (III) can be synthesized by route B in FIG.

Yields are low but require further optimization.

Example 3. (Method C in Figure 1) Compounds of formula (I[I) can also be obtained by method C.

The same notes as in Example 2 also apply to Case 2.

Example 4. (Pharmacological and pharmacodynamic evaluation) The derivative obtained in Example 1 was -Evaluated from the viewpoint of activity against Kinson's disease. There are two classical tests for evaluation. In other words, the oxotremorine test was carried out with Serpintes I- or Horst (t-I or st) etc. (Yobu G.A. Farmayol, 21,337-342.197 The procedure was carried out according to the general rules described in 3). Based on the reservin test, the efficiency is Suppression of ptosis and v4 tension as measured by 11iQ and oxotremorine test Suppression of face shake and hypothermia, Litchfield and cormorant Wilcoxon (Gie) 7-Macol Experiment The'ra p　,　,96.69-・-(1949)　)　) ED full's! ! Measured by tFi.

The operating criteria for these two tests are as follows.

A) Reservin test 1. Reservin is administered by intra-abdominal injection at ffi5mo/ka.

After 2.4 hours, the test compound ie L-dopa and its glycerol.

ester M conductor was administered orally at different doses, with 5 mice per dose. I went there.

3. Effects caused by reservin, namely ptosis and catatonic changes, 15.30. I watched it every 60, 90, and 120 minutes.

4 hours Is, 30, 60. '110, 120 minute reservine L-dopa and its lower form Disease and Sag / ka, i, p, glycerin ester catatonia derivative p, 0 ゜ B) Oxotremorine test 1. Test compounds, i.e., monodopa and its glycerin derivative, were administered orally at various doses. 5 mice per dose m.

2. Oxotremorine (0,510/kGIi, 9.) was administered to each pre-equipped mouse. The administration was performed after the seeding time of 15, 45, 90, and 120 minutes had elapsed.

3. The effects of xotremorine on animal reactions, namely hypothermia and tremor, respectively. Measurements were taken 15 and 30 minutes after administration of the drug.

Is, 45, 90, 120 minutes 15 minutes 15 minutes Glyceride O, Sn o / ka face-shaking derivative (D, O,) (i, p,) Male NMRI mice weighing 22-25Q were used for these two tests.

L-dopa and its glyceride derivatives were suspended in a 5% gum arabic solution and administered by gastric tube. It was administered using the prefectural food (gavag I).

The observed effects are recorded graphically in Figures 2-5 below.

These two tests show that glyceride derivatives are associated with Parkinson's disease. The activity is substantially the same as that of dopa, but However, it lasts about 2 hours longer than seen with L-dopa.

From a pharmacodynamic standpoint, Figures 6 and 7 show that The effects on the lymph that result from the combination of ions have been shown to be dramatic. Shido 0.5 m of either Pa or Shi-dopa glyceride derivative (Ill) After orally administering a dose m equivalent to l/kg, in the case of ■, the lymph level is L. - 40 i8 or more in case of dopa. Moreover, in the latter case, mainly its metabolites , in the form of dopamine.

(Margin below, continued on next page.) εD50 (mrnoL/Kg) FD5゜(rnmoL/ni9) ED5o (rnrnoL/ks) Mark so (rnmoLAH) Mi * & (ITIITIOL/lη and 9 turbidity (mypol/ml) international search report ANNEX To THE INTE Area ATIONAL 5ZARCHREPO RT ON

Claims (10)

[Claims] 1. L-dopa forms an ester bond with one hydroxyl group of glycerin. The remaining hydroxyl group position of glycerin is bonded to glycerin derivative. The other one is esterified with an acyl chain, and the remaining hydroxyl group is in the same position as the first chain. or esterified with another acyl chain or different in nature but pharmacologically acceptable. an L-dopa derivative characterized in that it is esterified with an esterifying agent having a body. 2. Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, the ★ mark indicates the L form, and R1 is the group. In the lyserine group, R2 and R3 may be the same or different, an acyl group containing 10 to 20 carbon atoms or a pharmacologically acceptable acid group; At least one of these two groups is an acyl group containing 4 to 22 carbon atoms . ] The L-dopa derivative according to claim 1, characterized in that it corresponds to the following. 3. Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, the ★ mark indicates the L form, and R2 and R 3 means an acyl group containing 4 to 22 carbon atoms. ] The L-dopa derivative according to claim 1, which corresponds to. 4. Formula (III) 3▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [★ indicates the L form. ] The L-dopa derivative according to claim 1, which corresponds to. 5. One of the groups R2 and R3 is an acyl group containing 4 to 22 carbon atoms and the other is an acyl group containing from 4 to 22 carbon atoms. Claims characterized in that the groups are different in nature but are pharmacologically acceptable acid groups. L-dopa derivative according to item 2. 6. Characterized by the fact that the acyl group of L-dopa is bonded to the 1st position of glycerin. L-dopa derivative according to claim 1. 7. A glycerin derivative is converted into an L-dopa derivative with one hydroxyl group of glycerin and an ester. the remaining hydroxyl groups of glycerin. At least one position is esterified with an acyl chain, and the remaining hydroxyl positions are an acyl chain that is the same or different from chain 1, or that is different in nature but pharmacologically acceptable. Claims 1 to 6 characterized in that the product is esterified with an esterifying agent that is A method for producing an L-dopa derivative according to any one of Items 1. 8. According to any one of claims 1 to 6 or by the method of claim 7 The derivatives obtained can be used as active ingredients in the treatment of Parkinson's disease or in this way. as an intermediate for the characterization, purification or synthesis of active products, especially by transesterification. The use provided by 9. According to at least one of claims 1 to 6 or claim 1 Certain derivatives obtained by , in the form of an emulsion, suspension, gelatin capsule or syrup A pharmaceutical preparation especially intended for oral administration, characterized in that: 10. Peripheral nerve dopa decarboxylate such as benserazide or carbidopa Pharmaceutical formulation according to claim 9, which also contains an inhibitor of sylase.