POSITION-SPECIFIC ASYMMETRIC DEUTERIUM ENRICHED CATECHOLAMINE DERIVATIVES AND MEDICAMENTS COMPRISING SAID COMPOUNDS

Abstract

Herein described are deuterated catecholamine derivatives of the general Formula I

##STR00001##

wherein, R.sub.1 is deuterium, R.sub.2, and R.sub.3 are independently selected from hydrogen and deuterium and wherein at least one of R.sub.2 and R.sub.3 has a deuterium enrichment in the range from 0.02 mol % to 100 mol % deuterium, and wherein the deuterium enrichment of R.sub.2 and R.sub.3 is different from each other and that the difference between the deuterium enrichment of R.sub.2 and R.sub.3 is at least 5 percentage points, R.sub.4 is hydrogen, deuterium, C.sub.1 to C.sub.6-alkyl or C.sub.5 to C.sub.6-cycloalkyl, deuterated C.sub.1 to C.sub.6-alkyl or C.sub.5 to C.sub.6-cycloalkyl, or a group that is easily hydrolytically or enzymatically cleavable under physiological conditions, as well as their physiologically acceptable salts and their stereoisomers, enantiomers or diastereomers in optically pure form. The compounds can easily be prepared by mixing deuterated and non-deuterated compounds in a predefined ratio. The compounds show anti-Parkinson effect at lower doses and show lower side effects.

Claims

1. A pharmaceutical composition comprising L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)propionic acid, or a physiologically acceptable salt thereof, having a deuterium enrichment above the natural abundance of deuterium; and L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid, or a physiologically acceptable salt thereof, having a deuterium enrichment above the natural abundance of deuterium.

Description

EXAMPLE 1

[0116] The effects on motor performance and the development of dyskinesia following administration of deuterated L-DOPA derivatives with different deuterium enrichment at specific position of the side chain have been compared among each other and to L-DOPA in the 6-hydroxydopamine (6-OHDA) rodent model of Parkinson's disease. The tested compounds and the specific deuterium enrichment of these compounds are displayed in Table 1.

TABLE-US-00001 TABLE 1 Test Items Deuterium Enrichment Name α βr βs A L-2-amino-3-(3,4-dihydroxyphenyl) NA NA NA propionic acid (L-DOPA) B S/S-2-amino-2,3-dideutero-3-(3,4- >98% <1% >98% dihydroxyphenyl) propionic acid (α,β-D2-L-DOPA) C L-2-amino-2,3,3-trideutero-3-(3,4- >98% >98%  >98% dihydroxyphenyl) propionic acid (α,β,β-D3-L-DOPA) D L-2-amino-2,3,3*-trideutero-3-(3,4- >98% 90% >98% dihydroxyphenyl) propionic acid (α,β,β*-D3-L-DOPA) (3* or β*, respectively, indicates that the position is not completely deuterated) (β.sub.R and β.sub.S relate to the commonly used R/S nomenclature indicating the relative positions in optically active compounds)

[0117] Female Sprague-Dawley rats weighing approximately 225 g were housed on a 12-hour light/dark cycle and kept on standard laboratory diet and water ad libitum. The rats were lesioned by unilateral injection of the neurotoxin 6-OHDA. The lesion was validated by measuring the rotational activity after i.p. injection of 2.5 mg/kg D-amphetamine.

[0118] The anti-Parkinson effect (effect on motor performance) was evaluated by measurement of drug induced contralateral rotations. A dose effect was established to determine the equipotent (equi-effective) dose.

[0119] Dyskinesia was evaluated after repeated treatment by scoring the animals for abnormal involuntary movements. The rats were scored, by an observer blinded to the experimental design for limb, axial and orolingual involuntary movements.

[0120] The equipotent dose as percent of L-DOPA dose that caused the same effect on motor performance and dyskinesia observed following repeated administration of these doses is shown in Table 2.

TABLE-US-00002 TABLE 2 Results Equipotent Dose Motor Ettect Dyskinesia Test [% of L-DOPA [% of L-DOPA [% of dyskinesia caused Item dose] effect] by L-DOPA] A 100%  100% 100% B 30% 100% 100% C 60% 100%  50% D 35% 100%  50%

[0121] The effect of α,β-D2-L-DOPA [B] on motor performance is significantly greater compared to α,β,β-D3-L-DOPA [C] and L-DOPA [A] as reflected by a lower equipotent dose. However dyskinesia after α,β-D2-L-DOPA [B] is not reduced in comparison to L-DOPA at equipotent dose whereas α,β,β-D3-L-DOPA [C] caused significantly less dyskinesia than L-DOPA at equipotent dose.

[0122] Surprisingly, test item D with almost 100% deuterium enrichment in position α and βs and 90% in position β.sub.R provides both a motor effect equivalent to the di-deuterated α,β-D2-L-DOPA [B] and a reduction of dyskinesia as the triple-deuterated α,β,β-D3-L-DOPA [C].

[0123] Test compound D is thus the optimal treatment for late stage Parkinson patients suffering from motor fluctuations and LIDs and requiring high doses of L-DOPA.

[0124] The example of compound D shows that asymmetric position specific deuterium enrichment can tune the known effects of position specific deuterated L-DOPA. This provides a powerful tool to adjust the treatment according to the symptoms and side effects that change during disease progression.

[0125] According to the stage of Parkinson's disease in the respective person, one can use a compounds with a deuterium enrichment adjusted to the need of the patient under treatment. This offers new opportunities for a medication that is tailor-made or customized to the patient.

EXAMPLE 2

[0126] Preparation of Test Compound D from Table 1

[0127] L-2-Amino-2,3,3*-trideutero-3-(3,4-dihydroxyphenyl)propionic acid (α,β,β*-D3-L-DOPA)

[0128] Test item D has a deuterium enrichment of 90% in β.sub.R position.

[0129] D is obtained by mixing 10 mol % L-2-amino-2,3(S)-dideutero-3-(3,4-dihydroxyphenyl)propionic acid with 90 mol % L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)propionic acid (deuterium enrichment >98% in all three positions). Experimental data for C.sub.9H.sub.8.1.sup.2H.sub.2.9NO.sub.4

TABLE-US-00003 Calculated: H 6.95 C 54.05 N 7.00 O 32.00 Analyt.: H 7.00 C 54.02 N 7.00 O 31.98

[0130] The degree of deuteration has also been determined by NMR spectroscopy. For that purpose NMR spectra with a 500 MHz spectrometer have been recorded. As a solvent, d.sub.6-DMSO was used. The following Table 3 shows the respective position within the compound of test item D and the integral (AUC=area under curve) of the registered spectra, reflecting the content of hydrogen at the respective positions.

TABLE-US-00004 TABLE 3 NMR results Position Integral (AUC) Ring 3.02 α 0.02 β 0.01 β* 0.10

[0131] The preparation of the starting material L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)propionic acid is described in WO-A 2004/056724, the preparation of the starting material L-2-Amino-2,3(S)-dideutero-3-(3,4-dihydroxyphenyl)propionic acid is described in WO-A 2007/093450.

[0132] After mixing the compounds the mixture may be processed further in order to obtain a suitable pharmaceutical product for the medication of Parkinson's disease as given in the following examples.

EXAMPLE 3

[0133] Tablet with film coating containing α,β,β*-D3-L-DOPA

TABLE-US-00005 Composition of the core: α,β,β*-D3-L-DOPA (Test Item D) 40.00 mg Povidone 20.00 mg Sorbitol  7.00 mg Silicon dioxide, highly dispersed    2 mg Pregelatinated starch 40.00 mg Croscarmellose-sodium 13.30 mg Carmellose-sodium 20.05 mg Microcrystalline cellulose 41.00 mg Magnesium stearate  2.00 mg Film coating: Hydroxypropylmethylcellulose 16.00 mg Macrogol 400 ™  2.50 mg Titanium oxide  3.00 mg Talc  3.00 mg

[0134] Preparation:

[0135] α,β,β*-D3-L-DOPA (Test Item D) and highly dispersed silicon dioxide are granulated in a compulsory mixer with a solution of povidone and sorbitol. The granules are dried, screened, mixed with pregelatinated starch, croscarmellose sodium, carmellose sodium and microcrystalline cellulose, then combined with magnesium stearate and compressed into tablets. The tablets are film coated with hydroxypropylmethylcellulose, Macrogol, titanium dioxide and talc.

EXAMPLE 4

[0136] Tablet with film coating containing α,β,β*-D3-L-DOPA and Carbidopa

TABLE-US-00006 Composition of the core: α,β,β*-D3-L-DOPA (Test Item D) 35.00 mg Carbidopa 25.00 mg Povidone 20.00 mg Sorbitol  7.00 mg Silicon dioxide, highly dispersed    2 mg Pregelatinated starch 40.00 mg Croscarmellose-sodium 13.30 mg Carmellose-sodium 20.05 mg Microcrystalline cellulose 41.00 mg Magnesium stearate  2.00 mg Film coating: Hydroxypropylmethylcellulose 16.00 mg Macrogol 400 ™  2.50 mg Titanium oxide  3.00 mg Talc  3.00 mg

[0137] Preparation:

[0138] α,β,β*-D3-L-DOPA (Test Item D), carbidopa and highly dispersed silicon dioxide are granulated in a compulsory mixer with a solution of povidone and sorbitol. The granules are dried, screened, mixed with pregelatinated starch, croscarmellose sodium, carmellose sodium and microcrystalline cellulose, then combined with magnesium stearate and compressed into tablets. The tablets are film coated with hydroxypropylmethylcellulose, Macrogol, titanium dioxide and talc.

EXAMPLE 5

[0139] Tablet with film coating containing microencapsulated α,β,β*-D3-L-DOPA and Carbidopa

TABLE-US-00007 Composition of the core: α,β,β*-D3-L-DOPA (Test Item D) 40.00 mg Carbidopa 25.00 mg Tartaric acid  5.00 mg Povidone 20.00 mg Sorbitol  7.00 mg Eudragit RL ™ solid 20.00 mg Silicon dioxide, highly dispersed    2 mg Pregelatinated starch 40.00 mg Croscarmellose-sodium 13.30 mg Carmellose-sodium 20.05 mg Microcrystalline cellulose 41.00 mg Magnesium stearate  2.00 mg Film coating: Hydroxypropylmethylcellulose 16.00 mg Macrogol 400 ™  2.50 mg Titanium oxide  3.00 mg Talc  3.00 mg

[0140] Preparation:

[0141] α,β,β*-D3-L-DOPA (Test Item D), Carbidopa, sorbitol and Eudragit are microencapsulated and homogenised in a barrel mixer with tartaric acid, highly dispersed silicon dioxide, povidone, pregelatinated starch, croscarmellose sodium, carmellose sodium and microcrystalline cellulose, then combined with magnesium stearate and compressed into tablets. The tablets are film coated with hydroxypropylmethylcellulose, Macrogol, titanium dioxide and talc.

EXAMPLE 6

[0142] Tablet with film coating containing microencapsulated α,β,β*-D3-L-DOPA and benserazide

TABLE-US-00008 Composition of the core: α,β,β*-D3-L-DOPA (Test Item D) 40.00 mg Benserazide 25.00 mg Tartaric acid  5.00 mg Povidone 20.00 mg Sorbitol  7.00 mg Eudragit RLTM solid 20.00 mg Silicon dioxide, highly dispersed    2 mg Pregelatinated starch 40.00 mg Croscarmellose-sodium 13.30 mg Carmellose-sodium 20.05 mg Microcrystalline cellulose 41.00 mg Magnesium stearate  2.00 mg Film coating: Hydroxypropylmethylcellulose 16.00 mg Macrogol 400TM  2.50 mg Titanium oxide  3.00 mg Talc  3.00 mg

[0143] The preparation of the film coated tablets is as given in Example 5.

EXAMPLE 7

[0144] Tablet with film coating containing α,β,β*-D3-L-DOPA and benserazide

TABLE-US-00009 Composition of the core: α,β,β*-D3-L-DOPA (Test Item D) 35.00 mg Benserazide 25.00 mg Povidone 20.00 mg Sorbitol  7.00 mg Silicon dioxide, highly dispersed    2 mg Pregelatinated starch 40.00 mg Croscarmellose-sodium 13.30 mg Carmellose-sodium 20.05 mg Microcrystalline cellulose 41.00 mg Magnesium stearate  2.00 mg Film coating: Hydroxypropylmethylcellulose 16.00 mg Macrogol 400 ™  2.50 mg Titanium oxide  3.00 mg Talc  3.00 mg

[0145] Preparation:

[0146] α,β,β*-D3-L-DOPA (Test Item D), carbidopa, and highly dispersed silicon dioxide are granulated in a compulsory mixer with a solution of povidone and sorbitol. The granules are dried, screened, mixed with pregelatinated starch, croscarmellose sodium, carmellose sodium and microcrystalline cellulose, then combined with magnesium stearate and compressed into tablets. The tablets are film coated with hydroxypropylmethylcellulose, Macrogol, titanium dioxide and talc.

EXAMPLE 8

[0147] Tablet with film coating containing α,β,β*-D3-L-DOPA and carbidopa and entacapone

TABLE-US-00010 Composition of the core: α,β,β*-D3-L-DOPA (Test Item D) 40.00 mg Carbidopa 25.00 mg Entacapone 200.00 mg  Povidon K30 20.00 mg Crospovidone Type B 15.00 mg Mannitol  9.00 mg Silicon dioxide, highly dispersed    2 mg Pregelatinated starch 40.00 mg Croscarmellose-sodium 13.30 mg Carmellose-sodium 20.05 mg Microcrystalline cellulose 41.00 mg Magnesium stearate  2.00 mg Film coating: Hydroxypropylmethylcellulose 16.00 mg Macrogol 400 ™  2.50 mg Titanium oxide  3.00 mg Talc  3.00 mg

[0148] The preparation of the film coated tablet is performed as described in Example 3.