FR2461725A1 - Mono and bis di:isopropylamine serine-phosphate(s) - are peripheral vasodilators and antiparkinson agents - Google Patents

Abstract

Mono- and bis-diisopropylamine phosphoserinates (I) (where n is 1 or 2) are new. Used as peripheral vasodilators, and are active against Parkinson's disease. Stoichiometric amts. of diisopropylamine (II) and phosphoserine (III) (1:1 or 2:1) are dissolved in a hydroxylated solvent such as ethanol, and then poured into at least 4 volumes of ether. The pptd. salt is recovered.

Description

The present invention relates to diisopyropylamine phosphoserates useful in therapy.
Diisopropylamine, NH (CH (CH 3) 2) 2 is already used in therapy in the form of salts; thus its dichloroacetate is used as a peripheral vasodilator. Various other salts are mentioned in the literature such as acetyl salicylate (French Patent No. 4573) and clofibrate (French Pat. No. 7854). Most of the time the activity claimed is that of the acid used to salify diisopropylamine. This amine also enters into the composition of vitamin B 15.

 We have now discovered that the phosphoseratinates of mono or diisopropylamine exhibit pharmacological activities of great interest allowing them to be used therapeutically not only in the generally recognized indications for diisopropylamine ie peripheral cardiovascular disorders, but also in the treatment of Parkinson's disease and extrapyramidal disorders induced by neuroleptics.

Parkinson's disease is the most common degenerative disorder of the nervous system. His medical treatment currently uses synthetic antiparkinsonian derivatives derived from atropine, amantadiyl and L-dopa. Synthetic antiparkinsonians have the disadvantage that they only act im- perfectly on akinesia and tremor. L-dopa performs substitutive therapy by acting as a precursor to dopamines.
Its action is however limited by side effects and a risk of exhaustion of its activity; its disadvantages could not be partially reduced by the addition of inhibitors of peripheral dopa-decarboxylase. Amantadine has brought about a very rapid improvement in the condition of the patients, but its action is often temporary.

 It is surprising that the new products according to the invention, despite their chemical structure totally different from that of the drugs mentioned, have sonic antiparkin activities.

 Diisopropylamine phosphoserates are generally prepared by dissolving the stoichiometric amounts of phosphoserine and diisopropylamine in a hydroxylated solvent such as ethanol. The solution obtained is poured with vigorous stirring in at least 4 times its volume of dry ether. The precipitate is collected and purified by known methods. These salts can also be prepared by lyophilization of an aqueous solution containing stoichiometric amounts of the acid and base.

2O,3 -g de phosphosérine. H20, 10,1 g de diisopropylamine sont dis
9 sous dans 100 cm3 d'éthanol absolu. Cette solution est versée sous forte agitation dans 1 l d'éther sec. Le précipité est recueilli par filtration et séché sous vide sur P2 05.EXAMPLE 1
Synthesis of diisopropylamine phosphoserinate

20% of phosphoserine. H 2 O, 10.1 g of diisopropylamine are
9% in 100 cm3 of absolute ethanol. This solution is poured with vigorous stirring into 1 l of dry ether. The precipitate is collected by filtration and dried under vacuum over P2 05.

Characteristics
Hygroscopic white solid, bottom with decomposition above 1300C, soluble in water, ethanol, methanol, insoluble in ether, chloroform, carbon tetrachloride.

 NMR in D20, tetradeutero-2,2,3,3-trimethylsilyl-3-sodium propionate internal standard.

20,3 g de phosphosérine. H20, 20,2 g de diisopropylamine sont dissous dans 100 cm3 d'méthanol absolu. Cette solution est versée sous forte agitation dans 1 l d'éther sec Le précipité est re cueilli par filtration et séché sous vide sur P205. 1 doublet 1,32 ppm 12 protons 4 CH3 isopropyl
3 1 septuplet 3.5 ppm 2 protons 2 CH isopropyl 1 massive complex 4.15 ppm 3 protons -CH -CH 2i
EXAMPLE 2
Synthesis of bis diisopropylamine phosphoserinate

20.3 g of phosphoserine. H2O, 20.2 g of diisopropylamine are dissolved in 100 cm3 of absolute methanol. This solution is poured with vigorous stirring into 1 l of dry ether. The precipitate is collected by filtration and dried under vacuum over P2O5.

Characteristics :
Hygroscopic white solid, bottom with decomposition above 150 C, soluble in water, ethanol, methanol, insoluble in ether, chloroform, carbon tetrachloride.

 RtZ in D20, internal standard tetradeutero-2,2,3,3-trimethylsilyl-3 sodium propionate.

1 doublet 1.32 ppm 24 protons 8 CH3 isopropyl 1 septuplet 3.5 ppm 4 protons 4 CH isopropyl 1 massive complex 4.15 ppm 3 protons -CH2-CH
The products which are the subject of the present invention have undergone various pharmacological tests, the results of which are given below. The diisopropylamine hydrochloride to which the two products described in the above examples are compared is designated by the acronym DIPA.

 The three derivatives are administered orally. Acute toxicity is determined in EOPS mice after administration in 6 g gum arabic julep. The LD 50 calculated by the method of Litchfield and Wilcoxon on the eighth day of observation are 4000 (2900-5525) mg / kg for the product of Example 1, 2100 (1480-2975) mg / kg for the product of Example 2 and 1250 (967-1613) mg / kg for DIPA.

 During the escape test in mice, the 3 derivatives induce sedation. The calculated ED 50 values are 160 (130-195) mg / kg for the product of Example 1, 135 (95-190) mg / kg for the product of Example 2 and 118 (84-165) mg / kg. kg for the DIPA.

The three products reduce the aggressive behavior thus caused in the mouse in the electric battle test. The diisopropylamine phosphoserinate has an ED 50 of 25 mg / kg, the bis diisopropylamine salt, an ED 50 of 26 mg / kg and DIPA an ED 50 of 14 (10-19) mg / kg.

The antiparkinsonian properties of the products forming the subject of the present invention are characterized in the following tests.
antagonism of tremor induced by ip administration of 0.5 mg / kg oxotremorine in mice according to Everett GM & Colt. Science 1956, 124, 79 and Levy JC & BR <roll. Therapy 1965, 265. Table 1 gives the percentages of animals with no tremor (at t = 201) relative to the control group as a function of dose.

- inhibition of catalepsy induced by ip administration of 15 mg / kg of prochlorperazine in the rat according to
Chermat R. & colt. J. Pharmacol., 1975, 6.4, 493-6. Table 2 gives the percent change in sugar over 5 hours compared to controls.

 The phosphoseratinates of diisopropylamine do not contain strong catalepsy, do not antagonize stereotypies with apomorphine, do not potentiate the hypnotic effect of lthexobarbital, do not possess anxiolytic action in the 4-plate test, do not antagonize ptosis to reserpine and do not consider the mortality induced by strychnine.

Table 1

<tb><SEP> dose <SEP> mg / kg <SEP> 25 <SEP> 50 <SEP> 100 <SEP> 200 <SEP> 300
<tb> Product
<tb> DIPA <SEP> O <SEP> O <SEP> 47 <SEP> 36 <SEP> 25
<tb> Phosphoserinate <SEP> of <SEP> 40 <SEP> 80 <SEP> 37 <SEP> 30
<tb> diis <SEP> opropylamine
<tb> Phosphoserinate <SEP> of <SEP> 60 <SEP> 60 <SEP> 45
<tb> bis <SEP> (diisopropylamine)
<Tb>
Percentage of animals with no tremor in the oxotremorine test compared to the control group.

Table 2

<tb> dose <SEP> jazz <SEP> mg / kg <SEP> 30 <SEP> 75 <SEP> 100 <SEP> 50 <SEP> 300
<tb> Product
<tb> DIPA <SEP> - <SEP> 53 <SEP> - <SEP> 47 <SEP> - <SEP> 23 <SEP> - <SEP> 41 <SEP> - <SEP> 44
<tb><SEP> s <SEP> s <SEP> Ns <SEP> s: <SEP> s
<tb> Phosphoserinate <SEP> from <SEP> - <SEP> 21 <SEP> - <SEP> 33 <SEP> - <SEP> 42 <SEP> - <SEP> 48
<tb> diisopropylamine <SEP> NS <SEP> NS <SEP>S;<SEP> S
<tb> diisopropylamine <SEP> NS <SEP> NS <SEP> S <SEP> S
<tb> PhosphoserUlate <SEP> from
<tb> Phosphoserine <SEP> of
<tb> bis <SEP> (diisopropylamine) <SEP>
<SEP> NE <SEP> NS <SEP> S <SEP> S
<Tb>
Percentage change from prochlorperazine to catalepsy compared with controls.

 Given their pharmacological properties, diisopropylamine phoserinates can be used in therapeutics, for example, in the treatment of parkinsonian rigidity and tremor, as well as Parkinson's syndromes induced in particular by neuroleptics.

 Phosphoserinates of diisopropylamine may be administered by injection at daily doses of 10 to 200 mg / day in one or two injections or orally at doses of 30 to 500 mg / day in two or three doses.

 Examples of formulation suitable for the treatment are given below.

Injectable ampoules
Phosphoserinate diisopropylamine 20 mg
Aqueous solute qsp 1 ampoule of 2 ml Tablets
Diisopropylamine phosphoserinate 50 mg
Excipient qsp 1 tablet
capsules
Diisopropylamine phosphoserinate 40 mg
Excipient qs 1 capsule

Claims (4)

 1 - New products characterized as phosphoserinate salts of diisopropylamine and bis diisopropylamine.  2 - A process for preparing the products according to claim 1 characterized in that the stoichiometric amounts of phosphoserine and diisopropylamine are dissolved in a hydroxylated solvent, in that the solution is poured into at least 4 times its volume of ether. dry and in that the precipitated salt is collected and purified.  3 - Process for preparing the products according to claims 1 and 2 characterized in that it lyophilizes an aqueous solution containing stoichiometric amounts of the acid and the base.  4 - New drugs of the central nervous system containing as active principle at least products according to claims 1 and 2.