CH673653A5 - - Google Patents

Description

DESCRIPTION The invention relates to pharmaceutical compositions which contain, as the active principle, cytidine-disphospho-dimethy-lethanolamine, which is also known as CDP-Deanol, with the formula I.

and a process for its manufacture. 45, do not lead to a real choline synthesis since they

CDP-Deanol is a well-known compound that redistributes a role only existing choline molecules, in which choline biosynthesis in nerve cells plays a role. Only the «transmethylation path», which in the

It is known that ZNC choline was discovered by Blusztain both in the past few years, allows the biosynthesis of acetylcholine as well as for the phosphatidyl synthesis of new phosphatidylcholine molecules starting from choline (lecithin). so of ethanolamine, through an enzymatic system that controls the

From many points of view of geriatric pathology catalyzes different methylation levels, the choline requirement of the nerve cells increases and it is therefore important to use S-adenosylmethionine as methyl donors to activate mechanisms that have a higher enzymatic system that is responsible for this transformation.

Enable production of it. is written as phosphatidylethanolamine-N-methyl

Three neuronal 55 transferase (PEMT) metabolic pathways are currently known. The PEMT activity became known level, which for phosphatidylcholine biosynthesis mainly in the membrane fraction of rat and

(JK Blusztajn e Coll. Brain Research 179,319-327, dergerhirn found and showed their maximum values on (1979); N. Chida eT. ArakawaTohoky J. Exp. Med. 104,359, level of the neural ends (synaptosomes) (JK Blusztajn ( 1971) e K. Dross e H. Kewitz Naunyn - Schmiedeberg's e Coll.Brain Research 179,319-327; (1979) e FT Crews - F.

Arch. Pharmacol. 27491, (1972)); Phosphatidylcholine is available as Hirata - J. Axelrod J. Neurochem. 34, 1494, (1980)).

Easily available choline deposit form known (J.K. 60 The PEMT activity at the neuronal level is obtained from Blusztain and R.J. Wurtman Science, 221, 614-620, (1983)). Activity of at least two different methyltransfer

In fact, the phosphatidylcholine can easily be made by a rase enzyme.

alkaline phosphatase to be hydrolyzed to free choline The first methyltransferase catalyzes the conversion (GB Ansell e Spanner Biochem. J.110,201 (1968) e GB from phosphatidyl-ethanolamine to phosphatidyl-N-mono-Ansell e spanner cholinergic mechanisms e Psychopharmaco- 65 methyl- ethanolamine (PME), whereas the second is logy (Plenum, New York, 1987)). Conversion of PME to phosphatidyl-N, N-dimethyl-etha-

Two of the metabolic pathways, one known as "CDP-nolamine (PDE) and PDE in phosphatidyl-choline cataly-choline pathway" and the other known as "base exchange" (FT Crews - F. Hirata - J. Axelrod J. Neurochem . 34,

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673 653

1494, (1980) e A. K. Percy - J. F. Moore - C. J. Waechter J. glycerin PPE and phosphatidyl-deanol, which are described in the «Trans-Neurochem. 30, 1404, (1982)). methylation path »occurs and it even takes over, as in

The CDP-Deanol is shown by reaction with a diacyl- the following scheme:

Ethanolamine j, ATP

Phosphorus ethanolamine

^ CTP CDP ethanolamine

^ Diacylglycerol Phosphatidylethanolamine Deanol br SAH

| ATP SAM

Pho sphory1-deano1 Pho sphat idy1-monomethy1-aminoethano1

SAW

CTP SAM

CDP-Deanol y -> Phosphatidyl-deanol f Wr SAH

Diacylglycerol. SAM

Pho s] j) ha t idy 1-cho 1 in

Choline + phosphatidic acid

The therapeutic use of Deanlo is already known (average age 76.5 years), divided into two: administered as a free base, it is not directly administered to groups of six, was used with CDP-Deanol by the nerve cells, but is first used ( 2 x 250 mg tablets twice a day) or in (500 mg activated, i.e., esterified with the cytidyl coenzyme that treats CDP: vials twice a day).

Deanol educates. The activity parameters of the drug were based on

This molecule has a very high energy bond, 40, the Birren test (modified), the Toulousa-Pieron test, the synthesis of phosphatidyl-deanol, a metabolite,; and the semi-quantitative scales by Kellner-Sheffield, which are valued by methylation into phosphatidyl-choline, whereas the tolerance parameters are converted by bio, which in turn choline has been studied for acetyl-choline-i chemical and clinical evaluations. The evaluation times were zero and past

The CDP-Deanol, which fixes a more direct metabolic pre-45.30-day treatment. The statistical analysis runner of phosphatidyl-choline as Deanol is, therefore, showed a significant improvement in memory-a role as a direct precursor for the synthesis of the latter, especially in the i.m. treated patients, called "key" metabolites. The basic biochemical parameters changed

The above biochemical requirements are not essential and there was little or no conclusion about the invention, since they have such undesirable effects.

The CDP-Deanol is generally effective in the pharmaceutical compositions according to the invention and is not effective in treating cerebral disorders. vascular-organic and traumatic

In fact, it turns out that the CDP-Deanol in origin, in the case of senile involvement phenomena, in cases of interference with dimethylaminoethanol (Deanol) hemisuccinate, ss. intellectual performance, as well as in all much less toxic, which is reflected in tests of cases of psychological stress.

Ac "te" tIicity on intraPeritoneal; em ° ™ lem way to FÜJ. The achievement of the desired therapeutic B ALB / c mice with a weight of 17-22 g show. CDP-Deanol can affect the patient in various ways.

leaves. The intraperitoneal LD 50 value for CDP-Deanol was the route to be administered, in pure form or higher than 45 g / kg, whereas Deanol-Hemisuccinate was a «form of pharmaceutical compositions.

almost twice the toxicity with an LD 50 value of

23 5 g / kg showed the formulation of suitable pharmaceutical

'cDP-Deanol was also found to be significantly more active, and measures can be carried out using the usual techniques.

more effective than Deanol (as hemisuccinate) in causing symptoms, such as that described in “Remington's Pharmaceutical Treatment of Senile Cerebral Decay, which is the 6s Sciences Handbook,” Hack Pub. Co. U.S.A.

by the clinical tests summarized below, the amount of CDP-Deanol administered orally showed. can range anywhere from 5 mg / kg / day to 30 mg / kg / day

12 elderly patients with cerebral involution (7M, 5F, lie. The amount of parenterally administered

673653

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The active principle can range from 1 mg / kg / day to 50 mg / kg / day, preferably from 5 mg / kg / day to 30 mg / kg / day.

For example, a unit dose for oral administration may comprise 100 to 1000 mg of active principle.

The compositions of the invention are generally administered once or twice a day, however more frequent administration may be appropriate at least in some cases and may vary depending on the condition of the patient and the route of administration.

For oral administration, the compound can be formulated in solid or liquid preparations, such as capsules, pills, tablets, powders, solutions, suspensions or emulsions, as well as slow-release forms, such as chro-noids, etc.

The unit dose form can be a soft or hard gelatin capsule containing lubricants and inert excipients such as lactose, sucrose or starch.

The compounds of the invention can also be formulated as tablets using conventional excipients such as lactose, sucrose, starch, gelatin, alginic acid, stearic acid, magnesium stearate, etc.

For parenteral administration, the compounds may be injectable formulations, dissolved or suspended in physiologically useful diluents, together with a carrier, which may be a sterile liquid, e.g. Water or an oil, with or without the addition of other excipients, can be formulated. Oils that can be used are vegetable, animal, mineral, or synthetic oils such as nut oil, soybean oil, and mineral oil.

In general, water, aqueous solutions of mineral salts, aqueous solutions of dextrose or other sugars, ethanol, glycols such as propylene or polyethylene glycol can be used as carriers for injectable solutions.

In addition to the above-mentioned excipient and CDP-Deanol, the compositions according to the invention can optionally also contain other active constituents which have complementary or otherwise useful effects.

Another feature of the invention is to provide a method for making cytidine dis-phosphodimethylaminoethanol.

The process consists in the reaction of a cytidine 5'-monophosphoric acid trialkylammonium salt with a phosphoryl-dimethylaminoethanol salt, in the presence of a carbodiimide, in a suitable solvent.

Preferably, 1 mole of cytidine 5'-monophosphoric acid (CMP) trialkylammonium salt with an amount equivalent to 2-8 moles of a phosphoryl-dimethylaminoethanol salt is in a formamide pyridine solution at a temperature between 15 and 40 ° C for a period of time from 5 to 25 hours.

s Dicyclohexylcarbodiimide is used as the carbodiimide and sodium, potassium, ammonium, calcium, magnesium, triethylammonium salts and the like can be used as phosphoryl-dimethylaminoethanol salts.

The following examples serve to explain the invention without restricting it.

example 1

A solution of 30 g of dicyclohexylcarbodiimide in 100 ml of pyridine slowly became a solution of 21 g of tributylam-15 monium-cytidine-5'-monophosphate (content of cytidine-5'-monophosphoric acid: 13.4 g) and 35.6 g of phosphoryl- Dimethy-lamino-ethanol sodium salt added in 200 ml of from amide. The mixture was reacted with stirring at 35 ° C for 15 hours; the precipitated dicyclohexylurea was then filtered and discarded, and the filtrates were concentrated by a reverse osmosis process to form a dry residue of about 30-35%.

11 acetone was slowly added to the obtained viscous residue with stirring, and a precipitate formed, which was obtained by centrifugation.

The acetone supernatants were discarded and the precipitate was washed twice with 250 ml of anhydrous acetone.

Drying gave 30 g of crude cytidine diphospho-30 deanol sodium salt. The crude product obtained (30 g) was diluted in 31 water, the pH was adjusted to 7.2 and the product was absorbed on a Dowex 1-X2 resin column in the formate form. The resin was washed with water and then eluted with a 0.005 M formic acid solution.

The eluate fraction containing the desired compound was neutralized with NaOH, concentrated to a syrup by a reverse osmosis process, then diluted lightly with water and subjected to an ultrafiltration process.

5 volumes of a cold 3: 2 (v / v) methanol: acetone mixture were added to the solution, which contained the produced molecule with a degree of purity of greater than 99%, until crystallization was complete. The crystals were then collected and dried under high vacuum, 19.3 g of cytidine diphosphodimethylaminoethanol trihydrate sodium salt being obtained.

yield: 87%

Mp = 231-235 ° C (swelling)

Elemental analysis found calculated (hydrated form) UV in HîO solution in 0.1 N HCl solution

HCl IN IR cm-1 = 2479.2670 cm "1

C H N 30.19 4.80 10.84 30.36 4.90 10.89 = max 270 nm, log = 3.942

224 nm = max 278 nm, log = 4.089 = max 278 nm, log = 4.090

Example 2

Injectable pharmaceutical formulations

673653

Injectable by intramuscular or intravenous route a) aqueous solution (pH 7 ± 0.5)

one vial contains: 2 ml 4 ml 4 ml

Cytidine diphosphodeanol 0.250 g 0.500 g 1,000 g

Sodium Merthiolate 0.080 mg 0.160 mg 0.160 mg water for injectables

Preparations q.s. to 2 ml 4 ml 4 ml b) freeze-dried a freeze-dried vial contains:

Cytidine diphosphodeanol 0.250 g 0.500 g 1,000 g

Glycocoll 0.150 g 0.300 g 0.300 g

Mannitol 0.100 g 0.200 g 0.200 g

Sodium merthiolate 0.050 mg 0.100 mg 0.100 mg

Example 3

Oral pharmaceutical formulations a) tablets

- one tablet contains cytidine diphosphodeanol

- Excipients of the nucleus:

Corn starch microgranular cellulose precipitated silicon oxide sodium carboxymethylamylopectin talc

Magnesium stearate

- Excipients of the coating: polymethyl methacrylate lactose

Polyethylene glycol 6000

talc

kaolin

Titanium dioxide

Polysorbate 80

Sodium citrate bihydrate b) capsules one capsule contains: cytidinediphosphodeanol microcrystalline cellulose precipitated silicon dioxide talc

Magnesium stearate c) fialoids per os

- a 10 ml fialoid contains: cytidinediphosphodeanol sorbitol 70% solution glycerin

Saccharin

Methyl p-hydroxybenzoate propyl p-hydroxybenzoate flavoring agents distilled water s.q. on

0.45 ~ / g

0.685 ~ / g

0.250 g

0.500 g

70.0 mg

0.70 mg

86.0 mg

0.56 mg

5.0 mg

6 mg

20.0 mg

30 mg

6.0 mg

8 mg

3.0 mg

4 mg

1.454 mg

1.650 mg

2,643 mg

3.040 mg

0.902 mg

1.037 mg

1.189 mg

1.367 mg

2.114 mg

2.431 mg

1.586 mg

1.824 mg

0.079 mg

0.090 mg

0.053 mg

0.060 mg

0.277 g

0.553 g

0.250 g

0.500 g

0.020 g

0.040 g

0.003 g

0.005 g

0.003 g

0.006 g

0.001 g

0.002 g

0.500 g

1,000 g

2,000 g

2,000 g

1,600 g

1,600 g

0.010 g

0.015 g

0.012 g

0.012 g

0.004 g

0.004 g

0.030 g

0.040 g

10 ml

10 ml

B

Claims (12)

673653 PATENT CLAIMS 1. Cytidine-diphosphodimethylethanolamine, CDP-Deanol, as a therapeutic agent. 2. Use of cytidine-diphosphodimethyl-ethano-lamin, CDP-Deanol, for the production of therapeutic agents. 3. Pharmaceutical compositions containing cytidine-diphosphodimethylethanolamine, CDP-Deanol, as an active ingredient in pharmaceutical compositions in a mixture with auxiliaries and excipients or pharmaceutically usable carriers or excipients. 4. Pharmaceutical composition according to claim 3, in a form suitable for oral administration. 5. A pharmaceutical composition according to claim 4 in unit dose form containing 100 to 1000 mg of the active ingredient. 6. Pharmaceutical composition according to claim 4 or 5 in the form of hard or soft gelatin capsules, tablets, pills coated with sugar, chronoids, solutions, suspensions, powders. 7. Pharmaceutical compositions according to claim 3, in a form suitable for parenteral administration. 8. Pharmaceutical compositions according to claim 7 in unit dose form, containing 100 to 1000 mg of active ingredient. 2nd 9. Pharmaceutical compositions according to claim 8 formulated in vials or ampoules, for intramuscular or intravenous administration. 10. Process for the preparation of cytidine diphosphopo- 5 dimethylethanolamine, characterized in that a Cytidine-5 '-monophosphoric acid trialkylammonium salt is reacted with phosphoryl-dimethylamino-ethanol in the presence of a carbodiimide. 11. The method according to claim 10, characterized in lo records that it is carried out in a formamide-pyridine solution at a temperature of 15 to 40 ° C. 12. The method according to any one of claims 10 or 11, characterized in that the phosphoryl-dimethyla-mino-ethanol salt is used in amounts which are 2 to 8 15 mol, based on the cytidine 5'-monophosphoric acid salt are equivalent. 20th