JPS60158152A - Non-hygroscopic salt of l-carnitine and alkanoyl l-carnitine, manufacture and medicinal composition - 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 [Industrial Field of Application] The present invention relates to the general formula (I): + (wherein, X- is aspartic acid
te), Quen [! (acid citrate),
Phosphate, fumaric acid, lactic acid
te), maleic acid (acid maleate),
oxalic acid, sulfuric acid
d 5ulphate) or orot acid (orot acid)
ate), R is a lower alkanoyl group selected from acetyl, propionyl, or butyryl, or a hydrogen atom (if X- is other than orotic acid), n is an anion selected from 1/2 in the case where X- is other than orotic acid, and 1 in the case where X- is other than orotic acid.

The present invention also relates to a method for producing soft earth salts and a pharmaceutical composition based on soft earth salts.

[Prior Art] Carnitine and its alkanoyl derivatives are known to be useful in various treatments.

Salts of carnitine and its alkanoyl derivatives have similar therapeutic effects to so-called "inner salts" and can be used as "pharmacologically acceptable salts" in the same manner as inner salts.

In practice, therefore, the choice between "inner salts" and true salts of carnitine and alkanoylcarnitines depends mostly on which form of the compound is more easily or economically available. , selected by pharmaceutical technology rather than therapeutic action.

[Problem to be Solved by the Invention] As far as the present invention is concerned, the usefulness of the salts of soft earth does not lie in a therapeutic action that is qualitatively or quantitatively different from already known therapeutic actions, but rather in a therapeutic action that is qualitatively or quantitatively different from already known therapeutic actions. They are not hygroscopic compared to internal salts or chlorides, and solutions of soft earth salts have a higher pH compared to the corresponding chloride solutions.

Due to their lack of hygroscopic properties, these salts can be handled and formulated more easily, especially for the production of solid dosage forms. On the other hand, the lower acidity of solutions of soft earth salts makes it possible to use them for the preparation of parenteral preparations, especially intravenous preparations.

SUMMARY OF THE INVENTION It is surprising that the salts of [-carnitine and alkanoyl L-carnitine according to the invention are not hygroscopic. This is because it is known that the salt of the racemic mixture of [-carnitine] has extremely high hygroscopicity; [-carnitine and alkanoyl 0. [-If some salts of carnitine are hygroscopic, the same salts of the optically resolved isomers, especially [any salt that believes that the monolithic salt should not be equally hygroscopic] This is because there is no theoretical basis for this. Therefore, for example, L-carnitine fumarate, L-carnitine oxalate (Chea+
, Abst, 60@, 12097.1964) are hygroscopic, the novel salts according to the invention [- the fumarate of carnitine and the oxalate of lunithine are substantially non-absorbent. It is hygroscopic.

If some salts of L-carnitine are hygroscopic,
That the corresponding alkameyl [-carnitine salts are not hygroscopic is surprising since there is no rationale to support a truth to the contrary. Furthermore, L-
It is surprising that while the salts of carnitine with certain polybasic acids are hygroscopic, the addition salts of the same polybasic acids of lurnitine and alkanoyl carnitine are not. Therefore, for example, phosphoric acid [−
Carnitine (L-carnitine phospha)
te) is hygroscopic (Medical Journal of Authorship University (Hedica IJo)).
urnal of 0saka University
), Vol. 21, No. 1, December 1970, pp. 7-12), a novel salt according to the present invention, L-carnitine acid pl+osph
ate) and acetyl trinithine phosphate (ac
etyl L-carnimouth neacid phosp
(hate) is not hygroscopic.

[Function and Examples] The method for producing a salt according to the present invention is as follows: (a) General formula (■): (OH3)3NaH20HOH2000H(n)l-0
(b) A water or alcohol solution of the salt obtained in step (a) is heated at room temperature. with an equimolar amount of an acid selected from aspartic acid, citric acid, phosphoric acid, fumaric acid, lactic acid, maleic acid, oxalic acid or sulfuric acid, or a half-molar amount of orotic acid, at a temperature between and about 50°C. and (C) concentrating the desired salt obtained in step (b) from an alcoholic solution or from an aqueous solution or by vacuum freeze-drying, and optionally subsequently. It consists of a step of separation by crystallization.

The step (a) of converting the chloride of the soft earth into the corresponding inner salt can be carried out by a known method. For example, a typical method is E, 5track.
"Darstellung von O-acyl-
carnitlnen) J (Iloppe-8eyl
ersZ, Physiol, Chem, Vol. 351, pp. 95-98, January 1970).

In addition, step (a) is performed by Sigma-Tau Industrie Pharmaceutisie Rinite φEtsse Pia (SIG
MA-TAUI Industry Farmaceut
iche Riunite S, P, A) and De Nora
It can also be carried out by the method disclosed in Italian Patent No. 24432A/82 filed jointly with DE NORAS, A.

Next, the non-hygroscopic salt according to the present invention will be explained with reference to Examples, but the present invention is not limited to these Examples.

Example 1 [-L-carnitine phosphate (L-carnitine a
cidpbophate) (ST 521) (
OH3)3N-(1!I(z-011-CJH2000
200 g (1.2 mol) of the inner salt of HOH 2S04 [-carnitine were dissolved in the minimum required amount of water. This solution contains 86% 113P0
461#+1! (1.2 mol) was added. The resulting solution was then concentrated under vacuum and the residue was crystallized from isopropanol. The title compound was obtained as a non-hygroscopic solid.

[αID = 20' (C=1, H2O) P II
= 3 mp: 145-150℃ (softened at 80℃) Hull
(δ (mouth 2 0)): 4.5 (covered, C!ri, 3.4
(2H, d, Milo-co2), 3.2 (9H1S
, (CHI)3N), 2.5(2H1d1-CH
2C00t+-) Example 2 Acetyl[-rnithine[-aspartate (ace
tyl L-carnitine acid L-as
(ST 450) Intramolecular HA 7.2a (0,
035 mol) was dissolved in 50 cc of water. This solution contains L-
Add aspartic acid 4,7Q (0,035 mol),
The solution was diluted to 5 oocc with water. A complete solution of the mixture was obtained, which was lyophilized. 11 g of a non-hygroscopic residue, the aspartate of lunithine, was obtained and crystallized from isopropanol/diethyl ether.

[α]25−−17.2° (C−1,820)PH=
3.5 (in 5% aqueous solution) ip: 190-195°C NHR (δ(D20)): 5.5 (iHlm, -
C8-), 3.2 (9fl, S, (C113)3N
), 3.9-2.5 (4H, m 1-CHC day 2,
-c112Cootl)H2 Example 3 Acetyl lunitin citrate (acetyl L
-carnitine acid citrate)
Preparation of (ST 455) A solution of 2.40 (0.01 mol) of acetyl[-rnithine chloride] dissolved in methanol was added to 1 of amparite 26 activated to the 011-form.
Stirred for 49 and 48 hours. It was confirmed that chlorine ions were disappearing from the methanol solution. Next, 2.1 g (0.01 mol) of citric acid containing one molecule of water of crystallization was added.

The resulting solution was vacuum freeze-dried to yield 4.5 g of a non-hygroscopic product consisting of the title compound.

[α]%' = 16@(C=1.H20)PH=2.9
(in 5% aqueous solution) 3.8 (2H, m, N-C)h-), 3.2 (9
H, s, (CH3)all), Cl2COO- 2,9~2.7 (6H, s and d, OHCCl2COO
H -C12COOH), 2.2 (3H, S, -COCHs) Example 4 Acetyl trichlornitine maleate (acety+L
-carnitine acid maleate)
Preparation of (ST 456) 10.1 g (O, OS mol) of the inner salt of acetyl[-rnithine] was dissolved in water. 5.8111 (0.05 mol) of maleic acid was added to this solution and the solution was freeze-dried in vacuo. A non-hygroscopic solid was obtained which was washed repeatedly with anhydrous acetone. The residue was open dried under vacuum to yield 8 g of the title compound as a non-hygroscopic solid.

[α125 = −22° (C=1.H2O)PH=
2.7 (in 5% aqueous solution) mp: 120-123°C NHR (δ(D20)) + 6.3 (2N, S,
-CH=CH-), 5.6 (IH, rn, -CH-
), OC〇- 3,8 (2H, m, ”; N-CH2-), 3.3
(9) 11s, (Ch ) SN), 2.9 (211, d
, -C12-COO old, 2.1 (311, S,
-COCHs) High performance liquid chromatography (+1.
P, L, c) Column Silica gel N[12 Detector U, V, 205nllll Mobile phase (NH+)2 HPO* 0.018-C1
13CN (40-60) p147.8 (concentrated phosphoric acid) Pressure 45 atm Outflow rate 2ae/min Chart feed rate 0.5 CIIl/min RF Acetylcarnitine 1.0cm Malein I! 1 1.5cm Example 5 Acetyl[-carnitine phosphate (acetylL-c
arnitine acid phosphate)
(ST 45th production of acetyl [-carnitine, intramolecular jl 7.2 (1 (0,035 mol)) was dissolved in 50 m of water.
035-E/lz) Wokaeta.

The resulting aqueous solution was freeze-dried in vacuo, and the residue was washed with anhydrous acetone. The product was dried in vacuo to give 7.8 g of the non-hygroscopic title compound.

[α]'7=-17.7° (C=1.)+20)PH
-2,75 (in 5% aqueous solution) mp: 155-157°C NHR (δ (020)): 5.6 < IL m
, -C8-), 3.8 (28, m, U'-N-CH
2-), 3.2(9tl, S, (C113)3N
), 2.8 (2H1d, -C12COO old, 2.
2 (311, S, -COCH3) elemental analysis value C9H
2ON06P Calculated value Actual value C(X) 35.87 34.95 H(%) 6.69 6.58 (CI <0.2X)
N (%) 4.64 4.50 P(X) 10.28 10.5 Example 6 Acetyl[-L-lunitine fumarate (acety+L
-carnitine acid fumarate)
Preparation of (ST 468) 14.95 (+ (0,025 mol)) of acetyl [-runithine in the molecule was dissolved in 100 d of water. 2.82 g (0,0 mol) of fumaric acid was dissolved in the resulting solution.
25 mol) was added and the solution was freeze-dried in vacuo. Solid consisting of non-hygroscopic acetyl lunitin fumarate 3
．． I gained 5g.

[α]25=-22,7° (C=1,820)PH
= 3.3 (in 0.5% aqueous solution) mp: 159-161°C HHR (δ(020)): 6.6 (2N, S,
-C! ! =C! ! -), 5.5 (111, m, -C
I-), 3.8 (2H, m, , l; N-CH2-
), + 3.2 (9H, S, (Cth)sN), 2.6
(2N, d, -CH2COO), 2.1 (3H,
s, -CO(Jls>Example 7 Propionyl lunitin fumarate (1) roD
ionyl L-carnitine acid fu
(ST 522) Propionyl [-carnitine chloride 2.671 J (0
, 01 mol) in water 10-, and this solution was
Elution was carried out on a 20 td IRA 402 Amberlite resin column activated in the s-form. 80 taf of an aqueous solution containing the inner salt of propionyl [-rnithine]! Fumaric acid 1.1617 (
0.01 mol) was added. The solution was heated to 50° C., kept at this temperature for 1 hour, and then vacuum freeze-dried. The product was crystallized from isobuOpanol to give the title compound as a non-hygroscopic solid.

[α = -20,9° (C = 1, H2O)mp:
122-125°C NHR (δ(D20)): 6.6 (2) 1, s,
-CH=CH-), 5.6 (IH, m, -CI+-
), Shin〇- 3,8 (28, Kawa, -N-CI-12-), 3.3 (9
H, S, (Cth)3N), 2.8-2.3 (
4H,m, -C12COOH1-C12-C)+3
), 1.2 (3H,t, -CH2-C width) Elemental analysis value C14''2308' Measured value Actual value C (%) 50.44 49.80 H (%) 6,95 7.32 N ( %) 4.20 4.05 Examples 8 to 1 were obtained by performing the same operation as in Example 7.
0 salts and all were non-hygroscopic.

The respective mp and [α] values are shown below.

Example 8 L-carn+ttne fumarate (L-carn+ttne
acid fu+garate) mp: 137-139°C (in ethanol) [α]7=
-16° (C=2.5, H2O) Example 9 [-Carnitine oxalate (L-Carnitine
acidoxa+ate) mp: 115-118°C (in ethanol) [α]':
=-20' (C=2.5, H2O) Example 10 [-carnitine sulfur Hj! A (L-carnitine
acidsulfate) mp: 109-113°C (in ethanol) [αf:=
-1s, s° (C = 2.5, H2O) Example 11 Propionyl orotate and lunithin (propio
nyl L-carniNne orota) (
ST 552) Production of propionyl [-carnitine inner salt 42.49 (0
, 2 mol) and orotic acid 17.4 g (0.1 mol)
was dissolved in 200 d of methanol. The solution was stirred at room temperature for 1 hour and then dried in vacuo. A white solid was obtained consisting of the salt of propionyl-rnithine with oxdic acid (2:1 ratio).

High performance liquid chromatography (H, P, L, C,)
Column μB on d a p a k N H2
Detector U, V, 205 nm Mobile phase H2PO40,05M - CH5CN (35-65) Pressure 60 atm Outflow rate 1.5 d/min Inch Grater 4210 dispersion chart feed rate 0.5 cm/min RF Orotic acid 2.70 cm Propionyl monocarnitine 4.95cm The ratio of orotic acid to propionyl monocarnitine is 32 by calculating the area ratio of the chart with reference to the standard.
%2 was obtained as 68%, while the theoretical value calculated as propionyl, lunitin 2 mol and orot 111 mol was 29%:11%. The salt produced a 5% solution in water.

This solution was stable for about 24 hours.

(3,9(48, fat, (N-CH2)2), 3.3(1
88, s 1 (CH3) sN ), 2.9 (4) 1, d
, (CH2CO)2 ), 2.6 (4N, q
, (OCOCH2) 2), 1.3 (61, j , (
-CH3) 2) By performing the same operation as in Example 11, the salts of Examples 12 and 13 were obtained. Each [α]2
The zero value is shown below.

Example 12 Acetyl orotate [-lunithine (acety+L-
carnitine rotate) [α]20=-
2'5゜Example 13 Butyryl orotate [-carnitine (acety+L-
carnitine rotate) [α]2°--
15° The acute toxicity and pharmacological activity of the compounds according to the invention are
The acute toxicity and pharmacological activity of [-carnitine and alkanoyl E-carnitine] are the same as those of carnitine and alkanoylnithine.
Publication No. 0, Publication No. 54-113409, Publication No. 54-
Publication No. 113442, Publication No. 54-151130,
Publication No. 54-151131 @ Publication No. 55-13622
It is disclosed in Publication No. 3 and Publication No. 55-136227.

The compounds according to the invention further constitute medicaments containing as active ingredient at least one of the non-hygroscopic salts mentioned above and pharmacologically acceptable solid or liquid excipients. In particular, solid preparations suitable for oral administration are preferred. Examples of tablets and capsules are shown below.

tablet According to the present invention Non-hygroscopic salt soon+g Starch 20mg Talc 1Gmg Calcium stearate 1mg 31mg capsules According to the present invention [-carnitine Non-hygroscopic salt of 380mg Lactose 50mg Starch 20+ng Talc 5n+g Calcium stearate 2mg 57mQ Continuation of page 1

Claims (1)

[Claims] 1 General formula (I): + (X di n.R (wherein, an anion selected from orotic acid, R is a lower alkanoyl group selected from acetyl group, propionyl group, or butyryl group, or a hydrogen atom when X- is other than orotic acid; n is X- is orotic acid; - is 1/2 in the case of , and 1 in the case where
Non-hygroscopic salt of carnitine or alkanoyl L-lunitine. 2(a) General formula (I): (α3)3Nα2Tlfflα2C00H (■) amount. , -〇R (wherein R is a lower alkanoyl group selected from an acetyl group, a propionyl group, or a butyryl group, or a hydrogen atom), and the corresponding inner salt is prepared by a known method. (b) The aqueous or alcoholic solution of the salt obtained in step (a) is heated to a temperature between room temperature and about 50°C, and equimolar amounts of aspartic acid, citric acid, phosphoric acid, and fumar are added. acid, lactic acid, maleic acid, oxalic acid or sulfuric acid;
or a step of reacting with a half molar amount of orotic acid to obtain the desired salt, and (C) concentrating the desired salt obtained in step (b) from an alcoholic solution, or from an aqueous solution, or by vacuum freeze-drying. of the general formula (I), and optionally by subsequent crystallization.
):+ (wherein, a lower alkanoyl group selected from or a hydrogen atom when X- is other than orotic acid; n is 1/2 when X- is orotic acid; A method for producing a non-hygroscopic salt of L-carnitine or an alkanoyl monolunithine prepared by formula (1). 3 General formula (■): + (wherein, A lower alkanoyl group selected from a propionyl group or a butyryl group, or a hydrogen atom when X- is other than orotic acid; n is 1/2 when X- is orotic acid; is 1 in the case of other than orotic acid).A pharmaceutical composition containing a non-hygroscopic salt of L-lunithine or an alkanoyl L-lunitine as an active ingredient and a pharmacologically acceptable excipient. . 4. The pharmaceutical composition according to claim 3, which is a solid preparation.