JPS58210083A - Enantiomer of naphthylidine derivative - 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] deguchi-1i]-indoro[3,2,]=de':
] [1.

Enantiomers (optical antipodes) of 5-naphthyridine]
, salts thereof, particularly pharmaceutically acceptable acid addition salts, methods for producing the same, and pharmaceutical compositions containing the same.

1 British Patent Publication No. 2077889 filed by a non-applicant
No. A (Patent Application No. 28135005) contains 2, which is useful as a medicine and is represented by the following formula.

3,3a+ 4+ 5.6-hexahide-]
H - Indolo C3.2,]-de)II,5-
A racemic form of Naphthyridine is disclosed.

In the structure of this compound, the carbon atom at the 1-3a-1 position is an asymmetric carbon, and therefore two optical antipodes exist.

Both of the two uninvented enantiomers are 2,
3-bis-(4-methylbenzoyloxy)-butanedioic acid-3
-Promocamphor-8-sulfonic acid, 3-promocamphor-10-sulfonic acid, camphor-10-sulfonic acid,
Tartaric acid, phthalic acid mono-N-' [α-methylbenzyl]
monoamide, chiral acids such as malic acid or mandelic acid (
It can be isolated by preparing an intermediate addition salt with one of the optically active enantiomers of chiral acid.

The formation of this salt starts from an enantiomeric mixture of a compound of formula +I+ in base form, e.g. the racemate, dissolved in a suitable solvent such as an alcohol, preferably ethanol, and at ambient temperature. and the boiling point of the solvent.

The two diastereomer salts obtained [ dlas tereo+sorner+c salt
s 1) fg, /i) Separate by separate crystals.

After separation, they can be cleaved from the chiral acids and reconverted into acid addition salts with suitable physiologically acceptable acids.

The enantiomers of a compound of formula (I+) can also be obtained from a base partially enriched in one enantiomer, for example derived from a mother liquor obtained from recrystallization of a mixture of diastereomeric salts. This type of enrichment Chiral acids are used to separate mixtures.

It is the enantiomer of the chiral acid that made it possible to obtain the mixture.

The purity of the optical isomer of the compound of formula (I+ is, for example, B.

Halpern's method for heptamino acids (Han
dbookof Derivatives for C
chromatography+ pages 457-476, edited by K. Blau and G. S. Gas chromatography according to King, Publisher: Heyden).
(GC) or liquid chromatography (HPL)
C).

This method converts isomers of the compound of formula (1) into formula (■):CJ(a
It consists of condensation with (1)-menthyl chloroformate represented by CH3 to obtain the corresponding menthyl carhamate. The latter compound was analyzed by GC or HPLC,
If it is effectively a single enantiomer of the compound of formula (moon), only one peak will appear; if the resolution is incomplete, two peaks will appear.

The pharmaceutically acceptable acid addition salts of the enantiomers of the compounds of formula (I), such as methanesulfonate, mandelate, fumarate, citrate, sulfate, etc., can be prepared by methods known per se, e.g. Enantiomeric bases in solvents such as ethers can be obtained by treatment with appropriate acids in solvents such as alkanols.

"Methods known per se" refer to methods conventionally used or methods described in literature.

Examples are given below to illustrate a method for separating isomers of a compound of formula (I+) and a method for testing its purity.

Example 1 (Mon-2, 3, 3a, 4, 5.6-Hexahi FO-II (-i, 7 Toro [3+ 2.1-de]
Formation of sheastereomeric salts with [1,5-naphthyridine] and its methanesulfonate (a)(+)-2,3-bis-(4-methylbenzoyloxy)-butanedioic acid British Patent Application Publication No. 2087889A Oily base-type laminates prepared according to Examples 2゜△3, 3a+ 4. 5; 6-hexahydro-I
H-IndoloC3,2,1-de) [134.41 g of 1,5-naphthyridine was dissolved in 250 m of absolute ethanol.
1 and placed in a 21 Erlenmeyer flask equipped with a magnetic stirrer, reflux condenser and oil bath. (+)-2,3-bis-+4- dissolved in absolute ethanol 250/
, methylbenzoyloxy)-butanedioic acid 32.7El
is gradually added with stirring at ambient temperature. A large amount of crystallization occurs before the addition is complete.

The mixture is gradually heated to reflux temperature and an additional 200 g of ethanol are added in order to completely dissolve the crystals. A small amount of insoluble crystals is filtered off and the p-liquid is heated again and allowed to cool to ambient temperature. After standing for 2.3 hours, the formed crystals are collected using a glass filter and dried at 50° C. under reduced pressure. White crystals 4356f are obtained.

(bl) The crystals obtained on recrystallization are recrystallized several times from 95% ethanol. For each recrystallization, about 025 g of crystals are removed and the base is liberated using a mixture of dilute aqueous ammonia and chloroform.
Measure optical rotation. When recrystallized four times, the optical rotation of this base is approximately [α]. -16329° [C-1, M e OH
7).

The optical rotation of the salt that liberates this base is approximately [α].

= +84.51° (C-1, MeOI-N is 1.

(C) 578 g of salt obtained from methanesulfonate (b), 100 g of hydrophilic ammonia
and 100 m/ml of ethyl acetate are placed in a 250 ml Erlenmeyer flask equipped with a magnetic stirrer. 2,
After stirring for 3 minutes, the organic phase was separated and the aqueous phase was dissolved in ethyl acetate 1
The two organic phases obtained are combined, washed with water, dried over magnesium sulfate, concentrated on a rotary evaporator and dried under reduced pressure. 296 g of this base in the form of a mixture of white crystals and an oil are obtained.

In a 250 ml round bottom flask equipped with a magnetic stirrer, the base is dissolved in 60 ml of diethyl ether and 134 g of the original methanesulfonic acid dissolved in 15 ml of absolute ethanol are added. Immediately crystallizes in large quantities. The mixture was stirred for a further half hour at ambient temperature and the crystals were filtered through a glass filter at 50 °C under reduced pressure.
Dry with. Recrystallization from 60IIIL of hot absolute ethanol, standing overnight at ambient temperature, filtration and drying under reduced pressure gives 303 g of methanesulfonate crystals. r
rt p, =222~224°C Optical rotation [α] D - 1,2158° (c = 1, M
The structure was confirmed by elemental analysis (eOH), IR, and NMR.

(d) Test for purity (+)-2+ dissolved in 10 ml of ethyl acetate 3.
3a.

4.5.6-hexahydro-IH-indolo [3°2.
1-de][]140m of 1.5-naphthyridine 7 was prepared with 66.71g (1 equivalent) of triethylamine, equipped with a magnetic stirrer and a calcium chloride drying tube]0
0m1! into a round bottom flask and cool the mixture in an ice water bath. 1 ml of a solution of 1 equivalent of (-)-menthyl chloroformate, ie 66×10 6 mol/l, dissolved in toluene is added and stirred for 15 minutes at 0° C. and then for 20 minutes at ambient temperature. Insoluble materials are removed and the organic phase is washed with water.
It is then washed with 5 multiple aqueous sodium carbonate solutions and finally again with water. This is dried over magnesium sulfate, rotary evaporated and concentrated under reduced pressure. yellow oil 251
mg was obtained, which was dissolved in ethyl acetate to give 01/
Prepare a solution of ml. When this solution is subjected to gas chromatography, a curve showing a unique peak is obtained.

Example 2 (-]-2, 3, 3a, 4+ 5.
6-hexahydro-IH-indoDC3,2,1-d
e] [1,5-naphthyridine] (a) 2. Liberation of base from the mother liquor obtained by recrystallization of the dextrorotary isomer in the form of 3-bis-(4-methylbenzoyloxy)-butanedioate From the first recrystallization carried out in Example 1(b) Dry the p solution on a rotary evaporator. Add to this 10% aqueous ammonia 200
ml, then 2-00 g/m of ethyl acetate. The mixture is stirred for a few minutes and filtered through a glass filter. The organic phase is separated, washed with water, dried over magnesium arsenate, rotary evaporated and concentrated under reduced pressure. Approximately 1 g of orange oil is obtained.

(bl Formation of diastereomeric salt with (-)-2,3-bis-(4-methylbenzoyloxy)-butanedioic acid) 9.08 g of the oil obtained in Example 2(a) were mixed with 6 g of absolute ethanol
(-)-
A solution of 2,3-bis-(4-methylbenzoyloxy)-butanedioic acid is added over a period of 1 hour at ambient temperature. A large amount of crystals precipitates before the addition is complete. The mixture is gradually heated to reflux temperature and 140 ml of absolute ethanol is added to completely dissolve the crystals. The small amount of insoluble crystals is filtered off, the furnace liquor is reheated and allowed to cool at ambient temperature. After recrystallization, the crystals are filtered through a glass filter and dried at 50° C. under reduced pressure. In this way, white crystal 11
2g is obtained.

(C) Recrystallization The crystals thus obtained are recrystallized several times from 95% ethanol. For each recrystallization, remove approximately 0.24 M - then liberate the base with aqueous ammonia and chloroform and measure the optical rotation.

When recrystallized five times, the optical rotation of this base is approximately [α]0=-
63.38° (C=1.39- in MeOH) becomes constant. The optical rotation of salt is approximately [α]. --89,21'(c
= 1, M e OH).

Example 3 ←) -2, 3, 33+ 4+ 5. 6
-hexahito o -I H-indoloC3,2,1-d
e) [1,5-naphthyridine] and its methanesulfonate (a) Formation of diastereomeric salts with t)-2,3-bis-(4-methylbenzoyloxy)-phthanedioic acid Example 1(a) and In the same manner, 250 ml of absolute ethanol
(-)-2,3-bis-(
4-Methylbenzoyloxythibutane-acid 32.7E
[2I with magnetic stirrer, reflux condenser and oil bath heater! (use an Erlenmeyer flask). At ambient temperature, a large amount of crystals precipitates out before the diacid addition is complete.

Heat the mixture under reflux and add 220 m of absolute ethanol.
ml and dissolve. A small amount of insoluble crystals is removed by furnace. The p-liquid is heated again and left at ambient temperature to crystallize,
Next, the crystals are filtered through a glass filter and dried under reduced pressure at 50°C. In this way, crystal 35.4'lFI is obtained.

(bl Recrystallization is carried out in the same manner as in Example 1 (C). When recrystallized four times, the optical rotation of the base is [α] 0 K 60.5° (C 2 115
, MeOH), and that of salt is approximately [α]0=-
87.9° (C-1, MeOI-()tonal.

(C) 1.159 of the enantiomer [oil] dissolved in methanesulfonic acid ethyl ether 20°C - Etched with a magnetic stirrer 250°C
ml round bottom flask and the equivalent amount, i.e. 0.529
of methanesulfonic acid is dissolved in 6 ynt of ethanol and rapidly added. Crystals form and after stirring for an additional half hour are filtered and dried at 50° C. under reduced pressure. Add this to 19*l of absolute ethanol! recrystallize from 112 g of methanesulfonate are obtained. m, p-=219-221°C Optical rotation: C(t'J D=-22,0°(c=l
-MeOH) The structure of this compound is determined by single-element analysis, NMR
and confirmed by IR spectrum.

(dl Purity test carried out analogously to Example 1(d). In gas chromatography, the menthyl carbamate obtained shows a curve with only one peak.

In order to investigate the usefulness of the uninvented compound as a medicine, it was subjected to pharmacological experiments.

CDI mice were placed under reduced pressure (190ff+gHg-oxygen 5
．． (equivalent to 25%) to maintain an oxygen-deficient atmosphere. The survival time of the animals was measured. organization,
This survival time is extended, especially by providing agents that can promote oxygen saturation of the brain.

The withdrawal compound was intraperitoneally administered at various doses 10 minutes before the start of the experiment. The relative survival time prolongation relative to the control group was calculated. The compound (average activity 1 (ADlool) that prolongs survival time by 100% for I+ was calculated by the graphical method and was -21 to 23 m9/kQ. AD50
was 7 to 10 μ/kq.

Saturated solution of magnesium chloride 0. ] After injecting the test compound together with ynl into the tail vein of the mice, the survival time of the test animals is determined. Cardiac arrest causes cerebral ischemia.

"Survival time" is the time from the injection of magnesium chloride to the last respiratory movement of each mouse, which is considered to indicate the end of central nervous system function.

The survival times of animals administered intraperitoneally with a compound according to the invention prior to the injection of magnesium chloride 10/7+ are compared to the survival times of control animals administered only with the vehicle used to administer this active compound.

Use 10 mice as a group, plot the mean values of each group to draw a curve, and use a graphical method to calculate the effective 1B (EDa) that prolongs survival time by 3 seconds as mg of active substance per gram of body weight. expressed.

The 3 second increase in survival time is 1M quantitatively significant and reproducible.

The EDs of the compounds according to the present invention were 7-10/kQ.

As a result of pharmacological experiments, the compound according to the invention has anoxic anoxic activity and is useful for the treatment of wakefulness disorders, especially for the treatment of vascular disorders in the brain and behavioral disorders caused by cerebral sclerosis seen in geriatric diseases, and It can be used to treat unconsciousness due to craniotraumatic systemic disorders, metabolic encephalophobia (brain damage), and depression.

Therefore, the non-invention includes all pharmaceutical compositions containing the non-inventive enantiomer or a salt thereof as an active ingredient, and particularly containing excipients suitable for oral or parenteral administration.

The administration method may be oral or parenteral, and the daily dosage of the enantiomer of the compound of the formula (1)
It can be between 0 and 100 fn9.

Patent applicant Syntherapo Representative Patent Attorney Aoyama Name

Claims (1)

[Claims] 1. An enantiomeric mixture of the compound represented by the formula (■) in the base form is reacted with one of the enantiomers of chiral acid, and one of the two diastereomeric salts obtained is subjected to fractional crystallization. and, if desired, converting this base into a pharmaceutically acceptable acid addition salt.2,3. 3
a, 4. 5. 6-hexahydro-IH-indoloC3,2,1-de] [1,5-naphthyridine]
A method for separating the enantiomers of. 2. The separation method according to item 1, wherein the 2-chiral acid is 2,3-bis-(4-methylbenzoyloxy)-butanedioic acid. 3. The separation method according to claim 1 or 2, wherein the mixture of enantiomers of the compound of formula tI+ is a racemate. 4. Separation according to paragraph 1 or 2, wherein the mixture of enantiomers of the compound of formula (I+) is the mother liquor in the previous separation operation. 5. The formation of the salt with the chiral acid and the recrystallization are carried out in ethanol. The separation method according to any one of paragraphs 1 to 4.
IH-indoloC3,2,1-de':l[1,5-naphthyridine] and its pharmaceutically acceptable acidified 7Il
I salt. 7←)-2, 3, 3a, 4. 5. ．． 6-hexahydro-IH-ia)'r3.2.1-de')[1
15-naphthyridine] and its pharmaceutically acceptable acid addition salts. 8, (+)-2, 3, 3a, 4+ 5. 6-hexahydro-IH-indoOC3,2,]-de ]
C.I. 5-naphthyridine] or (-)-2,3,3a+4
．． 5.6-hexahydro-IH-indolo [3゜2,
1-de ICI, 5-naphthyridine], or a pharmaceutically acceptable acid addition salt thereof.