JPS59112914A - Drug for parkinson's disease and antidepressant - Google Patents

Abstract

PURPOSE:A drug for Parkinson's disease and antidepressant suppressing more effectively drop in temperature caused by reserpine administration than L-threo- DOPS, improving myotonia, containing threo-adrenaline carboxylic acid as an active ingredient. CONSTITUTION:A drug for Parkinson's disease and antidepressant containing threo-3-(3,4-dihydroxyphenyl)-N-methylserine (threo-adrenaline carboxylic acid for short) shown by the formula (* is asymmetric carbon) as an active ingredient. Threo-adrenaline carboxylic acid suppresses harmaline inducing trembling, and suppresses drop in temperature caused by reserpine administration. The action is more effective than L-threo-DOPS (chemical name; L-threo-3,4-dihydroxyphenylserine). Threo-adrenalinecarboxylic acid used is preferably DL-form or L-form.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an anti-Parkinsonian and anti-depressant drug containing Hasleo-3-(3,4A-dihydroxyphenyl)-N-methylserine (hereinafter referred to as threo-adrenergic acid) as an active ingredient. Parkinson's disease is a progressive disease that exhibits symptoms such as tremor, muscle rigidity, akinesia, psychotic symptoms, and autonomic nervous symptoms, and is known to be caused by a decrease in catecholamines in the brain. L-DOPA is well known as a treatment for Parkinson's disease, but when administered for a long period of time, a 'freezing/' phenomenon is observed in walking, speaking, and writing in many cases, and the development of a new therapeutic agent is desired. There is. Furthermore, depression has the highest incidence among neuropsychiatric disorders and is one of the major problems facing modern society. Approximately 10 cases of depression are recurrent depression, but the remaining cases are depression without recurrent illness.
This includes environmental and psychogenic factors. −
Generally speaking, there are many types of depression, and research is underway to separate these subsystems, but at present, it is unclear whether both serotonin and catecholamines in the brain are related to depression. It is thought that there are 9 subsystems of depression that are strongly related to serotonin and those that are strongly related to catecholamines. Currently, bicyclic compounds are widely used as therapeutic drugs for the five diseases. However, bicyclic compounds have problems with side effects such as arrhythmia and liver damage. It is desired to develop drugs that require fewer drugs and are also effective for intractable depression.

The present inventors focused on the fact that these diseases are deeply related to the amount of catecholamines in the body, and as a result of intensive research,
The present inventors first obtained threo-adrenergic acid (
threo-adrena 11necarboxyl
ic2cid) was found to be effective against these diseases. That is, threo-adrenergic acid showed a suppressive effect on harmaline-induced tremor, and also suppressed the decrease in body temperature in mice caused by reserpine administration.

These effects have been shown in the Basic Association for Drug Development, Evaluation of Medicinal Efficacy (Pharmacological Test Methods, Vol. 1) published by Chijinshoin, published by Kazuhiro Edict, p. 71 to p. 77, and page J-j.
As described on page 7, it has been shown that 1-threo-adrenergic acid is useful as an anti-Parkinsonian drug and an anti-depressant drug.

The threo-adrenergic acid used in the present invention has the following formula [wherein,
The red stamp indicates an asymmetric carbon], and the threo-adrenergic acid used as an active ingredient in the present invention is preferably DL-unit or L-unit, DL-threo-adrenergic acid, that is, DL- Threo-J-(
The physicochemical properties and production method of N-methylserine (J,≠-dihydroxyphenyl) are disclosed in the patent application filed by the present applicant! 7-'/Of Hiroki≠Bunmei M, and the physicochemical properties and production method of L-threo-adrenergic acid, that is, L-threo-3-(3゜cudihydroxyphenyl)-N-methylserine, are disclosed in this application. Patent application filed by a person in 1972
−． It is described in detail in the specification of No. 22/727.

L-threo-3, goodihydroxyphenyla serine (hereinafter referred to as L-threo-DOPS), which has a similar chemical structure to the above-mentioned active ingredient compound used in the present invention, can be used as an antiparkinsonian or antidepressant. JP-A-62-1
26 Otsu No. 30 (Special Publications Sho! Otsu-4t2jtE No.) Publication and Unexamined Publications Shoj! -Although it is described in Publication No. 2074t7, compared to these, DL- or L- used in the present invention
Threoadrenergic acid or its salts are highly effective, and
Threo-adrenergic acid according to the present invention has been shown to move into the brain when administered intraperitoneally in animal tests, but L-threo-DOPS has not been shown to move into the brain.

Below, the physiological activity of the active ingredient compound of the present invention will be shown in experimental examples.

Example ddY mice (body weight 20-30 g, male) were used as one group, and poo of DL-threo-atrunalic acid was used.
■/k7 or 4ooη/k/ was administered intraperitoneally, and 30 minutes later, 10η/kg of Norumarin was further intraperitoneally administered to observe the shortening of the duration of the tremor. Then, the reduction rate of the shaking duration was calculated using the following formula.

The results are shown in Table 1, and a clear reduction in tremor duration was observed in the threo-adrenergic acid administration group, indicating that the drug is useful as an anti-Parkinsonian drug.

Case / Test drug (dose) Reduction rate (%) D
L-threo-adrenergic acid dodecharmaline (/□mg/ky) DL-threo-adrenergic acid C,t 00mv group) +21. stomach,
(/07nvk4) 37 Example ddY mice (body weight 20-301. After observing the descent, DL
- 750,097 kg or 20 of threo-adrenergic acid
00 Takumi/Moan was administered intraperitoneally. Body temperature was measured 2 hours after drug administration, and the results are shown in Table 2. Threoadrenergic acid clearly counteracts the decrease in body temperature caused by reserpine administration, and is useful as an antidepressant. It was shown that

Reserpine-2,! to 1 group of ddY mice (body size: 20-30 g, male) After subcutaneously administering L-threo-adrenergic acid of the present invention 100 μ/g, or D-threo-adrenergic acid synthesized in the same manner or DL-threo-adrenergic acid synthesized in the same manner, '-Adrenergic acid Zoo■/krk was administered intraperitoneally, and 1 hour later, body temperature was measured and improvement in muscle stiffness was observed. The results are 9 in Table 3.

Note) Number of individuals with marked improvement in muscle stiffness/Number of test animals. L-threo-adrenergic acid counteracts the hypothermia caused by reserpine, and also improves muscle strength, which is one of the main symptoms of Parkinson's disease. Improved stiffness. It is therefore clear that the compounds of the present invention are useful as antidepressants and antiparkinsonians.

The following experiment was conducted to investigate the acute toxicity of threo-adrenergic acid used in the present invention.

Threo-adrenergic acid was suspended in an O, S% OMO aqueous solution to male mice of the Example 1 group weighing 23 to 21 f' DDB l/-, the concentration was set to θr4/-, and the amount of liquid administered was 0. .3ff+7! /mouse and intraperitoneal administration was performed.

During the observation period for 7 days after administration, the body weight, feeding, and water intake of the threo-adrenergic acid administration group and the non-administration group were measured, but no differences were observed between the administration group and the non-administration group.

In addition, the results of autopsy, organ M amount, blood biochemical tests, and histopathological tests were also compared to the treated group.

There were no significant differences between the group and the non-administered group.

Since the threo-adrenergic acid used in the present invention is an amphoteric substance, it can form acid and base salts, and therefore can also be used as pharmaceutically acceptable acid and base addition salts.

For example, threo-adrenergic acid can be prepared and used in the form of a pharmaceutical composition containing threo-adrenergic acid as an active ingredient by blending it with a pharmaceutically compatible carrier. The carrier can be an inert organic or inorganic carrier material suitable for oral or parenteral administration, such as water.

Gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gum arabic, polyalkylene glycol, yellow petrolatum, etc.

The pharmaceutical composition may be in solid form (e.g. tablets, granules,
dragees, suppositories or capsules) or in liquid form (
eg solutions, suspensions or emulsions). The pharmaceutical composition may be sterile and may contain adjuvants such as preservatives, stabilizers, wetting agents, or emulsifying agents, salts or buffers for altering osmotic pressure.

The preparation may also contain other substances of therapeutic value.The dose of threo-adrenergic acid used in the invention is 18 p/d per adult for oral administration.
It is preferable to administer 0 mg to 2000 mg, but the dose may be increased or decreased as appropriate depending on age and symptoms.

EXAMPLES Below, examples will be given to illustrate specific aspects of the formulation according to the present invention, and reference examples will be given to illustrate production examples of the active ingredient compounds used in the present invention.

Example 1 DL-threo-adrenergic acid 100 mg, Avicel 4
10 my, calygoxymethyl cell o-su I my
, 3 parts of hydroxypropyl cellulose, and 2 parts of magnesium stearate are mixed together and processed into wet granulation method.
Ill tablets.

Example λ 20Qη of L-threo-adrenergic acid, lactose “Misaki” and magnesium stearate ξ■ were mixed and filled into No. 3 capsules using a filling machine S to prepare capsules.

Reference example/Manufacture of DL-threo-adrenergic acid (,) Ethanol, 3tnI! , in 3. II-
Dibenziluo beef cypenzaldehydoko. , Wf the puffer fish,
Add glycine, 21'f, while stirring well at room temperature.
Trigrams and sodium hydroxide 3. ．． An aqueous solution containing 2/rk/Qrnlf was added at once. The condensation reaction is carried out by heating the bath temperature to 77° C. over about 75 minutes. Heating was stopped immediately after the solution became clear. 37 in about 7 hours
When the mixture was allowed to cool to ℃ while stirring, a ten-oil-like precipitation occurred. 3
Add 2N hydrochloric acid, being careful not to let the internal temperature rise above 7℃.
The solution was added dropwise over a period of about J minutes/J minutes. During this time, the ushihaku-like precipitate υ′ (;! disappeared and became a suspended state. In the above reaction, the glycine/molecule first reacts with the aldehyde compound/molecule to form a ship base type compound. Nashi) The latter further reacts with another 7 molecules of aldehyde compound to undergo aldol condensation, and is further hydrolyzed with hydrochloric acid, resulting in ? −(3
, 4t-dibenzyloxyphenyl)serine took place. Furthermore, at room temperature? After stirring for a period of time, the precipitate was destroyed, the solid matter was washed with a mixture of 3N hydrochloric acid Jrl and ethanol Jrd, and the furnace washing liquid was combined with sodium acetate trihydrate at room temperature with stirring. was gradually added, and the amino acids began to precipitate during the operation. 2 under water cooling
Leave it for 7 days? : After the amino acid crude crystals are dissolved in P water, Z
After washing with Ord, the crystals are washed with water, concentrated hydrochloric acid,... 1-fnl and ethanol 10- was gradually added to a mixture of 1-fnl and ethanol 10- while stirring at room temperature to become a clear solution, and then activated carbon/, J? was added, stirred at room temperature for 20 minutes, and filtered. When the filtrate was gradually added with about 37% of 7-ethylamine (C) to bring the pH to 4, the amino acid gradually began to precipitate.The mixture was allowed to stand at 0°C overnight, and the crystals were separated, and then poured over phosphorus pentoxide. After drying under reduced pressure overnight, a mixture of DL-threo-3-(3,If--)benzyloxyphenyl)serine and DL-erythro, y-(a,q-dibenzyloxyphenyl)serine ( m, p.

/,? 3. g9fil'? Obtained.

(b) The above-mentioned DL-threo- and DL-erythro a-(3,t,t-dibenzyloxyphenyl)serine hybrid/gu? Total ethanol♂, DaIIno and JN
The mixture was added to a mixture of hydrochloric acid and water to dissolve it, the solvent was distilled off under reduced pressure, and the residue was thoroughly washed with diethyl ether and dried to obtain the corresponding hydrochloride salt 52.

This DL-Threo-/DL-Erythro J-(3, II
- Dibenzyloxyphenyl) serine hydrochloride mixture /, s2 is reconsolidated and converted from ingropanol - cDL
-Sureo,? -(,3,!-dibenzyloxinenyl)serine hydrochloride. , dotzv (melting point: /gJ~/gua°C) was obtained. 1. The mother liquor is concentrated under reduced pressure and the precipitate is P
DL-erythro, 7m(,3,,-dibenzyloxyphenyl)serine hydrochloride o,,y,2q? c.
Melting point: /3o~/37°C) was obtained.

(c) The above DI, -Threo-3-(,?,tt-
(dibenzyloxyphenyl) serine 2/, Off methanol (5OO-) and water (230 ml) was dissolved in a mixture of benzaldehyde/l, 0? 17um aqueous solution! 3Ornll was added, and the mixture was stirred and reacted at room temperature for 3 hours. Subsequently, sodium borohydride J, 70 W was added over 1S minutes under ice-cooling and stirring, and then stirring was continued for an additional 7 hours at room temperature to carry out a reduction reaction. The reaction solution was ice-cooled again and acetic acid was added to decompose the excess sodium borohydride (I) and neutralize it, resulting in the formation of a precipitate. After stirring for several hours under water cooling, the precipitate was dissolved in F.
Wash sequentially with water and metall, dry under reduced pressure and DL
-Sley J-3-(3,+-dibenzyloxyphenyl)-N-benzylserine, 2/, 0? f Obtained as a white powder.

Melting point: /73~/7℃ (decomposition) Elemental analysis: coo Calculated value as H29o5N: C7
4A, j6%, Hl, oo%, Nj, 90% actual value: a74t,, 2s%, HJ, Qli%, Ns, 7g% (d) DL-threo obtained in the previous section (C),
? -(,?,dacypenzyloxyphenyl)-N-benzylserine/0. OS"i?J% suspended in 300 ml of aqueous ethanol, and with stirring /N sodium hydroxide IJ
um aqueous solution tOg and 37% formalin water bath liquid 0g
When the mixture was added and stirred at room temperature for 3 hours, a reaction with formaldehyde took place and the reaction solution became transparent.

followed by sodium cyanoborohydride8. The. After stirring at RT for 1 hour, the reaction was carried out, the reaction mixture was cooled on ice, and acetic acid was added to make it acidic, and the product precipitated. After stirring for 2 hours under water cooling under VC, the washed carpet was washed with water and methanol in sequence, dried under reduced pressure and dried with DL-threo. -(,?,goodipenzyloxinenyl)-N
-Benzyl-N-methylserine glue, 0! ff Obtained as white crystals.

Melting point near 33-735°C Elemental analysis: 03. H31Ns and shite calculation value; c
7 q, s' s%, Hl, 211 Rini,
Nx, gx% actual measurement fM: 074.7? %,
Ht, 2. B (,, N, z, 7o% (e) previous section (d
) DL-, z, rheo-3-(,3,II-dibenzyloxyphenyl)-1'J-hensyl-N-methylserine s, o y obtained in acetic acid/Jo- and ethanol/J
Dissolved in a mixture of Oml and 10% palladium-carbon/,j
After adding Ot, the mixture was stirred for 3 hours under a cumulative flow of warm water to perform hydrolysis (elimination of benzyl group).

After removing the catalyst from the reaction solution, the furnace solution was concentrated under reduced pressure, and the residue was dissolved in some methanol (/c bath) and left to stand, resulting in the precipitation of a product. thing,
Z, /, 2? I got it. The above crude product was recrystallized from 30% aqueous methanol to obtain the desired "DL-threo 3-(3
, II-dihydroxyphenyl)-N-methylserine or DL-sunoadrenergic acid was obtained.

Melting point: /z3~/Jj℃ (decomposition) NM 几 (δ value 2M water-bihydrochloric acid, TMS as external reference) 23.0-! (s, j'H),'1.07 (
d, /H, J=7jJz)j,,5-. 2(d
, /H), 7.2.3~7.4', 2 (m, ,
3H) Elemental analysis: C16H@305N”1
12 (Calculated value as J: C Guza, Ri 7%, Ht, /2
%,N! ;, 7/% real Ill f direct: cqg, ri/
%, HA, 2g%, Nj,! t% Reference Mffi of reference mucothreo-adrenergic acid (a) DL-threo=, p-(3) obtained in the above reference example/(b)
, DL-threo-, ?, prepared by reacting N-p-methoxyhenzyloxy(alponyloxysuccinimide) serine with N-p-methoxyhenzyloxy(alponyloxysuccinimide) as an amino group-retaining reagent. -(,?,Hiroshi-
dibenzyloxyphenyl)-N-p-methoxybenzyloxycarminylserine was dissolved in 20rt''z, ethanol, ?go7. Optically active (to) was added to this solution.
-11 of ephedrine. / gr (0,7 equivalent) was solved in 6 ways. This mixture, i.e. the salt f' formed from both compounds? Containing solution? Left for 3 days in Murogo ◇ Optical resolution occurs due to the difference in '/6 solubility of the salt.

After that, the precipitated crystals were separated and washed with ethanol.
, ;'4 I did. The obtained crude crystals were completely recrystallized using a methanol:chloroform (,2:/) mixture.
D-threo 3-(,3, siedibenzyloxyphenyl)-N-p-methoxybenzyloxycal? Nilserine and (he)-ephedrine salt, zV obtained 1,
The analytical value of this compound is: l? It was 9.

1" point near 70~/7/℃ [α]L6=-3S0 (clo, dimethylformamide) elemental analysis 204□T-146N209 Calculated value: Cz7.77, H/,, lI/, N3. g
Measured value of %: 7.7g for C, HJ, /L-za,
N, 3.72% On the other hand, the mother liquor of residue 1 after separating the precipitated crystals by F was concentrated to dryness, and the remaining liquid was dissolved in 10 mp of ethyl acetate.
, vcH and washed with 1.9N salt & tomtvc.

The ethyl acetate layer was washed with 30 ml of water, and the washed water was extracted with ioml of ethyl acetate. Combine the ethyl acetate layers,
It was dried over anhydrous sodium panicate and concentrated to dryness. The obtained solid was recrystallized from a mixture of chloroform-hexane for two times to obtain L-threo-3-(,j',41-dibenzyloxyphenyl)-N-p-methoxybenzyloxycarbonylserine q. -sqv2 obtained.

The analytical values of the obtained compound were as follows.

Melting point: / J y, s ~ / , 3/, 0°C [α]%7
: -/7'(C(1), 7/, ri o o form:
Meta/-ru=10:/) Elemental analysis: Calculated value as O32N3INOB: (j,
l', '7. ? ,H,ff,Otsu0,N,2. j
/% Actual 611] Value: C, 7/, HJ, t2
, N, 2.110%゛(b) D-threo-a-(3,
dibenzyloxyphenyl)-N-p-methoxybenzyloxycarbonylserine-(he)-ephedrine salt,
In addition to step 7, perform all extractions and further add ethyl acetate layer to Vc, 3
It was washed with N-hydrochloric acid, followed by 30 vC of water. The water washing solution was dried with ethyl 100-glue (citrus extract, ethyl acetate layered with ethyl acetate, water chloride, ffunato IJum), and concentrated to dryness.The solid obtained was The product was recrystallized from a mixture of chloroform-hexa/, and D-threo-3-(,3,<t-dibenzyloxyphenyl)-
N-p-Metho dibenzyloxycarinylserine, <
, JJ7 was obtained. The analytical values of the obtained compound are as follows.

Point: / ,? o,s~/3/,,! ℃
[α] Amase+/g0 (cO, li/, chloroform:methanol-10:/) Elemental analysis: Calculated value as 032 N31 NO8:
Otg, 9G, N3. Ao, Nx,! ;/% Actual value:
OAl, 9g, HJ, 17. N, 2.110% (C)
The L-threo obtained in the previous section (b), ? -(,?.

(p-methoxybenzyloxyphenyl)-N-p-methoxybenzyloxycarbonylserine 41.7ff Impropatool/gomlK (elimination of oxycar-nyl group).

After collapsing under reduced pressure at a temperature of about 1/00 rnl, the mixture was stirred for 3 hours under water cooling. The precipitated crystals were dried under reduced pressure to obtain L-threo-,3-(3,II-dibenzyloxyphenyl)serine dichloride salt 3.0V77.
39(,). The physical properties of the obtained compound were as follows: Melting point: 743.5-757°C [α:) 2.7: -J, 3° (c/, 0, ethanol) Elemental analysis: Cz 3H23N O,s・H
Calculated value as OA: at<t,, zt,, Hs, t7
．． Na,,zt% actual measurement value: ctq,,2y,Hs,t
, y, Na, 71% (d) The thus obtained 1-threo-3-(,?, goo-dibenzyloxyphenyl) saison hydrochloride, 7 parts, was mixed with 2 m of anhydrous acetone at room temperature.
After adding anhydrous potassium carbonate/01F and stirring at room temperature for about 70 minutes, dimethyl sulfate, 3.9.3
The N-methylation reaction was carried out by adding a small amount of water and stirring overnight at room temperature.

As a result, L-threo-3-(,?,%-dibenzyloxyphenyl)-N-methylserine methyl ester was produced, and anhydrous potassium carbonate was removed from the reaction solution containing this compound, followed by washing with acetone. In the P washing liquid/N
Hydrochloric acid and j J rrrl were added, and the mixture was stirred at room temperature for 7 J minutes (saponification reaction). The reaction mixture containing L-sunoh, r-(3,gudibenzyloxyphenyl)-N-methylserine was filtered, and the tear washing liquid was distilled off into aceb7 at 30°C or below, and ethanol 3-gd and gN Sodium hydroxide 27π
After stirring at room temperature for about 30 minutes, stir under water cooling (・
When the mixture was neutralized with TE/N hydrochloric acid to a pH of ff-J, crystals were precipitated. Dry the precipitated crystals under reduced pressure.
-Sulfo3-(,y,4t-dibenzyloxyphenyl)-N-methylserine O♂1 was obtained*(yield q
s9g). The physical properties of the obtained compound are as follows.

Melting point: /12~/t 4t℃ [α] M: 10g, Q° (c/, 0, ethanol:
/N Hydrochloric acid/:/) Elemental analysis = C24■I2. Calculated value as NO5: 070.7'l, HA, 7g, N'3,
g+% actual 61J value: c7o, :zt, Ht, 2o,
N3. xy%(e) n/ζL-threo obtained in the previous section
,y-(,3,goodibenzyloxyphenyl)-N-
Methylserine/! ; Suspended in ethanol solution containing 10% gold and hydrochloric acid (3.7), further added with 70% palladium on carbon/JOη, and left overnight under a stream of hydrogen at normal pressure.
1j Stir to carry out the cumulative decomposition reaction of sword water. 7cc Desorption of benzyl group) 0 Reaction bath liquid 'k Filter, and remove solution F under water cooling.
Neutralization was performed with an ethanol solution containing 0% diethylamine.

After being left at -7.5'℃ for 3 hours, it was filtered, washed with a small amount of ethanol, and L-threo-8-(,y,
ta-,)hydroxyphenyl)-N-methylserine,
That is, gJOη of L-threo-adrenergic acid was obtained. The obtained L-threo-adrenergic acid somg contains ascolpi/acid/, 7η, STd! Recrystallize with
(2) was obtained (yield 72%). The physical properties of the obtained compound were as follows: Melting point: , zos-, zog'c
C decomposition) [α] = r) 72 -7g0 (c/, o, /N
N Hydrochloric acid 9 elements analysis a Q1oH+3NOs −// 'l
N20 Tol,, 'T-calculated value: C,! ;/, g
, 3. H, 3, g7. N1.0<t% Actual value: c, s
, :z,,z,3. H, s, po, N,! ;,
9.2% Nogaya 1007-8, Machida City Author: Hajime Morishima 1-1-32-301 Nakameguro, Meguro-ku, Tokyo Author: Hirotsugu Tomimoto 1-7-1-101 Hosoyama, Tama-ku, Kawasaki City

Claims (1)

[Claims] Antiparkinsonian and antidepressant drug containing threo-adrenergic acid as an active ingredient.