JPS62234029A - Remedy for central nervous disorder - Google Patents

Abstract

PURPOSE:An agent, containing 1-methyl-4,5-dihydroorotyl-histidyl-prolinamide as an active ingredient and useful for treating central nervous disorder, e.g. disturbance of consciousness, senile dementia, etc., and hardly causing side effect. CONSTITUTION:A remedy containing 1-methyl-4,5-dihydroorotyl-histidyl- prolinamide expressed by the formula or an acid addition salt thereof as an active ingredient. The compound expressed by the formula has improved arousal promoting action and pentobarbital anesthetic antagonistic action, is capable of remarkably activating acetylcholine neuron of hypothalamus, brain stem reticular formation, brain cortex and hippocampus and suitable as a remedy for disturbance of consciousness and senile dementia and further exhibiting increasing action on conductivity and excitability of spinal movement neuron membrane and usable for treating spinocerebellar deformity. The agent has relatively less side effect (TSH releasing action, etc.) and higher safety than TRH and various derivatives thereof.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to a therapeutic agent for central nervous system disorders.

(Prior Art) TRH (thyrotropin releasing hormone: L-pyroglutamyl-histidyl-prolinamide) has been known to be useful as a therapeutic agent for disorders of consciousness caused by brain dysfunction. ing. However, T
RH has the effect of releasing TSH (thyroid stimulating hormone) as a side effect, so TRH has less side effects.
As a derivative (2,3,4,5-tetrahydro-2-oxo-5-furancarbonyl)-L-histidyl-
Shi-prolinamide [JP-A-52-116465] and orothy-histidyl-prolinamide [Japanese Patent Publication No. 59-36612, Japanese Patent Publication No. 60-951
Publication No. 8] etc. have been reported.

(Structure and Effects of the Invention) The present invention relates to a novel therapeutic agent for central nervous system disorders containing 1-methyl-4,5-dihydroorotyl-histidyl-prolinamide or its acid addition salt represented by the following formula as an active ingredient.

H Compound (I) or its acid addition salt, which is the active ingredient of the present invention, has a central nervous system activating effect that is superior to TRH and various conventionally known TRH derivatives, such as an awakening promoting effect, a spinal reflex enhancing effect, Bendoparbital has anesthetic antagonistic effects, locomotor activity increasing effects, antireserpine effects, and dopaminergic effect enhancing effects, and also has relatively few side effects (e.g.
It has the characteristics of low TSH release effect) and high safety. Therefore, the therapeutic agent according to the present invention is useful as a central nervous system activator that is more excellent than TRH, various TRH derivatives, or compositions containing the same, and can be used for the treatment of various central nervous disorders. I can do it.

For example, as shown in the experimental examples described below, the therapeutic agent of the present invention has excellent wakefulness promoting effects and bendoparbital anesthetic antagonizing effects, and significantly inhibits acetylcholine neurons in the hypothalamus, brainstem reticular formation, cerebral cortex, and hippocampus. can be activated. Therefore, the therapeutic agent of the present invention can be used as a therapeutic agent for various symptoms based on these functional declines, such as impaired consciousness, senile dementia, coma, decreased attention, or language disorder.
In particular, it can be suitably used as a therapeutic agent for disorders of consciousness or a therapeutic agent for senile dementia. Furthermore, the therapeutic agent according to the present invention exhibits an effect of increasing the conductivity and excitability of the medullary motor neuron membrane, that is, an excellent effect of enhancing spinal reflexes, and can be used for the treatment of spinocerebellar degeneration. Furthermore, the therapeutic agent according to the present invention can activate dopamine neurons in the nucleus accumbens and striatum, as seen in its excellent locomotor activity increase and dopaminergic action enhancing effects, and these pharmacological effects It can also be used to treat Parkinson's disease, Lennox syndrome, autism, hyperactivity disorder, schizophrenia, and weak will. Furthermore, since the therapeutic agent of the present invention has an excellent anti-reserpine effect due to the activation of noradrenaline and serotonin neurons in the brain, it is effective against various symptoms associated with the decline in the function of the nervous system,
For example, it can be used to treat depression and the like.

Compound (f), which is the active ingredient of the present invention, contains three asymmetric carbon atoms and has eight optical isomers, but the present invention does not apply to all of these optical isomers or any mixture thereof. It is included in that scope. However, among these isomers, (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-7' lolinamide is particularly preferred for pharmaceutical use.

Compound (1), which is the active ingredient of the present invention, can be used as a free base or as an acid addition salt. When using the acid addition salt of compound (1), it is particularly desirable to use it as a pharmacologically acceptable acid addition salt, and preferred examples of such acid addition salts include -hydrochloride,
inorganic acid addition salts such as hydrobromides, sulfates, nitrates,
and organic acid addition salts such as acetate, tartrate, maleate, succinate, citrate, methanesulfonate, malate, oxalate, and benzenesulfonate. These salts can be produced, for example, by treating compound (I) with an acid.

In addition, therapeutic agents containing Compound (I) or an acid addition salt thereof (preferably a pharmacologically acceptable acid addition salt) as an active ingredient include:
It can be administered either orally or parenterally, and during administration, it is preferable to use compound (I) or its acid addition salt in a mixture with an excipient suitable for oral or parenteral administration. Suitable excipients include, for example, starch, lactose, potassium phosphate, cornstarch, acacia, stearic acid, and other known pharmaceutical excipients. The dosage form may be, for example, a solid preparation such as a tablet, powder, capsule, or granule, or a liquid preparation such as a solution or suspension. moreover,
When administered parenterally, it can also be used as an injection.

The dosage of the therapeutic agent according to the present invention varies depending on the route of administration; the patient's age, weight, condition; and the type of disease, but generally the dosage of compound (1) or its salt is 0.5 μg.
~5mg/kg/day, especially 10μ for oral administration
g -1 mg/kg/day, or 1 to 100 for parenteral administration (e.g., intravenous, intramuscular, subcutaneous)
Preferably, the amount is μg/kg/day.

Compound (1), which is an active ingredient of the present invention, is, for example, a reactive derivative of a compound represented by the general formula (where XI represents an imino group or a protected imino group) (e.g., acid halide, mixed acid anhydride, compounds, active esters, etc.) and general formulas (however, X2
represents an imino group or a protected imino group. ) or its acid addition salt (e.g. hydrochloride,
p-1-luenesulfonate, etc.), and in the product obtained above, if xl and/or , if desired, can be prepared by forming the product into its acid addition salt.

The above condensation reaction is carried out according to the conventional method for peptide synthesis, for example, in a suitable solvent, using a deoxidizing agent (for example, triethylamine).
It can be carried out in the presence or absence of.

When the group x1 and/or x2 is a protected imino group, removal of the protecting group can be easily carried out according to the appropriate conventional method depending on the type of the protecting group, and acid addition salts of compound (I) can be removed. can be obtained by treatment with a stoichiometric amount of acid.

All of the above reactions proceed without racemization.

Furthermore, the raw material compound (If) is, for example, 4,5-dihydroolfofthic acid [The Journal of the American Chemical Society (J, Am.

Chem, Soc, ), 75.6086 (1953
)) in the presence of a deoxidizing agent (e.g. triethylamine)
4 obtained by reacting with benzyl chloride at 50-50°C,
It can be produced by methylating 5-dihydrooroftic acid benzyl ester with methyl iodide, optionally introducing a protecting group into the 3-position, and debenzylating it by catalytic reduction.

In this specification, "l-methyl-4,5-dihydrooroftic acid" and "1-methyl-4,5-dihydroorotyl 1" refer to "1-methyl-1,2,3,4,5゜6-hexahydro-2,6-thioxo-4-pyrimidinecarboxylic acid” and “1-methyl-1,2,3,4,5,6-hexahydro-2,6-thioxo-4-pyrimidinecarbonyl” respectively. The specimens used in Experimental Examples 1 to 4 below are as follows.

(Specimen used in the experimental example) Compound of the present invention: (1-Methyl-L-4,5-dihydroorotyl)-L-histidyl-prolinamide Comparative sample No. 1: (2,3,4,5-tetrahydro -2-oxo-L-5-furancarbonyl) -L-histidyl-prolinamide [compound described in JP-A-52-116465] Comparative sample No. 2-niorothyl-L-histidyl-prolinamide Publication No. 59-36612 and Special Publication No. 6
Compound described in Publication No. 0-9518] TRH: L-pyroglutamyl-di-histidyl-prolinamide Experimental example 1 [Pharmacological test by oral administration] (Experimental method) (1) Anti-serbin ileserpine (dose: 3 mg /kg) was administered subcutaneously.
Male Std/ whose body temperature shows 30℃ or less after 7 to 20 hours
The sample aqueous solution was orally administered to ddY mice. Antireserpine effect of the specimen (i.e., reserpine-induced hypothermia antagonism)
The rectal temperature was measured at 30, 60, 120, 180, and 300 minutes later, and was determined from the area on the body temperature curve between them. The increase in body temperature in the sample administration group was compared with the increase in body temperature in the control group (group in which distilled water was administered instead of the sample solution).

(2) Male Std/ddY mice were placed in locomotor activity measurement bag W (Am
Each animal was placed in a bulometer (manufactured by Ohara Medical) for 30 minutes to acclimatize to the apparatus. Then, the aqueous sample solution was orally administered to mice, and the amount of locomotor activity was measured for 3 hours immediately after administration. Note that distilled water was administered to the control group instead of the sample solution.

(3) Pendoparbital Asaku U An aqueous sample solution was orally administered to male Std/ddY mice. 15 minutes after administering the sample, administer bentoparbital sodium (
Administration i1: 55 mg/kg) was administered intraperitoneally to mice. The anesthetic antagonism of bendoparbital in the sample was determined based on the time taken from the disappearance of the righting reflex of the mouse until its recovery. Note that distilled water was administered to the control group instead of the sample solution.

The test substance dissolved in distilled water was orally administered to male Std/ddY mice. 60 minutes after sample administration (in case of TRH, administration 3)
0 minutes later), a crane with a diameter of 12 mm and a weight of 20 mm was placed on the top of the mouse's head.
A stainless steel cylinder (g) was dropped from a height of 45 cm to apply a shock to experimentally induce unconsciousness, and the time from coma after the shock to the onset of the righting reflex was measured.

Note that distilled water was administered to the control group instead of the sample solution.

(result) The results are shown in Tables 1 and 2 below.

Table 1 Table 2 Experimental Example 2 [Pharmacological test by parenteral administration] (Experimental method) (1) Same as the method described in Experimental Example 1. (However, the specimen was physiological saline. (2) Bendoparbital bentoparbital sodium (dose: 55 mg) /
kg) was administered intraperitoneally to male Std/ddY mice.

Ten minutes after the administration of bentoparbital sodium, the specimen dissolved in physiological saline was intravenously administered to mice whose righting reflex had disappeared. The duration of anesthesia was measured as the time from the end of sample administration until the righting reflex recovered. Note that physiological saline was administered to the control group instead of the sample solution.

(3) 16 to 20 hours after the subcutaneous administration of reserpine (dose: 3 mg/kg) for dopamine action enhancement, L-dopa (administration t: 200a+g/kg) was intraperitoneally administered to male Std/ddY mice. Thirty minutes after L-dopa administration, the test substance dissolved in physiological saline was intraperitoneally administered to the mice (in the case of TRH, it was administered 45 minutes after L-dopa administration). A locomotor activity measurement device (A
Measured using NIMEX (manufactured by FARAD). Physiological saline was administered to the control group instead of the sample solution.

A specimen dissolved in physiological saline was administered intravenously to male and female (C+) cats with myelomysection cut (C+) placed under artificial respiration. The medullary reflex was measured using an electric stimulation device (Nihon Kohden, 5EN-320) on the left side peroneal nerve.
1) Electrical stimulation (0.1Hz, 1+sec.

2-3.5V) L, flexion reflex of ipsilateral tibialis anterior muscle 3 after administration
Observed continuously for hours.

look! A sample dissolved in physiological saline was intravenously administered to male Std/ddY mice. 30 minutes after administration of the sample (15 minutes after administration in the case of TRH), a tube with a diameter of 12 tm was placed on the top of the mouse's head.
A stainless steel cylinder weighing 20 g was dropped from a height of 451 m to apply a shock to experimentally induce unconsciousness, and the time from post-impact stupor to the onset of the righting reflex was measured.

Note that physiological saline was administered to the control group instead of the sample solution.

(result) The results are shown in Tables 3 and 4 below.

Table 3 c): Efficacy ratio of the sample when TRH efficacy is set to 1 (calculated by parallel line test method).

Table 4 d): Minimum effective dose represents the minimum dose required for drug efficacy.

Experimental Example 3 (Experimental Method) TSH I A sample dissolved in 0.1% BSA (saline solution containing bovine serum albumin) was intravenously administered to male JCL:SD rats. Fifteen minutes after administration, blood was collected from the abdominal aorta under anesthesia, and blood TSH levels were determined by a two-antibody radioimmunoassay method (Midgley et al., Endocrinology, Vol. 79, p. 10 (1966)). BSA-containing physiological saline was administered to the control group instead of the sample solution.

(result) The results are shown in Table 5 below.

Experimental example 4 (experimental method) Blood! The sample aqueous solution was intravenously administered to male Std/ddY mice. Acute toxicity (LDsa) from mortality rate 24 hours after administration
I asked for

(Results) The results are shown in Table 6 below.

Table 6 Production Example 1 1-Methyl-L-4,5-dihydroolfofthic acid 1.03
g and 760 mg of N-hydroxysuccinimide are dissolved in 20 ml of dimethylformamide, and 1.4 g of dicyclohexylcarbodiimide is added at 0°C. This mixture is 0
Stir at ℃ for 1.5 hours. Then, L-histidyl-
2.8 g of diprolinamide dihydrobromide and 2 ml of triethylamine were added to the reaction solution at -5°C, and the mixture was heated from 0°C to 15°C.
Stir at ℃ for 2 days. Insoluble matter was filtered off, and dimethylformamide was distilled off under reduced pressure. Dissolve the residual fragrance in 1% hydrochloric acid and filter off the insoluble matter again. After washing the filtrate with 70 roform, add sodium bicarbonate to make it alkaline (ρFI8
) and passed through a column (2.7 x 34 cm) packed with styrene-divinylbenzene copolymer resin (trade name: MICGEL CHP-20P, manufactured by Mitsubishi Chemical Corporation, hereinafter referred to as "CHP-20P resin"). After washing the column with 300 ml of water, elute with water. Both fractions positive for the Pauli reaction are collected and freeze-dried. The product is crystallized from water, recrystallized from water, and then dried at 60°C under reduced pressure for 3 days. Then, 1 g of (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-prolinamide 1/2 permanent product is obtained.

A, p, 158-160°C (decomposition) 7/2 permanent product: T, p, 72-75°C Production Example 2 1-Methyl-DL-4,5-dihydroolfofthic acid was prepared in the same manner as in Production Example 1 above. (1-methyl-DL-4,5
-dihydroorotyl)-L-histidyl-L-prolinamide is obtained.

Monohydrate:

Claims (1)

[Scope of Claims] A therapeutic agent for central nervous system disorders comprising 1,1-methyl-4,5-dihydroorotyl-histidyl-prolinamide or an acid addition salt thereof as an active ingredient. 2. The therapeutic agent for central nervous disorders according to claim 1, wherein the active ingredient is 1-methyl-L-4,5-dihydroorotyl-L-histidyl-L-prolinamide or an acid addition salt thereof. 3. The agent for treating a central nervous system disorder according to claim 1, wherein the central nervous system system disorder is a disorder of consciousness, senile dementia, or spinocerebellar degeneration.