JP2000247993A - Sigma receptor agonistic agent containing triterpenoid- based compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine acting through a σ-receptor without generating extrapyramidal tract disturbance, further having an affinity to the σ-receptor and useful for the treatment of psychosis, schizophrenia, etc., by including a specific triterpenoide-based compound as an active ingredient. SOLUTION: This agent contains a triterpenoid-based compound of the formula [X is O, CH(OH) or the like; Y1, Y2 are each H, a 1-6C alkyl or the like, and a substituting group on (CH2)n group; a double line composed of a solid line and a broken line is C-C single bond or double bond; (n) is 1-6], (e.g.; 3- epibetulinic acid) as an active ingredient. The compound of the formula is obtained by separating a methanol extract of a dried plant of Leptodermis potaninii with a column chromatography, evaluating the σ-receptor binding inhibitory activity of the obtained fractions, further repeating the separations and activity evaluations to follow and separate the active component and finally purifying and isolating as a single component.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a pharmaceutical use of a triterpenoid compound having an activity of specifically binding to a sigma receptor.

[0002]

2. Description of the Related Art Antipsychotics are used not only for the treatment of schizophrenia but also for the treatment of cerebrovascular disorders and problematic behaviors in senile dementia (aggressive behavior, mental excitement, wandering, delirium, etc.). For example, it is known that dopamine nervous system function in the brain is overactive in schizophrenic patients,
Conventional antischizophrenic drugs have been developed for the purpose of blocking dopamine receptors, and typical examples include haloperidol and chlorpromazine. However, these conventional anti-schizophrenia drugs frequently cause extrapyramidal side effects such as Parkinson's symptoms, akathisia, and acute dystonia.In addition, long-term administration may cause intractable delayed dyskinesia. It is a problem. In addition, there are many cases in which these conventional anti-schizophrenia drugs do not improve.

In order to solve this problem, in recent years, the development of antipsychotic drugs has taken an approach from a completely different aspect from the conventional mechanism of action of the drug. One of them is a sigma receptor antagonist. For example, rimcazole (JP-A-55-64585) and BMY-14802, which are being developed as anti-schizophrenic drugs with few side effects.
(British Patent No. 2155925) have been found to have an affinity for the σ receptor. Also,
U.S. Pat. No. 4,588,728 discloses cis-9- [3
The treatment of psychosis with-(3,5-dimethylpiperazinyl) propyl] carbazole has been described.

US Pat. No. 4,709,094 discloses 1,3-disubstituted guanidines and their use in the diagnosis and treatment of hallucinations associated with mental disorders and chronic mental depression. U.S. Pat. No. 4,929,734 discloses N-substituted-1- (1,2,2,3).
3,6-Tetrahydro-3-pyridinyl) oximes and their use in treating depression or psychosis are disclosed. U.S. Pat. No. 5,061,728 discloses 4
It describes the use of -phenyl-1,2,3,4-tetrahydro-1-naphthalenamide derivatives in the treatment of psychosis and the like. The compounds claimed in all these patents have affinity as sigma receptor ligands.

On the other hand, the biochemistry of the sigma receptor ligand is described in pharmacological and clinical aspects by B. et al. L. (Eur. J. Pharmacol., 145, 34)
5 (1988) and S.M. I. Deutsche etc. (Clin
ical Neuropharmacology, 1
1, 105 (1989). However, at present, sufficient knowledge has not been obtained regarding the drug efficacy and side effects of these compounds described above.

[0006]

DISCLOSURE OF THE INVENTION The present invention acts on a sigma receptor without causing extrapyramidal obstruction,
An object of the present invention is to provide a triterpenoid compound which is useful as a new type of antipsychotic drug having an affinity for a receptor, particularly for treating a sigma receptor-related psychiatric disorder, mainly psychosis and schizophrenia.

[0007]

Means for Solving the Problems The present inventors have extensively studied the pharmacological action of various natural products and found that a triterpenoid compound represented by the following general formula (1) has an affinity for the σ receptor. I found it to have. Accordingly, the present invention provides a compound of the general formula (I):

[0008]

Embedded image (Wherein X is an oxygen atom, or the following formula:

Embedded image

Y ₁ and Y ₂ are hydrogen atoms, C ₁
A straight or alkyl or alkenyl of branched -C ₆ and (CH ₂₎ represents a substituent on n; doublet consisting of a solid line and the broken line carbon - represents a carbon single bond or a double bond; n represents an integer of 1 to 6. The present invention provides a sigma receptor agonist containing as an active ingredient a triterpenoid compound represented by the formula (1): A sigma receptor agonist has an affinity for sigma receptor,
It is a useful drug for treating diseases involving the receptor.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The preferred active ingredient of the sigma receptor agonist of the present invention is a compound represented by the formula (I) wherein X is an oxygen atom,
Or the following formula:

Embedded image Y ₁ and Y ₂ are each independently a hydrogen atom,
Methyl or isopropenyl; a double line consisting of a solid line and a dashed line represents a carbon-carbon single bond or a double bond;
And n is an integer of 3 or 4.

Preferred triterpenoid compounds are oleanane-type and lupine-type triterpenoids. More specifically, oleanolic acid and betulinic acid. Representative diseases to be treated with the sigma receptor agonists of the present invention are stress, anxiety, depression, psychosis and schizophrenia. The compound of the present invention can be separated and purified from natural products. For example, Leptodermis, a medicinal plant native to Sichuan, China
potaniniii Batal. , Rubiaceae) dried plant extract was separated by column chromatography, and the obtained fraction was evaluated for σ receptor binding inhibitory activity (primary screening). Are tracked and separated, and finally purified and isolated as a single component.

In the general formula (I) of the present invention, X represents oxygen
An atom or a hydrogen atom and a hydroxyl group;
Y₁And Y_TwoMay be the same or different, and hydrogen,
Methyl, ethyl, propyl, isopropyl, vinyl, 1
-Or 2-propenyl or isopropenyl is preferred
New The substituent Y₁And Y_Two(CH_Two) Placement on n
The replacement position is not particularly limited. n is preferably 3, 4 or 5
No. When X is OH and H, α-OH is preferred. Further
And Y₁And Y_TwoIs particularly preferably methyl or isopropenyl.
More preferably, n is 3 or 4. Furthermore, if n is 3
And Y₁Is H and Y_TwoIs α-isopropenyl
And n is 4 and Y ₁And Y_TwoIs 2
Compounds forming 0,20-dimethyl are particularly preferred.
No.

[0013] σ was carried out in the step of separating and purifying the inhibitory active compound and in confirming the activity of the isolated compound.
Receptor binding studies revealed that the compounds of the invention act as ligands for sigma receptors. The compounds of the present invention have been found to have significant affinity as sigma receptor ligands, although they are quite chemically different from the compounds of the prior art patents. Due to such activity, the compounds of the present invention are potentially useful in the treatment and prevention of certain sigma receptor-related psychiatric disorders, mainly stress, anxiety, depression, psychosis and schizophrenia.
The affinity of the triterpene compound of the general formula (1) of the present invention or a non-toxic salt thereof for the σ receptor is measured as follows.

Reference (Proc. Natl. Acad. Sci., Vol. 83,
8784-8788 (1986), E. Weber et al), and the ability of the compound of the present invention to inhibit σ receptor binding is measured by the following procedure. 0.32 M sucrose is added to the whole brain excluding the cerebellum of a Hartley male guinea pig (6-week-old Japan SLC) and homogenized with a polytron homogenizer. This is 900 ×
g for 10 minutes at 2 ° C, and the supernatant was
Centrifuge at 2 ° C for minutes. 50 mM Tris / HC was added to the resulting precipitate.
l buffer (pH 7.4) was added, centrifuged at 18400 xg for 20 minutes at 2 ° C, and the precipitate was added to a 50 mM Tris / HCl buffer (pH
The mixture to which 7.4) has been added is lightly homogenized with a polytron to obtain a receptor crude membrane fraction sample. The obtained crude membrane fraction sample was quantified for protein by the Lowry method using BSA as a standard, and then dispensed into a tube.
And store frozen. Thaw these before use.

The obtained receptor crude membrane fraction sample (protein concentration 0.1-0.15 mg / tube) and 3H of final concentration 10 nM
-DTG ([5-3H] -1,3-di-o-triguanidine di- [p-ring-3H]-, [NEN]) and the test drug
After reacting at 90 ° C for 90 minutes, these
Using a glass filter (for Whatman GF / B30 probe) immersed in a Tris / HCl buffer (pH 7.4), the mixture was quickly suction-filtered with a cell harvester (manufactured by Brandel), and the ice-cooled Tris / HCl was used. Wash three times with HCl buffer.

The filter is punched into a scintillation vial, and after adding 8 ml of a scintillation cocktail, the filter is allowed to stand at room temperature for 24 hours, and its radioactivity (cpm) is measured by a liquid scintillation counter. To determine the total amount of binding, a solvent was added to the test drug, and to determine the amount of non-specific binding, haloperidol at a final concentration of 100 μM was added, and the measurement was similarly performed. The specific binding amount is obtained by subtracting the non-specific binding amount from the total binding amount, and the σ receptor binding inhibition rate of the test drug is determined by the following formula.

[0017]

(Equation 1)

The compounds of the present invention have a high affinity for the sigma receptor and certain central nervous system disorders involving the sigma receptor such as anoxia, anxiety, depression, convulsions, schizophrenia,
It is effective in treating hypoxia, cerebral ischemia, psychosis, stress and schizophrenia. The obtained general formula (I) of the present invention
The compound of formula (I) can be converted into a pharmaceutically acceptable non-toxic salt as required. Such salts include salts with inorganic or organic bases.

In this case, the cation forming a salt refers to a metal cation, ammonium NR ₄ (where R is hydrogen or a linear or branched alkyl group having 1 to 7 carbon atoms), and particularly preferred is a metal cation. The ions are cations of alkali metals such as sodium, potassium, lithium and the like, and alkaline earth metals such as magnesium and calcium. However, other metals, such as cations such as aluminum, zinc, iron, etc., are also included in the present invention. Ammonium includes ammonia, primary amine, secondary amine, tertiary amine ammonium and quaternary ammonium.

More specifically, ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, isopropylamine, diisopropylamine, butylamine, dibutylamine, isobutylamine, t-butylamine, Examples include ammonium such as ethanolamine, diethanolamine, and triethanolamine, and tetramethylammonium and tetraethylammonium.

In order to use a compound of the present invention or a non-toxic salt thereof as a medicament, a compound represented by the general formula (1) in combination with one or more pharmaceutically acceptable excipients or carriers for the preparation thereof: Or a pharmacologically acceptable salt thereof. The pharmaceutical composition according to the present invention is not limited thereto, but may be usually administered orally, parenterally, such as by nasal or intravenous injection, and the dosage may be in the form of administration, patient's age, weight, sex, symptoms, Although it varies depending on the like, it is generally about 0.1 mg to 500 mg, preferably 1 to 100 mg per day for an adult.
It can be administered in a daily dose in the range of mg.

Examples of the dosage form for the above formulation include tablets, pills, powders, granules, capsules and the like. For the production thereof, appropriate materials such as excipients, binders, disintegrants, surfactants and lubricants can be mixed and used as various carriers according to these preparations.

[0023]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Example 1 3-Epi-betulinic acid (3
-Epi -befulinic acid) (X = -CH in general formula (1)
(OH), solid line and dotted line = CC, Y1 = 19-isopro
Isolation of penil, Y2 = H, n = 3) Leptodermis po, a Chinese medicinal plant native to Sichuan Province, China and used as a folk medicine.
taninii Batal. , Rubiaceae) was separated by centrifugal liquid-liquid distribution chromatography (developing solvent system: chloroform / methanol / isopropanol / water), and the obtained fraction A (3.
58 g) showed inhibitory activity (inhibition rate 50%, substrate concentration 30 μg / ml).

Next, column chromatography (elution solvent: hexane / ethyl acetate) was carried out using a Si60 column, and the obtained fraction E (192 mg) exhibited inhibitory activity (inhibition rate 35%, substrate concentration 3 μg / ml). Was. This fraction was subsequently subjected to the same column chromatography on Si60 (solvent = hexane / chloroform / methanol), and the obtained fraction C (158 mg) showed inhibitory activity. This was subjected to column chromatography (solvent = hexane / ethyl acetate / methanol) using a Si60 rover column, and the obtained fraction B (108 mg) was again subjected to column chromatography under the same conditions. It became a substance and showed inhibitory activity. This compound was analyzed by spectroscopy such as NMR, MS and the like to give 3-ep-epoxy having the following structure (known).
It was found to be betulinic acid (3-epi-betulinic acid).

[0025]

Embedded image

Example 2 Its isolated as active ingredient
Other triterpenoid-based compounds The same medicinal plant as in Example 1 was subjected to the same separation procedure as in Example 1 and the same pharmacological evaluation was repeated to isolate and determine the structure of the compound exhibiting the σ receptor binding inhibitory activity. These compounds are known compounds oleanonic acid, 3-epi-oleanolic acid (3-ep
i-oleanolic acid) and betulonic acid
d).

[0027]

Embedded image

Example 3 σ of triterpenoid compound
Receptor binding inhibitory activity The affinity of the triterpenoid compounds obtained in Examples 1 and 2 for the sigma receptor was measured by the above-mentioned measurement method, and the results obtained are shown in Table 1.

[0029]

[Table 1]

[0030]

The triterpenoid compound of the general formula (1) according to the present invention has an affinity for the sigma receptor, and therefore has a disease associated with the sigma receptor, such as schizophrenia, depression, anxiety and cerebrovascular disorder, and senility. It is useful for treating behavior and for treating cognitive and motor dysfunctions such as neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease. It is also useful in treating addiction due to substance abuse (narcotics, stimulants, alcohol, psychotropic drugs, marijuana, etc.).

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61P 43/00 A61K 31/00 643D A61K 31/56 31/56 (72) Inventor Hideko Hanamura 1111 Tehiro, Kamakura City, Kanagawa Prefecture Toray Co., Ltd. Basic Research Laboratories (72) Inventor Wan Min Kui, People's Republic of China, Suit Ansen, Cheng Dous, Renmin Nanlu 4-9 (72) Inventor Din Li Sheng, People's Republic of China, Suit Ansen, Cheng Duus, Renmin Nanlu 4-9 F term (reference) 4C086 AA01 AA02 BA12 EA19 MA01 MA11 MA52 NA14 ZA02 4C091 AA06 BB02 CC01 DD01 EE04 EE07 EE10 FF02 FF06 GG01 HH01 JJ02 KK01 LL01 MM01 NN01 PA03 PA05 PB03 QB05 PB03 QB05

Claims (3)

[Claims] 1. The following general formula (1): (Wherein X is an oxygen atom or the following formula: Y ₁ and Y ₂ are hydrogen atoms or C ₁ -C ₆ linear or branched alkyl or alkenyl and represent a substituent on (CH ₂ ) n; The dash represents a carbon-carbon single or double bond; and n represents an integer from 1 to 6. A sigma receptor agonist comprising, as an active ingredient, a triterpenoid compound represented by the formula: 2. In the formula (1), X is an oxygen atom,
Or the following formula: Y ₁ and Y ₂ are each independently a hydrogen atom,
The sigma receptor agonist according to claim 1, wherein the double line consisting of a solid line and a dashed line represents a carbon-carbon single bond or a double bond; and n is an integer of 3 or 4. 3. The σ receptor agonist according to claim 1, wherein the target disease is stress, anxiety, depression, psychosis or schizophrenia.