WO1998035671A1

WO1998035671A1 - Remedies for parkinsonism

Info

Publication number: WO1998035671A1
Application number: PCT/JP1998/000517
Authority: WO
Inventors: Masaya Kato; Hiroshi Iwata; Hiroshi Narita; Taiichi Katayama
Original assignee: Tanabe Seiyaku Co., Ltd.
Priority date: 1997-02-14
Filing date: 1998-02-06
Publication date: 1998-08-20
Also published as: AU5781098A; JPH10226646A; JP3865450B2

Abstract

Remedies for parkinsonism having efficacious pharmacological effects even if administered alone; and levodopa potentiators efficacious as a drug to be used in combination with levodopa in treating parkinsonism, each containing as the active ingredient compounds represented by general formula (1) or pharmacologically acceptable salts thereof, wherein R1 represents lower alkyl optionally substituted by cycloalkyl; and R2 represents lower alkyl.

Description

Description Parkinsonism treatment

Technical field

The present invention relates to an agent for treating parkinsonism. More specifically, the present invention provides an effective therapeutic agent for parkinsonium alone or in combination with levodopa. Background art

The treatment of Parkinson's disease and Parkinson's syndrome (hereinafter collectively referred to as Parkinsonism) has focused on the administration of levodopa (L-13,4-dihydroxyphenylalanine; L-DOPA), a precursor of dopamine. I have been. Levodopa, unlike dopamine, can cross the blood-brain barrier, is converted to dopamine in the brain, and is known to improve symptoms of parkinsonism.

However, most of the administered levodopa is rapidly converted to dopamine in peripheral tissues, and the amount of levodopa taken into the brain is small. Large doses are mandatory. Repodopa also produces side effects such as gastrointestinal symptoms (nausea, vomiting, etc.), cardiovascular symptoms (orthostatic hypotension, etc.), mental symptoms (excitation, restlessness, etc.), and neurological symptoms (abnormal involuntary movement, etc.) Therefore, development of a therapeutic agent for parkinsonism that replaces levodopa or a combination drug that reduces the dose of levodopa is expected. Disclosure of the invention

An object of the present invention is to provide a therapeutic agent for parkinsonism which has an effective pharmacological action even when administered alone for parkinsonism, and a levodopa action enhancer which is effective in treating parkinsonism as a concomitant agent with levodopa. This technical problem is solved by the embodiments described in the claims. The present invention has surprisingly solved the problem of the present invention in a naphthyloxazolidone derivative (Japanese Patent Application Laid-Open No. 5-155772) which is known to have an antidepressant action. O It is based on the finding that there are compounds that have

In one embodiment, the present invention provides a compound of the general formula (1)

Wherein R ¹ represents a lower alkyl group which may be substituted with a cycloalkyl group, and R ² represents a lower alkyl group. Or a pharmacologically acceptable salt thereof as an active ingredient The present invention relates to a therapeutic agent for nism.

In another aspect, the present invention relates to a levodopa action enhancer comprising, as an active ingredient, a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof.

In still another aspect, the present invention relates to a method for treating parkinsonism, comprising administering to a patient having parkinsonism a therapeutically effective amount of a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof.

In still another aspect, the present invention relates to a method for enhancing the action of levodopa by administering a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof to a patient receiving levodopa.

In still another embodiment, the present invention relates to the use of a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof for producing a medicament effective for treating parkinsonium. BEST MODE FOR CARRYING OUT THE INVENTION

In the general formula (1), R ¹ represents a lower alkyl group which may be substituted with a cycloalkyl group. The cycloalkyl group preferably has 3 to 6 carbon atoms, and particularly preferably a cyclopropyl group. The lower alkyl group includes 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and particularly preferably a methyl group. R ² represents a lower alkyl group, preferably having 1 to 6 carbon atoms, more preferably having 1 to 4 carbon atoms, and particularly preferably a methyl group. The compound of the general formula (1) has optical isomers, and in the present invention, any of the isomers or a mixture thereof may be used.

Specific examples of preferred examples of the compound represented by the general formula (1) include a compound in which R ¹ is a lower alkyl group substituted with a cyclopropyl group. In this case, a compound in which R ² is a methyl group is more preferable. . That is, for example, (R) -3- (6- (cyclopropylpyrmethoxy) -12-naphthyl) -5-methoxymethyl-2-oxazolidone is a preferred example. In addition, (R) -3- (6- (n-propoxy) -12-naphthyl) -15-methoxymethyl-2-oxazolidone, (R) -3- (6- (n-butoxy) 1-2- Compounds such as [naphthyl] -15-methoxymethyl-2-oxazolidone and (R) -3 (6-ethoxy-2-naphthyl) -15-methoxymethyl-12-oxazolidone are also preferable. The compound of the general formula (1) used in the present invention is a known substance and can be easily synthesized, for example, by the method described in JP-A-3-218367. Japanese Unexamined Patent Publication No. 3-218368 (European Patent Application Publication No. 0 425 209) is incorporated herein by reference. The compound represented by the general formula (1) can be used as a therapeutic agent or a levodopa action enhancer of the present invention either in a free form or in the form of a pharmaceutically acceptable salt thereof. The pharmacologically acceptable salt is not particularly limited, but is a salt with an inorganic or organic base, for example, an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal such as a calcium salt or a magnesium salt. Salts, ammonium salts and the like, or inorganic or organic acid addition salts such as hydrochloride, sulfate, acetate and benzenesulfonate. I can do it.

The therapeutic agent and the levodopa action enhancer of the present invention contain the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient as described above. In addition, various pharmacological experiments using mice have shown that it has an effective pharmacological action as a therapeutic agent for parkinsonism alone or as a levodopa action enhancer when used in combination with levodopa. Accordingly, the therapeutic agent and the levodopa action enhancer of the present invention are useful as a therapeutic agent for parkin finism in mammals, thereby providing an effective method for treating parkinsonism and a method for enhancing levodopa action. . In particular, when used as a levodopa action enhancer, it is useful because it can be expected to reduce the levodopa dose in patients receiving levodopa.

(1) Increased dopamine levels in the striatum and enhanced levodopa

Drugs that increase the amount of dopamine in the brain or drugs that enhance the action of levodopa

Although it is considered to be effective in treating Parkinsonism, the compound of the general formula (1) is considered to be effective in treating Parkinsonism because it has any action.

That is, the compound of the general formula (1) is useful even when administered alone as a therapeutic agent for parkinsonism due to the action of increasing the amount of dopamine in the striatum, and can be used as a levodopa action enhancer due to the action of enhancing levodopa. It is considered to be effective for treatment.

(2) Life extension effect under low pressure and low oxygen condition

Parkinsonism is a disease involving degeneration and shedding of nerve cells. Therefore, administration of a compound having a nerve cell protective effect is expected to prevent the progression of parkinsonism. The compound of the general formula (1) has been shown to have a life-prolonging effect in a low-pressure and low-oxygen state, and is considered to have a neuroprotective effect. .

(3) Antagonism of reserpine-induced akinesia

Reserpine-induced akinesia is thought to be associated with parkinsonism akinesia. The compound of the general formula (1) exhibits a strong antagonistic effect on reserpine-induced akinesia, which is more effective than the effects of amanthuin gin and deprenyl hydrochloride, which are used as a therapeutic agent for parkinsonism. Since it is powerful, it is considered to be effective as a therapeutic agent for parkinsonism.

The amount of the compound of the present invention to be administered in the treatment method of the present invention and the method for enhancing levodopa action varies depending on the age / weight / status of a patient with parkinsonism requiring the treatment, the degree of disease, and the like. The compound of 1) or a pharmaceutically acceptable salt thereof is usually administered at 0.01 to 25 O mg Z kg per day. The therapeutic agent and the levodopa action enhancer of the present invention are capable of being administered orally or parenterally. In particular, it is preferably administered orally.

The dosage form for oral administration may be a solid preparation such as tablets, powders, capsules, and granules, or a liquid preparation such as a solution or a suspension, together with a pharmaceutical carrier suitable for oral administration. It can be used as a pharmaceutical preparation. Such pharmaceutical carriers include, for example, binders (syrup, gum arabic, gelatin, sorbite, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, phosphate, sorbite, glycine, etc.) Lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (potato starch, etc.) and wetting agents (sodium lauryl sulfate, etc.).

On the other hand, dosage forms for parenteral administration include, for example, distilled water for injection, physiological saline, and It is preferable to use an aqueous solution of dextrose or the like to prepare an injection or an infusion. Further, the compound of the general formula (1) has extremely low toxicity, and is an active ingredient of the present invention in five mice (SIc: ddY strain, male) (R) —3— [6- (cyclopropylmethine). Toxi) 12-naphthyl] -15-methoxymethyl-2-oxazolidone 2 / kg was orally administered and observed for 2 weeks. No deaths were observed. In addition, its pharmacological action is remarkable, and as shown in the Examples below, it shows a more remarkable effect as compared with amantadine hydrochloride and deprenyl hydrochloride which are used as therapeutic agents for parkinsonism. Highly useful as a levodopa effect enhancer.

In this specification, parkinsonism is a general term for Parkinson's disease and Parkinson's syndrome as described above. Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

The compound of the present invention (R) -3- [6- (cyclopropylmethoxy) -12-naphthyl] -15-methoxymethyl-2-oxazolidone used in each example is disclosed in Japanese Patent Application Laid-Open No. 3-218183. The compound was synthesized according to the description in Example 27 of JP-A No. 67. Amandine gin hydrochloride and deprenyl hydrochloride, which are used as therapeutic agents for parkinsonism, were used as comparative control drugs.

Example 1

Increased dopamine levels in rat striatum

The compound (R) -3- [6- (cyclopropylmethoxy) -2- (naphthyl) -1-5-methoxymethyl-2-oxazolidone of the compound of the present invention is converted to 0.5% carboxymethylcellulose Na (CMC. Na, And suspended orally at a dose of 1 OmgZkg to eight S1c: SD male rats (10 weeks old, Japan SLC, Inc.) in 8 animals per group. Two hours after administration, the brain tissue is excised, the striatum is divided and collected, Dopamine levels in stria were measured by high performance liquid chromatography-electrochemical detection.

. Using deprenyl hydrochloride as a control drug, the striatum was collected 4 hours after oral administration at a dose of 1 Omg / kg and the amount of dopamine was measured. As a control group, 0.5% of CMC. Na containing no drug was similarly administered.

As a result, as shown in Table 1, the compound of the present invention increased the amount of cerebral striatal dopamine by about 15% as compared with the control group. Deprenyl hydrochloride did not affect dopamine levels. table 1

*: Ρ <0.05 Example 2

Repodopa enhancement

One group of 10 CD-1 male mice (5-week-old, Charles River Japan, Inc.) were treated with (R) -3- (6- (cyclopropylmethoxy) -12-naphthyl) of the compound of the present invention. Oral administration of 5-methoxymethyl-2-oxazolidone or the control drug debrenyl hydrochloride, 60 minutes later, levodopa (L-3,4-dihydroxyphenylalanine: Sigma) 15 Omg / kg intraperitoneally Was administered internally. From 30 minutes later, the presence or absence of excitatory behavior was observed for 20 minutes, and the levodopa enhancement rate (%) was calculated based on the following equation. Test drug is the dose giving levodopa enhanced rate of 50% and ED _50, ED ₅ assumes a probit interface model. Values and 95% confidence limits were calculated. Repodopa enhancement rate (%) = 100 x (the number of individuals in the group that showed excitement behavior 10) Lepodopa was dissolved in physiological saline and administered intraperitoneally at a dose of 1 OmlZkg. The compound of the present invention was suspended in 0.5% carboxymethylcellulose Na (CMC. Na, manufactured by Wako Pure Chemical Industries, Ltd.) and orally administered at a dose of 1 OmlZkg. The comparative drug deprenyl hydrochloride was dissolved in distilled water and orally administered at a dose of 10 ml / kg. As a control group, 0.5% CMC. Na containing no drug was similarly administered.

As a result, an excitatory behavior was observed in the group administered with the compound of the present invention, and its ED ₅ was observed. The value was 5.9 Omg / kg, and levodopa potentiating effect was observed. On the other hand, deprenyl hydrochloride has a weak levodopa enhancing effect, and its ED ₅ . Values were greater than 10 OmgZkg. No excitement was observed in the control group. Example 3

Life extension effect in low pressure and low oxygen condition

One group of 10 CD-1 male mice (5-week-old, Charles River Japan, Inc.) were treated with (R) -3- (6- (cyclopropylmethoxy) -2-naphthyl) of the compound of the present invention. After oral administration of 10-methoxymethyl-12-oxazolidone (10 Omg / kg), 30 minutes later, the mouse was placed in a low-pressure hypoxic (170-172 mmHg) chamber, and body movement and respiration were performed. The time until survival was no longer observed (survival time) was measured. As a control group, 0.5% CMC. Na containing no drug was similarly administered.

As a result, the compound of the present invention increased the survival time by about 28% compared to the control group (p <0.05). It is generally known that a drug that exerts a central inhibitory effect has a prolonged life effect (neurocellular protective effect) at the dose at which it is expressed. Limited. The fact that the compound of the present invention exhibited a life-prolonging effect at a dose in which central depression was not recognized indicates that the compound of the present invention is useful in clinically for diseases associated with neurological deficits such as parkinsonism. It suggests the possibility of having a transcellular protective effect. Example 4

Antagonism of reserpine-induced akinesia

According to the method of Wo rms et al. [J. Ph. Rm. Exp. Ther., 240, 241-249 (19987)), the following method was used. One group of 10 CD-1 male mice (5-week-old, Charles River Japan, Inc.) were treated with (R) -3-3- [6- (cyclopropylmethoxy) 1-2-naphthyl] 1 of the compound of the present invention. Oral administration of 5-methoxymethyl-2-oxazolidone was followed immediately by intraperitoneal administration of reserpine (5 mgZkg). Ataxia was determined to be positive if the animal remained at the center of the 9.5 cm diameter circle on the white paper 2 hours after reserpine administration for more than 15 seconds. Effect on akinesia is a dose for inhibiting the onset of symptoms in 50% of animals ED _5. The ED ₅₀ value was determined using a probit model. In addition, a similar test was carried out using amandine gin hydrochloride and debrenyl hydrochloride as comparative control drugs.

In addition, reserpine (manufactured by Sigma) was prepared according to the method described in JP-B-32-145 and injected intraperitoneally at a dose of 10 m 1 / kg. That is, 12.5 cc of 1% orthophosphoric acid, 12.5 g of propylene glycol and 50 cc of distilled water are added to 25 Omg of reservin, and then 5.0 g of benzyl alcohol and distilled water are added to make the total amount. It was 500 cc. The compound of the present invention was suspended in 0.5% carboxymethylcellulose Na (CMC. Na, manufactured by Wako Pure Chemical Industries, Ltd.), and aman hydrochloride gin and deprenyl hydrochloride were dissolved in distilled water. Oral administration at a dose of Zkg. All doses were expressed as free body weight.

As a result, ED _{5 of} Amanyu Gin Hydrochloride. Is 42. SmgZkg, while the ED ₅₀ for hydrochloric fat Reniru is 1 4. 4mgZkg, ED ₅₀ of the compound of the present invention 3. a 3MgZkg, since was more potent than any of the comparative control agent Rece Excellent antagonism to Rubin-induced akinesia was observed. Equivalent

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents fall within the scope of the following claims. Industrial applicability

According to the present invention, there is provided a therapeutic agent effective for parkinsonism alone or in combination with levodopa. In particular, the therapeutic agent of the present invention has an effect of increasing the amount of dopamine in the striatum, an effect of enhancing levodopa, an effect of prolonging life under low pressure and hypoxia, and an effect of antagonizing reserpine-induced akinesia. It has excellent pharmacological effects. Further, according to the present invention, there is provided a levodopa action enhancer effective for treating parkinsonism as a concomitant drug with levodopa.

Claims

1. General formula (1):

Contract

(Wherein, R ¹ represents a lower alkyl group which may be substituted by a cycloalkyl group, and R ² represents a lower alkyl group.) Or a pharmaceutically acceptable salt thereof.

An agent for treating parkinsonism as an active ingredient.

2. The therapeutic agent for parkinsonism according to claim 1, wherein R ¹ is a lower alkyl group substituted with a cyclopropyl group.

3. The therapeutic agent for parkin sonism according to claim 1, wherein the active ingredient is (R) -3- [6- (cyclopropylmethoxy) -12-naphthyl] -5-methoxymethyl-2-oxazolidone.

-General formula (1):

(Wherein, R ¹ represents a lower alkyl group which may be substituted with a cycloalkyl group, and R ² represents a lower alkyl group.) Or a pharmaceutically acceptable salt thereof as an active ingredient Action enhancer.

5. The levodopa action enhancer according to claim 4, wherein R ¹ is a lower alkyl group substituted with a cyclopropyl group.

6. The levodopa action enhancer according to claim 4, wherein the active ingredient is (R) -3- (6- (cyclopropylmethoxy) -12-naphthyl) -15-methoxymethyl-2-oxazolidone.

-General formula (1)

(Wherein, R ¹ represents a lower alkyl group which may be substituted with a cycloalkyl group, and R ² represents a lower alkyl group.) Or a pharmaceutically acceptable salt thereof, which is therapeutically effective. A method for treating parkinsonism, comprising administering to a patient with parkinsonism.

8. The method according to claim 7, wherein R ¹ is a lower alkyl group substituted with a cyclopropyl group.

9. The method according to claim 7, wherein the active ingredient is (R) -3- [6- (cyclopropylmethoxy) -12-naphthyl] -5-methoxymethyl-2-oxazolidone. 10-General formula (1):

.OFT

(Wherein, R ¹ represents a lower alkyl group optionally substituted with a cycloalkyl group, and R ² represents a lower alkyl group.) Or a pharmaceutically acceptable salt thereof for enhancing the levodopa action of the compound or a pharmaceutically acceptable salt thereof. A method for enhancing levodopa action in a levodono, 'administered patient, comprising administering an effective amount to a levodopa-administered patient.

1 1. The method of claim 1 0, wherein R ¹ is a lower alkyl group substituted with a cyclopropyl group.

1 2. The method according to claim 10, wherein the active ingredient is (R) -3- (6- (cyclopropylmethoxy) -12-naphthyl) -15-methoxymethyl-2-oxazolidone.

1 3. General formula (1) for producing a medicament effective for treating Parkinsonism

14. The use according to claim 13, wherein R is a lower alkyl group substituted with a cyclopropyl group.

15. The use according to claim 13, wherein the active ingredient is (R) -3- [6- (cyclopropylmethoxy) -2-naphthyl] -5-methoxymethyl-2-oxazolidone.