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WO1999011266A1 - Remedes contre la sclerose en plaques - Google Patents

Remedes contre la sclerose en plaques Download PDF

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Publication number
WO1999011266A1
WO1999011266A1 PCT/JP1998/003897 JP9803897W WO9911266A1 WO 1999011266 A1 WO1999011266 A1 WO 1999011266A1 JP 9803897 W JP9803897 W JP 9803897W WO 9911266 A1 WO9911266 A1 WO 9911266A1
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WO
WIPO (PCT)
Prior art keywords
multiple sclerosis
salt
carbostyril
group
carbostyril derivative
Prior art date
Application number
PCT/JP1998/003897
Other languages
English (en)
Japanese (ja)
Inventor
Hiroshi Okazaki
Ko Tsutsui
Masakazu Adachi
Takao Taki
Original Assignee
Otsuka Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Otsuka Pharmaceutical Co., Ltd. filed Critical Otsuka Pharmaceutical Co., Ltd.
Priority to AU88887/98A priority Critical patent/AU8888798A/en
Publication of WO1999011266A1 publication Critical patent/WO1999011266A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a therapeutic agent for multiple sclerosis, comprising a specific carbostyril derivative or a salt thereof as an active ingredient.
  • Multiple sclerosis is a demyelinating disease of the central nervous system of unknown cause. It mainly affects young adults and multifocal demyelinating lesions occur in the central nervous system, such as the brain, spinal cord, and optic nerve, in a multiphasic manner. Progressive intractable neurological disease characterized by spatial multipleness.
  • Clinical symptoms can be any disorder of the central nervous system, but visual impairment due to disorders of the optic nerve and spinal cord, motor paralysis walking disorder, numbness, abnormal sensation, sensation, eye pain, etc. .
  • diplopia may occur in brainstem disorders and ataxia may occur in cerebellar lesions.
  • the most common age is between 20 and 40 years.
  • the etiology of the multiple sclerosis is unknown to date and there are autoimmune and viral theories, but none of them has been conclusive. As described above, the diagnosis of multiple sclerosis mainly depends on clinical characteristics because the etiology is unknown and there are no specific test abnormalities as described above.
  • MS multiple sclerosis
  • CM Poser
  • Treatment of multiple sclerosis can be divided into treatment for the etiology and symptomatic treatment for various CNS symptoms.
  • the etiology is unknown at present, so immunosuppressive drugs and anti-inflammatory drugs are used for its treatment, but its efficacy is difficult to determine.
  • corticosteroids are used, and when the symptoms are more acute and severe, pulsed steroids are administered.
  • Treatment for the chronic phase mainly consists of symptomatic treatment of neuropathy and rehabilitation.
  • IFN-1 / 3 IFN-1 / 3
  • IFN- / 3 IFN-1 / 3
  • S S has been approved.
  • a treatment method for multiple sclerosis has not yet been established, and the development of a drug having a preventive effect on the recurrence of multiple sclerosis and a therapeutic effect on various clinical symptoms has been developed in the art. It is desired.
  • an object of the present invention is to develop a drug having a preventive effect on multiple sclerosis and a therapeutic effect on various clinical symptoms, which are desired in the art.
  • R represents a benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring.
  • the carbon-carbon bond between the 3-position and the 4-position of the carbostyril skeleton indicates a single bond or a double bond.
  • a therapeutic agent for multiple sclerosis characterized by containing an effective amount of at least one selected from the carbostyril derivative represented by the formula (I) and a salt thereof, and a pharmaceutically acceptable carrier. Things.
  • the present invention also provides a multiple sclerosis, comprising administering to a patient at least one effective amount selected from the carbostyril derivative represented by the above general formula (1) and a salt thereof. It is concerned with the treatment of the disease.
  • the present invention relates to the use of at least one kind selected from the carbostyril derivative represented by the above general formula (1) and a salt thereof for the production of a therapeutic agent for multiple sclerosis. is there.
  • FIG. 1 is a graph showing the results of a test performed according to Pharmacological Test Example 1, and shows the effect of the compound of the present invention in a rat experimental allergic encephalomyelitis model.
  • Figure 2 shows the results of tests performed according to Pharmacological Test Example 1.
  • 4 is a graph showing the effect of the compound of the present invention on the average integrated clinical score in a rat experimental allergic encephalomyelitis model.
  • FIG. 3 is a graph showing the results of a test performed in accordance with Pharmacological Test Example 1, and shows the effect of the compound of the present invention on body weight change in a rat experimental allergic encephalomyelitis model.
  • R has 1 to 3 straight or branched alkoxy groups having 1 to 6 carbon atoms as substituents on the phenyl ring.
  • the therapeutic agent for multiple sclerosis which is a benzoyl group, is also provided.
  • the carbostyryl derivative is 6- [4— (3,4-dimethoxybenzoinole) -11-piperazinyl] 13,4—dihydronorrebostyryl
  • the above agent for treating multiple sclerosis which is a salt thereof, is also provided.
  • the carbostyril derivative represented by the above general formula (1) and a salt thereof used as an active ingredient for treating multiple sclerosis are described, for example, in Japanese Patent Publication No. As described in the official gazette and U.S. Pat.No. 4,415,572, it is a known substance and its production method is For example, it is described in the above publication. Further, these documents also describe that the carbostyril derivative represented by the above general formula (1) and a salt thereof are useful as a cardiotonic agent.
  • carbostyril derivative and one of its salts have also been demonstrated to improve hemodynamic parameters and exercise tolerance in patients with depressive heart failure [Inoue et al. 1. , Heart Vessels, 2, 166-171 (1986); Sasayama et a 1., Heart Vessels, 2, 23-28 (1986); Feldman et al., Am. Heart J., ⁇ 6, 771-777 (1988). ].
  • the mechanism related to the inotropic action of the above carbostyril derivatives is based on the reduction of the rhodium current CI ijima et al., J. Pharmacol. Exp.
  • the above-mentioned carbostyril derivative further comprises TNF-a, IL-6, IL-11; 8, IL-11 by peripheral blood mononuclear cell (PBMC) stimulated by lipopolysaccharide saccharide (LPS).
  • PBMC peripheral blood mononuclear cell
  • LPS lipopolysaccharide saccharide
  • the above carbostyril derivative has an effect of improving virus-induced myocardial injury and inhibiting natural killer cells (NK cells) at the time of improving the myocardial injury.
  • NK cells natural killer cells
  • the carbostyryl derivative has also been reported to have an apoptosis-regulating effect. Based on this effect, it is possible to treat cancer and suppress cancer metastasis, autoimmune diseases, and viruses. Its usefulness for diseases, etc. has also been reported [European Patent Publication EP0552373; Nakai et a 1., Jpn. J. Cancer Res., Abstruct, and Proc.
  • Carbostyril derivative which is the active ingredient of the drug of the present invention, More specifically, each group represented by the above general formula (1) can be exemplified by the following groups.
  • the lower alkoxy group is preferably a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butyl.
  • Examples include toxic, pentyloxy, and hexyloxy groups.
  • Benzoyl groups that may have a lower alkoxy group as a substituent on the phenyl ring include, for example, benzoyl, 2-methoxybenzoisole, 3-methoxybenzoyl, and 4-methoxy.
  • Cienzo Zinore 2—Etoxy Benzinole, 3—Etoxy Benzinore, 41—Ethoxy Benzinole, 3—Isopropoxybenzoyl, 4—butoxy Benzoinole, 21-pentinoleoxybenzole, 3 — hexinoleoxybenzole, 3, 4 — dimethoxybenzoinole, 2, 5 — dimethoxybenzoinole, 3, 4, 5 — Examples of the benzoyl group which may have 1 to 3 straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms as a substituent on a phenyl ring such as a trimethoxybenzoyl group. It can be.
  • carbostyril derivatives which are the active ingredient of the above-mentioned agent for treating multiple sclerosis
  • particularly preferred are, for example, 6- [4— (3,4-dimethoxybenzo).
  • the salt of the carbostyril derivative represented by the above general formula (1) includes a pharmacologically acceptable acid addition salt.
  • the acidic compound that forms the salt include inorganic acids such as sulfuric acid, phosphoric acid, nitric acid, hydrochloric acid, and hydrobromic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, and phosphorus.
  • Organic acids such as acid, tartaric acid, citric acid, succinic acid, ethanesulfonic acid, p-toluenesulfonic acid, and benzoic acid can be exemplified.
  • the carbostyril derivative represented by the general formula (1) or a salt thereof, which is an active ingredient of the drug of the present invention is usually used in the form of a general pharmaceutical preparation.
  • a preparation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants, and lubricants.
  • diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants, and lubricants.
  • Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment, and representative examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules Suppositories, injections (solutions, suspensions, etc.), eye drops and the like.
  • These dosage forms are formulated by conventional formulation methods generally known in the art.
  • this part is used as a carrier.
  • excipients such as sugar, sucrose, sodium chloride, sodium sucrose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and gay acid; water, ethanol, propanol , Single syrup, glucose solution, starch solution, gelatin solution, carboxymethyl phenol resin, lacquer, methyl phenol resin, lysate Binders such as vinylpyrrolidone; dry starch, sodium alginate, powdered starch, powdered laminarane-sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, Disintegrators for sodium lauryl sulfate, monoglyceride stearate, starch, lactose, etc .; Disintegrators for sucrose, stearin, cocoa batata, hydrogenated oil, etc.
  • Quaternary ammonium bases such as sodium lauryl sulfate; humectants such as glycerin and starch; starch, lactose, kaolin, bentonite coco Adsorbents such as Loidal gay acid; lubricating agents such as purified talc, stearate, powdered boric acid, polyethylene glycol, and the like.
  • tablets may be tablets coated with normal skin as required, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double-coated tablets or multilayer tablets. it can.
  • this part When molding into the form of pills, this part is used as a carrier.
  • excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, kaolin, and evening meal
  • arabic gum powder such as gelatin and ethanol
  • disintegrators such as laminarancanthene can be used.
  • suppository carriers For molding into suppository form, widely known carriers can be used, such as polyethylene glycol, cocoa butter, higher alcohol, and higher alcohol. Esters, gelatin, semi-synthetic glyceride, etc. can be used (when prepared as injections, solutions, emulsions, suspensions, etc. are sterilized and isotonic with blood). Preferably, these liquids, emulsions, suspensions, and other forms can be used in the form of diluents commonly used in this field, for example. For example, water, ethyl alcohol, propylene glycol, ethoxylated iso-norethanol, polyoxylated iso-stanol, ethanol, etc.
  • the pharmaceutical preparation may contain a sufficient amount of salt, glucose, glycerin, etc. to prepare an isotonic solution.
  • an ordinary solubilizing agent, a buffer, a soothing agent, etc. may be added, such as sodium citrate, sodium acetate, sodium phosphate, etc.
  • Triw Examples of the soothing agent include proforce hydrochloride and lidocaine hydrochloride.
  • a coloring agent a preservative, a flavoring agent, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained in the pharmaceutical preparation of the present invention, if necessary.
  • the amount of the compound represented by the general formula (1) contained as an active ingredient in the drug of the present invention is not particularly limited, and is appropriately selected from a wide range. Usually, it is suitably in the range of about 1 to 70% by weight, preferably about 1 to 30% by weight in the total composition.
  • the method of administration of the therapeutic agent for multiple sclerosis of the present invention is not particularly limited, and is appropriately determined depending on various preparation forms, the age and sex of the patient, other conditions, the degree of the disease, and the like.
  • pharmaceutical preparations in the form of injections can be administered by intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal administration, and the like. It can also be administered intravenously by mixing it with a normal replacement fluid such as glucose or amino acid, if necessary.
  • the pharmaceutical preparation of the present invention in a solid form such as a tablet, a pill, a granule, a capsule, or a liquid form for oral administration can be administered orally or enterally. Suppositories can be administered rectally. Eye drops can also be applied to the eyes.
  • the amount of the active ingredient of the present invention to be incorporated in each of the above dosage unit forms depends on the condition of the patient to which it is applied. Although it is not fixed depending on the dosage form and the like, it is generally appropriate to contain about 1 to 100 mg per dosage unit form.
  • the daily dose can be appropriately selected according to the patient's symptoms, weight, age, gender, other conditions, and the like, and is not particularly limited.
  • the carbostyril derivative (or salt thereof) of 1) is preferably selected from the range of about 0.5 to 30 mg Z kg per adult per day. It can be given once a day or divided into 3 to 4 times a day.
  • the preparation of the present invention is effective for improving various clinical symptoms of multiple sclerosis and for preventing and treating recurrence of multiple sclerosis.
  • Tablets were produced at a mixing ratio of 200 mg per tablet according to a conventional method.
  • the mixture After mixing and polishing the above-mentioned active ingredient compound, Avicel, Cornstarch and magnesium stearate, the mixture is tableted with sugar coating R10 mm kine.
  • the obtained tablets are coated with a phenolic coating agent composed of hydroxypropyl pilme tilsesolerose, polyethylene glycol 600, castor oil and methanol, and coated. 7 Lumco single tablets are manufactured.
  • the above mixture was sieved with a No. 600 screen, and polyvinylpyrrolidone, canolebo wax 150
  • Wet granulation was carried out with an alcoholic solution containing Bolux 600. If necessary, alcohol was added to them to make the powder into a pasty mass. To this, cone starch was added and mixing was continued until uniform particles were formed.
  • the particles were passed through a No. 10 screen, placed in a tray, and dried in an oven at 100 ° C. for 12 to 14 hours.
  • the resulting dried particles are sieved with a No. 16 screen, dried sodium lauryl sulfate and dried magnesium stearate are added, mixed, and mixed with a tableting machine to obtain the desired particles. It was compression molded into a shape.
  • the core was treated with varnish and talc was sprayed to prevent moisture absorption.
  • An undercoat layer was coated around the core. A sufficient number of varnish coatings were taken for internal use.
  • An additional subbing layer and a smooth coating were applied to make the tablets completely round and smooth. Color coating was performed until the desired color was obtained, and after drying, the resulting coated tablets were polished to prepare tablets of uniform gloss.
  • test compound 1 6- [4— (3,4-dimethylethoxybenzoyl) -1 1-piperazinyl] —3,4—dihydrorubostyril (hereinafter referred to as “compound 1”) was used.
  • compound 1 6- [4— (3,4-dimethylethoxybenzoyl) -1 1-piperazinyl] —3,4—dihydrorubostyril
  • the above animal model of EAE induces EAE by sensitizing (immunizing) animals with a central nervous tissue (eg, guinea pig spinal cord) and an adjuvant. On day 0, symptoms accompanied by paralysis of the tail and lower limbs appear. If a monoremot spinal cord (Guinea-Pig Spinal Cord; GPSC) homogenate and an adjuvant containing a high concentration of Mycobacterium Tube rculosis (T) are used, about 40 days after immunization Is a model for chronic progressive multiple sclerosis that repeats 2-3 onsets and recovery over a period of time (Chabannes, D., et al., J. Autoimmunity, 5, 199-211 (1992) ).
  • a monoremot spinal cord Guiinea-Pig Spinal Cord; GPSC
  • T Mycobacterium Tube rculosis
  • a 0.5% CMC solution (carboxy-methyl-cellulose solution) was used as the control.
  • the solution was prepared by using a CMC (Serogen F—SB (Lot No. 154455), manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd.) on an electronic balance (ER-182A; manufactured by Sartorius). After weighing 5.0 g, transfer to a plastic cylinder and dissolve in distilled water for injection (manufactured by Otsuka Pharmaceutical Factory Co., Ltd.) at 4 ° C for 24 hours to obtain a final concentration of 0.5%. After preparation, the solution was sterilized in an autoclave and stored at 4 ° C until use.
  • the guinea pig spinal cord (GPSC) homogenate used as an immunogen is a 9- to 10-week-old (500-600 g) male heart-shaped Mosolemot (Charles River Japan). (Purchased from one company) Prepared using all 20 animals. Guinea pigs were euthanized by cervical dislocation under light ether anesthesia, the meninges and blood vessels were detached from the spinal cord, and the excised spinal cord was transferred to an ice-cooled dish. The extirpated spinal cords of the 10 quintiles were weighed together, and weighed to 1 g of GPSC in a potter homogenizer.
  • An adjuvant solution containing M. tuberculosis was prepared using a commercially available complete adjuvant solution containing M. tuberculosis (M. tuberculosis killed H37 Ra concentration lmg Zml; catalog number 311) 3 — 60-5: manufactured by Difco Inc. l O ml Z bottle, and further killed tuberculosis H 37 Ra (catalog number 3 1 1 4 — 3 3 — 8: made by Difco Inc.) And added 15 mg. After sealing with Raffinorem, mix well by inverting, and then suspend uniformly to obtain a final MT concentration of 2.
  • EAE allergic monoencephalomyelitis
  • the induction of experimental allergic monoencephalomyelitis (EAE) as an animal model for multiple sclerosis was as follows. Immediately, the immunized emulsion prepared in (1) to (5) above was put on a foot pad of a rat under light ether anesthesia with a 23-gauge injection needle and a 1.0-m1 glass bottle. A total of 0.2 ml ⁇ (50 mg as GPSC + 250 as MT) ⁇ of 0.1 ml was injected intradermally using a syringe. After immunization, the animals were reared in the cage of 5 animals. The rat develops allergic encephalomyelitis symptoms around 10 days after immunization, and repeats relapse and remission, similar to human clinical symptoms, and therefore multiple sclerosis. Animal model.
  • 0.5 ml was administered by oral gavage to the body weight of 100 g of the rat.
  • the dose was determined for each animal based on the body weight on the day automatically input to the computer.
  • the group to which the 0.5% CMC solution was administered as the control group was administered in the same manner.
  • oral administration was performed once daily for up to 37 days after immunization, using 20 animals in each group.
  • test start date (immunization date) to the test end date (dissection date) Observation of body weight and symptoms (score judgment) was performed once a day.
  • the body weight was measured with an electronic balance (Sartorius; LC-4200: manufactured by Sartorius) and connected to a personal computer.
  • the scoring of symptoms was evaluated according to the evaluation criteria of Koh et al. (Koh, CS, et al., Cell Immunology, 107, 52-63 (1987)). That is, the rat's symptoms in each group were observed every day, the scores were determined for the rat tail and both hind limbs, and the total was recorded on a score record sheet. The score was 0 for asymptomatic, 0.25 for halfway relaxation, and 0.5 for complete relaxation of the entire tail for the tail, and 0 for asymptomatic and 1 for walking impairment in the hind limbs. Incomplete paralysis of both hind limbs and complete paralysis of one hind limb were evaluated as 2.0, and complete paralysis of both hind limbs was evaluated as 3.0. The deaths during the study were excluded from the statistical processing for scoring.
  • the body weight was measured using the control group as a control and the measured values for the group that received Compound 1 immediately after the onset of the first symptom and the group that received Compound 1 immediately before the onset of the second symptom.
  • Use Differences in response over time were tested by repeated measures (Repeated esurements) and performed at 5% and 1% significance levels.
  • the entire study period was divided into the first half and the second half according to the change in the clinical score of the control group. That is, at the time of the best recovery between two peaks (Chabannes, D., et al., J. Autoim raunity, 5, 199-211 (1992)), the score is divided into the first half and the second half.
  • the analysis was performed in three periods: the whole period, the first half, and the second half. More specifically, the score judgment results of the symptoms of each individual in each period are integrated, and the average integrated clinical score (Integrated Clinical Score) is calculated for each group (Branisteanu, DD, et al., J. Neuroimmunolog y, 61, 151-160 (1995); Martin, D., et al., J.
  • FIGS. 1, 2, and 3 The results of symptom score determination and changes in body weight are shown in FIGS. 1, 2, and 3, respectively.
  • the vertical axis represents the average clinical score
  • the horizontal axis represents the administration period (days) after immunization.
  • the vertical axis represents the average cumulative clinical score (the average of the cumulative clinical scores from 0 to 38), and the horizontal axis represents the cumulative clinical score.
  • the vertical axis shows the change in daily body weight
  • the horizontal axis shows the administration period (days) after immunization.
  • the compound 1 administration group showed a significant decrease in the average cumulative clinical score (P ⁇ 0.01) compared to the control group, ie, An improvement effect was observed.
  • the changes in body weight corresponded to the changes in symptom score judgment in Fig. 1, and the compound 1 administration group compared with the control group, as shown in Fig. 3.
  • an improvement tendency was recognized.
  • Compound 1 improves the symptom and suppresses the onset of the second symptom by administration immediately after the onset of the first symptom.
  • the group to which Compound 1 was administered immediately before the onset of the second symptom suppressed the recurrence of the symptom.
  • a remedy for multiple sclerosis comprising at least one active ingredient selected from the carbostyril derivatives represented by the general formula (1) and salts thereof, which is used in the pharmaceutical field. It improves various clinical symptoms of multiple sclerosis, which is difficult to treat, and is useful for preventing and treating recurrence of multiple sclerosis.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

L'invention porte sur différents remèdes contre la sclérose en plaques, comprenant chacun une quantité efficace d'au moins l'un des éléments choisis parmi des dérivés du carbostyril de formule générale (1), et ses sels, ainsi qu'un excipient pharmacocompatible, lesdits remèdes étant susceptibles de traiter la sclérose en plaques et d'en d'améliorer divers symptômes cliniques. Dans la formule (1) R est benzoyle facultativement substitué par un alkoxy inférieur sur le cycle phényle, et la liaison carbone entre les positions 3- et 4- du squelette carbostyrile est simple ou double.
PCT/JP1998/003897 1997-09-04 1998-09-01 Remedes contre la sclerose en plaques WO1999011266A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU88887/98A AU8888798A (en) 1997-09-04 1998-09-01 Multiple sclerosis remedies

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/239644 1997-09-04
JP23964497A JP4120713B2 (ja) 1997-09-04 1997-09-04 多発性硬化症治療剤

Publications (1)

Publication Number Publication Date
WO1999011266A1 true WO1999011266A1 (fr) 1999-03-11

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Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06311991A (ja) * 1993-05-06 1994-11-08 Denpatsukusu:Kk 汚染防止装置用使い捨て吸引フード
DE60041365D1 (de) * 1999-06-04 2009-02-26 Vereniging Voor Christelijk Wetenschappelijk Onderwijs Verwendung von Riluzol zur Behandlung Multipler Sklerose
EP1187612B1 (fr) * 1999-06-04 2005-01-26 Vereniging Voor Christelijk Wetenschappelijk Onderwijs Utilisation de riluzole pour le traitement de la sclerose en plaques

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06179621A (ja) * 1992-12-15 1994-06-28 Otsuka Pharmaceut Co Ltd 抗癌剤
JPH06511488A (ja) * 1991-10-09 1994-12-22 カビ・フアーマシア・アクチエボラーグ 置換キノリンカルボキシアミドの新規な使用
JPH0733664A (ja) * 1993-07-26 1995-02-03 Otsuka Pharmaceut Co Ltd 平滑筋細胞増殖抑制剤
JPH09165338A (ja) * 1995-12-12 1997-06-24 Otsuka Pharmaceut Co Ltd 梗塞サイズ減少剤
JPH09309877A (ja) * 1996-05-20 1997-12-02 Teijin Ltd 環状ジアミン誘導体並びにその製造及び使用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06511488A (ja) * 1991-10-09 1994-12-22 カビ・フアーマシア・アクチエボラーグ 置換キノリンカルボキシアミドの新規な使用
JPH06179621A (ja) * 1992-12-15 1994-06-28 Otsuka Pharmaceut Co Ltd 抗癌剤
JPH0733664A (ja) * 1993-07-26 1995-02-03 Otsuka Pharmaceut Co Ltd 平滑筋細胞増殖抑制剤
JPH09165338A (ja) * 1995-12-12 1997-06-24 Otsuka Pharmaceut Co Ltd 梗塞サイズ減少剤
JPH09309877A (ja) * 1996-05-20 1997-12-02 Teijin Ltd 環状ジアミン誘導体並びにその製造及び使用

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AU8888798A (en) 1999-03-22
JP4120713B2 (ja) 2008-07-16
JPH1179995A (ja) 1999-03-23

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