WO2004039404A1 - Agent therapeutique pour la stenose de canal rachidien - Google Patents

Agent therapeutique pour la stenose de canal rachidien Download PDF

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Publication number
WO2004039404A1
WO2004039404A1 PCT/JP2003/013776 JP0313776W WO2004039404A1 WO 2004039404 A1 WO2004039404 A1 WO 2004039404A1 JP 0313776 W JP0313776 W JP 0313776W WO 2004039404 A1 WO2004039404 A1 WO 2004039404A1
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WIPO (PCT)
Prior art keywords
spinal canal
compound
canal stenosis
nitric oxide
therapeutic agent
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PCT/JP2003/013776
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English (en)
Japanese (ja)
Inventor
Yoshifumi Takenobu
Yoshihisa Kamanaka
Takaaki Obata
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Ono Pharmaceutical Co., Ltd.
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Publication date
Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Priority to AU2003275709A priority Critical patent/AU2003275709A1/en
Publication of WO2004039404A1 publication Critical patent/WO2004039404A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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 an agent for treating spinal stenosis. More specifically, the present invention relates to a preventive and / or therapeutic agent for spinal canal stenosis, comprising a compound that inhibits nitric oxide synthase (abbreviated as NOS).
  • NOS nitric oxide synthase
  • spinal canals The vertebral bodies from the cervical spine to the sacral spine and the internal space surrounded by the spinous processes are called spinal canals.
  • spinal canal stenosis the spinal canal is narrowed due to the hypertrophy of the spine and yellow ligament that make up the spinal canal, and the spinal canal is narrowed due to the protrusion of the intervertebral disc, and the nerve tissue such as the nerve root and cauda equina contained in the spinal canal is compressed. It is a condition that presents various symptoms upon receiving.
  • Spinal canal stenosis is classified into broad spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, etc., depending on the narrow region of the spinal canal.
  • Symptoms include back pain, lower limb pain, and numbness due to nerve compression. Especially when the cauda equina is injured, lower back pain, lower limb pain, numbness, and weakness occur during walking, and this condition is called intermittent claudication.
  • macrophages one of the immunocompetent cells, produce a large amount of nitrate, discovered that nitric oxide (NO) is produced in vivo (Proc. Natl. Acad. Sci. USA, 82, 7738-7742 (1985), J. Immunol., 138. 550-565 (1987)).
  • vascular endothelium-derived relaxing factor a substance having a relaxing action released from vascular endothelial cells was discovered and named vascular endothelium-derived relaxing factor (EDRF). Furthermore, it has been found that the body of this EDRF is NO (Nature, 327, 524-526 (1987)).
  • NO that was found to be produced in vivo in this way was It is produced by nitric oxide synthase (NOS) using nin as a substrate by the following route.
  • NOS nitric oxide synthase
  • NOS includes at least non-inducible (endothelial and neuronal) and inducible isozymes.
  • Vascular endothelial NOS is mainly present in vascular endothelial cells, and its activity is controlled by the intracellular calcium concentration.
  • Nerve-type NOS is present in central nerve cells, peripheral nerve cells, or knee islands] 3 cells, gastrointestinal nerves, adrenal medulla, renal compact plaques, etc., and is activated by intracellular calcium concentration like vascular endothelial NOS Is controlled.
  • Endothelial NOS and nervous NOS are constantly present in cells, and there is almost no change in the amount of enzymes due to physiological changes.
  • Inducible NOS abbreviated as inducible NOS, i-NOS
  • i-NOS inducible NOS
  • islet cells vascular smoothing It is present in muscle cells or glial cells. This is not normally observed in cells, but is induced by stimulation with endotoxin or various cytokins.
  • NOS The effects of NO produced by NOS are diverse, for example, vasorelaxant, Inhibition of platelet aggregation, adhesion inhibition, leukocyte adhesion, migration inhibition, sympathetic nerve activity inhibition, endotoxin shock, hypotension due to endotoxin cytotoxicity, action as a signal transmitter between neurons, ischemic brain cell injury, anti- B severe ulcer, bactericidal action, autoimmune disease, insulin-dependent diabetes mellitus, arthritis, tissue damage after transplantation, rejection and the like.
  • vasorelaxant Inhibition of platelet aggregation, adhesion inhibition, leukocyte adhesion, migration inhibition, sympathetic nerve activity inhibition, endotoxin shock, hypotension due to endotoxin cytotoxicity, action as a signal transmitter between neurons, ischemic brain cell injury, anti- B severe ulcer, bactericidal action, autoimmune disease, insulin-dependent diabetes mellitus, arthritis, tissue damage after transplantation, rejection and the like.
  • NOS inhibitors are useful, and may be used as therapeutics for shock and ischemic diseases. Development is underway.
  • hypoxia due to impaired blood flow in nervous tissues is considered to be involved in addition to mechanical compression of nerves.
  • the symptom may be expressed by synergistic effects such as floating JB and metabolic disorder in nerve tissue.
  • oral prostaglandin E1 derivative preparations for improving circulation in nerve tissue are recognized as drugs for treating spinal canal stenosis. Therefore, the present inventors thought that a drug that acts directly on nerves and improves nerve cell death, neuroinflammation, and the like may be a therapeutic agent for spinal canal stenosis.
  • the present inventors have conducted extensive studies and found that NOS inhibitory compounds The present inventors have found that the symptom of the disease is improved, and completed the present invention. It has not been reported that NOS inhibitory compounds are effective for spinal canal stenosis, and the present inventors have proposed a cauda equina compression gait disorder model known as a model of spinal canal stenosis (J. Neurosci. Methods., 104 (2). 191-198 (2002)) was used to confirm for the first time that a NOS inhibitory compound was effective in spinal canal stenosis.
  • a preventive and / or therapeutic agent for spinal canal stenosis comprising a nitric oxide synthase inhibitory compound
  • spinal canal stenosis is cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, or extensive spinal canal stenosis Or therapeutic agent,
  • nitric oxide synthase inhibitory compound is an inducible nitric oxide synthase inhibitory compound or a neuronal nitric oxide synthase inhibitory compound.
  • nitric oxide synthase inhibiting compounds ⁇ ⁇ - Monomechiru L-arginine one, ⁇ ⁇ - two Torrox L- Anoreginin, ⁇ ⁇ - two Toro one L- ⁇ Roh the regulation Nin methylate Norre Este Lumpur, ⁇ ⁇ - amino-L - arginine, New omega - cyclopropyl one L- arginine, New omega - Ariru one L- arginine, New omega - two Toro one L- arginine one ⁇ - two Toro Anilide, ⁇ ⁇ , — ⁇ —Dimethi arginine, 2-iminobiotin, S—methylol L-thiocitrulline, S—ethyl-L-thiocytonorelin, L-thiocytonorrelin, L-homothiocitrin, 2-iminopiperidine, 2 —Iminohomopiperidine, S—Methylis
  • Nitric oxide synthase inhibitor compound is 2-fluoro-N- [3- (aminomethyl) phenyl] acetamidine, aminoguanidine, A-2492, CR-3294, S- [2- (1-iminoethino Reamino) ethyl] — L—Homo cysteine, 3— (2,4-difluorophenyl) 1 6— [2— [4- (1 H-imidazole-1-ylmethyl) phenoxy] ethoxy] —2-pheninolepyridine, .7-nitroindazonole, 6-nitroindazonole, indazole, 1- (2-trifluoromethylphenyl) Imidazole, 2- (2-fluorobiphenyl-4-inole) 4-nitrooxybutynole propionate, N 1 — [4- [4-—6-hydroxy-1,2,5,7,8-tetramethyl 3,4 dihydro 2 H— 1—Benzopyran
  • nitric oxide synthase inhibitor compound is (+) — trans-3-imino-5-methyl-17-clo-1-2-azabicyclo [4.1.0] heptane, N-
  • the preventive and / or therapeutic agent for spinal canal stenosis according to the above 1, which is [3- (aminomethyl) benzyl] acetamidine, a salt thereof or a solvate thereof,
  • R 2 represents a C 1-6 alkyl group
  • R 3 represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, or a halogen atom
  • R 4 represents a hydrogen atom, a carbocyclic ring which may be substituted with an amino-Cl-4 alkyl group, or an amino-Cl-4 alkyl group;
  • i 0 or an integer of 1 to 3
  • n 0 or an integer of 1 to 3.
  • R 2 or R 3 may be the same or different.
  • nitric oxide synthase inhibitor compound described in 11 above prostaglandins, prostaglandin derivative preparations, nonsteroidal anti-inflammatory drugs, vitamins, muscle relaxants, antidepressants, poly ADP- Pharmaceuticals in combination with one or more drugs selected from ribose polymerase inhibitors, excitatory amino acid receptor antagonists, radical scavengers, astrocyte function improvers, IL-18 receptor antagonists, and immunosuppressants Composition, 14) a method for preventing and treating spinal canal stenosis, which comprises administering an effective amount of a nitric oxide synthase inhibitory compound to a mammal;
  • the present invention relates to the use of a nitric oxide synthase inhibiting compound for the manufacture of a preventive and / or therapeutic agent for spinal stenosis.
  • the symbols ..., ⁇ indicate that they are attached to the other side of the paper (ie, ⁇ -configuration), Indicates that they are connected to the near side of the page (that is, one arrangement), ⁇ indicates that they are one arrangement, i3-configuration or a mixture thereof, and / ⁇ indicates ⁇ -configuration and j8-configuration. Represents a mixture, ⁇ represents a — or double bond, ⁇ ⁇ represents a double or triple bond, and ⁇ represents a single, double or triple bond.
  • alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, alkylene group, alkenylene group, and alkynylene group include linear and branched ones.
  • isomers in double bonds, rings and condensed rings (E, Z, cis, trans), isomers due to the presence of asymmetric carbon (R, S, ⁇ ,] 3 configuration, enantiomers, diastereomers) , Optically active substance with optical activity (D, L, d, 1 body), polar form (high polar form, low polar form) by chromatographic separation, equilibrium compound, rotamer, any ratio of these Mixtures and racemic mixtures are all included in the present invention.
  • the compound used in the present invention may be any compound as long as it is a nitric oxide synthase inhibitory compound, and preferably includes all substances having an inhibitory action on inducible and neuronal nitric oxide synthase.
  • all NOS-inhibiting compounds to be found in the future as well as NOS-inhibiting compounds known to date are included.
  • any compound having an action of inhibiting the synthesis of NO may be used, for example, a cofactor competition inhibitory compound that indirectly inhibits NOS. Is also included.
  • the NOS inhibiting compound New omega - monomethyl one L- arginine (L- NM ⁇ ; No. W091 / 04024), ⁇ ⁇ - nitro one L one-arginine (L one ⁇ ), ⁇ ⁇ - nitro one L- arginine methyl ester (L-NAME), ⁇ ⁇ - amino-L one-arginine (L one ⁇ ), ⁇ ⁇ - cyclopropyl one L one-arginine (L -CPA), ⁇ ⁇ - Ariru one L one-arginine (L- ALA), ⁇ ⁇ - two Torrox L- arginine one ⁇ - two Trois two Li de, New omega, New omega - dimethylarginine, 2 one Iminobiochin, S- methyl one L over thiocitrulline, S- Echiru one L- Ji Oshitorurin, L- thiocitrulline, L —Homothiocitrulline, 2-
  • Preferred NOS inhibiting compounds include compounds of the formula (I)
  • R 1 — is a force condensed with the carbon atom at the bonding position to d or e of the piperidine ring, or a 3- or 4-membered carbon ring spiro-bonded to the 4-position
  • R 2 3 ⁇ 4C represents a! -6 alkyl group
  • R 3 represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkyl group, or a halogen atom
  • R 4 represents a hydrogen atom, an amino-C 1-4 alkyl group, a carbocyclic mono-C 1-4 alkyl group which may be substituted with an amino-C 1-4 alkyl group,
  • i 0 or an integer of 1 to 3
  • n 0 or an integer of 1 to 3.
  • R 2 or R 3 may be the same or different.
  • a salt thereof, or a solvate thereof may be the same or different.
  • More preferred NOS inhibiting compounds include those of the formula (IA)
  • Particularly preferred NOS inhibiting compounds include those of the formula (la)
  • (+)-trans-3-imino-5-methyl-7-chloro-1-2-azabicyclo [4.1.0] heptane EP870763
  • a salt thereof or a solvate thereof. It is.
  • the C1-4 alkyl group means methyl, ethyl, propyl, ethyl and isomers thereof
  • the C1-6 alkyl group means methyl, ethyl, propyl , Butyl, pentyl, hexyl and their isomers
  • C2-6 alkenyl means ethenyl, propenyl, butyr, pentenyl, hexenyl and their isomers
  • An alkynyl group means ethule, propiel, petininole, penture, or hexinole.
  • Halogen atom means fluorine, chlorine, bromine or iodine atom.
  • Cofactor competitive inhibition compounds include diphenyrene (DPI), di-t-enolenodenium (DTI), and calcineu Phosphorus, N- (4-aminobutyl) -15-chloro-12-naphthalenesulfonamide, trifluoperazine, 2,4-diamino-16-hydroxypyrimidine, and the like, but are not limited thereto. is not.
  • the compounds represented by the formulas (I), (IA) and (la), salts or solvates thereof can be produced by the method described in EP870763.
  • the compound used in the present invention is WO95 / 11014, WO96 / 15120, W096 / 35677, W095 / 11231, W096 / 3315, W095 / 24382, W096 / 14844, W096 / 14842, W096 / 18616, W096 / 18617, EP448228, WO96 / 30350, WO96 / 06076, W097 / 36871, WO95 / 05363, W097 / 38977, WO01 / 46170, WO01 / 46171, WO02 / No.
  • the compound used in the present invention was effective in a cauda equina compression gait disorder model known as a model of spinal canal stenosis, as described later.
  • the nitric oxide synthesis inhibitory compound is effective for spinal canal stenosis, and has an effect of improving the motor ability of the patient, in particular, improving muscle weakness, improving intermittent claudication, or improving walking ability. It is also considered to be effective in improving the patient's paralysis, hypoesthesia, pain, or numbness, particularly lower limb paralysis, hypoesthesia, pain, or numbness. In addition, it is considered to be effective in treating bladder disorders or rectal disorders associated with spinal canal stenosis.
  • the therapeutic effect of the compounds used in the present invention for spinal canal stenosis is as follows: the effect of improving the function of the tissues surrounding the spinal canal, for example, the decrease in the function of the intervertebral disc or the thickening of the yellow ligament or the posterior ligament; It is considered to be based on the ameliorating effect on the decrease or the neuroprotective effect.
  • toxicity The toxicity of the compound used in the present invention was sufficiently low, and it was confirmed that the compound was sufficiently safe for use as a pharmaceutical.
  • the maximum tolerated dose of the compound represented by the formula (la) was 30 mg Zkg.
  • the combination drug of the compound used in the present invention and another drug may be administered in the form of a combination preparation in which both components are combined in one preparation, or may be in the form of separate preparations and administered .
  • simultaneous administration and administration at different times are included.
  • the administration with a time difference may be performed by administering the compound used in the present invention first and then administering the other drug later, or administering the other drug first and then administering the compound used in the present invention later.
  • each administration method may be the same or different.
  • Diseases in which a prophylactic and / or therapeutic effect is exhibited by the above concomitant drug are not particularly limited, and may be any disease that complements or enhances the prophylactic and / or therapeutic effects of the compound used in the present invention.
  • prostaglandins for preventing and / or enhancing the effect of the compound used in the present invention on spinal canal stenosis
  • prostaglandins for preventing and / or enhancing the effect of the compound used in the present invention on spinal canal stenosis
  • NSAID Nonsteroidal anti-inflammatory drug
  • PARP poly ADP-ribose polymerase
  • excitatory amino acid receptor antagonist eg, NMD A receptor antagonist, AM PA receptor antagonist Agents
  • radical scavengers eg, astrocytic function improvers
  • IL-8 receptor antagonists for preventing and / or enhancing the effect of the compound used in the present invention on spinal canal stenosis
  • Other drugs for preventing and / or enhancing the effect of the compound used in the present invention on spinal canal stenosis such as prostaglandins, prostaglandin derivative preparations, non-steroids
  • NSAID Nonsteroidal anti-inflammatory drug
  • vitamin drug e.g, muscle relaxant, antidepress
  • Prostaglandins include PG receptor agonists, PG receptor antagonists and the like.
  • PG receptors include PGE receptor (EP1, EP2, EP3, EP4), PGD receptor (DP, CRTH2), PGF receptor (FP), PGI receptor (IP), TX receptor ( TP) and the like.
  • Prostaglandin derivative preparations include limaprost, limaprost alfadex, and beraprost.
  • Non-steroidal anti-inflammatory drugs include, for example, sazapyrine, sodium salicylate, aspirin, aspirin. , Fenbufen, napmetone, proglumetasin, indomethacin fuarnesyl, acemethasin, proglumetasin maleate, ampfenac sodium, mofuezorak, etodolac, ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, flurbip Oral fenaxetil, ketoprofen, fenoprofen calcium, thiaprofen, oxaprozin, Ranoprofen, loxoprofen sodium, aluminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamate, tonolefenamic acid, floctafenin, ketofeninolebutazone, oxifenbutazone, piroxi
  • Muscle relaxants include, for example, triperizone hydrochloride, chlorzoxazone, kokulumezanone, metocarpamol, fenpronomate, pridinol mesylate, clofenesin olevaminate, baclofen, eperisone hydrochloride, afroqualone, tizanidine hydrochloride, alchloridium chloride, Examples include suxametonium chloride, ppokclarin chloride, dantrolene sodium, panclonium bromide, vecuronium bromide and the like.
  • tricyclic antidepressant examples include imibramine hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, trimipramine maleate, amitriptyline hydrochloride, nortriptyline hydrochloride, oral uebramine hydrochloride, amoxapine, doslevin hydrochloride and the like.
  • Tetracyclic antidepressants include maprotiline, mianserin and the like.
  • the weight ratio of the compound used in the present invention to the other drug is not particularly limited.
  • Other drugs may be administered in combination of any two or more of the same or different.
  • drugs that complement and / or enhance the prophylactic and / or therapeutic effects of the compounds used in the present invention include those that have been found to date and those that will be found in the future based on the above-mentioned mechanism. Is included.
  • the compound used in the present invention naturally includes a salt produced by a known method, and a pharmacologically acceptable salt is preferable, but the compound specified in the present specification and claims is a drug. It has been confirmed to be toxic to the extent that it is physically acceptable and safe enough for use as a pharmaceutical.
  • the pharmacologically acceptable salt mentioned here is an alkali metal salt, an alkaline earth metal salt, an ammonium salt, an amine salt or the like when the parent compound is an acidic compound, and the parent compound is a basic compound. In some cases, examples thereof include organic and inorganic acid addition salts. Further, the pharmacologically acceptable salt is preferably a water-soluble salt. Preferred salts include salts of alkali metals (eg, potassium, sodium, etc.), salts of alkaline earth metals (eg, calcium, magnesium, etc.), ammonium salts, and pharmaceutically acceptable organic amine amino acids (eg, tetramethylammonium).
  • Triethinoleamine Triethinoleamine, methinoleamine, dimethinoleamine, pentylamine, benzinoleamine, phenethyl ⁇ amine, piperidine, monoethanolanolamine, gentanolamine, tris (hydroxymethyl) aminoamino, lysine, arginine, N-methyl-D-damine Etc.).
  • the compounds used in the present invention may be administered in the form of the following acid addition salts.
  • the acid addition salt is preferably a non-toxic water-soluble salt.
  • Suitable acid addition salts include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, oxalic acid Salt, fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, dalcucate, dalconate
  • Organic salts such as salts are included.
  • it is a hydrochloride.
  • the compound used in the present invention or a salt thereof may be a solvate.
  • solvates are preferably non-toxic and water-soluble.
  • Preferred solvates include, for example, solvates such as water and alcohol solvents (eg, ethanol and the like).
  • the compound used in the present invention may be a prodrug produced by a known method.
  • the prodrug of the compound used in the present invention refers to a compound that is converted into the compound used in the present invention by a reaction with an enzyme or stomach acid in a living body.
  • the prodrug of the compound used in the present invention includes the compound used in the present invention.
  • the product has a hydroxyl group
  • a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or phosphorylated for example, the hydroxyl group of the compound used in the present invention is acetylated, palmitoylated, propanoylated, vivaloylated) Succinylation, fumarylation, alanylation, dimethylaminomethylcarboxylated compound, etc.
  • the compound used in the present invention has a carboxy group
  • the carboxy group is esterified or amidated.
  • the carboxy group of the compound used in the present invention is ethylesterified, phenylenostenolelated, canoleboximetylesterified, dimethylaminomethylesterified, bivaloyloxymethylesterified, ethoxycarponyloxyxethyl ester
  • Phthalidyl esterification (5-methyl-1-2 —Oxo-1,4-dioxolen-141-yl) Methyl esterification, hexahexyloxycarbonylethyl esterification, methylamidated compound, etc.
  • These compounds can be produced by a method known per se.
  • the prodrug of the compound used in the present invention may be either a hydrate or a non-hydrate.
  • the compound used in the present invention or an ester thereof can be prepared by using the method described in GB1351238 or GB1419221 using 1, J3- or ⁇ -cyclodextrin, or a mixture thereof. It can be converted to a dextrin clathrate. Conversion to a cyclodextrin clathrate compound is convenient for use as a drug because it increases stability and increases water solubility.
  • Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is generally within the range of Olng to 100 mg per adult, once per day. Oral administration several times or once per adult Parenteral administration (preferably intravenously) in the range of Olng to 100 mg once or several times daily, or intravenous administration in the range of 1 hour to 24 hours daily. Is administered continuously.
  • a solid preparation for oral administration When administering the compound used in the present invention or a combination of the compound used in the present invention and another drug, a solid preparation for oral administration, a liquid preparation for oral administration, and a parenteral administration method. It is used as an injection, external preparation, suppository, eye drop, inhalant, etc.
  • one or more of the active substances may be intact or excipients (ratatose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (hydroxypropylcellulose, polypropylpyrroli). Don, magnesium metasilicate aluminate, etc.), disintegrant (fiber calcium calcium dalycholate, etc.), lubricant (magnesium stearate, etc.), stabilizer, dissolution aid (glutamic acid, aspartic acid, etc.) It is formulated and used according to the usual method.
  • a coating agent sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.
  • capsules of absorbable materials such as gelatin.
  • the sublingual tablet is produced according to a known method.
  • one or more active substances include excipients (latatose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.), binders (hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.) ), Disintegrant (starch, L-hydroxypropylcellulose, carboxymethyl Senorelose, croscarmellose sodium, cellulose glycolate canolesum, etc.), lubricants (magnesium stearate, etc.), swelling agents (hydroxypropinoresezorelose, hydroxypropinolemethinoresenorelose, carboponole, force Lipoxymethylcellulose, polybutyl alcohol, xanthan gum, guar gum, etc., swelling aids (glucose, fructose, mannitol, xylitolone, erythritol, manoletose
  • Coating IJ sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.
  • additives such as preservatives, antioxidants, coloring agents, sweeteners and the like which are commonly used can be added.
  • the oral patch is manufactured according to a known method.
  • one or more active substances may include excipients (lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.), binders (hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminometasilicate).
  • Disintegrants starch, L-hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium, calcium cellulose glycolate, etc.
  • lubricants magnesium stearate, etc.
  • adhesives hydroxy, etc.
  • adhesion promoters glucose, fructose, man
  • Toe Honoré xylylene Tonore, erythritol Tonore, Manoretosu, trehalose, phosphate, Kuen salts, Kei salt, glycine, glutamic acid, Arugiyun etc.
  • a stabilizer It is mixed with a dissolution aid (polyethylene glycol, propylene dalicol, glutamic acid, aspartic acid, etc.), flavoring agent (orange, strawberry, mint, lemon, vanilla, etc.
  • the orally rapidly disintegrating tablet is produced according to a known method.
  • one or more active substances may be used as is, or as a powder or granulated bulk powder suitable for coating IJ (ethinoresenololose, hydroxypropinoresenorelose, hydroxypropyl methylcellulose, acrylic acid Active substances coated with plasticizers (eg, methacrylic acid copolymer), plasticizers (eg, polyethylene glycol, triethyl citrate), excipients (eg, lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch), binders (Hydroxypropylcellulose, polyvinylinolepyrrolidone, magnesium metaoleate and magnesium oleolenate), disintegrants (starch, L-hydroxypropylcellulose, carboxymethylcellulose, cros-canolemelose sodium, cellulose glycol) Noreic acid power, residum, etc.), lubricants (magnesium stearate, etc.), dispersing aids (
  • a coating agent sucrose, gelatin, hydroxypropylcellulose, hydroxypropyl methylcellulose monophthalate, etc.
  • a coating agent such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropyl methylcellulose monophthalate, etc.
  • additives such as preservatives, antioxidants, coloring agents, sweeteners and the like which are commonly used can be added.
  • Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like.
  • one or more active substances are dissolved, suspended, or emulsified in a commonly used diluent (such as purified water, ethanol, or a mixture thereof).
  • the liquid preparation may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
  • Topical dosage forms for parenteral administration include, for example, ointments, gels, tablets, poultices, patches, liniments, nebulizers, inhalants, sprays, aerosols, eye drops Agents, nasal drops and the like. These contain one or more active substances and are manufactured by known methods or commonly used formulations.
  • the ointment is manufactured by a known or commonly used formulation. For example, it is prepared by triturating or melting one or more active substances in a base.
  • the ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristate ester, palmitate ester, stearic acid ester, oleic acid ester, etc.), wax (E.g.
  • hydrocarbons hydrocarbons (hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (ethylene glycol, diethylene glycol cornole, propylene glycol cornole, polyethylene glycol cornole, macrogol, etc.), vegetable oils ( Castor oil, olive oil, sesame oil, turpentine oil, etc.), Animal oils (mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers and rash preventives can be used alone or as a mixture of two or more. In addition, it may contain humectants, preservatives, stabilizers, antioxidants, flavors and the like.
  • the gel is produced by a known or commonly used formulation. For example, it is prepared by melting one or more active substances in a base.
  • the gel base is selected from known or commonly used ones.
  • lower alcohols ethanol, isopropyl alcohol, etc.
  • gelling agents carboxymethinoresenolylose, hydroxyxetinoresenorelose, hydroxypropinoresenolose, ethylcellulose, etc.
  • medium A single agent or a mixture of two or more selected from a wetting agent triethanolamine, diisopropanolamine, etc.
  • a surfactant polyethylene glycol monostearate, etc.
  • gums water, an absorption promoter, and a rash inhibitor Used as Further, they may contain preservatives, antioxidants, flavoring agents and the like.
  • the cream is produced by a known or commonly used formulation. For example, it is prepared by melting or emulsifying one or more active substances in a base.
  • the cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.), emulsifiers (polyoxyethylene) Alkyl ethers, fatty acid esters, etc.), water, absorption promoters, and rash inhibitors are used alone or as a mixture of two or more. Further, they may contain preservatives, antioxidants, flavoring agents and the like.
  • the poultice is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material, spreading the mixture on a support as a kneaded product, and producing the mixture.
  • Compress bases are known or commonly used Selected from For example, thickeners (polyacrylic acid, polybutylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (urea, glycerin, propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, calcium) , Magnesium, etc.), water, a dissolution aid, a tackifier, and an antifoggant, used alone or as a mixture of two or more.
  • preservatives, antioxidants, flavoring agents and the like may be included.
  • the patch is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material, and spreading and coating on a support.
  • the base for the patch is selected from those known or commonly used. For example, one selected from a polymer base, oils and fats, higher fatty acids, tackifiers, and rash preventive agents may be used alone or in combination of two or more. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • the liniment is manufactured by a known or commonly used formulation.
  • one or more active substances may be dissolved or suspended in one or more selected from water, alcohols (ethanol, polyethylene glycol, etc.), higher fatty acids, glycerin, soap, emulsifiers, suspending agents, etc. It is prepared by turbidity or emulsification. Further, they may contain preservatives, antioxidants, flavoring agents and the like.
  • Atomizers, inhalants, and sprays may be used in addition to commonly used diluents, buffers that provide isotonicity with stabilizers such as sodium bisulfite, for example, sodium salt, sodium citrate Alternatively, it may contain an isotonic agent such as citric acid.
  • the method of producing the spray is described in detail in, for example, U.S. Pat. Nos. 2,868,691 and 3,095,355.
  • Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections that are used by dissolving or suspending in a solvent for use. Injectables are used by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • a solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glyco , Polyethylene glycol, alcohols such as ethanol, or a combination thereof.
  • this injection contains a stabilizer, a solubilizing agent (daltamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a soothing agent, a preservative, and the like.
  • a sterile solid preparation for example, a lyophilized product, can be manufactured and then used after dissolving in sterile or sterile distilled water for injection or other solvents before use.
  • Inhalants for parenteral administration include aerosols, powders for inhalation, and liquids for inhalation, which are used by dissolving or suspending in water or other appropriate medium at the time of use. It may be in a form to perform.
  • preservatives salts such as sodium chloride, paraben, etc.
  • coloring agents such as sodium chloride, paraben, etc.
  • buffering agents such as sodium phosphate, sodium acetate, etc.
  • isotonic agents sodium chloride
  • Concentrated glycerin, etc. a thickener (eg, riboxylvinyl polymer), an absorption enhancer, etc., as necessary.
  • lubricants stearic acid and its salts, etc.
  • binders starch, dextrin, etc.
  • excipients lactose, cellulose, etc.
  • coloring agents whitening agents (benzalkonium chloride) , Parabens, etc.), absorption promoters and the like are appropriately selected as necessary and prepared.
  • a nebulizer (atomizer, nebulizer) is usually used to administer inhaled liquids, and a powdered inhaler is usually used to administer inhaled powders.
  • compositions for parenteral administration include suppositories for rectal administration and pessaries for vaginal administration which contain one or more active substances and are formulated in a conventional manner.
  • the compound of the present invention is continuously administered directly to the site of the disease.
  • the dosage form may be an implant preparation.
  • the bioabsorbable polymer used as the base of the sustained-release preparation of the therapeutic agent of the present invention includes a fatty acid ester polymer or a copolymer thereof, polyacrylates, polyhydroxybutyrate, and polyalkylene oxalate. Rates, polyoresters, polycarbonates and polyamino acids, which may be used alone or in admixture of one or more.
  • Fatty acid ester polymers or copolymers thereof include polylactic acid, polyglycolic acid, polycunic acid, polymalic acid, poly- ⁇ -force prolatatatone, polydioxanone, polyphosphazene, and the like, and a graft comprising two or more of these components.
  • Block, alternating, and random copolymers can be used, and these can be used alone or in combination.
  • poly ⁇ -cyanoacrylate, poly] 3-hydroxybutyric acid, polytrimethylene oxalate, polyorthoester, polyonolesocarbonate, polyethylene carbonate, polyy-benzinole-L-glutamic acid and poly-L-alanine Yes, two or more of these components, a copolymer with the above-described materials, or a mixture of one or more of them can be used.
  • it is a polylactic acid, a polydalcholic acid, or a lactic acid-glycolic acid copolymer.
  • the lactic acid used in the polylactic acid or the lactic acid-dalicholic acid copolymer includes L-lactic acid or DL-lactic acid.
  • the average molecular weight of the bioabsorbable polymer used in the present invention is preferably from about 2,000 to about 800,000, more preferably from about 5,000 to about 200,000.
  • polylactic acid preferably has a weight average molecular weight of about 5,000 to about 100,000, more preferably about 6,000 to about 50,000.
  • Polylactic acid can be synthesized according to a production method known per se.
  • the composition ratio of lactic acid and glycolic acid is from about 100 Z0 to about 0 Z100 (W / W), more preferably Those having about 90 to about 370 (W / W) can be used according to the purpose.
  • the weight average molecular weight of the lactic acid-glycolic acid copolymer used is preferably about 5,000 to about 100,000, more preferably about 10,000 to about 80,000.
  • the lactic acid-glycolic acid copolymer can be synthesized according to a production method known per se. Industrial applicability
  • Nitric oxide synthase inhibiting compounds are effective in treating spinal stenosis such as cervical spinal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, or extensive spinal canal stenosis. Specifically, it has the effect of improving motor skills, especially improving muscle weakness, improving intermittent claudication, or improving walking ability.
  • Fig. 1 shows the compound A ((+)-trans-3-imino-5-methyl-17-chloro-1-2-azabicyclo [4.1.0] heptane monohydrochloride) in a rat cauda equina compression gait disorder model. It shows improvement of symptoms by administration.
  • Figure 2 shows compound B (N- [3- (aminomethyl) benzyl] acetamidine) and compound C (2-fluoro N- [3- (aminomethyl) phenyl] atamidine in a rat cauda equina compression gait disorder model. 'Dihydrobromide) indicates improvement in symptoms following administration. Best mode of implementation
  • a rat cauda equina nerve gait disorder model was prepared by the method of Takenobu et al. (J. Neurosci. Methods., 104 (2), 191-198 (2002)), ie, rats were anesthetized with pentobarbital sodium, and After disinfection of the back with a chlorhexidine dalconate (5% Hibitene solution; Sumitomo Pharmaceutical), the lower back was dissected along the midline to expose the spine.
  • a chlorhexidine dalconate 5% Hibitene solution; Sumitomo Pharmaceutical
  • the walking ability test was evaluated using a treadmill. After placing the rat on the running belt and applying electricity to the grid (0.04 mA to 4 mA) for at least 3 minutes to adapt to the environment, start walking at a speed of 1 Om / min, and then every 3 minutes The speed was increased by 5 m / min. Rats that stopped walking and transferred to the electrical stimulation dalid equipped before the running belt received electrical stimulation (0.04 mA to 4 mA). The distance from when the animal started walking to when it was unable to walk, that is, until it stopped walking when stimulated (sound, contact, electricity) by applying a stimulus (sound, contact, electricity) was measured with a rangefinder built into the device.
  • the cauda equina compression gait model has been reported as a model of spinal canal stenosis.
  • the compound (Compound A, B, or C) used in the present invention improved gait disturbance in rats with cauda equina compression gait disorder. That is, it was suggested that the compound having a nitric oxide synthase inhibitory effect used in the present invention is effective for spinal canal stenosis.
  • the following compounds were mixed by a conventional method and tabletted to obtain 100 tablets each containing 1 Omg of the active ingredient.
  • Heptane monohydrochloride (10 Omg) was dissolved in distilled water (100 ml). 10 ml was injected into a 50 ml ampoule and freeze-dried by a conventional method to obtain 10 ampoules containing 1 Omg of the active ingredient.

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  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un agent de prévention et/ou thérapeutique pour la sténose du canal rachidien, contenant un composé inhibant l'oxyde nitrique synthétase. Des exemples typiques de ce composé comprennent un composé représente par la formule (I): (dans laquelle les symboles ont la même signification que dans la description), un sel de ce composé, et un solvate de l'un ou de l'autre. L'agent thérapeutique est efficace dans la prévention et dans les traitements de, par exemple, la sténose de canal rachidien telle que la sténose de canal rachidien lombaire.
PCT/JP2003/013776 2002-10-29 2003-10-28 Agent therapeutique pour la stenose de canal rachidien WO2004039404A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003275709A AU2003275709A1 (en) 2002-10-29 2003-10-28 Therapeutic agent for spinal canal stenosis

Applications Claiming Priority (2)

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JP2002314084A JP2006096665A (ja) 2002-10-29 2002-10-29 脊柱管狭窄症治療剤
JP2002-314084 2002-10-29

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WO2012057248A1 (fr) 2010-10-29 2012-05-03 塩野義製薬株式会社 Dérivé de naphtyridine
US8541408B2 (en) 2007-04-24 2013-09-24 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
US8546380B2 (en) 2005-10-25 2013-10-01 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8637504B2 (en) 2008-06-13 2014-01-28 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US8653067B2 (en) 2007-04-24 2014-02-18 Shionogi & Co., Ltd. Pharmaceutical composition for treating Alzheimer's disease
US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
US8883779B2 (en) 2011-04-26 2014-11-11 Shinogi & Co., Ltd. Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them
US8999980B2 (en) 2009-12-11 2015-04-07 Shionogi & Co., Ltd. Oxazine derivatives
US9018219B2 (en) 2010-10-29 2015-04-28 Shionogi & Co., Ltd. Fused aminodihydropyrimidine derivative
US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity

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CA2543315A1 (fr) * 2003-11-13 2005-06-02 The General Hospital Corporation Methodes pour traiter la douleur

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Cited By (21)

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US8815851B2 (en) 2005-10-25 2014-08-26 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US9029358B2 (en) 2005-10-25 2015-05-12 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8546380B2 (en) 2005-10-25 2013-10-01 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8633188B2 (en) 2005-10-25 2014-01-21 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8895548B2 (en) 2007-04-24 2014-11-25 Shionogi & Co., Ltd. Pharmaceutical composition for treating alzheimer's disease
US8884062B2 (en) 2007-04-24 2014-11-11 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
US8653067B2 (en) 2007-04-24 2014-02-18 Shionogi & Co., Ltd. Pharmaceutical composition for treating Alzheimer's disease
US8541408B2 (en) 2007-04-24 2013-09-24 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
US9273053B2 (en) 2008-06-13 2016-03-01 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having Beta secretase inhibitory activity
US8637504B2 (en) 2008-06-13 2014-01-28 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US9650371B2 (en) 2008-06-13 2017-05-16 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
US9656974B2 (en) 2009-12-11 2017-05-23 Shionogi & Co., Ltd. Oxazine derivatives
US9290466B2 (en) 2009-12-11 2016-03-22 Shionogi & Co., Ltd. Oxazine derivatives
US8999980B2 (en) 2009-12-11 2015-04-07 Shionogi & Co., Ltd. Oxazine derivatives
US9018219B2 (en) 2010-10-29 2015-04-28 Shionogi & Co., Ltd. Fused aminodihydropyrimidine derivative
US8927721B2 (en) 2010-10-29 2015-01-06 Shionogi & Co., Ltd. Naphthyridine derivative
WO2012057248A1 (fr) 2010-10-29 2012-05-03 塩野義製薬株式会社 Dérivé de naphtyridine
US8883779B2 (en) 2011-04-26 2014-11-11 Shinogi & Co., Ltd. Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them
US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
US9758513B2 (en) 2012-10-24 2017-09-12 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity

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