WO2004039404A1

WO2004039404A1 - Therapeutic agent for spinal canal stenosis

Info

Publication number: WO2004039404A1
Application number: PCT/JP2003/013776
Authority: WO
Inventors: Yoshifumi Takenobu; Yoshihisa Kamanaka; Takaaki Obata
Original assignee: Ono Pharmaceutical Co., Ltd.
Priority date: 2002-10-29
Filing date: 2003-10-28
Publication date: 2004-05-13
Also published as: AU2003275709A1; JP2006096665A

Abstract

A preventive and/or therapeutic agent for spinal canal stenosis, which contains a compound inhibiting a nitric oxide synthase. Typical examples of the compound include a compound represented by the formula (I): (I) (wherein the symbols have the same meanings as in the description), a salt thereof, and a solvate of either. The therapeutic agent is effective in the prevention of and treatments for, e.g., spinal canal stenosis such as lumbar spinal canal stenosis.

Description

Description Spine stenosis therapeutic agent Technical field

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). Background art

The vertebral bodies from the cervical spine to the sacral spine and the internal space surrounded by the spinous processes are called spinal canals. In 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. On the other hand, the discovery that 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)). In the circulatory system field, 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 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 (abbreviated as constitutive NOS, c-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) is hepatic parenchymal cells, neutrophils, macrophages, smooth muscle, fibroblasts, renal mesangial cells, gastrointestinal epithelium, 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.

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.

In analyzing the physiological activity of NO in vivo, NOS inhibitors are useful, and may be used as therapeutics for shock and ischemic diseases. Development is underway.

The compound represented by the formula (I) described below has been reported as a NOS inhibitory compound (EP870763). Disclosure of the invention

For treatment of spinal canal stenosis, surgical treatment is selected for severe cases, but it is aimed at pharmacotherapy, gymnastics to strengthen abdominal muscles and back muscles, hyperthermia such as hot packs, and pain relief. Conservative treatment, such as buccal treatment and bracing with corsets, is fundamental. However, there is no treatment that satisfactorily improves the various symptoms of spinal canal stenosis.

As a mechanism of the manifestation of spinal stenosis such as intermittent claudication, hypoxia due to impaired blood flow in nervous tissues is considered to be involved in addition to mechanical compression of nerves. In other words, the symptom may be expressed by synergistic effects such as floating JB and metabolic disorder in nerve tissue. At present, only 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.

That is, the present invention

1) A preventive and / or therapeutic agent for spinal canal stenosis comprising a nitric oxide synthase inhibitory compound,

2) Prevention of spinal canal stenosis as described in 1 above, wherein the spinal canal stenosis is cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, or extensive spinal canal stenosis Or therapeutic agent,

3) The preventive and / or therapeutic agent for spinal canal stenosis according to the above item 1, which is an agent for improving paralysis, hypoesthesia, pain, or numbness,

4) The preventive and / or therapeutic agent for spinal canal stenosis according to the above item 1, which is an agent for improving athletic performance,

5) The preventive and / or therapeutic agent for spinal canal stenosis according to 4 above, wherein the improvement of the motor ability is improvement of muscle weakness, improvement of intermittent claudication or improvement of walking ability,

6) The preventive and / or therapeutic agent for spinal canal stenosis according to the above 1 which is a therapeutic agent for bladder disorder or rectal disorder,

7) The preventive and / or therapeutic agent for spinal canal stenosis according to the above 1, wherein the nitric oxide synthase inhibitory compound is an inducible nitric oxide synthase inhibitory compound or a neuronal nitric oxide synthase inhibitory compound.

8) nitric oxide synthase inhibiting ^compounds, Ν ω - Monomechiru L-arginine ^one, Ν ω - two Torrox L- ^Anoreginin, Ν ω - two Toro one L- § Roh the regulation Nin methylate Norre Este ^Lumpur, Ν ω - amino-L - arginine, New ^omega - cyclopropyl one L- arginine, New ^omega - Ariru one L- arginine, New ^omega - two Toro one L- arginine one ρ- two Toro Anilide, ^{ω ω} , — ^ω —Dimethi arginine, 2-iminobiotin, S—methylol L-thiocitrulline, S—ethyl-L-thiocytonorelin, L-thiocytonorrelin, L-homothiocitrin, 2-iminopiperidine, 2 —Iminohomopiperidine, S—Methylisothioprea, S—Ethylisothioprea, S—Isopropi ^ / Isothioprea, S, S, 1 (1,3-phenylenebis (1,2,1 ethanedyl)) ) bis I Seo Chio © rare, 2- Aminochiazorin, 2 § Minochiazo Ichiru, Ν- (3- (aminomethyl) benzyl) one ^Asetamijin, Ν δ - (4, 5- dihydro-thiazole one 2-I le) Onorenichin , New ^omega - Imino Echiru one ol two Chin, L one New ⁶ - (1-iminoethyl) one lysine, 2-Amino -5, 6- dihydro 6-methyl-4Η_ 1, 3- thiazine, New ^[delta] - (1-I Minoet ) — —Methyloroditin, 2— [4— [2— (7—Methylimidazo [1,2—3] pyridin-2-yl) ethyl] phenylamino] -2 monothiazoline, 2-imino-4,6 —Dimethylpiperidine, (4 S, 4 a S, 7 a S) 14-methylperhydro-1- 1-pyridine-12-imine, 6— [4— [2-(4-acetylbiperazine-1—) Yl) ethyl] phenyl] pyridine-2-ylamine, 1-amino-3- (2-fluorophenyl) 1-3,4-dihydroisoquinoline, 5-chloro-13- (monorephorin 1-4-inolemethinole) benzoxazonole One 2— (3H) one, diphenyrene, di-2-neodonium, canolecineurin, N— (4-aminobutyl) —5-chloro-one 2-naphthalenes-norenamide, trifonole Operadin, 2, 4-Jaminow 6-Hydroxypi The preventive and / or therapeutic agent for spinal canal stenosis according to the above 1, which is limidine, a salt thereof, or a solvate thereof,

9) 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 1 2 (S) ylcarbonyl] Pyrazine 1 11yl] —Tiophen 1 2—Carboxamidine, A—84643, 5— (7—Methyl 1 1,4 —Diazepan-1-ylsulfonyl) isoquinoline, (4aS, 8aR) -4a, 5,6,7,8,8a—Hexahydro-1H—3,1—Venzothiazine-12-amine N— [4— [2— (benzylaminocanoleponyl) ethyl] Hue Ninore] Thiophene-1 2-Canolepoxamidine, N— [4- [2- (3-Clo-benzinoleamino) etinole] feninole] Thiophene-1-2-potassylpoxamidine, N ⁶ — (1-Iminoethyl) ^-1 N ¹ — (1H-tetrazol-1-yl) 1L-lysine amide, SD_3651, GW-289013, BN_52296, ANG—500, a salt thereof, or a solvate of the spinal canal according to the above 1 Prophylactic and / or therapeutic agents for stenosis,

10) —The 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,

1 1) The compound that inhibits nitric oxide synthase has the formula (I)

H

[Wherein, one R ¹ — together with the carbon atom at the bonding position is d or Represents a 3- or 4-membered carbon ring fused to e or spiro-bonded to the 4-position,

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 represents 0 or an integer of 1 to 3,

n represents 0 or an integer of 1 to 3.

However, a plurality of R ² or R ³ may be the same or different. The agent for preventing and / or treating spinal canal stenosis according to the above 1, which is a compound represented by the formula (I), a salt thereof, or a solvate thereof:

1 2) The compound inhibiting the nitric oxide synthase has the formula (IA)

H

[The symbols in the formula have the same meaning as in the preceding item 11] Wherein the compound, a salt thereof, or a solvate thereof is used for the prevention and / or treatment of spinal canal stenosis according to item 11,

13) The 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;

15) 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.

In the formulas of the compounds according to the present invention, unless otherwise specified, as will be apparent to those skilled in the art, the symbols ..., ^χ indicate that they are attached to the other side of the paper (ie, α-configuration), Indicates that they are connected to the near side of the page (that is, one arrangement), Ζ indicates that they are one arrangement, i3-configuration or a mixture thereof, and / ^ indicates α-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.

For the compounds used in the present invention, all isomers are included unless otherwise indicated. For example, the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, alkylene group, alkenylene group, and alkynylene group include linear and branched ones. Furthermore, isomers in double bonds, rings and condensed rings (E, Z, cis, trans), isomers due to the presence of asymmetric carbon (R, S, α,] 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. In addition, all NOS-inhibiting compounds to be found in the future as well as NOS-inhibiting compounds known to date are included. Further, 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 ΜΑ; No. W091 / ^04024), Ν ω - nitro one L one-arginine (L one ^ΝΝΑ), Ν ω - nitro one L- arginine methyl ester ^{(L-NAME), Ν ω} - amino-L one-arginine (L one ^ΝΑΑ), Ν ω - cyclopropyl one L one-arginine (L ^-CPA), Ν ω - Ariru one L one-arginine (L- ^ALA), Ν ω - two Torrox L- arginine one ρ- 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-iminopiperidine, 2-iminohomopiperidine, S-methylisothioprea, S-ethylisothioprea (EI Τ), S-isopropylisothioprea, S,

5 '- (1, 3-phenylene Renbisu (1, 2 Etanjiiru)) Bisuisochio Urea, 2-Aminochiazorin, 2 Aminochiazoru, Nyu- (3- (amino Nomechiru) benzyl) one Asetamijin, New ^[delta] - ( 4, 5-dihydro-thiazole - 2-i le) d'two Chin, New ^omega - imino ethyl chromatography ol two Chin (L one ^{Ν Ι Ο), LN 6 -} (1 one Iminoechinore) one lysine, 2-amino one 5, 6-dihydro-1

6-methyl one 4 Η- 1, 3- thiazine ^{(ΑΜΤ), Ν δ - (} 1- Iminoechiru)-.alpha.-Mechiruoruyuchin (No. WO95 / 11014), 2- [4- [2 - (7- methylimidazo one [ 1,2-a] pyridin-2-yl) ethyl] phenylamino] -2-thiazoline (WO96 / 30350), 2-imino-1,4,6-dimethylbiperidine (W096 / 35677), (4S, 4 a S, 7 a S) — 4-Methyl perhydro —1-Pyridine-12-imine (W096 / 14844), 6— [4-—2- (4-A-cetino-lebiperazine-1-1-inole) [Feninole] pyridine-12-inoleamine (W097 / 36871), 1-amino-13- (2-fluorophenyl) -1,3,4-dihydroisoquinoline (W097 / 38977), 5-chloro-13 (Morpholine-4-ylmethyl) benzoxazole-2- (3H) one, its salt, Include solvates thereof.

In addition, EP870763, 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 / 20511, W098 / No. 42696, WO91 / 04024, WO98 / 30537, WO96 / 19440, EP670825, W098 / 42696, W098 / 58934, or the NOS inhibitory action described in the patent application of JP-A-10-265450. Compounds having these compounds are also useful, and the application of these compounds to the uses of the present invention is also included in the present invention. More preferably, N- [3- (aminomethyl) benzyl] acetamidine (1400W; WO96 / 19440), 2-fluoro-N- [3- (aminomethyl) phenyl] acetamidine (WO96 / 19440), aminoguadin (Pimagagedin; EP448228), A—2492, CR—3294, S— [2— (1 minoethylamino) ethyl) —L—homocysteine (GW—273362; WO98 / 30537), 3— (2, 4-difluorophenyl) —6 -— [2- [4- (1H-imidazole-1-ylmethyl) -phenoxy] ethoxy] —2—phenylpyridine (PPA-250; WO02 / 00648), 7-nitroindazole (7 — NI), 6—Nitroindazole, Indazole, 1— (2-Trifluoromethylphenyl) imidazole (TR IM), 2- (2—Fluorobiphenyl-1-yl) 4-Nitrooxy propionate Butyl Este Nore (Nito Nitroflurbiprofen, HCT-1026; EP670825), N ¹ — [4— [4- [6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H—1-benzopyran) 2 (S) ylcarbonyl] pyrazine-1 1-yl] -thiophene 1-2-l-potoxamidine (BN-80933; W098 / 42696), A-84643, 5- (7-methyl-1,4-diazepane) 1-ylsulfonyl) isoquinoline (HMN-1180), (4 aS, 8aR) -4a, 5,6,7,8,8a-Hexahydro-14H-3,1-benzothiazine-2-amine (L-770425; W096 / 14842), N -[4- [2 -— (benzylaminocarbonyl) ethyl] phenyl] thiophen-2-ene lipoxamidine (ARL-16556; WO95 / 05363), N— [4- [2- (3-chlorobenzylamino) ethyl) ] phenyl] Chiofen one 2 - carboxamidine (ARL- 17477; No. ^{WO95 / 05363), N 6 -} (1 - iminoethyl) Single N ¹ - (1 H- tetrazol Ichiru one 5- I le) Single L one Rijin'ami de ( SC-51; WO96 / 15120), SD-3651, GW-289013, BN-52296, ANG-500, a salt thereof, or a solvate thereof.

Preferred NOS inhibiting compounds include compounds of the formula (I)

[Wherein, one 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 Represents

R ² ¾C: 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 represents 0 or an integer of 1 to 3,

n represents 0 or an integer of 1 to 3.

However, a plurality of R ² or R ³ may be the same or different. ] Or a salt thereof, or a solvate thereof.

More preferred NOS inhibiting compounds include those of the formula (IA)

H

[The symbols in the formula have the same meanings as described above.] Or a salt thereof, or a solvate thereof.

Particularly preferred NOS inhibiting compounds include those of the formula (la)

Or (+)-trans-3-imino-5-methyl-7-chloro-1-2-azabicyclo [4.1.0] heptane (EP870763), a salt thereof, or a solvate thereof. It is.

In the formula (I), the C1-4 alkyl group means methyl, ethyl, propyl, ethyl and isomers thereof, and the C1-6 alkyl group means methyl, ethyl, propyl , Butyl, pentyl, hexyl and their isomers, and C2-6 alkenyl means ethenyl, propenyl, butyr, pentenyl, hexenyl and their isomers, C2- 6 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. Further, 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. 20511, W098 / 42696, WO91 / 04024, WO98 / 30537, WO96 / 19440, EP670825, W098 / 42696, W098 / 58934, or by the method described in JP-A-10-265450 Can be manufactured.

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. Thus, 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. For example, in the case of intravenous administration using a mouse, the maximum tolerated dose of the compound represented by the formula (la) was 30 mg Zkg.

[Application to pharmaceutical products]

The compound used in the present invention or a salt thereof,

1) complement and / or enhance the prophylactic and Z or therapeutic effects of the compound,

2) Kinetics of the compound.Improved absorption, reduced dosage, and Z or

3) Reduction of side effects of the compound

May be administered in combination with other drugs.

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 . When administered in the form of separate preparations, simultaneous administration and administration at different times are included. In addition, 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. And 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.

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 Nonsteroidal anti-inflammatory drug (NSAID), vitamin drug, muscle relaxant, antidepressant, poly ADP-ribose polymerase (PARP) inhibitor, excitatory amino acid receptor antagonist (eg, NMD A receptor antagonist, AM PA receptor antagonist Agents), radical scavengers, astrocytic function improvers, IL-8 receptor antagonists, immunosuppressants (eg, cyclosporine, FK506).

Prostaglandins (hereinafter abbreviated as PG) 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, piroxicam, tenoxicam, ampiloxicam, napageln ointment, , Tiaramid hydrochloride, tinolidine hydrochloride, morphazone, sulpyrine, migrenine, salidone, cedes G, amipiro-1 N, sorbone, pilin cold, acetaminophen, phenacetin, mesylate Examples include dimethothiazine, a combination drug of cimetride, and a non-pyrine cold drug. 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.

Examples of the tricyclic antidepressant 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.

In addition, other 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, 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. Preferably, it is a hydrochloride.

Further, the compound used in the present invention or a salt thereof may be a solvate.

The 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).

Further, 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. When 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.); when the compound used in the present invention has a carboxy group, the carboxy group is esterified or amidated. (E.g., 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 _γ -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.

In order to use the compound used in the present invention or a combination of the compound used in the present invention and another drug for the above purpose, it is usually administered systemically or locally, orally or parenterally. You.

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.

Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above-mentioned dose may be sufficient, or administration may be necessary beyond the range.

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.

In such solid dosage forms for oral use, 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. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. Also included are capsules of absorbable materials, such as gelatin.

The sublingual tablet is produced according to a known method. For example, 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, trenolulose, phosphate, citrate, caic acid Salts, glycine, glutamic acid, arginine, etc.) Stabilizers, dissolution aids (polyethylene glycol, propylene glycol, glutamic acid, aspartic acid, etc.), flavors (orange, strawberry, mint, remo) , Is mixed with Bruno Yura, etc.) or the like, according to usual methods. Further, if necessary, it may be coated with Coating IJ (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. If necessary, 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. For example, 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.) Propylcellulose, hydroxypropinolemethinoresenolellose, capopol, carboxymethylcellulose, polyvinyl alcohol, xanthan gum, guar gum, 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.), etc., and formulated into a formulation according to the usual method. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. If necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners and the like which are commonly used can be added. The orally rapidly disintegrating tablet is produced according to a known method. For example, 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 (darcose, fnorectose, mannitol, xylitole, erythritol tonole, maltose, trehalose, phosphate, citrate, caic acid) Mixed with salts, glycine, glutamate, arginine, etc.) stabilizers, solubilizers (polyethylene glycol, propylene glycol, glutamic acid, aspartic acid, etc.), flavors (orange, strawberry, mint, lemon, vanilla, etc.) It is formulated and used according to standard methods. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxypropylcellulose, hydroxypropyl methylcellulose monophthalate, etc.), or may be coated with two or more layers. Is also good. If necessary, 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. In such solutions, one or more active substances are dissolved, suspended, or emulsified in a commonly used diluent (such as purified water, ethanol, or a mixture thereof). Further, 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. beeswax, spermaceti, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphate, etc.), higher alcohols (cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oil

(Dimethylpolysiloxane, etc.), 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. For example, 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. In addition, 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. For example, 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. As a solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glyco , Polyethylene glycol, alcohols such as ethanol, or a combination thereof. Further, 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. You may go out. These are prepared by sterilizing or aseptic processing in the final step. In addition, 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.

These inhalants are manufactured according to a known method.

For example, in the case of liquids for inhalation, preservatives (salts such as sodium chloride, paraben, etc.), coloring agents, buffering agents (sodium phosphate, sodium acetate, etc.), isotonic agents (sodium chloride) , Concentrated glycerin, etc.), a thickener (eg, riboxylvinyl polymer), an absorption enhancer, etc., as necessary.

In the case of powders for inhalation, 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.

Other 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.

As a long-acting preparation, the compound of the present invention is continuously administered directly to the site of the disease. As long as it can be supplied, 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-ε-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. In addition, poly α-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. Preferably, 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. For example, 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.

In the lactic acid-glycolic acid copolymer, 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. BRIEF DESCRIPTION OF THE FIGURES

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

Hereinafter, the present invention will be described in detail with reference to Examples and Preparation Examples, but the present invention is not limited thereto. Example 1

Improvement effect of the compound of the present invention using a rat cauda equina compression gait disorder model <Model preparation method>

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. After resection of the lumbar spinous process, 1 x 4 x 1.25 mm (height x length x width) silicone rubber was introduced into the 4th and 6th lumbar vertebral canal through the small hole in the lamineum drilled with a mini drill. In order to avoid infection, benzylpenicillin power rim (crystal penicillin G power rim Meiji; Meiji Seika) was dropped on the wound site and intramuscularly injected into the thigh. Suture with surgical thread and apply iodine tincture to suture area It was. Although sham animals was also prepared according to the above method, 揷入 of silicone rubber or a performed ivy.

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. Before the surgery, a walking function test was performed once a day for 3 consecutive days to perform walking training. After surgery, the inducible NOS inhibitory compound (+)-trans-3-imino-5-methyl-17-chloro-1-azabicyclo [4.1.0] heptane.monohydrochloride (Compound A in FIG. 1) Is a compound of the formula (la)) or N— [3- (aminomethyl) benzyl] acetami Gin (compound B in FIG. 2), a neuronal NOS inhibitor, 2-fluoro-N- [3- (aminomethyl) phenyl] acetamidine / hydrobromide (compound C in FIG. 2) ) Was administered. Physiological saline or distilled water was administered as a negative control. The results were tested against the negative control by Dunnett's multiple comparison (* p 0.05).

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 results are shown in FIGS. 1 and 2. Formulation Example 1: Production of tablets

The following compounds were mixed by a conventional method and tabletted to obtain 100 tablets each containing 1 Omg of the active ingredient.

• (+) —trans-3-imino-5-methyl-7-chloro-2-azabizicro [4.1.0] heptane 'monohydrochloride 1 g

• Calcium cellulose glycolate (disintegrant) 20 Omg

'Magnesium stearate (lubricant) 10 Omg' Microcrystalline cellulose 18.7 g Formulation example 2: Production of injection

(+)-Trans-3-imino-5-methyl-17-chloro-1-2-azabicyclo [4.1.0] 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.

Claims

The scope of the claims

1. A preventive and / or therapeutic agent for spinal canal stenosis comprising a nitric oxide synthase inhibitory compound.

2. The prevention of spinal canal stenosis according to claim 1, wherein the spinal canal stenosis is cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, or extensive spinal canal stenosis. / Or therapeutic agent.

3. The preventive and / or therapeutic agent for spinal stenosis according to claim 1, which is an agent for improving paralysis, hypoesthesia, pain, or numbness.

4. The preventive and / or therapeutic agent for spinal stenosis according to claim 1, which is an agent for improving athletic ability.

5. The preventive and / or therapeutic agent for spinal canal stenosis according to claim 4, wherein the improvement in exercise ability is an improvement in muscle weakness, an improvement in intermittent claudication, or an improvement in walking ability.

6. The preventive and / or therapeutic agent for spinal stenosis according to claim 1, which is a therapeutic agent for bladder disorder or rectal disorder.

7. The prevention of spinal canal stenosis according to claim 1, wherein the nitric oxide synthase inhibitory compound is an inducible nitric oxide synthase inhibitory compound or a neuronal nitric oxide synthase inhibitory compound. Or a therapeutic agent.

8. — Nitric oxide synthase inhibitor compound is 、 ^ω — monomethyl-L-arginine, New ^omega - two Toro one L- Anoreginin, New ^omega - two Torrox L over § Bruno the regulation Nin methylate Honoré ester le, New ^omega - amino-L- arginine, New ^omega - cyclopropyl one L- arginine, New ^omega - Ariru one L - arginine, New ^omega - two Toro one L- arginine one ρ- two Toro Aniri de, New ^omega, New ^omega _ dimethyl § Roh the regulation Nin, 2 Iminobiochin, S- methylation one L- Chioshitonorerin, S- Echiru one L -Thiocitrulline, L-thiocitrulline, L-homothiocitrulline, 2-^-aminopiperidine, 2-iminohomopiridine, S-methylisothioprea, S-ethylisothioprea, S-isopropipropyl Noleisothioprea, S, S,-(1,3-phenylenebis (1,2-ethanediyl)) bisisothiopurea, 2-aminothiazoline, 2-aminothiazole, N- (3- (amino Methyl) ben Le) Single ^Asetamijin, Ν δ - (4, 5- dihydro-thiazole-2-I le) d'two Chin, New ^omega - Imino Echiru one ol two Chin, L- Ν ⁶ - (1- Iminoechinore) one lysine, 2- Amino -5, 6-dihydro-one 6-methyl one 4 H-1, 3- thiazine, New ^[delta] - (1-I Minoechiru) one _alpha - Mechiruoruyuchin, 2- [4- [2 - (7-Mechiruimi Dazo one [ 1,2-a] pyridin-2-yl) ethyl] phenylamino] -2 monothiazoline, 2-imino-1,4,6-dimethylbiperidine, (4S, 4aS, 7aS) 1-4 Methynorephydr-1 1-pyridine-1 2-imine, 6- [4-1

[2- (4-Acetylbiperazine-1-yl) ethyl] phenyl] pyridine—2-inoleamine, 1-amino-3- (2-phenylphenol) 1,3,4-dihydroisoquinoline, 5—Black mouth 1— (Monolefolin 1—41 Inolemethinole) Benzoxazonole 2— (3H) —On, Diphenyrenodonium, G2—Chenordonium, Calcineurin, N— (4-Aminobutyl) — The spinal canal stenosis according to claim 1, wherein the spinal canal stenosis is 5-naphthalene 2-norphthalene amide, trinoleoperazine, 2,4-diamino-16-hydroxypyrimidine, a salt thereof, or a solvate thereof. Prophylactic and Z or therapeutic agents.

9. The nitric oxide synthase inhibitor compound is 2-fluoro-N- [3- (aminomethyl) phenyl] acetamidine, aminoguadin, A-2492, CR-3294, S- [2- (1-iminoethyla). Mino) ethyl] 1 L-homo cysteine, 3— (2,4-difluorophenyl) 1 6— [2— [4— (1 H—imidazole / 1-ylmethyl) 1-phenoxy] ethoxy] —2—phenylpyridine , 7-ditroindazole, 6-ditroindazole, indazole, 1- (2-trifluoromethylphenyl) imidazole, 2- (2-furono-robifeninole 1-4-inole) propionic acid Noreester, N ¹ — [4— [4— [6-Hydroxy-1,2,5,7,8-tetramethyl-1,3,4-dihydro-1 2H— 1-benzopyran-1 2 (S) -ylcarbonyl] piperazine — 1] il] — Chofe 1- 2-carboxamidine, A- 84643, 5- (7-methinolay 1, 4-diazepan-1-ylsulfonyl) isoquinoline, (4 a S, 8 a R) -4 a, 5, 6, 7, 8, 8, 8 a Hexahydro-4H-3,1-benzothiazine-12-amine, N- [4- [2- (benzylaminocarbonyl) ethyl] phenyl] thiophene-2-carboxamidine, N- [4- [2- (3-cyclopentene benzonoramino) ethyl] phenyl] thiophene 1 2 _carboxamidine, N ⁶ — (1-iminoethyl) 1 N ¹ — (1 H-tetrazole-5-yl) 1 L-lysine amide, SD — 3651, GW — 289013, BN—52296, ANG—500, a salt thereof, or a solvate thereof, the agent for preventing and / or treating spinal canal stenosis according to claim 1.

10. —The nitric oxide synthase inhibiting compound is (+) — trans-3-iminin-5-methyl-17-chloro-1-2-azabisic [4.1.0] heptane, N— [3- (aminomethyl 2. The preventive and / or therapeutic agent for spinal canal stenosis according to claim 1, which is benzyl] acetamidine, a salt thereof, or a solvate thereof. The compound for inhibiting nitric oxide synthase has the formula (I)

H

[Wherein, R ¹ — is a 3- or 4-membered carbon ring fused to d or e of the piperidine ring or spiro-bonded to the 4-position together with the carbon atom at the bonding position. Represent,

R ² represents a C 1-6 alkyl group,

R ⁴ represents a hydrogen atom, a carbocyclic ring which may be substituted with an amino C 1-4 alkyl group, or an amino C 1-4 alkyl group; a C 1-4 alkyl group;

i represents 0 or an integer of 1 to 3,

n represents 0 or an integer of 1 to 3.

However, a plurality of R ² or R ³ may be the same or different. 3. The preventive and / or therapeutic agent for spinal canal stenosis according to claim 1, which is a compound represented by the formula: or a salt thereof, or a solvate thereof.

1 2. The compound inhibiting nitric oxide synthase has the formula (IA)

H [The symbols in the formula represent the same meaning as in claim 11. A compound represented by the formula: The agent for preventing and / or treating spinal stenosis according to claim 11, which is a salt thereof or a solvate thereof.

13. The nitric oxide synthase inhibitor compound according to claim 11, prostaglandins, prostaglandin derivative preparations, nonsteroidal anti-inflammatory drugs, vitamins, muscle relaxants, antidepressants, poly AD With one or more drugs selected from P-report polymerase inhibitors, excitatory amino acid receptor antagonists, radical scavengers, astrocytic function improvers, IL-18 receptor antagonists, and immunosuppressants A pharmaceutical composition comprising a combination.

14. A method for preventing and / or treating spinal canal stenosis, comprising administering an effective amount of a nitric oxide synthase inhibitory compound to a mammal.

15. Use of a nitric oxide synthase inhibiting compound for the manufacture of a prophylactic and / or therapeutic agent for spinal canal stenosis.