JP5527205B2 - 脊柱管狭窄症治療剤 - Google Patents
脊柱管狭窄症治療剤 Download PDFInfo
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- JP5527205B2 JP5527205B2 JP2010517991A JP2010517991A JP5527205B2 JP 5527205 B2 JP5527205 B2 JP 5527205B2 JP 2010517991 A JP2010517991 A JP 2010517991A JP 2010517991 A JP2010517991 A JP 2010517991A JP 5527205 B2 JP5527205 B2 JP 5527205B2
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- spinal canal
- canal stenosis
- acid
- present
- stenosis
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- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000005607 chanvre indien Nutrition 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical group C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Chemical class 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000011487 hemp Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Chemical class 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- OJZYRQPMEIEQFC-UAWLTFRCSA-N limaprost Chemical compound CCCC[C@H](C)C[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCC\C=C\C(O)=O OJZYRQPMEIEQFC-UAWLTFRCSA-N 0.000 description 1
- 229950009365 limaprost Drugs 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 206010025005 lumbar spinal stenosis Diseases 0.000 description 1
- 210000004705 lumbosacral region Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical class OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Chemical class 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical group 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 150000003165 prostaglandin E1 derivatives Chemical class 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000003497 sciatic nerve Anatomy 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 239000002893 slag Substances 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000003594 spinal ganglia Anatomy 0.000 description 1
- 210000001032 spinal nerve Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 229940063650 terramycin Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Description
R3、R4は、同一又は異なって、水素原子又はアルキルを表し;
R5は水素原子、アルキル又はハロゲン原子を表し;
YはN又はN→Oを表し;
AはNR6を表し、R6は水素原子、アルキル、アルケニル又はシクロアルキルを表し;
Dはヒドロキシで置換されていてもよいアルキレン又はアルケニレンを表すか、又はAとDとが一緒になって、次の式(2)で表される二価の基を表し;
Eは、フェニレン又は単結合を表すか、又はDとEとが一緒になって、次の式(3)で表される二価の基を表し;
Gは、O、S、SO又はSO2を表し;
Qは、カルボキシ、アルコキシカルボニル、テトラゾリル、カルバモイル、モノアルキルカルバモイル、ジアルキルカルバモイル又は次の式(4)で表される基を表す。
1)アルキル、
2)アリール、
3)アリールオキシ、
4)複素環基。]
R1、R2が、同一又は異なって、ハロゲン原子、アルキル及びアルコキシからなる群から選ばれる1〜3個の置換基で置換されていてもよいフェニルであり、
R3、R4が、同一又は異なって、水素原子又はアルキルであり、
R5が水素原子であり、
YがNであり、
AがNR6であり、R6がアルキルであり、
Dがアルキレンであり、
Eが単結合であり、
GがOであり、
Qが、カルボキシ又は式(4)で表される基であり、R7が、アミノ、モノアルキルアミノ、ジアルキルアミノ、若しくはヒドロキシ、又はハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる1〜3個の置換基で置換されていてもよい下記1)〜4)のいずれかの基である化合物が好ましい。
1)アルキル、
2)アリール、
3)アリールオキシ、
4)複素環基
(1)窒素原子、酸素原子及び硫黄原子から選択される1〜4個までのヘテロ原子を有する5又は6員の芳香環基、又はそれらのベンゼン縮合環であって、かかる環構成原子が窒素原子又は硫黄原子の場合、かかる窒素原子、硫黄原子はオキシドを形成していてもよい。例えば、1−ピロリル、2−ピロリル、3−ピロリル、3−インドリル、2−フラニル、3−フラニル、3−ベンゾフラニル、2−チエニル、3−チエニル、3−ベンゾチエニル、1,3−オキサゾール−2−イル、4−イソオキサゾリル、2−チアゾリル、5−チアゾリル、2−ベンゾチアゾリル、1−イミダゾリル、2−イミダゾリル、4−イミダゾリル、2−ベンズイミダゾリル、1H−1,2,4−トリアゾール−1−イル、1H−テトラゾール−5−イル、2H−テトラゾール−5−イル、2−ピリジル、3−ピリジル、4−ピリジル、3−ピラゾリル、2−ピリミジニル、4−ピリミジニル、2−ピラジニル、1,3,5−トリアジン−2−イルを挙げることができる。
(2)環構成原子として、窒素原子、酸素原子又は硫黄原子を、同一又は異なって、1〜4個含んでいてもよい、4〜8員環の飽和環基、又はそれらのベンゼン縮合環基であって、環構成原子が窒素原子又は硫黄原子の場合、かかる窒素原子、硫黄原子はオキシドを形成していてもよい。例えば、ピペリジノ、ピペラジニル、3−メチルピペラジン−1−イル、ホモピペラジニル、モノホリノ、チオモノホリノ、1−ピロリジニル、2−ピロリジニル、2−テトラヒドロフラニルを挙げることができる。
本複素環誘導体(1)が塩基性を示す場合の「塩」としては、例えば、塩酸、硫酸、硝酸、リン酸、フッ化水素酸、若しくは臭化水素酸の無機酸の塩、又は酢酸、酒石酸、乳酸、クエン酸、フマール酸、マレイン酸、コハク酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸、ナフタレンスルホン酸、若しくはカンファースルホン酸の有機酸の塩を挙げることができる。
本複素環誘導体(1)が酸性を示す場合の「塩」としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩、又はカルシウム塩等のアルカリ土類金属塩を挙げることができる。
粉末混合物は、適当に粉末化された本複素環誘導体(1)を希釈剤や基剤と混合することにより製造することができる。必要に応じて、結合剤(例えば、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシプロピルメチルセルロース、ゼラチン、ポリビニルピロリドン、ポリビニルアルコール)、溶解遅延化剤(例えば、パラフィン)、再吸収剤(例えば、四級塩)、吸着剤(例えばベントナイト、カオリン)等を添加することができる。
粉末混合物は、まず結合剤、例えば、シロップ、澱粉糊、アラビアゴム、セルロース溶液又は高分子物質溶液で湿らせ、攪拌混合し、これを乾燥、粉砕して顆粒とすることができる。このように粉末を顆粒化する代わりに、まず打錠機にかけた後、得られる不完全な形態のスラグを破砕して顆粒にすることも可能である。このようにして作られる顆粒に、滑沢剤としてステアリン酸、ステアリン酸塩、タルク、ミネラルオイル等を添加することにより、互いに付着することを防ぐことができる。
また、錠剤は、上述のように顆粒化やスラグ化の工程を経ることなく、本複素環誘導体(1)を流動性の不活性担体と混合した後に直接打錠することによっても製造することができる。
こうして製造された錠剤にフィルムコーティングや糖衣を施すことができる。シェラックの密閉被膜からなる透明又は半透明の保護被覆、糖や高分子材料の被覆及びワックスよりなる磨上被覆をも用いることができる。
(1)試験方法
Wistar系ラット(雄性、7週齢)(日本チャールス・リバー社製)に対して、トレッドミル(室町機械社製)を用いて、歩行トレーニングを1日1回3或いは4日間連続して行った。歩行トレーニングの最終日に動物の群分けを行い、その翌日に歩行時間を測定した後、偽手術又は下記i)に記載の馬尾神経圧迫手術を行った。手術実施後、3日目、7日目、14日目及び21日目に歩行時間をそれぞれ測定した。測定した歩行時間に基づき、歩行距離を算出した。
3日目の歩行時間の測定が終了した後、馬尾神経圧迫手術を行った群について、手術当日及び手術後3日目の歩行距離を指標として、対照群と薬物投与群に群分けを行った。
その後、偽手術群及び対照群には0.5w/v%メチルセルロース水溶液を、薬物投与群には0.2mg/mLで化合物Aを含有する懸濁液(媒体:0.5w/v%メチルセルロース水溶液)を、手術後13日目或いは20日目まで1日2回経口投与した。
i)馬尾神経圧迫手術の方法
馬尾神経圧迫手術は、竹信らの方法(基礎と臨床、30巻、第213−219頁、1996年)に準じて行った。
ラットにペントバルビタールナトリウムを用いて麻酔を行い、背部を剃毛後、腰部を切開し、第4腰椎から第6腰椎までを露出させた。第5腰椎棘突起を切除後、第4腰椎と第5腰椎の境界付近及び第5腰椎と第6腰椎の境界付近の2箇所に、ダイヤモンドバーを装着したハンドピース(ミニター社製)を用い、シリコンラバー(高さ×長さ×幅:1×4×1.25mm)を挿入するための適当な大きさの穴を空けた。第4腰椎及び第6腰椎脊柱管内にそれぞれシリコンラバーを挿入後、切開部位を縫合した。偽手術群にも同様の手術を実施し、シリコンラバーを挿入せずに切開部位を縫合した。縫合箇所にテラマイシン軟膏(ファイザー社製)を適量塗布し、更に注射用ビクシリンS(明治製菓社製)を2.5mLの生理食塩液(大塚製薬社製)に溶解し、このうちの0.5mLを後肢に筋肉内注射した。
ii)歩行時間の測定方法
3〜5匹のラットを水平状態の走行ベルトに乗せ、走行ベルトを始動させた。トレッドミルをまず10m/minの速度で始動させ、以降3分毎に5m/minずつ加速して、30分間の運転が終われば自動的に停止するようにプログラムを設定した。始動時及び速度変化時の加速は1m/sec2で、加速はただちに行われて次の速度に到達したと見なした。ラットが完全に電気刺激装置の上に乗ってしまった時に歩行が不能になったと判定し、トレッドミル始動から歩行不能に至るまでの時間を歩行時間とした。30分間歩行を続けたラットの歩行時間は30分とした。
iii)歩行トレーニングの方法
トレッドミルを運転し、個々のラットの歩行時間をタイマーを用いて測定した。歩行時間が24分より短かった場合、トレーニング効果を上げるために、ラットに歩行を続けさせ24分以降に再度歩行不能になった時点で、そのラットのトレーニングを終了した。
(2)結果
図1に示すように、化合物Aを投与することにより、馬尾神経を圧迫することにより生じる歩行障害が有意に改善された。
なお、評価は、対照群については、偽手術群に対して、Welch testにより評価した(##:p<0.01)。また、薬物投与群については、対照群に対して、t−test或いはWelch testにより評価した(**:p<0.01)。
文献(Pain Medicine 2002;94:1537−41)に記載の方法に準じて、ラット脊柱管狭窄症モデルを作製する。その後、化合物A又は化合物Bを投与し、脊髄神経の血流量の変化を調べることにより、化合物A、化合物Bの治療効果を評価する。
文献(SPINE 2008;33:2605−11)に記載の方法に準じて、イヌ馬尾神経圧迫モデルを作製する。その後、化合物A又は化合物Bを投与し、神経伝達速度の変化や馬尾神経の血流量の変化を調べることにより、化合物A、化合物Bの治療効果を評価する。
文献(J Orthopaedic Research 2005;23:420−24)に記載の方法に準じて、ラットL5神経根圧迫モデルを作製する。その後、化合物A又は化合物Bを投与し、後根神経節の血流量の変化を調べることにより、化合物A、化合物Bの治療効果を評価する。
ラットに化合物A又は化合物Bを投与し、文献(Evidence−based complementary and alternative medicine 2008;5:133−43)に記載の方法に準じて、坐骨神経の血流量の変化を調べることにより、化合物A、化合物Bの治療効果を評価する。
Claims (3)
- 2−{4−[N−(5,6−ジフェニルピラジン−2−イル)−N−イソプロピルアミノ]ブチルオキシ}酢酸若しくは2−{4−[N−(5,6−ジフェニルピラジン−2−イル)−N−イソプロピルアミノ]ブチルオキシ}−N−(メチルスルホニル)アセトアミド、又はその医薬上許容される塩を有効成分として含有する脊柱管狭窄症治療剤。
- 脊柱管狭窄症が、頚部脊柱管狭窄症、胸部脊柱管狭窄症、腰部脊柱管狭窄症、広範脊柱管狭窄症又は仙骨狭窄症である、請求項1に記載の脊柱管狭窄症治療剤。
- 脊柱管狭窄症が、腰部脊柱管狭窄症である、請求項2に記載の脊柱管狭窄症治療剤。
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