JP5190377B2 - 痛みを治療するためのベンゾ縮合複素環スルファミド誘導体の使用 - Google Patents
痛みを治療するためのベンゾ縮合複素環スルファミド誘導体の使用 Download PDFInfo
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- JP5190377B2 JP5190377B2 JP2008547472A JP2008547472A JP5190377B2 JP 5190377 B2 JP5190377 B2 JP 5190377B2 JP 2008547472 A JP2008547472 A JP 2008547472A JP 2008547472 A JP2008547472 A JP 2008547472A JP 5190377 B2 JP5190377 B2 JP 5190377B2
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- 230000002441 reversible effect Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229950000125 salcolex Drugs 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229960000953 salsalate Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229940116353 sebacic acid Drugs 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
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 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
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940045640 sodium aminobenzoate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- ZJXLSCXDGPDZOL-UHFFFAOYSA-M sodium;2-[5-(4-chlorobenzoyl)-1,4-dimethylpyrrol-2-yl]acetate;dihydrate Chemical compound O.O.[Na+].C1=C(CC([O-])=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZJXLSCXDGPDZOL-UHFFFAOYSA-M 0.000 description 1
- XETSAYZRDCRPJY-UHFFFAOYSA-M sodium;4-aminobenzoate Chemical compound [Na+].NC1=CC=C(C([O-])=O)C=C1 XETSAYZRDCRPJY-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000003238 somatosensory effect Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 229960001204 sufentanil citrate Drugs 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003356 suture material Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229950005100 talmetacin Drugs 0.000 description 1
- 229960005262 talniflumate Drugs 0.000 description 1
- 229950005400 talosalate Drugs 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 229950002345 tiopinac Drugs 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 229960003107 tramadol hydrochloride Drugs 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940072651 tylenol Drugs 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 229940000146 vicodin Drugs 0.000 description 1
- HQVHOQAKMCMIIM-UHFFFAOYSA-N win 55,212-2 Chemical compound C=12N3C(C)=C(C(=O)C=4C5=CC=CC=C5C=CC=4)C2=CC=CC=1OCC3CN1CCOCC1 HQVHOQAKMCMIIM-UHFFFAOYSA-N 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229960003516 zomepirac sodium Drugs 0.000 description 1
- YKPUWZUDDOIDPM-VURMDHGXSA-N zucapsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C/C(C)C)=CC=C1O YKPUWZUDDOIDPM-VURMDHGXSA-N 0.000 description 1
- 229960002860 zucapsaicin Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
- C07D321/02—Seven-membered rings
- C07D321/10—Seven-membered rings condensed with carbocyclic rings or ring systems
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Pyrane Compounds (AREA)
Description
本出願は、2005年12月19日付けで出願した米国仮出願60/751,686および2006年2月15日付けで出願した米国仮出願60/773,812(これらは引用することによって全体が本明細書に組み入れられる)の利点を請求するものである。
本発明は、痛みを治療する方法に向けたものであり、この方法は、それを必要としている被験体に式(I)
R1およびR2は、各々独立して、水素および低級アルキルから成る群から選択され;
R4は、水素および低級アルキルから成る群から選択され;
aは、1から2の整数であり;
bは0から4の整数であり;そしてcは0から2の整数であり;
各R5は、独立して、ハロゲン,低級アルキルおよびニトロから成る群から選択されるが;但し
で表される化合物またはこれの製薬学的に受け入れられる塩を治療的に有効な量で投与することを含んで成る。
本発明は、痛みを治療する方法に向けたものであり、この方法は、それを必要としている被験体に式(I)
で表される化合物またはこれの製薬学的に受け入れられる塩を治療的に有効な量で投与することを含んで成る。本発明は、更に、少なくとも1種の鎮痛薬と本明細書に記述する如き式(I)または式(II)で表される化合物を用いた共治療を施すことを含んで成る痛み治療方法にも向けたものである。
Hydrochloride);アニロラック(Anirolac);アニチピリン(Antipyrine);アスピリン(Aspirin);ベノキサプロフェン(Benoxaprofen);塩酸ベンジダミン(Benzydamine Hydrochloride);塩酸ビシファジン(Bicifadine Hydrochloride);塩酸ブリフェンタニル(Brifentanil Hydrochloride);マレイン酸ブロマドリン(Bromadoline Maleate);ブロムフェナックナトリウム(Bromfenac Sodium);塩酸ブプレノルフィン(Buprenorphine Hydrochloride);ブタセチン(Butacetin);ブチキシレート(Butixirate);ブトルファノール(Butorphanol);酒石酸ブトルファノール(Butorphanol Tartrate);カルバマゼピン(Carbamazepine);カルバスピリンカルシウム(Carbaspirin Calcium);塩酸カルビフェン(Carbiphene Hydrochloride);クエン酸カルフェンタニル(Carfentanil Citrate);こはく酸シプレファドール(Ciprefadol Succinate);シラマドール(Ciramadol);塩酸シラマドール(Ciramadol Hydrochloride);クロニキセリル(Clonixeril);クロニキシン(Clonixin);コデイン(Codeine);燐酸コデイン(Codeine Phosphate);硫酸コデイン(Codeine Sulfate);塩酸コノルフォン
(Conorphone Hydrochloride);シクラゾシン(Cyclazocine);塩酸デキソキサドロール(Dexoxadrol Hydrochloride);デキソペメドラック(Dexpemedolac);デゾシン(Dezocine);ジフルニサール(Diflunisal);重酒石酸ジヒドロコデイン(Dihydrocodeine Bitartrate);ジメファダン(Dimefadane);ジピロン(Dipyrone);塩酸ドキソピコミン(Doxpicomine Hydrochloride);ドリニデン(Drinidene);塩酸エナドリン(Enadoline Hydrochloride);エピリゾール(Epirizole);酒石酸エルゴタミン(Ergotamine Tartrate);塩酸エトキサゼン(Ethoxazene Hydrochloride);エトフェナメート(Etofenamate);エウゲノール(Eugenol);フェノプロフェン(Fenoprofen);フェノプロフェンカルシウム(Fenoprofen Calcium);クエン酸フェンタニル(Fentanyl Citrate);フロクタフェニン(Floctafenine);フルフェニサール(Flufenisal);フルニキシン(Flunixin);フルニキシンメグルミン(Flunixin Meglumine);マレイン酸フルピルチン(Flupirtine Maleate);フルプロクアゾン(Fluproquazone);塩酸フルラドリン(Fluradoline
Hydrochloride);フルルビプロフェン(Flurbiprofen);塩酸ヒドロモルフォン(Hydromorphone Hydrochloride);イブフェナック(Ibufenac);インドプロフェン(Indoprofen);ケタゾシン(Ketazocine);ケトルファノール(Ketorfanol);ケトロラックトロメタミン(Ketorolac Tromethamine);塩酸レチミド(Letimide Hydrochloride);酢酸レボメタジル(Levomethadyl Acetate);酢酸塩酸レボメタジル(Levomethadyl
Acetate Hydrochloride);塩酸レボナントラドール(Levonantradol Hydrochloride);酒石酸レボルファノール(Levorphanol Tartrate);塩酸ロフェミゾール(Lofemizole Hydrochloride);しゅう酸ロフェンタニル(Lofentanil Oxalate);ロルシナドール(Lorcinadol);ロモキシカム(Lomoxicam);サリチル酸マグネシウム;メフェナム酸;塩酸メナビタン(Menabitan Hydrochloride);塩酸メペリジン(Meperidine Hydrochloride);塩酸メプタジノール(Meptazinol Hydrochloride);塩酸メタドン(Methadone Hydrochloride);酢酸メタジル(Methadyl Acetate);メトフォリン(Methopholine);メトトリメプラジン(Methotrimeprazine);酢酸メトケファミド(Metkephamid Acetate);塩酸ミムバン(Mimbane Hydrochloride);塩酸ミルフェタニル(Mirfentanil Hydrochloride);モリナゾン(Molinazone);硫酸モルフィン(Morphine Sulfate);モキサゾシン(Moxazocine);塩酸ナビタン(Nabitan Hydrochloride);塩酸ナルブフィン(Nalbuphine Hydrochloride);塩酸ナルメキソン(Nalmexone Hydrochloride);ナモキシレート(Namoxyrate);塩酸ナントラドール(Nantradol Hydrochloride);ナプロキセン(Naproxen);ナプロキセンナトリウム(Naproxen Sodium);ナプロキソール(Naproxol);塩酸ネホパム(Nefopam Hydrochloride);塩酸ネキセリジン(Nexeridine Hydrochloride);塩酸ノラシメタドール(Noracymethadol Hydrochloride);塩酸オクフェンタニル(Ocfentanil Hydrochloride);オクタザミド(Octazamide);オルバニル(Olvanil);フマル酸オキセトロン(Oxetorone Fumarate);オキシコドン(Oxycodone);塩
酸オキシコドン(Oxycodone Hydrochloride);テレフタル酸オキシコドン(Oxycodone Terephthalate);塩酸オキシモルフォン(Oxymorphone Hydrochloride);ペメドラック(Pemedolac);ペンタモルフォン(Pentamorphone);ペンタゾシン(Pentazocine);塩酸ペンタゾシン(Pentazocine Hydrochloride);乳酸ペンタゾシン(Pentazocine Lactate);塩酸フェナゾピリジン(Phenazopyridine Hydrochloride);塩酸フェニラミドール(Phenyramidol Hydrochloride);塩酸ピセナドール(Picenadol Hydrochloride);ピナドリン(Pinadoline);ピルフェニドン(Pirfenidone);ピロキシカムオラミン(Piroxicam Olamine);マレイン酸プラバドリン(Pravadoline Maleate);塩酸プロジリジン(Prodilidine Hydrochloride);塩酸プロファドール(Profadol Hydrochloride);フマル酸プロピラルン(Propirarn Fumarate);塩酸プロポキシフェン(Propoxyphene Hydrochloride);ナプシル酸プロポキシフェン(Propoxyphene Napsylate);プロキサゾール(Proxazole);クエン酸プロキサゾール(Proxazole Citrate);酒石酸プロキソルファン(Proxorphan Tartrate);塩酸ピロリフェン(Pyrroliphene Hydrochloride);塩酸レミフェンタニル(Remifentanil Hydrochloride);サルコレックス(Salcolex);マレイン酸サレタミド(Salethamide Maleate);サリシラミド(Salicylamide);サリチル酸メグルミン(Salicylate Meglumine);サルサレート(Salsalate);サリチル酸ナトリウム;メシル酸スピラドリン(Spiradoline Mesylate);スフェンタニル(Sufentanil);クエン酸スフェンタニル(Sufentanil Citrate);タルメタシン(Talmetacin);タルニフルメート(Talniflumate);タロサレート(Talosalate);こはく酸タザドレン(Tazadolene Succinate);テブフェロン(Tebufelone);テトリダミン(Tetrydamine);チフラックナトリウム(Tifurac Sodium);塩酸チリジン(Tilidine Hydrochloride);チオピナック(Tiopinac);メシル酸トナゾシン(Tonazocine Mesylate);塩酸トラマドール(Tramadol Hydrochloride);塩酸トレフェンタニル(Trefentanil Hydrochloride);トロラミン(Trolamine);塩酸ベラドリン(Veradoline Hydrochloride);塩酸ベリロパム(Verilopam Hydrochloride);ボラゾシン(Volazocine);メシル酸キソルファノール(Xorphanol Mesylate);塩酸キシラジン(Xylazine Hydrochloride);メシル酸ゼナゾシン(Zenazocine Mesylate);ゾメピラックナトリウム(Zomepirac Sodium)およびズカプサイシン(Zucapsaicin)が含まれる。
tonまたは登録商標されていない薬品(パラセタモールとメトクロプラミドの組み合わせ),AbbottのVicodinまたは登録商標されていない薬品(アセトアミノフェンとヒドロコドンの組み合わせ),Stadol NS(ブトルファノール鼻スプレー;Bristol−Myers Squibb),Boehringer IngelheimのLonaridまたはPfizerのMigraleveまたは登録商標されていない薬品(パラセタモールとコデインの組み合わせ)などが含まれる。
DCC = ジシクロヘキシルカルボジイミド
DCE = ジクロロエタン
DCM = ジクロロメタン
DIPEAまたはDIEA = ジイソプロピルエチルアミン
DMF = N,N−ジメチルホルムアミド
DMSO = ジメチルスルホキサイド
EDC = エチルカルボジイミド
Et3NまたはTEA = トリエチルアミン
Et2O = ジエチルエーテル
EAまたはEtOAc = 酢酸エチル
EtOH = エタノール
IPA = 2−プロパノール
Hept = ヘプタン
HOBT = 1−ヒドロキシベンゾトリアゾール
HPLC = 高圧液クロ
LAH = 水素化リチウムアルミニウム
MまたはMeOH = メタノール
NMR = 核磁気共鳴
Pd−C = 炭素に担持されているパラジウム触媒
RP HPLC = 逆相高圧液クロ
RTまたはrt = 室温
TEA = トリエチルアミン
TFA = トリフルオロ酢酸
THF = テトラヒドロフラン
TLC = 薄層クロマトグラフィー
鏡像異性体として存在し得る。本化合物がキラル中心を2つ以上有する場合、それらは追加的にジアステレオマーとしても存在し得る。そのような異性体およびこれらの混合物の全部を本発明の範囲内に包含させると理解されるべきである。その上、本化合物が示す結晶形態のいくつかは多形として存在する可能性があり、このように、それらも本発明に包含させることを意図する。加うるに、本化合物の数種は水と一緒に溶媒和物(即ち水化物)または一般的有機溶媒と一緒に溶媒和物を形成する可能性があり、そのような溶媒和物もまた本発明の範囲内に包含させることを意図する。
酢酸塩、ベンゼンスルホン酸塩、安息香酸塩、重炭酸塩、重硫酸塩、重酒石酸塩、ホウ酸塩、臭化物、エデト酸カルシウム、カンシル酸塩、炭酸塩、塩化物、クラブラン酸塩、クエン酸塩、二塩酸塩、エデト酸塩、エジシル酸塩、エストレート、エシレート(esylate)、フマル酸塩、グルセプテート(gluceptate)、グルコン酸塩、グルタミン酸塩、グリコリルアルサニレート(glycollylarsanilate)、ヘキシルレゾルシネート(hexylresorcinate)、ヒドラバミン(hydrabamine)、臭化水素酸塩、塩酸塩、ヒドロキシナフトエ酸塩、ヨウ化物、イソチオン酸塩、乳酸塩、ラクトビオン酸塩、ラウリン酸塩、リンゴ酸塩、マレイン酸塩、マンデル酸塩、メシル酸塩、メチル臭化物、メチル硝酸塩、メチル硫酸塩、ムコ酸塩、ナプシル酸塩、硝酸塩、N−メチルグルカミンアンモニウム塩、オレイン酸塩、パモ酸塩(エンボネート)、パルミチン酸塩、パントテン酸塩、燐酸塩/二燐酸塩、ポリガラクツロネート、サリチル酸塩、ステアリン酸塩、硫酸塩、塩基性酢酸塩、こはく酸塩、タンニン酸塩、酒石酸塩、テオクレート(teoclate)、トシル酸塩、トリエチオジド(triethiodide)および吉草酸塩。
酢酸、2,2−ジクロロ酢酸、アシル化アミノ酸、アジピン酸、アルギン酸、アスコルビン酸、L−アスパラギン酸、ベンゼンスルホン酸、安息香酸、4−アセトアミド安息香酸、(+)−樟脳酸、樟脳スルホン酸、(+)−(1S)−樟脳−10−スルホン酸、カプリン酸、カプロン酸、カプリル酸、桂皮酸、クエン酸、シクラミン酸、ドデシル硫酸、エタン−1,2−ジスルホン酸、エタンスルホン酸、2−ヒドロキシ−エタンスルホン酸、蟻酸、フマル酸、ガラクタル酸、ゲンチシン酸、グルコヘプトン酸、D−グルコン酸、D−グルクロン酸、L−グルタミン酸、α−オキソ−グルタル酸、グリコール酸、馬尿酸、臭化水素酸、塩酸、(+)−L−乳酸、(±)−DL−乳酸、ラクトビオン酸、マレイン酸、(−)−L−リンゴ酸、マロン酸、(±)−DL−マンデル酸、メタンスルホン酸、ナフタレン−2−スルホン酸、ナフタレン−1,5−ジスルホン酸、1−ヒドロキシ−2−ナフトエ酸、ニコチン酸、硝酸、オレイン酸、オロチン酸、しゅう酸、パルミチン酸、パモ酸、燐酸、L−ピログルタミン酸、サリチル酸、4−アミノ−サリチル酸、セバシン酸、ステアリン酸、こはく酸、硫酸、タンニン酸、(+)−L−酒石酸、チオシアン酸、p−トルエンスルホン酸およびウンデシレン酸を包含する酸、および
アンモニア、L−アルギニン、ベネタミン、ベンザチン、水酸化カルシウム、コリン、デアノール、ジエタノールアミン、ジエチルアミン、2−(ジエチルアミノ)−エタノール、エタノールアミン、エチレンジアミン、N−メチル−グルカミン、ヒドラバミン、1H−イミダゾール、L−リシン、水酸化マグネシウム、4−(2−ヒドロキシエチル)−モルホリン、ピペラジン、水酸化カリウム、1−(2−ヒドロキシエチル)−ピロリジン、第二級アミン、水酸化ナトリウム、トリエタノールアミン、トロメタミンおよび水酸化亜鉛を包含する塩基。
式(X)で表される化合物の調製はスキーム4に概略を示す方法に従って実施可能である。
がある。これは通常の保護基、例えばProtective Groups in Organic Chemistry,J.F.W.McOmie編集,Plenum Press,1973およびT.W.Greene & P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley & Sons,1991などに記述されている如きそれらを用いて達成可能である。そのような保護基は本技術分野で公知の方法を用いて後の便利な段階で除去可能である。
しろ投薬療法全体に渡って連続的であろう。
MS(ESI):163.2(M+H+)
1H NMR(300MHz,CDCl3),δ:6.94(m,4H),5.07(s,2H),4.76(s,4H).
MS(ESI):180.1(M+H+)
1H NMR(300MHz,DMSO),δ:6.92(m,4H),4.21(m,2H),4.07(m,2H),3.33(幅広,2H),3.16(d,J=4Hz,1H),2.72(d,J=4Hz,1H),2.30(m,1H).
258.8(M+H+)
1H NMR(300MHz,DMSO),δ:6.92(m,4H),6.71(幅広,1H),6.59(幅広,2H),4.19(m,2H),4.04(m,2H),3.00(m,2H),2.39(m,1H).
融点:97.5−98.5℃
元素分析:
計算分析値: C,44.25;H,4.95;N,11.47;S,13.13
測定分析値: C,44.28;H,4.66;N,11.21;S,13.15
H1 NMR(DMSO d6)δ6.85(m,4H),6.68(bd s,3H,NH),4.28(m,2H),3.97(dd,J=6.9,11.4Hz,1H),3.20(m,1H),3.10(m,1H).
100mL)を用いた抽出を受けさせた。その有機溶液を一緒にしてMgSO4で乾燥させ、濃縮して褐色の固体を得た後、クロマトグラフィー(ヘキサン中2%の酢酸エチル)にかけることでベンゾ[1,3]ジオキソール−2−カルボン酸メチルエステルを無色の油として得た。
MS(ESI):195.10(M+H+).
1H NMR(300MHz,CDCl3),δ:6.89(幅広,4H),6.29(s,1H),4.34(q,J=7Hz,2H),1.33(t,J=7Hz,3H).
MS(ESI):160.00(M+H+)
1H NMR(300MHz,DMSO),δ:7.99(s,幅広,1H),7.72(s,幅広,1H),6.94(m,2H)6.86(m,2H),6.30(s,1H).
MS(ESI):152.1(M+H+)
1H NMR(300MHz,CDCl3),δ:6.87(m,4H),6.09(t,J=4Hz,1H),3.13(d,J=4Hz,2H)
MS(ESI):230.0(M+H+)
1H NMR(300MHz,CDCl3),δ:6.87(m,4H),6.25(t,J=4Hz,1H),4.79(幅広,1H),4.62(幅広,1H),3.64(d,J=4Hz,2H).
ラムクロマトグラフィー(DCM:メタノール−50:1)で精製することで((2S)−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−2−イル)−メタノールを固体として得た。
1.0にした後、撹拌を15分間実施した。白色の固体を濾過で取り出し、新鮮なEtOHで洗浄し(固体を廃棄)た後、その濾液に蒸発を真空下で受けさせることで固体を得て、それをジエチルエーテルと希NaOH水溶液の間で分離させた。そのジエチルエーテル溶液を乾燥(Na2SO4)させた後、真空下で蒸発させることで明黄色の油を得た。その油をフラッシュカラムクロマトグラフィー(DCM:MeOH−10:1)で精製することで油を得た。その油の一部(4.82g,29ミリモル)を2−プロパノール(250mL)に入れて1N HCl(30mL)で処理し、蒸気浴上で均一になるまで加熱した後、室温になるまで冷却した。3時間後の混合物を氷で2 時間冷却した。薄片状の白色固体((2S)−C−(2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−2−イル)−メチルアミンの相当するHCl塩)を濾過で取り出した後、2−プロパノールを用いて再び再結晶化させることで白色の固体を得た。
[α]D=−69.6(c=1.06,EtOH)
融点 102−103℃
[α]D=−45.1°(c=1.05,M);
1H NMR(DMSOd6)δ6.86(m,4H),6.81(bd s,3H,N
H),4.3(m,2H),3.97(dd,J=6.9,11.4Hz,1H),3.20(dd,J=5.5,13.7Hz,1H),3.10(dd,J=6.9,13.7Hz,1H)
元素分析:
計算分析値: C,44.25;H,4.95;N,11.47;S,13.13
測定分析値: C,44.20;H,4.69;N,11.40;S,13.22.
ジメチルスルファミド(化合物番号6)
融点76−78℃
MS 273(MH+)
元素分析:
計算分析値: C,48.52;H,5.92;N,10.29;S,11.78
測定分析値: C,48.63;H,5.62;N,10.20;S,11.90
1H NMR(CDCl3)δ6.87(m,4H),4.59(bd m,1H,NH),4.35(m,1H),4.27(dd,J=2.3,11.4Hz,1H),4.04(dd,J=7.0,11.4,1H),3.36(m,2H),2.82(s,6H).
MS 180(MH+)
1H NMR(CDCl3)δ6.85(m,4H),4.30(m,2H),4.02(dd,J=7.9,11.6Hz,1H),2.85(m,2H),2.50(s,3H)
融点 97−98℃
MS 257(M−1)
元素分析:
計算分析値: C,46.50;H,5.46;N,10.85;S,12.41
測定分析値: C,46.48;H,5.65;N,10.90;S,12.07
1H NMR(CDCl3)δ6.86(m,4H),4.52(bs,2H),4.46(m,1H),4.29(dd,J=2.3,11.5Hz,1H),4.05(dd,J=6.5,11.5Hz,1H),3.51(dd,J=6.7,14.9Hz,1H),3.40(dd,J=5.9,14.9Hz,1H),2.99(s,3H).
ロロ異性体が約3:1の比率)を得た。
[α]D=−67.8(c=1.51,CHCl3)
MS 277(M−1)
[α]D=−59.9°(c=1.11,M)
1H NMR(CDCl3)δ6.90(d,J=2.2Hz,1H),6.81(m,2H),4.76(m,1H),4.55(s,2H),4.40(m,1H),4.29(dd,J=2.4,11.5Hz,1H),4.05(dd,J=7.1,11.5Hz,1H),3.45(m,2H)
元素分析:
計算分析値: C,38.78;H,3.98;N,10.05
測定分析値: C,38.80;H,3.67;N,9.99.
MS 277(M−1)
1H NMR(CDCl3/CD3OD)δ6.88(d,J=0.7Hz,1H),6.81(m,2H),4.37(m,1H),4.30(dd,J=2.3,11.6Hz,1H),4.04(dd,J=7.0,11.6Hz,1H),3.38(m,2H).
融点 100−101℃
MS 241(M−1)
元素分析:
計算分析値: C,49.57;H,5.82;N,11.56;S,13.23
測定分析値: C,49.57;H,5.80;N,11.75;S,13.33.
,30ミリモル)に加えた後、周囲温度で20時間撹拌した。次に、その反応混合物を水(250mL)で希釈した後、ジエチルエーテルを用いた抽出を2回実施した。そのジエチルエーテルを水で洗浄した後、食塩水で2回洗浄し、乾燥(Na2SO4)させた後、真空下で蒸発させることで2−シアノメチル−(2,3ジヒドロベンゾ[1,4]ジオキシン)を白色の固体として得た。
1H NMR(CDCl3)δ6.89(m,4H),4.50(m,1H),4.31(dd,J=2.3,11.5Hz,1H),4.08(dd,J=6.2,11.6Hz,1H),2.78(d,J=6.1,Hz,2H)
HClをpH=1.0になるまで加えた。次に、その反応混合物を室温で1時間撹拌した後、真空下で蒸発させることで油を得た。その油を3N NaOHとジエチルエーテルの間で分離させ、そのジエチルエーテル溶液を食塩水で洗浄し、乾燥(Na2SO4)させた後、真空下で蒸発させることで粗2−(2,3ジヒドロベンゾ[1,4]ジオキシン−2−イル)エチルアミンを得た。
MS(M+H)+ 180.
MS(M−1)257
融点 101−103℃(corr)
1H NMR(CDCl3):δ6.86(m,4H),4.70(m,1H),4.52(s,2H),4.30(m,2H),3.94(dd,J=7.4,11.3Hz,1H),3.43(dd,J=6.4,12.9Hz,2H),1.94(dd,J=6.5,12.9,2H).
元素分析:
測定値: C,46.48;H,5.60;N,10.81;S,12.41
計算値: C,46.50;H,5.46;N,10.85;S,12.41
した。その反応混合物を室温に冷却した後、氷水(600mL)で希釈し、そしてジエチルエーテルを用いた抽出(4回)を実施した。その有機溶液を一緒にして10%の炭酸カリウムで3回、食塩水で2回洗浄し、乾燥(MgSO4)させた後、真空下で蒸発させることで(2S)−2−(6,7−ジクロロ−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン)メタノールの粘性のある油を得た。
1H NMR(CDCl3):δ7.79(d,J=8.3Hz,2H),7.36(d,J=8.0Hz,2H),6.94(s,1H),6.83(s,1H),4.37(m,1H),4.2(m,3H),4.03(dd,J=6.3,11.7Hz,1H),2.47(s,3H).
1H NMR(CDCl3):δ6.98(s,1H),6.96(s,1H),4.25(dd,J=2.0,11.2Hz,1H),4.15(m,1H),4.0(m,1H),2.97(d,J=5.5Hz,2H)
MS [M−H]−311.0
融点 119−121℃
[α]D=−53.4°(c=1.17,M)
1H NMR(DMSOd6):δ7.22(s,1H),7.20(s,1H),6.
91(bd s,1H),6.68(bd s,2H),4.35(m,2H),4.05(dd,J=6.5,11.5Hz,1H),3.15(m,2H)
元素分析:
元素分析:
測定値: C,34.52;H,3.22;N,8.95;Cl,22.64;S,10.24
計算値: C,34.64;H,2.68;N,8.87;Cl,22.94;S,10.35.
MS(M+H)+ 260
1H NMR(DMSO d6):δ10.2(bd s,3H),6.86(m,1H),6.85(s,1H),6.74(dd,J=2.5,8.4Hz,1H),4.22(m,2H),3.88(dd,J=6.7,11.4Hz,1H),3.04(m,2H)
ことで表題の化合物を白色の固体として得た。
MS [M−H]−257
1H NMR(CDCl3):δ6.76(m,1H),6.66(m,2H),4.80(m,1H),4.57(bd s,1H),4.40(m,1H),4.28(m,1H),4.03(dd,J=6.9,11.4Hz,1H),3.45(m,2H),2.25(s,3H).
元素分析
計算値: C,46.50;H,5.46;N,10.85;S,12.41
測定値: C,46.65;H,5.60;N,10.84;S,12.61.
このマウスホルマリン試験は、試験化合物が痛みの治療で示す能力を試験するに適した急性および慢性モデルである。
ラットChungモデルは、ある化合物が神経障害性痛の治療に有用であるか否かを測定する時に用いられる検定である(KimおよびChung,1994;Chaplan他,1994)。
過した時に段階的刺激(von Frey毛)を用いてその影響を与えた肢を引っ込める時の圧力を記録することで実施した。その結果を正規化した後、結果を薬剤が示す%MPE(最大保護効果)として表す。
神経障害性痛の腰部5(L5)脊椎神経結紮(Chung)モデル
このラットChungモデルは、ある化合物が神経障害性痛の治療に有用であるか否かを測定する時に用いられる検定である(KimおよびChung,1994;Chaplan他,1994)。この検定では、クロムガット縫合糸(chromic gut suture)で座骨神経を緩く結紮するか、絹縫合糸でL5脊椎神経をきつく結紮するか或は絹縫合糸である程度きつく結紮することによる損傷の各々で過敏からいろいろな様式の刺激(例えば接触、圧力、温度)をもたらして、それを数週間または数カ月持続させた。そのような損傷によって与えた過敏は、機械的神経損傷、糖尿病および化学療法によって引き起こされる神経障害性痛の臨床的状態で観察される異痛および痛覚過敏に類似している。この検定は試験化合物が示す鎮痛、抗異痛および/または抗痛覚過敏効果の予測である。
試験に関して、挙動分析を実施する調査者には如何なる個々の動物に施した処置も伏せておいた。
SNLラットに媒体、化合物番号8またはガバペンチン(正対照として)を経口投与した。触覚異痛の量化を投与してから30分,1時間,2時間,4時間,6時間,8時間および/または24時間後に一連の較正を受けさせておいたvon Freyフィラメント(0.4,0.7,1.2,2.0,3.6,5.5,8.5および15.1g;Stoelting;Wood Dale,IL)を当てることによって神経結紮と同側の肢を引っ込める時の力を記録することで実施した。中間的堅さ(2.0g)のフィラメントを用いて開始して、後肢の中央足底にフィラメントを約5秒間当てた。肢を強く引っ込めた時には次のより軽い刺激を与えそして引っ込める反応がない時には次のより強い刺激を与えることで反応閾値を決定した。最初の閾値検出後に全体で4反応を集めた。50%引っ込め閾値をDixon方法(Meert TFおよびVermeirsch,HA,Pharmacol.Biochem.Behav.;2005,80(2),309−326頁に記述されている如き)で補間し、そして反応閾値が検出範囲の上方または下方にある時、それぞれ15.0または0.25gの値を割り当てた。
1番目の検定として、化合物番号8に評価を120mg/kgおよび240mg/kgの量で受けさせそしてガバペンチンを480mg/kg用いた時および媒体を用いた時と比較した。
73.2 ± 14.7および73.7 ± 16.6%改善)。化合物番号8を120mg/kgの量で投与した時に化合物番号8が示した効果の方がガバペンチンを用いた時に観察した効果より若干低かったが、経口投与してから1時間(42.2 ± 13.8%改善)および4時間(45.4 ± 12.2%改善)経過した時の効果とベースライン(‘0’時)のそれには有意な差があった。化合物番号8を240mg/kg投与した時にもたらされた効果(4時間経過した時に65.6 ± 21.1%変化)はガバペンチンを用いた時に観察した効果(4時間経過した時に73.4 ± 15.2)と同様であった。このように、ガバペンチンおよび化合物番号8は両方ともが経口投与してから2時間,4時間および6時間経過した時の引っ込め閾値を有意に高くした。8時間経過すると効果が低くなり、投与してから24時間経過した投与の効果は媒体処置値と同様であった。
2番目の検定として、化合物番号8を7日間に渡って毎日投与した時の亜長期投与によって引っ込め閾値が変わるか否かを測定する評価を実施した。手術してから3週間後にベースラインの触覚過敏性を評価した。ラットを無作為に5グループに分けて、媒体(HPMC),化合物番号8を60mg/kg,120mg/kg,240mg/kgまたは480mg/kgの量で与えた。引っ込め閾値を1日目(最初の投与),3日目(3回目の投与)および7日目(7回目の投与)の投与を行ってから1時間,2時間,4時間,8時間および24時間後に評価した。
3番目の検定として、手術後4週間が経過した時に化合物番号8を100mg/kg,300mg/kgおよび560mg/kgの量でp.o.投与し、ガバペンチンを正対照として560mg/kg投与して、投与後2時間,4時間および6時間経過した時に機械的異痛を測定した。
4番目の検定として、化合物番号8を560mg/kgの用量で用いた時の効果をHPMC中10%のソルトール溶液を用いて評価した。ガバペンチンを正対照として560mg/kg投与した後、投与してから6時間に及んで選択した時間点で機械的異痛を測定した。
末梢神経障害は、外傷,病気,代謝不全または特定の薬剤および毒素によって神経が損傷を受けた時に生じる慢性状態である。化学療法薬、例えばパクリタキセル(Taxol(R))などの使用に伴う知覚障害は、軽度刺痛から自然発生的灼熱(典型的には手および足における)に至る範囲である。治療を継続すると症状がより強くなって、衰弱、運動失調、無感覚および痛みがもたらされる可能性があり、それの消失には数週間から数カ月要し得る。
by the chemotherapeutic drug,paclitaxel.Pain,94:293−304,2001;Flatters,SJL,Xiao,W−H,Bennett,GJ.Acetyl−L−carnitine prevents and reduces paclitaxel−induced painful peripheral neuropathy.Neurosci Lett 397:219−223,2006)。加うるに、前記化合物が自発運動に対して示す効果も測定した。
オスSprague−Dawleyラット(Harlan Sprague Dawley,Inc.から7週齢の時に受け取った)を下記の2処置グループ(n=10/グループ)に分けた:1番目のグループには2mg/kgのTaxol(R),i.p.+ 0.5% HPMC(ヒドロキシプロピルメチルセルロース)媒体,poによる処置を受けさせ、2番目のグループには2mg/kgのTaxol(R),i.p.+ 100mg/kg 化合物番号8(HPMC媒体に入れた),poによる処置を受けさせた。これらの動物をポリカーボネートプラスチック製ケージにケージ1個当たり2匹ずつ入れて、ケージの温度を18−26℃にし、湿度を30−70%にし、12時間の明/暗サイクルにして、餌と水を随意に摂取できるようにした。
を注射した1日目から開始して12日間に渡って毎日po(経口)投与した。
paw.J Neurosci Meth,53:55−63,1994に記述されている如き手順に従って)。触覚感受性(即ち機械的異痛)の測定では、較正を受けさせておいたフィラメントをその影響を受けさせた肢の足底表面に触れさせて肢を引っ込める閾値を測定することを利用して測定を実施した。簡単に述べると、ラットを底がワイヤーメッシュのPlexiglasケージに入れて10分間慣れさせた。その動物が落ち着いた後、右後肢の足底表面を2.0gのvon Freyフィラメントに触れさせた。この最初に選択したフィラメントに対して肢を引っ込める反応がない時には、より強い刺激を与え、肢を引っ込めた場合には、次の弱い刺激を選択した。このようにして、結果としてもたらされた正および負反応のパターンを用いて肢を引っ込める閾値を決定した。データを2方向ANOVA,1方向ANOVAおよびダネット検定で分析して、統計学的有意さをp<0.05にした。
peripheral neuropathy induced in adult rats by repeated intraperitoneal administration of Taxol(R).Exper Neurol 133:64−72,1995)。データを1方向ANOVAおよびダネット検定で分析して、統計学的有意さをp<0.05にした。
機械的異痛の測定をベースライン,Taxol(R)を投与してから5日目および12
日目に実施した。ベースラインにも5日目にもグループ間に有意な差は見られなかったが、しかしながら、12日目にはTaxol(R)単独(p<0.05)およびTaxol(R) + 100mg/kgの化合物番号8(p<0.001)で処置したグループはベースラインの反応と比較して高い痛み感受性を示した。化合物番号8はTaxol(R)単独に比べて痛み反応を高めると思われるが、しかしながら、その差は統計学的に有意ではなかった。
+ 化合物番号8(p<0.05)で処置した動物はTaxol(R)単独のそれに比べて垂直に立ち上がる動きの減少を示した。
化合物番号8がTaxol(R)誘発末梢神経障害の結果として起こり得る痛み、運動変化および神経損傷に対して示す効力を評価するパイロット試験を実施した。典型的には、Taxol(R)で処置したラットに注射してから数週間後に評価を受けさせた、と言うのは、結果としてもたらされる機械的異痛はTaxol(R)を与えてから12日から21日の範囲のどこかで生じるからである。本検定では、化合物が示す効力の評価をTaxol(R)を与えてから5日目および12日目に実施し、これは、以前に公開された研究の検定期間よりも短かったが、しかしながら、この時間枠内に有意な異痛が起こり得ることを注目されたい。
末梢神経障害は、神経が外傷,病気,代謝不全または特定の薬剤および毒素によって損傷を受けた時に生じる慢性状態である。化学療法薬、例えばパクリタキセル(Taxol(R))などの使用に関連した知覚障害は、軽度刺痛から自然発生的灼熱(典型的には手および足における)に至る範囲である。治療を継続すると症状がより強くなって、衰弱、運動失調、無感覚および痛みがもたらされる可能性があり、それの消失には数週間から数カ月要し得る。
パクリタキセル(Taxol(R),Bristol−Myers−Squibb;Cremophorとエタノールが50:50の混合物中6mg/ml)を使用直前に食塩水で希釈して2mg/mlの濃度にした後、1日おきに4日(0日目,2日目,4日目および6日目)、1ml/kgの体積でIP注射した。化合物番号8を各注射を行う直前に0.1N HCl:0.5%メチルセルロース(1:9)に60mg/mlおよび120mg/mlの濃度で入れて懸濁させた。
予測したように、媒体注射を受けさせたパクリタキセル処置ラットは機械的異痛(4gVFH試験)および機械的痛覚過敏(15gVFH試験)を発症した。
この検定の目的は、化合物番号8が内臓、炎症および神経障害痛モデルにおける過敏性を改善するか否かを測定することにあった。
した(2 x 0.25mL/腹部)。酢酸をi.p注射してから5分後に5匹の動物を個別のベルジャー(bell jars)[床材用のチップを少量入れておいた]に入れた後、動物毎に腹部伸縮の数を5分間記録した。これを各グループ毎に繰り返した(N=10匹のマウス/グループ)。
CFAをラットの足底に注射すると長く持続する炎症反応がもたらされ、これは、浮腫および熱および機械的刺激の両方に対する顕著な過敏性によって特徴づけられる。このような過敏性のピークは注射してから24−72時間の範囲にあり、これは数週間持続する可能性がある。この検定では、試験化合物が示す鎮痛、抗異痛および/または抗過敏性効果を予測する。
の動物を無作為に処置グループ全体に渡って割り当てた、即ちあるケージの中の齧歯類を異なる処置グループに疑似無作為に割り当てた。CFA試験では、示す反応(即ち痛覚過敏)の潜伏期間がベースラインに比べて少なくとも25%短いラットのみをさらなる試験および分析に含めた。あらゆる試験で、挙動分析を実施する調査者に如何なる個々の動物に施した処置も伏せておいた。
体重が2−0gの成オスCF−1マウスをCharles River(Wilmington,MA)から入手した。あらゆる動物を12:12の明:暗サイクル下のケージに入れて、実験操作の目的でホームゲージから移す時以外は餌と水の両方を自由に摂取できるようにした。
とで特徴づけられる顕著な2段階挙動プロファイルが現れる。注射直後のマウスは足を約10分間なめる。これは段階1(急性反応)に相当し、そしてその後、挙動活動が僅かである短時間の潜伏期間が存在する。約20−30分間の長時間に渡って足をなめる期間が続いて存在し、これが段階2(炎症)を構成する。
Claims (14)
- 式(I)で表される化合物またはこれの製薬学的に受け入れられる塩において、R1およびR2が各々独立して水素およびC 1-4 アルキルから成る群から選択され;
R4が水素およびメチルから成る群から選択され;
aが1から2の整数であり;
請求項2記載の方法。 - 式(I)で表される化合物またはこれの製薬学的に受け入れられる塩において、R1およびR2が各々独立して水素およびメチルから成る群から選択され;
R4が水素およびメチルから成る群から選択され;
aが1から2の整数であり;
請求項3記載の方法。 - 前記式(I)で表される化合物を(2S)−(−)−N−(6−クロロ−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−2−イルメチル)−スルファミドおよびこれの製薬学的に受け入れられる塩から成る群から選択する請求項1記載の方法。
- 痛みを治療するための製薬学的製剤の製造における、(2S)−(−)−N−(6−クロロ−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−2−イルメチル)−スルファミドおよびこれの製薬学的に受け入れられる塩から成る群から選択した化合物の使用方法。
- 前記痛みが急性痛または慢性痛である請求項1記載の方法。
- 前記痛みが炎症性痛である請求項1記載の方法。
- 前記痛みが神経障害性痛である請求項1記載の方法。
- 前記神経障害性痛が糖尿病性神経障害である請求項9記載の方法。
- 前記痛みが急性痛または慢性痛である請求項6記載の方法。
- 前記痛みが炎症性痛である請求項6記載の方法。
- 前記痛みが神経障害性痛である請求項6記載の方法。
- 前記神経障害性痛が糖尿病性神経障害である請求項13記載の方法。
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AU2006331734B2 (en) | 2012-12-20 |
EP1973540B1 (en) | 2009-11-11 |
HK1125039A1 (en) | 2009-07-31 |
CA2634115A1 (en) | 2007-07-05 |
US8716231B2 (en) | 2014-05-06 |
US20070155822A1 (en) | 2007-07-05 |
BRPI0620018A2 (pt) | 2011-10-25 |
EA200870091A1 (ru) | 2009-12-30 |
ATE447948T1 (de) | 2009-11-15 |
AU2006331734A1 (en) | 2007-07-05 |
PL1973540T3 (pl) | 2010-04-30 |
KR20080077025A (ko) | 2008-08-20 |
RS51249B (sr) | 2010-12-31 |
DK1973540T3 (da) | 2010-02-01 |
DE602006010442D1 (de) | 2009-12-24 |
NI200800169A (es) | 2012-05-28 |
CA2634115C (en) | 2014-11-18 |
MY150903A (en) | 2014-03-14 |
CN101378746B (zh) | 2013-07-17 |
WO2007075752A1 (en) | 2007-07-05 |
NZ569040A (en) | 2011-04-29 |
PT1973540E (pt) | 2010-01-28 |
CR10167A (es) | 2009-01-16 |
EP1973540A1 (en) | 2008-10-01 |
HRP20100007T1 (hr) | 2010-02-28 |
SI1973540T1 (sl) | 2010-03-31 |
EA016302B1 (ru) | 2012-04-30 |
CY1109732T1 (el) | 2014-09-10 |
IL192100A0 (en) | 2009-08-03 |
ES2335699T3 (es) | 2010-03-31 |
CN101378746A (zh) | 2009-03-04 |
NO20083005L (no) | 2008-09-16 |
JP2009520035A (ja) | 2009-05-21 |
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