JP2015232015A - 痛み治療用の医薬配合物 - Google Patents
痛み治療用の医薬配合物 Download PDFInfo
- Publication number
- JP2015232015A JP2015232015A JP2015151003A JP2015151003A JP2015232015A JP 2015232015 A JP2015232015 A JP 2015232015A JP 2015151003 A JP2015151003 A JP 2015151003A JP 2015151003 A JP2015151003 A JP 2015151003A JP 2015232015 A JP2015232015 A JP 2015232015A
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- JP
- Japan
- Prior art keywords
- pain
- administration
- formulation
- acid
- methylpropyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 230000036407 pain Effects 0.000 title claims abstract description 34
- 238000011282 treatment Methods 0.000 title claims abstract description 15
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- 238000009472 formulation Methods 0.000 claims abstract description 66
- 150000003839 salts Chemical class 0.000 claims abstract description 45
- 239000002253 acid Substances 0.000 claims abstract description 28
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 claims abstract description 15
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- 229960004640 memantine Drugs 0.000 claims abstract description 10
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- 238000007920 subcutaneous administration Methods 0.000 claims abstract description 4
- 238000007913 intrathecal administration Methods 0.000 claims abstract description 3
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 claims abstract 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- -1 PD-134705 Chemical compound 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 13
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 7
- 208000000094 Chronic Pain Diseases 0.000 claims description 7
- 208000005298 acute pain Diseases 0.000 claims description 7
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- 238000013270 controlled release Methods 0.000 claims description 4
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 claims description 4
- KWTWDQCKEHXFFR-RISCZKNCSA-N 3-[(2s,3s)-1-(dimethylamino)-2-methylpentan-3-yl]phenol Chemical compound CN(C)C[C@@H](C)[C@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-RISCZKNCSA-N 0.000 claims description 3
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 3
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- VOROEQBFPPIACJ-SCSAIBSYSA-N (2r)-2-amino-5-phosphonopentanoic acid Chemical compound OC(=O)[C@H](N)CCCP(O)(O)=O VOROEQBFPPIACJ-SCSAIBSYSA-N 0.000 claims description 2
- VBRJFXSFCYEZMQ-HNNXBMFYSA-N (2s)-2-amino-3-[3-(2-chlorophenyl)-5-(phosphonomethyl)phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC(CP(O)(O)=O)=CC(C=2C(=CC=CC=2)Cl)=C1 VBRJFXSFCYEZMQ-HNNXBMFYSA-N 0.000 claims description 2
- UCKHICKHGAOGAP-KGLIPLIRSA-N (2s,4r)-5,7-dichloro-4-(phenylcarbamoylamino)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid Chemical compound N([C@@H]1C[C@H](NC2=CC(Cl)=CC(Cl)=C21)C(=O)O)C(=O)NC1=CC=CC=C1 UCKHICKHGAOGAP-KGLIPLIRSA-N 0.000 claims description 2
- YQEZLKZALYSWHR-CYBMUJFWSA-N (R)-(+)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@]1(NC)CCCCC1=O YQEZLKZALYSWHR-CYBMUJFWSA-N 0.000 claims description 2
- BOTHKNZTGGXFEQ-UHFFFAOYSA-N 1-(2,2-diphenyloxolan-3-yl)-n,n-dimethylmethanamine Chemical compound CN(C)CC1CCOC1(C=1C=CC=CC=1)C1=CC=CC=C1 BOTHKNZTGGXFEQ-UHFFFAOYSA-N 0.000 claims description 2
- HQLHZNDJQSRKDT-UHFFFAOYSA-N 2-amino-4-(2-amino-4-chlorophenyl)-4-oxobutanoic acid Chemical compound OC(=O)C(N)CC(=O)C1=CC=C(Cl)C=C1N HQLHZNDJQSRKDT-UHFFFAOYSA-N 0.000 claims description 2
- KWTWDQCKEHXFFR-FZMZJTMJSA-N 3-[(2r,3s)-1-(dimethylamino)-2-methylpentan-3-yl]phenol Chemical group CN(C)C[C@H](C)[C@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-FZMZJTMJSA-N 0.000 claims description 2
- KWTWDQCKEHXFFR-BXUZGUMPSA-N 3-[(2s,3r)-1-(dimethylamino)-2-methylpentan-3-yl]phenol Chemical compound CN(C)C[C@@H](C)[C@@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-BXUZGUMPSA-N 0.000 claims description 2
- CUVGUPIVTLGRGI-UHFFFAOYSA-N 4-(3-phosphonopropyl)piperazine-2-carboxylic acid Chemical compound OC(=O)C1CN(CCCP(O)(O)=O)CCN1 CUVGUPIVTLGRGI-UHFFFAOYSA-N 0.000 claims description 2
- UYNVMODNBIQBMV-UHFFFAOYSA-N 4-[1-hydroxy-2-[4-(phenylmethyl)-1-piperidinyl]propyl]phenol Chemical compound C1CC(CC=2C=CC=CC=2)CCN1C(C)C(O)C1=CC=C(O)C=C1 UYNVMODNBIQBMV-UHFFFAOYSA-N 0.000 claims description 2
- BGKFPRIGXAVYNX-UHFFFAOYSA-N 5,7-dichloro-4-oxo-1H-quinoline-2-carboxylic acid Chemical compound ClC1=CC(Cl)=CC2=NC(C(=O)O)=CC(O)=C21 BGKFPRIGXAVYNX-UHFFFAOYSA-N 0.000 claims description 2
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 claims description 2
- FCBQJNCAKZSIAH-UHFFFAOYSA-N 6-[2-[4-[(4-fluorophenyl)methyl]piperidin-1-yl]ethylsulfinyl]-3h-1,3-benzoxazol-2-one Chemical compound C1=CC(F)=CC=C1CC1CCN(CCS(=O)C=2C=C3OC(=O)NC3=CC=2)CC1 FCBQJNCAKZSIAH-UHFFFAOYSA-N 0.000 claims description 2
- FLVRDMUHUXVRET-UHFFFAOYSA-N 7-chloro-4-hydroxy-3-(3-phenoxyphenyl)-1H-quinolin-2-one Chemical compound OC=1NC2=CC(Cl)=CC=C2C(=O)C=1C(C=1)=CC=CC=1OC1=CC=CC=C1 FLVRDMUHUXVRET-UHFFFAOYSA-N 0.000 claims description 2
- 101000944206 Conus geographus Conantokin-G Proteins 0.000 claims description 2
- SNDPXSYFESPGGJ-SCSAIBSYSA-N D-2-aminopentanoic acid Chemical compound CCC[C@@H](N)C(O)=O SNDPXSYFESPGGJ-SCSAIBSYSA-N 0.000 claims description 2
- DYDCUQKUCUHJBH-UWTATZPHSA-N D-Cycloserine Chemical compound N[C@@H]1CONC1=O DYDCUQKUCUHJBH-UWTATZPHSA-N 0.000 claims description 2
- DYDCUQKUCUHJBH-UHFFFAOYSA-N D-Cycloserine Natural products NC1CONC1=O DYDCUQKUCUHJBH-UHFFFAOYSA-N 0.000 claims description 2
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical group CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 claims description 2
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 claims description 2
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- 229960003805 amantadine Drugs 0.000 claims description 2
- YEESUBCSWGVPCE-UHFFFAOYSA-N azanylidyneoxidanium iron(2+) pentacyanide Chemical compound [Fe++].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.N#[O+] YEESUBCSWGVPCE-UHFFFAOYSA-N 0.000 claims description 2
- HTBKFGWATIYCSF-QGXIKSNHSA-N conantokin g Chemical compound NC(=O)C[C@@H](C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(C(O)=O)C(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C(O)=O)C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C(O)=O)C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C(O)=O)C(O)=O)NC(=O)[C@H](CC(C(O)=O)C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CN HTBKFGWATIYCSF-QGXIKSNHSA-N 0.000 claims description 2
- USSIQXCVUWKGNF-KRWDZBQOSA-N dextromethadone Chemical compound C=1C=CC=CC=1C(C[C@H](C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-KRWDZBQOSA-N 0.000 claims description 2
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Abstract
Description
(a)次式(I):
(b)少なくとも1種のNMDAアンタゴニストと
を含む医薬配合物に関する。
(1R,2R)−3−(3−ジメチルアミノ−1−エチル−2−メチルプロピル)−フェノール、
(1S,2S)−3−(3−ジメチルアミノ−1−エチル−2−メチルプロピル)−フェノール、
(1R,2S)−3−(3−ジメチルアミノ−1−エチル−2−メチルプロピル)−フェノール、
(1S,2R)−3−(3−ジメチルアミノ−1−エチル−2−メチルプロピル)−フェノール、
及びそれらの任意の混合物
から選択される。
(1R,2R)−3−(3−ジメチルアミノ−1−エチル−2−メチルプロピル)−フェノール、及び
(1S,2S)−3−(3−ジメチルアミノ−1−エチル−2−メチルプロピル)−フェノール、並びに
それらの任意の混合物
から選択される。
(a)次式(I’)の化合物(1R,2R)−3−(3−ジメチルアミノ−1−エチル−2−メチルプロピル)−フェノール
ラットでのランダルセリット試験
本発明の医薬組成物の相加効果(相乗効果)に至る成分(a)及び(b)の重量比は、炎症性の痛み又は神経障害性の痛みのモデルにおいて機械的痛覚過敏を評価するのに適合できる機械的痛覚試験である、Arch.Int.Pharmacodyn.,1957,111:409〜419に記載されたランダル及びセリットの試験により決定できる。この文献の各部は引用によりここに含まれ、本明細書の一部をなす。
Claims (18)
- 前記式(I)の化合物が
(1R,2R)−3−(3−ジメチルアミノ−1−エチル−2−メチルプロピル)−フェノール、
(1S,2S)−3−(3−ジメチルアミノ−1−エチル−2−メチルプロピル)−フェノール、
(1R,2S)−3−(3−ジメチルアミノ−1−エチル−2−メチルプロピル)−フェノール、
(1S,2R)−3−(3−ジメチルアミノ−1−エチル−2−メチルプロピル)−フェノール、及び
それらの任意の混合物
から選択されることを特徴とする、請求項1に記載の配合物。 - 前記式(I)の化合物が
(1R,2R)−3−(3−ジメチルアミノ−1−エチル−2−メチルプロピル)−フェノール、
(1S,2S)−3−(3−ジメチルアミノ−1−エチル−2−メチルプロピル)−フェノール、及び
それらの任意の混合物
から選択されることを特徴とする、請求項2に記載の配合物。 - 前記NMDAアンタゴニストがノルバリン(AP5)、D−ノルバリン(D−AP5)、4−(3−ホスホノ−プロピル)ピペラジン−2−カルボン酸(CPP)、D−(E)−4−(3−ホスホノプロプ−2−エニル)ピペラジン−2−カルボン酸(D−CPPene)、cis−4−(ホスホノメチル)−2−ピペラジンカルボン酸(Selfotel、CGS19755)、SDZ−220581、PD−134705、LY−274614、WAY−126090、キヌレン酸、7−クロロキヌレン酸、7−クロロチオキヌレン酸、5,7−ジクロロキヌレン酸、4−クロロキヌレニン、3−ヒドロキシキヌレニン、L−689,560、L−701,324、リコスチネル(ACEA−1021)、CGP−68,730A、MDL−105,519、ガベスチネル(GV−150,526)、GV−196,771A、ZD−9,379、MRZ−2/576、(+)−HA−966、デキストロメトルファン、デキストロファン、BIII−277CL、デキストロプロポキシフェン、ケトベミドン、デキストロメタドン、D−モルヒネ、アマンタジン、メマンチン、MRZ−2/579、イフェンプロジル、エリプロジル、PD−196,860、ニトロプルシド、D−シクロセリン、1−アミノシクロプロパン−カルボン酸、ジゾシルピン(MK 801)、フェンシクリジン(PCP)、ケタミン、(R,S)−ケタミン、(R)−ケタミン、(S)−ケタミン、ラマセミド、FPL−12,495、AR−R−15,896、メタドン、スルファゾシン、AN19/AVex−144、AN2/AVex−73、ベソンプロジル、CGX−1007、EAB−318、フェルバメート及びNPS−1407よりなる群から選択されることを特徴とする、請求項1〜4のいずれかに記載の配合物。
- 前記NMDAアンタゴニストが(R,S)−ケタミン、(S)−ケタミン及びメマンチンよりなる群から選択されることを特徴とする、請求項5に記載の配合物。
- 前記成分(a)及び(b)は、前記配合物が患者への投与に対して相乗効果を発揮する重量比で存在することを特徴とする、請求項1〜6のいずれかに記載の配合物。
- 請求項1〜7のいずれかに記載の配合物と、任意に1種以上の助剤とを含む医薬組成物。
- 請求項1〜7のいずれかに記載の配合物と、任意に1種以上の助剤とを含む製剤。
- 経口投与、静脈内投与、動脈内投与、腹腔内投与、皮内投与、経皮投与、くも膜下投与、筋肉内投与、鼻腔内投与、経粘膜投与、皮下投与又は直腸投与に好適であることを特徴とする、請求項9に記載の製剤。
- 前記成分(a)及び(b)の一方又は両方が放出制御形態で存在することを特徴とする、請求項9又は10に記載の製剤。
- 痛みの治療に使用するための請求項1〜7のいずれかに記載の配合物。
- 前記痛みが炎症性の痛み、神経障害性の痛み、急性の痛み、慢性の痛み、内臓痛、偏頭痛の痛み及び癌の痛みから選択される、請求項12に記載の配合物。
- 前記痛みが炎症性の痛みである、請求項13に記載の配合物。
- 哺乳類における痛みの治療方法であって、請求項1〜7のいずれかに記載の配合物の有効量を該哺乳類に投与することを含む方法。
- 前記配合物の成分(a)及び成分(b)を前記哺乳類に同時に又は連続的に投与し、ここで、該化合物(a)を該化合物(b)の前又は後に投与することができ、該化合物(a)又は(b)を同一の又は異なる投与経路により該哺乳類に投与することを特徴とする、請求項15に記載の方法。
- 前記痛みが炎症性の痛み、神経障害性の痛み、急性の痛み、慢性の痛み、内臓痛、偏頭痛の痛み及び癌の痛みから選択されることを特徴とする、請求項15又は16に記載の方法。
- 前記痛みが炎症性の痛みであることを特徴とする、請求項17に記載の方法。
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DK2948140T3 (en) * | 2013-01-22 | 2017-08-21 | Vistagen Therapeutics Inc | DOSAGE FORMS AND THERAPEUTIC APPLICATIONS OF L-4-CHLORCYNURENINE |
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