JP4447038B2 - メタニコチン化合物のヒドロキシ安息香酸塩 - Google Patents
メタニコチン化合物のヒドロキシ安息香酸塩 Download PDFInfo
- Publication number
- JP4447038B2 JP4447038B2 JP2007540196A JP2007540196A JP4447038B2 JP 4447038 B2 JP4447038 B2 JP 4447038B2 JP 2007540196 A JP2007540196 A JP 2007540196A JP 2007540196 A JP2007540196 A JP 2007540196A JP 4447038 B2 JP4447038 B2 JP 4447038B2
- Authority
- JP
- Japan
- Prior art keywords
- amine
- methyl
- penten
- bromo
- compounds
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Description
Cy−Hal+CH2=CH−CH2CH(CH3)N(CH3)(tBoc)→
(E) Cy−CH=CH−CH2CH(CH3)N(CH3)(tBoc)
+(Z) Cy−CH=CH−CH2CH(CH3)N(CH3)(tBoc)
+(E及び/又はZ) Cy−CH2CH=CHCH(CH3)N(CH3)(tBoc)
+Cy−C(=CH2)−CH2CH(CH3)N(CH3)(tBoc)(Cyは、5員又は6員のヘテロアリール環である。)。
E−メタニコチン及びヒドロキシ安息香酸に由来する、本明細書に記載されているヒドロキシ安息香酸塩は、E−メタニコチン及び他の酸に由来する他の塩に対して多数の利点を有する。一般に、E−メタニコチンのヒドロキシ安息香酸塩は、高度に結晶性で、他の塩より吸湿性が低い傾向がある水溶性物質である。例えば、(2S)−(4E)−N−メチル−5−[3−(5−イソプロポキシピリジン)イル)]−4−ペンテン−2−アミンのp−ヒドロキシ安息香酸塩は、物理的及び化学的に安定であり、自由流動性の結晶粉末である。このような特性は、薬学的製剤の開発及び医薬の製造にとって明確な利点である。必要であれば、この塩は、薬学的な処理のために、許容可能な粒径範囲へと製粉することが可能である。この塩は、固体の経口剤形の製造のために選択され得る多様な賦形剤と適合性を有する。これは、薬学的に確定された水和物である多糖誘導体などの賦形剤及び緩やかに結合した表面水のみを有する賦形剤の場合に、特に当てはまる。例示として、E−メタニコチンとフマル酸などのある種のE−メタニコチンに由来する塩は、塩内に不純物を形成する傾向がある。例えば、E−メタニコチン中の第2級アミンの、フマル酸中のオレフィンへのMichael付加反応から不純物が生じる。これらの不純物は、塩の化学的純度を低下させ、長期保存時に、塩の化学的完全性に対して悪影響を与える。
(E)−メタニコチン型化合物のヒドロキシ安息香酸塩を調製するために使用することが可能なヒドロキシ安息香酸は、以下の一般式:
E−メタニコチン化合物には、式:
E及びE’は、個別に、水素、アルキル、置換されたアルキル、ハロ置換されたアルキル、シクロアルキル、置換されたシクロアルキル、ヘテロシクリル、置換されたヘテロシクリル、、アリール、置換されたアリール、アルキルアリール、置換されたアルキルアリール、アリールアルキル又は置換されたアリールアルキルを表し、
Z’及びZ’’は、個別に、水素又はアルキル(シクロアルキルを含む。)を表し、好ましくは、Z’及びZ’’の少なくとも1つが水素であり、最も好ましくは、Z’は水素であり、並びにZ’’はメチルであり、あるいは、Z’、Z’’及び付随する窒素原子は、アジリジニル、アゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル、モルホリニルなどの環構造を形成することが可能であり、二重結合上の両方のE基は、好ましくは、水素であり、並びに、
mは、1、2、3、4、5又は6である。
のアリール置換されたアミン化合物である。好ましくは、全てのEが水素であり、E’はアルキル、好ましくはメチルである。好ましくは、Z’が水素であり、Z’’は水素又はメチルである。好ましくは、mは1又は2である。
代表的な好ましい化合物には、(E)−メタニコチン、(3E)−N−メチル−4−(5−エトキシ−3−ピリジニル)−3−ブテン−1−アミン、(2S)−(4E)−N−メチル−5−(3−ピリジニル)−4−ペンテン−2−アミン、(2R)−(4E)−N−メチル−5−(3−ピリジニル)−4−ペンテン−2−アミン、(2S)−(4E)−N−メチル−5−(5−メトキシ−3−ピリジニル)−4−ペンテン−2−アミン、(2R)−(4E)−N−メチル−5−(5−メトキシ−3−ピリジニル)−4−ペンテン−2−アミン、(2S)−(4E)−N−メチル−5−(5−イソプロポキシ−3−ピリジニル)−4−ペンテン−2−アミン、(2R)−(4E)−N−メチル−5−(5−イソプロポキシ−3−ピリジニル)−4−ペンテン−2−アミン、(3E)−N−メチル−4−(5−ニトロ−6−アミノ−3−ピリジニル)−3−ブテン−1−アミン、(3E)−N−メチル−4−(5−(N−ベンジルカルボキサミド)−3−ピリジニル)−3−ブテン−1−アミン、(2S)−(4E)−N−メチル−5−(5−ピリミジニル)−4−ペンテン−2−アミン、(2R)−(4E)−N−メチル−5−(5−ピリミジニル)−4−ペンテン−2−アミン、(4E)−N−メチル−5−(2−アミノ−5−ピリミジニル)−4−ペンテン−2−アミン、(4E)−N−メチル−5−(5−アミノ−3−ピリジニル)−4−ペンテン−2−アミン、(2S)−(4E)−N−メチル−5−(5−イソプロポキシ−1−オキソ−3−ピリジニル)−4−ペンテン−2−アミン、(3E)−N−メチル−4−(5−イソブトキシ−3−ピリジニル)−3−ブテン−1−アミン、(3E)−N−メチル−4−(1−オキソ−3−ピリジニル)−3−ブテン−1−アミン、(4E)−N−メチル−5−(l−オキソ−3−ピリジニル)−4−ペンテン−2−アミン、(3E)−N−メチル−4−(5−エチルチオ−3−ピリジニル)−3−ブテン−1−アミン、(4E)−N−メチル−5−(5−トリフルオロメチル−3−ピリジニル)−4−ペンテン−2−アミン、(4E)−N−メチル−5−(5−((カルボキシメチル)オキシ)−3−ピリジニル)−4−ペンテン−2−アミン、(4E)−5−(5−イソプロポキシ−3−ピリジニル)−4−ペンテン−2−アミン及び(4E)−N−メチル−5−(5−ヒドロキシ−3−ピリジニル)−4−ペンテン−2−アミンが含まれる。さらなる代表的な例には、(2S)−(4E)−N−メチル−5−(5−シクロヘキシルオキシ−3−ピリジニル)−4−ペンテン−2−アミン、(2R)−(4E)−N−メチル−5−(5−シクロヘキシルオキシ−3−ピリジニル)−4−ペンテン−2−アミン、(2S)−(4E)−N−メチル−5−(5−フェノキシ−3−ピリジニル)−4−ペンテン−2−アミン、(2R)−(4E)−N−メチル−5−(5−フェノキシ−3−ピリジニル)−4−ペンテン−2−アミン、(2S)−(4E)−N−メチル−5−(5−(4−フルオロフェノキシ)−3−ピリジニル)−4−ペンテン−2−アミン、(2R)−(4E)−N−メチル−5−(5−(4−フルオロフェノキシ)−3−ピリジニル)−4−ペンテン−2−アミン、(2S)−(4E)−N−メチル−5−(5−(4−クロロフェノキシ)−3−ピリジニル)−4−ペンテン−2−アミン、(2R)−(4E)−N−メチル−5−(5−(4−クロロフェノキシ)−3−ピリジニル)−4−ペンテン−2−アミン、(2S)−(4E)−N−メチル−5−(5−(3−シアノフェノキシ)−3−ピリジニル)−4−ペンテン−2−アミン、(2R)−(4E)−N−メチル−5−(5−(3−シアノフェノキシ)−3−ピリジニル)−4−ペンテン−2−アミン、(2S)−(4E)−N−メチル−5−(5−(5−インドリルオキシ)−3−ピリジニル)−4−ペンテン−2−アミン及び(2R)−(4E)−N−メチル−5−(5−(5−インドリルオキシ)−3−ピリジニル)−4−ペンテン−2−アミンが含まれる。
本明細書に記載されている(E)−メタニコチン型の化合物が合成的に産生される様式は、変化し得る。例えば、これら化合物は、パラジウムによって触媒される芳香族ハロゲン化物のカップリング反応、及び保護されたアミン置換基を含有する末端オレフィン、第1級又は第2級アミンを取得するための保護基の除去、及び第2級又は第3級アミンを提供するために場合によって行われるアルキル化によって調製することが可能である。特に、ある種のメタニコチン型化合物は、3−ハロ置換され、場合によって5−ハロ置換されたピリジン化合物又は5−ハロ置換されたピリミジン化合物を、保護されたアミン官能基を有するオレフィン(例えば、フタルイミド塩の、3−ハロ−1−プロペン、4−ハロ−1−ブテン、5−ハロ−1−ペンテン又は6−ハロ−1−ヘキセンとの反応によって提供されるオレフィンなど)を用いた、パラジウムによって触媒されるカップリング反応に供することによって調製することが可能である。「Frank et al., J. Org. Chem., 43(15):2947−2949 (1978)」;及び「Malek et al., J. Org. Chem., 47:5395−5397 (1982)」を参照されたい。
(E)−メタニコチンヒドロキシベンゾアートは、上述したE−メタニコチン型化合物をヒドロキシ安息香酸と反応させることによって形成される。塩を調製するために使用される各成分(E−メタニコチン及びヒドロキシ安息香酸)の化学量論は、変動することが可能である。ヒドロキシ安息香酸:塩基(E−メタニコチン)のモル比は、典型的には2:1ないし1:2、より典型的には2:1又は1:1であることが典型的であるが、他の比(3:2など)が可能である。酸:塩基のモル比は1:1であることが好ましい。本発明の塩が形成される様式に応じて、本発明の塩は、塩形成の際に存在する溶媒を閉塞し得る結晶構造を有し得る。このため、本発明の塩は、アリール置換されたアミンに対する溶媒の変動する化学量論の水和物及び他の溶媒和物として生じ得る。
所望であれば、ヒドロキシ安息香酸塩が一旦単離されたら、例えば、薬学的に許容される別の酸との直接反応によって、又は(強塩基との反応及び適切な溶媒中への抽出によって)遊離塩基をまず単離した後、薬学的に許容される別の酸との反応によって他の塩形態を形成することが可能である。このような手順は、当業者に公知である。
本発明の薬学的組成物は、純粋な状態で、又は前記化合物が他の何らかの薬学的に適合性のある生成物(不活性であってもよく、又は生理的に活性であってもよい。)と組み合わされた組成物の形態で、本明細書に記載されているヒドロキシベンゾアートを含む。このような組成物は、例えば、経口、非経口、直腸又は局所的に投与することが可能である。
本明細書に記載のヒドロキシ安息香酸塩は、ニコチン性化合物の他種が治療法として提案されている状態及び疾患の種類を治療するのに有用である。例えば、Williams et al.,DN&P 7(4):205−227(1994)、Arneric et al.,CNS Drug Rev.1(1):1−26(1995)、Arneric et al.,Exp.Opin.Invest.Drugs5(1):79−100(1996)、Bencherif et al.,J.Pharmacol.Exp.Ther.279:1413(1996)、Lippiello et al.,J.Pharmacol.Exp.Ther.279:1422(1996)、Damaj et al.,Neuroscience(1997)、Holladay et al.,J.Med.Chem.40(28):4169−4194(1997)、Bannon et al.,Science 279:77−80(1998)、PCT WO94/08992、PCT WO96/31475並びにBencherifらの米国特許第5,583,140号、Dullらの米国特許第5,597,919号及びSmithらの米国特許第5,604,231号を参照する。
ことによって現れる。
(2S)−(4E)−N−メチル−5−(5−イソプロポキシ−3−ピリジニル)−4−ペンテン−2−アミンp−ヒドロキシベンゾアート
p−ヒドロキシ安息香酸(2.62g、19.0mmol)を、酢酸イソプロピル(50mL)中の(2S)−(4E)−N−メチル−5−(5−イソプロポキシ−3−ピリジニル)−4−ペンテン−2−アミン(93%純度で4.79g、19.0mmol)の攪拌した溶液に少量ずつ添加した。添加中、塩の結晶化が明瞭であった。p−ヒドロキシ安息香酸を完全に添加した後、イソプロパノールをゆっくりと添加しながら、懸濁液を、その融点近くに加熱した。イソプロパノール15mLを添加した後、完全な溶解を得た。室温に溶液を冷却すると(一晩)、結晶状塊の沈殿物を生じ、この沈殿物を吸引ろ過により収集し、空気乾燥させた(4.3g)。アセトンの添加により、第二の結晶物(0.82g)を、濃縮したろ液から単離した。二つの結晶物を混合し、アセトン(50mL)から再結晶化した。吸引ろ過により固体を収集し、真空オーブン(50℃)で18時間乾燥させた。こうして白い結晶(GCMS及びLCMSにより98+%純度、融点99−101℃)を4.24g(60.0%)残した。
3−ブロモ−5−イソプロポキシピリジン
72Lの反応器に、ナトリウムtert−ペントキシド(2.2g、20mol)及び1−メチル−2−ピロリジノン(17.6L)を連続して投入した。この混合物を1時間攪拌し、次いで2−プロパノール(12L)を、2時間にわたり添加した。続いて3,5−ジブロモピリジン(3.0kg、13mol)を反応器に添加し、窒素雰囲気下にて、混合物を75℃で12時間加熱した。次いで混合物を冷却し、トルエン(15L)で希釈して、水(30L)で洗浄した。水相をトルエン(15L)で抽出し、混合したトルエン相を水(15L)で洗浄し、減圧下で濃縮して、暗色の油状物2.5kgを得た。この油状物を、均等サイズのバッチの第二処理段階からの物質と混合し、減圧蒸留して(0.3mmにて沸点65℃)、3−ブロモ−5−イソプロポキシピリジン3.1kg(57%)を淡黄色の油状物として生成した。
「A.Kalivretenos,J.K.Stille and L.S.Hegedus,J.Org.Chem.56:2883(1991)」に記載の方法に従って、(R)−(+)−プロピレンオキシドから(2R)−4−ペンテン−2−オールを82.5%の収率で調製した。
塩化p−トルエンスルホニル(18.6g、97.4mmol)を、3分間にわたって添加しながら、(R)−4−ペンテン−2−オール(7.62g、88.5mmol)、ピリジン(15mL)及び無水(水素化カルシウムから蒸留)ジクロロメタン(30mL)の混合物を氷浴中で攪拌した。重量の大きな沈殿物が形成したので、混合物を0℃で20分間攪拌し、室温で16時間攪拌した。飽和重炭酸ナトリウム水溶液(75mL)を添加し、二相混合物を激しく3時間攪拌した。ジクロロメタン相及び水相の二つのジクロロメタン抽出液(各50mL)を混合し、乾燥させ(Na2SO4)、ロータリーエバポレータにより濃縮した。高真空処理により、淡黄色の油状物18.7gを生成し、この油状物をジメチルホルムアミド(DMF)(35mL)及び40%メチルアミン水溶液(35mL)と混合した。この溶液を室温で48時間攪拌し、次いで飽和塩化ナトリウム水溶液(300mL)及び2.5M水酸化ナトリウム(50mL)の混合物中に注いだ。この混合物をエーテル(5×250mL)で抽出し、エーテル抽出物を乾燥させ(Na2SO4)、約250mLの量なるまで、ロータリーエバポレータにより(氷冷浴から)濃縮した。残りの溶液を、ジ−tert−ブチルジカルボナート(16.9g、77.4mmol)及びTHF(100mL)と混合し、混合物を室温で16時間攪拌した。揮発性物質をロータリーエバポレータにより蒸発し、残留物を5mmの圧力にて減圧蒸留し(沸点79−86℃)、透明で無色の液体7.74g(43.9%収率)を得た。
3−ブロモ−5−イソプロポキシピリジン(21.0g、97.2mmol)、(S)−N−メチル−N−(tert−ブトキシカルボニル)−4−ペンテン−2−アミン(24.0g、120mmol)、DMF(53mL)、K2CO3(22g、159mmol)、酢酸パラジウム(II)(0.22g、0.98mmol)及びトリ−o−トリルホスフィン(0.57g、1.9mmol)の混合物を脱気し、窒素下に置いた。次いで、攪拌した混合物を130℃で2.5時間加熱した。パラジウム塩を除去するため、SmopexTM(20g)及び酢酸エチル(100mL)を添加した。攪拌した混合物を50℃で5時間加熱し、室温で16時間加熱して、次いでろ過した。ろ液を減圧下で濃縮し、残留物(83g)をメタノール(25mL)中で溶解し、冷水浴(<5℃)中で冷却して、6M HCl(100mL)を滴下して処理した。この混合物を室温で3時間攪拌し、真空下の濃縮によりメタノールを取り除いた。残りの混合物水溶液を、ジクロロメタン(100mL)で洗浄し、3M NaOHを慎重に(冷却しながら)添加することにより塩基性化し、ジクロロメタンで抽出した(2×200mL)。これらの後者の抽出物を飽和NaCl水溶液で洗浄し、真空下で濃縮した。残留物をアセトン(150mL)中で溶解し、p−ヒドロキシ安息香酸(14.0g、101mmol)を添加した。多量の固体を形成したので、p−ヒドロキシ安息香酸を完全に溶解した後、溶液を室温に維持した(数時間)。−15℃にて数時間の冷却後、混合物を吸引ろ過した。生じた固体(24.8g)をアセトン(240mL)から再結晶化し、灰白色の結晶22.3g(61.6%)(GCMS及びLCMSにより97+%純度)を得た。
(2S)−(4E)−N−メチル−5−(5−メトキシ−3−ピリジニル)−4−ペンテン−2−アミン2,5−ジヒドロキシベンゾアート
無水エタノール(1mL)中の2,5−ジヒドロキシ安息香酸(ゲンチシン酸)(0.582g、3.78mmol)の熱い溶液を、無水エタノール(1mL)中の(2S)−(4E)−N−メチル−5−(5−メトキシ−3−ピリジニル)−4−ペンテン−2−アミン(1.00g、4.85mmol、GC−FIDによる86.7%E異性体)の温溶液へ添加し、転移に追加のエタノール(2mL)を使用した。生じた混合物を、ロータリーエバポレータで濃縮し、メタノールの溶液1.5mLが残存した。攪拌し、ほぼ還流まで加熱しながら、結晶化を生じた。生じた熱混合物を、酢酸エチル(5.5mL)を滴下して処理した。室温まで冷却した後、5℃で48時間、混合物を更に冷却した。生じた固体をろ過し、酢酸エチル(2×5mL)で洗浄し、50℃で乾燥させ、灰白色の粉末1.24g(91%)(遊離塩基に対し、GC−FIDにより98.0%E異性体)を得た。試料から色を取り除くため、物質をエタノール/イソプロパノール(3.5mL:5.5mL)から再結晶化して、灰白色の粉末1.03g(85%回収率)を得、続いてエタノール/酢酸エチル(3mL:12mL)から再結晶化して、白色の結晶性粉末0.90g(87%回収率)を得た。融点166−167℃。
E−メタニコチン2,5−ジヒドロキシベンゾアート
2,5−ジヒドロキシ安息香酸(ゲンチシン酸)(0.475g、3.08mmol)を、酢酸エチル(3mL)及びイソプロパノール(2.5mL)中のE−メタニコチン(0.500g、3.08mmol)の溶液へ添加し、全固体が溶解するまで、生じた混合物を徐々に加熱した。冷却すると、白い粒状沈殿物が沈殿し、混合物を5℃で冷却した。固体をろ過し、冷イソプロパノール(3×2mL)で洗浄し、40℃で4時間、真空下で乾燥させ、淡黄色のフレーク状の固体0.58g(29.7%)を得た。融点90−91.5℃。1H NMR(D2O):単塩化学量論。C10H14N2 C7H6O4 0.15H2Oに対し算出:C,64.00%;H,6.41%;N,8.78%。検出:C,63.92,64.00%;H,6.33,6.34%;N,8.79,8.84%。
E−メタニコチン3,5−ジヒドロキシベンゾアート
3,5−ジヒドロキシ安息香酸(0.475g、3.08mmol)を、イソプロパノール(11mL)及びメタノール(4.5mL)中のE−メタニコチン(0.500g、3.08mmol)の温溶液へ添加した。ほぼ還流になるまで加熱し、生じたゴム状物を溶解して、淡黄色の溶液を室温に冷却し、更に5℃で冷却した。沈殿して生じた暗黄色のゴム状物を酢酸イソプロピル(3mL)及びメタノール(4mL)中に溶解し、加熱によって補助した。室温に冷却し、更に5℃で冷却した後、灰白色の固体をろ過し、酢酸イソプロピルで洗浄し、ワックス状で褐色のフレーク状物0.505g(51.8%)を得た。融点160−161.5℃。1H NMR(D2O):単塩化学量論.C10H14N2 C7H6O4 0.15H2Oに対し算出:C,64.00%;H,6.41%;N,8.78%.検出:C,64.03,64.02%;H,6.38,6.38%;N,8.80,8.76%。
Dullらの米国特許第5,597,919号に記載の技術に従って、ヒドロキシ安息香酸塩と関連の受容体部位との相互作用を決定することが可能である。Cheng et al.,Biochem,Pharnacol.22:3099(1973)の方法を使用し、nMで報告した阻害定数(Ki値)を、IC50値から算出できる。低い結合定数は、本明細書に記載の塩の成分が、特定のCNSニコチン受容体との優れた高親和性結合を表すことを示している。
Claims (2)
- (2S)−(4E)−N−メチル−5−(5−イソプロポキシ−3−ピリジニル)−4−ペンテン−2−アミン p−ヒドロキシベンゾアート。
- 請求項1に記載の化合物と、薬学的に許容される担体と、を含む薬学的組成物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US62675104P | 2004-11-10 | 2004-11-10 | |
PCT/US2005/040650 WO2006053082A2 (en) | 2004-11-10 | 2005-11-09 | Hydroxybenzoate salts of metanicotine compounds |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008291862A Division JP4764911B2 (ja) | 2004-11-10 | 2008-11-14 | メタニコチン化合物のヒドロキシ安息香酸塩 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2008519768A JP2008519768A (ja) | 2008-06-12 |
JP2008519768A5 JP2008519768A5 (ja) | 2009-08-20 |
JP4447038B2 true JP4447038B2 (ja) | 2010-04-07 |
Family
ID=36168607
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007540192A Withdrawn JP2008519766A (ja) | 2004-11-10 | 2005-11-09 | メタニコチン化合物のヒドロキシ安息香酸塩 |
JP2007540196A Expired - Fee Related JP4447038B2 (ja) | 2004-11-10 | 2005-11-09 | メタニコチン化合物のヒドロキシ安息香酸塩 |
JP2008291862A Expired - Fee Related JP4764911B2 (ja) | 2004-11-10 | 2008-11-14 | メタニコチン化合物のヒドロキシ安息香酸塩 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007540192A Withdrawn JP2008519766A (ja) | 2004-11-10 | 2005-11-09 | メタニコチン化合物のヒドロキシ安息香酸塩 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008291862A Expired - Fee Related JP4764911B2 (ja) | 2004-11-10 | 2008-11-14 | メタニコチン化合物のヒドロキシ安息香酸塩 |
Country Status (26)
Country | Link |
---|---|
US (2) | US20060122238A1 (ja) |
EP (3) | EP1814853A2 (ja) |
JP (3) | JP2008519766A (ja) |
KR (1) | KR101268890B1 (ja) |
CN (3) | CN101068784A (ja) |
AU (2) | AU2005304526B2 (ja) |
BR (1) | BRPI0517621A (ja) |
CA (3) | CA2793138C (ja) |
CY (1) | CY1113542T1 (ja) |
DK (1) | DK2371818T3 (ja) |
ES (1) | ES2404506T3 (ja) |
HR (1) | HRP20130215T1 (ja) |
IL (2) | IL182573A (ja) |
ME (1) | ME01503B (ja) |
MX (1) | MX2007005710A (ja) |
NO (1) | NO20072160L (ja) |
NZ (1) | NZ554689A (ja) |
PL (1) | PL2371818T3 (ja) |
PT (1) | PT2371818E (ja) |
RS (1) | RS52681B (ja) |
RU (1) | RU2409566C2 (ja) |
SG (1) | SG157379A1 (ja) |
SI (1) | SI2371818T1 (ja) |
UA (1) | UA88792C2 (ja) |
WO (2) | WO2006053082A2 (ja) |
ZA (2) | ZA200703759B (ja) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7459469B2 (en) | 2004-11-10 | 2008-12-02 | Targacept, Inc. | Hydroxybenzoate salts of metanicotine compounds |
UA88792C2 (ru) * | 2004-11-10 | 2009-11-25 | Таргасепт, Інк. | Гидроксибензоатные соли метаникотиновых соединений |
WO2007055928A1 (en) * | 2005-11-03 | 2007-05-18 | Targacept, Inc. | 5-membered ring metanicotine analogs |
TWI389889B (zh) | 2006-05-09 | 2013-03-21 | Targacept Inc | (2s)-(4e)-n-甲基-5-〔3-(5-異丙氧基吡啶)基〕-4-戊烯-2-胺之新穎多晶型 |
CN101528698A (zh) | 2006-05-09 | 2009-09-09 | 阿斯利康公司 | (2s)-(4e)-n-甲基-5-[3-(5-异丙氧基吡啶)基]-4-戊烯-2-胺的盐形式 |
US20080085888A1 (en) * | 2006-09-15 | 2008-04-10 | Breining Scott R | Therapeutic Combinations |
JP5502494B2 (ja) * | 2007-01-22 | 2014-05-28 | ターガセプト・インコーポレイテッド | メタニコチンアナログの鼻腔内、バッカル、または舌下投与 |
US20080216828A1 (en) | 2007-03-09 | 2008-09-11 | Alexza Pharmaceuticals, Inc. | Heating unit for use in a drug delivery device |
WO2009018367A2 (en) * | 2007-07-31 | 2009-02-05 | Targacept, Inc. | Novel salt forms of (2s)-(4e)-n-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine |
AU2008282205A1 (en) * | 2007-07-31 | 2009-02-05 | Astrazeneca Ab | Transdermal administration of (2S)-(4E)-N-methyl-5-(3-( 5-isopropoxypyridin)yl)-4-penten-2-amine |
CN101774922B (zh) * | 2010-01-29 | 2012-12-26 | 浙江大学 | 2,3-二羟基苯甲酸酯类化合物及制备和应用 |
WO2011146009A1 (en) * | 2010-05-20 | 2011-11-24 | Targacept Inc. | New process for the preparation of aryl substituted olefinic amines |
KR20230013165A (ko) * | 2013-05-06 | 2023-01-26 | 쥴 랩스, 인크. | 에어로졸 장치를 위한 니코틴 염 제제 및 그 방법 |
WO2015006652A1 (en) | 2013-07-11 | 2015-01-15 | Alexza Pharmaceuticals, Inc. | Nicotine salt with m eta-salicylic acid |
CA2932464C (en) | 2013-12-05 | 2023-01-03 | Pax Labs, Inc. | Nicotine liquid formulations for aerosol devices and methods thereof |
CN113816940A (zh) * | 2014-05-27 | 2021-12-21 | R.J.雷诺兹烟草公司 | 烟碱盐、共晶体和盐共晶体络合物 |
US10508096B2 (en) | 2014-05-27 | 2019-12-17 | R.J. Reynolds Tobacco Company | Nicotine salts, co-crystals, and salt co-crystal complexes |
US9896429B2 (en) | 2014-05-27 | 2018-02-20 | R.J. Reynolds Tobacco Company | Nicotine salts, co-crystals, and salt co-crystal complexes |
CN113200967B (zh) * | 2021-05-07 | 2022-05-24 | 中国人民解放军陆军军医大学 | 吲哚苯醌类化合物、其制备方法及其应用 |
CN113475740B (zh) * | 2021-07-10 | 2022-10-21 | 深圳市真味生物科技有限公司 | 一种手性合成尼古丁的制备方法 |
Family Cites Families (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4192946A (en) | 1978-06-29 | 1980-03-11 | Ciba-Geigy Corporation | Process for producing 3-hydroxy-5-halopyridines |
DE3148651A1 (de) * | 1981-12-09 | 1983-07-21 | Henkel Kgaa | "haarfaerbemittel, enthaltend 5-halo-2,3-pyridindiole als kupplerkomponente" |
US4582823A (en) * | 1984-08-15 | 1986-04-15 | Warner-Lambert Company | Method for treating schizophrenia and medicaments therefor |
WO1989000158A1 (en) | 1987-07-02 | 1989-01-12 | Pfizer Inc. | Bridged-diazabicycloalkyl quinolone carboxylic acids and esters |
IT1226727B (it) * | 1988-07-29 | 1991-02-05 | Simes | Farmaci precursori della dopamina. |
US4922901A (en) | 1988-09-08 | 1990-05-08 | R. J. Reynolds Tobacco Company | Drug delivery articles utilizing electrical energy |
DE69016688T2 (de) * | 1989-04-20 | 1995-10-05 | Zambon Spa | Dopamin-Medikament-Vorstufe. |
US5187166A (en) | 1990-07-31 | 1993-02-16 | Nisshin Flour Milling Co., Ltd. | Azabicyclo derivatives and their use as antiemetics |
WO1992012122A1 (en) | 1990-12-27 | 1992-07-23 | Abbott Laboratories | N-protected aminoalkylaldehydes |
EP0516409B1 (en) | 1991-05-30 | 1996-09-11 | MITSUI TOATSU CHEMICALS, Inc. | Tetravinylpyrazine compound, method for preparing same and electroluminescent element and non-linear optical material using same |
US5212188A (en) | 1992-03-02 | 1993-05-18 | R. J. Reynolds Tabacco Company | Method for treatment of neurodegenerative diseases |
IL107184A (en) | 1992-10-09 | 1997-08-14 | Abbott Lab | Heterocyclic ether compounds that enhance cognitive function |
US5852041A (en) | 1993-04-07 | 1998-12-22 | Sibia Neurosciences, Inc. | Substituted pyridines useful as modulators of acethylcholine receptors |
IT1274018B (it) * | 1994-02-23 | 1997-07-14 | Riace Ets | Derivati del 3,8-diazabiciclo(3.2.1.)ottano ad attivita' analgesica |
GB2295387A (en) | 1994-11-23 | 1996-05-29 | Glaxo Inc | Quinazoline antagonists of alpha 1c adrenergic receptors |
US5604231A (en) * | 1995-01-06 | 1997-02-18 | Smith; Carr J. | Pharmaceutical compositions for prevention and treatment of ulcerative colitis |
US5616707A (en) * | 1995-01-06 | 1997-04-01 | Crooks; Peter A. | Compounds which are useful for prevention and treatment of central nervous system disorders |
US5597919A (en) | 1995-01-06 | 1997-01-28 | Dull; Gary M. | Pyrimidinyl or Pyridinyl alkenyl amine compounds |
US5585388A (en) | 1995-04-07 | 1996-12-17 | Sibia Neurosciences, Inc. | Substituted pyridines useful as modulators of acetylcholine receptors |
US5583140A (en) * | 1995-05-17 | 1996-12-10 | Bencherif; Merouane | Pharmaceutical compositions for the treatment of central nervous system disorders |
IL118279A (en) | 1995-06-07 | 2006-10-05 | Abbott Lab | Compounds 3 - Pyridyloxy (or Thio) Alkyl Heterocyclic Pharmaceutical Compositions Containing Them and Their Uses for Preparing Drugs to Control Synaptic Chemical Transmission |
US5616716A (en) * | 1996-01-06 | 1997-04-01 | Dull; Gary M. | (3-(5-ethoxypyridin)yl)-alkenyl 1 amine compounds |
AT403803B (de) * | 1996-04-19 | 1998-05-25 | Sanochemia Ltd | Neue benzazepinderivate, diese enthaltende arzneimittel und verwendung derselben zum herstellen von arzneimitteln |
US5663356A (en) | 1996-04-23 | 1997-09-02 | Ruecroft; Graham | Method for preparation of aryl substituted alefinic secondary amino compounds |
EP1997806A1 (en) | 1996-04-23 | 2008-12-03 | Targacept, Inc. | Pahrmaceutical compositions for prevention and treatment of central nervous system disorders |
US20020052497A1 (en) * | 2000-03-09 | 2002-05-02 | Targacept, Inc. | Compounds capable of activating cholinergic receptors |
US5861423A (en) | 1997-02-21 | 1999-01-19 | Caldwell; William Scott | Pharmaceutical compositions incorporating aryl substituted olefinic amine compounds |
US5811442A (en) | 1997-02-21 | 1998-09-22 | Bencherif; Merouane | Pharmaceutical compositions for the treatment of conditions associated with decreased blood flow |
DK0983249T3 (da) * | 1997-05-08 | 2002-07-08 | Pfizer Prod Inc | Fremgangsmåder og mellemprodukter til fremstilling af substituerede indazolderivater |
HU226859B1 (en) | 1997-10-27 | 2009-12-28 | Neurosearch As | Phenyl- or heteroaryl-homopiperazines, their use and medicaments containing them |
US6632823B1 (en) * | 1997-12-22 | 2003-10-14 | Merck & Co., Inc. | Substituted pyridine compounds useful as modulators of acetylcholine receptors |
DK1086082T3 (da) | 1998-06-16 | 2004-11-22 | Targacept Inc | Arylsubstituerede olefiniske aminer og deres anvendelse som cholinerge receptoragonister |
US6232316B1 (en) * | 1998-06-16 | 2001-05-15 | Targacept, Inc. | Methods for treatment of CNS disorders |
US6218383B1 (en) | 1998-08-07 | 2001-04-17 | Targacept, Inc. | Pharmaceutical compositions for the prevention and treatment of central nervous system disorders |
US6337351B1 (en) | 1998-10-22 | 2002-01-08 | Targacept, Inc. | Pharmaceutical compositions and methods for use |
GB9922271D0 (en) * | 1999-09-21 | 1999-11-17 | Zeneca Ltd | Formulation |
US6506769B2 (en) * | 1999-10-06 | 2003-01-14 | Boehringer Ingelheim Pharmaceuticals, Inc. | Heterocyclic compounds useful as inhibitors of tyrosine kinases |
PL358375A1 (en) * | 2000-04-13 | 2004-08-09 | Innovata Biomed Limited | Medicaments for treating respiratory disorders comprising formoterol and fluticasone |
US6432954B1 (en) * | 2000-07-14 | 2002-08-13 | Targacept, Inc. | Pharmaceutical compositions and methods for use |
US6743812B1 (en) * | 2000-07-14 | 2004-06-01 | Targacept, Inc. | Pharmaceutical compositions and methods for use |
GB2381750A (en) * | 2001-10-10 | 2003-05-14 | Inspire Pharmaceuticals Inc | Treatment for enhancing joint lubrication |
US20040044023A1 (en) * | 2002-08-30 | 2004-03-04 | Marc Cantillon | Compositions and methods for treating or preventing memory impairment |
US20050203130A1 (en) * | 2003-12-02 | 2005-09-15 | Erik Buntinx | Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists |
UA88792C2 (ru) * | 2004-11-10 | 2009-11-25 | Таргасепт, Інк. | Гидроксибензоатные соли метаникотиновых соединений |
US7459469B2 (en) * | 2004-11-10 | 2008-12-02 | Targacept, Inc. | Hydroxybenzoate salts of metanicotine compounds |
TWI389889B (zh) * | 2006-05-09 | 2013-03-21 | Targacept Inc | (2s)-(4e)-n-甲基-5-〔3-(5-異丙氧基吡啶)基〕-4-戊烯-2-胺之新穎多晶型 |
US20080085888A1 (en) * | 2006-09-15 | 2008-04-10 | Breining Scott R | Therapeutic Combinations |
-
2005
- 2005-09-11 UA UAA200706359A patent/UA88792C2/ru unknown
- 2005-11-09 RU RU2007121697/04A patent/RU2409566C2/ru not_active IP Right Cessation
- 2005-11-09 JP JP2007540192A patent/JP2008519766A/ja not_active Withdrawn
- 2005-11-09 AU AU2005304526A patent/AU2005304526B2/en not_active Ceased
- 2005-11-09 US US11/270,753 patent/US20060122238A1/en not_active Abandoned
- 2005-11-09 WO PCT/US2005/040650 patent/WO2006053082A2/en active Application Filing
- 2005-11-09 SG SG200907438-6A patent/SG157379A1/en unknown
- 2005-11-09 ES ES11002581T patent/ES2404506T3/es active Active
- 2005-11-09 RS RS20130081A patent/RS52681B/en unknown
- 2005-11-09 WO PCT/US2005/040588 patent/WO2006053039A2/en active Application Filing
- 2005-11-09 NZ NZ554689A patent/NZ554689A/en not_active IP Right Cessation
- 2005-11-09 CA CA2793138A patent/CA2793138C/en not_active Expired - Fee Related
- 2005-11-09 PL PL11002581T patent/PL2371818T3/pl unknown
- 2005-11-09 ME MEP-2013-25A patent/ME01503B/me unknown
- 2005-11-09 CN CNA2005800416139A patent/CN101068784A/zh active Pending
- 2005-11-09 CN CN2012100831307A patent/CN102643228A/zh active Pending
- 2005-11-09 PT PT110025814T patent/PT2371818E/pt unknown
- 2005-11-09 EP EP05851465A patent/EP1814853A2/en not_active Withdrawn
- 2005-11-09 EP EP11002581A patent/EP2371818B1/en active Active
- 2005-11-09 MX MX2007005710A patent/MX2007005710A/es active IP Right Grant
- 2005-11-09 SI SI200531683T patent/SI2371818T1/sl unknown
- 2005-11-09 BR BRPI0517621-2A patent/BRPI0517621A/pt not_active Application Discontinuation
- 2005-11-09 KR KR1020077010149A patent/KR101268890B1/ko not_active IP Right Cessation
- 2005-11-09 CA CA2584448A patent/CA2584448C/en not_active Expired - Fee Related
- 2005-11-09 EP EP05819967.0A patent/EP1814852B1/en active Active
- 2005-11-09 CA CA002584586A patent/CA2584586A1/en not_active Abandoned
- 2005-11-09 AU AU2005304575A patent/AU2005304575A1/en not_active Abandoned
- 2005-11-09 JP JP2007540196A patent/JP4447038B2/ja not_active Expired - Fee Related
- 2005-11-09 CN CNA2005800416143A patent/CN101068785A/zh active Pending
- 2005-11-09 DK DK11002581.4T patent/DK2371818T3/da active
-
2007
- 2007-04-16 IL IL182573A patent/IL182573A/en not_active IP Right Cessation
- 2007-04-26 NO NO20072160A patent/NO20072160L/no not_active Application Discontinuation
- 2007-05-09 ZA ZA200703759A patent/ZA200703759B/xx unknown
-
2008
- 2008-06-19 US US12/142,471 patent/US20080249142A1/en not_active Abandoned
- 2008-11-14 JP JP2008291862A patent/JP4764911B2/ja not_active Expired - Fee Related
-
2009
- 2009-04-16 ZA ZA2009/02634A patent/ZA200902634B/en unknown
-
2012
- 2012-12-17 IL IL223681A patent/IL223681A0/en unknown
-
2013
- 2013-01-14 CY CY20131100038T patent/CY1113542T1/el unknown
- 2013-03-12 HR HRP20130215TT patent/HRP20130215T1/hr unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4447038B2 (ja) | メタニコチン化合物のヒドロキシ安息香酸塩 | |
US9107915B2 (en) | Hydroxybenzoate salts of metanicotine compounds | |
US6492399B1 (en) | Pharmaceutical compositions and methods for use | |
US6455554B1 (en) | Oxopyridinyl pharmaceutical compositions and methods for use | |
JP2003501416A (ja) | 医薬組成物およびその使用法 | |
JP2002518373A (ja) | アリール置換オレフィンアミンと、コリン受容体アゴニストとしてのアリール置換オレフィンアミンの使用 | |
EP0973743B1 (en) | Pharmaceutical compositions incorporating aryl substituted olefinic amine compounds | |
US7060826B2 (en) | Compounds capable of activating cholinergic receptors | |
US20030087915A1 (en) | Pharmaceutical compositions and methods for use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20081106 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20081106 |
|
A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20081114 |
|
A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20081204 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20090106 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20090330 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20090406 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090703 |
|
A524 | Written submission of copy of amendment under article 19 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A524 Effective date: 20090703 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20090901 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20091126 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20091228 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20100119 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130129 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130129 Year of fee payment: 3 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |