JPH07508281A - Methods and compositions for treating depression and other disorders using optically pure (+)sibutramine - Google Patents
Methods and compositions for treating depression and other disorders using optically pure (+)sibutramineInfo
- Publication number
- JPH07508281A JPH07508281A JP6502537A JP50253793A JPH07508281A JP H07508281 A JPH07508281 A JP H07508281A JP 6502537 A JP6502537 A JP 6502537A JP 50253793 A JP50253793 A JP 50253793A JP H07508281 A JPH07508281 A JP H07508281A
- Authority
- JP
- Japan
- Prior art keywords
- sibutramine
- pharmaceutically acceptable
- composition
- stereoisomer
- humans
- 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.)
- Pending
Links
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Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 光学的に純粋な（＋）シブトラミンを用いるうつ病およびその他の障害を治療す る方法ならびに組成物１、背景技術 本発明は、光学的に純粋な（＋）シブトラミン（ｓｉｂｕｔｒａｍｉ ｎｅ）を 含む新規組成物に関する。本組成物はうつ病の治療に顕著な活性を有する。本組 成物は、シブトラミンのラセミ混合物投与に関連する心拍数の有意な増加、血圧 の増加、精神運動活性、０渇、および神経質を含む（ただしこれに限定されない ）副作用を回避しつつ、うつ病の治療に顕著な活性をも有する。本発明の新規組 成物は、上記副作用を回避する一方で、ラセミ形シブトラミンよりも作用開始が 早い。また、光学的に純粋な（＋）シブトラミンを含む本発明の新規組成物は、 ヒトの肥満または体重増加の治療に有用である。これらの組成物はまた、シブト ラミンのラセミ混合物投与に関連する副作用を回避しつつ、肥満および体重増加 の治療に顕著な活性を有する。[Detailed description of the invention] Treatment of Depression and Other Disorders with Optically Pure (+) Sibutramine Method and composition 1, background art The present invention provides optically pure (+) sibutramine. A novel composition comprising: The composition has significant activity in the treatment of depression. Main group The compound is associated with significant increases in heart rate and blood pressure associated with administration of the racemic mixture of sibutramine. including (but not limited to) increased psychomotor activity, thirst, and nervousness ) It also has remarkable activity in the treatment of depression while avoiding side effects. New set of the present invention The formulation has a faster onset of action than racemic sibutramine while avoiding the side effects mentioned above. early. Additionally, the novel composition of the present invention containing optically pure (+)sibutramine is Useful in the treatment of obesity or weight gain in humans. These compositions also contain Obesity and weight gain while avoiding the side effects associated with administration of racemic mixtures of lamins. It has remarkable activity in the treatment of.
また、（＋）シブトラミンはニューロン性モノアミン再取り込みの阻害剤として 作用するので、（＋）シブトラミンを含むこれらの新規組成物はニューロン性モ ノアミン再取り込みの阻害によって改善される障害の治療に有用である。シブト ラミンによってその再取り込みが阻害されるモノアミンには、ドーパミン、ノル アドレナリン（ノルエピネフリンとしても知られる）およびセロトニンが含まれ るが、これに限定されない（Ｋｉｎｇ ｅｔ ａｌ、、 Ｊ、 Ｃｌ１ｎ、 Ｐ ｈａｒｍａｃ、 ２６：６０７−６１１．１９８９； Ｒｅｅｓ、米国特許第４ ，８７１゜７７４号）。ニューロン性モノアミン再取り込みの阻害によって改善 される障害には、パーキンソン病およびうつ病が含まれるが、これに限定されな い。本発明の新規組成物はまた、ラセミ性シブトラミン投与に関連する副作用を 回避しつつ、ニューロン性モノアミン再取り込み阻害によって改善される障害の 治療にも顕著な活性を有する。In addition, (+)sibutramine is an inhibitor of neuronal monoamine reuptake. These novel compositions containing (+) sibutramine have been found to be It is useful in treating disorders that are ameliorated by inhibition of noamine reuptake. Shibuto Monoamines whose reuptake is inhibited by lamin include dopamine, nor Contains adrenaline (also known as norepinephrine) and serotonin but not limited to (King et al., J., Cl1n, P. harmac, 26:607-611.1989; Rees, U.S. Patent No. 4 , 871°774). Improved by inhibition of neuronal monoamine reuptake Disorders affected include, but are not limited to, Parkinson's disease and depression. stomach. The novel compositions of the present invention also eliminate side effects associated with racemic sibutramine administration. while avoiding the disorders that are ameliorated by neuronal monoamine reuptake inhibition. It also has significant therapeutic activity.
さらに、光学的に純粋な、または実質的に光学的に純粋な（＋）シブトラミンを 含む新規組成物は脳機能障害の治療に有用である。これらの障害には老年性痴呆 、アルツノ１イマー型痴呆、記憶喪失、記憶消失／健忘症、意識障害、昏睡、注 意力低下、言語障害、パーキンソン病、レノックス症、自閉、運動亢進症、およ び精神分裂症が含まれるが、これに限定されない。脳機能障害は、脳梗塞、脳出 血、脳前方硬化症、脳静脈血栓症、頭部損傷などであって、症状が意識障害、老 年性痴呆、昏睡、注意力低下、言語障害などである脳血管性疾患を含む要因によ って誘導されるが、これに限定されない。本発明の新規組成物は、ラセミ性シブ トラミン投与に関連する副作用を回避しつつ、脳機能障害の治療に顕著な活性を 有する。In addition, optically pure or substantially optically pure (+) sibutramine Novel compositions comprising the present invention are useful in treating brain dysfunction. These disorders include senile dementia , Alzheimer's type 1 dementia, memory loss, memory loss/amnesia, disturbance of consciousness, coma, note Decreased willpower, speech disorders, Parkinson's disease, Lennox disease, autism, hyperkinesia, and including, but not limited to, psychosis and schizophrenia. Brain dysfunction is caused by cerebral infarction, symptoms such as blood loss, anterior cerebral sclerosis, cerebral venous thrombosis, head injury, etc., and symptoms such as impaired consciousness and old age. Due to factors including cerebrovascular disease, such as senile dementia, coma, decreased attention, and language disorders. However, it is not limited to this. The novel composition of the present invention Demonstrates significant activity in the treatment of brain dysfunction while avoiding the side effects associated with tolamin administration have
さらに、本発明は、光学的に純粋な、または実質的に光学的に純粋な（＋）シブ トラミンをかかる治療を必要とするヒトに投与することによる、ヒトにおける上 記症状を治療する方法を包含する。本発明はまた、シブトラミンのラセミ混合物 に関連する副作用を回避しつつ、ヒトにおける上記症状を治療する方法を包含す る。Additionally, the present invention provides optically pure or substantially optically pure (+) The effects of administering Tolamin to humans in need of such treatment and methods of treating the conditions described above. The present invention also provides racemic mixtures of sibutramine. including methods of treating the above symptoms in humans while avoiding the side effects associated with Ru.
１、 １．立体関係と医薬作用 多くの有機化合物は光学的に活性な形態で存在し、つまりそれらは偏光面を回転 させる能力がある。光学活性化合物を記載するには、そのキラル中心のまわりの 分子の絶対配置を表すのに大文字のＤやＬまたはＲやＳが用いられる。化合物に よる偏光面の回転方向を表すには記号（−）や（＋）または亘や上が用いられる 、これらの化合物は立体異性体と呼ばれ、互いの鏡像であること以外は全く同一 である。このような立体異性体は対掌体と呼ばれることもあり、このような異性 体の混合物はしばしば対掌体またはラセミ混合物と呼ばれている。1, 1. Stereo-relationships and medicinal effects Many organic compounds exist in optically active forms, meaning they rotate the plane of polarized light. have the ability to do so. To describe an optically active compound, the Capital letters D, L, R, and S are used to represent the absolute configuration of molecules. into a compound The symbols (-), (+), or Wataru and Ue are used to represent the direction of rotation of the plane of polarization. , these compounds are called stereoisomers and are identical except that they are mirror images of each other. It is. Such stereoisomers are sometimes called enantiomers; A mixture of bodies is often called an enantiomer or racemic mixture.
医薬の分野では立体化学純度が重要であり、処方される薬剤２０種のうち１２種 はキラリティーを示すものである。適切な例はβ−アドレナリン遮断薬であるプ ロプラノロール（ｐｒｏｐｒａｎｏｌｏｌ）のＬ体であり、これは０体よりも１ ００倍効力のあることが知られている。Stereochemical purity is important in the pharmaceutical field, and 12 out of 20 prescribed drugs indicates chirality. A case in point is the β-adrenergic blocker It is the L form of lopranolol, which is 1 form rather than 0 form. It is known to be 00 times more effective.
さらに、ある種の異性体は単に不活性であるというよりは実際に有害であるため に、光学純度が重要となる。例えば、サリドマイドの０体は、妊娠中のつわり防 止のために処方されるとき、安全で有効な鎮静剤であるが、その対応するＬ体は 非常に強い催奇形性物質であると考えられている。Additionally, some isomers are actually harmful rather than simply inert, so Therefore, optical purity is important. For example, thalidomide is used to prevent morning sickness during pregnancy. is a safe and effective sedative when prescribed for hypnosis, but its corresponding L-form is It is considered to be a very strong teratogen.
本発明の組成物および方法の活性化合物は、米国特許第４，７４６．６８０号お よび４，５２２．８２８号に記載の化合物シブトラミンの光学異性体である。化 学的には、この光学異性体は（＋）［Ｎ−１−［１−（４−クロロフェニル）シ クロブチルコー３−メチルブチル］−Ｎ、Ｎ−ジメチルアミンである。この異性 体をこれ以後（＋）シブトラミンと呼び、光学的に純粋な、および実質的に光学 的に純粋な（＋）シブトラミンを含むものとする。The active compounds of the compositions and methods of the present invention are disclosed in U.S. Pat. and sibutramine, an optical isomer of the compound described in No. 4,522.828. transformation Scientifically, this optical isomer is (+)[N-1-[1-(4-chlorophenyl)cyan] Chlobutyl-3-methylbutyl]-N,N-dimethylamine. this opposite sex The body, hereafter referred to as (+)sibutramine, is an optically pure and substantially optical Contains essentially pure (+)sibutramine.
本発明の対象であるシブトラミンはラセミ混合物としてのみ入手可能である。シ ブトラミンは一般に塩酸塩として、そしてしばしば−水和物として投与される。Sibutramine, which is the subject of the present invention, is available only as a racemic mixture. S Butramine is generally administered as the hydrochloride salt, and often as the hydrate.
シブトラミンのラセミ混合物は、繰病とともに精神障害の範−に入るうつ病の治 療に主として用いられる。シブトラミンはノルアドレナリン（ノルエピネフリン としても知られる）に対して、および程度は少ないがセロトニンおよびドーパミ ンに対して活性を有するモノアミン再取り込み阻害剤である（Ｉｌｕｃｋｅｔｔ 、 Ｗ、Ｒ，ｅｔａｌ、、 Ｐｒｏｇ、 Ｎｅｕｒｏ−Ｐｓｙｃｈｏｐｈａｒｍ 、 ＆ ［１Ｉｏ１． Ｐｓｙｃｈｉａｔ、１２．５７５−５８４、１９８８； Ｋｉｎｇ、 Ｄ、Ｊ、 ｅｔ ａｔ、、 Ｂｒ１ｔ、Ｊ、 Ｃｌ１ｎ、 Ｐｈ ａｒｍａｃ、 ２６．６０７−６１１．１９８８）。シブトラミンはモノアミン 再取り込み阻害、脳アドレナリン作動性機構の迅速で強力な下方制御、その他の 種類の抗うつ薬と比較して抗コリン作動性の副作用が比較的なし）こと、ならび にモノアミンオキシダーゼ阻害剤としての活性がな５ｔことによってその他の抗 うつ薬と区別される。The racemic mixture of sibutramine is used to treat depression, which is classified as a mental disorder as well as chronic illness. Mainly used for medical treatment. Sibutramine is noradrenaline (norepinephrine) ), and to a lesser extent serotonin and dopamine It is a monoamine reuptake inhibitor with activity against monoamine reuptake inhibitors (Iluckett , W, R, etal, , Prog, Neuro-Psychopharm , & [1Io1. Psychiat, 12.575-584, 1988; King, D, J, et at, Br1t, J, Cl1n, Ph armac, 26.607-611.1988). Sibutramine is a monoamine reuptake inhibition, rapid and strong downregulation of brain adrenergic mechanisms, and other relatively free of anticholinergic side effects (compared to other antidepressants), and 5t has no activity as a monoamine oxidase inhibitor Distinguished from depressants.
繰病はうつ病とともに気分の変化を主症状にすることを特徴とする。これら２つ の極端な気分はいずれも、無秩序な考えと妄覚という精神病を伴う。精神病は二 次症状として気分変化をもっており、このうつ病との重複のために診断上の混乱 がおきる。精神病を伴わない重症の気分変化がしばしばうつ病で生じ、不安を伴 うことが多い。Reibyou is characterized by mood changes as the main symptoms along with depression. these two Both extreme moods are accompanied by psychosis of disordered thinking and delusions. Mental illness is two The secondary symptom is mood changes, and the diagnosis is confusing due to the overlap with depression. occurs. Severe mood changes without psychosis often occur in depression and may be accompanied by anxiety. Often.
主うつ病および二極繰うつ病を含む精神障害は気分の変化を主症状とする。主う つ病は重要な精神疾患のうちで最も多いものであり、正常の嘆き、悲しみ、失望 や医学疾患にしばしば伴う不快または士気阻喪とは臨床的に区別されなければな らない。うつ病は強い悲しみ、絶望、精神遅延、集中力欠如、悲観的悩み、激高 、および自己嫌悪などの感情を特徴とする。不眠症、食欲不振、体重低下、エネ ルギー低下、リビドの欠如、およびホルモン循環リズムの破壊を含む身体的変化 を伴うこともある。この症状は三環式または関連の抗うつ薬、モノアミンオキシ ダーゼ阻害剤に応答し、または抵抗性の場合や重症疾患では電気痙章ショック療 法に応答することが多い。うつ病の治療にラセミ体シブトラミンを使用すること が米国特許第４，５２２．８２８号に記載されている。Psychiatric disorders, including major depression and bipolar depression, have mood changes as their main symptom. Lord Depression is the most common of the major mental illnesses, and it It must be clinically distinguished from the discomfort or demoralization that often accompanies medical illness. No. Depression is a combination of intense sadness, despair, mental retardation, lack of concentration, pessimistic worries, and intense anxiety. , and is characterized by emotions such as self-loathing. Insomnia, loss of appetite, weight loss, energy Physical changes including decreased energy, lack of libido, and disruption of hormonal circulatory rhythms It may also be accompanied by This symptom may be associated with tricyclic or related antidepressants, monoamine oxy electroconvulsive shock therapy in cases of response or resistance to Dase inhibitors or severe disease. Often responds to the law. The use of racemic sibutramine in the treatment of depression is described in US Pat. No. 4,522,828.
ンブトラミンは痴呆の治療にも有用である。アルツハイマー型痴呆を含む痴呆は 、脳皮質細胞の欠如を含む退化過程によって発症し、記憶欠如が主症状である。Nbutramine is also useful in treating dementia. Dementia, including Alzheimer's dementia, , is caused by a degenerative process that involves the loss of brain cortical cells, and memory loss is the main symptom.
痴呆は脳神経病因性の変化と細胞欠如によって多分引き起こされる進行性で不可 逆的な機能障害を症状とする。この症状は認識困難を主とすると考えられ、うつ 、偏執狂、不安、およびその他の精神症状も多い。簡単に述べると、共通の臨床 症状は、洞察力と判断ノｊの障害や感情の欠如によって引き起こされる人格、知 性両方の緩慢な崩壊である。痴呆は通常潜行性でゆっくりと進行し、治療できな いことが多い。しかしながら、うって痴呆性の人では、ある種の抗うつ薬が全体 の機能を有意に改善できる。Dementia is a progressive disease probably caused by neuropathogenic changes and cell loss. Symptoms include reverse dysfunction. This symptom is thought to be mainly due to difficulty in recognition, and is associated with depression. , paranoia, anxiety, and other psychiatric symptoms are also common. Briefly, common clinical Symptoms are personality and intellectual disorders caused by impaired insight and judgment or lack of emotion. It is a slow collapse of both sexes. Dementia is usually insidious, progresses slowly, and cannot be treated. There are many bad things. However, in people with dementia, certain antidepressants may can significantly improve the functionality of
アルツハイマー型痴呆も抗うつ薬療法で治療できる。アルツハイマー型痴呆（Ａ ＴＤ）は特に８０歳以上の人の３０％に現れる荒廃型の痴呆である（ＩＥｖａｎ ｓ ｅｔ ａｔ、、 Ｊ、Ａ、Ｍ、Ａ、 ２６２：２５５１−２５５６゜１９８ ９）。ＡＴＤはゆっくりとした認識障害を特徴とする神経変性疾患である。この 痴呆の病因学および発病学は、主として脳の側頭葉と新皮質におけるアミロイド 塩、神経繊維濃縮体および神経集団欠如と組織病原学的に関連する。上述した症 状はいずれも脳機能障害または脳血管疾患の結果として生じるので、ラセミ体シ ブトラミンがＡＴＤの治療および改善をもたらすことができる。Alzheimer's dementia can also be treated with antidepressant therapy. Alzheimer's dementia (A TD) is a devastating type of dementia that appears in 30% of people over the age of 80 (IEvan set at, J, A, M, A, 262:2551-2556゜198 9). ATD is a neurodegenerative disease characterized by gradual cognitive impairment. this The etiology and pathogenesis of dementia is mainly due to amyloid in the temporal lobe and neocortex of the brain. Histopathologically associated with salts, neurofiber tangles and neuronal population absence. above-mentioned symptoms Both symptoms occur as a result of brain dysfunction or cerebrovascular disease, so racemic Butramine can provide treatment and amelioration of ATD.
ラセミ体シブトラミンは米国特許第４．９３９，１７５号に記載するように、脳 機能障害の治療にも使用できる。脳機能障害は複雑な病因でおこり、その原因に は脳梗塞、脳出血、脳前方硬化症、脳静脈血栓症、頭部損傷などの脳血管疾患が ある。脳機能障害は各種二次的症状、例えば意識障害、昏睡、注意力低下、健忘 症、老年性痴呆、言語障害などをもたらす。前シナプス性連結におけるモノアミ ン神経伝達物質レベルの上昇による中枢神経系の活性化に基つくこれらの症状の 治療にラセミ体シブトラミンが有益な効果をもつ。米国特許第４，９３９．１７ ５号に記載するように、老年性痴呆、記憶消失／健忘症、パーキンソン病、アル ツハイマー型痴呆、記憶喪失、意識障害、レノックス症、自閉、運動亢進症、お よびシブトラミンが提供する自発的運動とドーパミン活性の増強に基づく精神分 裂症などの知的障害に関連する症状の治療において脳機能を改善するのにラセミ 体シブトラミンが特に有用である。しかしながら、その使用に関連する逆作用（ 副作用）を排除または減少しながら、これらの脳機能障害の症状を治療するため に高い活性をもつ医薬がめられている。Racemic sibutramine has been shown to be effective in the brain, as described in U.S. Pat. No. 4,939,175. It can also be used to treat functional disorders. Brain dysfunction occurs due to complex etiology, and the cause cerebrovascular diseases such as cerebral infarction, cerebral hemorrhage, anterior cerebral sclerosis, cerebral venous thrombosis, and head injury. be. Brain dysfunction can lead to various secondary symptoms, such as impaired consciousness, coma, decreased attention span, and amnesia. symptoms, senile dementia, and speech disorders. Monoamid in presynaptic connections These symptoms are based on activation of the central nervous system due to increased levels of neurotransmitters. Racemic sibutramine has a beneficial effect in treatment. U.S. Patent No. 4,939.17 As described in issue 5, senile dementia, memory loss/amnesia, Parkinson's disease, alcohol Zheimer's dementia, memory loss, consciousness disorder, Lennox syndrome, autism, hyperkinesia, and and sibutramine provides psychoactive stimulation based on the enhancement of voluntary movement and dopamine activity. Racemic aids in improving brain function in treating symptoms associated with intellectual disability such as cleft syndrome Sibutramine is particularly useful. However, adverse effects associated with its use ( to treat symptoms of these brain dysfunctions while eliminating or reducing side effects) Drugs with high activity are being sought.
さらに、ラセミ体ンブトラミンは肥満または体重増加を含む体重障害の治療に有 用である。肥満は、標準よりも体重が２０％多くなるまて体脂肪が蓄積すること を特徴とする。この症状の重要性は肥満の人が関連する多数の合併症である。肥 満の病因は単純であり、消費するより以上のカロリーを摂取することに関連する のであるが、多くの要因がこの症状に関与する。Additionally, racemic nbutramine may be useful in the treatment of weight disorders, including obesity or weight gain. It is for use. Obesity is defined as being 20% heavier than normal and accumulating body fat. It is characterized by The significance of this condition is the numerous complications associated with obese individuals. fertilizer The etiology of mania is simple and is related to consuming more calories than you expend. However, many factors contribute to this condition.
肥満の予後は困難であり、治療抵抗性でありかつぶり返す傾向のある慢性症状で ある。ダイエツトによるカロリー減少、身体活動の増加、過激な外科治療、およ び投薬が個々の場合に応して用いられている治療である。肥満の医薬治療はしば しば制限的規制が多く、この治療後の体重増加はその他の治療の場合よりも大き いことが多い。安全かつ有効な医薬治療の開発のかなりの機会がある。肥満治療 へのラセミ体シブトラミンの使用がシャインバウム（Ｓｃｈｅｉｎｂａｕｍ）、 Ｊ、Ｌ、による１９９０年６月１４日公開の国際特許公開公報ＷＯ９０１０６１ １０に記載されている。Obesity has a difficult prognosis and is a chronic condition that is resistant to treatment and tends to relapse. be. Calorie reduction through diet, increased physical activity, radical surgical treatments, and Medication and treatment are used on a case-by-case basis. Medical treatment for obesity There are often restrictive regulations and weight gain after this treatment is greater than with other treatments. There are many bad things. There is considerable opportunity for the development of safe and effective pharmaceutical treatments. obesity treatment The use of racemic sibutramine to International Patent Publication WO901061 published June 14, 1990 by J.L. 10.
上述したように、ンブトラミンはニューロン性モノアミン再取り込みの阻害剤で あることが知られている。その再取り込みがシブトラミンによって阻害されるモ ノアミンには、ドーパミン、ノルアドレナリン（ノルエピネフリン）およびセロ トニンが含まれる。異常なモノアミン（ドーパミン）レベルに関連し、ニューロ ン性モノアミン（ドーパミン）再取り込み阻害によって治療できる症状の１つは 、脳基底の神経節における退化性変化によって引き起こされるパーキンソン病で ある。パーキンソン病の治療にラセミ体シブトラミンを使用することは米国特許 第４，８１６，４８８号および４，８７１，７７４号に記載されている。As mentioned above, nbutramine is an inhibitor of neuronal monoamine reuptake. It is known that there is. The model whose reuptake is inhibited by sibutramine Noamine contains dopamine, noradrenaline (norepinephrine) and sero Contains tonin. Associated with abnormal monoamine (dopamine) levels and One of the conditions that can be treated by inhibiting the reuptake of agonistic monoamines (dopamine) is , in Parkinson's disease caused by degenerative changes in the basal ganglia. be. U.S. patent for use of racemic sibutramine to treat Parkinson's disease No. 4,816,488 and No. 4,871,774.
特定の病因学は別として、パーキンソン病は通常生涯の後半部に潜行性で現れる 慢性で進行性の中枢神経系障害である。この疾患は意識的運動の能力が徐々に低 下する。主要な臨床症状はふるえ、運動緩徐、硬綿、および姿勢障害を特徴とす る。患者はしばしば痴呆を伴う。自然発生パーキンソン症では、黒質、銹斑、お よびその他の脳の色素ニューロンにおける細胞欠如、ならびに黒質から突出する 細胞の神経軸索末端におけるドーパミン含量の減少が通常見られる。パーキンソ ン病がドーパミン欠失症であるとの理解が、多くの基礎および臨床の観察から得 られている。Regardless of the specific etiology, Parkinson's disease usually presents in an insidious manner later in life. It is a chronic and progressive central nervous system disorder. This disease gradually reduces the ability to make conscious movements. down. The main clinical symptoms are characterized by tremor, bradykinesia, stiffness, and postural disturbances Ru. Patients often have dementia. In spontaneous parkinsonism, the substantia nigra, rust spots, and other pigmented neurons of the brain, as well as protruding from the substantia nigra A decrease in dopamine content in the nerve axon terminals of cells is usually seen. Parkinso The understanding that dopamine disease is a dopamine deficiency disorder is based on a number of basic and clinical observations. It is being
シブトラミンのラセミ混合物は上述した利点をもってはいるが、仰臥および直立 時の心拍数の有意な増加、血圧増加、精神運動活性の増加、０渇、緊張および神 経質を含む（ただしこれに限定されない）副作用を引き起こすなどの不利な点も もっている。これらの脳血管効果および精神刺激作用は医薬治療の用量レベル、 頻度、および持続を有意に限定しうる。さらに、ラセミ体シブトラミンはその他 の種類の抗うっ薬よりも早く作用するが、より迅速な作用開始が望ましい。した がって、上述した不利な点をもたずにラセミ体シブトラミンの利点をもっている 化合物を見いだすことが望まれている。Although the racemic mixture of sibutramine has the advantages mentioned above, it Significant increase in heart rate, increased blood pressure, increased psychomotor activity, 0 thirst, nervousness and nervousness There are also disadvantages such as causing side effects including (but not limited to) I have it. These cerebrovascular and psychostimulant effects vary depending on the dose level of the drug treatment, frequency, and duration may be significantly limited. In addition, racemic sibutramine is It works faster than the antidepressant class, but a more rapid onset of action is desirable. did Therefore, it has the advantages of racemic sibutramine without the disadvantages mentioned above. It is desired to find compounds.
２、発明の概要 本発明は、光学的に純粋な（＋）シブトラミンを含む新規組成物に関する。本組 成物は抗うっ薬として顕著な活性を有する。本組成物は、シブトラミンのラセミ 混合物投与に関連する心拍数の有意な増加、血圧の増加、精神運動活性、０渇、 および神経質を含む（ただしこれに限定されない）副作用を回避しつつ、抗うつ 薬としての顕著な活性をも有する。さらに、光学的に純粋な、または実質的に光 学的に純粋な（＋）シブトラミンは、該医薬のラセミ形よりもこの点における作 用開始が早い。また、（＋）シブトラミンを含む本発明の新規組成物は、ヒトの 肥満および体重増加の治療に有用である。これらの組成物はまた、シブトラミン のラセミ混合物投与に関連する副作用を回避しつつ、ヒトの肥満および体重増加 の治療に顕著な活性を有する。2. Overview of the invention The present invention relates to novel compositions containing optically pure (+)sibutramine. Main group The composition has significant activity as an antidepressant. This composition contains racemic sibutramine. Significant increase in heart rate, increase in blood pressure, psychomotor activity, 0 thirst, associated with mixture administration. antidepressant while avoiding side effects including but not limited to nervousness and nervousness. It also has significant medicinal activity. Additionally, optically pure or substantially optical Biologically pure (+) sibutramine is more effective in this respect than the racemic form of the drug. Start using it early. Furthermore, the novel composition of the present invention containing (+)sibutramine can be used in humans. Useful in treating obesity and weight gain. These compositions also contain sibutramine obesity and weight gain in humans while avoiding the side effects associated with administration of racemic mixtures of It has remarkable activity in the treatment of.
本発明ではまた、ニューロン性モノアミン再取り込みの阻害によって改善される 障害の治療に顕著な活性を有する、（＋）シブトラミンを含む新規組成物を開示 する。これらの組成物は、シブトラミンのラセミ混合物に関連する副作用を回避 しつつ、これらの障害（例えばパーキンソン病）の治療に顕著な活性を有する。The present invention also shows that neuronal monoamine reuptake is improved by inhibition of neuronal monoamine reuptake. Discloses novel compositions containing (+)sibutramine that have significant activity in the treatment of disorders do. These compositions avoid the side effects associated with racemic mixtures of sibutramine However, it has significant activity in the treatment of these disorders (eg Parkinson's disease).
さらに、（＋）シブトラミンを含む新規組成物は脳機能障害の治療に有用である 。これらの組成物は、シブトラミンのラセミ混合物投与に関連する副作用を回避 しつつ、脳機能障害の治療に顕著な活性を有する。Additionally, novel compositions containing (+)sibutramine are useful in treating brain dysfunction. . These compositions avoid the side effects associated with racemic mixture administration of sibutramine. However, it has remarkable activity in the treatment of brain dysfunction.
さらに、本発明は、光学的に純粋な、または実質的に光学的に純粋な（＋）シブ トラミンを投与することによる、ヒトにおける上記症状を治療する方法を開示す る。本発明はまた、シブトラミンのラセミ混合物に関連する副作用を回避しつつ 、光学的に純粋な、または実質的に光学的に純粋な（＋）シブトラミンを投与す ることによる、ヒトにおける上記症状を治療する方法を開示する。Additionally, the present invention provides optically pure or substantially optically pure (+) Discloses a method of treating the above symptoms in humans by administering tolamin Ru. The present invention also avoids the side effects associated with racemic mixtures of sibutramine. , administering optically pure or substantially optically pure (+) sibutramine. Disclosed are methods of treating the above-mentioned conditions in humans by.
３、発明の詳細な説明 本発明は、抗うつ薬治療を必要とするヒトに、ヒトのうつ病を軽減するのに十分 な量の実質的に（−）立体異性体を含まない（＋）シブトラミンまたはその薬剤 的に受容できる塩を投与することからなる、ヒトのうつ病治療法を包含する。3. Detailed description of the invention The present invention provides antidepressant treatment to humans in need of treatment sufficient to alleviate depression in humans. an amount of substantially (-) stereoisomer-free (+) sibutramine or its drug; The present invention encompasses a method of treating depression in humans consisting of administering a salt that is physically acceptable.
本発明はまた、抗うつ薬治療を必要とするヒトに、ヒトのうつ病を軽減するのに は十分であるが、ラセミ体シブトラミンと関連する副作用を起こすには不十分な 量の実質的に（−）立体異性体を含まない（＋）シブトラミンまたはその薬剤的 に受容できる塩を投与することからなる、ヒトのうつ病治療法を包含する。（＋ ）シブトラミンはラセミ体シブトラミンよりも迅速な作用開始を示し、うつ病を 治療できる。The present invention also provides a method for reducing depression in humans in need of antidepressant treatment. is sufficient, but not sufficient to cause the side effects associated with racemic sibutramine. Amount of substantially (-) stereoisomer-free (+) sibutramine or its pharmaceutical A method of treating depression in humans consists of administering an acceptable salt to. (+ ) Sibutramine has a more rapid onset of action than racemic sibutramine and is effective in treating depression. It can be treated.
本発明はまた、うつ病を軽減するのに十分な量の実質的に（−）立体異性体を含 まない（＋）シブトラミンまたはその薬剤的に受容できる塩を含む、抗うつ薬治 療を必要とするヒトの治療用抗うつ組成物を包含する。The present invention also provides a method comprising substantially the (-) stereoisomer in an amount sufficient to alleviate depression. (+) Antidepressant medications containing sibutramine or its pharmaceutically acceptable salts Antidepressant compositions for the treatment of humans in need of treatment.
本発明はまた、うつ病を軽減するのには十分であるが、ラセミ体シブトラミンと 関連する副作用を起こすには不十分な量の実質的に（−）立体異性体を含まない （＋）シブトラミンまたはその薬剤的に受容できる塩を含む、抗うつ薬治療を必 要とするヒトの治療用抗うつ組成物を包含する。これらの新規組成物はラセミ体 ンブトラミンよりも迅速な作用開始を示し、副作用を回避する。The present invention also shows that racemic sibutramine, which is sufficient to alleviate depression, Substantially free of the (-) stereoisomer in amounts insufficient to cause relevant side effects (+) Requires antidepressant therapy, including sibutramine or its pharmaceutically acceptable salts. Antidepressant compositions for human treatment. These new compositions are racemic It has a faster onset of action than nbutramine and avoids side effects.
さらに、本発明は体重軽減を必要とするヒトに、ヒトの体重軽減をするのに十分 な量の実質的に（−）立体異性体を含まない（＋）シブトラミンまたはその薬剤 的に受容できる塩を投与することからなる、ヒトの肥満または体重増加の治療法 を包含する。Additionally, the present invention provides a method for providing weight reduction to humans in need of weight reduction. an amount of substantially (-) stereoisomer-free (+) sibutramine or its drug; A method of treating obesity or weight gain in humans comprising administering a salt that is acceptable to the human body. includes.
さらに、本発明は体重軽減を必要とするヒトに、ヒトの体重軽減をするのには十 分であるが、ラセミ体シブトラミン投与と関連する副作用を起こすには不十分な 量の実質的に（−）立体異性体を含まない（＋）シブトラミンまたはその薬剤的 に受容できる塩を投与することからなる、ヒトの肥満または体重増加の治療法を 包含する。Furthermore, the present invention is suitable for reducing body weight in humans who require weight reduction. minutes, but insufficient to cause the side effects associated with racemic sibutramine administration. Amount of substantially (-) stereoisomer-free (+) sibutramine or its pharmaceutical A method of treating obesity or weight gain in humans consisting of administering acceptable salts to include.
本発明はまた、体重軽減を達成するのに十分な量の実質的に（−）立体異性体を 含まない（＋）シブトラミンまたはその薬剤的に受容できる塩を含む、肥満また は体重増加の治療用組成物を包含する。The present invention also provides a method for incorporating substantially the (-) stereoisomer in an amount sufficient to achieve weight reduction. Contains (+) sibutramine or its pharmaceutically acceptable salts, obese or includes compositions for the treatment of weight gain.
本発明はさらに、体重軽減を達成するのには十分な量であるが、ラセミ体シブト ラミンの副作用を起こすには不十分な量の実質的に（−）立体異性体を含まない （＋）シブトラミンまたはその薬剤的に受容できる塩を含む、肥満または体重増 加の治療用組成物を包含する。The present invention further provides that racemic sibutin in an amount sufficient to achieve weight reduction; Contains substantially no (-) stereoisomer in amounts insufficient to cause lamin side effects (+) Obesity or weight gain, including sibutramine or its pharmaceutically acceptable salts. and other therapeutic compositions.
本発明は、ニューロン性モノアミン再取り込み阻害を必要とするヒトに、このよ うな障害を治療するのに十分な量の実質的に（＝）立体異性体を含まない（＋） シブトラミンまたはその薬剤的に受容できる塩を投与することからなる、ヒトの ニューロン性モノアミン再取り込み阻害によって改善される障害の治療法を包含 する。ニューロン性モノアミン再取り込み阻害によって改善される障害にはパー キンソン病およびうつ病を含むが、これに限定されない。The present invention provides this method for humans in need of neuronal monoamine reuptake inhibition. substantially (=) stereoisomer-free (+) in sufficient amounts to treat disorders such as in humans, comprising administering sibutramine or a pharmaceutically acceptable salt thereof. Includes treatments for disorders ameliorated by neuronal monoamine reuptake inhibition do. There are no disorders ameliorated by neuronal monoamine reuptake inhibition. including, but not limited to, Kinson's disease and depression.
本発明は、ニューロン性モノアミン再取り込み阻害を必要とするヒトに、このよ うな障害を治療するのには十分な量であるが、ラセミ体シブトラミンの投与と関 連する副作用を起こすには不十分な量の実質的に（−）立体異性体を含まない（ ＋）シブトラミンまたはその薬剤的に受容できる塩を投与することからなる、ヒ トのニューロン性モノアミン再取り込み阻害によって改善される障害の治療法を 包含する。The present invention provides this method for humans in need of neuronal monoamine reuptake inhibition. Although the doses are sufficient to treat such disorders, there are Substantially free of the (-) stereoisomer in amounts insufficient to cause associated side effects ( +) administration of sibutramine or a pharmaceutically acceptable salt thereof; Treatment of disorders ameliorated by inhibition of neuronal monoamine reuptake include.
本発明はまた、このような障害を改善するのに十分な量の実質的に（−）立体異 性体を含まない（＋）シブトラミンまたはその薬剤的に受容できる塩を含む、ヒ トのニューロン性モノアミン再取り込み阻害によって改善される障害の治療用組 成物を包含する。The present invention also provides for substantially (-) stereoisomerization in sufficient amounts to ameliorate such impairments (+) sibutramine or its pharmaceutically acceptable salts; Treatment of disorders ameliorated by inhibition of neuronal monoamine reuptake includes products.
本発明は、このような障害を改善するのには十分な量であるが、ラセミ体ソブト ラミンと関連する副作用を起こすには不十分な量の実質的に（−）立体異性体を 含まない（＋）シブトラミンまたはその薬剤的に受容できる塩を含む、ヒトのニ ューロン性モノアミン再取り込み阻害によって改善される障害の治療用組成物を 包含する。Although the present invention is sufficient to ameliorate such disorders, racemic sobut lamin in substantially insufficient amounts to cause the side effects associated with the (-) stereoisomer. (+) sibutramine or its pharmaceutically acceptable salts; Compositions for the treatment of disorders ameliorated by neuronal monoamine reuptake inhibition include.
本発明はまた、脳機能障害の治療を必要とするヒトに、このような脳機能障害を 改善するのに十分な量の実質的に（−）立体異性体を含まない（＋）シブトラミ ンまたはその薬剤的に受容できる塩を投与することからなる、脳機能障害の治療 法を包含する。The present invention also provides methods for treating brain dysfunction in humans in need of such treatment. Substantially (−) stereoisomer-free (+) sibutrami in an amount sufficient to improve Treatment of brain dysfunction consisting of administering a drug or a pharmaceutically acceptable salt thereof. encompasses the law.
本発明はまた、脳機能障害の治療を必要とするヒトに、このような脳機能障害を 改善するのには十分であるが、ラセミ体シブトラミン投与と関連する副作用を起 こすには不十分な量の実質的に（−）立体異性体を含まない（＋）シブトラミン またはその薬剤的に受容できる塩を投与することからなる、脳機能障害の治療法 を包含する。本発明の範囲に含まれる脳機能障害には、老年性痴呆、アルツハイ マー型痴呆、記憶喪失、記憶消失／健忘症、意識障害、昏睡、注意力低下、言語 障害、パーキンソン病、し八ソクス症、自閉、運動亢進症、および精神分裂症が 含まれるが、これに限定されない。脳機能障害は、脳梗塞、脳出血、脳前方硬化 症、脳静脈血栓症、頭部損傷などの脳血管性疾患によって引き起こされうる。The present invention also provides methods for treating brain dysfunction in humans in need of such treatment. Although sufficient to improve symptoms, it may cause side effects associated with racemic sibutramine administration. Insufficient amount of substantially (-) stereoisomer-free (+) sibutramine to strain or a pharmaceutically acceptable salt thereof. includes. Brain dysfunction within the scope of this invention includes senile dementia, Alzheimer's disease, Ma dementia, memory loss, memory loss/amnesia, disturbance of consciousness, coma, decreased attention, language disorders, Parkinson's disease, schizophrenia, autism, hyperkinesia, and schizophrenia. Including, but not limited to. Brain dysfunction includes cerebral infarction, cerebral hemorrhage, and anterior cerebral stiffness. It can be caused by cerebrovascular diseases such as cerebral venous thrombosis, cerebral venous thrombosis, and head injury.
本発明はさらに、脳機能障害を治療するのに十分な量の実質的に（＝）立体異性 体を含まない（＋）シブトラミンまたはその薬剤的に受容できる塩を含む、脳機 能障害の治療用組成物を包含する。The present invention further provides for substantially (=) stereoisomers in an amount sufficient to treat brain dysfunction. Brain organ containing (+) sibutramine or its pharmaceutically acceptable salts and compositions for treating disability.
本発明はさらに、脳機能障害を治療するのには十分であるが、ラセミ体ンブトラ ミンと関連する副作用を起こすには不十分な量の実質的に（−）立体異性体を含 まない（＋）シブトラミンまたはその薬剤的に受容できる塩を含む、脳機能障害 の治療用組成物を包含する。The present invention further provides that racemic Nbutra is sufficient to treat brain dysfunction. contains a substantial amount of the (-) stereoisomer to cause the side effects associated with Brain dysfunction, including (+) sibutramine or its pharmaceutically acceptable salts therapeutic compositions.
ンブトラミンの入手可能なうセミ混合物（すなわち２つの対掌体の混合物）は抗 うつ活性を示し、各種状態や障害の症状の治療および／または軽減を提供する。The available caries mixtures (i.e. mixtures of the two enantiomers) of nbutramine are Exhibits depressant activity and provides treatment and/or relief of symptoms of various conditions and disorders.
しかしながら、このラセミ混合物は有効性が期待てきるにもかかわらず、副作用 を起こす。シブトラミンの光学的に純粋な、または実質的に光学的に純粋な（＋ ）異性体を用いると、有効性を団員関連でより明確に定義でき、副作用を減少し 、したがって治療率が改善される。したがって、ラセミ体シブトラミンを用いる よりもシブトラミンの（＋）異性体を用いるほうが好ましい。However, despite the promise of efficacy, this racemic mixture has side effects. wake up Sibutramine optically pure or substantially optically pure (+ ) Isomers allow efficacy to be more clearly defined in relation to members and reduce side effects. , thus improving the treatment rate. Therefore, using racemic sibutramine It is preferable to use the (+) isomer of sibutramine.
ここで使用する”副作用”の用語は、心拍数の増加、収縮性血圧を含む血圧増加 、精神運動活性の増加、口渇、緊張および神経質を含むが、これに限定されない 。As used herein, the term "side effects" refers to increased heart rate, increased blood pressure, including systolic blood pressure. , including but not limited to increased psychomotor activity, dry mouth, nervousness and nervousness .
ここで使用する”実質的にその（−）立体異性体を含まない”という用語は、組 成物がシブトラミンの（−）異性体に関して、シブトラミンの（＋）立体異性体 の方をより大きな比率で含むことを意味する。本発明の好ましい態様では、ここ で使用する”実質的にその（−）立体異性体を含まない”という用語は、組成物 が少なくとも９０重量％の（＋）シブトラミンと１０重量％またはそれ以下の（ −）シブトラミンを含むことを意味する。最も好ましい態様では、′実質的にそ の（−）立体異性体を含まない”という用語は、組成物が少なくとも９９重量％ の（＋）シブトラミンと１重量％またはそれ以下の（−）シブトラミンを含むこ とを意味する。別の好ましい態様では、ここで使用する”実質的に（−）立体異 性体を含まない”という用語は、組成物が１００重量％のシブトラミンの（＋） 異性体を含むことを意味する。上述したパーセントは組成物中に存在するシブト ラミンの全量に基づく。”実質的に光学的に純粋な（＋）シブトラミン”、”光 学的に純粋な（＋）シブトラミン”および”シブトラミンの（＋）異性体”とい う用語もまた上述した量に包含される。As used herein, the term "substantially free of its (-) stereoisomer" means With respect to the (-) isomer of sibutramine, the (+) stereoisomer of sibutramine This means that it includes a larger proportion of In a preferred embodiment of the invention, here The term "substantially free of its (-) stereoisomer" as used in is at least 90% by weight of (+)sibutramine and 10% by weight or less of (+)sibutramine. -) means containing sibutramine. In the most preferred embodiment, 'substantially the The term "free of the (-) stereoisomer of" means that the composition is at least 99% by weight free of the (-) stereoisomer of containing (+) sibutramine and 1% or less (−) sibutramine by weight. means. In another preferred embodiment, as used herein, "substantially (-)stereoisomer" The term "free of sibutramine" means that the composition contains 100% by weight of sibutramine (+). It means including isomers. The percentages mentioned above are based on the amount of sibbutylene present in the composition. Based on total amount of lamin. “Substantially optically pure (+)sibutramine”, “light ``chemically pure (+) sibutramine'' and ``(+) isomer of sibutramine.'' Also included in the above amounts are terms such as
ここで使用する”うつ病の治療法”という用語は、気分の変化、強い悲しみの感 情、絶望、精神遅延、集中力欠如、悲観的な心配、激高、および自己嫌悪を含む うつ病の症状からの救助を意味するが、これに限定されない。不眠症、食欲不振 、体重減少、エネルギーとリビドの減少、および正常なホルモン循環リズムの回 帰を含む身体的変化も救助される。As used here, the term "depression treatment" refers to mood changes, intense feelings of sadness, Includes feelings of despair, despair, mental retardation, lack of concentration, pessimistic worry, high spirits, and self-loathing. Means, but is not limited to, relief from symptoms of depression. insomnia, loss of appetite , weight loss, decreased energy and libido, and normal hormonal circulatory rhythms. Physical changes, including recovery, are also rescued.
ここで使用する”肥満または体重増加の治療法”という用語は、体重の減少、過 剰体重からの救助、増加体重からの救助、または肥満からの救助を意味し、これ らはすべて通常は食物の大いなる消費によるものである。As used herein, the term "obesity or weight gain treatment" refers to Rescue from excess weight, rescue from increased weight, or rescue from obesity; These are all usually due to large consumption of food.
ここで使用する”ニューロン性モノアミン再取り込みの阻害によって改善される 障害の治療法”という用語は、異常なニューロン性モノアミンレベルと関連する 病状からの救助を意味し、このような病状はニューロン性モノアミン再取り込み 阻害によって軽減される。その取り込みが本発明の組成物および方法によって阻 害されるモノアミンはノルアドレナリン（ノルエピネフリン）、セロトニンおよ びドーパミンを含むが、これに限定されない。ニューロン性モノアミン再取り込 み阻害によって治療できる障害の１つはパーキンソン病である。Here we use the term ``improved by inhibition of neuronal monoamine reuptake.'' The term "treatment for disorders" associated with abnormal neuronal monoamine levels Means rescue from pathologies, and such pathologies are associated with neuronal monoamine reuptake. Reduced by inhibition. The uptake is inhibited by the compositions and methods of the present invention. Monoamines that are harmful include noradrenaline (norepinephrine), serotonin, and including, but not limited to, dopamine. Neuronal monoamine reuptake One of the disorders that can be treated by inhibition is Parkinson's disease.
ここで使用する”パーキンソン病の治療法”という用語は、ヒトにおける意識的 運動能力のゆっくりとした低下、ふるえ、運動緩徐、硬綿、および姿勢障害を含 む（ただしこれに限定されない）パーキンソン病の症状からの救助を意味する。As used herein, the term “Parkinson's disease treatment” refers to the conscious Slow decline in motor skills, including tremors, bradykinesia, stiffness, and postural disturbances. Relief from the symptoms of Parkinson's disease, including but not limited to:
ここで使用する”脳機能障害の治療法”という用語は、老年性痴呆、アルツハイ マー型痴呆、記憶喪失、記憶消失／健忘症、意識障害、昏睡、注意力低下、言語 障害、パーキンソン病、レノツクス症、自閉、運動亢進症、および精神分裂症を 含む（ただしこれに限定されない）知的欠失を含む脳機能障害と関連する病状か らの救助を意味する。脳機能障害の意味には、脳梗塞、脳出血、脳前方硬化症、 脳静脈血栓症、頭部損傷なとを含む（ただしこれに限定されない）脳血管性疾患 によって引き起こされ、症状が意識障害、老年性痴呆、昏睡、注意力低下、言語 障害などを含む障害か含まれる。The term "therapy for brain dysfunction" as used here refers to senile dementia, Alzheimer's disease, etc. Ma dementia, memory loss, memory loss/amnesia, disturbance of consciousness, coma, decreased attention, language disorders, Parkinson's disease, rhenosis, autism, hyperkinesia, and schizophrenia. Medical conditions associated with brain dysfunction, including but not limited to intellectual deficiencies It means the rescue of others. Brain dysfunction includes cerebral infarction, cerebral hemorrhage, anterior cerebral sclerosis, Cerebrovascular disease, including but not limited to cerebral venous thrombosis, head injury, etc. Symptoms include impaired consciousness, senile dementia, coma, decreased attention span, and speech Includes disabilities, including disabilities.
シブトラミンの光学的に純粋な立体異性体は、米国特許第４゜５２２．８２８号 および第４，７４６，６８０号（その開示をここに参照として包含する）記載の 以下の合成法によって製造されるンブトラミンのラセミ混合物を分割することに よって最も容易に得られる。光学的に活性な分割剤とともに形成されるジアステ レオマー塩の分別結晶によるラセミ体の分割が通常用いられる慣用法である。例 えば、９対掌体、ラセミ体および分割”、Ｊ、 Ｊａｃｑｕｅｓ、 Ａ、 Ｃｏ １１ｅｔ、 ａｎｄ Ｓ、Ｈ，Ｗｉｌｅｎ、 （Ｗｉｌｅｙ−１ｎｔｅｎｓｃｉ ｅｎｃｅ、 ＮｅｗＹｏｒｋ、 １９８１）； Ｓ、Ｈ，Ｗｉｌｅｎ、 Ａ、 Ｃｏ１１ｅｔ、 ａｎｄ Ｊ、 Ｊａｃｑｕｅｓ、 Ｔｅｔｒａｈｅｄｒｏｎ、 ３３．２７２５ （１９７７）、 ”炭素化合物の立体化学”、Ｅ、Ｌ、 Ｅ ｌｉｅｌ （ＭｃＧｒａｗ−Ｈｌｌｌ、 ＮＹ、 １９６２）、 ａｎｄ Ｓ、 Ｈ，Ｗｉｌｅｎ、 ｐ、２６８．”分割剤の表および光学分割” （Ｅ、 Ｌ、 Ｅｌｉｅｌ、編集、Ｕｎｉｖ、 ｏｆ Ｎｏｒｔｒｅ Ｄａｍｅ Ｐｒｅｓｓ 、 Ｎｏｔｒｅ Ｄａｍｅ、ＩＮ、 １９７２）。Optically pure stereoisomers of sibutramine are disclosed in U.S. Pat. No. 4,522,828. and No. 4,746,680, the disclosure of which is incorporated herein by reference. To resolve the racemic mixture of nbutramine produced by the following synthetic method: Therefore, it is the easiest to obtain. Diastole formed with optically active resolving agent Resolution of the racemate by fractional crystallization of rheomer salts is a commonly used method. example For example, 9 enantiomers, racemates and resolution”, J. Jacques, A. Co. 11et, and S, H, Wilen, (Wiley-1ntensci ence, New York, 1981); S., H., Wilen, A. Co11et, and J, Jacques, Tetrahedron, 33.2725 (1977), “Stereochemistry of Carbon Compounds”, E, L, E Liel (McGraw-Hllll, NY, 1962), and S. H. Wilen, p. 268. “Table of resolving agents and optical resolution” (E, L, Edited by Eliel, Univ, of Nortre Dame Press , Notre Dame, IN, 1972).
シブトラミンは塩基性アミンであるから、分別結晶に適したジアステレオマー塩 は、光学的に純粋な形のキラルな酸分割剤を加えることによって容易に形成され る。ここで使用する好適な分割剤は、光学的に純粋な酒石酸およびその誘導体、 カンファースルフォン酸、マンデル酸およびその誘導体、ならびにその他の光学 活性な酸を含む。所望の（＋）シブトラミン異性体が、使用した特定の酸分割剤 の溶解性により、そして使用した特定の酸対車体により、結晶化ジアステレオマ ーまたは母液のいずれかから回収される。このようにして回収した特定のシブト ラミン異性体の同定および光学純度は偏光計またはその他の分析方法によって決 定できる。Since sibutramine is a basic amine, it is a diastereomeric salt suitable for fractional crystallization. is easily formed by adding a chiral acid resolving agent in optically pure form. Ru. Preferred resolving agents for use herein include optically pure tartaric acid and its derivatives; Camphorsulfonic acid, mandelic acid and its derivatives, and other optical Contains active acids. The desired (+) sibutramine isomer is determined by the specific acid resolving agent used. Depending on the solubility of the diastereomer and the particular acid used vs. It is recovered either from the mother liquor or from the mother liquor. The specific Shibuto collected in this way Identification and optical purity of lamin isomers are determined by polarimetry or other analytical methods. Can be determined.
急性または慢性疾患の管理における（＋）シブトラミンの予防的または治療的用 量は治療すべき症状の重症度および投与経路によって変化する。投与量およびお そらくは投与頻度も年齢、体重、応答性、および個々の患者の過去の病歴によっ て変化する。一般に、ここで上述した症状についての推奨される投与量範囲は１ 日当たり約１ｍｇから約６０ｍｇの範囲であり、朝に１日１回の単一投与しても よいし、あるいは１日数回にわけてもよい。好ましくは、投与量は１日当たり約 ２ｍｇから約５０ ｍ ｇであり、最も好ましくは１日当たり約５ ｍ ｇから 約４５ｍｇである。患者を管理するうえで、治療は低い投与量、おそらくは約５ ｍ ｇから１５ｍｇで開始し、患者の全体的応答に応して必要ならば１日当た り約４５ｍｇまで増加して単一投与または数回にわけて投与する。６５歳以上の 患者は全体的応答に応じて１日当たり約５ｍｇから約３０ｍｇの投与量とするこ とが推奨される。これらの範囲以外の投与量を用いることも必要となろう。Prophylactic or therapeutic use of (+)sibutramine in the management of acute or chronic diseases The amount will vary depending on the severity of the condition being treated and the route of administration. Dosage and Dosing frequency will likely also depend on age, weight, response, and past medical history of the individual patient. and change. Generally, the recommended dosage range for the conditions mentioned hereinabove is 1 It ranges from about 1 mg to about 60 mg per day, even as a single dose once a day in the morning. This is fine, or you can divide it into several times a day. Preferably, the dosage is about 2 mg to about 50 mg, most preferably about 5 mg to about 5 mg per day. It is about 45 mg. In managing patients, treatment is recommended at lower doses, perhaps around 5 mg to 15 mg per day if necessary depending on the patient's overall response. The dose may be increased to approximately 45 mg in a single dose or in divided doses. over 65 years old Patients should receive a dose of about 5 mg to about 30 mg per day depending on their overall response. is recommended. It may also be necessary to use dosages outside these ranges.
”うつ病を軽減するのに十分な量”、パーキンソン病を軽減するのに十分な量” 、′肥満または体重増加を軽減するのに十分な量”、”体重軽減をするのに十分 な量”、”ヒトにおける体重軽減をもたらすのに十分な量”、”痴呆を軽減する のに十分な量”、”ニューロン性モノアミン再取り込みの阻害によって改善され る障害を軽減するのに十分な量”、障害が老年性痴呆、アルツハイマー型痴呆、 記憶喪失、記憶消失／健忘症、意識障害、昏睡、注意力低下、言語障害、パーキ ンソン病、レノックス症、自閉、運動亢進症、精神分裂症、ならびに脳梗塞、脳 出血、脳前方硬化症、脳静脈血栓症、頭部損傷なとの脳血管性疾患からなる群か ら選択される場合における”脳機能障害を軽減するのに十分な量”という各種用 語には、上述した投与量および投与頻度予定を包含する。“Enough amount to reduce depression,” Enough amount to reduce Parkinson’s disease.” , 'an amount sufficient to reduce obesity or weight gain', 'an amount sufficient to reduce weight ``Amount sufficient to cause weight reduction in humans'' ``Amount sufficient to reduce dementia in humans'' ``Ameliorated by inhibition of neuronal monoamine reuptake'' in sufficient amounts to “A sufficient amount to reduce the impairment of senile dementia, Alzheimer’s dementia, Memory loss, memory loss/amnesia, disturbance of consciousness, coma, decreased attention span, language disorder, parki Nson's disease, Lennox disease, autism, hyperkinesia, schizophrenia, as well as cerebral infarction, brain A group consisting of cerebrovascular diseases such as hemorrhage, anterior cerebral sclerosis, cerebral venous thrombosis, and head injury. For various purposes, ``in an amount sufficient to reduce brain dysfunction'' in selected cases. The term encompasses the dosage and dosing frequency schedules described above.
”うつ病を軽減するのには十分であるが、ラセミ体シブトラミンの副作用を起こ すには不十分な量”、パーキンソン病を軽減するのには十分であるが、ラセミ体 シブトラミンの副作用を起こすには不十分な量”、”肥満または体重増加を軽減 するのには十分であるが、ラセミ体シブトラミンの副作用を起こすには不十分な Ｉ”、”体重軽減をするのには十分であるが、ラセミ体シブトラミンの副作用を 起こすには不十分な員”、”ヒトにおける体重軽減をもたらすのには十分である が、ラセミ体シブトラミンの副作用を起こすには不十分なｌ”、”痴呆を軽減す るのには十分であるが、ラセミ体シブトラミンの副作用を起こすには不十分な量 ”、”ニューロン性モノアミン再取り込みの阻害によって改善される障害を軽減 するのには十分であるが、ラセミ体シブトラミンの副作用を起こすには不十分な 量”、障害が老年性痴呆、アルツノ１イマー型痴呆、記憶喪失、記憶消失／健忘 症、意識障害、昏睡、注意力低下、言語障害、パーキンソン病、レノツクス症、 自閉、運動亢進症、精神分裂症、ならびに脳梗塞、脳出血、脳前方硬化症、脳静 脈血栓症、頭部損傷などの脳血管性疾患からなる群から選択される場合における ”脳機能障害を軽減するのには十分であるが、ラセミ体シブトラミンの副作用を 起こすには不十分な量”という各種用語には、上述した投与量および投与頻度予 定を包含する。``Although sufficient to alleviate depression, it may cause the side effects of racemic sibutramine.'' “Insufficient amounts to reduce Parkinson’s disease,” but not sufficient to reduce racemic Insufficient doses to cause side effects of sibutramine”, “reduce obesity or weight gain” but not enough to cause the side effects of racemic sibutramine. I”, “It is sufficient to reduce weight, but it does not have the side effects of racemic sibutramine.” ``Not enough to cause weight loss in humans'', ``sufficient to cause weight reduction in humans'' However, the effects of racemic sibutramine on reducing dementia are insufficient to cause side effects. an amount sufficient to cause the side effects of racemic sibutramine, but insufficient to cause the side effects of racemic sibutramine. ”,”Reducing disorders ameliorated by inhibition of neuronal monoamine reuptake but not enough to cause the side effects of racemic sibutramine. amount”, the disorder is senile dementia, Alzheimer type 1 dementia, memory loss, memory loss/amnesia disease, consciousness disorder, coma, decreased attention span, speech disorder, Parkinson's disease, rhenosis, Autism, hyperkinesia, schizophrenia, cerebral infarction, cerebral hemorrhage, anterior cerebral sclerosis, cerebral ischemia In cases selected from the group consisting of cerebrovascular diseases such as pulse thrombosis, head injury, etc. ``Although sufficient to reduce brain dysfunction, the side effects of racemic sibutramine The various terms "insufficient amount to cause a including the definition.
適当な投与経路であればいずれも有効量の（＋）シブトラミンを患者に投与する のに使用できる。例えば、経口、経直腸、非経口（静脈内、筋肉内）、経皮、皮 下などを使用できる。製剤形には錠剤、トローチ、分散剤、懸濁剤、溶液剤、カ プセル剤、バッチなどを含む。Administer an effective amount of (+)sibutramine to the patient by any appropriate route of administration. Can be used for. For example, oral, rectal, parenteral (intravenous, intramuscular), transdermal, You can use the bottom etc. Pharmaceutical forms include tablets, troches, dispersions, suspensions, solutions, and capsules. Including capsules, batches, etc.
本発明の医薬組成物は、活性成分として（＋）シブトラミンまたはその薬剤的に 受容できる塩からなり、また薬剤的に受容できる担体および当業者に公知のその 他の治療成分を含んでいてもよい。”薬剤的に受容できる塩”という用語は、無 機酸および有機酸を含む薬剤的に受容できる非毒性酸から調製される塩を意味す る。The pharmaceutical composition of the present invention comprises (+) sibutramine or its pharmaceutical composition as an active ingredient. an acceptable salt and a pharmaceutically acceptable carrier and its like known to those skilled in the art. Other therapeutic ingredients may also be included. The term "pharmaceutically acceptable salts" refers to means salts prepared from pharmaceutically acceptable non-toxic acids, including organic acids and organic acids. Ru.
本発明の化合物は塩基性であるので、無機および有機酸を含む薬剤的に受容でき る非毒性酸から塩を調製できる。このような酸は酢酸、ベンゼンスルホン酸、安 息香酸、カンフ７−スルホン酸、クエン酸、エテンスルホン酸、フマル酸、グル コン酸、グルタミン酸、臭化水素酸、塩酸、イセチオニン酸、乳酸、マレイン酸 、リンゴ酸、マンデル酸、メタンスルホン酸、粘液酸、硝酸、バモア酸、バント ティン酸、リン酸、コハク酸、硫酸、酒石酸、ｐ−トルエンスルホン酸などを含 む。特に好ましいのは塩酸、臭化水素酸、リン酸および硫酸であり、最も好まし いのは塩酸塩である。Since the compounds of the invention are basic, they are pharmaceutically acceptable, including inorganic and organic acids. Salts can be prepared from non-toxic acids. Such acids include acetic acid, benzenesulfonic acid, and Zozoic acid, camphor-7-sulfonic acid, citric acid, ethenesulfonic acid, fumaric acid, glycol Conic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid , malic acid, mandelic acid, methanesulfonic acid, mucilage acid, nitric acid, bamoic acid, bundt Contains tinic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. nothing. Particularly preferred are hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, most preferred Ino is hydrochloride.
組成物は経口、経直腸、非経口（皮下、筋肉内、静脈内を含む）投与に適した組 成物を含むが、特定の場合において最も適した経路は治療すべき症状と重症度に よる。本発明の最も好ましい投与経路は経口である。組成物は単位投与形態で調 製するので便利であり、医薬の分野で公知の方法により調製される。The compositions are suitable for oral, rectal, and parenteral (including subcutaneous, intramuscular, and intravenous) administration. The most appropriate route in a particular case will depend on the condition and severity being treated. evening. The most preferred route of administration of the invention is oral. The composition is prepared in unit dosage form. It is convenient to manufacture and is prepared by methods known in the pharmaceutical art.
経口組成物を用いる場合には、適当な投与範囲は例えば１日当たり約１ｍｇから 約６０ｍｇであり、一般に１日１回朝に単一投与される。好ましい投与範囲は１ 日当たり約２ｍｇから約５０ｍｇを一般に１日１回投与し、最も好ましくは１日 当たり約５ｍｇから約４５ｍｇである。上述したとおり、症状を十分に管理する には、患者に少ない量からこの投与範囲へと徐々に投与すべきである。When using oral compositions, suitable dosage ranges include, for example, from about 1 mg per day. It is approximately 60 mg, generally given in a single dose once a day in the morning. The preferred dosage range is 1 from about 2 mg to about 50 mg per day generally administered once daily, most preferably once daily. from about 5 mg to about 45 mg per serving. Adequately manage symptoms as described above patients should be given small doses gradually into this dosage range.
特定の使用においては、慣用の医薬製剤法にしたがい（＋）シブトラミンを活性 成分として薬剤担体とよく混合することができる。例えば、経口または非経口（ 例えば静脈内）投与に望ましい製剤形により、担体は各種の形でありうる。経口 投与形の組成物を調製するには、有用な医薬溶媒であれば何でも担体として使用 でき、例えば水、グリコール、オイル、アルコール、着香剤、保存料、着色剤な どを経口液体製剤（例えば懸濁剤、溶液剤およびエリキシル剤）またはエアロゾ ル剤に用いる；あるいは澱粉、糖分、微結晶セルロール、希釈剤、顆粒化剤、滑 沢剤、結合剤、崩壊剤などを例えば粉剤、カプセル剤、および錠剤などの経口固 体製剤の場合に用い、固体経口製剤が液体製剤よりも好ましい。最も好ましい固 体経口製剤は錠剤である。For certain uses, (+) sibutramine may be activated according to conventional pharmaceutical formulation methods. As a component, it can be mixed well with the drug carrier. For example, oral or parenteral ( The carrier can take a variety of forms depending on the form of preparation desired for administration (eg, intravenously). oral Any useful pharmaceutical solvent can be used as a carrier in preparing the composition in dosage form. For example, water, glycols, oils, alcohol, flavoring agents, preservatives, coloring agents, etc. oral liquid preparations (e.g. suspensions, solutions and elixirs) or aerosols. or starch, sugar, microcrystalline cellulose, diluents, granulating agents, and lubricants. Thickeners, binders, disintegrants, etc. are added to oral solids such as powders, capsules, and tablets. Solid oral formulations are preferred over liquid formulations. most preferred hard The oral formulation is a tablet.
投与の容易さから、錠剤およびカプセル剤が最も便利な経口投与単位剤形であり 、ここでは固体薬剤担体を用いる。場合により錠剤を標準の水性または非水性法 によってコーティングしてもよい。Because of their ease of administration, tablets and capsules are the most convenient oral dosage unit forms. , here a solid drug carrier is used. Tablets may be prepared using standard aqueous or non-aqueous methods. It may be coated with.
上述した慣用の投与剤形に加えて、本発明の化合物は米国特許第３，８４５．７ ７９；３，９１６，８９９，３，５３６，８０９．３，５９８，１２３．３，６ ３０，２００．４，００８，７１９；４，６８７，６６０および４，７６９，０ ２７号（その開示はここに参照として包含される）に記載された制御放出手段お よび／または送達装置によって投与することもできる。In addition to the conventional dosage forms described above, the compounds of the present invention are disclosed in U.S. Patent No. 3,845.7. 79; 3,916,899,3,536,809.3,598,123.3,6 30,200.4,008,719; 4,687,660 and 4,769,0 No. 27, the disclosure of which is incorporated herein by reference. Administration may also be by means of a device and/or a delivery device.
経口投与に適した本発明の医薬組成物は、それぞれあらかじめ定められた量の活 性成分を含有するカプセル剤、カシェ剤、または錠剤、またはエアロゾルスプレ ーなどのような個々の単位として提供してもよいし、粉剤または顆粒剤として、 または水性液体、非水性液体、水中油滴型エマルジョン、または油中水滴型エマ ルジョンの中の溶液または懸濁液として提供してもよい。このような組成物は製 剤学の任意の方法によって調製してよいが、あらゆる方法は活性成分を、１また はそれ以上の必要成分を構成する担体と結合するという工程を包含する。一般に 、組成物は活性成分と液体担体または細かく粉砕した固体担体またはその両方を 均一にかつよく混合し、次に、必要であればこうして得た混合物を所望の提示形 態に成型する。Pharmaceutical compositions of the present invention suitable for oral administration each contain a predetermined amount of the active ingredient. Capsules, cachets, or tablets or aerosol sprays containing sexual ingredients It may be provided as individual units such as - or as a powder or granules. or aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. It may also be provided as a solution or suspension in a liquid solution. Such compositions are It may be prepared by any method of pharmacy, all methods including the active ingredient(s) in one or more includes the step of combining with a carrier which constitutes further necessary ingredients. in general , the composition comprises the active ingredient and a liquid carrier or a finely divided solid carrier or both. Mix uniformly and well and then, if necessary, shape the mixture thus obtained into the desired presentation form. mold into a shape.
例えば、錠剤は所望する場合には１種またはそれ以上の補助成分と一緒に圧縮ま たは成形によって調製される。圧縮錠剤は、適切な機械で、随意選択により結合 剤、滑沢剤、不活性希釈剤、および／または界面活性剤または分散剤と混合した 粉末または顆粒などの自由流動形の活性成分を圧縮して調製する。成形錠剤は、 不活性液体希釈剤で湿らせた粉末化合物の混合物を適切な機械で成形して調製す る。For example, tablets may be compressed with one or more accessory ingredients if desired. or by molding. Compressed tablets may optionally be combined in a suitable machine. mixed with agents, lubricants, inert diluents, and/or surfactants or dispersants. The active ingredient is prepared by compressing the active ingredient in free-flowing form, such as a powder or granules. Molded tablets are Prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Ru.
望ましくは、各錠剤が約１ｍｇから約６０ｍｇの活性成分を含有し、各カシェ剤 またはカプセル剤が約１ ｍ ｇから約６０ｍｇの活性成分を含有する。最も好 ましくは、錠剤、カシェ剤、またはカプセル剤が以下の３つの投与量：例えば約 １０ｍｇ、約２０ｍｇ、または約３０ｍｇのいずれかの活性成分を含有する（数 えら １れる錠剤として、好ましい投与量列形）。Desirably, each tablet contains from about 1 mg to about 60 mg of active ingredient; Alternatively, the capsules contain from about 1 mg to about 60 mg of active ingredient. most preferred Preferably, the tablets, cachets, or capsules have three dosages: e.g. Contains either 10 mg, about 20 mg, or about 30 mg of active ingredient (number (Preferred dosage series)
本発明の組成物の調製を詳細に記載する以下の実施例を参照しながら、本発明を さらに明らかにする。The invention will now be described with reference to the following examples which describe in detail the preparation of compositions of the invention. To reveal more.
当業者には、材料と方法への多くの変更が、本発明の目的および対象から逸脱す ることなくなされ得ることが明らかであろう。Those skilled in the art will recognize that many modifications to materials and methods may depart from the purpose and scope of this invention. It will be obvious that this can be done without
すべての温度はセ氏で表しである。All temperatures are expressed in degrees Celsius.
４、実施例 ４、■、実施例１：モノアミン再取り込み阻害剤としての光学的純粋形およびラ セミ形シブトラミンの相対強度と特異性を決定するための薬理学的研究 ラットラミンの対掌体およびラセミ混合物の相対強度、比較有効度、結合親和性 、および毒性を決定するために薬理学的研究を実施する。モノアミン再収り込み 阻害の相対的特異性を、化合物の脳組織におけるノルエピネフリン（ＮＥ）（ノ ルアドレナリンとして広く知られている）再取り込みの阻害と、ドーパミン（Ｄ Ａ）およびセロトニン（５ＨＴ）再取り込みの阻害から決定する。4. Example 4, ■, Example 1: Optically pure form and label as monoamine reuptake inhibitors Pharmacological studies to determine the relative potency and specificity of semi-form sibutramine Relative strength, comparative potency, and binding affinity of rat lamin enantiomers and racemic mixtures , and conduct pharmacological studies to determine toxicity. Monoamine reconsolidation The relative specificity of inhibition was determined by compound norepinephrine (NE) in brain tissue. dopamine (widely known as adrenaline) and dopamine (D A) and inhibition of serotonin (5HT) reuptake.
文献記載の方法（Ｋｕｌａ ｅｔ ａｌ、、 Ｌｉｆｅ ５ｃｉｅｎｃｅ ３４ （２６）：２５６７−２５７５、１９８４； Ｂａ１ｄｅｓｓａｒｉｎｉ ｅｔ ａｌ、、 Ｌｉｆｅ ５ｃｉｅｎｃｅ ３９：１７６５−１７７７゜１９８６ ）を用いて、ラット線条体（ＤＡ再再収込みの阻害用）および大脳皮質（５ＨＴ およびＮＥ用）から調製したシナプトソーム（ｓｙｎａｐｔｏｓｏｍａｌ）調製 物において、３Ｈ−放射性モノアミンの高親和性取り込みを試験する。組織を新 たに氷上で切り出し、重態を測定する。テフロンコーティングガラスホモジエナ イザー中で手でホモジエナイズした（水冷等張０．３２Ｍ蔗糖ｌ０−３５容量中 で１４ストローク、ニラミド含有、３４μＭ）後、組織を９００ｘｇで１０分遠 心すると、得られる上溝「溶液」はさらに処理せずに使用できるシナブトソーム を含む。各ア・ソセイ管は脳ホモジエネート５０μしい放射性標識３Ｈ−モノア ミン、および試験化合物（例えば、純粋なシブトラミン対車体、ラセミ体、およ び適当な標準品）を、新たに調製した最終容量０゜５ｍＬの生理食塩バッファー 溶液中に含む。組織をアッセイ前に３７℃で１５分ブレインキュベートする。′ Ｈ−アミンを加えて最終濃度０．１ＨＭとして開始するインキュベーションを開 始するまで、管を氷上に保持する。管を’Ｈ−ＤＡ （２６Ｃｉ／ｍｍｏ＋）と ともに１０分、および’Ｈ−５ＨＴ（約２０Ｃｉ／ｍｍ０１）および”Ｈ−ＮＥ （約１０ Ｃｉ／ｍｍｏ １）とともに２０分インキュベートする。放射性ア ミンの特異的活性は入手可能な材料によって変化し絶対的なものでない。水中に 入れて、２０ｍＭトリスバッファー（ｐＨ７，０）を含む水冷生理食塩溶液３ｍ １で希釈することにより反応を止める。これらの溶液をセルースエステルミクロ フィルターで濾過し、次いで同じノく・ソファ−３ｍ１で２回洗浄する。次いで 、トリチウムの５０％効率でポリフロール（Ｐｏｌｙｆ Ｉｕｏｒ）３．５ｍＬ 中の３Ｈ−放射活性をフィルターでカウントする。ブランク（０℃でインキュベ ーションするか、あるいはＤＡ ［ＧＲＢ−１２９０９，１０ＨＭ］。５ＨＴ「 ジメリジン（ｚ ｉｍｅ ｌ ｉｄ １ｎｅ） 、１０ＨＭコ、またはＮＥＣデ シブラミン（ｄｅｓｉｐｒａｍｉｎｅ）１０ＨＭコの特異的かつ公知の取り込み 阻害剤とともにインキュベーションする）は、通常組織なしで行ったアッセイか ら区別できず、全ＣＰＭの平均２−３％である。Methods described in literature (Kula et al., Life 5 science 34 (26):2567-2575, 1984; Baldessarini et al, Life 5science 39:1765-1777゜1986 ) to inhibit rat striatum (for inhibition of DA reconcentration) and cerebral cortex (5HT and synaptosomal preparation prepared from The high-affinity incorporation of 3H-radioactive monoamines is tested in the present invention. new organization Cut it out on ice and measure its critical condition. Teflon coated glass homogenizer Homogenized by hand in a water cooler (in 0-35 volumes of water-cooled isotonic 0.32M sucrose) After 14 strokes (containing niramide, 34 μM), the tissue was centrifuged at 900 x g for 10 min. Mindfully, the resulting supra-sulcus "solution" is synabutosomes that can be used without further processing. including. Each assay tube was incubated with 50 µl of freshly radiolabeled 3H-monosomes of brain homogenate. sibutramine, and the test compound (e.g., pure sibutramine vs. sibutramine, racemic, and and appropriate standards) in freshly prepared saline buffer with a final volume of 0.5 mL. Contained in solution. Tissues are incubated for 15 minutes at 37°C prior to assay. ′ Begin the incubation by adding H-amine to a final concentration of 0.1 HM. Keep tubes on ice until starting. The tube is 'H-DA (26Ci/mmo+) Both for 10 minutes, and 'H-5HT (approximately 20Ci/mm01) and 'H-NE (approximately 10 Ci/mmo1) for 20 minutes. radioactive a The specific activity of min varies depending on the available materials and is not absolute. in the water Add 3 ml of water-cooled saline solution containing 20 mM Tris buffer (pH 7,0). Stop the reaction by diluting with 1. Add these solutions to cellulose ester micro Filter with a filter and then wash twice with the same 3 ml soap. then , Polyfluor (Polyf Iuor) 3.5mL with 50% efficiency of tritium The 3H-radioactivity in the sample is counted using a filter. Blank (incubate at 0℃) or DA [GRB-12909, 10HM]. 5HT" Zimelidine (z ime id 1ne) , 10HM Co., or NEC DE Specific and known uptake of desipramine 10HM (incubation with inhibitor) is usually an assay performed without tissue. It is indistinguishable and averages 2-3% of the total CPM.
フィルター上に保持される３Ｈ−放射活性の量の比較は、ラットラミンの純粋な 対掌体およびラセミ体混合物（ならびに公知０ＤＡ−１５ＨＴ−１またはＮＥ− 再取り込み阻害剤）の、これらの組織におけるこれらモノアミンの再取り込みを 阻害する相対能力を示唆する。この情報は、ラセミ体シブトラミンおよびその対 掌体の相対強度および有効度を測定するのに有用である。A comparison of the amount of 3H-radioactivity retained on the filter shows that rat lamin pure Enantiomers and racemic mixtures (as well as known ODA-15HT-1 or NE- reuptake inhibitors) inhibit the reuptake of these monoamines in these tissues. Suggests relative ability to inhibit. This information includes racemic sibutramine and its Useful for measuring relative strength and effectiveness of palms.
ラットラミンの対掌体およびそのラセミ混合物の急性毒性は、漸次高投与量（ｍ ｇ／ｋｇ）の純粋異性体またはラセミ体をラットに投与する試験で決定される。The acute toxicity of rat lamin enantiomers and their racemic mixtures increases with progressively higher doses (m g/kg) of the pure isomer or the racemate to rats.
経口投与したときに試験動物の５０％に死亡を引き起こす致死量をＬＤ、。とし て記録する。対掌体およびラセミ体のＬＤ、。値の比較は、組成物の相対毒性の 測定を提供する。LD, the lethal dose that causes death in 50% of the test animals when administered orally. year and record it. LD, enantiomers and racemates. Comparison of values shows the relative toxicity of the compositions. Provide measurements.
４．２．実施例２：経口製剤 カプセル剤： 成分 ｌカプセル当たりの量（ｍ ｇ）活性成分 Ａ Ｂ Ｃ （＋）ラットラミン １０．．０ ２０．０ ３０．０ラクトース ７０．０ ６０．０ ９５．０コーンスターチ １９．５ １９．５ ２４．５活性成分で ある（＋）ラットラミン、ラクトースおよびコーンスターチを均一になるまで混 合し、次いでステアリン酸マグネシウムを得られる粉末と混合する。得られる混 合物を適当な２片硬ゼラチンカプセルに封入する。4.2. Example 2: Oral formulation Capsule: Ingredients Amount per capsule (mg) Active ingredients A B C (+) Rat Lamin 10. ．． 0 20.0 30.0 Lactose 70.0 60.0 95.0 Corn starch 19.5 19.5 24.5 Active ingredients Mix the (+) latamine, lactose and cornstarch until homogeneous. and then mixed with the resulting powder to obtain magnesium stearate. The resulting mixture The mixture is encapsulated in suitable two-piece hard gelatin capsules.
４．３．実施例３：経口製剤 錠剤： 成分 １錠剤当たりの量（ｍｇ） 活性成分 Ａ Ｂ Ｃ （＋）シブトラミン １０ ２０ ３０ラクトース ９４ ８４ ７４ スターチＢＰ ３０ ３０ ３０ 前ゼラチン化マイズスターチ １５ １５ １５活性成分を適当な篩でふるい分 けし、ラクトース、スターチ、および前ゼラチン化マイズスターチと混合する。4.3. Example 3: Oral formulation tablet: Ingredients: Amount per tablet (mg) Active ingredient A B C (+) Sibutramine 10 20 30 Lactose 94 84 74 Starch BP 30 30 30 Pre-gelatinized maize starch 15 15 15 Sift the active ingredients through a suitable sieve Mix with poppy, lactose, starch, and pre-gelatinized maize starch.
適当量の水を加えて粉末を顆粒にする。乾燥後、顆粒を選別しステアリン酸マグ ネシウムと混合する。次いで顆粒を圧縮してパンチによって錠剤とする。Add appropriate amount of water to make the powder into granules. After drying, sort the granules and place them in a stearic acid mug. Mix with nesium. The granules are then compressed into tablets by punching.
ラクトースに対する活性成分の比率または圧縮重量に対する比率を変更し、また 適したパンチを使用することにより別の強度の錠剤を調製できる。By changing the ratio of active ingredient to lactose or to compressed weight, and Tablets of different strengths can be prepared by using a suitable punch.
フロントページの続き （８１）指定国 ＥＰ（ＡＴ、ＢＥ、ＣＨ，ＤＥ。Continuation of front page (81) Designated countries EP (AT, BE, CH, DE.
ＤＫ、ＥＳ、ＦＲ，ＧＢ、ＧＲ，ＩＥ、ＩＴ、ＬＵ、ＭＣ，ＮＬ、ＰＴ、ＳＥ） 、ＣＡ（ＢＦ、ＢＪ、ＣＦ、ＣＧ、 ＣＩ、 ＣＭ、 ＧＡ、 ＧＮ、 ＭＬ、 ＭＲ，ＮＥ、 ＳＮ。DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) , CA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN.
ＴＤ、 ＴＧ）、 ＡＵ、 ＢＢ、 ＢＧ、 ＢＲ，ＢＹ、 ＣＡ。TD, TG), AU, BB, BG, BR, BY, CA.
ＣＺ、ＦＩ、ＨＵ、ＪＰ、ＫＲ，ＫＺ、ＬＫ、ＭＧ、ＭＮ、ＭＷ、Ｎｏ、ＮＺ、 ＰＬ、ＲＯ，ＲＵ、ＳＤ、ＳＫ、ＵＡCZ, FI, HU, JP, KR, KZ, LK, MG, MN, MW, No, NZ, PL, RO, RU, SD, SK, UA
Claims (73)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US90303492A | 1992-06-23 | 1992-06-23 | |
| US903,034 | 1992-06-23 | ||
| PCT/US1993/005967 WO1994000047A1 (en) | 1992-06-23 | 1993-06-22 | Methods and compositions for treating depression and other disorders using optically pure (+) sibutramine |
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| JPH07508281A true JPH07508281A (en) | 1995-09-14 |
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| JP6502537A Pending JPH07508281A (en) | 1992-06-23 | 1993-06-22 | Methods and compositions for treating depression and other disorders using optically pure (+)sibutramine |
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| Country | Link |
|---|---|
| EP (1) | EP0708639A4 (en) |
| JP (1) | JPH07508281A (en) |
| AU (1) | AU4542993A (en) |
| CA (1) | CA2139000A1 (en) |
| WO (1) | WO1994000047A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003504303A (en) * | 1998-12-02 | 2003-02-04 | ピーター・スターリング・ミュラー | Treatment of disorders derived from organic disorders |
| JP2012051904A (en) * | 1999-03-19 | 2012-03-15 | Abbott Gmbh & Co Kg | Treatment of osteoarthritis |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20020006964A1 (en) * | 1995-05-16 | 2002-01-17 | Young James W. | Methods of using and compositions comprising (+) sibutramine optionally in combination with other pharmacologically active compounds |
| DE19518988A1 (en) * | 1995-05-29 | 1996-12-05 | Basf Ag | Use of aryl substituted cyclobutylalkylamines to treat obesity |
| GB9619962D0 (en) * | 1996-09-25 | 1996-11-13 | Knoll Ag | Medical treatment |
| US6476078B2 (en) | 1999-08-11 | 2002-11-05 | Sepracor, Inc. | Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction |
| US6331571B1 (en) | 1998-08-24 | 2001-12-18 | Sepracor, Inc. | Methods of treating and preventing attention deficit disorders |
| US6974838B2 (en) | 1998-08-24 | 2005-12-13 | Sepracor Inc. | Methods of treating or preventing pain using sibutramine metabolites |
| US6339106B1 (en) | 1999-08-11 | 2002-01-15 | Sepracor, Inc. | Methods and compositions for the treatment and prevention of sexual dysfunction |
| US6046242A (en) * | 1998-11-27 | 2000-04-04 | Basf Aktiengesellschaft | Use of aryl-substituted cyclobutylalkylamines for treating urinary incontinence |
| US6197828B1 (en) * | 1998-12-01 | 2001-03-06 | Sepracor, Inc. | Derivatives of (+)-venlafaxine and methods of preparing and using the same |
| US6342533B1 (en) * | 1998-12-01 | 2002-01-29 | Sepracor, Inc. | Derivatives of (−)-venlafaxine and methods of preparing and using the same |
| US6696495B2 (en) | 1998-12-02 | 2004-02-24 | Snowden Pharmaceuticals, Llc | Treatment of disorders secondary to organic impairments |
| DE60039132D1 (en) | 1999-04-06 | 2008-07-17 | Sepracor Inc | O-desmethylvenlafaxine succinate |
| RU2238084C2 (en) * | 1999-08-11 | 2004-10-20 | Сепракор Инк. | Compositions comprising inhibitors of dopamine re-uptake and methods for their using |
| US6399826B1 (en) | 1999-08-11 | 2002-06-04 | Sepracor Inc. | Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain |
| US20020115727A1 (en) * | 2000-12-04 | 2002-08-22 | Senanayake Chris H. | Synthesis, methods of using, and compositions of hydroxylated cyclobutylalkylamines |
| EP1864967A1 (en) | 2001-02-12 | 2007-12-12 | Wyeth | Method for preparing O-desmethyl-venlafaxine |
| US6610887B2 (en) | 2001-04-13 | 2003-08-26 | Sepracor Inc. | Methods of preparing didesmethylsibutramine and other sibutramine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE3008993A1 (en) * | 1980-03-08 | 1981-10-01 | Röhm Pharma GmbH, 6100 Darmstadt | PHARMACEUTICAL PREPARATIONS |
| GB2098601B (en) * | 1981-04-02 | 1985-07-24 | Sandoz Products Ltd | Improvements in or relating to organic compounds |
| ZA821577B (en) * | 1981-04-06 | 1983-03-30 | Boots Co Plc | Therapeutic agents |
| GB8531071D0 (en) * | 1985-12-17 | 1986-01-29 | Boots Co Plc | Therapeutic compound |
| JP2675573B2 (en) * | 1988-03-31 | 1997-11-12 | 科研製薬株式会社 | Brain function improver |
-
1993
- 1993-06-22 AU AU45429/93A patent/AU4542993A/en not_active Abandoned
- 1993-06-22 CA CA002139000A patent/CA2139000A1/en not_active Abandoned
- 1993-06-22 EP EP93915449A patent/EP0708639A4/en not_active Withdrawn
- 1993-06-22 JP JP6502537A patent/JPH07508281A/en active Pending
- 1993-06-22 WO PCT/US1993/005967 patent/WO1994000047A1/en not_active Ceased
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003504303A (en) * | 1998-12-02 | 2003-02-04 | ピーター・スターリング・ミュラー | Treatment of disorders derived from organic disorders |
| JP2012051904A (en) * | 1999-03-19 | 2012-03-15 | Abbott Gmbh & Co Kg | Treatment of osteoarthritis |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0708639A4 (en) | 1997-08-20 |
| EP0708639A1 (en) | 1996-05-01 |
| AU4542993A (en) | 1994-01-24 |
| WO1994000047A1 (en) | 1994-01-06 |
| CA2139000A1 (en) | 1994-01-06 |
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