JPWO2017090716A1 - Crystals of pyrazole derivatives - Google Patents
Crystals of pyrazole derivatives Download PDFInfo
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- JPWO2017090716A1 JPWO2017090716A1 JP2017552717A JP2017552717A JPWO2017090716A1 JP WO2017090716 A1 JPWO2017090716 A1 JP WO2017090716A1 JP 2017552717 A JP2017552717 A JP 2017552717A JP 2017552717 A JP2017552717 A JP 2017552717A JP WO2017090716 A1 JPWO2017090716 A1 JP WO2017090716A1
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- crystal
- pyrazole
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- crystals
- methyl
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
本発明は、優れたホスホジエステラーゼ10A阻害作用を有し、統合失調症などの治療剤および/または予防剤等として有用な、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのI型結晶、およびII型結晶、それら結晶の製造法、及び当該結晶を含有する医薬組成物を提供する。これにより、優れたPDE10A阻害作用を有し、統合失調症等の治療剤および/または予防剤等として有用であり、かつ、安定性に優れた性質を有するピラゾール誘導体の新規な結晶形、それら結晶の製造法、及び当該結晶を含有する医薬組成物が提供される。 The present invention has 4- (2,5-dimethylpyrimidin-4-yl) -N- (6), which has an excellent phosphodiesterase 10A inhibitory action and is useful as a therapeutic and / or prophylactic agent for schizophrenia and the like. -Fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide crystals of type I and II, A method for producing these crystals and a pharmaceutical composition containing the crystals are provided. Thus, novel crystal forms of pyrazole derivatives having excellent PDE10A inhibitory action, useful as therapeutic and / or preventive agents for schizophrenia and the like, and having excellent stability properties, and the crystals And a pharmaceutical composition containing the crystal.
Description
本発明は、優れたホスホジエステラーゼ10A阻害作用を有し、統合失調症などの治療剤および/または予防剤等として有用なピラゾール誘導体の新規な結晶形(I型結晶、およびII型結晶)、それら結晶の製造法、及び当該結晶を含有する医薬組成物に関する。 The present invention provides novel crystal forms (type I crystals and type II crystals) of pyrazole derivatives having excellent phosphodiesterase 10A inhibitory activity and useful as therapeutic and / or prophylactic agents for schizophrenia, etc. And a pharmaceutical composition containing the crystal.
ホスホジエステラーゼ(PDE、環状ヌクレオチドホスホジエステラーゼ)は、21種の異なる遺伝子でコードされる酵素のスーパーファミリーである。これまで、アミノ酸配列の相同性、生化学的性質、阻害薬による特徴付け等の構造的/機能的特性により11種類が哺乳動物において同定されている。(非特許文献1、2) Phosphodiesterases (PDEs, cyclic nucleotide phosphodiesterases) are a superfamily of enzymes encoded by 21 different genes. To date, 11 types have been identified in mammals due to structural / functional properties such as amino acid sequence homology, biochemical properties, and characterization by inhibitors. (Non-Patent Documents 1 and 2)
細胞シグナルカスケードにおけるPDEの役割は、環状ヌクレオチドである環状アデノシン一リン酸(adenosine 3’,5’−cyclic monophosphate:cAMP)および/または環状グアノシン一リン酸(guanosine 3’,5’−cyclic monophosphate:cGMP)のホスホジエステル結合を加水分解すること、即ち、3’−エステル結合の加水分解を選択的に触媒し、不活性な5’−一リン酸を形成することで、代謝的に不活性化することである。 The role of PDE in the cellular signal cascade is the cyclic nucleotides adenosine 3 ′, 5′-cyclic monophosphate (cAMP) and / or cyclic guanosine monophosphate (guanosineine 3 ′, 5′-cyclic monophosphate: cGMP) by hydrolyzing the phosphodiester bond, ie, selectively catalyzing the hydrolysis of the 3′-ester bond to form an inactive 5′-monophosphate, thereby metabolically inactivating it. It is to be.
11種類のPDEファミリーは基質特異性に基づき、cAMP特異的PDE(PDE4、7、8)、cGMP特異的PDE(PDE5、6、9)、及び二重基質PDE(PDE1、2、3、10、11)の3つに分類される。(非特許文献3、4) Eleven PDE families are based on substrate specificity, cAMP-specific PDEs (PDEs 4, 7, 8), cGMP-specific PDEs (PDEs 5, 6, 9), and dual substrate PDEs (PDEs 1, 2, 3, 10, 11). (Non-Patent Documents 3 and 4)
cAMPおよびcGMPは、Gタンパク質結合受容体(GPCR、G Protein Cuppled Receptor)を介した細胞内情報伝達における重要なセカンドメッセンジャーであるため、PDEは、広範な生理学的機序に関与し、生物の恒常性において重要な役割を果たす。具体的には、炎症促進性メディエータの産生および作用、イオンチャネル機能、筋弛緩、学習および記憶形成、分化、アポトーシス、脂質生成、グリコーゲン分解ならびに糖新生等の種々の生理学的プロセスの制御に関わっている。とりわけ、神経細胞においては、神経細胞の分化及び生存とともに神経伝達の制御に重要な役割を果たしている(非特許文献5)。 Since cAMP and cGMP are important second messengers in intracellular signaling through G protein-coupled receptors (GPCRs), PDEs are involved in a wide range of physiological mechanisms and are responsible for biological homeostasis. Plays an important role in sex. Specifically involved in the control of various physiological processes such as production and action of pro-inflammatory mediators, ion channel function, muscle relaxation, learning and memory formation, differentiation, apoptosis, lipogenesis, glycogenolysis and gluconeogenesis Yes. In particular, nerve cells play an important role in the control of neurotransmission along with the differentiation and survival of neurons (Non-Patent Document 5).
cAMPおよびcGMPによるこれらのプロセスの制御は、プロテインキナーゼA(PKA)及びプロテインキナーゼG(PKG)の活性化を伴い、転写因子、イオンチャネル及び受容体を含めた多様な生理的プロセスを制御している様々な基質がリン酸化される。cAMPおよびcGMPの細胞内濃度は、細胞外からのシグナルに応答して変動し、cAMP及びcGMPの合成に関与する酵素(アデニルシクラーゼ(AC)およびグアニルシクラーゼ(GC))と、それら酵素の加水分解に関与するPDEとのバランスによって調節されている。(非特許文献6) Control of these processes by cAMP and cGMP involves the activation of protein kinase A (PKA) and protein kinase G (PKG), and controls various physiological processes including transcription factors, ion channels and receptors. Various substrates are phosphorylated. The intracellular concentrations of cAMP and cGMP vary in response to signals from outside the cell, and enzymes involved in the synthesis of cAMP and cGMP (adenyl cyclase (AC) and guanyl cyclase (GC)) and hydrolysis of these enzymes It is regulated by the balance with PDE involved in (Non-patent document 6)
PDE10Aは、1999年にヒト、マウス、ラットでその存在が報告された。(非特許文献7、8)PDE10Aは主として、ヒトでは脳、精巣、甲状腺などに発現している。特に、脳内の線条体の中型有棘ニューロン(MSN、medium−sized spiny neuron)で高度に発現しており、視床、海馬、前頭皮質および嗅結節で中度に発現している。(非特許文献9、10)また、PDE10Aはマウス及びラットでも脳、精巣に高発現している。(非特許文献11)これらPDE10Aが発現している脳部位は、精神疾患の病理学的機序において重要な役割を示していることから、PDE10Aが精神障害、神経変性障害等の病理学的機序に関与することが示唆されている。(非特許文献12) The existence of PDE10A was reported in 1999 in humans, mice and rats. (Non-Patent Documents 7 and 8) PDE10A is mainly expressed in the brain, testis, thyroid gland and the like in humans. In particular, it is highly expressed in medium spiny neurons (MSN) in the striatum in the brain and moderately expressed in the thalamus, hippocampus, frontal cortex and olfactory nodule. (Non-Patent Documents 9 and 10) PDE10A is also highly expressed in the brain and testis in mice and rats. (Non-patent document 11) Since these brain parts where PDE10A is expressed show an important role in the pathological mechanism of mental illness, PDE10A is a pathological machine such as psychiatric disorder and neurodegenerative disorder. It has been suggested to be involved in the introduction. (Non-patent document 12)
MSNには、主にD1ドーパミン受容体を発現し、黒質線条体路(直接路)を形成するMSNと、主にD2ドーパミン受容体を発現し、線条体淡蒼球路(間接路)を形成するMSNの2つのMSNがある。直接路は運動遂行や報酬学習の機能に関与しており、間接路は運動の抑制に関わっている。例えば、パーキンソン病において動きが悪くなるのは間接路が過剰に働くことに起因し、ハンチントン病等の障害において動きが過剰になるのは直接路が過剰に働くことに起因するものである。大脳基底核の出力核の活動は、これら2種類の経路からの拮抗的な入力のバランスによって調節されている。PDE10Aは両方の経路のMSNに発現していることから、PDE10Aの阻害により、両方の経路が活性化されると考えられる。(非特許文献13)
既存の抗精神病薬は主としてD2受容体遮断作用薬であり、主に間接路の活性化を介したものである。一方、PDE10Aは、直接路および間接路の両MSNに発現しており、PDE10A阻害薬には、既存薬と同様の抗精神病作用を有することが期待される。直接路は運動遂行に関わることから、間接路の過剰な活性化による錐体外路障害に対し括抗して働くと考えられ、更に、本経路は線条体−視床回路からの出力を増強し、報酬学習や問題解決といった認知機能の促進する作用も期待できる。The MSN, mainly express D 1 dopamine receptors, expressed and MSN forming nigrostriatal path (direct path), the main D 2 dopamine receptor, striatopallidal path ( There are two MSNs of the MSN forming the indirect path. The direct path is involved in the performance of exercise and reward learning, and the indirect path is related to the suppression of movement. For example, in Parkinson's disease, the movement becomes worse due to the indirect road working excessively, and in the disorder such as Huntington's disease, the movement becomes excessive due to the direct road working excessively. The activity of the output nucleus of the basal ganglia is regulated by a balance of antagonistic inputs from these two pathways. Since PDE10A is expressed in MSN of both pathways, inhibition of PDE10A is thought to activate both pathways. (Non-patent document 13)
Existing antipsychotics are primarily D 2 receptor blocking agent, it is mainly through the activation of the indirect path. On the other hand, PDE10A is expressed in both direct and indirect MSN, and PDE10A inhibitors are expected to have the same antipsychotic effects as existing drugs. Since the direct path is involved in motor performance, it is thought to work against extrapyramidal disturbances due to excessive activation of the indirect path, and this path enhances the output from the striatum-thalamic circuit. Also, it can be expected to promote cognitive functions such as reward learning and problem solving.
D1受容体活性化による細胞内cAMPレベルが上昇することで、前頭前皮質における作業記憶に関与する一連の神経突起が調節されるようであり(非特許文献14)、また、D1受容体活性化により、統合失調症患者の作業記憶欠陥が改善しうることが報告されている。(非特許文献15)したがって、D1受容体が活性化されることで、統合失調症の認知症状の改善が期待できる。It is likely that a series of neurites involved in working memory in the prefrontal cortex are regulated by increasing intracellular cAMP levels due to D 1 receptor activation (Non-Patent Document 14), and D 1 receptor It has been reported that activation can improve working memory deficits in schizophrenic patients. [15] Therefore, by D 1 receptor is activated, it can be expected improvement of cognitive symptoms of schizophrenia.
PDE10A阻害剤の潜在的抗精神病作用は、さらにKostowskiらの研究により裏付けられている(非特許文献16)。米国特許出願公開第2003/0032579号パンフレットには、中程度の選択性を有するPDE10A阻害剤であるパパベリン(ケシ属植物に含まれるイソキノリン系のアルカロイド、papaverine)が、精神病の動物モデルであるラットにおけるアポモルフィン誘因性常同症を低減し、ラットにおけるハロペリドール誘因性カタレプシーを増加させる一方、ラット脳におけるドーパミン濃度を同時に低減して、従来の抗精神病薬の作用を有することが示されている。更に患者への適用からも裏付けられており、パパベリンは精神病処置用のPDE10A阻害剤として確立されている。(特許文献1) The potential antipsychotic effect of PDE10A inhibitors is further supported by the study of Kostowski et al. (Non-patent Document 16). In US 2003/0032579, Papaverine (an isoquinoline alkaloid contained in poppy plants, papaverine), a moderately selective PDE10A inhibitor, is used in rats, which are animal models of psychosis. It has been shown to reduce the apomorphine-induced stereotypes and increase haloperidol-induced catalepsy in rats while simultaneously reducing dopamine levels in the rat brain and having the effects of conventional antipsychotics. Further, it is supported by application to patients, and papaverine has been established as a PDE10A inhibitor for the treatment of psychosis. (Patent Document 1)
PDE10A阻害作用を有する化合物(PDE10A阻害剤)については、以下のような報告がある。例えば、国際公開第2005/082883号パンフレット(特許文献2)および欧州特許出願公開第EP1250923号パンフレット(特許文献3)に、PDE10A阻害剤としてパパベリン、および各種の芳香族複素環化合物(キナゾリンおよびイソキナゾリン化合物等)が開示されている。また、PDE10A阻害剤が、精神障害(例えば、統合失調症、統合失調症様障害、妄想性障害、物質誘発性精神病、妄想性人格障害、***病型人格障害等)、不安障害(例えば、パニック障害、広場恐怖、単一恐怖、対人恐怖、強迫性障害、外傷後ストレス性障害、急性ストレス障害、全般性不安障害等)、運動障害(例えば、ハンチントン病、ドーパミンアゴニスト治療に伴うジスキネジア、パーキンソン病、下肢静止不能症候群等)、薬物依存症(例えば、アルコール、アンフェタミン、コカイン又はアヘン薬中毒等)、認知障害の症状を伴う疾患(例えば、認知症(アルツハイマー病、多発脳梗塞性認知症等)、譫妄、健忘性障害、外傷後ストレス障害、精神遅滞、学習障害、注意欠陥多動性障害(ADHD)及び加齢関連認知機能低下等)、および気分障害(例えば、大うつ病性障害、気分変調性障害、小うつ病性障害、及び双極性障害(双極I型障害、双極II型障害)、気分循環性障害等)、又は気分症状(例えば、大うつ病エピソード、躁病性もしくは混合性エピソード、軽躁病エピソード等)等の疾患又は症状の治療又は予防のために有用であることが開示されている。更に、PDE10A阻害剤が、神経変性疾患(例えば、パーキンソン病及びハンチントン病等)の治療又は予防のために有用であることも開示されている。 About the compound (PDE10A inhibitor) which has PDE10A inhibitory effect, there exist the following reports. For example, International Publication No. 2005/082883 pamphlet (Patent Document 2) and European Patent Application Publication No. EP 1250923 pamphlet (Patent Document 3) include papaverine as a PDE10A inhibitor and various aromatic heterocyclic compounds (quinazoline and isoquinazoline). Compounds, etc.). In addition, PDE10A inhibitors may cause mental disorders (eg, schizophrenia, schizophrenia-like disorders, paranoid disorders, substance-induced psychosis, paranoid personality disorder, schizophrenic personality disorder, etc.), anxiety disorders (eg, panic) Disability, agoraphobia, single fear, interpersonal fear, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, etc.), movement disorder (eg, Huntington's disease, dyskinesia associated with dopamine agonist treatment, Parkinson's disease) , Restless leg syndrome, etc.), drug addiction (eg, alcohol, amphetamine, ***e or opiate addiction), diseases with cognitive impairment symptoms (eg, dementia (Alzheimer's disease, multiple cerebral infarction dementia, etc.)) , Delirium, amnestic disorder, post-traumatic stress disorder, mental retardation, learning disorder, attention deficit hyperactivity disorder (ADHD) and age-related cognitive function Lower), and mood disorders (eg, major depressive disorder, dysthymic disorder, minor depressive disorder, and bipolar disorder (bipolar I disorder, bipolar II disorder), mood circulatory disorder, etc.), Or it is disclosed that it is useful for the treatment or prevention of diseases or symptoms such as mood symptoms (eg major depression episodes, manic or mixed episodes, hypomania episodes, etc.). Furthermore, it is also disclosed that PDE10A inhibitors are useful for the treatment or prevention of neurodegenerative diseases such as Parkinson's disease and Huntington's disease.
Mennitiらの文献には、PDE10A阻害剤が、抗精神病薬としてのポテンシャルを有するとともに、統合失調症における認知機能障害を改善するポテンシャルを有することが報告されている。(非特許文献17) Menniti et al. Reports that a PDE10A inhibitor has potential as an antipsychotic and has the potential to improve cognitive impairment in schizophrenia. (Non-patent document 17)
国際公開第2003/000693号パンフレットには、PDE10A阻害剤としてイミダゾトリアジン化合物が開示されており、PDE10A阻害剤が、神経変性疾患(特にパーキンソン病)の治療又は予防のために有用であることが開示されている。(特許文献4) WO 2003/000693 discloses an imidazotriazine compound as a PDE10A inhibitor, and discloses that the PDE10A inhibitor is useful for the treatment or prevention of neurodegenerative diseases (particularly Parkinson's disease). Has been. (Patent Document 4)
以上より、PDE10A阻害剤は、PDE10Aが関与する精神障害(例えば、(1)妄想型、解体型、緊張型、鑑別不能型、または残遺型の統合失調症、(2)統合失調症様障害、(3)妄想型または抑うつ型の統合失調感情障害、(4)妄想性障害、(5)物質誘導性精神障害、例えば、アルコール、アンフェタミン、***、コカイン、幻覚剤、吸入剤、オピオイド、またはフェンシクリジンによって誘発された精神病、(6)妄想型人格障害、および(7)統合失調型の人格障害等)、および、神経変性障害(例えば、(1)パーキンソン病、(2)ハンチントン病、(3)認知症、たとえばアルツハイマー病、多発脳梗塞性認知症、AIDS関連認知症、および前頭側頭型認知症、(4)脳外傷に関連する神経変性、(5)脳卒中に関連する神経変性、脳梗塞に関連する神経変性、(6)低血糖誘発性神経変性、(7)てんかん発作に関連する神経変性、(8)神経毒中毒に関連する神経変性、および(9)多系統委縮症、(10)線条体中型有棘ニューロンの神経変性等)等に対する治療および/ または予防に有用かつ、副作用を軽減した治療薬としての可能性が期待される。 Based on the above, PDE10A inhibitors can be used for mental disorders involving PDE10A (for example, (1) delusional, dismantled, tension, indistinguishable or residual schizophrenia, (2) schizophrenia-like disorder , (3) delusional or depressive schizophrenic disorder, (4) delusional disorder, (5) substance-induced psychiatric disorders such as alcohol, amphetamine, cannabis, ***e, hallucinogens, inhalants, opioids, or Psychosis induced by phencyclidine, (6) delusional personality disorder, and (7) schizophrenic personality disorder) and neurodegenerative disorders (eg, (1) Parkinson's disease, (2) Huntington's disease, (3) Dementia such as Alzheimer's disease, multiple cerebral infarction dementia, AIDS-related dementia, and frontotemporal dementia, (4) neurodegeneration associated with brain trauma, (5) stroke Recurrent neurodegeneration, neurodegeneration associated with cerebral infarction, (6) hypoglycemia-induced neurodegeneration, (7) neurodegeneration associated with epileptic seizures, (8) neurodegeneration associated with neurotoxin poisoning, and (9) It is expected to be useful as a therapeutic agent that is useful for the treatment and / or prevention of multisystem atrophy, (10) neurodegeneration of striatal medium spiny neurons, etc., and with reduced side effects.
国際公開第2006/0072828号パンフレット(特許文献5)には、PDE10A阻害剤として、1−メチル−4−ヘテロアリールピラゾール構造を部分構造として有する化合物が開示されているが、本発明の結晶の構造とは異なるものである。 WO 2006/0072828 (Patent Document 5) discloses a compound having a 1-methyl-4-heteroarylpyrazole structure as a partial structure as a PDE10A inhibitor. Is different.
国際公開第2011/036127号パンフレット(特許文献6)、国際公開第2011/117264号パンフレット(特許文献7)、国際公開第2012/076430号パンフレット(特許文献8)には、PDE10A阻害剤としてピラゾール−5−カルボン酸アミド構造を有する化合物が開示されているが、特許文献6および特許文献8の化合物はジカルボン酸アミド構造である点、特許文献7の化合物は7−アミノイミダゾ[1,2−a]ピリミジンのカルボン酸アミドで有る点で、何れも本発明の結晶の構造とは異なるものである。 International Publication No. 2011/036127 Pamphlet (Patent Document 6), International Publication No. 2011-117264 Pamphlet (Patent Document 7), International Publication No. 2012/076430 Pamphlet (Patent Document 8) include pyrazole-as a PDE10A inhibitor. Although compounds having a 5-carboxylic acid amide structure are disclosed, the compounds of Patent Documents 6 and 8 have a dicarboxylic acid amide structure, and the compound of Patent Document 7 is 7-aminoimidazo [1,2-a. Each is different from the crystal structure of the present invention in that it is a carboxylic acid amide of pyrimidine.
国際公開第2014/133046号パンフレット(特許文献9)、国際公開第2016/017711号パンフレット(特許文献10)、国際公開第2016/017719号パンフレット(特許文献11)には、PDE10A阻害剤として4−ヘテロアリール−N−(2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1H−ピラゾール−5−カルボン酸アミド誘導体が開示されている。 In the international publication 2014/133046 pamphlet (patent document 9), the international publication 2016/017711 pamphlet (patent document 10), and the international publication 2016/017719 pamphlet (patent document 11), as PDE10A inhibitor, 4- Heteroaryl-N- (2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1H-pyrazole-5-carboxylic acid amide derivatives are disclosed.
優れたPDE10A阻害作用を有しており、統合失調症等の治療剤および/または予防剤等として有用なピラゾール誘導体の1つである、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの、安定性に優れた性質を有する結晶の開発が望まれている。 4- (2,5-dimethylpyrimidin-4-yl)-, which is one of pyrazole derivatives having an excellent PDE10A inhibitory action and useful as a therapeutic and / or prophylactic agent for schizophrenia and the like. N- (6-Fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide has excellent stability It is desired to develop a crystal having such properties.
「多形」は、物質に2つ以上の結晶形(結晶構造)が存在することを意味する。また、特定の物質の異なる結晶形は「多形体」と呼ばれる。「多形」は、一般に、立体配座を変化させるか、もしくは異分子間または分子内相互作用(特に、水素結合)の影響を受けることで、種々の多形体の結晶格子での異なる原子配置に反映されている。一方、物質の全体としての外形は「形態」と呼ばれており、これは、内部構造に関係なく、結晶の外部形状および存在面を表わす。結晶は、種々の条件(例えば、成長速度、撹拌方法(速度、温度)、および不純物の存在等)に依り、種々の形態を示すことがある。 “Polymorph” means that a substance has more than one crystal form (crystal structure). Different crystal forms of a particular substance are also called “polymorphs”. “Polymorphs” generally result in different atomic configurations in the crystal lattice of various polymorphs, either by changing the conformation or being affected by intermolecular or intramolecular interactions (particularly hydrogen bonding). It is reflected. On the other hand, the outer shape of the substance as a whole is called “form”, which represents the outer shape and the existence surface of the crystal, regardless of the inner structure. The crystals may exhibit various forms depending on various conditions (for example, growth rate, stirring method (speed, temperature), presence of impurities, etc.).
物質の種々の「多形」は、異なる結晶格子エネルギーを有し得る為、固体状態で多形は異なる物理的性質(例えば、形、密度、融点、色、安定性、溶解性、溶解速度等)を示すことがある。先の物理的性質は、医薬もしくは医薬組成物等で用いられる特定の多形の、安定性、溶解性、および生物学的利用能(体内吸収作用、薬剤の作用等)、並びに医薬品の保管寿命、製剤特性、および加工特性等に影響を及ぼす場合もある。多形によって、体内吸収速度が異なる点で、本来有している活性と比較して、高いもしくは低い生物活性が誘導される場合もあり得る。製造過程で、未知の多形形態が発生してしまうと、種々の多大な影響が及ぼされる。 Different “polymorphs” of a substance can have different crystal lattice energies, so that in the solid state the polymorphs have different physical properties (eg shape, density, melting point, color, stability, solubility, dissolution rate, etc. ) May be indicated. The previous physical properties are the stability, solubility, and bioavailability (absorption of the body, the action of the drug, etc.) of the specific polymorph used in the medicine or pharmaceutical composition, and the shelf life of the medicine. In some cases, it may affect formulation characteristics, processing characteristics, and the like. Polymorphism may induce higher or lower biological activity compared to the intrinsic activity in that the rate of absorption in the body is different. If an unknown polymorphic form occurs during the manufacturing process, it has a variety of significant effects.
医薬品の「多形」のコントロールは、新薬の研究開発において重要である。医薬品となる化合物の形成し得る多形を予測することで、他の多形形態による、製造過程もしくは保管過程での多形転位の可能性を減らせる場合がある。多形転位の可能性を見落とし、医薬品を流通させてしまった後に、製造過程で意図しない多形の結晶化が生じた場合には、数週間〜数ヶ月間の製造中断を要する事もあり得る。この間、研究者等は新たな結晶形態が生じた原因を究明し、再発しない策を講ずるか、または新結晶形態での製剤設計をやり直した上で、申請承認を得るのに臨床試験で製剤の同等性を示す再試験の実施の選択をせざる負えなくなる。従って、単一の多形であるか、又は複数の多形が存在するか否かを明らかにする事は重要である。更に、ある多形が他の多形よりも熱力学的安定性を示す場合、製剤作成時に他の多形よりも適する場合がありうるため、熱力学的安定性を確認する事も重要である。 Control of pharmaceutical “polymorphism” is important in the research and development of new drugs. Predicting the polymorphs that can be formed by a pharmaceutical compound may reduce the likelihood of polymorphic rearrangements during the manufacturing or storage process due to other polymorphic forms. After overlooking the possibility of polymorphic rearrangement and distributing pharmaceuticals, if unintended polymorph crystallization occurs in the manufacturing process, it may be possible to interrupt production for weeks to months. . In the meantime, researchers have investigated the cause of the new crystal form and have taken measures to prevent recurrence, or redesigned the drug product in the new crystal form, and obtained the product in clinical trials to obtain application approval. There is no choice but to choose to conduct a retest showing equivalence. Therefore, it is important to clarify whether there is a single polymorph or multiple polymorphs. In addition, if a polymorph exhibits more thermodynamic stability than other polymorphs, it may be more appropriate than other polymorphs when preparing the formulation, so it is important to check thermodynamic stability. .
また、研究者等が、どの様な製造条件や保管条件に医薬品をおく事で、如何なる「多形」が発生し得るのかを明確にすることで、医薬品の化合物に求められる特性(例えば、溶解性、製剤特性、加工特性、および貯蔵寿命等)を最大化することが可能となる。新薬の研究開発の早期段階で、これら「多形」に関する種々の要因を見出すことで、活性が高く、安定性が高く、さらに低製造コストの医薬品が提供する事が可能になる。 In addition, by clarifying what kind of “polymorphs” can be generated by placing pharmaceutical products under what manufacturing conditions and storage conditions, researchers etc. are required to have characteristics required for pharmaceutical compounds (for example, dissolution Properties, formulation characteristics, processing characteristics, shelf life, etc.) can be maximized. By finding various factors related to these “polymorphs” at the early stage of research and development of new drugs, it becomes possible to provide drugs with high activity, high stability, and low production costs.
本発明者は、上記課題を解決する為に鋭意研究した結果、固体の4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドを結晶化することに成功し、各々明瞭に異なる物理的性質を有する2つの結晶形態(本明細書において記載されるこれらの2つの結晶形は、本明細書において以後、I型結晶およびII型結晶と呼ぶ、又、I型結晶をFormI、II型結晶をFormIIと表記する場合もある)が存在し得ることを見出した。また、熱力学的、化学的かつ物理的に安定性が高い結晶形を得ることに成功した。
また、結晶化のプロセスを検討する事で、前記の2種の形態(I型結晶、もしくはII型結晶)の一方の選択的な形成を、結晶化の際のプロセスパラメーターを制御する事で達成する事ができた。
更に、得られた化学純度の高い結晶が優れたPDE10A阻害作用を有し、統合失調症等の治療剤および/または予防剤のための医薬として満足し得るものとして初めて見出した。これらの知見に基づいて、本発明を完成した。As a result of intensive studies to solve the above problems, the present inventors have found that solid 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2, 4] Two crystal forms succeeded in crystallizing triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide, each with distinctly different physical properties (These two crystal forms described in the present specification are hereinafter referred to as a type I crystal and a type II crystal in this specification. Also, a type I crystal may be referred to as Form I, and a type II crystal may be referred to as Form II. It was found that there may be). In addition, we succeeded in obtaining a crystal form with high thermodynamic, chemical and physical stability.
In addition, by studying the crystallization process, selective formation of one of the two forms (I-type crystals or II-type crystals) can be achieved by controlling the process parameters during crystallization. I was able to do it.
Further, the obtained crystals with high chemical purity have an excellent PDE10A inhibitory action, and have been found for the first time as being satisfactory as a medicament for a therapeutic and / or prophylactic agent such as schizophrenia. Based on these findings, the present invention has been completed.
本発明の4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの結晶は、PDE10A阻害作用を有する化合物であり、PDE10Aを阻害することにより、線条体GABA神経のcAMPのホスホジエステル結合の加水分解を阻害し、神経発火を増加させ、線条体の活性化を促進する事により、PDE10Aが関与する各種疾患(例えば、精神障害、神経変性障害等)の改善作用を有している。
本発明の4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの結晶を有効成分として含有する医薬は、好ましくは、経口投与可能であり、PDE10Aが関与する疾患の予防剤および/または治療剤として期待される。4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) of the present invention The crystal of -1-methyl-1H-pyrazole-5-carboxamide is a compound having PDE10A inhibitory activity, and inhibits hydrolysis of cAMP phosphodiester bond of striatal GABA nerve by inhibiting PDE10A, By increasing nerve firing and promoting activation of the striatum, it has an improving effect on various diseases (for example, mental disorders, neurodegenerative disorders, etc.) involving PDE10A.
4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) of the present invention A medicament containing crystals of -1-methyl-1H-pyrazole-5-carboxamide as an active ingredient is preferably administrable orally and is expected as a prophylactic and / or therapeutic agent for diseases involving PDE10A.
本発明の4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの結晶は、優れたPDE10A阻害作用を示し、毒性が低く、かつ安定性に優れるため、医薬品として有用である。 4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) of the present invention Crystals of -1-methyl-1H-pyrazole-5-carboxamide are useful as pharmaceuticals because they exhibit excellent PDE10A inhibitory action, low toxicity, and excellent stability.
本発明は、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのI型結晶、およびII型結晶に関する。また、前記結晶を含む医薬、医薬組成物、並びに該結晶の製造方法にも関する。 The present invention relates to 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl. ) -1-Methyl-1H-pyrazole-5-carboxamide type I crystal and type II crystal. The present invention also relates to a medicament containing the crystal, a pharmaceutical composition, and a method for producing the crystal.
本発明は、以下の態様[1]〜[25]を含む。
ここで、本明細書において、態様[1]〜態様[8−1]のいずれかに記載の結晶を、「本発明の4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの結晶」または「本発明の結晶」という場合がある。態様[1]〜態様[5−1]のいずれかの記載の結晶を、「本発明のI型結晶」という場合がある。態様[6]〜態様[8−1]のいずれかに記載の結晶を「本発明のII型結晶」という場合がある。
[1]本発明の第1の態様は、粉末X線回折による回折角(2θ)として7.8、 8.8、 10.9 、14.7 、15.7 、16.3 、18.7 、20.0 、21.4 、23.6 、24.9、 25.2、 25.7、 および26.5(°)に特徴的ピークを有する、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのII型結晶である。The present invention includes the following embodiments [1] to [25].
Here, in this specification, the crystal according to any one of the embodiments [1] to [8-1] is referred to as “4- (2,5-dimethylpyrimidin-4-yl) -N- ( Crystals of 6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide "or" crystals of the present invention " The crystal according to any one of the embodiments [1] to [5-1] may be referred to as “the type I crystal of the present invention”. The crystal according to any one of Embodiments [6] to [8-1] may be referred to as “type II crystal of the present invention”.
[1] In the first aspect of the present invention, the diffraction angle (2θ) by powder X-ray diffraction is 7.8, 8.8, 10.9, 14.7, 15.7, 16.3, 18.7. 4- (2,5-dimethylpyrimidine-4 having characteristic peaks at 20.0, 21.4, 23.6, 24.9, 25.2, 25.7, and 26.5 (°) II of -yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide It is a type crystal.
[2]本発明の第2の態様は、図3に示す粉末X線回折図により特徴付けられる、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのII型結晶である。 [2] The second embodiment of the present invention is characterized by 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-) characterized by the powder X-ray diffraction pattern shown in FIG. It is a type II crystal of phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide.
[3]本発明の第3の態様は、粉末X線回折において表3に示す回折角(2θ)、および強度を有する、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのII型結晶である。 [3] The third aspect of the present invention is 4- (2,5-dimethylpyrimidin-4-yl) -N- () having a diffraction angle (2θ) and intensity shown in Table 3 in powder X-ray diffraction. It is a type II crystal of 6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide.
[4]本発明の第4の態様は、示差走査熱量測定(DSC測定)外挿融点開始温度が225℃であることを特徴とする、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのII型結晶である。 [4] A fourth aspect of the present invention is 4- (2,5-dimethylpyrimidin-4-yl) characterized in that the differential scanning calorimetry (DSC measurement) extrapolation melting point starting temperature is 225 ° C. In a type II crystal of -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide is there.
[5]本発明の第5の態様は、図5に示すFT−IRスペクトル図、および表4に示すデータ値(cm−1)により特徴付けられる、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのII型結晶である。
[5−1]本発明の第5−1の態様は、柱状結晶の形態の前記態様[1]ないし態様[5]のいずれか1項に記載のII型結晶である。[5] A fifth aspect of the present invention is 4- (2,5-dimethylpyrimidine-4, which is characterized by the FT-IR spectrum diagram shown in FIG. 5 and the data value (cm −1 ) shown in Table 4. II of -yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide It is a type crystal.
[5-1] A mode 5-1 of the present invention is the type II crystal according to any one of the modes [1] to [5] in the form of a columnar crystal.
[6]本発明の第6の態様は、粉末X線回折による回折角(2θ)として4.4 、8.5、9.2、12.3 、15.6、16.0、16.4、18.5、19.4、21.2、23.1、23.7、24.5、27.0、および29.8(°)に特徴的ピークを有する、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのI型結晶である。 [6] In the sixth aspect of the present invention, the diffraction angle (2θ) by powder X-ray diffraction is 4.4, 8.5, 9.2, 12.3, 15.6, 16.0, 16.4. , 18.5, 19.4, 21.2, 23.1, 23.7, 24.5, 27.0, and 29.8 (°) with characteristic peaks, 4- (2,5- Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5 -Type I crystals of carboxamide.
[7]本発明の第7の態様は、図1に示す粉末X線回折図により特徴付けられる、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのI型結晶である。 [7] A seventh aspect of the present invention is characterized by 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-2, characterized by the powder X-ray diffraction pattern shown in FIG. It is a type I crystal of phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide.
[8]本発明の第8の態様は、粉末X線回折において表2に示す回折角(2θ)、および強度を有する、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのI型結晶である。
[8−1]本発明の第8−1の態様は、針状結晶の形態である前記態様[6]ないし態様[8]のいずれか1項に記載のI型結晶である。[8] In an eighth aspect of the present invention, 4- (2,5-dimethylpyrimidin-4-yl) -N- () having a diffraction angle (2θ) and intensity shown in Table 2 in powder X-ray diffraction. It is a type I crystal of 6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide.
[8-1] The 8-1st aspect of the present invention is the type I crystal according to any one of the above aspect [6] to aspect [8], which is in the form of a needle crystal.
[9]本発明の第9の態様は、前記態様[1]ないし態様[5−1]のいずれか1項に記載のII型結晶の製造方法であって、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの固体を溶媒に懸濁させ、続いて濃塩酸を加えて溶解させ、続いてアンモニア水を加え懸濁液とし放冷することで結晶を得る段階を含む方法である。 [9] A ninth aspect of the present invention is the method for producing a type II crystal according to any one of the aspects [1] to [5-1], wherein 4- (2,5-dimethyl) Pyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5 This is a method comprising a step of suspending a solid of carboxamide in a solvent, subsequently adding concentrated hydrochloric acid to dissolve, followed by adding aqueous ammonia and allowing to cool as a suspension to obtain crystals.
本発明の第9の態様の別の態様は、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドを溶媒に懸濁させた後、加温下にて懸濁液に濃塩酸を加え溶解させ溶液とし、続いて溶液にアンモニア水を加え懸濁液とし、更に懸濁液を放冷させ、室温で撹拌する工程を含む、前記態様[1]ないし態様[5−1]のいずれか1項に記載の4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのII型結晶の製造方法である。 Another aspect of the ninth aspect of the present invention is 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1, 5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide is suspended in a solvent, and then concentrated hydrochloric acid is added to the suspension under heating to obtain a solution. Ammonia water is added to the solution to form a suspension, and the suspension is further allowed to cool and stirred at room temperature, and the method according to any one of Embodiments [1] to [5-1]. -(2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl It is a manufacturing method of the II type crystal of -1H-pyrazole-5-carboxamide.
[9−1]前記態様[9]における溶媒は、好ましくは、含水エタノールであり、より好ましくは、10%含水エタノールである。 [9-1] The solvent in the embodiment [9] is preferably water-containing ethanol, more preferably 10% water-containing ethanol.
[10]本発明の第10の態様は、前記態様[6]ないし態様[8−1]のいずれか1項に記載のI型結晶の製造方法であって、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの固体を溶媒に溶解させた後、得られた溶液を急冷することで結晶を得る段階を含む方法である。 [10] A tenth aspect of the present invention is the process for producing a type I crystal according to any one of the above aspects [6] to [8-1], wherein 4- (2,5-dimethyl) Pyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5 This is a method comprising a step of dissolving a carboxamide solid in a solvent and then quenching the resulting solution to obtain crystals.
[10−1]前記態様[10]における溶媒は、好ましくは、アセトンである。 [10-1] The solvent in the above embodiment [10] is preferably acetone.
本発明における4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの結晶形態は水和物ではなく、すなわち無水物である。 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) in the present invention The crystalline form of -1-methyl-1H-pyrazole-5-carboxamide is not a hydrate, ie an anhydride.
本発明における4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドは重水素変換体であってもよい。 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) in the present invention -1-Methyl-1H-pyrazole-5-carboxamide may be a deuterium converter.
本発明の結晶は、複数の結晶形態を含む4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドを結晶転移させることにより製造できる。 The crystals of the present invention comprise 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5] containing multiple crystal forms. -A] Pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide can be produced by crystal transition.
結晶転移は、ある温度または圧力を越えたときに結晶構造が変化する現象である。
「結晶転移法」としては、自体公知の方法が挙げられ、例えば、溶液からの結晶化(例えば、濃縮法、徐冷法、反応法(拡散法、電解法)、水熱育成法、融剤法など)、蒸気からの結晶化(例えば、気化法(封管法、気流法)、気相反応法、化学輸送法)、溶融体からの結晶化(例えば、ノルマルフリージング法(引き上げ法、温度傾斜法、ブリッジマン法)、帯溶融法(ゾーンレベリング法、フロートゾーン法)、特殊成長法(VLS法、液相エピタキシー法))、蒸散法(結晶を溶媒に溶かし、ろ過後大気条件で溶媒を蒸発させる方法)、スラリー法(過剰の固体が残るように溶媒に結晶を添加して懸濁液とし、大気温度または加熱あるいは冷却下で攪拌後、固体を濾集する方法)、減圧乾燥、すり潰し、粉砕、加圧などが挙げられる。
本発明のI型結晶、もしくは本発明のII型結晶を得るには、上記方法中でも、徐冷法、もしくはスラリー法が好ましい。Crystal transition is a phenomenon in which the crystal structure changes when a certain temperature or pressure is exceeded.
Examples of the “crystal transition method” include methods known per se, such as crystallization from a solution (eg, concentration method, slow cooling method, reaction method (diffusion method, electrolytic method), hydrothermal growth method, flux method, etc. ), Crystallization from vapor (for example, vaporization method (sealed tube method, air flow method), gas phase reaction method, chemical transport method), crystallization from melt (for example, normal freezing method (pulling method, temperature gradient method) , Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method, liquid phase epitaxy method)), transpiration method (dissolve crystals in solvent, evaporate the solvent under atmospheric conditions after filtration) Method), slurry method (a method in which crystals are added to a solvent so that an excess solid remains, and a suspension is obtained, and the solid is collected by filtration after stirring at atmospheric temperature or heating or cooling), drying under reduced pressure, grinding, Examples thereof include pulverization and pressurization.
In order to obtain the type I crystal of the present invention or the type II crystal of the present invention, the slow cooling method or the slurry method is preferable among the above methods.
得られた結晶の解析方法としては、X線回折による結晶解析の方法が一般的である。さらに、結晶の方位を決定する方法としては、機械的な方法または光学的な方法(例えば、FT−ラマンスペクトル、固体NMRスペクトル)なども挙げられる。また、結晶の熱分析(示差走査熱量測定、Differential Scanning Calorimetry(DSC))、赤外吸収スペクトル(IR)分析(KBr法、溶液法)なども通常の方法に従って測定することができる。 As a method for analyzing the obtained crystal, a crystal analysis method by X-ray diffraction is generally used. Furthermore, examples of the method for determining the crystal orientation include a mechanical method or an optical method (for example, FT-Raman spectrum, solid-state NMR spectrum). In addition, thermal analysis of crystals (differential scanning calorimetry, differential scanning calorimetry (DSC)), infrared absorption spectrum (IR) analysis (KBr method, solution method) and the like can also be measured according to ordinary methods.
上記解析方法により得られるスペクトルのピークは、その性質上一定の測定誤差が必然的に生じる。スペクトルのピークの数値が当該誤差範囲のものも本発明の結晶に含まれる。例えば、粉末X線回折の回折角(2θ)においては、「±0.2」又は「±0.1」の誤差が、FT−IRスペクトルn赤外吸収(cm−1)においては、「±0.2」又は「±0.1」の誤差が、DSC測定温度(℃)においては「±1」の誤差が、許容されることを意味する。A spectrum peak obtained by the above analysis method inevitably has a certain measurement error due to its nature. Crystals of the present invention also include those having spectral peak values within the error range. For example, at the diffraction angle (2θ) of powder X-ray diffraction, an error of “± 0.2” or “± 0.1” is “±±” in the FT-IR spectrum n infrared absorption (cm −1 ). An error of “0.2” or “± 0.1” means that an error of “± 1” is allowed at the DSC measurement temperature (° C.).
本発明のII型結晶は、温度上昇率10℃/分の条件下における、示差走査熱量測定(DSC測定)外挿融点開始温度が、225℃であることを特徴とする。 The type II crystal of the present invention is characterized in that a differential scanning calorimetry (DSC measurement) extrapolation melting point starting temperature is 225 ° C. under a temperature increase rate of 10 ° C./min.
結晶化は、通常、適当な結晶化溶媒、例えば、水;メタノール、エタノール、2−プロパノール、ブタノール等のアルコール系溶媒;ジエチルエーテル、テトラヒドロフラン、1,2−ジメトキシエタン、1,4−ジオキサン、tert−ブチルメチルエーテル等のエーテル系溶媒;n−ヘキサン、シクロヘキサン、ヘプタン等の炭化水素系溶媒、ベンゼン、トルエン、キシレン等の芳香族炭化水素系溶媒;N,N‐ジメチルホルムアミド、N,N‐ジメチルアセトアミド、1,3‐ジメチル‐2‐イミダゾリジノン、ジメチルスルホキシド等の極性溶媒;クロロホルム、ジクロロメタン、1,2‐ジクロロエタン等のハロゲン化炭化水素系溶媒;アセトニトリル等のニトリル系溶媒;アセトン、ジフェニルケトン等のケトン系溶媒;酢酸メチル、酢酸エチル、酢酸イソプロピル等のエステル系溶媒;酢酸、トリフルオロ酢酸、メタンスルホン酸等の有機酸、等の溶媒が使用される。これらの溶媒は、単独で用いることもできるし、二種類以上の溶媒を適当な割合、例えば、1:1〜1:10の割合で混合して用いてもよい。 Crystallization is usually carried out by using a suitable crystallization solvent such as water; alcohol solvents such as methanol, ethanol, 2-propanol, butanol; diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, tert. Ether solvents such as butyl methyl ether; hydrocarbon solvents such as n-hexane, cyclohexane and heptane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; N, N-dimethylformamide, N, N-dimethyl Polar solvents such as acetamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide; halogenated hydrocarbon solvents such as chloroform, dichloromethane, 1,2-dichloroethane; nitrile solvents such as acetonitrile; acetone, diphenyl ketone Ketone solvents such as acetate Le, ethyl acetate, ester solvents such as isopropyl acetate; acetic acid, trifluoroacetic acid, organic acids such as methanesulfonic acid, solvent and the like are used. These solvents can be used alone, or two or more kinds of solvents may be mixed and used in an appropriate ratio, for example, a ratio of 1: 1 to 1:10.
本発明において、I型結晶を形成させる溶媒としては、アセトン、酢酸イソプロピル、アセトニトリル等の溶媒が挙げられる。好ましくは、アセトンである。 In the present invention, examples of the solvent for forming the I-type crystal include solvents such as acetone, isopropyl acetate, and acetonitrile. Acetone is preferred.
本発明において、II型結晶を形成させる溶媒としては、酢酸エチル、エタノール、2−プロパノール、含水エタノール等の溶媒が挙げられる。好ましくは、10%含水エタノールである。 In the present invention, examples of the solvent for forming the type II crystal include solvents such as ethyl acetate, ethanol, 2-propanol, and hydrous ethanol. Preferably, it is 10% water-containing ethanol.
本発明において、結晶化は、約−30℃から80℃の温度で実施され、I型結晶は好ましくは−20℃の温度で、II型結晶は室温(1℃〜30℃)で実施される。 In the present invention, crystallization is performed at a temperature of about -30 ° C to 80 ° C, type I crystals are preferably performed at a temperature of -20 ° C, and type II crystals are performed at room temperature (1 ° C to 30 ° C). .
本発明において、I型結晶は、ある条件下で結晶化することにより、図2の様な針状の形態(針状結晶)として得られる。 In the present invention, the I-type crystal is obtained as a needle-like form (needle-like crystal) as shown in FIG. 2 by crystallization under certain conditions.
本発明において、II型結晶は、ある条件下で結晶化することにより、図6の様な柱状の形態(柱状結晶)として得られる。 In the present invention, a type II crystal is obtained as a columnar form (columnar crystal) as shown in FIG. 6 by crystallization under certain conditions.
しかし、前記形態はある状況下では別の晶癖を形成し得るとも解され、従って、このような別の晶癖は全て本発明の範囲内に含まれるものと解する。 However, it is understood that the above forms may form other crystal habits under certain circumstances, and therefore all such other crystal habits are understood to be included within the scope of the present invention.
本明細書中、特に断りの無い限り、「針状」とは、針状のプリズムを意味する。この形状は「針糸状」ともいう。 In this specification, unless otherwise specified, “needle” means a needle-like prism. This shape is also called “needle thread”.
本明細書中、特に断りの無い限り、「柱状」とは、一つの方向に平行に成長した細長い角柱状の結晶を意味する。 In the present specification, unless otherwise specified, “columnar” means an elongated prismatic crystal grown in parallel in one direction.
本発明における、I型結晶、もしくはII型結晶の化学純度は、約95%〜100%、好ましくは、約97%〜100%、さらに好ましくは、約99%〜100%である。 In the present invention, the chemical purity of the type I crystal or type II crystal is about 95% to 100%, preferably about 97% to 100%, and more preferably about 99% to 100%.
本発明において、特にII型結晶は、長期保存安定性及び光安定性に良好であり、又吸湿性の問題もないことから、医薬品として有用な結晶である。 In the present invention, the type II crystal is particularly useful as a pharmaceutical because it has good long-term storage stability and light stability, and has no problem of hygroscopicity.
本発明において、特にII型結晶は、化学的及び物理的安定性が非常に高く、PDE10A阻害作用を有する統合失調症等の治療剤および/または予防剤に用いることができる。 In the present invention, the type II crystal is particularly high in chemical and physical stability and can be used as a therapeutic and / or prophylactic agent for schizophrenia having a PDE10A inhibitory action.
本発明において、特にII型結晶は、熱力学的安定性に優れている結晶であるため、取り扱いが容易であり、再現性良く固体の医薬組成物(医薬製剤)を製造することができ、有用な結晶となり得る。 In the present invention, since the type II crystal is particularly a crystal having excellent thermodynamic stability, it is easy to handle and can be used to produce a solid pharmaceutical composition (pharmaceutical preparation) with good reproducibility. Crystal.
前記様に得られた本発明のI型結晶もしくは本発明のII型結晶、とりわけ本発明のII型結晶は、優れたPDE10A阻害作用を有し、また毒性が低いため、医薬品として有用である。 The type I crystal of the present invention or the type II crystal of the present invention, particularly the type II crystal of the present invention obtained as described above is useful as a pharmaceutical because it has an excellent PDE10A inhibitory action and low toxicity.
前記様に得られた本発明のI型結晶もしくは本発明のII型結晶、とりわけ本発明のII型結晶は、医薬製剤の製造において、より好ましい溶解度、より好ましい吸収性等のより好ましい特性プロフィールを有する。 The type I crystal of the present invention or the type II crystal of the present invention, particularly the type II crystal of the present invention obtained as described above, exhibits more preferable characteristic profiles such as more preferable solubility and more preferable absorbability in the production of pharmaceutical preparations. Have.
[11]本発明の第11の態様は、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶を有効成分として含有する医薬組成物である。 [11] An eleventh aspect of the present invention is a pharmaceutical composition containing the crystal according to any one of the aspects [1] to [8-1] as an active ingredient.
[12]本発明の第12の態様は、精神障害、妄想性障害、および薬物誘発性精神病などのある種の精神障害および状態、恐慌性障害および強迫性障害などの不安障害、パーキンソン病およびハンチントン病を包含する運動障害、気分障害、神経変性障害、注意および/または認知の欠如を含む障害、肥満、ならびに薬物嗜癖からなる群から選択される少なくとも1つの疾患又は状態を治療するための医薬であって、前記疾患または状態を治療するのに有効なある量の、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶を有効成分として含有する医薬組成物である。 [12] A twelfth aspect of the invention relates to certain psychiatric disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychosis, anxiety disorders such as panic disorder and obsessive-compulsive disorder, Parkinson's disease and Huntington A medicament for treating at least one disease or condition selected from the group consisting of movement disorders including diseases, mood disorders, neurodegenerative disorders, disorders including attention and / or cognitive deficits, obesity, and drug addiction A pharmaceutical composition comprising, as an active ingredient, the crystal according to any one of the above embodiments [1] to [8-1], which is an amount effective for treating the disease or condition. .
本発明に従って治療することのできる「精神障害および状態」としては、例えば、(1)妄想型、解体型、緊張型、鑑別不能型、または残遺型の統合失調症、(2)統合失調症様障害、(3)妄想型または抑うつ型の統合失調感情障害、(4)妄想性障害、(5)物質誘導性精神障害、たとえばアルコール、アンフェタミン、***、コカイン、幻覚剤、吸入剤、オピオイド、またはフェンシクリジンによって誘発された精神病、(6)妄想型人格障害、および(7)統合失調型の人格障害等が挙げられる。但し、これらに限定されるものではない。 Examples of “mental disorders and conditions” that can be treated according to the present invention include (1) delusional, dismantled, tension, indistinguishable, or residual schizophrenia, and (2) schizophrenia. (3) delusional or depressive schizophrenic disorder, (4) delusional disorder, (5) substance-induced psychiatric disorders, such as alcohol, amphetamine, cannabis, ***e, hallucinogens, inhalants, opioids, Or psychosis induced by phencyclidine, (6) delusional personality disorder, and (7) schizophrenic personality disorder. However, it is not limited to these.
本明細書中、特に断りのない限り、「統合失調症、統合失調症様障害」の症状としては、例えば、(1)陽性症状、陰性症状、およびそれに関連する妄想および/または幻覚症状、(2)解体した会話(頻繁に脱線したり、支離滅裂な会話)、(3)感情の平板化(感情表現の幅と強さの著しい低下)、(4)アロギー(会話の内容と量の低下)、(5)アンヘドニア(快感能力の消失/減退)、(6)不相応な情動、(7)不快気分(例えば、抑うつ、不安、または怒り等)、(8)意欲低下、(9)非社会性(社会的交流から喜びを得る能力の欠如)および(10)認知機能障害の一部等が挙げられる。但し、これらに限定されるものではない。 In the present specification, unless otherwise specified, as symptoms of “schizophrenia, schizophrenia-like disorder”, for example, (1) positive symptoms, negative symptoms, and related delusions and / or hallucination symptoms, ( 2) Dissociated conversations (frequently derailed or disjointed conversations), (3) flattening of emotions (a significant decrease in the width and strength of emotional expression), (4) arogies (decreasing the content and volume of conversations) , (5) Anhedonia (disappearance / reduction of pleasant sensation), (6) disproportionate emotion, (7) discomfort (eg depression, anxiety, or anger), (8) reduced motivation, (9) non-social (Lack of ability to get joy from social exchange) and (10) some of cognitive dysfunction. However, it is not limited to these.
本発明に従って治療することのできる「運動障害」としては、例えば、(1)ハンチントン病、およびDopamineアゴニスト療法に関連する異常運動症、(2)パーキンソン病、(3)不穏下肢症候群(Restless Legs Syndrome:RLS)、および(4)本態性振戦等が挙げられる。但し、これらに限定されるものではない。 “Motor disorders” that can be treated according to the present invention include, for example, (1) Huntington's disease and aberrant motility associated with Dopamine agonist therapy, (2) Parkinson's disease, (3) Restless Leg Syndrome : RLS), and (4) essential tremor. However, it is not limited to these.
本発明に従って治療することのできる「他の障害」としては、例えば、(1)強迫性障害、(2)トゥーレット症候群、および(3)チック障害等が挙げられる。但し、これらに限定されるものではない。 Examples of “other disorders” that can be treated according to the present invention include (1) obsessive-compulsive disorder, (2) Tourette syndrome, and (3) tic disorder. However, it is not limited to these.
本発明に従って治療することのできる「不安障害」としては、例えば、(1)恐慌性障害、(2)広場恐怖症、(3)特定恐怖症、(4)社会恐怖症、(5)強迫性障害、(6)心的外傷後ストレス障害、(7)急性ストレス障害、および(8)全般性不安障害等が挙げられる。但し、これらに限定されるものではない。 Examples of “anxiety disorders” that can be treated according to the present invention include (1) panic disorder, (2) agoraphobia, (3) specific phobia, (4) social phobia, and (5) obsessive-compulsive disorder. Disorders, (6) post-traumatic stress disorder, (7) acute stress disorder, and (8) generalized anxiety disorder. However, it is not limited to these.
本明細書中、特に断りのない限り、「薬物嗜癖」は薬物に対する異常な欲望を意味し、一般に所望の薬物を摂取しようとする衝動強迫のような動機的障害、および強度の薬物切望のエピソードを特徴とする。例えば、アルコール、アンフェタミン、コカイン、またはアヘン嗜癖等が挙げられる。 In this specification, unless otherwise noted, “drug addiction” means an abnormal desire for a drug, generally a motivational disorder such as an impulsive compulsion trying to take a desired drug, and an episode of intense drug craving It is characterized by. Examples include alcohol, amphetamine, ***e, or opium addiction.
本明細書中、特に断りのない限り、「注意および/または認知の欠如を含む障害」における、「注意および/または認知の欠如」は、同じ年齢の他の個体と比較して特定の個体において、記憶、知力、または学習および論理能力などの1種または複数の認知的機能が正常以下であることを意味する。また、「注意および/または認知の欠如」は、例えば、加齢性認知低下で起こるような1種または複数の認知的局面の任意の特定の個体における機能の低下を意味する。 In this specification, unless otherwise noted, “deficit of attention and / or cognition” in “disorders including lack of attention and / or cognition” refers to a particular individual compared to other individuals of the same age. Mean that one or more cognitive functions, such as memory, intelligence, or learning and logic ability, are subnormal. Also, “lack of attention and / or cognition” means a loss of function in any particular individual of one or more cognitive aspects, such as occurs with age-related cognitive decline.
本発明に従って治療することのできる「注意および/または認知の欠如を含む障害」としては、例えば、(1)認知症、例えばアルツハイマー病、多発脳梗塞、アルコール性認知症もしくは他の薬物関連認知症、頭蓋内腫瘍もしくは脳外傷に関連する認知症、ハンチントン病もしくはパーキンソン病に関連する認知症、またはAIDS関連認知症、(2)せん妄、(3)健忘障害、(4)心的外傷後ストレス障害(Posttraumatic stress disorder:PTSD)、(5)精神遅滞、(6)学習障害、例えば読字障害、算数障害、または書字表出障害、(7)注意欠陥・多動性障害(Attention Deficit/Hyperactivity Disorder:ADHA)、および(8)加齢性認知低下等が挙げられる。但し、これらに限定されるものではない。 Examples of "disorders including attention and / or lack of cognition" that can be treated according to the present invention include (1) dementia such as Alzheimer's disease, multiple cerebral infarction, alcoholic dementia or other drug-related dementia , Dementia associated with intracranial tumors or brain trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia, (2) delirium, (3) amnestic disorder, (4) post-traumatic stress disorder (Posttraumatic stress disorder: PTSD), (5) Mental retardation, (6) Learning disorders such as reading disorders, math disorders, or written expression disorders, (7) Attention Defective / Hyperactivity Disorder : ADHA), and (8) low age-related cognition Etc. The. However, it is not limited to these.
本発明に従って治療することのできる「気分障害」および「気分エピソード」としては、例えば、(1)大うつ病エピソード(軽度、中等度、または重度型)、躁病エピソード、混合性エピソード、軽躁病エピソード、(2)非定型うつ病、(3)メランコリー型うつ病、(4)緊張病性うつ病、(5)産後発症気分エピソード、(6)脳卒中後うつ病、(7)大うつ病性障害、(8)気分変調性障害/気分変調症、(9)小うつ病性障害、(10)月経前不快気分障害、(12)統合失調症後うつ病性障害、(13)妄想性障害または統合失調症等の精神障害に併発する大うつ病性障害、(14)双極性障害、たとえば双極I型障害、双極II型障害、および(15)気分循環性障害等が挙げられる。但し、これらに限定されるものではない。 Examples of “mood disorders” and “mood episodes” that can be treated according to the present invention include (1) major depression episodes (mild, moderate, or severe type), manic episodes, mixed episodes, hypomania episodes , (2) atypical depression, (3) melancholic depression, (4) catatonic depression, (5) postpartum mood episodes, (6) poststroke depression, (7) major depressive disorder (8) Mood dysfunction disorder / dysthymia, (9) Minor depressive disorder, (10) Premenstrual dysphoric disorder, (12) Depressive disorder after schizophrenia, (13) Delusional disorder or Major depressive disorders that accompany psychiatric disorders such as schizophrenia, (14) Bipolar disorders such as bipolar I disorder, bipolar II disorder, and (15) mood circulatory disorder. However, it is not limited to these.
本明細書中、特に断りのない限り、「神経変性障害または状態」は、中枢神経系におけるニューロンの機能不全および/またはニューロン死に起因する神経機能障害または状態を意味する。該障害および状態の治療には、該障害または状態での、危機的状態にあるニューロンの機能不全および/またはニューロン死を防ぐか、かつ/または危機的状態にあるニューロンの機能不全またはニューロン死に起因する機能喪失を補う為に、損傷しているもしくは正常に働いているニューロンの機能を高められる薬剤を投与することなどが挙げられる。 As used herein, unless otherwise specified, “neurodegenerative disorder or condition” means a neurological dysfunction or condition resulting from neuronal dysfunction and / or neuronal death in the central nervous system. Treatment of the disorder and condition includes preventing dysfunction and / or death of neurons in a critical state and / or resulting from dysfunction or death of neurons in a critical state In order to compensate for the loss of function, administration of a drug capable of enhancing the function of damaged or normally functioning neurons can be mentioned.
本発明に従って治療することのできる「神経変性障害および状態」としては、例えば、(1)パーキンソン病、(2)ハンチントン病、(3)認知症、たとえばアルツハイマー病、多発脳梗塞性認知症、AIDS関連認知症、および前頭側頭型認知症、(4)脳外傷に関連する神経変性、(5)脳卒中に関連する神経変性、脳梗塞に関連する神経変性、(6)低血糖誘発性神経変性、(7)てんかん発作に関連する神経変性、(8)神経毒中毒に関連する神経変性、および(9)多系統委縮症、(10)線条体中型有棘ニューロンの神経変性等が挙げられる。但し、これらに限定されるものではない。 Examples of “neurodegenerative disorders and conditions” that can be treated according to the present invention include (1) Parkinson's disease, (2) Huntington's disease, (3) dementia such as Alzheimer's disease, multiple cerebral infarction dementia, AIDS Related dementia and frontotemporal dementia, (4) neurodegeneration related to brain trauma, (5) neurodegeneration related to stroke, neurodegeneration related to cerebral infarction, (6) hypoglycemia-induced neurodegeneration , (7) neurodegeneration associated with epileptic seizures, (8) neurodegeneration associated with neurotoxin poisoning, and (9) multisystem atrophy, (10) neurodegeneration of striatal medium spiny neurons, etc. . However, it is not limited to these.
本明細書中、特に断りのない限り、「神経毒中毒」とは、神経毒による中毒を指す。神経毒は、神経死、即ち神経学的損傷を引き起こしうる任意の化学物質または物質である。神経毒の例としてアルコールが挙げられる。アルコールが妊婦によって乱用された場合、新生児は胎児性アルコール症候群であるアルコール中毒および神経学的損傷を生じうる。他の神経毒の例としては、カイニン酸、ドウモイ酸、およびアクロメリン酸、ある種の農薬(例えば、ジクロロジフェニルトリクロロエタン(Dichloro diphenyl trichloroethane:DDT)等)、ある種の殺虫剤(例えば、有機リン酸類等)、揮発性有機溶媒(例えば、トルエン等)、金属(例えば、鉛、水銀、ヒ素、リン、およびアルミニウム等)、兵器として用いられるある種の化学物質(例えば、枯れ葉剤であるエージェントオレンジまたは神経ガス等)、および神経毒性抗腫瘍剤等が挙げられる。但し、これらに限定されるものではない。 In this specification, unless otherwise specified, “neurotoxic poisoning” refers to poisoning caused by a neurotoxin. A neurotoxin is any chemical or substance that can cause neuronal death, ie neurological damage. An example of a neurotoxin is alcohol. If alcohol is abused by pregnant women, the newborn can develop alcoholism and neurological damage, a fetal alcohol syndrome. Examples of other neurotoxins include kainic acid, domoic acid, and achromeric acid, certain pesticides (eg, dichlorodiphenyltrichloroethane (DDT)), certain insecticides (eg, organophosphates) ), Volatile organic solvents (eg, toluene, etc.), metals (eg, lead, mercury, arsenic, phosphorus, and aluminum, etc.), certain chemicals used as weapons (eg, Agent Orange, a defoliating agent, or Nerve gas and the like), and neurotoxic antitumor agents and the like. However, it is not limited to these.
本明細書中、特に断りのない限り、「疾患または状態を治療する」にあるような「治療する」とは、「疾患または状態」の進行、または1つもしくは複数の「疾患または状態」を回復させる、緩和する、または抑制することを意味する。また、本明細書中、「治療する」は、患者の状態に応じて、「疾患または状態」の発症またはその「疾患または状態」に関連する任意の症状の発症を予防することを包含する「疾患または状態」の予防、ならびに発症前に「疾患または状態」またはその任意の症状の重症度を低減することも包含する。本明細書では、「治療する」はある「疾患または状態」の再発を予防するおよび改善することも含むものとする。 In this specification, unless stated otherwise, “treating” as in “treating a disease or condition” refers to the progression of “disease or condition” or one or more “diseases or conditions”. Means to recover, alleviate or suppress. Further, in the present specification, “treating” includes preventing the onset of a “disease or condition” or any symptom associated with the “disease or condition” depending on the patient's condition. Also included is prevention of "disease or condition" as well as reducing the severity of "disease or condition" or any symptom thereof before onset. As used herein, “treating” is intended to include preventing and ameliorating the recurrence of a “disease or condition”.
[13]本発明の第13の態様は、精神障害、妄想性障害、および薬物誘発性精神病などのある種の精神障害および状態、恐慌性障害および強迫性障害などの不安障害、パーキンソン病およびハンチントン病を包含する運動障害、気分障害、神経変性障害、注意および/または認知の欠如を含む障害、肥満、ならびに薬物嗜癖からなる群から選択される少なくとも1つの疾患または状態を治療するための医薬組成物であって、PDE10Aを阻害するのに有効なある量の、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶を有効成分として含有する医薬組成物である。 [13] A thirteenth aspect of the invention relates to certain psychiatric disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychosis, anxiety disorders such as panic disorder and obsessive compulsive disorder, Parkinson's disease and Huntington A pharmaceutical composition for treating at least one disease or condition selected from the group consisting of movement disorders including diseases, mood disorders, neurodegenerative disorders, disorders including attention and / or cognitive deficits, obesity, and drug addiction A pharmaceutical composition comprising, as an active ingredient, a crystal according to any one of the above embodiments [1] to [8-1] in an amount effective to inhibit PDE10A.
[14]本発明の第14の態様は、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶を有効成分として含有する、精神障害、妄想性障害、および薬物誘発性精神病などのある種の精神障害および状態、恐慌性障害および強迫性障害などの不安障害、パーキンソン病およびハンチントン病を包含する運動障害、気分障害、神経変性障害、注意および/または認知の欠如を含む障害、肥満、ならびに薬物嗜癖からなる群から選択される少なくとも1つの疾患または状態の予防剤および/または治療剤である。 [14] A fourteenth aspect of the present invention is a psychiatric disorder, delusional disorder, and drug induction containing the crystal according to any one of the aspects [1] to [8-1] as an active ingredient. Certain mental disorders and conditions such as sexual psychosis, anxiety disorders such as panic disorder and obsessive compulsive disorder, movement disorders including Parkinson's disease and Huntington's disease, mood disorders, neurodegenerative disorders, lack of attention and / or cognition A preventive and / or therapeutic agent for at least one disease or condition selected from the group consisting of disorders including obesity, obesity, and drug addiction.
[14−1]前記態様[14]において、好ましくは、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶を有効成分として含有する、統合失調症の疾患または状態の予防剤および/または治療剤である。 [14-1] In the above aspect [14], preferably a disease or condition of schizophrenia comprising the crystal according to any one of the aspects [1] to [8-1] as an active ingredient. Preventive agent and / or therapeutic agent.
[15]本発明の第15の態様は、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶を有効成分として含有する、精神障害、妄想性障害、および薬物誘発性精神病などのある種の精神障害および状態、恐慌性障害および強迫性障害などの不安障害、パーキンソン病およびハンチントン病を包含する運動障害、気分障害、神経変性障害、注意および/または認知の欠如を含む障害、肥満、ならびに薬物嗜癖からなる群から選択される少なくとも1つの疾患または状態の治療剤である。 [15] A fifteenth aspect of the present invention is a psychiatric disorder, delusional disorder, and drug induction containing the crystal according to any one of the aspects [1] to [8-1] as an active ingredient. Certain mental disorders and conditions such as sexual psychosis, anxiety disorders such as panic disorder and obsessive compulsive disorder, movement disorders including Parkinson's disease and Huntington's disease, mood disorders, neurodegenerative disorders, lack of attention and / or cognition A therapeutic agent for at least one disease or condition selected from the group consisting of disorders including obesity, obesity, and drug addiction.
[15−1]前記態様[15]において、好ましくは、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶を有効成分として含有する、統合失調症の疾患または状態の治療剤である。 [15-1] In the above aspect [15], preferably a disease or condition of schizophrenia comprising the crystal according to any one of the aspects [1] to [8-1] as an active ingredient. It is a therapeutic agent.
[16]本発明の第16の態様は、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶を有効成分として含有することを特徴とする、PDE10A受容体が関与する疾患の予防剤および/または治療剤である。 [16] A sixteenth aspect of the present invention relates to a PDE10A receptor, characterized in that it contains the crystal according to any one of the aspects [1] to [8-1] as an active ingredient. It is a preventive agent and / or a therapeutic agent for the disease.
[17]本発明の第17の態様は、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶を有効成分として含有することを特徴とする、PDE10A受容体が関与する疾患の治療剤である。 [17] A seventeenth aspect of the present invention involves a PDE10A receptor comprising the crystal according to any one of the aspects [1] to [8-1] as an active ingredient. It is a therapeutic agent for diseases.
[18]本発明の第18の態様は、PDE10A阻害剤である、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶を有効成分として含有する医薬組成物である。 [18] An eighteenth aspect of the present invention is a pharmaceutical composition comprising, as an active ingredient, the crystal according to any one of the above aspects [1] to [8-1], which is a PDE10A inhibitor. .
[19]本発明の第19の態様は、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶の医薬組成物としての使用である。 [19] A nineteenth aspect of the present invention is the use of the crystal according to any one of the above aspects [1] to [8-1] as a pharmaceutical composition.
[20]本発明の第20の態様は、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶の医薬組成物の製造における使用である。 [20] A twentieth aspect of the present invention is the use of the crystal according to any one of the aspects [1] to [8-1] in the production of a pharmaceutical composition.
[21]本発明の第21の態様は、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶のPDE10A阻害剤としての使用である。 [21] A twenty-first aspect of the present invention is the use of the crystal according to any one of the aspects [1] to [8-1] as a PDE10A inhibitor.
[22]本発明の第22の態様は、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶のPDE10A阻害剤の製造における使用である。 [22] A twenty-second aspect of the present invention is the use of the crystal according to any one of aspects [1] to [8-1] in the production of a PDE10A inhibitor.
[23]本発明の第23の態様は、精神障害、妄想性障害、および薬物誘発性精神病などのある種の精神障害および状態、恐慌性障害および強迫性障害などの不安障害、パーキンソン病およびハンチントン病を包含する運動障害、気分障害、神経変性障害、注意および/または認知の欠如を含む障害、肥満、ならびに薬物嗜癖からなる群から選択される少なくとも1つの疾患または状態を治療する方法であって、前記疾患または状態を治療するのに有効なある量の、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶を前記疾患または状態の治療を必要とする対象に投与することを含む方法である。 [23] A twenty-third aspect of the present invention relates to certain psychiatric disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychosis, anxiety disorders such as panic disorder and obsessive-compulsive disorder, Parkinson's disease and Huntington A method of treating at least one disease or condition selected from the group consisting of movement disorders including disease, mood disorders, neurodegenerative disorders, disorders including attention and / or cognitive deficits, obesity, and drug addiction An amount of the crystal according to any one of aspects [1] to [8-1] effective for treating the disease or condition is applied to a subject in need of treatment for the disease or condition. Administration.
[24]本発明の第24の態様は、精神障害、妄想性障害、および薬物誘発性精神病などのある種の精神障害および状態、恐慌性障害および強迫性障害などの不安障害、パーキンソン病およびハンチントン病を包含する運動障害、気分障害、神経変性障害、注意および/または認知の欠如を含む障害、肥満、ならびに薬物嗜癖からなる群から選択される少なくとも1つの疾患または状態を治療する方法であって、PDE10Aを阻害するのに有効なある量の、前記態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶を前記疾患または状態の治療を必要とする対象に投与することを含む方法である。 [24] The twenty-fourth aspect of the invention relates to certain psychiatric disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychosis, anxiety disorders such as panic disorder and obsessive-compulsive disorder, Parkinson's disease and Huntington A method of treating at least one disease or condition selected from the group consisting of movement disorders including disease, mood disorders, neurodegenerative disorders, disorders including attention and / or cognitive deficits, obesity, and drug addiction , Administering an amount of a crystal effective in inhibiting PDE10A according to any one of the aspects [1] to [8-1] to a subject in need of treatment of the disease or condition. It is a method including.
[25]本発明の第25の態様は、前記疾患または状態が、(1)妄想型、解体型、緊張型、鑑別不能型、または残遺型の統合失調症、(2)統合失調症様障害、(3)妄想型または抑うつ型の統合失調感情障害、(4)妄想性障害、(5)物質誘導性精神障害、(6)アルコール、アンフェタミン、***、コカイン、幻覚剤、吸入剤、オピオイド、またはフェンシクリジンによって誘発された精神病、(7)妄想型人格障害、(8)統合失調型の人格障害、(9)ハンチントン病、(10)Dopamineアゴニスト療法に関連する異常運動症、(11)パーキンソン病、(12)不穏下肢症候群、(13)本態性振戦、(14)強迫性障害、(15)トゥーレット症候群、(16)チック障害、(17)恐慌性障害、(18)広場恐怖症、(19)特定恐怖症、(20)社会恐怖症、(21)心的外傷後ストレス障害、(22)急性ストレス障害、(23)全般性不安障害、(24)認知症;アルツハイマー病、多発脳梗塞、アルコール性認知症もしくは他の薬物関連認知症、頭蓋内腫瘍もしくは脳外傷に関連する認知症、ハンチントン病もしくはパーキンソン病に関連する認知症、AIDS関連認知症、または前頭側頭型認知症(25)せん妄、(26)健忘障害、(27)精神遅滞、(28)学習障害;読字障害、算数障害、または書字表出障害、(29)注意欠陥・多動性障害、(30)加齢性認知低下、(31)大うつ病エピソード(軽度、中等度、または重度型)、躁病エピソード、混合性エピソード、軽躁病エピソード、(32)非定型うつ病、(33)メランコリー型うつ病、(34)緊張病性うつ病、(35)産後発症気分エピソード、(36)脳卒中後うつ病、(37)大うつ病性障害、(38)気分変調性障害/気分変調症、(39)小うつ病性障害、(40)月経前不快気分障害、(41)統合失調症後うつ病性障害、(42)妄想性障害または統合失調症等の精神障害に併発する大うつ病性障害、(43)双極性障害;双極I型障害、双極II型障害、(44)気分循環性障害、(45)脳外傷に関連する神経変性、(46)脳卒中に関連する神経変性、脳梗塞に関連する神経変性、(47)低血糖誘発性神経変性、(48)てんかん発作に関連する神経変性、(49)神経毒中毒に関連する神経変性、(50)多系統委縮症、ならびに(51)線条体中型有棘ニューロンの神経変性からなる群から選択される少なくとも1つの疾患または状態である、前記態様[12]もしくは態様[13]に記載の医薬組成物、前記態様[14]もしくは態様[15]に記載の治療剤、又は態様[23]もしくは態様[24]に記載の方法である。 [25] In the twenty-fifth aspect of the present invention, the disease or condition is (1) delusional, dismantled, strained, indistinguishable, or residual schizophrenia, (2) schizophrenia-like Disorder, (3) delusional or depressive schizophrenic disorder, (4) delusional disorder, (5) substance-induced mental disorder, (6) alcohol, amphetamine, cannabis, ***e, hallucinogen, inhalant, opioid Or psychosis induced by phencyclidine, (7) delusional personality disorder, (8) schizophrenic personality disorder, (9) Huntington's disease, (10) aberrant motility associated with dopamine agonist therapy, (11 ) Parkinson's disease, (12) Restless leg syndrome, (13) Essential tremor, (14) Obsessive compulsive disorder, (15) Tourette syndrome, (16) Tic disorder, (17) Depressive disorder, (18) Square Fear (19) Specific phobia, (20) Social phobia, (21) Post-traumatic stress disorder, (22) Acute stress disorder, (23) Generalized anxiety disorder, (24) Dementia; Alzheimer's disease, frequent occurrence Cerebral infarction, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumor or brain trauma, dementia associated with Huntington's disease or Parkinson's disease, AIDS-related dementia, or frontotemporal dementia (25) Delirium, (26) Amnesia disorder, (27) Mental retardation, (28) Learning disorder; Reading disorder, arithmetic disorder, or written expression disorder, (29) Attention deficit / hyperactivity disorder, (30) Age-related cognitive decline, (31) major depression episodes (mild, moderate, or severe), manic episodes, mixed episodes, hypomania episodes, (32) atypical depression, (33) melan Lee depression, (34) catatonic depression, (35) postpartum mood episodes, (36) poststroke depression, (37) major depressive disorder, (38) mood modulation disorder / dysthymia , (39) minor depressive disorder, (40) premenstrual dysphoric disorder, (41) post-schizophrenic depressive disorder, (42) major depression associated with mental disorders such as delusional disorder or schizophrenia Pathological disorder, (43) bipolar disorder; bipolar type I disorder, bipolar type II disorder, (44) mood circulatory disorder, (45) neurodegeneration associated with brain trauma, (46) neurodegeneration associated with stroke, Neurodegeneration associated with cerebral infarction, (47) hypoglycemia-induced neurodegeneration, (48) neurodegeneration associated with epileptic seizures, (49) neurodegeneration associated with neurotoxin poisoning, (50) multisystem atrophy, and (51) From neurodegeneration of striatal medium spiny neurons The pharmaceutical composition according to the aspect [12] or the aspect [13], the therapeutic agent according to the aspect [14] or the aspect [15], or the aspect, which is at least one disease or condition selected from the group [23] or the method according to embodiment [24].
本発明の態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶のPDE10A阻害作用は適宜選択した方法、例えば、後述の薬理実験例1(ヒト由来PDE10A阻害作用)で測定する事ができる。 The PDE10A inhibitory action of the crystal according to any one of aspects [1] to [8-1] of the present invention is measured by a method selected as appropriate, for example, Pharmacological Experimental Example 1 (human-derived PDE10A inhibitory action) described later. I can do it.
本発明の態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶は、薬理実験例1(ヒトPDE10A阻害作用)において、優れたPDE10A阻害活性を有する。また、本発明の態様[1]ないし態様[8−1]のいずれかの態様に記載の結晶は、PDE10Aに対して非常に選択的であり、選択的PDE10A阻害剤である。 The crystal according to any one of aspects [1] to [8-1] of the present invention has an excellent PDE10A inhibitory activity in Pharmacological Experimental Example 1 (human PDE10A inhibitory action). In addition, the crystal according to any one of aspects [1] to [8-1] of the present invention is very selective to PDE10A and is a selective PDE10A inhibitor.
本明細書において特に断りが無い限り、「選択的PDE10A阻害剤」とは、PDE1〜9またはPDE11阻害活性と比して、大幅にPDE10A阻害活性を有する化合物を意味する。 Unless otherwise specified in the present specification, the “selective PDE10A inhibitor” means a compound having a PDE10A inhibitory activity significantly compared with the PDE1-9 or PDE11 inhibitory activity.
一実施形態において、「選択的PDE10A阻害剤」とは、好ましくは、他の任意のPDE酵素(例えば、PDE1A、2A、3A、4A、4B、5A、6、7A、7B、8A、9A、および11A)阻害に関して、その化合物が有するIC50値の約1/1000以下であるPDE10A阻害活性を有する化合物である。(言い換えると、該化合物は、他の任意のPDE酵素を阻害する場合に必要とされるIC50値の約1/1000以下でPDE10A活性を同程度阻害する。)In one embodiment, a “selective PDE10A inhibitor” preferably refers to any other PDE enzyme (eg, PDE1A, 2A, 3A, 4A, 4B, 5A, 6, 7A, 7B, 8A, 9A, and 11A) A compound having PDE10A inhibitory activity that is about 1/1000 or less of the IC 50 value of the compound with respect to inhibition. (In other words, the compound inhibits PDE10A activity to the same extent at about 1/1000 or less of the IC 50 value required to inhibit any other PDE enzyme.)
本発明の結晶には、同位元素(例えば、水素の同位体、2Hおよび3Hなど、炭素の同位体、11C、13C、および14Cなど、塩素の同位体、36Clなど、フッ素の同位体、18Fなど、ヨウ素の同位体、123Iおよび125Iなど、窒素の同位体、13Nおよび15Nなど、酸素の同位体、15O、17O、および18Oなど、リンの同位体、32Pなど、ならびに硫黄の同位体、35Sなど)で標識、又は置換された結晶も包含される。Crystals of the present invention include isotopes (eg, hydrogen isotopes, 2 H and 3 H, carbon isotopes, 11 C, 13 C, and 14 C, chlorine isotopes, 36 Cl, etc., fluorine Isotopes, 18 F, iodine isotopes, 123 I and 125 I, nitrogen isotopes, 13 N and 15 N, oxygen isotopes, 15 O, 17 O, and 18 O, phosphorus Crystals labeled or substituted with isotopes, such as 32 P, as well as sulfur isotopes, such as 35 S).
ある種の同位元素(例えば、11C、18F、15O、および13Nなどの陽電子放出同位元素)で標識または置換された本発明の結晶は、例えば、陽電子断層法(Positron Emission Tomography;PET)において使用するトレーサー(PETトレーサー)として用いることができ、医療診断などの分野において有用である。Crystals of the invention labeled or substituted with certain isotopes (eg, positron emitting isotopes such as 11 C, 18 F, 15 O, and 13 N) can be produced, for example, by Positron Emission Tomography (PET). ) Can be used as a tracer (PET tracer) for use in medical diagnosis and the like.
ある種の同位体標識で標識または置換された本発明の結晶は、薬物および/または基質の組織分布研究において有用である。例えば、3Hおよび14Cは、それらの標識または置換が容易であり、かつ検出手段が容易である点から、該研究目的において有用である。The crystals of the present invention labeled or substituted with certain isotopic labels are useful in drug and / or substrate tissue distribution studies. For example, 3 H and 14 C are useful for this research purpose because they are easy to label or displace and easy to detect.
同位体標識された本発明の結晶は、当業者に知られている通常の技法によって、または後述の実施例に記載する合成方法に類似する方法によって得る事ができる。また、非標識化合物の代わりに、得られた同位体標識化合物を薬理実験に用いる事ができる。 Isotopically labeled crystals of the present invention can be obtained by conventional techniques known to those skilled in the art or by methods analogous to the synthetic methods described in the examples below. In addition, the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.
[4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの製造方法]
以下に、本発明において結晶化に使用する4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの製造方法について説明する。4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドは、市販化合物または市販化合物から文献公知の製造方法により容易に得ることが出来る化合物を出発原料もしくは合成中間体として、既知の一般的化学的な製造方法を組み合わせることで容易に製造することが可能であり、下記Scheme1に示す代表的な製造方法に従い製造することができる。また、本発明は以下に説明する製造方法に、何ら限定されるものではない。[4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1 -Method for producing methyl-1H-pyrazole-5-carboxamide]
Hereinafter, 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-] used for crystallization in the present invention is described below. a] A method for producing pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide will be described. 4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Methyl-1H-pyrazole-5-carboxamide is a commercially available compound or a compound that can be easily obtained from a commercially available compound by a known production method in the literature, using a known general chemical production method as a starting material or a synthetic intermediate Therefore, it can be easily manufactured according to a typical manufacturing method shown in Scheme 1 below. Further, the present invention is not limited to the manufacturing method described below.
前記の4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの製造法において、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの製造に用いられる各原料化合物は、塩を形成していてもよく、このような塩としては、製薬学的に許容しうる塩であれば特に限定されないが、例えば、金属塩、アンモニウム塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性、又は酸性アミノ酸との塩などが挙げられる。
金属塩の好適な例としては、例えば、リチウム塩、ナトリウム塩、カリウム塩、セシウム塩などのアルカリ金属塩、カルシウム塩、マグネシウム塩、バリウム塩などのアルカリ土類金属塩、アルミニウム塩などが挙げられる(例えば、モノ塩の他、二ナトリウム塩、二カリウム塩も含む)。
有機塩基との塩の好適な例としては、例えば、メチルアミン、エチルアミン、t−ブチルアミン、t−オクチルアミン、ジエチルアミン、トリメチルアミン、トリエチルアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、ジベンジルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ピペリジン、モルホリン、ピリジン、ピコリン、リシン、アルギニン、オルニチン、エチレンジアミン、N−メチルグルカミン、グルコサミン、フェニルグリシンアルキルエステル、グアニジン、2,6−ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、N,N'−ジベンジルエチレンジアミン等との塩が挙げられる。
無機酸との塩の好適な例としては、例えば、塩酸、臭化水素酸、よう化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の好適な例としては、例えば、ギ酸、酢酸、トリフルオロ酢酸、プロピオン酸、酪酸、吉草酸、エナント酸、カプリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、乳酸、ソルビン酸、マンデル酸等の脂肪族モノカルボン酸等との塩、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、リンゴ酸、酒石酸等の脂肪族ジカルボン酸との塩、クエン酸等の脂肪族トリカルボン酸との塩、安息香酸、サリチル酸等の芳香族モノカルボン酸との塩、フタル酸等の芳香族ジカルボン酸の塩、桂皮酸、グリコール酸、ピルビン酸、オキシル酸、サリチル酸、N−アセチルシステイン等の有機カルボン酸との塩、メタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸等の有機スルホン酸との塩、アスパラギン酸、グルタミン酸等の酸性アミノ酸類との酸付加塩が挙げられる。
塩基性アミノ酸との塩の好適な例としては、例えば、アルギニン、リジン、オルニチンなどとの塩が挙げられ、酸性アミノ酸との塩の好適な例としては、例えば、アスパラギン酸、グルタミン酸などとの塩が挙げられる。
このうち、薬学的に許容し得る塩が好ましい。例えば、化合物内に酸性官能基を有する場合にはアルカリ金属塩(例、ナトリウム塩、カリウム塩など)、アルカリ土類金属塩(例、カルシウム塩、マグネシウム塩、バリウム塩など)などの無機塩、アンモニウム塩など、また、化合物内に塩基性官能基を有する場合には、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸など無機酸との塩、又は酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、p−トルエンスルホン酸などの有機酸との塩が挙げられる。
また、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの製造に用いられる各原料化合物は、反応液のままか粗製物として次の反応に用いることもできるが、常法に従って反応混合物から単離することもでき、それ自体が公知の手段、例えば、抽出、濃縮、中和、濾過、蒸留、再結晶、クロマトグラフィーなどの分離手段により容易に精製することができる。4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl)- In the process for producing 1-methyl-1H-pyrazole-5-carboxamide, 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo is used. Each raw material compound used in the production of [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide may form a salt. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic or acidic amino acid, And the like.
Preferable examples of the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt. (For example, besides a mono salt, a disodium salt and a dipotassium salt are also included).
Preferable examples of the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine. Ethanolamine, piperidine, morpholine, pyridine, picoline, lysine, arginine, ornithine, ethylenediamine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, N , N′-dibenzylethylenediamine and the like.
Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc. Salt with organic carboxylic acid, salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like.
Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned.
Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt), In the case where the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, Examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
Also, 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl)- Each raw material compound used in the production of 1-methyl-1H-pyrazole-5-carboxamide can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method. It can be easily purified by means known per se, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.
前記の4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの製造方法中の反応条件については、特に断らない限り、以下の如きとする。反応温度は、−78℃から溶媒が還流する温度の範囲であり、特に温度が記載されていない場合は、室温(1〜30℃;日本薬局方規定)であり、反応時間は、反応が十分進行する時間である。 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl)- The reaction conditions in the method for producing 1-methyl-1H-pyrazole-5-carboxamide are as follows unless otherwise specified. The reaction temperature ranges from −78 ° C. to the temperature at which the solvent is refluxed. When the temperature is not described, it is room temperature (1-30 ° C .; Japanese Pharmacopoeia), and the reaction time is sufficient for the reaction. It is time to progress.
また、製造方法中の各工程は、無溶媒、あるいは反応前に原料化合物を適当な反応に関与しない溶媒に溶解又は懸濁して行うことができる。反応に関与しない溶媒としては、具体的には、水;シクロヘキサン、ヘキサン等の飽和炭化水素系溶媒;ベンゼン、クロロベンゼン、トルエン、キシレン等の芳香族炭化水素溶媒;メタノール、エタノール、1−プロパノール、2−プロパノール、tert−ブチルアルコール、2−メトキシエタノール等のアルコール系溶媒;N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミド、ヘキサメチルホスホリックトリアミド、1,3‐ジメチル‐2‐イミダゾリジノン等の極性アミド系溶媒:ジメチルスルホキシド等のスルホキシド系溶媒;アセトニトリル、プロピオニトリル等のニトリル系溶媒;ジエチルエーテル、ジイソプロピルエーテル、ジフェニルエーテル、テトラヒドロフラン、1,4−ジオキサン、1,2−ジメトキシエタン等のエーテル系溶媒;酢酸メチル、酢酸エチル、酢酸ブチル等のエステル系溶媒;アセトン、メチルエチルケトン等のケトン系溶媒;ジクロロメタン、クロロホルム、四塩化炭素、1,2−ジクロロエタン等のハロゲン化炭化水素系溶媒;トリエチルアミン、N,N−ジイソプロピルエチルアミン、ピリジン、ルチジン等の塩基性溶媒;無水酢酸等の酸無水物;ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、メタンスルホン酸等の有機酸;塩酸、硫酸等の無機酸;であるが、一種の溶媒を単独で用いてもよく、または反応条件により適宜選択し二種以上の溶媒を適宜の割合で混合して用いてもよい。 Further, each step in the production method can be carried out without solvent or by dissolving or suspending the raw material compound in a solvent not involved in an appropriate reaction before the reaction. Specific examples of the solvent not involved in the reaction include water; saturated hydrocarbon solvents such as cyclohexane and hexane; aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene and xylene; methanol, ethanol, 1-propanol, 2 Alcohol solvents such as propanol, tert-butyl alcohol, 2-methoxyethanol; N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone Polar amide solvents such as: sulfoxide solvents such as dimethyl sulfoxide; nitrile solvents such as acetonitrile and propionitrile; diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxy Ether solvents such as tan; ester solvents such as methyl acetate, ethyl acetate and butyl acetate; ketone solvents such as acetone and methyl ethyl ketone; halogenated hydrocarbon systems such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane Solvent; basic solvent such as triethylamine, N, N-diisopropylethylamine, pyridine, lutidine; acid anhydride such as acetic anhydride; organic acid such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid; hydrochloric acid, sulfuric acid However, one kind of solvent may be used alone, or two or more kinds of solvents may be mixed and used at an appropriate ratio depending on the reaction conditions.
前記4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの製造法中において用いられる塩基(又は脱酸剤)として、具体的には、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸カルシウム、炭酸水素ナトリウム等の無機塩基;トリエチルアミン、N,N−ジイソプロピルエチルアミン、トリブチルアミン、シクロヘキシルジメチルアミン、ピリジン、ルチジン、4−ジメチルアミノピリジン(DMAP)、N,N−ジメチルアニリン、N−メチルピペリジン、N−メチルピロリジン、N−メチルモルホリン、1,5−ジアザビシクロ[4.3.0]−5−ノネン、1,4−ジアザビシクロ[2.2.2]オクタン、1,8−ジアザビシクロ[5.4.0]−7−ウンデセン、イミダゾール等の有機塩基;ソディウムメトキシド、ソディウムエトキシド、カリウムtert−ブトキシド、ソディウムtert−ブトキシド等金属アルコキシルド類;水素化ナトリウム、水素化カリウム等のアルカリ金属水素化物;ナトリウムアミド、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジド等の金属アミド;メチルリチウム、n−ブチルリチウム、sec−ブチルリチウム、tert−ブチルリチウム等の有機リチウム試薬;が挙げられる。また、本発明化合物の製造法において用いられる酸、又は酸触媒として、具体的には、塩酸、硫酸、硝酸、臭化水素酸、リン酸等の無機酸;酢酸、トリフルオロ酢酸、シュウ酸、フタル酸、フマル酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、p−トルエンスルホン酸、10−カンファースルホン酸等の有機酸;三フッ化ホウ素エーテル錯体、ヨウ化亜鉛、無水塩化アルミニウム、無水塩化亜鉛、無水塩化鉄等のルイス酸;が挙げられる。ただし、上記に記載したものに必ずしも限定されるわけではない。 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1 -As a base (or deoxidizer) used in the manufacturing method of methyl-1H-pyrazole-5-carboxamide, specifically, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, Inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate; triethylamine, N, N-diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP), N , N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, -Methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7- Organic bases such as undecene and imidazole; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; alkali metal hydrides such as sodium hydride and potassium hydride; sodium amide and lithium diisopropyl Metal amides such as amide and lithium hexamethyldisilazide; and organic lithium reagents such as methyllithium, n-butyllithium, sec-butyllithium, and tert-butyllithium. Examples of the acid or acid catalyst used in the method for producing the compound of the present invention include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and phosphoric acid; acetic acid, trifluoroacetic acid, oxalic acid, Organic acids such as phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid; boron trifluoride ether complex, zinc iodide, anhydrous chloride Lewis acids such as aluminum, anhydrous zinc chloride, and anhydrous iron chloride. However, it is not necessarily limited to those described above.
[本発明の結晶との併用剤]
本発明の結晶、もしくは該結晶を用いた医薬は、医療現場で行われている一般的な方法で、他の薬物もしくは薬剤と併用することも可能である。本発明の結晶と併用しうる薬物としては、例えば、(A)精神疾患、特に統合失調症、もしくは双極性障害、強迫性障害、大うつ病、パーキンソン病、ハンチントン病、アルツハイマー病、認知機能障害や記憶障害の治療薬、(B)統合失調症と併発し易い疾患の治療薬等が挙げられる。[Combination agent with crystal of the present invention]
The crystal of the present invention or a medicine using the crystal can be used in combination with other drugs or drugs by a general method performed in the medical field. Examples of the drug that can be used in combination with the crystal of the present invention include (A) mental illness, particularly schizophrenia, or bipolar disorder, obsessive compulsive disorder, major depression, Parkinson's disease, Huntington's disease, Alzheimer's disease, cognitive impairment And (B) therapeutic agents for diseases that are likely to accompany schizophrenia, and the like.
前記(A)の薬物としては、例えば、(1)非定型抗精神病薬[具体的には、オランザピン、クエチアピン、クロザピン、ジプラシドン、リスペリドン、パリペリドン、ペロスピロン、ブロナンセリン、ルラシドン、アリピプラゾール、セルチンドール、アミスルプリド、イロペリドン、ビフェプルノックス、アセナピン、メルペロン、ブレクスピプラゾール、ゾテピン等]、(2)定型抗精神病薬[具体的には、クロルプロマジン、プクロルペラジン、ペルフェナジン、レボメプロマジン、フルフェナジン、チオリダジン、プロペリシアジン、スピペロン、モペロン、ハロペリドール、チミペロン、ブロムペリドール、ピモジド、フロロピパミド、スルピリド、チアプリド、スルトプリド、ネモナプリド、オキシペルチン等]、(3)選択的セロトニン再取り込み阻害薬(SSRI)[具体的には、エスシタロプラム、シタロプラム、パロキセチン、セルトラリン、フルボキサミン、フルオキセチン等]、(4)選択的セロトニン・ノルアドレナリン再取り込み阻害薬(SNRI)[具体的には、ミルナシプラン、デュロキセチン、ベンラファキシン、ネファゾドン等]、(5)選択的ノルアドレナリン・ドーパミン再取り込み阻害薬(NDRI)[具体的には、ブブロピン等]、(6)ノルアドレナリン作動性・特異的セロトニン作動性抗うつ薬(NaSSA)[具体的には、ミルタザピン等]、(7)トリアゾロピリジン系抗うつ薬(SARI)[具体的には、トラゾドン等]、(8)四環系抗うつ薬[具体的には、セチプチリン、ミアンセリン、マプロチリン等]、(9)三環系抗うつ薬[具体的には、アミトリプチリン、トリミプラミン、イミプラミン、ノルトリプチリン、クロミプラミン、ロフェプラミン、アモキサピン、ドスレピン等]、(10)その他抗うつ薬[具体的には、NS−2359、Lu AA21004、DOV21947等]、(11)α7ニコチン受容体作動薬、(12)α7ニコチン受容体活性調節薬、(13)α7ニコチン受容体部分調節薬[具体的には、SSR−180711、PNU−120596等]、(14)その他のPDE阻害薬[PDE1阻害薬、PDE2阻害薬、PDE4阻害薬、PDE5阻害薬、PDE7阻害薬、PDE9阻害薬等]、(15)NK2拮抗薬、(16)NK3拮抗薬、(17)ムスカリン型M1アセチルコリン受容体活性調節薬、(18)ムスカリン型M2アセチルコリン受容体活性調節薬、(19)アデノシン受容体調節薬、(20)ムスカリン型M4アセチルコリン受容体活性調節薬、(21)ムスカリン型M5アセチルコリン受容体活性調節薬、(22)アデノシン受容体調節薬、(23)グリシントランスポーター1(GlyT1)阻害薬[具体的には、ALX5407、SSR504734等]、(24)グルタミン酸増強薬[具体的には、アンパカイン]、(25)NMDA受容体阻害薬[具体的には、塩酸メマンチン等]、(26)代謝性グルタミン酸受容体調節薬(mGlu)[具体的には、CDPPB、MPEP等]、(27)抗不安薬((i)ベンゾジアゼピン系抗不安薬[具体的には、クロルジアゼポキシド、ジアゼパム、オキサゾラム、メダゼパム、クロキサゾラム、ロラゼパム、クロラゼプ酸二カリウム、プラゼパム、ブロマゼパム、フルジアゼパム、メキサゾラム、アルプラゾラム、フルトプラゼパム、フルタゾラム、ロフラゼプ酸エチル等]、(ii)チエノジアゼピン系抗不安薬[具体的には、エチゾラム、クロチアゼパム等]、(iii)セロトニン5−HT1A作動薬[具体的には、タンドスピロン等])、(28)睡眠導入剤((i)ベンゾジアゼピン系睡眠導入剤[具体的には、ニトラゼパム、エスタゾラム、塩酸フルラゼパム、ニメタゼパム、フルラゼパム、ハロキサゾラム、フルニトラゼパム、塩酸リルマザポン、ロルメタゼパム、トリアゾラム等]、(ii)チエノジアゼピン系眠導入剤[具体的には、ブロチゾラム等]、(iii)非ベンゾジアゼピン系睡眠導入剤[具体的には、ゾルピデム等]、(iv)メラトニン受容体作動薬[具体的には、ラメルテオン等])、(v)シクロピロロン系眠導入剤[具体的には、ゾピクロン等]、(29)βアミロイドワクチン、(30)βアミロイド分解酵素等、(31)脳機能賦活薬[具体的には、アニラセタム、ニセルゴリン等]、(32)カンナビノイド調節薬、(33)コリンエステラーゼ阻害薬[具体的には、塩酸ドネペジル、リバスチグミン、臭化水素酸ガランタミン等]、(34)MAO−B阻害剤[具体的には、ラサリジン等](35)パーキンソン病治療薬((i)ドーパミン受容体作動薬[具体的には、レボドパ、塩酸アマンタジン、メシル酸ブロモクリプチン、メシル酸ペルゴリド、カベルゴリン、塩酸タリペキソール、塩酸プラミペキソール水和物、塩酸セレギリン、塩酸ロピニロール等]、(ii)モノアミン酸化酵素阻害薬[具体的には、デプレニル、セルジリン(セレギリン)、レマセミド,リルゾール等]、(iii)抗コリン剤[具体的には、トリヘキシフェニジル、プロフェナミン、ビペリデン、塩酸ピロヘプチン、塩酸メチキセン、塩酸マザチコール等]、(iv)COMT阻害剤[具体的には、エンタカポン等]、(v)筋萎縮性側索硬化症治療薬[具体的には、リルゾール等、神経栄養因子等]、(vi)アポトーシス阻害薬[具体的には、CPI−1189、IDN−6556、CEP−1347等]、(vii)神経分化・再生促進剤[具体的には、レテプリニム(Leteprinim]、キサリプローデン(Xaliproden;SR−57746−A]、SB−216763等])等が挙げられる。 Examples of the drug (A) include: (1) atypical antipsychotic drugs [specifically, olanzapine, quetiapine, clozapine, ziprasidone, risperidone, paliperidone, perospirone, blonanserin, lurasidone, aripiprazole, sertindol, amisulpride , Iloperidone, bifeprunox, asenapine, melperone, brexpiprazole, zotepine, etc.], (2) typical antipsychotics [specifically, chlorpromazine, pchlorperazine, perphenazine, levomepromazine, fluphenazine, thioridazine, propericazine, Spiperone, moperone, haloperidol, timiperone, bromperidol, pimozide, fluropipamide, sulpiride, thioprid, sultopride, nemonapride, oxypertin, etc.], (3) selection Serotonin reuptake inhibitor (SSRI) [specifically, escitalopram, citalopram, paroxetine, sertraline, fluvoxamine, fluoxetine, etc.], (4) selective serotonin / noradrenaline reuptake inhibitor (SNRI) [specifically, MIL Nasiplan, duloxetine, venlafaxine, nefazodone, etc.], (5) selective noradrenaline / dopamine reuptake inhibitor (NDRI) [specifically, bubropine, etc.], (6) noradrenergic / specific serotonergic Antidepressant (NaSSA) [specifically, mirtazapine etc.], (7) Triazolopyridine antidepressant (SARI) [specifically, trazodone etc.], (8) Tetracyclic antidepressant [specific Specifically, cetiptiline, mianserin, maprotiline, etc.], (9) Cyclic antidepressants [specifically, amitriptyline, trimipramine, imipramine, nortriptyline, clomipramine, lofepramine, amoxapine, doslepine, etc.], (10) other antidepressants [specifically, NS-2359, Lu AA21004, DOV21947 Etc.], (11) α7 nicotinic receptor agonist, (12) α7 nicotinic receptor activity modulator, (13) α7 nicotinic receptor partial modulator [specifically, SSR-180711, PNU-120596 etc.], (14) Other PDE inhibitors [PDE1 inhibitor, PDE2 inhibitor, PDE4 inhibitor, PDE5 inhibitor, PDE7 inhibitor, PDE9 inhibitor, etc.], (15) NK2 antagonist, (16) NK3 antagonist, ( 17) Muscarinic type M1 acetylcholine receptor activity modulator, (18) Muscarin M2 acetylcholine receptor activity modulator, (19) adenosine receptor modulator, (20) muscarinic M4 acetylcholine receptor activity regulator, (21) muscarinic M5 acetylcholine receptor activity regulator, (22) adenosine receptor modulator Drug, (23) glycine transporter 1 (GlyT1) inhibitor [specifically, ALX5407, SSR504734, etc.], (24) glutamate enhancer [specifically, ampakine], (25) NMDA receptor inhibitor [ Specifically, memantine hydrochloride, etc.], (26) Metabotropic glutamate receptor modulators (mGlu) [specifically, CDPPB, MPEP, etc.], (27) Anti-anxiety drugs ((i) benzodiazepine anti-anxiety drugs) [Specifically, chlordiazepoxide, diazepam, oxazolam, medazepam, cloxazola Lorazepam, dipotassium chlorazepate, prazepam, bromazepam, fludiazepam, mexazolam, alprazolam, fltoprazepam, flutazolam, ethyl lofrazepate, etc.] (ii) thienodiazepine anxiolytics [specifically, etizolam, clothiazepam, etc.] iii) serotonin 5-HT1A agonist [specifically, tandospirone etc.]), (28) sleep inducer ((i) benzodiazepine sleep inducer [specifically nitrazepam, estazolam, flurazepam hydrochloride, nimetazepam, flurazepam) Haloxazolam, flunitrazepam, rilmazapon hydrochloride, lormetazepam, triazolam, etc.], (ii) thienodiazepine sleep inducer [specifically, brotizolam, etc.], (iii) non-benzodiazepine sleep inducer [specifically, , Zolpidem, etc.], (iv) melatonin receptor agonists [specifically, ramelteon, etc.]), (v) cyclopyrrolone sleep inducers [specifically, zopiclone, etc.], (29) β-amyloid vaccine, (30) β-amyloid degrading enzyme, etc., (31) brain function activator [specifically, aniracetam, nicergoline, etc.], (32) cannabinoid modulator, (33) cholinesterase inhibitor [specifically, donepezil hydrochloride, Rivastigmine, galantamine hydrobromide, etc.], (34) MAO-B inhibitor [specifically, rasalidine, etc.] (35) Parkinson's disease therapeutic agent ((i) dopamine receptor agonist [specifically, levodopa , Amantadine hydrochloride, bromocriptine mesylate, pergolide mesylate, cabergoline, talipexol hydrochloride, pramipexole hydrochloride hydrate, salt Selegiline acid, ropinirole hydrochloride, etc.], (ii) monoamine oxidase inhibitors [specifically, deprenyl, sergiline (selegiline), remacemide, riluzole, etc.], (iii) anticholinergic agents [specifically, trihexypheny Zil, prophenamine, biperidene, pyroheptin hydrochloride, methixene hydrochloride, masaticol hydrochloride, etc.], (iv) COMT inhibitors [specifically, entacapone, etc.], (v) therapeutic agents for amyotrophic lateral sclerosis [specifically, Riluzole, etc., neurotrophic factors, etc.], (vi) apoptosis inhibitors [specifically, CPI-1189, IDN-6556, CEP-1347, etc.], (vii) neuronal differentiation / regeneration promoters [specifically, Leteprinim, Xaliproden (SR-57746-A), SB 216763, etc.]), and the like.
また、前記(B)の薬物としては、例えば、(36)糖尿病治療薬((i)PPARγ作用薬(作動薬、阻害薬)[具体的には、ピオグリタゾン、ロシグリタゾン、トログリタゾン、シグリタゾン、ダルグリタゾン、エングリタゾン、ネトグリタゾン等]、(ii)インスリン分泌促進薬[(a)スルホニル尿素剤(具体的には、トルブタミド、アセトヘキサミド、クロルプロパミド、グリベンクラミド、グリクラジド、グリピジド、グリメピリド、グリペンチド、グリキドン、グリソラミド、トラザミド等)、(b)非スルホニル尿素剤等]、(iii)速効型インスリン分泌促進剤(具体的には、ナテグリニド、ミチグリニド、レパグリニド等)、(iv)αグルコシダーゼ阻害薬[具体的には、アカルボース、ボグリボース、ミグリトール、カミグリボース、アジポシン、エミグリテート、プラジミシン−Q、サルボスタチン等]、(v)インスリン抵抗性改善薬[具体的には、(a)PPARγ作用薬、(b)PTP−1B阻害薬、(c)DPP−4阻害薬[具体的には、シタグリプチン、ビルダグリプチン、アログリプチン、サクサグリプチン、NVP−DPP−728等]、(d)GLP−1及びGLP−1作動薬[具体的には、エキセナチド、リラグルチド等]、(e)11β−HSD阻害薬等、(f)GPR40作動薬、(g)GPR119作動薬、(h)GPR120作動薬]、(vi)肝糖新生抑制剤[具体的には、グルカゴン拮抗薬等]、(vii)ビグアナイド剤[具体的には、メトホルミン、ブホルミン、フェンホルミン等]、(viii)インスリンまたはインスリン誘導体[具体的には、インスリン亜鉛懸濁液、インスリンリスプロ、インスリンアスパルト、レギュラーインスリン、NPHインスリン、インスリングラルギン、インスリンデテミル、混合型インスリン等]、(ix)α2拮抗薬[具体的には、ミダグリゾール、イサグリドール、デリグリドール、イダゾキサン、エファロキサン等])、(37)抗肥満薬((i)アドレナリンβ3受容体作動薬[具体的には、KRP−204、TRK−380/TAC−301等]、(ii)CB−1受容体拮抗薬[具体的には、リモナバン、SR−147778、BAY−65−2520等]、(iii)ニューロペプチドY(NPY)受容体拮抗薬[具体的には、S−2367等]、(iv)摂食抑制薬[モノアミン再取り込み阻害剤[具体的には、シブトラミン、マジンドール等]]、(v)リパーゼ阻害薬[具体的には、オルリスタット、セチリスタット等]、(vi)ペプチドYY(PYY)受容体拮抗薬等)、(38)コレステロール低下薬等の高脂血症治療薬((i)ω3脂肪酸類[具体的には、イコサペント酸エチル(EPA−E製剤、例えば、製品名:エパデール(登録商標)等)、ドコサヘキサエン酸(DHA)、イコサペント酸エチルおよびドコサヘキサエン酸エチルの混合製剤(例えば、製品名:ロバザTM、オマコール(登録商標)等)等]、(ii)HMG−CoA還元酵素阻害剤[具体的には、アトルバスタチン、シンバスタチン、ピタバスタチン、イタバスタチン、フルバスタチン、ロバスタチン、プラバスタチン、リバスタチン、ロスバスタチン等](iii)HMG−CoA合成酵素阻害剤、(iv)コレステロール吸収阻害剤[具体的には、エゼチミブ]、(v)アシル−CoA・コレステロールアシル転移酵素(ACAT)阻害剤、(vi)CETP阻害剤、(vii)スクアレン合成酵素阻害剤、(viii)抗酸化剤[具体的には、プロブコール等]、(ix)PPARα作動薬[具体的には、クロフィブラート、エトフィブラート、フェノフィブラート、ベザフィブラート、シプロフィブラート、ゲムフィブロジル、KRP−101等]、(x)PPARδ作動薬、(xi)LXR作動薬、(xii)FXR作動薬[具体的には、INT−747等]、(xiii)MTTP阻害剤、(xiv)スクアレンエポシダーゼ阻害剤等)、(39)降圧剤((i)利尿剤[具体的には、トリクロルメチアジド、ヒドロクロロチアジド、メフルシド、インダパミド、メチクラン、クロルタリドン、トリパミド、フロセミド、トラセミド、ブメタニド、エタクリン酸、スピロノラクトン、トリアムテレン、エプレレノン等]、(ii)カルシウム受容体拮抗薬[具体的には、アムロジピン、フェロジピン、ニカルジピン、ニフェジピン、ニモジピン、ニトレンジピン、ニルバジピン、アラニジピン、アゼルニジピン、マニジピン、バルニジピン、エホニジピン、シルニジピン、ベニジピン、ジルチアゼム等]、(iii)アンジオテンシン変換酵素阻害薬(ACEI)[具体的には、カプトプリル、リシノプリル、エナラプリル、デラプリル、ペリンドプリル、ベナゼプリル、トランドラプリル、キナプリル、アラセプリル、イミダプリル、テモカプリル、シラザプリル等]、(iv)アンジオテンシン受容体拮抗薬(ARB)[具体的には、ロサルタン、オルメサルタン、テルミサルタン、バルサルタン、カンデサルタンシレキセチル、イルベサルタン等]、(v)直接的レニン阻害薬[具体的には、アリスキレン等]、(vi)α受容体遮断薬[具体的には、トラゾリン、フェントラミン、ドキサゾシン、プラゾシン、ブナゾシン、テラゾシン、ウラピジル等]、(vii)β受容体遮断薬[具体的には、ボピンドロール、ピンドロール、チモロール、ジクロロイソプレナリン、アルプレノロール、カルテオロール、インデノロール、ブニトロロール、ペンブトロール、プロプラノロール、ナドロール、ニプラジロール、チリソロール、アセブトロール、セリプロロール、メトプロロール、アテノロール、ビソプロロール、ベタキソロール、プラクトロール、ベバントロール、ブトキサミン、カルベジロール、アモスラロール、アロチノロール、ラベタロール等]、(viii)α1β遮断薬[具体的には、カルベジロール、ラベタロール、アロチノロール、ベバントロール等]、(ix)α2受容体刺激薬[具体的には、クロニジン、メチルドパ、グアンファシン等])、(40)非ステロイド性抗炎症薬[具体的には、メロキシカム、テオキシカム、インドメタシン、イブプロフェン、セレコキシブ、ロフェコキシブ、アスピリン、インドメタシン等]、(41)疾患修飾性抗リウマチ薬(DMARDs)、(42)抗サイトカイン薬[具体的には、TNF阻害薬、MAPキナーゼ阻害薬]、(43)ステロイド薬[具体的には、デキサメサゾン、ヘキセストロール、酢酸コルチゾン等]、(44)性ホルモンまたはその誘導体[具体的には、プロゲステロン、エストラジオール、安息香酸エストラジオール等]、(45)副甲状腺ホルモン(PTH)等が挙げられる。Examples of the drug (B) include: (36) antidiabetic drugs ((i) PPARγ agonists (agonists, inhibitors) [specifically, pioglitazone, rosiglitazone, troglitazone, siglitazone, darglitazone] , Englitazone, Netoglitazone, etc.], (ii) Insulin secretagogues [(a) Sulfonylurea agents (specifically, tolbutamide, acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, glipentide, glypidone ), (B) non-sulfonylurea, etc.], (iii) fast-acting insulin secretagogues (specifically, nateglinide, mitiglinide, repaglinide, etc.), (iv) α-glucosidase inhibitors [specific The acarbose, voglibose, miglito , Camiglibose, Adiposin, Emiglitate, Pradimycin-Q, Salvostatin etc.], (v) Insulin resistance improver [specifically, (a) PPARγ agonist, (b) PTP-1B inhibitor, (c) DPP-4 inhibitors [specifically sitagliptin, vildagliptin, alogliptin, saxagliptin, NVP-DPP-728, etc.], (d) GLP-1 and GLP-1 agonists [specifically, exenatide, liraglutide, etc.] (E) 11β-HSD inhibitor, etc. (f) GPR40 agonist, (g) GPR119 agonist, (h) GPR120 agonist], (vi) hepatic gluconeogenesis inhibitor [specifically, glucagon antagonist Etc.], (vii) biguanides [specifically, metformin, buformin, phenformin, etc.], (viii) insulin or Is an insulin derivative [specifically, insulin zinc suspension, insulin lispro, insulin aspart, regular insulin, NPH insulin, insulin glargine, insulin detemir, mixed insulin, etc.], (ix) α2 antagonist [specifically ), (37) anti-obesity drugs ((i) adrenergic β3 receptor agonists [specifically, KRP-204, TRK-380 / TAC-301, etc.] , (Ii) CB-1 receptor antagonist [specifically, rimonabant, SR-147778, BAY-6-2520, etc.], (iii) Neuropeptide Y (NPY) receptor antagonist [specifically, Siv, etc.], (iv) Antifeedant [Monoamine reuptake inhibitor [Ingredients] Physically, sibutramine, mazindol, etc.]], (v) lipase inhibitors [specifically, orlistat, cetiristat, etc.], (vi) peptide YY (PYY) receptor antagonists, etc.), (38) cholesterol lowering Drugs for treating hyperlipidemia ((i) ω3 fatty acids [specifically, ethyl icosapentate (EPA-E preparation, for example, product name: Epadale (registered trademark) etc.), docosahexaenoic acid (DHA), Mixed preparations of ethyl icosapentate and ethyl docosahexaenoate (for example, product names: Lovaza ™ , Omacol (registered trademark), etc.), (ii) HMG-CoA reductase inhibitors [specifically, atorvastatin, simvastatin, pitavastatin , Itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, etc.] ( iii) HMG-CoA synthetase inhibitor, (iv) cholesterol absorption inhibitor [specifically ezetimibe], (v) acyl-CoA / cholesterol acyltransferase (ACAT) inhibitor, (vi) CETP inhibitor, (Vii) squalene synthase inhibitor, (viii) antioxidant [specifically, probucol, etc.], (ix) PPARα agonist [specifically, clofibrate, etofibrate, fenofibrate, bezafibrate, ciprofibrate , Gemfibrozil, KRP-101 etc.], (x) PPARδ agonist, (xi) LXR agonist, (xii) FXR agonist [specifically, INT-747, etc.], (xiii) MTTP inhibitor, (xiv) ) Squalene eposidase inhibitor), (39) antihypertensive agent ((i) diuretic [specifically, Lichlormethiazide, hydrochlorothiazide, mefluside, indapamide, methicrane, chlorthalidone, tripamide, furosemide, torasemide, bumetanide, ethacrynic acid, spironolactone, triamterene, eplerenone, etc.], (ii) calcium receptor antagonist [specifically, amlodipine, Felodipine, nicardipine, nifedipine, nimodipine, nitrendipine, nilvadipine, alanidipine, azelnidipine, manidipine, varnidipine, efonidipine, cilnidipine, benidipine, diltiazem, etc.], (iii) angiotensin converting enzyme inhibitor (ACEI) [specifically, capripril, capripril , Enalapril, delapril, perindopril, benazepril, trandolapril, quinapril, alacepril, imida Ril, temocapril, cilazapril, etc.], (iv) angiotensin receptor antagonist (ARB) [specifically, losartan, olmesartan, telmisartan, valsartan, candesartan cilexetil, irbesartan, etc.], (v) direct renin inhibitor [Specifically, aliskiren and the like], (vi) α receptor blocker [specifically, tolazoline, phentolamine, doxazosin, prazosin, bunazosin, terazosin, urapidil, etc.], (vii) β receptor blocker [specific In particular, bopindolol, pindolol, timolol, dichloroisoprenalin, alprenolol, carteolol, indenolol, bunitrolol, penbutolol, propranolol, nadolol, nipradilol, tilisolol, acebutolol, ceriprolol Metoprolol, atenolol, bisoprolol, betaxolol, practolol, bevantolol, butoxamine, carvedilol, amosulalol, arotinolol, labetalol, etc.], the (viii) alpha 1 beta-blockers [specifically, carvedilol, labetalol, arotinolol, bevantolol, etc.], ( ix) α 2 receptor stimulant [specifically clonidine, methyldopa, guanfacine and the like]), (40) non-steroidal anti-inflammatory drug [specifically, meloxicam, teoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, Aspirin, indomethacin, etc.], (41) disease-modifying anti-rheumatic drugs (DMARDs), (42) anti-cytokine drugs [specifically, TNF inhibitors, MAP kinase inhibitors], (43) stero Drugs (specifically, dexamethasone, hexestrol, cortisone acetate, etc.), (44) sex hormones or derivatives thereof (specifically, progesterone, estradiol, estradiol benzoate, etc.), (45) parathyroid hormone ( PTH) and the like.
前記疾患に対して既存薬と併用することにより、既存薬の投薬量を下げることが可能であり、既存薬の副作用を軽減することが可能となる。もちろん、当該薬物を用いた併用方法は、前記疾患に限定されるものではなく、且つ併用される薬物は前記に例示した化合物に限定されない。 By using in combination with existing drugs for the above diseases, the dosage of existing drugs can be reduced, and the side effects of existing drugs can be reduced. Of course, the combination method using the said drug is not limited to the said disease, and the drug used together is not limited to the compound illustrated above.
本発明の結晶と併用薬物の投与形態は、特に限定されず、投与時に、本発明の結晶と併用薬物とが組み合わされていればよい。このような投与形態としては、例えば、
(1)本発明の結晶と併用薬物とを同時に製剤化して得られる単一の製剤の投与、
(2)本発明の結晶と併用薬物とを別々に製剤化して得られる2種の製剤の同一投与経路での同時投与、
(3)本発明の結晶と併用薬物とを別々に製剤化して得られる2種の製剤の同一投与経路での時間差をおいての投与、
(4)本発明の結晶と併用薬物とを別々に製剤化して得られる2種の製剤の異なる投与経路での同時投与、
(5)本発明の結晶と併用薬物とを別々に製剤化して得られる2種の製剤の異なる投与経路での時間差をおいての投与(例えば、本発明の結晶−併用薬物の順序での投与、あるいは逆の順序での投与)などが用いられる。
以下、これらの投与形態をまとめて、本発明の結晶の併用剤と略記する。The administration mode of the crystal of the present invention and the concomitant drug is not particularly limited, as long as the crystal of the present invention and the concomitant drug are combined at the time of administration. Such dosage forms include, for example,
(1) administration of a single preparation obtained by simultaneously formulating the crystal of the present invention and a concomitant drug,
(2) Simultaneous administration by the same administration route of two kinds of preparations obtained by separately formulating the crystal of the present invention and a concomitant drug,
(3) Administration of two types of preparations obtained by separately formulating the crystal of the present invention and a concomitant drug at the same administration route with a time difference,
(4) Simultaneous administration of two preparations obtained by separately formulating the crystal of the present invention and a concomitant drug by different administration routes,
(5) Administration of two types of preparations obtained by separately formulating the crystal of the present invention and a concomitant drug at different administration routes (for example, administration of the crystal of the present invention in the order of the concomitant drug) Or administration in the reverse order).
Hereinafter, these administration forms are collectively abbreviated as the crystal combination of the present invention.
本発明の結晶の併用剤を投与するに際しては、併用薬物と本発明の結晶とを同時期に投与してもよいが、併用薬物の投与の後、本発明の結晶を投与してもよいし、本発明の結晶の投与後、併用薬物を投与してもよい。時間差をおいて投与する場合、時間差は投与する有効成分、剤形、及び投与方法により異なるが、例えば、併用薬物を先に投与する場合、併用薬物を投与した後1分〜3日以内、好ましくは10分〜1日以内、より好ましくは15分〜1時間以内に本発明の結晶を投与する方法が挙げられる。本発明の結晶を先に投与する場合、本発明の結晶を投与した後、1分〜1日以内、好ましくは10分〜6時間以内、より好ましくは15分〜1時間以内に併用薬物を投与する方法が挙げられる。 When administering the concomitant drug of the crystal of the present invention, the concomitant drug and the crystal of the present invention may be administered at the same time, or after administering the concomitant drug, the crystal of the present invention may be administered. The concomitant drug may be administered after the administration of the crystal of the present invention. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, dosage form, and administration method. For example, when administering the concomitant drug first, preferably within 1 minute to 3 days after administering the concomitant drug. Includes a method of administering the crystal of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the crystal of the present invention is administered first, the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the crystal of the present invention. The method of doing is mentioned.
併用薬物は、副作用が問題とならなければ、どのような量を設定することも可能である。併用薬物としての一日投与量は、投与対象、投与ルート、対象疾患、症状等によっても異なるが、例えば、統合失調症の患者(成人、体重約60kg)に経口投与する場合、通常1回量として約0.1〜約20mg/kg体重、好ましくは約0.2〜10mg/kg体重、さらに好ましくは約0.5〜約10mg/kg体重であり、この量を1日1回〜数回(例えば3回)投与するのが望ましい。 Any amount of the concomitant drug can be set as long as side effects are not a problem. The daily dose as a concomitant drug varies depending on the administration subject, administration route, target disease, symptom, etc. For example, when administered orally to a patient with schizophrenia (adult, body weight of about 60 kg), it is usually a single dose. About 0.1 to about 20 mg / kg body weight, preferably about 0.2 to 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight, and this amount is once to several times a day. It is desirable to administer (eg 3 times).
本発明の結晶が併用薬物と組み合せて使用される場合には、お互いの剤の量は、それらの剤の反対効果を考えて安全な範囲内で低減できる。 When the crystal of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of these agents.
本発明の結晶の併用剤は、毒性が低く、例えば、本発明の結晶、又は(及び)上記併用薬物を公知の方法に従って、薬理学的に許容される担体と混合して医薬、例えば、錠剤(糖衣錠、フイルムコーティング錠を含む)、散剤、顆粒剤、カプセル剤、(ソフトカプセルを含む)、液剤、注射剤、坐剤、徐放剤などとすることができ、それらは、経口的、又は非経口的に安全に投与することができる。 The crystal combination of the present invention has low toxicity. For example, the crystal of the present invention, or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, for example, a drug such as a tablet. (Including sugar-coated tablets and film-coated tablets), powders, granules, capsules, (including soft capsules), liquids, injections, suppositories, sustained-release agents, etc. It can be safely administered orally.
本発明の結晶の併用剤の製造に用いられてもよい薬理学的に許容される担体としては、上記した本発明の結晶の医薬に使用されるものと同様のものを使用することができる。 As the pharmacologically acceptable carrier that may be used in the production of the crystal concomitant agent of the present invention, the same carriers as those used for the crystal medicament of the present invention described above can be used.
本発明の結晶の併用剤における本発明の結晶と併用薬物との配合比は、投与対象、投与ルート、疾患などにより適宜選択することができる。上記併用薬物は、2種以上を適宜の割合で組み合せて用いてもよい。 The compounding ratio of the crystal of the present invention and the concomitant drug in the crystal concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like. Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
併用薬物の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明の結晶と併用薬物の配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせ等により適宜選択することができる。例えば、投与対象がヒトである場合、本発明の結晶1重量部に対し、併用薬物を0.01〜100重量部用いればよい。例えば、本発明の結晶の併用剤における本発明の結晶の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約0.01〜99.9重量%の範囲であり、好ましくは約0.1〜50重量%の範囲であり、さらに好ましくは約0.5〜20重量%程度の範囲である。 The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the crystal of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the crystal of the present invention. For example, the content of the crystal of the present invention in the crystal combination of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by weight with respect to the whole preparation, preferably The range is about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight.
本発明の結晶の併用剤における併用薬物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約0.01〜99.9重量%の範囲であり、好ましくは約0.1〜50重量%の範囲であり、さらに好ましくは約0.5〜20重量%の範囲である。 The content of the concomitant drug in the crystal combination of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by weight, preferably about 0.1 It is in the range of ˜50% by weight, more preferably in the range of about 0.5 to 20% by weight.
本発明の結晶の併用剤における担体などの添加剤の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約1〜99.99重量%の範囲であり、好ましくは約10〜90重量%の範囲である。 The content of an additive such as a carrier in the crystal combination of the present invention varies depending on the form of the preparation, but is usually in the range of about 1 to 99.99% by weight with respect to the whole preparation, preferably about 10 to 10%. It is in the range of 90% by weight.
本発明の結晶、及び併用薬物をそれぞれ別々に製剤化する場合も同様の含有量でよい。 The same content may be used when the crystal of the present invention and the concomitant drug are formulated separately.
上記したように投与量は種々の条件で変動するので、上記投与量より少ない量で十分な場合もあり、また範囲を超えて投与する必要がある場合もある As mentioned above, the dosage varies depending on various conditions, so an amount smaller than the above dosage may be sufficient, and it may be necessary to administer beyond the range.
本発明の結晶は、単回または多回投与のいずれかで、単独でまたは薬学的に許容できる担体と組み合わせて投与することができる。適切な医薬担体には、不活性固体希釈剤または充填剤、滅菌水溶液、および種々の有機溶媒が包含される。それにより形成される医薬組成物は次いで、錠剤、粉剤、ロゼンジ、液体調剤、シロップ剤、注射液などの様々な投与形態で容易に投与することができる。これらの医薬組成物は、香味剤、結合剤、賦形剤などの追加成分を場合により含有できる。したがって、本発明の結晶は、経口、口腔、鼻腔、非経口(たとえば、静脈内、筋内、または皮下)、経皮(たとえば、パッチ)、もしくは直腸投与用に、または吸入もしくは注入(insufflation)による投与に適した形態で製剤化することができる。 The crystals of the invention can be administered either alone or in combination with a pharmaceutically acceptable carrier, either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution, and various organic solvents. The pharmaceutical composition thereby formed can then be easily administered in various dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injection solutions and the like. These pharmaceutical compositions can optionally contain additional ingredients such as flavoring agents, binders, excipients and the like. Thus, the crystals of the invention can be used for oral, buccal, nasal, parenteral (eg, intravenous, intramuscular, or subcutaneous), transdermal (eg, patch), or rectal administration, or by inhalation or insufflation. Can be formulated in a form suitable for administration by.
[本発明の予防・治療剤の製剤化]
本発明の結晶の医薬は、医薬組成物の形態で投与される。
本発明の結晶の医薬組成物は、本発明の4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの結晶を含み、医薬上許容される添加剤と組み合わせて作られる。より詳細には、賦形剤(例;乳糖、白糖、マンニット、結晶セルロース、ケイ酸、トウモロコシデンプン、バレイショデンプン)、結合剤(例;セルロース類(ヒドロキシプロピルセルロース(HPC)、ヒドロキシプロピルメチルセルロース(HPMC))、結晶セルロース、糖類(乳糖、マンニット、白糖、ソルビトール、エリスリトール、キシリトール、)、デンプン類(トウモロコシデンプン、バレイショデンプン)、α化デンプン、デキストリン、ポリビニルピロリドン(PVP)、マクロゴール、ポリビニルアルコール(PVA))、滑沢剤(例;ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、カルボキシメチルセルロース)、崩壊剤(例;デンプン類(トウモロコシデンプン、バレイショデンプン)、カルボキシメチルスターチナトリウム、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポピドン)、被膜剤(例;セルロース類(ヒドロキシプロピルセルロース(HPC)、ヒドロキシプロピルメチルセルロース(HPMC)、アミノアルキルメタクリレートコポリマーE、メタクリル酸コポリマーLD)、可塑剤(例;クエン酸トリエチル、マクロゴール)、隠蔽剤(例;酸化チタン)、着色剤、香味剤、防腐剤(例;塩化ベンザルコニウム、パラオキシ安息香酸エステル)、等張化剤(例;グリセリン、塩化ナトリウム、塩化カルシウム、マンニトール、ブドウ糖)、pH調節剤(例;水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、塩酸、硫酸、リン酸緩衝液などの緩衝液)、安定化剤(例;糖、糖アルコール、キサンタンガム)、分散剤、酸化防止剤(例;アスコルビン酸、ブチルヒドロキシアニソール(BHA)、没食子酸プロピル、dl−α−トコフェロール)、緩衝剤、保存剤(例;パラベン、ベンジルアルコール、塩化ベンザルコニウム)、芳香剤(例;バニリン、l−メントール、ローズ油)、溶解補助剤(例;ポリオキシエチレン硬化ヒマシ油、ポリソルベート80、ポリエチレングリコール、リン脂質コレステロール、トリエタノールアミン)、吸収促進剤(例;グリコール酸ナトリウム、エデト酸ナトリウム、カプリン酸ナトリウム、アシルカルニチン類、リモネン)、ゲル化剤、懸濁化剤、または乳化剤、一般的に用いられる適当な添加剤または溶媒の類を、本発明の結晶と適宜組み合わせて種々の剤形とすることが出来る。[Formulation of the preventive / therapeutic agent of the present invention]
The crystalline medicament of the present invention is administered in the form of a pharmaceutical composition.
The crystalline pharmaceutical composition of the present invention comprises 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1, 5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide crystals, made in combination with pharmaceutically acceptable additives. More particularly, excipients (eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch), binders (eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose ( HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl Alcohol (PVA)), lubricants (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrants (eg; starches (corn starch, potato starch), carboxymethyl starch sodium, potassium Lumellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg, celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer LD), plastic) Agents (e.g. triethyl citrate, macrogol), masking agents (e.g. titanium oxide), colorants, flavoring agents, preservatives (e.g. benzalkonium chloride, paraoxybenzoate), isotonic agents (e.g .; Glycerin, sodium chloride, calcium chloride, mannitol, glucose), pH adjuster (eg; buffer solution such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, phosphate buffer), stabilizer (eg; Sugar, sugar alcohol, xanthan gum), dispersant, antioxidant (eg Asco Binic acid, butylhydroxyanisole (BHA), propyl gallate, dl-α-tocopherol), buffer, preservative (eg, paraben, benzyl alcohol, benzalkonium chloride), fragrance (eg, vanillin, l-menthol) , Rose oil), solubilizers (eg, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, phospholipid cholesterol, triethanolamine), absorption enhancers (eg, sodium glycolate, sodium edetate, sodium caprate) , Acylcarnitines, limonene), gelling agents, suspending agents, or emulsifiers, commonly used appropriate additives or solvents, and various combinations of the crystals of the present invention. I can do it.
種々の剤形とは、錠剤、カプセル剤、顆粒剤、散剤、丸剤、エアゾール剤、吸入剤、軟膏剤、貼付剤、坐剤、注射剤、トローチ剤、液剤、酒精剤、懸濁剤、エキス剤、エリキシル剤等があげられる。また、経口、皮下投与、筋肉内投与、鼻腔内投与、経皮投与、静脈内投与、動脈内投与、神経周囲投与、硬膜外投与、硬膜下腔内投与、脳室内投与、直腸内投与、吸入等により患者に投与し得る。 Various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, lozenges, liquids, spirits, suspensions, Examples include extract and elixir. Oral, subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration, intraventricular administration, intrarectal administration It can be administered to a patient by inhalation or the like.
本発明の結晶は、通常のカテーテル技法または注入(infusion)を用いることを含む、注射による非経口投与用に製剤化することができる。注射用製剤は、保存剤を添加して、たとえばアンプルまたは多回投与容器で、単位投与形態として提供することができる。これらの製剤は、油性または水性ビヒクル中の懸濁剤、液剤、またはエマルションなどの形態をとることができ、懸濁化剤、安定化剤、および/または分散剤などの製剤化剤を含有することができる。あるいは活性成分は、使用前に、適切なビヒクル、たとえば滅菌発熱物質除去水で再構成するための粉末形態であることもできる。 The crystals of the present invention can be formulated for parenteral administration by injection, including using conventional catheter techniques or infusion. Injectable formulations may be presented as unit dosage forms, for example, in ampoules or multi-dose containers, with the addition of preservatives. These formulations can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and contain formulation agents such as suspending, stabilizing, and / or dispersing agents. be able to. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.
製品溶液が必要とされる場合、製品溶液は患者への経口または非経口投与に必要とされる強度の溶液を生じるのに充分な量で、水(または他の水性媒質)に単離包接複合体を溶解することによって製造できる。これらの化合物は、口腔内で活性成分が放出されるように設計されている、迅速分散投与形態(fddf)に製剤化することができる。これらの製剤は多くの場合、急速溶解性ゼラチンをベースとしたマトリクスを用いて製剤化されている。これらの投与形態はよく知られており、広範な薬物を送達するために用いることができる。ほとんどの迅速分散投与形態は、担体または構造形成剤としてゼラチンを利用する。典型的に、ゼラチンは、包装から取り出すときに破損を防ぐ充分な強度を投与形態に付与するために用いられるが、ひとたび口に入れると、ゼラチンはその投与形態が即時分解することを可能にする。あるいは、同じ効果を得るために、種々のデンプンが用いられる。 If a product solution is required, the product solution is isolated and included in water (or other aqueous medium) in an amount sufficient to produce a solution of the strength required for oral or parenteral administration to the patient. It can be produced by dissolving the complex. These compounds can be formulated into rapidly dispersed dosage forms (fddf) that are designed to release the active ingredient in the oral cavity. These formulations are often formulated using a matrix based on fast dissolving gelatin. These dosage forms are well known and can be used to deliver a wide range of drugs. Most rapid dispersion dosage forms utilize gelatin as a carrier or structure-forming agent. Gelatin is typically used to give a dosage form sufficient strength to prevent breakage when removed from the package, but once in the mouth, gelatin allows the dosage form to break down immediately. . Alternatively, various starches are used to achieve the same effect.
本発明の結晶はまた、たとえば通常の坐剤基剤、たとえばカカオバターまたは他のグリセリドなどを含有する、坐剤または停留浣腸などの直腸組成物に製剤化することもできる。 The crystals of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, eg containing conventional suppository bases such as cocoa butter or other glycerides.
鼻腔内投与または吸入による投与の場合、本発明の結晶は、患者によって圧搾されるか、もしくはポンプで送り出されるポンプスプレー容器から溶液または懸濁液の形態で、または適切な噴射剤、たとえば、ジクロロジフルオロメタン、トリクロロフルオロメタン、ジクロロテトラフルオロエタン、二酸化炭素、もしくは他の適切なガスを用いて、加圧式容器もしくはネブライザからエアロゾルスプレー形(aerosol spray presentation)として、好都合に送達される。加圧式エアロゾルの場合、投与単位は、計量された量を送達する弁を提供することによって決定することができる。加圧式容器またはネブライザは、活性化合物の溶液または懸濁液を含有することができる。吸入器または注入器で用いるカプセル剤およびカートリッジ剤(たとえば、ゼラチンから製造される)は、本発明の結晶とラクトースまたはデンプンなどの適切な粉末基剤との混合粉末を含有させて製剤化することができる。 For intranasal administration or administration by inhalation, the crystals of the invention are in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or a suitable propellant such as dichloromethane. Conveniently delivered as an aerosol spray presentation from a pressurized container or nebulizer using difluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a metered amount. A pressurized container or nebulizer can contain a solution or suspension of the active compound. Capsules and cartridges (eg, made from gelatin) for use in an inhaler or insufflator should be formulated containing a mixed powder of the crystals of the invention and a suitable powder base such as lactose or starch. Can do.
平均的成人において上述の状態を治療するためのエアロゾル製剤は、好ましくはエアロゾルの各計量用量または「1吹き(puff)」が本発明の結晶約20mgから約1000mgを含有するように設定される。エアロゾルによる総日用量は、約100mgから約10mgの範囲内となる。投与は1日数回、たとえば2、3、4、または8回、たとえば各回1、2、または3用量の投与であることができる。 Aerosol formulations for treating the above conditions in the average adult are preferably set so that each metered dose or “puff” of aerosol contains from about 20 mg to about 1000 mg of crystals of the invention. The total daily dose with an aerosol will be within the range of about 100 mg to about 10 mg. Administration can be several times daily, for example 2, 3, 4 or 8 times, for example 1, 2 or 3 doses each time.
本発明の医薬組成物中の本発明の結晶の含量は、剤形、本発明の結晶の投与量等により異なるが、例えば、組成物全量に対して、約0.01〜100重量%、好ましくは0.1〜95重量%である。 The content of the crystal of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, the dose of the crystal of the present invention, etc., for example, about 0.01 to 100% by weight, preferably Is 0.1 to 95% by weight.
上述の状態を治療するために、本発明の結晶の投与量は、投与対象、投与ルート(経口、非経口、直腸、または口腔等)、対象疾患、症状等によっても異なるが、例えば、統合失調症の患者(成人、体重約60kg)に経口投与する場合、通常1回量として約0.1〜約20mg/kg体重、好ましくは約0.2〜10mg/kg体重、さらに好ましくは約0.5〜約10mg/kg体重であり、この量を1日1回〜数回(例えば3回)投与するのが望ましい。 In order to treat the above-mentioned conditions, the dosage of the crystal of the present invention varies depending on the administration subject, administration route (oral, parenteral, rectal, or oral cavity, etc.), target disease, symptom, etc. When orally administered to a patient with an illness (adult, body weight of about 60 kg), the dose is usually about 0.1 to about 20 mg / kg body weight, preferably about 0.2 to 10 mg / kg body weight, more preferably about 0.1. It is desirable to administer this amount once to several times a day (for example, 3 times).
[薬理実験例]
以下に実験例を挙げて、本発明を具体的に説明するが、本発明はこれらによって何ら限定されるものではない。
以下の薬理実施例1は、本発明の結晶の有効性を試験する方法を提供する。[Pharmacological experiment example]
Hereinafter, the present invention will be specifically described with reference to experimental examples, but the present invention is not limited to these examples.
The following Pharmacological Example 1 provides a method for testing the effectiveness of the crystals of the present invention.
薬理実験例1:in vitro化合物評価
(酵素阻害活性評価:ヒトPDE10A阻害作用)
IMAP TR−FRET Phosphodiersterase Evaluation Assay Kit(モレキュラーデバイス)を用いて測定した。384ウェルプレート(Corning)に希釈した各濃度の被検化合物10μLおよび1×IMAP Reaction Buffer containing 0.1%BSA(kit添付の5×より作成、10mM Tris−HCl、pH=7.2、10mM MgCl2、0.05%NaN3、および0.1% BSA)で2ng/mLに希釈したPDE10A酵素(BPAバイオサイエンス)5μLを加え、5分間室温にてプレインキュベーションした。1×IMAP Reaction Buffer containing 0.1%BSAで400nMに希釈したキット添付のcAMP基質を5μLを加えて60分間室温にて反応させた。さらにキット添付のIMAP TR−FRET Binding solution 60μLを添加して3時間以上放置したのち、ARVO SX(PerkinElmer)にて励起波長340nmでTerbiumの蛍光強度(Emission=490nm)及びTR−FRET(Emission=520nm)を測定することによって、産生された5’−AMPの量を算出した。被検化合物の代わりに溶媒を添加したウェルのカウントを0%、PDE10A酵素を加えていないウェルのカウントを100%として各被検化合物の阻害活性を算出した。Pharmacological Experiment Example 1: In vitro compound evaluation (Evaluation of enzyme inhibitory activity: human PDE10A inhibitory action)
It measured using IMAP TR-FRET Phosphodiesterase Evaluation Assay Kit (Molecular device). 10 μL of each concentration of test compound diluted in 384 well plate (Corning) and 1 × IMAP Reaction Buffer containing 0.1% BSA (prepared from 5 × attached to kit, 10 mM Tris-HCl, pH = 7.2, 10 mM MgCl 2 , 0.05% NaN 3 , and 0.1% BSA) was added to 5 μL of PDE10A enzyme (BPA bioscience) diluted to 2 ng / mL and preincubated for 5 minutes at room temperature. 1 × IMAP Reaction Buffer containing 5 μL of the cAMP substrate attached to the kit diluted to 400 nM with 0.1% BSA was added and reacted at room temperature for 60 minutes. Further, 60 μL of IMAP TR-FRET Binding solution attached to the kit was added and allowed to stand for 3 hours or more. Then, ARVO SX (PerkinElmer) was excited with Terbium fluorescence intensity (Emission = 490 nm) and TR-FRET (Emission = 520 nm) at an excitation wavelength of 340 nm. ) Was calculated to calculate the amount of 5′-AMP produced. The inhibitory activity of each test compound was calculated by setting the count of wells to which a solvent was added instead of the test compound to 0% and the count of wells to which the PDE10A enzyme was not added to 100%.
被検化合物である4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのPDE10A阻害活性はIC50値として表1に示した。Test compound 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7- Yl) -1-methyl-1H-pyrazole-5-carboxamide is shown in Table 1 as an IC 50 value.
以下に示す薬理実験例2(被検化合物をMK−801投与30分前にラットに経口投与することによる自発運動抑制に関する実験)により、精神障害および神経変性障害治療薬としての有効性が示される。 Pharmacological experiment example 2 shown below (experiment regarding suppression of locomotor activity by orally administering a test compound to rats 30 minutes before administration of MK-801) demonstrates its effectiveness as a therapeutic agent for mental disorders and neurodegenerative disorders. .
薬理実験例2:MK−801誘発ロコモーター活性評価
(動物)
雄性Sprague−Dawleyラットを購入し、飼育施設に到着後、動物を少なくとも一週間の馴化期間をおいて実験に使用する。動物は、温度と湿度をコントロールした実験室で、12時間明暗サイクル下で飼育し、食餌と水を自由摂取させる。Pharmacological experiment example 2: MK-801-induced locomotor activity evaluation (animal)
After purchasing male Sprague-Dawley rats and arriving at the breeding facility, the animals are used for experiments with an acclimatization period of at least one week. Animals are housed in a laboratory with controlled temperature and humidity under a 12 hour light / dark cycle, with free access to food and water.
(薬物投与)
被験化合物は、0.5w/v%メチルセルロース400溶液 (和光純薬工業株式会社、日本)に懸濁し、経口投与 (p.o.)する。(+)−MK−801 hydrogen maleate ((5R,10S)−(+)−5−メチル−10,11−ジヒドロ−5H−ジベンゾ[a,d]シクロヘプテン−5,10−イミンマレイン酸水素塩、シグマアルドリッチ、セントルイス、ミズーリ州) は、生理食塩水に溶解し、皮下投与(s.c.)する。ラットに対して被験化合物は5 mL/kg体重、MK−801は1 mL/kg体重の容量で投与する。(Drug administration)
The test compound is suspended in 0.5 w / v% methylcellulose 400 solution (Wako Pure Chemical Industries, Japan) and orally administered (po). (+)-MK-801 hydrogen maleate ((5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine maleic acid hydrogen salt, Sigma-Aldrich, St. Louis, MO) is dissolved in saline and administered subcutaneously (sc). Test compounds are administered to rats in a volume of 5 mL / kg body weight and MK-801 is administered in a volume of 1 mL / kg body weight.
(MK−801誘発自発運動量亢進に対する拮抗作用)
げっ歯類において精神刺激誘発薬 (例、アンフェタミン、コカイン、メタンフェタミン、MK−801及びフェンシクリジン)による自発運動量亢進の評価は、統合失調症の動物モデルとして広く汎用されている (Schizophrenia Bulletin 2010, vol.36:1066−1072; Psychopharmacology 1999, vol.145:237−250)。ラットにおける被験化合物のMK−801誘発自発運動量亢進に対する拮抗作用について試験を行う。試験まで、雄性Sprague−Dawleyラット (約300g)を、飼育ケージ内で測定を実施する部屋に60分以上馴化させる。馴化後、動物に溶媒又は化合物 (0.3または1 mg/kg体重)のいずれかを経口投与し、すぐに飼育ケージに戻す。被験化合物の投与60分後に、再び動物を飼育ケージより取り出し、溶媒 (生理食塩水)またはMK−801 (0.2 mg/kg体重)を皮下投与し、すぐに動物を赤外線センサーの付いた自発運動量測定チャンバー (室町機械株式会社、日本)に入れて測定を開始する。自発運動量は、10分ごとにカウントを行う。MK−801投与後120分間の累積カウントを各処置群について計算を行う。全てのデータは平均値と平均値の標準誤差として表す。統計解析は、コントロール群とMK−801単独投与群の比較についてはStudent’s t−testを用い (p<0.05で有意差あり)、MK−801単独投与群と被験化合物投与群の比較についてはDunnett’s test (p<0.05で有意差あり)を用いて解析を行う。(Antagonism against MK-801-induced spontaneous momentum enhancement)
Evaluation of locomotor activity enhancement by rodents with psychostimulants (eg, amphetamine, ***e, methamphetamine, MK-801 and phencyclidine) is widely used as an animal model of schizophrenia (Schizophrenia Bulletin 2010, vol. 36: 1066-1072; Psychopharmacology 1999, vol. 145: 237-250). The test compound is tested for antagonism against MK-801-induced increased locomotor activity of the test compound in rats. Until the test, male Sprague-Dawley rats (approximately 300 g) are acclimated to the room in which the measurements are performed in the housing cage for at least 60 minutes. After habituation, animals are dosed orally with either solvent or compound (0.3 or 1 mg / kg body weight) and immediately returned to their home cage. Sixty minutes after the administration of the test compound, the animal was again taken out of the cage, administered with a solvent (saline) or MK-801 (0.2 mg / kg body weight) subcutaneously, and immediately, the animal was spontaneously attached with an infrared sensor. Place in the momentum measurement chamber (Muromachi Kikai Co., Ltd., Japan) and start measurement. Spontaneous exercise is counted every 10 minutes. A cumulative count of 120 minutes after MK-801 administration is calculated for each treatment group. All data are expressed as mean and standard error of the mean. Statistical analysis uses Student's t-test for comparison between the control group and the MK-801 single administration group (significant difference at p <0.05), and comparison between the MK-801 single administration group and the test compound administration group Is analyzed using Dunnett's test (p <0.05 with significant difference).
薬理実験例3:溶解性試験
(1)DMSO析出溶解性(Kinetic Solubility)
本発明の結晶の10mMのDMSO 溶液を最終濃度100μMとなるように50mMリン酸緩衝液(pH7.4)に添加する。その溶液を室温で1.5時間、600rpmにて撹拌しながらインキュベーションした後、フィルタープレート(0.4μm、MultiScreen HTS−PCFフィルタープレート(MerckMillipore))でろ過し、プレートリーダー(Powerscan HT(大日本製薬))を用いて、ろ液の吸光度を最大吸収波長で測定する。同時に、試験化合物の既知濃度(1、3、10、30、100μM)を添加したDMSO溶液を検量線標準溶液として各々の標準溶液吸光度を測定し、検量線を作成する。ろ液および標準溶液の吸光度値より化合物の溶解度(μM)を算出する。Pharmacological Experiment Example 3: Solubility Test (1) DMSO Precipitation Solubility (Kinetic Solubility)
A 10 mM DMSO solution of the crystals of the present invention is added to a 50 mM phosphate buffer (pH 7.4) to a final concentration of 100 μM. The solution was incubated at room temperature for 1.5 hours with stirring at 600 rpm, filtered through a filter plate (0.4 μm, MultiScreen HTS-PCF filter plate (Merck Millipore)), and plate reader (Powerscan HT (Dainippon Pharmaceutical). )) To measure the absorbance of the filtrate at the maximum absorption wavelength. At the same time, the absorbance of each standard solution is measured using a DMSO solution to which a known concentration (1, 3, 10, 30, 100 μM) of the test compound is added as a calibration curve standard solution, and a calibration curve is created. The solubility (μM) of the compound is calculated from the absorbance values of the filtrate and standard solution.
(2)結晶溶解性(Thermodynamic Solubility)
本発明の結晶を1mg/mLとなるように水に添加する。その溶液を37℃で24時間1000rpmにて撹拌しながらインキュベーションした後、フィルタープレートでろ過する。ろ液をHPLCにて分析し、最大吸収波長にてピークを検出し、ピーク面積を測定する。同様に試験化合物の既知濃度(0.01、0.03、0.1、0.3、1μg/mL)を添加した1,4−ジオキサン溶液を検量線標準溶液として各々のピーク面積を測定し、検量線のピーク面積より化合物の溶解度(μg/mL)を算出する。(2) Crystal solubility (Thermodynamic Solubility)
The crystal of the present invention is added to water so as to be 1 mg / mL. The solution is incubated at 37 ° C. for 24 hours with stirring at 1000 rpm and then filtered through a filter plate. The filtrate is analyzed by HPLC, the peak is detected at the maximum absorption wavelength, and the peak area is measured. Similarly, each peak area was measured using a 1,4-dioxane solution to which a known concentration of a test compound (0.01, 0.03, 0.1, 0.3, 1 μg / mL) was added as a standard curve standard solution. The solubility (μg / mL) of the compound is calculated from the peak area of the calibration curve.
薬理実験例4:代謝安定性試験
本発明の結晶の10mMのDMSO 溶液を最終濃度1μMとなるように肝ミクロソーム溶液(ヒト、マウス;XenoTech)、NADPH生成溶液(β−NADP、Glucose−6−Phosphate、G−6−PDH(Y)、MgCl2を含む水)に添加する。その溶液を37℃で20分間インキュベートした後、アセトニトリルで反応停止する。反応液をフィルタープレート(MultiScreenHTS−HVプレート(Millipore))で遠心ろ過し、高速液体クロマトグラム/マススペクトロメトリーを用いて、ろ液中の試験化合物を測定する。同様に反応時間0分のサンプルをコントロールとして測定し、ミクロソーム反応サンプルとコントロールの比より、分解率(%)を算出する。Pharmacological experiment example 4: Metabolic stability test Liver microsome solution (human, mouse; XenoTech), NADPH generating solution (β-NADP, Glucose-6-phosphate) so that the final concentration of 10 mM DMSO solution of the crystal of the present invention becomes 1 μM. , G-6-PDH (Y), water containing MgCl 2 ). The solution is incubated at 37 ° C. for 20 minutes and then quenched with acetonitrile. The reaction solution is subjected to centrifugal filtration using a filter plate (MultiScreen HTS-HV plate (Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry. Similarly, a sample with a reaction time of 0 minutes is measured as a control, and the degradation rate (%) is calculated from the ratio of the microsome reaction sample and the control.
薬理実験例5:パッチクランプ法によるhERG阻害試験
hERG(human ether−a−go−go related gene)チャネルに対する作用を全自動パッチクランプシステム(Patchliner(Nanion))を用いて測定する。細胞(hERG−HEK(Upstate))のhERG IKr電流を確認するため、膜電位を−80mVに保持して定期的に脱分極パルスを加える。発生した電流が安定した後、試験化合物を添加する。試験化合物のhERGチャネルに対する作用は、40mV、0.5秒間の脱分極パルスに続く−40mV、0.5秒間の再分極パルスによって誘導されるテール電流の変化によって確認する。刺激は10秒に1回の頻度で行う。測定は室温で行う。hERGチャネル阻害率は、試験化合物適用前の最大テール電流に対する適用2分後のテール電流の減少率(抑制率)として算出する。Pharmacological Experiment Example 5: hERG Inhibition Test by Patch Clamp Method The effect on hERG (human ether-a-go related gene) channels is measured using a fully automatic patch clamp system (Patchliner (Nanion)). In order to confirm the hERG I Kr current of the cells (hERG-HEK (Upstate)), a depolarizing pulse is periodically applied while maintaining the membrane potential at −80 mV. After the generated current has stabilized, the test compound is added. The effect of the test compound on the hERG channel is confirmed by a change in tail current induced by a 40 mV, 0.5 second depolarizing pulse followed by a -40 mV, 0.5 second repolarizing pulse. Stimulation is performed once every 10 seconds. The measurement is performed at room temperature. The hERG channel inhibition rate is calculated as the reduction rate (suppression rate) of the tail current 2 minutes after application with respect to the maximum tail current before application of the test compound.
この抑制率を算出することにより、薬物によるQT延長とそれに続く致死的な副作用(心室頻拍や突然死など)を誘発する可能性が示される。 By calculating this suppression rate, the possibility of inducing QT prolongation by drugs and subsequent fatal side effects (such as ventricular tachycardia and sudden death) is shown.
薬理実験例6:ファーマコキネティクス試験(マウスカセットPK)
本発明の結晶を7あるいは8週齢の雄性C57BL/6J Jclに1mg/kg(投与溶媒は、DMSO:Tween80:超純水=1:1:8、10mL/kg)で経口単回投与した後、0.25、0.5、1、2時間後に腹大静脈より採血する。血液を遠心分離(3000rpm、15分間、4℃)して得られた血漿を用いて、高速液体クロマトグラム/マススペクトロメトリーにて、血漿中の試験化合物を測定する。同様に試験化合物の既知濃度(0.01、0.02、0.05、0.1、0.2、0.5、1μg/mL)を添加した標準溶液を測定し、作成した検量線より血漿中濃度(μg/mL)を算出し、最高血漿中濃度をCmax(μg/mL)とする。Pharmacological experiment example 6: pharmacokinetics test (mouse cassette PK)
After a single oral administration of the crystals of the present invention to 7 or 8 weeks old male C57BL / 6J Jcl at 1 mg / kg (administration solvent is DMSO: Tween80: Ultrapure water = 1: 1: 8, 10 mL / kg) 0.25, 0.5, 1, 2 hours later, blood is collected from the abdominal vena cava. Using plasma obtained by centrifuging blood (3000 rpm, 15 minutes, 4 ° C.), the test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry. Similarly, a standard solution to which a known concentration of a test compound (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 μg / mL) was added was measured, and a calibration curve was prepared. The plasma concentration (μg / mL) is calculated, and the maximum plasma concentration is defined as Cmax (μg / mL).
薬理実験例7:タンパク結合試験
本発明の結晶の10mMのDMSO 溶液を最終濃度10μMとなるように正常血漿(ヒト、ラット)に添加する。簡易平衡透析装置(RED Device(Linden Bioscience))にて37℃で4時間透析した後、透析膜の内側(血漿側)溶液と外側(PBS側)溶液を、高速液体クロマトグラム/マススペクトロメトリーを用いて、試料中の試験化合物を測定する。PBS側と血漿側の比から非結合分率(%)を算出し、100−非結合分率(%)より蛋白結合率(%)を算出する。Pharmacological Experiment Example 7: Protein Binding Test A 10 mM DMSO solution of the crystals of the present invention is added to normal plasma (human, rat) to a final concentration of 10 μM. After dialyzing for 4 hours at 37 ° C with a simple equilibrium dialysis machine (RED Device (Linden Bioscience)), the high-performance liquid chromatogram / mass spectrometry of the inner (plasma side) and outer (PBS side) solutions of the dialysis membrane was performed. Used to measure the test compound in the sample. The unbound fraction (%) is calculated from the ratio between the PBS side and the plasma side, and the protein binding rate (%) is calculated from 100-unbound fraction (%).
薬理実験例8:安全性試験
本発明の結晶をマウスまたはラットに単回で経口投与し、死亡例は認められず、目立った行動異常も観察されないことにより、本発明の結晶の安全性が示される。Pharmacological experiment example 8: Safety test The crystal of the present invention is demonstrated by the fact that the crystal of the present invention is orally administered to a mouse or rat once, no deaths are observed, and no remarkable behavioral abnormality is observed. It is.
以上の結果より、本発明の結晶は、優れたPDE10A阻害作用を有することが示された。また、安全性試験において何ら異常が認められず、本発明の結晶の低い毒性が示される。 From the above results, it was shown that the crystal of the present invention has an excellent PDE10A inhibitory action. In addition, no abnormality is observed in the safety test, indicating the low toxicity of the crystal of the present invention.
更に、本発明の結晶は、上記の試験を行うことにより、溶解性、代謝安定性、薬物動態、hERGチャネル阻害作用の回避等の1つの点において良好であることが確認される。 Furthermore, it is confirmed that the crystal of the present invention is good in one point such as solubility, metabolic stability, pharmacokinetics, and avoidance of hERG channel inhibitory effect by conducting the above test.
従って、本発明の結晶は、選択的PDE10A阻害剤として、精神障害、妄想性障害、および薬物誘発性精神病などのある種の精神障害および状態、恐慌性障害および強迫性障害などの不安障害、ならびにパーキンソン病およびハンチントン病を包含する運動障害、気分障害、神経変性障害、注意および/または認知の欠如を含む障害、肥満、および薬物嗜癖等の疾患の予防及び/または治療剤に用いることが期待される。 Thus, the crystals of the present invention are selective PDE10A inhibitors as certain mental disorders and conditions such as mental disorders, paranoid disorders, and drug-induced psychosis, anxiety disorders such as panic disorder and obsessive-compulsive disorder, and Expected to be used as a preventive and / or therapeutic agent for diseases such as movement disorders including Parkinson's disease and Huntington's disease, mood disorders, neurodegenerative disorders, disorders including attention and / or cognitive deficits, obesity, and drug addiction The
本発明の結晶は、以下に示す各種疾患に対して有望な予防、あるいは治療効果がを示すことが期待される。具体的には、(1)妄想型、解体型、緊張型、鑑別不能型、または残遺型の統合失調症、(2)統合失調症様障害、(3)妄想型または抑うつ型の統合失調感情障害、(4)妄想性障害、(5)物質誘導性精神障害、(6)アルコール、アンフェタミン、***、コカイン、幻覚剤、吸入剤、オピオイド、またはフェンシクリジンによって誘発された精神病、(7)妄想型人格障害、(8)統合失調型の人格障害、(9)ハンチントン病、(10)Dopamineアゴニスト療法に関連する異常運動症、(11)パーキンソン病、(12)不穏下肢症候群、(13)本態性振戦、(14)強迫性障害、(15)トゥーレット症候群、(16)チック障害、(17)恐慌性障害、(18)広場恐怖症、(19)特定恐怖症、(20)社会恐怖症、(21)心的外傷後ストレス障害、(22)急性ストレス障害、(23)全般性不安障害、(24)認知症;アルツハイマー病、多発脳梗塞、アルコール性認知症もしくは他の薬物関連認知症、頭蓋内腫瘍もしくは脳外傷に関連する認知症、ハンチントン病もしくはパーキンソン病に関連する認知症、AIDS関連認知症、または前頭側頭型認知症(25)せん妄、(26)健忘障害、(27)精神遅滞、(28)学習障害;読字障害、算数障害、または書字表出障害、(29)注意欠陥・多動性障害、(30)加齢性認知低下、(31)大うつ病エピソード(軽度、中等度、または重度型)、躁病エピソード、混合性エピソード、軽躁病エピソード、(32)非定型うつ病、(33)メランコリー型うつ病、(34)緊張病性うつ病、(35)産後発症気分エピソード、(36)脳卒中後うつ病、(37)大うつ病性障害、(38)気分変調性障害/気分変調症、(39)小うつ病性障害、(40)月経前不快気分障害、(41)統合失調症後うつ病性障害、(42)妄想性障害または統合失調症等の精神障害に併発する大うつ病性障害、(43)双極性障害;双極I型障害、双極II型障害、(44)気分循環性障害、(45)脳外傷に関連する神経変性、(46)脳卒中に関連する神経変性、脳梗塞に関連する神経変性、(47)低血糖誘発性神経変性、(48)てんかん発作に関連する神経変性、(49)神経毒中毒に関連する神経変性、(50)多系統委縮症、(51)線条体中型有棘ニューロンの神経変性等に対して有望な治療効果が期待できる。 The crystal of the present invention is expected to show promising preventive or therapeutic effects for various diseases shown below. Specifically, (1) delusion, dismantling, tension, indistinguishable or residual schizophrenia, (2) schizophrenia-like disorder, (3) delusion or depression schizophrenia Emotional disorders, (4) paranoid disorders, (5) substance-induced mental disorders, (6) alcohol, amphetamines, cannabis, ***e, hallucinogens, inhalants, opioids, or phencyclidine-induced psychosis (7 ) Delusional personality disorder, (8) schizophrenic personality disorder, (9) Huntington's disease, (10) abnormal motility associated with Dopamine agonist therapy, (11) Parkinson's disease, (12) restless leg syndrome, (13) ) Essential tremor, (14) obsessive compulsive disorder, (15) Tourette syndrome, (16) tic disorder, (17) panic disorder, (18) agoraphobia, (19) specific phobia, (20) Social phobia (21) post-traumatic stress disorder, (22) acute stress disorder, (23) generalized anxiety disorder, (24) dementia; Alzheimer's disease, multiple cerebral infarction, alcoholic dementia or other drug-related dementia, Dementia associated with intracranial tumor or brain trauma, dementia associated with Huntington's disease or Parkinson's disease, AIDS-related dementia, or frontotemporal dementia (25) delirium, (26) amnestic disorder, (27) mental Lag, (28) learning disabilities; reading disabilities, arithmetic disabilities, or written expression disabilities, (29) attention deficit / hyperactivity disorder, (30) age-related cognitive decline, (31) major depression episode (mild) , Moderate or severe), manic episodes, mixed episodes, hypomania episodes, (32) atypical depression, (33) melancholic depression, (34) catatonic depression, ( 5) Postpartum-onset mood episodes, (36) Post-stroke depression, (37) Major depressive disorder, (38) Dysthymia disorder / Dysthymia, (39) Minor depressive disorder, (40) Premenstrual disorder Discomfort disorder, (41) post-schizophrenic depressive disorder, (42) depressive disorder or major depressive disorder associated with mental disorders such as schizophrenia, (43) bipolar disorder; bipolar I disorder Bipolar type II disorder, (44) mood circulatory disorder, (45) neurodegeneration associated with brain trauma, (46) neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarction, (47) hypoglycemia induced For neurodegeneration, (48) neurodegeneration related to epileptic seizures, (49) neurodegeneration related to neurotoxin poisoning, (50) multisystem atrophy, (51) neurodegeneration of striatal medium spiny neurons, etc. And promising therapeutic effects can be expected.
なお、本明細書に記載した全ての文献および刊行物は、その目的にかかわらず参照によりその全体を本明細書に組み込むものとする。また、本明細書は、本願の優先権主張の基礎となる日本国特許出願である特願2015-230163 (2015年11月26日出願)の特許請求の範囲、明細書、および図面の開示内容を包含する。 It should be noted that all documents and publications described in this specification are incorporated herein by reference in their entirety regardless of their purposes. In addition, this specification is the disclosure of claims, description, and drawings of Japanese Patent Application No. 2015-230163 (filed on Nov. 26, 2015), which is a Japanese patent application on which the priority of the present application is claimed. Is included.
次に、本発明をさらに詳細に説明するために実施例、試験例をあげるが、これらの例は単なる実施であって、本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。 Next, in order to explain the present invention in more detail, examples and test examples will be given. However, these examples are merely implementations, and do not limit the present invention, and do not depart from the scope of the present invention. It may be changed with.
核磁気共鳴スペクトル(NMR)の測定には、ジェオールJNM−ECX400P(JEOL JNM−ECX400P)FT−NMR(日本電子(株)製)、ジェオールJNM−ECX300(JEOL JNM−ECX300)FT−NMR(日本電子(株)製)を用いた。LC −Massは以下の方法で測定した。Waters FractionLynx MSシステム(Waters製)を用い、カラムは資生堂製、CAPCELL Pakカラム(2.0mm×50mm、3μm)を用い、移動相は、メタノール:0.05%トリフルオロ酢酸水溶液=10:90(0分)〜100:0(2分)〜100:0(3分)のグラジエント条件を用いた。 For the measurement of nuclear magnetic resonance spectrum (NMR), Geol JNM-ECX400P (JEOL JNM-ECX400P) FT-NMR (manufactured by JEOL Ltd.), Geol JNM-ECX300 (JEOL JNM-ECX300) FT-NMR (JEOL) (Made by Co., Ltd.) was used. LC-Mass was measured by the following method. A Waters FractionLynx MS system (manufactured by Waters) was used, the column was a Shiseido product, a CAPCELL Pak column (2.0 mm × 50 mm, 3 μm), and the mobile phase was methanol: 0.05% trifluoroacetic acid aqueous solution = 10: 90 ( Gradient conditions from 0 min) to 100: 0 (2 min) to 100: 0 (3 min) were used.
(参考例)の(物性データ)において、LC−MSはLC −Mass(液体クロマトグラフィー−質量分析スペクトル)を意味し、LC−MS中、Mは分子量、RTは保持時間(リテンションタイム)、[M+H]+、[M+3H]3+、および[M+Na]+は分子イオンピークを意味するものとする。1H−NMR(プロトン核磁気共鳴)データ中、NMRシグナルのパターンで、sはシングレット、dはダブレット、tはトリプレット、qはカルテット、mはマルチプレット、brはブロード、Jはカップリング定数、Hzはヘルツ、CDCl3は重クロロホルム、DMSO−d6は重ジメチルスルホキシドを意味する。1H−NMRデータ中、水酸基(OH基)、アミノ基(NH2)、カルボキシル基(COOH)のプロトン等、ブロードバンドであるため確認ができないシグナルについては、データに記載していない。また、実施例中の「室温」は、通常1℃から30℃の温度(日本薬局方規定)を示すものとする。In (physical property data) of (Reference Example), LC-MS means LC-Mass (liquid chromatography-mass spectrometry spectrum), and in LC-MS, M is molecular weight, RT is retention time (retention time), [ M + H] + , [M + 3H] 3+ , and [M + Na] + shall mean molecular ion peaks. 1 H-NMR (proton nuclear magnetic resonance) data, NMR signal pattern, s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad, J is coupling constant, Hz means Hertz, CDCl 3 means deuterated chloroform, DMSO-d 6 means deuterated dimethyl sulfoxide. In 1 H-NMR data, signals that cannot be confirmed due to broadband such as hydroxyl group (OH group), amino group (NH 2 ), and carboxyl group (COOH) protons are not described in the data. In addition, “room temperature” in the examples usually indicates a temperature of 1 ° C. to 30 ° C. (Japanese Pharmacopoeia regulations).
結晶化に使用した溶媒は、市販品グレードであり、更に精製することなく使用した。 The solvent used for crystallization was commercial grade and was used without further purification.
粉末X線回折分析は、R‐AXIS IV diffractometer UltraX18(リガク社製)を用いて、debye−scherrer法(X−ray source : 50kV, 100mA、Wavelength :1.5418Å(CuKalpha)、Camera length: 200mm、温度:室温、Phi Position :0 度、Exposure time:10分、Delta Phi :120 度)で測定した。もしくはD8 Discover with GADDS CS(ブルカー社製)を用いて,Bragg−Brentano法(X−ray source : 40kV、40mA、Wavelength :1.5418Å(CuKalpha)、Camera length: 250mm、温度:室温、Phi Position :0 度、Exposure time:2分、Theta1:7度、Theta2:7度)で測定した。 The powder X-ray diffraction analysis was performed using R-AXIS IV diffractometer UltraX18 (manufactured by Rigaku Corporation) using the debye-scherrer method (X-ray source: 50 kV, 100 mA, Wavelength: 1.5418 mm, Camel: N Temperature: room temperature, Phi Position: 0 degree, Exposure time: 10 minutes, Delta Phi: 120 degree). Or, using D8 Discover with GADDS CS (manufactured by Bruker), Bragg-Brentano method (X-ray source: 40 kV, 40 mA, Wavelength: 1.5418 mm (CuKalpha), Camera length: 250 mmh, temperature: 250 mmh, P: 0 degree, Exposure time: 2 minutes, Theta 1: 7 degrees, Theta 2: 7 degrees).
示差走査熱量分析(DSC)は、示差走査熱量計DSC Q2000(TAinstruments社製)を用いて、昇温速度毎分10℃で40℃から300℃の範囲を測定した。FT−IRは、FT‐720(HORIBA社製)用いて、KBr法で測定した。顕微鏡写真は、Leica DFC450(Leica社製)を用いて測定した。 In the differential scanning calorimetry (DSC), a differential scanning calorimeter DSC Q2000 (manufactured by TA Instruments) was used to measure the temperature range of 40 ° C. to 300 ° C. at a temperature rising rate of 10 ° C./min. FT-IR was measured by KBr method using FT-720 (manufactured by HORIBA). The micrograph was measured using a Leica DFC450 (manufactured by Leica).
安定性試験は、小型環境試験器(エスペック社製)SH−641を用いて、試料約15mgを25℃/60%RH及び40℃/75%RH、1ヶ月、開放もしくは密閉下保存し、純度および結晶形の変化を測定した。 For the stability test, a small environmental tester (manufactured by Espec) SH-641 is used, and about 15 mg of a sample is stored at 25 ° C./60% RH and 40 ° C./75% RH for 1 month, open or sealed, and purity And the change of crystal form was measured.
純度測定は、装置:Waters ACQUITY UPLC H−Class(Waters社製)カラム:watersACQUITYBEHShieldRP18(粒子径1.7μm、サイズ2.1x50mm)を用いた。移動層には10mmol/L炭酸水素アンモニウム緩衝液pH9.0およびアセトニトルを用い、試料は50 μg/mLの 1、4―ジオキサン:アセトニトリル: 10 mmol/L 炭酸水素アンモニウム緩衝液= 20:20:60溶液を調製し実施した。 Purity measurement was performed using an apparatus: Waters ACQUITY UPLC H-Class (manufactured by Waters) column: waters ACQUITY BEHShield RP18 (particle diameter 1.7 μm, size 2.1 × 50 mm). For the moving layer, 10 mmol / L ammonium bicarbonate buffer pH 9.0 and acetonitrile were used, and the sample was 50 μg / mL 1,4-dioxane: acetonitrile: 10 mmol / L ammonium bicarbonate buffer = 20: 20: 60. A solution was prepared and carried out.
(参考例1)4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの合成 Reference Example 1 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7- Yl) -1-methyl-1H-pyrazole-5-carboxamide
(物性データ)LC−MS:M=246,RT=0.37(分),[M+H]+=247. 1H−NMR (CDCl3) δ:8.49(1H,s),7.57(1H,s),4.21(3H,s),3.70(3H,s),2.71(3H,s),2.15(3H,s).
(Physical property data) LC-MS: M = 246, RT = 0.37 (min), [M + H] + = 247.1 1H-NMR (CDCl 3 ) δ: 8.49 (1H, s), 7.57 ( 1H, s), 4.21 (3H, s), 3.70 (3H, s), 2.71 (3H, s), 2.15 (3H, s).
<工程2>4−(2,5−ジメチルピリミジン−4−イル)−1−メチル−1H−ピラゾール−5−カルボン酸の合成 <Step 2> Synthesis of 4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid
(物性データ)LC−MS:M=232,RT=0.65(分),[M+H]+=233. 1H−NMR (DMSO−d6) δ:8.49(1H,s),7.61(1H,s),4.07(3H,s),2.55(3H,s),2.15(3H,s).
(Physical data) LC-MS: M = 232 , RT = 0.65 ( min), [M + H] + = 233 1 H-NMR (DMSO-d 6) δ:. 8.49 (1H, s), 7 .61 (1H, s), 4.07 (3H, s), 2.55 (3H, s), 2.15 (3H, s).
<工程3>4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの合成 <Step 3> 4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl ) Synthesis of 1-methyl-1H-pyrazole-5-carboxamide
(物性データ)LC−MS:M=442,RT=1.13(分),[M+H]+=443. 1H−NMR(400MHz,CDCl3,δppm): 11.72(1H,s),8.78(1H,d,J=8Hz),8.63(1H,s),8.59(1H,d,J=8Hz),8.27−8.24(2H,m),7.70(1H,s),7.51−7.49(3H,m),4.31(3H,s),2.78(3H,s),2.42(3H,s).
(Physical data) LC-MS: M = 442 , RT = 1.13 ( min), [M + H] + = 443 1 H-NMR (400MHz, CDCl 3, δppm):. 11.72 (1H, s), 8.78 (1 H, d, J = 8 Hz), 8.63 (1 H, s), 8.59 (1 H, d, J = 8 Hz), 8.27-8.24 (2 H, m), 7. 70 (1H, s), 7.51-7.49 (3H, m), 4.31 (3H, s), 2.78 (3H, s), 2.42 (3H, s).
(実施例1)
4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのI型結晶
4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの固体(20mg)をアセトン(3mL)に外温90℃で溶解し、溶液を−20℃まで急冷し室温で1時間静地した。固体をろ取し、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミド(9.3mg)をI型結晶として得た。Example 1
4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Form 1 crystals of methyl-1H-pyrazole-5-carboxamide 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1, 5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide solid (20 mg) was dissolved in acetone (3 mL) at an external temperature of 90 ° C., and the solution was rapidly cooled to −20 ° C. at room temperature. I was quiet for 1 hour. The solid was collected by filtration and 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7. -Yl) -1-methyl-1H-pyrazole-5-carboxamide (9.3 mg) was obtained as Form I crystals.
I型結晶の粉末X線回折の測定結果を以下の表2および図1に示す。また、該結晶の顕微鏡写真を図2に示す。 The measurement results of powder X-ray diffraction of the type I crystal are shown in Table 2 below and FIG. A micrograph of the crystal is shown in FIG.
(実施例2)
4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのII型結晶
4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの固体(6.55g)を10%の水を含むエタノール(655mL)に懸濁し、濃塩酸(2.5mL)を加え、60から70℃で加熱溶解した。得られた溶液に28%アンモニア水(2.7mL)をおよそ50℃で加え、放冷した。得られた懸濁液を室温で2時間攪拌した。固体をろ取し、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミド(5.81g)をII型結晶として得た。(Example 2)
4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Type II crystals of methyl-1H-pyrazole-5-carboxamide 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1, 5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide solid (6.55 g) was suspended in ethanol (655 mL) containing 10% water and concentrated hydrochloric acid (2.5 mL). ) And dissolved by heating at 60 to 70 ° C. To the resulting solution, 28% aqueous ammonia (2.7 mL) was added at approximately 50 ° C. and allowed to cool. The resulting suspension was stirred at room temperature for 2 hours. The solid was collected by filtration and 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7. -Yl) -1-methyl-1H-pyrazole-5-carboxamide (5.81 g) was obtained as type II crystals.
II型結晶の粉末X線回折の測定結果を以下の表3および図3に示す。また、該結晶のDSC熱分析データを図4に示す。また、該結晶のFT−IRスペクトルデータを表4および図5に示す。また、該結晶の顕微鏡写真を図6に示す。 The measurement results of powder X-ray diffraction of type II crystals are shown in Table 3 below and FIG. The DSC thermal analysis data of the crystal is shown in FIG. Further, FT-IR spectrum data of the crystals are shown in Table 4 and FIG. A micrograph of the crystal is shown in FIG.
(試験例1)各種溶媒からの晶析検討
(参考例1)と同様の方法にて得られた、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの固体(125mg)を、ジメチルスルホキシド(7.5mL)に溶解させ、SY−06バイアル(日電理化硝子(株)0.6mLバイアル)24本に分注した。アセトンードライアイスで凍結後、凍結乾燥機FDU−2100(東京理化機械(株))を用いて凍結乾燥した。それそれのバイアルに100〜200 mg/mLの濃度となるように各種溶媒を加えた。本溶液を振とう機NR−3(タイテック社製)を用いて室温下100rpmで7日間振とう攪拌した。形成した4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの結晶をろ取し、晶出物の結晶形を確認した(スラリー法)。また数種の溶媒においては上記溶液にスターラーチップを加え100℃に過熱攪拌し溶解させ、その後室温まで放冷し、析出した固体を取し、晶出物の結晶形を確認した(徐冷法)。それら結果を表5に示す。(Test Example 1) Crystallization examination from various solvents 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2) obtained by the same method as in Reference Example 1 -Phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide solid (125 mg) and dimethyl sulfoxide (7.5 mL) And then dispensed into 24 SY-06 vials (Nichiden Rika Glass Co., Ltd. 0.6 mL vials). After freezing with acetone-dry ice, it was freeze-dried using a freeze dryer FDU-2100 (Tokyo Rika Kikai Co., Ltd.). Various solvents were added to each vial so as to have a concentration of 100 to 200 mg / mL. The solution was shaken and stirred at 100 rpm at room temperature for 7 days using a shaker NR-3 (manufactured by Taitec Corporation). 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl)-formed Crystals of 1-methyl-1H-pyrazole-5-carboxamide were collected by filtration to confirm the crystal form of the crystallized product (slurry method). In several solvents, a stirrer chip was added to the above solution and stirred by heating at 100 ° C., and then allowed to cool to room temperature. The precipitated solid was collected, and the crystal form of the crystallized product was confirmed (slow cooling method). The results are shown in Table 5.
(試験例2)結晶形混合物の溶媒懸濁試験
結晶化で得た4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの各結晶形(I型結晶、II型結晶)を同重量ずつ混合した結晶形混合物を調製し、総量を6mgとした。結晶形混合物を各種溶媒(0.05mL)と混合し懸濁させ、ガラスビーズ(ASONE社製、BZ−3)を1粒加え、恒温振とう機M・BR‐022UP(タイテック社製)を用いて25℃もしくは50℃で2500rpmにて72時間撹拌した。形成した4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドの結晶をろ取し、結晶形を確認した。結果を表6に示す。(Test Example 2) Solvent suspension test of crystalline mixture 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] obtained by crystallization ] A crystal form mixture obtained by mixing the same weight of each crystal form (type I crystal, type II crystal) of triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide. And the total amount was 6 mg. The crystalline mixture is suspended by mixing with various solvents (0.05 mL), one glass bead (ASONE, BZ-3) is added, and a constant temperature shaker M / BR-022UP (Tytec) is used. The mixture was stirred at 2500 rpm at 25 ° C. or 50 ° C. for 72 hours. 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl)-formed Crystals of 1-methyl-1H-pyrazole-5-carboxamide were collected by filtration to confirm the crystal form. The results are shown in Table 6.
上記のように、各種結晶形の混合物は、25℃もしくは50℃におけるの条件下における懸濁状態で、72時間後には全てII型結晶に転移した。この結果から、本発明のII型結晶は、25℃もしくは50℃の条件下における懸濁状態で、熱力学的に安定であることが明らかとなった。 As described above, the mixture of various crystal forms was in a suspended state at 25 ° C. or 50 ° C., and after 72 hours, all changed to type II crystals. From this result, it was clarified that the type II crystal of the present invention is thermodynamically stable in a suspended state at 25 ° C. or 50 ° C.
(試験例3) 保存安定性試験
結晶化で得られた、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのII型結晶(約15mg)をガラス瓶に入れ、表7に記載の各条件下で保存した。保存期間完了後、試料を取り出し、高速液体クロマトグラフィーにて純度測定および粉末X線にて結晶形の確認を行った。結果を表7に示す。Test Example 3 Storage Stability Test 4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo obtained by crystallization [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide type II crystals (about 15 mg) were placed in a glass bottle and stored under the conditions described in Table 7. After completion of the storage period, the sample was taken out, and the purity was measured by high performance liquid chromatography and the crystal form was confirmed by powder X-ray. The results are shown in Table 7.
(試験例3−2) 長期保存安定性試験
(試験例3)とは別に、結晶化で得られた、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのII型結晶(約2g)を2重のLDPE(低密度ポリエチレン)に入れたのちファイバードラムに入れ、表8に記載の各条件下で保存した。保存期間完了後、試料を取り出し、高速液体クロマトグラフィーにて純度測定および粉末X線にて結晶形の確認を行った。結果を表8に示す。(Test Example 3-2) Long-term storage stability test Separately from (Test Example 3), 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-) obtained by crystallization was used. Type II crystals of 2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide (about 2 g) were doubled into LDPE. (Low density polyethylene), then put into a fiber drum and stored under the conditions shown in Table 8. After completion of the storage period, the sample was taken out, and the purity was measured by high performance liquid chromatography and the crystal form was confirmed by powder X-ray. The results are shown in Table 8.
(試験例4) 光安定性試験
結晶化で得られた、4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのII型結晶(約2g)をガラス製の皿状容器に入れ、表9に記載のICH Q1B(新原薬及び新製剤の光安定性試験ガイドライン)に準じる光安定性試験に付した(光安定性試験のサンプルは、可視光及びUV−A光を放つ別個のランプの下に保存し、約25℃にて、総暴露が各々120万ルクス時間及び200ワット時間/m2以上となるようにする。5日間の試験を0.5ICH、10日間の試験を1ICHと表記する)。試験終了後、試料を取り出し、高速液体クロマトグラフィーにて純度測定および粉末X線にて結晶形の確認を行った。結果を表9に示す。Test Example 4 Light Stability Test 4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo obtained by crystallization [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide type II crystals (about 2 g) were placed in a glass dish-like container and ICH Q1B described in Table 9 (The photostability test sample was stored under separate lamps emitting visible light and UV-A light, and subjected to light stability test according to (Guidelines for light stability test of new drug substance and new drug product). The total exposure should be at least 1.2 million lux hours and 200 watt hours / m 2 at 25 ° C. The 5 day test is labeled 0.5 ICH and the 10 day test is labeled 1 ICH). After completion of the test, a sample was taken out, purity was measured by high performance liquid chromatography, and the crystal form was confirmed by powder X-ray. The results are shown in Table 9.
上記の結果から、本発明のII型結晶は、化学的及び物理的安定性が非常に高いことが明らかとなった。 From the above results, it was revealed that the type II crystal of the present invention has very high chemical and physical stability.
本発明の結晶は、優れたPDE10A阻害作用を示すので、統合失調症等の疾患の臨床上有用な予防剤および/または治療剤を提供することができる。また、本発明の結晶は、薬効、安全性、体内動態、安定性等(特に、安定性)の点で優れているので、医薬として有用である。 Since the crystal of the present invention exhibits an excellent PDE10A inhibitory action, it can provide a clinically useful prophylactic and / or therapeutic agent for diseases such as schizophrenia. In addition, the crystal of the present invention is useful as a medicine because it is excellent in terms of drug efficacy, safety, pharmacokinetics, stability, etc. (particularly stability).
以上、本発明の具体的な態様のいくつかを詳細に説明したが、当業者であれば示された特定の態様には、本発明の教示と利点から実質的に逸脱しない範囲で様々な修正と変更をなすことは可能である。従って、そのような修正および変更も、すべて特許請求の範囲で請求される本発明の精神と範囲内に含まれるものである。
Although several specific embodiments of the present invention have been described in detail, those skilled in the art will recognize that various modifications may be made to the specific embodiments shown without departing from the teachings and advantages of the invention. It is possible to make changes. Accordingly, all such modifications and changes are intended to be included within the spirit and scope of the present invention as claimed.
Claims (14)
4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドを溶媒に懸濁させた後、加温下にて懸濁液に濃塩酸を加え溶解させ溶液とし、続いて溶液にアンモニア水を加え懸濁液とし、更に懸濁液を放冷する工程を含む、請求項1ないし請求項4のいずれか1項に記載の4−(2,5−ジメチルピリミジン−4−イル)−N−(6−フルオロ−2−フェニル−[1,2,4]トリアゾロ[1,5−a]ピリジン−7−イル)−1−メチル−1H−ピラゾール−5−カルボキサミドのII型結晶の製造方法。
4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- After suspending methyl-1H-pyrazole-5-carboxamide in a solvent, concentrated hydrochloric acid is dissolved in the suspension under heating to form a solution. Subsequently, aqueous ammonia is added to the solution to form a suspension. The 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2- 1) according to any one of claims 1 to 4, comprising a step of allowing the suspension to cool. A process for producing type II crystals of phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide.
Treating at least one disease or condition selected from the group consisting of psychiatric disorders and conditions, anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, disorders including attention and / or cognitive deficits, obesity, and drug addiction 8. A method, wherein an amount of a crystal effective to treat the disease or condition is administered to a subject in need of treatment of the disease or condition. A method comprising:
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