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ANALGESIC DRUG USING PAC1 RECEPTOR ANTAGONISTIC DRUG

Foreign code F190009800
File No. S2017-1107-C0
Posted date May 8, 2019
Country WIPO
International application number 2018JP035831
International publication number WO 2019065794
Date of international filing Sep 27, 2018
Date of international publication Apr 4, 2019
Priority data
  • P2017-186447 (Sep 27, 2017) JP
Title ANALGESIC DRUG USING PAC1 RECEPTOR ANTAGONISTIC DRUG
Abstract The present invention relates to an analgesic drug containing: a compound represented by formula (I) or (II) (where, R1 is a C1-6-alkoxy group or a C1-6-haloalkoxy group; R2 is a hydrogen atom; R is an indazolyl group substituted with a halogen atom, a substituted or unsubstituted phenyl group, a pyrazolyl group, or a substituted or unsubstituted aralkyl group.); a salt thereof; or a solvate thereof.
Outline of related art and contending technology BACKGROUND ART
Pain is in need of treatment, and pathophysiological inflammatory pain and neuropathic pain can be classified. Inflammatory pain is, via the nociceptors and nociceptive pain, the site of tissue damage caused by the inflammatory mediators released in pain. On the other hand, the neuropathic pain, a disease or lesion of the somatosensory system is defined as pain caused by. Neuropathic pain is, not involved in the excitement of the nociceptors in some cases, peripheral nerve or central nervous system involved in change such as a plastic, a high degree resistant, often retardment treatment.
In accordance with the aging of the population in the industrialized countries, various pain disease are expected to increase. The US Congress, 2001 years 2010 years 10 years are called from and a declaration is adopted 'The Decade of Pain Control and Research', which is the investigation of the entity in the United States, a high degree of patient suffering from chronic pain of the adult population had been raised to 9%, a medical doctor to treat the invalid cost of wasted product, is difficult due to the employment of pain, such as care costs by year billions of dollars of socio-economic loss (about 8 trillion yen) 650 and estimates that up to and in some cases. Japan currently in, the number of patients with chronic pain is more than 2,000 million people has been calculated, refractory pain effective drug therapies to the establishment of social there is an urgent need.
Analgesic agents include NSAIDs current (non-steroidal anti-inflammatory drugs) and an opioid (narcotic analgesics) is widely used, particularly in patients with chronic pain from prolonged use, various adverse effects cannot be ignored, the quality of the patient's pain, offer, thereby significantly reducing the life. Therefore, can be used over a long period of development of a highly effective new analgesic strongly demanded.
NSAIDs or opioid pain management, stomach, kidney damage (mainly more NSAIDs), constipation, nausea, vomiting, dependent, respiratory (mainly opioid) such as the number of adverse effects, the neuropathic pain is often insufficient for analgesic effect and, which is received by the deleterious effect it is necessary to control pain state. Therefore, these drugs with different mechanisms of action desired new pain therapeutics.
PACAP(Pituitary Adenylate Cyclase Activating Polypeptide) is, in the year 1989, rat pituitary adenylate cyclase activity in the hypothalamic sheep as an index to be isolated, neuropeptides and the determined structure, through the receptor PAC1 the spinal cord pain sensitivity mechanical (mechanical allodynia: mechanical allodynia: a phenomenon in which the user may feel pain even touched) (Non-Patent Document 1) causes the, how the (human) clinical involved in pain or is not clear.
(Mouse, rat) level in the animal studies, peripheral nerve PACAP (spinal nerves) neuropathic pain (SNL model) has been suggested to be involved (non-patent document 2) is, PACAP receptor involved (PACAP receptor is, PAC1, VPAC1, at least 3 species exist VPAC2) is not clear with respect to.
Is the non-patent document 3, 400 million items or more existing registered in the compound of compound extracted from a database PA-8 and the PAC1 receptor antagonism PA-9 have been described, the chemical structure of the PA-8 is not clearly, the analgesic effect has not been studied.
Is the non-patent document 4, the compound with the structure of the PA-8 and PA-9, an analgesic effect of these compounds is shown.
PA-8 is a compound, the following formula (A) :
represented by the compound, compound PA-9 is, the following equation (B) :
compound represented.
The compounds, nitrogen atom 2 and nitrogen-containing heterocyclic structure containing one or more lactams having a structure in common.
Non-Patent Document 5 and is 6, the following formula (I ') :
(in the formula, Ar is a substituted phenyl group.) Indicated by 2, 3-d-4,7-dione and pyrido pyrimidine synthesis method is described, PAC1 receptor antagonism, has not been mentioned for the analgesic effect.
Scope of claims (In Japanese)請求の範囲 [請求項1]
 次式(I):
[化1]

(式中、R 1はC 1-6-アルコキシ基又はC 1-6-ハロアルコキシ基であり;R 2は水素原子である。)
で示される化合物もしくはその塩又はそれらの溶媒和物。

[請求項2]
 前記式(I)において、R 1がエトキシ基又はトリフルオロメトキシ基である請求項1記載の化合物もしくはその塩又はそれらの溶媒和物。

[請求項3]
 請求項1又は2記載の化合物もしくはその塩又はそれらの溶媒和物を含有する鎮痛薬。

[請求項4]
 神経障害性疼痛、がん化学療法に伴う疼痛、糖尿病性神経痛、糖尿病性末梢神経障害性疼痛及び片頭痛からなる群から選択される疾患又は症状を治療及び/又は予防するための請求項3記載の鎮痛薬。

[請求項5]
 次式(II):
[化2]

(式中、Rはハロゲン原子で置換されたインダゾリル基、置換又は無置換のフェニル基、ピラゾリル基、又は置換又は無置換のアラルキル基である。)
で示される化合物もしくはその塩又はそれらの溶媒和物を含有する鎮痛薬。

[請求項6]
 前記式(II)において、Rがハロゲン原子で置換されたインダゾリル基である請求項5記載の鎮痛薬。

[請求項7]
 前記式(II)において、Rが塩素原子で置換されたインダゾリル基である請求項5記載の鎮痛薬。

[請求項8]
 神経障害性疼痛、がん化学療法に伴う疼痛、糖尿病性神経痛、糖尿病性末梢神経障害性疼痛及び片頭痛からなる群から選択される疾患又は症状を治療及び/又は予防するための請求項5~7のいずれか1項に記載の鎮痛薬。

[請求項9]
 次式(IIa):
[化3]

(式中、R’はハロゲン原子で置換されたインダゾリル基;メチル基、フッ素原子、メトキシ基、シアノ基もしくは水酸基で置換されていてもよいフェニル基;ピラゾリル基;又は置換されたアラルキル基である。)
で示される化合物もしくはその塩又はそれらの溶媒和物。

[請求項10]
 前記式(IIa)において、R’がハロゲン原子で置換されたインダゾリル基である請求項9記載の化合物もしくはその塩又はそれらの溶媒和物。

[請求項11]
 前記式(IIa)において、R’が塩素原子で置換されたインダゾリル基である請求項9記載の化合物もしくはその塩又はそれらの溶媒和物。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • National university corporation Kagoshima University
  • TOYAMA UNIVERSITY
  • SHOWA UNIVERSITY
  • Inventor
  • KURIHARA Takashi
  • TAKASAKI Ichiro
  • TOYOOKA Naoki
  • GOUDA Hiroaki
IPC(International Patent Classification)
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