CN101115736A - Potassium channel modulating agents and their medical use - Google Patents

Abstract

This invention relates to novel potassium channel modulating agents, and their use in the preparation of pharmaceutical compositions. Moreover the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, in particular respiratory diseases, epilepsy, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic heart disease, angina pectoris, coronary heart disease, traumatic brain injury, psychosis, schizophrenia, anxiety, depression, dementia, memory and attention deficits, Alzheimer's disease, dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labour, baldness, cancer, immune suppression or pain.

Description

Potassium channel modulating agents and their medicinal use

Technical field

The present invention relates to novel potassium channel modulating agents and their purposes in preparation of pharmaceutical compositions.

And, the present invention relates to pharmaceutical composition, can be used for treating or alleviating and activity of potassium channels diseases associated or obstacle, particularly respiratory disease, epilepsy, faint from fear, epileptic seizures, petit mal, vasospasm, coronary vasospasm, nephropathy, polycystic kidney disease, cystospasm, the urinary incontinence, bladder outlet blocks, erective dysfunction, gastrointestinal dysfunction, secretory diarrhea, local asphyxia, cerebral ischemia, ischemic heart disease, stenocardia, coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, anxiety, depressed, mood disorder, dull-witted, memory and attention deficit, Alzheimer, amyotrophic lateral sclerosis (ALS), dysmenorrhoea, hypnolepsy, Raynaud disease, intermittent claudication, siogren's syndrome, irregular pulse, hypertension, the myotonic muscular dystrophy, spasticity, xerostomia (xerost0mi), type ii diabetes, hyperinsulinemia, premature labor, alopecia, cancer, irritable bowel syndrome, immunosuppression, migraine or pain.

Background technology

Ionic channel is a transmembrane protein, and their catalysis mineral ions are crossed over the transhipment of cytolemma.The generation of ionic channel participation action potential and time limit, cynapse transmission, the secretion of hormone, the various procedures such as contraction of muscle.

All Mammalss are all expressed potassium (K in their cytolemma ⁺) passage, these passages are played the part of the domination role in the adjusting of membrane potential.In the N﹠M cell, release and the segmental bronchus and the vasodilative degree of frequency of their adjusting action potentials and form, neurotransmitter.

From molecule viewpoint, K ⁺Passage is represented maximum and is changed one group of maximum ionic channels.As a whole, they can be divided into five extended familys: voltage-activatory K ⁺Passage (K _V), K that long QT is relevant ⁺Passage (KvLQT), inside rectifier (K _IP), diplopore K ⁺Passage (K _TP) and calcium-activated K ⁺Passage (K _Ca).

The latter, be Ca ²⁺-activatory K ⁺Passage is made up of three kinds of clear and definite hypotypes: SK passage, IK passage and BK passage.SK, IK and BK represent that the single passage electricity leads (little, neutralization big electricity lead the K passage).SK, IK and BK passage for example voltage-with calcium-susceptibility, pharmacology, distribution and function on show difference.

The SK passage is present in a lot of axoneurons and the neuroganglion, and their major function is a hyperpolarization neurocyte after one or several action potentials there, and purpose is to prevent that long consecutive (1ong trains) from causing the active generation of epilepsy.The SK passage also is present in several peripheral cells, comprises skeletal muscle, glandular cell, liver cell and T-lymphocyte.The meaning of SK passage in normal bone flesh it be unclear that, but their quantity significantly increases in Denervated muscle, and a large amount of SK passages has been pointed out role in disease incidence in myotonic muscular dystrophy patient's the muscle.

Studies show that K ⁺Passage may be the treatment target of treatment some diseases, comprises asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, faint from fear, vasospasm, coronary vasospasm, nephropathy, polycystic kidney disease, cystospasm, the urinary incontinence, bladder outlet blocks, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhea, local asphyxia, cerebral ischemia, ischemic heart disease, stenocardia, coronary heart disease, traumatic brain injury, psychosis, anxiety, depressed, dull-witted, memory and attention deficit, Alzheimer, dysmenorrhoea, hypnolepsy, Raynaud disease, intermittent claudication, siogren's syndrome, migraine, irregular pulse, hypertension, petit mal, the myotonic muscular dystrophy, xerostomia, type ii diabetes, hyperinsulinemia, premature labor, alopecia, cancer and immunosuppression.

Summary of the invention

The invention provides novel compound, they can selectivity regulate SK passage or SK passage hypotype.

And, the present invention relates to pharmaceutical composition, it can be used for treatment or alleviates and activity of potassium channels diseases associated or obstacle, comprise following disease or illness, resemble respiratory disease, epilepsy, faint from fear, epileptic seizures, petit mal, vasospasm, coronary vasospasm, nephropathy, polycystic kidney disease, cystospasm, the urinary incontinence, bladder outlet blocks, erective dysfunction, gastrointestinal dysfunction, secretory diarrhea, local asphyxia, cerebral ischemia, ischemic heart disease, stenocardia, coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, anxiety, depressed, mood disorder, dull-witted, memory and attention deficit, Alzheimer, amyotrophic lateral sclerosis (ALS), dysmenorrhoea, hypnolepsy, Raynaud disease, intermittent claudication, siogren's syndrome, irregular pulse, hypertension, the myotonic muscular dystrophy, spasticity, xerostomia, type ii diabetes, hyperinsulinemia, premature labor, alopecia, cancer, irritable bowel syndrome, immunosuppression, migraine or pain.

Therefore in its first aspect, the invention provides novel formula I pyrazolyl-quinazoline derivant

Its isomer or its isomer mixture, its N-oxide compound or its pharmacy acceptable salt, wherein

N is 0,1,2 or 3;

X represents O, S or NR '; Wherein

R ' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl;

Perhaps when n be 0 and X when being NR ', R ' constitutes heterocycle with Y and the nitrogen that is connected with them, this heterocycle can randomly be replaced by alkyl or phenyl;

Y represents alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, thiazolinyl, perhaps monocycle or polycyclic carbocyclic ring or heterocyclic group, the substituting group that this carbocyclic ring or heterocyclic group can randomly be selected from down group replaces one or many: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro, amino, methylene-dioxy, phenyl and morpholinyl;

Perhaps when n be 0 and X when being NR ', Y constitutes heterocycle with R ' and the nitrogen that is connected with them, this heterocycle can randomly be replaced by alkyl or phenyl;

R ¹, R ²And R ³Represent hydrogen, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino independently of one another.

On the other hand, the invention provides pharmaceutical composition, it comprises the The compounds of this invention of significant quantity.

On the other hand, the present invention relates to The compounds of this invention and be used to prepare treatment or alleviate purposes with the medicine of activity of potassium channels diseases associated or obstacle, also relate to treating or alleviating potassium channel regulated the obstacle of replying or the method for illness are arranged.

That invents is open in detail

Potassium channel modulating agents

In its first aspect, the invention provides novel pyrazolyl-quinazoline derivant by formula I representative

Its isomer or its isomer mixture, its N-oxide compound or its pharmacy acceptable salt, wherein

N is 0,1,2 or 3;

X represents O, S or NR '; Wherein

R ' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl;

Perhaps when n be 0 and X when being NR ', R ' constitutes heterocycle with Y and the nitrogen that is connected with them, this heterocycle can randomly be replaced by alkyl or phenyl;

Y represents alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, thiazolinyl, perhaps monocycle or polycyclic carbocyclic ring or heterocyclic group, the substituting group that this carbocyclic ring or heterocyclic group can randomly be selected from down group replaces one or many: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro, amino, methylene-dioxy, phenyl and morpholinyl;

Perhaps when n be 0 and X when being NR ', Y constitutes heterocycle with R ' and the nitrogen that is connected with them, this heterocycle can randomly be replaced by alkyl or phenyl; And

R ¹, R ²And R ³Represent hydrogen, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino independently of one another.

In preferred embodiment, pyrazolyl-quinazoline derivant of the present invention is a formula I compound, and wherein n is 0,1,2 or 3.

In preferred embodiment, n is 0,1 or 2.

So preferred embodiment in, n is 0 or 1.

In most preferred embodiments, n is 0.

In another preferred embodiment, pyrazolyl-quinazoline derivant of the present invention is a formula I compound, and wherein X represents O, S or NR '; Wherein R ' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl; Perhaps when n be 0 and X when being NR ', R ' constitutes heterocycle with Y and the nitrogen that is connected with them, this heterocycle can randomly be replaced by alkyl or phenyl.

In preferred embodiment, X represents NR '; Wherein R ' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl.

So preferred embodiment in, X represents NR '; Wherein R ' represents hydrogen or alkyl.

So preferred embodiment in, X represents NR '; Wherein R ' represents hydrogen, methyl, ethyl or propyl group.

So preferred embodiment in, X represents NH.

In another preferred embodiment, n is 0; X represents NR '; R ' constitutes heterocycle with Y and the nitrogen that is connected with them, and this heterocycle can randomly be replaced by alkyl or phenyl.

In preferred embodiment, n is 0; X represents NR '; R ' constitutes pyrrolidyl, piperidyl, piperazinyl or morpholine basic ring with Y and the nitrogen that is connected with them.

So preferred embodiment in, n is 0; X represents NR '; R ' constitutes the piperidines basic ring with Y and the nitrogen that is connected with them.

The third preferred embodiment in, pyrazolyl-quinazoline derivant of the present invention is a formula I compound, wherein Y represents alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, thiazolinyl, perhaps monocycle or polycyclic carbocyclic ring or heterocyclic group, the substituting group that this carbocyclic ring or heterocyclic group can randomly be selected from down group replaces one or many: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro, amino, methylene-dioxy, phenyl and morpholinyl; Perhaps when n be 0 and X when being NR ', Y constitutes heterocycle with R ' and the nitrogen that is connected with them, this heterocycle can randomly be replaced by alkyl or phenyl.

In preferred embodiment, Y represents alkyl, thiazolinyl or cycloalkyl.

So preferred embodiment in, Y represent methylidene, ethyl, propyl group, butyl, amyl group, allyl group, cyclopropyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group.

So preferred embodiment in, Y represents ethyl, allyl group, cyclopropyl, cyclopentyl, cyclohexyl or ring octyl group.

So preferred embodiment in, the Y representation ring alkyl is randomly replaced by alkyl.

So preferred embodiment in, Y represents cyclopropyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group, is randomly replaced by alkyl.

So preferred embodiment in, Y represents cyclopropyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group, is randomly replaced by the methyl or the tertiary butyl.

So preferred embodiment in, the cyclohexyl that Y representative is replaced by alkyl.

So preferred embodiment in, the cyclohexyl that Y representative is replaced by methyl or the tertiary butyl.

In another preferred embodiment, Y represents monocycle or polycyclic carbon ring group, is selected from phenyl, naphthyl or 1,2,3,4-tetrahydrochysene-naphthyl; Perhaps monocycle or polycyclic heterocyclic group are selected from pyrrolidyl, piperidyl, furyl, thienyl and pyrryl; This phenyl, naphthyl, 1,2,3, the substituting group that 4-tetrahydrochysene-naphthyl, pyrrolidyl, piperidyl, furyl, thienyl and pyrryl can randomly be selected from down group replaces once or twice: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro and amino.

In preferred embodiment, Y represents phenyl, naphthyl, 1,2,3,4-tetrahydrochysene-naphthyl, pyrrolidyl, piperidyl, furyl, thienyl or pyrryl; This phenyl, naphthyl, 1,2,3, the substituting group that 4-tetrahydrochysene-naphthyl, pyrrolidyl, piperidyl, furyl, thienyl and pyrryl can randomly be selected from down group replaces once or twice: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro and amino.

So preferred embodiment in, Y represents phenyl, naphthalene-1-base, naphthalene-2-base, 1,2,3,4-tetrahydrochysene-naphthalene-1-base, 1,2,3,4-tetrahydrochysene-naphthalene-2-base, tetramethyleneimine-1-base, piperidines-1-base, piperidin-4-yl, furans-2-base, furans-3-base, thiophene-1-base, thiophene-2-base, pyrroles-1-base or pyrroles-2-base; This phenyl, naphthyl, 1,2,3, the substituting group that 4-tetrahydrochysene-naphthyl, pyrrolidyl, piperidyl, furyl, thienyl and pyrryl can randomly be selected from down group replaces once or twice: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro and amino.

So preferred embodiment in, this phenyl, naphthyl, 1,2,3, the substituting group that 4-tetrahydrochysene-naphthyl, pyrrolidyl, piperidyl, furyl, thienyl and pyrryl can randomly be selected from down group replaces once or twice: alkyl, halogen, haloalkyl, alkoxyl group.

So preferred embodiment in, this phenyl, naphthyl, 1,2,3, the substituting group that 4-tetrahydrochysene-naphthyl, pyrrolidyl, piperidyl, furyl, thienyl and pyrryl can randomly be selected from down group replaces once or twice: methyl, ethyl, propyl group, chlorine, fluorine, bromine, trifluoromethyl, methoxy or ethoxy.

In further preferred embodiment, Y represents monocycle or polycyclic carbon ring group, be selected from phenyl, naphthyl, 1,2,3,4-tetrahydrochysene-naphthyl and dihydro indenyl, the substituting group that this carbon ring group can randomly be selected from down group replaces one or many: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro, amino, methylene-dioxy, phenyl and morpholinyl.

So preferred embodiment in, Y represents phenyl, naphthyl, 1,2,3,4-tetrahydrochysene-naphthyl and dihydro indenyl, the substituting group that this carbon ring group can randomly be selected from down group replaces once or twice: alkyl, halogen, haloalkyl, alkoxyl group, methylene-dioxy, phenyl and morpholinyl.

So preferred embodiment in, Y represents phenyl, naphthyl, 1,2,3,4-tetrahydrochysene-naphthyl and dihydro indenyl, the substituting group that this carbon ring group can randomly be selected from down group replaces once or twice: methyl, the tertiary butyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, methoxyl group, methylene-dioxy, phenyl and morpholinyl.

So preferred embodiment in, Y represents phenyl, the substituting group that randomly is selected from down group replaces once or twice: methyl, the tertiary butyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, methoxyl group, methylene-dioxy, phenyl and morpholinyl.

So preferred embodiment in, Y represents phenyl, is randomly replaced by alkyl, halogen, haloalkyl, alkoxyl group, methylene-dioxy, phenyl or morpholinyl.

So preferred embodiment in, Y represents phenyl, is randomly replaced by methyl, the tertiary butyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, methoxyl group, methylene-dioxy, phenyl or morpholinyl.

So preferred embodiment in, Y represents heterocyclic group, and the substituting group that this carbon ring group or heterocyclic group can randomly be selected from down group replaces one or many: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro, amino.

So preferred embodiment in, Y represents THP trtrahydropyranyl, pyrrolidyl, piperidyl, furyl, thienyl, pyrryl, pyridyl, indyl or quinolyl.

In most preferred embodiments, Y represents THP trtrahydropyranyl, pyridyl, indyl or quinolyl.

The 4th kind preferred embodiment in, pyrazolyl-quinazoline derivant of the present invention is formula I compound, wherein R ¹, R ²And R ³Represent hydrogen, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino independently of one another.

The 5th kind preferred embodiment in, pyrazolyl-quinazoline derivant of the present invention is formula I compound, wherein R ¹, R ²And R ³Represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro or amino independently of one another.

In preferred embodiment, R ¹, R ²And R ³Represent alkyl, cycloalkyl or cycloalkyl-alkyl independently of one another.

So preferred embodiment in, R ¹, R ²And R ³Represent hydrogen or alkyl independently of one another.

So preferred embodiment in, R ¹, R ²And R ³Represent methylidene, ethyl or propyl group independently of one another.

So preferred embodiment in, R ¹And R ²Represent hydrogen or alkyl independently of one another; And R ³Represent hydrogen.

In further preferred embodiment, R ¹And R ²Represent alkyl independently of one another; And R ³Represent hydrogen.

So preferred embodiment in, R ¹And R ²Represent methylidene or sec.-propyl; And R ³Represent hydrogen.

So preferred embodiment in, R ¹And R ²Represent methylidene; And R ³Represent hydrogen.

So preferred embodiment in, R ¹And R ²Represent sec.-propyl; And R ³Represent hydrogen.

So preferred embodiment in, R ¹Represent methylidene; And R ²And R ³Represent hydrogen.

So preferred embodiment in, R ¹, R ²And R ³Represent hydrogen.

The 6th kind preferred embodiment in, pyrazolyl-quinazoline derivant of the present invention is a formula I compound, wherein n is 0; X represents O, S or NR '; Wherein R ' represents hydrogen, methyl, ethyl or propyl group; Y represents alkyl, thiazolinyl, cycloalkyl, alkyl-cycloalkyl; R ¹And R ²Represent methylidene or sec.-propyl; And R ³Represent hydrogen.

In preferred embodiment, n is 0; X represents NH; Y represents alkyl, thiazolinyl, cycloalkyl, alkyl-cycloalkyl, naphthyl, 1,2,3,4-tetrahydrochysene-naphthyl, dihydro indenyl, THP trtrahydropyranyl, pyridyl, indyl or quinolyl; R ¹And R ²Represent methylidene or sec.-propyl; And R ³Represent hydrogen.

The 7th kind preferred embodiment in, pyrazolyl-quinazoline derivant of the present invention is a formula I compound, wherein n is 0; X represents NR '; Wherein R ' represents hydrogen, methyl, ethyl or propyl group; Y represents alkyl (ethyl, propyl group, butyl), cycloalkyl (cyclopropyl, cyclopentyl, cyclohexyl, ring octyl group), cycloalkyl-alkyl or alkenyl (allyl group), piperidyl or phenyl, and this phenyl can randomly be replaced once or twice by halogen or trifluoromethyl; And R ¹, R ²And R ³Represent methylidene, ethyl or propyl group independently of one another.

The 8th kind preferred embodiment in, pyrazolyl-quinazoline derivant of the present invention is a formula I compound, wherein n is 0 or 1; X represents NH; Y represents phenyl, and the substituting group that randomly is selected from down group replaces once or twice: alkyl, halogen, haloalkyl, alkoxyl group, methylene-dioxy, phenyl and morpholinyl; R ¹And R ²Represent methylidene or sec.-propyl; And R ³Represent hydrogen.

In preferred embodiment, n is 0; X represents NH; Y represents phenyl, and the substituting group that randomly is selected from down group replaces once or twice: alkyl, halogen, haloalkyl, alkoxyl group, methylene-dioxy, phenyl and morpholinyl; R ¹And R ²Represent methylidene or sec.-propyl; And R ³Represent hydrogen.

So preferred embodiment in, n is 1; X represents NH; Y represents phenyl, and the substituting group that randomly is selected from down group replaces once or twice: alkyl, halogen, haloalkyl, alkoxyl group, methylene-dioxy, phenyl and morpholinyl; R ¹And R ²Represent methylidene or sec.-propyl; And R ³Represent hydrogen.

So preferred embodiment in, n is 1; X represents NH; Y represents phenyl, and the substituting group that randomly is selected from down group replaces once or twice: halogen or haloalkyl; R ¹And R ²Represent methylidene; And R ³Represent hydrogen.

The 9th kind preferred embodiment in, pyrazolyl-quinazoline derivant of the present invention is a formula I compound, wherein n is 0; X represents NR '; R ' constitutes pyrrolidyl or piperidines basic ring with Y and the nitrogen that is connected with them; R ¹, R ²And R ³Represent methylidene, ethyl or propyl group independently of one another.

The tenth kind preferred embodiment in, pyrazolyl-quinazoline derivant of the present invention is a formula I compound, wherein n is 0; X represents NR '; R ' constitutes pyrrolidyl, piperidyl, piperazinyl or morpholine basic ring with Y and the nitrogen that is connected with them; R ¹And R ²Represent methylidene, ethyl or propyl group independently of one another; And R ³Represent hydrogen.

The 11 kind preferred embodiment in, pyrazolyl-quinazoline derivant of the present invention is a formula I compound, wherein n is 1; And X represents NR '; Wherein R ' represents hydrogen, methyl, ethyl or propyl group; Y represents furyl, thienyl or phenyl, and this phenyl can randomly be replaced once or twice by halogen or trifluoromethyl; And R ¹, R ²And R ³Represent methylidene, ethyl or propyl group independently of one another.

In most preferred embodiments, pyrazolyl-quinazoline derivant of the present invention is

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-propyl group amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-ethylamine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-diethyl-amine;

Butyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

Allyl group-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

Cyclopropyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

Cyclopentyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

Cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

Suberyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

Ring octyl group-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

2-(3,5-dimethyl-pyrazol-1-yl)-4-piperidines-1-base-quinazoline;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-piperidin-4-yl-amine;

Benzyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(4-chloro-benzyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(3,4-two fluoro-benzyls)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-furans-2-ylmethyl-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-thiophene-2-ylmethyl-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-phenyl-amine;

(4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(3-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(2-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(3,4-two chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(4-bromo-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(3-trifluoromethyl-phenyl)-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(3-methoxyl group-phenyl)-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-p-tolyl-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-m-tolyl-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-o-tolyl-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-naphthalene-2-base-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(1,2,3,4-tetrahydrochysene-naphthalene-1-yl)-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(2-tetramethyleneimine-1-base-ethyl)-amine;

Cyclohexyl-[2-(3-methyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

S-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(S)-1,2,3,4-tetrahydrochysene-naphthalene-1-base-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(1-ethyl-propyl group)-amine;

[2-(3,5-di-isopropyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-methyl-cyclohexyl base)-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-pyridine-2-base-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-methyl-cyclohexyl base)-amine;

(the 4-tertiary butyl-cyclohexyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(tetrahydrochysene-pyrans-4-yl)-amine;

Cyclohexyl-[2-(3,5-di-isopropyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-dihydro indenes-2-base-amine;

Benzo [1,3] dioxole-5-base-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(3,5-pair-trifluoromethyl-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-quinoline-8-base-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-iodo-phenyl)-amine;

Biphenyl-4-base-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(1H-indoles-7-yl)-amine; Or

Cyclohexyl-(2-pyrazol-1-yl-quinazoline-4-yl)-amine;

Or its pharmacy acceptable salt.

The arbitrary combination of two or more embodiments described herein is regarded as within the scope of the invention.

Substituent definition

In the context of the present invention, halogen is represented fluorine, chlorine, bromine or iodine.Thereby, the methyl of trihalomethyl group typical example such as trifluoromethyl, trichloromethyl and similar three halogen-replacements.

In the context of the present invention, haloalkyl is represented alkyl as herein defined, and this alkyl is replaced one or many by halogen.The preferred haloalkyl of the present invention comprises trihalomethyl group, preferred trifluoromethyl.

In the context of the present invention, alkyl is represented the straight or branched hydrocarbon chain that monovalence is saturated.Hydrocarbon chain preferably contains one to 18 carbon atom (C _1-18-alkyl), more preferably one to six carbon atom (C _1-6-alkyl; Low alkyl group), comprise amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl and isohexyl.In preferred embodiment, alkyl represent C _1-4-alkyl comprises butyl, isobutyl-, sec-butyl and the tertiary butyl.Other-individual preferred embodiment of the present invention in, alkyl represent C _1-3-alkyl, it can be methyl, ethyl, propyl group or sec.-propyl especially.

In the context of the present invention, thiazolinyl represents to contain the carbochain of one or more pair of key, comprises diene, triolefin and polyenoid.In preferred embodiment, thiazolinyl of the present invention comprises two to eight carbon atom (C _2-8-thiazolinyl), more preferably two to six carbon atom (C _2-6-thiazolinyl), comprise at least one pair of key.In most preferred embodiments, thiazolinyl of the present invention is a vinyl; 1-or 2-propenyl; 1-, 2-or 3-butenyl, perhaps 1, the 3-butenyl; 1-, 2-, 3-, 4-or 5-hexenyl, perhaps 1,3-hexenyl or 1,3,5-hexenyl; 1-, 2-, 3-, 4-, 5-, 6-or 7-octenyl, perhaps 1,3-octenyl, 1,3,5-octenyl or 1,3,5,7-octenyl.

In the context of the present invention, cycloalkyl is represented cyclic alkyl, preferably contains three to ten carbon atom (C _3-10-cycloalkyl), preferred three to eight carbon atom (C _3-8-cycloalkyl), comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.

In the context of the present invention, cycloalkyl-alkyl is represented cycloalkyl as defined above, and this cycloalkyl is being substituted on the alkyl equally as defined above.The example of the preferred cycloalkyl-alkyl of the present invention comprises cyclopropyl methyl and cyclopropyl ethyl.

In the context of the present invention, alkoxyl group is represented " alkyl-O-" group, and wherein alkyl is as defined above.

In the context of the present invention, the haloalkoxy basis representation is alkoxyl group as herein defined, and this alkoxyl group is replaced one or many by halogen.The preferred halogenated alkoxy of the present invention comprises three halogenated methoxies, preferred trifluoromethoxy.

In the context of the present invention, amino can be monobasic (NH ₂), binary (NH-alkyl) or ternary (N (alkyl) ₂) amino, that is to say that it can be replaced once or twice by alkyl as defined above.

In the context of the present invention, monocycle or encircle carbon ring group more and represent monocycle or polycyclic hydrocarbyl group, this group is aromatic hydrocarbon radical particularly, just monocycle or polyaromatic, perhaps stable hydrocarbon group, the perhaps hydrocarbyl group of fractional saturation.Preferred many carbon ring groups are two ring carbon ring groups.

In the context of the present invention, monocycle or encircle carbon ring group more and represent monocycle or polycyclic hydrocarbyl group.The example of the preferred carbon ring group of the present invention comprises cycloalkyl, phenyl, naphthyl, indenyl, Azulene base, anthryl and fluorenyl.The most preferred carbon ring group of the present invention comprises phenyl, naphthyl and 1,2,3,4-tetrahydrochysene-naphthyl.

In the context of the present invention, monocycle or encircle heterocyclic group more and represent monocycle or many cyclic groups, this group has one or more heteroatomss in its ring structure.Preferred heteroatoms comprises nitrogen (N), oxygen (O) and sulphur (S).One or more ring structures are (heteroaryl just), saturated or fractional saturation of aromatics particularly.The preferred heterocycle monocyclic groups of the present invention comprises 5-and 6-unit heterocycle monocyclic groups.The preferred many heterocyclic groups of the present invention are bicyclic heterocyclic groups.

The example of the preferred heterocycle monocyclic groups of the present invention comprises pyrrolidyl, particularly tetramethyleneimine-1-base, tetramethyleneimine-2-base and tetramethyleneimine-3-base; Piperidyl, particularly piperidines-1-base, piperidines-2-base, piperidines-3-base and piperidin-4-yl; Furyl, particularly furans-2-base and furans-3-base; Thienyl, particularly thiophene-2-base and thiene-3-yl-; And pyrryl, particularly pyrroles-1-base, pyrroles-2-base and pyrroles-3-base.

Isomer

To be for what those skilled in the art understanded, can there be different stereoisomeric forms in any ratio in The compounds of this invention, comprises enantiomorph, diastereomer and geometrical isomer (cis-trans isomer).The present invention includes all such isomer and its any mixture, comprise racemic mixture.

Racemic form can be split as optical antipode by known method and technology.The mode of a kind of enantiomer separation compound (comprising the enantiomorph intermediate) is to use the amine of optically active, discharges diastereomeric salt through splitting by acid treatment.The method that another kind of resolution of racemic thing is an optical antipode is based on the chromatography on the optical activity matrix.Racemic compound of the present invention thereby can be split as their optical antipode, for example fractional crystallization of D-or L-(tartrate, amygdalic acid or camphorsulfonic acid) salt.

The compounds of this invention also can followingly split, make The compounds of this invention and optically active activating carboxy acid, for example from the spread out survivor reaction of (+) or (-) phenylalanine, (+) or (-) phenylglycocoll, (+) or (-) dextrocamphoric acid, form diastereomeric acid amides, perhaps make the reactions such as chloro-formic ester of The compounds of this invention and optically active, form diastereomeric carbamate.

Other methods that split optical isomer are known in the art.These class methods comprise Jaques J, ColletA ， ﹠amp; WilenS " Enantiomers, Racemates and Resolutions", John Wi1ey and Sons, described in the New York (1981) those.

Also can be from optical activity raw material or intermediate preparation optically active compound.

Pharmacy acceptable salt

The compounds of this invention may be provided as and is suitable for the form of planning administration arbitrarily.The form that is fit to comprises The compounds of this invention pharmaceutically (being on the physiology) acceptable salt and prodrug or prodrug form.

The example of pharmaceutically acceptable addition salt comprises nontoxic inorganic and organic acid addition salt without limitation, for example from hydrochloric acid deutero-hydrochloride, from Hydrogen bromide deutero-hydrobromate, from nitric acid deutero-nitrate, from perchloric acid deutero-perchlorate, from phosphoric acid deutero-phosphoric acid salt, from sulfuric acid deutero-vitriol, from formic acid deutero-formate, from acetate deutero-acetate, from equisetic acid deutero-aconitate, from xitix deutero-ascorbate salt, from Phenylsulfonic acid deutero-benzene sulfonate, from phenylformic acid deutero-benzoate, from styracin deutero-cinnamate, from citric acid deutero-Citrate trianion, from pamoic acid deutero-embonate, from enanthic acid deutero-enanthate, fumarate from fumarate derivative, glutaminate from glutamic acid derivative, from hydroxyethanoic acid deutero-oxyacetate, from lactic acid deutero-lactic acid salt, from toxilic acid deutero-maleate, from propanedioic acid deutero-malonate, from amygdalic acid deutero-mandelate, from methylsulfonic acid deutero-mesylate, from naphthalene-2-sulfonic acid deutero-naphthalene-2-sulfonic acid salt, from phthalic acid deutero-phthalate, from Whitfield's ointment deutero-salicylate, from Sorbic Acid deutero-sorbate, the stearate of deriving from stearic acid, from succsinic acid deutero-succinate, the tartrate of deriving from tartrate, from toluene-right-sulfonate deutero-toluene-right-sulfonate etc.Can form such salt by technology well known in the art and that described.

Other acid, for example oxalic acid, they may not be considered to be pharmaceutically acceptable, but can be used in the preparation of salt, and described salt can be used as intermediate product in obtaining The compounds of this invention and pharmaceutically-acceptable acid addition thereof.

The metal-salt of The compounds of this invention comprises an alkali metal salt of the The compounds of this invention that contains carboxyl, for example sodium salt.

In the context of the present invention, " the  salt " that contains the N compound also is considered to be pharmacy acceptable salt.Preferably "  salt " comprises alkyl- salt, cycloalkyl- salt and cycloalkylalkyl- salt.

The compounds of this invention can provide with solubility or insolubility form with pharmaceutically acceptable solvent, and described solvent is water, ethanol etc. for example.Soluble form also can comprise hydrated form, for example monohydrate, dihydrate and semihydrate, trihydrate, tetrahydrate etc.Usually, with regard to purpose of the present invention, soluble form is regarded as being equal to insoluble form.

The preparation method

The compounds of this invention can be prepared by the conventional chemical synthetic method, for example described in an embodiment those.The raw material of the described process of the application be known or can be easily by ordinary method from commercially available chemical production.

The end product of reaction described herein can separate by routine techniques, for example extraction, crystallization, distillation, chromatogram etc.

Biological activity

The compounds of this invention finds to can be used as especially potassium channel modulating agents through experiment in vitro.More precisely, The compounds of this invention can optionally be regulated SK1, SK2 and/or SK3 passage.

Therefore on the other hand, the present invention relates to the purposes that The compounds of this invention prepares medicine, this medicine can be used for the treatment of or alleviate and activity of potassium channels diseases associated or obstacle, SK passage particularly, and more definite is SK1, SK2 and/or SK3 passage.

In preferred embodiment, with activity of potassium channels diseases associated or obstacle be respiratory disease, epilepsy, faint from fear, epileptic seizures, petit mal, vasospasm, coronary vasospasm, nephropathy, polycystic kidney disease, cystospasm, the urinary incontinence, bladder outlet blocks, erective dysfunction, gastrointestinal dysfunction, secretory diarrhea, local asphyxia, cerebral ischemia, ischemic heart disease, stenocardia, coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, anxiety, depressed, mood disorder, dull-witted, memory and attention deficit, Alzheimer, amyotrophic lateral sclerosis (ALS), dysmenorrhoea, hypnolepsy, Raynaud disease, intermittent claudication, siogren's syndrome, irregular pulse, hypertension, the myotonic muscular dystrophy, spasticity, xerostomia, type ii diabetes, hyperinsulinemia, premature labor, alopecia, cancer, irritable bowel syndrome, immunosuppression, migraine or pain.

In preferred embodiment, with activity of potassium channels diseases associated or obstacle be respiratory disease, the urinary incontinence, erective dysfunction, anxiety, epilepsy, psychosis, schizophrenia, amyotrophic lateral sclerosis (ALS) or pain.

In another preferred embodiment, with activity of potassium channels diseases associated or obstacle be respiratory disease, particularly asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or rhinorrhea.

The third preferred embodiment in, with activity of potassium channels diseases associated or obstacle be the urinary incontinence.

The 4th kind preferred embodiment in, with activity of potassium channels diseases associated or obstacle be purplish or white patches on the skin epilepsy, epileptic seizures, petit mal or convulsions.

The 5th kind preferred embodiment in, with activity of potassium channels diseases associated or obstacle be respiratory disease, particularly asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or rhinorrhea.

Test compounds all shows micromole and other biological activity of sub-micro mole level, just from being lower than 1 to being higher than 100 μ M.Preferred The compounds of this invention mensuration as described herein shows sub-micro mole and other biological activity of micromole's level, just from being lower than 0.1 to about 10 μ M.

Pharmaceutical composition

On the other hand, the invention provides the novel pharmaceutical combination thing, it comprises the The compounds of this invention for the treatment of significant quantity.

Although the The compounds of this invention that is used for the treatment of can become pharmaceutical composition but preferably activeconstituents (optional form for acceptable salt on the physiology) is introduced with one or more auxiliary agents, vehicle, carrier and/or thinner with the form administration of starting compound.

In preferred embodiment, the invention provides pharmaceutical composition, it comprises The compounds of this invention or its pharmacy acceptable salt or derivative and one or more pharmaceutically acceptable carriers and optional other treatment and/or preventative composition.Carrier compatible with other compositions of preparation and to the harmless meaning of its recipient on must be " acceptable ".

Pharmaceutical composition of the present invention can be to be suitable for those of oral, rectum, segmental bronchus, nose, part (comprising oral cavity and hypogloeeis), transdermal, vagina or parenteral (comprise in skin, subcutaneous, intramuscular, intraperitoneal, intravenously, intra-arterial, the brain, intraocular injection or infusion) administration, perhaps be suitable for sucking or be blown into those of administration, comprise pulvis and liquid aerosol drug delivery, perhaps by those of sustained release system administration.The suitable example of sustained release system comprises the semipermeability matrix of the solid hydrophobic polymkeric substance that contains The compounds of this invention, and this matrix can be the formed article form, for example film or micro-capsule.

Thereby The compounds of this invention and conventional auxiliary agent, carrier or thinner can be made into the form of pharmaceutical composition and unitary dose thereof.This class form comprises solid, particularly tablet, filled capsules, powder and pill form, and liquid, and particularly moisture or non-aqueous solution, suspension, emulsion, elixir and be filled with their capsule all are to orally use; Rectal administration suppository; With the parenteral sterile injectable solution.Such pharmaceutical composition and unit dosage thereof can comprise the conventional ingredient of conventional ratio, and have or do not have other active compounds or composition, and such unit dosage can contain the effective amount of actives that arbitrarily be fit to suitable with application dose scope every day of expection.

The compounds of this invention can various oral and parenteral dosage form administrations.For a person skilled in the art, it is evident that following formulation can comprise The compounds of this invention or the The compounds of this invention pharmacy acceptable salt as activeconstituents.

For from the The compounds of this invention pharmaceutical compositions, pharmaceutically acceptable carrier can be solid or liquid.The preparation of solid form comprises powder, tablet, pill, capsule, cachet, suppository and dispersible granules agent.Solid carrier can be one or more materials that can also play thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, sanitas, tablet disintegrant or coating material effect.

In powder agent, carrier is a fine-grained solids, and it mixes with the segmentation active ingredient.

In tablet, activeconstituents mixes in the proper ratio with the carrier with necessary binding capacity and is compressed into required shape and size.

Powder agent and tablet preferably contain 5% or 10% to about 70% active compound.Suitable carriers is magnesiumcarbonate, Magnesium Stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.Active compound and preparation as the coating material of carrier desired to comprise in term " preparation ", and described coating material provides capsule, wherein contains or carrier-free activeconstituents suppressed by vector surrounds, and carrier combines with active compound thus.Similarly, also comprise cachet and lozenge.Tablet, powder agent, capsule, pill, cachet and lozenge can be as the solid forms that is suitable for oral administration.

In order to prepare suppository, at first with low-melting wax, as the mixture melt of glycerin fatty acid ester or theobroma oil, by stirring activeconstituents is evenly dispersed in wherein then.In the suitable big or small mould of the uniform mixture impouring that will melt then, make its cooling and curing thus.

The composition that is suitable for vagina administration can vaginal suppository, the form of tampon, ointment, gelifying agent, paste, foam or sprays exists, and described composition also contains suitable carrier known in the art except that containing activeconstituents.

Liquid preparation comprises solution, suspension and emulsion, for example, and the aqueous solution or water-propylene glycol solution.For example, the parenteral injection liquid preparation can be mixed with the solution of moisture polyoxyethylene glycol.

Therefore, The compounds of this invention can be mixed with and be used for administered parenterally (for example injection, as inject or continuous infusion) preparation, and can provide with the unit dosage form of ampoule, pre-filled syringe, small volume transfusion or with multi-dose container with the sanitas that adds.Said composition can be taked the form of suspension, solution or the emulsion of oiliness or aqueous carrier, and can contain the preparation composition, as suspension agent, stablizer and/or dispersion agent.In addition, activeconstituents can be a powder type, and the aseptic separation by sterile solid or obtain by the solution freeze-drying is used for before use preparing with suitable carriers such as aseptic, pyrogen-free water.

The aqueous solution that is suitable for orally using can prepare by solubilization of active ingredient is also added suitable tinting material, seasonings, stablizer and thickening material as required in water.

The aq suspension that is suitable for orally using can be dispersed in by active ingredient that will segmentation contain viscous substance, as natural or synthetic is gummy, prepare in the water of resin, methylcellulose gum, Xylo-Mucine or other known suspension agent.

Also comprise the solid form preparation of desiring before facing usefulness, to be converted into the liquid form preparation that is used for oral administration.Such liquid form comprises solution, suspension and emulsion.Except that active ingredient, such preparation can comprise tinting material, seasonings, stablizer, buffer reagent, artificial and natural sweeting agent, dispersion agent, thickening material, solubilizing agent etc.

In order to locally apply to epidermis, The compounds of this invention can be mixed with ointment, creme, or lotion, or transdermal patch.For example, ointment and creme can add suitable thickening and/or jelling agent is formulated with water-based or oleaginous base.Lotion can be formulated with water-based or oleaginous base, and also contain one or more emulsifying agents, stablizer, dispersion agent, suspension agent, thickening material or tinting material usually.

Be suitable for that topical drug delivery composition is included in flavoured base in the oral cavity, be generally the lozenge that comprises activeconstituents in sucrose and kordofan gum or the tragacanth gum; The pastille (pastilles) that comprises activeconstituents at inert base, as gelatin and glycerine or sucrose and kordofan gum; And the mouth wash shua that in suitable liquid vehicle, comprises activeconstituents.

Solution or suspension for example can be applied directly to nasal cavity with dropper, transfer pipet or atomizer with ordinary method.Said composition can single dose or the form of multiple doses provide.Under the latter instance of dropper or transfer pipet, this can realize by the solution from suitable pre-determined volume to the patient or the suspension that give.Under the situation of atomizer, this can realize by for example measuring the atomisation pump.

Respiratory tract administration also can be realized by aerosol, wherein activeconstituents provides in pressurized package with suitable propelling agent, suitable propelling agent comprises chlorofluorocarbon (CFC) for example Refrigerant 12, trichlorofluoromethane or dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas.Aerosol also can contain tensio-active agent such as Yelkin TTS expediently.The dosage of medicine can be by being equipped with metering valve control.

Perhaps, activeconstituents can provide by dry powder form, for example the powdered mixture of compound in suitable powder matrix such as lactose, starch, starch derivative such as Vltra tears and polyvinylpyrrolidone (PVP).Expediently, powder carrier will form gel at nasal cavity.Powder composition can present by unit dosage form, for example with capsule or cartridge case (as the capsule or the cartridge case of gelatin) form, or can be by the sucker Blister Package form of administration therefrom with powder.

Comprise intranasal compositions at the composition of desiring to be used for respiratory tract administration, compound has little particle diameter usually, for example is 5 microns or the littler order of magnitude.Such particle diameter can be by methods known in the art, for example obtain by micronization.

When needing, can use the composition that is fit to provide the lasting release of activeconstituents.

Pharmaceutical preparation is preferably unit dosage form.In such form, preparation is subdivided into the unitary dose that contains an amount of active ingredient.Unit dosage form can be the preparation of packing, and this packing contains the preparation of fractional dose, as tablet, the capsule of packing, and the powder in bottle or the ampoule.In addition, unit dosage form can be capsule, tablet, cachet or a lozenge itself, maybe can be the packaged form that is fit to any of these formulation of quantity.

The tablet or the capsule that are used for oral administration are preferred compositions with the liquid and the continuous infusion liquid that are used for intravenously administrable.

About the more detailed data of preparation and medicine-feeding technology can (Maack PublishingCo.Easton finds on PA) at the Reminaton ' of latest edition s Pharmaceutical Sciences.

The treatment effective dose refers to the amount of activeconstituents, and it can improve symptom or symptom.Treatment effectiveness and toxicity, for example ED ₅₀And LD ₅₀Can in cell culture or laboratory animal, be measured by standard pharmacology program.But the dosage between result of treatment and the toxic action is than being therapeutic index and passing ratio LD ₅₀/ ED ₅₀Expression.Preferably show the pharmaceutical composition of big therapeutic index.

The dosage that gives certainly must be at age, body weight and the illness of the individuality of being treated, route of administration, dosage form and dosage regimen, and the result of expectation and adjusting carefully, and definite dosage should be determined by the doctor certainly.

Actual dosage depends on the character and the severity of the disease for the treatment of, and within doctor's determination range, and can be according to the present invention particular case the reaction of dosage is changed, to produce required result of treatment.Yet expection at present contains from about 0.1 to about 500mg, preferably from about 1 to about 100mg, most preferably the pharmaceutical composition from about activeconstituents of 1 to about 10mg/single dosage is suitable for therapeutic treatment.

Activeconstituents can every day one or several doses give.In some cases, can obtain gratifying result with the dosage that is low to moderate 0.1 μ g/ kilogram (intravenously) and 1 μ g/ kilogram (oral).Think that at present the upper limit of dosage range is about 10mg/ kilogram (intravenously) and 100mg/ kilogram (oral).Preferable range is from about 0.1 μ g/ kilogram/day to about 10mg/ kilogram/day (intravenously), and from about 1 μ g/ kilogram/day to about 100mg/ kilogram/day (oral).

Methods of treatment

On the other hand, the invention provides prevention, treat or alleviate animal body alive, comprise people's the disease or the method for obstacle or illness, this disease, obstacle or illness are replied potassium channel, the particularly adjusting of SK passage, and this method comprises a kind of like this animal body that the work of needs arranged, comprises that the people treats the The compounds of this invention of significant quantity.

The of the present invention preferred indication of expection is those of above stating.

The dosage range that expection at present is fit to is 0.1 to 1000 milligram of every day, 10-500 milligram every day, especially 30-100 milligram every day, usually depend on definite administering mode, institute's administration form, administration at indication, curee who is involved and the curee's who is involved body weight, and further, attending doctor or animal doctor's preference and experience.

In some cases, under the low dosage that reaches 0.005mg/kgi.v. and 0.01mg/kgp.o., can obtain gratifying result.Be limited to about 10mg/kgi.v. and 100mg/kgp.o. on the dosage range.Preferred range is about 0.001 to about 1mg/kgi.v. and about 0.1 to about 10mg/kgp.o..

Embodiment

Further set forth invention with reference to the following example, they do not plan to limit by any way the scope of the present invention for required protection.

Embodiment 1

Preparation embodiment

Method A

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-propyl group amine, hydrochloride (compd A 1)

With 2, (600mg 3.01mmol) is dissolved in acetonitrile (10mL) to 4-two chloro-quinazolines.Add propyl group amine (200mg, 3.3mmol) and triethylamine (2.1mL, 15mmol).Mixture at room temperature stirred spend the night.Filter, evaporated filtrate obtains yellow solid, and it is dissolved in ethyl acetate, washes with water three times.Dry (sal epsom) filters and evaporation, obtains (2-chloro-quinazoline-4-yl)-propyl group amine, is yellow solid.

With (2-chloro-quinazoline-4-yl)-propyl group amine (450mg 2.03mmol) is dissolved in acetonitrile (7.5mL), add 3 (215mg, 2.23mmol).Mixture was heated 20 minutes in 170 ℃ of microwave ovens.Filter, obtain [2-(3-1-yl)-quinazoline-4-yl]-propyl group amine, hydrochloride (290mg, 51%) is incarnadine crystallinity compound.Mp.208℃.

Similar with it preparation following compounds.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-ethylamine, hydrochloride (compd A 2)

According to method A preparation, start from 2,4-two chloro-quinazolines, ethylamine and 3.Mp.286℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-diethyl-amine, hydrochloric acid Salt (compound A-13)

According to method A preparation, start from 2,4-two chloro-quinazolines, diethylamide and 3.Mp.156.3℃.

Butyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine, hydrochloride (chemical combination Thing A4)

According to method A preparation, start from 2,4-two chloro-quinazolines, butylamine and 3.Mp.98.4℃.

Allyl group-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine, hydrochloride (is changed Compound A5)

According to method A preparation, start from 2,4-two chloro-quinazolines, allyl amine and 3.Mp.211-212℃.

Cyclopropyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine, hydrochloride (is changed Compound A6)

According to method A preparation, start from 2,4-two chloro-quinazolines, cyclopropylamine and 3.Mp.254℃.

Cyclopentyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine, hydrochloride (is changed Compound A7)

According to method A preparation, start from 2,4-two chloro-quinazolines, cyclopentyl amine and 3.Mp.263.2℃.

Cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine, hydrochloride (compound A-28)

According to method A preparation, start from 2,4-two chloro-quinazolines, cyclo-hexylamine and 3.Mp.137.6-142.7℃.

Suberyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinoline azoles beautiful jade-4-yl]-amine, hydrochloric acid Salt (compd A 9)

According to method A preparation, start from 2,4-two chloro-quinazolines, cycloheptylamino and 3.Mp.207℃.

Ring octyl group-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine, hydrochloric acid Salt (compd A 10)

According to method A preparation, start from 2,4-two chloro-quinazolines, ring octyl amine and 3.Mp.211℃.

2-(3,5-dimethyl-pyrazol-1-yl)-4-piperidines-1-base-quinazoline, hydrochloride (chemical combination Thing A11)

According to method A preparation, start from 2,4-two chloro-quinazolines, piperidines and 3.Mp.157℃.

Benzyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine, hydrochloride (compd A 12)

According to method A preparation, start from 2,4-two chloro-quinazolines, benzyl amine and 3.Mp.160.2℃.

(4-chloro-benzyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinoline azoles beautiful jade-4-yl]-amine, Hydrochloride (compd A 13)

According to method A preparation, start from 2,4-two chloro-quinazolines, 4-benzyl chloride base amine and 3 .LC-ESI-HRMS[M+H]+364.1319Da.Calc.364.132898Da.

(3,4-two fluoro-benzyls)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]- Amine, hydrochloride (compd A 14)

According to method A preparation, start from 2,4-two chloro-quinazolines, 3,4-difluorobenzyl amine and 3.Mp.165℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(1,2,3,4-tetrahydrochysene-naphthalene -1-yl)-and amine, hydrochloride (compd A 15)

According to method A preparation, start from 2,4-two chloro-quinazolines, 1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE and 3.Mp.221℃.

S-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(S)-1,2,3,4-four Hydrogen-naphthalene-1-base-amine, hydrochloride (compd A 16)

According to method A preparation, start from 2,4-two chloro-quinazolines, S-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE and 3.Mp.214℃.

Cyclohexyl-[2-(3-methyl-pyrazol-1-yl)-quinazoline-4-yl]-amine, hydrochloride (is changed Compound A17)

According to method A preparation, start from 2,4-two chloro-quinazolines, cyclo-hexylamine and 3-methylpyrazole.Mp.269-274.3℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(1-ethyl-propyl group)-amine, Hydrochloride (compd A 18)

According to method A preparation, start from 2,4-two chloro-quinazolines, 3-aminopentane and 3.Mp.96.4℃.

[2-(3,5-di-isopropyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-methyl-cyclohexyl Base)-and amine, hydrochloride (compd A 19)

According to method A preparation, start from 2,4-two chloro-quinazolines, 4-methylcyclohexyl amine and 3,5-di-isopropyl pyrazoles.Mp.134.6℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-methyl-cyclohexyl Base)-and amine, hydrochloride (compd A 20)

According to method A preparation, start from 2,4-two chloro-quinazolines, 4-methylcyclohexyl amine and 3.Mp.80.4-81.6℃.

(the 4-tertiary butyl-cyclohexyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4- Base]-amine, hydrochloride (compd A 21)

According to method A preparation, start from 2,4-two chloro-quinazolines, 4-tert-butylcyclohexyl amine and 3.Mp.253-255℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(tetrahydrochysene-pyrans-4-yl)- Amine, hydrochloride (compd A 22)

According to method A preparation, start from 2,4-two chloro-quinazolines, 4-amino tetrahydro pyran and 3.Mp.269-272.3℃.

Cyclohexyl-[2-(3,5-di-isopropyl-pyrazol-1-yl)-quinoline azoles beautiful jade-4-yl]-amine, salt Hydrochlorate (compd A 23)

According to method A preparation, start from 2,4-two chloro-quinazolines, cyclo-hexylamine and 3,5-di-isopropyl pyrazoles replaces triethylamine with sodium hydride as alkali.Mp.83.4-85.3℃

4-hexamethylene sulfane base-2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline, hydrochloride (chemical combination Thing A24)

According to method A preparation, start from 2,4-two chloro-quinazolines, hexanaphthene mercaptan and 3 replace triethylamine with sodium hydride as alkali.Mp.92.7-94.1℃.

4-cyclohexyl oxygen base-2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline, hydrochloride (chemical combination Thing A25)

According to method A preparation, start from 2,4-two chloro-quinazolines, hexalin and 3.Mp.152.9-153.5℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-dihydro indenes-2-base-amine, Hydrochloride (compd A 26)

According to method A preparation, start from 2,4-two chloro-quinazolines, 2-amido dihydro indenes and 3.Mp.212-215℃.

Cyclohexyl-(2-pyrazol-1-yl-quinoline azoles beautiful jade-4-yl)-amine (compd A 27)

According to method A preparation, start from 2,4-two chloro-quinazolines, cyclo-hexylamine and pyrazoles.[M+H]+LC-ESI-HRMS show 294.173Da.Calc.294.17187Da, dev.3.8ppm.

Method B

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-phenyl-amine (compound B-11)

With 2, (500mg 2.5mmol) is dissolved in acetonitrile (3mL) to 4-two chloro-quinazolines.Add aniline (260mg, 2.76mmol) and triethylamine (380mg, 3.75mmol).With mixture on 60 ℃ of sand-baths, jolting 12 hours in the bottle of sealing.Filter and evaporated filtrate, obtain yellow solid.Handle (ethyl acetate: hexane), obtain (2-chloro-quinazoline-4-yl)-propyl group amine (350mg, 55%) through column chromatography.

With (2-chloro-quinazoline-4-yl)-phenyl amine (250mg 0.98mmol) is dissolved in acetonitrile (4mL), add 3 (140mg, 1.47mmol).Mixture was heated 12 hours in the pipe of 130 ℃ of sealings.Mixture is concentrated, and resistates alkalizes with sodium bicarbonate, uses chloroform extraction, through anhydrous sodium sulfate drying, filters and evaporation.Crude product obtains [2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-phenyl-amine (150mg, 49%) through column chromatography purifying (ethyl acetate/hexane).Mp.262.4-265.3℃.

Similar with it preparation following compounds:

(4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine (is changed Compound B2)

According to method B preparation, start from 2,4-two chloro-quinazolines, 4-chloroaniline and 3.Mp.209.3-211.2℃.

(3-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine (is changed Compound B3)

According to method B preparation, start from 2,4-two chloro-quinazolines, 3-chloroaniline and 3.Mp.259.1-262.4℃.

(2-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine (is changed Compound B4)

According to method B preparation, start from 2,4-two chloro-quinazolines, 2-chloroaniline and 3.Mp.210.4-217.1℃.

(3,4-two chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]- Amine (compd B 5)

According to method B preparation, start from 2,4-two chloro-quinazolines, 3,4-dichlorphenamide bulk powder and 3.Mp.223.9-226.5℃.

(4-bromo-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine (is changed Compound B6)

According to method B preparation, start from 2,4-two chloro-quinazolines, 4-bromaniline and 3.Mp.116.2-168.3℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-trifluoromethyl-benzene Base)-amine (compd B 7)

According to method B preparation, start from 2,4-two chloro-quinazolines, 4-5-trifluoromethylaniline and 3.Mp.218.8-220.1℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(3-methoxyl group-phenyl)- Amine (compd B 8)

According to method B preparation, start from 2,4-two chloro-quinazolines, m-methyl oxyaniline and 3.Mp.193.1-194.7℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-p-tolyl-amine (chemical combination Thing B9)

According to method B preparation, start from 2,4-two chloro-quinazolines, p-Tolylamine and 3.Mp.210.4-216.2℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-m-tolyl-amine (chemical combination Thing B10)

According to method B preparation, start from 2,4-two chloro-quinazolines, m-Tolylamine and 3.Mp.249.2-250.4℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-o-tolyl-amine (chemical combination Thing B11)

According to method B preparation, start from 2,4-two chloro-quinazolines, o-Tolylamine and 3.Mp.240.1-244.4℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-naphthalene-2-base-amine (compound B12)

According to method B preparation, start from 2,4-two chloro-quinazolines, 2-ALPHA-NAPHTHYL AMINE and 3.Mp.213.3-215.6℃.

Benzo [1,3] dioxole-5-base-[2-(3,5-dimethyl-pyrazol-1-yl)- Quinazoline-4-yl]-amine (compound B-11 3)

According to method B preparation, start from 2,4-two chloro-quinazolines, 3,4-(methylene-dioxy) aniline and 3.[M+H]+LC-ESI-HRMS show 360.148Da.Calc.360.14605Da, dev.5.4ppm.

(3,5-couple-trifluoromethyl-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline -4-yl]-amine (compound B-11 4)

According to method B preparation, start from 2,4-two chloro-quinazolines, 3, two (trifluoromethyl methyl) aniline and the 3 of 5-.Mp.169.2-172.4C.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-morpholine-4-base-benzene Base)-amine (compound B-11 5)

According to method B preparation, start from 2,4-two chloro-quinazolines, N-(4-aminophenyl)-morpholine and 3.Mp.268.2-270.4℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinoline azoles beautiful jade-4-yl]-quinoline beautiful jade-8-base-amine (chemical combination Thing B16)

According to method B preparation, start from 2,4-two chloro-quinazolines, 8-quinolylamine and 3.Mp.183.5-184.8℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-iodo-phenyl)-amine (is changed Compound B17)

According to method B preparation, start from 2,4-two chloro-quinazolines, 4-Iodoaniline and 3.Mp.226.5-229.1℃.

Biphenyl-4-base-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine (chemical combination Thing B18)

According to method B preparation, start from 2,4-two chloro-quinazolines, 4-phenylaniline and 3.Mp.267.5-270.3℃.

2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(3-trifluoromethyl-phenyl)- Amine (compound B-11 9)

According to method B preparation, start from 2,4-two chloro-quinazolines, 3-5-trifluoromethylaniline and 3.Mp.233.1-239.6℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-pyridine-2-base-amine (chemical combination Thing B20)

According to method B preparation, start from 2,4-two chloro-quinazolines, 2-aminopyridine and 3.Mp.126.1-126.8℃.

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(1H-indoles-7-yl)- Amine, hydrochloride (compd B 21)

According to method B preparation, start from 2,4-two chloro-quinazolines, 6-amino indole and 3.Mp.298.5-303.4℃.

Embodiment 2

Biological activity

The biological activity of present embodiment proof representative compounds of the present invention (compound A-28).Utilize the whole-cell configuration of patch clamp technology to write down little electricity and lead Ca ²⁺-activation K ⁺The ion(ic)current of passage (SK passage, hypotype 3).

Clone little electricity from people's skeletal muscle and lead Ca ²⁺-activation K ⁺Passage hypotype 3 (SK ₃), and in the HEK293 cell stably express.

SK in the HEK293 cell ₃Stably express

With people SK ₃(hSK3) subclone is in expression vector pNS3n, and this is a kind of from pcDNA3 deutero-custom carrier (InVitrogen), obtains plasmid construction body pNS3_hSK3.At 37 ℃ of following and 5%CO ²In, the HEK293 tissue culture cells is grown in DMEM (DulbeccoShi modification Eagle substratum), wherein be supplemented with 10%FCS (foetal calf serum).Culturing cell to 50% merges in T25 cell cultures flask, utilizes lipofectamin (InVitrogen) with 2.5 μ gpNS3-hSK3 transfections.In the substratum that is supplemented with 0.25mg/ml Zeocin, select through cells transfected.Choose single clone, in selecting substratum, breed, until obtaining enough refrigerated cells.Culturing cell in not having the conventional substratum of selective agent then.Expression by patch clamp method of masurement authentication functionality hSK3 passage.

Full cell record

One of several patch clamp settings are experimentized.Place in the 15 μ L filling cavities that are installed on the IMT-2 microscope (flow velocity～1mL/min) with being tiled in cell on the cover glass.Microscope is placed on the friction platform of flooring Faraday cage.All experiment all is (20-22 ℃) that at room temperature carries out.(HEKA-electronics, Lambrect Germany) are connected with macintosh computer with EPC-9 patch clamp amplifier via the ITC16 interface.Data directly are stored on the hard disk, and with the IGOR software analysis (Wavemetrics, LakeOswega, OR, USA).

Adopt the whole-cell configuration of patch clamp technology.In brief: utilize tele-control system that the tip of borosilicate transfer pipet (resistance 2-4M Ω) is placed on the cytolemma gently.Slight suction causes the formation (resistance of transfer pipet increases to more than the 1G Ω) of gigabit (giga) sealing, makes the membranolysis of transfer pipet below then by more strong suction.The electronic compensation cell capacitance, and the resistance between measurement and compensation transfer pipet and the cell interior (series resistance, Rs).Usually, cell capacitance is 5 to 20pF (depending on the cell size), and series resistance is in the scope of 3 to 6M Ω.Upgrade Rs and capacitance compensation (before each the stimulation) at experimental session.All have the experiment of drift Rs-value and give it up.Do not carry out the seepage deduction.

Solution

Extracellular (bath) solution contains (in mM): 140NaCl, 4KCl, 0.1CaCl ₂, 3MgCl ₂, 10HEPES (pH=7.4, HCl).Test-compound is dissolved in 1000 times of diluents of dense stock solution in DMSO, in the solution of extracellular, dilutes then.

(transfer pipet) solution has following composition (in mM) in the cell: 105KCl, 45KOH, 10EGTA, 1.21MgCl ₂, 7.63CaCl ₂And 10HEPES (pH=7.2, HCl).As calculated, the Free Ca in this solution ²⁺Concentration is 300nM, and free Mg ²⁺Concentration is 1mM.

Quantize

After setting up whole-cell configuration, from keeping current potential-80mV, per 5 seconds to cell apply the voltage gradient (normal for-120 to+30mV).Obtain stable base current in second at 100-500, add compound by becoming the extracellular solution that contains test-compound then.Under these situations, very small endogenous electric current in natural HEK293 cell (under 30mV＜and 200pA, with SK ₃Electric current is that 2-10nA compares) be activated.

By the variation of the base current under the calculating-20mV active compound is carried out quantitatively.There is not the electric current under the compound existence to be set to 100%.The numerical value of activator will be greater than 100, and numerical value is 200% to show current doubles.On the other hand, numerical value is 50% to show that compound reduces base current to one half value.

With regard to activator, can estimate SC ₁₀₀Value.SC ₁₀₀Value is defined as increasing base current and reaches 100% required irritating concentration.The SC of the The compounds of this invention A8 that measures ₁₀₀Value is 0.035 μ M, and this is its powerful SK ₃The indication of activation character.

Claims (21)

1. pyrazolyl-quinazoline derivant of formula I

Its isomer or its isomer mixture, its N-oxide compound or its pharmacy acceptable salt, wherein

N is 0,1,2 or 3;

X represents O, S or NR '; Wherein

R ' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl;

Perhaps when n be 0 and X when being NR ', R ' constitutes heterocycle with Y and the nitrogen that is connected with them, this heterocycle can randomly be replaced by alkyl or phenyl;

Y represents alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, thiazolinyl, perhaps monocycle or polycyclic carbocyclic ring or heterocyclic group, the substituting group that this carbocyclic ring or heterocyclic group can randomly be selected from down group replaces one or many: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro, amino, methylene-dioxy, phenyl and morpholinyl;

Perhaps when n be 0 and X when being NR ', Y constitutes heterocycle with R ' and the nitrogen that is connected with them, this heterocycle can randomly be replaced by alkyl or phenyl; And

R ¹, R ²And R ³Represent hydrogen, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino independently of one another.

2. pyrazolyl-the quinazoline derivant of claim 1, wherein

N is 0,1,2 or 3.

3. each pyrazolyl-quinazoline derivant of claim 1-2, wherein

X represents O, S or NR '; Wherein

R ' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl;

Perhaps when n be 0 and X when being NR ', R ' constitutes heterocycle with Y and the nitrogen that is connected with them, this heterocycle can randomly be replaced by alkyl or phenyl.

4. pyrazolyl-the quinazoline derivant of claim 1, wherein

N is 0;

X represents NR '; And

R ' constitutes heterocycle with Y and the nitrogen that is connected with them, and this heterocycle can randomly be replaced by alkyl or phenyl.

5. any one the pyrazolyl-quinazoline derivant of claim 1-4, wherein

Y represents alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, thiazolinyl, perhaps monocycle or polycyclic carbocyclic ring or heterocyclic group, the substituting group that this carbocyclic ring or heterocyclic group can randomly be selected from down group replaces one or many: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro, amino, methylene-dioxy, phenyl and morpholinyl;

Perhaps when n be 0 and X when being NR ', Y constitutes heterocycle with R ' and the nitrogen that is connected with them, this heterocycle can randomly be replaced by alkyl or phenyl.

6. pyrazolyl-the quinazoline derivant of claim 5, wherein Y represents alkyl, thiazolinyl or cycloalkyl.

7. pyrazolyl-the quinazoline derivant of claim 5, wherein Y representative

Monocycle or polycyclic carbon ring group are selected from phenyl, naphthyl or 1,2,3,4-tetrahydrochysene-naphthyl; Perhaps monocycle or polycyclic heterocyclic group are selected from pyrrolidyl, piperidyl, furyl, thienyl and pyrryl; This phenyl, naphthyl, 1,2,3, the substituting group that 4-tetrahydrochysene-naphthyl, pyrrolidyl, piperidyl, furyl, thienyl and pyrryl can randomly be selected from down group replaces once or twice: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro and amino.

8. pyrazolyl-the quinazoline derivant of claim 5, wherein Y representative

Monocycle or polycyclic carbon ring group, be selected from phenyl, naphthyl, 1,2,3,4-tetrahydrochysene-naphthyl and dihydro indenyl, the substituting group that this carbon ring group can randomly be selected from down group replaces one or many: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro, amino, methylene-dioxy, phenyl and morpholinyl.

9. pyrazolyl-the quinazoline derivant of claim 5, wherein Y representative

Heterocyclic group, the substituting group that this carbon ring group or heterocyclic group can randomly be selected from down group replaces one or many: alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, cyano group, nitro, amino.

10. any one the pyrazolyl-quinazoline derivant of claim 1-9, wherein

R ¹, R ²And R ³Represent hydrogen, alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxyl-alkyl, alkoxyl group-alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, halogen, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, alkoxyl group-carbonyl, cyano group, nitro and amino independently of one another.

11. the pyrazolyl-quinazoline derivant of claim 10, wherein

R ¹And R ²Represent hydrogen or alkyl independently of one another; And

R ³Represent hydrogen.

12. the pyrazolyl-quinazoline derivant of claim 1, wherein

N is 0;

X represents O, S or NR '; Wherein R ' represents hydrogen, methyl, ethyl or propyl group;

Y represents alkyl, thiazolinyl, cycloalkyl, alkyl-cycloalkyl; And

R ¹And R ²Represent methylidene or sec.-propyl; And

R ³Represent hydrogen.

13. the pyrazolyl-quinazoline derivant of claim 1, wherein

N is 0 or 1;

X represents NH;

Y represents phenyl, and the substituting group that randomly is selected from down group replaces once or twice: alkyl, halogen, haloalkyl, alkoxyl group, methylene-dioxy, phenyl and morpholinyl;

R ¹And R ²Represent methylidene or sec.-propyl; And

R ³Represent hydrogen.

14. the pyrazolyl-quinazoline derivant of claim 1, wherein

N is 0;

X represents NR '; And

R ' constitutes pyrrolidyl, piperidyl, piperazinyl or morpholine basic ring with Y and the nitrogen that is connected with them; And

R ¹And R ²Represent methylidene, ethyl or propyl group independently of one another; And

R ³Represent hydrogen.

15. the pyrazolyl-quinazoline derivant of claim 1, it is

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-propyl group amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-ethylamine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-diethyl-amine;

Butyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

Allyl group-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

Cyclopropyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

Cyclopentyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

Cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

Suberyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

Ring octyl group-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

2-(3,5-dimethyl-pyrazol-1-yl)-4-piperidines-1-base-quinazoline;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-piperidin-4-yl-amine;

Benzyl-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(4-chloro-benzyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(3,4-two fluoro-benzyls)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-furans-2-ylmethyl-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-thiophene-2-ylmethyl-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-phenyl-amine;

(4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(3-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(2-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(3,4-two chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(4-bromo-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(3-trifluoromethyl-phenyl)-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(3-methoxyl group-phenyl)-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-p-tolyl-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-m-tolyl-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-o-tolyl-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-naphthalene-2-base-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(1,2,3,4-tetrahydrochysene-naphthalene-1-yl)-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(2-tetramethyleneimine-1-base-ethyl)-amine;

Cyclohexyl-[2-(3-methyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

S-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(S)-1,2,3,4-tetrahydrochysene-naphthalene-1-base-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(1-ethyl-propyl group)-amine;

[2-(3,5-di-isopropyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-methyl-cyclohexyl base)-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-pyridine-2-base-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-methyl-cyclohexyl base)-amine;

(the 4-tertiary butyl-cyclohexyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(tetrahydrochysene-pyrans-4-yl)-amine;

Cyclohexyl-[2-(3,5-di-isopropyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-dihydro indenes-2-base-amine;

Benzo [1,3] dioxole-5-base-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

(3,5-pair-trifluoromethyl-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-quinoline-8-base-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(4-iodo-phenyl)-amine;

Biphenyl-4-base-[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-amine;

[2-(3,5-dimethyl-pyrazol-1-yl)-quinazoline-4-yl]-(1H-indoles-7-yl)-amine; Or

Cyclohexyl-(2-pyrazol-1-yl-quinazoline-4-yl)-amine;

Or its pharmacy acceptable salt.

16. pharmaceutical composition comprises pyrazolyl-quinazoline derivant or its pharmaceutically acceptable addition salt or its prodrug any one according to claim 1-15 for the treatment of significant quantity, and at least a pharmaceutically acceptable carrier or thinner.

17. be used to prepare the purposes of medicine according to any one the pyrazolyl-quinazoline derivant of claim 1-15, this medicine is used for the treatment of, prevents or alleviates Mammals, comprises people's disease or obstacle or illness, and this disease, obstacle or illness are relevant with the activity of potassium channel.

18., be respiratory disease wherein with activity of potassium channels diseases associated or obstacle according to the purposes of claim 17, epilepsy, faint from fear, epileptic seizures, petit mal, vasospasm, coronary vasospasm, nephropathy, polycystic kidney disease, cystospasm, the urinary incontinence, bladder outlet blocks, erective dysfunction, gastrointestinal dysfunction, secretory diarrhea, local asphyxia, cerebral ischemia, ischemic heart disease, stenocardia, coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, anxiety, depressed, mood disorder, dull-witted, memory and attention deficit, Alzheimer, amyotrophic lateral sclerosis (ALS), dysmenorrhoea, hypnolepsy, Raynaud disease, intermittent claudication, siogren's syndrome, irregular pulse, hypertension, the myotonic muscular dystrophy, spasticity, xerostomia, type ii diabetes, hyperinsulinemia, premature labor, alopecia, cancer, irritable bowel syndrome, immunosuppression, migraine or pain.

19., be respiratory disease, the urinary incontinence, erective dysfunction, anxiety, epilepsy, psychosis, schizophrenia, amyotrophic lateral sclerosis (ALS) or pain wherein with activity of potassium channels diseases associated or obstacle according to the purposes of claim 17.

20. according to the purposes of claim 17, be respiratory disease wherein with activity of potassium channels diseases associated or obstacle, particularly asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or rhinorrhea.

21. treat, prevent or alleviate animal body alive, comprise people's the disease or the method for obstacle or illness, this disease, obstacle or illness are replied the adjusting of potassium channel, this method comprises the animal body that the work of needs is arranged to a kind of like this, comprises that the people treats any one the pyrazolyl-quinazoline derivant of claim 1-15 of significant quantity.