CN101060847B

CN101060847B - Loxapine analogs and methods of use thereof

Info

Publication number: CN101060847B
Application number: CN2005800397301A
Authority: CN
Inventors: 戴尔·M·爱德佳; 戴维·G·汉格尔; 潮崎和美; 麦克·索罗蒙; 詹姆斯·F·怀特
Original assignee: Hypnion Inc
Current assignee: Hypnion Inc
Priority date: 2004-09-21
Filing date: 2005-09-21
Publication date: 2010-05-05
Anticipated expiration: 2025-09-21
Also published as: CN101060847A; UA86265C2; ZA200702334B; SI1804804T1

Abstract

The invention relates to novel compounds and methods of using them for modulating sleep.

Description

Loxapine analogs and using method thereof

Technical field

The compositions that the present invention relates to treat the method for sleep disorder and be used for the method.

Background technology

Difficulty falling asleep or often because a variety of causes and clear-headed maintenance dyskoimesis is a great difficult medical problem.In some cases, this problem is owing to intrinsic situation is brought such as sleep apnea or insomnia.Also in some cases, this problem is owing to external pressure brings, for example, and the change of operating schedule or the time difference.No matter be exogenous or immanent cause, difficulty falling asleep or maintenance dyskoimesis can cause the problem sleep, thereby weaken patient's health, quality of life and safety.

The Therapeutic Method of existing induced hypnotic comprises tranquilizer or sleeping pill for example benzene diazonium and barbiturates derivant.These Therapeutic Method have a lot of defectives, comprise insomnia repeatedly, the sedation effect of delay, the sedation that still continues after the sleep period, and the side effect relevant for example ideomotor movement or dysmnesia with non-specific activity, anxiety, and the upset Sleep architecture, comprise that the REM sleep suppresses.In addition, tranquilizer or sleeping pill may form the habit, thereby lose effect in the use afterwards, and some people can be slack-off to the metabolism of this class medicine.

Therefore, when tranquilizer was inappropriate, the doctor recommended or uses the therapy of hydryllin medicine as sleep disordered a kind of milder.But a lot of hydryllin have multiple side effect.These side effect comprise makes in patient's the electrocardiogram QT interval elongated, also also have central nervous system's side effect for example to reduce the muscle retractility and eyelid sagging.At last, these chemical compounds combine with M-ChR, and this just causes for example dimness of vision of cholinolytic side effect, xerostomia, constipation, diseases of urinary system, dizzy and anxiety.

Based on above reason, need a kind of sleep and little therapy of side effect of stimulating.In addition, although the chemical compound of known induced hypnotic to when beginning insomnia, that is, the patient has difficulty in going to sleep effectively, does not but have Drug therapy to be difficult to keep insomnia, that is, maintenance is slept between the whole common sleep period of patient after sleeping.Therefore, for patient's demand, exist the needs of raising at the Therapeutic Method that is difficult to keep the type insomnia.

Summary of the invention

The present invention relates to the purposes of loxapine analogs and their adjusting sleeps.(LOXAPACTM is a kind of three ring dibenzoxazepines antipsychotic drug LOXITANETM) to loxapine, is used for the administration of treatment of schizophrenia.Loxapine (2-chloro-1)-(4-methyl isophthalic acid-piperazinyl) hexichol [b, f] [1,4] oxazepine) have following structure:

On the one hand, the present invention relates to regulate the method for sleep, this method is the chemical compound that imposes the formula I of treatment effective dose to the patient:

Or it has the salt of pharmaceutical active, and wherein: m, n, o, p and q be respectively, 0,1,2,3,4,5, or the integer in 6; X and Y are disappearance, O, S, C (O), SO or SO respectively ₂R ₁, R ₂, R ₁, R ₄, R ₅, R ₆, R ₇, and R ₈Be selected from H, F, Cl, Br, OH, CH respectively ₃, CF ₃, C ₂-C ₆Straight chained alkyl, C ₃-C ₆Branched alkyl, C ₃-C ₇Cycloalkyl, C ₃-C ₇Heterocyclic radical, OCH ₃, OCF ₃, CH ₂OCH ₃, CH ₂OCH ₂CH ₃, C ₁-C ₆Hydroxyalkyl or C ₁-C ₆Alkoxyl; CH in the linking group ₂On any hydrogen atom can be by H, F, Cl, Br, OH, CF ₃, CH ₃, C ₂-C ₆Straight chained alkyl, C ₃-C ₆Branched alkyl, C ₃-C ₇Cycloalkyl, C ₃-C ₇Heterocyclic radical, OCH ₃, OCF ₃, CH ₂OCH ₃, CH ₂OCH ₂CH ₃, C ₁-C ₆Hydroxyalkyl or C ₁-C ₆Alkoxyl is optional to be replaced; R ₉, R ₁₀, R ₁₁, and R ₁₂Be respectively H, C ₁-C ₆Straight chained alkyl, C ₂-C ₆Branched alkyl, perhaps R ₉And R ₁₀The carbon atom that adheres to jointly with them lacks, or is connected to form 3,4,5,6, or 7 yuan volution, or R ₁₁And R ₁₂The carbon atom that adheres to jointly with them is connected to form 3,4,5,6, or 7 yuan volution, or the substituent group on two different carbon atoms is connected to form 3,4,5,6, or 7 yuan of rings; Z is selected from CO ₂H, CO ₂R ₁₃, CONR ₁₄R ₁₅, CONHS (O) ₂-alkyl, CONHS (O) ₂-cycloalkyl, CONHS (O) ₂-assorted alkyl, CONHS (O) ₂-aryl, CONHS (O) ₂-heteroaryl, S (O) ₂The NHCO-alkyl, S (O) ₂The NHCO-cycloalkyl, S (O) ₂The NHCO-alkyl of mixing, S (O) ₂The NHCO-aryl, S (O) ₂The NHCO-heteroaryl, CONHS (O) ₂The NH-alkyl, CONHS (O) ₂The NH-cycloalkyl, CONHS (O) ₂The NH-alkyl of mixing, CONHS (O) ₂The NH-aryl, CONHS (O) ₂The N-heteroaryl, SO ₃H, SO ₂H, S (O) NHCO-alkyl, S (O) NHCO-aryl, S (O) NHCO-heteroaryl, P (O) is (OH) ₂, P (O) OH,

(tetrazolium), or

R wherein ₁₃Be C ₁-C ₆Alkyl, and R ₁₄And R ₁₅Be respectively hydrogen or low alkyl group, prerequisite be when Z be COOH, COOR ₁₃And R ₆When being hydrogen or halogen, R ₁-R ₅And R ₇-R ₁₂All not hydrogen; Further when m was zero, X lacked.

In one embodiment, Z is a sulfonamide.The example of sulfonamide comprises the acyl group sulfonamide, and Z can have following structural formula

Wherein substituted radical W is to reach required oral absorption, CNS infiltration and to enter urine or biliary metaboilic level is chosen according to the surface polarization area effect of adjusting the Z molecule.The example of suitable substituents W for this purpose comprises that alkyl group (can randomly comprise two or triple bond or replaced by hetero atom, for example CH ₂OCH ₃Or CH ₂OCH ₂CH ₃), group of naphthene base (can randomly comprise two keys), heterocycloalkyl, aryl or heteroaryl, it all can be chosen wantonly by following radicals and replace:

Wherein V is one or more side chains, and its selecteed standard is the PKa value of regulating this acyl group sulfonamide, or influences the physical property or the internal metabolism of this chemical compound.The example of V comprises F, Cl, Br, C ₁-C ₆Alkoxyl is OCH for example ₃Or OCH ₂CH ₃ C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl is CH for example ₃CF ₃Or cyclopropyl; The C that hetero atom replaces ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl is CH for example ₂OCH ₃Or CH ₂OCH ₂CH ₃Electron withdraw group is CN for example, ketone, and amino or sulfone, (pyridine radicals isomer arbitrarily),

(arbitrarily pyrimidine radicals isomer) or

In one embodiment, Z is a sulfonamide, comprises the acyl group sulfonamide.For example, Z can have structural formula,

R wherein _aAnd R _bFor example be respectively, alkyl, cycloalkyl, heterocyclic radical, optional aryl, the heteroaryl that replaces.Concrete example comprises,

(wherein, V is a halogen atom, for example, and F, Cl or Br, C ₁-C ₆Alkoxyl, for example, OCH ₃Or OCH ₂CH ₃C ₁-C ₆Alkyl, or C ₃-C ₈Cycloalkyl, for example, CH ₃, CF ₃, or the cyclopropane base; The C that hetero atom replaces ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl, for example CH ₂OCH ₃, CH ₂OCH ₂CH ₃An electron withdraw group, for example, CN, ketone group, amino or sulfo group),

(with the pyridine isomer), or

(or pyrimidine isomer).

In another embodiment, be used for the formula I chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 500nM; Suppress constant greater than 500nM and/or to be compared to the inhibition constant of H1 receptor big 5 times for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 13 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 3 minutes; Average sleep cycle was greater than 5 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

In one embodiment, be used for the formula I chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 300nM; Suppress constant greater than 1 μ M for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 13 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 3 minutes; Average sleep cycle was greater than 5 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound does not also suppress the relevant mobility of ortho sleep irrelevantly.

In another embodiment, be used for the formula I chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 150nM; Suppress constant greater than 10 μ M for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 17 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 5 minutes; Average sleep cycle was greater than 6 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₆It or not hydrogen or halogen.In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₆Be methyl, methoxyl group, methoxyl group methylene (CH ₂OCH ₃), or hydroxyl.In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₆Be methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₁-R ₅And R ₇-R ₈All be hydrogen.

In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₁-R ₈In at least one is non-hydrogen substituted radical, and other are hydrogen.In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₁-R ₈In at least one is that non-hydrogen substituent group is independently selected from methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₁-R ₈In at least two be non-hydrogen substituted radical, and other are hydrogen.In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₁-R ₈In at least two non-hydrogen substituent groups be independently selected from methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₁-R ₈In at least three be non-hydrogen substituted radical, and other are hydrogen.In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₁-R ₈In at least three non-hydrogen substituent groups be independently selected from methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, be used for the formula I chemical compound of the inventive method, R ₂It is non-hydrogen substituted radical.For example, R ₂Be such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, be used for the formula I chemical compound of the inventive method, R ₃It is non-hydrogen substituted radical.For example, R ₃Be such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, be used for the formula I chemical compound of the inventive method, R ₇It is non-hydrogen substituted radical.For example, R ₇Be such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, be used for the formula I chemical compound of the inventive method, R ₂And R ₃It is non-hydrogen substituted radical.For example, R ₂And R ₃Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, be used for the formula I chemical compound of the inventive method, R ₂And R ₆It is non-hydrogen substituted radical.For example, R ₂And R ₆Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, be used for the formula I chemical compound of the inventive method, R ₂And R ₇It is non-hydrogen substituted radical.For example, R ₂And R ₇Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, be used for the formula I chemical compound of the inventive method, R ₃And R ₆Be non-hydrogen substituted radical. for example, R ₃And R ₆Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, be used for the formula I chemical compound of the inventive method, R ₃And R ₇It is non-hydrogen substituted radical.For example, R ₃And R ₇Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, be used for the formula I chemical compound of the inventive method, R ₆And R ₇It is non-hydrogen substituted radical.For example, R ₆And R ₇Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₆Be methoxyl group, R ₁-R ₅And R ₇-R ₈Be hydrogen.

In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₂Be methyl or methoxy, R ₁And R ₃-R ₈Be hydrogen.

In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₃Be methyl, R ₁-R ₂And R ₄-R ₈Be hydrogen.

In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₇Be methoxyl group, R ₁-R ₆With R8 be hydrogen.

In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₂, R ₆, R ₇In at least one be hydrogen.In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₂, R ₆, R ₇In at least one be fluorine, methyl or methoxy.

In one embodiment, be used for the formula I chemical compound of method of the present invention, R ₉And R ₁₀And the carbon atom that they link to each other jointly lacks.In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₁₁And R ₁₂It all is methyl.In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₁₁And R ₁₂It all is ethyl.In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₁₁And R ₁₂Form 3 to 7 yuan volution with the carbon atom that they link to each other jointly.Described volution is, for example, and a cyclopropyl.

In one embodiment, be used for the formula I chemical compound of method of the present invention, q is 0.In another embodiment, q is 0, R ₉And R ₁₀The carbon atom disappearance that links to each other with them.In another embodiment, q is 0, R ₉And R ₁₀The carbon atom that links to each other with them all lacks, and X and Y lack.In another embodiment, q is 0, R ₉And R ₁₀The carbon atom that links to each other with them all lacks, and X and Y lack, and m, n, o and p and be 1 or 2.

In another embodiment, be used for the formula I chemical compound of method of the present invention, be selected from chemical compound 1-88.For example, the formula I that is used for method of the present invention is a chemical compound 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87 and 88.

In another embodiment, the chemical compound that is used for method of the present invention is a chemical compound 1,12,13,40,61,62,63,70,71,74,75,76,77,78,79,80,81,82,83 and 84.

In one embodiment, method of the present invention is to regulate sleep by imposing formula I chemical compound, for example, shortens time for falling asleep by this method, improves each sleep cycle average length, and/or prolongs maximum sleep cycle length.In another embodiment, method of the present invention is by using formula I compounds for treating sleep disorder.This sleep disorder is the circadian rhythm imbalance, insomnia, and parasomnia is (for example, somnambulism, fright at night, REM disturbance in sleep behavior, sleep bruxism, the sleep enuresis), the sleep-apnea shape, as, the centric sleep apnea syndrome, obstructive sleep apnea syndrome and mixing sleep-apnea, sleep apnea, somnolence or hypersomnia.

In one embodiment, method of the present invention is used for the treatment of the circadian rhythm imbalance. in another embodiment, method of the present invention is used for the treatment of insomnia, comprise, for example, the insomnia of exopathogenic factor type, Psychophysiological insomnia, the high-altitude aypnia, restless legs syndrome, nocturnal periodicity limb movement disturbance, the insomnia of medication dependency, the drug dependence aypnia, the alcohol dependence aypnia, and with the relevant insomnia of obstacle at heart. in another embodiment, method of the present invention is used for the treatment of the sleep-apnea shape. in another embodiment, method of the present invention is used for the treatment of somnolence. and in another embodiment, method of the present invention is used for the treatment of hypersomnia.

In one embodiment, in the method for the present invention, the chemical compound of formula I or its pharmaceutically acceptable salt form the pharmaceutical composition administration with other pharmaceutically acceptable carriers.

In another embodiment, in the method for the present invention, the chemical compound of formula I or its pharmaceutically acceptable salt are with one or more other treatment agent administering drug combinations.

In another embodiment, the main body of accepting method of the present invention treatment is selected from the mankind, companion animals, farm-animals, laboratory animal, or wild animal.In one embodiment, receptor is the people.

On the other hand, the present invention relates to regulate the method for patient's sleep, by apply the pharmaceutically chemical compound of the formula II of live vol to the patient:

Or it has the salt of pharmaceutical active, and m, n, o be respectively, 0,1,2,3,4,5, or the integer in 6; X is disappearance, O, S, C (O), SO or SO ₂R ₂, R ₃, R ₆And R ₇Be selected from H, F, Cl, Br, OH, CF respectively ₃, CH ₃, CH ₂CH ₃, CH (CH ₃), cyclopropane, OCH ₃, OCF ₃, CH ₂OCH ₃, and CH ₂OCH ₂CH ₃R ₉And R ₁₀Be respectively H, C ₁-C ₆Straight chained alkyl, C ₂-C ₆Branched alkyl, perhaps R ₉And R ₁₀The carbon atom that adheres to jointly with them lacks, or is connected to form 3,4,5,6, or 7 yuan volution, and Z is selected from COOH, CO ₂R ₁₃(R wherein ₁₃Be C ₁-C ₆Alkyl), CONHS (O) ₂-alkyl, CONHS (O) ₂-assorted alkyl, CONHS (O) ₂-aryl, CONHS (O) ₂-heteroaryl, S (O) ₂The NHCO-alkyl, S (O) ₂The NHCO-alkyl of mixing, S (O) ₂The NHCO-aryl, S (O) ₂The NHCO-heteroaryl, CONHS (O) ₂The NH-alkyl, CONHS (O) ₂The NH-alkyl of mixing, CONHS (O) ₂The NH-aryl, CONHS (O) ₂N-heteroaryl, or tetrazolium, prerequisite be when Z be COOH, COOR ₁₃And R ₆When being hydrogen or halogen, R ₁-R ₅And R ₇-R ₁₂All not hydrogen; Further when m was zero, X lacked.

In one embodiment, be used for the formula II chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 500nM; Suppress constant greater than 500nM and/or be that inhibition constant for the H1 receptor is greater than 5 times for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 13 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 3 minutes; Average sleep cycle was greater than 5 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

In another embodiment, be used for the formula II chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 300nM; Suppress constant greater than 1 μ M for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 13 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 3 minutes; Average sleep cycle was greater than 5 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

In another embodiment, be used for the formula II chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 150nM; Suppress constant greater than 10 μ M for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 17 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 5 minutes; Average sleep cycle was greater than 6 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

In one embodiment, be used for the formula II chemical compound of method of the present invention, R ₆Not hydrogen, fluorine, chlorine, bromine.In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₆Be methyl, methoxyl group, methoxyl group methylene, or hydroxyl.

In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₂-R ₃And R ₇All be hydrogen.In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₂-R ₃And R ₆-R ₇Be hydrogen, methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl respectively.In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₂It is non-hydrogen substituted radical.In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₃It is non-hydrogen substituted radical.In another embodiment, be used for the formula II chemical compound of the inventive method, R ₆It is non-hydrogen substituted radical.In another embodiment, be used for the formula II chemical compound of the inventive method, R ₇It is non-hydrogen substituted radical.In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₂And R ₃It is non-hydrogen substituted radical.In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₂And R ₆It is non-hydrogen substituted radical.In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₂And R ₇It is non-hydrogen substituted radical.In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₃And R ₆It is non-hydrogen substituted radical.In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₃And R ₇Be non-hydrogen substituted radical. in another embodiment, be used for the formula II chemical compound of method of the present invention, R ₆And R ₇It is non-hydrogen substituted radical.

In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₆Be methoxyl group, and, R ₂, R ₃And R ₇Be hydrogen.

In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₂Be methyl or methoxy, and, R ₃, R ₆And R ₇Be hydrogen.

In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₃Be methyl, and, R ₂, R ₆And R ₇Be hydrogen.

In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₇Be methoxyl group, and, R ₂, R ₃And R ₆Be hydrogen.

In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₉And R ₁₀It all is methyl.In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₉And R ₁₀It all is ethyl.In another embodiment, be used for the formula II chemical compound of method of the present invention, R ₉And R ₁₀Form 3 to 7 yuan volution with the carbon atom that they link to each other jointly.Described volution is, for example, and a kind of cyclopropyl.

In one embodiment, be used for the formula II chemical compound of method of the present invention, o is 0.In another embodiment, be used for the formula II chemical compound of method of the present invention, o is 0, and X is a disappearance.In another embodiment, be used for the formula II chemical compound of method of the present invention, o is 0, X be the disappearance, m and n and be 1 or 2.

In one embodiment, method of the present invention is to regulate sleep by imposing formula II chemical compound, for example, shortens time for falling asleep by this method, improves each sleep cycle average length, and/or prolongs maximum sleep cycle length.In another embodiment, method of the present invention is by using formula II compounds for treating sleep disorder.This sleep disorder is that for example, parasomnia, sleep-apnea shape, somnolence or hypersomnia are had a sleepless night in the circadian rhythm imbalance.

On the other hand, the present invention relates to regulate the method for patient's sleep, by apply the pharmaceutically chemical compound of the formula III of live vol to the patient:

Or it has the salt of pharmaceutical active, and wherein, m, n, o, p and q be respectively, 0,1,2,3,4,5, or the integer in 6; X is disappearance, O, S, C (O), SO or SO ₂R ₂, R ₃, R ₆, R ₇Be selected from H, F, Cl, Br, OH, CF respectively ₃, CH ₃, CH ₂CH ₃, CH (CH ₃) ₂, OCH ₃, OCF ₃, CH ₂OCH ₃, and CH ₂OCH ₂CH ₃R ₉And R ₁₀Be respectively H, C ₁-C ₆Straight chained alkyl, C ₂-C ₆Branched alkyl, perhaps R ₉And R ₁₀Form 3,4,5,6 jointly with the carbon atom that they are connected jointly, or 7 yuan volution; Z is selected from CO ₂H, CONHS (O) ₂-alkyl, CONHS (O) ₂-cycloalkyl, CONHS (O) ₂-assorted alkyl, CONHS (O) ₂-aryl, CONHS (O) ₂-heteroaryl and tetrazolium; Prerequisite be when Z be COOH and R ₆Be hydrogen, fluorine, chlorine, or during bromine, R ₂, R ₃, R ₇And R ₉-R ₁₀All be not hydrogen, further when m was zero, X lacked.

In one embodiment, be used for the formula III chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 500nM; Suppress constant greater than 500nM and/or be that inhibition constant for the H1 receptor is greater than 5 times for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 13 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 3 minutes; Average sleep cycle was greater than 5 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

In another embodiment, be used for the formula III chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 300nM; Suppress constant greater than 1 μ M for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 13 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 3 minutes; Average sleep cycle was greater than 5 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

In another embodiment, be used for the formula III chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 150nM; Suppress constant greater than 10 μ M for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 17 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 5 minutes; Average sleep cycle was greater than 6 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

In one embodiment, be used for the formula III chemical compound of method of the present invention, R ₆Not hydrogen, fluorine, chlorine, bromine.In another embodiment, be used for the formula III chemical compound of method of the present invention, R ₂, R ₃And R ₇Be hydrogen.In another embodiment, be used for the formula III chemical compound of method of the present invention, R ₂, R ₃And R ₆-R ₇Be, independently, hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group, methoxyl group methylene or hydroxyl.In another embodiment, be used for the formula III chemical compound of method of the present invention, R ₆It is methoxyl group.

In another embodiment, be used for the formula III chemical compound of method of the present invention, R ₆Be methoxyl group, R ₂, R ₃And R ₇Be hydrogen.

In another embodiment, be used for the formula III chemical compound of method of the present invention, R ₂Be methyl or methoxy, R ₃, R ₆And R ₇Be hydrogen.

In another embodiment, be used for the formula III chemical compound of method of the present invention, R ₃Be methyl, R ₂, R ₆And R ₇Be hydrogen.

In another embodiment, be used for the formula III chemical compound of method of the present invention, R ₇Be methoxyl group, R ₂, R ₃And R ₆Be hydrogen.

In another embodiment, be used for the formula III chemical compound of method of the present invention, R ₉And R ₁₀It all is methyl.In another embodiment, be used for the formula III chemical compound of method of the present invention, R ₉And R ₁₀It all is ethyl.In another embodiment, be used for the formula III chemical compound of method of the present invention, R ₉And R ₁₀Form 3 yuan volution with the carbon atom that they link to each other jointly.

In one embodiment, be used for the formula III chemical compound of method of the present invention, X is a disappearance.In another embodiment, be used for the formula III chemical compound of method of the present invention, X be the disappearance, m and n and be 1 or 2.

In one embodiment, method of the present invention is to regulate sleep by imposing the formula III chemical compound, for example, shortens time for falling asleep by this method, improves each sleep cycle average length, and/or prolongs maximum sleep cycle length.In another embodiment, method of the present invention is by using formula III compounds for treating sleep disorder.This sleep disorder is that for example, parasomnia, sleep-apnea shape, somnolence or hypersomnia are had a sleepless night in the circadian rhythm imbalance.

On the other hand, the present invention relates to regulate the method for patient's sleep, by apply the pharmaceutically chemical compound of the formula IV of live vol to the patient:

Or it has the salt of pharmaceutical active, and wherein, t is 1,2,3, or 4; R ₂, R ₅, R ₆, and R ₇Be respectively H, F, Cl, Br, OH, CF ₃, CH ₃, CH ₂CH ₃, CH (CH ₃) ₂, OCH ₃, OCF ₃, CH ₂OCH ₃And CH ₂OCH ₂CH ₃R ₉And R ₁₀Be H, CH ₃, CH ₂CH ₃, perhaps R ₉And R ₁₀Form 3,4,5,6 jointly with the carbon atom that they are connected jointly, or 7 yuan volution; Z is selected from CO ₂H, CONHS (O) ₂-alkyl, CONHS (O) ₂-cycloalkyl, CONHS (O) ₂-assorted alkyl, CONHS (O) ₂-aryl, CONHS (O) ₂-heteroaryl, and tetrazolium; Prerequisite be when Z be COOH and R ₆Be hydrogen, fluorine, chlorine, or during bromine, R ₁, R ₂, R ₃, R ₇And R ₉-R ₁₀All not hydrogen.

In one embodiment, be used for the formula IV chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 500nM; Suppress constant greater than 500nM and/or be that inhibition constant for the H1 receptor is greater than 5 times for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 13 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 3 minutes; Average sleep cycle was greater than 5 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

In another embodiment, be used for the formula IV chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 300nM; Suppress constant greater than 1 μ M for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 13 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 3 minutes; Average sleep cycle was greater than 5 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

In another embodiment, be used for the formula IV chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 150nM; Suppress constant greater than 10 μ M for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 17 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 5 minutes; Average sleep cycle was greater than 6 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

In one embodiment, in the formula IV chemical compound that uses in the method for the present invention, t is 1 or 2.

In one embodiment, in the formula IV chemical compound that uses in the method for the present invention, be selected from compound IV a, IVb, IVc, IVd and IVe.

In one embodiment, method of the present invention is to regulate sleep by imposing formula IV chemical compound, for example, reduces the shortening time for falling asleep by this method, improves each sleep cycle average length, and/or prolongs maximum sleep cycle length.In another embodiment, method of the present invention is by using formula IV compounds for treating sleep disorder.This sleep disorder is that for example, parasomnia, sleep-apnea shape, somnolence or hypersomnia are had a sleepless night in the circadian rhythm imbalance.

On the other hand, method of the present invention is to regulate sleep by imposing pharmaceutically the following chemical compound of live vol: 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87 and 88.

On the other hand, the present invention relates to the chemical compound of formula I:

(tetrazolium), or

Wherein V is one or more side chains, and its selecteed standard is the PKa value of regulating this acyl group sulfonamide, or influences the physical property or the internal metabolism of this chemical compound.The example of V comprises F, Cl, Br, C ₁-C ₆Alkoxyl is OCH for example ₃Or OCH ₂CH ₃ C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl is CH for example ₃CF ₃Or cyclopropyl; The C that hetero atom replaces ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl is CH for example ₂OCH ₃Or CH ₂OCH ₂CH ₃Electron withdraw group is CN for example, ketone, and amino or sulfone,

(pyridine radicals isomer arbitrarily),

(arbitrarily pyrimidine radicals isomer) or

(with the pyridine isomer), or

(or pyrimidine isomer).

In another embodiment, in the formula I chemical compound, R ₆It or not hydrogen or halogen.In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₆Be methyl, methoxyl group, methoxyl group methylene (CH2OCH3), or hydroxyl.In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₆Be methyl, methoxyl group, methoxyl group methylene, or hydroxyl.

In one embodiment, in the formula I chemical compound, R ₁-R ₅And R ₇-R ₈All be hydrogen.

In another embodiment, in the formula I chemical compound, R ₁-R ₈In at least one is non-hydrogen substituted radical, and other are hydrogen.In another embodiment, be used for the formula I chemical compound of method of the present invention, R ₁-R ₈In at least one non-hydrogen substituent group be independently selected from methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, in the formula I chemical compound, R ₁-R ₈In at least two be non-hydrogen substituted radical, and other are hydrogen.In another embodiment, formula I chemical compound, R ₁-R ₈In at least two non-hydrogen substituent groups be independently selected from methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, in the formula I chemical compound, R ₁-R ₈In at least three be non-hydrogen substituted radical, and other are hydrogen.In another embodiment, formula I chemical compound, R ₁-R ₈In at least three non-hydrogen substituent groups be independently selected from methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment in, the formula I chemical compound, R ₂It is non-hydrogen substituted radical.For example, R ₂Be such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula I chemical compound, R ₃It is non-hydrogen substituted radical.For example, R ₃Be such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula I chemical compound, R ₇It is non-hydrogen substituted radical.For example, R ₇Be such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula I chemical compound, R ₂And R ₃It is non-hydrogen substituted radical.For example, R ₂And R ₃Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula I chemical compound, R ₂And R ₆It is non-hydrogen substituted radical.For example, R ₂And R ₆Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, formula I chemical compound, R ₂And R ₇It is non-hydrogen substituted radical.For example, R ₂And R ₇Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula I chemical compound, R ₃And R ₆It is non-hydrogen substituted radical.For example, R ₃And R ₆Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula I chemical compound, R ₃And R ₇It is non-hydrogen substituted radical.For example, R ₃And R ₇Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula I chemical compound, R ₆And R ₇It is non-hydrogen substituted radical.For example, R ₆And R ₇Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment in, the formula I chemical compound, R ₆Be methoxyl group, R ₁-R ₅And R ₇-R ₈Be hydrogen.In another embodiment, in the formula I chemical compound, R ₂Be methyl or methoxy, R ₁And R ₃-R ₈Be hydrogen.In another embodiment, in the formula I chemical compound, R ₃Be methyl, R ₁-R ₂And R ₄-R ₈Be hydrogen.In another embodiment, in the formula I chemical compound, R ₇Be methoxyl group, R ₁-R ₆And R ₈Be hydrogen.

In one embodiment, in the formula I chemical compound, R ₂, R ₆, R ₇In at least one be hydrogen.In another embodiment, in the formula I chemical compound, R ₂, R ₆, R ₇In at least one be fluorine, methyl or methoxy.

In another embodiment, in the formula I chemical compound, R ₉And R ₁₀And the carbon atom that they link to each other does not jointly exist.In another embodiment, in the formula I chemical compound, R ₁₁And R ₁₂It all is methyl.In another embodiment, in the formula I chemical compound, R ₁₁And R ₁₂It all is ethyl.In another embodiment, in the formula I chemical compound, R ₁₁And R ₁₂Form 3 to 7 yuan volution with the carbon atom that they link to each other jointly.Described volution is, for example, and a kind of cyclopropyl.

In another embodiment, in the formula I chemical compound, q is 0.In another embodiment, q is 0, R ₉And R ₁₀The carbon atom that links to each other with them does not exist.In another embodiment, q is 0, R ₉And R ₁₀The carbon atom that links to each other with them does not exist, and X and Y are disappearances.In another embodiment, q is 0, R ₉And R ₁₀The carbon atom that links to each other with them does not exist, and X and Y are disappearances, and m, n, o and p and be 1 or 2.

In another embodiment, formula I chemical compound is selected from chemical compound 1-88.

For example, formula I is a chemical compound 1,12,13,40,61,62,63,70,71,74,75,76,77,78,79,80,81,82,83 and 84

On the other hand, the present invention relates to the chemical compound of formula II:

Or it has the salt of pharmaceutical active, and m, n, o be respectively, 0,1,2,3,4,5, or the integer in 6; X is disappearance, O, S, C (O), SO or SO ₂R ₂, R ₃, R ₆And R ₇Be selected from H, F, Cl, Br, OH, CF respectively ₃, CH ₃, CH ₂CH ₃, CH (CH ₃), cyclopropane, OCH ₃, OCF ₃, CH ₂OCH ₃, and CH ₂OCH ₂CH ₃R ₉And R ₁₀Be respectively H, C ₁-C ₆Straight chained alkyl, C ₂-C ₆Branched alkyl, perhaps R ₉And R ₁₀The carbon atom that adheres to jointly with them lacks, or is connected to form 3,4,5,6, or 7 yuan volution, and Z is selected from COOH, CO ₂R ₁₃(R wherein ₁₃Be C ₁-C ₆Alkyl), CONHS (O) ₂-alkyl, CONHS (O) ₂-assorted alkyl, CONHS (O) ₂-aryl, CONHS (O) ₂-heteroaryl, S (O) ₂The NHCO-alkyl, S (O) ₂The NHCO-alkyl of mixing, S (O) ₂The NHCO-aryl, S (O) ₂The NHCO-heteroaryl, CONHS (O) ₂The NH-alkyl, CONHS (O) ₂The NH-alkyl of mixing, CONHS (O) ₂The NH-aryl, CONHS (O) ₂NH-heteroaryl, or tetrazolium, prerequisite be when Z be COOH, COOR ₁₃And R ₆When being hydrogen or halogen, R ₁-R ₅And R ₇-R ₁₂All not hydrogen; Further when m was zero, X lacked.

In one embodiment, in the formula II chemical compound, R ₆Not hydrogen, fluorine, chlorine, bromine.In another embodiment, formula II chemical compound, R ₆Be methyl, methoxyl group, methoxyl group methylene or hydroxyl.

In another embodiment, in the formula II chemical compound, R ₂-R ₃And R ₇All be hydrogen.

In another embodiment, in the formula II chemical compound, R ₂-R ₃And R ₆-R ₇Be, independently, hydrogen, methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.

In another embodiment, in the formula II chemical compound, R ₂It is non-hydrogen substituted radical.For example, R ₂Be such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula II chemical compound, R ₃It is non-hydrogen substituted radical.For example, R ₃Be such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula II chemical compound, R ₇It is non-hydrogen substituted radical.For example, R ₇Be such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula II chemical compound, R ₂And R ₃It is non-hydrogen substituted radical.For example, R ₂And R ₃Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula II chemical compound, R ₂And R ₆It is non-hydrogen substituted radical.For example, R ₂And R ₆Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, formula II chemical compound, R ₂And R ₇Be non-hydrogen substituted radical. for example, R ₂And R ₇Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula II chemical compound, R ₃And R ₆It is non-hydrogen substituted radical.For example, R ₃And R ₆Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula II chemical compound, R ₃And R ₇It is non-hydrogen substituted radical.For example, R ₃And R ₇Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment, in the formula II chemical compound, R ₆And R ₇It is non-hydrogen substituted radical.For example, R ₆And R ₇Be respectively, such as methyl, methoxyl group, methoxyl group methylene, fluorine, chlorine, bromine or hydroxyl.In another embodiment in, the formula II chemical compound, R ₆Be methoxyl group, R ₁-R ₅And R ₇-R ₈Be hydrogen.In another embodiment, in the formula II chemical compound, R ₂Be methyl or methoxy, R ₁And R ₃-R ₈Be hydrogen.In another embodiment, in the formula II chemical compound, R ₃Be methyl, R ₁-R ₂And R ₄-R ₈Be hydrogen.In another embodiment, in the formula II chemical compound, R ₇Be methoxyl group, R ₁-R ₆And R ₈Be hydrogen.

In another embodiment, in the formula II chemical compound, R ₉And R ₁₀It all is methyl.In another embodiment, in the formula II chemical compound, R ₉And R ₁₀It all is ethyl.In another embodiment, in the formula II chemical compound, R ₉And R ₁₀Form 3 to 7 yuan volution with the carbon atom that they link to each other jointly.Described volution is, for example, and a kind of cyclopropyl.

In another embodiment, in the formula II chemical compound, o is 0.In another embodiment, in the formula II chemical compound, o is 0, and X is a disappearance.In another embodiment, in the formula II chemical compound, o is 0, X be the disappearance, m and n and be 1 or 2.

On the other hand, the present invention relates to the chemical compound of formula III:

In one embodiment, in the formula III chemical compound, R ₆Not hydrogen, fluorine, chlorine, bromine.

In one embodiment, in the formula III chemical compound, R ₆Not hydrogen, fluorine, chlorine, bromine, R ₂, R ₃And R ₇Be hydrogen.

In one embodiment, in the formula III chemical compound, R ₂, R ₃And R ₆-R ₇Be, independently, hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group, methoxyl group methylene or hydroxyl.

In one embodiment, in the formula III chemical compound, R ₆It is methoxyl group.In another embodiment, in the formula III chemical compound, R ₆Be methoxyl group, R ₂, R ₃And R ₇Be hydrogen.In another embodiment, in the formula III chemical compound, R ₂Be methyl or methoxy, R ₃, R ₆And R ₇Be hydrogen.In another embodiment, in the formula III chemical compound, R ₃Be methyl, R ₂, R ₆And R ₇Be hydrogen.In another embodiment, in the formula III chemical compound, R7 is a methoxyl group, R ₂, R ₃And R ₆Be hydrogen.

In another embodiment, in the formula III chemical compound, R ₉And R ₁₀It all is methyl.In another embodiment, in the formula III chemical compound, R ₉And R ₁₀It all is ethyl.In another embodiment, in the formula III chemical compound, R ₉And R ₁₀Form 3 to 7 yuan volution with the carbon atom that they link to each other jointly.Described volution is, for example, and a kind of cyclopropyl.

In another embodiment, in the formula III chemical compound, X is a disappearance.In another embodiment, in the formula III chemical compound, X disappearance, m and n and be 1 or 2.

On the other hand, the present invention relates to the chemical compound of formula IV:

On the other hand, the chemical compound that the present invention relates to is selected from following: 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87 and 88.

On the other hand, the chemical compound that the present invention relates to is selected from following: 1,12,13,40,61,62,63,70,71,74,75,76,77,78,79,80,81,82,83 and 84.

In one embodiment, the present invention relates to have the chemical compound 1 of following structural formula:

Or its salt, solvate, hydrate or prodrug.For example, the present invention relates to the solvate of chemical compound 1.In one embodiment, the present invention relates to the hydrate of chemical compound 1.In one embodiment, the present invention relates to the prodrug of chemical compound 1.

In another embodiment, the present invention relates to the pharmaceutically acceptable salt of chemical compound 1.For example, this salt can be a kind of acid-addition salts, for example hydrochlorate.

In one aspect, the present invention relates to chemical compound:

On the other hand, the present invention relates to chemical compound:

On the other hand, the present invention relates to comprise the following structural compound or its salt, solvate, hydrate or prodrug and at least a pharmaceutically acceptable excipient, compositions:

(chemical compound 1).In one embodiment, the hydrate of said composition inclusion compound 1.In one embodiment, said composition comprises the solvent of chemical compound 1.In one embodiment, said composition comprises the hydrate of chemical compound 1.In one embodiment, said composition comprises the prodrug of chemical compound 1.In another embodiment, said composition comprises chemical compound 1 pharmaceutically acceptable carrier.For example, this salt can be a kind of acid-addition salts.In one embodiment, this acid-addition salts is a hydrochlorate.

In one embodiment, the present invention relates to

Compositions with at least a pharmaceutically acceptable excipient.

In another embodiment, the present invention relates to

Compositions with at least a pharmaceutically acceptable excipient.

On the other hand, the present invention relates to regulate the method for the sleep of a main body, by to there being the main body that needs to impose the chemical compound 1 of treatment effective dose:

Or its pharmaceutically acceptable salt, solvate, hydrate, or prodrug. for example, this main body is the people. in one embodiment, this sleep is regulated and is selected from, for example, reduce time for falling asleep, improve each sleep cycle average length, and/or prolong maximum sleep cycle length. in another embodiment, method of the present invention is by using formula II compounds for treating sleep disorder. this sleep disorder is, for example, the circadian rhythm imbalance, insomnia, parasomnia, sleep-apnea shape, somnolence or hypersomnia.

On the other hand, the present invention relates to regulate the method for the sleep of main body, by to there being the main body that needs to impose the chemical compound 1 of treatment effective dose:

Or its pharmaceutically acceptable salt, solvate, hydrate, or prodrug form the pharmaceutical composition that comprises at least a pharmaceutical acceptable excipient.For example, this main body is the people.

In one embodiment, chemical compound 1, or its pharmaceutically acceptable salt, solvate, hydrate, or prodrug, with one or more additional treatment agent to a main body co-administered.For example, this main body is the people.

Describe the aspect of having pointed out outbalance of the present invention quite widely above, can be understood, also can be accepted better simultaneously for contribution to prior art for following detailed description part.Be described in detail and consider in conjunction with the embodiments through following, other purpose and feature of the present invention will be more apparent.

The specific embodiment

Introduce one or more embodiments of the present invention below in detail.Although can practical application or check the present invention to the similar of following description or any method that is equal to or material, these methods and material be described now.Other feature of the present invention, purpose and advantage can clearly obtain from description.In description, singulative clearly hint based on context also might comprise plural form.Unless point out in addition, all technology of using among the present invention and scientific terminology are the same with one skilled in the art's common sense of the present invention.When conflict is arranged, the implication of using description of the present invention to point out.

Definition

For convenience, the particular term of using in embodiment and the claim in the description is in following concentrated description.

" processing " comprises any effect, for example, alleviates, and reduces, and regulates or eliminates, and causes physiological situation, the improvement of disease or disease or the like." processing " comprises any effect, for example, alleviates, and reduces, and regulates or eliminates, and causes physiological situation, the improvement of disease or disease or the like." processing " or " treatment " certain morbid state comprises: (1) stops morbid state, for example, those cause state no longer development in main body of disease symptoms, and this main body may be exposed or this disease of easy infection, but the symptom of this disease also do not occur or show; (2) suppress this morbid state, for example, stop the development of this morbid state or its symptom; (3) remove this morbid state, for example, bring the decline of temporary transient or permanent this morbid state or its symptom." morbid state " represents any disease, physiological situation, symptom or sign.

" alkyl " comprises and comprises saturated aliphatic groups, straight chained alkyl (methyl for example, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl), branched alkyl (for example isopropyl, tertiary butyl, isobutyl group), cycloalkyl is (for example, alicyclic alkyl) group (for example, cyclopropyl, cyclopenta, ring octyl group, suberyl, the ring octyl group), the group of naphthene base that alkyl replaces and the alkyl group of cycloalkyl substituted." alkyl " further comprises all groups that is replaced carbon atom on one or more hydrocarbon keys by oxygen, nitrogen, sulfur or phosphorus atoms that comprises, for example, and the CH that hetero atom replaces ₂OCH ₃Or CH ₂OCH ₂CH ₃In specific embodiment, the straight or branched alkyl has six or carbon atom (C still less ₁-C ₆Straight chained alkyl or C ₃-C ₆Branched alkyl), in other embodiment, contain four or carbon atom still less. similarly, have carbon atom in the carbocyclic ring of cycloalkyl, in other embodiment, have five or six carbon atom on the carbocyclic ring from three to eight. " C ₁-C ₆" comprise and comprise the group of 1,2,3,4,5 or 6 carbon atom.C ₂-C ₆" comprise comprise 2,3,4,5 or 6 carbon former in group.

Term " alkyl " also comprises " unsubstituted alkyl " and " alkyl of replacement ", and wherein the latter refers to have substituent group and replaces one or more hydrogen atoms on the hydrocarbon key or the alkyl of carbon atom.Substituent group wherein comprises, for example, and alkyl, thiazolinyl, alkynyl, halogen, hydroxyl, alkyl carbonate base, aryl carbonates base, the alkoxyl carbonate group, aryloxy group carbonate group, carboxyl, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino-carbonyl, two alkyl amino-carbonyls, alkyl thiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano group, amido (comprises NH ₂, alkylamino radical, two alkyl amine group, aryl amine, two aryl amines; and alkylarylamine base), acylamino-(comprising alkylamidoalkyl, aryl amido group, carbamyl and urea groups), amidino groups; imino group, sulfonamido, alkylthio group, arylthio, carbothioic acid ester; sulphuric acid, alkyl sulphonyl, sulfonic group, sulfonamides; sulfonamido, nitro, trifluoromethyl, cyano group; azido, heterocyclic radical, alkylaryl, or aromatic group or heteroaryl.Cycloalkyl can further be substituted, and for example, is replaced by above-mentioned substituent group.The alkyl that one " alkylaryl " or " aralkyl " are replaced by aryl (for example benzyl (benzyl))." alkyl " also comprises natural or the alpha-non-natural amino acid side chain.

" aryl " comprises all armaticity groups, comprise, and 5-and 6-unit " not combination " or monocycle, aromatic group can comprise 0,1,2,3 or 4 hetero atom, also comprises " bonded " or the polycyclic system that contain at least one aromatic ring.The example of aromatic yl group comprises, benzene, phenyl, pyrroles, furan, thiophene, thiazole, isothiazole, imidazoles, triazole, tetrazolium, pyrazoles ， oxazole ， isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and similar compound.Further, term " aryl " comprises polyaromatic, for example, and three rings, dicyclo, as, naphthalene, benzoxazoles, the benzo dioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinolin, napthridine, indole, benzofuran, purine, benzofuran, azapurine, or indolizine.In ring structure, contain heteroatomic aromatic yl group and be called as " fragrant heterocycle ", " heterocycle ", " heteroaryl " or " aromatic heterocycle ".Any one or more annular atomses can be replaced by above-mentioned substituent group on the aromatic rings, for example, and alkyl, halogen; hydroxyl, alkoxyl, alkyl carbonate base, aryl carbonates base; the alkoxyl carbonate group, aryloxy group carbonate group, carboxyl, alkyl-carbonyl; aryl carbonyl, alkyl amino-carbonyl, aryl alkyl amino carbonyl, alkenyl amino carbonyl; alkyl-carbonyl, aryl carbonyl, aromatic alkyl carbonyl, alkenyl carbonyl; alkoxy carbonyl, amido carbonyl, alkyl thiocarbonyl, phosphate; phosphonato, phosphinato, cyano group, amido (comprises alkylamino radical; two alkyl amine group, aryl amine, two aryl amines, and alkylarylamine base); acylamino-(comprising alkylamidoalkyl, aryl amido group, carbamyl and urea groups), amidino groups; imino group, sulfonamido, alkylthio group, arylthio; carbothioic acid ester, sulphuric acid, alkyl sulphonyl, sulfonic group; sulfonamides, sulfonamido, nitro; trifluoromethyl, cyano group, azido; heterocyclic radical, alkylaryl, or aromatic group or heteroaryl.Aromatic group equally can with other carbocyclic rings or heterocyclic fused or bridge joint, form the polycyclic system (for example, tetrahydronaphthalene, methylene dihydroxyphenyl) of non-fragrance.

" thiazolinyl " comprise chain length and possible substituent group all with the homologous unsaturated aliphatic group of abovementioned alkyl, but contain a two key at least.For example, term " thiazolinyl " comprises straight-chain alkenyl (for example, vinyl, acrylic, cyclobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonene base and decene base), branched-chain alkenyl, cycloalkenyl group (for example alicyclic) group (for example, cyclopropanyl, cyclopentenyl, cyclohexenyl group, cycloheptenyl, the cyclo-octene base), the alkyl or alkenyl that is replaced by cycloalkenyl group, and by the cycloalkyl of alkenyl substituted or cycloalkenyl group.Term " thiazolinyl " further comprises, comprises the alkenyl group that oxygen, nitrogen, sulfur or phosphorus atoms replace one or more carbon atoms on the carbochain.In specific embodiment, comprise 1,2,3,4,5 on the carbochain of this straight or branched alkenyl group, or 6 carbon atoms (for example, C2-C6 straight chain, C3-C6 side chain).Similarly, can contain 3,4,5,6,7 on the carbocyclic ring of cycloalkenyl groups, or 8 carbon atoms, in other embodiment, contain 5 or 6 carbon atoms on the cycloalkenyl groups.Term " C2-C6 " comprises and contains 2,3,4,5, or the alkenyl group of 6 carbon atoms.

Term " thiazolinyl " comprises " unsubstituted thiazolinyl " and " thiazolinyl of replacement " equally, and the latter comprises the hydrogen atom substituted alkenyl group on the carbon atom on those one or more hydrocarbon key. substituted radical comprises, for example; alkyl, thiazolinyl, halogen; hydroxyl, alkyl carbonate base, aryl carbonates base; the alkoxyl carbonate group, aryloxy group carbonate group, carboxyl; alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl; amino carbonyl, alkyl amino-carbonyl, two alkyl amino-carbonyls; alkyl thiocarbonyl, alkoxyl, phosphate; phosphonato, phosphinato, cyano group; amido (comprises alkylamino radical, two alkyl amine group, aryl amine; two aryl amines, and alkylarylamine base), acylamino-(comprises alkylamidoalkyl; aryl amido group; carbamyl and urea groups), amidino groups, imino group; sulfonamido; alkylthio group, arylthio, carbothioic acid ester; sulphuric acid; alkyl sulphonyl, sulfonic group, sulfonamides; sulfonamido; nitro, trifluoromethyl, cyano group; azido; heterocyclic radical, alkylaryl, or aromatic group or heteroaryl.

" alkynyl " comprise chain length and possible substituent group all with the homologous unsaturated aliphatic group of abovementioned alkyl, but contain a triple bond at least.For example, term " alkynyl " comprises straight-chain alkynyl (for example, acetenyl, propinyl, butynyl, pentynyl, hexin base, heptyne base, octyne base, n-heptylacetylene base, and decynyl), alkynyl group and the alkynyl that is replaced by cycloalkyl or cycloalkynyl radical.Term " alkynyl " further comprises, comprises the alkynyl group that oxygen, nitrogen, sulfur or phosphorus atoms replace one or more carbon atoms on the carbochain.In specific embodiment, comprise 2,3,4,5 on the carbochain of this straight or branched alkynyl group, or 6 carbon atoms (for example, C2-C6 straight chain, C3-C6 side chain).Term " C2-C6 " comprises and contains 2,3,4,5, or the alkenyl group of 6 carbon atoms.

Term " alkynyl " comprises " unsubstituted alkynyl " and " alkynyl of replacement " equally, and the latter comprises the hydrogen atom substituted alkynyl group on the carbon atom on those one or more hydrocarbon key.Substituted radical comprises, for example, and alkyl, thiazolinyl, halogen; hydroxyl, alkyl carbonate base, aryl carbonates base, alkoxyl carbonate group; the aryloxy group carbonate group, carboxyl, alkyl-carbonyl, aryl carbonyl; alkoxy carbonyl, amino carbonyl, alkyl amino-carbonyl, two alkyl amino-carbonyls; alkyl thiocarbonyl, alkoxyl, phosphate, phosphonato; phosphinato, cyano group, amido (comprises alkylamino radical, two alkyl amine group; aryl amine, two aryl amines, and alkylarylamine base), acylamino-(comprises alkylamidoalkyl; aryl amido group, carbamyl and urea groups), amidino groups, imino group; sulfonamido, alkylthio group, arylthio, carbothioic acid ester; sulphuric acid, alkyl sulphonyl, sulfonic group, sulfonamides; sulfonamido, nitro, trifluoromethyl, cyano group; azido, heterocyclic radical, alkylaryl, or aromatic group or heteroaryl.

Unless otherwise specifically identified, " low alkyl group " comprises the alkyl group of above-mentioned definition, but contains 1,2,3,4,5,6,7,8,9, or 10 carbon atoms, and in other embodiment scheme, an alkyl group contains 1,2,3,4,5 or 6 carbon atoms." low-grade alkenyl " and " low-grade alkynyl " chain length, for example, 2,3,4,5 or 6 carbon atoms.

" acyl group " comprises and contains acyl group (CH ₃CO) or the group of carbonyl." acyl group of replacement " comprises the acyl group that one or more hydrogen atoms are replaced by following substituent group, for example, and alkyl, thiazolinyl; halogen, hydroxyl, alkyl carbonate base, aryl carbonates base; the alkoxyl carbonate group, aryloxy group carbonate group, carboxyl, alkyl-carbonyl; aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino-carbonyl; two alkyl amino-carbonyls, alkyl thiocarbonyl, alkoxyl, phosphate; phosphonato, phosphinato, cyano group, amido (comprises alkylamino radical; two alkyl amine group, aryl amine, two aryl amines, and alkylarylamine base); acylamino-(comprising alkylamidoalkyl, aryl amido group, carbamyl and urea groups); amidino groups, imino group, sulfonamido; alkylthio group, arylthio, carbothioic acid ester; sulphuric acid, alkyl sulphonyl, sulfonic group; sulfonamides, sulfonamido, nitro; trifluoromethyl, cyano group, azido; heterocyclic radical, alkylaryl, or aromatic group or heteroaryl.

" amide " comprises the group that acyl group and amido key connect (C (O) N-or-NC (O)-).For example, this term comprises, alkylamide, aryl amide, carbamyl and urea groups.

" aroyl " comprises, chemical compound and group that aryl or heteroaryl and acyl bond connect.For example, the example of aroyl comprises the phenyl carboxyl, the naphthyl carboxyl, or the like.

" alkoxyalkyl ", " alkyl amine group alkyl " and " thio alkoxy alkyl " comprises the abovementioned alkyl group, comprises that further oxygen, nitrogen or sulphur atom replace the carbon atom on one or more hydrocarbon keys, for example, CH ₃OCH ₂-, CH ₃NHCH ₂, or CH ₃SCH ₂-

Term " alkoxyl " or " alkoxyl " comprise, replace or the unsubstituted alkyl that links to each other with covalent bond with oxygen atom thiazolinyl, and alkynyl group.The example of (or alkoxyl) group of alkoxyl comprises, methyl alkoxy, ethyl alkoxyl, isopropyl alkoxyl, propoxyl group, butoxy and amoxy group.On the alkoxyl substituent group because of example comprise halogenated alkoxy.Alkoxy base can be replaced by following radicals, for example, and thiazolinyl, alkynyl; halogen, hydroxyl, alkyl carbonate base, aryl carbonates base; the alkoxyl carbonate group, aryloxy group carbonate group, carboxyl, alkyl-carbonyl; aryl carbonyl, alkoxy carbonyl, amido carbonyl, alkyl amino-carbonyl; two alkyl amino-carbonyls, alkyl thiocarbonyl, alkoxyl, phosphate; phosphonato, phosphinato, cyano group, amido (comprises NH2; alkylamino radical, two alkyl amine group, aryl amine, two aryl amines; and alkylarylamine base), amide groups (comprising alkylamidoalkyl, aryl amido group, carbamyl and urea groups); amidino groups, imino group, sulfonamido; alkylthio group, arylthio, carbothioic acid ester; sulphuric acid, alkyl sulphonyl, sulfonic group; sulfonamides, sulfonamido, nitro; trifluoromethyl, cyano group, azido; heterocyclic radical, alkylaryl, or aromatic group or heteroaryl.The example of the alkoxyl that is replaced by halogen is, but is not limited to fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, chlorine methoxyl group, dichloro methoxyl group and trichlorine methoxyl group.

Term " heterocycle " or " heterocyclic " comprise the ring structure of sealing, for example, and 3,4,5,6,7,8,9, or 10-, or 4,5,6, or 7-unit ring, comprising one or more hetero atoms.In one embodiment, this ring is 5 or 6-unit ring." hetero atom " comprises the atom outside any de-carbon and the hydrogen.Heteroatomic example comprises nitrogen, oxygen, sulfur and phosphorus.

Heterocyclic radical can be saturated or unsaturated, for example comprises, and pyrrolidine, oxolane, Tetramethylene sulfide, piperidines, piperazine, morpholine, lactone, lactams, for example, azetidinones and ketopyrrolidine, sultam and sultone.Heterocyclic group, for example, pyrroles and furan can possess armaticity.Heterocyclic group comprises condensed heterocycle for example quinoline and isoquinolin.Other examples of heterocyclic group comprise pyrimidine and purine.One or more annular atomses on the heterocycle can be replaced by above-mentioned substituent group, for example, and halogen, hydroxyl; the alkyl carbonate base, aryl carbonates base, alkoxyl carbonate group, aryloxy group carbonate group; carboxyl, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl; amino carbonyl, alkyl amino-carbonyl, two alkyl amino-carbonyls, alkyl thiocarbonyl; alkoxyl, phosphate, phosphonato, phosphinato; cyano group, amido (comprises-NH2 alkylamino radical, two alkyl amine group; aryl amine, two aryl amines, and alkylarylamine base); acylamino-(comprising alkylamidoalkyl, aryl amido group, carbamyl and urea groups); amidino groups, imino group, sulfonamido; alkylthio group, arylthio, carbothioic acid ester; sulphuric acid, alkyl sulphonyl, sulfonic group; sulfonamides, sulfonamido, nitro; trifluoromethyl, cyano group, azido; heterocyclic radical, alkylaryl, or aromatic group or heteroaryl.One or more atoms on the heterocyclic group can be by for example low alkyl group, low-grade alkenyl, and low-grade alkynyl, lower alkoxy, lower alkylthio, the low alkyl group amido, lower alkylcarbonyl, nitro, hydroxyl ,-CF3, or-CN, or similarly group replaces.

Term " thiocarbonyl " or " thiocarboxyl group " comprise and contain the carbon atom that links to each other with two keys with sulphur atom

Chemical compound or molecule.

Term " ether " comprises chemical compound or the molecule that contains the oxygen atom that connects with two different carbon atoms or heteroatomic bond.For example, this term comprises " alkoxyalkyl ", refer to, and alkyl, alkenyl or alkynyl connects oxygen atom with another alkyl with covalent bond and is connected with covalent bond with one.

Term " ester " comprises that a carbon atom or hetero atom are connected in chemical compound or the molecule on the oxygen atom that links to each other with acyl group carbon.Term " ester " comprises that the alkoxyl carboxyl is methoxycarbonyl for example, ethoxy carbonyl, and propoxycarbonyl, butoxy carbonyl, pentyloxy carbonyl, or the like.Alkyl, alkenyl or alkynyl are all as defined above.

Term " thioether " comprises the chemical compound or the molecule of the sulphur atom that connects with two different carbon atoms or heteroatomic bond. the example of thioether comprises, but be not limited to, alkane sulfur alkyl ether, alkane sulfur alkene ether, alkane sulfur alkynyl ether. term " alkane sulfur alkyl ether " comprises alkyl, an alkenyl or alkynyl and is connected in the chemical compound or the molecule of the sulphur atom key company on another alkyl. proximate, chemical compound or molecule that term " alkane sulfur alkene ether " and " alkane sulfur alkynyl ether " refer to comprise an alkyl, alkenyl or alkynyl and is connected in the sulphur atom key company on another alkynyl with covalent bond.

Term " hydroxyl " or " hydroxyl " comprise have-OH or-O ^-Group.

Term " halogen " comprises fluorine, bromine, and iodine, etc.Term " perhalogenation " refers to that the wherein all hydrogen of molecule is all replaced by halogen atom.

Term " non-hydrogen substituent group " refers to other substituent groups that dehydrogenation is outer.Unrestriced example is an alkyl, alkoxyl, halogen, hydroxyl, aryl.

" multi-ring base " or " multi-ring group " refers to two or more carbocyclic rings (for example, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl and/or heteroaryl) and the adjacent shared two or more carbon atoms of ring.The ring that connects by non-conterminous atom is called " bridge " ring.Each carbocyclic ring on the multi-ring base can be replaced by aforesaid substituent group, for example, and halogen, hydroxyl; the alkyl carbonate base, aryl carbonates base, alkoxyl carbonate group, aryloxy group carbonate group; carboxyl, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl; amino carbonyl, alkyl amino-carbonyl, two alkyl amino-carbonyls, alkyl thiocarbonyl; alkoxyl, phosphate, phosphonato, phosphinato; cyano group, amido (comprises-NH2 alkylamino radical, two alkyl amine group; aryl amine, two aryl amines, and alkylarylamine base); acylamino-(comprising alkylamidoalkyl, aryl amido group, carbamyl and urea groups); amidino groups, imino group, sulfonamido; alkylthio group, arylthio, carbothioic acid ester; sulphuric acid, alkyl sulphonyl, sulfonic group; sulfonamides, sulfonamido, nitro; trifluoromethyl, cyano group, azido; heterocyclic radical, alkylaryl, or aromatic group or heteroaryl.

The term of Shi Yonging " anion group " refers to electronegative group under physiology PH condition herein.The anion group comprises carboxylic acid ester groups, sulfate radical, and sulfonic group, sulfino, sulfamide groups, tetrazole radical, phosphate radical, phosphate-based, phosphonous acid ester group, thiophosphate, or the group of other functional equivalents.The anion intention of " functional equivalent " comprises bioisostere, for example, and the bioisostere of carboxylate.Bioisostere comprises classical bioisosteric equivalent and non-classicalbioisosteric equivalent.Classical bioisosteric equivalent and non-classical bioisosteric equivalent are that prior art is known.(referring to, Silverman for example, R.B.The Organic Chemistry of Drug Design and DrugAction, Academic Press, Inc.:San Diego, Calif., 1992, pp.19-23).An example of anion group is the carboxylic acid group.

" blocking group " refers to combine a class atom that reduces or stop reactivity with reactive group in the molecule.The example of blocking group can obtain Wiley, 2 in following document ^NdEd.1991); Harrison and Harrison et ah, Compendium of Synthetic OrganicMethods, VoIs.1-8 (John Wiley and Sons, 1971-1996); And Kocienski, Protecting Groups, (Verlag, 3 ^RdEd.2003)

On behalf of those, term " amido protecting group " intention ammonia, amine or other nitrogen moieties can be changed into the inert functional group of particular chemical reaction condition.The amido protecting group can easily be removed usually, and has very high selectivity and do not influence with other functional groups in a part.The example of amido blocking group comprises; but be not limited to formyl, acetyl group; benzyl; t-tert-butyl group dimethylsilyl, t-tert-butyl diphenyl silylation, t-tertbutyloxycarbonyl (Boc); the p-methoxybenzyl; methoxy, tosyl, trifluoroacetyl group; trimethyl silane (TMS); fluorenyl-methoxycarbonyl, 2-trimethyl silane-ethoxy carbonyl (CBZ), 2-trimethyl silane-ethyl sulphonyl (SES); the trityl of trityl and replacement; 9-fluorenes methoxy carbonyl acyl (FMOC), nitro-veratryloxycarbonyl (NVOC) and similar other groups.Other amido blocking group can directly be determined by those skilled in the art.

The hydroxy-protective group of representative comprises those with acylated hydroxy or alkylation, for example benzyl and trityl ether, or alkyl ether, oxolane ether, trialkyl silane ether and allyl ether.

" stable compound " and " rock-steady structure " refers to the enough stabilization energies of this chemical compound and survives in the separation process from reactant mixture, and can form the preparation that effectiveness is pharmaceutically arranged.

In description of the present invention, in some cases, for convenience, the molecular structural formula of chemical compound is represented a kind of specific isomer, but present invention includes all isomers, such as based on geometric isomer, optical isomer based on an asymmetric carbon atom, stereoisomer, tautomer and other structural isomers similarly, and isomer mixture, be not limited in the description of the present invention for convenience and the molecular formula of using can be a kind of of isomer or its mixture.Therefore, an asymmetric carbon atoms can be indicated in the molecular formula, and optically active chemical compound and racemic compound can be embodied in the chemical compound of the present invention, but the present invention is not limited to these and comprises in them any one.In addition, the crystalline polymorph chemical compound is also contained among the present invention, but is not limited to this, but any crystal formation can be monocrystalline or mixed crystal, or dehydrate or hydrate.Further, The compounds of this invention metabolite in vivo is also contained within the scope of the present invention.

It is pointed out that also some chemical compounds of the present invention comprise asymmetric (chirality) carbon atom.Be understandable that, because the isomer that this chiral carbon atom brings is also within the scope of the present invention involved, unless point out in addition.Such isomer can be by conventional isolation technics purification and synthetic with stereochemical method.Chemical compound of the present invention can stereoisomer form exist, promptly can be manufactured as individual isomer or mixture.

But " isomers " refers to have the same molecular formula has the different atom order of connection or the chemical compound of atom spatial arrangement.The isomer that has the different spaces atom to arrange is called " steric isomer ".The isomer that is not mirror image each other is called " diastereomer ", belong to each other can not overlapping mirror image isomer be called " enantiomer ", be also sometimes referred to as optical isomer.Connect four different substituent carbon atoms and be called as " chiral centre ".

" chiral isomer " means the chemical compound that has a chiral centre at least.It has the diastereomer of two opposite optical activitys, can exist with the form of independent isomer or mixture.The mixture that contains two diastereomers of equal quantities is called as " racemic mixture ".The chemical compound that has more than 1 chiral centre has 2n-1 to enantiomer, and wherein n is the number of chiral centre.Have the mixture existence that can be used as independent diastereomer existence or diastereomer more than the chemical compound of a chiral centre, be called " non-enantiomer mixture ".When a chiral centre existence, a steric isomer can use the absolute configuration (R or S) based on this chiral centre to characterize.The substituent spatial arrangement that absolute configuration refers to connect on this chiral centre (inserting the 39th page of 6-9 style of writing of original text offers) according to the Cahn sequence rules.

" geometric isomer " refers to because two keys and the diastereomer that can not rotate freely.According to the Cahn-Ingold-Prelog rule, these not isomorphism type sewed cis and trans name in the past, or Z and E, this has represented substituted radical is homonymy or heteropleural at two keys.

Further chemical compound and the structure of being discussed among the application all comprised all isomers." atropic isomer " is meant the different isomers of atom spatial arrangement all in two isomers.The existence of atropic isomer is because the substituent group of a middle key causes and can not rotate.The existence typical case of this class atropic isomer exists with mixture, and still, the development of chromatographic technique can separate two kinds of atropicisomer in some instances recently.

Term " polymorphic " or " polycrystalline " or " crystal form " refer to that chemical compound (or its salt or solvate) plants the crystal structure that crystallization forms at different accumulation branches, all these contains identical component. and different crystal formations has different X-ray diffraction models, infrared spectrum, fusing point, density, crystal formation, optics and electrical properties, stability and dissolubility. recrystallization solvent, percent crystallization in massecuite, reserve temperature, may to cause certain crystal formation to account for leading with other character. and the polycrystalline of chemical compound can be by preparing under different conditions. and for example, use different solvents or different mixed solvents to come recrystallization; Recrystallization under different temperature; Different refrigerating modes, cooling or slowly cooling rapidly in crystallization process, and other are similar. and polycrystalline can by heating or dissolve to cool off gradually or rapidly behind this chemical compound equally and obtain. and polycrystalline existence can be passed through solid probe nuclear magneticresonance spectroscopy, infrared spectrum, differential calorimetric scanning method, powder x-ray diffraction, or other well known to a person skilled in the art that technological means is definite.

In addition, chemical compound of the present invention, for example, the salt of this chemical compound can exist with hydration or dehydration (anhydrous) form, or form solvate with other solvent molecules.Unrestriced embodiment comprises, monohydrate, and dihydrate or the like, the non-limitative example of solvate comprises, alcoholate, acetone solvate.

" tautomer " refers to the chemical compound that difference can be distinguished from structure because atom is arranged, but is in easily and in the dynamic equilibrium rapidly.Be understandable that the chemical compound of formula I-IVe can be represented different tautomers.Be understandable that equally when chemical compound had tautomer, all isomers all within protection scope of the present invention, were not got rid of tautomer to the name of chemical compound.

Chemical compounds more of the present invention can exist with a kind of form of tautomer, and this is also contained within the scope of the present invention equally.

Chemical compound of the present invention and salt thereof and prodrug can exist with the form of multiple tautomer, comprise enol and imines form, and keto-acid and enamine form, and geometric isomer or its mixture.All tautomers are included within protection scope of the present invention.Tautomer can the form with mixture coexist in solution.In solid forms, normally a certain isomer comprises leading position.Although may only describe a kind of tautomer, present invention includes whole tautomers of this chemical compound.

Tautomer is that two or more are in one of constitutional isomer under the poised state, can easily be transformed into another kind from a kind of isomer.This reaction has caused the migration of hydrogen atom to be obtained by another adjacent conjugated double bond.Tautomerization is possible in solution, reaches the chemical equilibrium between the tautomer.The accurate ratio of tautomer depends on multiple factor, comprises temperature, solvent, and pH value.This notion of tautomer of being brought by tautomerism is called as enantiotropy.

In multiple possible tautomer, there are two kinds to be usually obtainable.Keto-enol formula tautomerism is to change between electronics and the hydrogen atom time.The tautomerism of loop chain embodies in glucose.This isomery is because the aldehyde radical on the glycan molecule medium chain (CHO) with a hydroxyl in a part (OH) reacts the formation endless belt.

Tautomerism can be done following classification: alkali: 1. deprotonation 2. forms the 3. anionic protonation of diverse location of anion delocalization (for example enolate); Acid: 1. protonation 2. forms the different ortho position deprotonation of cation delocalization 3. cationes.

Common tautomer is to being: keto-enol, amide-cyanogen, lactams-lactim, the amino-imidic acid on the heterocycle (for example, nuclear base guanine, thymus pyrimidine, and cytosine), amine-enamine and enamine-enamine.Example comprises:

" solvate " refers to comprise the material of solvent addition form of the solvent molecule of stoichiometry or non-stoichiometry amount.Some chemical compounds have the tendency at crystalline solid combinations of states some solvent molecules, to form solvate.If solvent is a water, just form hydrate, when solvent is an ethanol, the solvate of this formation is an alcoholate.Hydrate forms in conjunction with one or more hydrones, and in this material, hydrone still keeps the state of its H2O molecule, and such combination can form water or polyhydrate.

" analog " of Shi Yonging refers to herein, and to chemical compound similar on another compound structure, its difference only is certain position (atom or a specific functional group of replacing this position as another atom are replaced by another functional group).So, analog be similar or function on comparable chemical compound, but on the structure with known compound and dissmilarity also homology not.

Term " derivant " refers to contain the chemical compound of identical main structure, is replaced by different substituents described herein.For example, all chemical compounds of being represented by formula I all are the loxapine derivants, have common main structure formula I.

Term " bioisostere " is meant by an atom or the one group of atom result to other roughly similar atoms or one group of atom exchange.The result of bioisostere obtains and parental generation chemical compound similar noval chemical compound on biological property.Bioisostere is based on physical chemistry or topologically principle.The bioisostere of carboxylic acid comprises sulfimide, tetrazolium, sulfonate and phosphate.Offer referring to inserting the 42nd page of 3-4 style of writing of original text

Word " class loxapine chemical compound " or " loxapine derivant " " loxapine similar compound " are intended to comprise and comprise loxapine or the antihistaminic analog that is connected in two aryl of same atom by a three-ring system, for example, one seven yuan contain oxygen and contain azo-cycle (for example, being similar to loxapine) and be connected on the piperazine ring.

Term " hydryllin " refers to be incorporated into the H1 receptor and stops the histamine activity, and/or reduces the active chemical compound of receptor tissue.

The term of Shi Yonging " sleep disorder " comprises that all those skilled in the art can be defined as the situation of sleep disorder herein, for example, known in the artly is used as or is found to be the sleep disorder situation.Sleep disorder also can appear at one suffer from other diseases, disease or injury be subjected to other drug treatment or the patient of therapeutic treatment on one's body, this moment this patient, have difficulty in going to sleep and/or keep prolonged sleep, or experiencing invalid sleep or non-restorative sleep, for example, the patient is experiencing sleep deprivation.

Term " treatment sleep disorder " also comprises the sleep disorder of treatment as other disease parts, for example CNS disease (for example, psychology or sacred disease such as anxiety).In addition, term " treatment sleep disorder " comprises the effect that other related symptoms are improved.

Term " non-quick peak value the length of one's sleep " (the nonREM peak value length of one's sleep) is defined as, in 24 hours periods (CT) administration, the absolute maximum of nonREM sleep per hour after the treatment, this cycle is that 6th hour .55%nonREM occurring mouse daytime of laboratory rearing under LD12:12 (light was arranged in 12 hours, 12 hours are unglazed) the light and shade condition standard hourly of sleeping is that nonREM sleep hourly is equivalent to 33 minutes.

The accumulation of the term of Shi Yonging " sleep of accumulation no rapid eye movement " nonREM sleep herein has a net increase of length, at the measurements action period of whole hypnotic, usually typically, but without the appearance in 6 hours after the treatment of being everlasting, the sleep accumulation of the number of minutes of nonREM is had a net increase of the long fiducial time that is adjusted into before the treatment 24 hours, with respect to treating with adjuvant.

Definition herein, term " sleep cycle " refers to continuously or near successive one section concrete sleep, comprises nonREM sleep, REM sleep, or nonREM sleep and REM Sleep stages, with before and the continuous afterwards 10 seconds clear-headed period for cutting apart.

Definition herein, term " the longest sleep cycle length " refers to sleep total the number of minutes of (nonREM and/or REM Sleep stages) of the maintenance in the longest single sleep cycle that a mammal occurred or " stage " during one hour after the specific treatment.The assessment sleep of " sleep cycle length " measurement standard write down the most outstanding state in the cycle in 10 seconds, as or be defined as the independent Sleep stages (wherein Sleep stages is defined as the REM sleep, nonREM sleep, or regain consciousness) of 10 seconds tempus intercalares.

Term " average sleep cycle length " is defined as specific one hour average sleep cycle (in minute), is independent of each single cycle or stage.

After the stimulation sleeper effect of " knock-on aypnia " hypnotic or sleeping pill stops, the bounce-back of Chu Xianing again, unusual, compensatory clear-headed.

" REM sleep inhibition " be meant the CT-18 after the treatment (after light is arranged the 6th hour, LD12:12) or CT-15 (have behind the light the 5th hour, REM LD12:12) reduces the length of one's sleep.CT-18 after the administration or CT-15 reduce REM length of one's sleep more than 15 minutes (proofreading and correct with respect to benchmark and adjuvant treatment), are considered to unacceptable.

Compare with NREM or waking state, the REM sleep brings respiration inhibition and intermittently cardiovascular variation.During the knock-on aypnia, the physiological action highly significant of REM sleep is also broken the ortho sleep circulation.

Definition herein, " disproportion ground motor behavior suppresses " refers to that the reduction of motor behavior has exceeded the reduction of the sleep of normal and expection to motor behavior.

" combination medicine therapy " (or " therapeutic alliance ") comprises that chemical compound of the present invention and another kind of at least second kind of preparation are as specific intensive treatment, to obtain to unite the beneficial effect that uses these preparations.The beneficial effect of therapeutic alliance includes, but are not limited to and since these medicaments be used in combination the pharmacokinetics brought or the combined effect of pharmacodynamics.Chemical compound of the present invention and other active ingredients can be with single composition forms or isolating form administrations.When adopting the unpack format administration, a kind of administration of composition can prior to, simultaneously or be next to another kind of composition.The administering drug combinations of these medicaments be in the time period that limits (normally minute, hour, day or week, depend on selected combination).In one embodiment, " therapeutic alliance " comprise the independent use of determining and at random producing two or more medicaments of combination of the present invention.In another embodiment, " therapeutic alliance " intention comprises the administration successively of these medicaments, that is, although every kind of medicament is at different time administrations, these medicaments or wherein at least two kinds are at simultaneously time administration almost.Almost administration simultaneously can realize by following manner, for example, takes in addition a kind of medicine of fixed proportion or the single capsule of multiple medicine, the single capsule of every kind of medicament to the patient.Successively or almost administration simultaneously can be worked by any suitable manner, includes, but not limited to oral way, intravenous injection, intramuscular injection and directly absorb by mucosal tissue liquid.

Therapeutic agent of the present invention can be by same or different mode administrations. for example, the intravenous mode administration of selecting during beginning of composition of medicine, other therapeutic agent can pass through oral administration simultaneously. perhaps, all therapeutic agents can be by oral or intravenous administration. and the order of administration of these therapeutic agents is not very fixed. and " therapeutic alliance " (for example comprises above-mentioned therapeutic agent and the active therapeutic agent of other biological or non-drug therapy equally, surgical operation, radiotherapy or medical apparatus and instruments) co-administered. when therapeutic alliance further comprises other non-drug therapies, this non-drug therapy can be implemented with from medicine and the non-medication combined beneficial effect that obtains in any suitable time. for example, in suitable example, when non-drug therapy is given up several days or after a few week, this beneficial effect still can obtain from therapeutic alliance.

The term of Shi Yonging " parenteral administration " or " parenteral " are meant any other administering mode that removes intestinal and topical herein, and normally injection also comprises, is not limited to, vein, muscle, intra-arterial is in the sheath, in the capsule, in the socket of the eye, intracardiac, Intradermal, intraperitoneal is through trachea, subcutaneous, under the epidermis, intraarticular, under the tunicle, under the arachnoidea, mantle interior and breastbone inner injection and injection.

The term of Shi Yonging " lung " refers to that the intravital any part of patient, tissue or its premiere feature of organ are to carry out gas exchange with external environment condition herein, for example, and the O2/CO2 exchange." lung " is typically referred to as respiratory tract." pulmonary administration " refers to that it is to carry out any part, tissue or organ (for example, mouth, nose, the pharynx of gas exchange with external environment condition that the pharmaceutical composition that the present invention describes is imposed on premiere feature like this, oropharynx, throat, larynx, trachea, carina, bronchus, bronchioles, alveolar).In order to reach purpose of the present invention, " lung " also comprises the subsidiary tissue and the chamber of respiratory tract, and be special, nasal sinuses.

ViaA " pharmaceutical composition " is meant and comprises compound compositions disclosed by the invention that it is in the form that is suitable for to patient's administration.In one embodiment, said composition is in bulk or presented in unit dosage form.Presented in unit dosage form refers to comprise any in a lot of forms, for example, and capsule, IV bag, tablet, the aerosol respiratory organ of single pump, or dose jar.Amount at each unitary active component (compound or its salt disclosed by the invention) is an effective dose, and changes according to the particular treatment mode that is adopted.Those skilled in the art can change the dosage of administering mode according to age and patient's state.Dosage equally also depends on administering mode.Much administering modes all within expection, comprise, and are oral, pulmonary, and rectum, parenteral, percutaneous waits similarly.The dosage form that The compounds of this invention is used for part or percutaneous dosing comprises, powder, and spraying, ointment is stuck with paste, Emulsion, water preparation, gel, solution, ointment and inhalant, and similar type.In one embodiment, reactive compound of the present invention mixes with a kind of pharmaceutically acceptable carrier, antiseptic, buffer agent or required volatilizer under conditions for sterilization.

Term " flash dose " refers to the compound formulas of rapid dispersive finished product preparation.

Term " discharges immediately " and refers to discharge chemical compound in the very short relatively time from finished product preparation, is approximately 60 minutes basically.Term " slow release " comprises, postpones to discharge controlled release, and pulse release.Term " pulse release " is defined as and discharges medicine serially from preparation.Term " slow release " and " controlled release " are defined as at one and discharge chemical compound continuously in long-time from medicament.

" main body " comprises mammal, for example, the people, house pet (bird is waited similarly for Canis familiaris L. for example, cat), farm-animals (as, cattle, sheep, horse, poultry is waited similarly).Most preferred, this main body is the people.

Use herein, term " pharmaceutically acceptable " refers to those chemical compounds, material, compositions, carrier and/or finished product preparation, they are within the scope of medical judgment, be applicable to the in-vivo tissue of people and animal and do not have excessive toxicity, inflammation, anaphylaxis, or other problems or complication, it is suitable with the ratio of risk to be benefited.

" pharmaceutically acceptable excipient " refers to the excipient that uses when pharmaceutical compositions, it is normally safety, nontoxic, physiology or other aspects are all expected, comprises the excipient that can be used for veterinary drug and people's medicine." the pharmaceutically acceptable excipient " that use in description of the present invention and the claim comprises the excipient that one or more are such.

Chemical compound of the present invention is salify further.These all forms are all in the protection domain of claim expection of the present invention.

" pharmaceutically acceptable salt " of chemical compound refer to, and be pharmaceutically acceptable, and the salt with parent compound expection pharmaceutical properties.

" pharmaceutically acceptable salt " of Shi Yonging refers to the derivant of chemical compound disclosed by the invention herein, and wherein parent compound forms acid or basic salt. the example of pharmaceutically acceptable salt includes, but are not limited to, inorganic or acylate on the base residue is amine for example, the organic salt on alkali or the sour residue for example carboxylic acid and etc. analog. pharmaceutically acceptable salt comprises the conventional nontoxic salts or the level Four amine salt of The compounds of this invention, for example, form by nontoxic mineral acid or organic acid. for example, so conventional nontoxic salts comprises, but be not limited to, those are from being selected from the following deutero-salt of inorganic or organic acid, 2-aspirin, 2-hydroxy ethylene sulfonic group, acetic acid, ascorbic acid, benzenesulfonic acid, two carbonic acid, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethionic acid, 1,2-ethionic acid, fumaric acid, glucoheptonic acid, Portugal (grape) saccharic acid, glutamic acid, ethylene glycol, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic acid, hydrochloric acid, hydroxymaleic, naphthoic acid, isethionic acid, lactic acid, lactobionic acid, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, pyrovinic acid, napsylic, nitric acid, oxalic acid is pounced on acid, pantothenic acid, phenylacetic acid, phosphoric acid, Poly Gal A Galacturonan, propanoic acid, salicylic acid, stearic acid, subacetic, succinic acid, the amine sulphonyl, sulfanilic acid, sulfonic acid, tannic acid, tartaric acid, toluenesulfonic acid and conventional aminoacid, for example, glycine, alanine, phenylamino acid, arginine, etc.

Other examples comprise caproic acid, cyclopentanepropanoiacid acid, acetone acid, malonic acid, 3-(4-hydroxy benzenes) benzoic acid, cinnamic acid, the 4-chlorobenzenesulfonic acid, 2-LOMAR PWA EINECS 246-676-2,4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl bicyclic-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-benzenpropanoic acid, trimethylace tonitric, butylacetic acid, muconic acid waits similarly.The present invention comprises equally, the salt that the proton in chemical compound of the present invention is replaced by metal ion or produces with the organic base coordination, and the example of metal ion is, alkali metal ion, alkaline-earth metal ions, or aluminium ion, the example of organic base is, ethanolamine, diethanolamine, triethanolamine, tromethane, N-methyl glucoside amine waits similarly.

Be understandable that all pharmaceutically acceptable salts described herein comprise the solvent addition form (solvate) or the crystal form (polymorphic) of same salt.

Pharmaceutically acceptable salt among the present invention can obtain from the The compounds of this invention that comprises alkali or the acid molecule chemical method by routine.Usually, such salt can be by the free acid or the alkali form of these chemical compounds, and with stoichiometric suitable acid or alkali or the solution of both blended water or organic solvent or both mixture, reaction obtains; Usually the medium of non-water commonly used is an ether for example, ethyl acetic acid salt, ethanol, isopropyl alcohol, or acetonitrile.For example, following reaction equation has represented that parent compound forms the process of pharmaceutically acceptable salt hydrochlorate, and chemical compound 1 is used the salt acid treatment.

The number of protonated atom in this salt and corresponding coordination ion, the amount of acid that can be by acid/alkali atom number on the control parent compound and use is controlled.In one embodiment of the invention, the mono-hydrochloric salts of parent compound is by obtaining with the salt acid treatment.In another embodiment, the dihydrochloride of parent compound is by obtaining with the salt acid treatment.

The tabulation of suitable salt can be at Remington ' s Pharmaceutical Sciences, and 18th ed. obtains in (Mack Publishing Company, 1990).For example, these salt include, but are not limited to, the hydrochlorate and the acetate of the The compounds of this invention of fatty family amine, carboxylic acid amine and imines.

Chemical compound of the present invention also can be prepared to ester, for example, and pharmaceutically acceptable ester.For example the carboxylic acid functional on the chemical compound can be converted into corresponding ester, as methyl ester, and ethyl ester or other esters.Equally, the alcohol functional group on the chemical compound also can be converted into corresponding ester, as ethyl ester, and propyl ester or other esters.

Chemical compound of the present invention also can be prepared to prodrug form, for example, and pharmaceutically acceptable prodrug.The term of Shi Yonging " prodrug " is consistent with " prodrug " implication herein, refers to any chemical compound that can discharge active medicine in vivo.Since prodrug can strengthen this medicine some desired character (for example, dissolubility, bioavailability, easily preparation, etc.), chemical compound of the present invention can be with the prodrug form administration.Therefore, the invention is intended to cover the prodrug of the chemical compound of claim, and use the method for these prodrug and the method for these prodrug of preparation." prodrug " intention comprises any carrier that connects by covalent bond, after this prodrug is applied to main body, can discharge active medicine of the present invention in vivo.Prodrug of the present invention can obtain by some functional groups of modifying The compounds of this invention, and these modifications can obtain parent compound by what control or be removed in vivo.Prodrug comprises that the hydroxyl in the chemical compound of the present invention, amino, sulfydryl, carboxyl or carbonyl and other group keys connect the chemical compound that forms, and it can be separated into free hydroxyl, amino, carboxyl or carbonyl respectively in vivo.

The ion of prodrug includes, but are not limited to, in the formula I-IV chemical compound; hydroxy functional group forms ester (for example, acetas, dialkyl amino ester; formic acid esters, phosphate ester, sulphonic acid ester; and benzoate derivatives) and amino methyl (for example, N, N-dimethylformamide); carboxyl functional group forms ester group (for example, ethyl ester, morpholinyl ethyl ester); N-acyl derivative (for example, N-acetyl) N-Mannich alkali, Schiff alkali and enamine ketone that amidine functional group forms.Oxime, ketal and enol ester that ketone and aldehyde functional group form.Referring to Bundegaard, H. " Design of Prodrugs " pi-92, Elesevier, NewYork-Oxford (1985).

In the description, the singulative page or leaf has comprised plural form, unless context has spelt out opposite implication.Unless otherwise, all technology herein used and scientific terminology all have the implication of the affiliated field of the present invention routine.Under contradictory situation, be as the criterion with description of the present invention.

All percentage ratios and the ratio of Shi Yonging unless otherwise, all is meant weight herein.

" effective dose " chemical compound disclosed by the invention is meant such amount, when imposing on the main body that disease or disease arranged, can cause the decline of the disease or the disease of this main body.The amount that imposes on the chemical compound disclosed by the invention of this main body depends on specific disease, administering mode, and if other chemical compounds of the co-administered that has and the body constitution of main body, health status at ordinary times for example, other diseases, age, sex, genotype, body weight and drug resistance.Those skilled in the art can determine according to above-mentioned and other factors

The present invention's " effective dose " chemical compound is meant a certain amount of chemical compound of the present invention or compositions, when being applied to medicine alone or in combination as a sleep promoter, can play effectiveness.For example, effective dose refers to that The compounds of this invention in preparation or device is enough to cause the amount of physiological activity when imposing on a main body or patient.Synergistic composition during compositions of the present invention.Synergism as previously mentioned, for example, inserts the 49th page of capable document name of 18-19 of original text, appear at, when combination medicine-feeding the effect of this chemical compound greater than these chemical compounds the effect of addition during as single agent administration.Usually, synergy can clearly be proved under chemical compound suboptimum concentration.Synergism also can show the sleep effect of stimulation of low cytotoxicity or increase, low-residual, or with individually dosed other beneficial effects that bring by co-administered of comparing.

" therapeutic activity amount " refers to a certain amount of chemical compound, when these chemical compounds are applied in to a mammal when treating certain disease, the amount of effect is enough to obtain medical treatment. should " therapeutic activity amount " may be according to chemical compound, the mammiferous disease and the order of severity thereof of being treated, with age, body weight etc., change.

" therapeutic effect " of Shi Yonging is included in by the Expected Results of the used treatment that produces in the body of treatment main body herein.In one embodiment, the most basic therapeutic effect symptom of being treated main body is prevented from, relaxes or alleviates.For example, the fundamental symptoms of the therapeutic effect main body of being treated is prevented from, alleviates and alleviates.In another embodiment, the therapeutic effect disease or the symptom of being treated main body is prevented from, relaxes or alleviate.For example, the fundamental symptoms of the main body that can be treated of therapeutic effect is prevented from, alleviates and one of alleviates.

The invention provides the method for regulating sleep, this method is the loxapine analogs of the present invention that applies effective dose, and this material is that histamine receptor or one group of histamine receptor are had resistant function.The present invention also relates to new loxapine analogs.

The effective sleep regulator has specific character, and effect improves and side effect reduces.These character comprise the intravital half-life of the main body of expection, by the expection sedation effect of control of seizures, (for example, memory is not enough for minimum spirit that can be measured or other central nervous system's (CNS) side effect, reduce the muscle retractility, eyelid is dispirited or drowsiness).For example, the human body half-life of the regulator of effectively sleeping is less than 7 hours, is less than 6 hours, is less than 5 hours, is less than 4 hours, and about 3 hours, or in 3-7 hour scope.

Preparation effectively method of sleep regulator is to derive from known chemical compound with sleep regulating action or a compounds to obtain.The derivant of a known compound may be strengthened the chemical compound that one or more biological properties obtain and show a kind of character of raising.Better the example of biological property comprises, but be not limited to, induce discrete sleep or sleep state, the acting in one section discrete time durations of this medicinal compound, pass the blood cerebral disorders and enter CNS, for example, since lipophilic substituent group or lipophilic conformation (for example, lipotropy is as a result of specific structure picture, for example between carboxyl and proton amine, form inner salt), regulate the half-life of chemical compound, change electronegativity, change drug metabolism, change logP by the one or many assessment, improve receptor-selective, reduce the neural half-life, improve dosage, increase nerve metabolism, reduce anti-muscarine activity, reduce the acetylcholine resistance, or above-mentioned combination.(the 50th page of 15-27 is capable for original text)

Deriving of certain chemical compound can cause multiple effect and can change the mechanism of action.For example, under certain conditions, the chemical compound than not possessing these functional groups contains the particular functional group, for example ester, carboxylic acid or alcohol groups, chemical compound, with respect to receptor, the receptor of expectation is had high selectivity to non-expectation.Under other conditions, than the chemical compound that does not possess some functional group, contain the medicament of particular functional group's chemical compound as the treatment sleep disorder, activity is more arranged.The effect of derivant depends on specific additional group.

For the physiological property of strengthening certain expectation and the side effect that reduces non-expectation certain chemical compound of deriving, it is possible carrying out design based on potential effect or reciprocal action.For example, in some chemical compound, the existence of carboxyl causes forming the ability of intermolecular ionic bond, comprises the corresponding carboxylic acid ion, for example, and the bridging nitrogen atom form in dipole ion and this compound or its salt.These inner reciprocal actions cause for example lipophilic on the conformation of the physiologic effect expected, as, improve the lipotropy of specific structure picture, for example between carboxylic ions and protonated amines, form inner salt.Such lipophilic conformation allows to pass the blood cerebral disorders and arrives CNS, although two ionic existence of polarity are considered to suppress to pass through nonpolar blood cerebral disorders.Another benefit that carboxylic acid exists is to improve the bonding selectivity of this chemical compound to intended recipient.

Chemical compound of the present invention also can be derived is prodrug. " prodrug " comprises the precursor of this medicine, in the organism of living, can metabolic conversion produce this active medicine. the present invention further comprises the use of prodrug, this prodrug can be converted into the chemical compound (inserting document name in the 51st page of capable bracket of 19-21 of original text) of the adjusting sleep of using among the present invention in the organism of living. and such prodrug can be used to change sleep and (for example regulate in the body of chemical compound decomposition, the chemical compound that allows to pass through the blood cerebral disorders usually passes through the blood cerebral disorders) or metabolism. for example, anionic group such as carboxyl, sulfate radical, sulfonate radical, can be esterified, for example, with alkyl group (as methyl) or phenyl, obtain ester. when this ester is applied in to main body, this ester bond is because enzymatic or non-enzymatic, reduction reaction or hydrolysis, and rupture, can obtain original anionic group. such ester can be cyclic, for example sulfate radical on the carbocyclic ring or sulfonate radical, perhaps two or more anionic groups form ring by a linking group. and an anionic group can form ester with other groups, this ester bond can rupture and obtain to regulate the intermediate of the chemical compound of sleeping immediately, this intermediate can decompose the reactive compound of adjusted sleep. in one embodiment, prodrug is a carboxyl, the reduction form of sulfate radical or sulfonate radical, for example alcohol or mercaptan, this reduction form can be oxidized in vivo regulates the sleep chemical compound. and further, anionic group can be by in vivo can the active group that transforms or to Target organ group esterification selectively.

This method is applied to sleep, and to regulate chemical compound be in order to improve their effect and safeties when the clinical practice.One group of chemical compound that is used to regulate sleep is relevant with loxapine, belongs to spirit commonly used and regulates chemical compound tricyclic antidepressants (" TCAs ").Loxapine is the dibenzoxazepines psychosis, can produce the drug reaction of common most of psychosis in multiple organism.Although the accurate mechanism of effect is also indeterminate, applies the succinic acid loxapine and can cause strong inhibition the SMA vigor.The recommended schizophrenia that is used for of loxapine.

Z is selected from CO ₂H, CO ₂R ₁₃, R wherein ₁₃Be C ₁-C ₆Alkyl, CONR ₁₄R ₁₅, R wherein ₁₄And R ₁₅Be respectively hydrogen, low alkyl group, CONHS (O) ₂-alkyl, CONHS (O) ₂-cycloalkyl, CONHS (O) ₂-assorted alkyl, CONHS (O) ₂-aryl, CONHS (O) ₂-heteroaryl, S (O) ₂The NHCO-alkyl, S (O) ₂The NHCO-cycloalkyl, S (O) ₂The NHCO-alkyl of mixing, S (O) ₂The NHCO-aryl,, S (O) ₂The NHCO-heteroaryl, CONHS (O) ₂The NH-alkyl, CONHS (O) ₂The NH-cycloalkyl, CONHS (O) ₂The NH-alkyl of mixing, CONHS (O) ₂The NH-aryl, CONHS (O) ₂The N-heteroaryl, SO ₃H, SO ₂H, S (O) NHCO-alkyl, S (O) NHCO-aryl, S (O) NHCO-heteroaryl, P (O) is (OH) ₂, P (O) OH,

(tetrazolium), or R wherein ₁₃Be C ₁-C ₆Alkyl, and R ₁₄And R ₁₅Be respectively hydrogen or low alkyl group, prerequisite be when Z be COOH, COOR ₁₃And R ₆When being hydrogen or halogen, R ₁-R ₅And R ₇-R ₁₂All not hydrogen; Further when m was zero, X lacked.

In another embodiment, be used for the formula I chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 500nM; Suppress constant greater than 500nM and/or be that inhibition constant for the H1 receptor is greater than 5 times for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 13 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 3 minutes; Average sleep cycle was greater than 5 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

In one embodiment, be used for the formula I chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 300nM; Suppress constant greater than 1 μ M for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 13 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 3 minutes; Average sleep cycle was greater than 5 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

Use, " linking group " is the atomic link that the nitrogen on the piperazine and Z group are coupled together herein.

Accept method of the present invention and can be used for treating multiple main body, comprise, for example, the mankind, companion animals, farm-animals, laboratory animal, or wild animal.

In one embodiment, the chemical compound that uses in the method for the adjusting sleep of the present invention's use is 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87 and 88.

In one embodiment, be used for the formula I chemical compound of method of the present invention, R9 does not exist with R10 and their common carbon atoms that links to each other.In one embodiment, R9 forms 3 to 7 yuan volution with R10 with the carbon atom that they link to each other jointly.In one embodiment, be used for the formula I chemical compound of method of the present invention, R11 forms 3 to 7 yuan volution with R12 with the carbon atom that they link to each other jointly.For example, R9 forms 3 yuan cyclopropane base with R12 with the carbon atom that they link to each other jointly with carbon atom or the R11 that they link to each other jointly with R10.

In one embodiment, Z is CO2H, tetrazolium, or sulfonamide.The example of sulfonamide comprises the acyl group sulfonamide, and Z can have following structural formula

Wherein substituted radical W is to reach required oral absorption, CNS infiltration and to enter urine or biliary metaboilic level is chosen according to the surface polarization area effect of adjusting the Z molecule.The example of suitable substituents W for this purpose comprises that alkyl group (can randomly comprise two or triple bond or replaced by hetero atom, for example CH2OCH3 or CH2OCH2CH3), group of naphthene base (can randomly comprise two keys), heterocycloalkyl, aryl or heteroaryl, it all can be chosen wantonly by following radicals and replace:

Wherein V is one or more side chains, and its selecteed standard is the PKa value of regulating this acyl group sulfonamide, or influences the physical property or the internal metabolism of this chemical compound.The example of V comprises F, Cl, Br, C ₁-C ₆Alkoxyl is OCH for example ₃Or OCH ₂CH ₃C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl is CH for example ₃CF ₃Or cyclopropyl; The C that hetero atom replaces ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl is CH for example ₂OCH ₃Or CH ₂OCH ₂CH ₃Electron withdraw group is CN for example, ketone, and amino or sulfone,

(pyridine radicals isomer arbitrarily),

(arbitrarily pyrimidine radicals isomer) or

In one embodiment, Z is a sulfonamide, comprises the acyl group sulfonamide.For example, Z can have structural formula, R wherein _aAnd R _bFor example be respectively, alkyl, cycloalkyl, heterocyclic radical, optional aryl, the heteroaryl that replaces.Concrete example comprises,

(with the pyridine isomer), or

(or pyrimidine isomer).

In another embodiment, when Z is COOH, R ₁-R ₈In at least one and R ₉-R ₁₂In at least one be not hydrogen.

In one embodiment, R ₆It or not hydrogen or halogen.In another embodiment, R ₁-R ₅And R ₇-R ₈All be hydrogen, R ₆It or not hydrogen or halogen.

In one embodiment, R ₁At least one is non-hydrogen substituted radical among the-R8, and other are hydrogen.In another embodiment, R ₁-R ₈In at least one is non-hydrogen substituted radical, and other are hydrogen.In another embodiment, at least two is non-hydrogen substituted radical among the R1-R8, and other are hydrogen.In another embodiment, at least three is non-hydrogen substituted radical among the R1-R8, and other are hydrogen.In another embodiment, at least four is non-hydrogen substituted radical among the R1-R8, and other are hydrogen.In one embodiment, R2 is not a hydrogen.In one embodiment, R3 is not a hydrogen.In one embodiment, R6 is not a hydrogen.In one embodiment, R7 is not a hydrogen.In one embodiment, R3 and R6 are not hydrogen.In another embodiment, R2 and R6 are not hydrogen.In another embodiment, R3 and R7 are not hydrogen.In another embodiment, R2 and R7 are not hydrogen.In another embodiment, R2 and R3 are not hydrogen.In another embodiment, R6 and R7 are not hydrogen.

In one embodiment, at least one is a methyl among the R1-R8, chlorine, fluorine, bromine, hydroxyl, methoxyl group methylene or methoxyl group. in another embodiment, R2 is a methyl, chlorine, fluorine, bromine, hydroxyl, methoxyl group methylene or methoxyl group. in another embodiment, R3 is a methyl, chlorine, fluorine, bromine, hydroxyl, methoxyl group methylene or methoxyl group. in another embodiment, R6 is a methyl, chlorine, fluorine, bromine, hydroxyl, methoxyl group methylene or methoxyl group. in another embodiment, R7 is a methyl, chlorine, fluorine, bromine, hydroxyl, methoxyl group methylene or methoxyl group.

In one embodiment, at least two is methyl among the R1-R8, chlorine, fluorine, bromine, hydroxyl, methoxyl group methylene or methoxyl group.In another embodiment, at least two is methyl among the R1-R8, chlorine, fluorine, bromine, hydroxyl, methoxyl group methylene or methoxyl group; With Z be COOH.In another embodiment, at least two is methyl among the R1-R8, chlorine, fluorine, bromine, hydroxyl, methoxyl group methylene or methoxyl group; R9 and R10 hydrogen; With Z be COOH.

In one embodiment, R3 and R6 are methyl, methoxyl group, and hydroxyl, the methoxyl group methylene, fluorine, chlorine, bromine, remaining R1-R2, R4-R5 and R7-R8 are hydrogen.In another embodiment, R2 and R6 are methyl, methoxyl group, and hydroxyl, the methoxyl group methylene, fluorine, chlorine, bromine, remaining R1, R3-R5 and R7-R8 are hydrogen.In one embodiment, R3 and R7 are methyl, methoxyl group, and hydroxyl, the methoxyl group methylene, fluorine, chlorine, bromine, remaining R1-R2, R4-R5 and R8 are hydrogen.In one embodiment, R2 and R7 are methyl, methoxyl group, and hydroxyl, the methoxyl group methylene, fluorine, chlorine, bromine, remaining R1, R3-R5 and R8 are hydrogen.In one embodiment, R2 and R3 are methyl, methoxyl group, and hydroxyl, the methoxyl group methylene, fluorine, chlorine, bromine, remaining R1, R4-R8 are hydrogen.

In one embodiment, R6 is a methyl.In one embodiment, R6 is a methyl, and R2 or R3 are methyl, methoxyl group, hydroxyl, methoxyl group methylene, fluorine, chlorine, bromine.In another embodiment, R6 is a fluorine, and R2 or R3 are methyl, methoxyl group, hydroxyl, methoxyl group methylene, fluorine, chlorine, bromine.In one embodiment, R6 is a methoxyl group, and R2 or R3 are methyl, methoxyl group, hydroxyl, methoxyl group methylene, fluorine, chlorine, bromine.In another embodiment, R6 is a fluorine, and R2 or R3 are methoxyl groups.

In one embodiment, R9 and R10 are hydrogen.

In one embodiment, R9 and R10 are methyl.In another embodiment, R9 and R10 are methyl, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen.In another embodiment, R9 and R10 are methyl.In another embodiment, R9 and R10 are methyl, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In one embodiment, R9 and R10 are ethyls.In another embodiment, R9 and R10 are ethyls, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen.In another embodiment, R9 and R10 are methyl.In another embodiment, R9 and R10 are ethyls, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In one embodiment, R9 forms ternary spiral shell (cyclopropane base) ring with R10 with the carbon atom that they link to each other jointly.In another embodiment, R9 and R10 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen.In another embodiment, R9 and R10 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In another embodiment, R9 and R10 are methyl, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen.In another embodiment, R9 and R10 are methyl, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In another embodiment, R9 and R10 are ethyls, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen.In another embodiment, R9 and R10 are ethyls, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In another embodiment, R9 forms ternary spiral shell (cyclopropane base) ring with R10 with the carbon atom that they link to each other jointly, R6 is a methoxyl group. in another embodiment, R9 and R10 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen. in another embodiment, R9 forms ternary spiral shell (cyclopropane base) ring with R10 with the carbon atom that they link to each other jointly, R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In one embodiment, R11 and R12 are methyl.In another embodiment, R9 and R12 are methyl, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen.In another embodiment, R11 and R12 are methyl.In another embodiment, R9 and R10 are methyl, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In one embodiment, R11 and R12 are ethyls.In another embodiment, R11 and R12 are ethyls, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen.In another embodiment, R11 and R12 are methyl.In another embodiment, R11 and R12 are ethyls, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In one embodiment, R11 forms ternary spiral shell (cyclopropane base) ring with R12 with the carbon atom that they link to each other jointly.In another embodiment, R11 and R12 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen.In another embodiment, R11 and R12 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In one embodiment, R11 and R12 are methyl, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen.In another embodiment, R11 and R12 are methyl, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In one embodiment, R11 and R12 are ethyls, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen.In another embodiment, R11 and R12 are ethyls, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In one embodiment, R11 forms ternary spiral shell (cyclopropane base) ring with R12 with the carbon atom that they link to each other jointly, and R6 is a methoxyl group.In another embodiment, R11 and R12 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen.In another embodiment, R11 and R112 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In one embodiment, be used for the formula I chemical compound of method of the present invention, q is 0.In another embodiment, q is 0, and R9 does not exist with the carbon atom that R10 links to each other with them.In another embodiment, q is 0, and R9 does not exist with the carbon atom that R10 links to each other with them, and X and Y are disappearances.In another embodiment, q is 0, and R9 does not exist with the carbon atom that R10 links to each other with them, and X and Y are disappearances, and m, n, o and p and be 1 or 2.

On the one hand, chemical compound of the present invention is used for regulating sleep, for example, shortens time for falling asleep by reducing, and improves each sleep cycle average length, and/or prolongs maximum sleep cycle length.In another embodiment, method of the present invention is by using formula I compounds for treating sleep disorder.This sleep disorder is the circadian rhythm imbalance, insomnia, and parasomnia is (for example, somnambulism, fright at night, REM disturbance in sleep behavior, sleep bruxism, the sleep enuresis), the sleep-apnea shape, as, the centric sleep apnea syndrome, obstructive sleep apnea syndrome and mixing sleep-apnea, sleep apnea, somnolence or hypersomnia.

In one embodiment, loxapine analogs of the present invention is used for the treatment of the circadian rhythm imbalance, for example, and the time difference, the disorder that break tour brings, Delayed sleep phase syndrome, Advanced sleep phase syndrome and non-24 hours sleep Arousal disorders.

In another embodiment, loxapine analogs is used for the treatment of insomnia, comprises, for example, the insomnia of exopathogenic factor type, Psychophysiological insomnia, high-altitude aypnia, restless legs syndrome, the nocturnal periodicity limb movement disturbance, the insomnia of medication dependency, drug dependence aypnia, the alcohol dependence aypnia, and with the relevant insomnia of obstacle at heart.

In one embodiment, the loxapine analogs parasomnia, for example, sleep-walking, fright at night, REM disturbance in sleep behavior, sleep odontorisis and the sleep enuresis.

In another embodiment, loxapine analogs of the present invention is used for the treatment of sleep apnea syndrome, such as, example has, CSAS, obstructive sleep suffocate disease and Combination sleep apnea.

Comprise the chemical compound of formula I or the pharmaceutical composition of its pharmaceutically acceptable salt and be used for regulating sleep.In one embodiment, the therapy co-administered of the chemical compound of formula I or its pharmaceutically acceptable salt and other one or more other.

In one embodiment, Z is CO2H or tetrazolium.In another embodiment, when Z is COOH, among R2, R3, R6 and the R7 one of at least and R9-R10 one of at least, be not hydrogen.In one embodiment, o is zero.

In one embodiment, when Z was COOH, at least one among R2, R3, R6 and the R7 and R9-R10 were not hydrogen one of at least.In one embodiment, R2, R3 and R7 are hydrogen, and R6 is a methyl, methoxyl group, methoxyl group methylene, or hydroxyl.

In one embodiment, at least two among R2, R3, R6 and the R7 is not hydrogen, other be hydrogen.In another embodiment, at least three among R2, R3, R6 and the R7 is not hydrogen, other be hydrogen.In one embodiment, R2 is not a hydrogen.In one embodiment, R3 is not a hydrogen.In one embodiment, R6 is not a hydrogen.In one embodiment, R7 is not a hydrogen.In one embodiment, R3 and R6 are not hydrogen.In one embodiment, R2 and R6 are not hydrogen.In one embodiment, R3 and R7 are not hydrogen.

In one embodiment, R9 and R10 are methyl.In one embodiment, R9 and R10 are ethyls.In one embodiment, R9 and R10 are hydrogen.

In one embodiment, R9 forms three to heptatomic volution with R10 with the carbon atom that they link to each other jointly.For example, R9 forms ternary spiral shell (cyclopropane base) ring with R10 with the carbon atom that they link to each other jointly.

In another embodiment, R9 and R10 are methyl, and R6 is that hydrogen or halogen and R3, R6 and R7 are hydrogen.R9 and R10 are methyl, and R6 is that hydrogen or halogen and R3, R6 and R7 are hydrogen, and Z is COOH.

In another embodiment, R9 and R10 are ethyls, and R6 is that hydrogen or halogen and R3, R6 and R7 are hydrogen.R9 and R10 are ethyls, and R6 is that hydrogen or halogen and R3, R6 and R7 are hydrogen, and Z is COOH.

In another embodiment, R9 forms ternary spiral shell (cyclopropane base) ring with R10 with the carbon atom that they link to each other jointly.In another embodiment, R9 and R10 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that hydrogen or halogen and R3, R6 and R7 are hydrogen.In another embodiment, R9 and R10 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that hydrogen or halogen and R3, R6 and R7 are hydrogen, and Z is COOH.

In one embodiment, be used for the formula II chemical compound of method of the present invention, o is 0. in another embodiment, and o is 0, and X is a disappearance. in another embodiment, o is 0, and X is a disappearance, and m, n's and be 1 or 2.

In one embodiment, sleep is that for example, time for falling asleep is shortened in minimizing, improves each sleep cycle average length, and/or prolongs maximum sleep cycle length.In another embodiment, method of the present invention is by using formula II compounds for treating sleep disorder.

Comprise the chemical compound of formula II or the pharmaceutical composition of its pharmaceutically acceptable salt and be used for regulating sleep.In one embodiment, the therapy co-administered of the chemical compound of formula II or its pharmaceutically acceptable salt and other one or more other.

In one embodiment, be used for the formula III chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 500nM; Suppress constant greater than 500nM and/or be that inhibition constant for the H1 receptor is greater than 5 times for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 13 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 3 minutes; Average sleep cycle was greater than 5 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound does not also suppress the relevant mobility of ortho sleep irrelevantly.

In one embodiment, Z is CO2H or tetrazolium.In one embodiment, m is zero.In one embodiment, when Z is COOH, among R2, R3, R6 and the R7 one of at least and R9-R10 one of at least, be not hydrogen.In one embodiment, R2, R3 and R7 are that hydrogen and R6 are not hydrogen or halogens.In one embodiment, R2, R3 and R7 are hydrogen, and R6 is a methyl, methoxyl group, methoxyl group methylene, or hydroxyl.

In one embodiment, R ₂, R ₃And R ₇Each all is that hydrogen and R6 are not hydrogen or halogens.In one embodiment, R2, R3 and R7 are hydrogen, and R6 is a methyl, methoxyl group, methoxyl group methylene, or hydroxyl.

In one embodiment, R9 and R10 are methyl.In another embodiment, R9 and R10 are ethyls.In one embodiment, R9 and R10 are hydrogen.

In another embodiment, R9 forms ternary spiral shell (cyclopropane base) ring with R10 with the carbon atom that they link to each other jointly. in another embodiment, R9 forms ternary spiral shell (cyclopropane base) ring with R10 with the carbon atom that they link to each other jointly, R6 is a hydrogen or halogen, with R3, R6 and R7 be hydrogen. in another embodiment, R9 and R10 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is a hydrogen or halogen, with R3, R6 and R7 be hydrogen, Z is COOH.

In one embodiment, be used for the formula III chemical compound of method of the present invention, o is 0.In another embodiment, X is a disappearance.In another embodiment, X is a disappearance, and m, n's and be 1 or 2.

In one embodiment, sleep is that for example, time for falling asleep is shortened in minimizing, improves each sleep cycle average length, and/or prolongs maximum sleep cycle length.In another embodiment, method of the present invention is by using formula III compounds for treating sleep disorder.

Comprise the chemical compound of formula III or the pharmaceutical composition of its pharmaceutically acceptable salt and be used for regulating sleep.In one embodiment, the therapy co-administered of the chemical compound of formula III or its pharmaceutically acceptable salt and other one or more other.

In one embodiment, t=1 or 2.

In one embodiment, be used for the formula IV chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 500nM; Suppress constant greater than 500nM and/or be that inhibition constant for the H1 receptor is greater than 5 times for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 13 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 3 minutes; Average sleep cycle was greater than 5 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound does not also suppress the relevant mobility of ortho sleep irrelevantly.

In another embodiment, be used for the formula IV chemical compound of method of the present invention, have following one or more features: to the inhibition constant (Ki) of H1 receptors bind less than 150nM; Suppress constant greater than 10 μ M for being selected from missing the target of the M1 that misses the target, M2, M3, M4, D1, D2, α 1 and α 2; Be applied to the patient the 3rd hour from this chemical compound, per hour the time to peak value of non REM sleep is bigger than the 55%REM sleep; The non REM sleep time of consolidating the chemical compound accumulation lifting of sleep is no less than 20 minutes; The longest during this time sleep cycle was greater than 13 minutes; When using the baseline value that obtained at least 24 hours before to the described chemical compound of main body administration to adjust, the longest sleep cycle was more than or equal to 3 minutes; Average sleep cycle was greater than 5 minutes when absolute peak; Main body is imposed this chemical compound do not cause the knock-on aypnia; Main body is imposed the REM sleep that this chemical compound also suppresses needs; Main body is imposed this chemical compound also do not suppress the relevant mobility of ortho sleep irrelevantly.

In one embodiment, Z is CO2H or tetrazolium.In one embodiment, when Z is COOH, among R2, R3, R6 and the R7 one of at least and R9-R10 one of at least, be not hydrogen.

In one embodiment, R9 and R10 are methyl.In another embodiment, R9 and R10 are ethyls.In one embodiment, R9 forms ternary spiral shell (cyclopropane base) ring with R10 with the carbon atom that they link to each other jointly.For example, in one embodiment, R9 forms ternary spiral shell (cyclopropane base) ring with R10 with the carbon atom that they link to each other jointly.

In one embodiment, R9 and R10 are methyl, and R6 is that hydrogen or halogen and R3, R6 and R7 are hydrogen.R9 and R10 are methyl, and R6 is that hydrogen or halogen and R3, R6 and R7 are hydrogen, and Z is COOH.

In one embodiment, R9 and R10 are ethyls, and R6 is that hydrogen or halogen and R3, R6 and R7 are hydrogen.R9 and R10 are ethyls, and R6 is that hydrogen or halogen and R3, R6 and R7 are hydrogen, and Z is COOH.

In one embodiment, R9 forms ternary spiral shell (cyclopropane base) ring with R10 with the carbon atom that they link to each other jointly.In another embodiment, R9 and R10 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that hydrogen or halogen and R3, R6 and R7 are hydrogen.In another embodiment, R9 and R10 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that hydrogen or halogen and R3, R6 and R7 are hydrogen, and Z is COOH.

In one embodiment, sleep is that for example, time for falling asleep is shortened in minimizing, improves each sleep cycle average length, and/or prolongs maximum sleep cycle length.In another enforcement side, method of the present invention is by using formula IV compounds for treating sleep disorder.

The pharmaceutical composition that comprises the chemical compound of formula IV or its pharmaceutically acceptable salt is used for regulating sleep. in one embodiment, and the therapy co-administered of the chemical compound of formula IV or its pharmaceutically acceptable salt and other one or more other.

In one embodiment, in the formula IV chemical compound that uses in the method for the present invention, be IVa, IVb, IVc, IVd and IVe.

For example, when R9 and R10 were methyl, chemical compound had following general formula I Va:

When R9 and R10 when carbon atom that they link to each other jointly forms ternary spiral shell (cyclopropane base) ring, chemical compound has following general formula I Vb:

When R9 and R10 were ethyl, chemical compound had following general formula I Vc:

When R9 and R10 are ethyls, and the C-1 carbon atom is when being connected to form ternary spiral shell (cyclopropane base) ring, and chemical compound has following general formula I Vd:

When R9 and R10 are hydrogen, chemical compound has following general formula I Ve:

On the other hand, the invention provides the chemical compound of formula I:

In one embodiment, this chemical compound is a chemical compound 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87 and 88.

In one embodiment, Z is COOH, tetrazolium, sulfonamide or sulphamide.In another embodiment, when Z was COOH, at least one was not a hydrogen among at least one and the R9-R12 among the R1-R8.

In one embodiment, R6 is not a hydrogen or halogen.In another embodiment, R1-R5 and R7-R8 are hydrogen, and R6 is not a hydrogen or halogen.In another embodiment, at least one is non-hydrogen substituted radical among the R1-R8, and other are hydrogen.

In one embodiment, at least one is non-hydrogen substituted radical among the R1-R8, and other are hydrogen.In another embodiment, at least two is non-hydrogen substituted radical among the R1-R8, and other are hydrogen.In another embodiment, at least three is non-hydrogen substituted radical among the R1-R8, and other are hydrogen.In another embodiment, at least four is non-hydrogen substituted radical among the R1-R8, and other are hydrogen.In one embodiment, R2 is not a hydrogen.In one embodiment, R3 is not a hydrogen.In one embodiment, R6 is not a hydrogen.In one embodiment, R7 is not a hydrogen.In one embodiment, R3 and R6 are not hydrogen.In another embodiment, R2 and R6 are not hydrogen.In another embodiment, R3 and R7 are not hydrogen.In another embodiment, R2 and R7 are not hydrogen.In another embodiment, R2 and R3 are not hydrogen.In another embodiment, R6 and R7 are not hydrogen.

In one embodiment, at least one is methyl, methoxyl group methylene, chlorine, fluorine, bromine, hydroxyl or methoxyl group among the R1-R8.In another embodiment, R2 is methyl, methoxyl group methylene, chlorine, fluorine, bromine, hydroxyl or methoxyl group.In another embodiment, R3 is methyl, methoxyl group methylene, chlorine, fluorine, bromine, hydroxyl or methoxyl group.In another embodiment, R6 is methyl, methoxyl group methylene, chlorine, fluorine, bromine, hydroxyl or methoxyl group.In another embodiment, R7 is methyl, methoxyl group methylene, chlorine, fluorine, bromine, hydroxyl or methoxyl group.

In one embodiment, R9 forms three to heptatomic volution with R10 with the carbon atom that they link to each other jointly.In another embodiment, R9 is disappearance with R10 with the carbon atom that they link to each other jointly, and their common carbon atoms that links to each other of R11 and R12 form three to heptatomic volution.For example, R9 forms ternary cyclopropane basic ring with R10 with carbon atom or their common carbon atoms that links to each other of R11 and R12 that they link to each other jointly.

In one embodiment, R9 and R10 are hydrogen.

In one embodiment, R9 and R10 are methyl.In another embodiment, R9 and R10 are methyl, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen.In another embodiment, R9 and R10 are methyl, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In one embodiment, R9 and R10 are ethyls.In another embodiment, R9 and R10 are ethyls, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen.In another embodiment, R9 and R10 are ethyls, and R6 is that hydrogen or halogen and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In another embodiment, R9 and R10 are methyl, and R6 is that methoxyl group methylene and R1-R5 and R7-R8 are hydrogen.In another embodiment, R9 and R10 are methyl, and R6 is that methoxyl group methylene and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In another embodiment, R9 and R10 are ethyls.R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen.In another embodiment, R9 and R10 are ethyls, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In one embodiment, R9 forms ternary spiral shell (cyclopropane base) ring with R10 with the carbon atom that they link to each other jointly, R6 is a methoxyl group. in another embodiment, R9 and R10 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen. in another embodiment, R9 forms ternary spiral shell (cyclopropane base) ring with R10 with the carbon atom that they link to each other jointly, R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In another embodiment, R9 is disappearance with R10 with the carbon atom that they link to each other jointly.

In another embodiment, R11 and R12 are methyl, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen.In another embodiment, R11 and R12 are methyl, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In another embodiment, R11 and R12 are ethyls, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen.In another embodiment, R11 and R12 are ethyls, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In another embodiment, R11 forms ternary spiral shell (cyclopropane base) ring with R12 with the carbon atom that they link to each other jointly, and R6 is a methoxyl group.In another embodiment, R11 and R12 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen.In another embodiment, R11 and R112 form ternary spiral shell (cyclopropane base) ring with the carbon atom that they link to each other jointly, and R6 is that methoxyl group and R1-R5 and R7-R8 are hydrogen, and Z is COOH.

The pharmaceutical composition that comprises the chemical compound of formula I or its pharmaceutically acceptable salt all can be used in the method that the present invention regulates sleep.

On the other hand, the invention provides chemical compound with formula II:

Or it has the salt of pharmaceutical active, and m, n, o, p and q be respectively, 0,1,2,3,4,5, or the integer in 6; X is disappearance, O, S, C (O), SO or SO ₂R ₂, R ₃, R ₆And R ₇Be selected from H, F, Cl, Br, OH, CF respectively ₃, CH ₃, CH ₂CH ₃, CH (CH ₃), cyclopropane, OCH ₃, OCF ₃, CH ₂OCH ₃, and CH ₂OCH ₂CH ₃R ₉And R ₁₀Be respectively H, C ₁-C ₆Straight chained alkyl, C ₂-C ₆Branched alkyl, perhaps R ₉And R ₁₀The carbon atom that adheres to jointly with them lacks, or is connected to form 3,4,5,6, or 7 yuan volution, and Z is selected from COOH, CO ₂R ₁₃(R wherein ₁₃Be C ₁-C ₆Alkyl), CONHS (O) ₂-alkyl, CONHS (O) ₂-assorted alkyl, CONHS (O) ₂-aryl, CONHS (O) ₂-heteroaryl, S (O) ₂The NHCO-alkyl, S (O) ₂The NHCO-alkyl of mixing, S (O) ₂The NHCO-aryl, S (O) ₂The NHCO-heteroaryl, CONHS (O) ₂The NH-alkyl, CONHS (O) ₂The NH-alkyl of mixing, CONHS (O) ₂The NH-aryl, CONHS (O) ₂N-heteroaryl, or tetrazolium, prerequisite be when Z be COOH, COOR ₁₃And R ₆When being hydrogen or halogen, R ₁-R ₅And R ₇-R ₁₂All not hydrogen; Further when m was zero, X lacked.

In one embodiment, R9 forms three to heptatomic volution with R10 with the carbon atom that they link to each other jointly. and for example, R9 forms ternary spiral shell (cyclopropane base) ring with R10 with the carbon atom that they link to each other jointly.

In one embodiment, be used for the formula II chemical compound of method of the present invention, o is 0.In another embodiment, o is 0, and X is a disappearance.In another embodiment, o is 0, and X is a disappearance, and m, n's and be 1 or 2.

Comprising the chemical compound of formula II or the pharmaceutical composition of its pharmaceutically acceptable salt all can be used in the method for adjusting sleep of the present invention.

On the other hand, the invention provides the chemical compound of formula III:

In one embodiment, Z is CO2H or tetrazolium. in one embodiment, m is zero. in one embodiment, when Z is COOH, among R2, R3, R6 and the R7 one of at least and R9-R10 one of at least, not hydrogen. in one embodiment, R2, R3 and R7 are that hydrogen and R6 are not hydrogen or halogens. in one embodiment, R2, R3 and R7 are hydrogen, R6 is a methyl, methoxyl group, methoxyl group methylene, or hydroxyl.

In one embodiment, R2, R3 and R7 are hydrogen, and R6 is not a hydrogen or halogen.In one embodiment, R2, R3 and R7 are hydrogen, and R6 is not a methyl, methoxyl group, methoxyl group methylene, or hydroxyl.

In one embodiment, X is a disappearance.In another embodiment, X is a disappearance, and m, n's and be 1 or 2.

The pharmaceutical composition that comprises the chemical compound of formula III or its pharmaceutically acceptable salt all can be used in the method that the present invention regulates sleep.

On the other hand, the invention provides the chemical compound of formula IV:

In one embodiment, in the chemical compound, t=1 or 2.

Comprising the chemical compound of formula IV or the pharmaceutical composition of its pharmaceutically acceptable salt all is used in the method for the present invention's adjusting sleep.

In one embodiment, Z is CO2H, sulfonamide, sulphamide or tetrazolium.In one embodiment, when Z is COOH, among R2, R3, R6 and the R7 one of at least and R9-R10 one of at least, be not hydrogen.

In one embodiment, formula IV chemical compound is that molecular formula is IVa, IVb, IVc, the chemical compound of IVd and IVe.

Representative compounds more of the present invention see Table 1:

Table one loxapine derivant

Cmpd #	R ₂	R ₃	R ₆	R ₇	R ₉，R ₁₀	T	Size Ring	Z
Cmpd #	R ₂	R ₃	R ₆	R ₇	R ₉，R ₁₀	T	Size Ring	Z	1	H	H	H	H	CH ₃	1	none	COOH
2	H	H	H	H	CH ₃	1	3	COOH	1	H	H	H	H	CH ₃	1	none	COOH
2	H	H	H	H	CH ₃	1	3	COOH	3	H	H	H	H	CH ₃	2	none	COOH
4	H	H	F	H	CH ₃	1	none	COOH	3	H	H	H	H	CH ₃	2	none	COOH
4	H	H	F	H	CH ₃	1	none	COOH	5	H	H	Cl	H	CH ₃	1	none	COOH
6	H	H	Cl	H	CH ₃	2	none	COOH	5	H	H	Cl	H	CH ₃	1	none	COOH
6	H	H	Cl	H	CH ₃	2	none	COOH	7	H	H	Cl	H	CH ₃	1	3	COOH
8	H	H	Br	H	CH ₃	1	none	COOH	7	H	H	Cl	H	CH ₃	1	3	COOH
8	H	H	Br	H	CH ₃	1	none	COOH	9	H	H	Br	H	CH ₃	1	3	COOH
10	H	H	CH ₃	H	CH ₃	1	none	COOH	9	H	H	Br	H	CH ₃	1	3	COOH
10	H	H	CH ₃	H	CH ₃	1	none	COOH	11	H	H	CH ₃	H	CH ₃	2	none	COOH

Cmpd #	R ₂	R ₃	R ₆	R ₇	R ₉，R ₁₀	T	Size Ring	Z
Cmpd #	R ₂	R ₃	R ₆	R ₇	R ₉，R ₁₀	T	Size Ring	Z	12	H	H	OCH ₃	H	CH ₃	1	none	COOH
13	H	H	OCH ₃	H	CH ₃	2	none	COOH	12	H	H	OCH ₃	H	CH ₃	1	none	COOH
13	H	H	OCH ₃	H	CH ₃	2	none	COOH	14	H	H	OH	H	CH ₃	1	none	COOH
15	H	F	H	H	CH ₃	1	none	COOH	14	H	H	OH	H	CH ₃	1	none	COOH
15	H	F	H	H	CH ₃	1	none	COOH	16	H	F	CH ₃	H	CH ₃	1	none	COOH
17	H	Br	H	H	CH ₃	1	none	COOH	16	H	F	CH ₃	H	CH ₃	1	none	COOH
17	H	Br	H	H	CH ₃	1	none	COOH	18	H	Br	Br	H	CH ₃	1	none	COOH
19	H	CH ₃	H	H	CH ₃	1	none	COOH	18	H	Br	Br	H	CH ₃	1	none	COOH
19	H	CH ₃	H	H	CH ₃	1	none	COOH	20	H	CH ₃	CH ₃	H	CH ₃	1	none	COOH
21	H	OCH ₃	H	H	CH ₃	1	none	COOH	20	H	CH ₃	CH ₃	H	CH ₃	1	none	COOH
21	H	OCH ₃	H	H	CH ₃	1	none	COOH	22	H	OCH ₃	F	H	CH ₃	1	none	COOH
23	H	OCH ₃	OCH ₃	H	CH ₃	1	none	COOH	22	H	OCH ₃	F	H	CH ₃	1	none	COOH
23	H	OCH ₃	OCH ₃	H	CH ₃	1	none	COOH	24	H	OH	H	H	CH ₃	1	none	COOH
25	H	OH	OH	H	CH ₃	1	none	COOH	24	H	OH	H	H	CH ₃	1	none	COOH
25	H	OH	OH	H	CH ₃	1	none	COOH	26	F	H	H	H	CH ₃	1	none	COOH
27	F	H	CH ₃	H	CH ₃	1	none	COOH	26	F	H	H	H	CH ₃	1	none	COOH
27	F	H	CH ₃	H	CH ₃	1	none	COOH	28	Br	H	H	H	CH ₃	1	none	COOH
29	Br	H	Br	H	CH ₃	1	none	COOH	28	Br	H	H	H	CH ₃	1	none	COOH
29	Br	H	Br	H	CH ₃	1	none	COOH	30	CH ₃	H	H	H	CH ₃	1	none	COOH

Cmpd #	R ₂	R ₃	R ₆	R ₇	R ₉，R ₁₀	T	Size Ring	Z
Cmpd #	R ₂	R ₃	R ₆	R ₇	R ₉，R ₁₀	T	Size Ring	Z	31	CH ₃	H	CH ₃	H	CH ₃	1	none	COOH
32	OCH ₃	H	H	H	CH ₃	1	none	COOH	31	CH ₃	H	CH ₃	H	CH ₃	1	none	COOH
32	OCH ₃	H	H	H	CH ₃	1	none	COOH	33	OCH ₃	H	F	H	CH ₃	1	none	COOH
34	OCH ₃	H	CH ₃	H	CH ₃	1	none	COOH	33	OCH ₃	H	F	H	CH ₃	1	none	COOH
34	OCH ₃	H	CH ₃	H	CH ₃	1	none	COOH	35	OCH ₃	H	OCH ₃	H	CH ₃	1	none	COOH
36	OCH ₃	CH ₃	H	H	CH ₃	1	none	COOH	35	OCH ₃	H	OCH ₃	H	CH ₃	1	none	COOH
36	OCH ₃	CH ₃	H	H	CH ₃	1	none	COOH	37	OH	H	H	H	CH ₃	1	none	COOH
38	OH	H	OH	H	CH ₃	1	none	COOH	37	OH	H	H	H	CH ₃	1	none	COOH
38	OH	H	OH	H	CH ₃	1	none	COOH	39	H	H	H	OCH ₃	CH ₃	1	none	COOH
40	H	H	H	H	CH ₃	1	none	CONHSO ₂CH ₃	39	H	H	H	OCH ₃	CH ₃	1	none	COOH
40	H	H	H	H	CH ₃	1	none	CONHSO ₂CH ₃	41	H	H	H	H	CH ₃	1	none	tetrazole
42	H	OCH ₃	H	OCH ₃	CH ₃	1	none	COOH	41	H	H	H	H	CH ₃	1	none	tetrazole
42	H	OCH ₃	H	OCH ₃	CH ₃	1	none	COOH	43	H	OCH ₃	CH ₃	H	CH ₃	2	none	COOH
44	H	Br	H	CH ₃	CH ₃	1	none	COOH	43	H	OCH ₃	CH ₃	H	CH ₃	2	none	COOH
44	H	Br	H	CH ₃	CH ₃	1	none	COOH	45	H	H	H	Br	CH ₃	1	none	COOH
46	H	H	H	CH ₃	CH ₃	1	none	COOH	45	H	H	H	Br	CH ₃	1	none	COOH
46	H	H	H	CH ₃	CH ₃	1	none	COOH	Cmpd #	R ₂	R ₃	R ₆	R ₇	?R ₉，R ₁₀	T	Size Ring	Z
47	H	F	Br	H	?CH ₃	1	none	COOH	Cmpd #	R ₂	R ₃	R ₆	R ₇	?R ₉，R ₁₀	T	Size Ring	Z
47	H	F	Br	H	?CH ₃	1	none	COOH	48	H	F	OCH ₃	H	?CH ₃	1	none	COOH

Cmpd #	R ₂	R ₃	R ₆	R ₇	R ₉，R ₁₀	T	Size Ring	Z
Cmpd #	R ₂	R ₃	R ₆	R ₇	R ₉，R ₁₀	T	Size Ring	Z	49	H	Br	H	Br	?CH ₃	1	none	COOH
50	H	Br	CH ₃	H	?CH ₃	1	none	COOH	49	H	Br	H	Br	?CH ₃	1	none	COOH
50	H	Br	CH ₃	H	?CH ₃	1	none	COOH	51	H	Br	OCH ₃	H	?CH ₃	1	none	COOH
52	H	CH ₃	H	CH ₃	?CH ₃	1	none	COOH	51	H	Br	OCH ₃	H	?CH ₃	1	none	COOH
52	H	CH ₃	H	CH ₃	?CH ₃	1	none	COOH	53	H	CH ₃	F	H	?CH ₃	1	none	COOH
54	H	CH ₃	OCH ₃	H	?CH ₃	1	none	COOH	53	H	CH ₃	F	H	?CH ₃	1	none	COOH
54	H	CH ₃	OCH ₃	H	?CH ₃	1	none	COOH	55	H	OCH ₃	H	CH ₃	?CH ₃	1	none	COOH
56	H	OCH ₃	CH ₃	H	?CH ₃	1	none	COOH	55	H	OCH ₃	H	CH ₃	?CH ₃	1	none	COOH
56	H	OCH ₃	CH ₃	H	?CH ₃	1	none	COOH	57	CH ₃	H	Br	H	?CH ₃	1	none	COOH
58	CH ₃	H	OCH ₃	H	?CH ₃	1	none	COOH	57	CH ₃	H	Br	H	?CH ₃	1	none	COOH
58	CH ₃	H	OCH ₃	H	?CH ₃	1	none	COOH	59	H	H	CH ₃	H	?H	1	none	COOH
60	H	H	CH ₃	H	?H	2	none	COOH	59	H	H	CH ₃	H	?H	1	none	COOH
60	H	H	CH ₃	H	?H	2	none	COOH	61	H	H	OCH ₃	H	?H	1	none	COOH
62	H	H	OCH ₃	H	?H	2	none	COOH	61	H	H	OCH ₃	H	?H	1	none	COOH
62	H	H	OCH ₃	H	?H	2	none	COOH	63	H	H	OCH ₃	H	?CH ₃	1	3	COOH
64	H	Br	Br	H	?CH ₃	2	none	COOH	63	H	H	OCH ₃	H	?CH ₃	1	3	COOH
64	H	Br	Br	H	?CH ₃	2	none	COOH	65	H	CH ₃	Br	H	?CH ₃	1	none	COOH
66	H	OH	OH	H	?CH ₃	2	none	COOH	65	H	CH ₃	Br	H	?CH ₃	1	none	COOH
66	H	OH	OH	H	?CH ₃	2	none	COOH	67	H	OCH ₃	H	F	?CH ₃	1	none	COOH

Cmpd #	R ₂	R ₃	R ₆	R ₇	R ₉，R ₁₀	T	Size Ring	Z
Cmpd #	R ₂	R ₃	R ₆	R ₇	R ₉，R ₁₀	T	Size Ring	Z	68	H	CH ₃	H	F	?CH ₃	1	none	COOH
69	H	H	H	F	?CH ₃	1	none	COOH	68	H	CH ₃	H	F	?CH ₃	1	none	COOH
69	H	H	H	F	?CH ₃	1	none	COOH	70	H	H	OCH ₃	H	?CH ₃	1	none	tetrazole
71	H	H	OCH ₃	H	?CH ₃	1	none	CONHSO ₂CH ₃	70	H	H	OCH ₃	H	?CH ₃	1	none	tetrazole
71	H	H	OCH ₃	H	?CH ₃	1	none	CONHSO ₂CH ₃	72	Br	H	OCH ₃	H	?CH ₃	1	none	COOH
73	OH	H	OCH ₃	H	?CH ₃	1	none	COOH	72	Br	H	OCH ₃	H	?CH ₃	1	none	COOH
73	OH	H	OCH ₃	H	?CH ₃	1	none	COOH	74	H	H	OCH ₃	H	?H	1	none	tetrazole
75	H	H	OCH ₃	H	?H	1	none	CONHSO ₂CH ₃	74	H	H	OCH ₃	H	?H	1	none	tetrazole
75	H	H	OCH ₃	H	?H	1	none	CONHSO ₂CH ₃	76	H	H	OCH ₃	H	?H	2	none	tetrazole
77	H	H	OCH ₃	H	?H	2	none	CONHSO ₂CH ₃	76	H	H	OCH ₃	H	?H	2	none	tetrazole
77	H	H	OCH ₃	H	?H	2	none	CONHSO ₂CH ₃	78	H	H	OCH ₃	H	?CH ₃	2	none	tetrazole
79	H	H	OCH ₃	H	?CH ₃	2	none	CONHSO ₂CH ₃	78	H	H	OCH ₃	H	?CH ₃	2	none	tetrazole
79	H	H	OCH ₃	H	?CH ₃	2	none	CONHSO ₂CH ₃	80	H	H	OCH ₃	H	?CH ₃	1	3	tetrazole
81	H	H	OCH ₃	H	?CH ₃	1	3	CONHSO ₂CH ₃	80	H	H	OCH ₃	H	?CH ₃	1	3	tetrazole
81	H	H	OCH ₃	H	?CH ₃	1	3	CONHSO ₂CH ₃	82	H	H	OCH ₃	H	?CH ₃	2	3	tetrazole
83	H	H	OCH ₃	H	?CH ₃	2	3	CONHSO ₂CH ₃	82	H	H	OCH ₃	H	?CH ₃	2	3	tetrazole
83	H	H	OCH ₃	H	?CH ₃	2	3	CONHSO ₂CH ₃	84	H	H	OCH ₃	H	?CH ₃	2	3	COOH
85	H	OCH ₃	F	H	?CH ₃	1	none	COOH	84	H	H	OCH ₃	H	?CH ₃	2	3	COOH
85	H	OCH ₃	F	H	?CH ₃	1	none	COOH	86	H	Br	H	OCH ₃	?CH ₃	1	none	COOH

Cmpd #	R ₂	R ₃	R ₆	R ₇	R ₉，R ₁₀	T	Size Ring	Z
Cmpd #	R ₂	R ₃	R ₆	R ₇	R ₉，R ₁₀	T	Size Ring	Z	87	H	CH ₃	H	OCH ₃	?CH ₃	none	COOH
88	CH ₃	H	F	H	?CH ₃		none	COOH	87	H	CH ₃	H	OCH ₃	?CH ₃	none	COOH

Some examples comprise:

Chemical compound 1 chemical compound 2 chemical compounds 3 chemical compounds 4

Chemical compound 5 chemical compounds 6 chemical compounds 7 chemical compounds 8

Chemical compound 9 chemical compounds 10 chemical compounds 11 chemical compounds 12

Chemical compound 22 chemical compounds 23 chemical compounds 24

Chemical compound 25 chemical compounds 26 chemical compounds 27

Chemical compound 28 chemical compounds 29 chemical compounds 30

Chemical compound 31 chemical compounds 32 chemical compounds 33

Chemical compound 34 chemical compounds 35 chemical compounds 36

Chemical compound 37 chemical compounds 38 chemical compounds 39

Chemical compound 40 chemical compounds 41 chemical compounds 42

Chemical compound 43 chemical compounds 44 chemical compounds 45

Chemical compound 46 chemical compounds 47 chemical compounds 48

Chemical compound 49 chemical compounds 50 chemical compounds 51

Chemical compound 52 chemical compounds 53 chemical compounds 54

Chemical compound 55 chemical compounds 56 chemical compounds 57

Chemical compound 58 chemical compounds 59 chemical compounds 60

Chemical compound 61 chemical compounds 62 chemical compounds 63

Chemical compound 64 chemical compounds 65 chemical compounds 66

Chemical compound 67 chemical compounds 68

Chemical compound 69 chemical compounds 70 chemical compounds 71

Chemical compound 72 chemical compounds 73 chemical compounds 74

Chemical compound 75 chemical compounds 76

Chemical compound 77 chemical compounds 78

Chemical compound 79 chemical compounds 80

Chemical compound 81 chemical compounds 82

Chemical compound 83 chemical compounds 84 chemical compounds 85

Chemical compound 86 chemical compounds 87 chemical compounds 88

As a rule, on the other hand, the loxapine analogs that the present invention relates to formula I-IVe is regulated the purposes of sleeping.More particularly, the chemical compound of formula I-IVe is regulated sleep and is had low side effect: for example, these chemical compounds do not suppress the REM sleep and (that is to say, by the more approaching mankind's of the inductive sleep of these chemical compounds natural sleep), use chemical compound of the present invention can not cause the aypnia that rebounds, and/or these chemical compounds can not influence mobility and can harmful effect do not arranged to body temperature yet.

Loxapine derivant of the present invention choice criteria in vitro is shown in table 2.

Table 2

In one embodiment, missing the target in conjunction with Ki is 50 times of H1 receptor Ki measured value.In other embodiments, missing the target in conjunction with Ki is 100 times of H1 receptor Ki measured value.

In vitro in conjunction with assessment be used for determining H1 in conjunction with (for example, basic target in conjunction with) and M1, M2 and M3 in conjunction with (for example, miss the target combination).These measure the ability of loxapine analogs from H1, M1, M2 and M3 receptor replacement known standard in conjunction with assessment, and wherein H1 is a histamine receptor, and M1, M2 and M3 are cholinergic (muscarine) receptors.Similar assessment is also carried out on H1 and dopamine receptor (D1 and D2) and H1 and adrenoreceptor (α 1 and α 2).

Combination at histamine receptor H1 studies show that binding affinity, so represented the activity of loxapine similar compound in conjunction with the result of assessment. the combination at muscarinic receptor H1 studies show that the degree of this chemical compound in conjunction with muscarinic receptor, the anticholinergic activity of this chemical compound. combine with muscarinic receptor and to cause some known antihistaminic negative interactions of not expecting, for example, xerostomia. with respect to combination to the H1 receptor, chemical compound is to M1, the bonded reduction of M2 and M3 receptor, show that this chemical compound is with respect to the specificity of muscarinic receptor to histamine receptor. further, medicine then possesses the anticholinergic side effect of reduction to the specific raising of histamine receptor.

Loxapine analogs of the present invention (being also referred to as " test compounds " or " The compounds of this invention " herein) passes through the combination of H1, measure given test compounds or a series of test compounds, specific bond to the H1 receptor is determined, and relatively with itself and known specific bond standard (for example, reference compound).Comprise in conjunction with the reference compound of using in assessing at this H1, for example, triprolidine (Ki 3.3nm), chlorpheniramine (Ki103.0nm), pyrimidinamine (Ki 1.9nm) Cyproheptadine (Ki 8.5nm), cimetidine (Ki＞10,000) and dimaprit (Ki＞10,000) (referring to inserting the 99th page of capable document name of 1-3 of original text).

For example, in an embodiment in conjunction with assessment of H1 receptor, the H1 receptor is from the cattle cell membrane, and radioligand, and [3H] pyrilamine (15-25Ci/nmol) that final ligand concentration is 2.0nM is used to measure the specific bond of H1 receptor.This assessment character comprises the KD (binding affinity) of 1.3nM and the Bmax (receptor number) of 6.2fmol/mg tissue (weight in wet base).Triprolidine (10 μ M) is used as non-special determinant, reference compound and positive control.Association reaction carried out 60 minutes under 50mMNAKPO4 (PH7.5) 25 degrees celsius.This is reflected under the glass fiber filter fast vacuum sucking filtration condition and stops.Measure the radiation level that this filter is caught, and compare, to find out the reciprocal action between given test compounds and the H1 binding site with controlling value.

M1 is in conjunction with assessment, by test compounds to the specific bond of M1 and with the specific bond of a reference compound relatively, determine the M1 combination of test compounds.(referring to inserting the 99th page of capable document name of 16-17 of original text).Comprise in conjunction with the reference compound of using in assessing at this H1, for example, scopolamine, methyl bromide (Ki 0.09nM), 4-DAMP methiodide (Ki 0.27nM), pirenzepine (Ki 2.60nM); HHSID (Ki 5.00nM); And Methoctramine (Ki 29.70nM).

For example, in the embodiment of a M1 in conjunction with assessment, the M1 muscarinic receptor is a human recombinant M1 who expresses in Chinese hamster ovary celI, and radioligand, [3H] pyrilamine, final ligand concentration is the methyl chloride (80-100Ci/nmol) of 0.5nM, is used to detect the specific bond to M1.This assessment character comprises KD (binding affinity) and the proteic Bmax of 4.2pmol/mg (receptor number) of 0.05nM.(-) scopolamine, methyl-, bromine (epoxytropine tropate bromine) (1.0 μ M) is used as non-special determinant, reference compound and positive control.Association reaction carried out under 25 degrees celsius 60 minutes in PBS.This is reflected under the glass fiber filter fast vacuum sucking filtration condition and stops.Measure the radiation level that this filter is caught, and compare, to find out the reciprocal action between given test compounds and the M1 binding site with controlling value.

M2 is in conjunction with assessment, by test compounds to the specific bond of M2 and with the specific bond of a reference compound relatively, determine the M2 combination of test compounds.(referring to inserting the 99th page of capable document name of 32-33 of original text).Comprise in conjunction with the reference compound of using in assessing at this H1, for example, scopolamine, methyl bromide (Ki 0.3nM), 4-DAMP methiodide (Ki 20.7nM), pirenzepine (Ki 20.460nM); HHSID (Ki 212.7nM); And Methoctramine (Ki 832.9nM).

For example, in the embodiment of a M2 in conjunction with assessment, the M2 muscarinic receptor is a human recombinant M2 who expresses in Chinese hamster ovary celI, and radioligand, [3H] pyrilamine, final ligand concentration is the methyl chloride (80-100Ci/nmol) of 0.5nM, is used to detect the specific bond to M2.This assessment character comprises KD (binding affinity) and the proteic Bmax of 2.1pmol/mg (receptor number) of 0.29nM.(-) scopolamine, methyl-, bromine (epoxytropine tropate bromine) (1.0 μ M) is used as non-special determinant, reference compound and positive control.Association reaction carried out under 25 degrees celsius 60 minutes in PBS.This is reflected under the glass fiber filter fast vacuum sucking filtration condition and stops.Measure the radiation level that this filter is caught, and compare, to find out the reciprocal action between given test compounds and the M2 binding site with controlling value.

M3 is in conjunction with assessment, by test compounds to the specific bond of M3 and with the specific bond of a reference compound relatively, determine the M3 combination of test compounds. (referring to inserting the 100th page of capable document name of 15-16 of original text). comprise in conjunction with the reference compound of using in assessing at this H1, for example, scopolamine, methyl bromide (Ki 0.3nM), 4-DAMP methiodide (Ki 0.8nM), pirenzepine (Ki 14.5nM); HHSID (Ki 153.3nM); And Methoctramine (Ki 700.0nM).

For example, in the embodiment of a M3 in conjunction with assessment, the M3 muscarinic receptor is a human recombinant M3 who expresses in Chinese hamster ovary celI, and radioligand, [3H] pyrilamine, final ligand concentration is the methyl chloride (80-100Ci/nmol) of 0.5nM, is used to detect the specific bond to M3.This assessment character comprises KD (binding affinity) and the proteic Bmax of 4.0pmol/mg (receptor number) of 0.14nM.(-) scopolamine, methyl-, bromine (epoxytropine tropate bromine) (1.0 μ M) is used as non-special determinant, reference compound and positive control.Association reaction is containing the 50MmTRIS-HCL of 10mMMgCl2 (PH7.4), carries out under 25 degrees celsius 60 minutes among the 1mM EDTA.This is reflected under the glass fiber filter fast vacuum sucking filtration condition and stops.Measure the radiation level that this filter is caught, and compare, to find out the reciprocal action between given test compounds and the M3 binding site with controlling value.

Loxapine derivant of the present invention choice criteria in vitro is shown in table 3.

Table 3

Other loxapine derivants of the present invention choice criteria in vitro is shown in table 4.

Table 4

H1 combination (basic target combination) and M1, M2 and M3 combination (combination of missing the target) use H1, M1, M2 and M3 are in conjunction with the assessment description as above.

The external choice criteria of other of loxapine analogs of the present invention comprises the hERG combination.The basic target combination and the combination of missing the target adopt aforementioned manner to determine.If test compounds shows basic target (H1) combination of expection and target/combining ratio misses the target substantially, hERG passes through in conjunction with (combination of missing the target), hERG retardance comparative study is determined to assess the effect of given test compounds to the clone hERG passage of expressing in mammalian cell.(referring to, Brown and Rampe, Pharmaceutical News 7:15-20 (2000); Rampe et al, FEBS Lett., 417:28-32 (1997); Weirich and Antoni, Basic Res.Cardiol.93 Suppl.1:125-32 (1998); With Yap and Camm, Clin.Exp.Allergy, 29Suppl 3,174-81 (1999))

The combination of missing the target of hERG, the cardiac potassium ion channel of the responsible delayed rectification electric current (IKr) in the human ventricle, evaluated, be by the vntricular action potential that non-heart medicine the brings modal reason of delaying owing to suppressing IKr.(referring to Brown and Rampe (2000), Weirich and Antoni (1998); And Yap and Camm (1999)).The action potential period that improves causes the QT interval to prolong, and the QT interval prolongs and ventricle allorhythmic pulse, torsades de pointes type chamber fast relevant (the Brown and Rampe (2000)) of danger.

In the hERG assessment, the hERG passage is expressed in human embryos kidney cell system (HEK293 cell), lacks endogenous IKr.Expression in mammal system is preferably the transcriptional expression in the xenopus leavis oocytes, and the latter shows the low sensitivity doubly to hERG channel blocker 10-100.(referring to Rampe1997).

In an embodiment of hERG assessment, positive control (for example, reference compound) is terfenadine (Sigma, St.Louis MO), be shown, and under 60nM concentration, can about 75% retardance hERG electric current.The primer solution of test compounds is HEPES-buffer normal saline+0.1% dimethyl sulfoxide (DMSO).Each test compounds all is applied to the hERG (n 〉=3, wherein n=cell number) of HEK293 cellular expression under the concentration conditions of 10 μ M.The time that is exposed to the test compounds of cell blocks to being enough to reach stable state, but no longer than 10 minutes.Positive control (60nM terfenadine) is applied to two cells.(n≥2)

The cell transfer that hERG-is exposed to track is also used the HB-PS solution casting then.The pipet solution that is used for full cell record comprises Potassium Aspartate (130mM), magnesium chloride (5mM), EGTA (5mM), ATP (4mM) and be adjusted to the HEPES (10mM) of PH7.2 with KOH.(depolarization :+20mV continues 2 seconds to use the held stationary amplitude; Repolarization :-50mV continues 2 seconds) the pulse mode initial sum of measuring the hERG electric current that test compounds brings stablize the retardance state, with 10 seconds be during repetition, from the electromotive force of-80mV.Measure the tail of the peak electric current of arrival-50mV2 in second.Before adding test compounds or positive control chemical compound 30 seconds, reach steady statue.Arrive to next steady statue, measure the tail of the peak electric current.

Except above-mentioned in vitro selectivity standard, loxapine analogs of the present invention is also selected by following intravital dormancy-awake assessment with physiological situation:

The NonREM sleep: loxapine analogs is with selected, if it is individual to grow up, male Wistar rat (i) was being received treatment the 3rd hour in, and per hour peak value nonREM amount surpasses nonREM55%; (ii) the character of the growth of nonREM is, the clean cumulative growth of nonREM sleep is (according to the benchmark adjustment of 24 hours physiological periods before corresponding after treating initial 6 hours, handle with respect to excipient) sum is no less than 20 minutes, when by oral administration, can maximize the consolidation sleep by measuring this chemical compound of sleep cycle length specification.

Term " the nonREM peak value length of one's sleep " is defined as treatment back nonREM sleep hourly absolute peak amount, administration time is in the physiological period time (CT) 18, and this time is for after the daybreak of the laboratory mice under LD12:12 (12 hour daytime and the 12 hour night) periodic condition at day-night the 6th hour.Per hour 55%nonREM sleep nominal standard be 33 minutes nonREM sleep per hour.

The term of Shi Yonging " accumulation nonREM sleep " is defined as the growth of nonREM sleep the number of minutes aggregate net accumulation total amount herein, at medicine whole action period of measurements, this is common, but always do not appear at six hours after the treatment yet, do not treat the number of minutes that benchmark adjustment in 24 hours before add up to total amount nonREM sleep only according to corresponding physiological period, handle with respect to similar excipient.

What the term of Shi Yonging " sleep cycle " referred to disperse herein is a series of continuously or near sleep continuously, comprises nonREM sleep, REM sleep, nonREM sleep and REM sleep, and demarcation is to have two before and afterwards greater than clear-headed cycle of 10 seconds.Following non restrictive description has illustrated this notion: WWWW SSSSWSSSSSSSWWSSSS SSSWWWW,, wherein the main state (S=sleep, W=is clear-headed) in this cycle of observing in per 10 seconds represented in each letter.The sleep that records " cycle " is 21 10-cycles second or 3.5 minute persistent period.

Sleep is consolidated: loxapine analogs is selected, if it is individual to grow up, male Wistar rat, (i) after the treatment the absolute persistent period in the longest prolonged sleep cycle (for example, " sleep cycle ") greater than 13 minutes; (ii) the longest sleep cycle only after the treatment is more than or equal to 3 minutes, with respect to excipient treatment according to benchmark adjustment and calculating before 24 hours; (iii) according to average absolute persistent period of each sleep cycle of average computation per hour, in hour one hour, more than or equal to 5 minutes.Aforesaid choice criteria adopt determine sleep or waking state be continuous ten seconds (for example, 10 seconds hypnographs are " period "), use sleep of EEG and EMG standard duplex measurement or waking state, (comprise nonREM sleep and/or REM sleep) between sleep period and be defined as that successive " cycle " interrupt up between the 10 second lucid interval that is closed on by two during this period.

The term of Shi Yonging " the longest sleep cycle length " is defined as herein, appears in initial hour after the treatment, and animal of a sleep cycle the longest keeps total the number of minutes of sleep (nonREM sleep and/or REM sleep).The continuous sleep that " sleep cycle length " measurement standard hypothesis was measured in 10 second cycle, and on the basis of advantage state record, counting, or (wherein Sleep stages is defined as the nonREM sleep to be defined as a discrete Sleep stages, the REM sleep, or clear-headed) in the ten second interim that is defined as one-period.

Term " average sleep cycle length " is defined as, and in each given hour, between each and all sleep period or the average duration in cycle (in minute), is independent of during each or persistent period that the cycle is independent.

Simultaneously-measured side effect: loxapine analogs is selected, if it is individual to grow up, male Wistar rat (i) does not produce any bounce-back aypnia; (ii) do not suppress the REM sleep at all; (iii), can suppress locomotor activity and/or sports coordination pro rata with respect to the normal effect of sleep itself.The basic definition of these three kinds of side effect is as follows:

" bounce-back aypnia " is defined as, and be the bounce-back that occurs after the sleep that the hypnotic or sedative drug agent excites, abnormality or compensatory clear-headed.The bounce-back aypnia is common, in remaining 6-18 hour of the conventional cycle after CT-18 (after the darkness under the LD:12:12 condition 6 hours) treatment, is observed, but can occurs any time in initial 30 hours after treatment.When, it is individual to grow up, and male Wistar rat is in the remaining cycle time after receiving treatment (daybreak during), with clear-headed greater than NonREM sleep decreased average per hour 1/10th o'clock of the relevant excessive buildup of bounce-back aypnia, rebounding is considered to unacceptable.

It is individual to grow up, male Wistar rat, with respect to the corresponding time after the drug-induced sleep effect (before 24 hours) be benchmark, the bounce-back aypnia shows the recovery time of increase, the bounce-back cumulative measurement of having a sleepless night.

" REM sleep inhibition " is defined as, after CT-18 (after the darkness under the LD:12:12 condition 6 hours) or CT-5 (after the daybreak under the LD:12:12 condition 5 hours or) treatment, and the minimizing of REM length of one's sleep.The chemical compound that cuts down sleep greater than 15 minutes (handling with respect to the excipient of benchmark and adjustment) is considered to unacceptable, no matter is CT-18 or CT-5 administration.

" the disproportionately locomotor activity inhibition " of Shi Yonging herein is meant the reduction to locomotor activity, exceeded the degree of the sleep of normal and expection to the locomotor activity reduction. logically, if an animal enters sleep, if then its locomotor activity can corresponding reduction. a kind of hypnosis or calm chemical compound have exceeded 20% of the independent exposure level of sleeping to the reduction of locomotor activity, this chemical compound is considered to unacceptable. and locomotor activity (LMA) or coordination can be by objective evaluations, use (the non-concrete action of any type of locomotor activity detector, motion detector based on remote measurement, the three-dimensional motion sniffer, running cage always does, experiment measuring, the flesh streaming current is traced record), as long as measure the allogenic animal of objective sleeping-wake up simultaneously.

In one embodiment, the locomotor activity of animal passes through to implant the intraperitoneal biological remote sensing measurement device of this animal in the cage; The device of this implantation and corresponding remote sensing receptor detect whether and how animal moves in the cage.Sleep during ten seconds and clear-headed simultaneously measured.The sum of locomotor activity that calculates each unit time is divided by this recovery time of unit in the time, obtain " locomotor activity density " (LMAI) of this unit time estimate.In CT-18 (after the darkness under the LD:12:12 condition 6 hours) administration, each unit time handles big 20% hypnosis or calm compounds to the reduction of locomotor activity than excipient and is judged as unacceptable.

In another embodiment, with the in vivo sleep-wake and the physiology evaluation criteria of record in the table five, select loxapine analogs of the present invention:

Table five

Record-2000	Absolute value	The variation of the reference value of excipient processing relatively separately
Record-2000	Absolute value		The nonREM time to peak of sleeping	＞55% sleep/hour peak value	Inapplicable
Accumulation nonREM	Inapplicable	＞20 minutes at ED100at MSBL T _1-6	The nonREM time to peak of sleeping	＞55% sleep/hour peak value	Inapplicable
Accumulation nonREM	Inapplicable	＞20 minutes at ED100at MSBL T _1-6	The longest sleep cycle	＞17 minutes absolute peaks	＞5 minutes
Average sleep cycle	＞6 minutes absolute peaks	Under SARcuts, use	The longest sleep cycle	＞17 minutes absolute peaks	＞5 minutes
Average sleep cycle	＞6 minutes absolute peaks	Under SARcuts, use	The bounce-back aypnia	The physiological period residue period after treatment is decreased average＜10% per hour	Inapplicable
The REM inhibition of sleeping	Inapplicable	Be no more than 15 minutes, Rx at CT5	The bounce-back aypnia		Inapplicable
The REM inhibition of sleeping	Inapplicable	Be no more than 15 minutes, Rx at CT5	LMAI	Inapplicable	Be no more than the minimizing of 20%LMAI

The method of measurement sleep-wake and physiology evaluation criteria as previously mentioned." absolute value " that is shown in second hurdle of table five refers to the value of each test compounds of measuring, and " change " that be shown in table five third column simultaneously reacted, when the excipient processing costs is adjusted into benchmark, and the difference that the relative excipient of absolute value is handled.

In some embodiments, the longest sleep cycle continued above 13 minutes.In other embodiments, continue above 17 minutes.In some embodiments, the longest only sleep cycle after the treatment increases more than or equal to continuing 3 minutes.In other therapeutic schemes, more than or equal to 6 minutes.

Other be used to select the in vivo sleep-wake of loxapine analogs of the present invention and physiology evaluation criteria to comprise, measure acute stage body temperature and incubation period body temperature with respect to the variation of the reference value of handling with excipient.In 1-6 hour time, the acute stage variation of body temperature can not surpass-0.50 degree centigrade, and the variation of body temperature incubation period can not be above+0.50 degree centigrade.Acute stage body temperature (T1-6) is adjusted to the benchmark before 24 hours, with respect to excipient.Incubation period, body temperature was measured behind 7-18 hour of Drug therapy, be adjusted into 24 hours before corresponding benchmark, with respect to excipient (reduction of comparing with excipient).

The invention provides a kind of method of regulating sleep, apply pharmaceutically the chemical compound of the formula I-IVe of live vol or the salt of its pharmaceutical active to main body.The multiple mode of these chemical compounds is regulated sleep, comprises, reduces time for falling asleep, increases the maximum of average sleep cycle length and increase sleep cycle length.

These chemical compounds, or its pharmaceutically acceptable salt, administration in the following manner, oral, per nasal, transdermallly, pulmonary sucks, the oral cavity, the Sublingual, intraperitoneal, intravenous, rectum, in the pleura, the interior and parenteral of sheath.In one embodiment, these chemical compounds pass through oral administration.Those skilled in the art can understand the advantage of specific administration mode.

The method of this adjusting sleep of the chemical compound by applying the formula I-IVe of live vol pharmaceutically to main body or the salt of its pharmaceutical active can be used for treating multiple sleep disorder, comprises the circadian rhythm imbalance, insomnia, parasomnia, sleep-apnea shape, somnolence and/or hypersomnia.In one embodiment, this method is used for the treatment of, the time difference, the disorder that break tour brings, Delayed sleep phase syndrome, Advanced sleep phase syndrome and non--24 hours Sleep-Wake obstacles.In another embodiment, method of the present invention is used for the treatment of insomnia, comprises, for example, the insomnia of exopathogenic factor type, Psychophysiological insomnia, high-altitude aypnia, restless legs syndrome, the nocturnal periodicity limb movement disturbance, the insomnia of medication dependency, drug dependence aypnia, the alcohol dependence aypnia, and with the relevant insomnia of obstacle at heart.

The term of Shi Yonging " sleep disorder " comprises herein, and those are thought the situation of sleep disorder by those skilled in the art, and for example, this area is considered to the situation of sleep disorder or is defined or is found to be the situation of sleep disorder.Referring to, for example, Thorpy, MJInternational Classification of Sleep Disorders, Revised:Diagnostic andCoding Manual.American Sleep Disorders Association; Rochester, Minnesota1997; And ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification, National Center for Health Statistics, Hyattsville, MD..

For example, sleep disorder can be divided into usually, sleep disorder, for example, endogenous, exogenous and circadian rhythm imbalance; Parasomnia, for example awake, awakening one sleep transition period illness and fast quick-action eye (REM) relevant disease and other parasomnias; With psychology, neural relevant disease and other internal diseases; With other sleep disorder.

The endogenous sleep disorder comprises, for example, and Psychophysiological insomnia, the subjective sensation aypnia, the special property sent out hypersomnia, narcolepsy, the recurrent hypersomnia, special aypnia, hypersomnia after the wound, the obstructive sleep apnea syndrome sent out, CSAS, central alveolar hypoventilation syndrome, periodically limbs move obstacle, restless legs syndrome.

Exogenous sleep disorder comprises, for example, and Inadequate sleep hygiene, the environment sleep disorder, high-altitude aypnia, sleep insufficiency of accommodation, the syndrome of not having enough sleep, limiting property sleep disorder, sleeping dependency obstacle, the food anaphylaxis aypnia, eat (drink at night) syndrome, hypnotic drug dependency sleep disorder, analeptic dependency sleep disorder night, the alcohol dependence sleep disorder, bringing out property of toxin sleep disorder.

Night, the biorhythm sleep disorder comprised, for example, the time zone changes syndrome, the shift work sleep disorder, and erratic Sleep-Wake pattern, delayed sleep phase syndrome shifts to an earlier date syndrome, non-24 hours sleep-awake patterns mutually during sleep.

Wake obstacle up and comprise, for example, entanglement wakes up, sleep walking, sleep frightened or fright at night.

Sleep-awake conversion disorder comprises, for example, the rhythmic exercise obstacle, sleep startles, sleep the language disease, night the shank cramp.

The normal parasomnia that occurs together with the REM sleep comprises, for example, nightmare, the sleep paralysis, the relevant erectile disfunction of sleep, the relevant chordee of sleep, the REM sleep Dou Xingxing that occurs together stops fighting, the REM behavior disorder that occurs together of sleeping.

Other parasomnias for example, comprise, sleep is ground one's teeth in sleep, the sleep enuresis, with the sleep relevant abnormalities swallow syndrome, night the paroxysmal myodystonia, agnogenic night sudden-death syndrome, the constitutional snoring, infant breathes is suspended, congenital central hypoventilation syndrome, sudden infant death syndrome, optimum neonate sleep myoclonus.

" sleep disorder " occurs in the patient who suffers from other diseases, disease, sufferer or wound equally, perhaps occur in accepting the patient of other treatment, these patients have difficulty in going to sleep or keep prolonged sleep or experience invalid sleep, or non-restorative sleep, for example, the patient is experiencing sleep deprivation.For example, some patients that have difficulty in going to sleep are accepting the therapeutic treatment at other diseases, for example, and chemotherapy or surgical operation, or because the influence of other physical injuries of pain.

Known in this field, some disease, for example, and central nervous system's (CNS) disease such as psychology or sacred disease, for example, anxiety can be the part of symptom with the insomnia, for example, sleep deprivation.Therefore, " treatment sleep disorder " comprises the sleep disorder of treatment as other diseases part symptom, for example CNS disease equally.Further, to treatment as the sleep disorder of a CNS disease symptoms part, also can be useful to other related symptoms of this disease.For example, the patient in the concurrent sleep deprivation of some experience anxiety has also treated anxiety symptom simultaneously to the treatment of sleep deprivation.Therefore, the present invention has equally also comprised the method for the treatment of these diseases.

The spirit that occurs together sleep disorder neural or other internal medicine problems comprise, for example, and the mental disorder sleep disorder that occurs together, psychosis companion sleep disorder, mood disorders companion sleep disorder, anxiety disorder companion sleep disorder, panic disorder companion sleep disorder, alcoholism companion sleep disorder.

The sleep disorder of nervous system disorders of occurring together comprises, for example, and cerebral degeneration's disease sleep disorder that occurs together, the dementia sleep disorder that occurs together, the parkinson sleep disorder that occurs together, the insomnia of familial lethal, sleep dependency epilepsy, sleep period epilepsy electricity is provided persistent state, the sleep associated headache.Relevant with other internal medicine problems, comprise, for example, sleeping sickness, Nocturnal cardiac ischemia companion sleep disorder, chronic obstructive disease of lung companion sleep disorder, sleep dependency asthma, sleep dependency gastroesophageal reflux companion sleep disorder, peptic ulcer companion sleep disorder, fibromyalgia companion sleep disorder.

In some cases, sleep disorder is also relevant with pain, for example, and the neuropathic pain that ekbom syndrome brings; Migraine, hyperpathia, fiber pain; Strengthen or exaggerative sensitivity pain, for example, hyperpathia, scorching hot pain and allodynia; Sharp pain; Scorching hot pain; The atypia prosopodynia; Neuropathic pain; Backache; Complexity zone pain syndrome I and II; Arthralgia; The athletic injury pain; The pain relevant with infection, these for example infect, HIV, poliomyelitis sequela, and postherpetic neuralgia; Phantom pain; Paroxysmal pain; Cancer pain; Pain after the chemotherapy; Pain after the apoplexy; Postoperative pain; Neuralgia; The situation relevant with visceral pain comprises, irritable bowel syndrome, migraine and pharyngalgia.

Other sleep disorder comprise, for example, sleeper in short-term, long time sleeper, inferior awake syndrome, the intermittence myoclonus, the sleep hyperhidrosis, the sleep disorder that occurs together menstrual period, trimester of pregnancy the sleep disorder that occurs together, the terror hypnagogic hallucination, sleep dependency neurogenic dyspnea, sleep dependency laryngospasm, sleep apnea syndrome.

Insomnia when insomnia can be divided into beginning usually, this patient will enter sleep with the time more than 30 minutes; Have a sleepless night with persistence, this patient has in during should sleeping and keeps clear-headed more than 30 minutes, or, for example, before day waking up and cannot or hardly fall asleep again. insomnia and persistence insomnia when chemical compound disclosed by the invention can effectively be treated beginning, the insomnia that the periodicity arrhythmia brings, or the insomnia that brings of CNS disease. an embodiment is treatment one-period arrhythmia patient. another embodiment is the insomniac that the treatment affective disorder causes. in other embodiment, the patient who is treated suffers from sleep apnea, somnambulism, fright at night, ekbom syndrome, insomnia or retentivity insomnia during beginning. insomnia was effectively when chemical compound disclosed by the invention can begin treatment. and chemical compound disclosed by the invention is also effective to the insomnia of treatment persistence.

Use the dosage regimen of The compounds of this invention to select, comprise patient's blood group, race, age, body weight, sex, and disease condition according to multiple factor; The order of severity of the disease of being treated; Administering mode; Patient's hepatic and renal function; And the concrete compound or its salt that adopts.This area gengral practitioner or veterinary can easily determine and leave prescription, determine to stop, suppress the required effective amount of drug of this disease progression.

Oral dose of the present invention, when being used to reach described effect, scope is in oral 0.05 to 5000 mg/day.The active dose of chemical compound disclosed by the invention is usually in about 0.01 mg/kg mg/kg every day to 100 between every day, preferably between 0.1 mg/kg mg/kg/day every day to 10.The concrete medicine-feeding technology of chemical compound disclosed by the invention can be referring to Remington:the Science and Practice of Pharmacy, 19 ^ThEdition, Mack Publishing Co., Easton, PA (1995).

For example, in some embodiments, the acid salt of chemical compound that contains amido or other basic groups is by with the arriving of this chemical compound and suitable organic or inorganic acid reaction, such acid for example, hydrochloric acid, hydrobromic acid, acetic acid, other are similar for perchloric acid etc.The chemical compound that contains the level Four ammonium group also contains an anion ratio such as chloride ion, bromide ion, and iodide ion, acetate, perchlorates etc. are similar.Other examples of such salt comprise hydrogen chloride, hydrogen bromide, sulfate, sulfonyloxy methyl, nitrate, maleate, acetate, citrate, fumarate, tartrate (for example, (+)-tartrate, (-)-tartrate or its mixture, comprise racemic mixture), succinate, benzoate and contain for example glutamic acid of amino acid whose salt.

The salt that contains the chemical compound of carboxyl or other acidic functionalities can be by obtaining this chemical compound and the alkali reaction that is fit to.Pharmaceutically acceptable alkali like this can comprise alkali metal salt (particularly sodium salt and potassium salt) by making with pharmaceutically acceptable cationic alkali can be provided, alkali salt (particularly calcium salt and magnesium salt), aluminum salt and ammonium salt also can be by getting with the physiologically-acceptable organic base number, as, Trimethylamine, morpholine, pyridine, piperidines, picoline, dicyclohexylamine, N, N '-diphenyl-ethyl diamidogen, 2 hydroxy ethylamine, bis-(2-hydroxyethyl) amine, three-(2-hydroxyethyl) amine, procaine, diphenyl-piperidine, N-phenyl-β-phenethyl amine, dehydroabietylamine, N, N '-two dehydroabietylamines, glycosamine, the N-methylglucosamine, trimethylpyridine, quinine, quinoline and primary amino acid be lysine and arginine for example.

In some embodiments, specific chemical compound and its salt can all exist with solvate forms, and for example, hydrate the present invention includes all solvates and their mixture.

In one embodiment, chemical compound described herein and its pharmaceutically acceptable salt are used for preparing Pharmaceutical composition together with acceptable carrier or diluent.With make carrier comprise inert solid filler or diluent and aqueous antiseptic solution or organic solution.The amount of the The compounds of this invention of use in pharmaceutical composition is the amount that is enough to provide aforementioned dosage range.The preparation of The compounds of this invention and medicine-feeding technology can be referring to Remington:the Science and Practice of Pharmacy.

Usually, this compound is used for oral administration, and compound or its salt wherein disclosed by the invention and suitable solid or liquid-carrier or diluent form capsule, tablet, and pill, powder, syrup, solution, suspensions etc. are similar.

These tablets, pill, capsule wait similarly, comprise the active component of about 1 weight % to 99 weight %, and binding agent, for example, and Tragacanth, Radix Acaciae senegalis, corn starch or gel; Excipient for example, dicalcium phosphate; Disintegrating agent for example, corn starch, potato starch or alginic acid; Lubricant for example, magnesium stearate; And/or sweeting agent, for example, sucrose, lactose, glucide, xylitol waits similarly. and when preparation unit is a capsule, it also often contains, and except that above-mentioned material, a kind of liquid-carrier is fatty oil for example.

In some embodiments, multiple material is used as coating or in order to modify the unitary profile of said preparation.For example, in some embodiments, tablet can be coated with Lac, sugar, or the both has.In some embodiments, contain in slurry agent or the elixir, except that active component, sucrose is as sweeting agent, and methyl and propyl p-hydroxybenzoate are as antiseptic, and a kind of stain and flavoring agent be Fructus Pruni pseudocerasi or orange flavoring agent for example, or the like.

For some embodiments relevant with the injection administration, chemical compound disclosed by the invention, or its salt, solvate or its polycrystal can be combined to form injection solution or suspension with nontoxic aqueous solution or organic media.The compositions that injectable is used is isotonic solution or suspension preferably.Said composition can be sterilized and/or comprise accessory drugs, for example, and antiseptic, stabilizing agent, wetting agent or emulsifying agent, solution catalyst, the salt and/or the buffer of adjusting osmotic pressure.In addition, also can contain the material that other have pharmacy value.Said composition independently, prepares, and comprises about 0.1% to 75% preferred 1% to 50% active component by conventional mixing, granulation or painting method.

For example, the solution that can be used for injecting is used solvent, and for example Oleum sesami or Oleum Arachidis hypogaeae semen or aqueous solution of propylene glycol with the aqueous solution of the water-soluble salt of The compounds of this invention, prepare.In some embodiments, dispersant prepares at glycerol, liquid propylene glycol and its mixture in oil.Under normal condition, store and use, use antiseptic in these preparation process to stop microbial growth.The term of Shi Yonging " administration of injection mode " and " injection drug " are meant other administering modes except intestinal and topical herein, normally by injection, and comprise, be not limited to intravenous injection, intramuscular injection, intra-arterial, in the sheath, in the capsule, in the socket of the eye, in the heart, in the cortex, intraperitoneal is through trachea, subcutaneous, intraarticular is under the capsule, under the arachnoidea, inject and injection in the mantle and in the film.

Be rectally, suitable pharmaceutical compositions is, for example, and topical formulations, suppository, or enema.Suppository is preferably by lipomul or suspending agent.Said composition can be sterilized and/or comprise accessory drugs, for example, and antiseptic, stabilizing agent, wetting agent or emulsifying agent, solution catalyst, the salt and/or the buffer of adjusting osmotic pressure.In addition, also can contain the material that other have pharmacy value.Said composition independently, prepares, and comprises about 0.1% to 75% preferred 1% to 50% active component by conventional mixing, granulation or painting method.

In some embodiments, chemical compound of the present invention is prepared to this reactive compound is passed through pulmonary administration, for example, comes administration by this reactive compound mist agent that comprises from following apparatus, for example, and hand spray pump, aerosol apparatus or sealing metered dose inhaler.In some embodiments, suitable this type of preparation also comprises other compositions, for example, antistatic additive, with keep chemical compound disclosed by the invention in aerosol effectively.

The explosive-feeding processing device that is used to apply aerosol comprises the suitable hermetically sealed can that possesses metering valve, and the sealing jar comprises aforesaid pharmaceutical aerosol formulations and controls this valve and the brake unit of control drug delivery.At this explosive-feeding processing device valve the top headspace is arranged, this space approximately is 15% of this valve total measurement (volume).Usually, plan disperses, suspends or be emulsified in the mixture of a solvent, surfactant and propellant formation by the polymer of pulmonary administration.This mixture is kept under the pressure of valve, with a metering bolt sealing.

For being used for nasal-cavity administration, can use solid or liquid-carrier.Solid carrier comprises the corase meal with specified particle diameter, and particle diameter is at about 20 to about 500 microns, and such preparation can pass through the quick inhalation of nasal cavity.In some embodiments, when using liquid-carrier, said preparation can or drip the form administration that reveals by nasal spray, and preparation comprises the oil or the aqueous solution of this reactive compound.

Comprise equally in this application be quick dispersible preparation form, be also referred to as " flash dose ". special, in embodiments more of the present invention, formulation preparation is become to discharge the composition forms of reactive compound in very short time, for example, usually be less than about 5 minutes, preferably being less than about 90 seconds, more having choosing to be less than 30 seconds, have choosing to be less than 10 seconds or 15 seconds most. such preparation is fit to by a lot of mode administrations, for example, by injecting body cavity or to the body surface or the wound administration of humidity.

Therefore usually, " flash dosage " is the solid preparation form, by the oral way administration, disperses in the oral cavity rapidly, and do not need to swallow and make this chemical compound be swallowed rapidly or absorbed by oral mucosa.In some embodiments, suitable fast-dispersing equally also is used for, and handles wound and other health wound and other diseases, and in these situations, medicament is not impossible by the administration of external humidification state.

" flash dose " preparation is known in this field, referring to, for example, United States Patent (USP) 5,578, the effervescent in 322 and 5,607,697 and the rapid release coat of non-soluble particles; United States Patent (USP) 4,642, cold drying foams and fluid in 903 and 5,631,023; United States Patent (USP) 4,855, the melt spinning of dosageform in 326 and 5,380,473; United States Patent (USP) 6,741, the free solid modelling of solid in 992; United States Patent (USP) 5,587, glycosyl carrier and liquid adhesive and other dosage forms well known in the art in 172,5,616,344,6,277,406 and 5,622,719.

Loxapine analogs of the present invention can be prepared as " pulsed release " preparation, and this analog discharges (for example, pulsed) serially from pharmaceutical composition in said preparation.Loxapine analogs also can be prepared into " continue discharge " preparation, and this analog discharges in over a long time constantly at one from pharmaceutical composition in said preparation.

The present invention comprises following dosage form equally, for example, liquid preparation comprises ring-type or open chain compound encystation or solvent, for example, cyclodextrin, polyethers, or polysaccharide (for example, methylcellulose), or more preferably, have from the lipophilic end with the isolating sulfonate sodium group of alkyl ether space key polyion β-cyclodextrin derivant or polysaccharide.In one embodiment, this reagent is methylcellulose.In another embodiment, this reagent is to have from the lipophilic end with the isolating sulfonate sodium group of alkyl ether space key polyion β-cyclodextrin derivant or polysaccharide, for example,

(CyDex, Overland, KS).Those skilled in the art can assess the suitable reagent/proper ratio of chemical compound disclosed by the invention when obtained aqueous solution, for example the solution of 40% weight prepares serial dispersion liquid, for example, configuration 20%, 10,5%, 2.5%, 0% (control) waits similarly; Add excessive (with can dissolved amount comparing) chemical compound disclosed by the invention, mix under appropriate condition, for example, heating is stirred, and sonication waits similarly; The mixture that centrifugal filtration or filtration obtain obtains settled solution, analyzes compound concentrations disclosed by the invention in this solution.

Except above-mentioned medicine type, the treatment that comprises The compounds of this invention randomly comprises, with another or a plurality of other treatment administering drug combinations, for example, medicine or physics or behavior therapy (for example, light treatment, galvanism, behavior is proofreaied and correct, cognitive therapy, physiological period is proofreaied and correct, and waits similarly).Such practice is considered to " therapeutic alliance ".Other treatment or therapy in the therapeutic alliance are known by those skilled in the art, expectability its can with chemical compound combined effect of the present invention, for example, treatment well known in the art or therapy, can treat sleep disorder and the disease relevant with sleep disorder, for example, can treat the therapy of any sleep disorder disclosed herein or disease.In some embodiments, chemical compound of the present invention is a kind of as co-administered, and in other embodiments, chemical compound of the present invention is treated separately.

Usually, chemical compound of the present invention is as treatment administration separately.

Those skilled in the art can learn suitable and other therapies The compounds of this invention co-therapy, this therapy can with compound effects of the present invention in identical or different disease.With the The compounds of this invention administration, carry out other treatment then earlier; Perhaps, on the contrary, he treats advanced Xingqi.Any symptom that can treat, stop or alleviate target disease well known in the art during this other treatment, for example, sleep disorder, perhaps other diseases is as other CNS diseases.In addition, in some other embodiment of the present invention, chemical compound of the present invention with at the therapy therapeutic alliance known in this field of target disease.Further, these other therapies comprise any therapy that can be useful to the patient when with chemical compound therapeutic alliance disclosed by the invention.

For example, in some embodiments, this other treatment is a kind of medicine, and it can be used as independent medicament administration, perhaps with chemical compound of the present invention administration in same medicament.Chemical compound of the present invention can be with any or multiple commercially available, or the medicine co-administered of not obtainable by transaction or prescribed treatment, these medicines include, but are not limited to, hydryllin, antimicrobial, fungistat, antibacterial, hormone, antipyretic, bronchodilator, antidiabetic drug, anti-arrhythmic, the coronary artery expansion medicine, glucoside, spasmolytic, antihypertensive, antidepressant, antianxiety drugs, other psychotropic drugs, steroid, cortex steroid (class), analgesics, frigotherapy, vitamin, tranquilizer, hypnotic, contraceptive, nonsteroid anti-inflammatory drugs, other antuepileptics, immunomodulator, anticholinergic agents, sympatholytic medicine, class sympathetic nerve medicine, vasodilation, anticoagulant, anti-arrhythmic agents contains the prostaglandin of multiple pharmacologically active, diuretic helps SLEEP AGENT, hydryllin, antineoplastic agent, oncolytic agent, antiandrogen, antimalarial, the medicine of antileprotic and multiple other types.Referring to Goodman and Gilman ' s The Basis of Therapeutics (Eighth Edition, Pergamon Press, Inc., USA, 1990) and The Merck Index (Eleventh Edition, Merck ﹠amp; Co., Inc., USA, 1989).

Can include, but not limited to the example of chemical compound co-administered of the present invention

(Zolpidemtar Trate), indiplon, ESTORRA ^TM((+)-Zopiclone),

(gabapentin), (lyrica), eplivanserin,

(Zaleplon), ESTORRA ^TM((+)-Zopiclone), ZOPICLONE ^TM(imovane), DESYREL ^TM(trazodone hydrochloride),

(quetiapine fumarate),

(clozapine), ZYPREXA ^TM(olanzapine),

(risperidone), M100907 and LUNESTA ^TM

In one embodiment, chemical compound of the present invention is used for for example being called as " CPAP ", therapy therapeutic alliance with a kind of." CPAP " or " CIP " is a kind of medical treatment device, is used for the treatment of the sleep apnea respiratory disorder (comprise snoring) relevant with other sleeps.Use the treatment of CPAP device normally to pass through patient's nose or mouth administration.

Under the CACP treatment, the patient puts on a plastic mask of being close on nose when sleep.This mask links to each other with a compressor, and the nasal cavity that this compressor forces gas to enter the patient produces malleation.The ultimate principle of this method is to obtain a machinery " splice " effect in the nasal cavity supercharging, and this effect stops or alleviated subsiding of nasal cavity, answers this prevention or has alleviated obstructive sleep and suffocate.Although carry out finding to truly have therapeutic effect among the patient of CPAP treatment, a lot of patients are impatient at this device or pressure and refusal and use.Further, nearest blank investigation proof is considerably less about the secular complaint of CPAP treatment.The well-known patient of being removes this mask when sleep.

On the one hand, chemical compound of the present invention is with CPAP device administering drug combinations.On the other hand, chemical compound of the present invention is slept to improve with CPAP device administering drug combinations.On the other hand, chemical compound of the present invention with CPAP device administering drug combinations to reduce patient's discontented to the CPAP device.Do not need bondingly in theory, can stimulate the sleep chemical compound to impose on the patient the present invention of live vol by uniting the treatment of CPAP device, this patient can sleep better, and so is not inclined to this mask is removed.

In one embodiment, chemical compound of the present invention administration before using the CPAP device.In another embodiment, chemical compound of the present invention is using the almost administration simultaneously of CPAP device.In another embodiment, increase a spray valve by the treatment of the air pressure in this CPAP device part, carry chemical compound of the present invention by aerosol form via nasal cavity or the oral cavity mask of CPAP like this, realize the parallel administration of The compounds of this invention of effective dose.Equally, the The compounds of this invention of effective dose also can add in water storage or the liquid reservoir, and this device is the part of CPAP therapy equipment normally

Use this CPAP mask treatment, chemical compound of the present invention can as injecting fast, begin at different time points in All Through The Night low concentration or high concentration administration, continues All Through The Night.

All are all quoted as proof at this at this patent of quoting and publication and all are incorporated in this paper, just as each patent document and publication all by clear and definite quoting as proof and be incorporated in this paper one by one respectively.Quote publication and patent document and do not show that it is the prior art document, also do not show the perhaps approval on date in it.The present invention is described by written description and the mode of giving an example, those skilled in the art will recognize that the present invention can put into practice in multiple different embodiments.The description of front and the following examples all be in order to set forth rather than to the restriction of claims.

Embodiment 1: loxapine analogs synthetic

Chemical compound of the present invention, and related derivatives can be synthetic by method well known to those skilled in the art.

Embodiment 2: the character of inducing-sleeping of The compounds of this invention

Mammiferous sleep can be divided into the sleep apparition, and this is during fast quick-action eye (REM), is accompanied by competent cerebral activity and non-REM (NREM) sleep period during this, is being accompanied by the cerebral activity minimizing during this period.Usually, all be the NREM sleep basically during the normal nighttime sleep, therefore, the NREM accumulated time can be used as the standard of weighing whole sleep accumulated time, for example, the remarkable minimizing of NREM sleep can be relevant with insomnia and forms cumulative " sleep debt ", and for example the accumulation to the psychological need of sleep can last till up to the competent unnecessary sleep of acquisition.Therefore, the increase of the NREM that brings of a certain treatment shows the effectiveness of this kind treatment to Cure for insomnia.

Sleep quality keeps relevant with sleep seriality or sleep.For example, the patient of a sleep-apnea may wake up many times between sleep period, and for example, this patient has any problem in the sleep continuously in maintenance very much.Although the common nighttime sleep length of this patient's accumulation has, for example 8 hours, this this sleep was invalid or is helpless to recover, and interrupted because this section sleep is equipped with based on bring clear-headed of sleep-apnea.Therefore, follow the prolongation of the long-time continual sleep cycle (LUSB is also referred to as the longest sleep cycle) of certain treatment, can show this kind treatment, therefore can treat the insomnia of sleep retentivity at the effectiveness of strengthening on the sleep seriality.

Sleep-wake, mobility, the body temperature of the male Wistar rat after monitoring is handled with test compounds (for example loxapine analogs), this compound concentrations is 10mg/kg at first.To selected chemical compound with higher or lower dosage assessment (for example, up to 45mg/kg and hang down reach invalid dosage).Treatment and administration are at CT-18, activity peak in the control cycle (after daybreak the 6th hour), produce the effect of hypnosis (induced hypnotic), the feature of this effect is the non-REM length of one's sleep that prolongs, the sleep persistence that improves, and do not have evidence to illustrate that it suppresses the REM sleep or brings the bounce-back aypnia.

Specific sleep derivation chemical compound disclosed by the invention (for example, chemical compound 1,2,3,5,6 have been used, 7,8,9,10,12,14,17,19,20,21,23,30,31,32,39,40,42,46,50,51,52,54,56 and 58) live body of chemical compound and in other tables 1, intravital sleep-wake, mobility and body temperature are monitored.Grow up, male Wistar rat (250 gram Charles River Laboratories WilmingtonMA when receiving treatment) is anaesthetized (2%isoflourane medical grade oxygen) and intracranial is implanted to allow to continue record electroencephalogram (EEG) and electromyogram (EMG).By small-sized transmiter (Mini-Mitter, Bend, OR) a detected activity ability and a body temperature of implanting abdominal part.The intracranial implant by stainless steel bolt (two frontal (+3.2AP from bregma, ± 2.0ML)) and be used for writing down EEG two pillow pages or leaves (6.9AP, ± 5.5ML).The stainless steel metal wire of two Teflon-coatings places under the dorsal ligaments muscle with record EMG.All conduits all were welded on the micro connector before operation, and gas is sterilized under oxirane.This implant is fixed on the skull with dentistry synthetic resin.The convalescent period in the rarest three weeks after the operation.

Each rat is all closed in record cage separately, on the rustless steel shelf of competent customization that ventilates, to place in the compartment respectively. each cage all uses filter-top riser and low torque swivel-commutator to strengthen. the quantity-unlimiting supply of things and water. in research process, keep (12 hour daytime at 24-hour daytime-night, 12 hour night) circulation. in 48 hours before receiving treatment and after the treatment, this animal is not disturbed.

Sleep and clear-headed, use " SCORE-2000TM " (Hypnion, Worcester, MA), based on network sleep-wake and physiological detection system.This system detects the EEG (being with logical 1-30Hz) that amplifies, in conjunction with the EMG that obtains by telemetry (the logical 10-100Hz of band), body temperature and non-special mobility (LMA) and drinking-water activity, continuously also side by side.Wakefulness can be divided into non-REM sleep (NREM), and the REM sleep is clear-headed, or θ-control is regained consciousness per ten seconds.Add up all drinking-water and mobilities, body temperature of per minute record uses the EEG feature to take passages and the Model Matching algorithm.From these data, draw the longest sleep cycle that is not interrupted (LUSB).Use individual contact EEG-awakening-state masterplate as pigeon-hole principle, on the different REM clear-headed from θ-control sleeps, add the REM benchmark, add some rules (for example, if this animal is drinking water then shows that it regains consciousness) of behavior dependence.Drinking-water and motor capacity density (LMA) write down once per ten seconds, and the body temperature per minute writes down once.Remote sensing receptor (Mini-Mitter) monitoring of mobility below cage.Remote sensing survey device (LMA and body temperature) is not the part of record rule, and therefore, hypnograph and telemetry device data are independently to estimate mutually.

Chemical compound is in the CT-18 administration, and this is movable leading period peak value, preceding competent time observation therapeutic effect arranged in daybreak (after the administration the 6th hour).Chemical compound is suspended in 0.25% or 0.5% the sterilization methylcellulose (1-2ml/kg).Preparation is with the form oral administration of pill.

Adopt one parallel group research.From a big sample cluster (N＞200), extract the sample of subclass, be matched with the preceding benchmark of treatment in 24-hour of reactive compound treatment group based on calculating as adjuvant control.

Measure the NERM and the LUSB parameter result of following loxapine analogs, for example, chemical compound inserts the 119th page of 12-13 line number word and 58 of original text, and the chemical compound in other tables 1.Their the results are shown in the table 6 separately.

Table 6: the sleep derivation character of chemical compound ^*

^*Dosage is unit with mg/kg; NREM and LUSB are minute being unit

Embodiment 3: the Irwin at side effect detects

Irwin detects and can provide about the potential side effect of chemical compound to conventional physiology and behavioral function.The enforcement that this detection is is by with the oral male Wistar rat that imposes on of the methylated cellulose aqueous solution of test compounds 0.25%, and this animal is the species that are commonly used in this class research, because background data is easy to obtain.

It is the multiple factor that detects in being applied in the animal body of test compounds that Irwin detects.For example, this detection can comprise: effect in the cage, for example, and dispersion, breathing rate, mobility, uneasiness, bellicose, and expophthalmos; Site response effect, for example, transfer wakes up, space motion, the eyelid that hangs down, scaring, tail is jumped, piloerection, contact is hidden, and the position is blunt, catalepsy, reflection is nervous, visual placing, grip, auricle, keratalgia reaction and wire manoeuvre; The factor of finding in the processing procedure, for example, cyanosis, skin blood flow, hypothermia, health color, pupil size, pupillary light reflex, tear secretion, grooming, red colouring, ptyalism and wrathful baiting; Generalscores, for example, fear, irritability, abnormal gait, improper figure, vibration is twitched, spasm, unusual action, twisting health, pronunciation, diarrhoea is drained number of times, and the urine number of times is dull, mortality rate, and distortion ratio. in Irwin, can be observed further details; Observation assessment comprehensively: a system of Ia., quantized program, with behavior and the physiological status of assessment rat, Psychopharmacologia (Berl.) 13:222-257,1968, whole instructions of the document are incorporated in full by being cited in this.

(Princetion NJ) carries out according to Irwin according to Covance in the Irwin detection of induced hypnotic preparation disclosed by the invention; Covance Standard OperatingProcedure (current revision of SOP PHARM8.10); Correlation-corrected authority guide is ICH (International Committee for Harmonization) guide (TopicS7A; CPMP/ICH/539/00) about the pharmacy safety research (Novermber 2000) of human medicine; And all operations on live animal all meet regulation, especially the Animals (Scientific Procedure) Act of English law, 1986.This bill requires in the breadboard all operations process of all Britain to keep moral custom, guarantees the enough love of all animals that are used and just; All reductions, improvement or alternate may be by suitable consideration, and obtain high-level caring attention.

All chemical substances used herein are bought from Colorcon, and Ltd, Dartford, UK and are that the ACS reagent pure grade is other or higher unless otherwise.All test compounds preparations all are to be prepared by Covance Harrogate Dispensary the same day in administration.Test compounds prepares preparation with required Cmax in 0.25% methocel solution.The preparation of low concentration by with high concentrate formulation with 0.25% methocel solution dilution acquisition.Dosage level is with by the amount calculating of the test compounds of administration rather than purity or active component.All preparations all store in room temperature (normally 10 to 30 degrees centigrade) lower seal lucifuge.

The male Wistar rat of sufficient amount (Crl:WI (Glx/BRL/Han) BR:WH)..About 5 weeks of these rats are big, on average focus between 150 to 170 grams.The grouping of these toys is raised, and every group is no more than 6, in the polypropylene cage (33x15x13cm) or (45x28x20cm), this cage has solid floor, makes (Datesand Ltd, Cheshire, United Kingdom) bedding with 10 grades wooden thin slice.Before use, this cage is clean and exsiccant.The horn of plenty environment is inserted poplar and is chewed piece in cage.Conventional, receptacle keeps temperature and relative humidity to remain in the acceptable limit (being respectively 19 to 25 degrees centigrade and 40%-70% usually).This receptacle in circulation in per 24 hours with fluorescence irradiation 12 hours, per hour ventilation 15 times at least.(RM1. (E) .SQC. (Special Diets Services Ltd.Witham, UnitedKingdom)) and water come from faucet, unconfined providing (except in processing procedure) to recipe.These do not find to comprise the material that causes the disturbed test system of any biological or chemical through the conventional analysis at concrete composition.When arriving, all toys have all been done disease-health detection.These animals are at least through laundering period of 5 days.In the meantime, distinguish these animals with the numbering on the cage.Before any experimental arrangement begins, detect, be suitable for research to guarantee them through the veterinary.Before the research beginning, these toy random assortment are become treatment group, the tail to each before handling carries out labelling.Finish in research, these toys are implemented euthanasia.

Each toy obtains oral administration or excipient or test substances, uses constant 1mg/kg.Each dosage depends on individual body weight, and this body weight obtained on the same day of dispenser.

Above Irwin detected parameters is carried out system evaluation according to control corresponding.Usually, induced drug changes, or in some intact animal really, all by with the parameter that occurs among integer record " 0 " representative normal (+/-, existence/the disappearance also is used) intact animal by with the integer record, can increase or reduce.After administration, observe in detail after 30,60,90,180 and 300 minutes.After administration 7 days during in these animals be held observation every day, observe its total toxic effect and mortality rate.

Embodiment 4: the hERG side effect of medicament disclosed by the invention

The cardiac potassium ion channel, hERG, the indoor quick sluggish correcting current in director body-centered (IKr).Selecting this passage as assessment, is the common cause that the heart action potential of not expecting that non-cardiac drug brings prolongs based on the inhibition of IKr.The heart action potential time limit of improving causes the QT prolongation of interval, and this is relevant with dangerous cardiac arrhythmias, Brown, AM; Rampe, D. (2000) .Drug-induced long QT syndrome:is hERGthe root of all evil? With Pharmaceutical News 7,15-20; Rampe, D; Roy, ML; Dennis, A; Brown, AM. (1997).The hERG passage is expressed in human embryo's kidney (HEK293) cell line, gives birth to IKr in lacking in this cell line.Expression in mammal cell line is preferably at the intracellular transient expression of Rana ovum, because the latter is low 10-100 times to the sensitivity of hERG channel blocker.Equally referring to, for example: A mechanism forthe pro-arrhythmic effects of cisapride (Propulsid): high affinity blockade ofthe human cardiac potassium channel hERG.FEBS Lett.411,28-32; Weirich, J; Antoni, H. (1998); Rate-dependence of anti-arrhythmic and pro-arrhythmicproperties of class I and class III anti-arrhythmic drugs.Basic Res Cardiol 93Suppl 1,125-132; And Yap, YG; Camm, AJ. (1999); And Arrhythmogenicmechanisms of non-sedating antihistamines.Clin.Exp.Allergy 29 Suppl 3, whole instructions of these aforementioned documents of 174-181. are all incorporated this paper into by being cited in this.

Sleep derivation medicament disclosed by the invention is in vitro to the effect of hERG (human ether-a-go-go-related gene) channel current (IKr fast stress delay rectification potassium current), by ChanTest (Cleveland, OH) determine, carry out according to the S.O.P. of ChanTest.

(St.Louis MO) unless otherwise, is that the ACS reagent pure grade is other or higher to all chemical substances used herein available from Sigma.The storing solution of test substances and terfenadine (positive control) are by dimethyl sulfoxide (DMSO) preparation and cold preservation.Test substances and positive control concentration by storing solution at HEPES (N-[2-hydroxyethyl] piperazine-N '-[acid of 2-ethylmercapto group]) buffering physiology salt (HB-PS) solution (component is with mM): insert the 124th page of capable component of 1-2 of original text; PH is adjusted to 7.4 with sodium hydroxide (prepared before the week, cold preservation is to using).Because aforementioned result shows that 0.3% DMSO does not influence channel current, all tests and control solution only contain 0.1% DMSO.If the DMSO ultimate density must for reaching specific test substances concentration, under the highest final DMSO concentration, be carried out the test of the excipient control of independent n＞2 greater than 0.3%.Test and control solution are from storing solution preparation on the same day.

The cell that uses is human embryo's kidney cell (HEK293; The source strain, AmericanType Culture Collection, Manassas, VA; Inferior strain, ChanTest, Cleveland, OH), DNA transcribes with the adenosine virus 5, and with hERG cDNA transfection.Stable transfectant is by selecting with the G418-disease-resistant gene coexpression of introducing expression plasmid.Selection pressure is kept by the G418 that comprises in the culture medium.Cell replenishes 10% N of embryo's serum, 100U/ml penicillin G sodium, 100 μ g/ml streptomycin sulfates and 500 μ g/mlG418 at Dulbecco ' sModified Eagle Meidum/Nutrient Mixture F-12 (D-MEN/F).

All experiments are all carried out under room temperature (18 to 24 degrees centigrade). and each cell acts on alone. and a concentration of test substances (10 μ M) is applied to expressing hERG (n 〉=3, wherein n is a cell number) cell on. be exposed under each concentration the duration be enough to reach stable state retardance, but being no more than 10 minutes. a concentration (60nM Te Feinading) of positive control material is applied to two cells (n 〉=2). and these cells are transcribed to recording room and water lid in HB-PS solution. and the pipet solution that is used for all cells record is (component is with mM): acid, aspartic potassium, 130; Magnesium chloride, 5; EGTA (ethyleneglycol bistetraacetic acid) 5; ATP (adenosine triphosphate), 4; HEPES, 10; With potassium hydroxide the ph value is adjusted to 7.2. and prepares pipet solution in batch, and by five equilibrium, cold preservation, thaw every day diaphragm pipet by capillary glass tube use the little pipet drawing device preparation of P-97 (Sutter Instrument, CA).Commercially available patch clamp amplifier is used in omnidistance cell record.Before digitized, electric current is recorded in 1/5th sample frequencies and is filtered by the low pass ripple.

Because the hERG electric current that brings of test formulation begins and stablize retardance, on the basis of-80mv fixed potential, the use fixed amplitude (removes the utmost point ,+20mv 2 seconds; Multipole-50mv 2 seconds) a pulse mode is measured, and is interrupted once in per ten seconds.Forwarding to-2 seconds measurements tail of the peak electric currents of 50mv.At least 30 seconds arrival steady statues before using test substances or positive control.Up to obtaining to survey the tail of the peak electric current again after another new steady statue.

Table 7 has shown under multiple sleep derivation chemical compound disclosed by the invention indication concentration the retardance to the hERG passage.Usually, 10% or still less be counted as expectation, be acceptable if this chemical compound has the effect of strong induced hypnotic not have that 12%-30% of other side effect; Be considered to not expect greater than 30% item.

Table 7hERG retardance

Chemical compound	HERG under 10 micromoles	Chemical compound	HERG under 10 micromoles
Chemical compound	HERG under 10 micromoles	Chemical compound	HERG under 10 micromoles	1	6.2％	30	4.50％
2	19％	31	3.80％	1	6.2％	30	4.50％
2	19％	31	3.80％	3	3.8％	32	1.60％
4	8％	35	0.10％	3	3.8％	32	1.60％
4	8％	35	0.10％	5	36％	39	61.40％
6	27％	40	5.6％	5	36％	39	61.40％
6	27％	40	5.6％	7	42.8％	42	5.80％
8	49％	44	65.90％	7	42.8％	42	5.80％
8	49％	44	65.90％	9	59％	46	20.40％
10	14％	50	45.00％	9	59％	46	20.40％
10	14％	50	45.00％	12	7.20％	51	32％
14	0.30％	52	19.80％	12	7.20％	51	32％
14	0.30％	52	19.80％	17	30.10％	54	6.10％
19	9.90％	56	0.30％	17	30.10％	54	6.10％

Chemical compound	HERG under 10 micromoles	Chemical compound	HERG under 10 micromoles
Chemical compound	HERG under 10 micromoles	Chemical compound	HERG under 10 micromoles	20	5.30％	58	0.20％
21	0％	72	10.90％	20	5.30％	58	0.20％
21	0％	72	10.90％	23	8.90％	86	86.90％

Embodiment 5: at the specificity of H1 histamine receptor

Use the sleep derivation chemical compound or derivatives thereof that is selected from table 1 disclosed by the invention, with known at the H1 histamine receptor.And M1, M2, M3 muscarinic receptor, α 1 and alpha-2 receptor and D1, D2 receptor, competition is carried out combination and is assessed in conjunction with evaluation criteria.

Histamine H I assessment is described in Chang, et al., Heterogeneity of Histamine H ₁-Receptors:Species Variation in[ ³H] Mepyramine Binding of Brain Membranes.Journal of Heurochemistry.32:1653-1663 (1979); Martinez-Mir, M.I., Pollard, H., Moreau, J., et al.Three Histamine Receptors (H ₁, H ₂, and H ₃) Visualized inthe Brain of Human and Non-Human Primates.Brain Res.526:322-327 (1990); Haaksma, E.E.J., Leurs, R.and Timmerman, H.Histamine Receptors:Subclasses and Specific Ligands.Pharmac.Ther.47:73-104 (1990) .muscarinic tests below and is described Buckley in the document, NJ., Bonner, T.I., Buckley, CM., and Brann, M.R.Antagonist Binding Properties of Five ClonedMuscarinic Receptors Expressed in CHO-Kl Cells.MoI.Pharmacol.35:469-476 (1989). experimentize according to above-mentioned article, but some improvement.Chemical reagent in the following method is available from Sigma, St.Louis, MO.

For carrying out histamine H I assessment, this receptor derives from the little meningeal tissue of cattle, and Bmax (receptor number) is that 6.2 femtos mole/milligram tissue (weight in wet base) and KD are 1.3nM.Adopt radioligand (ultimate density is 2.0nM for [3H] pyrilamine (15-25Ci/nmol), Ki 1.9nM), triprolidine (10 μ M) is used as non-special determinant, reference compound, and positive control.Receptor and radioligand in test compounds concentration range 10-10-10-6M, mix with test compounds, and this mixture carried out 60 minutes under 50mMNAKPO4 (PH7.5) 25 degrees celsius.This is reflected under the glass fiber filter fast vacuum sucking filtration condition and stops.Measure the radiation level that this filter is caught, and compare, to find out the reciprocal action between given test compounds and the H1 binding site with controlling value.

For muscarine assessment, receptor derive from a human recombinant receptor of in Chinese hamster ovary celI, expressing (PerkinElmer, Inc.Wellesley, MA).Adopt to such an extent that radioligand is [3H] pyrilamine, N-methyl chloride (80-100Ci/nmol), (-)-epoxytropine tropate bromine 1.0 μ M are used as non-special determinant, reference compound, and positive control.After the hatching, this is reflected under the glass fiber filter fast vacuum sucking filtration condition and stops.Determine the radioactivity of the substituted radioligand that this filter is caught, and with controlling value relatively, to find out given test compounds and the reciprocal action between the part separately.

Assess for the M1 receptor, Bmax (receptor number) is a 4.2pmol/mg protein, the KD of receptor (binding affinity) is that the final ligand concentration of 0.05nM. is 0.5nM, and the Ki of (-) epoxytropine tropate bromine is 0.09nM. receptor and radioligand, in test compounds concentration range 10 ^-12-10 ^-5In the M, mixed 60 minutes in Dulbecco ' s phosphate-buffered salt (PBS) in 25 degrees centigrade, adopt aforementioned operation then with test compounds.

For the assessment of M2 receptor, Bmax (receptor number) is a 2.1pmol/mg protein, and the KD of receptor (binding affinity) is 0.29nM.Final ligand concentration is 0.5nM, and the Ki of (-) epoxytropine tropate bromine is 0.3nM.Receptor and radioligand are in test compounds concentration range 10 ^-12-10 ^-5In the M, mixed 60 minutes in Dulbecco ' s phosphate-buffered salt (PBS) in 25 degrees centigrade, adopt aforementioned operation then with test compounds.

For the assessment of M3 receptor, Bmax (receptor number) is a 4.0pmol/mg protein, and the KD of receptor (binding affinity) is 0.14nM.Final ligand concentration is 0.2nM, and the Ki of (-) epoxytropine tropate bromine is 0.3nM.Receptor and radioligand are in test compounds concentration range 10 ^-12-10 ^-5In the M, in 25 degrees centigrade of 50mM TRIS-HCL (PH7.4) that comprising 10mM magnesium chloride, 1mM EDTA, mixed 60 minutes, adopt aforementioned operation then with test compounds.

Adenosine purine A1 carries out according to disclosed program in conjunction with assessment, referring to Bruns, and etal., Naunyn Schmiedebergs Arch.Pharmacol, 335 (1): 59-63 (1987) has some improvement; And Ferlany, et al.Drug Dev.Res.9:85-93 (1986).

Adenosine purine A2 carries out according to disclosed program in conjunction with assessment, referring to Jarvis, and etal., J.Pharmacol.Exper.Ther.251 (3): 888-93 (1989) has some improvement; And Bruns, et al., MoI.Pharmacol.29 (4): 331-46 (1986) has some improvement.

Carry out dopamine D according to following document disclosed method ₁(reorganization of people source).Referring to, for example, Jarvie, et al.J.ReceptRes., 13 (1-4): 573-90 (1993); And Billard, et al.Life Sciences, 35 (18): 1885-93 (1984) has some improvement.

Carry out dopamine D according to following document disclosed method ₁(reorganization of people source).Referring to, for example, Jarvie, et al.J.ReceptRes., 13 (1-4): 573-90 (1993); And Gundlach, et al.Life Sciences, 35 (19): 1981-8 (1984) with modifications has some improvement.

Can regard the performance of the sleep derivation character of this chemical compound expectation as with combining of H1.Reveal non-specific bond with the associative list of muscarinic receptor, this may cause the side effect do not expected to have shown anticholinergic character, for example, and many known antihistamine side effect, for example, the dimness of vision, xerostomia, constipation; urine is unusual, and is dizzy, anxiety etc. are similar.With respect to the H1 receptors bind, the bonded reduction of this chemical compound and M1-M3 receptor illustrates that this chemical compound has higher specificity to histamine receptor comparison muscarinic receptor.And, there is the medicine of high specific will have low anti-acetylcholine side effect to histamine receptor.

Table 8 has shown the inhibition constant K i to H1 and muscarinic receptor, and unit is nM.Chemical compound disclosed by the invention as can be seen has high specificity to the H1 receptor than muscarinic receptor.Therefore, chemical compound disclosed by the invention can expect that the side effect of the also relevant muscarinic receptor inhibition of the character that can demonstrate sleep derivation is very limited.

Table 8: to the specificity of H1 histamine receptor

CMPD #	?H1(bovine)	M1	M2	M3	Alpha1	Alpha2	?D1	D2
CMPD #	?H1(bovine)	M1	M2	M3	Alpha1	Alpha2	?D1	D2	1	?40.3 ¹	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?＞10,000rat?and?human	＞10,000rat and?human
2	?51.4	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000	1	?40.3 ¹	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?＞10,000rat?and?human	＞10,000rat and?human
2	?51.4	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000	3	?7.33	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?4920	1190
4		＞10,000		＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000 ³	3	?7.33	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?4920	1190
4		＞10,000		＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000 ³	5	?23.9	＞10,000	＞10,000	＞10,000	3020	＞10,000	?4520	1610
6	?13.8	＞10,000	＞10,000	＞10,000	2730	＞10,000	?7170	96.1	5	?23.9	＞10,000	＞10,000	＞10,000	3020	＞10,000	?4520	1610
6	?13.8	＞10,000	＞10,000	＞10,000	2730	＞10,000	?7170	96.1	7	?217	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?1730	222
8	?11.7	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?3350	434	7	?217	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?1730	222
8	?11.7	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?3350	434	9	?36	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?1120	53.3
10	?39.6	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?3160	1670	9	?36	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?1120	53.3
10	?39.6	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?3160	1670	12	?137	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?5220	1240

CMPD #	?H1(bovine)	M1	M2	M3	Alpha1	Alpha2	?D1	D2
CMPD #	?H1(bovine)	M1	M2	M3	Alpha1	Alpha2	?D1	D2	14	?283	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?942	＞10,000
17	?12	＞10,000	＞10,000	＞10,000	1990		?3450	883	14	?283	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?942	＞10,000
17	?12	＞10,000	＞10,000	＞10,000	1990		?3450	883	19	?39.5	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?6800	3160
20	?76.8	＞10,000	＞10,000	＞10,000	1960	＞10,000	?1930	1590	19	?39.5	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?6800	3160
20	?76.8	＞10,000	＞10,000	＞10,000	1960	＞10,000	?1930	1590	21	?57.2	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000
23	?135	＞10,000	＞10,000	＞10.000	＞10,000	＞10,000	?＞10,000	＞10,000	21	?57.2	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000
23	?135	＞10,000	＞10,000	＞10.000	＞10,000	＞10,000	?＞10,000	＞10,000	30	?90.6	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?5060	＞10,000
31	?239；337；244	＞10,000		＞10,000	＞10,000	＞10,000	?873	2200	30	?90.6	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?5060	＞10,000
31	?239；337；244	＞10,000		＞10,000	＞10,000	＞10,000	?873	2200	32	?3770	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000
35		＞10,000		＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000	32	?3770	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000
35		＞10,000		＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000	39	?98.7	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000

CMPD #	?H1(bovine)	M1	M2	M3	Alpha1	Alpha2	?D1	D2
CMPD #	?H1(bovine)	M1	M2	M3	Alpha1	Alpha2	?D1	D2	40	?22.8 ²	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?＞10,000rat?and?human	＞10,000rat 1870in human
42	?1120	＞10,000		＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000	40	?22.8 ²	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?＞10,000rat?and?human	＞10,000rat 1870in human
42	?1120	＞10,000		＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000	44	?41.4	＞10,000		＞10,000	＞10,000	＞10,000
46	?18.8	＞10,000		＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000	44	?41.4	＞10,000		＞10,000	＞10,000	＞10,000
46	?18.8	＞10,000		＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000	48	?27.1	＞10,000		＞10,000	＞10,000
50	?31.8	＞10,000	＞10,000	＞10,000	595	1,950	?1140	360	48	?27.1	＞10,000		＞10,000	＞10,000
50	?31.8	＞10,000	＞10,000	＞10,000	595	1,950	?1140	360	51	?27.8	＞10,000	＞10,000	＞10,000	148	966	?1040	170
52	?55.4	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000		＞10,000	51	?27.8	＞10,000	＞10,000	＞10,000	148	966	?1040	170
52	?55.4	＞10,000	＞10,000	＞10,000	＞10,000	＞10,000		＞10,000	54	?40.4	＞10,000	＞10,000		1210	5820	?4970	1080
56	?117	＞10,000		＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000	54	?40.4	＞10,000	＞10,000		1210	5820	?4970	1080
56	?117	＞10,000		＞10,000	＞10,000	＞10,000	?＞10,000	＞10,000	58		＞10,000	＞10,000	＞10,000	＞10,000	＞10,000	?2000	4030

CMPD #	?H1(bovine)	M1	M2	M3	Alpha1	Alpha2	?D1	D2
CMPD #	?H1(bovine)	M1	M2	M3	Alpha1	Alpha2	?D1	D2	72		＞10,000		＞10,000	＞10,000		?514	470

¹11.5?in?rat，23.7?in?human；2?58.8?in?rat，31.7?in?human； ³2730?in?rat

Embodiment 6: loxapine analogs

Below pharmacokinetic parameter be to use the concentration of antihistamine compounds in individual blood plasma of the correction that no chamber method and suitable checking pharmacokinetics software (for example, WinNonlin Professional) obtains to calculate.The concentration value that is reported as BLQ is designated as zero.If concentration data can obtain, if possible, (non-QC.d data) calculated in the transition between during carrying out.The increase of dosage does not also rely on the calculating of pharmacokinetics.

Descriptive statistics comprises meansigma methods, standard error, and the coefficient of variation, geometrical mean, mediant, minimum and maximum are carried out aforementioned calculation at the pharmacokinetic parameter of each dosage group.At each dosage level, carry out AUC (0-t), AUC (0-inf) and the such descriptive statistics of Cmax of natural logrithm conversion.In addition, also provide meansigma methods and the curve chart of half concentration VS time.

Dose ratio after the treatment research, by the variables A UC (0-t) that the natural logrithm conversion has been carried out in analysis, AUC (0-inf) and Cmax measure, and use linear model to comprise that the dosage of natural logrithm conversion is as correlated variables.If 95% confidence interval of correlated variables slope comprise numerical value 1, then dose ratio can be obtained by summary.AUC (0-t), the also available linear model research of the dosage linear relationship of AUC (0-inf) and Cmax is referring to inserting the 130th page of capable document name of 19-21 of original text.The nominal sample collection time is used to calculate, unless the actual sample time has dropped in the particular treatment acceptable time scope.Following parameters is evaluated.

C _MaxMaximal plasma concentration

T _MaxArrive the time of Cmax

C _MaxAnd T _MaxDirectly obtain from concentration-time data

AUC _0-tThe zone of plasma concentration-time graph under from the time 9 to the final time point that can measure concentration assessed with linear trapezoid method

AUC _0-00Plasma concentration-time graph is extrapolated to infinity, and calculate with following formula: AUC in the zone under the curve _0-00=AUC _0-1+ C ₀/ λ ₀

Wherein Ct can measure concentration in the blood plasma at last, and λ z eliminates the stage in terminal, uses the terminal stage elimination rate constant of logarithm-linear regression estimation.Calculate the number of the point of λ z use, depend on the visual information of the data of describing the terminal stage.At least, last three time points of measurable magnitude are used to calculate λ z.Calculate the number of the point of n λ z use, eliminate the best relevant (r2 correction) of stage time point based on getting the self-described terminal.If the r2 corrected value of linear regression is considered to accurately define terminal and eliminates this value of stage greater than 0.7.

T _1/2Eliminate the half-life, determined by In (2) λ z.

The CL whole body is removed; With intravenous injection medicament or injection, calculate with following formula: CL=Dose/AUC0-00Report CL/F is the F=absolute bioavailability wherein, at other all administering modes

The discrete volume of all administering modes of V2 is calculated with following formula: the V2/F when Vz=CL λ z CL/F is used to calculate extravascular administration

Use WinNonlin Professional Edition (Pharsight Corporation, Version 3.3 or4.1) to carry out pharmacokinetic analysis.Descriptive statistics is meansigma methods and standard error Microsoft Excel (Version 8.0e) for example

Test compounds is assessed as follows at the monkey of cold preservation and the metabolism of human hepatocytes:

Material

Pre-cultivation before the preparation

Sample dilutes with DMSO, to prepare the storing solution of 100 μ M and 10 μ M.By in 1 liter of acetonitrile (at room temperature storing 3 months), adding 1 milliliter formic acid, the acetonitrile solution of the formic acid of preparation 0.1%.10 minutes, in the quenching dish in 60 minutes and 120 minutes 96 hole, in each hole, add 150 μ L acetonitrile+0.1% formic acid.In storage or cold preservation on ice.

Then, hepatocyte is thawed, and the cell suspending liquid of 100 μ L and 100 μ L0.4% trypan blue solution place microcentrifugal tube, and slight the inversion mixed.A spot of cell suspending liquid (about 15 μ L) is placed in the hemocytometer and covers with coverslip.Hemocytometer is placed on the microscope stage, adjust focus and multiplying power and fill up whole zone up to can single number going out square.Cell number in the square that four exterior angles of hemocytometer are divided into is calculated.Visual cell is milky, circular, and the outer edge of black.Not visible cell is dark, opaque.

The computational methods of the percentage ratio of visual cell number are that visual cell number be multiply by 100 again divided by total cell number.

Visual cell density and total visual cell number are calculated:

The Mean 3 of visual cell density (D)=visual cell number (C) x104x f2; But the sum of visual cell (E)=Dx26 (resuspending volume).For reaching the computational methods of the additional agents that 1x106 cells/ml concentration need add:

Cell at room temperature dilutes and stores

Cultivate

198 μ L hepatocyte change in the relevant pitting of dosage dish.Remaining cell suspending liquid mixes with approaching ebullient water and places a suitable containers, places to make cell inactivation (being used for the preparation of nonactive control and standard curve) in 5 minutes

The nonactive hepatocyte of 198 μ L is transferred in the control pitting, the blank medium of 198 μ L is transferred in the dash-control pitting. and this dosage dish is pre-to be cultivated 15 minutes at least. and the test compounds dilute solution that 2 μ L are suitable from the dosage dish begins reaction. the cultivation 10 minutes during being set to 37 degrees centigrade incubator of this dish, 50 μ L cultures are transferred on the record quenching dish then, this dish comprises 150 μ L acetonitrile+0.1% formic acid, and cold preservation or place on ice after .60 minute, 50 μ L cultures are transferred on the 60 record quenching dishes, this dish comprises 150 μ L acetonitrile+0.1% formic acid, and cold preservation or place on ice after .120 minute, 50 μ L cultures are transferred on the 120 record quenching dishes, this dish comprises 150 μ L acetonitrile+0.1% formic acid, and cold preservation or place on ice. 50 remaining μ L are freezing on the culture plate. test tube centrifugalize under～4 degrees centigrade～1400xg. dilute with 100 μ L water at analysis disc 100 μ L supernatant, this coils in subzero 20 degrees centigrade of cold preservations before analysis.

The preparation of standard curve

10 μ M dosage solution with 2 μ L in the standard fabrication dish add in the nonactive hepatocyte of 198 μ L, prepare 0.1 μ M standard sample.On standard quenching dish, add 150 μ L acetonitrile+0.1% formic acid.The 0.1 μ M standard sample of 150 μ L is transferred to the string in the standard plate.The nonactive hepatocyte of 75 μ L adds in the remaining pitting.75 μ L from 0.1 μ M standard sample are transferred in the upward adjacent pitting of this dish, mix with titrating mode.Continue the dilution of series.75 μ L shift out (comprise and contain 75 μ L) from ultimate criterion.These dishes were cultivated about 10 minutes under 37 degrees centigrade condition.50 μ L are transferred to the standard quenching dish that comprises 150 μ L acetonitrile+0.1% formic acid.These dishes dilute the supernatant centrifugalize with sample and with water at 1: 1.Sample subzero 20 degrees centigrade freezing.

For chemical compound 5, this hepatocyte kept 120 minutes after 1 μ m treatment, and 75.105 is that primate and 90.405 is for human.

Embodiment 7: the clinical assessment of loxapine analogs

The target of human clinical experiment is to collect the effect data of loxapine derivant.Such data comprise, for example, the symptom of clinical manifestation and health test, deleterious situation, experiment safety is (for example, the hematology, serum clinical chemistry test, urine examination), the health sign is (for example, blood pressure, the rhythm of the heart, body temperature, respiratory frequency) and electrocardiogram (ECG) data.

Clinical experiment is carried out according to following:

The I main body is selected

18 main bodys of minimum use (9 one components become 2 groups).Candidate's main body meets the following standard that institute needs of carrying out:

Healthy adult male main body age 18-45

Minimum 60 kilograms of body weight, ideal body weight 15% with interior (referring to the desirable form of adult standard, Metropolitan Life Company, 1983)

Clinical non-important testing result (for example, lab testing analysis, history of disease, ECGS, health check-up) shows that main body is medically healthy

The candidate's main body that meets one of following condition does not satisfy the requirement of studying:

Suffered from the past or just suffering from cardiovascular, pulmonary, liver, kidney, blood, gastrointestinal, endocrine, disease that is immunity, skin, neural, spirit.

Suffered from the past or just suffering from sleep disorder

Study in preceding 90 days, suffer from the chronic or seasonal allergy of the H1 of needs receptor antagonist treatment (for example, terfenadine, astemizole)

Excessive drinking or drug dependence history were arranged in 2 years

Study in preceding 90 days and used Nicotiana tabacum L. or nicotine

Known to research medicine and the adjuvant that may use (

Sodiumsaccharin, F.C.C.; Glycerin, U.S.P.; Orange flavor; Methylcellulose 400centipoise, U.S.P.;

Water) and the hypersensitivity of related compound or idiosyncrasy.

Study preceding 90 days and contributed blood (the standard amount of donating blood or more) or blood products

Before first dosage, carry out other clinical trials in 90 days

Once suffering from or just suffering from anyly can influence drug absorption, metabolism, dispersion or excretory disease, morbid state or wound

Lose weight in preceding 30 days or increase (± 10%) in research

Regular luxus consumption (for example having taken every day unwanted) contains the beverage of caffeine in preceding 30 days of research

Any situation that in Investigator or Sponsor viewpoint, is considered to be not suitable for doing this research

Use any before or the treatment of forbidding followed

Each is accepted the present invention and studies the detection assessment, satisfies all criterion of acceptability, is accepted and numbers, the hydryllin of the modification of acceptance setting dosage or placebo at random.This random order only knows to those clinical pharmaceutical personnels that prepared these medicines that the evaluator of experiment main body, analyst, responsible tester and negative effect does not know.

Owing to following reason, main body can be withdrawn from from this research according to Principal Investigator:

Main exclusion standard appears for the second time

For protecting their health

Negative effect

Collection blood encounters difficulties

The integrity of protection research

Not pressing planning of experiment carries out

Inconsistent with research direction

The clinical experiment report has comprised main body that withdraws from and the detailed reason that withdraws from.All main bodys that withdrawed from before research is finished are also finished all research steps.The main body that withdraws from owing to any reverse side sign (no matter still serious not serious) or clinical improper laboratory tests value is detected by Ivestigator or doctor; and treated, be returned to by Ivestigator up to all symptoms or value and think normal or acceptable level.

II studies restriction

The main body that adopts prescription or opposite drug treating (comprising the medical herbs goods) is finished this research last sample during the pharmacokinetics sample in during 7 days and is collected.In addition, F﹠B comprises will being under an embargo of following composition:

Methylxanthine: before any one administration 72 hours and and during whole sample collection, for example, caffeine beverage or equivalent (for example, chocolate plate) are under an embargo.

Ethanol: before any one administration 72 hours and and during whole sample collection.

Any medical treatment of accepting during preceding 30 days in research all is recorded.Preceding 90 days medical treatments at chronic and seasonal Sensitive disease of any research all are recorded.

Subject detection before the test: Informed Consent Form administration before detection.In administration preceding 14 days, the historical and demography data of treatment comprised that name, sex, age, race, body weight (kg), height (cm), ethanol use and the Nicotiana tabacum L. use, all are recorded.Each main body is all accepted health check-up, comprises whole vital sign, 12-leadECG and laboratory specific detection.Laboratory tests comprise following:

A) hematology comprises hematochrome, MCV, erythrocyte number, hematocrit, MCHC, leukocyte number and the MCH different with number of platelets;

B) hematochemistry comprises ethanol, albumin, ALT (SGOT), creatinine, alkali phosphatase, special proportion, total bilirubin, sarcosine phosphokinase (CPK), sodium salt, uric acid, AST (SGOT) and triglyceride.

Urine examination comprises outward appearance and color, glucose, nitrite anions, PH, ketone, urobilinogen, special proportion, total bilirubin, leukocyte, protein and blood;

Other detection comprises HIV, and the urine medicine inspection is surveyed, HbsAg, and Fructus Cannabis, HCV, benzodiasepine, HCV, amphetamine, hepatitis A (lgM), Opiate, ethanol, cocaine and Yan grass are plain.

The main body management: incident after finishing administration in 24-hour, main body was put up a guest for the night before administration 36 hours.They withdraw from will return in a week after the administration or in advance the last time and carry out follow-up observation.

After administration 4 hours, main body will partly lie on a bed.Yet negative condition can occur at any time, and main body is placed in a suitable position or allows them to lie down on the right side.Any time main body during being kept in detention all can not get involved any arduous activity.

Standard meal was provided at first day and second day.At first day, main body be required before the minimum administration minimum spent the night 10 hours and administration after fasting in 4 hours.Yet if be feed back state used administration in the 2nd group of Period3 before, a standard food rich in fat will provide in administration in preceding 30 minutes.In this case, this high fat breakfast (for example, about 50% calorie from fat) comprises two eggs of coating butter, two bacon, and two bread of coating butter, four ounces of grey Rhizoma Solani tuber osi mixed sweetmeats are guessed, eight ounces of milk.Between term of commitment, the Food ﹠ Drink that comprise caffeine or coordinate (for example, chocolate plate) are under an embargo.

2 hours drinking-water that is under an embargo after from preceding 2 hours of administration to administration.Allow drinking-water at other times.After administration, provided standard meal in about 4 and 9 hours, and the time that is fit to thereafter.

The III administration

Give each dosage (distribution) group according to dosage order randomization form, determine good during to the main body administration.Definite dose drug that main body is accepted in a vitrifying agent measuring cup, in each dosage group, all dosage, active and placebo, all administrations under same volume are to keep all ignorant.Main body is instructed to obey fully medicament down.

The water of 240 milliliters of total amounts is provided when administration.Adding preestablishes a part of water (according to giving medicament # amount) in empty dose cup, stirs clarification, is obeyed down by main body.This process repeats twice, and remaining water is drunk by main body.

The initial dose of first human dosage depends on the whole toxicity and the safety of this clinical research.The people is 1/6 (inserting document name in the 137th page of the 9th capable bracket of original text) to the equal-volume surf zone conversion of rat.According to rat 30mg/kg/ days and the body surface area equivalent standard of NOAEL, are 300 mg/day (1/6x30mg/kg/day x[rat NOAEL] x60kg) to one 60 kilograms man equivalent dosage.According to the dosage (30mg/kg/ days) of the rat of NOAEL, dosage approximately is about 1/10 of NOAEL rat dosage for 3 milligrams.Maximum permissible dose (MPD) at NOAEL rat dosage is 160mg.

If the dosage of a limited toxicity (according to third and fourth grade of the WHO Common ToxicityCriteria-Appendix I rate range of revising), be counted as relevant with the treatment that is studied, appear among any 2 in 6 main bodys of any dosage level, the dosage increase just is stopped, and dosage before just is considered to maximum toxicity dose (MTD).

If in any limited toxicity of main body experience dosage with dosage level, PrincipalInvestigator (consulting Sponsor) decision, use good medical judgment, whether carry out the test of next dosage level according to schedule, perhaps next dosage level is than low in the original plan.In addition, if because the medication that continues safety occurs or toxicity problem becomes obviously (for example, needn't arrive 3 grades or 4 grades), show that the process need that raises gradually is slower, then original intended dose can be replaced by middle dosage.

Have only, according to the viewpoint of Principal Investigator, but enough safety and endurances are proved to be in low dosage test before, and rising dosage just is allowed to.In all cases, Principal Investigator uses good clinical judgment, assesses based on all factors of relevant this main body safety, determines whether adjusting dosage or stops research.

Principal Investigator examination primary data (for example, the health check-up data, vital sign, questionnaire and clinical experiment result (for example, hematochemistry, the hematology, urine examination and urine medication detect)), to have determined since detecting or the clinical important change in stage before. on the basis in this assessment, Principal Investigator determines that this main body is whether by administration or withdraw from research.

The IV clinical observation

Begin and ensuing 24 hours in each administration, the week after the last administration, or before withdrawing from, blood testing, hematochemistry detect and urine examination is carried out.Blood sample (about 7 milliliters) is collected into the vacuum glass test tube from the venous indwelling pipe, this vacuum glass test tube comprises the heparin sodium of inserting in advance, respectively after administration 0.25,0.5,0.75,1.0,1.5,2,3,4,6,8,10,12,18 and 24 hour.Before administration and collected urine sample in intermediary 0-8 of each interval hour.The sample of obtaining in interruption is not as sample pool.Each blank is considered a sample.Blank number of times is random, is not (exception is to wanting preceding blank and the end of interval 8 hours) of prearranging.

Vital sign is detected between these detection periods.When the detection time of vital sign was consistent with ECG, vital sign detected at ECG in preceding 10 minutes.When detection time of vital sign and blood drawing or blood drawing and ECG were consistent, vital sign detected in blood drawing in preceding 10 minutes.Breathe and body temperature when beginning, week after 24 hours and the last administration after each administration, or before withdrawing from, detection.The test of the independent blood pressure and the rhythm of the heart is carried out in after adopting half lying posture minimum 5 minutes.During studying, test machine monitoring, at first by AVS; 0 (before the administration), after the administration 0.25,0.5,0.75,1.0,1.5,2,3,4,6,8,10,12,18 and 24 hour; With a week after the last administration with before withdrawing from advance.For rhythm of the heart test, per minute was then resurveyed once after two minutes greater than 100.At first day, preceding about 24 hours of administration, blood pressure and rhythm of the heart test 3 times 2 minutes at interval, are described as described above.

Carry out the 12-lead ECG test of standard at each main body, at first day, preceding 1 hour of time and first day administration, after the administration 1,1.5,2,3,4, consistent with 6 hours.If be considered to needs, that also can carry out extra ECG test at other times.All 12-lead ECG records 10 seconds.Time and recording technique at the ECGs of all main bodys are standardized.Principal Investigator estimates PR, QRS, and QT and QTc are interrupted.Consistent with the time of blood drawing when the time of ECGs test, then ECG will be carried out after blood drawing.

The doctor check in each test to picture, in when beginning, after each administration 24 hours, stop a week after the administration, or before withdrawing from administration.If be considered to needs, can carry out additional inspection at other times.After preceding 1 hour of administration and administration 1,2, the vital sign of carrying out in 6 and 24 hours is (in these times, the vital sign test is predefined in blood drawing and carried out before 10 minutes) test before, these main bodys are carried out visual analogue scale, and between Very Sleppy and Alert/Wide Awake, be required line drawing straight line along a 100mm, the description that this is best their alert and resourceful degree at that time.

These main bodys are informed at duration of test by guidance, notify any negative condition of doctor and medical worker and concurrent symptom.In addition, before administration, administration 2,4, after 8 and 24 hours, a week after the last administration, or before withdrawing from, carry out special inquiry about negative condition.Under a kind of non-special state, carry out during inquiry, prevent to cause prejudice.

Any main body that any negative condition (no matter sternly not serious) occurred or clinical remarkable improper laboratory tests value occurred; all by Investigator or supervision doctor assessment; and treated up to these symptoms or value; determined by Investigator, return normal or acceptable level.A doctor no matter be then and there or near hospital emergency rooms, manages the treatment of any serious negative condition.Suitable medical treatment test and detection are to write down the solution of these situations.The result is classified, and for example, solves, and improves, and is constant, serious, fatal or unknown (failing to continue to probe into).

V. report

All all are recorded in negative condition that duration of test occurs. negative condition is numbered according to MedDRA (4.1 editions). a kind of negative condition/experience (AE) in patient or clinical observation main body, occur not should medical conditions, this patient or main body are applied in pharmaceutical product, this situation and this treatment (ICH/WHO) must not have common relation. therefore, negative situation (AE) is, the sign of any that do not expect and beyong contemplation, (comprise, for example, an improper experimental result), symptom, or disease, of short duration relevant with use certain medical product, no matter whether be considered to relevant with this medical product (ICH/WHO).

Investigator examines each situation and estimates it and the relation of Drug therapy (for example, uncorrelated, impossible, possible, similar, almost definite).Each situation of report or symptom be according to three kinds of serious standards gradings (slight, medium, or serious) and the date and time that takes place, with dosage, during time relationship, the result of each situation is recorded.The definition of following serious ratio is used: (1) is slight, and this negative condition is stood easily and do not influenced daily routines; (2) medium: this negative condition is disturbed daily life, but main body still can keep function; (3) serious: this negative condition is impatient at and is needed the treatment intervention.

If any above-mentioned negative situation is serious, then carry out separate procedure.All serious negative condition reported to Sponsor in 24 hours, and provided reading report in 48 hours, no matter whether this negative situation is relevant with this medicine.

A kind of serious negative situation (SAE) is the medical conditions of hell and high water, under any dosage, cause death, threaten life, cause permanent disability or or lose ability, need patient's hospitalization, prolong patient's time of hospitalization, congenital anomaly may make that main body is on the line maybe may to need to interfere to stop one or more other above-mentioned results.

The VI pharmacokinetics

Dose ratio after the treatment research, by the variables A UC (0-t) that the natural logrithm conversion has been carried out in analysis, AUC (0-inf) and Cmax measure, and use linear model to comprise that the dosage of natural logrithm conversion is as correlated variables.If 95% confidence interval of correlated variables slope comprise numerical value 1, then dose ratio can be obtained by summary.AUC (0-t), the also available linear model research of the dosage linear relationship of AUC (0-inf) and Cmax.

The VII safety evaluation

A less important main body treatment-acute negative condition tables of data provides, and comprises word for word term, preferred term, treatment, the order of severity and with the relation of treatment.

The number usage frequency that the number of main body of negative situation and negative condition occur is counted according to dosage level and is summed up.

Data of safety comprises Laboratory Evaluation and vital sign assessment, and according to dosage level and acquisition time are summarized.Describe for obtaining quantity data of safety counting statistics, the frequency data are classified according to data of safety.In addition, be listed from the vital sign that mainly is changed to of datum line form, having described normal range alternate substitution table for one provides for the clinical experiment result.

ECG result presses normal and improper two groups, according to dosage group and acquisition time usage frequency, summarizes.To PR, QRS, QT and QTc interruption are carried out descriptive statistics.

Variation in the health check-up is in the final description of Next Report.

Rhythm of the heart data, according to treatment group and time point, use descriptive statistics, summarize, owing to know from experience and to change from reference value. from the main result of variations of reference value, be used for active dose group and placebo on each time point of comparison. level can provide 80% power of a test to the difference under the detection per minute 20 before the administration of six main bodys of finishing. to carrying out interim analysis after each cycle.

The VIII efficacy assessment

The calm data of VAS by the acquisition time point of each dosage level, use descriptive statistics to sum up.

Embodiment 8: the clinical preceding assessment of loxapine analogs

Before carrying out the human clinical trial of chemical compound, carry out clinical Pre-Evaluation test.Clinical Pre-Evaluation comprises following test:

Absorption before i is clinical, dispersion, metabolism and drainage

This chemical compound is imposed on rat, Canis familiaris L. and macaque, and dosage is the oral or intravenous injection of about 3mg/kg.The blood sample of collecting all animals is to carry out pharmacokinetic analysis.Measure rat, Canis familiaris L. and the intravital Tmax of macaque and half-life (hour meter).Protein bound percentage ratio in rat and the human blood is also measured.

Rat brain behind the collection oral administration is to determine the cerebral levels of medicine of the present invention.

Cytochrome P450 is suppressed in vitro research.In addition, measure the external metabolic rate of rat, Canis familiaris L., monkey and the human hepatocytes culture fluid of each chemical compound.

In the ii cardiac tonic active set

In basic toxicology pathological study, the clinical sample of this experiment is that the QT interval is elongated mutually.Through examining, the H1 antagonism was relevant with this effect from the past.Under few cases, QT is elongated may to cause life-threatening cardiac arrhythmia.Predict whether a chemical compound causes the elongated best experiment in vitro of QT to be, hERG is in conjunction with assessment, and this is the system that chemical compound of best selectable research causes the potential of this effect.Human hERG passage, transfection to a stable cell line, the research electrocardiogram, and report is to the inhibition of channel current.

Determine whether a chemical compound can produce the QT interval and change, and this chemical compound is studied in the Bi Erge of remote sensing dog.The device of implanted continuous monitoring ECG of these Canis familiaris L.s and arteriotony.These Canis familiaris L.s (being divided into 4 groups) are studied under Latin square cross-over design mode, and each Canis familiaris L. obtains 3 kinds of different dosage and a placebo.To dosage 0.3,1,3,10 and 30mg/kg research 2 times.

The acute Mus experiment of iii

The purpose of this research is an evaluate toxicity and when standing dosage (MTD) with oral way maximum of test substances to the rat administration time.Male Crl:

(SD) IGS BR rat (3/group) is divided into 5 groups.When administration begins, the situation of animal be minimum 7 weeks big, weight range restrain at 172-206.The preparation that each winding is comprised The compounds of this invention in succession 5 days once a day, dosage be 50,100,150,200 or 250mg/kg in one.Be killed the 6th day all animals that survive.To toxic assessment based on mortality rate, clinic observation and weight data.

The acute Canis familiaris L. experiment of iv

The purpose of this research is an evaluate toxicity and when standing dosage (MTD) with oral way maximum of test substances to the Canis familiaris L. administration time.Two male purebred complete erg dogs are used for this with research.When administration began, the situation of animal was that minimum 6 months big, weight ranges are at the 8.0-10.9 kilogram.The preparation that these Canis familiaris L.s accept to comprise The compounds of this invention in succession 5 days once a day, dosage increases gradually, and 25,50 or 75mg/kg.

These Canis familiaris L.s after administration 0.25,0.5,0.75,1.0,1.5 and 2.0 hours ± 5 minutes and 4,6,8 and 24 hours ± 5 minutes, the time observed.All weighed by the 6th day at first day.

Before administration, and after the administration of the 5th day dosage 40mg/kg the 1.4th and 24 hour, measure electrocardiogram and blood pressure.

On the seriousness basis of scope of observing and clinical symptoms, the MTD of this chemical compound is calculated.

Rat research in v14-days and recovery research

The purpose of this research is, with oral way to rat administration at least 14 days the time, assess the toxicity and the assessment reversibility of this chemical compound, persistence, or the effect that any delay occurs after reaching convalescent period of 14 days.

Male and female Crl:

(SD) IGS BR rat is divided into seven groups, and wherein four main seminar and three groups are used for toxicokinetics research.Each winding is comprised the preparation of 0.25% methylcellulose, 400cps in the 200mM acetate buffer, or 10,30, or 150 milligrams of test compounds/kg body weight (mg/kg/ days), the volume 5mL/kg of preparation.

Based on mortality rate, clinical and ophthalmology is observed body weight, food consumption, clinical pathology, organ weight and naked eyes or microscopic examination result to toxic assessment.Collect blood sample and be used for toxicokinetics research.

Has Canis familiaris L. research in convalescent 14-days

With oral tube feed (stage 1) or capsule (stage 2) mode every day to Canis familiaris L. administration at least 14 days, determine the toxicity and the toxicokinetics of The compounds of this invention.Reversibility, persistence, or the effect that is observed that any delay occurs after the convalescent period in 7 days (stage 1) or 14 days (stage 2), also evaluated.3,10,30 and 70mg/kg/ days dosage be studied.The Canis familiaris L. in all stages 1 and stage 2 all survives up to being killed as per the schedule.

Above chemical compound and scheme are useful in the assessment before loxapine chemical compound of the present invention clinical.

Embodiment 9: the assessment of analgesia character

The analgesia character of loxapine analogs behind oral administration is analyzed.Analgesia character is by the waist spasm testing evaluation in rat and the mice.Also using mouse tail folder test and rat to hit tail tests and assesses analgesia character.Rat Randall-Selitto tests and relatively, carries out simultaneously with adjuvant control group.Reference compound ASA (aspirin) and morphine also are included in the comparison.

Tail folder test and hit the tail experiment and provide Useful Information for the central analgesia character of tested chemical compound.The Randall-Selitto test provides information for the hyperalgesia state of chemical compound, and the test of waist spasm provides information for the character of easing pain around the tested chemical compound.Test compounds is by the mode administration of oral tube feed, and this is the clinical administration route of expection.The dosage level expection of adopting comprises effective dose and safe enough.

Test substances, reference compound and stimulus object preparation

All preparations are preparation every day according to dosage.Test substances prepares with 0.25% (w/v) MC by maximum desired concn.Lower dosage is by using 0.25% (w/v) MC serial dilution to obtain maximum concentration.Reference compound, aspirin is pressed the desired concn formulated in 0.25% (w/v) MC.Brewer ' s yeast makes injection preparation by desired concn in water.The acetic acid dilute with water is used for injection, to provide administration required concentration.

Dosage level reaches with the scale of test compounds, and no matter reference compound/stimulus object is purity and active component.

Animal

The male Crl of sufficient number:

(SD) IGS BR Mus and Wistar rat be from Charles River (UK) Ltd., Margate, and when Kent. arrived, about 4 weeks of these Mus were big, and weight is between 18 and 22 grams.About 5 weeks of rat are big, and weight is between 150 and 170 grams.Age and the body weight of these animals when the research beginning is recorded in initial data and the Final Report.

These animals are divided into suitable group according to the size of the cage that uses to be raised, and these rearging cages meet the Code of Practice that uses about stable breeding with look after the regulation of animal in Scientific Procedure Act.(Home Office Animals ScientificProcedure Act 1986). bedding uses clean Aspen veneer to make (Datesand Ltd, Manchester UK).Analyze bedding at specific pollutants, outcome record is in Covance.Before using cage is cleaned and drying.The horn of plenty environment is put into poplar and is chewed piece.Conventional, receptacle keeps temperature and relative humidity to remain in the acceptable limit (being respectively 19 to 25 degrees centigrade and 40%-70% usually).This receptacle in circulation in per 24 hours with fluorescence irradiation 1.2 hours, per hour ventilation 15 times at least.

RM1. (E) .SQC. (Special Diets Services Ltd.Witham, UnitedKingdom)) and water come from faucet, unconfined providing, unless below particularly point out.These do not find to comprise the material that causes the disturbed test system of any biological or chemical through the conventional analysis at concrete composition.The treatment group that is used to study is shown in the table 9:

Table 9 processed group

Group	Therapeutic agent	Dosage level (mg/kg)	Concentration (mg/ml)	The #of animal
Group	Therapeutic agent	Dosage level (mg/kg)	Concentration (mg/ml)	The #of animal	1	Adjuvant			?8
2	Loxapine analogs	3	0.3	?8	1	Adjuvant			?8
2	Loxapine analogs	3	0.3	?8	3	Loxapine analogs	10	1.0	?8
4	Loxapine analogs	30	3.0	?8	3	Loxapine analogs	10	1.0	?8
4	Loxapine analogs	30	3.0	?8	5	Morphine	100	10.0	?8

For each animal pressure measxurement is rear solid end from left to right, before applying adjuvant, test substances or reference compound oral administration or behind the oral administration after 30,60,120 and 240 minutes.Tonometric order is the left back right side of elder generation.

The test of rat waist spasm

Each animal obtains the individually dosed of one of adjuvant, test substances or reference compound, and by oral tube feed, constant dosage is at 10mg./kg.Each individual dosage based on each individuality in the administration body weight on the same day.Processed group is shown in table 10.

Table 10 processed group

Group	Therapeutic agent	Dosage level (mg/kg)	Concentration (mg/ml)	The #of animal
Group	Therapeutic agent	Dosage level (mg/kg)	Concentration (mg/ml)	The #of animal	1	Adjuvant			?6
2	Loxapine analogs	3	0.3	?6	1	Adjuvant			?6
2	Loxapine analogs	3	0.3	?6	3	Loxapine analogs	10	1.0	?6
4	Loxapine analogs	30	3.0	?6	3	Loxapine analogs	10	1.0	?6
4	Loxapine analogs	30	3.0	?6	5	ASA	100	10.0	?6

Each animal oral administration is after 45 minutes, 1 milliliter of 1% acetic acid of peritoneal injection.Place individual observation ward immediately, the number that occurred the waist spasm in 25 minutes thereafter is recorded.

The test of mouse waist spasm

Each animal obtains the individually dosed of one of adjuvant, test substances or reference compound, and by oral tube feed, constant dosage is at 10mg./kg.Each individual dosage based on each individuality in the administration body weight on the same day.Processed group is shown in table 11.

Table 11 processed group

Each animal oral administration is after 45 minutes, 0.25 milliliter of 0.5% acetic acid of peritoneal injection.Place individual observation ward immediately, the number that occurred the waist spasm in 25 minutes thereafter is recorded.

Final step

Last in test, these animals kill benignly with the chemical compound (for example, for example, being exposed to after twisting off in the carbon dioxide of concentration rising at cervical region) of table 1, do not dissect to abandon.If an animal shows any serious uncomfortable sign in research process, it is killed immediately benignly.Anyly in research process, be found premature dead or killed animal is dissected research.After opening thoracic cavity and abdominal cavity, carry out perusal, tissues observed outward appearance in position.Any improper phenomenon is recorded.

Synthesizing of embodiment 10 acyl group sulfonamide compoundss

The synthetic scheme I that is summarized in of acyl group sulfonamide compounds 40.It is synthetic from the routine of corresponding acid beginning herein that this process can be used as the acyl group sulfonamide compounds.

At N, under the condition that the toluene solution of accelerine exists, handle three ring 10H-hexichol [b, f] [1,4] oxygen azatropylidene-11-ketone (3) with phosphorus oxychlorination thing, be converted into 11-piperazine-1-base-hexichol [b, f] [1,4] oxygen azatropylidene (5) with excessive piperazine reaction.Obtain alkylating piperazine (6) with 2-carbonyl methoxyl group 2 methyl propanal reduction amination three ring amidines (5), use silica gel purification.The hydrolysis in ethanol water of 5 methyl ester, acidify obtains carboxylic acid (7) then.Combine with water-soluble carbodiimide, carboxylic acid (7) is converted into acyl group sulfonyloxy methyl amine, and the EDCI that is dissolved in dichloromethyl and dimethyl amine pyrimidine is as catalyst.Acidify obtains the bis-hydrochlorate of acyl group sulfonamide compounds 40 (HY-10427) in conjunction with product.

Other embodiments

Although the present invention is illustrated in conjunction with detailed description, the detailed description of front is intended to explain the present invention, rather than limits the scope of the invention, and scope of the present invention is limited by appended claim.Comprise other aspects within the scope of the appended claims, advantage, and modify.It will be understood by those skilled in the art that and under the situation that does not exceed claim coverage of the present invention, can have multiple variation in form and details.

Claims

1. the chemical compound that has chemical compound 1 molecular formula:

Or its salt.

2. according to the chemical compound of claim 1, wherein chemical compound 1 is a kind of pharmaceutically acceptable salt.

3. according to the chemical compound of claim 2, wherein said salt is a kind of acid-addition salts.

4. according to the chemical compound of claim 3, wherein said salt is a kind of hydrochlorate.

5. according to the chemical compound of claim 4, wherein said chemical compound is:

6. compositions comprises chemical compound shown in the following structural formula:

Or its salt and at least a pharmaceutically acceptable excipient.

7. according to the compositions of claim 6, wherein this chemical compound is a kind of pharmaceutically acceptable salt.

8. according to the compositions of claim 7, wherein said salt is a kind of acid-addition salts.

9. compositions according to Claim 8, wherein said salt is a kind of hydrochlorate.

10. according to the compositions of claim 9, wherein, said composition comprises

11. any described compound or its salt is used for the treatment of application in the medicine of regulating the main body sleep in preparation among the claim 1-10.

12. according to the application of claim 11, described sleep regulating action treatment dyssomnias disease.

13. according to the application of claim 11, wherein said main body is human.