CN1628109A - Novel aryl- and heteroarylpiperazines - Google Patents

Novel aryl- and heteroarylpiperazines Download PDF

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Publication number
CN1628109A
CN1628109A CNA038033607A CN03803360A CN1628109A CN 1628109 A CN1628109 A CN 1628109A CN A038033607 A CNA038033607 A CN A038033607A CN 03803360 A CN03803360 A CN 03803360A CN 1628109 A CN1628109 A CN 1628109A
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compound
alkyl
aryl
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R·霍尔威格
F·Z·多沃德
H·斯蒂芬森
I·彼得森
B·佩施克
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vTv Therapeutics LLC
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Novo Nordisk AS
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Abstract

Novel aryl- and heteroarylpiperazines, use of these compounds as pharmaceutical compositions, pharmaceutical compositions comprising the compounds, and a method of treatment employing these compounds and compositions. The compounds show a high and selective binding affinity to the histamine H3 receptor indicating histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. As a result, the compounds are useful for the treatment of diseases and disorders related to the histamine H3 receptor.

Description

Novel aryl-with heteroaryl-piperazine
Invention field
The present invention relates to novel aryl-, relate to the purposes of these compounds, relate to the pharmaceutical composition that comprises these compounds, also relate to the methods of treatment of these compounds of employing and composition as pharmaceutical composition with the heteroaryl piperazine.The compounds of this invention shows high selective binding affinity to histamine H 3 receptor, shows to have histamine H 3 receptor antagonism, anti-excitement or agonist activity.Consequently, these compounds can be used for treating disease and the obstacle that relates to histamine H 3 receptor.
Background of invention
Knew the existence of histamine H 3 receptor before several years already, this receptor is the interest place of present novel drugs exploitation.Recently, human histamine H 3 receptor is cloned.Histamine H 3 receptor is a kind of presynaptic autoreceptor, is arranged in maincenter and peripheral nervous system, skin and organ, and for example lung, intestines mainly are spleen and gi tract.Prompting on evidence recently, the H3 acceptor shows the intrinsic constitutive activity, in the external and body all be so (that is to say, do not have agonist in the presence of also be activated).The compound that serves as inverse agonist can suppress this activity.Histamine H 3 receptor has been proved to be the release of regulating histamine and other neurotransmitters, for example thrombotonin and vagusstoff.Therefore histamine H 3 receptor antagonists or inverse agonist will be increased the release of these neurotransmitters in brain by expection.On the contrary, the histamine H 3 receptor agonist causes the inhibition that biosynthetic inhibition of histamine and histamine and other neurotransmitters discharge, for example thrombotonin and vagusstoff.It may be the important medium of neuron activity that histamine H 3 receptor agonist, inverse agonist and antagonist have been pointed out in these discoveries.Therefore, histamine H 3 receptor is the important goal of novel treatment.
The compound similar to The compounds of this invention disclosed in the past, referring to J.Med.Chem.1999,42,336, J.Med.Chem.1992,35,2369, DE 2804096, J.Org.Chem.1996,61,3849, Bull.Soc.Chim.Fr.1969,319, WO 00/66578, WO 99/21845 and J.Med.Chem.1968,11 (6), 1144-1150.But, these reference had not both had openly, have not pointed out these compounds may have histamine H 3 receptor antagonism or agonist activity yet.
Some publications disclose the preparation and the purposes of histamine H 3 agonists and antagonist.Their great majority are imdazole derivatives.But, the no imidazole ligands of some histamine H 3 receptors had been described recently (for example referring to Linney et al., J.Med.Chem.2000,43,2362-2370; US 6,316,475, WO 01/66534 and WO 01/74810).But, these compounds structurally are different from The compounds of this invention.
In view of the interest of this area, will make very desirable contribution to this area with the interactional compounds of histamine H 3 receptor to histamine H 3 receptor agonist, inverse agonist and antagonist.The present invention is based on following discovery and for this area provides a kind of like this contribution, i.e. the aryl of a class novelty-histamine H 3 receptor is had high specificity affinity with heteroaryl-piperazine.
Because the interaction of they and histamine H 3 receptor, The compounds of this invention can be used for treating illness and obstacle widely, and wherein the interaction with histamine H 3 receptor is useful.Thereby these compounds for example can be used for the treatment of the disease of central nervous system, peripheral nervous system, cardiovascular systems, pulmonary system, gastro-intestinal system and endocrine system.
Definition
Here with the given structural formula of this specification in, implication shown in following term has.
Term " halogen " expression F, Cl, Br or I.
The straight or branched alkyl that term used herein " alkyl " representative is saturated, the carbon atom of quantity shown in having.Thereby, term " C used herein 1-3-alkyl ", " C 1-8-alkyl " and " C 1-10-alkyl " represent saturated straight chain or branched hydrocarbyl, have 1 to 3 carbon atom, 1 to 8 carbon atom and 1 to 10 carbon atom respectively.Typical alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl etc.
The straight or branched alkyl represented in term used herein " thiazolinyl ", the carbon atom of quantity shown in having and at least one pair of key.Thereby, term " C used herein 2-8-thiazolinyl " and " C 2-10-thiazolinyl " represent the straight or branched alkyl, have 2 to 8 carbon atoms and 2 to 10 carbon atoms and at least one pair of key respectively.This class examples of groups includes but not limited to vinyl, 1-propenyl, 2-propenyl, allyl group, pseudoallyl, 1,3-butadiene base, 1-butylene base, crotyl, 1-pentenyl, pentenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl, 1-octenyl, 2-octenyl, 2-nonene base, 2-decene base etc.
The straight or branched alkyl represented in term used herein " alkynyl ", carbon atom of quantity shown in having and at least one 3 keys.Thereby, term " C used herein 2-8-alkyl " represent the straight or branched alkyl, have 2 to 8 carbon atoms and at least one 3 keys.This class examples of groups includes but not limited to ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, valerylene base, 1-hexin base, 2-hexin base, 2-heptyne base, 1-octyne base, 2-octyne base etc.
Term used herein " side chain C 4-6-alkyl " the saturated branched hydrocarbyl of representative, have 4 to 6 carbon atoms.Typical side chain C 4-8-alkyl includes but not limited to 1-methyl-propyl, the tertiary butyl, 1-ethyl propyl, 1,1-(dimethyl) propyl group, isopentyl, 1-ethyl-butyl, 1,1-(dimethyl) butyl, 1,1-(dimethyl) amyl group, 1-ethyl pentyl group, 1,1-(dimethyl) hexyl, 1-ethylhexyl etc.
Term used herein " side chain C 4-6-thiazolinyl " represent branched hydrocarbyl, have 4 to 6 carbon atoms and at least one pair of key.Typical side chain C 4-6-thiazolinyl includes but not limited to 1-ethyl third-2-thiazolinyl, 1,1-(dimethyl) third-2-thiazolinyl, 1-ethyl fourth-3-thiazolinyl, 1,1-(dimethyl) but-2-ene base, 1,1-(dimethyl) penta-3-thiazolinyl, 1-ethyl penta-2-thiazolinyl, 1,1-(dimethyl) penta-3-thiazolinyl, 1,1-(dimethyl) oneself-3-thiazolinyl, 1-ethyl oneself-4-thiazolinyl etc.
Term used herein " side chain C 4-6-alkynyl " represent branched hydrocarbyl, have 4 to 6 carbon atoms and at least one 3 keys.Typical side chain C 4-6-alkynyl includes but not limited to 1-ethyl Propargyl, 1,1-(dimethyl) Propargyl, 1-ethyl fourth-3-alkynyl, 1,1-(dimethyl) fourth-2-alkynyl, 1,1-(dimethyl) penta-3-alkynyl, 1-ethyl penta-2-alkynyl, 1,1-(dimethyl) penta-3-alkynyl, 1,1-(dimethyl) oneself-3-alkynyl, 1-ethyl oneself-4-alkynyl etc.
Term " C used herein 1-6-alkoxyl group " expression atomic group-O-C 1-6-alkyl, wherein C 1-6-alkyl is as defined above.Representative example has methoxyl group, oxyethyl group, positive propoxy, isopropoxy, butoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, hexyloxy, different hexyloxy etc.
Term " C used herein 2-10-alkyloyl " expression atomic group-C (=O) C 1-9-alkyl, wherein C 1-9The straight or branched alkyl that-alkyl represent is saturated has 1 to 9 carbon atom.Representative example has ethanoyl, propionyl, butyryl radicals, pentanoyl, caproyl, oenanthyl, capryloyl, nonanoyl, decanoyl etc.
Term " C used herein 1-6-alkylamino " expression atomic group-NH-C 1-6-alkyl, wherein C 1-6-alkyl is as defined above.Representative example has methylamino-, ethylamino, isopropylamino, n-propylamine base, fourth amino, penta amino, own amino etc.
Term " two-C used herein 1-6-alkylamino " expression atomic group-N (C 1-6-alkyl) 2, C wherein 1-6-alkyl is as defined above.Should be understood that C 1-6-alkyl can be identical or different.Representative example has dimethylamino, first and second amino, diethylin, diisopropylaminoethyl, two n-propylamine bases, dibutylamino, diamyl amino, two own amino etc.
Term " C used herein 3-5-cycloalkyl " represent the monocycle carbon ring group, have 3 to 8 carbon atoms.Representative example has cyclopropyl, cyclobutyl, cyclopentyl etc.
According to identical mode, term " C used herein 3-6-cycloalkyl " and " C 3-8-cycloalkyl " represent the monocycle carbon ring group, have 3 to 6 carbon atoms and 3 to 8 carbon atoms respectively.
Term " C used herein 3-7-cycloalkenyl group " represent the non-aromatic group of monocycle isocyclic, have 3 to 7 carbon atoms and at least one pair of key.Representative example has cyclopropenyl radical, cyclobutene base, cyclopentenyl etc.
According to identical mode, term " C used herein 3-6-cycloalkenyl group " represent the non-aromatic group of monocycle isocyclic, have 3 to 6 carbon atoms and at least one pair of key.
Term " C used herein 3-6-cycloalkyl-C 1-3-alkyl " expression atomic group-C 1-3-alkyl-C 3-6-cycloalkyl, wherein C 3-6-cycloalkyl and C 1-3-alkyl is as defined above.
Term " C used herein 3-6-cycloalkenyl group-C 1-3-alkyl " expression atomic group-C 1-3-alkyl-C 3-6-cycloalkenyl group, wherein C 3-6-cycloalkenyl group and C 1-3-alkyl is as defined above.
Term " C used herein 3-8-cycloalkyloxy " expression atomic group-O-C 3-8-cycloalkyl, wherein C 3-8-cycloalkyl is as defined above.Representative example has ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, ring octyloxy etc.
Term " C used herein 4-9-cycloalkanes acyl group " expression atomic group-C (=O)-C 3-8-cycloalkyl, wherein C 3-8-cycloalkyl is as defined above.Representative example has cyclopropyl carbonyl, cyclobutyl carbonyl, cyclopentylcarbonyl, cyclohexyl-carbonyl, suberyl carbonyl, ring octyl group carbonyl etc.
Term " C used herein 1-6-alkyl sulphonyl " expression atomic group-S (=O) 2-C 1-6-alkyl, wherein C 1-6-alkyl is as defined above.Representative example has methyl sulphonyl, ethylsulfonyl, sec.-propyl alkylsulfonyl, n-propyl alkylsulfonyl, butyl alkylsulfonyl, amyl group alkylsulfonyl etc.
Term " C used herein 1-6-alkylthio " expression atomic group-S-C 1-6-alkyl, wherein C 1-6-alkyl is as defined above.Representative example has methylthio group, ethylmercapto group, iprotiazem base, positive rosickyite base, butylthio, penta sulfenyl etc.
Term " C used herein 3-8-heterocyclic radical " 3 to 8 yuan of saturated monocycles of expression, contain one or more heteroatomss that are selected from nitrogen, oxygen and sulphur.Representative example has aziridinyl, pyrrolidyl, piperidyl, morpholinyl, piperazinyl, tetrahydrofuran base etc.
Term " C used herein 4-9-heterocycle alkyloyl " expression atomic group-C (=O)-C 3-8-heterocyclic radical, wherein C 3-8-heterocyclic radical is as defined above.Representative example has aziridinyl carbonyl, pyrrolidyl carbonyl, piperidino carbonyl, morpholinyl carbonyl, piperazinyl carbonyl, tetrahydrofuran base carbonyl etc.
Term used herein " aryl " plan comprises carbocyclic aromatic ring system, for example phenyl, xenyl, naphthyl, anthryl, phenanthryl, fluorenyl, indenyl, pentalene base, Azulene base etc.Aryl also plans to comprise the partial hydrogenation derivative of above-named carbon-loop system.The limiting examples of this class partial hydrogenation derivative has 1,2,3,4-tetralyl, 1,4-dihydro naphthyl etc.
Term used herein " aryloxy " expression atomic group-O-aryl, wherein aryl is as defined above.Limiting examples has phenoxy group, naphthyloxy, anthracene oxygen base, luxuriant and rich with fragrance oxygen base, fluorenes oxygen base, indenes oxygen base etc.
Term used herein " aroyl " expression atomic group-C (=O)-and aryl, wherein aryl is as defined above.Limiting examples has benzoyl, naphthoyl, anthryl carbonyl, phenanthryl carbonyl, fluorenyl carbonyl, indenyl carbonyl etc.
Term used herein " arylamino " expression atomic group-NH-aryl, wherein aryl is as defined above.Limiting examples has phenyl amino, naphthyl amino, anthryl amino, phenanthryl amino, fluorenyl amino, indenyl amino etc.
Term used herein " heteroaryl " plan comprises the heterocyclic aromatic ring system, contain one or more nitrogen that are selected from, the heteroatoms of oxygen and sulphur, furyl for example, thienyl, pyrryl oxazolyl, thiazolyl, imidazolyl isoxazolyl, isothiazolyl, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,2, the 3-triazinyl, 1,2, the 4-triazinyl, 1,3, the 5-triazinyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, tetrazyl, the thiadiazine base, indyl, pseudoindoyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl-, benzothiazolyl, benzisothiazole base benzoxazolyl, the benzoisoxazole base, purine radicals, quinazolyl, quinolizinyl, quinolyl, isoquinolyl, quinoxalinyl, naphthyridinyl, pteridyl, carbazyl, the azatropylidene base, diaza base, acridyl etc.Heteroaryl also plans to comprise the partial hydrogenation derivative of above-named heterocyclic ring system.The limiting examples of this class partial hydrogenation derivative has 2,3-dihydro benzo furyl, pyrrolinyl, pyrazolinyl, dihydro indenyl, indolinyl, oxazolidinyl, oxazolinyl, oxygen azatropylidene base etc.
Term used herein " heteroaryloxy " expression atomic group-O-heteroaryl, wherein heteroaryl is as defined above.
Term used herein " 4-hetaroylpyrazol " expression atomic group-C (=O)-and heteroaryl, wherein heteroaryl is as defined above.
Term used herein " heteroaryl amino " expression atomic group-NH-heteroaryl, wherein heteroaryl is as defined above.
More than some above-mentioned defined term may occur once in structural formula, each term should be defined independently of one another in this case.
" aryl-C 1-6-alkyl ", " aryl-C 1-6-alkoxyl group " etc. represent C as defined above 1-6-alkyl or C 1-6-alkoxyl group, by aryl replacement as defined above, for example:
Term used herein " optional substituted " means that relevant group is unsubstituted or is replaced by one or more specified substituting groups.When relevant group was replaced by an above substituting group, substituting group can be identical or different.
Term used herein " treatment " is represented for the purpose of antagonism disease, obstacle or illness management and the nursing that the patient did.The healing or the elimination of alleviating or alleviating of the delaying of disease, obstacle or illness progress, symptom and complication and/or disease, obstacle or illness planned to comprise in this term.The patient who treats is Mammals preferably, and is particularly human.
Invention description
The present invention relates to general formula (I) compound:
Wherein
(i) R 1Representative
Side chain C 4-8-alkyl, side chain C 4-8-thiazolinyl or side chain C 4-8-alkynyl, they can be replaced by one or more halogenic substituents alternatively,
C 3-5-cycloalkyl, C 3-7-cycloalkenyl group, C 3-6-cycloalkyl-C 1-3-alkyl or C 3-6-cycloalkenyl group-C 1-3-alkyl, they can be replaced by one or more halogenic substituents alternatively at an arbitrary position,
The A representative
Figure A0380336000222
Or
Figure A0380336000223
Perhaps
(ii) R 1Represent ethyl, n-propyl or sec.-propyl and
The A representative
Z and X represent independently-N=,-CH=,-CF=or-C (CF 3)=,
W representative-N=or-CR 3=,
Y representative-N=or-CR 4=,
R 2a, R 2b, R 3And R 4Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-10-alkyl, C 2-10-thiazolinyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, aryl-C 1-6-alkyl, amino, C 1-6-alkylamino, two-C 1-6-alkylamino, C 3-8-cycloalkyloxy, cyano group, nitro, C 1-6-alkylthio, C 1-6-alkyl sulphonyl or-C (=O) NR 4aR 4b, R wherein 4aAnd R 4bBe hydrogen, C independently 1-6-alkyl or aryl-C 1-6-alkyl,
C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 3-8-heterocyclic radical or C 4-9-heterocycle alkyloyl, they can be replaced by one or more substituting groups alternatively at an arbitrary position, and substituting group is selected from aryl, heteroaryl, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy and C 1-6-alkoxyl group, aryl, aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or heteroaryl,
They can be replaced by one or more substituting groups alternatively, substituting group be selected from halogen, hydroxyl,
Trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, C 1-6-alkyl, amino, C 1-6-alkyl ammonia
Base, two-C 1-6-alkylamino, cyano group, aryl, heteroaryl and C 3-8-cycloalkyl,
Aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryloxy, arylamino or heteroaryl amino, they can be replaced by one or more substituting groups alternatively, and substituting group is selected from aryl, heteroaryl, C 1-10-alkyl, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, cyano group, amino, C 1-6-alkylamino, two-C 1-6-alkylamino and hydroxyl,
Perhaps R 2a, R 2b, R 3And R 4Two of middle consecutive position constitute C together 1-6-alkylidene bridge,
Its condition is that this compound must not be
Figure A0380336000241
Or
Figure A0380336000253
And arbitrarily diastereomer or enantiomorph or change form, comprise their mixture or its pharmacy acceptable salt.
In one embodiment, R 1Be side chain C 4-8-alkyl, C 3-5-cycloalkyl or C 3-6-cycloalkyl-C 1-3-alkyl, they can be replaced by one or more halogenic substituents alternatively.
In another embodiment, R 1Be side chain C 4-8-alkyl, C 3-5-cycloalkyl or C 3-6-cycloalkyl-C 1-3-alkyl.
In another embodiment, R 1Be 1,1-(dimethyl) propyl group, 1-ethyl propyl, cyclopropyl methyl, cyclopropyl, cyclobutyl, cyclopentyl or 1-cyclopropyl-1-methylethyl.
In another embodiment, R 1Be 1-ethyl propyl, cyclopropyl methyl, cyclopropyl or cyclopentyl.
In another embodiment, R 1Be side chain C 4-8-alkyl or C 3-5-cycloalkyl, they can be replaced by one or more halogenic substituents alternatively.
In another embodiment, R 1Be side chain C 4-8-alkyl or C 3-5-cycloalkyl.
In another embodiment, R 1Be 1-ethyl propyl, cyclopropyl or cyclopentyl.
In another embodiment, R 1It is sec.-propyl.
In another embodiment, A is
Figure A0380336000261
Or
Figure A0380336000263
R wherein 2a, R 2b, R 3And R 4Be defined suc as formula (I).
In another embodiment, A is
R wherein 2a, R 3And R 4Be defined suc as formula (I).
In another embodiment, A is
Figure A0380336000265
R wherein 2a, R 3And R 4Be defined suc as formula (I).
In another embodiment, A is
Figure A0380336000266
R wherein 2a, R 2b, R 3And R 4Be defined suc as formula (I).
In another embodiment, R 2a, R 2b, R 3And R 4Be independently selected from
Hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group or C 4-9-heterocycle alkyloyl, perhaps
Aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or aroyl,
They can define suc as formula (I) alternatively and be substituted.
In another embodiment, R 2a, R 2b, R 3And R 4Be independently selected from
Hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group or C 4-9-heterocycle alkyloyl,
Phenyl-C 1-6-alkyl, phenyl-C 1-6-alkoxyl group or benzoyl, they can be replaced by one or two substituting group alternatively, and substituting group is selected from halogen and C 1-6-alkoxyl group.
In another embodiment, R 2a, R 2bAnd R 4Be hydrogen, R 3Not hydrogen.
In another embodiment, R 3Be halogen, trifluoromethyl or trifluoromethoxy.
In another embodiment, the present invention relates to general formula (I 1) compound:
Figure A0380336000271
Wherein A is that any one is defined suc as formula (I) or above-mentioned embodiment.
In another embodiment, the present invention relates to general formula (I 2) compound:
Figure A0380336000272
Wherein A is that any one is defined suc as formula (I) or above-mentioned embodiment.
In another embodiment, the present invention relates to general formula (I 3) compound:
R wherein 1Be
Side chain C 4-8-alkyl, side chain C 4-8-thiazolinyl or side chain C 4-8-alkynyl, they can be replaced by one or more halogenic substituents alternatively,
C 3-5-cycloalkyl, C 3-7-cycloalkenyl group, C 3-6-cycloalkyl-C 1-3-alkyl or C 3-6-cycloalkenyl group-C 1-3-alkyl, they can be replaced by one or more halogenic substituents alternatively at an arbitrary position,
Ethyl, n-propyl or sec.-propyl,
R 2a, R 2b, R 3And R 4Be defined suc as formula (I).
In another embodiment, the present invention relates to be selected from following compound:
4-(4-cyclopentyl-based piperazine-1-yl) phenol,
1-cyclopentyl-4-[4-(4-fluorine benzyloxy) phenyl] piperazine,
1-(3-chloro-phenyl-)-4-cyclopentyl-based piperazine,
1-[4-(4-cyclopentyl-based piperazine-1-yl) phenyl] ethyl ketone,
1-(3, the 4-dichlorophenyl)-4-(1-ethyl propyl) piperazine,
4-[4-(1-ethyl propyl) piperazine-1-yl] and phenyl } phenyl ketone,
1-(4-benzyl phenyl)-4-(1-ethyl propyl) piperazine,
Cyclopropyl-and 4-[4-(1-ethyl propyl) piperazine-1-yl] phenyl } ketone,
(2-chloro-phenyl-)-and 4-[4-(1-ethyl propyl) piperazine-1-yl] phenyl } ketone,
4-[4-(1-ethyl propyl) piperazine-1-yl] phenyl }-(4-fluorophenyl) ketone,
1-cyclopentyl-4-(6-5-flumethiazine-2-yl) piperazine,
1-cyclopentyl-4-(5-5-flumethiazine-2-yl) piperazine,
1-cyclopentyl-4-(3-5-flumethiazine-2-yl) piperazine,
2-[4-(1-ethyl propyl) piperazine-1-yl] quinoline,
7-chloro-4-[4-(1-ethyl propyl) piperazine-1-yl] quinoline,
[4-(4-cyclopentyl-based piperazine-1-yl) phenyl]-(3, the 4-Dimethoxyphenyl) ketone,
[4-(4-cyclopentyl-based piperazine-1-yl)-3,5-difluorophenyl] phenyl ketone,
2-(4-cyclopentyl-based piperazine-1-yl) quinoxaline,
2-(4-cyclopropyl methylpiperazine-1-yl) quinoxaline,
[6-(4-cyclopentyl-based piperazine-1-yl) pyridin-3-yl] piperidines-1-base ketone,
2-(4-cyclopentyl-based piperazine-1-yl) quinoline,
2-(4-cyclopentyl-based piperazine-1-yl)-7-methoxyl group-3-(4-p-methoxy-phenyl) quinoline,
6-[4-(1-cyclopropyl-1-methylethyl) piperazine-1-yl] and pyridin-3-yl } phenyl ketone,
4-[4-(1-cyclopropyl-1-methylethyl) piperazine-1-yl] and-3, the 5-difluorophenyl } phenyl ketone,
4-[4-(1-cyclopropyl-1-methylethyl) piperazine-1-yl] and-3, the 5-difluorophenyl } phenyl methanol,
[4-(4-cyclopropyl methylpiperazine-1-yl)-3,5-difluorophenyl]-(4-fluorophenyl) ketone,
4-[4-(1-ethyl propyl) piperazine-1-yl] and-3, the 5-difluorophenyl }-(4-fluorophenyl) ketone,
2-[4-(1-ethyl propyl) piperazine-1-yl]-6, the 7-dimethoxy-quinoline,
2-[4-(1-ethyl propyl) piperazine-1-yl]-the 4-Trifluoromethylquinocarboxylic,
2-(4-cyclopropyl methylpiperazine-1-yl)-6-methoxyl group-4-Trifluoromethylquinocarboxylic,
[4-(4-cyclopropyl methylpiperazine-1-yl)-3,5-difluorophenyl] phenyl ketone,
[4-(4-cyclopropyl methylpiperazine-1-yl)-3,5-difluorophenyl]-(3-fluoro-4-p-methoxy-phenyl)-ketone,
6-[4-(1-ethyl propyl) piperazine-1-yl] and pyridin-3-yl } phenyl ketone,
2-[4-(1-ethyl propyl) piperazine-1-yl] and pyridin-4-yl } phenyl ketone,
4-[4-(1-ethyl propyl) piperazine-1-yl] phenyl }-(4-hydroxy phenyl) ketone,
6-[4-(1-ethyl propyl) piperazine-1-yl] and pyridin-3-yl } piperidines-1-base-ketone,
N-benzyl-6-[4-(1-ethyl propyl) piperazine-1-yl]-the N-methylnicotinamide,
2-[4-(1-ethyl propyl) piperazine-1-yl]-the 6-methoxy quinoline,
6-[4-(1-ethyl propyl) piperazine-1-yl]-N-methyl-N-phenyl niacinamide,
6-[4-(1-ethyl propyl) piperazine-1-yl] pyridin-3-yl }-(4-fluorophenyl) ketone,
2-[4-(1-ethyl propyl) piperazine-1-yl]-the 4-toluquinoline,
2-[4-(1-ethyl propyl) piperazine-1-yl]-5,6,7, the 8-tetrahydroquinoline,
2-(4-cyclopropyl methylpiperazine-1-yl)-6-methoxy quinoline,
2-(4-sec.-propyl piperazine-1-yl)-6-methoxy quinoline,
2-[4-(1-ethyl propyl) piperazine-1-yl]-6-fluoro-4-toluquinoline,
2-(4-cyclopropyl piperazine-1-yl)-6-Trifluoromethylquinocarboxylic,
2-(4-cyclopropyl piperazine-1-yl)-6-propyl group quinoline,
2-(4-ethyl piperazidine-1-yl) quinoline, and arbitrarily diastereomer or enantiomorph or change form, comprise their mixture or its pharmacy acceptable salt.
On the other hand, the present invention relates to general formula (I ") compound:
Wherein
R 1Representative
Side chain C 4-8-alkyl, side chain C 4-8-thiazolinyl or side chain C 4-8-alkynyl, they can be replaced by one or more halogenic substituents alternatively,
C 3-5-cycloalkyl, C 3-7-cycloalkenyl group, C 3-6-cycloalkyl-C 1-3-alkyl or C 3-6-cycloalkenyl group-C 1-3-alkyl, they can be replaced by one or more halogenic substituents alternatively,
The A representative
Figure A0380336000302
Or
Figure A0380336000303
Z and X represent independently-N=,-CH=,-CF=or-C (CF 3)=,
W representative-N=or-CR 3=,
Y representative-N=or-CR 4=,
R 2, R 3And R 4Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-10-alkyl, C 2-10-thiazolinyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, aryl-C 1-6-alkyl, amino, C 1-6-alkylamino, two-C 1-6-alkylamino, C 3-8-cycloalkyloxy or cyano group, or
C 2-10-alkyloyl or C 4-9-cycloalkanes acyl group,
They can be replaced by one or more substituting groups alternatively, and substituting group is selected from aryl, assorted virtue
Base, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy and C 1-6-alkoxyl group, aryl, aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or heteroaryl, they can be replaced by one or more substituting groups alternatively, and substituting group is selected from halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, C 1-6-alkyl, amino, C 1-6-alkylamino, two-C 1-6-alkylamino, cyano group, aryl, heteroaryl and C 3-8-cycloalkyl, or
Aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryloxy, arylamino or heteroaryl amino, they can be replaced by one or more substituting groups alternatively, and substituting group is selected from aryl, heteroaryl, C 1-10-alkyl, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, cyano group, amino, C 1-6-alkylamino, two-C 1-6-alkylamino and hydroxyl,
Its condition is that this compound must not be
Figure A0380336000311
Figure A0380336000331
Figure A0380336000332
Or
Figure A0380336000333
And arbitrarily diastereomer or enantiomorph or change form, comprise their mixture or its pharmacy acceptable salt.
In one embodiment, R 1Be side chain C 4-8-alkyl, C 3-5-cycloalkyl or C 3-6-cycloalkyl-C 1-3-alkyl, they can be replaced by one or more halogenic substituents alternatively.
In another embodiment, R 1Be side chain C 4-8-alkyl, C 3-5-cycloalkyl or C 3-6-cycloalkyl-C 1-3-alkyl, for example 1,1-(dimethyl) propyl group, 1-ethyl propyl, cyclopropyl methyl, cyclopropyl, cyclobutyl or cyclopentyl, for example 1-ethyl propyl, cyclopropyl methyl or cyclopentyl.
In another embodiment, R 1Be side chain C 4-8-alkyl or C 3-5-cycloalkyl, they can be replaced by one or more halogenic substituents alternatively, for example side chain C 4-8-alkyl or C 3-5-cycloalkyl, for example 1-ethyl propyl or cyclopentyl.
In further embodiment, A is
Or
R wherein 2, R 3And R 4Be defined suc as formula (I ").
In another embodiment, A is
R wherein 2, R 3And R 4Be defined suc as formula (I ").
In further embodiment, A is
R wherein 2, R 3And R 4Be defined suc as formula (I ").
In one embodiment, R 2, R 3And R 4Be independently selected from
Hydrogen, hydroxyl, halogen, trifluoromethyl, C 2-10-alkyloyl or C 4-9-cycloalkanes acyl group, perhaps
Aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or aroyl, they can be alternatively suc as formula (I ") define and be substituted.
In another embodiment, R 2, R 3And R 4Be independently selected from
Hydrogen, hydroxyl, halogen, trifluoromethyl, C 2-10-alkyloyl or C 4-9-cycloalkanes acyl group,
Phenyl-C 1-6-alkyl, phenyl-C 1-6-alkoxyl group or benzoyl, they can be replaced by one or two substituting group alternatively, and substituting group is selected from halogen and C 1-6-alkoxyl group.
In another embodiment, R 2And R 4All be hydrogen, R 3Not hydrogen.
In another embodiment, the present invention relates to general formula (I 1) compound:
Wherein A is that any one is defined suc as formula (I ") or above-mentioned embodiment.
In another embodiment, the present invention relates to general formula (I 2) compound:
Figure A0380336000351
Wherein A is that any one is defined suc as formula (I ") or above-mentioned embodiment.
Therefore, the present invention relate on the other hand as pharmaceutical composition general formula (I) compound and arbitrarily diastereomer or enantiomorph or change form, comprise their mixture or its pharmacy acceptable salt.
The invention still further relates to pharmaceutical composition, comprise at least a formula (I) compound or its any diastereomer or enantiomorph or change form, the mixture that comprises them or its pharmacy acceptable salt as activeconstituents, and one or more pharmaceutically acceptable carrier or thinners.
In addition, the present invention relates to general formula (I ') compound
Wherein
R 1Representative
C 1-8-alkyl, C 2-8-thiazolinyl or C 2-8-alkynyl, they can be replaced by one or more halogenic substituents alternatively,
C 3-5-cycloalkyl, C 3-7-cycloalkenyl group, C 3-6-cycloalkyl-C 1-3-alkyl or C 3-6-cycloalkenyl group-C 1-3-alkyl, they can be replaced by one or more halogenic substituents alternatively,
The A representative
Figure A0380336000353
Or
Z and X represent independently-N=,-CH=,-CF=or-C (CF 3)=,
W representative-N=or-CR 3=,
Y representative-N=or-CR 4=,
R 2a, R 2b, R 3And R 4Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-10-alkyl, C 2-10-thiazolinyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, aryl-C 1-6-alkyl, amino, C 1-6-alkylamino, two-C 1-6-alkylamino, C 3-a-cycloalkyloxy, cyano group, nitro, C 1-6-alkylthio, C 1-6-alkyl sulphonyl or-C (=O) NR 4aR 4b, R wherein 4aAnd R 4bBe hydrogen, C independently 1-6-alkyl or aryl-C 1-6-alkyl, or
C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 3-8-heterocyclic radical or C 4-9-heterocycle alkyloyl, they can be replaced by one or more substituting groups alternatively at an arbitrary position, and substituting group is selected from aryl, heteroaryl, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy and C 1-6-alkoxyl group, aryl, aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or heteroaryl, they can be replaced by one or more substituting groups alternatively, and substituting group is selected from halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, C 1-6-alkyl, amino, C 1-6-alkylamino, two-C 1-6-alkylamino, cyano group, aryl, heteroaryl and C 3-8-cycloalkyl, perhaps
Aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryloxy, arylamino or heteroaryl amino, they can be replaced by one or more substituting groups alternatively, and substituting group is selected from aryl, heteroaryl, C 1-10-alkyl, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, cyano group, amino, C 1-6-alkylamino, two-C 1-6-alkylamino and hydroxyl,
Perhaps R 2a, R 2b, R 3And R 4Two of middle consecutive position constitute C together 1-6-alkylidene bridge, and arbitrarily diastereomer or enantiomorph or change form, comprise their mixture, or the purposes of its pharmacy acceptable salt in preparation of pharmaceutical compositions, this pharmaceutical composition is used for the treatment of obstacle and the disease that relates to histamine H 3 receptor.
The present invention provides general formula (II) compound on the other hand:
Wherein
R 2Be hydrogen or C 1-4-alkyl,
(i) R 1Representative
Side chain C 4-6-alkyl, side chain C 4-6-thiazolinyl or side chain C 4-6-alkynyl, its condition is R 1Not isobutyl-,
C 3-5-cycloalkyl, C 3-7-cycloalkenyl group, C 3-6-cycloalkyl-C 1-3-alkyl or C 3-6-cycloalkenyl group-C 1-3-alkyl,
R 1And R 2Constitute C together 3-6-alkylidene bridge and
The A representative
Figure A0380336000371
Or
Figure A0380336000372
Perhaps
(ii) R 1Representative
Ethyl, n-propyl or sec.-propyl,
R 1And R 2Constitute C together 3-6-alkylidene bridge and
The A representative
Or
R 3Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-10-alkyl, C 2-10-thiazolinyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, aryl, aryl-C 1-6-alkyl, amino, C 1-6-alkylamino, two-C 1-6-alkylamino, C 3-8-cycloalkyl, C 3-8-cycloalkyloxy, cyano group, nitro, C 1-6-alkylthio or C 1-6-alkyl sulphonyl,
Z and X represent independently-N=,-C (H)=,-C (F)=,-C (Cl)=,-C (CN)=or-C (CF 3)=,
W representative-N=or-C (R 10)=,
Y representative-N=or-C (R 11)=,
R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy ,-SCF 3, amino, cyano group, nitro or-C (=O) NR 14R 15,
C 1-10-alkyl, C 2-10-thiazolinyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, C 3-8-cycloalkyl-C 1-6-alkoxyl group, C 1-6-alkylamino, two-C 1-6-alkylamino, C 3-8-cycloalkyloxy, C 1-6-alkylthio, C 1-6-alkyl sulphonyl, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 3-8-heterocyclic radical or C 4-9-heterocycle alkyloyl, C 4-9-heterocycle alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl, aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or heteroaryl, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryloxy, arylamino or heteroaryl amino, they can be alternatively by one or more R that are selected from 18Substituting group replace,
Perhaps R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkylidene group-O-bridge,
R 14And R 15Be hydrogen, C independently 1-6-alkyl, aryl-C 1-6-alkyl, perhaps R 14And R 15Can constitute C together 3-6-alkylidene bridge,
R 16Be independently selected from aryl, heteroaryl, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR 19R 20And C 1-6-alkoxyl group,
R 17Be independently selected from halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, C 1-6-alkyl, amino, C 1-6-alkyl sulphonyl, C 1-6-alkylamino, two-C 1-6-alkylamino, cyano group, aryl, heteroaryl and C 3-8-cycloalkyl,
R 18Be independently selected from aryl, heteroaryl, C 1-10-alkyl, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, cyano group, amino, C 1-6-alkylamino, two-C 1-6-alkylamino and hydroxyl,
R 19And R 20Be hydrogen or C independently 1-6-alkyl, R 19And R 20Can constitute C together 3-6-alkylidene bridge,
Its condition is that this compound must not be
Figure A0380336000391
Figure A0380336000401
Or
Figure A0380336000412
And arbitrarily diastereomer or enantiomorph or change form, comprise their mixture or its pharmacy acceptable salt.
In another aspect of this invention, R 1Be side chain C 4-6-alkyl, C 3-5-cycloalkyl or C 3-6-cycloalkyl-C 1-3-alkyl, its condition is R 1It or not isobutyl-.
In another aspect of this invention, R 1Be 1,1-(dimethyl) propyl group, 1-ethyl propyl, cyclopropyl methyl, cyclopropyl, cyclobutyl, cyclopentyl or 1-cyclopropyl-1-methylethyl.
In another aspect of this invention, R 1Be 1-ethyl propyl, cyclopropyl methyl, cyclopropyl or cyclopentyl.
In another aspect of this invention, R 1Be side chain C 4-6-alkyl or C 3-5-cycloalkyl, its condition is R 1It or not isobutyl-.
In another aspect of this invention, R 1Be 1-ethyl propyl, cyclopropyl or cyclopentyl.
In another aspect of this invention, Z be-C (H)=,-N=or-C (F)=.
In another aspect of this invention, Z be-C (H)=or-N=.
In another aspect of this invention, Z be-C (H)=.
In another aspect of this invention, Z is-N=.
In another aspect of this invention, X be-C (H)=,-N=or-C (F)=.
In another aspect of this invention, Z be-C (H)=or-N=.
In another aspect of this invention, Z be-C (H)=.
In another aspect of this invention, Z is-N=.
In another aspect of this invention, W is-N=.
In another aspect of this invention, W is-C (R 10)=.
In another aspect of this invention, Y is-N=.
In another aspect of this invention, Y is-C (R 11)=.
In another aspect of this invention, R 2Be hydrogen.
In another aspect of this invention, R 2Be C 1-4-alkyl.
In another aspect of this invention, R 2Be methyl or ethyl.
The present invention provides general formula (III) compound on the other hand
Wherein A and R 3Be defined as general formula (II) compound.
In another aspect of this invention, R 3Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-10-alkyl, C 1-6-alkoxyl group, aryl, aryl-C 1-6-alkyl, amino, C 3-8-cycloalkyl, C 3-8-cycloalkyloxy, cyano group or nitro.
In another aspect of this invention, R 3Be hydrogen, halogen, hydroxyl, trifluoromethyl, C 1-10-alkyl, C 1-6-alkoxyl group, cyano group or nitro.
In another aspect of this invention, R 3Be hydrogen, halogen, hydroxyl, trifluoromethyl, C 1-6-alkyl or cyano group.
In another aspect of this invention, R 3Be hydrogen, halogen or C 1-6-alkyl.
In another aspect of this invention, R 3Be hydrogen or methyl.
In another aspect of this invention, R 4, R 5, R 6, R 7, R 8And R 9Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy ,-SCF 3, amino or cyano group,
C 1-10-alkyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, C 3-8-cycloalkyloxy, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 3-8-heterocyclic radical or C 4-9-heterocycle alkyloyl, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl, aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or heteroaryl, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryloxy, they can be alternatively by one or more R that are selected from 18Substituting group replace,
Perhaps R 5, R 6, R 7, R 8, R 9Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkylidene group-O-bridge.
In another aspect of this invention, R 4, R 5, R 6, R 7, R 8And R 9Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy ,-SCF 3Or cyano group,
C 1-10-alkyl, C 1-6-alkoxyl group, C 3-8-cycloalkyloxy, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl or aryl-C 1-6-alkyl, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl or aryloxy, they can be alternatively by one or more R that are selected from 18Substituting group replace perhaps R 5, R 6, R 7, R 8, R 9Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkylidene group-O-bridge.
In another aspect of this invention, R 4, R 5, R 6, R 7, R 8And R 9Representative independently
Hydrogen, halogen or cyano group,
C 1-10-alkyl or C 1-6-alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl is alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl or aryloxy, they can be alternatively by one or more R that are selected from 18Substituting group replace perhaps R 5, R 6, R 7, R 8, R 9Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkylidene group-O-bridge.
In another aspect of this invention, R 4, R 5, R 6, R 7, R 8And R 9Representative independently
Hydrogen, halogen or cyano group,
Methyl, ethyl, propyl group, sec.-propyl or C 1-6-alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl is alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl or aryloxy, they can be alternatively by one or more R that are selected from 18Substituting group replace perhaps R 5, R 6, R 7, R 8, R 9Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkylidene group-O-bridge.
In another aspect of this invention, R 4, R 5, R 6, R 7, R 8And R 9Representative independently
Hydrogen, halogen or cyano group,
C 1-10-alkyl, methoxyl group, oxyethyl group or propoxy-, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl is alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl or aryloxy, they can be alternatively by one or more R that are selected from 18Substituting group replace perhaps R 5, R 6, R 7, R 8, R 9Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkylidene group-O-bridge.
In another aspect of this invention, R 4, R 5, R 6, R 7, R 8And R 9Representative independently
Hydrogen, halogen or cyano group,
C 1-10-alkyl or methoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl is alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl or aryloxy, they can be alternatively by one or more R that are selected from 18Substituting group replace perhaps R 5, R 6, R 7, R 8, R 9Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkylidene group-O-bridge.
In another aspect of this invention, R 4, R 5, R 6, R 7, R 8And R 9Representative independently
Hydrogen, halogen or cyano group,
C 1-10-alkyl or C 1-6-alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Phenyl is alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl or aryloxy, they can be alternatively by one or more R that are selected from 18Substituting group replace perhaps R 5, R 6, R 7, R 8, R 9Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkylidene group-O-bridge.
In another aspect of this invention, R 4, R 5, R 6, R 7, R 8And R 9Representative independently
Hydrogen, halogen or cyano group,
C 1-10-alkyl or C 1-6-alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl is alternatively by one or more R that are selected from 17Substituting group replace,
-C (=O)-and phenyl or aryloxy, they can be alternatively by one or more R that are selected from 18Substituting group replace perhaps R 5, R 6, R 7, R 8, R 9Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkylidene group-O-bridge.
In another aspect of this invention, R 4, R 5, R 6, R 7, R 8And R 9Representative independently
Hydrogen, halogen or cyano group,
C 1-10-alkyl or C 1-6-alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl is alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl or-the O-phenyl, they can be alternatively by one or more R that are selected from 18Substituting group replace perhaps R 5, R 6, R 7, R 8, R 9Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkylidene group-O-bridge.
In another aspect of this invention, R 1Be ethyl or sec.-propyl.
In another aspect of this invention, R 1It is sec.-propyl.
In another aspect of this invention, R 1It is ethyl.
In another aspect of this invention, R 1And R 2Constitute C together 3-4-alkylidene bridge.
In another aspect of this invention, R 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano group or-C (=O) NR 14R 15,
C 1-10-alkyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 3-8-heterocyclic radical or C 4-9-heterocycle alkyloyl, C 4-9-heterocycle alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl, aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or heteroaryl, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl is alternatively by one or more R that are selected from 18Substituting group replace,
Perhaps R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge.
In another aspect of this invention, R 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano group or-C (=O) NR 14R 15,
C 1-10-alkyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 3-8-heterocyclic radical or C 4-9-heterocycle alkyloyl, C 4-9-heterocycle alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl, aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or heteroaryl, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl is alternatively by one or more R that are selected from 18Substituting group replace perhaps R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge.
In another aspect of this invention, R 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, trifluoromethyl or-C (=O) NR 14R 15,
C 1-10-alkyl, C 1-6-alkoxyl group, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 4-9-heterocycle alkyloyl or C 4-9-heterocycle alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl, aryl-C 1-6-alkyl or aryl-C 1-6-alkoxyl group, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl is alternatively by one or more R that are selected from 18Substituting group replace perhaps R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge.
In another aspect of this invention, R 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, trifluoromethyl or-C (=O) NR 14R 15,
C 1-10-alkyl or C 4-9-heterocycle alkyloyl, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl is alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl is alternatively by one or more R that are selected from 18Substituting group replace perhaps R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge.
In another aspect of this invention, R 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, trifluoromethyl or-C (=O) NR 14R 15,
Methyl, ethyl, propyl group or C 4-9-heterocycle alkyloyl, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl is alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl is alternatively by one or more R that are selected from 18Substituting group replace perhaps R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge.
In another aspect of this invention, R 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, trifluoromethyl or-C (=O) NR 14R 15,
C 1-10-alkyl, piperidines-alkyloyl or tetramethyleneimine-alkyloyl, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl is alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl is alternatively by one or more R that are selected from 18Substituting group replace perhaps R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge.
In another aspect of this invention, R 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, trifluoromethyl or-C (=O) NR 14R 15,
C 1-10-alkyl or C 4-9-heterocycle alkyloyl, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Phenyl is alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl is alternatively by one or more R that are selected from 18Substituting group replace perhaps R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge.
In another aspect of this invention, R 14And R 15Be methyl, ethyl or benzyl independently.
In another aspect of this invention, R 16Be halogen, trifluoromethyl, trifluoromethoxy and C 1-6-alkoxyl group.
In another aspect of this invention, R 17Be halogen, hydroxyl, trifluoromethyl, C 1-6-alkoxyl group, C 1-6-alkyl, C 1-6-alkyl sulphonyl or cyano group.
In another aspect of this invention, R 17Be halogen, trifluoromethyl, C 1-6-alkoxyl group or C 1-6-alkyl sulphonyl.
In another aspect of this invention, R 18Be C 1-10-alkyl, halogen, trifluoromethyl, C 1-6-alkoxyl group, cyano group, amino and hydroxyl.
In another aspect of this invention, R 18Be halogen, C 1-6-alkoxyl group and hydroxyl.
The present invention provides on the other hand according to formula (II) or compound (III) purposes as pharmaceutical composition.In another aspect of this invention, pharmaceutical composition can comprise at least a according to formula (II) or compound (III) as activeconstituents, and one or more pharmaceutically acceptable carrier or vehicle.The present invention provides a kind of like this pharmaceutical composition of unit dosage on the other hand, comprise about 0.05mg to about 1000mg, preferably about 0.1mg extremely about 500mg, especially preferably about 0.5mg extremely about 200mg according to formula (II) or compound (III).
The present invention provides general formula (II ') compound on the other hand
Figure A0380336000481
Wherein
R 2Be hydrogen or C 1-4-alkyl,
R 1Representative
C 1-8-alkyl, C 2-8-thiazolinyl or C 2-8-alkynyl, they can be replaced by one or more halogenic substituents alternatively,
C 3-5-cycloalkyl, C 3-7-cycloalkenyl group, C 3-6-cycloalkyl-C 1-3-alkyl or C 3-6-cycloalkenyl group-C 1-3-alkyl, they can be replaced by one or more halogenic substituents alternatively,
R 1And R 2Constitute C together 3-6-alkylidene bridge,
The A representative
Figure A0380336000482
Or
Figure A0380336000483
R 3Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-10-alkyl, C 2-10-thiazolinyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, aryl, aryl-C 1-6-alkyl, amino, C 1-6-alkylamino, two-C 1-6-alkylamino, C 3-8-cycloalkyl, C 3-8-cycloalkyloxy, cyano group, nitro, C 1-6-alkylthio or C 1-6-alkyl sulphonyl,
Z and X represent independently-N=,-C (H)=,-C (F)=,-C (Cl)=,-C (CN)=or-C (CF 3)=,
W representative-N=or-C (R 10)=,
Y representative-N=or-C (R 11)=,
R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy ,-SCF 3, amino, cyano group, nitro or-C (=O) NR 14R 15,
C 1-10-alkyl, C 2-10-thiazolinyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, C 3-8-cycloalkyl-C 1-6-alkoxyl group, C 1-6-alkylamino, two-C 1-6-alkylamino, C 3-8-cycloalkyloxy, C 1-6-alkylthio, C 1-6-alkyl sulphonyl, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 3-8-heterocyclic radical or C 4-9-heterocycle alkyloyl or C 4-9-heterocycle alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl, aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or heteroaryl, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryloxy, arylamino or heteroaryl amino, they can be alternatively by one or more R that are selected from 18Substituting group replace,
Perhaps R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkylidene group-O-bridge,
R 14And R 15Be hydrogen, C independently 1-6-alkyl, aryl-C 1-6-alkyl, perhaps R 14And R 15Can constitute C together 3-6-alkylidene bridge,
R 16Be independently selected from aryl, heteroaryl, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR 19R 20And C 1-6-alkoxyl group,
R 17Be independently selected from halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, C 1-6-alkyl, amino, C 1-6-alkyl sulphonyl, C 1-6-alkylamino, two-C 1-6-alkylamino, cyano group, aryl, heteroaryl and C 3-8-cycloalkyl,
R 18Be independently selected from aryl, heteroaryl, C 1-10-alkyl, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, cyano group, amino, C 1-6-alkylamino, two-C 1-6-alkylamino and hydroxyl,
R 19And R 20Be hydrogen or C independently 1-6-alkyl, R 19And R 20Can constitute C together 3-6-alkylidene bridge, and arbitrarily diastereomer or enantiomorph or change form, comprise their mixture, or the purposes of its pharmacy acceptable salt in preparation of pharmaceutical compositions, this pharmaceutical composition is used for the treatment of obstacle and the disease that relates to histamine H 3 receptor.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition is used for the treatment of and wherein suppresses disease and the obstacle that the H3 Histamine Receptors has beneficial effect.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition has histamine H 3 antagonistic activities or histamine H 3 anti-agonist activities.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition is used to reduce body weight.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition is used for the treatment of overweight or fat.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition is used for depress appetite or is used to bring out satiety.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition is used to prevent and/or treat and relates to overweight or fat obstacle and disease.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition is used to prevent and/or treat eating disorder, for example Bulimia nerovsa and binge eating.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition is used for the treatment of IGT.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition is used for the treatment of diabetes B.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition is used to delay or prevents that IGT from developing into diabetes B.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition is used to delay or prevents that non-insulin demand type diabetes B from developing into insulin requirements type diabetes B.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition is used for the treatment of disease and the obstacle that its moderate stimulation H3 Histamine Receptors has beneficial effect.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition has histamine H 3 agonist activities.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition is used for the treatment of rhinallergosis, ulcer or anorexia.
The present invention provides as defined above general formula (the II ') purposes of compound in preparation of pharmaceutical compositions on the other hand, and this pharmaceutical composition is used for the treatment of Alzheimer, lethargy or distractibility disease.
The present invention provides treatment to relate to the obstacle of H3 Histamine Receptors or the method for disease on the other hand, and this method comprises when needed gives general formula as defined above (the II ') compound of significant quantity or comprise a kind of like this pharmaceutical composition of compound the curee.
The present invention provides treatment to relate to the obstacle of H3 Histamine Receptors or the method for disease on the other hand, wherein as defined above the significant quantity of general formula (II ') compound be every day about 0.05mg to about 2000mg, preferred extremely about 1000mg, especially preferred about 0.5mg about 500mg extremely of about 0.1mg.
The present invention provides treatment to relate to the disease of histamine H 3 receptor and the method for obstacle on the other hand, and this method comprises the pharmaceutical composition of when needed curee being given formula (I) compound or its any diastereomer or enantiomorph or tautomer form, the mixture that comprises them or its pharmacy acceptable salt of significant quantity or comprising them.
The present invention relates to the compound with histamine H 3 receptor antagonistic activity or anti-agonist activity on the one hand, and therefore they can be used for the treatment of multiple wherein histamine H 3 receptor retardance is useful illness and obstacle.
The present invention relates to the compound with histamine H 3 receptor agonist activity on the other hand, and therefore they can be used for the treatment of multiple wherein histamine H 3 receptor activation is useful illness and obstacle.
In preferred invention embodiment, The compounds of this invention is used to prepare the pharmaceutical composition that reduces body weight.
In preferred invention embodiment, The compounds of this invention is used to prepare the overweight or fat pharmaceutical composition of treatment.
At another preferably in the invention embodiment, The compounds of this invention is used to the pharmaceutical composition for preparing depress appetite or bring out satiety.
In further preferred invention embodiment, The compounds of this invention is used to prepare prevent and/or treat and relates to the overweight or fat obstacle and the pharmaceutical composition of disease, for example atherosclerosis, hypertension, IGT (impaired glucose tolerance), diabetes (especially diabetes B (NIDDM (non insulin dependent diabetes))), dyslipidemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer (for example cancer of uterine endometrium, mammary gland, prostate gland and colon).
In further preferred invention embodiment, The compounds of this invention is used to prepare the pharmaceutical composition that prevents and/or treats eating disorder, for example Bulimia nerovsa and binge eating.
In further preferred invention embodiment, The compounds of this invention is used to prepare the pharmaceutical composition for the treatment of IGT.
In further preferred invention embodiment, The compounds of this invention is used to prepare the pharmaceutical composition for the treatment of diabetes B.The treatment of this class especially comprises for delaying or preventing that IGT from developing into diabetes B and delay or prevent that non-insulin demand type diabetes B from developing into the treatment that the purpose of insulin requirements type diabetes B is carried out.
The compounds of this invention can also be used for the treatment of thick wind, and for example asthma is used as anti-purgatives and is used to modulate gastric acid secretion.
In addition, The compounds of this invention can be used for the treatment of with sleep adjusting and insomnia diseases associated and be used for the treatment of lethargy and distractibility disease.
And The compounds of this invention can be used as CNS stimulant or tranquilizer.
The compounds of this invention can also be used for the treatment of the illness relevant with epilepsy.In addition, The compounds of this invention can be used for the treatment of motion sickness and dizzy.In addition, they can be used as hypothalamus-hypophysis regulation of secretion agent, antidepressive, cerebral circulation modulator and be used for the treatment of irritable bowel syndrome.
In addition, The compounds of this invention can be used for the treatment of dementia and Alzheimer.
The compounds of this invention can also be used for the treatment of rhinallergosis, ulcer or anorexia.
The compounds of this invention can be used for the treatment of migraine in addition, referring to McLeod et al., TheJournal of Pharmacology and Experimental Therapeutics 287 (1998), 43-50, be used for the treatment of myocardial infarction, referring to Mackins et al., Expert Opinion onInvestigational Drugs 9 (2000), 2537-2542.
At further inventive aspect, combine with diet and/or exercise with The compounds of this invention treatment patient.
At further inventive aspect, other active substances of The compounds of this invention and one or more are in being fit to the ratio Combined Preparation arbitrarily.Other promoting agents of this class can be selected from antiadipositas drug, antidiabetic, anti-lipid unusual agent, hypotensive agent, by the therapeutical agent of complications associated with arterial system due to the diabetes or with it with by the therapeutical agent of complications associated with arterial system and obstacle due to the obesity or with it.
Thereby, at further inventive aspect, The compounds of this invention and one or more antiadipositas drugs or appetite stimulator Combined Preparation.
This class medicine can be selected from down group: CART (transcribing of Cocaine amphetamine adjusting) agonist, NPY (neuropeptide tyrosine) antagonist, MC4 (melanocortin 4) agonist, MC3 (melanocortin 3) agonist, the orexin antagonist, TNF (tumour necrosis factor) agonist, CRF (corticotropin releasing factor (CRF)) agonist, CRF BP (corticotropin releasing factor (CRF) is conjugated protein) antagonist, the urocortin agonist, 'beta '3 adrenergic agonists (CL-316243 for example, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140), MSH (melanotropin) agonist, MCH (melanophore concentrates hormone) antagonist, CCK (pancreozymin) agonist, serotonin reuptake inhibitors (fluoxetine for example, Paro gram plug or citalopram), thrombotonin and NRI, mixed type thrombotonin and norepinephrine energy compound, 5HT (thrombotonin) agonist, the bombesin agonist, the neuroganglion peptide antagonists, tethelin, somatomedin (for example prolactin or galactagogin), growth hormone releasing compounds, TRH (thyrotrophin-releasing hormone) agonist, UCP 2 or 3 (uncoupling protein 2 or 3) modulator, the leptin agonist, DA agonist (bromocriptine, doprexin), lipase/amylase inhibitor, PPAR (peroxisome proliferation activated receptor) modulator, RXR (retinoic acid-like X acceptor) modulator, the TR beta-agonists, AGRP (agouti dependency albumen) inhibitor, opioid antagonists (for example TREXUPONT), exendin-4, GLP-1 and ciliary neurotrophic factor.
In a kind of invention embodiment, antiadipositas drug is a leptin.
In another embodiment, antiadipositas drug is Dextroamphetamine or amphetamine.
In another embodiment, antiadipositas drug is Phenfluoramine or Isomeride.
In another embodiment, antiadipositas drug is a sibutramine.
In further embodiment, antiadipositas drug is an orlistat.
In another embodiment, antiadipositas drug is Mazindol or phentermine.
In another embodiment, antiadipositas drug is phendimetrazine, Diethylpropion, fluoxetine, Bupropion, topiramate or ecopipam.
Aspect further, The compounds of this invention and one or more antidiabetic Combined Preparation.
Relevant antidiabetic comprises Regular Insulin, insulin analog and derivative, for example is disclosed in the following document those: EP 0 792 290 (Novo Nordisk A/S), for example N ε B29-myristoyl des (B30) insulin human; EP 0 214 826 and EP 0 705 275 (NovoNordisk A/S), for example Asp B28The insulin human; US 5,504,188 (Eli Lilly), for example Lys B28Pro B29The insulin human; EP 0 368 187 (Aventis), Lantus  for example, they are all quoted at this as a reference; The GLP-1 derivative for example is disclosed among the WO 98/08871 (Novo Nordisk A/S) those, quotes as a reference at this, and orally active Hypoylycemic agents.
Orally active Hypoylycemic agents preferably comprises imidazolines; Sulfonylurea; Biguanides; Meglitinides; Oxadiazole alkane two ketones; Thiazolidinediones; Insulin sensitizers; Alpha-glucosidase inhibitor; Act on the medicine of ATP dependent form beta cell potassium channel, potassium channel openers for example for example is disclosed among WO 97/26265, WO 99/03861 and the WO 00/37474 (Novo NordiskA/S) those, quotes at this as a reference; Or mitiglinide; Or potassium channel antagonists, for example BTS-67582, Nateglinide; Glucagon antagonists, for example be disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.) in those are quoted at this as a reference; The GLP-1 agonist, for example be disclosed in WO00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.) in those are quoted at this as a reference; DPP-IV (dipeptidyl peptidase-IV) inhibitor; PTP enzyme (Protein Tyrosine Phosphatases) inhibitor; The liver enzyme inhibitors that involved in sugar heteroplasia and/or glycogenolysis stimulate; The glucose uptake modulator; GSK-3 (glycogen synthase kinase-3) inhibitor; Change the compound of lipid metabolism, for example anti-lipid unusual agent; Reduce the compound of ingestion of food; PPAR (peroxisome proliferation activated receptor); RXR (retinoic acid-like X acceptor) agonist, for example ALRT-268, LG-1268 or LG-1069.
In a kind of invention embodiment, The compounds of this invention and Regular Insulin or insulin analog or derivative Combined Preparation, for example N ε B29-myristoyl des (B30) insulin human, Asp B28Insulin human, Lys B28Pro B29Insulin human, Lantus  or comprise in them one or more be mixed with thing.
In further invention embodiment, The compounds of this invention and a kind of sulfonylurea Combined Preparation, for example tolbutamide, P-607, tolazamide, Glyburide, Glipizide, glimepiride, gliclazide (glicazide) or Glyburide.
In another kind of invention embodiment, The compounds of this invention and a kind of biguanides Combined Preparation, for example metformin.
In another embodiment, The compounds of this invention and a kind of meglitinide Combined Preparation, for example repaglinide or Nateglinide.
In another kind of invention embodiment, The compounds of this invention and a kind of thiazolidinedione insulin sensitizers Combined Preparation, for example troglitazone, ciglitazone, pioglitazone, rosiglitazone, Netoglitazone (isaglitazone), darglitazone, englitazone, CS-011/CI-1037 or T 174 or be disclosed in compound among WO 97/41097, WO 97/41119, WO 97/41120, WO00/41121 and the WO 98/45292 (Dr.Reddy ' s Research Foundation) quote at this as a reference.
In another kind of invention embodiment, The compounds of this invention can with a kind of insulin sensitizers Combined Preparation, for example GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or be disclosed in WO 99/19313, WO 00/50414, WO00/63191, WO 00/63192, WO 00/63193 (Dr.Reddy ' s ResearchFoundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, compound among WO 00/63190 and the WO 00/63189 (Novo Nordisk A/S) is quoted at this as a reference.
In further invention embodiment, The compounds of this invention and a kind of alpha-glucosidase inhibitor Combined Preparation, for example voglibose, emiglitate, miglitol or acarbose.
In another kind of invention embodiment, The compounds of this invention is with a kind of medication combined administration of the ATP dependent form potassium channel that acts on beta cell, for example tolbutamide, Glyburide, Glipizide, gliclazide, BTS-67582 or repaglinide.
In another invention embodiment, The compounds of this invention can with the Nateglinide Combined Preparation.
In another embodiment, The compounds of this invention and a kind of lipidemia agent or antilipemic agent Combined Preparation, for example Colestyramine, colestipol, chlorine Bei Te, gemfibrozil, lovastatin, Pravastatin, Simvastatin, probucol or dextrothyroxine.
In another invention embodiment, The compounds of this invention and a kind of antilipemic agent Combined Preparation, for example Colestyramine, colestipol, chlorine Bei Te, gemfibrozil, lovastatin, Pravastatin, Simvastatin, probucol or dextrothyroxine.
In invention on the other hand, The compounds of this invention and more than one above-claimed cpd Combined Preparation, for example metformin and a kind of sulfonylurea, for example Glyburide; A kind of sulfonylurea and Acarbose; Nateglinide and metformin; Acarbose and metformin; A kind of sulfonylurea, metformin and troglitazone; Regular Insulin and a kind of sulfonylurea; Regular Insulin and metformin; Regular Insulin, metformin and a kind of sulfonylurea; Regular Insulin and troglitazone; Regular Insulin and lovastatin; Or the like.
In addition, The compounds of this invention can with one or more hypotensive agent Combined Preparation.The example of hypotensive agent is a beta-Blocking agent, for example alprenolol, atenolol USP 23, timolol, pindolol, Proprasylyte and metoprolol; ACE (angiotensin-converting enzyme) inhibitor, for example benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and Ramipril; Calcium channel blocker, for example nifedipine, felodipine, nicardipine, Isrodipine, nimodipine, diltiazem and verapamil; And α-Zu Zhiji, for example Doxazosin, urapidil, Prazosin and terazosin.Further can be with reference to Remington:The Scienceand Practice of Pharmacy, 19 ThEdition, Gennaro, Ed., MackPublishing Co., Easton, PA, 1995.
Should be appreciated that The compounds of this invention and diet and/or exercise, one or more above-claimed cpds and optionally the combination that is fit to arbitrarily of one or more other active substances all be regarded as belonging to scope of the present invention.
The compounds of this invention can be a chirality, means, isolating enantiomorph, pure or partially purified enantiomorph or its racemic mixture all comprise within the scope of the invention arbitrarily.
In addition, when in molecule, having the limited key of two keys or saturated wholly or in part ring system or above asymmetric center or rotatory, can generate diastereomer.Isolating diastereomer, pure or partially purified diastereomer or its mixture all comprise within the scope of the invention arbitrarily.
In addition, can there be different change forms in some The compounds of this invention, any compound the change form that can generate all comprise within the scope of the invention.
The pharmacy acceptable salt of The compounds of this invention is also contained in the present invention.This class salt comprises pharmaceutically-acceptable acid addition, pharmaceutically acceptable metal-salt, ammonium and alkylated ammonium.Acid salt comprises mineral acid and organic acid salt.The representative example of the mineral acid that is fit to comprises hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, sulfuric acid, nitric acid etc.The organic acid representative example that is fit to comprises formic acid, acetate, trichoroacetic acid(TCA), trifluoroacetic acid, propionic acid, phenylformic acid, styracin, citric acid, fumaric acid, oxyacetic acid, lactic acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, oxalic acid, picric acid, pyruvic acid, Whitfield's ointment, succsinic acid, methylsulfonic acid, ethyl sulfonic acid, tartrate, xitix, pounce on acid, the dimethylene Whitfield's ointment, ethionic acid, glyconic acid, citraconic acid, aspartic acid, stearic acid, palmitinic acid, EDTA, oxyacetic acid, Para-Aminobenzoic, L-glutamic acid, Phenylsulfonic acid, right-toluenesulphonic acids etc.Pharmaceutically acceptable further example inorganic or organic acid addition salt is included in J.Pharm.Sci.1977, and cited pharmacy acceptable salt in 66,2 is quoted at this as a reference.The example of metal-salt comprises the salt of lithium, sodium, potassium, magnesium etc.The example of ammonium and alkylated ammonium comprises ammonium, ammonium methyl, Dimethyl Ammonium, trimethyl ammonium, ethyl ammonium, hydroxyethyl ammonium, diethyl ammonium, butyl ammonium, tetramethyl ammonium etc.
As pharmaceutically-acceptable acid addition also comprise The compounds of this invention the hydrate that can generate.
Acid salt can be used as the synthetic direct product of compound and obtains.In alternative, free alkali can be dissolved in the solvent that is fit to that contains suitable acid, evaporating solvent or separately salt and solvent, thereby separated salt.
Utilize method well known to those skilled in the art, The compounds of this invention can generate solvate with the low molecular weight solvent of standard.This kind solvent thing also covered in the scope of the present invention.
The prodrug of The compounds of this invention is also contained in the present invention, and they experienced the chemical conversion of metabolic process before becoming active pharmacological agents after administration.Generally speaking, this class prodrug will be the functional deriv of The compounds of this invention, be converted into required formula (I) compound in their easy bodies.The routine of the prodrug derivatives that is fit to is selected for example to be described in " Designof Prodrugs " with preparation technology, ed.H.Bundgaard, and Elsevier is in 1985.
The active metabolite of The compounds of this invention is also contained in the present invention.
The compounds of this invention and histamine H 3 receptor interact, and therefore can be used for treating multiple wherein histamine H 3 receptor interaction is useful illness and obstacle.
Pharmaceutical composition
The compounds of this invention can be individually dosed or with pharmaceutically acceptable carrier or vehicle Combined Preparation, divide single agent or multi-agent.Can prepare like this according to pharmaceutical composition of the present invention,, for example be disclosed in Remington:The Science and Practice ofPharmacy, 19 according to routine techniques ThEdition, Gennaro, Ed., Mack Publishing Co., Easton, PA, those in 1995 use pharmaceutically acceptable carrier or thinner and other known auxiliary agent and vehicle arbitrarily.
Pharmaceutical composition can specifically be mixed with to be used for by being fit to administration arbitrarily, in for example oral, rectum, nose, lung, part (comprising cheek and hypogloeeis), transdermal, the brain pond, intraperitoneal, vagina and parenteral (comprise in subcutaneous, intramuscular, the sheath, intravenously and intradermal) approach, oral route is preferred.What will be understanded is that preferred approach will depend on curee's general condition and age, the sanatory attribute of institute and selected activeconstituents.
Be used for pharmaceutical composition for oral administration and comprise solid dosage, for example capsule, tablet, dragee, pill, lozenge, pulvis and granule.In due course, they can have dressing, enteric coating for example, and perhaps they can be prepared like this according to method well known in the art, so that the sustained release of activeconstituents to be provided, for example release that continues or prolong.
The liquid dosage form that is used for oral administration comprises solution, emulsion, suspension, syrup and elixir.
The pharmaceutical composition that is used for administered parenterally comprises aseptic water-based and non-aqueous Injectable solution, dispersion, suspension or emulsion, and aseptic pulvis, is regenerated as aseptic Injectable solution or dispersion before use.The Drug Storage injection formulations also covered in the scope of the present invention.
Other form of administration that are fit to comprise suppository, sprays, ointment, creme, gelifying agent, inhalation, skin patch, implant etc.
Typical oral dosage is about 0.001 to the about 100mg/kg body weight scope of every day, preferred about 0.01 to about 50mg/kg body weight every day, 0.05 to about 10mg/kg body weight every day more preferably from about, branch potion or multi-agent administration, for example 1 to 3 dose.Accurate dose will depend on the frequency of administration and mode, curee sex, age, body weight and general condition, the illness for the treatment of and conspicuous other factors of any disease accompanied attribute and seriousness and those skilled in the art for the treatment of.
By method known to those skilled in the art, preparation can present unit dosage aptly.Typically be used for unit dosage every day one of oral administration or repeatedly, every day 1 to 3 time for example, can contain 0.05 to about 1000mg, preferred about 0.1 to about 500mg, 0.5mg about 200mg extremely more preferably from about.
With regard to parenteral route, for example in the intravenously, sheath, intramuscular and similar administration, typical dosage is the only about half of of the dosage that adopts of oral administration.
The compounds of this invention generally adopts dissociant or its pharmacy acceptable salt.An example is the acid salt with compound of free alkali practicality.When formula (I) when compound contains free alkali, this class salt prepares in a conventional manner, with the solution of formula (I) free alkali or suspension with stoichiometric pharmaceutically acceptable acid treatment, for example inorganic and organic acid.Representative example was above being mentioned.Have negatively charged ion that acceptable salt on the physiology of compound of hydroxyl comprises described compound and be fit to cationic combination, for example sodium or ammonium ion.
With regard to administered parenterally, can adopt the novel solution of formula (I) compound in aseptic aqueous solution, aqueous propylene glycol or sesame or peanut oil.If necessary, this class aqueous solution should suitably be cushioned, and liquid diluent is at first given isotonicity by capacity salt solution or glucose.The aqueous solution is particularly suitable for intravenously, intramuscular, subcutaneous and peritoneal injection.The sterile aqueous media that is adopted all is to obtain for technology well known by persons skilled in the art easily.
The pharmaceutical carrier that is fit to comprises inert solid diluent or weighting agent, aseptic aqueous solution and various organic solvent.The example of solid carrier has lactose, carclazyte, sucrose, cyclodextrin, talcum, gelatin, agar, pectin, gum arabic, Magnesium Stearate, stearic acid or cellulosic lower alkyl ether.The example of liquid vehicle has syrup, peanut oil, sweet oil, phosphatide, lipid acid, fatty acid amine, polyoxyethylene or water.Similarly, carrier or thinner can comprise any lasting releasable material known in the art, and for example Zerol or Stearic diglyceride are independent or mix with a kind of wax.Formula (I) compound of novelty and pharmaceutically acceptable carrier are combined the pharmaceutical composition that constituted then easily with the multiple formulation administration that is suitable for disclosed route of administration.By the known method of pharmaceutical field, preparation can present unit dosage aptly.
The preparation of the present invention that is suitable for oral administration can present discrete unit, for example capsule or tablet, and each unit contains the activeconstituents of predetermined amount, and can comprise suitable vehicle.These preparations can be pulvis or granule, the solution in water-based or non-aqueous liquid or suspension or oil-in-water-type or water-in-oil emulsion.
If use solid carrier to be used for oral administration, prepared product can be by compressing tablet so, to place hard gelatin capsule or it with powder or particle form can be the form of dragee or lozenge.The amount of solid carrier will change on a large scale, but will be that about 25mg is to about 1g usually.
If the use liquid vehicle, prepared product can be the form of syrup, emulsion, Gelseal or sterile injectable liquid so, for example water-based or non-aqueous liquid suspension or solution.
Typical tablet can contain: the sheet heart by conventional pressed disc technique preparation:
Active compound (free cpds or its salt) 5.0mg
Lactose Ph.Eur. 67.8mg
Microcrystalline Cellulose (Avicel) 31.4mg
AmberliteIRP88 * 1.0mg
Magnesium Stearate Ph.Eur. q.s.
Dressing:
The about 9mg of Vltra tears
Mywacett 9-40T *About 0.9mg
*Polacrillin potassium NF, tablet disintegrant, Rohm and Haas
*The acidylate monoglyceride is as film clothing softening agent
If necessary, pharmaceutical composition of the present invention can comprise the combination of formula (I) compound and other pharmacological active substance, for example mentioned above those.
Embodiment
Among the embodiment, the following term plan has following general implication:
DIPEA: diisopropylethylamine
DMSO: dimethyl sulfoxide (DMSO)
THF: tetrahydrofuran (THF)
HPLC (method A)
NMR spectrum writes down on Bruker 300MHz and 400MHz instrument.HPLC-MS carries out on Perkin Elmer instrument (API 100).Used pillar is X-Terra C18,5 μ m, and 50 * 3mm, wash-out is performed such, and under 1.5ml/min, at room temperature, uses the gradient of 5% to 90% acetonitrile/water/0.01% trifluoroacetic acid, in 7.5 minutes.
HPLC (method B)
Anti-phase analysis is to utilize 214 with the following UV detection of 254nm, carry out on 218TP54 4.6mm * 150mm C-18 silica column, under 42 ℃ with the 1ml/min wash-out.With the 0.5% trifluoroacetic acid aqueous solution balance of pillar with 5% acetonitrile, 85% water and 10%, with linear gradient elution, went through 15 minutes from 0.5% trifluoroacetic acid solution of 5% acetonitrile, 85% water and 10% to 0.5% trifluoroacetic acid solution of 90% acetonitrile and 10%.
HPLC (method C)
It is to utilize the Alliance Waters2695 system that Waters 2487 two waveband detectors are housed to carry out that RP analyzes.It is to utilize Symmetry C18 that UV detects, 3.5 μ m, and 3.0mm * 100mm post is collected.With the linear gradient elution of 5-90% acetonitrile, 90-0% water and 5% trifluoroacetic acid (1.0%) aqueous solution, went through flow velocity 1.0mL/min 8 minutes.
Common processes (A)
Common processes (A) can be used to prepare general formula (Ia) compound:
Figure A0380336000621
Wherein-CH (R 20R 21) represent ethyl, sec.-propyl, side chain C 4-6-alkyl, side chain C 4-6-thiazolinyl, side chain C 4-6-alkynyl, C 3-5-cycloalkyl, C 3-7-cycloalkenyl group, C 3-6-cycloalkyl-C 1-3-alkyl or C 3-6-cycloalkenyl group-C 1-3-alkyl, they can be replaced by one or more halogenic substituents alternatively.
Add ketone or aldehyde (22.6mmol), water, acetate (45.0mmol), be NaCNBH then at the solvent that is fit to, mixture among for example THF to mono-substituted piperazine (15.2mmol) 3(18mmol).Mixture is stirred down 5.5 hours (ketone) or at room temperature stirs and spend the night in (aldehyde) at 55 ℃, under reduced pressure concentrate then.Add saturated NaHCO 3The aqueous solution (100ml), the mixture solvent extraction, for example ethyl acetate (3 * 40ml).Combining extraction liquid is used the salt water washing, through dried over mgso, under reduced pressure concentrates.Can following resistates be converted into suitable salt, hydrochloride for example, with a kind of acid, for example 1 molar aqueous hydrochloric acid, ethanol and toluene co-evaporated, resistates passes through recrystallization purifying then.
Common processes (B)
General formula (I) compound can prepare by common processes (B):
Mono-substituted piperazine (2.00mmol), DMSO (1.0ml), the aryl that is fit to or heteroaryl halogenide (2.00mmol) mixture with a kind of alkali, for example DIPEA (0.20ml) was stirred 1 hour down at 100 ℃, stirred 18 hours down at 120 ℃ then.Add entry and salt of wormwood, the mixture solvent extraction, for example ethyl acetate (3 * 20ml).Same common processes (A) is separated and purifying.
The 2-chloroquinoline of available replacement on the non-commercial is as preparation: F.Effenberger as described in the document, W.Hartmann, Chemische Berichte 1969,102,3260-3267.
Common processes (C)
General formula (I) compound can prepare by common processes (C):
Figure A0380336000631
Formula I compound can prepare like this, from the mono-substituted piperazine that is fit to and the aryl bromide of being fit to, in the presence of the catalyzer that is fit to, three (dibenzalacetones), two palladiums for example, in the solvent that is fit to, toluene for example, under the temperature that is fit to, for example between 0 ℃ and 150 ℃.
Embodiment 1
4-(4-cyclopentyl-based piperazine-1-yl) phenol
To 1-(4-hydroxy phenyl) piperazine (2.70g, THF 15.2mmol) (28ml) suspension add cyclopentanone (1.90ml, 22.6mmol), water (0.15ml), (2.70ml is NaCNBH to acetate 45.0mmol), then 3(18ml, 1M THF solution, 18mmol).Mixture was stirred 5.5 hours down at 55 ℃, under reduced pressure concentrate then.Add saturated NaHCO 3The aqueous solution (100ml) and ethyl acetate (40ml) are filtered mixture.The gained solid is suspended in the methyl alcohol (30ml) again, is heated to backflow, at room temperature place and spend the night.Filter, drying under reduced pressure obtains title compound (1.82g, 49%), is solid.
1H?NMR(DMSO-d 6)δ1.34(m，2H)，1.49(m，2H)，1.60(m，2H)，1.79(m，2H)，2.43(m，1H)，2.51(m，4H)，2.92(m，4H)，6.62(d，J＝8Hz，2H)，6.77(d，J＝8Hz，2H)，8.78(s，1H)；HPLC-MS：m/z?247(MH +)；Rf：2.70min.
Embodiment 2
1-cyclopentyl-4-[4-(4-fluorine benzyloxy) phenyl] piperazine
To potassium hydroxide (0.165g, ethanol 2.95mmol) (4ml) suspension add 4-(4-cyclopentyl-based piperazine-1-yl) phenol (0.25g, 1.02mmol).After 10 minutes, (0.18ml, 0.22g 1.51mmol), stir mixture 5 hours down at 70 ℃ to add the 4-fluorobenzyl chloride.Add saturated NaHCO 3The aqueous solution (20ml), mixture ethyl acetate extraction (3 * 20ml).Combining extraction liquid is used the salt water washing, through dried over mgso, concentrates.Recrystallization from methyl alcohol (4ml) obtains 0.125g (35%) title compound.
1H?NMR(DMSO-d 6)δ1.34(m，2H)，1.50(m，2H)，1.62(m，2H)，1.81(m，2H)，2.45(m，1H)，2.51(m，4H)，2.99(m，4H)，5.00(s，2H)，6.87(m，4H)，7.19(t，J＝8Hz，2H)，7.46(m，2H)；HPLC-MS：m/z?355(MH +)；Rf：4.73min.
Embodiment 3
1-(3-chloro-phenyl-)-4-cyclopentyl-based piperazine
From 1-(3-chloro-phenyl-)-piperazine, as this compound of preparation as described in the embodiment 1.
1H?NMR(DMSO-d 6)δ1.34(m，2H)，1.50(m，2H)，1.60(m，2H)，1.80(m，2H)，2.45(m，1H)，2.51(m，4H)，3.14(m，4H)，6.78(d，J＝8Hz，1H)，6.88(m，2H)，7.19(t，J＝8Hz，1H)；HPLC-MS：m/z265(MH +)；Rf：3.88min.
Embodiment 4
1-[4-(4-cyclopentyl-based piperazine-1-yl) phenyl] ethyl ketone
From 1-(4-acetylphenyl)-piperazine, as this compound of preparation as described in the embodiment 1.
1H?NMR(DMSO-d 6)δ1.30-1.88(m，8H)，2.45(s，3H)，2.45(m，1H)，2.51(m，4H)，3.31(m，4H)，6.95(d，J＝8Hz，2H)，7.79(d，J＝8Hz，2H)；HPLC-MS：m/z?273(MH+)；Rf：3.25min.
Embodiment 5
1-(3, the 4-dichlorophenyl)-4-(1-ethyl propyl) piperazine
Begin from 1-(3,4-two chloro-phenyl) piperazine and propione, as this compound of preparation as described in the embodiment 1.
1H?NMR(DMSO-d 6)δ0.88(t，J＝7Hz，6H)，1.28(m，2H)，1.45(m，2H)，2.19(m，1H)，2.56(br?s，4H)，3.12(br?s，4H)，6.91(m，1H)，7.09(br?s，1H)，7.36(d，J＝8Hz，1H)；HPLC-MS：m/z?301(MH+)；Rf：4.25min.
Embodiment 6
4-[4-(1-ethyl propyl) piperazine-1-yl] and phenyl } the phenyl ketone hydrochloride
Figure A0380336000653
With 1-(3-amyl group) piperazine (0.31g, 2.00mmol), (0.40g, 2.00mmol) mixture with DIPEA (0.20ml) stirred 1 hour down at 100 ℃, stirred 18 hours down at 120 ℃ then for DMSO (1.0ml), 4-fluorine benzophenone.Add entry (50ml) and salt of wormwood (2g), mixture ethyl acetate extraction (3 * 20ml).Combining extraction liquid is used the salt water washing, uses dried over mgso, under reduced pressure concentrates.Crude product is dissolved in ethanol (10ml) and the moisture HCl of 1M (4ml), under reduced pressure concentrated solution again.After ethanol and toluene co-evaporated, resistates solidifies, recrystallization from acetonitrile (100ml).Obtain 0.20g (27%) title compound.
1H?NMR(DMSO-d 6)δ0.95(m，6H)，1.62(m，2H)，1.89(m，2H)，3.04-3.27(m，3H)，3.48(m，4H)，4.05(m，2H)，7.08(m，2H)，7.51(m，2H)，7.65(m，5H)，10.75(br?s，1H)；HPLC-MS：m/z337(MH +)；Rf：4.27min.
Embodiment 7
1-(4-benzyl phenyl)-4-(1-ethyl propyl) piperazine hydrochloride
Will { 4-[4-(1-ethyl propyl) piperazine-1-yl] phenyl } phenyl ketone hydrochloride (77mg, 0.21mmol), trifluoroacetic acid (2.0ml) stirred 20 hours down at 60 ℃ with the mixture of triethyl-silicane (0.5ml).Under reduced pressure enriched mixture mixes with water and salt of wormwood.Mixture ethyl acetate extraction (3 * 20ml).Combining extraction liquid is used the salt water washing, uses dried over mgso, under reduced pressure concentrates.Crude product is dissolved in ethanol and the moisture HCl of 1M, under reduced pressure concentrated solution again.After ethanol and toluene co-evaporated, resistates solidifies.Obtain 45mg (61%) title compound.
1H?NMR(DMSO-d 6)δ0.98(t，J＝7Hz，6H)，1.64(m，2H)，1.89(m，2H)，3.04-3.23(m，5H)，3.48(m，2H)，3.72(m，2H)，3.85(s，2H)，6.93(d，J＝8Hz，2H)，7.10-7.30(m，7H)，10.05(brs，1H)；HPLC-MS：m/z?323(MH +)；Rf：4.93min.
Embodiment 8
Cyclopropyl-and 4-[4-(1-ethyl propyl) piperazine-1-yl] phenyl } the ketone hydrochloride
Figure A0380336000671
From 4-fluorophenyl (cyclopropyl) ketone, as this compound of preparation as described in the embodiment 6.
1H?NMR(DMSO-d 6)δ0.98(m，10H)，1.64(m，2H)，1.89(m，2H)，2.82(br?s，1H)，3.04-3.23(m，3H)，3.49(m，4H)，4.04(m，2H)，7.07(d，J＝8Hz，2H)，7.96(d，J＝8Hz，2H)，10.95(brs，1H)；HPLC-MS：m/z301(MH +)；Rf：4.03min.
Embodiment 9
(2-chloro-phenyl-)-and 4-[4-(1-ethyl propyl) piperazine-1-yl] phenyl } the ketone hydrochloride
Figure A0380336000672
From 4-fluorophenyl-(2-chloro-phenyl-) ketone, as this compound of preparation as described in the embodiment 6.
1H?NMR(DMSO-d 6)δ0.98(t，J＝7Hz，6H)，1.64(m，2H)，1.88(m，2H)，3.08-3.23(m，3H)，3.50(m，4H)，4.06(m，2H)，7.08(d，J＝8Hz，2H)，7.31(m，1H)，7.48(m，1H)，7.50-7.61(m，4H)，10.85(br?s，1H)；HPLC-MS：m/z?371(MH +)；Rf：4.43min.
Embodiment 10
4-[4-(1-ethyl propyl) piperazine-1-yl] phenyl }-(4-fluorophenyl) ketone hydrochloride
From 4,4 '-difluoro benzophenone begins, as this compound of preparation as described in the embodiment 6.
1H?NMR(DMSO-d 6)δ0.98(t，J＝7Hz，6H)，1.66(m，2H)，1.89(m，2H)，3.08-3.25(m，3H)，3.41-3.53(m，4H)，4.05(m，2H)，7.09(d，J＝8Hz，2H)，7.38(m，2H)，7.69(d，J＝8Hz，2H)，7.76(m，2H)，10.80(br?s，1H)；HPLC-MS：m/z?355(MH +)；Rf：4.37min.
Embodiment 11
1-cyclopentyl-4-(6-5-flumethiazine-2-yl) piperazine
From 1-(6-trifluoromethyl-pyridine-2-yl) piperazine, as this compound of preparation as described in the embodiment 1.
1H?NMR(DMSO-d 6)δ1.34(m，2H)，1.50(m，2H)，1.60(m，2H)，1.80(m，2H)，2.45-2.51(m，5H)，3.52(m，4H)，7.02(d，J＝8Hz，1H)，7.11(d，J＝8Hz，1H)，7.71(t，J＝8Hz，1H)；HPLC-MS：m/z?300(MH +)；Rf：4.10min.
Embodiment 12
1-cyclopentyl-4-(5-5-flumethiazine-2-yl) piperazine
Figure A0380336000683
From 1-(5-trifluoromethyl-pyridine-2-yl) piperazine, as this compound of preparation as described in the embodiment 1.
1H?NMR(DMSO-d 6)δ1.36(m，2H)，1.50(m，2H)，1.60(m，2H)，1.80(m，2H)，2.45-2.52(m，5H)，3.58(m，4H)，6.92(d，J＝8Hz，1H)，7.78(br?d，J＝8Hz，1H)，8.39(s，1H)；HPLC-MS：m/z?300(MH +)；Rf：3.87min.
Embodiment 13
1-cyclopentyl-4-(3-5-flumethiazine-2-yl) piperazine
From 1-(3-trifluoromethyl-pyridine-2-yl) piperazine, as this compound of preparation as described in the embodiment 1.
1H?NMR(DMSO-d 6)δ1.29-1.65(m，6H)，1.80(m，2H)，2.45(m，1H)，2.52(m，4H)，3.18(m，4H)，7.16(m，1H)，8.02(m，1H)，8.49(m，1H)；HPLC-MS：m/z?300(MH +)；Rf：3.70min.
Embodiment 14
2-[4-(1-ethyl propyl) piperazine-1-yl] quinoline hydrochloride
From the 2-chloroquinoline, as this compound of preparation as described in the embodiment 6.
1H?NMR(DMSO-d6)δ0.99(t，J＝7Hz，6H)，1.65(m，2H)，1.94(m，2H)，3.12(br?s，1H)，3.33(m，2H)，3.57(m，2H)，3.93(m，2H)，?4.83(m，2H)，7.44-7.58(m，2H)，7.76(m，1H)，7.92(m，1H)，8.25(br?s，1H)，8.42(m，1H)，11.20(br?s，H)；HPLC-MS：m/z?284(MH +)；Rf：3.03min.
Embodiment 15
7-chloro-4-[4-(1-ethyl propyl) piperazine-1-yl] quinoline hydrochloride
Figure A0380336000701
From 4, the 7-dichloroquinoline begins, as this compound of preparation as described in the embodiment 6.
1H?NMR(DMSO-d 6)δ1.00(t，J＝7Hz，6H)，1.67(m，2H)，1.95(m，2H)，3.15(br?s，1H)，3.30-3.70(m，4H)，4.05(m，2H)，4.20(m，2H)，7.32(m，1H)，7.73(m，1H)，8.28(m，2H)，8.83(m，1H)，11.35(br?s，H)；HPLC-MS：m/z?318(MH +)；Rf：3.13min.
Embodiment 16
[4-(4-cyclopentyl-based piperazine-1-yl) phenyl]-(3, the 4-Dimethoxyphenyl) ketone hydrochloride
From 4 '-fluoro-3,4-dimethoxy benzophenone begins, as this compound of preparation as described in the embodiment 6.
1H?NMR(DMSO-d 6)δ1.55(m，2H)，1.65-1.90(m，4H)，2.02(m，2H)，3.05-3.40(m，4H)，3.55(m，3H)，3.81(s，3H)，3.88(s，3H)，4.08(m，2H)，7.10(m，3H)，7.29(m，2H)，7.69(d，J＝8Hz，2H)，10.78(br?s，1H)；HPLC-MS：m/z?395(MH +)；Rf：3.03min.
Embodiment 17
[4-(4-cyclopentyl-based piperazine-1-yl)-3,5-difluorophenyl] phenyl ketone hydrochloride
From 3,4,5-trifluoro benzophenone begins, as this compound of preparation as described in the embodiment 6.
1H?NMR(DMSO-d 6)δ1.55(m，2H)，1.65-1.90(m，4H)，2.02(m，2H)，3.15(m，2H)，3.50-3.71(m，7H)，7.42(m，2H)，7.58(m，2H)，7.68-7.78(m，3H)，10.90(br?s，1H)；HPLC-MS：m/z371(MH +)；Rf：2.77min.
Embodiment 18
2-(4-cyclopentyl-based piperazine-1-yl) quinoxaline hydrochloride
From the 2-chloro-quinoxaline, use propionitrile as solvent, as embodiment 6 these compounds of preparation.
1H?NMR(DMSO-d 6)δ1.55(m，2H)，1.64-1.90(m，4H)，2.02(m，2H)，3.15(m，2H)，3.42-3.65(m，5H)，4.71(m，2H)，7.49(m，1H)，7.67(m，2H)，7.88(br?d，J＝8Hz，1H)，8.91(s，1H)，10.92(br?s，1H)；HPLC-MS：m/z?283(MH +)；Rf：1.70min.
Embodiment 19
2-(4-cyclopropyl methylpiperazine-1-yl) quinoxaline hydrochloride
1H?NMR(DMSO-d 6)δ0.41(m，2H)，0.66(m，2H)，1.18(m，1H)，3.02(m，2H)，3.13(m，2H)，3.52-3.69(m，4H)，4.71(m，2H)，7.48(m，1H)，7.66(m，2H)，7.88(d，J＝8Hz，1H)，8.90(s，1H)，11.17(br?s，1H)；HPLC-MS：m/z?269(MH +)；Rf：1.73min.
Embodiment 20
[6-(4-cyclopentyl-based piperazine-1-yl) pyridin-3-yl] piperidines-1-base ketone hydrochloride
Figure A0380336000721
1H?NMR(DMSO-d 6)δ1.45-2.08(m，14H)，3.06(m，2H)，3.38-3.61(m，9H)，4.44(m，2H)，7.02(d，J＝8Hz，1H)，7.70(dd，J＝8Hz，1Hz，1H)，8.19(d，J＝1Hz，1H)；HPLC-MS：m/z(MH +).
Use 1-(6-chloronicotinoyl base) piperidines (Thunus, Ann.Pharm.Fr.1977,35,197), with embodiment 6 preparation these compounds (common processes B).
Embodiment 21
2-(4-cyclopentyl-based piperazine-1-yl) quinoline hydrochloride
Figure A0380336000722
1H?NMR(DMSO-d 6)δ1.62(m，2H)，1.82(m，2H)，1.96(m，2H)，2.09(m，2H)，3.25(m，2H)，3.55-3.70(m，5H)，4.83(m，2H)，7.46-7.60(m，2H)，7.80(m，1H)，7.94(m，1H)，8.13(m，1H)，8.42(m，1H)，11.52(br?s，1H)；HPLC-MS：m/z282(MH +)；Rf：0.34min.
From the 2-chloroquinoline, with embodiment 6 these compounds of preparation.
Embodiment 22
2-(4-cyclopentyl-based piperazine-1-yl)-7-methoxyl group-3-(4-p-methoxy-phenyl) quinoline hydrochloride
1H?NMR(DMSO-d 6)δ1.53(m，2H)，1.63-1.86(m，4H)，1.98(m，2H)，3.05(m，2H)，3.33-3.52(m，5H)，3.75(m，2H)，3.82(s，3H)，3.91(s，3H)，7.08(d，J＝8Hz，2H)，7.13(dd，J＝8Hz，1Hz，1H)，7.49(brs，1H)，7.61(d，J＝8Hz，2H)，7.83(d，J＝8Hz，1H)，8.15(s，1H)，11.29(brs，1H)；HPLC-MS：m/z?418(MH +)；Rf：3.40min.
Embodiment 23
6-[4-(1-cyclopropyl-1-methylethyl) piperazine-1-yl] and pyridin-3-yl } the phenyl ketone hydrochloride
1H?NMR(DMSO-d 6)δ0.48-0.62(m，4H)，1.22-1.39(m，7H)，3.14(m，2H)，3.69(m，4H)，4.64(m，2H)，7.08(d，J＝8Hz，1H)，7.55(m，2H)，7.61-7.72(m，3H)，8.00(dd，J＝8Hz，1Hz，1H)，8.52(d，J＝1Hz，1H)，11.27(br?s，1H)；HPLC-MS：m/z350(MH +)；Rf：3.03min.
From 2-chloro-5-benzoyl pyridine (T.D.Penning et al., J.Med.Chem.2000,43,721-735) beginning is with these compounds of embodiment 6 preparation.
Embodiment 24
4-[4-(1-cyclopropyl-1-methylethyl) piperazine-1-yl] and-3, the 5-difluorophenyl } the phenyl ketone hydrochloride
1H?NMR(DMSO-d 6)δ0.48-0.63(m，4H)，1.23-1.40(m，7H)，3.18(m，2H)，3.56(m，2H)，3.69(m，2H)，3.84(m，2H)，7.42(m，2H)，7.58(m，2H)，7.66-7.76(m，3H)，10.90(br?s，1H)；HPLC-MS：m/z?385(MH +)；Rf：3.73min.
Embodiment 25
4-[4-(1-cyclopropyl-1-methylethyl) piperazine-1-yl] and-3, the 5-difluorophenyl } the phenyl methanol hydrochloride
Figure A0380336000741
1H?NMR(DMSO-d 6)δ0.47-0.61(m，4H)，1.23-1.34(m，7H)，3.12(m，2H)，3.29(m，2H)，3.65(m，4H)，5.66(m，1H)，6.08(m，1H)，7.06(m，2H)，7.19-7.40(m，5H)，10.40(br?s，1H)；HPLC-MS：m/z?387(MH +)；Rf：3.40min.
With sodium borohydride reduction embodiment 24, prepare this compound.
Embodiment 26
[4-(4-cyclopropyl methylpiperazine-1-yl)-3,5-difluorophenyl]-(4-fluorophenyl) ketone hydrochloride
Figure A0380336000742
1H?NMR(DMSO-d 6)δ0.40(m，2H)，0.66(m，2H)，1.13(m，1H)，3.02-3.23(m，5H)，3.52-3.68(m，5H)，7.40(m，4H)，7.82(m，2H)，10.55(br?s，1H)；HPLC-MS：m/z?375(MH +)；Rf：2.78min.
Use 3,4,5,4 '-the tetrafluoro benzophenone, with embodiment 6 these compounds of preparation.Raw material is by fluorobenzene and 3,4, the Friedel Crafts acylation preparation of 5-trifluorobenzoyl chloride.
Embodiment 27
4-[4-(1-ethyl propyl) piperazine-1-yl] and-3, the 5-difluorophenyl }-(4-fluorophenyl) ketone hydrochloride
Figure A0380336000751
1H?NMR(DMSO-d 6)δ0.97(t，J＝7Hz，6H)，1.68(m，2H)，1.88(m，2H)，3.06-3.26(m，3H)，3.52(m，4H)，3.75(m，2H)，7.41(m，4H)，7.82(m，2H)，10.31(br?s，1H)；HPLC-MS：m/z?391(MH +)；Rf：3.00min.
Embodiment 28
2-[4-(1-ethyl propyl) piperazine-1-yl]-6,7-dimethoxy-quinoline hydrochloride
1H?NMR(DMSO-d 6)δ0.99(t，J＝7Hz，6H)，1.66(m，2H)，1.91(m，2H)，3.11(m，1H)，3.29(m，2H)，3.56(m，4H)，3.88(s，3H)，3.92(s，3H)，4.72(m，2H)，7.31-7.43(m，2H)，7.82(br?s，1H)，8.30(br?s，1H)，10.95(br?s，1H)；HPLC-MS：m/z?344(MH +)；Rf：2.00min.
From 2-chloro-6,7-dimethoxy-quinoline (Pettit, Can.J.Chem.1964,42,1764) beginning is with embodiment 6 these compounds of preparation.
Embodiment 29
2-[4-(1-ethyl propyl) piperazine-1-yl]-4-Trifluoromethylquinocarboxylic hydrochloride
Figure A0380336000753
1H?NMR(DMSO-d 6)δ0.99(t，J＝7Hz，6H)，1.65(m，2H)，1.91(m，2H)，3.08(m，1H)，3.19(m，2H)，3.52(m，2H)，3.75(m，2H)，4.77(m，2H)，7.48(t，J＝7Hz，1H)，7.72(m，2H)，7.88(m，2H)，11.19(br?s，1H)；HPLC-MS：m/z?352(MH +)；Rf：3.70min.
Prepare this compound from 2-chloro-4-Trifluoromethylquinocarboxylic.Raw material is as preparation as described in the document: R.D.Westland et al.J.Med.Chem.1973,16,319-327.
Embodiment 30
2-(4-cyclopropyl methylpiperazine-1-yl)-6-methoxyl group-4-Trifluoromethylquinocarboxylic hydrochloride
1H?NMR(DMSO-d 6)δ0.40(m，2H)，0.67(m，2H)，1.14(m，1H)，3.01-3.16(m，4H)，3.46(m，2H)，3.64(m，2H)，3.87(s，3H)，4.66(m，2H)，7.16(br?s，1H)，7.43(dd，J＝7Hz，1Hz，1H)，7.68(s，1H)，7.73(d，J＝7Hz，1H)，10.70(br?s，1H)；HPLC-MS：m/z366(MH +)；Rf：3.63min.
Embodiment 31
[4-(4-cyclopropyl methylpiperazine-1-yl)-3,5-difluorophenyl] phenyl ketone hydrochloride
1H?NMR(DMSO-d 6)δ0.40(m，2H)，0.67(m，2H)，1.14(m，1H)，3.03-3.20(m，4H)，3.60(m，6H)，7.40(m，2H)，7.58(m，2H)，7.70(m，3H)，10.60(br?s，1H)；HPLC-MS：m/z?357(MH +)；Rf：3.53min.
Embodiment 32
[4-(4-cyclopropyl methylpiperazine-1-yl)-3,5-difluorophenyl]-(3-fluoro-4-p-methoxy-phenyl)-ketone hydrochloride
Figure A0380336000771
1H?NMR(DMSO-d 6)δ0.41(m，2H)，0.65(m，2H)，1.15(m，1H)，3.06(m，2H)，3.18(m，2H)，3.50-3.70(m，6H)，3.95(s，3H)，7.33(t，J＝8Hz，1H)，7.41(m，2H)，7.60(m，2H)，10.79(brs，1H)；HPLC-MS：m/z?405(MH +)；Rf：3.67min.
Embodiment 33
6-[4-(1-ethyl propyl) piperazine-1-yl] and pyridin-3-yl } the phenyl ketone hydrochloride
1H?NMR(DMSO-d 6)δ0.97(t，J＝7Hz，6H)，1.65(m，2H)，1.90(m，2H)，3.02-3.22(m，3H)，3.49-3.69(m，4H)，4.60(m，2H)，7.08(d，J＝8Hz，1H)，7.56(m，2H)，7.68(m，3H)，7.99(dd，J＝8Hz，1Hz，1H)，8.50(d，J＝1Hz，1H)，10.90(brs，1H)；HPLC-MS：m/z338(MH +)；Rf：3.00min.
Embodiment 34
2-[4-(1-ethyl propyl) piperazine-1-yl] and pyridin-4-yl } the phenyl ketone hydrochloride
Figure A0380336000773
1H?NMR(DMSO-d 6)δ0.97(t，J＝7Hz，6H)，1.63(m，2H)，1.85(m，2H)，3.12(m，3H)，3.47(m，4H)，4.43(m，2H)，6.91(d，J＝6Hz，1H)，7.14(s，1H)，7.58(t，J＝8Hz，2H)，7.70-7.84(m，3H)，8.33(d，J＝6Hz，1H)，10.43(br?s，1H)；HPLC-MS：m/z?338(MH +)；Rf：2.97min.
Prepare this compound from 2-chloro-4-benzoyl pyridine, raw material is by the preparation of the Friedel-Crafts acylation of benzene and 2-chloro-4-chloro carbonyl pyridine.
Embodiment 35
4-[4-(1-ethyl propyl) piperazine-1-yl] phenyl }-(4-hydroxy phenyl) ketone hydrochloride
1H?NMR(DMSO-d 6)δ0.97(t，J＝7Hz，6H)，1.65(m，2H)，1.92(m，2H)，3.05-3.25(m，3H)，3.35-3.55(m，4H)，4.02(m，2H)，6.89(d，J＝8Hz，2H)，7.08(d，J＝8Hz，2H)，7.59(d，J＝8Hz，2H)，7.63(d，J＝8Hz，2H)，10.36(s，1H)，10.60(br?s，1H)；HPLC-MS：m/z?353(MH +)；Rf：2.13min.
Embodiment 36
6-[4-(1-ethyl propyl) piperazine-1-yl] and pyridin-3-yl } piperidines-1-base-ketone hydrochloride
1H?NMR(DMSO-d 6)δ0.97(t，J＝7Hz，6H)，1.50(m，4H)，1.63(m，4H)，1.89(m，2H)，3.05-3.20(m，3H)，3.50(m，8H)，4.46(m，2H)，7.04(m，1H)，7.70(m，1H)，8.18(br?s，1H)，10.90(br?s，1H)；HPLC-MS：m/z?345(MH +)；Rf：2.27min.
Embodiment 37
N-benzyl-6-[4-(1-ethyl propyl) piperazine-1-yl]-N-methylnicotinamide hydrochloride
Figure A0380336000791
1H?NMR(DMSO-d 6)δ0.97(t，J＝7Hz，6H)，1.63(m，2H)，1.88(m，2H)，2.89(s，3H)，3.09(m，3H)，3.50(m，4H)，4.45(m，2H)，4.62(br?s，2H)，7.02(d，J＝8Hz，1H)，7.25-7.41(m，5H)，7.78(m，1H)，8.28(br?s，1H)，10.78(br?s，1H)；HPLC-MS：m/z381(MH +)；Rf：3.10min.
Embodiment 38
2-[4-(1-ethyl propyl) piperazine-1-yl]-6-methoxy quinoline hydrochloride
1H?NMR(DMSO-d 6)δ0.98(t，J＝7Hz，6H)，1.66(m，2H)，1.92(m，2H)，3.11(m，1H)，3.31(m，2H)，3.57(m，2H)，3.82(m，2H)，3.88(s，3H)，4.74(m，2H)，7.41(br?s，2H)，7.53(m，1H)，8.12(br?s，1H)，8.34(br?s，1H)，10.95(br?s，1H)；HPLC-MS：m/z314(MH +)；Rf：2.17min.
Embodiment 39
6-[4-(1-ethyl propyl) piperazine-1-yl]-N-methyl-N-phenyl niacinamide hydrochloride
1H?NMR(DMSO-d 6)δ0.95(t，J＝7Hz，6H)，1.62(m，2H)，1.83(m，2H)，3.05(m，3H)，3.34(s，3H)，3.43(m，4H)，4.35(m，2H)，6.76(d，J＝8Hz，1H)，7.21(m，3H)，7.31(m，2H)，7.42(dd，J＝8Hz，1Hz，1H)，8.01(d，J＝1Hz，1H)，10.54(br?s，1H)；HPLC-MS：m/z?367(MH +)；Rf：2.90min.
Embodiment 40
6-[4-(1-ethyl propyl) piperazine-1-yl] pyridin-3-yl }-(4-fluorophenyl) ketone hydrochloride
Figure A0380336000801
1H?NMR(DMSO-d 6)δ0.95(t，J＝7Hz，6H)，1.62(m，2H)，1.83(m，2H)，3.10(m，3H)，3.45-3.65(m，4H)，4.55(m，2H)，7.05(d，J＝8Hz，1H)，7.38(d，J＝8Hz，2H)，7.78(dd，J＝8Hz，4Hz，2H)，7.96(dd，J＝8Hz，1Hz，1H)，8.48(d，J＝1Hz，1H)，10.85(br?s，1H)；HPLC-MS：m/z?356(MH +)；Rf：2.40min.
Embodiment 41
2-[4-(1-ethyl propyl) piperazine-1-yl]-4-toluquinoline hydrochloride
1H?NMR(DMSO-d 6)δ0.98(t，J＝7Hz，6H)，1.64(m，2H)，1.92(m，2H)，2.69(s，3H)，3.12(m，1H)，3.32(m，2H)，3.57(m，2H)，3.94(m，2H)，4.86(m，2H)，7.53(br?s，2H)，7.80(m，1H)，8.01(m，1H)，8.32(br?s，1H)，11.20(br?s，1H)；HPLC-MS：m/z?298(MH +)；Rf：1.26min.
Embodiment 42
2-[4-(1-ethyl propyl) piperazine-1-yl]-5,6,7,8-tetrahydroquinoline hydrochloride
1H?NMR(DMSO-d 6)δ0.98(t，J＝7Hz，6H)，1.50-2.03(m，8H)，2.63(m，2H)，2.90(m，2H)，3.00-3.33(m，3H)，3.50(m，2H)，3.75(m，2H)，4.48(m，2H)，7.13(br?s，1H)，7.75(br?s，1H)，11.10(br?s，1H)；HPLC-MS：m/z?288(MH +)；Rf：1.83min.
From 2-chloro-5,6,7, and the 8-tetrahydroquinoline (S.C.Zimmerman, Z.Zeng, J.Org.Chem.1990,55,4789-5791) prepare this compound.
Embodiment 43
2-(4-cyclopropyl methylpiperazine-1-yl)-6-methoxy quinoline hydrochloride
1H?NMR(DMSO-d 6)δ0.41(m，2H)，0.66(m，2H)，1.18(m，1H)，3.02(m，2H)，3.13(m，2H)，3.52-3.69(m，4H)，3.85(s，3H)，4.71(m，2H)，7.41(br?s，2H)，7.53(m，1H)，8.12(br?s，1H)，8.34(br?s，1H)，11.38(br?s，1H)；HPLC-MS：m/z?298(MH +)；Rf：1.87min.
Embodiment 44
2-(4-sec.-propyl piperazine-1-yl)-6-methoxy quinoline hydrochloride
Figure A0380336000813
1H?NMR(DMSO-d 6)δ1.32(d，J＝7Hz，6H)，3.28(m，2H)，3.53(m，3H)，3.80(m，1H)，3.85(s，3H)，4.85(m，2H)，7.43(br?s，2H)，7.59(d，J＝8Hz，1H)，8.27(br?s，1H)，8.34(br?s，1H)，8.40(d，J＝8Hz，1H)，11.60(br?s，1H)；HPLC-MS：m/z?286(MH +)；Rf：1.77min.
Embodiment 45
2-[4-(1-ethyl propyl) piperazine-1-yl]-6-fluoro-4-toluquinoline hydrochloride
1H?NMR(DMSO-d 6)δ0.98(t，J＝7Hz，6H)，1.64(m，2H)，1.92(m，2H)，2.67(s，3H)，3.12(m，1H)，3.32(m，2H)，3.57-4.00(m，4H)，4.85(m，2H)，7.57(br?s，2H)，7.68(m，1H)，7.82(m，1H)，8.33(br?s，1H)，11.10(br?s，1H)；HPLC-MS：m/z?316(MH +)；Rf：1.92min.
Prepare this compound from 2-chloro-6-fluoro-4-toluquinoline, raw material is preparation like this: the acetoacetylization of 4-fluoroaniline, processing is converted into chloroquinoline with the gained quinolone succeeded by acid mediated ring closure with by phosphoryl chloride.
Embodiment 46
2-(4-sec.-propyl piperazine-1-yl) quinoline hydrochloride
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.19(m，2H)，3.52(m，3H)，3.72(m，2H)，4.79(m，2H)，7.45(m，2H)，7.68(m，1H)，7.86(m，1H)，8.03(m，1H)，8.31(m，1H)，11.45(br?s，1H)；HPLC-MS：m/z?256(MH +)；Rf：1.47min.
Embodiment 47
2-(4-cyclopropyl piperazine-1-yl)-6-methoxy quinoline hydrochloride
Figure A0380336000823
1H?NMR(DMSO-d 6)δ0.81(m，2H)，1.20(br?s，2H)，2.86(br?s，1H)，3.25-3.75(m，4H)，3.85(s，3H)，4.09(m，2H)，4.73(m，2H)，7.41(m，2H)，7.55(m，1H)，8.14(m，1H)，8.37(m，1H)，11.51(br?s，1H)；HPLC-MS：m/z284(MH +)；Rf：1.80min.
Embodiment 48
2-(4-sec.-propyl-piperazine-1-yl)-6-trifluoromethoxy quinoline hydrochloride
Figure A0380336000831
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.17(m，2H)，3.52(m，3H)，3.68(m，2H)，4.79(m，2H)，7.56(d，J＝8Hz，1H)，7.68(br?d，J＝7Hz，1H)，7.91(br?s，1H)，8.04(br?s，1H)，8.35(br?d，J＝7Hz，1H)，11.28(br?s，1H)；HPLC-MS：m/z?340(MH +)；Rf：3.04min.
Embodiment 49
6-chloro-2-(4-cyclopropyl-piperazine-1-yl)-quinoline hydrochloride
Figure A0380336000832
1H?NMR(DMSO-d 6)δ0.81(m，2H)，1.14(br?s，2H)，2.88(br?s，1H)，3.25-3.70(m，6H)，4.67(m，2H)，7.44(d，J＝8Hz，1H)，7.61(d，J＝8Hz，1H)，7.72(m，1H)，7.91(br?s，1H)，8.18(brd，J＝8Hz，1H)，10.75(br?s，1H)；HPLC-MS：m/z?288(MH +)；Rf：1.77min.
Embodiment 50
2-(4-cyclopropyl-piperazine-1-yl)-6-trifluoromethoxy quinoline hydrochloride
1H?NMR(DMSO-d 6)δ0.81(m，2H)，1.15(br?s，2H)，2.88(br?s，1H)，3.20-3.70(m，6H)，4.68(m，2H)，7.49(d，J＝8Hz，1H)，7.59(br?d，J＝8Hz，1H)，7.82(m，2H)，8.27(d，J＝8Hz，1H)，10.89(br?s，1H)；HPLC-MS：m/z?338(MH +)；Rf：2.24min.
Embodiment 51
2-(4-sec.-propyl-piperazine-1-yl)-8-Trifluoromethylquinocarboxylic hydrochloride
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.10(m，2H)，3.51(m，5H)，4.72(m，2H)，7.38(t，J＝8Hz，1H)，7.46(d，J＝8Hz，1H)，7.95(br?d，J＝7Hz，1H)，8.05(br?d，J＝7Hz，1H)，8.26(d，J＝8Hz，1H)，10.66(br?s，1H)；HPLC-MS：m/z?324(MH +)；Rf：3.08min.
Embodiment 52
2-(4-sec.-propyl-piperazine-1-yl)-6-Trifluoromethylquinocarboxylic hydrochloride
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.12(m，2H)，3.50-3.68(m，5H)，4.78(m，2H)，7.52(d，J＝7Hz，1H)，7.88(m，2H)，8.26(br?s，1H)，8.36(d，J＝7Hz，1H)，10.95(br?s，1H)；HPLC-MS：m/z?324(MH +)；Rf：2.11min.
Embodiment 53
2-(4-sec.-propyl-piperazine-1-yl)-6-propyl group quinoline hydrochloride
Figure A0380336000844
1H?NMR(DMSO-d 6)δ0.91(t，J＝7Hz，3H)，1.31(d，J＝7Hz，6H)，1.66(sext，J＝7Hz，2H)，2.70(t，J＝7Hz，2H)，3.23(m，2H)，3.48-3.90(m，5H)，4.81(m，2H)，7.52(m，1H)，7.63(m，1H)，7.70(br?s，1H)，8.09(br?s，1H)，8.34(br?s，1H)，11.35(br?s，1H)；HPLC-MS：m/z?298(MH +)；Rf：1.97min.
Embodiment 54
6,8-two fluoro-2-(4-sec.-propyl piperazine-1-yl) quinoline hydrochloride
Figure A0380336000851
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.09(m，2H)，3.51(m，5H)，4.66(m，2H)，7.45-7.58(m，3H)，8.18(d，J＝7Hz，1H)，10.92(br?s，1H).
Embodiment 55
8-fluoro-2-(4-sec.-propyl piperazine-1-yl) quinoline hydrochloride
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.09(m，2H)，3.52(m，5H)，4.70(m，2H)，7.24(m，1H)，7.40(m，2H)，7.59(d，J＝7Hz，1H)，8.20(d，J＝7Hz，1H)，10.84(br?s，1H).
Embodiment 56
2-(4-cyclopropyl piperazine-1-yl)-6-Trifluoromethylquinocarboxylic hydrochloride
Figure A0380336000853
1H?NMR(DMSO-d 6)δ0.81(m，2H)，1.19(br?s，2H)，2.88(br?s，1H)，3.20-3.70(m，6H)，4.73(m，2H)，7.52(d，J＝8Hz，1H)，7.88(m，2H)，8.26(br?s，1H)，8.33(d，J＝8Hz，1H)，11.12(brs，1H)；HPLC-MS：m/z?322(MH +)；Rf：2.41min.
Embodiment 57
2-(4-cyclopropyl piperazine-1-yl)-6-propyl group quinoline hydrochloride
Figure A0380336000861
1H?NMR(DMSO-d 6)δ0.82(m，2H)，0.91(t，J＝7Hz，3H)，1.18(br?s，2H)，1.66(sext，J＝7Hz，2H)，2.69(t，J＝7Hz，2H)，2.85(br?s，1H)，3.30-3.75(m，6H)，4.72(m，2H)，7.51(m，1H)，7.62(m，1H)，7.69(br?s，1H)，7.97(br?s，1H)，8.33(br?s，1H)，11.20(br?s，1H)；HPLC-MS：m/z296(MH +)；Rf：1.97min.
Embodiment 58
2-(4-ethyl piperazidine-1-yl) quinoline hydrochloride
Figure A0380336000862
Also can be with reference to S.Cacchi et al., SynLett 1997,1400-1402.
1H?NMR(DMSO-d 6)δ1.30(t，J＝7Hz，3H)，3.15(m，4H)，3.55-3.85(m，4H)，4.81(m，2H)，7.47(m，1H)，7.53(m，1H)，7.74(m，1H)，7.89(d，J＝8Hz，1H)，8.13(br?s，1H)，8.40(br?s，1H)，11.34(brs，1H)；HPLC-MS：m/z?242(MH +)；Rf：1.04min.
Embodiment 59 (common processes (B))
3-(4-sec.-propyl-piperazine-1-yl)-6-phenyl-pyridazine, hydrochloride
From 1-sec.-propyl piperazine with as J.Heterocycl.Chem., the 3-chloro-6-phenyl pyridazine of 15,881 (1978) described preparations begins, and (B) prepares this compound according to common processes.
1H?NMR(D 2O)：δ1.46(d，6H)；3.28(m，2H)；3.48(m，2H)；3.64-3.84(m，3H)；4.57(m，2H)；7.63-7.72(m，4H)；7.90(m，2H)；8.12(d，1H)；HPLC-MS：m/z＝283.2(M+1)；R t＝1.52min.
Embodiment 60 (common processes (B))
3-(4-cyclopentyl-piperazine-1-yl)-6-(4-methylsulfonyl-phenyl)-pyridazine
From the 1-cyclopentyl-based piperazine with as J.Heterocycl.Chem., 3-chloro-6-(4-methylsulfonyl-phenyl)-pyridazine of 15,881 (1978) described preparations begins, and (B) prepares this compound according to common processes.
1H?NMR(CDCl 3)：δ1.38-1.80(m，6H)，1.92(m，2H)；2.56(quint，1H)；2.66(dd，4H)；3.10(s，3H)；3.97(dd，4H)；6.99(d，1H)；7.69(d，1H)；8.03(d，2H)；8.20(d，2H)；HPLC-MS：m/z＝387.0(M+1)；R t＝2.20min.
Embodiment 61 (common processes (B))
3-(4-cyclopropyl methyl-piperazine-1-yl)-6-(4-methylsulfonyl-phenyl)-pyridazine
Figure A0380336000872
From the 1-cyclopentyl-based piperazine with as J.Heterocycl.Chem., 3-chloro-6-(4-methylsulfonyl-phenyl)-pyridazine of 15,881 (1978) described preparations begins, and (B) prepares this compound according to common processes.
1H?NMR(CDCl 3)：δ0.15(q，2H)；0.57(m，2H)；0.92(m，1H)；2.34(d，2H)；2.69(dd，4H)；3.10(s，3H)；3.80(dd，4H)；7.01(d，1H)；7.70(d，1H)；8.03(d，2H)；8.21(d，2H)；HPLC-MS：m/z＝373.4(M+1)；R t＝2.04min.
Embodiment 62 (common processes (B))
3-(4-sec.-propyl-piperazine-1-yl)-6-(4-methylsulfonyl-phenyl)-pyridazine
From 1-sec.-propyl piperazine with as J.Heterocycl.Chem., 3-chloro-6-(4-methylsulfonyl-phenyl)-pyridazine of 15,881 (1978) described preparations begins, and (B) prepares this compound according to common processes.
1H?NMR(DMSO-d 6)：δ1.01(d，6H)；2.57(m，4H)；2.71(m，1H)；3.26(s，3H)；3.67(m，4H)；7.39(d，1H)；8.02(d，2H)；8.06(d，1H)；8.30(d，2H)；HPLC-MS：m/z＝360.8(M+1)；R t＝1.43min.
Embodiment 63 (common processes (B))
3-(4-chloro-phenyl)-6-(4-sec.-propyl-piperazine-1-yl)-4-methyl-pyridazine, dihydrochloride
From 1-sec.-propyl piperazine with as J.Heterocycl.Chem., the 6-chloro-3-of 15,881 (1978) described preparations (4-chloro-phenyl)-4-methyl-pyridazine begins, and (B) prepares this compound according to common processes.
1H?NMR(D 2O)：δ1.08(d，6H)；2.10(s，1H)；3.01(m，2H)；3.23(m，2H)；3.28-3.44(m，3H)；4.31(broad?d，2H)；7.27(d，2H)；7.34(d，2H)；7.58(s，1H)；HPLC-MS：m/z＝331.1(M+1)；R t＝3.1min.
C18H23N4Cl，2HCl
Calculated value C53.54 H6.24 N13.88
Measured value C53.34 H6.31 N13.70.
Embodiment 64 (common processes (B))
3-(4-chloro-phenyl)-6-(4-cyclopentyl-piperazine-1-yl)-4-methyl-pyridazine, hydrochloride
From the 1-cyclopentyl-based piperazine with as J.Heterocycl.Chem., the 6-chloro-3-of 15,881 (1978) described preparations (4-chloro-phenyl)-4-methyl-pyridazine begins, and (B) prepares this compound according to common processes.
1H?NMR(D 2O)：δ1.29-1.60(m，6H)；1.91(m，2H)；2.12(s，3H)；3.00(m，2H)；3.24(m，2H)；3.36(m，1H)；3.51(broad?d，2H)；4.29(broad?d，2H)；7.29(d，2H)；7.36(d，2H)；7.60(s，1H)；HPLC-MS：m/z＝357.1(M+1)；R t＝3.25min.
C20H25N4Cl，2HCl
Calculated value C55.89 H6.33 N13.04
Measured value C55.83 H6.47 N12.93.
Embodiment 65 (common processes (B))
3-(4-chloro-phenyl-)-6-(4-cyclopentyl-based piperazine-1-yl)-pyridazine
Figure A0380336000892
From the 1-cyclopentyl-based piperazine with as J.Heterocycl.Chem., the 3-chloro-6-of 15,881 (1978) described preparations (4-chloro-phenyl)-pyridazine begins, as this compound of preparation as described in the embodiment 6.Obtain the free alkali of title compound.
1H?NMR(CDCl 3)：δ1.39-1.81(m，6H)，1.91(m，2H)，2.56(q，1H)，2.66(dd，4H)，3.74(dd，4H)，6.96(d，J＝9.5Hz，1H)，7.43(d，J＝8.7Hz，2H)，7.61(d，J＝9.5Hz，1H)，7.93(d，J＝8.7Hz，2H)；HPLC-MS(Method?#)：m/z＝343(M+1)；R t＝2.93min.
Embodiment 66 (common processes (B))
3-(4-cyclopentyl-based piperazine-1-yl)-6-(3-fluoro-4-p-methoxy-phenyl)-pyridazine, dihydrochloride
Figure A0380336000901
From the 1-cyclopentyl-based piperazine with as J.Heterocycl.Chem., the 3-chloro-6-of 15,881 (1978) described preparations (3-fluoro-4-p-methoxy-phenyl)-pyridazine begins, as this compound of preparation as described in the embodiment 6.
1H?NMR(DMSO-d 6)：δ1.45-2.15(m，8H)，3.17(m，2H)，3.40-3.77(m，5H)，3.92(s，3H)，7.34(t，J＝8.7Hz，1H)，7.80(d，J＝9.8Hz，1H)，7.85-8.05(m，2H)，8.29(d，J＝9.8Hz，1H)，11.75(bs，1H)；HPLC-MS：m/z＝357(M+1)；R t＝2.47min.
Embodiment 67 (common processes (B))
3-(4-cyclopentyl-based piperazine-1-yl)-6-(3, the 4-Dimethoxyphenyl)-pyridazine
From the 1-cyclopentyl-based piperazine with as J.Heterocycl.Chem., the 3-chloro-6-of 15,881 (1978) described preparations (3, the 4-Dimethoxyphenyl)-pyridazine begins, as this compound of preparation as described in the embodiment 6.Obtain the free alkali of title compound.
1H?NMR(CDCl 3)：δ1.40-1.65(m，4H)，1.73(m，2H)，1.91(m，2H)，2.55(q，1H)，2.66(t，4H)，3.72(t，4H)，3.93(s，3H)，3.98(s，3H)，6.93(d，1H)，6.97(d，1H)，7.36(dd，1H)，7.64(d，1H)，7.86(d，1H)；HPLC-MS：m/z＝370(M+1)；R t＝1.90min.
Embodiment 68 (common processes (B))
3-(4-chloro-phenyl-)-6-(4-cyclopropyl methylpiperazine-1-yl)-pyridazine
From 1-cyclopropyl methylpiperazine with as J.Heterocycl.Chem., 3-chloro-6-(4-the chloro-phenyl-)-pyridazine of 15,881 (1978) described preparations begins, as this compound of preparation as described in the embodiment 6.Obtain the free alkali of title compound.
1H?NMR(CDCl 3)：δδ0.46(m，2H)，0.88(m，2H)，1.33(m，1H)，2.90(d，2H)，3.1-3.5(m，4H)，4.1-4.35(m，4H)，7.05(d，1H)，7.46(d，2H)，7.72(d，1H)，7.95(d，2H)；HPLC-MS：m/z＝329(M+1)；R t＝2.11min.
Embodiment 69 (common processes (B))
[title]
Figure A0380336000912
From the 1-cyclopentyl-based piperazine with as J.Heterocycl.Chem., 3-chloro-6-(4-the trifluoromethyl)-pyridazine of 15,881 (1978) described preparations begins, as this compound of preparation as described in the embodiment 6.Obtain the free alkali of title compound.
1H?NMR(CDCl 3)：δ1.40-1.65(m，4H)，1.65-1.80(m，2H)，1.92(m，2H)，2.55(q，1H)，2.65(t，4H)，3.76(t，4H)，6.99(d，1H)，7.67(d，1H)，7.72(d，2H)，8.12(d，2H)；HPLC-MS)：m/z＝377(M+1)；R t＝2.68min.
Embodiment 70 (common processes (B))
3-(4-sec.-propyl piperazine-1-yl)-6-(4-trifluoromethyl)-pyridazine
From 1-sec.-propyl piperazine with as J.Heterocycl.Chem., 3-chloro-6-(4-the trifluoromethyl)-pyridazine of 15,881 (1978) described preparations begins, as this compound of preparation as described in the embodiment 6.Obtain the free alkali of title compound.
1H?NMR(DMSO-d 6)：δ1.20(d，6H)，2.8-4.2(m，9H)，7.47(d，1H)，7.85(d，2H)，8.12(d，1H)，8.28(d，2H)；HPLC-MS：m/z＝351(M+1)；R t＝2.51min.
Embodiment 71 (common processes (B))
3-(4-cyclopropyl methylpiperazine-1-yl)-6-(4-trifluoromethyl)-pyridazine
From 1-cyclopropyl methylpiperazine with as J.Heterocycl.Chem., 3-chloro-6-(4-the trifluoromethyl)-pyridazine of 15,881 (1978) described preparations begins, as this compound of preparation as described in the embodiment 6.Obtain the free alkali of title compound.
1H?NMR(CDCl 3)：δ0.15(m，2H)，0.57(m，2H)，0.92(m，1H)，2.33(d，2H)，2.69(t，4H)，3.79(t，4H)，7.00(d，1H)，7.67(d，1H)，7.72(d，2H)，8.12(d，2H)；HPLC-MS：m/z＝363(M+1)；R t＝2.65min.
Embodiment 72 (common processes (B))
3-(4-chloro-phenyl-)-6-(4-sec.-propyl piperazine-1-yl)-pyridazine
From 1-sec.-propyl piperazine with as J.Heterocycl.Chem., 3-chloro-6-(4-the chloro-phenyl-)-pyridazine of 15,881 (1978) described preparations begins, as this compound of preparation as described in the embodiment 6.Obtain the free alkali of title compound.
1H?NMR(CDCl 3)：δ1.10(d，6H)，2.68(t，4H)，2.75(q，1H)，3.73(t，4H)，6.97(d，1H)，7.43(d，2H)，7.61(d，1H)，7.94(d，2H)；HPLC-MS：m/z＝317(M+1)；R t＝2.03min.
Embodiment 73 (common processes (B))
3-(4-cyclopropyl methylpiperazine-1-yl)-6-(3-fluoro-4-p-methoxy-phenyl)-pyridazine
Figure A0380336000931
From 1-cyclopropyl methylpiperazine with as J.Heterocycl.Chem., the 3-chloro-6-of 15,881 (1978) described preparations (3-fluoro-4-p-methoxy-phenyl)-pyridazine begins, as this compound of preparation as described in the embodiment 6.Obtain the free alkali of title compound.
1H?NMR(DMSO-d 6)：δ0.40(m，2H)，0.65(m，2H)，1.15(m，1H)，2.8-3.7(m，10H)，3.90(s，3H)，7.29(t，1H)，7.47(d，1H)，7.88(d，1H)，7.93(d，1H)，8.06(d，1H)；HPLC-MS：m/z＝343(M+1)；R t＝1.90min，
Embodiment 74 (common processes (B))
3-(3-fluoro-4-p-methoxy-phenyl)-6-(4-sec.-propyl piperazine-1-yl)-pyridazine
Figure A0380336000932
From 1-sec.-propyl piperazine with as J.Heterocycl.Chem., the 3-chloro-6-of 15,881 (1978) described preparations (3-fluoro-4-p-methoxy-phenyl)-pyridazine begins, as this compound of preparation as described in the embodiment 6.Obtain the free alkali of title compound.
1H?NMR(CDCl 3)：δ1.11(d，6H)，2.70(m，4H)，2.80(q，1H)，3.74(m，4H)，3.94(s，3H)，6.96(d，1H)，7.04(t，1H)，7.57(d，1H)，7.72(d，1H)，7.78(m，1H)；HPLC-MS：m/z＝331(M+1)；R t＝1.57min.
Embodiment 75 (common processes (B))
3-(3, the 4-Dimethoxyphenyl)-6-(4-sec.-propyl piperazine-1-yl)-pyridazine, dihydrochloride
Figure A0380336000933
From 1-sec.-propyl piperazine with as J.Heterocycl.Chem., the 3-chloro-6-of 15,881 (1978) described preparations (3, the 4-Dimethoxyphenyl)-pyridazine begins, as this compound of preparation as described in the embodiment 6.Obtain the free alkali of title compound.
1H?NMR(DMSO-d 6)：δ1.32(d，6H)，3.17(q，1H)，3.3-4.1(m，6H)，3.84(s，3H)，3.87(s，3H)，4.56(d，2H)，7.09(d，1H)，7.62(d，1H)，7.68-7.73(m，2H)，8.23(d，1H)，11.35(s，1H)；HPLC-MS：m/z＝343(M+1)；R t＝1.50min.
Embodiment 76 (common processes (B))
(9a-R)-2-(6-trifluoromethoxy quinoline-2-yl) octahydro pyrido [1,2-a] pyrazine hydrochloride
Utilize common processes (B), prepare this compound from (9a-R)-octahydro pyrido [1,2-a] pyrazine and 2-chloro-6-trifluoromethoxy quinoline.
1H?NMR(DMSO-d 6)δ1.40-1.65(m，1H)，1.65-2.08(m，5H)，2.93(m，1H)，3.18(m，1H)，3.25-3.55(m，4H)，3.71(m，1H)，4.85(m，2H)，7.61(d，J＝8Hz，1H)，7.70(d，J＝8Hz，1H)，7.93(s，1H)，8.19(br?s，1H)，8.39(d，J＝8Hz，1H)，11.60(br?s，1H)；HPLC-MS：m/z?352(MH +)；Rt＝2.67min.
Embodiment 77 (common processes (B))
7-fluoro-2-(4-sec.-propyl piperazine-1-yl)-6-toluquinoline hydrochloride
Utilize common processes (B), prepare this compound from 1-sec.-propyl piperazine and 2-chloro-7-fluoro-6-toluquinoline.
1H?NMR(DMSO-d 6)δ1.32(d，J＝7Hz，6H)，2.38(s，3H)，3.26(m，2H)，3.54(m，3H)，3.83(m，2H)，4.88(br?s，2H)，7.49(d，J＝8Hz，1H)，7.85(d，J＝8Hz，H)，8.09(br?s，1H)，8.35(d，J＝8Hz，1H)，11.57(br?s，1H)；HPLC-MS：m/z287(MH +)；Rt＝1.47min.
Embodiment 78 (common processes (B))
7-chloro-2-(4-sec.-propyl piperazine-1-yl) quinoline hydrochloride
Figure A0380336000951
Utilize common processes (B), from 1-sec.-propyl piperazine and 2, the 7-dichloroquinoline prepares this compound.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3，23(m，2H)，3.53(m，3H)，3.79(m，2H)，4.87(br?s，2H)，7.48(d，J＝8Hz，1H)，7.54(d，J＝8Hz，1H)，7.92(d，J＝8Hz，1H)，8.26(br?s，1H)，8.38(d，J＝8Hz，1H)，11.50(br?s，1H)；HPLC-MS：m/z289(MH +)；Rt＝1.61min.
Embodiment 79 (common processes (B))
6-fluoro-2-(4-sec.-propyl piperazine-1-yl) quinoline hydrochloride
Figure A0380336000952
Utilize common processes (B), prepare this compound from 1-sec.-propyl piperazine and 2-chloro-6-fluorine quinoline.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.22(m，2H)，3.53(m，3H)，3.79(m，2H)，4.85(br?s，2H)，7.55-7.70(m，2H)，7.45(d，J＝8Hz，1H)，8.26(br?s，1H)，8.36(d，J＝8Hz，1H)，11.52(br?s，1H)；HPLC-MS：m/z?274(MH +)；Rt＝1.21min.
Embodiment 80 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl)-7-fluoro-6-toluquinoline hydrochloride
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 2-chloro-7-fluoro-6-toluquinoline.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.20(m，2H)，2.36(s，3H)，2.87(m，1H)；3.25-4.15(m，6H)，4.74(br?s，2H)，7.43(d，J＝8Hz，1H)，7.80(m，2H)，8.28(d，J＝8Hz，1H)，11.36(br?s，1H)；HPLC-MS：m/z?287(MH +)；Rt＝1.47min.
Embodiment 81 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl)-7-fluoro-6-methoxy quinoline hydrochloride
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 2-chloro-7-fluoro-6-methoxy quinoline.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.18(m，2H)，2.88(m，1H)，3.25-4.10(m，6H)，3.93(s，3H)，4.64(br?s，2H)，7.40(d，J＝8Hz，1H)，7.55(d，J＝8Hz，1H)，7.73(br?s，1H)，8.24(d，J＝8Hz，1H)，11.11(br?s，1H)；HPLC-MS：m/z?301(MH +)；Rt＝1.37min.
Embodiment 82 (common processes (B))
7-fluoro-2-(4-sec.-propyl piperazine-1-yl)-6-methoxy quinoline hydrochloride
Utilize common processes (B), prepare this compound from 1-sec.-propyl piperazine and 2-chloro-7-fluoro-6-methoxy quinoline.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.16(m，2H)，3.45-4.05(m，5H)，3.93(s，3H)，4.72(m，2H)，7.42(d，J＝8Hz，1H)，7.56(d，J＝8Hz，1H)，7.83(br?s，1H)，8.25(d，J＝8Hz，1H)，11.13(br?s，1H)；HPLC-MS：m/z?303(MH +)；Rt＝1.41min.
Embodiment 83 (common processes (B))
(9a-R)-2-(7-fluoro-6-methoxy quinoline-2-yl) octahydro pyrido [1,2-a] pyrazine hydrochloride
Utilize common processes (B), prepare this compound from (9a-R) octahydro pyrido [1,2-a] pyrazine and 2-chloro-7-fluoro-6-methoxy quinoline.
1H?NMR(DMSO-d 6)δ1.40-1.55(m，1H)，1.65-2.08(m，5H)，2.93(m，1H)，3.20(m，1H)，3.25-3.55(m，4H)，3.73(m，1H)，4.81(m，2H)，7.50(d，J＝8Hz，1H)，7.62(d，J＝8Hz，1H)，8.13(br?s，1H)，8.34(d，J＝8Hz，1H)，11.59(br?s，1H)；HPLC-MS：m/z?315(MH +)；Rt＝1.41min.
Embodiment 84 (common processes (B))
(9a-R)-2-(6-Trifluoromethylquinocarboxylic-2-yl) octahydro pyrido [1,2-] pyrazine hydrochloride
Utilize common processes (B), prepare this compound from (9a-R)-octahydro pyrido [1,2-a] pyrazine and 2-chloro-6-Trifluoromethylquinocarboxylic.
1H?NMR(DMSO-d 6)δ1.40-1.55(m，1H)，1.65-2.05(m，5H)，2.92(m，1H)，3.20(m，1H)，3.30-3.55(m，4H)，3.70(m，1H)，4.88(m，2H)，7.61(d，J＝8Hz，1H)，7.93(d，J＝8Hz，1H)，8.15(br?s，1H)，8.31(s，1H)，8.43(d，J＝8Hz，1H)，11.60(br?s，1H)；HPLC-MS：m/z?335(MH +)；Rt＝2.27min.
Embodiment 85 (common processes (B))
7-fluoro-2-(4-sec.-propyl piperazine-1-yl) quinoline hydrochloride
Figure A0380336000973
Utilize common processes (B), prepare this compound from 1-sec.-propyl piperazine and 2-chloro-7-fluorine quinoline.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.19(m，2H)，3.45-4.20(m，5H)，4.84(m，2H)，7.32(m，1H)，7.45(d，J＝8Hz，1H)，7.83(br?s，1H)，7.95(m，1H)，8.35(m，1H)，11.35(br?s，1H)；HPLC-MS：m/z274(MH +)；Rt＝1.31min.
Embodiment 86 (common processes (B))
6-chloro-2-(4-sec.-propyl piperazine-1-yl) quinoline hydrochloride
Figure A0380336000981
Utilize common processes (B), from 1-sec.-propyl piperazine and 2, the 6-dichloroquinoline prepares this compound.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.19(m，2H)，3.45-3.80(m，5H)，4.82(m，2H)，7.55(d，J＝8Hz，1H)，7.72(d，J＝8Hz，1H)，7.99(s，1H)，8.07(br?s，1H)，8.29(d，J＝8Hz，1H)，11.38(br?s，1H)；HPLC-MS：m/z290(MH +)；Rt＝1.64min.
Embodiment 87 (common processes (B))
6-sec.-propyl-2-(4-sec.-propyl piperazine-1-yl) quinoline hydrochloride
Figure A0380336000982
Utilize common processes (B), prepare this compound from 1-sec.-propyl piperazine and 2-chloro-6-isopropyl quinoline.
1H?NMR(DMSO-d 6)δ1.27(d，J＝7Hz，6H)，1.32(d，J＝7Hz，6H)，3.05(sept，J＝7Hz，1H)，3.26(m，2H)，3.40-3.95(m，5H)，4.86(m，2H)，7.55(d，J＝8Hz，1H)，7.72(d，J＝8Hz，1H)，7.77(s，1H)，8.21(br?s，1H)，8.42(d，J＝8Hz，1H)，11.55(br?s，1H)；HPLC-MS：m/z?298(MH +)；Rt＝1.87min.
Embodiment 88 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl)-6-isopropyl quinoline hydrochloride
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 2-chloro-6-isopropyl quinoline.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.20(m，2H)，1.27(d，J＝7Hz，6H)，2.86(br?s，1H)，3.04(sept，J＝7Hz，1H)，3.25-3.85(m，5H)，4.15(brs，1H)，4.74(m，2H)，7.53(m，1H)，7.70(d，J＝8Hz，1H)，7.75(s，1H)，8.06(br?s，1H)，8.38(m，1H)，11.41(br?s，1H)；HPLC-MS：m/z(MH +)；Rt＝min.
Embodiment 89 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl) quinoline hydrochloride
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 2-chloroquinoline.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.19(m，2H)，2.87(br?s，1H)，3.30-3.80(m，6H)，4.74(m，2H)，7.45(m，1H)，7.52(d，J＝8Hz，1H)，7.73(m，1H)，7.89(d，J＝8Hz，1H)，8.02(br?s，1H)，8.38(m，1H)，11.22(br?s，1H)；HPLC-MS：m/z(MH +)；Rt＝min.
Embodiment 90 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl)-6,7-dimethoxy-quinoline hydrochloride
Figure A0380336000992
Utilize common processes (B), from 1-cyclopropyl piperazine and 2-chloro-6, the 7-dimethoxy-quinoline prepares this compound.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.20(m，2H)，2.87(br?s，1H)，3.25-3.75(m，6H)，3.86(s，3H)，3.90(s，3H)，4.66(m，2H)，7.25-7.50(m，3H)，8.24(br?s，1H)，11.38(br?s，1H)；HPLC-MS：m/z?314(MH +)；Rt＝1.27min.
Embodiment 91 (common processes (B))
2-(4-sec.-propyl piperazine-1-yl)-6,7-dimethoxy-quinoline hydrochloride
Figure A0380336001001
Utilize common processes (B), from 1-sec.-propyl piperazine and 2-chloro-6, the 7-dimethoxy-quinoline prepares this compound.
1H?NMR(DMSO-d 6)δ1.32(d，J＝7Hz，6H)，3.25(m，2H)，3.45-4.00(m，5H)，3.87(s，3H)，3.91(s，3H)，4.80(m，2H)，7.39(m，2H)，7.96(br?s，1H)，8.34(br?s，1H)，11.50(br?s，1H)；HPLC-MS：m/z?316(MH +)；Rt＝1.27min.
Embodiment 92 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl)-7-quinoline fluoride hydrochloride
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 2-chloro-7-fluorine quinoline.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.22(m，2H)，2.87(br?s，1H)，3.30-3.80(m，6H)，4.79(m，2H)，7.34(m，1H)，7.47(d，J＝8Hz，1H)，7.85(br?s，1H)，7.96(m，1H)，8.37(m，1H)，11.55(br?s，1H)；HPLC-MS：m/z?271(MH +)；Rt＝1.24min.
Embodiment 93 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl)-6,8-difluoro-quinoline hydrochloride
Figure A0380336001003
Utilize common processes (B), from 1-cyclopropyl piperazine and 2-chloro-6, the 8-difluoro-quinoline prepares this compound.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.19(m，2H)，2.87(brs，1H)，3.20-3.70(m，6H)，4.63(m，2H)，7.48(m，3H)，8.19(d，J＝8Hz，1H)，11.11(br?s，1H)；HPLC-MS：m/z290(MH +)；Rt＝2.27min.
Embodiment 94 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl)-6-quinoline fluoride hydrochloride
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 2-chloro-6-fluorine quinoline.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.21(m，2H)，2.87(br?s，1H)，3.30-3.80(m，6H)，4.73(m，2H)，7.56(d，J＝8Hz，1H)，7.62(m，1H)，7.71(d，J＝8Hz，1H)，8.09(br?s，1H)，8.33(d，J＝8Hz，1H)，11.42(br?s，1H)；HPLC-MS：m/z?272(MH +)；Rt＝1.27min.
Embodiment 95 (common processes (B))
7-chloro-2-(4-cyclopropyl piperazine-1-yl) quinoline hydrochloride
Figure A0380336001012
Utilize common processes (B), from 1-cyclopropyl piperazine and 2, the 7-dichloroquinoline prepares this compound.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.20(m，2H)，2.87(br?s，1H)，3.25-3.75(m，6H)，4.72(m，2H)，7.40(d，J＝8Hz，1H)，7.46(d，J＝8Hz，1H)，7.87(d，J＝8Hz，1H)，7.94(br?s，1H)，8.29(d，J＝8Hz，1H)，11.29(br?s，1H)；HPLC-MS：m/z288(MH +)；Rt＝1.71min.
Embodiment 96 (common processes (B))
(9a-R)-2-quinoline-2-base-octahydro pyrido [1,2-a] pyrazine hydrochloride
Figure A0380336001013
Utilize common processes (B), prepare this compound from (9a-R)-octahydro pyrido [1,2-a] pyrazine and 2-chloroquinoline.
1H?NMR(DMSO-d 6)δ1.40-1.55(m，1H)，1.65-2.10(m，5H)，2.92(m，1H)，3.25(m，1H)，3.35-3.90(m，5H)，4.90(m，2H)，7.49(m，1H)，7.59(d，J＝8Hz，1H)，7.77(m，1H)，7.92(d，J＝8Hz，1H)，8.32(br?s，1H)，8.46(m，1H)，11.69(br?s，1H)；HPLC-MS：m/z?268(MH +)；Rt＝1.07min.
Embodiment 97 (common processes (B))
(9a-R)-2-(6-chloroquinoline-2-yl) octahydro pyrido [1,2-a] pyrazine hydrochloride
Figure A0380336001021
Utilize common processes (B), from (9a-R)-octahydro pyrido [1,2-a] pyrazine and 2, the 6-dichloroquinoline prepares this compound.
1H?NMR(DMSO-d 6)δ1.40-1.55(m，1H)，1.65-2.05(m，5H)，2.93(m，1H)，3.18(m，1H)，3.25-3.55(m，4H)，3.68(m，1H)，4.90(m，2H)，7.56(d，J＝8Hz，1H)，7.71(d，J＝8Hz，1H)，7.98(s，1H)，8.07(br?s，1H)，8.29(d，J＝8Hz，1H)，11.47(br?s，1H)；HPLC-MS：m/z302(MH +)；Rt＝1.81min.
Embodiment 98 (common processes (B))
(9a-R)-2-(7-fluoro-6-toluquinoline-2-yl) octahydro pyrido [1,2-a] pyrazine hydrochloride
Figure A0380336001022
Utilize common processes (B), prepare this compound from (9a-R)-octahydro pyrido [1,2-a] pyrazine and 2-chloro-7-fluoro-6-toluquinoline.
1H?NMR(DMSO-d 6)δ1.40-1.55(m，1H)，1.65-2.10(m，5H)，2.36(s，3H)，2.92(m，1H)，3.23(m，1H)，3.30-3.60(m，4H)，3.80(m，1H)，4.87(m，2H)，7.51(d，J＝8Hz，1H)，7.84(d，J＝8Hz，1H)，8.13(br?s，1H)，8.36(d，J＝8Hz，1H)，11.77(br?s，1H)；HPLC-MS：m/z300(MH +)；Rt＝1.54min.
Embodiment 99 (common processes (B))
(9a-R)-2-(6-propyl group quinoline-2-yl) octahydro pyrido [1,2-a] pyrazine hydrochloride
Utilize common processes (B), prepare this compound from (9a-R)-octahydro pyrido [1,2-a] pyrazine and 2-chloro-6-propyl group quinoline.
1H?NMR(DMSO-d 6)δ0.91(t，J＝7Hz，3H)，1.40-1.55(m，1H)，1.60-2.10(m；7H)，2.70(t，J＝7Hz，2H)，2.92(m，1H)，3.24(m，1H)，3.30-3.85(m，5H)，4.88(m，2H)，7.57(d，J＝8Hz，1H)，7.65(d，J＝8Hz，1H)，7.72(s，1H)，8.28(br?s，1H)，8.41(m，1H)，11.69(br?s，1H)；HPLC-MS：m/z?309(MH +)；Rt＝2.27min.
Embodiment 100 (common processes (B))
2-(4-sec.-propyl piperazine-1-yl) quinoxaline hydrochloride
Utilize common processes (B), prepare this compound from 1-sec.-propyl piperazine and 2-chloro-quinoxaline.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.13(m，2H)，3.45-3.65(m，5H)，4.75(m，2H)，7.48(m，1H)，7.66(m，2H)，7.88(d，J＝8Hz，1H)，8.91(s，1H)，11.15(br?s，1H)；HPLC-MS：m/z257(MH +)；Rt＝1.25min.
Embodiment 101 (common processes (B))
[4-(4-cyclopropyl piperazine-1-yl) phenyl] phenyl ketone hydrochloride
Figure A0380336001033
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 4-fluorine benzophenone.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.16(m，2H)，2.92(br?s，1H)，3.30-3.40(m，4H)，3.56(brs，2H)，4.09(m，2H)，7.12(d，J＝8Hz，2H)，7.54(m，2H)，7.60-7.75(m，5H)，10.82(br?s，1H)；HPLC-MS：m/z307(MH +)；Rt＝2.00min.
Embodiment 102 (common processes (B))
[4-(4-cyclopropyl piperazine-1-yl)-3,5-difluorophenyl] phenyl ketone hydrochloride
Utilize common processes (B), from 1-cyclopropyl piperazine and 3,4,5-trifluoro benzophenone prepares this compound.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.16(m，2H)，2.96(br?s，1H)，3.30-3.75(m，8H)，7.43(d，J＝8Hz，2H)，7.58(t，J＝8Hz，2H)，7.65-7.78(m，3H)，10.90(br?s，1H)；HPLC-MS：m/z?343(MH +)；Rt＝2.29min.
Embodiment 103 (common processes (B))
2-(4-sec.-propyl piperazine-1-yl)-5,6,7-trimethoxy quinoline hydrochloride
Utilize common processes (B), from 1-sec.-propyl piperazine and 2-chloro-5,6,7-trimethoxy quinoline prepares this compound.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.21(m，2H)，3.45-3.85(m，5H)，3.82(s，3H)，3.93(s，3H)，3.99(s，3H)，4.78(m，2H)，7.31(m，1H)，7.56(m，1H)，8.31(m，1H)，11.36(br?s，1H)；HPLC-MS：m/z?346(MH +)；Rt＝1.22min.
Embodiment 104 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl)-5,6,7-trimethoxy quinoline hydrochloride
Utilize common processes (B), from 1-cyclopropyl piperazine and 2-chloro-5,6,7-trimethoxy quinoline prepares this compound.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.22(m，2H)，2.87(br?s，1H)，3.30-4.10(m，6H)，3.83(s，3H)，3.93(s，3H)，4.00(s，3H)，4.76(m，2H)，7.33(m，1H)，7.65(br?s，1H)，8.34(m，1H)，11.62(br?s，1H)；HPLC-MS：m/z344(MH +)；Rt＝1.46min.
Embodiment 105 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl)-6-trifluoromethylthio quinoline hydrochloride
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 2-chloro-6-trifluoromethylthio quinoline.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.20(m，2H)，2.86(br?s，1H)，3.20-3.70(m，6H)，4.75(m，2H)，7.53(m，1H)，7.86(m，2H)，8.20-8.40(m，2H)，11.28(br?s，1H)；HPLC-MS：m/z?354(MH +)；Rt＝2.61min.
Embodiment 106 (common processes (B))
7-chloro-2-(4-cyclopropyl piperazine-1-yl)-6-methoxy quinoline hydrochloride
Figure A0380336001053
Utilize common processes (B), from 1-cyclopropyl piperazine and 2,7-two chloro-6-methoxy quinolines prepare this compound.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.16(m，2H)，2.88(m，1H)，3.25-3.70(m，6H)，3.94(s，3H)，4.62(m，2H)，7.45(d，J＝8Hz，1H)，7.51(s，1H)，7.96(br?s，1H)，8.23(d，J＝8Hz，1H)，10.98(br?s，1H)；HPLC-MS：m/z?318(MH +)；Rt＝1.80min.
Embodiment 107 (common processes (B))
5,7-two chloro-2-(4-cyclopropyl piperazine-1-yl) quinoline hydrochloride
Utilize common processes (B), from 1-cyclopropyl piperazine and 2,5, the 7-trichloro-quinoline prepares this compound.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.19(m，2H)，2.86(m，1H)，3.20-3.65(m，6H)，4.69(m，2H)，7.51(d，J＝8Hz，1H)，7.56(s，1H)，7.68(s，1H)，8.30(d，J＝8Hz，1H)，11.24(br?s，1H)；HPLC-MS：m/z?322(MH +)；Rt＝2.78min.
Embodiment 108 (common processes (B))
1-cyclopropyl-4-[5-(4-trifluoromethyl) pyridine-2-yl] piperazine hydrochloride
Required 2-chloro-5-(4-trifluorophenyl) pyridine is as R.Church, R.Trust, and J.D.Albright, and D.Powell, J.Org.Chem.1995,60, the described preparation of 3750-3758, according to following manner:
Under 10 ℃, to from dimethyl formamide (5.98g, 0.082mol) and phosphoryl chloride (22.5g, 0.146mol) the Vilsmeier reagent solution of preparation add 4-(trifluoromethyl) phenylacetic acid (6.64g, 0.033mol).Mixture was stirred 8 hours down at 70 ℃.After being cooled to envrionment temperature, mixture is slowly joined in the mixture of ice and water (temperature＜10 ℃), slowly add Na then 2CO 3Solution is until reaching pH11.The alkalitropism mixture adds toluene (125ml), and the gained mixture was refluxed 1.5 hours.After being cooled to envrionment temperature, separate water layer, with toluene (100ml) extraction.Merge organic layer, wash with water, dry (Na 2SO 4), under reduced pressure concentrate.Make gained solid recrystallization from the mixture of methylene dichloride and heptane, obtain 6.98g (87%) 3-dimethylamino-2-(4-trifluoromethyl) propenal, be yellow crystals, mp.97 ℃.
1H NMR spectrum (CDCl 3) δ 9.10 (s, 1H), 7.57 (m, 2H), 7.32 (m, 2H), 6.95 (s, 1H), 2.85 (s, 6H); R F(SiO 2, chloroform/methanol 95: 5) and 0.34.
To sodium methylate (3.64g, methyl alcohol 0.068mol) (68ml) solution add malonamide nitrile (6.95g, 0.082mol) and aforementioned product (6.98g, 0.029mol).Mixture was stirred 1.5 hours at ambient temperature, refluxed then 8 hours.Be settled out yellow solid during this period.With reaction mixture water (75ml) dilution, with 10% aqueous hydrochloric acid acidifying.Leach yellow solid, water, ethanol, diethyl ether, use hexane wash then.Obtain 2-hydroxyl-5-(4-trifluoromethyl) cigarette nitrile (6.66g, 87%), be yellow solid, mp.235-242 ℃.
1H NMR (DMSO-d 6) δ 8.42 (m, 1H), 7.91 (m, 1H), 7.66 (m, 4H); R F(SiO 2, chloroform/methanol 95: 5) and 0.18.
To the mixture of acetate (100ml) and concentrated hydrochloric acid (70ml) add aforementioned product (6.66g, 0.025mol).With reaction mixture refluxed 18 hours, water (200ml) dilution was cooled to room temperature, stirs simultaneously.Leach solid, water, then with 50% aqueous ethanol washing obtains 5.42g (77%) 2-hydroxyl-5-(4-trifluoromethyl) nicotinic acid, is light gray solid, mp.305-315 ℃.
1H NMR (DMSO-d 6) δ 8.71 (d, 1H), 8.43 (d, 1H), 7.96 (m, 2H), 7.81 (m, 2H); R F(SiO 2, chloroform/methanol 95: 5) and 0.13.
(5.42g, 0.019mol) mixture with fresh distillatory quinoline (50ml) stirred 12 hours down at 215 ℃ with aforementioned product.Reaction mixture is cooled to envrionment temperature, adds heptane (250ml).Leach solid, use heptane wash, recrystallization from the mixture of methylene dichloride and heptane obtains 3.92g (86%) 2-hydroxyl-5-(4-trifluoromethyl) pyridine, mp.178-182 ℃.
1H NMR (CDCl 3) δ 7.79 (dd, 2H), 7.68 (d, 3H), 7.52 (d, 2H), 6.73 (d, 1H); R F(SiO 2, chloroform/methanol 95: 5) and 0.23.
(27.6g, 0.18mol) (3.92g, mixture 0.016mol) stirred 10 hours down at 105 ℃ with aforementioned product with phosphoryl chloride.Vapourisation under reduced pressure excessive phosphorus chloride, resistates are with toluene (75ml) stripping once.Add entry (75ml) and methylene dichloride (75ml) to resistates, the separate dichloromethane layer, water extracts with methylene dichloride (75ml).Combining extraction liquid, water, then with sodium hydrogen carbonate solution washing, dry (MgSO 4), under reduced pressure concentrate, obtain 2.95g (72%) 2-chloro-5-(4-trifluoromethyl) pyridine, be light brown crystal, mp.98-101 ℃.
1H NMR (CDCl 3) δ 8.62 (dd, 1H), 7.86 (dd, 1H), 7.44 (dd, 1H), 7.66 (m, 2H), 7.75 (m, 2H); R F(SiO 2, chloroform/methanol 95: 5) and 0.94.
As described in common processes (B), this product is handled with 1-cyclopropyl piperazine, obtain title compound.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.13(m，2H)，2.85(m，1H)，3.25-3.75(m，6H)，4.51(m，2H)，7.12(d，J＝8Hz，1H)，7.79(d，J＝8Hz，2H)，7.89(d，J＝8Hz，2H)，8.05(m，1H)，8.59(m，1H)，10.56(br?s，1H)；HPLC-MS：m/z348(MH +)；Rt＝2.77min.
Embodiment 109 (common processes (B))
3-(4-cyclopropyl piperazine-1-yl)-6-(4-trifluoromethyl) pyridazine hydrochloride
Figure A0380336001081
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 3-chloro-6-(4-trifluoromethyl) pyridazine.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.19(m，2H)，2.89(m，1H)，3.30-3.70(m，6H)，4.61(m，2H)，7.61(d，J＝8Hz，1H)，7.88(d，J＝8Hz，2H)，8.22(d，J＝8Hz，1H)，8.29(d，J＝8Hz，2H)，11.11(br?s，1H)；HPLC-MS：m/z349(MH +)；Rt＝2.40min.
Embodiment 110 (common processes (B))
6-(4-cyclopropyl piperazine-1-yl)-[1,3] dioxolane is [4,5-g] quinoline hydrochloride also
Utilize common processes (B), from 1-cyclopropyl piperazine and 6-chlorine [1,3] dioxolane also [4,5-g] quinoline prepare this compound.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.15(m，2H)，2.88(m，1H)，3.20-3.70(m，6H)，4.59(m，2H)，6.17(s，2H)，7.29(m，3H)，8.13(m，1H)，10.80(br?s，1H)；HPLC-MS：m/z?298(MH +)；Rt＝0.68min.
Embodiment 111 (common processes (B))
6-cyclohexyl-2-(4-cyclopropyl piperazine-1-yl) quinoline hydrochloride
Figure A0380336001092
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 2-chloro-6-cyclohexyl quinoline.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.10-1.55(m，8H)，1.70-1.93(m，4H)，2.65(m，1H)，2.86(m，1H)，3.30-3.70(m，6H)，4.72(m，2H)，7.50(m，1H)，7.66(m，1H)，7.72(m，1H)，7.99(br?s，1H)，8.35(br?s，1H)，11.29(br?s，1H)；HPLC-MS：m/z?336(MH +)；Rt＝2.55min.
Embodiment 112 (common processes (B))
6-cyclohexyl-2-(4-sec.-propyl piperazine-1-yl) quinoline hydrochloride
Utilize common processes (B), prepare this compound from 1-sec.-propyl piperazine and 2-chloro-6-cyclohexyl quinoline.
1H?NMR(DMSO-d 6)δ1.10-1.55(m，8H)，1.31(d，J＝7Hz，6H)，1.70-1.93(m，4H)，2.65(m，1H)，3.23(m，2H)，3.50-3.85(m，3H)，4.80(m，2H)，7.51(m，1H)，7.67(m，1H)，7.73(m，1H)，8.08(br?s，1H)，8.36(br?s，1H)，11.31(br?s，1H)；HPLC-MS：m/z?338(MH +)；Rt＝2.50min.
Embodiment 113 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl)-6,7-dimethoxy-3-toluquinoline hydrochloride
Required 2-chloro-6,7-dimethoxy-3-toluquinoline are according to TetrahedronLetters 1979,4885 disclosed prepared, according to following manner:
To 3, the 4-dimethoxyaniline (4.70g, methylene dichloride 30.7mmol) (50ml) solution add pyridine (8.0ml, 3 equivalents), drip then propionyl chloride (3.5ml, 40.5mmol).At room temperature stir 1 hour again after 50 minutes, mixture is poured in the mixture of water (200ml) and concentrated hydrochloric acid (8ml).Separate each phase, water with dichloromethane extraction once.Merge organic phase, use the salt water washing, use dried over mgso, concentrate, obtain 6.89g oil, the several minutes post crystallization.Recrystallization from the mixture of ethyl acetate and heptane obtains 3.60g (49%) N-(3, the 4-Dimethoxyphenyl) propionic acid amide, is dark crystal.
(2.1g, 10.0mmol) (1.1ml 15mmol) mixes, and at room temperature drips POCl to this mixture with DMF with this anilid 3(6.5ml, 70mmol).When adding end, mixture was stirred 2 hours down at 75 ℃.Mixture is poured in the frozen water (100ml), stirred 30 minutes, filter.Solid obtains 1.60g (67%) 2-chloro-6 with toluene and acetonitrile stripping, and 7-dimethoxy-3-toluquinoline is solid.As described in common processes (B), this product is handled with 1-cyclopropyl piperazine, obtain title compound.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.23(m，2H)，2.42(s，3H)，2.94(m，1H)，3.40-4.50(m，8H)，3.88(s，3H)，3.91(s，3H)，7.29(s，1H)，7.48(br?s，1H)，8.12(br?s，1H)，11.24(br?s，1H)；HPLC-MS：m/z?328(MH +)；Rt＝1.63min.
Embodiment 114 (common processes (B))
6-(4-sec.-propyl piperazine-1-yl)-[1,3] dioxolane is [4,5-g] quinoline hydrochloride also
Utilize common processes (B), from 1-sec.-propyl piperazine and 6-chlorine [1,3] dioxolane also [4,5-g] quinoline prepare this compound.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.40(m，2H)，3.45-4.00(m，5H)，4.72(m，2H)，6.21(s，2H)，7.34(m，2H)，7.62(br?s，1H)，8.21(m，1H)，11.12(br?s，1H)；HPLC-MS：m/z?300(MH +)；Rt＝0.65min.
Embodiment 115 (common processes (B))
[3,5-two fluoro-4-(4-sec.-propyl-piperazine-1-yl)-phenyl]-piperidines-1-base-ketone hydrochloride
Utilize common processes (B), by 1-sec.-propyl piperazine and 3,4, this compound of prepared in reaction of 5-trifluoro-benzoic acid piperidide.This reaction obtains two kinds of products, i.e. present embodiment and embodiment 121.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，1.40-1.62(m，6H)，3.09(m，2H)，3.20-3.65(m，11H)，7.12(m，2H)，10.42(br?s，1H)；HPLC-MS：m/z?352(MH +)；Rt＝3.75min.
Embodiment 116 (common processes (B))
(9a-R)-2-(6,7-dimethoxy-quinoline-2-yl) octahydro pyrido [1,2-a] pyrazine hydrochloride
Utilize common processes (B), from (9a-R) octahydro pyrido [1,2-a] pyrazine and 2-chloro-6, the 7-dimethoxy-quinoline prepares this compound.
1H?NMR(DMSO-d 6)δ1.40-1.55(m，1H)，1.65-2.05(m，5H)，2.93(m，1H)，3.22(m，1H)，3.25-3.60(m，4H)，3.65-4.20(m，1H)，3.87(s，3H)，3.90(s，3H)，4.79(m，2H)，7.40(m，2H)，8.00(br?s，1H)，8.33(br?s，1H)，11.55(br?s，1H)；HPLC-MS：m/z?328(MH +)；Rt＝0.97min.
Embodiment 117 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl)-5,6,7,8-tetrahydroquinoline hydrochloride
Figure A0380336001121
Utilize common processes (B), from 1-cyclopropyl piperazine and 2-chloro-5,6,7, the 8-tetrahydroquinoline prepares this compound.
1H?NMR(DMSO-d 6)δ0.81(m，2H)，1.17(m，2H)，1.67-1.82(m，4H)，2.62(m，2H)，2.75-2.95(m，3H)，3.20-3.65(m，6H)，4.37(m，2H)，7.02(br?s，1H)，7.63(br?s，1H)，11.10(br?s，1H)；HPLC-MS：m/z?258(MH +)；Rt＝0.62min.
Embodiment 118 (common processes (B))
[5-chloro-6-(4-cyclopropyl piperazine-1-yl) pyridin-3-yl] piperidines-1-base ketone hydrochloride
Figure A0380336001122
Utilize common processes (B), from 1-cyclopropyl piperazine and 5,6-dichloro-nicotinic acid piperidide prepares this compound.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.12(m，2H)，1.45-1.65(m，6H)，2.96(m，1H)，3.30-3.60(m，10H)，3.96(m，2H)，7.89(s，1H)，8.27(s，1H)，10.68(br?s，1H)；HPLC-MS：m/z?349(MH +)；Rt＝1.50min.
Embodiment 119 (common processes (B))
(9a-R)-[6-(octahydro pyrido [1,2-a] pyrazine-2-yl) pyridin-3-yl] piperidines-1-base ketone hydrochloride
Utilize common processes (B), prepare this compound from (9a-R)-octahydro pyrido [1,2-a] pyrazine and 6-chlorine apellagrin piperidide.
1H?NMR(DMSO-d 6)δ1.51(m，3H)，1.60(m，2H)，1.78-1.98(m，3H)，2.90-3.25(m，4H)，3.30-3.50(m，5H)，3.74(m，6H)，4.50(m，2H)，7.02(d，J＝7Hz，1H)，7.66(d，J＝7Hz，1H)，8.19(s，1H)，10.86(br?s，1H)；HPLC-MS：m/z329(MH +)；Rt＝1.31min.
Embodiment 120 (common processes (B))
[6-(4-cyclopropyl piperazine-1-yl) pyridin-3-yl] piperidines-1-base ketone hydrochloride
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 6-chlorine apellagrin piperidide.
1H?NMR(DMSO-d 6)δ0.81(m，2H)，1.17(m，2H)，1.51(m，4H)，1.60(m，2H)，2.87(m，1H)，3.20-3.60(m，10H)，4.47(m，2H)，7.01(d，J＝7Hz，1H)，7.67(d，J＝7Hz，1H)，8.21(s，1H)，11.04(br?s，1H)；HPLC-MS：m/z315(MH +)；Rt＝1.22min.
Embodiment 121 (common processes (B))
[3,4-two fluoro-5-(4-sec.-propyl-piperazine-1-yl)-phenyl]-piperidines-1-base-ketone hydrochloride
Figure A0380336001133
Utilize common processes (B), by 1-sec.-propyl piperazine and 3,4, this compound of prepared in reaction of 5-trifluoro-benzoic acid piperidide.This reaction obtains two kinds of products, i.e. present embodiment and embodiment 115.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，1.40-1.65(m，6H)，3.12-3.62(m，13H)，6.89(d，J＝8Hz，1H)，7.09(m，1H)，11.09(br?s，1H)；HPLC-MS：m/z?352(MH +)；Rt＝3.95min.
Embodiment 122 (common processes (B))
[4-(4-sec.-propyl-piperazine-1-yl)-3-trifluoromethyl-phenyl]-piperidines-1-base-ketone hydrochloride
Utilize common processes (B), prepare this compound by 1-sec.-propyl piperazine and 4-fluoro-3-trifluoromethylbenzoic acid piperidide.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，1.40-1.65(m，6H)，3.05(m，1H)，3.15(m，1H)，3.28(m，8H)，3.52(m，3H)，7.57(br?d，J＝8Hz，1H)，7.68(br?s，1H)，7.71(br?d，J＝8Hz，1H)，10.39(br?s，1H)；HPLC-MS：m/z?384(MH +)；Rt＝4.21min.
Embodiment 123
2-(4-cyclopropyl-3-methyl-piperazine-1-yl)-6,7-dimethoxy-quinoline hydrochloride
Figure A0380336001142
As Gillaspy, M.L.; Lefker, B.A.; Hada, W.A.; And Hoover, D.J.in Tetrahedron Lett.1995,36 (41), 7399-7402 is described, and by 6, the reductibility cyclopropyl of 7-dimethoxy-2-(3-methylpiperazine-1-yl) quinoline turns into this compound of preparation.
1H?NMR(DMSO-d 6)δ0.82(m，1H)，0.99(m，2H)，1.40(m，1H)，1.55(d，J＝7Hz，3H)，2.76(m，1H)，3.30-3.80(m，5H)，3.87(s，3H)，3.90(s，3H)，4.65-4.83(m，2H)，7.38(br?s，2H)，7.82(br?s，1H)，8.31(br?s，1H)，11.30(br?s，1H)；HPLC-MS：m/z328(MH +)；Rt＝3.09min.
Embodiment 124 (common processes (B))
[6-(4-cyclopropyl piperazine-1-yl) pyridin-3-yl] tetramethyleneimine-1-base-ketone hydrochloride
Figure A0380336001151
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 6-chlorine apellagrin pyrrolidide.
1H?NMR(DMSO-d 6)δ0.81(m，2H)，1.15(m，2H)，1.84(m，4H)，2.88(m，1H)，3.15-3.60(m，10H)，4.49(m，2H)，7.00(d，J＝7Hz，1H)，7.83(d，J＝7Hz，1H)，8.38(s，1H)，10.91(br?s，1H)；HPLC-MS：m/z301(MH +)；Rt＝1.22min.
Embodiment 125 (common processes (B))
2-(4-sec.-propyl piperazine-1-yl) quinoline-6-formonitrile HCN hydrochloride
Figure A0380336001152
To 3, (62g, 326mmol) mixture with water (100ml) adds NaOH (16.0g) to 3-diethoxy ethyl propionate, stirs simultaneously.Stir (opening flask) down at 110 ℃.After 40 minutes, mixture is uniformly, interrupts heating, makes mixture be cooled to room temperature.(approximately the dense HCl of 35ml pH3-2), extracts (4 * methylene dichloride) with the mixture acidifying.Combining extraction liquid, (1 * 50ml), dry (sal epsom) concentrates with the salt water washing.Obtain 48g oil.
Add thionyl chloride (80ml) to this oil droplet.Mixture was stirred 1 hour 30 minutes down at reflux (80 ℃).After concentrating carefully, resistates is weighed as 48g (theoretical weight should be 43g).Acyl chlorides is remained under-20 ℃ to spend the night.
This product is mixed with methylene dichloride (70ml), with 5/7 (approximately 230mmol) of this solution join the 4-bromaniline (34.5g, 201mmol) with methylene dichloride (150ml) solution of pyridine (50ml) in, with mixture shaken over night at room temperature.Mixture is filtered, gained solid washed with dichloromethane, drying obtains 21g N-(4-bromophenyl)-3-ethoxy propylene acid amides, is colorless solid.The mixture that adds entry (700ml) and concentrated hydrochloric acid (50ml) to filtrate.Shake postprecipitation and go out solid, leach, with methylene dichloride and AcOEt washing, drying.Obtain other 14.4g product.With filtrate extraction (3 * methylene dichloride), with the salt water washing once, drying concentrates.Obtain other 18g product.Total recovery: 53.4g.
(58.8g 218mmol) mixes with the ice-cold vitriol oil (390ml), and mixture is stirred 15 minutes (until almost all acrylamides dissolvings) down at 0 ℃ earlier, at room temperature stirs 4 hours again with this product.Mixture is poured in the frozen water (3L) then, placement is spent the night.Mixture is filtered, and solid washes with water.By acetonitrile, ethanol and methylene dichloride, solid transfer to flask, is under reduced pressure concentrated suspension.Resistates is suspended in the acetonitrile (300ml) again, is heated to backflow, at room temperature place and spend the night.Filter, the drying under reduced pressure solid obtains 31.3g (64%) 6-bromo-2-quinolone, is yellow solid.
With this quinolone (6.28g, 28.0mmol) with cupric cyanide (I) (5.02g, 56.1mmol) and NMP (15ml) mix, mixture was stirred 6 hours down at reflux (202 ℃), at room temperature stirring is spent the night then.Add entry (150ml), mixture is filtered, solid washes with water.Solid is suspended in the 1N hydrochloric acid (200ml) again, adds iron(ic) chloride (III) hexahydrate (17.8g).The gained mixture was at room temperature stirred 3 days, filter, solid is washed with water once, use the ethanol stripping, drying under reduced pressure obtains 4.33g (91%) 6-cyano group-2-quinoline promise copper, is gray solid.As described in common processes (B), with this product POCl 3, handle with 1-sec.-propyl piperazine again, obtain title compound.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.10(m，2H)，3.52(m，5H)，4.79(m，2H)，7.49(d，J＝8Hz，1H)，7.71(d，J＝8Hz，1H)，7.86(d，J＝8Hz，1H)，8.23(d，J＝8Hz，1H)，8.35(s，1H)，10.73(br?s，1H)；HPLC-MS：m/z?281(MH +)；Rt＝1.62min.
Embodiment 126 (common processes (B))
3-(4-cyclopropyl piperazine-1-yl)-6-phenyl pyridazine hydrochloride
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 3-chloro-6-phenyl pyridazine.
1H?NMR(DMSO-d 6)δ0.82(m，2H)，1.22(m，2H)，2.88(br?s，1H)，3.37(m，2H)，3.59(m，4H)，4.57(m，2H)，7.53(m，3H)，7.80(d，J＝8Hz，1H)，8.06(m，2H)，8.29(d，J＝8Hz，1H)，11.47(br?s，1H)；HPLC-MS：m/z281(MH +)；Rt＝1.43min.
Embodiment 127 (common processes (B))
3-(4-cyclopropyl piperazine-1-yl)-6-(3, the 4-Dimethoxyphenyl) pyridazine hydrochloride
Figure A0380336001172
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 3-chloro-6-(3, the 4-Dimethoxyphenyl) pyridazine.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.22(m，2H)，2.88(br?s，1H)3.36(m，2H)，3.60(m，4H)，3.84(s，3H)，3.87(s，3H)，4.53(m，2H)，7.14(d，J＝8Hz，1H)，7.66(m，2H)，7.86(d，J＝8Hz，1H)，8.37(d，J＝8Hz，1H)，11.43(br?s，1H)；HPLC-MS：m/z341(MH +)；Rt＝1.45min.
Embodiment 128 (common processes (B))
7-(4-sec.-propyl piperazine-1-yl)-2,3-dihydro-[1,4] dioxine is [2,3-g] quinoline also
Utilize common processes (B), from 1-sec.-propyl piperazine and 7-chloro-2,3-dihydro [1,4 ,] dioxine also [2,3-g] quinoline prepares this compound.
1H?NMR(DMSO-d 6)δ1.00(d，J＝7Hz，6H)，2.67(hept，J＝7Hz，1H)，3.33(s，4H)，3.56(m，4H)，4.29(m，4H)，6.95(s，1H)，7.02(d，J＝8Hz，1H)，7.13(s，1H)，7.84(d，J＝8Hz，1H)；HPLC-MS：m/z?314(MH +)；Rt＝1.14min.
Embodiment 129
2-(4-cyclopropyl-3-methylpiperazine-1-yl) quinoline hydrochloride
Figure A0380336001181
As Gillaspy, M.L.; Lefker, B.A.; Hada, W.A.; And Hoover, D.J.in Tetrahedron Lett.1995,36 (41), 7399-7402 is described, turns into this compound of preparation by the reductibility cyclopropyl of 2-(3-methylpiperazine-1-yl) quinoline.
1H?NMR(DMSO-d 6)δ0.82(m，1H)，1.00(m，2H)，1.41(m，1H)，1.56(d，J＝7Hz，3H)，2.76(m，1H)，3.25-3.80(m，5H)，4.81(m，2H)，7.44(br?s，1H)，7.55(m，1H)，7.72(m，1H)，7.88(m，1H)，8.11(br?s，1H)，8.37(br?s，1H)，11.40(br?s，1H)；HPLC-MS：m/z268(MH +)；Rt＝1.18min.
Embodiment 130 (common processes (B))
6-cyclo propyl methoxy-2-(4-cyclopropyl piperazine-1-yl) quinoline hydrochloride
Figure A0380336001182
Utilize common processes (B), prepare this compound from 1-sec.-propyl piperazine and 2-chloro-6-(cyclo propyl methoxy) quinoline.Required 2-chloro-6-(cyclo propyl methoxy) quinoline is to use POCl 3It is prepared to handle 6-(cyclo propyl methoxy)-2-quinolone.6-(cyclo propyl methoxy)-2-quinolone is from the preparation of the 6-hydroxyl quinolone of correspondence, in dimethyl formamide, in the presence of the catalytic amount sodium iodide, handles with (brooethyl) cyclopropane and salt of wormwood.
1H?NMR(DMSO-d 6)δ0.35(m，2H)，0.60(m，2H)，0.82(m，2H)，1.20(m，2H)，1.28(m，1H)，2.87(br?s，1H)，?3.25-4.20(m，6H)，3.92(d，J＝7Hz，2H)，4.70(m，2H)，7.30-7.60(m，3H)，8.08(br?s，1H)，8.32(br?s，1H)，11.37(br?s，1H)；HPLC-MS：m/z324(MH +)；Rt＝1.94min.
Embodiment 131 (common processes (B))
2-(4-sec.-propyl piperazine-1-yl)-6-pyrazol-1-yl quinoline hydrochloride
Figure A0380336001191
Utilize common processes (B), prepare this compound from 1-sec.-propyl piperazine and 2-chloro-6-(1-pyrazolyl) quinoline.Required 2-chloro-6-(1-pyrazolyl) quinoline is to use POCl 36-(1-pyrazolyl)-the 2-quinolone is prepared in processing.6-(1-pyrazolyl)-2-quinolone prepares according to following manner:
With 6-bromo-2-quinolone (3.58g, 16.0mmol), DMF (15ml), pyrazoles (1.66g, 24.4mmol), (3.33g, 24.1mmol) (0.76g, mixture 3.99mmol) stirred 22 hours down at 160 ℃ salt of wormwood with cupric iodide (I).Add entry (300ml), fully after the development, mixture is filtered, solid washes with water.With solid EtOH stripping, be suspended in again in acetonitrile and the alcoholic acid mixture (100ml, 1: 1), be heated to backflow, keep at room temperature spending the night.Filter, with some acetonitrile washings, drying under reduced pressure obtains 1.7g (50%) 6-(1-pyrazolyl)-2-quinolone, is the metal green solid.
1H?NMR(DMSO-d 6)δ1.32(d，J＝7Hz，6H)，3.10-3.70(m，7H)，4.81(m，2H)，6.60(m，1H)，7.56(d，J＝8Hz，1H)，7.81(s，1H)，8.09(m，1H)，8.22(d，J＝8Hz，1H)，8.32(s，1H)，8.38(d，J＝8Hz，1H)，8.58(m，1H)，11.11(br?s，1H)；HPLC-MS：m/z322(MH +)；Rt＝1.67min.
Embodiment 132 (common processes (B))
2-(4-sec.-propyl piperazine-1-yl) quinoline-6-alcohol hydrochloride
Utilize common processes (B), prepare this compound from 1-sec.-propyl piperazine and 2-chloro-6-hydroxyquinoline.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.15-3.90(m，7H)，4.79(m，2H)，7.22(m，1H)，7.33(d，J＝8Hz，1H)，7.53(d，J＝8Hz，1H)，8.13(br?s，1H)，8.35(d，J＝8Hz，1H)，10.17(brs，1H)，11.41(br?s，1H)；HPLC-MS：m/z?272(MH +)；Rt＝0.40min.
Embodiment 133 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl) quinoline-6-formonitrile HCN hydrochloride
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 2-chloro-6-cyano quinolines.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.15(m，2H)，2.87(brs，1H)，3.20-3.65(m，6H)，4.74(m，2H)，7.49(d，J＝8Hz，1H)，7.72(d，J＝8Hz，1H)，7.86(d，J＝8Hz，1H)，8.24(d，J＝8Hz，1H)，8.35(s，1H)，10.88(brs，1H)；HPLC-MS：m/z279(MH +)；Rt＝1.43min.
Embodiment 134 (common processes (B))
(9a-R)-2-(octahydro pyrido [1,2-a] pyrazine-2-yl) quinoline-6-formonitrile HCN hydrochloride
Figure A0380336001202
Utilize common processes (B), prepare this compound from (9a-R)-octahydro pyrido [1,2-a] pyrazine and 2-chloro-6-cyano quinolines.
1H?NMR(DMSO-d 6)δ1.40-1.60(m，1H)，1.65-2.00(m，5H)，2.85-3.65(m，7H)，4.80(m，2H)，7.53(d，J＝8Hz，1H)，7.79(d，J＝8Hz，1H)，7.89(d，J＝8Hz，1H)，8.26(d，J＝8Hz，1H)，8.37(s，1H)，11.31(br?s，1H)；HPLC-MS：m/z293(MH +)；Rt＝1.72min.
Embodiment 135 (common processes (B))
4-chloro-6-(4-sec.-propyl piperazine-1-yl)-3-phenyl pyridazine hydrochloride
Utilize common processes (B), from 1-sec.-propyl piperazine and 4,6-two chloro-3-phenyl pyridazines prepare this compound.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，3.13(m，2H)，3.40-3.65(m，5H)，4.63(m，2H)，7.50(m，3H)，7.63(m，2H)，7.78(s，1H)，11.01(br?s，1H)；HPLC-MS：m/z317(MH +)；Rt＝2.11min.
Embodiment 136 (common processes (B))
3-(4-cyclopropyl piperazine-1-yl)-6-(3-trifluoromethyl) pyridazine hydrochloride
Figure A0380336001212
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 3-chloro-6-(3-trifluoromethyl) pyridazine.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.22(m，2H)，2.89(br?s，1H)，3.35(m，2H)，3.59(m，4H)，4.63(m，2H)，7.68(d，J＝8Hz，1H)，7.77(m，1H)，7.84(m，1H)，8.32(d，J＝8Hz，1H)，8.40(m，2H)，11.40(br?s，1H)；HPLC-MS：m/z?349(MH +)；Rt＝2.43min.
Embodiment 137
1-[2-(4-sec.-propyl piperazine-1-yl) quinoline-6-yl] acetophenone hydrochloride
In tetrahydrofuran (THF), 2-(4-sec.-propyl piperazine-1-yl) quinoline-6-formonitrile HCN is handled with excessive methylmagnesium-bromide, prepared this compound.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，2.65(s，3H)，3.18(m，2H)，3.40-3.80(m，5H)，4.82(m，2H)，7.52(d，J＝8Hz，1H)，7.91(br?s，1H)，8.15(d，J＝8Hz，1H)，8.40(d，J＝8Hz，1H)，8.54(s，1H)，11.16(br?s，1H)；HPLC-MS：m/z298(MH +)；Rt＝1.47min.
Embodiment 138 (common processes (B))
3-(4-sec.-propyl piperazine-1-yl)-6-phenyl pyridazine-4-formonitrile HCN hydrochloride
Figure A0380336001221
Utilize common processes (B), prepare this compound from 1-sec.-propyl piperazine and 3-chloro-6-phenyl pyridazine-4-formonitrile HCN.
1H?NMR(DMSO-d 6)δ1.32(d，J＝7Hz，6H)，3.23(m，2H)，3.50-3.75(m，5H)，4.46(m，2H)，7.55(m，3H)，8.13(d，J＝7Hz，2H)，8.72(s，1H)，10.67(br?s，1H)；HPLC-MS：m/z?308(MH +)；Rt＝2.16min.
Embodiment 139 (common processes (B))
6-bromo-2-(4-sec.-propyl piperazine-1-yl) quinoline
Utilize common processes (B), prepare this compound from 1-sec.-propyl piperazine and 6-bromo-2-chloroquinoline.
1H?NMR(DMSO-d 6)δ1.00(d，J＝7Hz，6H)，2.52(m，4H)，2.69(sept，J＝7Hz，1H)，3.68(m，4H)，7.28(d，J＝8Hz，1H)，7.48(d，J＝8Hz，1H)，7.60(dd，J＝1Hz，8Hz，1H)，7.93(d，J＝1Hz，1H)，8.00(d，J＝8Hz，1H).
Embodiment 140 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl)-6-pyrazol-1-yl quinoline hydrochloride
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 2-chloro-6-pyrazol-1-yl quinoline.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.22(m，2H)，2.88(m，1H)，3.30-3.80(m，6H)，4.79(m，2H)，6.61(m，1H)，7.59(d，J＝6Hz，1H)，7.81(s，1H)，8.10-8.30(m，2H)，8.34(s，1H)，8.41(d，J＝6Hz，1H)，8.59(s，1H)，11.47(br?s，1H)；HPLC-MS：m/z320(MH +)；Rt＝1.64min.
Embodiment 141 (common processes (B))
7-chloro-2-(4-cyclopropyl piperazine-1-yl) quinoline-6-alcohol hydrochloride
Utilize common processes (B), from 1-cyclopropyl piperazine and 2,7-two chloro-6-hydroxyquinolines prepare this compound.Required 2,7-two chloro-6-hydroxyquinolines are preparations like this, in methylene dichloride, carry out 2 with boron tribromide, the demethylation of 7-two chloro-6-methoxy quinolines, the latter prepares from 3-chloro-4-anisidine, as F.Effenberger and W.Hartmann inChemische Berichte 1969,102,3260-3267 is described.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.14(m，2H)，2.88(m，1H)，3.20-3.80(m，6H)，4.61(m，2H)，7.32(s，1H)，7.42(m，1H)，7.96(m，1H)，8.21(m，1H)，10.65(br?s，1H)，10.84(br?s，1H)；HPLC-MS：m/z304(MH +)；Rt＝1.06min.
Embodiment 142
[2-(4-cyclopropyl piperazine-1-yl) quinoline-6-yl]-(4-fluorophenyl) ketone hydrochloride
In tetrahydrofuran (THF), 2-(4-cyclopropyl piperazine-1-yl) quinoline-6-formonitrile HCN is handled with excessive bromination (4-fluorophenyl) magnesium, prepared this product.
1H?NMR(DMSO-d 6)δ0.84(m，2H)，1.14(m，2H)，2.89(m，1H)，3.25-3.90(m，6H)，4.77(m，2H)，7.44(m，3H)，7.76(m，1H)，7.86(m，2H)，7.98(m，1H)，8.21(s，1H)，8.34(d，J＝8Hz，1H)，10.65(br?s，1H)；HPLC-MS：m/z376(MH +)；Rt＝2.61min.
Embodiment 143 (common processes (B))
Cyclopropyl-[2-(4-cyclopropyl piperazine-1-yl) quinoline-6-yl] ketone hydrochloride
Figure A0380336001242
In tetrahydrofuran (THF), 2-(4-cyclopropyl piperazine-1-yl) quinoline-6-formonitrile HCN is handled with excessive brominated propyl group magnesium, prepared this product.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.07(m，4H)，1.18(m，2H)，2.88(m，1H)，3.00(quint，J＝7Hz，1H)，3.30-3.70(m，6H)，4.76(m，2H)，7.50(d，J＝8Hz，1H)，7.82(br?s，1H)，8.18(d，J＝8Hz，1H)，8.37(d，J＝8Hz，1H)，8.66(s，1H)，11.05(br?s，1H)；HPLC-MS：m/z322(MH +)；Rt＝1.98min.
Embodiment 144 (common processes (B))
2-(4-cyclopropyl piperazine-1-yl)-6-(4-fluorine benzyloxy) quinoline hydrochloride
Utilize common processes (B), prepare this compound from 1-cyclopropyl piperazine and 2-chloro-6-(4-fluorine benzyloxy) quinoline.
1H?NMR(DMSO-d 6)δ0.83(m，2H)，1.20(m，2H)，2.87(m，1H)，3.30-3.80(m，6H)，4.70(m，2H)，5.18(s，2H)，7.25(t，J＝8Hz，2H)，7.54(m，5H)，8.08(br?s，1H)，8.33(m，1H)，11.34(brs，1H)；HPLC-MS：m/z?378(MH +)；Rt＝2.53min.
Embodiment 145
6-hexamethylene-1-thiazolinyl-2-(4-sec.-propyl piperazine-1-yl) quinoline hydrochloride
Figure A0380336001251
6-bromo-2-(4-sec.-propyl piperazine-1-yl) quinoline with butyllithium, again with the pimelinketone processing, is prepared this product.After the acid treatment, tertiary alcohol experience cancellation effect obtains title compound.
1H?NMR(DMSO-d 6)δ1.31(d，J＝7Hz，6H)，1.60-1.80(m，4H)，2.22(m，2H)，2.45(m，2H)，3.23(m，2H)，3.45-4.00(m，5H)，4.78(m，2H)，6.34(m，1H)，7.50(m，1H)，7.86(m，2H)，7.98(br?s，1H)，8.34(m，1H)，11.06(br?s，1H)；HPLC-MS：m/z336(MH +)；Rt＝2.50min.
Embodiment 146 (common processes (C))
1-(biphenyl-3-yl)-4-(cyclopentyl) piperazine
Figure A0380336001252
With 3-bromo biphenyl (300mg, 1.28mmol), 1-cyclopentyl-based piperazine (238mg, 1.54mmol), sodium tert-butoxide (173mg, 1.8mmol), three (dibenzalacetone) two palladium (12mg, 0.01mmol) and racemize 2,2 '-two (diphenyl phosphine)-1, (24mg, 0.04mmol) mixture in toluene (11ml) is blended in the reaction vessel of sealing under nitrogen 1 '-dinaphthalene.In the reaction vessel of sealing, reaction mixture was stirred 3 days down at 80 ℃.It is cooled to room temperature, washes (2 * 10ml) with water.Merge organic layer, with 1N hcl as extraction agent (2 * 20ml).Merge aqueous extraction liquid, transfer to alkalescence, with t-butyl methyl ether extraction (3 * 20ml) with the 1N aqueous sodium hydroxide solution.The t-butyl methyl ether layer is through dried over mgso.Remove in a vacuum and desolvate, obtain the 220mg title compound.
1H-NMR (CDCl 3, two groups of signals, bandwidth signals) and δ 1.35-1.85 (m, 6H); 1.95 (m, 2H); 2.55 (m, 1H); 2.70 (m, 4H); 3.30 (m, 4H); 6.95 (d, 1H); 7.05 (d, 1H); 7.15 (s, 1H); 7.35 (t, 2H); 7.45 (t, 2H); 7.60 (d, 2H) .HPLC method B: wash-out in the time of 10.45 minutes
The following hydrochloride that title compound is converted into it: it is dissolved in ethyl acetate (5ml).The ethyl acetate solution (5ml) that adds 3.2M hydrogenchloride.Remove in a vacuum and desolvate.Resistates is dissolved in ethanol (50ml).Remove in a vacuum and desolvate.
Embodiment 147 (common processes (C))
1-cyclopentyl-4-[4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl] piperazine
As described in about 1-(biphenyl-3-yl)-4-(cyclopentyl) piperazine, use 1-(2-(4-bromine phenoxy group) ethyl) tetramethyleneimine to replace the 3-bromo biphenyl, synthetic 86mg title compound.
1H-NMR (DMSO-d 6) δ 1.55 (m, 2H); 1.75 (m, 2H); 1.85 (m, 4H); 2.00 (m, 4H); 3.10 (m, 6H); 3.40-3.70 (m, 9H); 4.30 (t, 2H); 7.00 (AB, 4H); 10.80 (br, 1H); 11.10 (br, 1H) .HPLC method C: wash-out in the time of 2.24 minutes.MS: calculated value [M+H] +: 344; Measured value: 344.
Following title compound is converted into its hydrochloride, it is dissolved in ethyl acetate (5ml).The ethyl acetate solution (5ml) that adds 3.2M hydrogenchloride.Remove in a vacuum and desolvate.Resistates is dissolved in ethanol (50ml).Remove in a vacuum and desolvate.
Embodiment 148 (common processes (C))
1-(biphenyl-4-yl)-4-(cyclopentyl) piperazine
As described in about 1-(biphenyl-3-yl)-4-(cyclopentyl) piperazine, use the 4-bromo biphenyl to replace the 3-bromo biphenyl, synthetic 180mg title compound.
1H-NMR (CDCl 3) δ 1.80-2.00 (m, 8H); 2.55 (m, 1H); 2.70 (m, 4H); 3.20 (m, 4H); 7.00 (d, 2H); 7.30 (m, 1H); 7.40 (t, 2H); And 7.55 (m, together 4H), HPLC method C: wash-out in the time of 4.52 minutes.
Following title compound is converted into its hydrochloride, it is dissolved in ethyl acetate (5ml).The ethyl acetate solution (5ml) that adds 3.2M hydrogenchloride.Remove in a vacuum and desolvate.Resistates is dissolved in ethanol (50ml).Remove in a vacuum and desolvate.
Embodiment 149 (common processes (C))
[3-(4-(cyclopentyl) piperazine-1-yl) phenyl]-(4-fluorophenyl) ketone
Figure A0380336001272
As described in about 1-(biphenyl-3-yl)-4-(cyclopentyl) piperazine, use 3-bromo-4 '-fluorine benzophenone to replace the 3-bromo biphenyl, synthetic 300mg title compound.
1H-NMR (CDCl 3) δ 1.45 (m, 2H); 1.60 (m, 2H); 1.75 (m, 2H); 1.90 (m, 2H); 2.55 (quintet, 1H); 2.70 (m, 4H); 3.30 (m, 4H); 7.15 (m, 4H); 7.35 (m, 2H); 7.85 (m, 2H) .HPLC method C: wash-out in the time of 4.22 minutes.MS: calculated value [M+H] +: 353; Measured value: 353.
Following title compound is converted into its hydrochloride, it is dissolved in ethyl acetate (5ml).The ethyl acetate solution (5ml) that adds 3.2M hydrogenchloride.Remove in a vacuum and desolvate.Resistates is dissolved in ethanol (50ml).Remove in a vacuum and desolvate.
Following compounds also belongs to scope of the present invention:
Figure A0380336001281
Pharmacological method
Following external binding assay can be measured compound and the interactional ability of histamine H 3 receptor.
Binding assay I
With rat cerebral cortex at ice-cold K-Hepes, 5mM MgCl 2Homogenize in the pH7.1 damping fluid.Behind twice differential centrifugation, back one pellet is suspended in the fresh Hepes damping fluid that contains the 1mg/ml bacitracin again.The aliquots containig (400 μ g/ml) of film suspension is descended and 30pM[at 25 ℃ 125I]-iodoproxifan (a kind of known histamine H 3 receptor antagonists) and different concns test compound cultivated 60 minutes.Cultivation is such terminated, with ice-cold substratum dilution, filters with 1 hour Whatman GF/B filter of 0.5% polymine pre-treatment succeeded by rapid passing through.Utilize the radioactivity that is kept on the automatic gamma counter counting of the Cobra II filter.The radioactivity of filter and the binding affinity of test compound are proportional indirectly.By nonlinear regression analysis, analytical results.
Binding assay II
With H3 receptor stimulant part R-Alpha-Methyl [ 3H] histamine (RAMHA) and isolated rat cortex cell film cultivated 1 hour down at 25 ℃, cultivates thing succeeded by filtering by Whatman GF/B filter.Utilize the radioactivity that is kept on the β counter measures filter.
(150-200g) beheads with male Wistar rat, cuts pallium fast, is chilled on the dry ice immediately.Tissue is kept under-80 ℃ until membrane prepare.During membrane prepare, will organize always to be kept on ice.Utilize the Ultra-Turrax homogenizer with rat cerebral cortex at the ice-cold Hepes damping fluid of 10 volumes (w/w) (20mM Hepes, 5mM MgCl 2PH7.1 (KOH)+1mg/ml bacitracin) homogenized 30 seconds in.With tissue homogenate under 140g centrifugal 10 minutes.Supernatant liquor is transferred to new test tube, under 23000g centrifugal 30 minutes.Pellet is suspended in the 5-10ml Hepes damping fluid again, homogenizes, under 23000g centrifugal 10 minutes.This short centrifugation step repeats twice.After for the last time centrifugal, pellet is suspended in the 2-4mlHepes damping fluid again, measures protein concn.It is 5mg/ml that film is diluted to protein concn with the Hepes damping fluid, and five equilibrium is stored in-80 ℃ and descends standby.
Mixing 50 μ l test compounds, 100 μ l films (200 μ g/ml), 300 μ l Hepes damping fluids and 50 μ l R-Alpha-Methyls in test tube [ 3H] histamine (1nM).The compound that will test is dissolved in DMSO, further at H 2Be diluted to desired concn among the O.Radioligand and film are diluted in Hepes damping fluid+1mg/ml bacitracin.Mixture was cultivated 60 minutes down at 25 ℃.Cultivation is such terminated, adds the ice-cold 0.9%NaCl of 5ml, filters with 1 hour Whatman GF/B filter of 0.5% polymine pre-treatment succeeded by rapid passing through.Filter is washed with the ice-cold NaCl of 2 * 5ml.Add 3ml flicker cocktail reagent, the radioactivity of utilizing PackardTri-Carb β counter measures to be kept to every filter.Utilize Windows program GraphPadPrism, GraphPad Software, USA calculates IC by the nonlinear regression analysis of binding curve (minimum 6 points) 50Value.
Binding assay III
By PCR human cloning H3 acceptor, subclone is to the pcDNA3 expression vector.To HEK 293 cells, and use G418 to select the H3 clone body by transfection H3 expression vector, generate the cell of stably express H3 acceptor.At 37 ℃ and 5%CO 2People H3-HEK 293 clone body are cultivated in containing the DMEM (GIBCO-BRL) of glutamax, 10% foetal calf serum, 1% penicillin/streptavidin and 1mg/mlG418 down.Before results, fused cell is cleaned with PBS, (proteolytic enzyme GIBCO-BRL) was cultivated about 5 minutes with Versene.Cell with PBS and DMEM flushing, is collected in cell suspension in the test tube in Heraeus Sepatech Megafuge 1.0, under 1500rpm centrifugal 5-10 minute.Pellet is suspended in 10-20 volume Hepes damping fluid (20mM Hepes, 5mM MgCl again 2, pH7.1 (KOH)) in, utilize the Ultra-Turrax homogenizer to homogenize 10-20 second.With tissue homogenate under 23000g centrifugal 30 minutes.Pellet is suspended in the 5-10ml Hepes damping fluid again, utilizes Ultra-Turrax to homogenize 5-10 second, under 23000g centrifugal 10 minutes.After this centrifugation step, the film pellet is suspended in the 2-4ml Hepes damping fluid again, utilize syringe or teflon homogenizer to homogenize, measure protein concn.It is 1-5mg/ml that film is diluted to protein concn with the Hepes damping fluid, and five equilibrium is kept at-80 ℃ and descends standby.
The aliquots containig of film suspension is descended and 30pM[at 25 ℃ 125I]-iodoproxifan (a kind of known compound that the H3 acceptor is had high-affinity) and different concns test compound cultivated 60 minutes.Cultivation is such terminated, with ice-cold substratum dilution, filters with 1 hour Whatman GF/B filter of 0.5% polymine pre-treatment succeeded by rapid passing through.Utilize the radioactivity that is kept on the automatic gamma counter counting of the Cobra II filter.The radioactivity of filter and the binding affinity of test compound are proportional indirectly.By nonlinear regression analysis, analytical results.
When test, formula of the present invention (I) compound generally shows high binding affinity to histamine H 3 receptor.
Preferably, measure as one or multinomial assay method, according to the IC of compound of the present invention 50Value is more preferably less than 1 μ M, and then is more preferably less than 500nM, for example less than 100nM less than 10 μ M.
Functional examination method I
Adopt the film of HEK 293 cells of expressing human H3 acceptor, the ability of measuring compound and histamine H 3 receptor interaction, serving as agonist, inverse agonist and/or antagonist by external functional examination method.
By PCR clone H3 acceptor, subclone is to the pcDNA3 expression vector.To HEK 293 cells, and use G418 to select the H3 clone body by transfection H3 expression vector, generate the cell of stably express H3 acceptor.At 37 ℃ and 5%CO 2People H3-HEK 293 clone body are cultivated in the DMEM that contains glutamax, 10% foetal calf serum, 1% penicillin/streptavidin and 1mg/mlG418 down.
With H3 expression of receptor cell once, with Versene (GIBCO-BRL) results with phosphate buffered saline (PBS) (PBS) washing.Add PBS, with cell under 188g centrifugal 5 minutes.With the cell pellet be suspended in again stimulate in the damping fluid to concentration be 1 * 10 6Cell/ml.Utilize FlashPlate  cAMP assay method (NEN TMLife Science Products) measures accumulating of cAMP.Measure and generally as described in manufacturer, carry out.In brief, add 50 μ l cell suspensions to the every hole of Flashplate, wherein also contain 25 μ l, 40 μ M Racemic isoproterenols to stimulate generation and the 25 μ l test compounds (independent agonist or inverse agonist, the perhaps combination of agonist and antagonist) of cAMP.Mensuration can be carried out according to " agonist pattern ", this means the test compound that adds independent progressive concentration to cell, measures cAMP.If cAMP rises, it is a kind of inverse agonist so; If cAMP does not change, it is a kind of neutral antagonist so; If cAMP descends, it is a kind of agonist so.Measure and also can carry out, this means the test compound of adding progressive concentration and the known H3 agonist (for example RAMHA) of progressive concentration according to " antagonist pattern ".If compound is a kind of antagonist, its progressive concentration causes H3 agonist dose response curve to be offset to the right so.Final volume in every hole is 100 μ l.Test compound is dissolved in DMSO, uses H 2The O dilution.Mixture was shaken 5 minutes, at room temperature placed 25 minutes.With every hole 100 μ l " detection mixture " termination reaction.With the flat board plastic seal, shook 30 minutes then, placement is spent the night, and counts radioactivity at last in the automatic γ Top of Cobra II counter.Utilize GraphPad Prism, calculate EC by the nonlinear regression analysis of dose response curve (minimum 6 points) 50Value.By Schild map analysis calculating K b value.
Functional examination method II
By by name [ 35S] the functional examination method of the GTP γ S assay method ability measuring compound and people H3 receptors bind and interaction, serve as agonist, inverse agonist and/or antagonist.This assay method by guanosine 5 '-triphosphoric acid (GTP) displacement, is measured the proteic activation of G by guanosine 5 '-bisphosphate (GDP) in catalysis α-subunit.Dissociate into two subunits, G α with GTP bonded G albumen GTPWith G β γ, they regulate desmo enzyme and ionic channel then.GTP is by G alpha subunit (GTP enzyme) hydrolysis rapidly, and G albumen inactivation is prepared to enter new GTP period of a permutation.
Increase the activatory function in order to study part inductive g protein coupled receptor (GPCR) because of the proteic guanylic acid displacement of G, measured [ 35S]-guanosine-5 '-O-(3-sulfo-) triphosphoric acid [ 35S] combination of GTP γ S, it is the non-hydrolysis analogue of GTP.Following can this process of external monitoring, will contain the cytolemma of g protein coupled receptor H3 and GDP and [ 35S] GTP γ S cultivation.Cytolemma is to obtain from the Chinese hamster ovary celI of stably express people H3 acceptor.With cell PBS washed twice, use PBS+1mM EDTA, pH7.4 results, under 1000rpm centrifugal 5 minutes.Utilize the Ultra-Turrax homogenizer that the cell pellet was homogenized 30 seconds in the ice-cold Hepes damping fluid of 10ml (20mMHepes, 10mM EDTA pH7.4 (NaOH)), 20, under the 000rpm centrifugal 15 minutes.After this centrifugation step, the film pellet is suspended in the ice-cold Hepes damping fluid of 10ml (20mM Hepes, 0.1mM EDTA pH7.4 (NaOH)) again, homogenize as mentioned above.This technology repeats twice, except the homogenization step, measures protein concn for the last time, and it is 2mg/ml that film is diluted to protein concn, and five equilibrium is kept at-80 ℃ and descends standby.
For existence and the effectiveness of studying inverse agonist/antagonist, add H3 receptor stimulant part R-Alpha-Methyl histamine (RAMHA).Measure test compound and offset the ability of RAMHA effect.In the time spent of doing of research agonist, do not add RAMHA to measuring medium.Test compound is being measured damping fluid (20mM HEPES, 120mM NaCl, 10mM MgCl 2PH 7.4 (NaOH)) is diluted to different concns in, succeeded by adding 10 -8NM RAMHA (only under the situation of checking inverse agonist/antagonist), 3 μ M GDP, 2.5 μ g films, 0.5mg SPA bead and 0.1nM[ 35S] GTP γ S, at room temperature slightly shake and cultivated 2 hours.With flat board under 1500rpm centrifugal 10 minutes, utilize Top counter measures radioactivity.By the nonlinear regression analysis result, measure IC 50Value.
RAMHA and the stimulation of other H3 agonists [ 35S] GTP γ S combines with the film of expressing the H3 acceptor.In antagonist/inverse agonist test, measure the incremental change test compound and suppress by 10 -8The MRAMHA increase [ 35S] GTP γ S bonded ability, show as the minimizing of radiated signal.The antagonist IC that is measured 50Value is that this compound suppresses 10 -8M RAMHA effect reaches 50% ability.In the agonist test, measure the ability of incremental change test compound, show as the increase of radiated signal.The agonist EC that is measured 50Value is that this compound increase signal reaches 10 -550% ability of M RAMHA gained peak signal.
Preferably, measure as one or multinomial assay method, according to the IC of antagonist of the present invention and agonist 50/ EC 50Value preferably less than 1 μ M, and then is more preferably less than 500nM, for example less than 100nM less than 10 μ M.
The plan of the open cage rat model of feeding
Utilize the plan of open cage in the body rat model of feeding to measure the ability that The compounds of this invention reduces body weight.
Buy Sprague-Dawley (SD) male rat from M φ lleg  rd Breeding and Research Centre A/S (Denmark), about 1.5 to 2 monthly ages of size, the about 200-250g of body weight.After arrival, allow them to adapt to several days, be placed on then in the plastics cage of independent opening.Make them get used to food every day (Altromin pelleted rat chow) and in cage, only have 7 hours, from 07.30 to 14.30, last a week.Water is freely to obtain.Along with the consumption of food reached stable after 7 to 9 days, animal prepares to come into operation.
Every animal is only used once, with the delay effect between avoiding disposing.At duration of test, preceding 30 minutes of beginning with compound intraperitoneal or oral administration.Give the test compound of various dose to a treated animal, give carrier to control animals.The picked-up of 1,2 and 3 hour monitoring food and water after administration.
Any side effect can be found rapidly (tubbiness rolls, dense hair etc.), because animal is limited in the transparent plastics cage, can carry out the successive monitoring.

Claims (74)

1, general formula (II) compound:
Figure A038033600002C1
Wherein
R 2Be hydrogen or C 1-4-alkyl,
(i) R 1Representative
Side chain C 4-6-alkyl, side chain C 4-6-thiazolinyl or side chain C 4-6-alkynyl, its condition is R 1Not isobutyl-,
C 3-5-cycloalkyl, C 3-7-cycloalkenyl group, C 3-6-cycloalkyl-C 1-3-alkyl or C 3-6-cycloalkenyl group-C 1-3-alkyl,
R 1And R 2Constitute C together 3-6-alkylidene bridge and
The A representative
Or
Figure A038033600002C3
Perhaps
(ii) R 1Representative
Ethyl, n-propyl or sec.-propyl,
R 1And R 2Constitute C together 3-6-alkylidene bridge and
The A representative
Or
R 3Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-10-alkyl, C 2-10-thiazolinyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, aryl, aryl-C 1-6-alkyl, amino, C 1-6-alkylamino, two-C 1-6-alkylamino, C 3-8-cycloalkyl, C 3-8-cycloalkyloxy, cyano group, nitro, C 1-6-alkylthio or C 1-6-alkyl sulphonyl,
Z and X represent independently-N=,-C (H)=,-C (F)=,-C (Cl)=,-C (CN)=or-C (CF 3)=,
W representative-N=or-C (R 10)=,
Y representative-N=or-C (R 11)=,
R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy ,-SCF 3, amino, cyano group, nitro or-C (=O) NR 14R 15,
C 1-10-alkyl, C 2-10-thiazolinyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, C 3-8-cycloalkyl-C 1-6-alkoxyl group, C 1-6-alkylamino, two-C 1-6-alkylamino, C 3-8-cycloalkyloxy, C 1-6-alkylthio, C 1-6-alkyl sulphonyl, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 3-8-heterocyclic radical or C 4-9-heterocycle alkyloyl, C 4-9The heterocycle alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl, aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or heteroaryl, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryloxy, arylamino or heteroaryl amino, they can be alternatively by one or more R that are selected from 18Substituting group replace,
Perhaps R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkylidene group-O-bridge,
R 14And R 15Be hydrogen, C independently 1-6-alkyl, aryl-C 1-6-alkyl, perhaps R 14And R 15Can constitute C together 3-6-alkylidene bridge,
R 16Be independently selected from aryl, heteroaryl, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR 19R 20And C 1-6-alkoxyl group,
R 17Be independently selected from halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, C 1-6-alkyl, amino, C 1-6-alkyl sulphonyl, C 1-6-alkylamino, two-C 1-6-alkylamino, cyano group, aryl, heteroaryl and C 3-8-cycloalkyl,
R 18Be independently selected from aryl, heteroaryl, C 1-10-alkyl, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, cyano group, amino, C 1-6-alkylamino, two-C 1-6-alkylamino and hydroxyl,
R 19And R 20Be hydrogen or C independently 1-6-alkyl, R 19And R 20Can constitute C together 3-6-alkylidene bridge,
Its condition is that this compound must not be
Figure A038033600005C1
Or
And arbitrarily diastereomer or enantiomorph or change form, comprise their mixture or its pharmacy acceptable salt.
2, according to the compound of claim 1, R wherein 1Be side chain C 4-6-alkyl, C 3-5-cycloalkyl or C 3-6-cycloalkyl-C 1-3-alkyl, its condition is R 1It or not isobutyl-.
3, according to the compound of claim 2, R wherein 1Be 1,1-(dimethyl) propyl group, 1-ethyl propyl, cyclopropyl methyl, cyclopropyl, cyclobutyl, cyclopentyl or 1-cyclopropyl-1-methylethyl.
4, according to the compound of claim 3, R wherein 1Be 1-ethyl propyl, cyclopropyl methyl, cyclopropyl or cyclopentyl.
5, according to the compound of claim 1, R wherein 1Be side chain C 4-6-alkyl or C 3-5-cycloalkyl, its condition is R 1It or not isobutyl-.
6, according to the compound of claim 5, R wherein 1Be 1-ethyl propyl, cyclopropyl or cyclopentyl.
7, the compound any according to claim 1 to 6, wherein Z be-C (H)=,-N=or-C (F)=.
8, according to the compound of claim 7, wherein Z be-C (H)=or-N=.
9, compound according to Claim 8, wherein Z be-C (H)=.
10, compound according to Claim 8, wherein Z is-N=.
11, the compound any according to claim 1 to 10, wherein X be-C (H)=,-N=or-C (F)=.
12, according to the compound of claim 11, wherein Z be-C (H)=or-N=.
13, according to the compound of claim 12, wherein Z be-C (H)=.
14, according to the compound of claim 12, wherein Z is-N=.
15, the compound any according to claim 1 to 14, wherein W is-N=.
16, the compound any according to claim 1 to 14, wherein W is-C (R 10)=.
17, the compound any according to claim 1 to 16, wherein Y is-N=.
18, the compound any according to claim 1 to 16, wherein Y is-C (R 11)=.
19, the compound any, wherein R according to claim 1 to 18 2Be hydrogen.
20, the compound any, wherein R according to claim 1 to 18 2Be C 1-4-alkyl.
21, according to the compound of claim 20, R wherein 2Be methyl or ethyl.
22, according to general formula (III) compound of claim 1
Figure A038033600008C1
Wherein A and R 3Be defined as claim 1.
23, the compound any, wherein R according to claim 1 to 22 3Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-10-alkyl, C 1-6-alkoxyl group, aryl, aryl-C 1-6-alkyl, amino, C 3-8-cycloalkyl, C 3-8-cycloalkyloxy, cyano group or nitro.
24, according to the compound of claim 23, R wherein 3Be hydrogen, halogen, hydroxyl, trifluoromethyl, C 1-10-alkyl, C 1-6-alkoxyl group, cyano group or nitro.
25, according to the compound of claim 24, R wherein 3Be hydrogen, halogen, hydroxyl, trifluoromethyl, C 1-6-alkyl or cyano group.
26, according to the compound of claim 25, R wherein 3Be hydrogen, halogen or C 1-6-alkyl.
27, according to the compound of claim 25, R wherein 3Be hydrogen or methyl.
28, the compound any, wherein R according to claim 1 to 27 4, R 5, R 6, R 7, R 8And R 9Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy ,-SCF 3, amino or cyano group,
C 1-10-alkyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, C 3-8-cycloalkyloxy, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 3-8-heterocyclic radical or C 4-9-heterocycle alkyloyl, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl, aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or heteroaryl, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryloxy, they can be alternatively by one or more R that are selected from 18Substituting group replace,
Perhaps R 5, R 6, R 7, R 8, R 9Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkyl-O-bridge.
29, according to the compound of claim 28, R wherein 4, R 5, R 6, R 7, R 8And R 9Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy ,-SCF 3Or cyano group,
C 1-10-alkyl, C 1-6-alkoxyl group, C 3-8-cycloalkyloxy, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl or aryl-C 1-6-alkyl, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl or aryloxy, they can be alternatively by one or more R that are selected from 18Substituting group replace,
Perhaps R 5, R 6, R 7, R 8, R 9Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkyl-O-bridge.
30, according to the compound of claim 28, R wherein 4, R 5, R 6, R 7, R 8And R 9Representative independently
Hydrogen, halogen or cyano group,
C 1-10-alkyl or C 1-6-alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl is alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl or aryloxy, they can be alternatively by one or more R that are selected from 18Substituting group replace,
Perhaps R 5, R 6, R 7, R 8, R 9Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkyl-O-bridge.
31, according to the compound of claim 30, C wherein 1-10-alkyl represent methyl, ethyl, propyl group or sec.-propyl.
32, according to the compound of claim 30, C wherein 1-6-alkoxyl group representation methoxy, oxyethyl group or propoxy-.
33, according to the compound of claim 32, C wherein 1-6-alkoxyl group representation methoxy.
34, according to the compound of claim 30, wherein aryl is represented phenyl.
35, according to the compound of claim 30, wherein aroyl representative-C (=O)-phenyl.
36, according to the compound of claim 30, aryloxy representative-O-phenyl wherein.
37, according to the compound of claim 1, R wherein 1Be ethyl or sec.-propyl.
38, according to the compound of claim 37, R wherein 1It is sec.-propyl.
39, according to the compound of claim 37, R wherein 1It is ethyl.
40, according to the compound of claim 39, R wherein 1And R 2Constitute C together 3-4-alkylidene bridge.
41, the compound any, wherein R according to claim 37 to 40 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano group or-C (=O) NR 14R 15,
C 1-10-alkyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 3-8-heterocyclic radical, C 4-9-heterocycle alkyloyl, C 4-9-heterocycle alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl, aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or heteroaryl, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl is alternatively by one or more R that are selected from 18Substituting group replace perhaps R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge.
42, according to the compound of claim 41, R wherein 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano group or-C (=O) NR 14R 15,
C 1-10-alkyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 3-8-heterocyclic radical or C 4-9-heterocycle alkyloyl, C 4-9-heterocycle alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl, aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or heteroaryl, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl is alternatively by one or more R that are selected from 18Substituting group replace perhaps R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge.
43, according to the compound of claim 42, wherein 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, trifluoromethyl or-C (=O) NR 14R 15,
C 1-10-alkyl, C 1-6-alkoxyl group, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 4-9-heterocycle alkyloyl or C 4-9-heterocycle alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl, aryl-C 1-6-alkyl or aryl-C 1-6-alkoxyl group, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl is alternatively by one or more R that are selected from 18Substituting group replace perhaps R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge.
44, according to the compound of claim 43, R wherein 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, trifluoromethyl or-C (=O) NR 14R 15,
C 1-10-alkyl or C 4-9-heterocycle alkyloyl, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl is alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl is alternatively by one or more R that are selected from 18Substituting group replace perhaps R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge.
45, according to the compound of claim 44, C wherein 1-10-alkyl represent methyl, ethyl or propyl group.
46, according to the compound of claim 44, C wherein 4-9-heterocycle alkyloyl is represented piperidines-alkyloyl or tetramethyleneimine-alkyloyl.
47, according to the compound of claim 44, wherein aryl is represented phenyl.
48, the compound any, wherein R according to claim 1 to 47 14And R 15Be methyl, ethyl or benzyl independently.
49, the compound any, wherein R according to claim 1 to 48 16Be halogen, trifluoromethyl, trifluoromethoxy and C 1-6-alkoxyl group.
50, the compound any, wherein R according to claim 1 to 49 17Be halogen, hydroxyl, trifluoromethyl, C 1-6-alkoxyl group, C 1-6-alkyl, C 1-6-alkyl sulphonyl or cyano group.
51, according to the compound of claim 50, R wherein 17Be halogen, trifluoromethyl, C 1-6-alkoxyl group or C 1-6Alkyl sulphonyl.
52, the compound any, wherein R according to claim 1 to 51 18Be C 1-10-alkyl, halogen, trifluoromethyl, C 1-6-alkoxyl group, cyano group, amino and hydroxyl.
53, according to the compound of claim 52, R wherein 18Be halogen, C 1-6-alkoxyl group and hydroxyl.
54, according to the purposes of any one compound of claim 1 to 53 formerly as pharmaceutical composition.
55, pharmaceutical composition, comprise at least a according to any one compound of claim 1 to 53 as activeconstituents and one or more pharmaceutically acceptable carrier or vehicle.
56, according to the pharmaceutical composition of claim 55, be unit dosage, comprise about 0.05mg to about 1000mg, preferred extremely about 500mg, especially preferred about 0.5mg about 200mg compound any extremely of about 0.1mg according to claim 1 to 53.
57, general formula (II ') compound
Figure A038033600012C1
Wherein
R 2Be hydrogen or C 1-4-alkyl,
R 1Representative
C 1-8-alkyl, C 2-8-thiazolinyl or C 2-8-alkynyl, they can be replaced by one or more halogenic substituents alternatively,
C 3-5-cycloalkyl, C 3-7-cycloalkenyl group, C 3-6-cycloalkyl-C 1-3-alkyl or C 3-6-cycloalkenyl group-C 1-3-alkyl, they can be replaced by one or more halogenic substituents alternatively,
R 1And R 2Constitute C together 3-6-alkylidene bridge,
The A representative
Or
Figure A038033600012C3
R 3Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-10-alkyl, C 2-10-thiazolinyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, aryl, aryl-C 1-6-alkyl, amino, C 1-6-alkylamino, two-C 1-6-alkylamino, C 3-8-cycloalkyl, C 3-8-cycloalkyloxy, cyano group, nitro, C 1-6-alkylthio or C 1-6-alkyl sulphonyl,
Z and X represent independently-N=,-C (H)=,-C (F)=,-C (Cl)=,-C (CN)=or-C (CF 3)=,
W representative-N=or-C (R 10)=,
Y representative-N=or-C (R 11)=,
R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12And R 13Representative independently
Hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy ,-SCF 3, amino, cyano group, nitro or-C (=O) NR 14R 15,
C 1-10-alkyl, C 2-10-thiazolinyl, C 3-8-cycloalkyl, C 1-6-alkoxyl group, C 3-8-cycloalkyl-C 1-6-alkoxyl group, C 1-6-alkylamino, two-C 1-6-alkylamino, C 3-8-cycloalkyloxy, C 1-6-alkylthio, C 1-6-alkyl sulphonyl, C 2-10-alkyloyl, C 4-9-cycloalkanes acyl group, C 3-8-heterocyclic radical or C 4-9-heterocycle alkyloyl, C 4-9-heterocycle alkoxyl group, they can be alternatively by one or more R that are selected from 16Substituting group replace,
Aryl, aryl-C 1-6-alkyl, aryl-C 1-6-alkoxyl group or heteroaryl, they can be alternatively by one or more R that are selected from 17Substituting group replace,
Aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryloxy, arylamino or heteroaryl amino, they can be alternatively by one or more R that are selected from 18Substituting group replace,
Perhaps R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12And R 13Two of middle consecutive position constitute C together 1-6-alkylidene bridge or-O-C 1-6-alkylidene group-O-bridge,
R 14And R 15Be hydrogen, C independently 1-6-alkyl, aryl-C 1-6-alkyl, perhaps R 14And R 15Can constitute C together 3-6-alkylidene bridge,
R 16Be independently selected from aryl, heteroaryl, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR 19R 20And C 1-6-alkoxyl group,
R 17Be independently selected from halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, C 1-6-alkyl, amino, C 1-6-alkyl sulphonyl, C 1-6-alkylamino, two-C 1-6-alkylamino, cyano group, aryl, heteroaryl and C 3-8-cycloalkyl,
R 18Be independently selected from aryl, heteroaryl, C 1-10-alkyl, C 3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6-alkoxyl group, cyano group, amino, C 1-6-alkylamino, two-C 1-6-alkylamino and hydroxyl,
R 19And R 20Be hydrogen or C independently 1-6-alkyl, R 19And R 20Can constitute C together 3-6-alkylidene bridge,
And arbitrarily diastereomer or enantiomorph or change form, comprise their mixture, or the purposes of its pharmacy acceptable salt in preparation of pharmaceutical compositions, this pharmaceutical composition is used for the treatment of obstacle and the disease that relates to histamine H 3 receptor.
58, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition is used for the treatment of and wherein suppresses disease and the obstacle that the H3 Histamine Receptors has beneficial effect.
59, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition has histamine H 3 antagonistic activities or histamine H 3 anti-agonist activities.
60, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition is used to reduce body weight.
61, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition is used for the treatment of overweight or fat.
62, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition is used for depress appetite or brings out satiety.
63, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition is used to prevent and/or treat and relates to overweight or fat obstacle and disease.
64, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition is used to prevent and/or treat eating disorder, for example Bulimia nerovsa and binge eating.
65, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition is used for the treatment of IGT.
66, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition is used for the treatment of diabetes B.
67, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition is used to delay or prevents that IGT from developing into diabetes B.
68, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition is used to delay or prevents that non-insulin demand type diabetes B from developing into insulin requirements type diabetes B.
69, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition is used for the treatment of disease and the obstacle that its moderate stimulation H3 Histamine Receptors has beneficial effect.
70, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition has histamine H 3 agonist activities.
71, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition is used for the treatment of rhinallergosis, ulcer or anorexia.
72, as the purposes of the defined compound of claim 57 in preparation of pharmaceutical compositions, this pharmaceutical composition is used for the treatment of Alzheimer, lethargy or distractibility disease.
73, treatment relates to the obstacle of H3 Histamine Receptors or the method for disease, this method comprise when needed to the curee give significant quantity as the defined compound of claim 57 or according to the pharmaceutical composition of claim 55 or 56.
74, according to the method for claim 73, wherein the significant quantity of compound be every day about 0.05mg to about 2000mg, preferred extremely about 1000mg, especially preferred about 0.5mg about 500mg extremely of about 0.1mg.
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