CN1617743A - New pharmaceutical combinations for nos inhibitors - Google Patents

New pharmaceutical combinations for nos inhibitors Download PDF

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Publication number
CN1617743A
CN1617743A CNA008078785A CN00807878A CN1617743A CN 1617743 A CN1617743 A CN 1617743A CN A008078785 A CNA008078785 A CN A008078785A CN 00807878 A CN00807878 A CN 00807878A CN 1617743 A CN1617743 A CN 1617743A
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CN
China
Prior art keywords
pyridine
phenyl
amino
base
base amine
Prior art date
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Pending
Application number
CNA008078785A
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Chinese (zh)
Inventor
M·D·萨尔塔利
J·A·勒沃三世
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Pfizer Products Inc
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Pfizer Products Inc
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Publication of CN1617743A publication Critical patent/CN1617743A/en
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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Abstract

The present invention relates to new pharmaceutical uses for compounds that exhibit activity as nitric oxide synthase (NOS) inhibitors. Specifically, it relates to the use of NOS inhibitors, particularly selective neuronal NOS (nNOS) inhibitors, alone or in combination with another active agent, in particular, either an SSRI or an NK-1 receptor antagonist, for the treatment of disorders or conditions the treatment which can be effected or facilitated by altering circadian rhythms. Examples of such disorders and conditions are blindness, obesity, seasonal affective disorder, bipolar disorder, jet lag, circadian sleep rhythms disorder, sleep deprivation, parasomnias, REM sleep disorders, hypersomnia, sleep-wake cycle disorders, narcolepsy and sleep disorders associated with shift work or irregular work schedules; nocturnal enuresis, and restless-legs syndrome.

Description

The novel drugs use in conjunction that is used for nitric oxide synthase inhibitors
Background of the present invention
The present invention relates to demonstrate active is the novel drugs application of the chemical compound of nitricoxide synthase (NOS) inhibitor.Specifically, the present invention relates to no inhibitor, especially selective neuronal NOS (nNOS) inhibitor combines separately or with other activating agent and is used for the treatment of the purposes of some diseases and symptom, and this treatment can be implemented or promotes by changing physiological rhythm.This type of disease and examples of disorders are blind, obesity, seasonal affective disorder, dipolar disease; Trouble with jet lag, sleep rhythm disorders round the clock, the sleep function forfeiture, the fast sleep disease, hypersomnia disease, the disease of sleeping deeply, Sleep-Wake cycle disorder disease, narcolepsy disease with shiftwork or the relevant sleep disorder of irregular operating schedule; Nocturnal enuresis and insufficient lower limb complication that causes of having a rest.
The conjugate that the present invention relates to no inhibitor and nk 1 receptor antagonist (for example, Substance P receptor antagonist) in addition combines separately or with one or more other activating agents and is used for the treatment of the purposes of any aforementioned disease.The invention still further relates to the conjugate of no inhibitor and selective serotonin reuptake inhibitor (SSRI), optional combining with one or more other activating agents is used for the treatment of the purposes of any aforementioned disease.The conjugate that the invention still further relates to no inhibitor and nk 1 receptor antagonist and SSRI combines separately or with one or more other activating agents and is used for the treatment of the purposes of any aforementioned disease.
The form (iNOS) of three kinds of known isomers forms of NOS-derivable and the form of two kinds of compositions are arranged now, be called neuronal NOS (nNOS) and endothelial NO S (eNOS) respectively.In these enzymes each is carried out the conversion of arginine to citrulline, and has produced nitric oxide (NO) molecule that responds various stimulations simultaneously.It is believed that too much nitric oxide (NO) generation that is caused by NOS can cause the pathological change of interior many diseases of mammalian body and symptom.For example, the NO that is produced by iNOS is considered to involve systemic hypopiesia such as toxic shock and the cause that involves with the some diseases of some cytokine treatment.Show, with cytokine such as B5 interleukin 1 (IL-1), the cancer patient of interleukin 2 (IL-2) or tumor necrosis factor (TNF) treatment can suffer inductive shock of cytokine and because the caused hypopiesia of NO that produces from macrophage.(referring to Chemical ﹠amp; Engineering News, Dec.20.p.33，(1993))。The iNOS inhibitor can make this process reverse.Can also believe that iNOS plays effect in for example ischemic pathology of central nervous system's disease.For example, the inhibition of iNOS has shown the cerebral ischemic response infringement that alleviates Mus; Referring to Am.J.Physiol., 268, R 286 pages (1995).Suppress the inductive arthritic constrain effect of adjuvant (adjuvant) at Eur.J.Pharmacol. by the selectivity of iNOS, 273, p.15-24 in (1995) report is arranged.
The NO that is produced by nNOS is considered to influence bringing into play in the disease such as cerebral ischemia, pain and Opiate toleration.For example, the inhibition of nNOS has reduced the infarct volume of Mus after immediate middle cerebral artery occlusion, referring to J.Cerebr.Blood Flow Metab., and 14,924-929 page or leaf (1994).NNOS suppresses also to have shown the effectiveness on antinociception, activity in this later stage that can analyze by the abdominal constriction of bringing out at the hindpaw of formalin-induced licking and acetic acid (abdominal constriction) confirms, referring to Br.J.Pharmacol., 110,219-224 page or leaf (1993).In addition, Freund has been induced the male neuronic increase of NOS in spinal cord to the subcutaneous injection of Mus, and this is embodied in the more hypersensitivity to pain that can enough no inhibitor treatments, referring to Japanese Journalof Pharmacology, 75,327-335 page or leaf (1997).At last, crow is levied the sample material and shrinks back and report by nNOS and suppress to bring out in rodent.(referring to Neuropsychopharmacol., 13, p.269-293 (1995)).
General introduction of the present invention
The present invention relates to treat some can comprise the disease that people's mammiferous physiological rhythm is treated or the method for symptom by change, and this method comprises this administration:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt; With
(b) nk 1 receptor antagonist or its pharmaceutically useful salt;
Wherein above-mentioned activating agent " a " and " b " are with a certain amount of administration, and this amount makes the conjugate of two kinds of medicaments can treat such disease or symptom effectively.
The invention still further relates to and be used for the treatment of and can comprise those diseases that people's mammiferous physiological rhythm is treated or the pharmaceutical composition of symptom by change, it comprises:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt;
(b) nk 1 receptor antagonist or its pharmaceutically useful salt; With
(c) pharmaceutically useful carrier;
Wherein activating agent " a " and " b " are present in the said composition with a certain amount of, and this amount makes the conjugate of two kinds of medicaments can treat such disease effectively.
Some can comprise the symptom that people's mammiferous physiological rhythm is treated or the method for disease by change to the invention still further relates to treatment, and this method comprises this administration:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt;
(b) nk 1 receptor antagonist or its pharmaceutically useful salt; With
(c) selective serotonin reuptake inhibitor (SSRI) or its pharmaceutically useful salt;
Wherein above-mentioned activating agent " a ", " b " and " c " uses with a certain amount of, and this amount makes the conjugate of three kinds of medicaments can treat such disease or symptom effectively.
The invention still further relates to and be used for the treatment of and can comprise those diseases that people's mammiferous physiological rhythm is treated or the pharmaceutical composition of symptom by change, it comprises:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt;
(b) nk 1 receptor antagonist or its pharmaceutically useful salt;
(c) SSRI or its pharmaceutically useful salt; With
(d) pharmaceutically useful carrier;
Activating agent " a " wherein, " b " and " c " is present in the said composition with a certain amount of, and this amount makes the conjugate of three kinds of medicaments can treat such disease or symptom effectively.
The invention still further relates to treatment can comprise those diseases that people's mammiferous physiological rhythm is treated or the method for symptom by change, and this method comprises this administration:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt; With
(b) SSRI or its pharmaceutically useful salt;
Wherein activating agent " a " and " b " use with a certain amount of, and this amount makes the conjugate of two kinds of medicaments can treat such disease or symptom effectively.
The invention still further relates to and be used for the treatment of and can comprise those diseases that people's mammiferous physiological rhythm is treated or the pharmaceutical composition of symptom by change, it comprises:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt;
(b) SSRI or its pharmaceutically useful salt; With
(c) pharmaceutically useful carrier;
Wherein activating agent " a " and " b " are present in the said composition with a certain amount of, and this amount makes the conjugate of two kinds of medicaments can treat such disease or symptom effectively.
The invention still further relates to treatment can comprise those diseases that people's mammiferous physiological rhythm is treated or the method for symptom by change, and this method comprises that the NOS that can effectively treat that consumption of this type of disease or symptom to this administration suppresses chemical compound or its pharmaceutically useful salt.
The invention still further relates to and be used for the treatment of and comprise those diseases that people's mammiferous physiological rhythm is treated or the pharmaceutical composition of symptom by change, said composition comprises NOS inhibition chemical compound or its pharmaceutically useful salt and the pharmaceutically useful carrier that presents in an amount at least sufficient to effectively treat this type of disease or symptom.
Term used herein " treatment " be meant reverse, alleviate, suppress or slow down disease that this term was suitable for or symptom development process or prevent this disease or symptom, or one or more reveal any symptomses of this type of disease or symptom.Term used herein " treatment (noun) " is meant the action of treatment (process), and " treatment (process) " definition in the above just.
The invention still further relates to be used for the treatment of comprise the people mammiferous be selected from following these disease or the pharmaceutical composition of symptom: blind, obesity, seasonal affective disorder, dipolar disease; Trouble with jet lag, sleep rhythm disorders round the clock, the sleep function forfeiture, the fast sleep disease, hypersomnia disease, the disease of sleeping deeply, Sleep-Wake cycle disorder disease, narcolepsy disease with shiftwork or the relevant sleep disorder of erratic operating schedule; How moving enuresis nocturna and lower limb complication, said composition comprises that the NOS of that consumption of this type of symptom of effective treatment or disease suppresses chemical compound or its pharmaceutically useful salt and pharmaceutically useful carrier.
The invention still further relates to that treatment comprises the people mammiferous be selected from following these disease or the method for symptom: blind, obesity, seasonal affective disorder, dipolar disease; Trouble with jet lag, sleep rhythm disorders round the clock, the sleep function forfeiture, the fast sleep disease, hypersomnia disease, the disease of sleeping deeply, Sleep-Wake cycle disorder disease, narcolepsy disease with shiftwork or the relevant sleep disorder of irregular operating schedule; How moving nocturnal enuresis and lower limb complication, this method comprise can treat effectively or prevent that to administration the NOS of that consumption of this type of symptom or disease from suppressing chemical compound or its pharmaceutically useful salt.
It is the said method that loses one's sight that more specific embodiment of the present invention relates to disease or the symptom that wherein will treat.
It is the said method of the inadequate lower limb complication of rest that another more specific embodiment of the present invention relates to disease or the symptom that wherein will treat.
Another more specific embodiment of the present invention relates to the said method that the disease that wherein will treat or symptom are trouble with jet lag.
It is the said method of disease of sleeping deeply that another more specific embodiment of the present invention relates to the disease that wherein will treat or symptom.
Another more specific embodiment of the present invention relates to the said method that the disease that wherein will treat or symptom are nocturnal enuresis.
It is the said method of Sleep-Wake cycle disorder disease that another more specific embodiment of the present invention relates to disease or the symptom that wherein will treat.
It is the said method of hypersomnia disease that another more specific embodiment of the present invention relates to disease or the symptom that wherein will treat.
Another more specific embodiment of the present invention relates to the said method that the disease that wherein will treat or symptom are seasonal affective disorder.
Another more specific embodiment of the present invention relates to the said method that the disease that wherein will treat or symptom are the sleep disorder diseases relevant with shiftwork or irregular operating schedule.
It is the said method of sleep rhythm disorders round the clock that another more specific embodiment of the present invention relates to the disease that wherein will treat or symptom.
It is the said method of fast sleep disease that another more specific embodiment of the present invention relates to disease or the symptom that wherein will treat.
Another more specific embodiment of the present invention relates to the said method that the disease that wherein will treat or symptom are dipolar disease.
It is the said method of sleep function forfeiture disease that another more specific embodiment of the present invention relates to disease or the symptom that wherein will treat.
It is the said method of narcolepsy disease disease that another more specific embodiment of the present invention relates to disease or the symptom that wherein will treat.
Another more specific embodiment of the present invention relates to the said method that the disease that wherein will treat or symptom are obesity.
The invention still further relates to that treatment comprises the people mammiferous be selected from following these disease or the method for symptom: dysthymia, main oppressive disease, dipolar disease, seasonal affective disorder and other mood disease; Anxiety disease (for example generalized anxiety disease, obsession, Panic disorder, post-traumatic nervous disease, social phobia's disease, agoraphobia and other phobia), blind, fat, apoplexy, trouble with jet lag, sleep disorder as sleep rhythm disorders round the clock, narcolepsy disease, sleep apnea, fast sleep disease, deeply sleep disease, Sleep-Wake cycle disorder disease, sleep function forfeiture disease, insomnia, hypersomnia disease and with the age, shiftwork or the relevant sleep disorder of irregular operating schedule that increase; Nocturnal enuresis, the disease of moving lower limb complication and cognitive aspect comprises this administration as dull-witted (for example relevant with the age dementia and the alzheimer disease of A Ercimoshi type) and memory loss disease more:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt; With
(b) nk 1 receptor antagonist or its pharmaceutically useful salt;
Wherein above-mentioned activating agent " a " and " b " use with a certain amount of, and this amount makes the conjugate of two kinds of medicaments can treat such disease or symptom effectively.
The invention still further relates to be used for the treatment of comprise the people mammiferous be selected from following these disease or the pharmaceutical composition of symptom: dysthymia, main oppressive disease, dipolar disease, seasonal affective disorder and other mood disease; Anxiety disease (for example generalized anxiety disease, obsession, Panic disorder, post-traumatic nervous disease, social phobia's disease, agoraphobia and other phobia), blind, fat, apoplexy, trouble with jet lag, sleep disorder as sleep rhythm disorders round the clock, narcolepsy disease, sleep apnea, fast sleep disease, deeply sleep disease, sleep one wake cycle disorders, sleep function forfeiture disease, insomnia, hypersomnia disease and with the age, shiftwork or the relevant sleep disorder of irregular operating schedule that increase; Nocturnal enuresis, the disease of moving lower limb complication and cognitive aspect as dull-witted (for example relevant with the age dementia and the alzheimer disease of A Ercimoshi type) and memory loss disease more, and said composition comprises:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt;
(b) nk 1 receptor antagonist or its pharmaceutically useful salt; With
(c) pharmaceutically useful carrier;
Wherein activating agent " a " and " b " are present in the said composition with a certain amount of, and this amount makes the conjugate of two kinds of medicaments can treat such disease effectively.
The invention still further relates to that treatment comprises the people mammiferous be selected from following these disease or the method for symptom: dysthymia, main oppressive disease, dipolar disease, seasonal affective disorder and other mood disease; Anxiety disease (for example generalized anxiety disease, obsession, Panic disorder, post-traumatic nervous disease, social phobia's disease, agoraphobia and other phobia), blind, fat, apoplexy, trouble with jet lag, sleep disorder as sleep rhythm disorders round the clock, narcolepsy disease, sleep apnea, fast sleep disease, deeply sleep disease, Sleep-Wake cycle disorder disease, sleep function forfeiture disease, insomnia, hypersomnia disease and with the age, shiftwork or the relevant sleep disorder of irregular operating schedule that increase; Nocturnal enuresis, the disease of moving lower limb complication and cognitive aspect comprises this administration as dull-witted (for example relevant with the age dementia and the alzheimer disease of A Ercimoshi type) and memory loss disease more:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt;
(b) nk 1 receptor antagonist or its pharmaceutically useful salt; With
(c) selective serotonin reuptake inhibitor (SSRI) or its pharmaceutically useful salt;
Wherein above-mentioned activating agent " a ", " b " and " c " uses with a certain amount of, and this amount makes the conjugate of three kinds of medicaments can treat such disease or symptom effectively.
The invention still further relates to be used for the treatment of comprise the people mammiferous be selected from following these disease or the pharmaceutical composition of symptom: dysthymia, main oppressive disease, dipolar disease, seasonal affective disorder and other mood disease; Anxiety disease (for example generalized anxiety disease, obsession, Panic disorder, post-traumatic nervous disease, social phobia's disease, agoraphobia and other phobia), blind, fat, apoplexy, trouble with jet lag, sleep disorder as sleep rhythm disorders round the clock, narcolepsy disease, sleep apnea, fast sleep disease, deeply sleep disease, Sleep-Wake cycle disorder disease, sleep function forfeiture disease, insomnia, hypersomnia disease and with the age, shiftwork or the relevant sleep disorder of irregular operating schedule that increase; Nocturnal enuresis, the disease of moving lower limb complication and cognitive aspect as dull-witted (for example relevant with the age dementia and the alzheimer disease of A Ercimoshi type) and memory loss disease more, and said composition comprises:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt;
(b) nk 1 receptor antagonist or its pharmaceutically useful salt;
(c) SSRI or its pharmaceutically useful salt; With
(d) pharmaceutically useful carrier;
Activating agent " a " wherein, " b " and " c " is present in the said composition with a certain amount of, and this amount makes the conjugate of three kinds of medicaments can treat such disease or symptom effectively.
The invention still further relates to be used for the treatment of comprise the people mammiferous be selected from following these disease or the method for symptom: dysthymia, main oppressive disease, dipolar disease, seasonal affective disorder and other mood disease; Anxiety disease (for example generalized anxiety disease, obsession, Panic disorder, post-traumatic nervous disease, social phobia's disease, agoraphobia and other phobia), blind, fat, apoplexy, trouble with jet lag, sleep disorder as sleep rhythm disorders round the clock, narcolepsy disease, sleep apnea, fast sleep disease, deeply sleep disease, Sleep-Wake cycle disorder disease, sleep function forfeiture disease, insomnia, hypersomnia disease and with the age, shiftwork or the relevant sleep disorder of irregular operating schedule that increase; Nocturnal enuresis, the disease of moving lower limb complication and cognitive aspect comprises this administration as dull-witted (for example relevant with the age dementia and the alzheimer disease of A Ercimoshi type) and memory loss disease more:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt; With
(b) SSRI or its pharmaceutically useful salt;
Wherein activating agent " a " and " b " use with a certain amount of, and this amount makes the conjugate of two kinds of medicaments can treat such disease or symptom effectively.
The invention still further relates to be used for the treatment of comprise the people mammiferous be selected from following these disease or the pharmaceutical composition of symptom: dysthymia, main oppressive disease, dipolar disease, seasonal affective disorder and other mood disease; Anxiety disease (for example generalized anxiety disease, obsession, Panic disorder, post-traumatic nervous disease, social phobia's disease, agoraphobia and other phobia), blind, fat, apoplexy, trouble with jet lag, sleep disorder as sleep rhythm disorders round the clock, narcolepsy disease, sleep apnea, fast sleep disease, deeply sleep disease, Sleep-Wake cycle disorder disease, sleep function forfeiture disease, insomnia, hypersomnia disease and with the age, shiftwork or the relevant sleep disorder of irregular operating schedule that increase; Nocturnal enuresis, the disease of moving lower limb complication and cognitive aspect as dull-witted (for example relevant with the age dementia and the alzheimer disease of A Ercimoshi type) and memory loss disease more, and said composition comprises:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt;
(b) SSRI or its pharmaceutically useful salt; With
(c) pharmaceutically useful carrier;
Wherein activating agent " a " and " b " are present in the said composition with a certain amount of, and this amount makes the conjugate of two kinds of medicaments can treat such disease or symptom effectively.
The invention still further relates to any one in preceding method and the pharmaceutical composition, wherein disease or symptom are selected from hypersomnia disease, dark dormancy disease, moving lower limb complication how, Sleep-Wake cycle disorder disease with shiftwork or the relevant sleep disorder of irregular operating schedule.
The invention still further relates to any one in the above method and the pharmaceutical composition, wherein this NOS inhibition chemical compound is the chemical compound as following defined general formula I, II, III, IV, V or VI.
The example that can be used for the NOS inhibition chemical compound in the inventive method and the pharmaceutical composition is the chemical compound of following formula:
Its medium ring A condenses the saturated or unsaturated ring of 5-7 joint, and the 0-2 in the joint of its medium ring is the hetero atom that is independently selected from nitrogen, oxygen and sulfur, and precondition is that two adjacent links are not hetero atom simultaneously;
X is an oxygen or a key;
N is the integer of 2-6; With
R 1And R 2Be independently selected from (C 1-C 6) alkyl, aryl, naphthane and aralkyl, wherein the aryl structure division of this aryl and this aralkyl be phenyl or naphthyl and this alkyl structure partly be straight chain or branching and contain 1-6 carbon atom and this (C wherein 1-C 6) alkyl, this aryl, the aryl structure division of this naphthane and this aralkyl is optional preferably to be replaced by 0-2 substituent group by 1-3 substituent group, and this substituent group is independently selected from halogen (for example, chlorine, fluorine, bromine, iodine), nitro, hydroxyl, cyano group, amino, (C 1-C 4) alkoxyl and (C 1-C 4) alkyl amino;
Or R 1And R 2Form piperazine with the nitrogen that they connected, azetidine, piperidines or pyrrolidine ring or contain the azabicyclo of 6-14 link, in these joints 1-3 is that nitrogen and remaining are carbon, wherein the example of this azabicyclo be following these:
Figure A0080787800411
Figure A0080787800412
With
Same R 1Or R 2Can be connected to (CH 2) on the n group, formed ring with 4-7 joint;
R wherein 3And R 4Be to be selected from hydrogen, (C 1-C 6) alkyl, phenyl, naphthyl, (C 1-C 6) alkyl C (=O)-, HC (=O)-, (C 1-C 6) alkoxyl-(C=O)-, phenyl-C (=O)-, naphthyl-C (=O)-, and R 6R 7NC (=O)-wherein R 6And R 7Be independently selected from hydrogen and (C 1-C 6) alkyl;
R 5Be to be selected from hydrogen, (C 1-C 6) alkyl, phenyl, naphthyl, phenyl-(C 1-C 6) alkyl and naphthyl (C 1-C 6) alkyl;
This piperazine wherein, azetidine, piperidines and pyrrolidine ring can be chosen wantonly by one or more substituent groups, are preferably replaced by 0-2 substituent group, and this substituent group is independently selected from (C 1-C 6) alkyl, amino, (C 1-C 6) alkyl amino, [two-(C 1-C 6) alkyl] amino; 5 to the 6 joint heterocycles that contain nitrogen-atoms in 1-4 the ring that phenyl replaces; benzoyl, benzoyl methyl, benzyloxycarbonyl group; the phenyl amino carbonyl; any one phenyl structure division can be chosen wantonly by one or more substituent groups in phenethyl and phenyloxycarbonyl and the wherein aforementioned substituent group, is preferably replaced by 0-2 substituent group; this substituent group is independently selected from halogen, (C 1-C 3) alkyl, (C 1-C 3) alkoxyl, nitro, amino, cyano group, CF 3And OCF 3
Officinal salt with this compounds.
Following chemical compound is the no inhibitor of preferred general formula I:
6-[4-(3-amino-cyclohexyl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclopentyloxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclobutyl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(4-amino-cyclohexyl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclopentyloxy)-indane-4-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclobutyl oxygen base)-indane-4-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclopropyl oxygen base)-indane-4-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclohexyl oxygen base)-indane-4-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclopentyloxy)-indane-4-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclobutyl oxygen base)-indane-4-yl]-pyridine-2-base amine;
6-[4-(4-amino-cyclohexyl oxygen base)-indane-4-yl]-pyridine-2-base amine;
6-[4-piperidines-3-ylmethoxy)-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-1-yl]-pyridine-2-base amine;
6-[4-(2-pyrrolidinyl-ethyoxyl)-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclohexyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-1-yl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-pyrrolidine-1-base-ethyoxyl)-naphthalene-1-yl]-pyridine-2-base amine:
6-(4-{2-[(benzo [1,3] dioxole-5-ylmethyl)-amino]-ethyoxyl }-naphthalene-1-yl)-pyridine-2-base amine;
6-{4-[2-(6,7-dimethoxy 3,4-dihydro-1H-isoquinolin-2-yl)-ethyoxyl]-naphthalene-1-yl } pyridine-2-base amine;
3-{2-[4-(6-amino-pyridine-2-yl)-naphthalene-1-base oxygen base]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
6-(4-[2-(4-phenethyl-piperazine-1-yl)-ethyoxyl]-naphthalene-1-yl } pyridine-2-base amine;
6-(4-[2-(3-amino-pyrrolidine-1-yl) ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
6-[4-(1-benzyl-piperidin-4-yl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-benzyl-pyrrolidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(piperidin-4-yl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(pyrrolidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-isobutyl group-piperidin-4-yl oxygen base }-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-furan-2-ylmethyl-piperidin-4-yl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-isobutyl group-pyrrolidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-furan-2-ylmethyl-pyrrolidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-morpholine-4-base-ethyoxyl)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-diisopropylaminoethyl-ethyoxyl)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-methyl-piperidin-4-yl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-methyl-pyrrolidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(3-dimethylamino-propoxyl group)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-aza-bicyclo [2.2.2] oct-3-yl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-piperidines-1-base-ethyoxyl)-naphthalene-1-yl]-pyridine-2-base amine
6-{4-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
6-{4-[2-(4-dimethylamino-piperidines-1-yl)-ethyoxyl]-naphthalene-1-yl } pyridine-2-base amine;
6-{4-[2-(tert-butyl group-methyl-amino)-ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
6-{4-[2-(4-methyl-piperazine-1-yl)-ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
6-{4-[2-(4-phenyl-piperidines-1-yl)-ethyoxyl)-naphthalene-1-yl }-pyridine-2-base amine;
6-{4-[2-(7,8-dihydro-5H-[1,3] dioxole also [4,5-g] isoquinolin-6-yl)-ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
6-[4-(piperidines-2-ylmethoxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-methyl-piperidines-2-ylmethoxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-methyl-piperidines-3-ylmethoxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclohexyl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(piperidines-3-ylmethoxy)-naphthalene-1-yl)-pyridine-2-base amine;
6-[4-(1-isobutyl group-azetidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-furan-2-ylmethyl-azetidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(azetidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-methyl-pyrrolidine-2-ylmethoxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(azetidine-2-ylmethoxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[7-(2-dimethylamino-ethyoxyl)-indane-4-yl]-pyridine-2-base amine;
6-[7-(2-pyrrolidine-1-base-ethyoxyl)-indane-4-yl]-pyridine-2-base amine;
6-(7-[2-(benzyl-methyl-amino)-ethyoxyl]-indane-4-yl }-pyridine-2-base amine;
6-{7-[2-(4-phenethyl-piperazine-1-yl)-ethyoxyl]-indane-4-yl }-pyridine-2-base amine;
6-{7-(2-(4-isobutyl group-piperazine-1-yl)-ethyoxyl]-indane-4-yl }-pyridine-2-base amine;
6-[7-(2-morpholine-4-base-ethyoxyl)-indane-4-yl]-pyridine-2-base amine;
6-[7-(2-diisopropylaminoethyl-ethyoxyl)-indane-4-yl]-pyridine-2-base amine;
6-(7-[2-(7,8-dihydro-5H-[1,3] dioxole also [4,5-g] isoquinolin-6-yl)-ethyoxyl]-indane-4-yl }-pyridine-2-base amine;
6-{7-[2-(4-methyl-piperazine-1-yl)-ethyoxyl]-indane-4-yl }-pyridine-2-base amine;
6-{7-[2-(tert-butyl group-methyl-amino)-ethyoxyl]-indane-4-yl }-pyridine-2-base amine;
6-{7-[2-(4-dimethylamino-piperidines-1-yl)-ethyoxyl]-indane-4-yl }-pyridine-2-base amine;
6-[8-(2-dimethylamino-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-methylene naphthalene-5-yl]-pyridine-2-base amine;
6-[8-(2-pyrrolidine-1-base-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-5-yl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-pyrrolidine-1-base-ethyoxyl)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-{4-[2-(tert-butyl group-methyl-amino)-ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl }-pyridine-2-base amine;
6-[4-(2-diisopropylaminoethyl-ethyoxyl)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-lignocaine-ethyoxyl)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-{4-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl }-pyridine-2-base amine;
6-[4-(2-piperidines-1-base-ethyoxyl)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-morpholine-4-ethyoxyl)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-{4-[2-(7,8-dihydro-5H-[1,3] dioxole also [4,5-g] isoquinolin-6-yl)-ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl }-pyridine-2-base amine;
6-{4-[2-(4-methyl-piperazine-1-yl }-ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl }-pyridine-2-base amine;
6-{4-[2-(4-dimethylamino-piperidines-1-yl)-ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl }-pyridine-2-base amine;
6-{4-[2-(7,8-dihydro-5H-[1,3] dioxole also [4,5-g] isoquinolin-6-yl)-ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl }-pyridine-2-base amine;
6-[4-(1-isobutyl group-piperidines-3-ylmethoxy)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-methyl-piperidines-3-ylmethoxy)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-{4-[2-(2-diethylamino-ethyoxyl)-ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl }-pyridine-2-base amine;
6-[4-(piperidines-3-ylmethoxy)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclohexyl oxygen base)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(pyrrolidine-2-ylmethoxy)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine; With
6-[4-(2-dimethylamino-ethyoxyl)-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-1-yl]-pyridine-2-base amine;
And the pharmaceutically useful salt of aforesaid compound.
Be the additional examples of the NOS inhibition chemical compound of general formula I below:
6-[4-(2-amino-cyclopentyloxy)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclobutyl oxygen base)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclopropyl oxygen base)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclohexyl oxygen base)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclopentyloxy)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclobutyl oxygen base)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(4-amino-cyclohexyl oxygen base)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclopentyloxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclobutyl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclopropyl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-(4-dimethylamino-piperidines-1-yl)-ethyoxyl))-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-1-yl]-pyridine-2-base amine; With
6-[4-(2-(4-methyl-piperazine-1-yl)-ethyoxyl))-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-1-yl]-pyridine-2-base amine.
Other example that can be used for the NOS inhibition chemical compound in the inventive method and the pharmaceutical composition is the chemical compound of following formula:
Figure A0080787800471
With its officinal salt, wherein each () nExpression (CH 2) n
R 1And R 2Be independently selected from hydrogen, (C 1-C 6) alkyl, naphthane and aralkyl, wherein this aryl structure division of this aralkyl is that phenyl or naphthyl and this alkyl structure partly are straight or brancheds and contain 1-6 carbon atom and wherein be somebody's turn to do (C 1-C 6) the aryl structure division of alkyl and this naphthane and this aralkyl is optional is preferably replaced by 0-2 substituent group by 1-3 substituent group, this substituent group is independently selected from halogen (for example, chlorine, fluorine, bromine, iodine), nitro, hydroxyl, cyano group, amino, (C 1-C 4) alkoxyl and (C 1-C 4) alkyl amino;
Or R 1And R 2Form piperazine with the nitrogen that they connected, piperidines or pyrrolidine ring or contain the azabicyclo of 6-14 link, in these joints 1-3 be nitrogen and remaining be carbon, wherein the example of this azabicyclo be following these:
Figure A0080787800481
With
Figure A0080787800483
R wherein 3And R 4Be to be selected from hydrogen, (C 1-C 6) alkyl, phenyl, naphthyl, (C 1-C 6) alkyl-C (=O)-, HC (=O)-, (C 1-C 6) alkoxyl-(C=O)-, phenyl-C (=O)-, naphthyl-C (=O)-, and R 7R 8NC (=O)-wherein R 7And R 8Be independently selected from hydrogen and (C 1-C 6) alkyl;
R 5Be to be selected from hydrogen, (C 1-C 6) alkyl, phenyl, naphthyl, phenyl-(C 1-C 6) alkyl and naphthyl (C 1-C 6) alkyl;
This piperazine wherein, piperidines and pyrrolidine ring can be chosen wantonly by one or more substituent groups, are preferably replaced by 0-2 substituent group, and this substituent group is independently selected from (C 1-C 6) alkyl, amino, (C 1-C 6) alkyl amino, [two (C 1-C 6) alkyl] amino, cyclohexyl, mesyl; the phenoxy group acetyl group, furyl carbonyl, trifluoromethyl; the phenoxy group acetyl group, benzenesulfonyl, isoquinolin alkyl; the quinoline alkyl, hydroxy phenyl ethyl, aminophenyl ethyl; 5 to 6 of phenyl replacement has the heterocycle of limb to comprise from 1 to 4 ring nitrogen, benzoyl, aminoethyl; the aminophenyl propiono, cyclohexyl amino carbonyl, benzylamino carbonylamino; morpholinyl carbonyl, pyrrolidinyl carbonyl, phenyl thiazole base; the ethoxy carbonyl methyl, benzoyl methyl, benzyloxycarbonyl group; benzyloxycarbonyl group amino, phenyl amino carbonyl, phenethyl; phenylpropyl; benzhydryl, methyl carbonyl, methoxy carbonyl; the phenyl amino propiono; the phenoxymethyl carbonyl, cyclopentylcarbonyl and phenyloxycarbonyl, and any one phenyl moiety is also optional by one or more substituent groups in the aforementioned substituent group; preferably replaced by 0-2 substituent group; this substituent group is independently selected from halogen, (C 1-C 3) alkyl, (C 1-C 3) alkoxyl, nitro, amino, cyano group, CF 3And OCF 3
N is 0,1 or 2;
M is 0,1 or 2;
Each R 8With each R 9Be independently selected from (C 1-C 4) alkyl, aryl-(C 1-C 4) alkyl, wherein this aryl is to be selected from phenyl and naphthyl; Pi-allyl and phenyl pi-allyl;
X and Y are independently selected from methyl, methoxyl group, hydroxyl and hydrogen; With
R 10Be hydrogen or (C 1-C 6) alkyl;
Precondition is R when n is 0 8There is not R when m is 0 9Do not exist.
The example of the preferred compound of general formula I I is NR wherein 1R 2Be those chemical compounds of following group:
4-phenyloxycarbonyl piperazine-1-base;
4-(4-fluorophenyl acetyl group) piperazine-1-base;
4-phenylethyl piperazine-1-base;
4-phenoxymethyl carbonyl piperazine-1-base;
4-phenyl amino carbonyl piperazine-1-base;
4-benzoyl methyl piperazine-1-base; Or
4-benzyloxycarbonyl group piperazine-1-base.
Other preferred compound of general formula I I is NR wherein 1R 2Those chemical compounds for the following formula group
NR wherein 3R 4Be NH 2
Other preferred compound of general formula I I is NR wherein 1R 2Those chemical compounds for the following formula group
Figure A0080787800502
Or
Figure A0080787800503
R wherein 5Be aralkyl, for example, benzyl, and R 6It is (4-fluoro) phenylacetyl group.
The particularly preferred chemical compound of general formula I I comprises:
1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-ethyl ketone;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-2-methoxyl group-ethyl ketone;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-2-phenoxy group-ethyl ketone;
(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-cyclopenta-ketone;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-2-phenyl-ethyl ketone;
3-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl-ethyl ketone;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-2-(4-fluoro-phenyl)-ethyl ketone;
6-{4-[2-(4-phenethyl-piperazine-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl-ethanol;
{ 2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-(3-oxa--9-aza-bicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine;
6-(4-{2-[4-(2-amino-2-phenyl-ethyl)-piperazine-1-yl]-ethyl }-phenyl)-pyridine-2-base amine;
6-{4-[2-(4-amino-2,6-dimethyl-piperidines-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
6-{4-[2-(4-methyl-piperazine-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
(3-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl-3-aza-bicyclo [3.1.0] oneself-the 6-yl)-dimethyl-amine;
6-[4-(2-amino-ethyl)-phenyl]-pyridine-2-base amine;
6-{4-[2-(8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-ethyl]-phenyl }-pyridine-2-base amine;
6-{4-[2-(4-isobutyl group-piperazine-1-yl)-ethyl]-phenylpyridine-2-base amine;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-N-isopropyl-acetamide;
4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-carboxylic acid p-tolyl-amide;
6-(4-{2-[4-(3-phenyl-propyl group)-piperazine-1-yl]-ethyl }-phenyl)-pyridine-2-base amine;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-2-(4-chloro-phenyl)-ethyl ketone;
8-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-3-benzyl-1,3,8-three azepines-spiral shell [4.5] decane-2,4-diketone;
N-(1-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-pyrrolidine-3-yl)-2-(4-fluoro-phenyl)-acetamide;
8-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-8-aza-bicyclo [3.2.1] oct-3-yl amine;
3-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl)-3-aza-bicyclo [3.2.1] suffering-8-base amine;
2-amino-1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-3-phenyl-third-1-ketone;
6-{4-[2-(4-amino-piperadine-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
6-{4-[2-(4-benzhydryl-piperazine-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
6-{4-[2-(4-benzhydryl-piperidines-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
6-{4-[(cyclohexyl-methyl-amino)-methyl]-phenyl }-pyridine-2-base amine;
6-{4-[(cyclohexyl-methyl-amino)-methyl]-2-methoxyl group-phenyl }-pyridine-2-base amine;
6-[4-(phenethyl amino-methyl)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(phenethyl amino-methyl)-phenyl]-pyridine-2-base amine;
6-[4-(4-amino-piperadine-1-ylmethyl)-phenyl }-pyridine-2-base amine;
6-{4-[(cyclohexyl-methyl-amino)-methyl]-2-fluoro-phenyl }-pyridine-2-base amine;
Other chemical compound of general formula I I comprises:
1-(4-(2-[4-(6-amino-pyridine-2-yl)-2-methoxyl group-phenyl]-ethyl }-piperazine-1-yl)-2-phenyl-ethyl ketone;
6-(4-[2-(4-isobutyl group-piperazine-1-yl)-ethyl]-2-methoxyl group-phenyl }-pyridine-2-base amine;
3-(2-[4-(6-amino-pyridine-2-yl)-2-methoxyl group-phenyl]-ethyl)-3-aza-bicyclo [3.1.0] oneself-6-base amine;
(2-[4-(6-amino-pyridine-2-yl)-2-methoxyl group-phenyl]-ethyl }-(3-oxa--9-aza-bicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl) amine;
6-(4-(2-[4-(2-amino-2-phenyl-ethyl)-piperazine-1-yl]-ethyl }-2-methoxyl group-phenyl)-pyridine-2-base amine;
6-(4-[2-(4-amino-2-methoxyl group-piperidines-1-yl)-ethyl]-2-methoxyl group-phenyl }-pyridine-2-base amine;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-2-methoxyl group-phenyl]-ethyl }-piperazine-1-yl)-N-isopropyl-acetamide;
6-[4-(4-amino-piperadine-1-ylmethyl)-2-methoxyl group-phenyl }-pyridine-2-base amine;
1-(4-(2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl]-ethyl }-piperazine-1-yl)-2-phenyl-ethyl ketone;
6-(4-[2-(4-isobutyl group-piperazine-1-yl)-ethyl]-2-methyl-phenyl }-pyridine-2-base amine;
3-(2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl-ethyl ketone;
1-(4-(2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl]-ethyl }-piperazine-1-yl)-2-(4-fluoro-phenyl)-ethyl ketone;
6-(4-[2-(4-phenethyl-piperazine-1-base-ethyl]-2-methyl-phenyl }-pyridine-2-base amine;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl-ethanol;
(2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl]-ethyl }-(3-oxa--9-aza-bicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl) amine;
6-(4-(2-[4-(2-amino-2-phenyl-ethyl)-piperazine-1-yl]-ethyl }-2-methyl-phenyl)-pyridine-2-base amine;
6-(4-[2-(4-amino-2,6-dimethyl-piperidines-1-yl)-ethyl]-2-methyl-phenyl }-pyridine-2-base amine;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl]-ethyl }-piperazine-1-yl)-N-isopropyl acetamide;
6-[4-(4-amino-piperadine-1-ylmethyl)-2-methyl-phenyl }-pyridine-2-base amine;
N-(1-(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-pyrrolidine-3-yl)-2-phenyl-acetamide;
N-(1-(2-[4-(6-amino-pyridine-2-yl)-phenyl)-ethyl }-pyrrolidine-3-yl)-2-(3-trifluoromethyl) acetamide;
N-(1-(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-pyrrolidine-3-yl)-2-(4-tolyl)-acetamide;
N-(1-(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-pyrrolidine-3-yl)-2-(4-methoxyphenyl)-acetamide;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-2-methoxyl group-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl ethyl ketone;
1-(4-(2-[4-(6-amino-pyridine-2-yl)-2-methoxyl group-phenyl]-ethyl }-piperazine-1-yl)-2-(4-fluoro-phenyl)-ethyl ketone;
N-(1-(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl)-pyrrolidine-3-yl)-2-cyclohexyl-acetamide;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-1-(4-tolyl)-ethyl ketone;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl } piperazine-1-yl)-1-(4-methoxyphenyl) ethyl ketone;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl } piperazine-1-yl)-1-(4-chlorphenyl) ethyl ketone;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-1-(4-fluorophenyl)-ethyl ketone;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl } piperazine-1-yl)-1-cyclohexyl-ethyl ketone;
1-(4-(2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl }-piperazine-1-yl)-2-phenyl-ethyl ketone;
6-(4-[2-(4-isobutyl group-piperazine-1-yl)-ethyl]-2-fluoro-phenyl }-pyridine-2-base amine;
3-(2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl-ethyl ketone;
1-(4-(2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl }-piperazine-1-yl)-2-(4-fluoro-phenyl)-ethyl ketone;
6-(4-[2-(4-phenethyl-piperazine-1-yl)-ethyl]-2-fluoro-phenyl }-pyridine-2-base amine;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl-ethanol;
(2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl }-(3-oxa--9-aza-bicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine;
6-(4-(2-[4-(2-amino-2-phenyl-ethyl)-piperazine-1-yl]-ethyl }-2-fluoro-phenyl)-pyridine-2-base amine;
6-(4-[2-(4-amino-2-fluoro-piperidine-1-yl)-ethyl]-2-fluoro-phenyl }-pyridine-2-base amine;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl }-piperazine-1-yl)-N-isopropyl-acetamide;
6-[4-(4-amino-piperadine-1-ylmethyl)-2-fluoro-phenyl }-pyridine-2-base amine;
6-(4-[2-(4-amino-2,6-diethyl-piperidines-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
6-(4-[2-(4-amino-2,6-dibenzyl-piperidines-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-(9-(4-fluoro)-benzyl-3-oxa--9-azabicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine;
(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-(9-(4-chloro)-benzyl-3-oxa--9-aza-bicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine;
(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-(9-(4-methyl)-benzyl-3-oxa--9-aza-bicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine; With
(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-(9-(4-methoxyl group)-benzyl-3-oxa--9-azabicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine.
Other example that can be used for the NOS inhibition chemical compound in the inventive method and the pharmaceutical composition is the chemical compound of following formula:
Figure A0080787800561
Wherein X is CHOH, CH 2, or CHR 10, R wherein 10With X, adjoin the CH of X 2Group and NR 1R 2Nitrogen-atoms form together five the joint or six the joint saturated rings;
R 1, R 2, R 3And R 4Be independently selected from hydrogen, (C 1-C 6) alkyl, tetralyl, aryl and aralkyl, wherein the aryl structure division of this aryl and this aralkyl is that phenyl or naphthyl and this alkyl structure partly are straight or brancheds and contain 1-6 carbon atom and wherein be somebody's turn to do (C 1-C 6) this aryl structure division of alkyl and this tetralyl and this aralkyl is optional by 1-3 substituent group, preferably 0-2 substituent group replaces, and this substituent group is independently selected from halogen (for example, chlorine, fluorine, bromine, iodine), nitro, hydroxyl, cyano group, amino, (C 1-C 4) alkoxyl and (C 1-C 4) alkyl amino;
Or R 1And R 2Form piperazine with the nitrogen that they connected, piperidines or pyrrolidine ring or contain the azabicyclo of 6-14 link, in these joints 1-3 be nitrogen and remaining be carbon, wherein the example of this azabicyclo be following these:
Figure A0080787800562
Figure A0080787800563
With
R wherein 5And R 6Be to be selected from hydrogen, (C 1-C 6) alkyl, phenyl, naphthyl, (C 1-C 6) alkyl-C (=O)-, HC (=O)-, (C 1-C 6) alkoxyl-(C=O)-, phenyl-C (=O)-, naphthyl-C (=O)-, and R 8R 9NC (=O)-, R wherein 8And R 9Be independently selected from hydrogen and (C 1-C 6) alkyl;
R 7Be to be selected from hydrogen, (C 1-C 6) alkyl, phenyl, naphthyl, phenyl-(C 1-C 6) alkyl-and naphthyl (C 1-C 6) alkyl-;
This piperazine wherein, piperidines and pyrrolidine ring can be chosen wantonly by one or more substituent groups, are preferably replaced by 0-2 substituent group, and this substituent group is independently selected from (C 1-C 6) alkyl, amino, (C 1-C 6) alkyl amino, [two-(C 1-C 6) alkyl] amino; 5 to the 6 joint heterocycles that contain nitrogen-atoms in 1-4 the ring that phenyl replaces; benzoyl, benzoyl methyl, benzyloxycarbonyl group; the phenyl amino carbonyl; any one phenyl structure division can be chosen wantonly by one or more substituent groups in phenethyl and phenyloxycarbonyl and the wherein aforementioned substituent group, is preferably replaced by 0-2 substituent group; this substituent group is independently selected from halogen, (C 1-C 3) alkyl, (C 1-C 3) alkoxyl, nitro, amino, cyano group, CF 3And OCF 3
R wherein 3And R 4Form carbocyclic ring with the carbon that they connected with 3-8 optional replacement that saves;
Officinal salt with this compounds.
The more specific example of the chemical compound of general formula III comprises:
(a) chemical compound of general formula III, wherein R 1, R 2, R 3And R 4Be independently selected from (C 1-C 6) alkyl;
(b) chemical compound of general formula III, wherein R 3And R 4Be independently selected from (C 1-C 6) alkyl, and R 1And R 2Form ring with the nitrogen that they connected;
(c) chemical compound of general formula III, wherein R 1And R 2In one be to be selected from (C 1-C 6) alkyl and another be to be selected from phenyl or phenyl-(C 1-C 6) alkyl;
(d) chemical compound of general formula III, wherein R 1And R 2Form piperazine with the nitrogen that they connected, piperidines or pyrrolidine ring; With
(e) chemical compound of general formula III, wherein R 3And R 4Be independently selected from (C 1-C 6) alkyl, and R 3And R 4Form ring with the carbon that they connected.
The example of the preferred compound of general formula III is:
6-[2-isopropoxy-4-((4-phenethyl piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-isobutoxy-4-((4-phenethyl piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-isobutoxy-4-((4-phenethyl piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine
6-[2-isobutoxy-4-((4-dimethyl aminoethyl)-phenyl]-pyridine-2-base amine;
6-[2-isopropoxy-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
1-[4-(6-amino-pyridine-2-yl)-3-isopropoxy-phenyl]-2-(4-phenethyl-piperazine-1-yl)-ethanol;
6-[2-cyclopentyloxy-4-((4-dimethyl aminoethyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclopentyloxy-4-((4-phenethyl piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
And the pharmaceutically useful salt of aforesaid compound.
Other example of the specific compound of general formula III is:
6-[2-cyclohexyl oxygen base-4-((4-phenethyl piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclobutyl oxygen base-4-((4-phenethyl piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclopropyl oxygen base-4-((4-phenethyl piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-isoamoxy-4-((4-phenethyl piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-isohesyl oxygen base-4-((4-phenethyl piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclopentyloxy-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
6-[2-cyclohexyl oxygen base-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
6-[2-cyclobutyl oxygen base-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
6-[2-cyclopropyl oxygen base-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
6-[2-isoamoxy-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
6-[2-isohesyl oxygen base-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
[2-isohesyl oxygen base-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine
1-[4-(6-amino-pyridine-2-yl)-3-isobutoxy-phenyl]-2-(4-phenethyl-piperazine-1-yl)-ethanol;
1-[4-(6-amino-pyridine-2-yl)-3-isopropoxy-phenyl]-2-(6,7-dimethoxy-tetrahydroisoquinoline-2-yl)-ethanol;
1-[4-(6-amino-pyridine-2-yl)-3-isopropoxy-phenyl]-2-(4-dimethylamino-piperidines-1-yl)-ethanol;
1-[4-(6-amino-pyridine-2-yl)-3-isopropoxy-phenyl]-2-(dimethylamino)-ethanol; With
1-[4-(6-amino-pyridine-2-yl)-3-cyclopentyloxy-phenyl]-2-(4-phenethyl-piperazine-1-yl)-ethanol;
And the pharmaceutically useful salt of aforesaid compound.
Other example that can be used for the NOS inhibition chemical compound in the inventive method and the pharmaceutical composition is the chemical compound of following formula:
R wherein 1And R 2Be independently selected from hydrogen, halogen, hydroxyl, (C 1-C 6) alkoxyl, (C 1-C 7) alkyl, (C 2-C 6) alkenyl and (C 2-C 10) alkoxyalkyl; With
G is selected from hydrogen, (C 1-C 6) alkyl, (C 1-C 6) alkoxyl-(C 1-C 3) alkyl, amino carbonyl-(C 1-C 3) alkyl, (C 1-C 3) alkyl amino-carbonyl-(C 1-C 3) alkyl, two-[(C 1-C 3) alkyl] amino carbonyl-(C 1-C 3) alkyl, and N (R 3) (R 4) (C 0-C 4) alkyl, wherein R 3And R 4Be independently selected from hydrogen, (C 1-C 7) alkyl, tetralyl and aralkyl, wherein this aryl structure division of this aralkyl is that phenyl or naphthyl and this alkyl structure partly are straight or brancheds and contain 1-6 carbon atom and wherein be somebody's turn to do (C 1-C 7) the aryl structure division of alkyl and this tetralyl and this aralkyl is optional is preferably replaced by 0-2 substituent group by 1-3 substituent group, this substituent group is independently selected from halogen, nitro, hydroxyl, cyano group, amino, (C 1-C 4) alkoxyl and (C 1-C 4) alkyl amino;
Or R 3And R 4Form piperazine with the nitrogen that they connected, piperidines, azetidine or pyrrolidine ring or contain the saturated or undersaturated azabicyclo of 6-14 link, 1-3 in these joints is nitrogen, in these joints 0-2 be oxygen and remaining be carbon;
This piperazine wherein, piperidines, azetidine and pyrrolidine ring and this azabicyclo system are optional preferably to be replaced by 0-2 substituent group by one or more substituent groups, and this substituent group is independently selected from (C 1-C 6) alkyl, amino, (C 1-C 6) alkyl amino, [two-(C 1-C 6) alkyl] amino; 5 to the 6 joint heterocycles that contain nitrogen-atoms in 1-4 the ring that phenyl replaces; benzoyl, benzoyl methyl, benzyloxycarbonyl group; the phenyl amino carbonyl; any one phenyl structure division can be chosen wantonly by one or more substituent groups in phenethyl and phenyloxycarbonyl and the wherein aforementioned substituent group, is preferably replaced by 0-2 substituent group; this substituent group is independently selected from halogen, (C 1-C 3) alkyl, (C 1-C 3) alkoxyl, nitro, amino, cyano group, CF 3And OCF 3
This piperazine wherein, piperidines, azetidine and pyrrolidine ring and this azabicyclo system can be at NR 3R 4The ring nitrogen-atoms on or on any other atom of this type of ring with available keyed jointing position, be incorporated into-(C 0-C 4) alkyl-O-(and wherein should-(C 0-C 4) oxygen of alkyl-O-is the oxygen atom of describing in structural formula I);
Or G is the group of general formula A
Figure A0080787800611
Wherein Z is nitrogen or CH, and n is 0 or 1, and q is 0,1,2 or 3 and p be 0,1 or 2;
Wherein the 2-amino piperidine ring of describing among the structural formula I in front is optional is substituted by following these:
Or
Figure A0080787800613
Officinal salt with this compounds.
The example of the chemical compound of general formula I V is those chemical compounds that meet the following conditions: wherein G is N (R 3) (R 4) (C 0-C 4) alkyl and N (R 3) (R 4) be amino, dimethyl amido, methyl-benzyl amino, (C 1-C 4) alkyl amino, two-[(C 1-C 4) alkyl] a kind of in amino or the following groups:
Figure A0080787800621
Figure A0080787800631
The preferred compound of general formula I V comprises those chemical compounds that meet the following conditions: R wherein 2Be hydrogen and R 1Be (C 1-C 3) alkoxyl is in the ortho position of the pyridine ring of general formula I V.
Other chemical compound of general formula I V is that wherein G is the group of general formula A, and as defined above, wherein Z is those chemical compounds of nitrogen.
Other chemical compound of general formula I V is R wherein 1And R 2Be independently selected from (C 1-C 2) those chemical compounds of alkoxyl.
Other chemical compound of general formula I V is that wherein G is the group of general formula A, and as defined above, wherein Z is a nitrogen, among p and the n each be 1 and q be those chemical compounds of 2.
Other chemical compound of general formula I V be wherein have in above general formula I V, describe those chemical compounds of 2-aminopyridine ring.
The example of the preferred compound of general formula I V is:
6-[4-(2-dimethylamino-ethyoxyl)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2,3-dimethyl-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-3-methoxyl group-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-3-ethyoxyl-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-isopropyl-phenyl]-pyridine-2-base amine;
6-[2-cyclopropyl-4-(2-dimethylamino-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclobutyl-4-(2-dimethylamino-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclopenta-4-(2-dimethylamino-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-methoxyl group-5-propyl group-phenyl]-pyridine radicals amine;
6-[4-(1-methyl azietine-3-base oxygen base)-2-methoxyl group-5-ethyl-phenyl]-pyridine-2-base amine
2-(6-amino-pyridine-2-yl)-5-(2-dimethylamino-ethyoxyl)-phenol;
6-[4-(2-dimethylamino-ethyoxyl)-2-propoxyl group phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-isopropoxy-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-ethyoxyl-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-methoxyl group-5-propyl group-phenyl]-pyridine-2-base amine;
6-[5-pi-allyl-4-(2-dimethylamino-ethyoxyl)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-[3-pi-allyl-4-(2-dimethylamino-ethyoxyl)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2,6-dimethyl-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-isopropyl-phenyl]-pyridine-2-base amine; With
The 6-[2-tert-butyl group-4-(2-dimethylamino-ethyoxyl)-phenyl]-pyridine-2-base amine.
Other example of the specific compound of general formula I V is:
4-(6-amino-pyridine-2-yl)-3-methoxyphenol;
6-[4-(2-pyrrolidinyl-ethyoxyl)-2,3-dimethyl-phenyl]-pyridine-2-base amine;
6-[4-(4-N-methyl-pyridine radicals oxygen base)-2,3-dimethyl-phenyl]-pyridine-2-base amine;
6-[4-(2-pyrrolidinyl-ethyoxyl)-3-methoxyl group-phenyl]-pyridine-2-base amine;
6-{4-[2-(6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)-ethyoxyl]-3-methoxyl group-phenyl } pyridine-2-base amine;
6-{3-methoxyl group-4-[2-(4-phenethyl-piperazine-1-yl)-ethyoxyl]-phenyl }-pyridine-2-base amine;
6-{3-methoxyl group-4-[2-(4-methyl-piperazine-1-yl)-ethyoxyl]-phenyl)-pyridine-2-base amine;
6-{4-[2-(4-dimethylamino-piperidines-1-yl)-ethyoxyl]-3-methoxyl group-phenyl }-pyridine-2-base amine;
6-[4-(2-pyrrolidinyl-ethyoxyl)-3-ethyoxyl-phenyl]-pyridine-2-base amine;
4-(the 6-amino-pyridine-yl)-3-cyclopropyl-phenol;
6-[2-cyclopropyl-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
3-[3-(6-amino-pyridine-2-yl)-4-cyclopropyl-contain phenoxy group]-pyrrolidine-1-carboxylic acid tertiary butyl ester;
6-[2-cyclopropyl-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
4-(6-amino-pyridine-2-yl)-3-cyclobutyl-phenol;
6-[2-cyclopropyl-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclobutyl-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
4-(6-amino-pyridine-2-yl)-3-cyclopenta-phenol;
6-[2-cyclopenta-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
3-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-pyrrolidine-1-carboxylic acid tertiary butyl ester;
6-[4-(1-methyl-pyrrolidine-3-base oxygen base)-2-methoxyl group-phenyl]-pyridine-2-base amine;
4-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-piperidines-1-carboxylic acid tertiary butyl ester;
6-[2-methoxyl group-4-(1-methyl-piperidin-4-yl oxygen base)-phenyl]-pyridine-2-base amine;
6-[4-(allyloxy)-2-methoxyl group-phenyl]-pyridine-2-base amine;
4-(6-amino-pyridine-2-yl)-3-methoxyl group-6-pi-allyl-phenol;
4-(6-amino-pyridine-2-yl)-3-methoxyl group-2-pi-allyl-phenol;
4-(6-amino-pyridine-2-yl)-3-methoxyl group-6-propyl group-phenol;
6-[2-isopropyl-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(piperidines-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(1-methyl-azetidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(1-methyl-piperidin-4-yl oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(2-methyl-2-aza-bicyclo [2.2.1] heptane-5-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-{4-[2-(benzyl-methyl-amino)-ethyoxyl]-2-methoxyl group-phenyl }-pyridine-2-base amine;
6-[2-methoxyl group-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
2-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-acetamide;
6-[4-(2-amino-ethyoxyl)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-{4-[2-(3,4-dihydro-1h-isoquinolin-2-yl)-ethyoxyl]-2-methoxyl group-phenyl }-pyridine-2-base amine;
2-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-ethanol;
6-{2-methoxyl group-4-[2-(2,2,6,6-tetramethyl-piperidines-1-yl)-ethyoxyl]-phenyl }-pyridine-2-base amine;
6-{4-[2-(2,5-dimethyl-pyrrolidine-1-yl)-ethyoxyl]-2-methoxyl group-phenyl }-pyridine-2-base amine;
6-{4-[2-(2,5-dimethyl-pyrrolidine-1-yl)-ethyoxyl]-2-methoxyl group-phenyl }-pyridine-2-base amine;
2-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-1-(2,2,6,6-tetramethyl-piperidines-1-yl)-ethyl ketone;
6-[2-methoxyl group-4-(1-methyl-pyrrolidine-2-ylmethoxy)-phenyl]-pyridine-2-base amine;
6-{4-[2-(benzyl-methyl-amino)-ethyoxyl]-2-propoxyl group phenyl }-pyridine-2-base amine;
6-[4-(2-ethyoxyl-ethyoxyl)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-[4-(2-ethyoxyl-ethyoxyl)-2-isopropoxy-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(3-methyl-butoxy)-phenyl]-pyridine-2-base amine;
6-{4-[2-(benzyl-methyl-amino)-ethyoxyl]-2-ethyoxyl-phenyl }-pyridine-2-base amine;
6-[2-ethyoxyl-4-(3-methyl-butoxy)-phenyl]-pyridine-2-base amine;
1-(6-amino-3-aza-bicyclo [3.1.0] oneself-3-yl)-2-[4-(6-amino-pyridine-2-yl)-3-ethyoxyl-phenoxy group]-ethyl ketone;
6-[2-ethyoxyl-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
3-{2-[4-(6-amino-pyridine-2-yl)-3-ethyoxyl-phenoxy group]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
1-(6-amino-3-aza-bicyclo [3.1.0] oneself-3-yl)-2-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-ethyl ketone;
3-{2-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-amine;
6-[2-isopropyl-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-(4-[2-(benzyl-methyl-amino)-ethyoxyl]-2-isopropoxy-phenyl }-pyridine-2-base amine;
6-[5-pi-allyl-2-methoxyl group-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-ethyoxyl-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropoxy-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(piperidin-4-yl oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(2,2,6,6-tetramethyl-piperidin-4-yl oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropoxy-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
3-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-azetidine-1-carboxylic acid tertiary butyl ester;
6-[4-(azetidine-3-base oxygen base)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(1-methyl-azetidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropoxy-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropoxy-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(2-methyl-2-aza-bicyclo [2.2.1] heptane-5-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(1-methyl-piperidin-4-yl oxygen base)-phenyl]-pyridine-2-base amine;
6-[4-(1-ethyl-piperidin-4-yl oxygen base)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-[5-pi-allyl-2-methoxyl group-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2,6-dimethyl-4-(3-piperidines-1-base-propoxyl group)-phenyl]-pyridine-2-base amine;
6-[2,6-dimethyl-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-(2,6-dimethyl-4-[3-(4-methyl-piperazine-1-yl)-propoxyl group]-phenyl }-pyridine-2-base amine;
6-[2,6-dimethyl-4-(2-morpholine-4-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-(4-[2-(benzyl-methyl-amino)-ethyoxyl]-2,6-dimethyl-phenyl }-pyridine-2-base amine;
2-[4-(6-amino-pyridine-2-yl)-3,5-dimethyl-phenoxy group]-acetamide;
6-[4-(2-amino-ethyoxyl)-2,6-dimethyl-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
2-(2,5-dimethyl-pyrrolidine-1-yl)-6-[2-isopropyl-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine;
6-(4-[2-(3,5-dimethyl-piperidines-1-yl)-ethyoxyl]-2-isopropyl-phenyl }-pyridine-2-base amine; With
The 6-[2-tert-butyl group-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine.
Other example that can be used for the no inhibitor in the inventive method and the pharmaceutical composition is the chemical compound of following formula:
Figure A0080787800691
R wherein 1And R 2Be independently selected from hydrogen, hydroxyl, methyl and methoxyl group; With G be the group of following formula
Wherein n is 0 or 1;
Y is NR 3R 4, (C 1-C 6) alkyl or aralkyl, wherein the aryl structure division of this aralkyl is that phenyl or naphthyl and this alkyl structure partly are straight or brancheds and contain 1-6 carbon atom and wherein be somebody's turn to do (C 1-C 6) the aryl structure division of alkyl and this aralkyl can be by 1-3 substituent group, preferably 0-2 substituent group replaces, and this substituent group is independently selected from halogen (for example, chlorine, fluorine, bromine or iodine), nitro, hydroxyl, cyano group, amino, (C 1-C 4) alkoxyl and (C 1-C 4) alkyl amino;
When Y is (C 1-C 6) alkyl, aralkyl, or replace (C 1-C 6) during alkyl X be N and when Y be NR 3R 4The time X be CH;
Q is 0,1 or 2;
M is 0,1 or 2; With
R 3And R 4Be independently selected from (C 1-C 6) alkyl, tetralyl and aralkyl, wherein this aryl structure division of this aralkyl is that phenyl or naphthyl and this alkyl structure partly are straight or brancheds and contain 1-6 carbon atom and wherein be somebody's turn to do (C 1-C 6) the aryl structure division of alkyl and this tetralyl and this aralkyl is optional is preferably replaced by 0-2 substituent group by 1-3 substituent group, this substituent group is independently selected from halogen (for example, chlorine, fluorine, bromine or iodine), nitro, hydroxyl, cyano group, amino, (C 1-C 4) alkoxyl and (C 1-C 4) alkyl amino;
Or R 3And R 4Form piperazine with the nitrogen that they connected, piperidines or pyrrolidine ring or contain the azabicyclo of 6-14 link, in these joints 1-3 be nitrogen and remaining be carbon, wherein the example of this azabicyclo is 3-aza-bicyclo [3.1.0] hexane-6-base amine ring:
This piperazine wherein, piperidines and pyrrolidine ring are optional preferably to be replaced by 0-2 substituent group by one or more substituent groups, and this substituent group is independently selected from amino, (C 1-C 6) alkyl amino, [two-(C 1-C 6) alkyl] amino; 5 to the 6 joint heterocycles that contain nitrogen-atoms in 1-4 the ring that phenyl replaces; benzoyl, benzoyl methyl, benzyloxycarbonyl group; the phenyl amino carbonyl; any one phenyl structure division can be chosen wantonly by one or more substituent groups in phenethyl and phenyloxycarbonyl and the wherein aforementioned substituent group, is preferably replaced by 0-2 substituent group; this substituent group is independently selected from halogen, (C 1-C 3) alkyl, (C 1-C 3) alkoxyl, nitro, amino, cyano group, CF 3And OCF 3
Officinal salt with this compounds.
The example of the preferred compound of general formula V is NR wherein 3R 4Be those chemical compounds of following group:
4-phenylethyl piperazine-1-base;
4-methyl piperazine-1-base;
Phenylethyl amino; Or
3-azabicyclo [3.1.0] hexane-6-base amine.
The example of other preferred compound of general formula V is NR wherein 3R 4Be those chemical compounds of following formula group:
NR wherein 5R 6Be NH 2
The particularly preferred chemical compound of general formula V comprises:
3-{2-[4 '-(6-amino-pyridine-2-yl)-biphenyl-4-yl]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
6-[4 '-(4-phenethyl-piperazine-1-ylmethyl)-biphenyl-4-yl]-pyridine-2-base amine;
3-[4 '-(6-amino-pyridine-2-yl)-biphenyl-4-ylmethyl]-3-aza-bicyclo [3.1.0] oneself-6-base amine;
3-[4 '-(6-amino-pyridine-2-yl)-biphenyl-3-ylmethyl]-3-aza-bicyclo [3.1.0] oneself-6-base amine;
2-amino-N-[4 '-(6-amino-pyridine-2-yl)-biphenyl-3-yl]-propionic acid amide.;
2-amino-N-[4 '-(6-amino-pyridine-2-yl)-biphenyl-3-yl]-3-phenyl-propionic acid amide.;
6-[4-(1-benzyl-1,2,5,6-tetrahydrochysene-pyridin-3-yl)-phenyl]-pyridine-2-base amine;
6-[4-(1-benzyl-piperidines-3-yl)-phenyl]-pyridine-2-base amine;
6-[4-(1-benzyl-piperidines-2-ylmethyl)-phenyl]-pyridine-2-base amine;
6-{4-[1-(2,2-diphenyl-ethyl)-piperidines-2-ylmethyl]-phenyl }-pyridine-2-base amine;
6-[3-(2-dimethylamino-cyclopentyl-methyl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(4-methyl piperazine-1-yl)-cyclopentyl-methyl)-phenyl]-pyridine-2-base amine;
6-[4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(N-cyclohexyl amino)-cyclopentyl-methyl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(N-cyclohexyl amino)-cyclopentyl-methyl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(N-phenethyl amino)-cyclopentyl-methyl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(N-phenethyl amino)-cyclopentyl-methyl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(4-methyl piperazine-1-yl)-cyclohexyl methyl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(N-benzyl amino)-cyclohexyl methyl)-phenyl]-pyridine-2-base amine;
6-(4-[2-(2-ethyoxyl-ethylamino-)-cyclohexyl methyl]-phenyl }-pyridine-2-base amine;
6-[4-(2-(4-benzyl diethylenediamine-1-yl)-cyclohexyl methyl)-phenyl]-pyridine-2-base amine;
6-[4-(2-(4-(N-isopropyl acetamido) piperazine-1-yl)-cyclohexyl methyl)-phenyl]-pyridine-2-base amine;
6-[4-((2-(phenethyl)-[2.2.1] dicyclo heptan-1-yl) methyl)-phenyl]-pyridine-2-base amine;
6-[4-((2-(3-aza-bicyclo [3.1.0] oneself-6-base is amino)-[2.2.1] dicyclo heptan-1-yl) methyl)-and phenyl] pyridine-2-base amine;
6-[2-(N-phenethyl amino)-5-phenyl-cyclohexyl methyl) methyl)-phenyl]-pyridine-2-base amine;
6-[4-((2-(phenethyl)-[2.2.1] dicyclo heptan-1-yl) methyl)-phenyl]-pyridine-2-base amine;
6-[((2-(3-aza-bicyclo [3.1.0] oneself-6-base is amino)-5-phenyl-cyclohexyl methyl) methyl)-phenyl]-pyridine-2-base amine;
N-methyl-(2-aminopyridine-6-base-benzal base)-hydroxyindole;
N-methyl-(2-aminopyridine-6-base-benzyl)-hydroxyindole;
N-(2-dimethyl aminoethyl)-(2-aminopyridine-6-base-benzal base)-hydroxyindole;
N-(2-dimethyl aminoethyl)-(2-aminopyridine-6-base-benzyl)-hydroxyindole;
6-[(N-5-isoxazolyl methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
The 6-[(N-acetamido)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-benzoyl methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(3, the 4-dimethoxy-benzyl))-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(3,4-methylene dioxy base benzyl))-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(2-furyl) methyl) 4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
N-[4 '-(6-amino-pyridine-2-yl)-biphenyl-4-ylmethyl]-5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
6-[(N-(5-isothiazolyl) methyl) 4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(5-thiazolyl) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(2-pyridine radicals) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(3-pyridine radicals) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(2-imidazole radicals) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(4-imidazole radicals) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(4-pyridine radicals) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(2-furyl) methyl)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
8-[4-(6-amino-pyridine-2-yl)-phenyl]-3-isobutyl group-3-aza-bicyclo [3.2.1] octan-8-ol;
8-[4-(6-amino-pyridine-2-yl)-phenyl]-3-furan-2-ylmethyl-3-aza-bicyclo [3.2.1] octan-8-ol; With
8-[4-(6-amino-pyridine-2-yl)-phenyl]-3-benzyl-3-aza-bicyclo [3.2.1] octan-8-ol.
Other example that can be used for the no inhibitor in the inventive method and the pharmaceutical composition is the chemical compound of following formula:
Wherein n in bridged ring and m be independently 1,2 or 3 and in the middle of these bridged rings-hetero atom that carbon in individual can be selected from O, S and N replaces; Precondition is that end of the bridge carbon can only be replaced by nitrogen, and R 1And R 2Be independently selected from C 1-C 6Alkyl, it can be linear a, branching or cyclic or contain linear and cyclic simultaneously or branching and cyclic structure division, wherein R 1And R 2In every-individual can choose independently by 1-3 substituent group, preferably 0-2 substituent group replaces, this substituent group is independently selected from halogen (for example, chlorine, fluorine, bromine, iodine), nitro, hydroxyl, cyano group, amino, (C 1-C 4) alkoxyl and (C 1-C 4) alkyl amino;
Or R 1And R 2The nitrogen that is connected with them-rise to form piperazine, azetidine, piperidines or pyrrolidine ring or contain the azabicyclo of 6-14 link, the 1-3 in these joints is individual be nitrogen and remaining be carbon,
Wherein the far-end nitrogen on this piperazine or azabicyclo is optional by radicals R 3And R 4Replace, wherein R 3And R 4Be selected from hydrogen, C 1-C 6Alkyl, phenyl, naphthyl, C 1-C 6Alkyl-C (=O)-, HC (=O)-, C 1-C 6Alkoxyl-(C=O)-, phenyl-C (=O)-, naphthyl-C (=O)-, and R 6R 7NC (=O)-, R wherein 6And R 7Be independently selected from hydrogen and C 1-C 6Alkyl, precondition are when azabicyclo is volution, and the far-end nitrogen on volution is optional by R 5Replace, wherein R 5Be selected from hydrogen, C 1-C 6Alkyl, phenyl, naphthyl, phenyl-C 1-C 6Alkyl-and naphthyl C 1-C 6Alkyl-;
This piperazine wherein, azetidine, piperidines and pyrrolidine ring can be chosen wantonly by one or more substituent groups, are preferably replaced by 0-2 substituent group, and this substituent group is independently selected from (C 1-C 6) alkyl, amino, (C 1-C 6) alkyl amino, [two-(C 1-C 6) alkyl] amino; 5 to the 6 joint heterocycles that contain nitrogen-atoms in 1-4 the ring that phenyl replaces; benzoyl, benzoyl methyl, benzyloxycarbonyl group; the phenyl amino carbonyl; any one phenyl structure division can be chosen wantonly by one or more substituent groups in phenethyl and phenyloxycarbonyl and the wherein aforementioned substituent group, is preferably replaced by 0-2 substituent group; this substituent group is independently selected from halogen, C 1-C 3Alkyl, C 1-C 3Alkoxyl, nitro, amino, cyano group, CF 3And OCF 3
Precondition is that carbon atom is not replaced by an above substituent group, and this substituent group is selected from hydroxyl, amino, alkoxyl, alkyl amino and dialkyl amido;
Officinal salt with this chemical compound.
In the chemical compound of above general formula VI by NR 1R 2The example of the azabicyclo that forms is
Figure A0080787800761
With
R wherein 3And R 4Be to be selected from hydrogen, C 1-C 6Alkyl, phenyl, naphthyl, C 1-C 6Alkyl-C (=O)-, HC (=O)-, C 1-C 6Alkoxyl-(C=O)-, phenyl-C (=O)-, naphthyl-C (=O)-, and R 6R 7NC (=O)-, R wherein 6And R 7Be independently selected from hydrogen and C 1-C 6Alkyl; With
R 5Be to be selected from hydrogen, C 1-C 6Alkyl, phenyl, naphthyl, phenyl-C 1-C 6Alkyl-and naphthyl C 1-C 6Alkyl-;
The preferred compound of general formula I V comprises wherein NR 1R 2Be optional substituted piperidines, azetidine, piperazine or pyrrolidine ring or 3-azabicyclo [3.1.0] oneself-those chemical compounds of 6-base amine ring;
This piperazine wherein, azetidine, piperidines, pyrrolidine and 3-azabicyclo [3.1.0] hexane-6-base amine ring can be chosen wantonly by one or more substituent groups, is preferably replaced by 0-2 substituent group, and this substituent group is selected from C 1-C 6Alkyl, amino, C 1-C 6Alkyl amino, [two-C 1-C 6Alkyl] amino; phenyl, the 5-6 joint heterocycle that contains nitrogen-atoms in 1-4 the ring of replacement, benzoyl; the benzoyl methyl; benzyloxycarbonyl group, phenyl amino carbonyl, phenethyl and phenyloxycarbonyl; any one phenyl structure division can be chosen wantonly by one or more substituent groups in the wherein aforementioned substituent group; preferred 0-2 substituent group replaces, and this substituent group is independently selected from halogen, C 1-C 3Alkyl, C 1-C 3Alkoxyl, nitro, amino, cyano group, CF 3And OCF 3
Officinal salt with this chemical compound.
Following chemical compound is the preferred compound of general formula VI:
6-[8-(2-dimethylamino-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-5-yl]-pyridine-2-base amine;
And 6-[8-(2-pyrrolidine-1-base-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-5-yl]-pyridine-2-amine.
Other chemical compound of general formula VI be following these:
6-[8-(2-dimethylamino-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-ethylene-naphthalene-5-yl]-pyridine-2-base amine;
6-[8-(2-pyrrolidine-1-base-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-ethylene-naphthalene-5-yl]-pyridine-2-base amine;
6-[8-(2-(4-dimethylamino-piperidines-1-yl)-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-5-yl]-pyridine-2-base amine;
6-[8-(2-(6,7-dimethoxy-tetrahydroisoquinoline-2-yl)-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-5-yl]-pyridine-2-base amine; With
6-[8-(2-(4-methyl piperazine-1-yl)-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-5-yl]-pyridine-2-base amine.
The chemical compound of general formula I-VI can contain chiral centre, therefore can exist with different enantiomers and diastereomeric form.The present invention relates to use the above-mentioned Therapeutic Method of above pharmaceutical composition, said composition comprises all optical isomers and all stereoisomers and composition thereof of the chemical compound of general formula I-VI.
Term used herein " alkyl ", except as otherwise noted, otherwise comprise have straight chain, the saturated monovalence alkyl of side chain or circulus part or their combination.
Term used herein " one or more substituent group " is meant substituent number, and it equals the substituent group of coming fixed possible maximum number to the number according to available keyed jointing position from 1.
Term used herein " halogen " and " halogen " except as otherwise noted, comprise chlorine, fluorine, bromine and iodine.
Above general formula I-VI also comprises some chemical compounds, and they are equal to those that described, but must consider that one or more hydrogen, carbon or other atom are by the alternate fact of its isotope.This compounds can be used as research and diagnostic tool in the metabolic drug dynamics research and in binding analysis.
The example that can be used in the SSRI in method of the present invention and the pharmaceutical composition is Sertraline (sertraline), fluoxetine, Paroxetine (paroxetine), Citalopram (citalopram) and Clovoxamine (fluvoxamine).
The example that can be used in the nk 1 receptor antagonist in the inventive method and the pharmaceutical composition is following chemical compound and their officinal salt:
2-(benzhydryl)-N-((2-difluoro-methoxy) phenyl) methyl isophthalic acid-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(2-methoxyl group-5-Trifluoromethoxyphen-l) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-2-phenyl-3-[2-(2,2, the 2-trifluoro ethoxy) benzyl]-amino piperidine;
(2S, 3S)-3-(2-methoxyl group-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-1-(5,6-dimethoxy hexyl)-3-(2-methoxyl group-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-2-phenyl-3-(2-trifluoro-methoxybenzyl) amino piperidine;
(2S, 3S)-3-(2-hydroxyl-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-[5-chloro-2-(2,2, the 2-trifluoro ethoxy)-benzyl] amino-2-Phenylpiperidine;
(2S, 3S)-2-phenyl-3-(3-trifluoro-methoxybenzyl)-amino piperidine;
(2S, 3S)-3-(the 5-tert-butyl group-2-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-[5-isopropyl-2-(2,2, the 2-trifluoro ethoxy)-benzyl] amino-2-phenylpiperazine;
(2S, 3S)-3-[5-dimethylamino-2-(2,2, the 2-trifluoro ethoxy)-benzyl] amino-2-phenylpiperazine;
(2S, 3S)-3-[2-difluoro-methoxy-5-N, N-dimethylamino-benzyl) amino-2-phenylpiperazine;
(2S, 3S)-3-[2, two (difluoro-methoxy) benzyls of 5-] amino-2-Phenylpiperidine;
(2S, 3S)-3-(the 5-tert-butyl group-2-difluoro-methoxy benzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-isopropoxy-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-ethyoxyl-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-nitrobenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-isopropyl benzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-[5-acetamido-2-(2,2, the 2-trifluoro ethoxy)-benzyl] amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-Ethylbenzyl) amino-2-Phenylpiperidine;
Suitable-3-(the 5-tert-butyl group-2-methoxybenzyl) amino-2-(3-Trifluoromethoxyphen-l) piperidines;
Suitable-2-(3, the 5-dibromo phenyl)-3-(2-methoxyl group-5-trifluoro-methoxybenzyl) amino piperidine; With
(2S-3S)-3-(2-difluoro-methoxy-5-methylbenzyl) amino-2-Phenylpiperidine.
Other example of nk 1 receptor antagonist is:
(2S, 3S)-3-(the 5-tert-butyl group-2-methoxybenzyl) amino-2-(3-Trifluoromethoxyphen-l) piperidines;
(2S, 3S)-3 (the 5-tert-butyl group-2-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
2-(diphenyl methyl)-N-(2-methoxyl group-5-trifluoromethoxy-phenyl) methyl isophthalic acid-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-2-phenyl-3-[2-(2,2,2-trifluoro ethoxy benzyl)-amino piperidine;
Suitable-3-(2-benzyl chloride base amino)-2-Phenylpiperidine;
Suitable-3-(2-trifluoromethyl benzyl amino)-2-phenyl-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(2-fluorophenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(2-chlorphenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(2-aminomethyl phenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-methoxyphenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-fluorophenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-chlorphenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-aminomethyl phenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(4-fluorophenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-thienyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-phenyl azepan;
3-(2-methoxy-benzyl amino)-4-methyl-2-Phenylpiperidine;
3-(2-methoxy-benzyl amino)-5-methyl-2-Phenylpiperidine;
3-(2-methoxy-benzyl amino)-6-methyl-2-Phenylpiperidine;
(2S, 3S)-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-1-(5-carbonyl ethoxy pentane-1-yl)-3-(2-methoxybenzyl-amino)-2-Phenylpiperidine;
(2S, 3S)-1-(the 6-hydroxyl-oneself-the 1-yl)-3-(2-methoxybenzyl-amino)-2-Phenylpiperidine;
(2S, 3S)-1-(4-hydroxy-4-phenyl butane-1-yl)-3-(2-methoxyl group-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-1-(4-oxo-4-phenyl butane-1-yl)-3-(2-methoxybenzyl-amino)-2-Phenylpiperidine;
(2S, 3S)-1-(5,6-dihydroxy-hexane-1-yl)-3-(2-methoxybenzyl-amino)-2-Phenylpiperidine;
Suitable-3-(5-fluoro-2-methoxy-benzyl amino)-2-phenyl-piperidines;
(2S, 3S)-1-[4-(4-fluorophenyl)-4-oxo-butanes-1-yl]-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-the 1-[4-[4-fluorophenyl)-4-hydroxyl butane-1-yl]-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
Suitable-3-(2-methoxyl group-5-methyl-benzyl amino)-2-phenyl-piperidines;
(2S, 3S)-1-(4-benzamido fourth-1-yl)-3-(2-methoxybenzyl-amino)-2-Phenylpiperidine;
Suitable-3-(2-methoxynaphthalene-1-ylmethyl amino)-2-phenyl-piperidines;
(2S, 3S)-3-(2-methoxy-benzyl amino)-1-(5-N-methyl-carboxamide groups pentane-1-yl)-2-Phenylpiperidine;
(2S, 3S)-1-(4-cyano group butane-1-yl)-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-1-[4-(2-naphthoyl amido) fourth-1-yl]-3-(2-methoxyl group-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-1-(5-benzamido pentane-1-yl)-3-(2-methoxy-benzyl-amino)-2-Phenylpiperidine;
(2S, 3S)-1-(5-aminopentane-1-yl)-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-3-(5-chloro-2-methoxy-benzyl amino)-2-phenyl-piperidines;
(2S, 3S)-3-(2,5-dimethoxy-benzyl amino)-2-phenyl-piperidines;
Suitable-3-(3,5-difluoro-2-methoxyl benzylamino)-2-phenyl-piperidines;
Suitable-3-(4,5-difluoro-2-methoxyl benzylamino)-2-phenyl-piperidines;
Suitable-3-(2,5-dimethoxy-benzyl amino)-1-[4-(4-fluorophenyl)-4-oxo-butanes-1-yl]-the 2-Phenylpiperidine;
Suitable-3-(5-chloro-2-methoxy-benzyl amino)-1-(5,6-dihydroxy-hexane-1-yl)-2-Phenylpiperidine;
Suitable-1-(5,6-dihydroxy-hexane-1-yl)-3-(2,5-dimethoxy-benzyl amino)-2-Phenylpiperidine;
Suitable-2-phenyl-3-[-2 (third-2-base oxygen base) benzyl amino] piperidines;
Suitable-3-(2, the 5-dimethoxy-benzyl) amino-2-(3-methoxyl group-phenyl) piperidine hydrochlorate;
Suitable-3-(5-chloro-2-methoxy-benzyl) amino-2-(3-methoxyl group-phenyl) piperidines dihydrochloride;
Suitable-3-(5-chloro-2-methoxy-benzyl) amino-2-(3-chloro-phenyl) piperidines dihydrochloride;
3-(2-methoxy-benzyl amino)-2, the 4-diphenyl-piperidine;
Suitable-3-(2-methoxy-benzyl amino)-2-Phenylpyrrolidine;
(2S, 3S)-3-(5-ethyl-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(5-normal-butyl-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(2-methoxyl group-5-n-pro-pyl benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(5-isopropyl-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(5-sec-butyl-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(the 5-tert-butyl group-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(2-methoxyl group-5-phenylbenzyl) amino-2-phenyl-piperidines;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxyl group-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-methyl nitrosourea;
N-(4,5-dimethylthiazole-2-yl)-N-[4-methoxyl group-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-amsacrine;
(5-[(4,5-dimethylthiazole-2-yl) methylamino]-the 2-methoxy-benzyl)-((2S, 3S)-2-Phenylpiperidine-3-yl) amine;
(5-(4,5-dimethylthiazole-2-base is amino)-2-methoxy-benzyl }-((2S, 3S)-2-Phenylpiperidine-3-base amine;
4,5-dimethylthiazole-2-sulfonic acid methyl-[3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl)-the 4-Trifluoromethoxyphen-l]-amide;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-methyl nitrosourea;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-the isopropyl amide;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxyl group-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-the isopropyl amide;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxyl group-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-the isobutyl group amide;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-the isobutyl group amide;
(2S, 3S)-N-(5-isopropyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(the 5-tert-butyl group-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-methyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-ethyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-isopropyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-sec-butyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-just-propyl group-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine,
(3R, 4S, 5S, 6S)-and N, N-diethyl-5-(5-isopropyl-2-methoxyl group-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid amides;
(3R, 4S, 5S, 6S)-and N, N-diethyl-5-(2,5-dimethoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid amides;
(3R, 4S, 5S, 6S)-5-(5-isopropyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-2-methyl sulfenyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2,5-dimethoxy-benzyl amino)-6-benzhydryl-1-azabicyclo-[2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-ethyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-n-pro-pyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-sec-butyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-N-methyl-sulfonyl methane amido-2-methoxyl group-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methylsulfinyl benzyl-amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-trifluoro-methoxybenzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl sulphonyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-dimethylamino-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-isopropyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl sulfenyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2,5-dimethoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-ethyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-n-pro-pyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-sec-butyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-N-methyl-sulfonyl methane amido-2-methoxy-benzyl-amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methylsulfinyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-trifluoro-methoxybenzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl sulphonyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; With
(3R, 4S, 5S, 6S)-5-(5-dimethylamino-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
With
Figure A0080787800862
These chemical compounds can prepare described in the PCT patent application WO95/08549 that publishes March 30 nineteen ninety-five.
Other example that can be used in the nk 1 receptor antagonist in method of the present invention and the pharmaceutical composition is those that relate in following list of references, all these documents are for reference with its full content this paper that induced one: United States Patent (USP) 5, announced on November 11st, 162,339,1992; United States Patent (USP) 5,232 was announced on August 3rd, 929,1993; World patent application WO published on November 26th, 92/20676,1992; World patent application WO published on January 7th, 93/00331,1993; US patent No.5,773,450,92/21677,1992 year December of world patent application WO was published on the 10th; World patent application WO published on January 7th, 93/00330,1993; World patent application WO93/06099, on April 1st, 1993 published; World patent application WO published on May 27th, 93/10073,1993; World patent application WO published on April 16th, 92/06079,1992; World patent application WO published on July 23rd, 92/12151,1992; World patent application WO92/15585, JIUYUE was published on the 17th in 1992; World patent application WO published on May 27th, 93/10073,1993; 93/19064,1993 year JIUYUE of world patent application WO was published on the 30th; World patent application WO published on April 28th, 94/08997,1994; World patent application WO94/04496, on March 3rd, 1994 published; U.S. Patent application 988,653, December was submitted on the 10th in 1992; U.S. Patent application 026,382, on March 4th, 1993 submitted to; U.S. Patent application 123,306, JIUYUE was submitted to and U.S. Patent application submission on June 4th, 072,629,1993 on the 17th in 1993.All aforementioned world patent applications have been specified the U.S. and have been proposed in the US of PCT office of acceptance: European patent application EP 499,313, and on August 19th, 1992 published; European patent application EP 520,555, December was published on the 30th in 1992; European patent application EP 522,808, on January 13rd, 1993 published; European patent application EP 528,495, on February 24th, 1993; PCT patent application WO published on July 22nd, 93/14084,1993; PCT patent application WO published on January 21st, 93/01169,1993; PCT patent application WO published on January 21st, 93/01165,1993; PCT patent application WO published on January 21st, 93/01159,1993; PCT patent application WO92/20661, on November 26th, 1992 published; European patent application EP 517,589, December was published on the 12nd in 1992; European patent application EP 428,434, on May 22nd, 1991 published; European patent application EP 360,390, publish March 28 nineteen ninety; PCT patent application WO95/19344, publish July 20 nineteen ninety-five; PCT patent application WO 95/23810, the publication on the 8th of nineteen ninety-five JIUYUE; PCT patent application WO 95/20575, publish August 3 nineteen ninety-five; With PCT patent application WO 95/28418, publish August 26 nineteen ninety-five.
The preferred embodiments of the invention relate to said method and the pharmaceutical composition that uses SSRI, and wherein SSRI is a Sertraline.Other preferred embodiment of the present invention is with Sertraline and general formula I, above-described method and pharmaceutical composition that II, III, IV, the NOS composite inhibiting of V or VI combine and use.
Other preferred embodiment of the present invention is above-described pharmaceutical composition and the method that Sertraline is combined with the nk 1 receptor antagonist and uses, and wherein this nk 1 receptor antagonist is to be selected from a kind of in the following compounds that belongs to pharmaceutical acceptable salt:
2-(benzhydryl)-N-((2-difluoro-methoxy) phenyl) methyl isophthalic acid-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(2-methoxyl group-5-Trifluoromethoxyphen-l) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-2-phenyl-3-[2-(2,2, the 2-trifluoro ethoxy) benzyl]-amino piperidine;
(2S, 3S)-3-(2-methoxyl group-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-1-(5,6-dimethoxy hexyl)-3-(2-methoxyl group-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-2-phenyl-3-(2-trifluoro-methoxybenzyl) amino piperidine;
(2S, 3S)-3-(2-hydroxyl-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-[5-chloro-2-(2,2, the 2-trifluoro ethoxy)-benzyl] amino-2-Phenylpiperidine;
(2S, 3S)-2-phenyl-3-(3-trifluoro-methoxybenzyl)-amino piperidine;
(2S, 3S)-3-(the 5-tert-butyl group-2-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-[5-isopropyl-2-(2,2, the 2-trifluoro ethoxy)-benzyl] amino-2-Phenylpiperidine;
(2S, 3S)-3-[5-dimethylamino-2-(2,2, the 2-trifluoro ethoxy)-benzyl] amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-N, N-dimethylamino-benzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-[2, two (difluoro-methoxy) benzyls of 5-] amino-2-Phenylpiperidine;
(2S, 3S)-3-(the 5-tert-butyl group-2-difluoro-methoxy benzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-isopropoxy-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-trifluoro-methoxybenzyl)-amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-ethyoxyl-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-nitrobenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-isopropyl benzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-[5-acetamido-2-(2,2, the 2-trifluoro ethoxy)-benzyl] amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-Ethylbenzyl) amino-2-Phenylpiperidine;
Suitable-3-(the 5-tert-butyl group-2-methoxybenzyl) amino-2-(3-Trifluoromethoxyphen-l) piperidines;
Suitable-2-(3, the 5-dibromo phenyl)-3-(2-methoxyl group-5-trifluoro-methoxybenzyl) amino piperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-methylbenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(the 5-tert-butyl group-2-methoxybenzyl) amino-2-(3-Trifluoromethoxyphen-l) piperidines;
(2S, 3S)-3 (the 5-tert-butyl group-2-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
2-(diphenyl methyl)-N-(2-methoxyl group-5-trifluoromethoxy-phenyl) methyl isophthalic acid-azabicyclo [2.2.2] octane-3-amine;
Suitable-3-(2-benzyl chloride base amino)-2-Phenylpiperidine;
Suitable-3-(2-trifluoromethyl benzyl amino)-2-phenyl-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(2-fluorophenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(2-chlorphenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(2-aminomethyl phenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-methoxyphenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-fluorophenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-chlorphenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-aminomethyl phenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(4-fluorophenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-thienyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-phenyl azepan;
3-(2-methoxy-benzyl amino)-4-methyl-2-Phenylpiperidine;
3-(2-methoxy-benzyl amino)-5-methyl-2-Phenylpiperidine;
3-(2-methoxy-benzyl amino)-6-methyl-2-Phenylpiperidine;
(2S, 3S)-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-1-(5-carbonyl ethoxy pentane-1-yl)-3-(2-methoxybenzyl-amino)-2-Phenylpiperidine;
(2S, 3S)-1-(the 6-hydroxyl-oneself-the 1-yl)-3-(2-methoxy-benzyl-amino)-2-Phenylpiperidine;
(2S, 3S)-1-(4-hydroxy-4-phenyl butane-1-yl)-3-(2-methoxyl group-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-1-(4-oxo-4-phenyl butane-1-yl)-3-(2-methoxy-benzyl-amino)-2-Phenylpiperidine;
(2S, 3S)-1-(5,6-dihydroxy-hexane-1-yl)-3-(2-methoxy-benzyl-amino)-2-Phenylpiperidine;
Suitable-3-(5-fluoro-2-methoxy-benzyl amino)-2-phenyl-piperidines;
(2S, 3S)-1-[4-(4-fluorophenyl)-4-oxo-butanes-1-yl]-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-the 1-[4-[4-fluorophenyl)-4-hydroxyl butane-1-yl]-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
Suitable-3-(2-methoxyl group-5-methyl-benzyl amino)-2-phenyl-piperidines;
(2S, 3S)-1-(4-benzamido fourth-1-yl)-3-(2-methoxy-benzyl-amino)-2-Phenylpiperidine;
Suitable-3-(2-methoxynaphthalene-1-ylmethyl amino)-2-phenyl-piperidines;
(2S, 3S)-3-(2-methoxy-benzyl amino)-1-(5-N-methyl-carboxamide groups pentane-1-yl)-2-Phenylpiperidine;
(2S, 3S)-1-(4-cyano group butane-1-yl)-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-1-[4-(2-naphthoyl amido) fourth-1-yl]-3-(2-methoxyl group-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-1-(5-benzamido pentane-1-yl)-3-(2-methoxy-benzyl-amino)-2-Phenylpiperidine;
(2S, 3S)-1-(5-aminopentane-1-yl)-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-3-(5-chloro-2-methoxy-benzyl amino)-2-phenyl-piperidines;
(2S, 3S)-3-(2,5-dimethoxy-benzyl amino)-2-phenyl-piperidines;
Suitable-3-(3,5-difluoro-2-methoxyl benzylamino)-2-phenyl-piperidines;
Suitable-3-(4,5-difluoro-2-methoxyl benzylamino)-2-phenyl-piperidines;
Suitable-3-(2,5-dimethoxy-benzyl amino)-1-[4-(4-fluorophenyl)-4-oxo-butanes-1-yl]-the 2-Phenylpiperidine;
Suitable-3-(5-chloro-2-methoxy-benzyl amino)-1-(5,6-dihydroxy-hexane-1-yl)-2-Phenylpiperidine;
Suitable-1-(5,6-dihydroxy-hexane-1-yl)-3-(2,5-dimethoxy-benzyl amino)-2-Phenylpiperidine;
Suitable-2-phenyl-3-[-2 (third-2-base oxygen base) benzyl amino] piperidines;
Suitable-3-(2, the 5-dimethoxy-benzyl) amino-2-(3-methoxyl group-phenyl) piperidines hydrogen chloride;
Suitable-3-(5-chloro-2-methoxy-benzyl) amino-2-(3-methoxyl group-phenyl) piperidines dihydrochloride;
Suitable-3-(5-chloro-2-methoxy-benzyl) amino-2-(3-chloro-phenyl) piperidines dihydrochloride;
3-(2-methoxy-benzyl amino)-2, the 4-diphenyl-piperidine;
Suitable-3-(2-methoxy-benzyl amino)-2-Phenylpyrrolidine;
(2S, 3S)-3-(5-ethyl-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(5-normal-butyl-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(2-methoxyl group-5-n-pro-pyl benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(5-isopropyl-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(5-sec-butyl-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(the 5-tert-butyl group-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(2-methoxyl group-5-phenylbenzyl) amino-2-phenyl-piperidines;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxyl group-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-methyl nitrosourea;
N-(4,5-dimethylthiazole-2-yl)-N-(4-methoxyl group-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-amsacrine;
(5-[(4,5-dimethylthiazole-2-yl) methylamino]-the 2-methoxy-benzyl }-((2S, 3S)-2-Phenylpiperidine-3-yl) amine;
(5-(4,5-dimethylthiazole-2-base is amino)-2-methoxy-benzyl }-((2S, 3S)-2-Phenylpiperidine-3-base amine;
4,5-dimethylthiazole-2-sulfonic acid methyl-[3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl)-the 4-Trifluoromethoxyphen-l]-amide;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-methyl nitrosourea;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-the isopropyl amide;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxyl group-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-the isopropyl amide;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxyl group-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-the isobutyl group amide;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-the isobutyl group amide;
(2S, 3S)-N-(5-isopropyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(the 5-tert-butyl group-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-methyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-ethyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-isopropyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-sec-butyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-just-propyl group-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine,
(3R, 4S, 5S, 6S)-and N, N-diethyl-5-(5-isopropyl-2-methoxyl group-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid amides;
(3R, 4S, 5S, 6S)-and N, N-diethyl-5-(2,5-dimethoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid amides;
(3R, 4S, 5S, 6S)-5-(5-isopropyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-2-methyl sulfenyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2,5-dimethoxy-benzyl amino)-6-benzhydryl-1-azabicyclo-[2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-ethyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-n-pro-pyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-sec-butyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-N-methyl-sulfonyl methane amido-2-methoxyl group-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methylsulfinyl benzyl-amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-trifluoro-methoxybenzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl sulphonyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-dimethylamino-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-isopropyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl sulphonyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2,5-dimethoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-ethyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-n-pro-pyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-sec-butyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-N-methyl-sulfonyl methane amido-2-methoxy-benzyl-amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methylsulfinyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-trifluoro-methoxybenzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl sulphonyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; With
(3R, 4S, 5S, 6S)-5-(5-dimethylamino-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
With
Figure A0080787800952
Of the present invention being described in detail
In the following discussion, general formula I, II, III, IV, V is identical with the above definition that provides in general introduction of the present invention with VI.
The officinal salt of the chemical compound of general formula I and they can be according to following described and according to (on August 27th, 1997 submitted in US provisional application 601057094, title is " 2-aminopyrindines Containing Fused Ring Substituents "), prepare with described in the world patent application 99/10339 (published on March 4th, 1999, have identical title and required the priority of provisional application 60/057094).It is for reference that aforementioned application is introduced into this paper with its full content.
In reaction mechanism mechanism of reaction 1-3 below and the discussion of reaction mechanism mechanism of reaction 1-3, all substituent groups are identical with above definition for compound of Formula I.
The reaction mechanism mechanism of reaction 1
Figure A0080787800961
The reaction mechanism mechanism of reaction 2
Figure A0080787800971
The reaction mechanism mechanism of reaction 2 is continuous
Figure A0080787800981
(X=O, ring A=benzo)
The reaction mechanism mechanism of reaction 3
Figure A0080787800991
(ring A=benzo,
X＝ O)
The reaction mechanism mechanism of reaction 1 has illustrated that preparing wherein X is that chemical bond and ring A are the methods of the compound of Formula I of benzo.The reaction mechanism mechanism of reaction 2 and 3 has illustrated that preparing wherein X is that oxygen and ring A are the methods of the compound of Formula I of benzo.The initiation material that is used for the program of the reaction mechanism mechanism of reaction 1 and 2 can be purchased, and is well known in the prior art or saved by those technology people in affiliated field easily that familiar method obtains from known compound.
Referring to the reaction mechanism mechanism of reaction 1, the chemical compound of general formula (2) is cooled to-70 ℃ and then the solution of n-BuLi is added wherein in dry tetrahydrofuran (THF).The solution that is obtained is handled with triethyl borate then, allows it rise to room temperature to form the chemical compound of general formula (3).
The chemical compound of general formula (3) is the chemical compound that forms general formula (5) with the chemical compound reaction of general formula (4).This reaction in the presence of sodium carbonate and tetrakis triphenylphosphine palladium, is approximately being carried out under the reflux temperature normally in aqueous alcohol solvent.
The chemical compound of general formula (6) can form by following mode.At first, the chemical compound of general formula (5) and N-bromosuccinimide (NBS) and two-(1-cyano group-1-azepine) cyclohexane extraction reacted in carbon tetrachloride and refluxed about 8 hours, added the initiator of extention at about 1,2 and 4 hour.After solvent evaporation, the product of this reaction and triethyl ammonium cyanide are approximately reacting under the room temperature in dichloromethane, form the chemical compound of general formula (6).
The solution of the chemical compound of general formula (6) in ethanol is saturated with hydrogen chloride, refluxes and heats in aqueous hydrochloric acid solution then with the relief mixture, obtains the chemical compound of general formula (7).
The chemical compound of the general formula that forms in previous step (7) can change into the chemical compound of general formula I A by following mode.At first, the chemical compound and the general formula R of general formula (7) 2R 1The suitable chemical compound of NH and N-ethyl-N-dimethylamino-propyl carbodiimides (EDAC) reacts in the presence of alkali.The example of appropriate base is to be selected from trialkylamine, those of alkali carbonate and alkaline earth metal carbonate.This reaction is typically at solvent such as acetonitrile, and dichloromethane or N in the dinethylformamide (DMF),, are preferably approximately carrying out under the room temperature under about 100 ℃ temperature in about room temperature.Preferably, this reaction is to carry out in the presence of catalytic additive such as N-hydroxy-succinamide or hydroxybenzotriazole.
The product of previous reaction uses the method for being known by technology people joint in the affiliated field to reduce then.For example, this reduction reaction can be used the solution of lithium aluminium hydride in oxolane, be with or without aluminum chloride, or the solution of use borine methyl sulfide in oxolane, approximately-78 ℃ under about 0 ℃ temperature, preferably under approximately-70 ℃, carry out, obtain the required compound of general formula I A.
Reference reaction course 2, chemical compound of this general formula (8) and tetrabutylammonium terbromide are approximately being reacted under the room temperature in the 2-dichloroethanes 1.The product of this reaction then with benzyl bromide a-bromotoluene and potassium carbonate in solvent such as acetonitrile, under the reflux temperature of about this reactant mixture, react, form the chemical compound of general formula (9).
The chemical compound of general formula (9) is converted to 1-benzyloxy-naphthalene-4-boric acid for the described program of boronic acid derivatives for preparing general formula (3) by above then in the reaction mechanism mechanism of reaction 1.
The chemical compound of 1-benzyloxy-naphthalene-4-boric acid and general formula (10) in the presence of sodium carbonate and tetrakis triphenylphosphine palladium, reacts under the reflux temperature of about this reactant mixture in alcohol solvent, obtains the chemical compound of general formula (11).
The chemical compound of general formula (11) can use following two-stage process to be converted to the chemical compound of general formula (3).The chemical compound of general formula (11) and ammonium formate and 10% palladium/carbon are in alcohol solvent, under the reflux temperature of about this reactant mixture, react, obtain and have the chemical compound similar compounds of general formula (11), the benzyloxy of its formula of (11) is substituted by hydroxyl.Then by above hydroxy derivatives and acetic acid 2-bromo-ethyl ester and potassium carbonate in acetonitrile, under the reflux temperature of about this reactant mixture, react the chemical compound that forms general formula (12).
The basic hydrolysis of the chemical compound of general formula (12) is subsequently with N-ethyl-N-3-dimethylaminopropyl carbodiimides (EDAC) with have general formula R 1R 2The suitable chemical compound of NH reacts, and obtains the required compound of general formula (13).This basic hydrolysis is typically by using alkali metal or alkaline earth metal hydroxide approximately carrying out under the room temperature in the mixture of THF, first alcohol and water.With R 1R 2The reaction of NH and EDAC generally is abovely to carry out for the described program of those compound general formula Is A chemical compound from general formula (7) in the reaction mechanism mechanism of reaction 1 by using.
The chemical compound of general formula (13) can be converted to the required compound of general formula I B as follows.The chemical compound of general formula (13) is reduced into wherein carbonyl and is removed 2 after this by the alternate respective compound of methylene, 5-dimethyl pyrrole blocking group.Under this reduction reaction can be used in the field technology people save known method-for example the use lithium aluminium hydride in oxolane, be with or without aluminum chloride, or the borine methyl sulfide of use in oxolane, approximately-78 ℃ under about 0 ℃ temperature, preferably under approximately-70 ℃, carry out.
2, removing of 5-dimethyl pyrrole protecting group can be finished by reacting with oxammonium hydrochloride..This reaction under the temperature the reflux temperature from about room temperature to about reactant mixture, preferably under about this reflux temperature, was carried out about 8 to about 72 hours normally in alcohol or aqueous alcoholic solvent.
Be equal to those chemical compounds of general formula I B but ring A is not that the compound of Formula I of benzo can be in a similar manner, with beginning to prepare with suitable chemical compound like general formula (8) compounds, unsubstituting phenenyl of its formula of (8) and ring are not that the ring of benzo substitutes in the definition of ring A.
Referring to the reaction mechanism mechanism of reaction 3, known 1-fluoronaphthalene (14) with bromine in acetic acid under the temperature the reflux temperature from about room temperature to about reactant mixture bromination about 1 by about 48 hours, this bromide is cooled to approximately-70 ℃ in dry tetrahydrofuran (THF), add the solution of n-BuLi then to it.The solution that is obtained is handled with triethyl borate then, allows it rise to room temperature to form the chemical compound of general formula (15).The chemical compound of general formula (15) is the chemical compound that forms general formula (16) with the chemical compound reaction of general formula (4).This reaction in the presence of sodium carbonate and tetrakis triphenylphosphine palladium, is approximately being carried out under the reflux temperature normally in aqueous alcohol solvent.The chemical compound of general formula (16) is used (CH from general formula HO then 2) nNR 1R 2The alkali metal alcoholates of compound and sodium hydride in polar solvent such as dimethyl formamide, under the temperature of room temperature to 140 ℃, handling about 1 to about 48 hours.The respective compound of general formula (17) is produced in this reaction, and it by being disengaged sealing with the oxammonium hydrochloride. reaction, has removed 2,5-dimethyl pyrrole protecting group then.This reaction under the temperature the reflux temperature from about room temperature to about reactant mixture, preferably under about this reflux temperature, was carried out about 8 to about 72 hours normally in alcohol or aqueous alcoholic solvent.
Be equal to those chemical compounds of general formula I A and IB but ring A is not that the compound of Formula I of benzo can be in a similar manner, with with suitable initiation material like those compounds of general formula (2), (8) and (14), preparation in the reaction mechanism mechanism of reaction 1,2 and 3 respectively, wherein the unsubstituting phenenyl of this type of initiation material and ring are not that the ring of benzo substitutes in the definition of ring A.
There is not particularly the preparation of other chemical compound of the general formula I described in the test portion in front can use the combination of those reactions of knowing by technology people joint in the affiliated field to finish.
In in those reactions of above discussion or explanation each, pressure is not crucial, except as otherwise noted.It is normally acceptable to be pressed onto about 5 atmospheric pressure from about 0.5 atmosphere, and ambient pressure, and promptly about 1 atmospheric pressure is because convenient but preferred.
The chemical compound of general formula I I and their officinal salt can be according to preparing described in published PCT patent application WO 97/36871, and it is specified the U.S. and publishes on October 9th, 1997.It is for reference that aforementioned application is introduced into this paper with its full content.
The officinal salt of the chemical compound of general formula I I and they can be according to following described and according at John A.Lowe, in the US temporary patent application 60/057739 of III (title is " Phenylpyridin-2-yl-amine Derivatives ", on August 28th, 1997 proposed) with described in relevant world patent application WO 99/11620 (publication on March 11st, 1999), prepare.It is for reference that aforementioned patent applications is introduced into this paper with its full content.
The following reaction mechanism mechanism of reaction 4 and 5 is used to illustrate the method for the chemical compound for preparing general formula III.
The reaction mechanism mechanism of reaction 4
Figure A0080787801041
The reaction mechanism mechanism of reaction 4 is continuous
Figure A0080787801051
The reaction mechanism mechanism of reaction 5
(X＝CH 2)
Referring to the reaction mechanism mechanism of reaction 4, the chemical compound of general formula (18) and general formula CHR 3R 4Br or CHR 2R 4The chemical compound of I and potassium carbonate react under the reflux temperature of about this reactant mixture in solvent such as acetonitrile, the hydroxyl of general formula (18) are changed into have general formula-OCHR 3R 4Group.The chemical compound that is obtained under about room temperature, in the presence of 10% palladium/carbon, by using hydrogen to reduce, has formed 3-OCHR then in alcohol solvent 3R 4-4-amino toluene, it reacts in concentrated sulphuric acid with sodium nitrite and cuprous bromide then and has formed 3-OCHR 3R 4-4-toluene bromide.
The 3-OCHR that in previous reaction, produces 3R 4-4-toluene bromide is cooled to-70 ℃ approximately then in dry tetrahydrofuran (THF), add the solution of n-BuLi to it.The solution that is obtained is handled with triethyl borate then, allows it rise to room temperature to form the chemical compound of general formula (19).
The chemical compound of the chemical compound of general formula (19) and general formula (20) reacts and the chemical compound of formation general formula (21).This reaction in the presence of sodium carbonate and tetrakis triphenylphosphine palladium, is carried out under about reflux temperature of reactant mixture normally in aqueous alcohol solvent.
The chemical compound of general formula (23) can form by following mode.At first, the chemical compound of general formula (21) and N-bromosuccinimide (NBS) and two-(1-cyano group-1-azepine) cyclohexane extraction (general formula (22)) reacted in carbon tetrachloride and refluxed about 8 hours, added the initiator of extention at about 1,2 and 4 hour.After solvent evaporation, the product of this reaction and triethyl ammonium cyanide are approximately reacting under the room temperature in dichloromethane, form the chemical compound of general formula (23).
The solution of the chemical compound of general formula (23) in ethanol is saturated with hydrogen chloride, refluxes and heats in aqueous hydrochloric acid solution then with the relief mixture, obtains the chemical compound of general formula (24).The hydrolysis of the chemical compound of general formula VIII obtains the respective compound of general formula (25).This basic hydrolysis is typically by using alkali metal or alkaline earth metal hydroxide to carry out under the temperature the reflux temperature from about room temperature to about this solvent in the mixture of second alcohol and water.
The chemical compound of the general formula that forms in previous step (25) can change into the chemical compound of general formula III by following mode, and (wherein X is CH 2).At first, the chemical compound and the general formula R of general formula (25) 2R 1The suitable chemical compound of NH and N-ethyl-N-dimethylamino-propyl carbodiimides (EDAC) reacts in the presence of alkali.The example of appropriate base is to be selected from trialkylamine, those of alkali carbonate and alkaline earth metal carbonate.This reaction is typically at solvent such as acetonitrile, and dichloromethane or N in the dinethylformamide (DMF),, are preferably approximately carrying out under the room temperature under about 100 ℃ temperature in about room temperature.Preferably, this reaction is to carry out in the presence of catalytic additive such as N-hydroxy-succinamide or hydroxybenzotriazole.
The product of previous reaction uses the method for being known by technology people joint in the affiliated field to reduce then.For example, this reduction reaction can be used the lithium aluminium hydride in oxolane, be with or without aluminum chloride, or the borine methyl sulfide of use in oxolane, approximately-78 ℃ under about 0 ℃ temperature, preferably carry out under approximately-70 ℃, (wherein X is CH to obtain the required compound of general formula III 2).
Referring to the reaction mechanism mechanism of reaction 5,4-bromo-3-fluorotoluene at first changes into boronic acid derivatives, is coupled on 6-bromo-2-(tert-butyl group carbonylamino) pyridine according to following mode then and forms the chemical compound of general formula (26).Halogen-metal exchange reaction is at oxolane, ether, dimethoxy-ethane, in hexane or another the suitable ether or hydrocarbon flux, under-100 ℃ of temperature that arrive between about room temperature, by using butyl lithium or another suitable alkyl lithium reagents that 3-fluoro-4-toluene bromide is carried out, approximately-100 ℃ reacting about 1 to about 48 hours with the borate of boric acid three esters such as triethyl group or triisopropyl to the about temperature between the reflux temperature subsequently.This intermediate boronic acid derivatives is then in aqueous alcohol solvent, in the presence of sodium carbonate and tetrakis triphenylphosphine palladium, under the reflux temperature of reactant mixture, be converted to the chemical compound of general formula (26) as the coupling partner by using 6-bromo-2-(tert-butyl group carbonylamino) pyridine.The chemical compound of general formula (26) is by replacing the fluorine-based chemical compound that be converted to general formula (27) in alcohol with suitable alkoxide (it forms) and metal hydride such as sodium hydride through about 5 minutes to about 5 hours time solvent such as dimethyl formamide, oxolane Huo diox under from about room temperature to the about temperature between the reflux temperature.And this reaction of the chemical compound of general formula (26) is to carry out about 1 hour to about 48 hours to the temperature between about reflux temperature from room temperature in this reaction system.
In the following manner the chemical compound of general formula (27) is changed into the respective compound of general formula (25) then.At first, the chemical compound of general formula (27) and N-bromosuccinimide (NBS) and two-(1-cyano group-1-azepine)-cyclohexane extraction (general formula in the reaction mechanism mechanism of reaction 4 (22)) react in carbon tetrachloride and refluxed about 8 hours, about 1, add the initiator of extention after 2 and 4 hours, with the methyl bromination of this chemical compound.After solvent evaporation, the product of this reaction and triethyl ammonium cyanide are approximately reacting under the room temperature in dichloromethane, have formed the respective compound that bromine substituent is wherein replaced by cyano group.The cyano derivative that is obtained is hydrolyzed then, forms the respective compound of general formula (25).This basic hydrolysis is typically by using alkali metal or alkaline earth metal hydroxide to carry out under the temperature the reflux temperature from about room temperature to about this solvent in the mixture of second alcohol and water.
The chemical compound of the general formula that forms in previous step (25) can change into the chemical compound of general formula I by following mode.At first, the chemical compound and the general formula R of general formula (25) 2R 1The suitable chemical compound of NH and N-ethyl-N-dimethylamino-propyl carbodiimides (EDAC) reacts in the presence of alkali.The example of appropriate base is to be selected from trialkylamine, those of alkali carbonate and alkaline earth metal carbonate.This reaction is typically at solvent such as acetonitrile, and dichloromethane or N in the dinethylformamide (DMF),, are preferably approximately carrying out under the room temperature under about 100 ℃ temperature in about room temperature.Preferably, this reaction is to carry out in the presence of catalytic additive such as N-hydroxy-succinamide or hydroxybenzotriazole.
The product of previous reaction is reduced by the method that technology people's joint in field under using is known then, and (wherein X is CH to obtain the required compound of general formula III 2).For example, this reduction reaction can be used the lithium aluminium hydride in oxolane, is with or without aluminum chloride, or uses the borine methyl sulfide in oxolane, approximately-78 ℃ under about 0 ℃ temperature, preferably carries out under approximately-70 ℃.
Wherein X be CHOH general formula III chemical compound can by use with described in the application's the embodiment 1 similarly program prepare.Wherein X be 5 joints or 6 joint saturated rings a part general formula I chemical compound can by use with described in the embodiment 2 similarly program prepare.
The initiation material that is used for the program of the reaction mechanism mechanism of reaction 4 and 5 can be purchased, and is well known in the prior art or saved by those technology people in affiliated field easily that familiar method obtains from known compound.
There is not particularly the preparation of other chemical compound of the general formula III described in the test portion in front can use the combination of those reactions of knowing by technology people joint in the affiliated field to finish.
In in those reactions of above discussion or explanation each, pressure is not crucial, except as otherwise noted.It is normally acceptable to be pressed onto about 5 atmospheric pressure from about 0.5 atmosphere, and ambient pressure, and promptly about 1 atmospheric pressure is because convenient but preferred.
The chemical compound of general formula I V and their officinal salt can be according to (title is " 4-amino-(2-replaces-the 4-phenoxy group)-replace-pyridine " at world's patent application WO98/34919, published on August 13rd, 1998) and US apply for provisionally preparing described in 60/037533 (proposition on February 10th, 1997, this international patent application has required the priority of this application).It is for reference that aforementioned patent applications is introduced into this paper with its full content.
Following reaction mechanism mechanism of reaction 6-14 is used to illustrate the method for the chemical compound for preparing general formula I V.
The reaction mechanism mechanism of reaction 6
The reaction mechanism mechanism of reaction 6 is continuous
The reaction mechanism mechanism of reaction 7
The reaction mechanism mechanism of reaction 8
Figure A0080787801131
The reaction mechanism mechanism of reaction 9
The reaction mechanism mechanism of reaction 10
The reaction mechanism mechanism of reaction 11
The reaction mechanism mechanism of reaction 12
Figure A0080787801171
The reaction mechanism mechanism of reaction 12 is continuous
The reaction mechanism mechanism of reaction 13
Figure A0080787801191
The reaction mechanism mechanism of reaction 14
The reaction mechanism mechanism of reaction 6 has illustrated and has prepared wherein that G is a hydrogen, R 1Be-OR or wherein R be (C 1-C 6) alkyl and R 2It is the method for chemical compound of the general formula I of hydrogen.These chemical compounds are called the chemical compound of general formula " IA " in reaction mechanism mechanism of reaction I.
Referring to the reaction mechanism mechanism of reaction 6, chemical compound of this general formula (28) and excessive potassium carbonate and-individual normal toluene sulfochloride in acetone, under the temperature between from about 0 ℃ to about 80 ℃, preferably under the reflux temperature of reactant mixture, react.Wherein R is (C 1-C 6) alkyl and X be iodine, the chemical compound of the general formula R X of chlorine or bromine is added in the reactant mixture then, allows then under the temperature of this mixture between from about 0 ℃ to about 80 ℃, preferably reacts under the reflux temperature of mixture.This reaction obtains the chemical compound of general formula (29).The chemical compound of general formula (29) is then by making water as solvent, reacts with potassium hydroxide in the ethanol and is converted to the respective compound of general formula (30).This reaction can be carried out under the temperature between the reflux temperature from about room temperature to about reactant mixture.Preferably, this reactant mixture is heated to backflow, reacts under this temperature.
The chemical compound of general formula (30) then with potassium carbonate and benzyl bromide a-bromotoluene in acetone, under the temperature of about room temperature between, reacting, formed the respective compound of general formula (31) to about 80 ℃.Preferably, this reaction is approximately to carry out under this reflux temperature.The chemical compound of the general formula that is obtained (31) and butyl lithium in approximately-78 ℃ reaction down, add triethyl borate subsequently and allow this reactant mixture rise to ambient temperature in oxolane (THF), obtain the corresponding phenylboric acid derivant of general formula (32).
The phenylboric acid derivant of general formula (32) and 2-bromo-6-(2,5-dimethyl-pyrroles-1-yl)-pyridine (33), sodium carbonate and tetrakis triphenylphosphine palladium (O) are in ethanol/water or THF/ water, under the temperature the reflux temperature from about room temperature to about this reactant mixture, preferably, obtain the respective compound of general formula (34) approximately reacting under this reflux temperature.In addition, the reactant of general formula (33) replaces with the another kind of chemical compound of following formula then:
Wherein P is that nitrogen-protecting group group is as trityl; acetyl group; benzyl, pivaloyl group, tert-butoxycarbonyl; benzyl oxygen base carbonyl; three chloroethyl oxygen base carbonyls or another suitable nitrogen-protecting group group and the hydrogen that wherein is bonded on this protected nitrogen are non-existent, when P is when forming the blocking group of ring with shielded nitrogen; with P=2, the situation of 5-dimethyl pyrrole is the same.This type of protecting group is that the technology people saves well-known in the affiliated field.The above-claimed cpd of general formula (33A) can be purchased, and is known or easy by using well-known method and reagent preparation in the scientific literature.
By allowing the chemical compound of general formula (34) and ammonium formate in water or lower alcohol solvent or in the mixture of one or more these solvents, under the temperature between the reflux temperature from about room temperature to about this reactant mixture, react, from this chemical compound, remove the benzyl substituent group.This reaction is preferably carried out under reflux temperature in the presence of about 20% tetrahydrochysene Palladium monoxide/carbon.The chemical compound of the general formula that obtains by allowing (35) and azanol are in the solvent of selecting from the mixture of water, lower alcohol and these solvents, under the temperature between the reflux temperature from about room temperature to about solvent, preferably, the chemical compound of general formula (35) is changed into the required compound of general formula I VA approximately reacting under the reflux temperature.
The program of the reaction mechanism mechanism of reaction 6 also can be used in makes wherein R 1And R 2Not discussed above and be not the chemical compound of the general formula I V that in this reaction mechanism mechanism of reaction, described.This can pass through to use the chemical compound of following formula:
Figure A0080787801221
Realize that as initiation material and the serial reaction that carries out as previously discussed then these are reflected at and are expressed as reaction (30) → (31) → (32) → (33) → (34) → (35) → (IVA) in the reaction mechanism mechanism of reaction 6.
The reaction mechanism mechanism of reaction 7 illustrated from G wherein be hydrogen general formula I V compound wherein G be not the method for respective compound of the general formula I V of hydrogen.
Referring to the reaction mechanism mechanism of reaction 7, by allowing the chemical compound of general formula I VA and the X wherein be iodine, chlorine or bromine and G are CH 2CH 2NR 3R 4The chemical compound of general formula GX, with potassium carbonate in dimethyl formamide (DMF) or acetone, under the temperature between the reflux temperature from about room temperature to about mixture, preferably, the chemical compound of general formula I VA can be changed into the respective compound of general formula I VC approximately reacting under the reflux temperature.As shown in the reaction mechanism mechanism of reaction 7, by at first preparing the respective compound of general formula I VB, (if necessary) changes into the respective compound of general formula I VC with them then, also can form the chemical compound of general formula I VC.By allowing the respective compound of general formula I VA and the X wherein be CH with G as defined above 2C (=O) NR 3R 4The chemical compound of general formula GX, and potassium carbonate in DMF or acetone, reacts under the temperature the reflux temperature from about room temperature to about this reactant mixture, can form the chemical compound of general formula I VB.This reaction is also preferably approximately being carried out under this reflux temperature.
The chemical compound of the general formula I VB that obtains by allowing and lithium aluminium hydride and aluminum chloride or react in THF with borine in the THF solvent, this chemical compound can be changed into the respective compound of general formula I VC.Can also use other alanate Reducing agent, as the diisobutyl alanate.Can also use diborane.This reaction generally can preferably be carried out under reflux temperature under the temperature between the reflux temperature from room temperature to about this reactant mixture.Other appropriate solvent comprises other organic ether such as ether ， diox and glyme.THF is preferred solvent.
The reaction mechanism mechanism of reaction 8 illustrated how can prepare in the process of the reaction mechanism mechanism of reaction 6, described have a different substituents R 1And R 2The chemical compound of general formula I V.Utilize with the reaction mechanism mechanism of reaction 6 in the similar method of the method described prepare this compounds, exception be to go up those replacements that the process of the reaction mechanism mechanism of reaction 6 that uses is described in can enough reaction mechanisms mechanism of reaction 8 chemical compound (32) synthetic.Specifically, referring to the reaction mechanism mechanism of reaction 8, according to the reaction mechanism mechanism of reaction (6) in the chemical compound from general formula (31) change into the similar mode of process of those chemical compounds of general formula (32), work as R 2Be hydrogen and R 1Be when adjacent fluorine, the chemical compound of general formula (36) is converted to corresponding phenylboric acid.The phenylboric acid derivant that is obtained is called chemical compound (32A) in the reaction mechanism mechanism of reaction 8.Similarly, as shown in the reaction mechanism mechanism of reaction 8, according to the reaction mechanism mechanism of reaction 6 in the chemical compound from general formula (31) change into the similar mode of mode of the chemical compound of general formula (32), wherein R 1And R 2All be methyl and all the chemical compound of the general formula I V on the ortho position of pyridine ring can change into corresponding phenylboric acid derivant (being expressed as chemical compound (32B)) by chemical compound (as shown in the reaction mechanism mechanism of reaction 8) and prepare general formula (37).Then by using and similar program shown in the reaction mechanism mechanism of reaction 6, general formula (32A) and chemical compound (32B) are transformed into the required respective compound of general formula I V.
The reaction mechanism mechanism of reaction 9 is for example understood and is prepared wherein that G is NR 3R 4And NR 3R 4The method of the chemical compound of the general formula I V of formation N-crassitude quinoline-2-basic ring.Can be in a similar way, can preparing wherein, G is NR 3R 4And NR 3R 4Form the another kind of chemical compound that contains the general formula I V of azo-cycle.Referring to the reaction mechanism mechanism of reaction 9, the chemical compound of general formula I VD and methane sulfonyl oxygen base-pyrrolidine-1-carboxylic acid tertiary butyl ester reaction forms the chemical compound of general formula (38).Other nitrogen-protecting group group as-C (=O) CCH 2C 6H5 and COO (wherein R is a benzyl, phenyl, the tert-butyl group or similar group) can be used in this pyrrolidine nitrogen of protection.Simultaneously, this methanesulfonate leaving group can be enough in addition-suitable leaving group substitutes.Preferably, the tetrabutylammonium iodide (TBAI) with catalytic amount joins in this reactant mixture.This alkylated reaction is typically at alkali metal alcoholates, and preferred potassium tert-butoxide exists down, at high boiling polar organic solvent such as dimethyl sulfoxine (DMSO) or DMF, carries out among the preferred DMSO.This reaction temperature can be about 50 ℃ to about 100 ℃ of scopes and preferably about 100 ℃.
The reduction reaction of the chemical compound of general formula X II obtains the respective compound of general formula I VF.This reduction reaction is preferably by using lithium aluminium hydride to carry out as solvent as Reducing agent and oxolane (THF) or another organic ether (for example, ether or glyme).Can also use other alanate Reducing agent, as the diisobutyl alanate.Can also use diborane.Previous reaction generally is under the temperature between the reflux temperature from about room temperature to about this reactant mixture, is preferably approximately carrying out under the reflux temperature.
As shown in the reaction mechanism mechanism of reaction 10, the chemical compound of general formula I VD has obtained the chemical compound of general formula I VE with 1-(2-the chloroethyl)-alkylation of pyrrolidine.This reaction is normally at alkali such as cesium carbonate, potassium carbonate or sodium carbonate, and preferred cesium carbonate exists down, and at solvent such as acetone, DMSO or acetonitrile in the preferred acetone, under from about room temperature to the about temperature between the reflux temperature, are preferably approximately carrying out under the reflux temperature.
NR wherein 3R 4The chemical compound that does not form the general formula I V of ring also can prepare by the described method of formation with above chemical compound for general formula I VE of explanation in the reaction mechanism mechanism of reaction 10.The structural formula IVG that describes in the reaction mechanism mechanism of reaction 5 comprises this compounds.
The reaction mechanism mechanism of reaction 11 has illustrated that preparation is used for the method for the phenylboric acid intermediate in the above reaction mechanism mechanism of reaction 6 and 8 synthetic reactions of describing, and wherein the phenyl ring of phenylboric acid contains naphthenic substituent.This type of intermediate can be used in the method for the reaction mechanism mechanism of reaction 6 and 8 and forms wherein R 1And R 2In one or two is the chemical compound of the general formula I V of cycloalkyl base.Referring to the reaction mechanism mechanism of reaction 11, the chemical compound of general formula (39) refluxed about 8 hours in THF or ether in the presence of magnesium metal, after this cyclobutanone was joined in the reactant mixture.This reaction obtains the chemical compound of general formula (40).Use for example hydrogen and 10% palladium/carbon, in lower alcohol solvent such as ethanol, under the temperature of about room temperature, the reduction reaction of the chemical compound of general formula (40) has obtained the respective compound of general formula (41).
At alkali such as potassium, the carbonate of caesium or sodium exists down, at solvent such as acetone, dichloroethanes, in chloroform or the dichloromethane, under the temperature between the reflux temperature from about room temperature to about reactant mixture, preferably under about reflux temperature, the chemical compound of general formula (41) and the reaction of benzyl bromide a-bromotoluene have obtained the respective compound of general formula (42).
The chemical compound of the general formula that in above step, forms (42) then by with N-bromosuccinimide (NBS) and silica gel at chlorinated hydrocarbon solvent such as carbon tetrachloride, reaction in dichloromethane or the chloroform and by bromination.This reaction is typically at room temperature carried out.The chemical compound of the general formula (43) that will produce in this reaction in the following manner changes into the phenylboric acid derivant of general formula (44).At first, the chemical compound of general formula (43) is cooled to approximately-78 ℃ to about-70 ℃ temperature in solvent such as THF, add n-BuLi after this.Stirring this reactant mixture after about 1 hour, adding triethyl borate and mixture and be stirred exception 1-3 hour.The phenylboric acid intermediate saves known method by the technology people in the affiliated field then and separates (for example, use the ammonium chloride quenching, add water, add concentrated hydrochloric acid then and use ethyl acetate extraction).
The reaction mechanism mechanism of reaction 12 for example understand prepare G wherein be alkenyl general formula I V chemical compound and wherein G be hydrogen and R 2It is the method for chemical compound of the general formula I V of alkyl or alkenyl.Referring to the reaction mechanism mechanism of reaction 12, by using and in the reaction mechanism mechanism of reaction 11, be used for alkylated reaction like the response class of chemical compound that chemical compound with general formula I VD changes into general formula I VG, the chemical compound of general formula I VA is changed into the respective compound with general formula I VH.The chemical compound of the general formula I VH that obtained is heated to about 230 ℃, has obtained the respective compound of general formula I VJ and IVK.(for example use about 50 pounds/square inch hydrogen in ethanol by the method that technology people joint in the field under using is known, in the presence of 10% palladium/carbon, under about room temperature), the hydrogenation of the chemical compound of general formula I VJ and IVK has obtained having respectively the corresponding alkyl derivative of general formula I VL and IVM.By using any method in the alkylation of describing and suitable alkylating agent in the reaction mechanism mechanism of reaction 7,9 and 10, the alkylation of the chemical compound of general formula I VL and IVM (wherein G is a hydrogen) has obtained wherein that G is not the corresponding required compound of hydrogen.
The reaction mechanism mechanism of reaction 13 explanations prepare wherein, and G is NR 3R 4(C 0-C 4) the another kind of method of chemical compound of general formula I V of alkyl.Referring to the reaction mechanism mechanism of reaction 13, the chemical compound of general formula (45) and bromine in acetic acid about 0 ℃ to about 60 ℃ temperature, preferably approximately reacting under the room temperature.This reaction has produced the respective compound that bromine substituent is arranged in the para-position of fluoro substituents, according to the synthetic described method of above chemical compound for general formula (32) (reaction mechanism mechanism of reaction 6) and (44) (reaction mechanism mechanism of reaction 11), be converted to the corresponding boronic acid derivatives of general formula (46) then.
According to the synthetic described method (reaction mechanism mechanism of reaction 6) of above chemical compound for general formula (34), 2, the addition of 5-dimethyl pyrrole protecting group has obtained the respective compound of general formula (47).The chemical compound of general formula (47) then with general formula R 3R 4The chemical compound of NOH and alkali metal hydride (preferred sodium hydride) are in polar organic solvent such as DMF or DMSO (preferred DMF); under the temperature between about 50 ℃ and about 110 ℃; preferably under about 100 ℃ temperature, react and formed a kind of chemical compound; it is equal to the corresponding required compound of general formula I VN; but have 2,5-dimethyl pyrrole protecting group.According to the described method of preparation (reaction mechanism mechanism of reaction 6) of above chemical compound for general formula I VA, protecting group remove the required compound that has obtained general formula I VN.
The reaction mechanism mechanism of reaction 14 has illustrated that synthetic wherein G is the method for chemical compound of the general formula I of optional substituted pyrrolidine-2-base or pyrrolidine-3-base group.Referring to the reaction mechanism mechanism of reaction 14, the chemical compound of general formula I VA and the chemical compound of following formula:
Figure A0080787801261
Triphenylphosphine and azoethane dicarboxylic ester or another kind of water-soluble azo dicarboxylic ester react at standard Mitsunobo reaction condition in THF.Typically, this reactant mixes down at about 0 ℃, rises to room temperature then.If (need be on pyrrolidine nitrogen in the end product of the general formula I VP alkyl substituent except that methyl, this can be by with general formula-C (=O) group of the R BOC group that replaces general formula (49) realizes that wherein R is required alkyl).
(or corresponding-C (=O) chemical compound of R protection) can change into the required product (or the methyl substituents of wherein describing is by the alternate similar compound of another kind of alkyl) with general formula I VP by reduction to the chemical compound of the general formula that forms in above reaction (48) in structural formula IVP.This reaction can be implemented by the product of previous step and lithium aluminium hydride and aluminum chloride are reacted in THF in THF or with borine, according to the described method of formation of above chemical compound for general formula I VC.
Wherein the alkyl substituent on the pyrrolidine nitrogen of general formula I VP can be by allowing alkyl analog (as previously discussed) and the trifluoroacetic acid of the chemical compound of general formula (48) or general formula (48) or hydrochloric acid at solvent such as diox by the respective compound of the displaced general formula I V of hydrogen, or ether, in the You Xuan diox, from about 0 ℃ under the temperature the reflux temperature of about this reactant mixture, preferably under about this reflux temperature, react and obtain.
This initiation material that uses in the program of reaction mechanism mechanism of reaction 6-14 (it synthetic described above) can be purchased, and is well known in the prior art or easily by using those technology people joint is known in affiliated field method to obtain from known compound.
There is not particularly the preparation of other chemical compound of the general formula I V that describes in the test portion in front can use the combination of those reactions of knowing by technology people joint in the affiliated field to finish.
In in those reactions of above discussion or explanation each, pressure is not crucial, except as otherwise noted.It is normally acceptable to be pressed onto about 5 atmospheric pressure from about 0.5 atmosphere, and ambient pressure, and promptly about 1 atmospheric pressure is because convenient but preferred.
The chemical compound of general formula V and their officinal salt can be according to preparing described in the U.S. Provisional Application serial number No.60/032793 (last application has required the priority of a back application) of world's patent application WO 98/24766 (title is " derivant ", and on June 11st, 1998 published) and December in 1996 submission on the 6th.It is for reference that aforementioned patent applications is introduced into this paper with its full content.
The method of the chemical compound of following reaction mechanism mechanism of reaction 15-19 explanation preparation general formula V.
The reaction mechanism mechanism of reaction 15
G＝B
The reaction mechanism mechanism of reaction 16
Figure A0080787801291
The reaction mechanism mechanism of reaction 17
Figure A0080787801301
G＝A，X＝N
N=1, q=1, Y benzyl
The reaction mechanism mechanism of reaction 18
Figure A0080787801311
G＝A，q＝1
X＝CH，Y＝NR 3R 4
The reaction mechanism mechanism of reaction 19
G＝A，q＝0，X＝N
Y＝H
The initiation material that is used for the program of reaction mechanism mechanism of reaction 15-19 can be purchased, and those technology people in field saves that familiar method obtains from known compound under the well known in the prior art or easy use.
Referring to the reaction mechanism mechanism of reaction 15, chemical compound (50) is by 1,4-dibromobenzene and organolithium reagent (preferred butyl lithium) react to about 0 ℃ temperature at-100 ℃, in ether solvents (preferred ether), pass through to add on 2-(2, the 5-dimethyl pyrrole)-pyridine in about 1-24 hour under about 50 ℃ temperature at about 0 ℃ subsequently and prepare.Chemical compound (51) is to use palladium type catalyst, and palladium-O or palladium-II oxidation state typically has phosphine ligand, and preferred four-(triphenylphosphine) palladiums are by (50) and general formula p-OHC (CH 2) M-2(C 6H 3R 1R 2) boronic acid derivatives of B (OH) 2 is mixed with in the solvent of water and halogenated hydrocarbons that is made up of alcohol (preferred alcohol), optional, react under the temperature from about 25 ℃ to about 150 ℃ to prepare in about 1-24 hour.
Chemical compound (52) be by (51) and tosyl methyl-isocyanide in the presence of potassium tert-butoxide and ethanol,,, react under the temperature between approximately-100 ℃ to about 100 ℃ and prepared in about 1-24 hour in the 2-dimethoxy-ethane as 1 at ether solvents.Chemical compound (53) is by using alkali metal hydroxide in aqueous alcohols solvent such as aquiferous ethanol, under the temperature between about 25 ℃-about 125 ℃, prepares from (52) through the basic hydrolysis by nitrile in about 30 minutes to 48 hours.Chemical compound (54) be by with general formula R 3R 4The dehydration coupling reaction of the ammonia of NH, primary amine or secondary amine prepares from (53), this reaction is to utilize dehydrant such as carbodiimides, N-ethyl-N-(dimethylamino-propyl) carbodiimides for example, (it is halogenated hydrocarbons or N at solvent, N-dialkyl amide such as dimethyl formamide) in, process was carried out in about 1-48 hour under the temperature between about 0 ℃-about 100 ℃.Chemical compound (55) is to use oxammonium hydrochloride.; aqueous or contain alcohol solvent in; preferably in aqueous ethanol; under about 25 ℃-about 100 ℃ temperature; carrying out deblocking through about 1-48 hour prepares from (54); and comprise by with trifluoroacetic acid or relevant many halogenations acetic acid or gaseous hydrogen halide such as HCl; in halogenated hydrocarbons, ether solvents or ethyl acetate; approximately-70 ℃-reacted about 10 minutes to 24 hours under the about 100 ℃ temperature, protecting group such as butoxy carbonyl are implemented deblocking.
Final chemical compound VB (wherein G=B) in the reaction mechanism mechanism of reaction 15 is by using borine, trialkylborane, alane or lithium aluminium hydride are in ether solvents such as ether or oxolane, approximately-100 ℃-about 100 ℃ temperature under, through about 30 minutes to 24 hours, with the optional carbonate that uses cesium fluoride and alkali metal or alkaline-earth metal in aqueous alcoholic solvent, under about 25 ℃-about 125 ℃ temperature,, will (55) also prepare originally through 1-72 hour.
Referring to the reaction mechanism mechanism of reaction 16, chemical compound (56) be by (50) and 3-pyridine radicals boric acid and the palladium catalyst that is in palladium-O or palladium-II oxidation state with ligand that the typical case is made up of trialkyl or triaryl phosphine as four-(triphenylphosphine) palladiums, in aqueous alcoholic solvent, under about 25 ℃-about 125 ℃ temperature, react and to prepare in about 1-48 hour.Chemical compound (57) is by in ether, alcohol, aqueous alcohol or dialkylamine type solvent such as dimethyl formamide, under about 0 ℃-about 125 ℃ temperature through about 30 minutes to 72 hours time with alkyl or aralkyl halogen or sulphonic acid ester to (56) in addition alkylation, then in ether, alcohol or aqueous alcoholic solvent, the typical case in methanol, under about 0 ℃-about 125 ℃ temperature through about 1-72 hour with boron hydride-or aluminum hydride-type reagent go back originally as sodium borohydride and prepared.End-product at reaction mechanism mechanism of reaction work, chemical compound VA-a, G=A wherein, n=1, and q=0, be by in alcohol or aqueous alcoholic solvent, the typical case carries out with oxammonium hydrochloride. through about 1-72 hour under about 25 ℃-about 125 ℃ temperature that deblocking comes from (57) preparation in aqueous ethanol.
In the method for the reaction mechanism mechanism of reaction 16, the preferred value of Y is a benzyl in general formula (57) and Va-a.Wherein Y is that the chemical compound of the general formula VA-a of benzyl can be by in the presence of noble metal catalyst such as palladium, at ether, halogenated hydrocarbons, in the pure or aqueous alcoholic solvent, under 0 ℃-100 ℃ temperature, use hydrogen or ammonium formate to carry out debenzylation through 30 minutes to 24 hours time, then in the presence of boron hydride-reagent such as sodium cyanoborohydride or sodium triacetoxy borohydride, at ether, halogenated hydrocarbons, in the pure or aqueous alcoholic solvent, time through 1-72 hour under 0 ℃-100 ℃ temperature is carried out reduction amination with alkyl or aralkyl aldehyde, and finally being converted to wherein, Y is not the respective compound of benzyl.
Referring to the reaction mechanism mechanism of reaction 17, chemical compound (58) is by in ether, halogenated hydrocarbons, alcohol or aqueous alcohol, and the time through about 1-72 hour under about 0 ℃-about 100 ℃ temperature carries out reduction amination and prepares 2-(4-bromophenyl methyl) piperidines as sodium cyanoborohydride or sodium triacetoxy borohydride with benzaldehyde and boron hydride type reagent.Chemical compound (59) is by chemical compound (58) and organolithium reagent (being typically butyl lithium) reaction, subsequently approximately-70 ℃-in ether solvents such as ether, the organolithium reagent that is obtained is added on 2-(2, the 5-dimethyl pyrrole)-pyridine to prepare from chemical compound (58) through about 30 minutes to 48 hours time under the about 100 ℃ temperature.End-product in the reaction mechanism mechanism of reaction 17, IA-b, G=A wherein, n=1, q=1 and Y are benzyls, be by in alcohol or aqueous alcoholic solvent, the typical case carries out with oxammonium hydrochloride. through about 1-72 hour under about 25 ℃-about 125 ℃ temperature that deblocking comes from chemical compound (59) preparation in aqueous ethanol.
Abovely change into wherein for the chemical compound with general formula I A-a that Y is not the described program of similar compound of benzyl by using, the chemical compound of general formula I A-b can be converted to wherein that Y is not the respective compound of benzyl.
Referring to the reaction mechanism mechanism of reaction 18; chemical compound (60) be the palladium catalyst that is in palladium-O or palladium-II oxidation state with ligand of forming by trialkyl or triaryl phosphine of typical case as four-(triphenylphosphine) palladiums in the presence of; in aqueous alcoholic solvent; under about 25 ℃-about 125 ℃ temperature through about 1-48 hour from 6-bromo-2-(2, the 5-dimethyl pyrrole)-pyridine and the preparation of 4-formoxyl phenylboric acid.Chemical compound (61) is by in aromatic hydrocarbon, hydrocarbon or halogenated hydrocarbon solvent (preferred toluene) then, under about 25 ℃-about 150 ℃ temperature, allow enamine (typical case has morpholine or the pyrrolidine enamine) reaction about 1-72 hour of chemical compound (60) and ketone or aldehyde, then in the presence of noble metal catalyst such as palladium, in ether, halogenated hydrocarbons, alcohol or aqueous alcoholic solvent, under about 0 ℃-about 100 ℃ temperature through about 30 minutes to 24 hours with hydrogen or ammonium formate reduction, come from (60) preparation.End-product in the reaction mechanism mechanism of reaction 18, general formula VA, G=A wherein, q=1, X=CH, and Y=NR 3R 4Be by in the presence of boron hydride type reagent such as sodium cyanoborohydride or sodium triacetoxy borohydride, in ether, halogenated hydrocarbons, alcohol or aqueous alcoholic solvent, under about 0 ℃-about 100 ℃ temperature, with ammonia, primary amine or secondary amine chemical compound (61) was carried out reduction amination through about 1-72 hour, subsequently in alcohol or aqueous alcoholic solvent, the typical case carried out deblocking through about 1-72 hour with oxammonium hydrochloride. and finally makes in aqueous ethanol under about 25 ℃-about 125 ℃ temperature.
Referring to the reaction mechanism mechanism of reaction 19, chemical compound (62) is by with acetic anhydride or similar dehydrated reagent 3-(4-bromophenyl)-1,3-propanedicarboxylic acid being dewatered, subsequently with benzyl amine in hydrocarbon, aromatic hydrocarbon or halogenated hydrocarbon solvent, reaction is about 1-48 hour under about 25 ℃-about 180 ℃ temperature, then with acetic anhydride or similar dehydrated reagent, about 1-48 hour time of process dewaters and finally makes under the temperature between about 25 ℃-about reflux temperature.Chemical compound (63) is by in ether or hydrocarbon flux, under about 0 ℃-about 100 ℃ temperature through will (64) also preparing originally with borine, borine methyl sulfide, alane or lithium aluminium hydride in about 30 minutes to 48 hours.Chemical compound (64) is by chemical compound (63) and organolithium reagent (being typically butyl lithium) reaction, subsequently approximately-70 ℃-in ether solvents such as ether, the organolithium reagent that is obtained added to 2-(2 through about 30 minutes to 48 hours time under the about 100 ℃ temperature, the 5-dimethyl pyrrole)-pyridine on, come to prepare from chemical compound (63).End-product in the reaction mechanism mechanism of reaction 19, VA-a, G=A wherein, Y=H, q=0, and X=N, be by in the presence of noble metal catalyst such as palladium, in ether, halogenated hydrocarbons, alcohol or aqueous alcoholic solvent, under 0 ℃-100 ℃ temperature, with hydrogen or ammonium formate chemical compound (64) was carried out debenzylation through 30 minutes to 24 hours, subsequently in alcohol or aqueous alcoholic solvent (being typically aqueous ethanol), under about 25 ℃-about 125 ℃ temperature, carried out deblocking with oxammonium hydrochloride. and finally make through about 1-72 hour.
The chemical compound of the prepared general formula VA-d of program by using the reaction mechanism mechanism of reaction 19, can be in the presence of boron hydride type reagent such as sodium cyanoborohydride or sodium triacetoxy borohydride, in ether, halogenated hydrocarbons, alcohol or aqueous alcoholic solvent, time through 1-72 hour under 0 ℃-100 ℃ temperature is carried out reduction amination with alkyl or aralkyl aldehyde, and Y is the similar compound of alkyl or aralkyl and be converted to wherein
There is not particularly the preparation of other chemical compound of the general formula V that describes in the test portion in front can use the combination of those reactions of knowing by technology people joint in the affiliated field to finish.
In in those reactions of above discussion or explanation each, pressure is not crucial, except as otherwise noted.It is normally acceptable to be pressed onto about 5 atmospheric pressure from about 0.5 atmosphere, and ambient pressure, and promptly about 1 atmospheric pressure is because convenient but preferred.
The chemical compound of general formula VI can (on June 3rd, 1998 submits to according to the following stated with in US provisional application 60/087881, title is " the 2-aminopyridine that contains fused ring substituents ") and world patent application PCT/IB 99/00825 (proposition on May 7th, 1999, specify the U.S., it has required the priority of provisional application 60/087881) described in prepare.It is for reference that aforementioned patent applications is introduced into this paper with its full content.
The following reaction mechanism mechanism of reaction 20 is used to illustrate the method for the chemical compound for preparing general formula VI.
The reaction mechanism mechanism of reaction 20
Referring to the reaction mechanism mechanism of reaction 20, the chemical compound of general formula (65) is according at Syn.Commun., described in 5,461 (1975), by norborene and the reaction of 2-hydroxy pyrone, carries out aromatisation with Palladium monoxide subsequently and prepares.It then with the tetrabutylammonium terbromide 1, reaction about 10 minutes to about 10 hours under about room temperature in the 2-dichloroethanes.The product of this reaction then with benzyl bromide a-bromotoluene and potassium carbonate in solvent such as acetonitrile, reaction is about 1-48 hour under the reflux temperature of about this reactant mixture, forms the chemical compound of general formula (66).
In dry tetrahydrofuran (THF), be cooled to approximately-70 ℃ and add the solution of n-BuLi by chemical compound, the chemical compound of general formula (66) is changed into 5-benzyloxy-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-8-boric acid to it with general formula III.The solution that is obtained was handled with triethyl borate through about 1-48 hour then and is risen to room temperature, had formed 5-benzyloxy-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-8-boric acid.5-benzyloxy-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-8-boric acid and 6-bromo-2-(2, the 5-dimethyl pyrrole) pyridine is in alcohol solvent, in the presence of sodium carbonate and four-(triphenylphosphine) palladium, reaction is about 1-48 hour under the reflux temperature of about this reactant mixture, obtains the chemical compound of general formula (67).
The chemical compound of general formula (67) can use following two-stage process to be converted to the chemical compound of general formula V.The chemical compound of general formula (67) and ammonium formate and 10% palladium/carbon are in alcohol solvent, reaction is about 10 minutes-about 10 hours under the reflux temperature of about this reactant mixture, obtain and have the chemical compound similar compounds of general formula (67), the benzyloxy of its formula of (67) is substituted by hydroxyl.Then by above hydroxy derivatives and acetic acid 2-bromo-ethyl ester and potassium carbonate in acetonitrile, reaction formed the chemical compound of general formula (68) in about 1-48 hour under the reflux temperature of about this reactant mixture.
The basic hydrolysis of the chemical compound of general formula (68) is subsequently with N-ethyl-N-3-dimethylaminopropyl carbodiimides (EDAC) with have general formula R 1R 2The suitable chemical compound of NH reacts, and obtains the required compound of general formula (69).This basic hydrolysis is typically by using alkali metal or alkaline earth metal hydroxide approximately carrying out about 1-48 hour under the room temperature in the mixture of THF, first alcohol and water.With general formula R 1R 2The reaction of the suitable chemical compound of NH and N-ethyl-N-dimethylamino-propyl carbodiimides (EDAC) is carried out in the presence of alkali.The example of appropriate base is to be selected from trialkylamine, those of alkali carbonate and alkaline earth metal carbonate.This reaction is typically at solvent such as acetonitrile, and dichloromethane or N in the dinethylformamide (DMF),, were preferably approximately carrying out about 1-48 hour under the room temperature under about 100 ℃ temperature in about room temperature.Preferably, this reaction is to carry out in the presence of catalytic additive such as N-hydroxy-succinamide or hydroxybenzotriazole.
The chemical compound of general formula (69) can be converted to the required compound of general formula I as follows.The chemical compound of general formula (69) is reduced into wherein carbonyl and is removed 2 after this by the alternate respective compound of methylene, 5-dimethyl pyrrole protecting group.Under this reduction reaction can be used in the field technology people save known method, for example use the lithium aluminium hydride in oxolane, be with or without aluminum chloride, or the borine methyl sulfide of use in oxolane, approximately-78 ℃ under the temperature of about reflux temperature, preferably approximately-70 ℃ under the temperature between the room temperature, carrying out about 1-about 24 hours.
2, removing of 5-dimethyl pyrrole protecting group can be finished by reacting with oxammonium hydrochloride..This reaction, preferably under about reflux temperature, was carried out about 8 to about 72 hours under the temperature between the reflux temperature of about reactant mixture in about room temperature normally in alcohol or aqueous alcoholic solvent (preferably using ethanol as alcohol).
Wherein there is the chemical compound of heteroatomic general formula VI can be among in these bridged rings by similar mode, with beginning to prepare with suitable chemical compound like the compounds of general formula (65), the involved heteroatomic bridged ring of unsubstituted bridged ring of its formula of (65) substitutes.
There is not particularly the preparation of other chemical compound of the general formula VI that describes in the test portion in front can use the combination of the above those reaction of knowing by technology people joint in the affiliated field to finish.
In in those reactions of above discussion or explanation each, pressure is not crucial, except as otherwise noted.It is normally acceptable to be pressed onto about 5 atmospheric pressure from about 0.5 atmosphere, and ambient pressure, and promptly about 1 atmospheric pressure is because convenient but preferred.
The chemical compound that belongs to the general formula I-VI of alkalescence can form various salt with various inorganic and organic acid.Though this type of salt must be mammiferous pharmaceutically useful salt, but usually wish from reactant mixture, to isolate at first the I of unacceptable salt form on the materia medica in practice, II, III, IV, the chemical compound of V or VI is handled simply this salt to be transformed with alkaline reagent then and is got back to free alkali compound, subsequently this free alkali is changed into pharmaceutically acceptable acid-adducting salt.The acid-adducting salt of active alkali chemical compound of the present invention can be easily handled this alkali cpd with the selected inorganic or organic acid of equivalent basically and is prepared in aqueous solvent medium or appropriate organic solvent such as methanol or ethanol.After evaporating solvent carefully, easily obtained required solid salt.
The chemical compound of general formula I, II, III, IV, V or VI and their pharmaceutically useful salt can be used as no inhibitor, be that they can suppress the intravital NOS enzyme of mammal, so they can be used for the treatment of ridden mammiferous above-mentioned disease and disease as therapeutic agent.
The ability that suppresses NOS by the chemical compound that uses the program determination general formula I-IV that describes in the literature.The ability of the chemical compound inhibition endothelial NO S of general formula I can be by people such as use Schmidt at Proc.Natl.Acad.Sci.U.S.A, 88, pp.365-369 (1991) neutralizes by people such as Pollock at Proc.Natl.Acad.Sci.U.S.A., 88, the program wax of describing among the pp.10480-10484 (1991) is measured.The chemical compound of general formula I suppresses the ability of derivable NOS can be by using people such as Schmidt at Proc.Natl.Acad Sci.U.S.A., 88, pp.365-369 (1991) and by people such as Garvey at J.Biol.Chem., 269, the program described in the pp.26669-26676 (1994) is measured.The chemical compound of general formula I suppresses the ability of neuronal NOS can be by using by Bredt and Snyder at Proc.Natl.Acad.Sci.U.S.A., and 87, the program of describing among the 682-685 (1990) is measured.
The chemical compound of general formula I-IV and their pharmaceutically useful salt can pass through the administration of oral, parenteral or partial path.Usually, when as single plant that activating agent is used for the treatment of can be when changing those diseases that physiological rhythm treats or symptom, wish most that these chemical compounds are to use with about 0.01 to about 250mg/ day dosage, single dose or divided dose are (promptly, 1-4 dosage/every day), though change dosage according to kind, body weight and the symptom of the main body that will treat and selected concrete route of administration needs.Yet, wish most to use to the dosage level in the scope in about 21mg/ kg body weight/sky at about 0.07mg.Yet, need be according to the kind of the animal that will treat and they separately to the response of this medicament, and according to the type of selected pharmaceutical formulation and time span and the interval of using, dosage is changed.In some cases, perhaps, the dosage level that is lower than the lower limit of above-mentioned scope is enough, and can use bigger dosage in other cases and do not cause any deleterious side effect, as long as this bigger dosage at first is divided into several low doses for using all day.
The chemical compound of general formula I-VI can be separately or is combined with pharmaceutically useful carrier or diluent and to use by any approach in foregoing three kinds of approach, and this is used and can carry out with single dosage or a plurality of dosage.More particularly, this type of therapeutic agent can be used with various different dosage forms, that is, they can combine with various pharmaceutically useful inert carriers, form is a tablet, capsule, dragee, lozenge, the hard sugar piece, powder, spray, ointment, the ointment medicine, suppository, fruit jelly agent, gel, the slurry agent, washing liquid, ointment, water suspension, injectable solution, elixir, syrup, etc.Examples of such carriers comprises solid diluent or filler, aseptic water-bearing media and various nontoxic organic solvents etc.And combination of oral medication can be regulated sweet taste and/or taste suitably.Usually, treatment compounds effective of the present invention is to be present in this type of dosage form with the concentration level in about 5.0%-about 70% (by weight) scope.
For oral, contain various excipient such as microcrystalline Cellulose, sodium citrate, calcium carbonate, the tablet of dicalcium phosphate and glycine has also used various disintegrating agents such as starch (with preferred corn starch together, potato starch or tapioca), alginic acid and some composition silicate, and adhesive for granulating such as polyvinylpyrrolidone, sucrose, gelatin and Radix Acaciae senegalis.In addition, lubricant such as magnesium stearate, sodium lauryl sulfate and Talcum usually can be used for the tabletting purpose.The solid composite of similar type also can be used as filler in capsule; Preferred in this respect raw material also comprises lactose or toffee and high molecular weight polyethylene glycol.When water suspension and/or elixir are wished when oral, this active component can with various sweeteners or flavoring agent, pigment or dyestuff and if desired, emulsifying agent and/suspending agent combines, and also has such as water ethanol together, propylene glycol, glycerol and their various types of diluent like conjugate and so on.
For parenteral admistration, can use the chemical compound of general formula I, II, III, IV, V or VI or its pharmaceutically useful salt in Oleum sesami or Oleum Arachidis hypogaeae semen or the solution in aqueous propylene glycol.This aqueous solution should suitably cushion (preferred pH is greater than 8) as required and liquid diluent is at first given isotonicity.These aqueous solutions are suitable for the intravenous injection purpose.This oily solution is suitable for intraarticular, intramuscular and subcutaneous injection purpose.The standard drug technology that the preparation of all these solutions under aseptic condition can easily be known by those technology people joint in the affiliated field is carried out.
In addition, it is the chemical compound of possibility local application general formula I-VI also, and when treating the inflammation of skin, and this can utilize ointment, the fruit jelly agent, and gel, the slurry agent, tablet, ointment etc. carry out according to the medicinal practice of standard.
The present invention relates to treat can be by changing those diseases that physiological rhythm prepares or the method for symptom, wherein NOS inhibition chemical compound and SSRI and/or nk 1 receptor antagonist are used together, as same part of pharmaceutical compositions, with relate to a kind of like this Therapeutic Method, wherein these activating agents are to require the part of (regimen) (being designed to obtain the benefit of combined therapy) to use as suitable dose separately.The appropriate dosage requirement, the amount of the dosage each time that is applied, and the specific interval between the dosage of each activating agent will depend on the main body of being treated, and the source of symptom and the order of severity.Usually, in carrying out this method of the present invention, it is the body weight/every day (single dose or divided dose) that will treat main body with the about 10mg/kg of about 0.01-that this NOS suppresses chemical compound, amount in the preferred about 3mg/kg scope of about 1-is applied to average 70kg adult, SSRI uses and this nk 1 receptor antagonist is to use with the interior amount of the about 500mg/ of about 0.16-every day (single dose or divided dose) scope with the amount of body weight/every day in (single dose or the divided dose) scope that the about 30mg/kg of about 0.2-will treat main body.Yet, need be according to the kind of the animal that will treat and they separately to the response of this medicament, and according to the type of selected pharmaceutical formulation and time span and the interval of using, dosage is changed.In some cases, perhaps, the dosage level that is lower than the lower limit of above-mentioned scope is enough, and can use bigger dosage in other cases and do not cause any deleterious side effect, as long as this bigger dosage at first is divided into several low doses for using all day.

Claims (12)

1. being used for the treatment of can be by changing those diseases that mammiferous physiological rhythm treats or the pharmaceutical composition of symptom, and it comprises that NOS suppresses chemical compound or its pharmaceutically useful salt:
2. according to the pharmaceutical composition of claim 1, comprising:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt; With
(b) nk 1 receptor antagonist or its pharmaceutically useful salt;
Wherein activating agent " a " and " b " are present in the said composition with a certain amount of, and this amount makes that the conjugate of two kinds of medicaments can be treated effectively can be by changing this class disease or symptom that physiological rhythm is treated.
3. according to the pharmaceutical composition of claim 1, comprising:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt;
(b) nk 1 receptor antagonist or its pharmaceutically useful salt; With
(c) SSRI or its pharmaceutically useful salt;
Activating agent " a " wherein, " b " and " c " is present in the said composition with a certain amount of, and this amount makes that the conjugate of three kinds of medicaments can be treated effectively can be by changing this class disease or symptom that physiological rhythm is treated.
4. according to the pharmaceutical composition of claim 1, comprising:
(a) NOS suppresses chemical compound, or its pharmaceutically useful salt; With
(b) SSRI or its pharmaceutically useful salt;
Wherein activating agent " a " and " b " are present in the said composition with a certain amount of, and this amount makes that the conjugate of two kinds of medicaments can be treated effectively can be by changing this class disease or symptom that physiological rhythm is treated.
5. according to the pharmaceutical composition of claim 1, wherein this disease or symptom be selected from blind, obesity, seasonal affective disorder, dipolar disease; Trouble with jet lag, sleep rhythm disorders round the clock, sleep function forfeiture disease, the fast sleep disease, hypersomnia disease, the disease of sleeping deeply, Sleep-Wake cycle disorder disease, narcolepsy disease with shiftwork or the relevant sleep disorder of irregular operating schedule; Nocturnal enuresis and how moving lower limb complication.
6. according to any one pharmaceutical composition in the claim 2,3 or 4, wherein this disease or symptom are to be selected from dysthymia, main oppressive disease, dipolar disease, seasonal affective disorder and other mood disease; Comprise generalized anxiety disease, obsessive pressure disease, panic disorder, post-traumatic nervous disease, the phobia of society, agoraphobia and other phobia are in interior anxiety disease; Blind, obesity, apoplexy, trouble with jet lag, sleep disorder is as sleep rhythm disorders round the clock, narcolepsy disease, sleep apnea, the fast sleep disease, the disease of sleeping deeply, Sleep-Wake cycle disorder disease, the sleep function forfeiture, the insomnia, hypersomnia disease, with the age, shiftwork or the relevant sleep disorder of irregular operating schedule that increase; Nocturnal enuresis is moved lower limb complication and cognitive disease as dull-witted and memory disease more.
7. according to the pharmaceutical composition of claim 3 or 4, wherein SSRI is a Sertraline, fluoxetine, Clovoxamine, Citalopram or Paroxetine.
8. according to the pharmaceutical composition of claim 2 or 3, this nk 1 receptor antagonist that wherein is used for this method is to be selected from following compounds and their pharmaceutically useful salt:
2-(benzhydryl)-N-((2-difluoro-methoxy) phenyl) methyl isophthalic acid-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(2-methoxyl group-5-Trifluoromethoxyphen-l) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-2-phenyl-3-[2-(2,2, the 2-trifluoro ethoxy) benzyl]-amino piperidine;
(2S, 3S)-3-(2-methoxyl group-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-1-(5,6-dimethoxy hexyl)-3-(2-methoxyl group-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-2-phenyl-3-(2-trifluoro-methoxybenzyl) amino piperidine;
(2S, 3S)-3-(2-hydroxyl-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-[5-chloro-2-(2,2, the 2-trifluoro ethoxy)-benzyl] amino-2-Phenylpiperidine;
(2S, 3S)-2-phenyl-3-(3-trifluoro-methoxybenzyl)-amino piperidine;
(2S, 3S)-3-(the 5-tert-butyl group-2-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(5-isopropyl-2-(2,2, the 2-trifluoro ethoxy)-benzyl] amino-2-Phenylpiperidine;
(2S, 3S)-3-[5-dimethylamino-2-(2,2, the 2-trifluoro ethoxy)-benzyl] amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-N, N-dimethylamino-benzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-[2, two (difluoro-methoxy) benzyls of 5-] amino-2-Phenylpiperidine;
(2S, 3S)-3-(the 5-tert-butyl group-2-difluoro-methoxy benzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-isopropoxy-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-trifluoro-methoxybenzyl)-amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-ethyoxyl-5-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-nitrobenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-isopropyl benzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-[5-acetamido-2-(2,2, the 2-trifluoro ethoxy)-benzyl] amino-2-Phenylpiperidine;
(2S, 3S)-3-(2-difluoro-methoxy-5-Ethylbenzyl) amino-2-Phenylpiperidine;
Suitable-3-(the 5-tert-butyl group-2-methoxybenzyl) amino-2-(3-Trifluoromethoxyphen-l) piperidines;
Suitable-2-(3, the 5-dibromo phenyl)-3-(2-methoxyl group-5-trifluoro-methoxybenzyl) amino piperidine;
(2S-3S)-3-(2-difluoro-methoxy-5-methylbenzyl) amino-2-Phenylpiperidine;
(2S, 3S)-3-(the 5-tert-butyl group-2-methoxybenzyl) amino-2-(3-Trifluoromethoxyphen-l) piperidines;
(2S, 3S)-3 (the 5-tert-butyl group-2-trifluoro-methoxybenzyl) amino-2-Phenylpiperidine;
2-(diphenyl methyl)-N-(2-methoxyl group-5-trifluoromethoxy-phenyl) methyl isophthalic acid-azabicyclo [2.2.2] octane-3-amine;
Suitable-3-(2-benzyl chloride base amino)-2-Phenylpiperidine;
Suitable-3-(2-trifluoromethyl benzyl amino)-2-phenyl-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(2-fluorophenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(2-chlorphenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(2-aminomethyl phenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-methoxyphenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-fluorophenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-chlorphenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-aminomethyl phenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(4-fluorophenyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-(3-thienyl)-piperidines;
Suitable-3-(2-methoxy-benzyl amino)-2-phenyl azepan;
3-(2-methoxy-benzyl amino)-4-methyl-2-Phenylpiperidine;
3-(2-methoxy-benzyl amino)-5-methyl-2-Phenylpiperidine;
3-(2-methoxy-benzyl amino)-6-methyl-2-Phenylpiperidine;
(2S, 3S)-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-1-(5-carbonyl ethoxy pentane-1-yl)-3-(2-methoxybenzyl-amino)-2-Phenylpiperidine;
(2S, 3S)-1-(the 6-hydroxyl-oneself-the 1-yl)-3-(2-methoxy-benzyl-amino)-2-Phenylpiperidine;
(2S, 3S)-1-(4-hydroxy-4-phenyl butane-1-yl)-3-(2-methoxyl group-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-1-(4-oxo-4-phenyl butane-1-yl)-3-(2-methoxy-benzyl-amino)-2-Phenylpiperidine;
(2S, 3S)-1-(5,6-dihydroxy-hexane-1-yl)-3-(2-methoxy-benzyl-amino)-2-Phenylpiperidine;
Suitable-3-(5-fluoro-2-methoxy-benzyl amino)-2-phenyl-piperidines;
(2S, 3S)-1-[4-(4-fluorophenyl)-4-oxo-butanes-1-yl]-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-the 1-[4-[4-fluorophenyl)-4-hydroxyl butane-1-yl]-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
Suitable-3-(2-methoxyl group-5-methyl-benzyl amino)-2-phenyl-piperidines;
(2S, 3S)-1-(4-benzamido fourth-1-yl)-3-(2-methoxy-benzyl-amino)-2-Phenylpiperidine;
Suitable-3-(2-methoxynaphthalene-1-ylmethyl amino)-2-phenyl-piperidines;
(2S, 3S)-3-(2-methoxy-benzyl amino)-1-(5-N-methyl-carboxamide groups pentane-1-yl)-2-Phenylpiperidine;
(2S, 3S)-1-(4-cyano group butane-1-yl)-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-1-[4-(2-naphthoyl amido) fourth-1-yl]-3-(2-methoxyl group-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-1-(5-benzamido pentane-1-yl)-3-(2-methoxy-benzyl-amino)-2-Phenylpiperidine;
(2S, 3S)-1-(5-aminopentane-1-yl)-3-(2-methoxy-benzyl amino)-2-Phenylpiperidine;
(2S, 3S)-3-(5-chloro-2-methoxy-benzyl amino)-2-phenyl-piperidines;
(2S, 3S)-3-(2,5-dimethoxy-benzyl amino)-2-phenyl-piperidines;
Suitable-3-(3,5-difluoro-2-methoxyl benzylamino)-2-phenyl-piperidines;
Suitable-3-(4,5-difluoro-2-methoxyl benzylamino)-2-phenyl-piperidines;
Suitable-3-(2,5-dimethoxy-benzyl amino)-1-[4-(4-fluorophenyl)-4-oxo-butanes-1-yl]-the 2-Phenylpiperidine;
Suitable-3-(5-chloro-2-methoxy-benzyl amino)-1-(5,6-dihydroxy-hexane-1-yl)-2-Phenylpiperidine;
Suitable-1-(5,6-dihydroxy-hexane-1-yl)-3-(2,5-dimethoxy-benzyl amino)-2-Phenylpiperidine;
Suitable-2-phenyl-3-[-2 (third-2-base oxygen base) benzyl amino] piperidines;
Suitable-3-(2, the 5-dimethoxy-benzyl) amino-2-(3-methoxyl group-phenyl) piperidines hydrogen chloride;
Suitable-3-(5-chloro-2-methoxy-benzyl) amino-2-(3-methoxyl group-phenyl) piperidines dihydrochloride;
Suitable-3-(5-chloro-2-methoxy-benzyl) amino-2-(3-chloro-phenyl) piperidines dihydrochloride;
3-(2-methoxy-benzyl amino)-2, the 4-diphenyl-piperidine;
Suitable-3-(2-methoxy-benzyl amino)-2-Phenylpyrrolidine;
(2S, 3S)-3-(5-ethyl-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(5-normal-butyl-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(2-methoxyl group-5-n-pro-pyl benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(5-isopropyl-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(5-sec-butyl-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(the 5-tert-butyl group-2-methoxy-benzyl) amino-2-phenyl-piperidines;
(2S, 3S)-3-(2-methoxyl group-5-phenylbenzyl) amino-2-phenyl-piperidines;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxyl group-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-methyl nitrosourea;
N-(4,5-dimethylthiazole-2-yl)-N-[4-methoxyl group-3-((2S, 3S)-2-Phenylpiperidine-3-base-amino methyl) phenyl]-amsacrine;
5-[(4,5-dimethylthiazole-2-yl) methylamino]-the 2-methoxy-benzyl }-((2S, 3S)-2-Phenylpiperidine-3-yl) amine;
{ 5-(4,5-dimethylthiazole-2-base is amino)-2-methoxy-benzyl }-((2S, 3S)-2-Phenylpiperidine-3-base amine;
4,5-dimethylthiazole-2-sulfonic acid methyl-[3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl)-the 4-Trifluoromethoxyphen-l]-amide;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-methyl nitrosourea;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-the isopropyl amide;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxyl group-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-the isopropyl amide;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxyl group-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-the isobutyl group amide;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-Phenylpiperidine-3-base amino methyl) phenyl]-the isobutyl group amide;
(2S, 3S)-N-(5-isopropyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(the 5-tert-butyl group-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-methyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-ethyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-isopropyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-sec-butyl-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S)-N-(5-just-propyl group-2-methoxyphenyl) methyl-2-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-amine,
(3R, 4S, 5S, 6S)-and N, N-diethyl-5-(5-isopropyl-2-methoxyl group-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid amides;
(3R, 4S, 5S, 6S)-and N, N-diethyl-5-(2,5-dimethoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid amides;
(3R, 4S, 5S, 6S)-5-(5-isopropyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-2-methyl sulfenyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2,5-dimethoxy-benzyl amino)-6-benzhydryl-1-azabicyclo-[2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-ethyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-n-pro-pyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-sec-butyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-N-methyl-sulfonyl methane amido-2-methoxyl group-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methylsulfinyl benzyl-amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-trifluoro-methoxybenzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl sulphonyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-dimethylamino-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-3-carboxyl acid;
(3R, 4S, 5S, 6S)-5-(5-isopropyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl sulfenyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2,5-dimethoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-ethyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-n-pro-pyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-sec-butyl-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-N-methyl-sulfonyl methane amido-2-methoxy-benzyl-amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methylsulfinyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-trifluoro-methoxybenzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl group-5-methyl sulphonyl benzylamino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; With
(3R, 4S, 5S, 6S)-5-(5-dimethylamino-2-methoxy-benzyl amino)-6-diphenyl methyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
With
Figure A008078780010C2
9. according to claim 1, the pharmaceutical composition of any one in 2,3 or 4, wherein NOS suppresses chemical compound and is selected from following compounds and their pharmaceutically useful salt:
6-[4-(3-amino-cyclohexyl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclopentyloxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclobutyl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(4-amino-cyclohexyl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclopentyloxy)-indane-4-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclobutyl oxygen base)-indane-4-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclopropyl oxygen base)-indane-4-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclohexyl oxygen base)-indane-4-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclopentyloxy)-indane-4-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclobutyl oxygen base)-indane-4-yl]-pyridine-2-base amine;
6-[4-(4-amino-cyclohexyl oxygen base)-indane-4-yl]-pyridine-2-base amine;
6-[4-piperidines-3-ylmethoxy)-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-1-yl]-pyridine-2-base amine;
6-[4-(2-pyrrolidinyl-ethyoxyl)-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclohexyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-1-yl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-pyrrolidine-1-base-ethyoxyl)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-[(benzo [1,3] dioxole-5-ylmethyl)-amino]-ethyoxyl }-naphthalene-1-yl)-pyridine-2-base amine;
6-(4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
3-{2-[4-(6-amino-pyridine-2-yl)-naphthalene-1-base oxygen base]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
6-(4-[2-(4-phenethyl-piperazine-1-yl)-ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
6-(4-[2-(3-amino-pyrrolidine-1-yl)-ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
6-[4-(1-benzyl-piperidin-4-yl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-benzyl-pyrrolidine-3-base oxygen base)-naphthalene-1-yl)-pyridine-2-base amine;
6-[4-(piperidin-4-yl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(pyrrolidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-isobutyl group-piperidin-4-yl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-furan-2-ylmethyl-piperidin-4-yl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-isobutyl group-pyrrolidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-furan-2-ylmethyl-pyrrolidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-morpholine-4-base-ethyoxyl)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-diisopropylaminoethyl-ethyoxyl)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-methyl-piperidin-4-yl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-methyl-pyrrolidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(3-dimethylamino-propoxyl group)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-aza-bicyclo [2.2.2] oct-3-yl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-piperidines-1-base-ethyoxyl)-naphthalene-1-yl]-pyridine-2-base amine;
6-{4-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
6-{4-[2-(4-dimethylamino-piperidines-1-yl)-ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
6-{4-[2-(tert-butyl group-methyl-amino)-ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
6-{4-[2-(4-methyl-piperazine-1-yl)-ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
6-{4-[2-(4-phenyl-piperidines-1-yl)-ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
6-{4-[2-(7,8-dihydro-5H-[1,3] dioxole also [4,5-g] isoquinolin-6-yl)-ethyoxyl]-naphthalene-1-yl }-pyridine-2-base amine;
6-[4-(piperidines-2-ylmethoxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-methyl-piperidines-2-ylmethoxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-methyl-piperidines-3-ylmethoxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclohexyl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(piperidines-3-ylmethoxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-isobutyl group-azetidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-furan-2-ylmethyl-azetidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(azetidine-3-base oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-methyl-pyrrolidine-2-ylmethoxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(azetidine-2-ylmethoxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[7-(2-dimethylamino-ethyoxyl)-indane-4-yl]-pyridine-2-base amine;
6-[7-(2-pyrrolidine-1-base-ethyoxyl)-indane-4-yl]-pyridine-2-base amine;
6-{7-[2-(benzyl-methyl-amino)-ethyoxyl]-indane-4-yl }-pyridine-2-base amine;
6-{7-[2-(4-phenethyl-piperazine-1-yl)-ethyoxyl]-indane-4-yl }-pyridine-2-base amine;
6-{7-[2-(4-isobutyl group-piperazine-1-yl)-ethyoxyl]-indane-4-yl }-pyridine-2-base amine;
6-[7-(2-morpholine-4-base-ethyoxyl)-indane-4-yl]-pyridine-2-base amine;
6-[7-(2-diisopropylaminoethyl-ethyoxyl)-indane-4-yl]-pyridine-2-base amine;
6-{7-[2-(7,8-dihydro-5H-[1,3] dioxole also [4,5-g] isoquinolin-6-yl)-ethyoxyl]-indane-4-yl } pyridine-2-base amine;
6-{7-[2-(4-methyl-piperazine-1-yl)-ethyoxyl]-indane-4-yl }-pyridine-2-base amine;
6-{7-[2-(tert-butyl group-methyl-amino)-ethyoxyl]-indane-4-yl }-pyridine-2-base amine;
6-{7-[2-(4-dimethylamino-piperidines-1-yl)-ethyoxyl]-indane-4-yl }-pyridine-2-base amine;
6-[8-(2-dimethylamino-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-5-yl]-pyridine-2-base amine;
6-[8-(2-pyrrolidine-1-base-ethyoxyl)-1,2,3,4-tetrahydrochysene-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-pyrrolidine-1-base-ethyoxyl)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-{4-[2-(tert-butyl group-methyl-amino)-ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl } pyridine-2-base amine;
6-[4-(2-diisopropylaminoethyl-ethyoxyl)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-lignocaine-ethyoxyl)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-{4-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl }-pyridine-2-base amine;
6-[4-(2-piperidines-1-base-ethyoxyl)-5-, 6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-morpholine-4-base-ethyoxyl)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-{4-[2-(7,8-dihydro-5H-[1,3] dioxole also [4,5-g] isoquinolin-6-yl)-ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl }-pyridine-2-base amine;
6-(4-[2-(4-methyl-piperazine-1-yl)-ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl } pyridine-2-base amine;
6-{4-[2-(4-dimethylamino-piperidines-1-yl)-ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl }-pyridine-2-base amine;
6-{4-[2-(7,8-dihydro-5H-[1,3] dioxole also [4,5-g] isoquinolin-6-yl) ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl }-pyridine-2-base amine;
6-[4-(1-isobutyl group-piperidines-3-ylmethoxy)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(1-methyl-piperidines-3-ylmethoxy)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-(4-[2-(2-lignocaine-ethyoxyl)-ethyoxyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-yl } pyridine-2-base amine;
6-[4-(piperidines-3-ylmethoxy)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclohexyl oxygen base)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(pyrrolidine-2-ylmethoxy)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine; With
6-[4-(2-dimethylamino-ethyoxyl)-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-1-yl] pyridine-2-base amine;
6-[4-(2-amino-cyclopentyloxy)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclobutyl oxygen base)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclopropyl oxygen base)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclohexyl oxygen base)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclopentyloxy)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(3-amino-cyclobutyl oxygen base)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(4-amino-cyclohexyl oxygen base)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclopentyloxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclobutyl oxygen base)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-amino-cyclopentyloxy)-naphthalene-1-yl]-pyridine-2-base amine;
6-[4-(2-(4-dimethylamino-piperidines-1-yl)-ethyoxyl))-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-1-yl]-pyridine-2-base amine;
6-[4-(2-(4-methyl-piperazine-1-yl)-ethyoxyl))-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-1-yl]-pyridine-2-base amine;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-ethyl ketone;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-2-methoxyl group-ethyl ketone;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl }-2-phenoxy group-ethyl ketone;
(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-cyclopenta-ketone;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-2-phenyl-ethyl ketone;
3-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl-ethyl ketone;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-2-(4-fluoro-phenyl)-ethyl ketone;
6-{4-[2-(4-phenethyl-piperazine-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl-ethanol;
{ 2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-(3-oxa--9-aza-bicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine;
6-(4-{2-[4-(2-amino-2-phenyl-ethyl)-piperazine-1-yl]-ethyl }-phenyl)-pyridine-2-base amine;
6-{4-[2-(4-amino-2,6-dimethyl-piperidines-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
6-{4-[2-(4-methyl-piperazine-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
(3-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl-3-aza-bicyclo [3.1.0] oneself-the 6-yl) dimethyl-amine;
6-[4-(2-amino-ethyl)-phenyl]-pyridine-2-base amine;
6-{4-[2-(8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-ethyl]-phenyl }-pyridine-2-base amine;
6-{4-[2-(4-isobutyl group-piperazine-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-N-isopropyl-acetamide;
4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-carboxylic acid is right-the tolyl amide;
6-(4-{2-[4-(3-phenyl-propyl group)-piperazine-1-yl]-ethyl }-phenyl)-pyridine-2-base amine;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-2-(4-chloro-phenyl)-ethyl ketone;
8-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-3-benzyl-1,3,8-three azepines-spiral shell [4.5] decane-2,4-diketone;
N-(1-{2-4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-pyrrolidine-3-yl)-2-(4-fluoro-phenyl)-acetamide;
8-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-8-aza-bicyclo [3.2.1] oct-3-yl amine;
3-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-3-aza-bicyclo [3.2.1] suffering-8-base amine;
2-amino-1-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-3-phenyl-third-1-ketone;
6-(4-[2-(4-amino-piperadine-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
6-{4-[2-(4-benzhydryl-piperazine-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
6-{4-[2-(4-benzhydryl-piperidines-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
6-{4-[(cyclohexyl-methyl-amino)-methyl]-phenyl }-pyridine-2-base amine;
6-{4-[(cyclohexyl-methyl-amino)-methyl]-2-methoxyl group-phenyl }-pyridine-2-base amine;
6-[4-(phenethyl amino-methyl)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(phenethyl amino-methyl)-phenyl]-pyridine-2-base amine;
6-[4-(4-amino-piperadine-1-ylmethyl)-phenyl }-pyridine-2-base amine;
6-{4-[(cyclohexyl-methyl-amino)-methyl]-2-fluoro-phenyl }-pyridine-2-base amine;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-2-methoxyl group-phenyl]-ethyl }-piperazine-1-yl)-2-phenyl-ethyl ketone;
6-{-4-[2-(4-isobutyl group-piperazine-1-yl)-ethyl]-2-methoxyl group-phenyl }-pyridine-1-base amine;
3-{2-[4-(6-amino-pyridine-2-yl)-2-methoxyl group-phenyl]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
{ 2-[4-(6-amino-pyridine-2-yl)-2-methoxyl group-phenyl]-ethyl }-(3-oxa--9-aza-bicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine;
6-(4-{2-[4-(2-amino-2-phenyl-ethyl)-piperazine-1-yl]-ethyl }-2-methoxyl group-phenyl)-pyridine-2-base amine;
6-{4-[2-(4-amino-2-methoxyl group-piperazine-1-yl)-ethyl]-2-methoxyl group-phenyl }-pyridine-2-base amine;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-2-methoxyl group-phenyl]-ethyl }-piperazine-1-yl)-N-isopropyl-acetamide;
6-[4-(4-amino-piperadine-1-ylmethyl)-2-methoxyl group-phenyl }-piperidines-2-base amine;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl]-ethyl }-piperazine-1-yl)-2-phenyl-ethyl ketone;
6-{4-[2-(4-isobutyl group-piperazine-1-yl)-ethyl]-2-methyl-phenyl }-piperidines-2-base amine;
3-{2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl-ethyl ketone;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl]-ethyl }-piperazine-1-yl)-2-(4-fluoro-phenyl)-ethyl ketone;
6-{4-[2-(4-phenethyl-piperazine-1-yl)-ethyl]-2-methyl-phenyl }-pyridine-2-base amine;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl-ethanol;
{ 2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl-ethyl }-(3-oxa--9-aza-bicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine;
6-(4-{2-[4-(2-amino-2-phenyl-ethyl)-piperazine-1-yl]-ethyl }-2-methyl-phenyl)-pyridine-2-base amine;
6-{4-[2-(4-amino-2,6-dimethyl-piperidines-1-yl)-ethyl]-2-methyl-phenyl }-pyridine-2-amine;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-2-methyl-phenyl]-ethyl }-piperazine-1-yl)-N-isopropyl-acetamide;
6-[4-(4-amino-piperadine-1-ylmethyl)-2-methyl-phenyl }-pyridine-2-base amine;
N-(1-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-pyrrolidine-3-yl)-2-phenyl-acetamide;
N-(1-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-pyrrolidine-3-yl)-2-(3-trifluoromethyl)-acetamide;
N-(1-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-pyrrolidine-3-yl)-2-(4-tolyl)-acetamide;
N-(1-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-pyrrolidine-3-yl)-2-(4-methoxyphenyl)-acetamide;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-2-methoxyl group-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl-ethyl ketone;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-2-methoxyl group-phenyl]-ethyl }-piperazine-1-yl)-2-(4-fluoro-phenyl)-ethyl ketone;
N-(1-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-pyrrolidine-3-yl)-2-cyclohexyl-acetamide;
2-(4-{2-4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-1-(4-tolyl)-ethyl ketone;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-1-(4-methoxyphenyl)-ethyl ketone;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-1-(4-chlorphenyl)-ethyl ketone;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-1-(4-fluorophenyl)-ethyl ketone;
2-(4-(2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-piperazine-1-yl)-1-cyclohexyl-ethyl ketone;
1-(4-(2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl }-piperazine-1-yl)-2-phenyl ethyl ketone;
6-(4-[2-(4-isobutyl group-piperazine-1-yl)-ethyl]-2-fluoro-phenyl }-pyridine-2-base amine;
3-{2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl ethyl ketone;
1-(4-{2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl }-piperazine-1-yl)-2-(4-fluoro-phenyl)-ethyl ketone;
6-(4-[2-(4-phenethyl-piperazine-1-yl)-ethyl]-2-fluoro-phenyl }-pyridine-2-base amine;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl }-piperazine-1-yl)-1-phenyl-ethanol;
{ 2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl }-(3-oxa--9-aza-bicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine;
6-(4-{2-[4-(2-amino-2-phenyl-ethyl)-piperazine-1-yl]-ethyl }-2-fluoro-phenyl)-pyridine-2-base amine;
6-(4-[2-(4-amino-2-fluoro-piperidine-1-yl)-ethyl]-2-fluoro-phenyl }-pyridine-2-base amine;
2-(4-{2-[4-(6-amino-pyridine-2-yl)-2-fluoro-phenyl]-ethyl }-piperazine-1-yl)-N-isopropyl-acetamide;
6-[4-4-amino-piperadine-1-ylmethyl)-2-fluoro-phenyl }-pyridine-2-base amine;
6-(4-[2-(4-amino-2,6-diethyl-piperidines-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
6-(4-[2-(4-amino-2,6-dibenzyl-piperidines-1-yl)-ethyl]-phenyl }-pyridine-2-base amine;
{ 2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-(9-(4-fluoro)-benzyl-3-oxa--9-azabicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine;
{ 2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-(9-(4-chloro)-benzyl-3-oxa--9-azabicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine;
{ 2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-(9-(4-methyl)-benzyl-3-oxa--9-azabicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine;
{ 2-[4-(6-amino-pyridine-2-yl)-phenyl]-ethyl }-(9-(4-methoxyl group)-benzyl-3-oxa--9-azabicyclo [3.3.1] ninth of the ten Heavenly Stems-7-yl)-amine;
6-[2-isopropoxy-4-((4-phenethyl piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-isobutoxy-4-((4-phenethyl piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-isopropoxy-4-((4-dimethyl aminoethyl)-phenyl]-pyridine-2-base amine;
6-[2-isopropoxy-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
1-[4-(6-amino-pyridine-2-yl)-3-isopropoxy-phenyl]-2-(4-phenethyl-piperazine-1-yl)-ethanol;
6-[2-cyclopentyloxy-4-((4-dimethyl aminoethyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclopentyloxy-4-((4-phenethyl-piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclohexyl oxygen base-4-((4-phenethyl piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclopentyloxy-4-((4-phenethyl-piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclopentyloxy-4-((4-phenethyl-piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-isoamoxy-4-((4-phenethyl-piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-isohesyl oxygen base-4-((4-phenethyl piperazine-1-yl)-ethyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclopentyloxy-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
6-[2-cyclohexyl oxygen base-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
6-[2-cyclobutyl oxygen base-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
6-[2-cyclopropyl oxygen base-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
6-[2-isoamoxy-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
6-[2-isohesyl oxygen base-(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
1-[4-(6-amino-pyridine-2-yl)-3-isobutoxy-phenyl]-2-(4-phenethyl-piperazine-1-yl)-ethanol;
1-[4-(6-amino-pyridine-2-yl)-3-isopropoxy-phenyl]-2-(6,7-dimethoxy-tetrahydroisoquinoline-2-yl)-ethanol;
1-[4-(6-amino-pyridine-2-yl)-3-isopropoxy-phenyl]-2-(4-dimethylamino-piperidines-1-yl)-ethanol;
1-[4-(6-amino-pyridine-2-yl)-3-isopropoxy-phenyl]-2-(dimethylamino)-ethanol;
1-[4-(6-amino-pyridine-2-yl)-3-cyclopentyloxy-phenyl]-2-(4-phenethyl-piperazine-1-yl)-ethanol;
6-[4-(2-dimethylamino-ethyoxyl)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2,3-dimethyl-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-3-methoxyl group-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-3-ethyoxyl-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-isopropyl-phenyl]-pyridine-2-base amine;
6-[2-cyclopropyl-4-(2-dimethylamino-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclobutyl-4-(2-dimethylamino-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclopenta-4-(2-dimethylamino-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-methoxyl group-5-propyl group-phenyl]-pyridine radicals amine;
6-[4-(1-methyl azietine-3-base oxygen base)-2-methoxyl group-5-ethyl-phenyl]-pyridine-2-base amine;
2-(6-amino-pyridine-2-yl)-5-(2-dimethylamino-ethyoxyl)-phenol;
6-[4-(2-dimethylamino-ethyoxyl)-2-propoxyl group phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-isopropoxy-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-ethyoxyl-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-methoxyl group-5-propyl group-phenyl]-pyridine-2-base amine;
6-[5-pi-allyl-4-(2-dimethylamino-ethyoxyl)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-[3-pi-allyl-4-(2-dimethylamino-ethyoxyl)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2,6-dimethyl-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-isopropyl-phenyl]-pyridine-2-base amine;
The 6-[2-tert-butyl group-4-(2-dimethylamino-ethyoxyl)-phenyl]-pyridine-2-base amine;
4-(6-amino-pyridine-2-yl)-3-methoxyphenol;
6-[4-(2-pyrrolidinyl-ethyoxyl)-2,3-dimethyl-phenyl]-pyridine-2-base amine;
6-[4-(4-(N-methyl) pyridine radicals oxygen base)-2,3-dimethyl-phenyl]-pyridine-2-base amine;
6-[4-(2-pyrrolidinyl-ethyoxyl)-3-methoxyl group-phenyl]-pyridine-2-base amine;
6-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyoxyl]-3-methoxyl group-phenyl } pyridine-2-base amine;
6-{3-methoxyl group-4-[2-(4-phenethyl-piperazine-1-yl)-ethyoxyl]-phenyl }-pyridine-2-base amine;
6-{3-methoxyl group-4-[2-(4-methyl-piperazine-1-yl)-ethyoxyl]-phenyl)-pyridine-2-base amine;
6-{4-[2-(4-dimethylamino-piperidines-1-yl)-ethyoxyl]-3-methoxyl group-phenyl)-pyridine-2-base amine;
6-[4-(2-pyrrolidinyl-ethyoxyl)-3-ethyoxyl-phenyl]-pyridine-2-base amine;
4-(the 6-amino-pyridine-yl)-3-cyclopropyl-phenol;
6-[2-cyclopropyl-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
3-[3-(6-amino-pyridine-2-yl)-4-cyclopropyl-contain phenoxy group]-pyrrolidine-1-carboxylic acid tertiary butyl ester;
6-[2-cyclopropyl-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
4-(6-amino-pyridine-2-yl)-3-cyclobutyl-phenol;
6-[2-cyclobutyl-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-[2-cyclobutyl-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
4-(6-amino-pyridine-2-yl)-3-cyclopenta-phenol;
6-[2-cyclopenta-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
3-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-pyrrolidine-1-carboxylic acid tertiary butyl ester;
6-[4-(1-methyl-pyrrolidine-3-base oxygen base)-2-methoxyl group-phenyl]-pyridine-2-base amine;
4-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-piperidines-1-carboxylic acid tertiary butyl ester;
6-[2-methoxyl group-4-(1-methyl-piperidin-4-yl oxygen base)-phenyl]-pyridine-2-base amine;
6-[4-(allyloxy)-2-methoxyl group-phenyl]-pyridine-2-base amine;
4-(6-amino-pyridine-2-yl)-3-methoxyl group-6-pi-allyl-phenol;
4-(6-amino-pyridine-2-yl)-3-methoxyl group-2-pi-allyl-phenol;
4-(6-amino-pyridine-2-yl)-3-methoxyl group-6-propyl group-phenol;
6-[2-isopropyl-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(piperidines-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(1-methyl-azetidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(1-methyl-piperidin-4-yl oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(2-methyl-2-aza-bicyclo [2.2.1] heptane-5-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[4-(2-dimethylamino-ethyoxyl)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-(4-[2-(benzyl-methyl-amino)-ethyoxyl]-2-methoxyl group-phenyl }-pyridine-2-base amine;
6-[2-methoxyl group-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
2-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-acetamide;
6-[4-(2-amino-ethyoxyl)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-(4-[2-(3,4-dihydro-1h-isoquinolin-2-yl)-ethyoxyl]-2-methoxyl group-phenyl }-pyridine-2-base amine;
2-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-ethanol;
6-(2-methoxyl group-4-[2-(2,2,6,6-tetramethyl-piperidines-1-yl)-ethyoxyl]-phenyl }-pyridine-2-base amine;
6-(4-[2-(2,5-dimethyl-pyrrolidine-1-yl)-ethyoxyl]-2-methoxyl group-phenyl }-pyridine-2-base amine;
6-(4-[2-(2,5-dimethyl-pyrrolidine-1-yl)-ethyoxyl]-2-methoxyl group-phenyl }-pyridine-2-base amine;
2-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-1-(2,2,6,6-tetramethyl-piperidines-1-yl) ethyl ketone;
6-[2-methoxyl group-4-(1-methyl-pyrrolidine-2-ylmethoxy)-phenyl]-pyridine-2-base amine;
6-(4-[2-(benzyl-methyl-amino)-ethyoxyl]-2-propoxyl group phenyl }-pyridine-2-base amine;
6-[4-(2-ethyoxyl-ethyoxyl)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-[4-(2-ethyoxyl-ethyoxyl)-2-isopropoxy-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(3-methyl-butoxy)-phenyl]-pyridine-2-base amine;
6-(4-[2-(benzyl-methyl-amino)-ethyoxyl]-2-ethyoxyl-phenyl }-pyridine-2-base amine;
6-[2-ethyoxyl-4-(3-methyl-butoxy)-phenyl]-pyridine-2-base amine;
1-(6-amino-3-aza-bicyclo [3.1.0] oneself-3-yl)-2-[4-(6-amino-pyridine-2-yl)-3-ethyoxyl-phenoxy group]-ethyl ketone;
6-[2-ethyoxyl-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
3-{2-[4-(6-amino-pyridine-2-yl)-3-ethyoxyl-phenoxy group]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
1-(6-amino-3-aza-bicyclo [3.1.0] oneself-3-yl)-2-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-ethyl ketone;
3-(2-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
6-[2-isopropoxy-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-(4-[2-(benzyl-methyl-amino)-ethyoxyl]-2-isopropoxy-phenyl }-pyridine-2-base amine;
6-[5-pi-allyl-2-methoxyl group-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-ethyoxyl-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropoxy-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(piperidin-4-yl oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(2,2,6,6-tetramethyl-piperidin-4-yl oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropoxy-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
3-[4-(6-amino-pyridine-2-yl)-3-methoxyl group-phenoxy group]-azetidine-1-carboxylic acid tertiary butyl ester;
6-[4-(azetidine-3-base oxygen base)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(1-methyl-azetidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropoxy-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-isopropoxy-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(2-methyl-2-aza-bicyclo [2.2.1] heptane-5-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2-methoxyl group-4-(1-methyl-piperidin-4-yl oxygen base)-phenyl]-pyridine-2-base amine;
6-[4-(1-ethyl-piperidin-4-yl oxygen base)-2-methoxyl group-phenyl]-pyridine-2-base amine;
6-[5-pi-allyl-2-methoxyl group-4-(1-methyl-pyrrolidine-3-base oxygen base)-phenyl]-pyridine-2-base amine;
6-[2,6-dimethyl-4-(3-piperidines-1-base-propoxyl group)-phenyl]-pyridine-2-base amine;
6-[2,6-dimethyl-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-(2,6-dimethyl-4-[3-(4-methyl-piperazine-1-yl)-propoxyl group]-phenyl }-pyridine-2-base amine;
6-[2,6-dimethyl-4-(2-morpholine-4-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
6-(4-[2-(benzyl-methyl-amino)-ethyoxyl]-2,6-dimethyl-phenyl }-pyridine-2-base amine;
2-[4-(6-amino-pyridine-2-yl)-3,5-dimethyl-phenoxy group]-acetamide;
6-[4-(2-amino-ethyoxyl)-2,6-dimethyl-phenyl]-pyridine-2-base amine;
6-[2-isopropyl-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
2-(2,5-dimethyl-pyrrolidine-1-yl)-6-[2-isopropyl-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine;
6-(4-[2-(3,5-dimethyl-piperidines-1-yl)-ethyoxyl]-2-isopropyl-phenyl }-pyridine-2-base amine;
The 6-[2-tert-butyl group-4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-pyridine-2-base amine;
3-(2-[4 '-(6-amino-pyridine-2-yl) biphenyl-4-yl]-ethyl-3-aza-bicyclo [3.1.0] oneself-6-base amine;
6-[4 '-(4-phenethyl-piperazine-1-ylmethyl)-biphenyl-4-yl]-pyridine-2-base amine;
3-[4 '-(6-amino-pyridine-2-yl)-biphenyl-4-ylmethyl]-3-aza-bicyclo [3.1.0] oneself-6-base amine;
3-[4 '-(6-amino-pyridine-2-yl)-biphenyl-3-ylmethyl]-3-aza-bicyclo [3.1.0] oneself-6-base amine;
2-amino-N-[4 '-(6-amino-pyridine-2-yl)-biphenyl-3-yl]-propionic acid amide.;
2-amino-N-[4 '-(6-amino-pyridine-2-yl)-biphenyl-3-yl]-3-phenyl-propionic acid amide.;
6-[4-(1-benzyl-1,2,5,6-tetrahydrochysene-pyridin-3-yl)-phenyl]-pyridine-2-base amine;
6-[4-(1-benzyl-piperidines-3-yl)-phenyl]-pyridine-2-base amine;
6-[4-(1-benzyl-piperidines-2-ylmethyl)-phenyl]-pyridine-2-base amine;
6-(4-[1-(2,2-diphenyl-ethyl)-piperidines-2-ylmethyl]-phenyl }-pyridine-2-base amine;
6-[3-(2-dimethylamino-cyclopentyl-methyl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(4-methyl piperazine-1-yl)-cyclopentyl-methyl)-phenyl]-pyridine-2-base amine;
6-[4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(N-cyclohexyl amino)-cyclopentyl-methyl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(N-cyclohexyl amino)-cyclopentyl-methyl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(N-phenethyl amino)-cyclopentyl-methyl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(N-phenethyl amino)-cyclopentyl-methyl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(4-methyl piperazine-1-yl)-cyclohexyl methyl)-phenyl]-pyridine-2-base amine;
6-[3-(2-(N-benzyl amino)-cyclohexyl methyl)-phenyl]-pyridine-2-base amine;
6-(4-[2-(2-ethyoxyl-ethylamino-)-cyclohexyl methyl]-phenyl }-pyridine-2-base amine;
6-[4-(2-(4-benzyl diethylenediamine-1-yl)-cyclohexyl methyl)-phenyl]-pyridine-2-base amine;
6-[4-(2-(4-(N-isopropyl acetamido) piperazine-1-yl)-cyclohexyl methyl)-phenyl]-pyridine-2-base amine;
6-[4-((2-(phenethyl)-[2.2.1] dicyclo heptan-1-yl) methyl)-phenyl]-pyridine-2-base amine;
6-[4-((2-(3-aza-bicyclo [3.1.0] oneself-6-base is amino)-[2.2.1] dicyclo heptan-1-yl) methyl)-phenyl]-pyridine-2-base amine;
6-[2-(N-phenethyl amino)-5-phenyl-cyclohexyl methyl) methyl)-phenyl]-pyridine-2-base amine;
6-[4-((2-(phenethyl)-[2.2.1] dicyclo heptan-1-yl) methyl)-phenyl]-pyridine-2-base amine;
6-[((2-(3-aza-bicyclo [3.1.0] oneself-6-base is amino)-5-phenyl-cyclohexyl methyl) methyl)-phenyl]-pyridine-2-base amine;
N-methyl-(2-aminopyridine-6-base-benzal base)-hydroxyindole;
N-methyl-(2-aminopyridine-6-base-benzyl)-hydroxyindole;
N-(2-dimethyl aminoethyl)-(2-aminopyridine-6-base-benzal base)-hydroxyindole;
N-(2-dimethyl aminoethyl)-(2-aminopyridine-6-base-benzyl)-hydroxyindole;
6-[(N-5-isoxazolyl methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
The 6-[(N-acetamido)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-benzoyl methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(3, the 4-dimethoxy-benzyl))-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(3,4-methylene dioxy base benzyl))-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(2-furyl) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
N-[4 '-(6-amino-pyridine-2-yl)-biphenyl-4-ylmethyl]-5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline;
6-[(N-(5-isothiazolyl) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(5-thiazolyl) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(2-pyridine radicals) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(3-pyridine radicals) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(2-imidazole radicals) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(4-imidazole radicals) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(4-pyridine radicals) methyl)-4-(piperidin-4-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(2-furyl) methyl)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
6-[(N-(2-methyl) propyl group)-4-(pyrrolidine-3-yl)-phenyl]-pyridine-2-base amine;
8-[4-(6-amino-pyridine-2-yl)-phenyl]-3-isobutyl group-3-aza-bicyclo [3.2.1] octan-8-ol;
8-[4-(6-amino-pyridine-2-yl)-phenyl]-3-furan-2-ylmethyl-3-aza-bicyclo [3.2.1] octan-8-ol;
8-[4-(6-amino-pyridine-2-yl)-phenyl]-3-benzyl-3-aza-bicyclo [3.2.1] octan-8-ol;
6-[8-(2-dimethylamino-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-5-yl] pyridine-2-base amine;
6-[8-(2-pyrrolidine-1-base-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-5-yl] pyridine-2-base amine;
6-[8-(2-dimethylamino-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-ethylene-naphthalene-5-yl]-pyridine-2-base amine;
6-[8-(2-pyrrolidine-1-base-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-ethylene-naphthalene-5-yl]-pyridine-2-base amine;
6-[8-(2-(4-dimethylamino-piperidines-1-yl)-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-5-yl]-pyridine-2-base amine;
6-[8-(2-(6,7-dimethoxy-tetrahydroisoquinoline-2-yl)-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-5-yl]-pyridine-2-base amine; With
6-[8-(2-(4-methyl piperazine-1-yl)-ethyoxyl)-1,2,3,4-tetrahydrochysene-1,4-methylene-naphthalene-5-yl]-pyridine-2-base amine.
10. being used for the treatment of can be by changing those diseases that mammiferous physiological rhythm treats or the method for symptom, and it comprises this administration according to any one pharmaceutical composition in the claim 1,2,3 or 4.
11. treat the method for mammiferous disease or symptom, this disease or symptom are selected from: blind, obesity, seasonal affective disorder, dipolar disease; Trouble with jet lag, sleep rhythm disorders round the clock, the sleep function forfeiture, the fast sleep disease, hypersomnia disease, the disease of sleeping deeply, Sleep-Wake cycle disorder disease, narcolepsy disease with shiftwork or the relevant sleep disorder of irregular operating schedule; How moving nocturnal enuresis and lower limb complication, this method comprise administration according to any one pharmaceutical composition in the claim 1,2,3 or 4.
12. treat the method for mammiferous disease or symptom, this disease or symptom are selected from: dysthymia, main oppressive disease, dipolar disease, seasonal affective disorder and other mood disease; Comprise generalized anxiety disease, obsession, panic disorder, post-traumatic nervous disease, social phobia's disease, agoraphobia and other phobia are in interior anxiety disease; Blind, obesity, apoplexy, trouble with jet lag, sleep disorder is as sleep rhythm disorders round the clock, narcolepsy disease, sleep apnea, the fast sleep disease, the disease of sleeping deeply, Sleep-Wake cycle disorder disease, the sleep function forfeiture, the insomnia, hypersomnia disease, with the age, shiftwork or the relevant sleep disorder of irregular operating schedule that increase; How moving nocturnal enuresis, lower limb complication and cognitive disease as dull-witted and memory disease, comprises this administration according to any one pharmaceutical composition in the claim 2,3 or 4.
CNA008078785A 1999-05-21 2000-03-16 New pharmaceutical combinations for nos inhibitors Pending CN1617743A (en)

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