CN1767829A - 4-(2-phenyloxyphenyl)-piperidine or -1,2,3,6-tetrahydropyridine derivatives as serotonin reuptake inhibitors. - Google Patents
4-(2-phenyloxyphenyl)-piperidine or -1,2,3,6-tetrahydropyridine derivatives as serotonin reuptake inhibitors. Download PDFInfo
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- CN1767829A CN1767829A CNA200480008884XA CN200480008884A CN1767829A CN 1767829 A CN1767829 A CN 1767829A CN A200480008884X A CNA200480008884X A CN A200480008884XA CN 200480008884 A CN200480008884 A CN 200480008884A CN 1767829 A CN1767829 A CN 1767829A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention provides compounds represented by the general formula (I) wherein the substituents are defined in the application. The compounds are useful in the treatment of an affective disorder, including depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder.
Description
The noval chemical compound that the present invention relates to is a serotonin reuptake inhibitor, and therefore for example depression and anxiety etc. are effective to treatment.
Background of invention
Selective serotonin reuptake inhibitor (SSRI hereinafter referred to as) has become first-selected therapy when anxiety for the treatment of depression, certain form and social phobia, because it compares tool effectiveness, good tolerability and good safety profile with classical tricyclics.
Yet, the clinical research of depression is shown SSRI unresponsive quite a lot of, be up to 30%.In addition, usually unheeded factor is a compliance in anti depressant therapy, and this factor continues pharmacotherapy and has suitable deep effect driving the patient.
At first, the curative effect of SSRI is slow.Sometimes, the first all symptoms even the deterioration of treatment.The second, all handicapped side effect of universal existence of all SSRI.Do not mention these problems, pharmacotherapy then depressed and anxiety can not produce real progress.
At chemical compound duloxetine (Wong for example, duloxetine (LY-248686): an inhibitorof serotonin and noradrenaline uptake and an antidepressant drugcandidate, Expert Opinion on Investigational Drugs, 1998,7,10,1691-1699) and venlafaxine (Khan-A etc., Venlafaxine in depressed outpatients, Psychopharmacology Bulletin7,1991,27, investigated serotonin reuptake transporter inhibition and norepinephrine uptake inhibition joint effect in clinical research 141-144) to depression.
The invention provides noval chemical compound with serotonin reuptake transporter inhibition and norepinephrine uptake inhibition joint effect, be used for the treatment of affective disorder, psychentonia obstacle, obsession, Panic-stricken, panic attack, specific phobias, social fear and square fear after for example depressed, as to comprise generalized anxiety disorder anxiety disorder, social phobia, the wound.
Summary of the invention
The invention provides the chemical compound of general formula I
Wherein dotted line, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8And R
9Be defined as follows.
The invention provides above-claimed cpd as medicine.
Pharmaceutical composition provided by the invention comprises above-claimed cpd or the acceptable acid-addition salts of its medicine and at least a medicine acceptable carrier or diluent.
The invention provides above-claimed cpd or the acceptable acid-addition salts of its medicine purposes on the medicine of preparation treatment affective disorder, psychentonia obstacle, obsession, Panic-stricken, panic attack, specific phobias, social fear and square fear after the anxiety disorder that described affective disorder is for example depressed, comprise generalized anxiety disorder, social phobia, the wound.
The invention provides that the intravital affective disorder of live animal that a kind of treatment comprises the people is for example depressed, the method for psychentonia obstacle, obsession, Panic-stricken, panic attack, specific phobias, social fear and square fear behind the anxiety disorder that comprises generalized anxiety disorder, social phobia, wound, described method comprises the above-claimed cpd or the acceptable acid-addition salts of its medicine for the treatment of effective dose.
Substituent definition
Halogen is meant fluorine, chlorine, bromine or iodine.
Expression formula C
1-6-alkane (alkene/alkynes) base is meant C
1-6-alkyl, C
2-6-thiazolinyl or C
2-6-alkynyl.
Term C
1-6Alkyl is meant side chain or the unbranched alkyl that includes 1-6 carbon atom, includes but not limited to methyl, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, 2-methyl-2-propyl group and 2-methyl isophthalic acid-propyl group.
Similarly, C
2-6-thiazolinyl and C
2-6-alkynyl refers to have 2-6 carbon atom respectively, comprises two keys and a triple-linked group respectively, includes but not limited to vinyl, acrylic, cyclobutenyl, acetenyl, propinyl and butynyl.
Term C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6Alkane (alkene/alkynes) sulfenyl, hydroxyl-C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6Alkane (alkene/alkynes) base, NR
zR
w-C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base-C
1-6-alkane (alkene/alkynes) base and halo-C
1-6-alkane (alkene/alkynes) oxygen base is meant wherein C
1-6-alkane (alkene/alkynes) base definition group as above.Halo represents that halogen replaces.NR
zR
w-C
1-6-alkane (alkene/alkynes) base is meant group
Term C
3-8Cycloalkyl is meant monocycle or the bicyclic carbocyclic with 3-8 C atom, includes but not limited to cyclopropyl, cyclopenta, cyclohexyl etc.
Term C
3-8Cycloalkenyl group is meant monocycle or the bicyclic carbocyclic that has 3-8 C atom and comprise two keys.
Term C
3-8-cycloalkanes (alkene) base-C
1-6C in-alkane (alkene/alkynes) base
3-8-cycloalkanes (alkene) base and C
1-6-alkane (alkene/alkynes) base as defined above.
Term used herein is chosen wantonly and is contained other hetero atom, for example the 3-7 of N, O or S unit encircles, be meant member ring systems for example 1-morpholinyl, piperidino, 1-azepine all these can be selected from following group and further be replaced: C because of base, 1-piperazinyl, the high piperazinyl of 1-, 1-imidazole radicals, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrole radicals or pyrazolyl heptan
1-6-alkane (alkene/alkynes) base, hydroxyl, hydroxyl-C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base-C
1-6-alkane (alkene/alkynes) base.
Detailed Description Of The Invention
The 4-that the present invention relates to (2-Phenoxyphenyl)-piperidines or-1,2,3, the 6-5,6-tetrahydropyridine derivative is a serotonin reuptake inhibitor, and therefore for example depression and anxiety etc. are effective to treatment.Particularly described piperidines also is good norepinephrine uptake inhibitors.
Therefore the present invention relates to the compound or its salt represented by general formula I:
Wherein, dotted line----expression singly-bound or two key;
R
1, R
2, R
3, R
4, R
5Independently be selected from hydrogen, halogen, cyano group, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, hydroxyl, hydroxyl-C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) oxygen base or NR
xR
y, R wherein
xAnd R
YIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6Alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base, C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base or NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
zAnd R
wIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base; Or R
xAnd R
yForm the optional first ring of other heteroatomic 3-7 that contains with the nitrogen that connects them; Or
R
2And R
3Form with phenyl ring is condensed together and be selected from
Heterocycle; And R
1, R
4, R
5As defined above;
R
6, R
7, R
8, R
9Independently be selected from hydrogen, halogen, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, hydroxyl, hydroxyl-C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) oxygen base or NR
xR
y, R wherein
xAnd R
yIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base, C
3-8Cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base or NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
2And R
wIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base; Or R
xAnd R
yForm the optional first ring of other heteroatomic 3-7 that contains with the nitrogen that connects them;
Condition is R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8And R
9In at least one is not a hydrogen.
In an embodiment of formula I chemical compound, R wherein
1Be selected from hydrogen, halogen, cyano group, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, halo-C
1-6-alkane (alkene/alkynes) base or NR
xR
y, R wherein
xAnd R
yIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base, C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base or NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
zAnd R
wIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base, condition is if R
xAnd R
yOne of be NR
zR
w-C
1-6-alkane (alkene/alkynes) base, then another is selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base; Or R
xAnd R
yForm the optional first ring of other heteroatomic 3-7 that contains with the nitrogen that connects them.In another embodiment of formula I chemical compound, R
1Be selected from hydrogen, halogen, cyano group, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, halo-C
1-6-alkane (alkene/alkynes) base.In another embodiment, R
1Be NR
xR
yR wherein
xAnd R
yIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base, C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base, for example hydrogen, cyanogen methyl, C
1-6-alkane (alkene/alkynes) base.In another embodiment, R
1Be NR
xR
yR wherein
xBe NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
zAnd R
wIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base, and R
yBe selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base.In another embodiment, R
1Be NR
xR
yR wherein
xAnd R
yForm the optional first ring of other heteroatomic 3-7 that contains with the nitrogen that connects them, for example 1-morpholinyl, piperidino, 1-azepine heptan is because of base, 1-piperazinyl, the high piperazinyl of 1-, 1-imidazole radicals, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrole radicals or pyrazolyl, and they are optional to be selected from following group and to replace by one or more: C
1-6-alkane (alkene/alkynes) base, hydroxyl, hydroxyl-C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base-C
1-6-alkane (alkene/alkynes) base, for example one or two is selected from hydroxyl, hydroxyl-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkyl, especially one or two is selected from hydroxyl, methoxyl group-methyl, methyl.Typically, R
1Be selected from hydrogen; Halogen; Cyano group; C
1-6Alkyl; C
1-6-alkoxyl; C
1-6-alkylthio group; Halo-C
1-6-alkyl; NR
xR
yR wherein
XAnd R
YIndependently be selected from hydrogen, C
1-6-alkyl, cyanogen methyl; NR
xR
yR wherein
yBe selected from hydrogen or C
1-6-alkyl, and R
xBe NR
zR
w-C
1-6-alkane (alkene/alkynes) base is R wherein
zAnd R
wIndependently be selected from hydrogen or C
1-6-alkyl; 1-morpholinyl, piperidino, 1-azepine heptan is because of base, 1-piperazinyl, the high piperazinyl of 1-, 1-imidazole radicals, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrole radicals or pyrazolyl, and they are optional to be selected from following group by one or two and to replace: hydroxyl, hydroxyl-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkyl, especially one or two is selected from hydroxyl, methoxyl group-methyl, methyl.For further specifying unrestricted the present invention, R
1An embodiment be hydrogen; R
1Another embodiment be C
1-6-alkyl, for example methyl; R
1Another embodiment be halogen, for example fluorine or chlorine.
In another embodiment of formula I chemical compound, R
2Be selected from hydrogen, halogen, cyano group, C
1-6-alkane (alkene/alkynes) base, C
1-6Alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, halo-C
1-6-alkane (alkene/alkynes) base.Typically, R
2Be selected from hydrogen, halogen, cyano group, C
1-6-alkyl, C
1-6-alkoxyl, C
1-6-alkylthio group, halo-C
1-6-alkyl.For further specifying unrestricted the present invention, R
2An embodiment be hydrogen; R
2Another embodiment be C
1-6-alkoxyl, for example methoxyl group; R
2Another embodiment be halo-C
1-6-alkyl, for example trifluoromethyl; R
2Another embodiment be C
1-6-alkyl, for example methyl; R
2Another embodiment be halogen, for example chlorine.
In another embodiment of formula I chemical compound, R
3Be selected from hydrogen, halogen, cyano group, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, halo-C
1-6-alkane (alkene/alkynes) base.Typically, R
3Be selected from hydrogen, halogen, cyano group, C
1-6-alkyl, C
1-6-alkoxyl, C
1-6-alkylthio group, halo-C
1-6-alkyl.For further specifying unrestricted the present invention, R
3An embodiment be hydrogen; R
3Another embodiment be C
1-6-alkyl, for example methyl; R
3Another embodiment be C
1-6-alkoxyl, for example methoxyl group; R
3Another embodiment be halogen, for example chlorine or fluorine; R
3Another embodiment be halo-C
1-6-alkyl, for example trifluoromethyl.
In another embodiment of formula I chemical compound, R
2And R
3Form with phenyl ring is condensed together and be selected from
Heterocycle.
In another embodiment of formula I chemical compound, R
4Be selected from hydrogen, halogen, cyano group, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, halo-C
1-6-alkane (alkene/alkynes) base.Typically, R
4Be selected from hydrogen, halogen, cyano group, C
1-6-alkyl, C
1-6-alkoxyl, C
1-6-alkylthio group, halo-C
1-6-alkyl.For further specifying unrestricted the present invention, R
4An embodiment be hydrogen; R
4Another embodiment be C
1-6-alkoxyl, for example methoxyl group; R
4Another embodiment be halo-C
1-6-alkyl, for example trifluoromethyl; R
4Another embodiment be C
1-6-alkyl, for example methyl; R
4Another embodiment be halogen, for example chlorine.
In another embodiment of formula I chemical compound, R
5Be selected from hydrogen, halogen, cyano group, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, halo-C
1-6-alkane (alkene/alkynes) base or NR
xR
y, R wherein
xAnd R
yIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base, C
3-8Cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base or NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
zAnd R
wIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base, condition is if R
xAnd R
yOne of be NR
zR
w-C
1-6-alkane (alkene/alkynes) base, then another is selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base; Or R
xAnd R
yForm the optional first ring of other heteroatomic 3-7 that contains with the nitrogen that connects them.In another embodiment of formula I chemical compound, R
5Be selected from hydrogen, halogen, cyano group, C
2-6-alkane (alkene/alkynes) base, C
2-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, halo-C
1-6-alkane (alkene/alkynes) base.In yet another embodiment, R
5Be NR
xR
yR wherein
xAnd R
yIndependently be selected from hydrogen, C
2-6-alkane (alkene/alkynes) base, cyano group-C
2-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base, C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base, for example hydrogen, cyanogen methyl, C
1-6-alkane (alkene/alkynes) base.In yet another embodiment, R
5Be NR
xR
yR wherein
xBe NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
zAnd R
wIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base, R
yBe selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base.In yet another embodiment, R
5Be NR
xR
yR wherein
XAnd R
YForm the optional first ring of other heteroatomic 3-7 that contains with the nitrogen that connects them, for example 1-morpholinyl, piperidino, 1-azepine heptan is because of base, 1-piperazinyl, the high piperazinyl of 1-, 1-imidazole radicals, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrole radicals or pyrazolyl, and they are optional to be selected from following group and to replace by one or more: C
1-6-alkane (alkene/alkynes) base, hydroxyl, hydroxyl-C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base-C
1-6-alkane (alkene/alkynes) base, for example one or two is selected from hydroxyl, hydroxyl-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkyl, especially one or two is selected from hydroxyl, methoxyl group-methyl, methyl.Typically, R
5Be selected from hydrogen; Halogen; Cyano group; C
1-6Alkyl; C
1-6-alkoxyl; C
1-6-alkylthio group; Halo-C
1-6-alkyl; NR
xR
yR wherein
XAnd R
YIndependently be selected from hydrogen, C
1-6-alkyl, cyanogen methyl; NR
xR
yR wherein
yBe selected from hydrogen or C
1-6-alkyl, R
xBe NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
zAnd R
wIndependently be selected from hydrogen or C
1-6-alkyl; 1-morpholinyl, piperidino, 1-azepine heptan is because of base, 1-piperazinyl, the high piperazinyl of 1-, 1-imidazole radicals, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrole radicals or pyrazolyl, and they are optional to be selected from following group by one or two and to replace: hydroxyl, hydroxyl-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkyl, especially one or two is selected from hydroxyl, methoxyl group-methyl, methyl.For further specifying unrestricted the present invention, R
5An embodiment be hydrogen; R
5Another embodiment be C
1-6-alkyl, for example methyl; R
5Another embodiment be halogen, for example chlorine or fluorine.
In another embodiment of formula I chemical compound, R
6Be selected from hydrogen, halogen, C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base.Typically, R
6Be selected from hydrogen, halogen, C
1-6-alkyl, halo-C
1-6-alkyl.For further specifying unrestricted the present invention, R
6An embodiment be hydrogen; R
6Another embodiment be halogen, for example fluorine.
In another embodiment of formula I chemical compound, R
7Be selected from hydrogen, halogen, C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base.Typically, R
7Be selected from hydrogen, halogen, C
1-6-alkyl, halo-C
1-6-alkyl.For further specifying unrestricted the present invention, R
7An embodiment be hydrogen; R
7Another embodiment be halogen, for example fluorine.
In another embodiment of formula I chemical compound, R
8Be selected from hydrogen, halogen, C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base or NR
xR
y, R wherein
xAnd R
yIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base, C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base or NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
zAnd R
wIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base, condition is if R
xAnd R
yOne of be NR
zR
w-C
1-6-alkane (alkene/alkynes) base, then another is selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base; Or R
xAnd R
yForm the optional first ring of other heteroatomic 3-7 that contains with the nitrogen that connects them; In another embodiment of formula I chemical compound, R
8Be selected from hydrogen, halogen, C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base.In another embodiment, R
8Be NR
xR
yR wherein
xAnd R
yIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base, C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base, for example hydrogen, cyanogen methyl, C
1-6-alkane (alkene/alkynes) base.In another embodiment, R
8Be NR
xR
yR wherein
xBe NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
zAnd R
wIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base, and R
yBe selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base.In another embodiment, R
8Be NR
xR
yR wherein
xAnd R
yForm the optional first ring of other heteroatomic 3-7 that contains with the nitrogen that connects them, for example 1-morpholinyl, piperidino, 1-azepine heptan is because of base, 1-piperazinyl, the high piperazinyl of 1-, 1-imidazole radicals, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrole radicals or pyrazolyl, and they are optional to be selected from following group and to replace by one or more: C
1-6-alkane (alkene/alkynes) base, hydroxyl, hydroxyl-C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base-C
1-6-alkane (alkene/alkynes) base, for example one or two is selected from hydroxyl, hydroxyl-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkyl, especially one or two is selected from hydroxyl, methoxyl group-methyl, methyl.Typically, R
8Be selected from hydrogen; Halogen; Cyano group; C
1-6Alkyl; C
1-6-alkoxyl; C
1-6-alkylthio group; Halo-C
1-6-alkyl; NR
xR
yR wherein
XAnd R
YIndependently be selected from hydrogen, C
1-6-alkyl, cyanogen methyl; NR
xR
yR wherein
yBe selected from hydrogen or C
1-6-alkyl, R
xBe NR
zR
w-C
1-6-alkane (alkene/alkynes) base is R wherein
zAnd R
wIndependently be selected from hydrogen or C
1-6-alkyl; 1-morpholinyl, piperidino, 1-azepine heptan is because of base, 1-piperazinyl, the high piperazinyl of 1-, 1-imidazole radicals, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrole radicals or pyrazolyl, and they are optional to be selected from by one or two that following group replaces: hydroxyl, hydroxyl-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkyl, especially one or two is selected from hydroxyl, methoxyl group-methyl, methyl.For further specifying unrestricted the present invention, R
8An embodiment be hydrogen; R
8Another embodiment be halogen, for example fluorine or bromine; R
8Another embodiment be C
1-6-alkyl, for example methyl; R
8Another embodiment be halo-C
1-6-alkyl, for example CF
3
In another embodiment of formula I chemical compound, R
9Be selected from hydrogen, halogen, C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base.Typically, R
9Be selected from hydrogen, halogen, C
1-6-alkyl, halo-C
1-6-alkyl.For further specifying unrestricted the present invention, R
9An embodiment be hydrogen.
In another embodiment of formula I chemical compound, dotted line----expression singly-bound.
In another embodiment of formula I chemical compound, the two keys of dotted line----expression.
Typically, formula I chemical compound has at least one and is selected from R on phenyl ring
1-R
9Any be not the substituent group of hydrogen, for example on phenyl ring, have 1,2,3 or 4 to be selected from R
1-R
9Any be not the substituent group of hydrogen, all the other substituent groups are hydrogen.Therefore, in yet another embodiment 1 be selected from R
1-R
9Any not for the substituent group of hydrogen is present in any of two phenyl ring, for example 1 substituent group is selected from R
1-R
5Or this substituent group is selected from R
6-R
92 are selected from R in yet another embodiment
1-R
9Not for the substituent group of hydrogen is present in any of two phenyl ring, for example 1 substituent group is selected from R
1-R
5, another substituent group is selected from R
6-R
9Or two substituent groups all are selected from R
1-R
5This moment R
2And R
3Can form the heterocycle of above definition together.In yet another embodiment, 3 are selected from R
1-R
9Not for the substituent group of hydrogen is present in any of two phenyl ring, for example 2 substituent groups are selected from R
1-R
5, and last substituent group is selected from R
6-R
9In each embodiment, all the other substituent groups are hydrogen as described.For further specifying unrestricted the present invention, some typical embodiments have hereinafter been summarized.
Therefore, in another embodiment of formula I chemical compound, have a substituent group, this substituent group be above definition be not the R of hydrogen
2In another embodiment of formula I chemical compound, have a substituent group, this substituent group be above definition be not the R of hydrogen
3In another embodiment of formula I chemical compound, two substituent groups of existence are R
3And R
8, R wherein
3And R
8As above definition but be not hydrogen.In another embodiment of formula I chemical compound, two substituent groups of existence are R
3And R
6, R wherein
3And R
6As defined above but be not hydrogen.In another embodiment of formula I chemical compound, two substituent groups of existence are R
3And R
7, R wherein
3And R
7As defined above but be not hydrogen.In another embodiment of formula I chemical compound, two substituent groups of existence are R
1And R
3, R wherein
1And R
3As defined above but be not hydrogen.In another embodiment of formula I chemical compound, two substituent groups of existence are R
2And R
3, R wherein
2And R
3As defined above but be not hydrogen, this moment R
2And R
3Can form heterocycle as defined above together.In another embodiment of formula I chemical compound, three substituent groups of existence are R
1, R
3And R
8, R wherein
1, R
3And R
8As defined above but be not hydrogen.In each embodiment, remaining substituent group is a hydrogen as mentioned above.
In another embodiment of formula I chemical compound, described chemical compound is selected from
1) 4-[2-(2, the 4-dimethyl phenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
2) 4-[2-(4-chlorophenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
3) 4-[2-(4-oxygen-2-methylphenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
4) 4-[2-(4-phenoxy base) phenyl]-1,2,3, the 6-tetrahydropyridine,
5) 4-[2-(4-methylphenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
6) 4-[2-(4-methoxyl group phenoxy group) phenyl]-1,2,3, the 6-tetrahydropyridine,
7) 4-[2-(2, the 4-dimethyl phenoxy) phenyl] piperidines,
8) 4-[2-(4-chlorophenoxy) phenyl] piperidines,
9) 4-[2-(4-fluoro-2-methylphenoxy) phenyl] piperidines,
10) 4-[2-(4-fluorophenoxy) phenyl] piperidines,
11) 4-[2-(4-methylphenoxy) phenyl] piperidines,
12) 4-[2-(4-chloro-2-methyl-phenoxy group)-phenyl]-piperidines,
13) 4-[2-(2-chloro-4-methyl-phenoxy group)-phenyl]-piperidines,
14) 4-[2-(2,4-two chloro-phenoxy groups)-phenyl]-piperidines,
15) 4-[2-(benzo [b] thiophene-5-base oxygen base)-phenyl]-piperidines,
16) 4-[2-(benzo [1,3] dioxole-5-base oxygen base)-phenyl]-piperidines,
17) 4-[2-(4-methoxyl group-2-methyl-phenoxy group)-phenyl]-piperidines,
18) 4-[2-(3,4-two chloro-phenoxy groups)-phenyl]-piperidines,
19) 4-[2-(3,4-dimethyl-phenoxy group)-phenyl-piperidines,
20) 4-[2-(2,3,4,5-tetramethyl-phenoxy group)-phenyl]-piperidines,
21) 4-[2-(4-trifluoromethyl-phenoxy group)-phenyl]-piperidines,
22) 4-[2-(4-methoxyl group-phenoxy group)-phenyl]-piperidines,
23) 4-[2-(2-chloro-4-methoxyl group-phenoxy group)-phenyl]-piperidines,
24) 4-[2-(3,4-dimethoxy-phenoxy group)-phenyl]-piperidines,
25) 4-[2-(4-chloro-3-trifluoromethyl-phenoxy group)-phenyl]-piperidines, or the acceptable salt of its medicine.Each of these chemical compounds all is counted as specific embodiment, can be claimed individually.
As mentioned above, most of test compounds have the joint effect that serotonin reuptake transporter suppresses and norepinephrine uptake suppresses, show the serotonin reuptake transporter depression effect yet in the present invention's test, have only a few to be selected from following chemical compound, and do not show the norepinephrine uptake depression effect:
1) 4-[2-(2, the 4-dimethyl phenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
2) 4-[2-(4-chlorophenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
3) 4-[2-(4-fluoro-2-methylphenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
4) 4-[2-(4-fluorophenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
5) 4-[2-(4-methylphenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
6) 4-[2-(4-methoxyl group phenoxy group) phenyl]-1,2,3, the 6-tetrahydropyridine,
7) 4-[2-(3,4-dimethyl-phenoxy group)-phenyl]-piperidines,
8) 4-[2-(2,3,4,5-tetramethyl-phenoxy group)-phenyl]-piperidines,
9) 4-[2-(3,4-dimethoxy-phenoxy group)-phenyl]-piperidines.
The present invention also comprises the salt of The compounds of this invention, is typically the acceptable salt of medicine.This salt comprises the acceptable acid-addition salts of medicine, the acceptable slaine of medicine, ammonium salt and alkylated ammonium.Acid-addition salts comprises inorganic acid salt and acylate.
The representative example of suitable mineral acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulphuric acid, sulfamic acid, nitric acid etc.The representational example of appropriate organic comprises formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propanoic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic, the itaconic acid, lactic acid, methanesulfonic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, acetone acid, salicylic acid, succinic acid, methanesulfonic acid, ethyl sulfonic acid, tartaric acid, ascorbic acid, pamoic acid, the dimethylene salicylic acid, ethane disulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, Palmic acid, ethylenediaminetetraacetic acid, glycolic, para-amino benzoic acid, glutamic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, acetic acid theophylline and 8-halo theophylline, for example 8-bromine theophylline etc.
The example of slaine comprises lithium salts, sodium salt, potassium salt, magnesium salt etc.
The example of ammonium salt or alkylated ammonium comprises ammonium salt, methyl ammonium salt, dimethyl ammonium, leptodactyline, ethyl ammonium salt, ethoxy ammonium salt, diethyl ammonium salt, normal-butyl ammonium salt, sec-butyl ammonium salt, tert-butyl group ammonium salt, tetramethyl ammonium salt etc.
In addition, The compounds of this invention not solvation and with the medicine acceptable solvent for example the form of water, ethanol, equal solventization exist.Generally speaking, for the purposes of the present invention, think that the solvation form is equal to not solvation form.
Chemical compound of the present invention can have one or more asymmetric centers, and any optical isomer (being enantiomer or diastereomer), as isolating, pure or partially purified optical isomer and comprise any mixture of racemic mixture, be included in the scope of the present invention.
Racemic form can split into optical antimer by known method, and for example the diastereoisomeric salt by optically active acid separates, and with alkali treatment the optically active amines is discharged.Another method that racemic modification is split into optical antimer is based on the chromatograph on the optically active substrate.Racemic compound of the present invention also may be split into its optical antimer, for example passes through the salt of fractional crystallization d-or 1-(tartaric acid, mandelic acid or camphorsulfonic acid).The compounds of this invention also can split by forming non-enantiomer derivative.
Also can use other optical isomer method for splitting well known by persons skilled in the art.This method comprises J.Jaques, and A.Collet and S.Wilen exist " Enantiomers, Racemates, and Resolutions " (" enantiomer, racemic modification and fractionation "), the method for discussing among John Wiley and the Sons, New York (1981).
Activity of optically active compounds also can be by the optically active feedstock production, or selects synthetic preparation by three-dimensional.
In addition, when having two keys or saturated wholly or in part member ring systems in the molecule, can form geometric isomer.Any geometric isomer is included in the scope of the invention as isolating, pure or partially purified geometric isomer or its mixture.Equally, have the molecule that rotates limited key and can form geometric isomer.These also are included in the scope of the invention.
In addition, some chemical compound of the present invention can exist with different tautomeric forms, and any tautomeric forms that described chemical compound can form is included in the scope of the invention.
The present invention also comprises the prodrug of The compounds of this invention, and this prodrug has experienced chemical conversion by metabolic process when medication, becomes pharmaceutically active substances then.Generally speaking, this prodrug is general formula (I) compound functions derivant, and this derivant can easily be transformed into required formula (I) chemical compound in vivo.For example, at " Design ofProdrugs ", H.Bundgaard writes, and Elsevier has described the conventional method of selecting and prepare suitable prodrug derivant in 1985.
The present invention also comprises the active metabolite of The compounds of this invention.
As mentioned above, formula (I) chemical compound is a serotonin reuptake inhibitor, therefore is applicable to treatment to comprise prevention emotion disease, for example depressed, as to comprise generalized anxiety disorder anxiety disorder, Panic-stricken and obsession.
Therefore, on the other hand, the present invention relates to formula I chemical compound as medicine.
The present invention also relates to pharmaceutical composition, described compositions comprises formula I chemical compound and medicine acceptable carrier or diluent.Described compositions can comprise arbitrary embodiment of above-mentioned formula I.
In the embodiment of pharmaceutical composition, the amount of formula I chemical compound is that every day about 0.001 is to about 100mg/kg body weight.
The present invention also relates to the purposes on formula I chemical compound is used for the treatment of disease or obstacle in preparation the medicine, wherein serotonin reuptake inhibitor is useful.Described medicine can comprise the embodiment of arbitrary above-mentioned formula I.
Specifically, the present invention also relates to purposes on formula I chemical compound is used for the treatment of affective disorder in preparation the medicine.
The present invention also relates to formula I chemical compound in yet another embodiment and be used for the treatment of purposes on the depressed medicine in preparation.
In yet another embodiment, the present invention also relates to purposes on formula I chemical compound is used for the treatment of anxiety disorder in preparation the medicine.
In yet another embodiment, the present invention also relates to purposes on formula I chemical compound is used for the treatment of generalized anxiety disorder in preparation the medicine.
In yet another embodiment, the present invention also relates to purposes on formula I chemical compound is used for the treatment of social phobia in preparation the medicine.
In yet another embodiment, the present invention also relates to purposes on the medicine of formula I chemical compound psychentonia obstacle after preparation is used for the treatment of wound.
In yet another embodiment, the present invention also relates to purposes on formula I chemical compound is used for the treatment of obsession in preparation the medicine.
In yet another embodiment, the present invention also relates to purposes on formula I chemical compound is used for the treatment of Panic-stricken in preparation the medicine.
In yet another embodiment, the present invention also relates to purposes on formula I chemical compound is used for the treatment of panic attack in preparation the medicine.
In yet another embodiment, the present invention also relates to purposes on formula I chemical compound is used for the treatment of specific phobias in preparation the medicine.
In yet another embodiment, the present invention also relates to formula I chemical compound and be used for the treatment of purposes on the social frightened medicine in preparation.
In yet another embodiment, the present invention also relates to purposes on formula I chemical compound is used for the treatment of the square fear in preparation the medicine.
Another aspect of the invention relate to treat that the affective disorder that is present in the living animal that comprises the people is for example depressed, the method for psychentonia obstacle, obsession, Panic-stricken, panic attack, specific phobias, social fear and square fear behind the anxiety disorder that comprises generalized anxiety disorder, social phobia, wound, described method comprises that the experimenter that this needs are arranged treats the formula I chemical compound of effective dose.
Aspect another, the present invention relates to the method for preparation I compound, described method comprises
A) with the chemical compound deprotection of formula II or cracking from the polymer support
Wherein dotted line, R
1-R
9As mentioned above, and R ' be that the tert-butyl group, methyl, ethyl, pi-allyl or benzyl or R ' OCO are the carbamate groups that solid is supported; Or
B) with dehydration of formula III chemical compound and optional deprotection simultaneously
R wherein
1-R
9Be hydrogen atom or carbamate groups R ' OCO as mentioned above, and R ", wherein R ' is that the tert-butyl group, methyl, ethyl, pi-allyl or benzyl or RO ' CO are the carbamate groups that solid is supported; Or
C) the two keys in the reduction-type IV chemical compound
R wherein
1-R
9As mentioned above.
Pharmaceutical composition
The compounds of this invention can single dose multiple dose is individually dosed or with medicine acceptable carrier or excipient administering drug combinations.Pharmaceutical composition of the present invention can be with medicine acceptable carrier or diluent and any other known accessory drugs and excipient, according to being disclosed in Remington:The Science and Practice of Pharmacy, the 19th edition, Gennaro compiles, Mack Publishing Co., Easton, PA, the routine techniques preparation of 1995 grades.
Pharmaceutical composition can specifically be prepared with by any suitable pathways administration, described approach is for example oral, in rectum, nasal cavity, lung, part (mouthful cheek and Sublingual), transdermal, the brain pond, intraperitoneal, vagina and parenteral (comprise that subcutaneous, intramuscular, sheath are interior, intravenous and intradermal) approach, the preferred oral approach.It should be understood that described optimization approach will depend on the experimenter's who is treated general health situation and age, the character and the selected active component of the disease of being treated.
Pharmaceutical composition for oral administration comprises solid dosage forms for example capsule, tablet, dragee, pill, lozenge, powder and granule.In the time of suitable, can be prepared into according to approach well known and have coating such as enteric coating, or prepare this solid dosage forms with slow release that active component is provided or prolong sustained release such as release.
The liquid oral dosage form comprises solution, Emulsion, suspensoid, syrup and elixir.
The pharmaceutical composition of parenteral comprises aseptic water and non-water injection solution, dispersion, suspension or Emulsion and with the sterilized powder that before is redeveloped in aseptic injectable solution or the dispersion.The long-acting injection dosage form also is considered within the scope of the present invention.
Other suitable form of medication comprises suppository, spray, ointment, ointment, gel, inhalant, skin patch, implant etc.
Typical oral dose scope from every day about 0.001 to about 100mg/kg body weight, preferably from every day about 0.01 to about 50mg/kg body weight, more preferably from every day about 0.05 to about 10mg/kg body weight, with one or multiple dose 1-3 dosed administration for example.Precise dosage will depend on character and seriousness and any complication for the treatment of and other factor that it will be apparent to those skilled in the art of administration frequency and mode, sex, age, body weight and the experimenter's that treats general health situation, the disease for the treatment of.
Can provide preparation of the present invention easily with unit dosage forms by method known to those skilled in the art.Oral administration every day one or repeatedly the typical flat dosage form of (for example 1-3 time/day) can contain 0.01 to about 1000mg, preferably from about 0.05 to about 500mg, more preferably from about 0.5mg about 200mg extremely.
Parenteral route for example in the intravenous, sheath, intramuscular and similar route of administration, its typical dosage is about half of the dosage that is used for oral administration.
The compounds of this invention is usually with dissociant or with the acceptable salt utilization of its medicine.An example is the acid-addition salts with chemical compound of free alkali purposes.When formula (I) when chemical compound contains free alkali, this salt prepares by free base solution or the suspension that the chemical equivalence thing that can accept acid with medicine is handled formula (I) in a usual manner.Representational example as mentioned above.
As for parenteral, can use aseptic aqueous solution, aqueous propylene glycol solution, vitamin E aqueous solution or the Oleum sesami or the peanut oil solution of formula (I) noval chemical compound.In case of necessity, this aqueous solution should suitably cushion, and at first with capacity saline or glucose liquid diluent etc. is oozed.Described aqueous solution is specially adapted to intravenous, intramuscular, subcutaneous and intraperitoneal administration.Used aseptic aqueous medium all can easily prepare by those skilled in the art's known technology.
Suitable pharmaceutical carrier comprises inert solid diluent or filler, aseptic aqueous solution and various organic solvent.The example of solid carrier is lactose, Gypsum Fibrosum powder, sucrose, cyclodextrin, Pulvis Talci, gelatin, agar, pectin, arabic gum, magnesium stearate, stearic acid and cellulosic lower alkyl ether.The example of liquid-carrier is syrup, Oleum Arachidis hypogaeae semen, olive oil, phospholipid, fatty acid, fatty acid ammonium, polyoxyethylene and water.Similarly, described carrier or diluent can comprise any slow-release material known in the art, for example use separately or glyceryl monostearate or the distearin mixed with wax.Give easily with the various dosage forms of open route of administration that are applicable to then by the pharmaceutical composition that the combination of formula (I) noval chemical compound and drug acceptable carrier is formed.The unit dosage forms that can prepare described preparation easily by the pharmaceutical field known method.
The preparation of the present invention that is applicable to oral administration can provide by discontinuous unit, for example contains the scheduled volume active component separately and wherein can comprise the capsule or the tablet of appropriate excipients.In addition, be applicable to that oral preparation can be powder or granule, the solution in water or on-aqueous liquid or suspensoid or oil-in-water or water in oil emulsion.
If solid carrier is used for oral administration, then preparation can be tablet, places the powder or the pill of hard gelatin capsule, or it can be buccal tablet or lozenge form.
The moving scope of the quantitative change of solid carrier is very big, but is generally from about 25mg to about 1g.
If used is liquid-carrier, then preparation can be syrup, Emulsion, Gelseal or aseptic parenteral solution form, for example water or on-aqueous liquid suspensoid or solution.
The compounds of this invention prepares by following conventional method, or as preparation as described in this patent experimental section:
A) with the chemical compound deprotection of formula II or cracking from the polymer support
R wherein
1-R
9As mentioned above, and R ' is that the tert-butyl group, methyl, ethyl, pi-allyl or benzyl or RO ' CO are the carbamate groups that solid is supported, for example based on the carbamate linking group of Wang resin;
B) with dehydration of formula III chemical compound and optional deprotection simultaneously
R wherein
1-R
9As mentioned above, and R " for hydrogen atom or carbamate groups R ' OCO wherein R ' be that the tert-butyl group, methyl, ethyl, pi-allyl or benzyl or RO ' CO are the carbamate groups of solid support, for example based on the carbamate linking group of Wang resin;
C) the two keys in the reduction-type IV chemical compound
R wherein
1-R
9As mentioned above.
Method deprotection a) is undertaken by those skilled in the art's known standard technology; be specified in textbook Protective Groups in Organic Synthesis T.W.Greene and P.G.M.Wuts; Wiley Interscience, (1991) ISBN 0471623016.Method cracking from the polymer support a), for example from cracking based on the carbamate linking group of Wang resin, can carry out (Zaragoza Tetrahedron Lett.1995 according to the document known steps, 36, .Tetrahedron such as 8677-8678 and Conti Lett.1997,38,2915-2918).
The raw material of formula II can be by many this areas chemist's known method by removing the hydroxyl preparation of formula III chemical compound, for example by using triethyl-silicane/trifluoroacetic acid and ether to close boron trifluoride (referring to Encyclopaedia of Reagents for Organic Synthesis, vol 7, Paquette, e d.; John Wiley﹠amp; Sons, Chichester, 1995,5122-5123).When the raw material of formula II is piperidines, can by the standard step of hydrogenation for example in the Parr device in low pressure (＜3atm.) catalytic hydrogenation is reduced two keys of corresponding tetrahydropyridine and is prepared.
According to method b) with the formula III chemical compound being similar to J.Med.Chem.1997 such as Palmer, 40, the described mode of 1982-1989 is carried out dehydration and optional deprotection simultaneously.
By the 1-bromo-2-phenoxy group benzene of the formula VI of corresponding suitable replacement (R wherein
1-R
9As mentioned above, and G is the bromine or iodine atom) by metal-halogen exchange, add the suitable electrophilic reagent (wherein R ' is as mentioned above) of formula V then, with .J.Med.Chem.1997 such as Palmer, 40, the described similar fashion of 1982-1989. prepares the raw material of formula III.
By the reaction under high temperature in dimethyl formamide (DMF) of phenol (sodium salt for preparing described phenol with sodium hydride in position) that makes suitable replacement and the 1-bromo-2-fluorobenzene that suitably replaces, the 1-bromo-2-phenoxy group benzene that preparation suitably replaces.Also can be by the various amending methods of this method (referring to J.Org Chem.1993 such as for example Schmittlinger, 58,3229-3230; Tetrahedron Lett.1994 such as Beugelmans, 35,5649-5652; J.Org.Claem.1998 such as Sawyer, 63,6338-6343), under the Ullmann condition or through the arylation of phenol and aryl boric acid (Tetrahedron Lett 1998,39 such as Evans, 2937-2940) preparation diaryl ether.Phenol and 1-bromo-2-fluorobenzene are commercially available.
Usually reduce by two keys in the Parr device in low pressure (＜3atm.) catalytic hydrogenation is carried out method c).Can be by the raw material of formula II chemical compound by above-mentioned deprotection preparation formula IV.
Embodiment
On the PESciex API 150EX equipment that is equipped with IonSpray source and Shimadzu LC-8A/SLC-10A LC system, obtain the LC-MS analytical data.Post: 30 * 4.6mm WatersSymmetry C18 post, particle diameter 3.5 μ m; Dicyandiamide solution: A=water/trifluoroacetic acid (100: 0.05), and B=water/acetonitrile/trifluoroacetic acid (5: 95: 0.03); Method: the linear gradient elution of 90%A to 100%B in 4 minutes, flow velocity 2mL/ minute.Purity is measured by the integration of UV (254nm) and micro-evaporative light scattering detector (ELSD trace).Retention time (RT) is with a minute expression.
Preparation type LC-MS-purification carries out on identical device.Post: 50 * 20mm YMCODS-A, particle diameter 5 μ m; Method: the linear gradient elution of 80%A to 100%B in 7 minutes, flow velocity are 22.7mL/ minute.By shunting MS detection carrying out fraction collection.
Be reflected under the microwave environment, in from the SmithSynthesizer of Personal Chemistry, carry out in 2450MHz.
The preparation of intermediate
The preparation of the 2-bromo-that replaces (replacement-phenoxy group) benzene
1-bromo-2-(2,4-dimethyl-phenoxy group)-benzene
With 2, anhydrous dimethyl formamide (DMF) solution (10mL) of 4-xylenol (2.4g) is added drop-wise in sodium hydride (1.0g, in the mineral oil 60%) and dry DMF (25mL) mixture, and the gained mixture was stirred 30 minutes in 100 ℃.The 1-bromo-2-fluorobenzene (3.5g) in the dry DMF (5mL) is added in the described mixture, the gained mixture stirred 6 hours in 150 ℃ again.Subsequently, this mixture is poured on ice/aqueous mixtures, and uses the ether extraction water.Merge organic facies, with the washing of 2N sodium hydroxide, (MgSO
4) drying, filter and vacuum concentration.By flash chromatography purification residue (eluant: heptane), obtain crude product (1.2g, 70% purity) on silica gel.Described crude product need not to be further purified and is used for next step.
Prepare following chemical compound in a similar manner:
1-bromo-2-(4-chlorophenoxy)-benzene
1-bromo-2-(4-fluoro-2-methylphenoxy)-benzene
1-bromo-2-(4-fluorophenoxy)-benzene
1-bromo-2-(4-methylphenoxy)-benzene
1-bromo-2-(4-methoxyl group phenoxy group)-benzene
4-[2-(replacement-phenoxy group)-replace-phenyl]-preparation 4-[2-(2, the 4-dimethyl phenoxy) phenyl of 4-hydroxy piperidine-1-alkyl formate]-4-hydroxy-piperdine-1-t-butyl formate
In-78 ℃, anhydrous tetrahydro furan (THF) solution (3mL) of 1-bromo-2-(2,4-dimethyl-phenoxy group)-benzene (0.7g) is joined nBuLi (in the 1.6M hexane, in anhydrous THF (15mL) solution 2mL).The gained mixture adds anhydrous THF (3mL) solution of 4-oxo-piperidines-1-t-butyl formate (1.0g) subsequently in-78 ℃ of stirrings 1 hour.Mixture in stirring at room 16 hours, is poured on the saturated ammonium chloride solution then.The water ether extraction merges organic facies, and water and salt water washing are with after (MgSO
4) drying, filter and vacuum concentration.By flash chromatography purification residue (eluant: heptane/ethyl acetate 4: 1) obtain crude product (0.55g) on silica gel.Described crude product need not to be further purified and is used for next step.
Prepare following chemical compound in a similar manner:
4-[2-(2, the 4-dimethyl phenoxy) phenyl]-4-hydroxy-piperdine-1-Ethyl formate
4-[2-(4-chlorophenoxy) phenyl]-4-hydroxy-piperdine-1-Ethyl formate
4-[2-(4-fluoro-2-methylphenoxy) phenyl]-4-hydroxy-piperdine-1-t-butyl formate
4-[2-(4-fluoro-2-methylphenoxy) phenyl]-4-hydroxy-piperdine-1-Ethyl formate
4-[2-(4-fluorophenoxy) phenyl]-4-hydroxy-piperdine-1-Ethyl formate
4-[2-(4-methylphenoxy) phenyl]-4-hydroxy-piperdine-1-t-butyl formate
4-[2-(4-methylphenoxy) phenyl]-4-hydroxy-piperdine-1-Ethyl formate
4-[2-(4-methoxyl group phenoxy group) phenyl]-preparation of 4-hydroxy-piperdine-1-t-butyl formate 4-(2-methoxyl group-phenyl)-piperidines-1-Ethyl formate
In 0 ℃, add 28.6mmol triethylamine and 78mmol ethyl chloroformate in the 26mmol 4-in the 100ml anhydrous methylene chloride (2-methoxyphenyl)-piperidines (Maybridge).Described solution in stirred overnight at room temperature, is used 0.5M HCl (125ml) washed twice, then through MgSO
4Dry also evaporation.This degree of purity of production is enough to be used in following step.The preparation of 4-(2-hydroxyl-phenyl)-piperidines-1-Ethyl formate
In 0 ℃, add 48mmol BBr in the 24mmol 4-in the 150ml anhydrous methylene chloride (2-methoxyl group-phenyl)-piperidines-1-Ethyl formate
3Solution in stirred overnight at room temperature, is used 0.5M HCl (125mL) washed twice, then through MgSO
4Dry also evaporation.This degree of purity of production is enough to be used in following step.
Chemical compound of the present invention:
4-[2-(replacement-phenoxy group)-replace-phenyl]-1,2,3, the preparation of 6-tetrahydropyridine
1a, 4-[2-(2, the 4-dimethyl phenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine
With 4-[2-(2, the 4-dimethyl phenoxy) phenyl]-mixture boiled of 4-hydroxy-piperdine-1-t-butyl formate (0.5g) and acetic acid (acidic acid) and concentrated hydrochloric acid (mixing at 3: 1) refluxed 16 hours.With the mixture cooling, pour in the aqueous alkali, use ethyl acetate extraction.Merge organic facies, through (MgSO
4) drying, filter and vacuum concentration.By flash chromatography purification residue (eluant: ethyl acetate/methanol/triethylamine 8: 2: 1), obtain target compound (11mg, 3%) on silica gel.LC/MS (m/z) 280 (MH
+); RT=2.16; Purity (UV, ELSD): 85%, 97%.
Prepare following chemical compound in a similar manner:
1b, 4-[2-(4-chlorophenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine
By 4-[2-(4-chlorophenoxy) phenyl]-4-hydroxy-piperdine-1-Ethyl formate preparation.
LC/MS (m/z) 286 (NH
+); RT=2.10; Purity (UV, ELSD): 85%, 95%; Yield: 33mg (6%).
1c, 4-[2-(4-fluoro-2-methylphenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine
By 4-[2-(4-fluoro-2-methylphenoxy) phenyl]-4-hydroxy-piperdine-1-t-butyl formate preparation.LC/MS (m/z) 284 (MH
+); RT=2.08; Purity (UV, ELSD): 97%, 99%; Yield: 100mg (21%).
1d, 4-[2-(4-fluorophenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine
By 4-[2-(4-fluorophenoxy) phenyl]-4-hydroxy-piperdine-1-Ethyl formate preparation.
LC/MS (m/z) 270 (MH
+); RT=1.93; Purity (UV, ELSD): 87%, 97%; Yield: 45mg (11%).
1e, 4-[2-(4-methylphenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine
By 4-[2-(4-methylphenoxy) phenyl]-4-hydroxy-piperdine-1-t-butyl formate preparation.
LC/MS (m/z) 266 (MH
+); RT=2.04; Purity (UV, ELSD): 98%, 99%; Yield: 250mg (24%).
1f, 4-[2-(4-methoxyl group phenoxy group) phenyl]-1,2,3, the 6-tetrahydropyridine
By 4-[2-(4-methoxyl group phenoxy group) phenyl]-4-hydroxy-piperdine-1-t-butyl formate preparation.LC/MS (m/z) 282 (MH
+); RT=1.95; Purity (UV, ELSD): 79%, 99%; Yield: 14.7mg (19%).
4-[2-(replacement-phenoxy group)-replace-phenyl] preparation of piperidines
Method A
2a, 4-[2-(2, the 4-dimethyl phenoxy) phenyl] piperidines
With 4-[2-(2, the 4-dimethyl phenoxy) phenyl]-mixture that 4-hydroxy-piperdine-1-Ethyl formate (0.6g), dichloromethane (25mL), trimethyl silyl (1mL), trifluoroacetic acid (0.1mL) and ether close boron trifluoride (0.2mL) is in stirring at room 16 hours.The mixture of gained is poured on the aqueous alkali, uses ethyl acetate extraction subsequently.Merge organic facies, through (MgSO
4) drying, filter and vacuum concentration (0.4g).Residue is dissolved in concentrated hydrochloric acid and acetic acid (1: 3) (25mL), boiling reflux 16 hours.Mixture is poured on the aqueous alkali, and uses ethyl acetate extraction subsequently.Merge organic facies,, filter and vacuum concentration through (MgSO4) drying.By flash chromatography purification residue (eluant: ethyl acetate/methanol/triethylamine 8: 2: 2), obtain target compound (10.6mg, 3%) on silica gel.LC/MS (m/z) 282 (MH
+); RT=2.22; Purity (UV, ELSD): 67%, 83%.
Prepare following chemical compound in a similar manner:
2b, 4-[2-(4-chlorophenoxy) phenyl] piperidines
By 4-[2-(4-chlorophenoxy) phenyl]-4-hydroxy-piperdine-1-Ethyl formate preparation.
LC/MS (m/z) 288 (MH
+); RT=2.1; Purity (UV, ELSD): 96%, 97%; Yield: 41mg (7%).
2c, 4-[2-(4-fluoro-2-methylphenoxy) phenyl] piperidines
By 4-[2-(4-fluoro-2-methylphenoxy) phenyl]-4-hydroxy-piperdine-1-Ethyl formate preparation.LC/MS (m/z) 286 (MH
+); RT=2.1; Purity (UV, ELSD): 89%, 99%; Yield: 51mg (8%).
2d, 4-[2-(4-fluorophenoxy) phenyl] piperidines
By 4-[2-(4-fluorophenoxy) phenyl]-4-hydroxy-piperdine-1-Ethyl formate preparation.
LC/MS (m/z) 272 (MH
+); RT=1.97; Purity (UV, ELSD): 91%, 99%; Yield: 7mg (5%).
2e, 4-[2-(4-methylphenoxy) phenyl] piperidines
By 4-[2-(4-methylphenoxy) phenyl]-4-hydroxy-piperdine-1-Ethyl formate preparation.
LC/MS (m/z) 268 (MH
+); RT=2.12; Purity (UV, ELSD): 88%, 93%; Yield: 8mg (1%).
Method B
4-(2-hydroxyl-phenyl)-piperidines-1-Ethyl formate (0.1mmol) is closed with suitable aryl bromide or the iodate of 0.12mmol in 0.5mL 1-methyl-pyrrolidin-2-one.Add CuI catalyst (0.037mmol), after the bottle sealing, put into microwave oven in 220 ℃ of heating 1 hour.Remove the solvent in the sample, and add KOH aqueous solution (3.7mmol), diox and ethanol (99,9%), and with mixture in microwave oven in 130 ℃ of heating 1 hour.Add entry and solid NaCl in the described sample, then use ethyl acetate extraction then.Boil off organic facies, crude product is by preparation type LC-MS purification.SCX post on the described isolating product, and free alkali paid check as DMSO solution.Prepare following chemical compound by this method, measured molecular weight, the HPLC-retention time (RT, minute) that records and UV-and ELSD-purity (%) are listed in table 1.
3a, 4-[2-(4-chloro-2-methyl-phenoxy group)-phenyl]-piperidines
3b, 4-[2-(3-chloro-2-methyl-phenoxy group)-phenyl]-piperidines
3c, 4-[2-(2-chloro-4-methyl-phenoxy group)-phenyl]-piperidines
3d, 4-[2-(2,4-two chloro-phenoxy groups)-phenyl]-piperidines
3e, 4-[2-(benzo [1,3] dioxole-5-base oxygen base)-phenyl]-piperidines
3f, 4-[2-(4-methoxyl group-2-methyl-phenoxy group)-phenyl]-piperidines
3g, 4-[2-(3,4-two chloro-phenoxy groups)-phenyl]-piperidines
3h, 4-[2-(3,4-dimethyl-phenoxy group)-phenyl]-piperidines
3i, 4-[2-(2,3,4,5-tetramethyl-phenoxy group)-phenyl]-piperidines
3j, 4-[2-(4-trifluoromethyl-phenoxy group)-phenyl]-piperidines
3k, 4-[2-(4-methoxyl group-phenoxy group)-phenyl]-piperidines
3l, 4-[2-(2-chloro-4-methoxyl group-phenoxy group)-phenyl]-piperidines
3m, 4-[2-(3,4-dimethoxy-phenoxy group)-phenyl]-piperidines
3n, 4-[2-(4-chloro-3-trifluoromethyl-phenoxy group)-phenyl]-piperidines
The measured molecular weight of table 1., the HPLC-retention time (RT, minute) and UV-and the ELSD-purity (%) that record.
| Chemical compound | M+H + | RT (minute) | UV-purity (%) | ELSD purity (%) |
| 3a | 2.1 | 88.6％ | 99.1％ | |
| 3b | 302.1 | 2.19 | 92.43 | 92.56 |
| 3c | 302.1 | 2.18 | 88.64 | 94.63 |
| 3d | 321.9 | 2.23 | 87.08 | 92.55 |
| 3e | 297.9 | 1.90 | 92.96 | 89.84 |
| 3f | 298.3 | 2.02 | 97.69 | 96.69 |
| 3g | 322.1 | 2.21 | 97.55 | 85.38 |
| 3h | 282.2 | 2.18 | 96.25 | 91.84 |
| 3i | 310.2 | 2.42 | 83.51 | 95.12 |
| 3j | 321.9 | 2.19 | 96.8 | 99.05 |
| 3k | 284.3 | 1.92 | 99.14 | 97.5 |
| 3l | 318.1 | 2.07 | 73.27 | 85.01 |
| 3m | 314.1 | 1.78 | 97.94 | 99.05 |
| 3n | 356.2 | 2.34 | 98.68 | 88.11 |
Picked-up go into rat cortical process contact [
3H]-measurement of 5-HT
The full brain of extracting male Wistar rat (125-225g) removes decerebellation, is added with in the sucrose of 1mM nialamide at 0.32M, with glass/politef homogenizer homogenate.Homogenate is centrifugal 10 minutes in 4 ℃ with 600 * g.Discard precipitation, supernatant centrifugal 55 minutes with 20,000 * g.Final be deposited in homogenate in this test buffer (20 seconds) (0.5mg original structure/hole).With test compound (or buffer) and 10nM[
3H]-5-HT adds in 96 orifice plates jolting in short-term.The composition of test buffer: 123mM NaCl, 4.82mM KCl, 0.973mM CaCl
2, 1.12mM MgSO
4, 12.66mM Na
2HPO
4, 2.97mMNaH
2PO
4, 0.162mM EDTA, 10mM glucose and 1mM ascorbic acid.Buffer 95%O
2/ 5%CO
2In 37 ℃ of oxygenates 10 minutes, pH transferred to 7.4.Add and organize, begin to hatch to testing final volume 0.2mL.With radioligand in 37 ℃ hatch 15 minutes after, sample is directly gone up vacuum filtration at Unifilter GF/C glass fibre filter (soak 1 hour) in 0.1% polyaziridine, and uses the washing of 3 * 0.2ml test buffer immediately.Non-specific uptake is measured with citalopram (10 μ M final concentration).Citalopram is included in all dose-effect curve experiments as a reference.
Picked-up go into rat cortical process contact [
3H] measurement of norepinephrine
The fresh cortex of extracting male Wistar rat (125-225g) places 0.4M sucrose, with glass/politef homogenizer homogenate.Homogenate is centrifugal 10 minutes in 4 ℃ with 600 * g.Discard precipitation, supernatant centrifugal 55 minutes with 20,000 * g.Final be deposited in homogenate in this test buffer (20 seconds) (6mg original structure/mL=4mg/ hole).With test compound (or buffer) and 10nM[
3H]-the 5-norepinephrine adds in 96 orifice plates jolting in short-term.The composition of test buffer: 123mM NaCl, 4.82mM KCl, 0.973mM CaCl
2, 1.12mM MgSO
4, 12.66mM Na
2HPO
4, 2.97mM NaH
2PO
4, 0.162mMEDTA, 10mM glucose and 1mM ascorbic acid.Buffer 95%O
2/ 5%CO
2In 37 ℃ of oxygenates 10 minutes, pH transferred to 7.4.Add and organize, begin to hatch to testing final volume 1mL.With radioligand in 37 ℃ hatch 15 minutes after, sample is directly gone up vacuum filtration at UnifilterGF/C glass fibre filter (soak 1 hour) in 0.1% polyaziridine, and uses the washing of 3 * 1ml test buffer immediately.Non-specific uptake is measured with talsupram (10 μ M final concentration).Duloxetine is included in all dose-effect curve experiments as a reference.
Experimental result shows that The compounds of this invention suppresses norepinephrine and serotonin reuptake transporter, its IC
50Value is lower than 200nM.
Claims (19)
1. compound or its salt of representing by general formula I:
Wherein, dotted line---expression singly-bound or two key;
R
1, R
2, R
3, R
4, R
5Independently be selected from hydrogen, halogen, cyano group, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, hydroxyl, hydroxyl-C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) oxygen base or NR
xR
y, R wherein
xAnd R
YIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base, C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base or NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
zAnd R
wIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base; Or R
xAnd R
yForm the optional first ring of other heteroatomic 3-7 that contains with the nitrogen that connects them; Or
R
2And R
3Form with phenyl ring is condensed together and be selected from
Heterocycle; And R
1, R
4, R
5As above-mentioned definition;
R
6, R
7, R
8, R
9Independently be selected from hydrogen, halogen, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, hydroxyl, hydroxyl-C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) oxygen base or NR
xR
y, R wherein
xAnd R
yIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base, C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base or NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
zAnd R
wIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base; Or R
xAnd R
yForm the optional first ring of other heteroatomic 3-7 that contains with the nitrogen that connects them;
Condition is R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8And R
9In at least one is not a hydrogen.
2. the chemical compound of claim 1, wherein R
1Be selected from hydrogen, halogen, cyano group, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, halo-C
1-6-alkane (alkene/alkynes) base or NR
xR
y, R wherein
xAnd R
yIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base, C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base or NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
zAnd R
wIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base, condition is if R
xAnd R
yOne of be NR
zR
w-C
1-6-alkane (alkene/alkynes) base, then another is selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base; Or R
xAnd R
yForm the optional first ring of other heteroatomic 3-7 that contains with the nitrogen that connects them; Typically, R
1Be selected from hydrogen, C
1-6-alkyl or halogen.
3. each chemical compound of claim 1-2, wherein R
2Be selected from hydrogen, halogen, cyano group, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, halo-C
1-6-alkane (alkene/alkynes) base; Typically, R
2Be selected from hydrogen, C
1-6-alkoxyl, halo-C
1-6-alkyl, C
1-6-alkyl or halogen; More typically, R
2Be selected from hydrogen or C
1-6-alkoxyl.
4. each chemical compound of claim 1-3, wherein R
3Be selected from hydrogen, halogen, cyano group, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, halo-C
1-6-alkane (alkene/alkynes) base; Typically, R
3Be selected from hydrogen, C
1-6-alkyl, C
1-6-alkoxyl, halogen or halo-C
1-6-alkyl; More typically, R
3Be selected from hydrogen, C
1-6-alkyl, C
1-6-alkoxy or halogen.
5. each chemical compound of claim 1-2, wherein R
2And R
3Form together with phenyl ring is condensed and be selected from
Heterocycle.
6. each chemical compound of claim 1-5, wherein R
4Be selected from hydrogen, halogen, cyano group, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, halo-C
1-6-alkane (alkene/alkynes) base; Typically, R
4Be selected from hydrogen, C
1-6-alkoxyl, halo-C
1-6-alkyl, C
1-6-alkyl or halogen; More typically, R
4Be selected from hydrogen or C
1-6-alkoxyl.
7. each chemical compound of claim 1-6, wherein R
5Be selected from hydrogen, halogen, cyano group, C
1-6-alkane (alkene/alkynes) base, C
1-6-alkane (alkene/alkynes) oxygen base, C
1-6-alkane (alkene/alkynes) sulfenyl, halo-C
1-6-alkane (alkene/alkynes) base or NR
xR
y, R wherein
xAnd R
YIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base, C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base or NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
zAnd R
wIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base, condition is if R
xAnd R
yOne of be NR
zR
w-C
1-6-alkane (alkene/alkynes) base, then another is selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base; Or R
xAnd R
yForm the optional first ring of other heteroatomic 3-7 that contains with the nitrogen that connects them; Typically, R
5Be selected from hydrogen, C
1-6-alkyl or halogen.
8. each chemical compound of claim 1-7, wherein R
6Be selected from hydrogen, halogen, C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base; Typically, R
6Be selected from hydrogen or halogen.
9. each chemical compound of claim 1-8, wherein R
7Be selected from hydrogen, halogen, C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base; Typically, R
7Be selected from hydrogen or halogen.
10. each chemical compound of claim 1-9, wherein R
8Be selected from hydrogen, halogen, C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base or NR
xR
y, R wherein
xAnd R
yIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base, C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base or NR
zR
w-C
1-6-alkane (alkene/alkynes) base, wherein R
zAnd R
wIndependently be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base, condition is if R
xAnd R
yOne of be NR
zR
w-C
1-6-alkane (alkene/alkynes) base, then another is selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, cyano group-C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base or C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base; Or R
xAnd R
yForm the optional first ring of other heteroatomic 3-7 that contains with the nitrogen that connects them; Typically, R
8Be selected from hydrogen, halo-C
1-6-alkyl, C
1-6-alkyl or halogen.
11. each chemical compound of claim 1-10, wherein R
9Be selected from hydrogen, halogen, C
1-6-alkane (alkene/alkynes) base, halo-C
1-6-alkane (alkene/alkynes) base; Typically, R
9Be selected from hydrogen.
12. each chemical compound of claim 1-11, wherein dotted line----expression singly-bound.
13. each chemical compound of claim 1-11, the wherein two keys of dotted line----expression.
14. each chemical compound of claim 1-13, the chemical compound of its Chinese style I have 1-4 to be selected from R on phenyl ring
1-R
9Any be not the substituent group of hydrogen, all the other substituent groups are hydrogen.
15. the chemical compound of claim 1, described chemical compound is
1) 4-[2-(2, the 4-dimethyl phenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
2) 4-[2-(4-chlorophenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
3) 4-[2-(4-fluoro-2-methylphenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
4) 4-[2-(4-fluorophenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
5) 4-[2-(4-methylphenoxy) phenyl]-1,2,3, the 6-tetrahydropyridine,
6) 4-[2-(4-methoxyl group phenoxy group) phenyl]-1,2,3, the 6-tetrahydropyridine,
7) 4-[2-(2, the 4-dimethyl phenoxy) phenyl] piperidines,
8) 4-[2-(4-chlorophenoxy) phenyl] piperidines,
9) 4-[2-(4-fluoro-2-methylphenoxy) phenyl] piperidines,
10) 4-[2-(4-fluorophenoxy) phenyl] piperidines,
11) 4-[2-(4-methylphenoxy) phenyl] piperidines,
12) 4-[2-(4-chloro-2-methyl-phenoxy group)-phenyl]-piperidines,
13) 4-[2-(3-chloro-2-methyl-phenoxy group)-phenyl]-piperidines,
14) 4-[2-(2-chloro-4-methyl-phenoxy group)-phenyl]-piperidines,
15) 4-[2-(2,4-two chloro-phenoxy groups)-phenyl]-piperidines,
16) 4-[2-(benzo [1,3] dioxole-5-base oxygen base)-phenyl]-piperidines,
17) 4-[2-(4-methoxyl group-2-methyl-phenoxy group)-phenyl]-piperidines,
18) 4-[2-(3,4-two chloro-phenoxy groups)-phenyl]-piperidines,
19) 4-[2-(3,4-dimethyl-phenoxy group)-phenyl]-piperidines,
20) 4-[2-(2,3,4,5-tetramethyl-phenoxy group)-phenyl]-piperidines,
21) 4-[2-(4-trifluoromethyl-phenoxy group)-phenyl]-piperidines,
22) 4-[2-(4-methoxyl group-phenoxy group)-phenyl]-piperidines,
23) 4-[2-(2-chloro-4-methoxyl group-phenoxy group)-phenyl]-piperidines,
24) 4-[2-(3,4-dimethoxy-phenoxy group)-phenyl]-piperidines,
25) 4-[2-(4-chloro-3-trifluoromethyl-phenoxy group)-phenyl]-piperidines,
Or the acceptable salt of its medicine.
16. a pharmaceutical composition, described pharmaceutical composition comprise each chemical compound or the acceptable acid-addition salts of its medicine of claim 1-15, and at least a medicine acceptable carrier or diluent.
17. each chemical compound or its medicine of claim 1-15 can be accepted the purposes of acid-addition salts on the medicine of preparation treatment affective disorder, described affective disorder for example is psychentonia obstacle, obsession, Panic-stricken, panic attack, specific phobias, social fear and square fear after depressed, as to comprise generalized anxiety disorder anxiety disorder, social phobia, the wound.
18. a treatment comprises the method for affective disorder in people's the animal body of work, described affective disorder for example is psychentonia obstacle, obsession, Panic-stricken, panic attack, specific phobias, social fear and square fear after depressed, as to comprise generalized anxiety disorder anxiety disorder, social phobia, the wound, and described method comprises each the chemical compound or the acceptable acid-addition salts of its medicine of claim 1-15 for the treatment of effective dose.
19. each chemical compound of claim 1-15, described chemical compound is as medicine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200300519 | 2003-04-04 | ||
| DKPA200300519 | 2003-04-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1767829A true CN1767829A (en) | 2006-05-03 |
Family
ID=36701494
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200480008884XA Pending CN1767829A (en) | 2003-04-04 | 2004-04-02 | 4-(2-phenyloxyphenyl)-piperidine or -1,2,3,6-tetrahydropyridine derivatives as serotonin reuptake inhibitors. |
Country Status (8)
| Country | Link |
|---|---|
| KR (1) | KR20050119682A (en) |
| CN (1) | CN1767829A (en) |
| AR (1) | AR043966A1 (en) |
| CL (1) | CL2004000726A1 (en) |
| EA (1) | EA009417B1 (en) |
| IS (1) | IS7901A (en) |
| UA (1) | UA81469C2 (en) |
| ZA (1) | ZA200505031B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102216272A (en) * | 2008-11-14 | 2011-10-12 | 施万制药 | 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds |
| WO2015090160A1 (en) * | 2013-12-17 | 2015-06-25 | 江苏恩华药业股份有限公司 | Compound for preparing 4-(2-(4-methylphenylthio))phenylpiperidine, and preparation method and use thereof |
| CN105294554A (en) * | 2015-11-18 | 2016-02-03 | 乳源瑶族自治县大众药品贸易有限公司 | Phenylpiperazine derivative, use method and uses thereof |
| CN105348204A (en) * | 2015-11-18 | 2016-02-24 | 乳源瑶族自治县大众药品贸易有限公司 | 1-heterocyclyl-2-(heteroarylthio) benzene derivative and use method and application |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101613347B (en) * | 2008-06-23 | 2012-07-04 | 中国人民解放军军事医学科学院毒物药物研究所 | Amine compound and medical application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4241071A (en) * | 1977-01-27 | 1980-12-23 | American Hoechst Corporation | Antidepressant (α-phenyl-2-tolyl)azacycloalkanes |
| US4198417A (en) * | 1979-01-10 | 1980-04-15 | American Hoechst Corporation | Phenoxyphenylpiperidines |
| KR100524159B1 (en) * | 1999-10-13 | 2005-10-25 | 화이자 프로덕츠 인코포레이티드 | Biaryl ether derivatives useful as monoamine reuptake inhibitors |
| UA81749C2 (en) * | 2001-10-04 | 2008-02-11 | Х. Луннбек А/С | Derivated of phenylpiperazine as serotonin reuptake inhibitorS |
-
2004
- 2004-04-02 EA EA200501580A patent/EA009417B1/en not_active IP Right Cessation
- 2004-04-02 KR KR1020057018912A patent/KR20050119682A/en not_active Application Discontinuation
- 2004-04-02 ZA ZA200505031A patent/ZA200505031B/en unknown
- 2004-04-02 UA UAA200509295A patent/UA81469C2/en unknown
- 2004-04-02 CL CL200400726A patent/CL2004000726A1/en unknown
- 2004-04-02 AR ARP040101132A patent/AR043966A1/en unknown
- 2004-04-02 CN CNA200480008884XA patent/CN1767829A/en active Pending
-
2005
- 2005-06-20 IS IS7901A patent/IS7901A/en unknown
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102216272A (en) * | 2008-11-14 | 2011-10-12 | 施万制药 | 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds |
| CN102216271A (en) * | 2008-11-14 | 2011-10-12 | 施万制药 | Crystalline form of a 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compound |
| CN102216271B (en) * | 2008-11-14 | 2013-09-25 | 施万制药 | Crystalline form of a 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compound |
| CN102216272B (en) * | 2008-11-14 | 2014-02-05 | 施万制药 | 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds |
| WO2015090160A1 (en) * | 2013-12-17 | 2015-06-25 | 江苏恩华药业股份有限公司 | Compound for preparing 4-(2-(4-methylphenylthio))phenylpiperidine, and preparation method and use thereof |
| CN104710345B (en) * | 2013-12-17 | 2017-09-05 | 江苏恩华药业股份有限公司 | For preparing 4（2‑（4 aminomethyl phenyl sulfenyls））Compound, its preparation method and the application of Phenylpiperidine |
| CN105294554A (en) * | 2015-11-18 | 2016-02-03 | 乳源瑶族自治县大众药品贸易有限公司 | Phenylpiperazine derivative, use method and uses thereof |
| CN105348204A (en) * | 2015-11-18 | 2016-02-24 | 乳源瑶族自治县大众药品贸易有限公司 | 1-heterocyclyl-2-(heteroarylthio) benzene derivative and use method and application |
| CN105348204B (en) * | 2015-11-18 | 2018-09-14 | 乳源瑶族自治县大众药品贸易有限公司 | 1- heterocycles -2- (Heteroarylthio) benzene derivatives and its application method and purposes |
Also Published As
| Publication number | Publication date |
|---|---|
| IS7901A (en) | 2005-06-20 |
| EA009417B1 (en) | 2007-12-28 |
| AR043966A1 (en) | 2005-08-17 |
| KR20050119682A (en) | 2005-12-21 |
| EA200501580A1 (en) | 2006-04-28 |
| UA81469C2 (en) | 2008-01-10 |
| ZA200505031B (en) | 2006-09-27 |
| CL2004000726A1 (en) | 2005-05-20 |
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