ZA200505031B - 4-(2-Phenyloxyphenyl)-piperidine or -1,2,3,6-tetrahy-dropyridine derivatives as serotonin reuptake inhibitors - Google Patents

4-(2-Phenyloxyphenyl)-piperidine or -1,2,3,6-tetrahy-dropyridine derivatives as serotonin reuptake inhibitors Download PDF

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ZA200505031B
ZA200505031B ZA200505031A ZA200505031A ZA200505031B ZA 200505031 B ZA200505031 B ZA 200505031B ZA 200505031 A ZA200505031 A ZA 200505031A ZA 200505031 A ZA200505031 A ZA 200505031A ZA 200505031 B ZA200505031 B ZA 200505031B
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alk
hydrogen
compound
phenyl
cycloalk
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ZA200505031A
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Benny Bang-Andersen
Friedrich Kroll
Jan Kehler
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Lundbeck & Co As H
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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
    • 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
    • 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
    • C07D211/68—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • 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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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Hydrogenated Pyridines (AREA)

Description

Rr WO 2004/087155 PCT/DK2004/000241 4-(2-Phenyloxyphenyl)-piperidine or -1,2,3,6-tetrahydropyridine derivatives as serotonin reuptake inhibitors
The present invention relates to novel compounds which are serotonin reuptake ’ 5s inhibitors and as such effective in the treatment of for example depression and anxiety.
Background of the invention
Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) have become first choice therapeutics in the treatment of depression, certain forms of anxiety and social phobias, because they are effective, well tolerated and have a favourable safety profile compared to the classic tricyclic antidepressants.
However, clinical studies on depression indicate that non-response to SSRIs is substantial, up to 30%. Another, often neglected, factor in antidepressant treatment 1S compliance, which has a rather profound effect on the patient’s motivation to continue pharmacotherapy.
First of all, there is the delay in therapeutic effect of SSRIs. Sometimes symptoms even worsen during the first weeks of treatment. Secondly, sexual dysfunction is a side effect common to all SSRIs. Without addressing these problems, real progress in the pharmacotherapy of depression and anxiety disorders is not likely to happen.
The combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition on depression is explored in clinical studies of compounds such as
Duloxetine (Wong, Duloxetine (L'Y-248686): an inhibitor of serotonin and noradrenaline uptake and an antidepressant drug candidate Expert Opinion on
Investigational Drugs, 1998, 7, 10, 1691-1699) and Venlafaxine (Khan-A et al, . 30 Venlafaxine in depressed outpatients Psychopharmacology Bulletin, 1991, 27, 141- 144).
The present invention provides novel compounds which posses the combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition for the treatment of
(tg WO 2004/087155 PCT/DK2004/000241 affective disorders, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive i disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia. . 5
Summary of the invention
The present invention provides compounds of the general formula I 4
R
3
R? R 2
O R
HN R’ . 6 _. - 0 9 7
R R
8
R wherein the dotted line, R!, R?, R3, RY R®, RS, rR, R®, and R? are as defined below.
The invention provides a compound according to the above for use as a medicament.
The invention provides a pharmaceutical composition comprising a compound according to the above or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.
The invention provides the use of a compound according to the above or a pharmaceutically acceptable acid addition salt thereof for the preparation of a - medicament for the treatment of affective disorders, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia.
The invention provides a method for the treatment of an affective disorders, such as depression, anxiety disorders including general anxiety disorder, social anxiety . disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia in a living animal body, . 5 including a human, comprising administering a therapeutically effective amount of a compound according to the above or a pharmaceutically acceptable acid addition salt thereof.
Definition of substituents
Halogen means fluoro, chloro, bromo or iodo.
The expression C,¢-alk(en/yn)yl means a C;.-alkyl, Cs.¢-alkenyl or a Cys-alkynyl group.
The term C,.¢ alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1-propyl, 2- propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
Similarly, Ca alkenyl and C,.¢ alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one triple bond respectively, including but not limited to ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
The terms C;¢-alk(en/yn)yloxy, C,.s alk(en/yn)ylsulfanyl, hydroxy-C;.¢-alk(en/yn)yl, halo-C,_¢-alk(en/yn)yl, cyano-C,¢-alk(en/yn)yl, NR*R“-Ci¢-alk(en/yn)yl, C.¢- alk(en/yn)yloxy-C,¢-alk(en/yn)yl and halo-C,¢-alk(en/yn)yloxy designate such - groups in which the C-alk(en/yn)yl are as defined above. Halo means halogen.
NR*R"-C_-alk(en/yn)yl designate the group . REL “ rv-N=Cygalk(en/ynyyl fa WO 2004/087133 PCT/DK2004/000241
The term Css cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, . etc. . 5 The term Csg cycloalkenyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms and including one double bond.
In the term Csg-cycloalk(en)yl-Cig-alk(en/yn)yl, Cssg-cycloalk(en)yl and C.4- alk(en/yn)yl are as defined above.
The term 3-7-membered ring optionally containing one further heteroatom, such as N,
O, or S, as used herein refers to ring systems such as 1-morpholinyl, 1-piperidinyl, 1- azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, all of which may be further substituted with a group selected from a Cyg¢-alk(en/yn)yl, hydroxy, hydroxy-C,.¢-alk(en/yn)yl, C,¢-alk(en/yn)yloxy-
C,.¢-alk(en/yn)yl .
Description of the invention
The present invention relates to 4-(2-phenyloxyphenyl)-piperidine or -1,2,3,6- tetrahydropyridine derivatives which are serotonin reuptake inhibitors and as such effective in the treatment of for example depression and anxiety. In particular the piperidines are also good norepinephrine uptake inhibitors.
Accordingly the present invention relates to a compound represented by the general formula I bi WO 2004/087155 PCT/DK2004/000241
R*
RS Rr
HN rR’ - R°® (1
R® R’
RS wherein the dotted line ---- indicates a single bond or a double bond; 5
R',R% R3 R* R® are independently selected from hydrogen, halogen, cyano, C;.- alk(en/yn)yl, C,_¢-alk(en/yn)yloxy, C,_¢-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C,.¢- alk(en/yn)yl, halo-C,.¢-alk(en/yn)yl, halo-C;_¢-alk(en/yn)yloxy, or NR*R* wherein R* and RY are independently selected from hydrogen, Ci.¢-alk(en/yn)yl, cyano-C.¢- alk(en/yn)yl, Csg-cycloalk(en)yl, Cs.g-cycloalk(en)yl-C; s-alk(en/yn)yl, or NR*R%-C,. s-alk(en/yn)yl, wherein R* and RY are independently selected from hydrogen, Ci_¢- alk(en/yn)yl, Csg-cycloalk(en)yl, or C;.g-cycloalk(en)yl-C.¢-alk(en/yn)yl; or R* and
RY together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; or
R” and R® together form a heterocycle fused to the phenyl ring selected from _-0 _ ; and R', RY R?® are as defined above; - RS, R’, RR’ are independently selected from hydrogen, halogen, C,.¢-alk(en/yn)yl, Cj_¢-alk(en/yn)yloxy, Cis-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C, ¢-alk(en/ym)yl, ) halo-C,_¢-alk(en/yn)yl, halo-C,_¢-alk(en/yn)yloxy, or NR*RY wherein R* and R” are independently selected from hydrogen, C,.s-alk(en/yn)yl, cyano-C,.¢-alk(en/yn)yl, Cs. s-cycloalk(en)yl, Cs.s-cycloalk(en)yl-C;s-alk(en/yn)yl, or NR’R"-C ¢-alk(en/yn)yl, wherein R” and RY are independently selected from hydrogen, C,-alk(en/yn)yl, C;.g-
cycloalk(en)yl, or Cs_g-cycloalk(en)yl-C,_¢-alk(en/yn)yl; or R* and RY together with the nitrogen to which they are attached form a 3-7-membered ring which optionally . contains one further heteroatom; provided that at least one of RY R%L RRR, RS RY, R®, and R’ is different from ) 5 hydrogen; or a salt thereof.
In one embodiment of the compound of formula I, R! is selected from hydrogen, halogen, cyano, C).s-alk(en/yn)yl, C,_¢-alk(en/yn)yloxy, Ci.s-alk(en/yn)ylsulfanyl, halo-C,s-alk(en/yn)yl, or NR*R” wherein R* and R” are independently selected from hydrogen, C,_-alk(en/yn)yl, cyano-C;¢-alk(en/yn)yl, Cs.g-cycloalk(en)yl, Cs.s- cycloalk(en)yl-C,¢-alk(en/yn)yl, or NR*R"-C.s-alk(en/yn)yl, wherein R* and R™ are independently selected from hydrogen, C.¢-alk(en/yn)yl, Cs s-cycloalk(en)yl, or Css- cycloalk(en)yl-C,.¢-alk(en/yn)yl, provided that if one of R* and R” is NR’R"-Ci.4- alk(en/yn)yl then the other is selected from hydrogen, C,-alk(en/yn)yl, cyano-C.¢- alk(en/yn)yl, Cs.g-cycloalk(en)yl, or Cs.s-cycloalk(en)yl-Ci.¢-alk(en/yn)yl; or R* and
RY together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom. In a further embodiment of the compound of formula I R! is selected from hydrogen, halogen, cyano, Ci.¢- alk(en/yn)yl, Ci_¢-alk(en/yn)yloxy, C,.c-alk(en/yn)ylsulfanyl, halo-C,_¢-alk(en/yn)yl.
In a further embodiment R' is NR*R” wherein R* and R” are independently selected from hydrogen, C).s-alk(en/yn)yl, cyano-C,.¢-alk(en/yn)yl, C3.s-cycloalk(en)yl, Cs.s- cycloalk(en)yl-C,.¢-alk(en/yn)yl, such as hydrogen, cyanomethyl, Ci.¢-alk(en/yn)yl. In a farther embodiment R' is NR*RY wherein R* is NR*R"-C.s-alk(en/yn)yl, wherein R* and RY are independently selected from hydrogen, C.¢-alk(en/yn)yl, Cs.s- cycloalk(en)yl, or Cs.g-cycloalk(en)yl-Cj.¢-alk(en/yn)yl, and RY is selected from hydrogen, C,.¢-alk(en/yn)yl, cyano-C).s-alk(en/yn)yl, Cs.s-cycloalk(en)yl, or Cs.g- ’ cycloalk(en)yl-Cy.¢-alk(en/yn)yl. In a further embodiment R'is NR*R” wherein R* and RY together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom, such as 1-morpholinyl], 1- piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1- pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or more selected from a C,_¢-alk(en/yn)yl, hydroxy, hydroxy-Ci_¢-alk(en/yn)yl, C.¢-
alk(en/yn)yloxy-C,¢-alk(en/yn)yl, e.g. one or two selected from hydroxy, hydroxy-C;- o-alkyl, C;_¢-alkyloxy-C,.¢-alkyl, Ci ¢-alkyl, in particular one or two selected from . hydroxy, methoxy-methyl, methyl. Typically, R' is selected from hydrogen; halogen; cyano; C¢-alkyl; C_¢-alkyloxy; C).¢-alkylsulfanyl; halo-C;¢-alkyl; NR*RY wherein : 5 R"and R” are independently selected from hydrogen, C;¢-alkyl, cyanomethyl; NR*R’ wherein R” is selected from hydrogen, or C;¢-alkyl, and R* is NR’R"-C.¢- alk(en/yn)yl wherein R” and RY are independently selected from hydrogen, or Ci.¢- alkyl; 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1- imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrroly! or pyrazolyl, optionally substituted with one or two selected from hydroxy, hydroxy-C;_¢-alkyl, Ci.¢-alkyloxy-C,.¢-alkyl,
Ci6-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl.
To further illustrate without limiting the invention an embodiment of R' is hydrogen; another embodiment of R' is Ci-¢-alkyl, such as methyl; a further embodiment of R'is halogen, such as fluoro, or chloro.
In a further embodiment of the compound of formula I, R? is selected from hydrogen, halogen, cyano, C;_¢-alk(en/yn)yl, C,_¢-alk(en/yn)yloxy, C1 o-alk(en/yn)ylsulfanyl, halo-C,.¢-alk(en/yn)yl. Typically, R* is selected from hydrogen, halogen, cyano, Ci.¢- alkyl, C,_s-alkyloxy, C,.¢-alkylsulfanyl, halo-C;¢-alkyl. To further illustrate without limiting the invention an embodiment of R? is hydrogen; another embodiment of R*is
C,.s-alkoxy, such as methoxy; another embodiment of R%is halo-C,.¢-alkyl, such as trifluoromethyl; another embodiment of R?is Ci.¢-alkyl, such as methyl; another embodiment of R? is halogen, such as chloro.
In a further embodiment of the compound of formula I, R? is selected from hydrogen, halogen, cyano, C.¢-alk(en/yn)yl, Ci_s-alk(en/yn)yloxy, C,.¢-alk(en/yn)ylsulfanyl, halo-C;.¢-alk(en/yn)yl. Typically, R® is selected from hydrogen, halogen, cyano, C.¢- . alkyl, C_¢-alkyloxy, C.¢-alkylsulfanyl, halo-C;.¢-alkyl. To further illustrate without limiting the invention an embodiment of R? is hydrogen, another embodiment of R® is
CC) ¢-alkyl, such as methyl; a further embodiment of R? is C,¢-alkoxy, such as methoxy; a further embodiment of R® is halogen, such as chloro, or fluoro; another embodiment of R? is halo-C,¢-alkyl, such as trifluoromethyl.
In a further embodiment of the compound of formula I, R* and R’ together form a heterocycle fused to the phenyl ring selected from : J
I
In a further embodiment of the compound of formula I, R* is selected from hydrogen, halogen, cyano, C;¢-alk(en/yn)yl, Ci_s-atk(en/yn)yloxy, Ci-all(en/yn)ylsulfanyl, halo-C.¢-alk(en/yn)yl. Typically, R* is selected from hydrogen, halogen, cyano, Ci.- alkyl, C,_¢-alkyloxy, C;.c-alkylsulfanyl, halo-C,¢-alkyl. To further illustrate without limiting the invention an embodiment of R? is hydrogen; another embodiment of R'is Ci¢-alkoxy, such as methoxy; another embodiment of R*is halo-C,_¢-alkyl, such as trifluoromethyl; another embodiment of R* is C,6-alkyl, such as methyl; another embodiment of R* is halogen, such as chloro.
In a further embodiment of the compound of formula I, R’ is selected from hydrogen, halogen, cyano, Cj.¢-alk(en/yn)yl, Ci_¢-alk(en/yn)yloxy, Ci.¢-alk(en/yn)ylsulfanyl, halo-C, ¢-alk(en/yn)yl, or NR*R” wherein R* and R” are independently selected from hydrogen, C,.s-alk(en/yn)yl, cyano-Cy.¢-alk(en/yn)yl, Cs.s-cycloalk(en)yl, Css- cycloalk(en)yl-C;¢-alk(en/yn)yl, or NR*R"-C\.¢-alk(en/yn)yl, wherein R* and RY are independently selected from hydrogen, C,.¢-alk(en/yn)yl, Cs_g-cycloalk(en)yl, or Cs_s- cycloalk(en)yl-C,s-alk(en/yn)yl, provided that if one of R* and R” is NR*R%-Ci.¢- alk(en/yn)yl then the other is selected from hydrogen, Ci.s-alk(en/yn)yl, cyano-C¢- alk(en/yn)yl, Css-cycloalk(en)yl, or Cs.g-cycloalk(en)yl-Ci.¢-alk(en/yn)yl; or R* and
RY together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom. In a further embodiment of the compound of formula I R’ is selected from hydrogen, halogen, cyano, Ci- ) alk(en/yn)yl, Cis-alk(en/yn)yloxy, Ci.¢-alk(en/yn)ylsulfanyl, halo-C,.¢-alk(en/yn)yl.
In a further embodiment R> is NR*RY wherein R* and R” are independently selected : from hydrogen, C ¢-alk(en/yn)yl, cyano-Ci¢-alk(en/yn)yl, Cs.g-cycloalk(en)yl, Css- cycloalk(en)yl-C,.¢-alk(en/yn)yl, such as hydrogen, cyanomethyl, C;.¢-alk(en/yn)yl. In a further embodiment R® is NR*RY wherein R* is NR*R"-C,s-alk(en/yn)yl, wherein R® and RY are independently selected from hydrogen, Cis-alk(en/yn)yl, Ci.g-
cycloalk(en)yl, or Cs.3-cycloalk(en)yl-Ci_¢-alk(en/yn)yl, and R” is selected from hydrogen, Ci.s-alk(en/yn)yl, cyano-C,-alk(en/yn)yl, Css-cycloalk(en)yl, or Cs.5- cycloalk(en)yl-Cy.g-alk(en/yn)yl. In a further embodiment R® is NR*RY wherein R* and RY together with the nitrogen to which they are attached form a 3-7-membered . 5 ring which optionally contains one further heteroatom, such as 1-morpholinyl, 1- piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1- pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or more selected from a C).¢-all(en/yn)yl, hydroxy, hydroxy-Ci.s-alk(en/yn)yl, Ci.¢- alk(en/yn)yloxy-Cj_¢-alk(en/yn)yl, e.g. one or two selected from hydroxy, hydroxy-Cj. ¢-alkyl, C ¢-alkyloxy-Ci alkyl, C,-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl. Typically, R’ is selected from hydrogen; halogen; cyano; C,¢-alkyl, Ci_¢-alkyloxy; Ci.¢-alkylsulfanyl; halo-C,.¢-alkyl; NR*R’ wherein
R* and R” are independently selected from hydrogen, C;.¢-alkyl, cyanomethyl, NR'R” wherein RY is selected from hydrogen, or Ci-alkyl, and R* is NR’R"-C).¢- alk(en/yn)yl wherein R” and R" are independently selected from hydrogen, or Ci.¢- alkyl; 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1- imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or two selected from hydroxy, hydroxy-Ci.¢-alkyl, Ci.¢-alkyloxy-Ci.¢-alkyl,
Ci.¢-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl.
To further illustrate without limiting the invention an embodiment of R® is hydrogen; another embodiment of R® is C;.¢-alkyl, such as methyl; a further embodiment of R’ is halogen, such as chloro, or fluoro.
In a further embodiment of the compound of formula I RS is selected from hydrogen, halogen, C-alk(en/yn)yl, halo-C;.¢-alk(en/yn)yl. Typically, RS is selected from hydrogen, halogen, C,.¢-alkyl, halo-C,¢-alkyl. To further illustrate without limiting the invention an embodiment of R® is hydrogen; another embodiment of RC is . halogen, such as fluoro. : 30 In a further embodiment of the compound of formula I, R’ is selected from hydrogen, halogen, C).¢-alk(en/yn)yl, halo-C,_¢-alk(en/yn)yl. Typically, R’ is selected from hydrogen, halogen, C;_¢-alkyl, halo-C,.¢-alkyl. To further illustrate without limiting
~ WO 2004/087155 PCT/DK2004/000241 the invention an embodiment of R’ is hydrogen; another embodiment of R” is halogen, such as fluoro.
In a further embodiment of the compound of formula I, R® is selected from hydrogen, : 5 halogen, C¢-alk(en/yn)yl, halo-C, ¢-alk(en/yn)yl, or NR*R* wherein R* and R” are independently selected from hydrogen, C,.¢-alk(en/yn)yl, cyano-C,.s-alk(en/yn)yl, Cs. g-cycloalk(en)yl, C;_g-cycloalk(en)yl-C.¢-alk(en/yn)yl, or NR*R"-C,_¢-alk(en/yn)yl, wherein R* and R" are independently selected from hydrogen, C,.¢-alk(en/yn)yl, Cs.¢- cycloalk(en)yl, or Cs.g-cycloalk(en)yl-C,.¢-alk(en/yn)yl, provided that if one of R* and 10 R”is NR’R"-C,_s-alk(en/yn)yl then the other is selected from hydrogen, C;.4- alk(en/yn)yl, cyano-C,¢-alk(en/yn)yl, C;_s-cycloalk(en)yl, or Cs.g-cycloalk(en)yl-C;_s- all(en/yn)yl; or R* and RY together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom. In a further embodiment of the compound of formula I R%is selected from hydrogen, halogen, C,. s-alk(en/yn)yl, halo-C,-alk(en/yn)yl. In a further embodiment R? is NR*R’ wherein
R* and RY are independently selected from hydrogen, C;_¢-alk(en/yn)yl, cyano-C, ¢- alk(en/yn)yl, C;g-cycloalk(en)yl, C;.s-cycloalk(en)yl-C, ¢-alk(en/yn)yl, such as hydrogen, cyanomethyl, C,.¢-alk(en/yn)yl. In a further embodiment R® is NR*RY wherein R* is NR*R"¥-C, s-alk(en/yn)yl, wherein R* and R" are independently selected from hydrogen, C,.¢-alk(en/yn)yl, Cs.s-cycloalk(en)yl, or Csg-cycloalk(en)yl-Ci.s- alk(en/yn)yl, and R” is selected from hydrogen, C).¢-alk(en/yn)yl, cyano-Ci.s- alk(en/yn)yl, Cs.s-cycloalk(en)yl, or Cs.g3-cycloalk(en)yl-C,_¢-alk(en/yn)yl. In a further embodiment R® is NR*R” wherein R* and RY together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom, such as 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1- homopiperazinyl, 1-imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or more selected from a C,_¢-alk(en/yn)yl, hydroxy, . hydroxy-C,.¢-alk(en/yn)yl, C,.¢-alk(en/yn)yloxy-C,.¢-alk(en/yn)yl, e.g. one or two selected from hydroxy, hydroxy-C,_-alkyl, C,.¢-alkyloxy-C,.¢-alkyl, Ci¢-alkyl, in ’ 30 particular one or two selected from hydroxy, methoxy-methyl, methyl. Typically, R® is selected from hydrogen; halogen; cyano; C;_¢-alkyl; C1_¢-alkyloxy; Cis alkylsulfanyl; halo-C,¢-alkyl; NR*RY wherein R* and R” are independently selected from hydrogen, C).¢-alkyl, cyanomethyl; NR*RY wherein R? is selected from
~ WO 2004/087155 PCT/DK2004/000241 hydrogen, or Ci_¢-alkyl, and R* is NR*R"-C, ¢-alk(en/yn)yl wherein R* and RY are independently selected from hydrogen, or C,.¢-alkyl; 1-morpholinyl, 1-piperidinyl, 1- } azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or two selected from hydroxy, . 5 hydroxy-C,¢-alkyl, C)-alkyloxy-Ci.¢-alkyl, C|¢-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl. To further illustrate without limiting "the invention an embodiment of R® is hydrogen; another embodiment of RS is halogen, such as fluoro, or bromo; a further embodiment of R® is Ci-alkyl, such as methyl; a further embodiment of R® is halo-C,¢-alkyl, such as CFs.
In a further embodiment of the compound of formula I, R® is selected from hydrogen, halogen, C_¢-alk(en/yn)yl, halo-C.¢-alk(en/yn)yl. Typically, R’ is selected from hydrogen, halogen, C,.s-alkyl, halo-C,¢-alkyl. To further illustrate without limiting the invention an embodiment of R® is hydrogen.
In a further embodiment of the compound of formula I, the dotted line ---- indicates a single bond.
In a further embodiment of the compound of formula I, the dotted line ---- indicates a double bond.
Typically, the compound of formula I has at least one substituent in the phenyl ring(s), selected from any one of R'-R’, which is different from hydrogen, such as 1, 2, 3, or 4 substituents in the phenyl ring(s), selected from any one of R'-R®, which is/are different from hydrogen, and the remaining substituents are hydrogen. Thus, in a further embodiment 1 substituent selected from any one of R'-R’, which is different from hydrogen, is present in either of the two phenyl rings, such as 1 substituent . selected from R'-R? , or the substituent is selected from R®-R’. In a further embodiment 2 substituents selected from R'-R®, which are different from hydrogen, : 30 are present in either of the two phenyl rings, such as 1 substituent selected from R'-
R®, and the other selected from R®-R’, or both substituents are selected from R!-R® ; In this respect R? and R® may be taken together to form the heterocycle as defined above.
In a further embodiment 3 substituents selected from R'-R’, which are different from hydrogen, are present in either of the two phenyl rings, such as 2 substituents selected from R'-R>, and the last substituent is selected from RR’. In each embodiment, as mentioned the remaining substituents are hydrogen. To illustrate this further without limiting the invention, some typical embodiments are outlined hereafter.
Thus, in a further embodiment of the compound of formula I one substituent is present which is R? as defined above, except hydrogen. In a further embodiment of the compound of formula I one substituent is present which is R? as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R’ and R®, wherein R> and R® are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being
R’ and R®, wherein R® and R% are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R* and
R’, wherein R’ and R” are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R! and
R’, wherein R' and R? are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R? and
R?, wherein R? and R® are as defined above, except hydrogen, in this respect R? and
R’ may be taken together to form the heterocycle as defined above. In a further embodiment of the compound of formula I three substituents are present being R', R® and R®, wherein R', R® and R® are as defined above, except hydrogen. In each embodiment, as mentioned above the remaining substituents are hydrogen.
In a further embodiment of the compound of formula I, said compound is selected from 4-[2-(2,4-Dimethylphenoxy)phenyl]-1,2,3,6-tetrahydropyridine, 4-[2-(4-Chlorophenoxy)phenyl]-1,2,3,6-tetrahydropyridine, } 4-[2-(4-Fluoro-2-methylphenoxy)phenyl]-1,2,3, 6-tetrahvdropyridine, 4-[2-(4-Fluorophenoxy)phenyl]-1,2, 3, 6-tetrahydropyridine, . 30 4-[2-(4-Methylphenoxy)phenyl]-1,2,3,6-tetrahvdropyridine, 4-[2-(4-Methoxyphenoxy)phenyi]-1,2,3,6-tetrahydropyridine, 4-[2-(2,4-Dimethylphenoxy)phenyl piperidine, 4-[2-(4-Chlorophenoxy)phenyl]piperidine,
~ WO 2004/087155 PCT/DK2004/000241 4-[2-(4-Fluoro-2-methylphenoxy)phenyl]piperidine, 4-[2-(4-Fluorophenoxy)phenyl]piperidine, } 4-[2-(4-Methviphenoxy)phenyl]piperidine, 4-[2-(4-Chloro-2- methyl-phenoxy)-phenyl]-piperidine, : 5 4-[2-(2-Chloro-4-methyl-phenoxy)-phenyl]-piperidine, 4-[2-(2,4-Dichloro-phenoxy)-phenyl]-piperidine, 4-[2-(Benzo[b]thiophen-5-yloxy)-phenyl]-piperidine, 4-[2-(Benzo[1,3]dioxol-5-yloxy)-phenyl]-piperidine, 4-[2-(4-Methoxy-2-methyl-phenoxy)-phenyl]-piperidine, 4-[2-(3,4-Dichloro-phenoxy)-phenyl]-piperidine, 4-[2-(3,4-Dimethyl-phenoxy)-phenyl]-piperidine, 4-[2-(2,3,4,5-Tetramethyl-phenoxy)-phenyl]-piperidine, 4-[2-(4-Trifluoromethyl-phenoxy)-phenyl]-piperidine, 4-[2-(4-Methoxy-phenoxy)-phenyl]-piperidine, 4-[2-(2-Chloro-4-methoxy-phenoxy)-phenyl]-piperidine, 4-[2-(3,4-Dimethoxy-phenoxy)-phenyl]-piperidine, 4-[2-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-piperidine, or a pharmaceutically acceptable salt thereof. Each of these compounds is considered a specific embodiment and may be subject to individual claims.
As mentioned above, most of the tested compounds posses the combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition, however, a few compounds selected from 4-[2-(2,4-Dimethylphenoxy)phenyl]-1,2,3,6-tetrahydropyridine, 4-[2-(4-Chlorophenoxy)phenyl]-1,2,3, 6-tetrahydropyridine, 4-[2-(4-Fluoro-2-methylphenoxy)phenyl]-1,2,3,6-tetrahydropyridine, - 4-[2-(4-Fluorophenoxy)phenvl]-1,2,3,6-tetralydropyridine, 4-[2-(4-Methylphenoxy)phenyl]-1,2,3,6-tetrahydropyridine, ‘ 30 4-[2-(4-Methoxyphenoxy)phenyl]-1,2,3,6-tetrahydropyridine, 4-[2-(3,4-Dimethyl-phenoxy)-phenyl]-piperidine, 4-[2-(2,3,4,5-Tetramethyl-phenoxy)-phenyl]-piperidine, 4-[2-(3,4-Dimethoxy-phenoxy)-phenyl]-piperidine,
~ WO 2004/087155 PCT/DK2004/000241 did show serotonin reuptake inhibition, but did not show norepinephrine uptake inhibition in the test herein. : 5 The present invention also comprises salts of the present compounds, typically, pharmaceutically acceptable salts. Such salts include pharmaceutical acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids.
Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconmic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p- toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like.
Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like.
Examples of ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts and the like.
Further, the compounds of this invention may exist in unsolvated as well as in : 30 solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
The compounds of the present invention may have one or more asymmetric centres and 1t is intended that any optical isomers (i.e. enantiomers or diastereomers), as separated, pure or partially purified optical isomers and any mixtures thereof including racemic mixtures are included within the scope of the invention. . 5
Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can also be resolved into their optical antipodes, e.g. by fractional crystallization of d- or I- (tartrates, mandelates or camphorsulphonate) salts. The compounds of the present invention may also be resolved by the formation of : diastereomeric derivatives.
Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet and S.
Wilen in “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, New
York (1981).
Optically active compounds can also be prepared from optically active starting materials, or by stereoselective synthesis.
Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules . having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention. ’ 30
Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms that the compounds are able to form are included within the scope of the present invention.
The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances. In general, such prodrugs will be functional derivatives of the compounds of the general formula (I), which are readily convertible . 5 in vivo into the required compound of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
The invention also encompasses active metabolites of the present compounds.
As mentioned above, the compounds of formula I are serotonin reuptake inhibitors, and accordingly may be applicable for the treatment, including prevention, of affective disorders, such as depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder.
Accordingly, in a further aspect the invention relates to a compound of formula I for use as a medicament.
The present invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier or diluent. The composition may comprise any one of the embodiments of formula I described above.
In an embodiment of the pharmaceutical composition, the compound of formula I is present in an amount of from about 0.001 to about 100 mg/kg body weight per day.
The present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of a disease or disorder, wherein a . serotonin reuptake inhibitor is beneficial. The medicament may comprise any one of the embodiments of formula I described above. ‘ 30
In particular, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of affective disorders.
In a further embodiment the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of depression.
In a further embodiment, the present invention also relates to use of a compound of : 5 formula for the preparation of a medicament for the treatment of anxiety disorders.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of general anxiety disorder.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of social anxiety disorder.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of post traumatic stress disorder.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of obsessive compulsive disorder.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of panic disorder.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of panic attacks.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of specific phobias.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of social phobia.
In a further embodiment, the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of agoraphobia.
A further aspect of the invention relates to a method for the treatment of a disease or : 5 disorder selected from the group consisting of an affective disorder, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia in a living animal body, including a human, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I.
In a further aspect, the present invention relates to a method of preparing a compound of formula I, comprising a) Deprotection or cleavage from a polymer support of a compound with formula II
R* 3
R? R
OQ 2
Big NR
R'O N R § = R® rR’ R’
Rr
II wherein the dotted line, R'-R’ are as previously described, and R is a tert-butyl, methyl, ethyl, allyl or benzyl group or R'OCO is a solid supported carbamate group; or b) Dehydrating and optionally simultaneously deprotecting a compound of formula III
Rr? 3 . ,
R
R" 0
N OH 3 /
R®
R® R’
Rr m wherein R'-R’ are as previously described, and R”’ is either a hydrogen atom or a carbamate group R'OCO wherein R is a tert-butyl, methyl, ethyl, allyl or benzyl group or ROCO is a solid supported carbamate group; or ¢) Reduction of the double bond in a compound of formula IV
Rr 2 0 1 R
HN R
= R®
R’ R’
Re
Iv wherein R'-R’ are as previously described. . Pharmaceutical compositions : The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in
Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack . Publishing Co., Easton, PA, 1995.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention. - Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day

Claims (34)

Claims:
1. A compound represented by the general formula I R* R? R® 2 0 R HN R' - N R® R’ RS Wherein the dotted line ---- indicates a single bond or a double bond; R!, R?, rR? , RY, R° are independently selected from hydrogen, halogen, cyano, C,¢- alk(en/yn)yl, Ci.¢-alk(en/yn)yloxy, C,s-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-Ci.¢- alk(en/yn)yl, halo-C;_¢-alk(en/yn)yl, halo-C,.¢-alk(en/yn)yloxy, or NR*R” wherein R* and R” are independently selected from hydrogen, C,_¢-alk(en/yn)yl, cyano-C,.¢- alk(en/yn)yl, Css-cycloalk(en)yl, Cs g-cycloalk(en)yl-C,.¢-alk(en/yn)yl, or NR’R"-Cy. s-alk(en/yn)yl, wherein R* and R” are independently selected from hydrogen, C;.¢- alk(en/yn)yl, Cs.s-cycloalk(en)yl, or C_¢-cycloalk(en)yl-C,.¢-alk(en/yn)yl; or R* and R’ together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; or R? and R? together form a heterocycle fused to the phenyl ring selected from 0 ; and R!, RY, R’ are as defined above; RS, rR’, RE, R® are independently selected from hydrogen, halogen, C,.¢-alk(en/yn)yl, C_¢-alk(en/yn)yloxy, C,.¢-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C.¢-alk(en/yn)yl, halo-C;_¢-alk(en/yn)yl, halo-C.s-alk(en/yn)yloxy, or NR*R” wherein R* and R” are independently selected from hydrogen, C;¢-alk(en/yn)yl, cyano-C,_¢-alk(en/yn)yl, C;.g- cycloalk(en)yl, Cs.g-cycloalk(en)yl-C,-alk(en/yn)yl, or NR*R%-C, ¢-alk(en/yn)yl, wherein R” and R" are independently selected from hydrogen, C¢-alk(en/yn)yl, C.¢- cycloalk(en)yl, or C;.3-cycloalk(en)yl-C,4-alk(en/yn)yl; or R* and R” together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; provided that at least one of R!, R?, rR’ , RY, R’ , RS, R, RS, and R® is different from hydrogen; or a salt thereof.
2. The compound of claim 1, wherein R! is selected from hydrogen, halogen, cyano, Ci.¢- alk(en/yn)yl, C,_¢-alk(en/yn)yloxy, Ci.¢-alk(en/yn)ylsulfanyl, halo-C;¢-alk(en/yn)yl, or NR*R” wherein R* and R? are independently selected from hydrogen, C,s-alk(en/yn)yl, cyano-Cj.¢-alk(en/yn)yl, Cs.s-cycloalk(en)yl, Cs.s-cycloalk(en)yl-C.¢-alk(en/yn)yl, or NR*R"-C,.¢-alk(en/yn)yl, wherein R* and R" are independently selected from hydrogen,
Ci.¢-alk(en/yn)yl, Cs.g-cycloalk(en)yl, or C;g-cycloalk(en)yl-Ci.¢-alk(en/yn)yl, provided that if one of R* and RY is NR*R"-C, ¢-alk(en/yn)yl then the other is selected from hydrogen, C.¢-alk(en/yn)yl, cyano-C,.¢-alk(en/yn)yl, C;_g-cycloalk(en)yl, or C;.s- cycloalk(en)yl-C,¢-alk(en/yn)yl; or R* and R together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom.
3. The compound of claim 2, wherein R' is selected from hydrogen, Ci.¢-alkyl, or halogen.
4. The compound of any one of claims 1-3, wherein R? is selected from hydrogen, halogen, cyano, C.¢-alk(en/yn)yl, C _¢-alk(en/yn)yloxy, C.¢-alk(en/yn)ylsulfanyl, halo-C,.¢- alk(en/yn)yl.
5. The compound of claim 4, wherein R? is selected from hydrogen, C,.¢-alkoxy, halo-C,.¢- alkyl, C;.¢-alkyl, or halogen.
6. The compound of claim 4, wherein R% is selected from hydrogen or Cy.¢-alkoxy. Amended sheet 14/09/2006
7. The compound of any one of claims 1-6, wherein R? is selected from hydrogen, halogen, cyano, Cjs-alk(en/yn)yl, Ci-alk(en/yn)yloxy, C;¢-alk(en/yn)ylsulfanyl, halo-C,.¢- alk(en/yn)yl.
8. The compound of claim 7, wherein R? is selected from hydrogen, C;.¢-alkyl, Cy.¢- alkoxy, halogen, or halo-C;_¢-alkyl.
9. The compound of claim 7, wherein R3 is selected from hydrogen, C,.¢-alkyl, Cj.¢- alkoxy, or halogen.
10. The compound of any one of claims 1-3, wherein R? and R? together form a heterocycle fused to the phenyl ring selected from 1D et ]
11. The compound of any one of claims 1-10 wherein R* is selected from hydrogen, halogen, cyano, C.s-alk(en/yn)yl, Ci_¢-alk(en/yn)yloxy, Ci.s-alk(en/yn)ylsulfanyl, halo-C,. ¢-alk(en/yn)yl.
12. The compound of claim 11, wherein R* is selected from hydrogen, C;_¢-alkoxy, halo- Cis-alkyl, C.¢-alkyl, or halogen.
13. The compound of claim 11, wherein R* is selected from hydrogen or C,_¢-alkoxy.
14. The compound of any one of claims 1-13 wherein R’ is selected from hydrogen, halogen, cyano, C;¢-alk(en/yn)yl, Ci_¢-alk(en/yn)yloxy, C¢-alk(en/yn)ylsulfanyl, halo-C,. ¢-alk(en/yn)yl, or NR*RY wherein R* and R” are independently selected from hydrogen, C. s-alk(en/yn)yl, cyano-C, ¢-alk(en/yn)yl, Csg-cycloalk(en)yl, Cs.s-cycloalk(en)yl-C,.¢- alk(en/yn)yl, or NR’R"-C¢-alk(en/yn)yl, wherein R* and R" are independently selected from hydrogen, C;_¢-alk(en/yn)yl, Cs.3-cycloalk(en)yl, or Cs.s-cycloalk(en)yl-C¢- alk(en/yn)yl, provided that if one of R* and R” is NR’R"-C,.¢-alk(en/yn)y! then the other is selected from hydrogen, C,¢-alk(en/yn)yl, cyano-C,.¢-alk(en/yn)yl, Cs.3-cycloalk(en)yl, or Amended sheet 14/09/2006
Cs.3-cycloalk(en)yl-C¢-alk(en/yn)yl; or R* and RY together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom.
15. The compound of claim 14, wherein R® is selected from hydrogen, C).¢-alkyl, or halogen.
16. The compound of any one of claims 1-15 wherein R® is selected from hydrogen, halogen, C,¢-alk(en/yn)yl, halo-C.¢-alk(en/yn)yl.
17. The compound of claim 16, wherein R® is selected from hydrogen or halogen.
18. The compound of any one of claims 1-17 wherein R’ is selected from hydrogen, halogen, C;.¢-alk(en/yn)yl, halo-C.¢-alk(en/yn)yl.
19. The compound of claim 18, wherein R is selected from hydrogen or halogen.
20. The compound of any one of claims 1-19 wherein R% is selected from hydrogen, halogen, C,.¢-alk(en/yn)yl, halo-C.¢-alk(en/yn)yl, or NR*R* wherein R* and RY are independently selected from hydrogen, C,.¢-alk(en/yn)yl, cyano-C,.¢-alk(en/yn)yl, C;.s- cycloalk(en)yl, Cs.g-cycloalk(en)yl-C,-alk(en/yn)yl, or NR’R"-C,.¢-alk(en/yn)yl, wherein R” and RY are independently selected from hydrogen, C,_¢-alk(en/yn)yl, C;.¢- cycloalk(en)yl, or Cy.s-cycloalk(en)yl-C.¢-alk(en/yn)yl, provided that if one of R* and R” is NR’R¥-C,¢-alk(en/yn)yl then the other is selected from hydrogen, C;.s-alk(en/yn)yl, cyano-C)_¢-alk(en/yn)yl, Cs.g-cycloalk(en)yl, or Cs.g-cycloalk(en)yl-C,.¢-alk(en/yn)yl; or R* and RY together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom.
21. The compound of claim 20, wherein R3 is selected from hydrogen, halo-C, ¢-alkyl, C,. ¢-alkyl, or halogen.
22. The compound of any one of claims 1-21 wherein R’ is selected from hydrogen, halogen, C.¢-alk(en/yn)yl, halo-C;.¢-alk(en/yn)yl. Amended sheet 14/09/2006
23. The compound of claim 22, wherein R’ is hydrogen.
24. The compound of any one of claims 1-23 wherein the dotted line ---- indicates a single bond.
25. The compound of any one of claims 1-23 wherein the dotted line ---- indicates a double bond.
26. The compound of any one of claims 1-25 wherein the compound of formula I has 1-4 substituents in the phenyl ring(s), selected from any one of R'-R’, which are different from hydrogen, and the remaining substituents are hydrogen.
27. The compound of claim 1, said compound being 4-[2-(2,4-Dimethylphenoxy)phenyl]-1,2,3,6-tetrahydropyridine, 4-[2-(4-Chlorophenoxy)phenyl]-1,2,3,6-tetrahydropyridine, 4-[2-(4-Fluoro-2-methylphenoxy)phenyl]-1,2,3,6-tetrahydropyridine, 4-[2-(4-Fluorophenoxy)phenyl]-1,2,3,6-tetrahydropyridine, 4-[2-(4-Methylphenoxy)phenyl]-1,2,3,6-tetrahydropyridine, 4-[2-(4-Methoxyphenoxy)phenyl]-1,2,3,6-tetrahydropyridine, 4-[2-(2,4-Dimethylphenoxy)phenyl]piperidine, 4-[2-(4-Chlorophenoxy)phenyl]piperidine, 4-[2-(4-Fluoro-2-methylphenoxy)phenyl]piperidine, 4-[2-(4-Fluorophenoxy)phenyl]piperidine, 4-[2-(4-Methylphenoxy)phenyl]piperidine, 4-[2-(4-Chloro-2- methyl-phenoxy)-phenyl]-piperidine 4-[2-(3-Chloro-2- methyl-phenoxy)-phenyl]-piperidine 4-[2-(2-Chloro-4-methyl-phenoxy)-phenyl]-piperidine 4-[2-(2,4-Dichloro-phenoxy)-phenyl]-piperidine 4-[2-(Benzo[1,3]dioxol-5-yloxy)-phenyl]-piperidine, 4-[2-(4-Methoxy-2-methyl-phenoxy)-phenyl]-piperidine, 4-[2-(3,4-Dichloro-phenoxy)-phenyl]-piperidine, 4-[2-(3,4-Dimethyl-phenoxy)-phenyl]-piperidine, 4-[2-(2,3,4,5-Tetramethyl-phenoxy)-phenyl]-piperidine, 4-[2-(4-Trifluoromethyl-phenoxy)-phenyl]-piperidine, Amended sheet 14/09/2006
4-[2-(4-Methoxy-phenoxy)-phenyl]-piperidine, 4-[2-(2-Chloro-4-methoxy-phenoxy)-phenyl]-piperidine, 4-[2-(3,4-Dimethoxy-phenoxy)-phenyl]-piperidine, 4-[2-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-piperidine, or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising a compound of any one of claims 1-27 or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.
29. The use of a compound of any one of claims 1 to 27 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders.
30. The use according to claim 29, wherein the affective disorders are selected from depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia.
31. The use according to either of claims 29 or 30, wherein the treatment comprises administering a therapeutically effective amount of a compound of any one of claims 1-27 or a pharmaceutically acceptable acid addition salt thereof.
32. A compound of any one of claims 1-27 for use as a medicament.
33. The compound of claim 32, wherein the medicament is for treatment of an affective disorder.
34. The compound of claim 33, wherein the affective disorder is selected from depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia. Amended sheet 14/09/2006
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