CA2521030C - 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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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
4-(2-Phenyloxyphenyl)-piperidine or -1,2,3,6-tetrahydropyridine derivatives as serotonin reuptake inhibitors The present invention relates to novel compounds which arc serotonin reuptake inhibitors and as such effective in the treatment of for example depression and anxiety.
l~aekground of the invention to Selective serotonin reuptal~e 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 a~zd have a favourable safety profile compared to the classic tricyclic antidepressants.
15 However, clinical studies on depression indicate that non-response to SSRIs is substantial, up to 30%. Another, often neglected, factor in antidepressant treatment is compliance, which has a rather profound effect on the patient's motivation to continue pharmacother apy.
2o First of all, there is the delay in therapeutic effect of SSRIs. Sometimes symptoms even worsen during the first weeps 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 lilcely to happen.
25 The combined effect of serotonin reuptake inhibition and norepinephrine uptalce iWibition on depression is explored in clinical studies of compounds such as Duloxetine (along, Duloxetine (LY-248686): an inhibitor of serotonin and noradrenaline uptalce and an antidepressant drug candidate Expey~t Opihiora ofZ
Irzvestigutioraal Dr°ugs, 1998, 7, 10, 1691-1699) and Venlafaxine (Khan-A et al, 3o Venlafaxine in depressed outpatients 1'syelz.~p7icza°macolog~
Bulletif~, 1991, ~'7, 14.1-144).
The present invention provides novel compounds which posses the combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition 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 attacl~s, specific phobias, social phobia and agoraphobia.
~urramaxy 0f the i~tventi~n The present invention provides compounds of the general formula I
HN R~
.. / . R6 R9'~ R7 R$
to wherein the dotted line, R1, R2, R3, R4, R5, R~, R', R8, and R~ are as defined below.
The invention provides a compound according to the above for use as a medicament.
15 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 20 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 attacl~s, 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, including a human, comprising administering a therapeutically effective amount of a compound according to the above or a pharmaceutically acceptable acid addition salt thereof.
~efiniti0ii 0f ~ub~tituent~
to Halogen means fluoro, chloro, bromo or iodo.
The expression C1_~-allc(enlyn)yl means a C1_~-alkyl, CZ_~-alkenyl or a CZ_G-allcynyl group.
The term C 1 _~ alkyl refer s to a branched or unbranched allcyl 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, C2_~ alkenyl and C2_~ 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 C1_~-alk(euyn)yloxy, C1_~ allc(en/yn)ylsulfanyl, hydroxy-C1_~-alk(eWyn)yl, halo-C1_~-allc(en/yn)yl, cyano-C1_~-alk(en/yn)yl, NRZRW-C1_~-allc(enyn)yl, C1_~-allc(enlyn)yloxy-C1_~-allc(en/yn)yl and halo-C1_~-allc(en/yn)yloxy designate such groups in which the C1_~-allc(en/yn)yl are as defined above. Halo means halogen.
NR~RW-C1_G-alk(euyn)yl designate the group R~
RW N-G~-6a~k(en/yn)yl The term C3_8 cycloall~yl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, etc.
The term C3_8 cycloal~eriyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms and including ogle double bond.
I11 the te1111 C3_$-cycloallc(en)yl-C1_G-allc(en/y11)yl, C3_8-cycloall~(en)yl alld Ci-G-all~(en/yn)yl are as defined above.
to The term 3-7-membered ring optionally containing one ful-ther heteroatom, such as N, O, or S, as used herein refers to ring systems such as 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, all of which may be further substituted with a group selected from a C1_G-all~(en/yn)yl, hydroxy, hydroxy-C1_G-allc(en/yn)yl, C1_G-allc(en/yn)yloxy-C 1 _G-all~(en/yn)yl .
Description of the invention 2o The present invention relates to 4-(2-phenyloxyphenyl)-piperidine or -1,2,3,6-tetrahydropyridine derivatives which are serotonin reuptal~e inhibitors and as such effective in the treatment of for example depression and anxiety. In particular the piperidines are also good norepinephrine uptal~e inhibitors.
Accordingly the present invention relates to a compound represented by the general formula I
H~
R
RV
when ein the dotted line ---- indicates a single bond or a double bond;
RI, R2, R3, R4, RS are independently selected from hydrogen, halogen, cyano, C1-~-allc(en/yn)yl, C1_~-alk(en/yn)yloxy, C1_~-alk(euyn)ylsulfanyl, hydroxy, hydroxy-C1_~-alk(en/yn)yl, halo-C1_~-alk(en/yn)yl, halo-C1_~-allc(en/yn)yloxy, or NR"Ry wherein R"
and Ry are independently selected from hydrogen, C1_~-alk(eWyn)yl, cyano-C1_~-to allc(en/yn)yl, C3_g-cycloalk(en)yl, C3_$-cycloallc(en)yl-C1_~-alk(enlyn)yl, or NRZRW-C1_ ~-alk(enJyn)yl, wherein RZ and RW are independently selected from hydrogen, C1_~-alk(en/yn)yl, C3_$-cycloalk(en)yl, or C3_g-cycloalk(en)yl-C1_~-alk(enyn)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 RZ and R3 together form a heterocycle fused to the phenyl ring selected from ~o ~o ; and R1, R4, R5 are as defined above;
R~, R', R8, R~ are independently selected from hydrogen, halogen, C1_~-allc(euyn)yl, 2o C1_~-allc(euyn)yloxy, CI_~-alk(eW~m)ylsulfanyl, hydroxy, hydroxy-C1_~-alk(euyn)yl, halo-C1_~-allc(en/yn)yl, halo-C1_~-allc(enyn)yloxy, or NRXRy wherein R" and RY
axe independently selected from hydrogen, C1_~-alk(en/yn)yl, cyano-C1_~-allc(en/yn)yl, C3_ 8-cycloalk(en)yl, C3_8-cycloall~(en)yl-C1_~-allc(en/yn)yl, or NR~R'~'-C1_~-allc(en/yn)yl, wherein RZ and RW are independently selected from hydrogen, C1_~-alk(en/yn)yl, C3_8-cycloalk(en)yl, or C3_8-cycloallc(en)yl-Cl_~-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 Rl, R2, R3, R4, R5, R~, R~, R8, and R~ is different from hydrogen;
or a salt thereof.
In one embodiment of the compound of formula I, Rl is selected from hydrogen, halogen, cyano, C1_~-alk(en/yn)yl, C1_~-alk(en/yn)yloxy, C1_~-alk(en/yn)ylsulfanyl, to halo-CI_~-alk(en/yn)yl, or NR"Ry wherein RX and RY are independently selected from hydrogen, C1_~-alk(en/yn)yl, cyano-C1_~-allc(en/yn)yl, C3_8-cycloallc(en)yl, C3_8-cycloalk(en)yl-C1_~-allc(en/yn)yl, or NRZRW-C1_~-alk(en/yn)yl, wherein RZ and RW are independently selected from hydrogen, C1_~-alk(en/yn)yl, C3_8-cycloallc(en)yl, or C3_8-cycloallc(en)yl-C1_~-alk(en/yn)yl, provided that if one of R" and RY is NRZRW-C1_~-15 alk(en/yn)yl then the other is selected from hydrogen, C1_~-allc(en/yn)yl, cyano-C1_~-alk(en/yi)yl, C3_8-cycloalk(en)yl, or C3_g-cycloalk(en)yl-C1_~-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 Rl is selected from hydrogen, halogen, cyano, C1_~-2o alk(eWyn)yl, C1_~-alk(en/yn)yloxy, C1_~-alk(en/yn)ylsulfanyl, halo-C1_~-alk(euyn)yl.
In a further embodiment Rl is NR"Ry wherein R" and RY are independently selected from hydrogen, C1_~-allc(en/yn)yl, cyano-C1_~-allc(en/yn)yl, C3_8-cycloalk(en)yl, C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl, such as hydrogen, cyanomethyl, C1_~-alk(en/yn)yl. In a fiuther embodiment Rl is NR"RY wherein R" is NRZRW-C1_~-allc(en/yn)yl, wherein RZ
25 and RW are independently selected from hydrogen, C1_~-allc(en/yn)yl, C3_8-cycloalk(en)yl, or C3_8-cycloalk(en)yl-C1_~-allc(euyn)yl, and RY is selected from hydrogen, C1_~-allc(en/yn)yl, cyano-C1_~-alk(en/yn)yl, C3_8-cycloallc(en)yl, or C3_g-cycloalk(en)yl-C1_~-allc(enyn)yl. In a further embodiment Rl is NR"Ry wherein R"
and RY together with the nitrogen to which they are attached form a 3-7-membered 30 ring which optionally contains one further hetcroatom, 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 C1_~-allc(en/yn)yl, hydroxy, hydroxy-C1_~-allc(euyn)yl, C1_~-alk(en/yn)yloxy-C1_~-alk(euyn)yl, e.g. one or two selected from hydroxy, hydroxy-C1_ ~-all~yl, C1_~-alkyloxy-C1_~-alkyl, C1_~-allcyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl. Typically, Rl is selected from hydrogen;
halogen;
cyano; C~_~-alkyl; C1_~-alhyloxy; C1_~-alkylsulfanyl; halo-C1_~-alkyl; NR"RY
wherein R~ and Ry are independently selected from hydrogen, C1_~-allcyl, cyanomethyl;
NR"Ry wherein Ry is selected from hydrogen, or C1_~-alkyl, and R~ is NR~R"'-C1-~-allc(el~/yn)yl wherein RZ and RW are independently selected from hydrogen, or C1_~-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-Cl_~-allcyl, C1_~-allcyloxy-Cl_~-alkyl, C1_~-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl.
To further illustrate without limiting the invention an embodiment of Rl is hydrogen;
another embodiment of Rl is C1_~-all~yl, such as methyl; a further embodiment of Rl is halogen, such as fluoro, or chloro.
In a further embodiment of the compound of formula I, R2 is selected from hydrogen, halogen, cyano, C1_~-allc(el~/yn)yl, C1_~-alk(en/yn)yloxy, C1_~-alk(en/yn)ylsulfanyl, halo-C1_~-alk(en/yn)yl. Typically, RZ is selected from hydrogen, halogen, cyano, C1_~-allcyl, C1_~-allcyloxy, C1_~-alkylsulfanyl, halo-C1_~-alkyl. To ful-ther illustrate without limiting the invention an embodiment of RZ is hydrogen; another embodiment of RZ is C1_~-alkoxy, such as methoxy; another embodiment of R2 is halo-C1_~-alkyl, such as trifluoromethyl; another embodiment of RZ is C1_~-alkyl, such as methyl;
another embodiment of R2 is halogen, such as chloro.
In a further embodiment of the compound of formula I, R3 is selected from hydrogen, halogen, cyano, C1_~-alk(en/yn)yl, C1_~-alk(en/yn)yloxy, C1_~-alk(enlyn)ylsulfanyl, halo-C1_~-alk(en/yn)yl. Typically, R3 is selected from hydrogen, halogen, cyano, C1_~-allcyl, C1_~-allcyloxy, C1_~-allcylsulfanyl, halo-C1_~-alkyl. To fiu-ther illustrate without limiting the invention an embodiment of 8315 hydrogen; another embodiment of R3 is 3o C1_~-alkyl, such as methyl; a further embodiment of 8315 C1_~-allcoxy, such as methoxy; a further embodiment of R3 is halogen, such as chloro, or fluoro;
another embodiment of R3 is halo-C1_~-alkyl, such as trifluoromethyl.
In a further embodiment of the compound of formula I, R2 and R3 together form a heterocycle fused to the phenyl ring selected from ~o _~
In a further embodiment of the compound of formula I, R4 is selected from hydrogen, halogen, cyano, C1_~-allc(euyn)yl, C1_~-allc(en/yn)yloxy, C1_~-alk(en/yn)ylsulfanyl, halo-C1_~-alk(en/yn)yl. Typically, R4 is selected from hydrogen, halogen, cyano, C1_~-alkyl, C1_~-alkyloxy, C1_~-alkylsulfanyl, halo-C1_~-allcyl. To further illustrate without limiting the invention an embodiment of R4 is hydrogen; another embodiment of R4 is to C1_~-allcoxy, such as methoxy; another embodiment of R4 is halo-C1_~-alkyl, such as trifluoromethyl; another embodiment of R4 is C1_~-alkyl, such as methyl;
another embodiment of R4 is halogen, such as chloro.
In a further embodiment of the compound of formula I, RS is selected from hydrogen, 15 halogen, cyano, C1_~-alk(en/yn)yl, C1_~-alk(euyn)yloxy, C1_~-alk(en/yn)ylsulfanyl, halo-C1_~-alk(en/yn)yl, or NR"RY wherein R" and Ry are independently selected from hydrogen, C1_~-alk(en/yn)yl, cyano-C1_~-alk(en/yn)yl, C3_8-cycloalk(en)yl, C3_8-cycloalk(en)yl-C1_~-alk(en/~m)yl, or NRZRW-C1_G-alk(en/yn)yl, wherein RZ and RW are independently selected from hydrogen, C1_~-alk(en/yn)yl, C3_$-cycloall~(en)yl, or C~_8-2o cycloallc(en)yl-C1_~-alk(en/yn)yl, provided that if one of R" and RY is NRZRW-C1_~-alk(eWyn)yl then the other is selected from hydrogen, C1_~-alk(euyn)yl, cyano-C1_~-allc(euyn)yl, C3_g-cycloallc(en)yl, or C3_8-cycloallc(en)yl-C1_~-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 25 compound of formula I R5 is selected from hydrogen, halogen, cyano, C1_~-alk(eWyn)yl, C1_~-alk(en/yn)yloxy, C1_~-alk(en/yn)ylsulfanyl, halo-C1_~-alk(en/yn)yl.
In a further embodiment RS is NR"R'' wherein R" and RY are independently selected from hydrogen, C1_~-allc(en/yn)yl, cyano-C1_~-alk(enyn)yl, C3_$-cycloallc(en)yl, C3_8-cycloallc(en)yl-C1_~-alk(en/yn)yl, such as hydrogen, cyanomethyl, C1_~-all~(en/yl)yl. In 3o a further embodiment RS is NRAR'' wherein R~ is NR~R'~'-C1_~-allc(en/yn)yl, wherein R
and RW are independently selected from hydrogen, C1_~-allc(euyn)yl, C3_8-cycloalk(en)yl, or C3_8-cycloall~(en)yl-C1_~-alk(en/yn)yl, and Ry is selected from hydrogen, C1_~-all~(en/yn)yl, cyano-C1_~-alk(en/yn)yl, C3_8-cycloalk(en)yl, or C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl. In a further embodiment RS is NR"Ry 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, 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 C1_~-allc(en/yn)yl, hydroxy, hydroxy-C1_~-allc(en/yn)yl, C1_~-alh(en/yn)yloxy-C1_~-allc(euyn)yl, e.g. one or two selected from hydroxy, hydroxy-Cl_ to ~-alkyl, C~_~-allcyloxy-C1_~-alkyl, C1_~-alkyl, in pauticular one or two selected from hydroxy, methoxy-methyl, methyl. Typically, RS is selected from hydrogen;
halogen;
cyano; C1_~-allcyl; C1_~-alkyloxy; C1_~-alkylsulfanyl; halo-C1_~-alkyl; NR"R'' wherein R" and Ry are independently selected from hydrogen, C1_~-alkyl, cyanomethyl;
NR"RY
wherein R'' is selected from hydrogen, or C1_~-alkyl, and R" is NRZRW-C1_~-alk(eWyn)yl wherein RZ and RW are independently selected from hydrogen, or C1_~-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-C1_~-alkyl, C1_~-alkyloxy-C1_~-alkyl, Cl_~-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl.
2o To further illustrate without limiting the invention an embodiment of RS is hydrogen;
another embodiment of RS is C1_~-alkyl, such as methyl; a further embodiment of RS is halogen, such as chloro, or fluoro.
In a further embodiment of the compound of formula I R~ is selected from hydrogen, halogen, C~_~-allc(euyn)yl, halo-C1_~-allc(euyn)yl. Typically, R~ is selected from hydrogen, halogen, C1_~-alkyl, halo-C1_~-allcyl. To further illustrate without limiting the invention an embodiment of R~ is hydrogen; another embodiment of R~ is halogen, such as fluoro.
~0 In a further embodiment of the compound of formula I, R' is selected from hydrogen, halogen, C1_~-alk(en/yn)yl, halo-C1_~-alk(enlyn)yl. Typically, R~ is selected from hydrogen, halogen, C1_~-alkyl, halo-C1_~-alkyl. To further illustrate without limiting 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, halogen, C1_~-alk(en/yn)yl, halo-C1_~-alk(en/yn)yl, or IVR~Ry wherein R" and Ry are independently selected from hydrogen, C1_~-alk(en/yn)yl, cyano-Cl_~-allc(en/yn)yl, C3_ 8-cycloalk(en)yl, C3_8-cycloalk(en)yl-C1_~-all~(en/yn)yl, or NR~R~''-C1_~-alk(enlyn)yl, wherein RZ and RW are independently selected from hydrogen, C1_~-alk(en/yn)yl, C3_$-cycloalk(en)yl, or C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl, provided that if one of R" and to Ry is NRzRW-C1_~-alk(en/yn)yl then the other is selected from hydrogen, Cl_~-alk(en/yn)yl, cyano-C1_~-alk(en/yn)yl, C3_8-cycloallc(en)yl, or C3_$-cycloalk(en)yl-C1_~-allc(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 R8 is selected from hydrogen, halogen, C1_ ~-alk(en/yn)yl, halo-C1_~-allc(en/yn)yl. In a further embodiment R8 is NR"RY
wherein R" and Ry are independently selected from hydrogen, C1_~-alk(en/yn)yl, cyano-C1_~-allc(en/yn)yl, C3_8-cycloalk(en)yl, C3_8-cycloallc(en)yl-C1_~-alk(euyn)yl, such as hydrogen, cyanomethyl, C1_~-alk(enlyn)yl. In a further embodiment R8 is NR"R'' wherein R" is NRZRW-C1_~-alk(en/yn)yl, wherein RZ and RW are independently selected 2o from hydrogen, C1_~-allc(en/yn)yl, C3_8-cycloalk(en)yl, or C3_8-cycloallc(en)yl-C1_~-allc(eWyn)yl, and RY is selected from hydrogen, C1_~-allc(euyn)yl, cyano-C1_~-alk(en/yn)yl, C3_8-cycloalk(en)yl, or C3_8-cycloalk(en)yl-C1_~-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 ring which optionally contains one further heteroatom, such as 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pynolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substiW ted with one or more selected from a C1_~-allc(enlyn)yl, hydroxy, hydroxy-C1_~-allc(enyn)yl, C1_~-allc(enlyn)yloxy-C1_~-allc(enyn)yl, e.g. one or two selected from hydroxy, hydroxy-C1_~-alkyl, C1_~-allcyloxy-C1_~-allcyl, C1_~-allcyl, in 3o particular one or two selected from hydroxy, methoxy-methyl, methyl.
Typically, R$
is selected from hydrogen; halogen; cyano; C1_G-allcyl; C1_~-alkyloxy; CI_~-alkylsulfanyl; halo-Cl_~-alkyl; NR~RY wherein RX and Ry are independently selected from hydrogen, C1_~-allcyl, cyanomethyl; NR"Ry wherein Ry is selected from hydrogen, or C1_6-all~yl, and RX is NRZRW-C1_~-alk(en/yn)yl wherein RZ and RW
are independently selected from hydrogen, or C1_~-alkyl; 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imida~olyl, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or two selected from hydroxy, hydro~y-C1_~-alkyl, C1_~-alkyloxy-C1_~-alkyl, C1_~-all~yl, in particular one or tv,~o selected from hydroxy, methoxy-methyl, methyl. To further illustrate without limiting the invention an embodiment of R8 is hydrogen; another embodiment of R$ is halogen, such as fluoro, or bromo; a further embodiment of R8 is C1_~-alkyl, such as methyl; a further embodiment of R8 is halo-C1_~-allcyl, such as CF3.
to In a further embodiment of the compound of formula I, R~ is selected from hydrogen, halogen, C1_~-allc(euyn)yl, halo-C1_~-alk(en/yn)yl. Typically, R~ is selected from hydrogen, halogen, Cl_~-alkyl, halo-C1_~-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 Rl-R~, which is different from hydrogen, such as 1, 2, 3, or 4 substituents in the phenyl ring(s), selected from any one of Rl-R9, which is/are different fr0111 hydrogen, and the remaining substituents are hydrogen.
Thus, in a further embodiment 1 substituent selected from any one of Rl-R~, which is different from hydrogen, is present in either of the two phenyl rings, such as 1 substituent selected from Rl-R5, or the substituent is selected from R~-R~. In a further embodiment 2 substituents selected from Rl-R~, which are different from hydrogen, 3o are present in either of the two phenyl rings, such as 1 substituent selected from Rl-R5, and the other selected from R~-R~, or both substituents are selected from Rl-R5; in this respect R2 and R3 may be talcen together to form the heterocycle as defined above.
In a further embodiment 3 substituents selected from Rl-R9, which are different from hydrogen, are present in either of the two phenyl rings, such as 2 substituents selected from Rl-R5, and the last substituent is selected from R~-R~. 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 R2 as defined above, except hydrogen. In a further embodiment of the compound of formula I one substituent is present which is R3 as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are to present being R3 and R8, wherein R3 and R$ are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R3 and RG, 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 R3 and R~, wherein R3 and R' are as defined above, except hydrogen. In a further 15 embodiment of the compound of formula I two substituents are present being Rl and R3, wherein Rl and R3 are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R2 and R3, wherein R2 and R3 are as defined above, except hydxogen, in this respect R2 and R3 may be tal~en together to form the heterocycle as defined above. In a further 2o embodiment of the compound of formula I three substituents are present being Rl, R3 and R8, wherein Rl, R3 and R8 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 25 from 4-~2-(2, 4-Di>7zethylplzetzoxy)phe>zylJ-1, 2, 3, 6-tetrahyd>~opyt~idine, 4-~2-(4-Chlor~oplzet2oxy)phertylJ-1, 2, 3, 6-tetz"a7zyd>"opy>~idi>ze, 4-~2-(4-Fluoz~o-2-metlzylphe~~.~y)pherzylJ-1, ~, 3, 6-tetf-alzyd>"~pyt°idihe, 4-~2-(~-Fluot°~plze>zoxy)phenylJ-1, ~, 3, 6-tett~ahydropyt~idi>ze, 30 ~-~2-(4-Methylphenoxy)plz~ttylJ-1,x,3,6-tett~altydt°~pyriditte, 4-~2-(~-Meth~xyplz etz~xy)plzetzylJ-1, 2, 3, 6-tett~ahydropyr~idizte, 4-~~',-(2, ~-DinzethylplTez~oxy)plzeraylJpiperidin.e, 4-~~-(4-ClaloYOplzenoxy)phenylJpipez~idi>?e, 4- j2-(4-Fluoy-o-2-methylphehoxy)phenylJpipe~idihe, 4-j2-(4-FIuoYOpheh.oxy)phe~2ylJpipef°idiyae, 4- j2-(4-Metlaylphenoxy)p7zeraylJpiperidih.e, 4-j2-(4-Chlof°o-2- methyl plaenoxy) plaefZylJ piper~idine, -l-j?-(2-Clzloro-4-fraeth3rl phenoxy) plaeazylJwiper°idine, 4-j2-(2,4-Dichlo~~o phef2oxy) phenyl) piper°idiyae, 4-j2-(penzo jbJthiophen-5 yloxy) phehylJ pipe~idine, 4-j2-(~enzzojl,3Jdioxol-5-yloxy) pheh>>lJ pipes°idine, 4-j2-(4-Metlaoxy-2-methyl ~ahenoxy) plaeraylJ ~aipef°idine, 4-j2-(3,4-Diclalo~°o pherzoxy) phei~ylJ pipe~~idiyae, 4-j2-(3,4-Diuaetlzyl plaehoxy) plaerrylJ piper°idiy~e, 4-j2-(2,3,4,5-Tetramethyl phef2oxy) phefZylJ pipey~idihe, 4-j2-(4-Trifluo~omethyl phenoxy) phenyl) pipe~idihe, 4-j2-(4-Metl2oxy plae~zoxy) phenyl) piperidine, 4-j2-(2-Chloro-4-methoxy phehoxy) plaenylJ pipe~~idine, 4-j2-(3,4-Dimetlaoxy phenoxy) phe~zylJ piperidi~2e, 4-j2-(4-Clalo~°o-3-tf°ifluo~°omethyl phenoxy) phenyl) pipe~~idine, or a pharmaceutically acceptable salt thereof. Each of these compounds is considered a 2o specific embodiment and may be subject to individual claims.
As mentioned above, most of the tested compounds posses the combined effect of serotonin reuptalce inhibition and norepinephrine uptal~e inhibition, however, a few compounds selected from 4-j2-(2,4-Dinaethylplaef2oxy)phefzylJ-1,2,3,6-tetralaydy~opy~idih.e, 4- j2-(4-Chloy~oplaenoxy)plaenylJ-1, 2, 3, 6-tet~~alaydy~opyridine, 4-j2-(4-Fluof~o-2-nzethylplze~2oxy)phenylJ-1,2, 3, 6-tety°alaydropy~idiue, 4- j2-(4-Fluoroplnenoxy)phenylJ-1, 2, 3, 6-tetralaydf~opyYidine, 4- j2-(4-Methylplae~2oxy)phenylJ-1, 2, 3, 6-tetJ°alaydr~opy°idih.e, 4-j2-(4-Metlno~.yplneraoxy)ph.erzylJ-1,2,3,x-tetrealaydYOpyr-idiyae, 4- j2-(3, 4-Dinaethyl phenoxy) plaef2ylJ piperidine, 4-j2-(2,3,4,5-Tetrarn.etlayl phert.oxy) plaenylJ piperidih.e, 4-j2-(3,4-Di~aet7aoxy plZefaoxy) phetaylJ pipet~idirae, did show serotonin reuptal~e inhibition, but did not show norepinephrine uptal~e iWibition in the test herein.
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 allcylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids.
to Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfiuic, sulfamic, nitric acids and the life.
Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cimzamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, malefic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, pahnitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for 2o example 8-bromotheophylline and the life.
Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like.
Examples of ammonium and allcylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts and the life.
Further, the compounds of this invention may exist in unsolvated as well as in 3o solvated forms with pharmaceutically acceptable solvents such as Water, ethanol arid the life. 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 it is intended that any optical isomers (i.e. enantiomers or diastereomers), as separated, pure or partially purified optical isomers and any mixtures thereof 111Cltldlllg racelnic mixtures are included within the scope of the invention.
Racelnic forms can be resolved into the optical antipodes by lgrlown 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 to 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 1- (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, l~rlown to those slcilled 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 Yorl~ (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. Lil~ewise, 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.
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 in vivo into the required compomzd of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodnzgs", ed. H. Bundgaard, Elsevier, 1985.
The invention also encompasses active metabolites of the present compounds.
to As mentioned above, the compounds of formula I are serotonin reuptal~e 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 2o 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/lcg 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 reuptalce inhibitor is beneficial. The medicament may comprise any one of the embodiments of formula I described above.
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 foumula I 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.
to 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.
15 In a further embodiment, the present invention also relates to use of a compound of fornula 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 2o fornula 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 fornula 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 attaclcs.
In a further embodiment, the present invention also relates to use of a compound of 3o fornula 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 fornula 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 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 attacl~s, specific phobias, social phobia and agoraphobia in a living animal body, including a human, comprising administering to a subj ect in need thereof a to 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 fiom a polymer support of a compound with formula II
O \ ~ 2 ~ o R
R'O- _N R1 .. \ Rs R / R~
R$
II
wherein the dotted line, Rl-R~ are as previously described, and R is a tent-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
R5 Rs \ R2 R"\~~ OH ~ R~
III
wherein Ri-R~ are as previously described, and R" is either a hydrogen atom or a carbamate group R~OCO wherein R is a tef°t-butyl, methyl, ethyl, allyl or benzyl group or R OCO is a solid supported carbamate group; or c) Reduction of the double bond in a compound of formula IV
/
\ R2 HN~ ~ R~
/ \ R6 R / R' R$
IV
wherein R1-R~ are as previously described.
to 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 lalown adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mach 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 to prefeiTed 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 15 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 lmown in the art.
Liquid dosage forms for oral administration include solutions, emulsions, 2o suspensions, syrups and elixirs.
Phamnaceutical 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/lcg body weight per day, preferably from about 0.01 to about 50 mg/lcg body weight per day, and more prefeiTed fiom about 0.05 to about 10 mg/lcg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods lmown to those spilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.01 to l0 about 1000 mg, preferably from about 0.05 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for 15 oral administration.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of the formula (I) 2o contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the formula (1) with a chemical equivalent of a pharmaceutically acceptable acid. Representative examples are mentioned above.
For parenteral administration, solutions of the novel compounds of the formula (I) in 25 sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous 30 media employed are all readily available by standard teclmliques known to those slcilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower all~yl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospho lipids, fatty acids, fatty acid amines, polyoxyethylenc and water. similarly, the carrier or diluent may include any sustained release material l~nown in the art, such as glyccryl monostearate or glyceryl distearatc, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutical acceptable carriers arc then readily administered in a variety of dosage forms suitable for the disclosed routes of 1o administration. The formulations may conveniently be presented in unit dosage form by methods l~nown in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
2o If a solid carrier is used for oral administration, the preparation may be a tablet, placed in a hard gelatine capsule in powder or pellet fore or it can be in the forn of a troche or lozenge.
The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
The compounds of the invention are prepared by the following general methods, or as described in the experimental section of this patent:
a) Deprotection or cleavage from a polymer support of a compound with formula II
R~~ N
R
.. \ R6 -, 8 II
wherein R1-R~ are as previously described, and R~ is a tef°t-butyl, methyl, ethyl, allyl or benzyl group or ROCO is a solid supported carbamate group, such as the Wang resin-based carbasnate linlcer;
b) Dehydrating and optionally simultaneously deprotecting a compound of formula III
\ R2 R,yN OH o R~
Rg / R~
R$
io wherein Rl-R~ are as previously described, and R" is either a hydrogen atom or a carbamate group R OCO wherein R~ is a tee°t-butyl, methyl, ethyl, allyl or benzyl group or R~OCO is a solid suppouted carbamate group, such as the Wang resin-based carbamate linlcer;
is c) Reduction of the double bond in a compound of formula IV
R5 Rs \ R2 Hi~~ ~ R~
IV
wherein R1-R~ are as previously described.
The deprotection according to method a) was performed by standard techniques, knowledgeable to those skilled in the art and detailed in the textboolc Pf-otective GT°oups in Organic Synthesis T.W.Greene and P.G.M. Wuts, Wiley Interscience, (1991) ISBN 0471623016. The cleavage from a polymer support, such as from the Wang resin-based carbamate linker, according to method a) may be performed according to literature known procedures (Zaragoza Tetrah.edf°ora Lett.
1995, 36, 8677-8678 and Conti et al. Tetnahed~on Lett. 1997, 38, 2915-2918).
Starting materials of formula II can be prepared by removal of the hydroxy group of compounds of formula III by a number of methods lmown to the chemist skilled in the art, e.g. by the use of triethylsilane in trifluoro acidic acid and boron trifluoride diethyl etherate (see Encyclopaedia of Reagefats foy° Organic Synthesis, vol 7, Paquette, ed.;
John Wiley & Sons, Chichester, 1995, 5122-5123). Starting materials of formula II, which are piperidines, may be prepared by reduction of the double bond of the corresponding tetrahydropyridines by standard hydrogenation procedures, such as e.g.
catalytic hydrogenation at low pressure (< 3 atm.) in a Parr apparatus.
The dehydration reaction and optional simultaneous deprotection of a compound of fOr111ll1a III according to method b) was performed in a similar manner as described in Pahner et al J. Mcd. Glaern. 1997, 40, 1982-1989.
Starting materials of formula III were prepared from the corresponding properly substituted 1-bromo-2-phenoxybenzenes of formula VI (wherein Rl-R~ are as previously described, and G is a bromine or iodine atom) by metal-halogen exchange followed by addition of an appropriate electrophile of the formula V (wherein R' is as previously described) in a similar manner as described in Pahner et al. .~
Ihfed. C7ze~az.
1997, 40, 1982-1989.
R~
~5 ~3 W~ ~ \ ~2 O
G G
V
VI
The properly substituted 1-bromo-2-phenoxybenzenes were prepared by reaction of properly substituted phenols (the sodium salt of the phenols were prepared in situ by to the use of sodium hydride) with properly substituted 1-bromo-2-fluorobenzenes in dimethyl formamide (DMF) at elevated temperature. The diaryl ethers may also be prepared by various modifications of this method (see e.g. Schmittlinger et al J.Org. Claena. 1993, 58, 3229-3230; Beugelmans et al Tetralzedf°ora Lett. 1994, 35, 5649-5652; Sawyer et al J.Org.Claem. 1998, 63, 6338-6343), under Ullmann 15 conditions or via arylation of phenols with arylboronic acids (Evans et al Tetrahedron Lett 1998, 39, 2937-2940). Phenols and 1-bromo-2-fluorobenzenes are commercially available.
The reduction of the double bond according to method c) is generally performed by 2o catalytic hydrogenation at low pressure (< 3 atm.) in a Parr apparatus.
Starting materials of formula IV may be prepared from compounds of formula II by deprotection as described above.
Examples Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with IonSpray source and Shimadzu LC-8A/SLC-l0A LC system. Column: 30 X 4.6 mm Waters Symmmetry C18 column with 3.5 Nm particle size; Solventsystem: A =
water/trifluoroacetic acid (100:0.05) and B =
water/acetolutrile/trifluoroacetic acid (5:95:0.03); Method: Linear gradient elution with 90% A to 100% B in 4 min and with a flow rate of 2 111L/mlll. Purity was determined by integration of the LTA (254 lnn) and ELSD trace. The retention times (RT) are expressed in minutes.
to Preparative LC-MS-purification was performed on the same instrument.
Column: 50 X 20 mln YMC ~DS-A with 5 ~.m particle size; Method: Linear gradient elution with 80% A to 100% B in 7 min and with a flow rate of 22.7 mLlmin. Fraction collection was performed by split-flow MS detection.
Reactions carried out under , microwave conditions were performed in a SmithSynthesizer from Personal Chemistry operating at 2450 MHz.
Preparation of intermediates Preparation of substituted 2-bromo-(substituted-phenoxy)benzenes 1-B~omo-2-(2,4-clifr~ethyl plaeuox~)-benzene A solution 2,4-dimethylphenol (2.4 g) in dry dimethyl formamide (DMF) (10 mL) was added drop wise to a mixture of sodium hydride (1.0 g, 60% in mineral oil) and dry DMF (25 mL), and the resulting mixture was stirred at 100 °C for 30 min. To this mixture was further added 1-bromo-2-fluorobenzene (3.5 g) in dry DMF (5 mL), and the resulting mixture was stirred at 150 °C for 6 hours. The mixture was subsequently poured onto an ice/water mixture, and the aqueous phase was extracted with diethyl ether. The combined organic phase was washed with 2N sodium hydroxide, dried (MgS04), filtered and concentrated iya vacuo. The residue was purified by flash chromatography on silica gel (eluent: heptane) to give the cl-ude product (1.2 g, 70%
pure). The chide product was used in the next step without further purification.
The following compounds were prepared in a similar manner:
1-BY'oTno-2-(4-chloa~opTzenoxy)-benzene 1-By~omo-2-(4 flzzoz~o-2-znetlzylphenoxy)-benzene 1-Bz-omo-2-(4 fluoy~ophenoxy)-beazzezze 1-Br-omo-2-(4-nzethylplzenoxy)-benzene 1-Bz-omo-2-(~-meth oxyplz.enoxy)-benzene Preparation of alkyl 4-[B-(substituted-plieno~y)-substituted-phenyl]-4-hydro~.ypiperidine-1-carbo~ylate~
tent-Butyl 4-~2-(2, 4-Dimethylplzenoxy)plaenylJ-4-hydf-oxv piperidine-1-caf~boxylate A solution of 1-bromo-2-(2,4-dimethyl-phenoxy)-benzene (0.7 g) in diy tetrahydrofuran (THF) (3 mL) was added to a solution of nBuLi (1.6 M in hexane, 2 mL) in dry THF (15 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 1 hour and subsequently added a solution of teat-butyl 4-oxo-piperidine-1-carboxylate (1.0 g) in dry THF (3 mL). The mixture was stirred for 16 hour at room temperature, and then poured onto a saturated solution of ammonium chloride. The aqueous phase was extracted with diethyl ether, and the combined organic phase was washed with water and brine, and subsequently dried (MgS04), filtered and concentrated in vacuo.
2o The residue was purified by flash chromatography on silica gel (eluent:
heptane/ethyl acetate 4:1) to give the crude product (0.55 g). The crude product was used in the next step without further purification.
The following compounds were prepared in a similar manner:
Ethyl 4-~2-(2, 4-Dinzethylplzenoxy)plzeaaylJ-4-lzyd~oxy pipes°idine-1-cay~boxylate Ethyl 4-~2-(4-Clzlorophenoxy)phenylJ-4-hydt~oxy piper-idine-1-ca~boxylate tent-Butyl 4-~2-(4-Fluoa°o-2-methylphenoxy)ph.enylJ-4-hydy~oxy pipe~idine-1-caYboxylate Ethyl 4-~2-(4-Flzzo~o-~-nzetlzylplzenoxy)plzenylJ-4-hydroxy pipey-idine-1-car~boxylate Et7zyl 4-~2-(~1-Fluoroplzenoxy)plTeraylJ-4-hydrroxy piperidine-1-cay~boxylccte tea°t-Butyl 4-~2-(4-Metlzylplzeraoxy)phenylJ-4-lzydroxy pipezridirae-1-carboxylate Ethyl ~-~2-(4-Metlzylplzefzoxy)plzenylJ-4-Izydnoxy piperidine-1-cccr-boxylate test-Butyl 4-~2-(4-Methoxyp7zenoxy)plaenylJ-4-lzyda°oxy piper~idine-1-caa°boxylate Preparation of ethyl 4-(2-methoxy-phenyl)-piperidine-1-carboxylate To 26 mmol 4-(2-methoxyphenyl)-piperidine (Maybridge) in 100 ml chy dichloromethane were added 28.6 mmol triethylamine and 78 mmol ethylchlorofonnate at 0 °C. The solution was stirred at room temperature overnight, washed twice with 0.5 M HCl (125 ml) then dried over MgSO4 and evaporated. The product was sufficiently pure to be used in the following steps.
Preparation of ethyl 4-(2-hydroxy-phenyl)-piperidine-1-carboxylate To 24 mmol ethyl 4-(2-methoxy-phenyl)-piperidine-1-carboxylate in 150 ml dry to dichloromethane were added 48 mmol BBr3 at 0 °C. The solution was stirred at room temperature overnight, washed twice with 0.5 M HCl (125 mL) then dried over MgS04 and evaporated. The product was sufficiently pure to be used in the following steps.
15 Compounds of the invention:
Preparation of 4-[2-(substituted-phenoxy)-substituted-phenyl]-1,2,3,6-tetrahydropyridines 20 1 a, 4-~2-(2, 4-Dim.etlaylplaefaoxy)plaehyl -1, 2, 3, 6-teti°ahydf°opyridifze A mixture of test-butyl 4-[2-(2,4-dimethylphenoxy)phenyl]-4-hydroxy-piperidine-carboxylate (0.5 g) and a mixture of acidic acid and conc. hydrochloride acid (3:1) was boiled under reflux for 16 hours. The mixture was cooled, poured into allcaline 25 water and extracted with ethyl acetate. The combined organic phase was dried (MgS04), filtered and concentrated ih vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/methanol/triethylamine 8:2:1) to give the target compound (11 mg, 3%). LC/MS (m/z) 280 (MH+); RT = 2.16; purity (W, ELSD): 85%, 97%.
The following compounds were prepared in a similar mariner:
lb, 4-j2-(4-Chlof~ophenoxy)pheyaylJ-1,2,3,6-tetf~ahyd~~opy~idiyae From ethyl 4-[2-(4-chlorophenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate.
LC/MS (m/z) 286 (MH+); RT = 2.10; purity (UV, ELSD): 85%, 95%; yield: 33 mg (6°/~).
lc, 4-j2-(~-Flzco~o-2-rnetlaylphenoxy)plze~aylJ-1,2,3,6-tetr~ahyda~opy~idirte From ter°t-butyl 4-[2-(4-fluoro-2-methylphenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate. LC/MS (m/z) 284 (MH+); RT = 2.08; purity (UV, ELSD): 97%, 99%;
yield: 100 mg (21 %).
to ld, 4-j2-(4-Fluo~ophefaoxy)plaenylJ-1,2,3,6-tet~alzyd~opyridiyae From ethyl 4-[2-(4-fluorophenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate.
LC/MS (m/z) 270 (MH+); RT = 1.93; purity (UV, ELSD): 87%, 97%; yield: 45 mg ( 11 %).
1 e, 4- j2-(4-Methylphenoxy)phehylJ-1, 2, 3, 6-tet~~ahyd~opy~~idih.e From test-butyl 4-[2-(4-methylphenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate.
LC/MS (m/z) 266 (MH+); RT = 2.04; purity (LJV, ELSD): 98%, 99%; yield: 250 mg (24%).
lf, 4-j2-(4-Metlaoxyp7xenoxy)pheraylJ-1,2,3,6-tetr~ahyd~opyf~idine From test-butyl 4-[2-(4-methoxyphenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate. LC/MS (m/z) 282 (MH+); RT = 1.95; purity (LTV, ELSD): 79%, 99%;
yield: 14.7 mg (19%).
Preparation of 4-[2-(substituted-phenoxy)-substituted-phenyl)piperidines Method A
2a, 4-j2-(2,4-l~imetlzylpheraoxy)plaeraylJpipef~idiyi.e A mixture of ethyl 4-[2-(2,4-dimethylphenoxy)phenyl]-4-hydroxy-piperidine-1-3o carboxylate (0.6 g), dichloromethane (25 mL), triethylsilane (1 mL), trifluoro acidic acid (0.1 mL) and boron trifluoride diethyl etherate (0.2 mL) was stirred at room temperature for 16 hours. The resulting mixture was poured onto all~aline water and subsequently extracted with ethyl acetate. The combined organic phase was dried (MgS04), filtered and concentrated in vacuo (0.4 g). The residue was dissolved in a mixture of conc. hydrochloric acid and acidic acid (1:3) (25 mL) and boiled under reflux for 16 hours. The mixture was poured onto all~aline water and subsequently extracted with ethyl acetate. The combined organic phase was dried (MgSO4), filtered 5 and concentrated iaa vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/methanol/triethylamine 8:2:2) to give the target compound (10.6 mg, 3%). LC/MS (m/z) 282 (MH+); RT = 2.22; purity (UV, ELSD):
G7%, 83%.
to The following compounds were prepared in a similar manner:
2b, 4-~2-(4-Chlo~ophenoxy)phenylJpiperidihe From ethyl 4-[2-(4-chlorophenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate.
LC/MS (m/z) 288 (MH+); RT = 2.1; purity (UV, ELSD): 96%, 97%; yield: 41 mg is (7%).
2c, 4-~2-(4-Fluo~o-2-methylpheyaoxy)plaenylJpipe~~idis~e From ethyl 4-[2-(4-fluoro-2-methylphenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate. LC/MS (m/z) 286 (MH+); RT = 2.1; purity (UV, ELSD): 89%, 99%;
2o yield: 51 mg (8%).
2d, 4-~2-(4-FluoYOphenoxy)plaerayl jpiperidihe From ethyl 4-[2-(4-fluorophenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate.
LC/MS (m/z) 272 (MH+); RT = 1.97; purity (UV, ELSD): 91 %, 99%; yield: 7 mg 25 (5%).
2e, 4-~2-(4-Metlaylplaeyaoxy)phenyl piperidih.e From ethyl 4-[2-(4-methylphenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate.
LC/MS (m/z) 268 (MH+); RT = 2.12; purity (UV, ELSD): 88%, 93%; yield: 8 mg 3o (1%).
Method B
Ethyl 4-(2-Hydroxy-phenyl)-piperidine-1-carboxylate (0.1 mmol ) was combined in 0.5 mL 1-methyl-pyrrolidin-2-one with 0.12 mmol of an appropriate aryl bromide or iodide. CuI catalyst (0.037 rrunol) was added and the vial sealed before it was heated for 1 hour in a microwave oven at 220 °C. The solvent was removed from the samples, and a solution of I~~H in water (3.7 mmol), dioxane and ethanol (99,9%) were added, and the mixture was heated at 130 °C for 1 hour in the microwave oven.
The samples were then added water and solid IVaCI and then subsequently extracted to with ethyl acetate. The organic phase was evaporated and the crude product purified by preparative LC-MS. The isolated products were subjected to SCX columns and the flee amines submitted for testing as DMSO solutions. The following compounds were prepared by this method and measured molecular mass, measured HPLC-retention time (RT, min) and LTV- and ELSD-purities (%) is described in Table 1.
3a, 4-[2-(4-Chloro-2- methyl-phenoxy)-phenyl]-piperidine 3b, 4-[2-(3-Chloro-2- methyl-phenoxy)-phenyl]-piperidine 3c, 4-[2-(2-Chloro-4-methyl-phenoxy)-phenyl]-piperidine 3d, 4-[2-(2,4-Dichloro-phenoxy)-phenyl]-piperidine 3e, 4-[2-(Benzo[1,3]dioxol-5-yloxy)-phenyl]-piperidine 3f, 4-[2-(4-Methoxy-2-methyl-phenoxy)-phenyl]-piperidine 3g, 4-[2-(3,4-Dichloro-phenoxy)-phenyl]-piperidine 3h, 4-[2-(3,4-Dimethyl-phenoxy)-phenyl]-piperidine 3i, 4-[2-(2,3,4,5-Tetramethyl-phenoxy)-phenyl]-piperidine 3j, 4-[2-(4-Trifluoromethyl-phenoxy)-phenyl]-piperidine 3k, 4-[2-(4-Methoxy-phenoxy)-phenyl]-piperidine 31, 4-[2-(2-Chloro-4-methoxy-phenoxy)-phenyl]-piperidine 3m, 4-[2-(3,4-Dimethoxy-phenoxy)-phenyl]-piperidine 3n, 4-[2-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-piperidine Table 1. Measured molecular mass, measured HPLC-retention time (RT, min) and UV- and ELSD-purities (%).
UV-purity ELSDpurity compound M+H RT min.
(%) (%) 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 3~ 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 31c 284,3 1,92 99,14 97,5 31 318,1 2,07 73,27 85,01 3m 314,1 1,78 97,94 99,05 3n 356,2 2,34 98,68 88,11 Measurements of [3H]-5-HT uptake into rat cortical synaptosomes.
Whole brains from male Wistar rats (125-225 g), excluding cerebellum, are homogenized in 0.32 M sucrose supplemented with 1mM nialamid with a glass/teflon homogenizes. The homogenate is centrifuged at 600 x g for 10 min at 4 °C. The pellet is discarded and the supernatant is centrifuged at 20.000 x g for 55 min. The final pellet is homogenized (20 sec) in this assay buffer (0.5 mg original tissue/well). Test compounds (or buffer) and 10 mM [3H]-5-HT are added to 96 well plates and shalcen briefly.
to Composition of assay buffer: 123 mM NaCI, 4.82 mM KCI, 0.973 mM CaCl2, 1.12 mM
MgS04, 12.66 mM Na2HP04, 2.97 mM NaH2P04, 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid. Buffer is oxygenated with 95% Oz/5% COZ for 10 min at 37 °C
and pH is adjusted 7.4. The incubation is started by adding tissue to a final assay volume of 0.2 mL. After 15 min incubation with radioligand at 37 °C, samples are filtered is directly on Unifilter GF/C glass fiber filters (soaked for 1 hour in 0.1%
polyethylenimine) under vacuum and immediately washed with 3 x 0.2 ml assay buffer.
Non-specific uptalce is determined using citalopram (10 ~.M final concentration).
Citalopram is included as reference in all experiments as dose-response curve.
Measurements of [3H]noradrenaline uptake into rat cortical synaptosomes.
Fresh cortex from male Wistar rats (125-225 g) are homogenized in 0.4M sucrose with a glass/teflon homogenizer. The homogenate is centrifuged at 600 x g for 10 min at 4 °C. The pellet is discarded and the supernatant is centrifuged at 20.000 x g for 55 min. The final pellet is homogenized (20 sec) in this assay buffer (6 mg original tissuchnL = 4 mg/well). Test compounds (or buffer) and 10 nM [3H]-noradrenaline are added to deep 96 well plates and shapen briefly. Composition of assay buffer: 123 mM NaCI, 4.82 mM KCI, 0.973 mM CaCl2, 1.12 mM MgS~4, 12.66 mM Na2HP~4, 2.97 mM NaH2P~4, 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid.
to )3uffer is oxygenated with 95% 02/5% C02 for 10 min at 37 °C and pH
is adjusted 7.4.
The incubation is started by adding tissue to a final assay volume of 1 ml.
After 15 min incubation with radioligand at 37 °C, samples are filtered directly on Unifilter GF/C glass fiber filters (soaped for 1 hour in 0.1 % polyethylenimine) under vacuum and immediately washed with 3 x 1 mL assay buffer. Non-specific uptape is 15 determined using talsupram (10 ~.M final concentration). Duloxetine is included as reference in all experiments as dose-response curve.
Results of the experiments showed that the tested compounds of the invention inhibit the norepinephrine and serotonine reuptalce with ICso below 200 nM.
l~aekground of the invention to Selective serotonin reuptal~e 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 a~zd have a favourable safety profile compared to the classic tricyclic antidepressants.
15 However, clinical studies on depression indicate that non-response to SSRIs is substantial, up to 30%. Another, often neglected, factor in antidepressant treatment is compliance, which has a rather profound effect on the patient's motivation to continue pharmacother apy.
2o First of all, there is the delay in therapeutic effect of SSRIs. Sometimes symptoms even worsen during the first weeps 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 lilcely to happen.
25 The combined effect of serotonin reuptake inhibition and norepinephrine uptalce iWibition on depression is explored in clinical studies of compounds such as Duloxetine (along, Duloxetine (LY-248686): an inhibitor of serotonin and noradrenaline uptalce and an antidepressant drug candidate Expey~t Opihiora ofZ
Irzvestigutioraal Dr°ugs, 1998, 7, 10, 1691-1699) and Venlafaxine (Khan-A et al, 3o Venlafaxine in depressed outpatients 1'syelz.~p7icza°macolog~
Bulletif~, 1991, ~'7, 14.1-144).
The present invention provides novel compounds which posses the combined effect of serotonin reuptake inhibition and norepinephrine uptake inhibition 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 attacl~s, specific phobias, social phobia and agoraphobia.
~urramaxy 0f the i~tventi~n The present invention provides compounds of the general formula I
HN R~
.. / . R6 R9'~ R7 R$
to wherein the dotted line, R1, R2, R3, R4, R5, R~, R', R8, and R~ are as defined below.
The invention provides a compound according to the above for use as a medicament.
15 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 20 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 attacl~s, 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, including a human, comprising administering a therapeutically effective amount of a compound according to the above or a pharmaceutically acceptable acid addition salt thereof.
~efiniti0ii 0f ~ub~tituent~
to Halogen means fluoro, chloro, bromo or iodo.
The expression C1_~-allc(enlyn)yl means a C1_~-alkyl, CZ_~-alkenyl or a CZ_G-allcynyl group.
The term C 1 _~ alkyl refer s to a branched or unbranched allcyl 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, C2_~ alkenyl and C2_~ 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 C1_~-alk(euyn)yloxy, C1_~ allc(en/yn)ylsulfanyl, hydroxy-C1_~-alk(eWyn)yl, halo-C1_~-allc(en/yn)yl, cyano-C1_~-alk(en/yn)yl, NRZRW-C1_~-allc(enyn)yl, C1_~-allc(enlyn)yloxy-C1_~-allc(en/yn)yl and halo-C1_~-allc(en/yn)yloxy designate such groups in which the C1_~-allc(en/yn)yl are as defined above. Halo means halogen.
NR~RW-C1_G-alk(euyn)yl designate the group R~
RW N-G~-6a~k(en/yn)yl The term C3_8 cycloall~yl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, etc.
The term C3_8 cycloal~eriyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms and including ogle double bond.
I11 the te1111 C3_$-cycloallc(en)yl-C1_G-allc(en/y11)yl, C3_8-cycloall~(en)yl alld Ci-G-all~(en/yn)yl are as defined above.
to The term 3-7-membered ring optionally containing one ful-ther heteroatom, such as N, O, or S, as used herein refers to ring systems such as 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, all of which may be further substituted with a group selected from a C1_G-all~(en/yn)yl, hydroxy, hydroxy-C1_G-allc(en/yn)yl, C1_G-allc(en/yn)yloxy-C 1 _G-all~(en/yn)yl .
Description of the invention 2o The present invention relates to 4-(2-phenyloxyphenyl)-piperidine or -1,2,3,6-tetrahydropyridine derivatives which are serotonin reuptal~e inhibitors and as such effective in the treatment of for example depression and anxiety. In particular the piperidines are also good norepinephrine uptal~e inhibitors.
Accordingly the present invention relates to a compound represented by the general formula I
H~
R
RV
when ein the dotted line ---- indicates a single bond or a double bond;
RI, R2, R3, R4, RS are independently selected from hydrogen, halogen, cyano, C1-~-allc(en/yn)yl, C1_~-alk(en/yn)yloxy, C1_~-alk(euyn)ylsulfanyl, hydroxy, hydroxy-C1_~-alk(en/yn)yl, halo-C1_~-alk(en/yn)yl, halo-C1_~-allc(en/yn)yloxy, or NR"Ry wherein R"
and Ry are independently selected from hydrogen, C1_~-alk(eWyn)yl, cyano-C1_~-to allc(en/yn)yl, C3_g-cycloalk(en)yl, C3_$-cycloallc(en)yl-C1_~-alk(enlyn)yl, or NRZRW-C1_ ~-alk(enJyn)yl, wherein RZ and RW are independently selected from hydrogen, C1_~-alk(en/yn)yl, C3_$-cycloalk(en)yl, or C3_g-cycloalk(en)yl-C1_~-alk(enyn)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 RZ and R3 together form a heterocycle fused to the phenyl ring selected from ~o ~o ; and R1, R4, R5 are as defined above;
R~, R', R8, R~ are independently selected from hydrogen, halogen, C1_~-allc(euyn)yl, 2o C1_~-allc(euyn)yloxy, CI_~-alk(eW~m)ylsulfanyl, hydroxy, hydroxy-C1_~-alk(euyn)yl, halo-C1_~-allc(en/yn)yl, halo-C1_~-allc(enyn)yloxy, or NRXRy wherein R" and RY
axe independently selected from hydrogen, C1_~-alk(en/yn)yl, cyano-C1_~-allc(en/yn)yl, C3_ 8-cycloalk(en)yl, C3_8-cycloall~(en)yl-C1_~-allc(en/yn)yl, or NR~R'~'-C1_~-allc(en/yn)yl, wherein RZ and RW are independently selected from hydrogen, C1_~-alk(en/yn)yl, C3_8-cycloalk(en)yl, or C3_8-cycloallc(en)yl-Cl_~-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 Rl, R2, R3, R4, R5, R~, R~, R8, and R~ is different from hydrogen;
or a salt thereof.
In one embodiment of the compound of formula I, Rl is selected from hydrogen, halogen, cyano, C1_~-alk(en/yn)yl, C1_~-alk(en/yn)yloxy, C1_~-alk(en/yn)ylsulfanyl, to halo-CI_~-alk(en/yn)yl, or NR"Ry wherein RX and RY are independently selected from hydrogen, C1_~-alk(en/yn)yl, cyano-C1_~-allc(en/yn)yl, C3_8-cycloallc(en)yl, C3_8-cycloalk(en)yl-C1_~-allc(en/yn)yl, or NRZRW-C1_~-alk(en/yn)yl, wherein RZ and RW are independently selected from hydrogen, C1_~-alk(en/yn)yl, C3_8-cycloallc(en)yl, or C3_8-cycloallc(en)yl-C1_~-alk(en/yn)yl, provided that if one of R" and RY is NRZRW-C1_~-15 alk(en/yn)yl then the other is selected from hydrogen, C1_~-allc(en/yn)yl, cyano-C1_~-alk(en/yi)yl, C3_8-cycloalk(en)yl, or C3_g-cycloalk(en)yl-C1_~-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 Rl is selected from hydrogen, halogen, cyano, C1_~-2o alk(eWyn)yl, C1_~-alk(en/yn)yloxy, C1_~-alk(en/yn)ylsulfanyl, halo-C1_~-alk(euyn)yl.
In a further embodiment Rl is NR"Ry wherein R" and RY are independently selected from hydrogen, C1_~-allc(en/yn)yl, cyano-C1_~-allc(en/yn)yl, C3_8-cycloalk(en)yl, C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl, such as hydrogen, cyanomethyl, C1_~-alk(en/yn)yl. In a fiuther embodiment Rl is NR"RY wherein R" is NRZRW-C1_~-allc(en/yn)yl, wherein RZ
25 and RW are independently selected from hydrogen, C1_~-allc(en/yn)yl, C3_8-cycloalk(en)yl, or C3_8-cycloalk(en)yl-C1_~-allc(euyn)yl, and RY is selected from hydrogen, C1_~-allc(en/yn)yl, cyano-C1_~-alk(en/yn)yl, C3_8-cycloallc(en)yl, or C3_g-cycloalk(en)yl-C1_~-allc(enyn)yl. In a further embodiment Rl is NR"Ry wherein R"
and RY together with the nitrogen to which they are attached form a 3-7-membered 30 ring which optionally contains one further hetcroatom, 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 C1_~-allc(en/yn)yl, hydroxy, hydroxy-C1_~-allc(euyn)yl, C1_~-alk(en/yn)yloxy-C1_~-alk(euyn)yl, e.g. one or two selected from hydroxy, hydroxy-C1_ ~-all~yl, C1_~-alkyloxy-C1_~-alkyl, C1_~-allcyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl. Typically, Rl is selected from hydrogen;
halogen;
cyano; C~_~-alkyl; C1_~-alhyloxy; C1_~-alkylsulfanyl; halo-C1_~-alkyl; NR"RY
wherein R~ and Ry are independently selected from hydrogen, C1_~-allcyl, cyanomethyl;
NR"Ry wherein Ry is selected from hydrogen, or C1_~-alkyl, and R~ is NR~R"'-C1-~-allc(el~/yn)yl wherein RZ and RW are independently selected from hydrogen, or C1_~-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-Cl_~-allcyl, C1_~-allcyloxy-Cl_~-alkyl, C1_~-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl.
To further illustrate without limiting the invention an embodiment of Rl is hydrogen;
another embodiment of Rl is C1_~-all~yl, such as methyl; a further embodiment of Rl is halogen, such as fluoro, or chloro.
In a further embodiment of the compound of formula I, R2 is selected from hydrogen, halogen, cyano, C1_~-allc(el~/yn)yl, C1_~-alk(en/yn)yloxy, C1_~-alk(en/yn)ylsulfanyl, halo-C1_~-alk(en/yn)yl. Typically, RZ is selected from hydrogen, halogen, cyano, C1_~-allcyl, C1_~-allcyloxy, C1_~-alkylsulfanyl, halo-C1_~-alkyl. To ful-ther illustrate without limiting the invention an embodiment of RZ is hydrogen; another embodiment of RZ is C1_~-alkoxy, such as methoxy; another embodiment of R2 is halo-C1_~-alkyl, such as trifluoromethyl; another embodiment of RZ is C1_~-alkyl, such as methyl;
another embodiment of R2 is halogen, such as chloro.
In a further embodiment of the compound of formula I, R3 is selected from hydrogen, halogen, cyano, C1_~-alk(en/yn)yl, C1_~-alk(en/yn)yloxy, C1_~-alk(enlyn)ylsulfanyl, halo-C1_~-alk(en/yn)yl. Typically, R3 is selected from hydrogen, halogen, cyano, C1_~-allcyl, C1_~-allcyloxy, C1_~-allcylsulfanyl, halo-C1_~-alkyl. To fiu-ther illustrate without limiting the invention an embodiment of 8315 hydrogen; another embodiment of R3 is 3o C1_~-alkyl, such as methyl; a further embodiment of 8315 C1_~-allcoxy, such as methoxy; a further embodiment of R3 is halogen, such as chloro, or fluoro;
another embodiment of R3 is halo-C1_~-alkyl, such as trifluoromethyl.
In a further embodiment of the compound of formula I, R2 and R3 together form a heterocycle fused to the phenyl ring selected from ~o _~
In a further embodiment of the compound of formula I, R4 is selected from hydrogen, halogen, cyano, C1_~-allc(euyn)yl, C1_~-allc(en/yn)yloxy, C1_~-alk(en/yn)ylsulfanyl, halo-C1_~-alk(en/yn)yl. Typically, R4 is selected from hydrogen, halogen, cyano, C1_~-alkyl, C1_~-alkyloxy, C1_~-alkylsulfanyl, halo-C1_~-allcyl. To further illustrate without limiting the invention an embodiment of R4 is hydrogen; another embodiment of R4 is to C1_~-allcoxy, such as methoxy; another embodiment of R4 is halo-C1_~-alkyl, such as trifluoromethyl; another embodiment of R4 is C1_~-alkyl, such as methyl;
another embodiment of R4 is halogen, such as chloro.
In a further embodiment of the compound of formula I, RS is selected from hydrogen, 15 halogen, cyano, C1_~-alk(en/yn)yl, C1_~-alk(euyn)yloxy, C1_~-alk(en/yn)ylsulfanyl, halo-C1_~-alk(en/yn)yl, or NR"RY wherein R" and Ry are independently selected from hydrogen, C1_~-alk(en/yn)yl, cyano-C1_~-alk(en/yn)yl, C3_8-cycloalk(en)yl, C3_8-cycloalk(en)yl-C1_~-alk(en/~m)yl, or NRZRW-C1_G-alk(en/yn)yl, wherein RZ and RW are independently selected from hydrogen, C1_~-alk(en/yn)yl, C3_$-cycloall~(en)yl, or C~_8-2o cycloallc(en)yl-C1_~-alk(en/yn)yl, provided that if one of R" and RY is NRZRW-C1_~-alk(eWyn)yl then the other is selected from hydrogen, C1_~-alk(euyn)yl, cyano-C1_~-allc(euyn)yl, C3_g-cycloallc(en)yl, or C3_8-cycloallc(en)yl-C1_~-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 25 compound of formula I R5 is selected from hydrogen, halogen, cyano, C1_~-alk(eWyn)yl, C1_~-alk(en/yn)yloxy, C1_~-alk(en/yn)ylsulfanyl, halo-C1_~-alk(en/yn)yl.
In a further embodiment RS is NR"R'' wherein R" and RY are independently selected from hydrogen, C1_~-allc(en/yn)yl, cyano-C1_~-alk(enyn)yl, C3_$-cycloallc(en)yl, C3_8-cycloallc(en)yl-C1_~-alk(en/yn)yl, such as hydrogen, cyanomethyl, C1_~-all~(en/yl)yl. In 3o a further embodiment RS is NRAR'' wherein R~ is NR~R'~'-C1_~-allc(en/yn)yl, wherein R
and RW are independently selected from hydrogen, C1_~-allc(euyn)yl, C3_8-cycloalk(en)yl, or C3_8-cycloall~(en)yl-C1_~-alk(en/yn)yl, and Ry is selected from hydrogen, C1_~-all~(en/yn)yl, cyano-C1_~-alk(en/yn)yl, C3_8-cycloalk(en)yl, or C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl. In a further embodiment RS is NR"Ry 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, 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 C1_~-allc(en/yn)yl, hydroxy, hydroxy-C1_~-allc(en/yn)yl, C1_~-alh(en/yn)yloxy-C1_~-allc(euyn)yl, e.g. one or two selected from hydroxy, hydroxy-Cl_ to ~-alkyl, C~_~-allcyloxy-C1_~-alkyl, C1_~-alkyl, in pauticular one or two selected from hydroxy, methoxy-methyl, methyl. Typically, RS is selected from hydrogen;
halogen;
cyano; C1_~-allcyl; C1_~-alkyloxy; C1_~-alkylsulfanyl; halo-C1_~-alkyl; NR"R'' wherein R" and Ry are independently selected from hydrogen, C1_~-alkyl, cyanomethyl;
NR"RY
wherein R'' is selected from hydrogen, or C1_~-alkyl, and R" is NRZRW-C1_~-alk(eWyn)yl wherein RZ and RW are independently selected from hydrogen, or C1_~-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-C1_~-alkyl, C1_~-alkyloxy-C1_~-alkyl, Cl_~-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl.
2o To further illustrate without limiting the invention an embodiment of RS is hydrogen;
another embodiment of RS is C1_~-alkyl, such as methyl; a further embodiment of RS is halogen, such as chloro, or fluoro.
In a further embodiment of the compound of formula I R~ is selected from hydrogen, halogen, C~_~-allc(euyn)yl, halo-C1_~-allc(euyn)yl. Typically, R~ is selected from hydrogen, halogen, C1_~-alkyl, halo-C1_~-allcyl. To further illustrate without limiting the invention an embodiment of R~ is hydrogen; another embodiment of R~ is halogen, such as fluoro.
~0 In a further embodiment of the compound of formula I, R' is selected from hydrogen, halogen, C1_~-alk(en/yn)yl, halo-C1_~-alk(enlyn)yl. Typically, R~ is selected from hydrogen, halogen, C1_~-alkyl, halo-C1_~-alkyl. To further illustrate without limiting 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, halogen, C1_~-alk(en/yn)yl, halo-C1_~-alk(en/yn)yl, or IVR~Ry wherein R" and Ry are independently selected from hydrogen, C1_~-alk(en/yn)yl, cyano-Cl_~-allc(en/yn)yl, C3_ 8-cycloalk(en)yl, C3_8-cycloalk(en)yl-C1_~-all~(en/yn)yl, or NR~R~''-C1_~-alk(enlyn)yl, wherein RZ and RW are independently selected from hydrogen, C1_~-alk(en/yn)yl, C3_$-cycloalk(en)yl, or C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl, provided that if one of R" and to Ry is NRzRW-C1_~-alk(en/yn)yl then the other is selected from hydrogen, Cl_~-alk(en/yn)yl, cyano-C1_~-alk(en/yn)yl, C3_8-cycloallc(en)yl, or C3_$-cycloalk(en)yl-C1_~-allc(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 R8 is selected from hydrogen, halogen, C1_ ~-alk(en/yn)yl, halo-C1_~-allc(en/yn)yl. In a further embodiment R8 is NR"RY
wherein R" and Ry are independently selected from hydrogen, C1_~-alk(en/yn)yl, cyano-C1_~-allc(en/yn)yl, C3_8-cycloalk(en)yl, C3_8-cycloallc(en)yl-C1_~-alk(euyn)yl, such as hydrogen, cyanomethyl, C1_~-alk(enlyn)yl. In a further embodiment R8 is NR"R'' wherein R" is NRZRW-C1_~-alk(en/yn)yl, wherein RZ and RW are independently selected 2o from hydrogen, C1_~-allc(en/yn)yl, C3_8-cycloalk(en)yl, or C3_8-cycloallc(en)yl-C1_~-allc(eWyn)yl, and RY is selected from hydrogen, C1_~-allc(euyn)yl, cyano-C1_~-alk(en/yn)yl, C3_8-cycloalk(en)yl, or C3_8-cycloalk(en)yl-C1_~-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 ring which optionally contains one further heteroatom, such as 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pynolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substiW ted with one or more selected from a C1_~-allc(enlyn)yl, hydroxy, hydroxy-C1_~-allc(enyn)yl, C1_~-allc(enlyn)yloxy-C1_~-allc(enyn)yl, e.g. one or two selected from hydroxy, hydroxy-C1_~-alkyl, C1_~-allcyloxy-C1_~-allcyl, C1_~-allcyl, in 3o particular one or two selected from hydroxy, methoxy-methyl, methyl.
Typically, R$
is selected from hydrogen; halogen; cyano; C1_G-allcyl; C1_~-alkyloxy; CI_~-alkylsulfanyl; halo-Cl_~-alkyl; NR~RY wherein RX and Ry are independently selected from hydrogen, C1_~-allcyl, cyanomethyl; NR"Ry wherein Ry is selected from hydrogen, or C1_6-all~yl, and RX is NRZRW-C1_~-alk(en/yn)yl wherein RZ and RW
are independently selected from hydrogen, or C1_~-alkyl; 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imida~olyl, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or two selected from hydroxy, hydro~y-C1_~-alkyl, C1_~-alkyloxy-C1_~-alkyl, C1_~-all~yl, in particular one or tv,~o selected from hydroxy, methoxy-methyl, methyl. To further illustrate without limiting the invention an embodiment of R8 is hydrogen; another embodiment of R$ is halogen, such as fluoro, or bromo; a further embodiment of R8 is C1_~-alkyl, such as methyl; a further embodiment of R8 is halo-C1_~-allcyl, such as CF3.
to In a further embodiment of the compound of formula I, R~ is selected from hydrogen, halogen, C1_~-allc(euyn)yl, halo-C1_~-alk(en/yn)yl. Typically, R~ is selected from hydrogen, halogen, Cl_~-alkyl, halo-C1_~-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 Rl-R~, which is different from hydrogen, such as 1, 2, 3, or 4 substituents in the phenyl ring(s), selected from any one of Rl-R9, which is/are different fr0111 hydrogen, and the remaining substituents are hydrogen.
Thus, in a further embodiment 1 substituent selected from any one of Rl-R~, which is different from hydrogen, is present in either of the two phenyl rings, such as 1 substituent selected from Rl-R5, or the substituent is selected from R~-R~. In a further embodiment 2 substituents selected from Rl-R~, which are different from hydrogen, 3o are present in either of the two phenyl rings, such as 1 substituent selected from Rl-R5, and the other selected from R~-R~, or both substituents are selected from Rl-R5; in this respect R2 and R3 may be talcen together to form the heterocycle as defined above.
In a further embodiment 3 substituents selected from Rl-R9, which are different from hydrogen, are present in either of the two phenyl rings, such as 2 substituents selected from Rl-R5, and the last substituent is selected from R~-R~. 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 R2 as defined above, except hydrogen. In a further embodiment of the compound of formula I one substituent is present which is R3 as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are to present being R3 and R8, wherein R3 and R$ are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R3 and RG, 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 R3 and R~, wherein R3 and R' are as defined above, except hydrogen. In a further 15 embodiment of the compound of formula I two substituents are present being Rl and R3, wherein Rl and R3 are as defined above, except hydrogen. In a further embodiment of the compound of formula I two substituents are present being R2 and R3, wherein R2 and R3 are as defined above, except hydxogen, in this respect R2 and R3 may be tal~en together to form the heterocycle as defined above. In a further 2o embodiment of the compound of formula I three substituents are present being Rl, R3 and R8, wherein Rl, R3 and R8 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 25 from 4-~2-(2, 4-Di>7zethylplzetzoxy)phe>zylJ-1, 2, 3, 6-tetrahyd>~opyt~idine, 4-~2-(4-Chlor~oplzet2oxy)phertylJ-1, 2, 3, 6-tetz"a7zyd>"opy>~idi>ze, 4-~2-(4-Fluoz~o-2-metlzylphe~~.~y)pherzylJ-1, ~, 3, 6-tetf-alzyd>"~pyt°idihe, 4-~2-(~-Fluot°~plze>zoxy)phenylJ-1, ~, 3, 6-tett~ahydropyt~idi>ze, 30 ~-~2-(4-Methylphenoxy)plz~ttylJ-1,x,3,6-tett~altydt°~pyriditte, 4-~2-(~-Meth~xyplz etz~xy)plzetzylJ-1, 2, 3, 6-tett~ahydropyr~idizte, 4-~~',-(2, ~-DinzethylplTez~oxy)plzeraylJpiperidin.e, 4-~~-(4-ClaloYOplzenoxy)phenylJpipez~idi>?e, 4- j2-(4-Fluoy-o-2-methylphehoxy)phenylJpipe~idihe, 4-j2-(4-FIuoYOpheh.oxy)phe~2ylJpipef°idiyae, 4- j2-(4-Metlaylphenoxy)p7zeraylJpiperidih.e, 4-j2-(4-Chlof°o-2- methyl plaenoxy) plaefZylJ piper~idine, -l-j?-(2-Clzloro-4-fraeth3rl phenoxy) plaeazylJwiper°idine, 4-j2-(2,4-Dichlo~~o phef2oxy) phenyl) piper°idiyae, 4-j2-(penzo jbJthiophen-5 yloxy) phehylJ pipe~idine, 4-j2-(~enzzojl,3Jdioxol-5-yloxy) pheh>>lJ pipes°idine, 4-j2-(4-Metlaoxy-2-methyl ~ahenoxy) plaeraylJ ~aipef°idine, 4-j2-(3,4-Diclalo~°o pherzoxy) phei~ylJ pipe~~idiyae, 4-j2-(3,4-Diuaetlzyl plaehoxy) plaerrylJ piper°idiy~e, 4-j2-(2,3,4,5-Tetramethyl phef2oxy) phefZylJ pipey~idihe, 4-j2-(4-Trifluo~omethyl phenoxy) phenyl) pipe~idihe, 4-j2-(4-Metl2oxy plae~zoxy) phenyl) piperidine, 4-j2-(2-Chloro-4-methoxy phehoxy) plaenylJ pipe~~idine, 4-j2-(3,4-Dimetlaoxy phenoxy) phe~zylJ piperidi~2e, 4-j2-(4-Clalo~°o-3-tf°ifluo~°omethyl phenoxy) phenyl) pipe~~idine, or a pharmaceutically acceptable salt thereof. Each of these compounds is considered a 2o specific embodiment and may be subject to individual claims.
As mentioned above, most of the tested compounds posses the combined effect of serotonin reuptalce inhibition and norepinephrine uptal~e inhibition, however, a few compounds selected from 4-j2-(2,4-Dinaethylplaef2oxy)phefzylJ-1,2,3,6-tetralaydy~opy~idih.e, 4- j2-(4-Chloy~oplaenoxy)plaenylJ-1, 2, 3, 6-tet~~alaydy~opyridine, 4-j2-(4-Fluof~o-2-nzethylplze~2oxy)phenylJ-1,2, 3, 6-tety°alaydropy~idiue, 4- j2-(4-Fluoroplnenoxy)phenylJ-1, 2, 3, 6-tetralaydf~opyYidine, 4- j2-(4-Methylplae~2oxy)phenylJ-1, 2, 3, 6-tetJ°alaydr~opy°idih.e, 4-j2-(4-Metlno~.yplneraoxy)ph.erzylJ-1,2,3,x-tetrealaydYOpyr-idiyae, 4- j2-(3, 4-Dinaethyl phenoxy) plaef2ylJ piperidine, 4-j2-(2,3,4,5-Tetrarn.etlayl phert.oxy) plaenylJ piperidih.e, 4-j2-(3,4-Di~aet7aoxy plZefaoxy) phetaylJ pipet~idirae, did show serotonin reuptal~e inhibition, but did not show norepinephrine uptal~e iWibition in the test herein.
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 allcylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids.
to Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfiuic, sulfamic, nitric acids and the life.
Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cimzamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, malefic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, pahnitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for 2o example 8-bromotheophylline and the life.
Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like.
Examples of ammonium and allcylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts and the life.
Further, the compounds of this invention may exist in unsolvated as well as in 3o solvated forms with pharmaceutically acceptable solvents such as Water, ethanol arid the life. 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 it is intended that any optical isomers (i.e. enantiomers or diastereomers), as separated, pure or partially purified optical isomers and any mixtures thereof 111Cltldlllg racelnic mixtures are included within the scope of the invention.
Racelnic forms can be resolved into the optical antipodes by lgrlown 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 to 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 1- (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, l~rlown to those slcilled 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 Yorl~ (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. Lil~ewise, 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.
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 in vivo into the required compomzd of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodnzgs", ed. H. Bundgaard, Elsevier, 1985.
The invention also encompasses active metabolites of the present compounds.
to As mentioned above, the compounds of formula I are serotonin reuptal~e 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 2o 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/lcg 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 reuptalce inhibitor is beneficial. The medicament may comprise any one of the embodiments of formula I described above.
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 foumula I 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.
to 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.
15 In a further embodiment, the present invention also relates to use of a compound of fornula 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 2o fornula 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 fornula 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 attaclcs.
In a further embodiment, the present invention also relates to use of a compound of 3o fornula 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 fornula 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 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 attacl~s, specific phobias, social phobia and agoraphobia in a living animal body, including a human, comprising administering to a subj ect in need thereof a to 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 fiom a polymer support of a compound with formula II
O \ ~ 2 ~ o R
R'O- _N R1 .. \ Rs R / R~
R$
II
wherein the dotted line, Rl-R~ are as previously described, and R is a tent-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
R5 Rs \ R2 R"\~~ OH ~ R~
III
wherein Ri-R~ are as previously described, and R" is either a hydrogen atom or a carbamate group R~OCO wherein R is a tef°t-butyl, methyl, ethyl, allyl or benzyl group or R OCO is a solid supported carbamate group; or c) Reduction of the double bond in a compound of formula IV
/
\ R2 HN~ ~ R~
/ \ R6 R / R' R$
IV
wherein R1-R~ are as previously described.
to 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 lalown adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mach 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 to prefeiTed 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 15 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 lmown in the art.
Liquid dosage forms for oral administration include solutions, emulsions, 2o suspensions, syrups and elixirs.
Phamnaceutical 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/lcg body weight per day, preferably from about 0.01 to about 50 mg/lcg body weight per day, and more prefeiTed fiom about 0.05 to about 10 mg/lcg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods lmown to those spilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.01 to l0 about 1000 mg, preferably from about 0.05 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for 15 oral administration.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of the formula (I) 2o contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the formula (1) with a chemical equivalent of a pharmaceutically acceptable acid. Representative examples are mentioned above.
For parenteral administration, solutions of the novel compounds of the formula (I) in 25 sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous 30 media employed are all readily available by standard teclmliques known to those slcilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower all~yl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospho lipids, fatty acids, fatty acid amines, polyoxyethylenc and water. similarly, the carrier or diluent may include any sustained release material l~nown in the art, such as glyccryl monostearate or glyceryl distearatc, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutical acceptable carriers arc then readily administered in a variety of dosage forms suitable for the disclosed routes of 1o administration. The formulations may conveniently be presented in unit dosage form by methods l~nown in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
2o If a solid carrier is used for oral administration, the preparation may be a tablet, placed in a hard gelatine capsule in powder or pellet fore or it can be in the forn of a troche or lozenge.
The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
The compounds of the invention are prepared by the following general methods, or as described in the experimental section of this patent:
a) Deprotection or cleavage from a polymer support of a compound with formula II
R~~ N
R
.. \ R6 -, 8 II
wherein R1-R~ are as previously described, and R~ is a tef°t-butyl, methyl, ethyl, allyl or benzyl group or ROCO is a solid supported carbamate group, such as the Wang resin-based carbasnate linlcer;
b) Dehydrating and optionally simultaneously deprotecting a compound of formula III
\ R2 R,yN OH o R~
Rg / R~
R$
io wherein Rl-R~ are as previously described, and R" is either a hydrogen atom or a carbamate group R OCO wherein R~ is a tee°t-butyl, methyl, ethyl, allyl or benzyl group or R~OCO is a solid suppouted carbamate group, such as the Wang resin-based carbamate linlcer;
is c) Reduction of the double bond in a compound of formula IV
R5 Rs \ R2 Hi~~ ~ R~
IV
wherein R1-R~ are as previously described.
The deprotection according to method a) was performed by standard techniques, knowledgeable to those skilled in the art and detailed in the textboolc Pf-otective GT°oups in Organic Synthesis T.W.Greene and P.G.M. Wuts, Wiley Interscience, (1991) ISBN 0471623016. The cleavage from a polymer support, such as from the Wang resin-based carbamate linker, according to method a) may be performed according to literature known procedures (Zaragoza Tetrah.edf°ora Lett.
1995, 36, 8677-8678 and Conti et al. Tetnahed~on Lett. 1997, 38, 2915-2918).
Starting materials of formula II can be prepared by removal of the hydroxy group of compounds of formula III by a number of methods lmown to the chemist skilled in the art, e.g. by the use of triethylsilane in trifluoro acidic acid and boron trifluoride diethyl etherate (see Encyclopaedia of Reagefats foy° Organic Synthesis, vol 7, Paquette, ed.;
John Wiley & Sons, Chichester, 1995, 5122-5123). Starting materials of formula II, which are piperidines, may be prepared by reduction of the double bond of the corresponding tetrahydropyridines by standard hydrogenation procedures, such as e.g.
catalytic hydrogenation at low pressure (< 3 atm.) in a Parr apparatus.
The dehydration reaction and optional simultaneous deprotection of a compound of fOr111ll1a III according to method b) was performed in a similar manner as described in Pahner et al J. Mcd. Glaern. 1997, 40, 1982-1989.
Starting materials of formula III were prepared from the corresponding properly substituted 1-bromo-2-phenoxybenzenes of formula VI (wherein Rl-R~ are as previously described, and G is a bromine or iodine atom) by metal-halogen exchange followed by addition of an appropriate electrophile of the formula V (wherein R' is as previously described) in a similar manner as described in Pahner et al. .~
Ihfed. C7ze~az.
1997, 40, 1982-1989.
R~
~5 ~3 W~ ~ \ ~2 O
G G
V
VI
The properly substituted 1-bromo-2-phenoxybenzenes were prepared by reaction of properly substituted phenols (the sodium salt of the phenols were prepared in situ by to the use of sodium hydride) with properly substituted 1-bromo-2-fluorobenzenes in dimethyl formamide (DMF) at elevated temperature. The diaryl ethers may also be prepared by various modifications of this method (see e.g. Schmittlinger et al J.Org. Claena. 1993, 58, 3229-3230; Beugelmans et al Tetralzedf°ora Lett. 1994, 35, 5649-5652; Sawyer et al J.Org.Claem. 1998, 63, 6338-6343), under Ullmann 15 conditions or via arylation of phenols with arylboronic acids (Evans et al Tetrahedron Lett 1998, 39, 2937-2940). Phenols and 1-bromo-2-fluorobenzenes are commercially available.
The reduction of the double bond according to method c) is generally performed by 2o catalytic hydrogenation at low pressure (< 3 atm.) in a Parr apparatus.
Starting materials of formula IV may be prepared from compounds of formula II by deprotection as described above.
Examples Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with IonSpray source and Shimadzu LC-8A/SLC-l0A LC system. Column: 30 X 4.6 mm Waters Symmmetry C18 column with 3.5 Nm particle size; Solventsystem: A =
water/trifluoroacetic acid (100:0.05) and B =
water/acetolutrile/trifluoroacetic acid (5:95:0.03); Method: Linear gradient elution with 90% A to 100% B in 4 min and with a flow rate of 2 111L/mlll. Purity was determined by integration of the LTA (254 lnn) and ELSD trace. The retention times (RT) are expressed in minutes.
to Preparative LC-MS-purification was performed on the same instrument.
Column: 50 X 20 mln YMC ~DS-A with 5 ~.m particle size; Method: Linear gradient elution with 80% A to 100% B in 7 min and with a flow rate of 22.7 mLlmin. Fraction collection was performed by split-flow MS detection.
Reactions carried out under , microwave conditions were performed in a SmithSynthesizer from Personal Chemistry operating at 2450 MHz.
Preparation of intermediates Preparation of substituted 2-bromo-(substituted-phenoxy)benzenes 1-B~omo-2-(2,4-clifr~ethyl plaeuox~)-benzene A solution 2,4-dimethylphenol (2.4 g) in dry dimethyl formamide (DMF) (10 mL) was added drop wise to a mixture of sodium hydride (1.0 g, 60% in mineral oil) and dry DMF (25 mL), and the resulting mixture was stirred at 100 °C for 30 min. To this mixture was further added 1-bromo-2-fluorobenzene (3.5 g) in dry DMF (5 mL), and the resulting mixture was stirred at 150 °C for 6 hours. The mixture was subsequently poured onto an ice/water mixture, and the aqueous phase was extracted with diethyl ether. The combined organic phase was washed with 2N sodium hydroxide, dried (MgS04), filtered and concentrated iya vacuo. The residue was purified by flash chromatography on silica gel (eluent: heptane) to give the cl-ude product (1.2 g, 70%
pure). The chide product was used in the next step without further purification.
The following compounds were prepared in a similar manner:
1-BY'oTno-2-(4-chloa~opTzenoxy)-benzene 1-By~omo-2-(4 flzzoz~o-2-znetlzylphenoxy)-benzene 1-Bz-omo-2-(4 fluoy~ophenoxy)-beazzezze 1-Br-omo-2-(4-nzethylplzenoxy)-benzene 1-Bz-omo-2-(~-meth oxyplz.enoxy)-benzene Preparation of alkyl 4-[B-(substituted-plieno~y)-substituted-phenyl]-4-hydro~.ypiperidine-1-carbo~ylate~
tent-Butyl 4-~2-(2, 4-Dimethylplzenoxy)plaenylJ-4-hydf-oxv piperidine-1-caf~boxylate A solution of 1-bromo-2-(2,4-dimethyl-phenoxy)-benzene (0.7 g) in diy tetrahydrofuran (THF) (3 mL) was added to a solution of nBuLi (1.6 M in hexane, 2 mL) in dry THF (15 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 1 hour and subsequently added a solution of teat-butyl 4-oxo-piperidine-1-carboxylate (1.0 g) in dry THF (3 mL). The mixture was stirred for 16 hour at room temperature, and then poured onto a saturated solution of ammonium chloride. The aqueous phase was extracted with diethyl ether, and the combined organic phase was washed with water and brine, and subsequently dried (MgS04), filtered and concentrated in vacuo.
2o The residue was purified by flash chromatography on silica gel (eluent:
heptane/ethyl acetate 4:1) to give the crude product (0.55 g). The crude product was used in the next step without further purification.
The following compounds were prepared in a similar manner:
Ethyl 4-~2-(2, 4-Dinzethylplzenoxy)plzeaaylJ-4-lzyd~oxy pipes°idine-1-cay~boxylate Ethyl 4-~2-(4-Clzlorophenoxy)phenylJ-4-hydt~oxy piper-idine-1-ca~boxylate tent-Butyl 4-~2-(4-Fluoa°o-2-methylphenoxy)ph.enylJ-4-hydy~oxy pipe~idine-1-caYboxylate Ethyl 4-~2-(4-Flzzo~o-~-nzetlzylplzenoxy)plzenylJ-4-hydroxy pipey-idine-1-car~boxylate Et7zyl 4-~2-(~1-Fluoroplzenoxy)plTeraylJ-4-hydrroxy piperidine-1-cay~boxylccte tea°t-Butyl 4-~2-(4-Metlzylplzeraoxy)phenylJ-4-lzydroxy pipezridirae-1-carboxylate Ethyl ~-~2-(4-Metlzylplzefzoxy)plzenylJ-4-Izydnoxy piperidine-1-cccr-boxylate test-Butyl 4-~2-(4-Methoxyp7zenoxy)plaenylJ-4-lzyda°oxy piper~idine-1-caa°boxylate Preparation of ethyl 4-(2-methoxy-phenyl)-piperidine-1-carboxylate To 26 mmol 4-(2-methoxyphenyl)-piperidine (Maybridge) in 100 ml chy dichloromethane were added 28.6 mmol triethylamine and 78 mmol ethylchlorofonnate at 0 °C. The solution was stirred at room temperature overnight, washed twice with 0.5 M HCl (125 ml) then dried over MgSO4 and evaporated. The product was sufficiently pure to be used in the following steps.
Preparation of ethyl 4-(2-hydroxy-phenyl)-piperidine-1-carboxylate To 24 mmol ethyl 4-(2-methoxy-phenyl)-piperidine-1-carboxylate in 150 ml dry to dichloromethane were added 48 mmol BBr3 at 0 °C. The solution was stirred at room temperature overnight, washed twice with 0.5 M HCl (125 mL) then dried over MgS04 and evaporated. The product was sufficiently pure to be used in the following steps.
15 Compounds of the invention:
Preparation of 4-[2-(substituted-phenoxy)-substituted-phenyl]-1,2,3,6-tetrahydropyridines 20 1 a, 4-~2-(2, 4-Dim.etlaylplaefaoxy)plaehyl -1, 2, 3, 6-teti°ahydf°opyridifze A mixture of test-butyl 4-[2-(2,4-dimethylphenoxy)phenyl]-4-hydroxy-piperidine-carboxylate (0.5 g) and a mixture of acidic acid and conc. hydrochloride acid (3:1) was boiled under reflux for 16 hours. The mixture was cooled, poured into allcaline 25 water and extracted with ethyl acetate. The combined organic phase was dried (MgS04), filtered and concentrated ih vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/methanol/triethylamine 8:2:1) to give the target compound (11 mg, 3%). LC/MS (m/z) 280 (MH+); RT = 2.16; purity (W, ELSD): 85%, 97%.
The following compounds were prepared in a similar mariner:
lb, 4-j2-(4-Chlof~ophenoxy)pheyaylJ-1,2,3,6-tetf~ahyd~~opy~idiyae From ethyl 4-[2-(4-chlorophenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate.
LC/MS (m/z) 286 (MH+); RT = 2.10; purity (UV, ELSD): 85%, 95%; yield: 33 mg (6°/~).
lc, 4-j2-(~-Flzco~o-2-rnetlaylphenoxy)plze~aylJ-1,2,3,6-tetr~ahyda~opy~idirte From ter°t-butyl 4-[2-(4-fluoro-2-methylphenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate. LC/MS (m/z) 284 (MH+); RT = 2.08; purity (UV, ELSD): 97%, 99%;
yield: 100 mg (21 %).
to ld, 4-j2-(4-Fluo~ophefaoxy)plaenylJ-1,2,3,6-tet~alzyd~opyridiyae From ethyl 4-[2-(4-fluorophenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate.
LC/MS (m/z) 270 (MH+); RT = 1.93; purity (UV, ELSD): 87%, 97%; yield: 45 mg ( 11 %).
1 e, 4- j2-(4-Methylphenoxy)phehylJ-1, 2, 3, 6-tet~~ahyd~opy~~idih.e From test-butyl 4-[2-(4-methylphenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate.
LC/MS (m/z) 266 (MH+); RT = 2.04; purity (LJV, ELSD): 98%, 99%; yield: 250 mg (24%).
lf, 4-j2-(4-Metlaoxyp7xenoxy)pheraylJ-1,2,3,6-tetr~ahyd~opyf~idine From test-butyl 4-[2-(4-methoxyphenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate. LC/MS (m/z) 282 (MH+); RT = 1.95; purity (LTV, ELSD): 79%, 99%;
yield: 14.7 mg (19%).
Preparation of 4-[2-(substituted-phenoxy)-substituted-phenyl)piperidines Method A
2a, 4-j2-(2,4-l~imetlzylpheraoxy)plaeraylJpipef~idiyi.e A mixture of ethyl 4-[2-(2,4-dimethylphenoxy)phenyl]-4-hydroxy-piperidine-1-3o carboxylate (0.6 g), dichloromethane (25 mL), triethylsilane (1 mL), trifluoro acidic acid (0.1 mL) and boron trifluoride diethyl etherate (0.2 mL) was stirred at room temperature for 16 hours. The resulting mixture was poured onto all~aline water and subsequently extracted with ethyl acetate. The combined organic phase was dried (MgS04), filtered and concentrated in vacuo (0.4 g). The residue was dissolved in a mixture of conc. hydrochloric acid and acidic acid (1:3) (25 mL) and boiled under reflux for 16 hours. The mixture was poured onto all~aline water and subsequently extracted with ethyl acetate. The combined organic phase was dried (MgSO4), filtered 5 and concentrated iaa vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/methanol/triethylamine 8:2:2) to give the target compound (10.6 mg, 3%). LC/MS (m/z) 282 (MH+); RT = 2.22; purity (UV, ELSD):
G7%, 83%.
to The following compounds were prepared in a similar manner:
2b, 4-~2-(4-Chlo~ophenoxy)phenylJpiperidihe From ethyl 4-[2-(4-chlorophenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate.
LC/MS (m/z) 288 (MH+); RT = 2.1; purity (UV, ELSD): 96%, 97%; yield: 41 mg is (7%).
2c, 4-~2-(4-Fluo~o-2-methylpheyaoxy)plaenylJpipe~~idis~e From ethyl 4-[2-(4-fluoro-2-methylphenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate. LC/MS (m/z) 286 (MH+); RT = 2.1; purity (UV, ELSD): 89%, 99%;
2o yield: 51 mg (8%).
2d, 4-~2-(4-FluoYOphenoxy)plaerayl jpiperidihe From ethyl 4-[2-(4-fluorophenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate.
LC/MS (m/z) 272 (MH+); RT = 1.97; purity (UV, ELSD): 91 %, 99%; yield: 7 mg 25 (5%).
2e, 4-~2-(4-Metlaylplaeyaoxy)phenyl piperidih.e From ethyl 4-[2-(4-methylphenoxy)phenyl]-4-hydroxy-piperidine-1-carboxylate.
LC/MS (m/z) 268 (MH+); RT = 2.12; purity (UV, ELSD): 88%, 93%; yield: 8 mg 3o (1%).
Method B
Ethyl 4-(2-Hydroxy-phenyl)-piperidine-1-carboxylate (0.1 mmol ) was combined in 0.5 mL 1-methyl-pyrrolidin-2-one with 0.12 mmol of an appropriate aryl bromide or iodide. CuI catalyst (0.037 rrunol) was added and the vial sealed before it was heated for 1 hour in a microwave oven at 220 °C. The solvent was removed from the samples, and a solution of I~~H in water (3.7 mmol), dioxane and ethanol (99,9%) were added, and the mixture was heated at 130 °C for 1 hour in the microwave oven.
The samples were then added water and solid IVaCI and then subsequently extracted to with ethyl acetate. The organic phase was evaporated and the crude product purified by preparative LC-MS. The isolated products were subjected to SCX columns and the flee amines submitted for testing as DMSO solutions. The following compounds were prepared by this method and measured molecular mass, measured HPLC-retention time (RT, min) and LTV- and ELSD-purities (%) is described in Table 1.
3a, 4-[2-(4-Chloro-2- methyl-phenoxy)-phenyl]-piperidine 3b, 4-[2-(3-Chloro-2- methyl-phenoxy)-phenyl]-piperidine 3c, 4-[2-(2-Chloro-4-methyl-phenoxy)-phenyl]-piperidine 3d, 4-[2-(2,4-Dichloro-phenoxy)-phenyl]-piperidine 3e, 4-[2-(Benzo[1,3]dioxol-5-yloxy)-phenyl]-piperidine 3f, 4-[2-(4-Methoxy-2-methyl-phenoxy)-phenyl]-piperidine 3g, 4-[2-(3,4-Dichloro-phenoxy)-phenyl]-piperidine 3h, 4-[2-(3,4-Dimethyl-phenoxy)-phenyl]-piperidine 3i, 4-[2-(2,3,4,5-Tetramethyl-phenoxy)-phenyl]-piperidine 3j, 4-[2-(4-Trifluoromethyl-phenoxy)-phenyl]-piperidine 3k, 4-[2-(4-Methoxy-phenoxy)-phenyl]-piperidine 31, 4-[2-(2-Chloro-4-methoxy-phenoxy)-phenyl]-piperidine 3m, 4-[2-(3,4-Dimethoxy-phenoxy)-phenyl]-piperidine 3n, 4-[2-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-piperidine Table 1. Measured molecular mass, measured HPLC-retention time (RT, min) and UV- and ELSD-purities (%).
UV-purity ELSDpurity compound M+H RT min.
(%) (%) 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 3~ 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 31c 284,3 1,92 99,14 97,5 31 318,1 2,07 73,27 85,01 3m 314,1 1,78 97,94 99,05 3n 356,2 2,34 98,68 88,11 Measurements of [3H]-5-HT uptake into rat cortical synaptosomes.
Whole brains from male Wistar rats (125-225 g), excluding cerebellum, are homogenized in 0.32 M sucrose supplemented with 1mM nialamid with a glass/teflon homogenizes. The homogenate is centrifuged at 600 x g for 10 min at 4 °C. The pellet is discarded and the supernatant is centrifuged at 20.000 x g for 55 min. The final pellet is homogenized (20 sec) in this assay buffer (0.5 mg original tissue/well). Test compounds (or buffer) and 10 mM [3H]-5-HT are added to 96 well plates and shalcen briefly.
to Composition of assay buffer: 123 mM NaCI, 4.82 mM KCI, 0.973 mM CaCl2, 1.12 mM
MgS04, 12.66 mM Na2HP04, 2.97 mM NaH2P04, 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid. Buffer is oxygenated with 95% Oz/5% COZ for 10 min at 37 °C
and pH is adjusted 7.4. The incubation is started by adding tissue to a final assay volume of 0.2 mL. After 15 min incubation with radioligand at 37 °C, samples are filtered is directly on Unifilter GF/C glass fiber filters (soaked for 1 hour in 0.1%
polyethylenimine) under vacuum and immediately washed with 3 x 0.2 ml assay buffer.
Non-specific uptalce is determined using citalopram (10 ~.M final concentration).
Citalopram is included as reference in all experiments as dose-response curve.
Measurements of [3H]noradrenaline uptake into rat cortical synaptosomes.
Fresh cortex from male Wistar rats (125-225 g) are homogenized in 0.4M sucrose with a glass/teflon homogenizer. The homogenate is centrifuged at 600 x g for 10 min at 4 °C. The pellet is discarded and the supernatant is centrifuged at 20.000 x g for 55 min. The final pellet is homogenized (20 sec) in this assay buffer (6 mg original tissuchnL = 4 mg/well). Test compounds (or buffer) and 10 nM [3H]-noradrenaline are added to deep 96 well plates and shapen briefly. Composition of assay buffer: 123 mM NaCI, 4.82 mM KCI, 0.973 mM CaCl2, 1.12 mM MgS~4, 12.66 mM Na2HP~4, 2.97 mM NaH2P~4, 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid.
to )3uffer is oxygenated with 95% 02/5% C02 for 10 min at 37 °C and pH
is adjusted 7.4.
The incubation is started by adding tissue to a final assay volume of 1 ml.
After 15 min incubation with radioligand at 37 °C, samples are filtered directly on Unifilter GF/C glass fiber filters (soaped for 1 hour in 0.1 % polyethylenimine) under vacuum and immediately washed with 3 x 1 mL assay buffer. Non-specific uptape is 15 determined using talsupram (10 ~.M final concentration). Duloxetine is included as reference in all experiments as dose-response curve.
Results of the experiments showed that the tested compounds of the invention inhibit the norepinephrine and serotonine reuptalce with ICso below 200 nM.
Claims (35)
1. A compound represented by the general formula I
wherein the dotted line ---- indicates a single bond or a double bond;
R1, R2, R3, R4, R5 are independently hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, or NR x R y wherein R x and R y are independently hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NR z R w-C1-6-alk(en/yn)yl, wherein R z and R w are independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R x and R y together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; or R2 and R3 together form a heterocycle fused to the phenyl ring, said heterocycle being of formula:
; and R1, R4, R5 are as defined above;
R6, R7 , R8, R9 are independently hydrogen, halogen, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, or NR x R y wherein R x and R y are independently hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NR z R w-C1-6-alk(en/yn)yl, wherein R z and R w are independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R x and R y 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 R1, R2, R3, R4, R5, R6, R7, R8, and R9 is different from hydrogen;
or a salt thereof.
wherein the dotted line ---- indicates a single bond or a double bond;
R1, R2, R3, R4, R5 are independently hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, or NR x R y wherein R x and R y are independently hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NR z R w-C1-6-alk(en/yn)yl, wherein R z and R w are independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R x and R y together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; or R2 and R3 together form a heterocycle fused to the phenyl ring, said heterocycle being of formula:
; and R1, R4, R5 are as defined above;
R6, R7 , R8, R9 are independently hydrogen, halogen, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, or NR x R y wherein R x and R y are independently hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NR z R w-C1-6-alk(en/yn)yl, wherein R z and R w are independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R x and R y 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 R1, R2, R3, R4, R5, R6, R7, R8, and R9 is different from hydrogen;
or a salt thereof.
2. The compound of claim 1, wherein R1 is hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, halo-C1-6-alk(en/yn)yl, or NR
x R y wherein R x and R y are independently hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NR z R w-C1-6-alk(en/yn)yl, wherein R z and R w are independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, provided that if one of R x and R y is NR z R w-C1-6-alk(en/yn)yl then the other is hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R x and R y together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom.
x R y wherein R x and R y are independently hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NR z R w-C1-6-alk(en/yn)yl, wherein R z and R w are independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, provided that if one of R x and R y is NR z R w-C1-6-alk(en/yn)yl then the other is hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R x and R y 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 R1 is hydrogen, C1-6-alkyl, or halogen.
4. The compound of any one of claims 1-3, wherein R 2 is hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, or halo-C1-6-alk(en/yn)yl.
5. The compound of claim 4, wherein R2 is hydrogen, C1-6-alkoxy, halo-C1-6-alkyl, C1-6-alkyl or halogen.
6. The compound of claim 5, wherein R2 is hydrogen, or C1-6-alkoxy.
7. The compound of any one of claims 1-6, wherein R3 is hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, or halo-C1-6-alk(en/yn)yl.
8. The compound of claim 7, wherein R3 is hydrogen, C1-6-alkyl ,C1-6-alkoxy, halogen, or halo-C I-6-alkyl.
9. The compound of claim 8, wherein R3 is hydrogen, C1-6-alkyl, C1-6-alkoxy, or halogen.
10. The compound of any one of claims 1-2, wherein R2 and R3 together form the heterocycle fused to the phenyl ring, the heterocycle being of formula:
11. The compound of any one of claims 1-10 wherein R4 is hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, or halo-C1-6-alk(en/yn)yl.
12. The compound of claim 11, wherein R4 is hydrogen, C1-6-alkoxy, halo-C1-6-alkyl, C1-6-alkyl, or halogen.
13. The compound of claim 12, wherein R4 is hydrogen, or C1-6-alkoxy.
14. The compound of any one of claims 1-13 wherein R5 is hydrogen, halogen, cyano, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, halo-C1-6-alk(en/yn)yl, or NR x R y wherein R x and R y are independently hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NR z R w-C1-6-alk(en/yn)yl, wherein R z and R w are independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, provided that if one of R x and R y is NR z R w-C1-6-a1k(en/yn)yl then the other is hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R x and R y 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 R5 is hydrogen, C1-6-alkyl, or halogen.
16. The compound of any one of claims 1-15 wherein R6 is hydrogen, halogen, C1-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl.
17. The compound of claim 16, wherein R6 is hydrogen, or halogen.
18. The compound of any one of claims 1-17 wherein R7 is hydrogen, halogen, C1-alk(en/yn)yl, or halo-C1-6-alk(en/yn)yl.
19. The compound of claim 18, wherein R7 is hydrogen, or halogen.
20. The compound of any one of claims 1-19 wherein R 8 is hydrogen, halogen, alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, or NR x R y wherein R x and R y are independently hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-cycloalk(en)yl-C1-6-alk(en/yn)yl, or NR z R w-C1-6-alk(en/yn)yl, wherein R z and R w are independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, provided that if one of R x and R x is NR z R w-C1-6-alk(en/yn)yl then the other is hydrogen, C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R x and R y 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 R 8 is hydrogen, halo-C1-6-alkyl, C1-6-alkyl, or halogen.
22. The compound of any one of claims 1-21 wherein R9 is hydrogen, halogen, C1-alk(en/yn)yl, or halo-C1-6-alk(en/yn)yl.
23. The compound of claim 22, wherein R9 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), said substitutent being any one of R1-R9 and being different from hydrogen, and the remaining substituents are hydrogen.
has 1-4 substituents in the phenyl ring(s), said substitutent being any one of R1-R9 and being 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] -piperi dine 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] -piperi dine, 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.
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, anxiety disorders, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia or agoraphobia.
30. The use of a compound of any one of claims 1 to 27 for the treatment of affective disorder, anxiety disorders, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia or agoraphobia.
31. The use of claim 29 or 30 wherein said affective disorder is depression.
32. The use of claim 29 or 30 wherein said anxiety disorder is general anxiety disorder.
33. A compound of any one of claims 1-27 for use as a medicament for the treatment of affective disorder, anxiety disorders, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia or agoraphobia.
34. The compound of claim 33, wherein said affective disorder is depression.
35. The compound of claim 33, said anxiety disorder is general anxiety disorder.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US46026503P | 2003-04-04 | 2003-04-04 | |
| US60/460,265 | 2003-04-04 | ||
| PCT/DK2004/000241 WO2004087155A1 (en) | 2003-04-04 | 2004-04-02 | 4-(2-phenyloxyphenyl)-piperidine or -1,2,3,6-tetrahydropyridine derivatives as serotonin reuptake inhibitors |
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| Publication Number | Publication Date |
|---|---|
| CA2521030A1 CA2521030A1 (en) | 2004-10-14 |
| CA2521030C true CA2521030C (en) | 2009-01-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002521030A Expired - Fee Related CA2521030C (en) | 2003-04-04 | 2004-04-02 | 4-(2-phenyloxyphenyl)-piperidine or -1,2,3,6-tetrahydropyridine derivatives as serotonin reuptake inhibitors |
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| Country | Link |
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| CA (1) | CA2521030C (en) |
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| CA2521030A1 (en) | 2004-10-14 |
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