ZA200507181B - 4-(2-phenylsulfanyl-phenyl)-piperidine derivatives as serotonin reuptake inhibitors - Google Patents
4-(2-phenylsulfanyl-phenyl)-piperidine derivatives as serotonin reuptake inhibitors Download PDFInfo
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- 239000003772 serotonin uptake inhibitor Substances 0.000 title description 10
- OITWUTJGZGVOKQ-UHFFFAOYSA-N 4-(2-phenylsulfanylphenyl)piperidine Chemical class C1CNCCC1C1=CC=CC=C1SC1=CC=CC=C1 OITWUTJGZGVOKQ-UHFFFAOYSA-N 0.000 title description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 113
- 239000001257 hydrogen Substances 0.000 claims description 113
- 150000002431 hydrogen Chemical class 0.000 claims description 89
- -1 4-[2-(2,4-Dimethyl-phenylsulfanyl)-5-methyl-phenyl]-piperidine 4-[2-(4-Methoxy-phenylsulfanyl)-5-methyl-phenyl]-piperidine Chemical compound 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 53
- 229910052736 halogen Inorganic materials 0.000 claims description 53
- 150000002367 halogens Chemical class 0.000 claims description 50
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
- 208000019901 Anxiety disease Diseases 0.000 claims description 12
- 206010041250 Social phobia Diseases 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 208000019906 panic disease Diseases 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 208000008811 Agoraphobia Diseases 0.000 claims description 4
- 208000019022 Mood disease Diseases 0.000 claims description 4
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 4
- 206010033664 Panic attack Diseases 0.000 claims description 4
- 206010034912 Phobia Diseases 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 4
- 201000001716 specific phobia Diseases 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- YTOCFFKOSBTJBB-UHFFFAOYSA-N 4-[2-(4-chlorophenyl)sulfanyl-4-fluorophenyl]piperidine 4-[4-fluoro-2-(4-methoxyphenyl)sulfanylphenyl]piperidine 4-[5-methyl-2-(4-methylphenyl)sulfanylphenyl]piperidine Chemical compound C1=CC(C)=CC=C1SC1=CC=C(C)C=C1C1CCNCC1.C=1C=C(Cl)C=CC=1SC1=CC(F)=CC=C1C1CCNCC1.C1=CC(OC)=CC=C1SC1=CC(F)=CC=C1C1CCNCC1 YTOCFFKOSBTJBB-UHFFFAOYSA-N 0.000 claims 1
- OMRJQDSRZONZEQ-UHFFFAOYSA-N 4-[2-(4-chlorophenyl)sulfanyl-5-(trifluoromethyl)phenyl]piperidine 4-[2-(2,4-dimethylphenyl)sulfanyl-5-(trifluoromethyl)phenyl]piperidine 4-[2-(4-methoxyphenyl)sulfanylphenyl]piperidine Chemical compound C1=CC(OC)=CC=C1SC1=CC=CC=C1C1CCNCC1.C1CNCCC1C1=CC(C(F)(F)F)=CC=C1SC1=CC=C(Cl)C=C1.CC1=CC(C)=CC=C1SC1=CC=C(C(F)(F)F)C=C1C1CCNCC1 OMRJQDSRZONZEQ-UHFFFAOYSA-N 0.000 claims 1
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 17
- 125000001153 fluoro group Chemical group F* 0.000 description 10
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 7
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 7
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 7
- 125000003226 pyrazolyl group Chemical group 0.000 description 7
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 125000005322 morpholin-1-yl group Chemical group 0.000 description 6
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 230000001430 anti-depressive effect Effects 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 229940126570 serotonin reuptake inhibitor Drugs 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 230000003416 augmentation Effects 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 229940044551 receptor antagonist Drugs 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 208000020401 Depressive disease Diseases 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001690 micro-dialysis Methods 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 238000001050 pharmacotherapy Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 2
- 230000000697 serotonin reuptake Effects 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 1
- 102000007527 Autoreceptors Human genes 0.000 description 1
- 108010071131 Autoreceptors Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001653 citalopram Drugs 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000004050 mood stabilizer Substances 0.000 description 1
- 229940127237 mood stabilizer Drugs 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- QXLNAYIFEMXTDZ-UHFFFAOYSA-N n-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-[2-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]benzamide Chemical compound C1=C(N2CCN(C)CC2)C(OC)=CC=C1NC(=O)C(C=C1)=CC=C1C(C(=C1)C)=CC=C1C1=NN=C(C)O1 QXLNAYIFEMXTDZ-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Description
4-(2-Phenylsulfanyl-phenyl)-piperidine derivatives as serotonin reuptake inhibitors , The present invention relates to novel compounds which are serotonin reuptake inhibitors and as such effective in the treatment of for example depression and anxiety.
Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) have become first choice therapeutics in the treatment of depression, certain forms of anxiety and social phobias, because they are effective, well tolerated and have a favourable safety profile compared to the classic tricyclic antidepressants.
However, clinical studies on depression indicate that non-response to SSRIs is substantial, up to 30%. Another, often neglected, factor in antidepressant treatment is compliance, which has a rather profound effect on the patient’s motivation to continue pharmacotherapy.
First of all, there is the delay in therapeutic effect of SSRIs. Sometimes symptoms even worsen during the first weeks of treatment. Secondly, sexual dysfunction is a side effect common to all SSRIs. Without addressing these problems, real progress in the pharmacotherapy of depression and anxiety disorders is not likely to happen.
In order to cope with non-response, psychiatrists sometimes make use of augmentation strategies. ~~ Augmentation of antidepressant therapy may be accomplished through the co-administration of mood stabilizers such as lithium ‘ carbonate or triiodothyronin or by the use of electroshock. ’ 30 The effect of combined administration of a compound that inhibits serotonin reuptake and a 5-HT,4 receptor antagonist has been evaluated in several studies (Innis ef al.
Eur. J. Pharmacol. 1987, 143, 1095-204 and Gartside Br. J. Pharmacol. 1995, 115, 1064-1070, Blier et al. Trends in Pharmacol. Science 1994, 15, 220). In these studies, it was found that 5-HTa receptor antagonists would abolish the initial brake on 5-HT neurotransmission induced by the serotonin reuptake inhibitors and thus produce an immediate boost of 5-HT transmission and a rapid onset of therapeutic . action.
Several patent applications have been filed, which cover the use of a combination of a 5-HT antagonist and a serotonin reuptake inhibitor for the treatment of depression (see e.g. EP-A2-687472 and EP-A2-714663).
Another approach to increase terminal 5-HT would be through blockade of the 5-
HT)p autoreceptor. Microdialysis experiments in rats have indeed shown that increase of hippocampal 5-HT by citalopram is potentiated by GMC 2-29, an experimental 5-
HT,p receptor antagonist.
Several patent applications covering the combination of an SSRI and a 5-HTis antagonist or partial agonist have also been filed (WO 97/28141, WO 96/03400, EP-
A-701819 and WO 99/13877).
It has previously been found that the combination of a serotonin reuptake inhibitor with a compound having 5-HT,c antagonistic or inverse agonistic effect (compounds having a negative efficacy at the 5-HT,c receptor) provides a considerable increase in the level of 5-HT in terminal areas, as measured in microdialysis experiments (WO 01/41701). This would imply a shorter onset of antidepressant effect in the clinic and an augmentation or potentiation of the therapeutic effect of the serotonin reuptake inhibitor (SRI).
The present invention provides compounds which are serotonin reuptake inhibitors for } the treatment of affective disorders, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, ’ 30 obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia. Some of the compounds also have a combined effect of serotonin reuptake inhibition and 5-HTc receptor modulation, which according to
W001/41701 would imply a faster onset of antidepressant activity.
The present invention provides compounds of the general formula I
Rr 3
R? R s rR’
HN R' l i. 0
Rr’ rR 8
R wherein R', R?, R, RY RS, RS, R7, R?, and R? are as defined below.
The invention provides a compound according to the above for use as a medicament.
The invention provides a pharmaceutical composition comprising a compound according to the above or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.
The invention provides the use of a compound according to the above or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia.
The invention provides a method for the treatment of an affective disorders, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia in a living animal body, including a human, comprising administering a therapeutically effective amount of a compound according to the above or a pharmaceutically acceptable acid addition salt thereof.
Definition of substituents
S
Halogen means fluoro, chloro, bromo or iodo.
The expression Cj.¢-alk(en/yn)yl means a C,.¢-alkyl, Cs.¢-alkenyl or a C,.¢-alkynyl group.
The term Ci. alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1-propyl, 2- propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
Similarly, Cy. alkenyl and C,. alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one triple bond . respectively, including but not limited to ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
The terms Ci.¢-alk(en/yn)yloxy, Ci. alk(en/yn)ylsulfanyl, hydroxy-C,.s-alk(en/yn)yl, halo-C¢-alk(en/yn)yl, cyano-C,¢-alk(en/yn)yl, NR’R"-Cjs-alk(en/yn)yl, Cis alk(en/yn)yloxy-C,.¢-alk(en/yn)yl and halo-Cs-alk(en/yn)yloxy designate such groups in which the Cy.¢-alk(en/yn)yl are as defined above. Halo means halogen.
NR’RY-C;.¢-alk(en/yn)yl designate the group
RN s RrN=Crealkenymyl : The term Cs.g cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, etc.
The term Cs cycloalkenyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms and including one double bond.
In the term Cjs-cycloalk(en)yl-C;¢-alk(en/yn)yl, Csg-cycloalk(en)yl and C;¢- alk(en/yn)yl are as defined above. i The term 3-7-membered ring optionally containing one further heteroatom, such as N, 5 0, orS, 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 C,¢-alk(en/yn)yl, hydroxy, hydroxy-C,.s-alk(en/yn)yl, Ci.s-alk(en/yn)yloxy-
C,.¢-alk(en/yn)yl. :
The present invention relates to 4-(2-phenylsulfanyl-phenyl)-piperidine derivatives which are serotonin reuptake inhibitors and as such effective in the treatment of for example depression and anxiety.
Accordingly the present invention relates to a compound represented by the general formula I
R* 3 * 9 g 2
S 1 R
HN R
Rr
R® R’
RS
I wherein
R!, R? R® R* R’ are independently selected from hydrogen, halogen, cyano, C- alk(en/yn)yl, Ci-¢-alk(en/yn)yloxy, C,s-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-Ci.c- alk(en/yn)yl, halo-C.¢-alk(en/yn)yl, halo-C.¢-alk(en/yn)yloxy, or NR*R’ wherein R*
and R’ are independently selected from hydrogen, Ci.¢-alk(en/yn)yl, cyano-C,,- alk(en/yn)yl, Cs.g-cycloalk(en)yl, Cs.¢-cycloalk(en)yl-C;.¢-alk(en/yn)yl, or NR*R"-C;. ] c-all(en/yn)yl, wherein R” and R" are independently selected from hydrogen, Ci.- ] alk(en/yn)yl, Css-cycloalk(en)yl, Cs.g-cycloalk(en)yl-C,.¢-alk(en/yn)yl; or R* and RY together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom;
RS, R7, R®, R’ are independently selected from hydrogen, halogen, Cs-alk(en/yn)yl,
Cis-alk(en/yn)yloxy, Ci.¢-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C;.¢-alk(en/yn)yl, halo-C¢-alk(en/yn)yl, halo-C;.¢-alk(en/yn)yloxy, or NR*R’ wherein R* and R’ are independently selected from hydrogen, C,s-alk(en/yn)yl, cyano-Cy.¢-alk(en/yn)yl, Cs. g-cycloalk(en)yl, Cs.g-cycloalk(en)yl-Ci¢-alk(en/yn)yl, or NR’R¥-Cj¢-alk(en/yn)yl, wherein R” and R¥ are independently selected from hydrogen, Ci ¢-alk(en/yn)yl, Cs- cycloalk(en)yl, Ci.g-cycloalk(en)yl-Cy.¢-alk(en/yn)yl; or R* and R’ together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; provided that at least one of RY, R% R, RY RS, RS, R’, R®, and R® is different from hydrogen; also provided that when R? is methyl, then at least one of R!, R2, RY R’,
R&R, R®, R’ is different from hydrogen, or a salt thereof.
In one embodiment of the compound of formula I, R! is selected from hydrogen, halogen, cyano, C¢-alk(en/yn)yl, Cis-alk(en/yn)yloxy, Ci.¢-alk(en/yn)ylsulfanyl, halo-Cy¢-alk(en/yn)yl, or NR*RY wherein R* and R’ are independently selected from hydrogen, Ci¢-alk(en/yn)yl, cyano-Ci.¢-alk(en/yn)yl, Css-cycloalk(en)yl, Cas- cycloalk(en)yl-C;s-alk(en/yn)yl, or NR’R"-C,_s-alk(en/yn)yl, wherein R* and R™ are independently selected from hydrogen, C.g-alk(en/yn)yl, Cs.s-cycloalk(en)yl, or Cs-
A cycloalk(en)yl-C.s-alk(en/yn)yl, provided that if one of R* and RY is NR*R"-Cy.- alk(en/yn)yl then the other is selected from hydrogen, Ci.¢-alk(en/yn)yl, cyano-Ci.- : 30 alk(en/yn)yl, Cag-cycloalk(en)yl, or Csg-cycloalk(en)yl-C;.s-alk(en/yn)yl; or R* and
R’ together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom. In a further embodiment of the compound of formula I R! is selected from hydrogen, halogen, cyano, C-
alk(en/yn)yl, Ci_¢-alk(en/yn)yloxy, C,.c-alk(en/yn)ylsulfanyl, halo-C;.s-alk(en/yn)yl.
In a further embodiment R' is NR*RY wherein R* and R” are independently selected from hydrogen, C,¢-alk(en/yn)yl, cyano-C,¢-alk(en/yn)yl, Css-cycloalk(en)yl, Ci.s- cycloalk(en)yl-C;_¢-alk(en/yn)yl, such as hydrogen, cyanomethyl, C,.¢-alk(en/yn)yl. In a further embodiment R' is NR*RY wherein R* is NR“R¥-C ¢-alk(en/yn)yl, wherein R’ and RY are independently selected from hydrogen, C.s-alk(en/yn)yl, Cssg- cycloalk(en)yl, or Cig-cycloalk(en)yl-Ci¢-alk(en/yn)yl, and R” is selected from hydrogen, C,-alk(en/yn)yl, cyano-Ci.s-alk(en/yn)yl, Css-cycloalk(en)yl, or Cs.g- cycloalk(en)yl-C¢-alk(en/yn)yl. In a further embodiment R! is NR*R’ wherein R* and RY together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom, such as 1-morpholinyl, 1- piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1- pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or more selected from a C;¢-alk(en/yn)yl, hydroxy, hydroxy-C,.s-alk(en/yn)yl, Ci- alk(en/yn)yloxy-C,.¢-alk(en/yn)yl, e.g. one or two selected from hydroxy, hydroxy-C;. ¢-alkyl, C;.¢-alkyloxy-C;.¢-alkyl, Ci.¢-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl. Typically, R' is selected from hydrogen; halogen; cyano; Cj.s-alkyl; C_g¢-alkyloxy; C;s-alkylsulfanyl; halo-C;.c-alkyl; NR*RY wherein
R* and R’ are independently selected from hydrogen, Ci.¢-alkyl, cyanomethyl; NR*RY wherein RY is selected from hydrogen, or C)¢-alkyl, and R* is NR*R"-C,¢- alk(en/yn)yl wherein R* and R" are independently selected from hydrogen, or C;.¢- alkyl; 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1- imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or two selected from hydroxy, hydroxy-C, 4-alkyl, Cy.¢-alkyloxy-C;¢-alkyl,
C-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl.
To further illustrate without limiting the invention an embodiment of R! is hydrogen; another embodiment of R! is Cy.¢-alkyl, such as methyl; a further embodiment of R' is . halogen, such as fluoro, or chloro. : 30 In a further embodiment of the compound of formula I, R? is selected from hydrogen, halogen, cyano, Ci¢-alk(en/yn)yl, Ci-s-alk(en/yn)yloxy, Ci¢-alk(en/yn)ylsulfanyl, halo-C.¢-alk(en/yn)yl. Typically, R? is selected from hydrogen, halogen, cyano, C;.¢- alkyl, Ci_¢-alkyloxy, Ci.¢-alkylsulfanyl, halo-C;-alkyl. To further illustrate without limiting the invention an embodiment of R? is hydrogen; another embodiment of R? is
Ci.c-alkoxy, such as methoxy; a further embodiment of R?is halogen, such as fluoro, ) or chloro; a further embodiment of R? is Ci.s-alkyl, such as methyl.
In a further embodiment of the compound of formula I, R? is selected from hydrogen, halogen, cyano, C,¢-alk(en/yn)yl, Ci-¢-alk(en/yn)yloxy, C,.¢-alk(en/yn)ylsulfanyl, halo-C,¢-alk(en/yn)yl. Typically, R? is selected from hydrogen, halogen, cyano, C.¢- alkyl, Ci_¢-alkyloxy, C;¢-alkylsulfanyl, halo-C,¢-alkyl. To further illustrate without limiting the invention an embodiment of R? is hydrogen; another embodiment of R? is
Cig-alkyl, such as methyl; a further embodiment of R? is Cj¢-alkoxy, such as methoxy; a further embodiment of R® is halogen, such as bromo, chloro, or fluoro; a further embodiment of R? is halo-C;¢-alkyl, such as CFs; a further embodiment of R® is hydroxy-C,.¢-alkyl, such as hydroxy-methyl; a further embodiment of R? is NR*RY wherein R* is hydrogen and R’ is C;¢-alkyl, such as methylamino; a further embodiment of R? is C,4-alkenyl, such as ethenyl.
In a further embodiment of the compound of formula I, R* is selected from hydrogen, halogen, cyano, C;¢-alk(en/yn)yl, Ci¢-alk(en/yn)yloxy, Ci.s-alk(en/yn)ylsulfanyl, halo-C,.¢-alk(en/yn)yl. Typically, R* is selected from hydrogen, halogen, cyano, C;.¢- alkyl, Ci¢-alkyloxy, C,¢-alkylsulfanyl, halo-C,.¢-alkyl. To further illustrate without * limiting the invention an embodiment of R* is hydrogen; another embodiment of R%is
Ci.¢-alkoxy, such as methoxy; a further embodiment of R*is halogen, such as fluoro, or chloro; a further embodiment of R* is C,-alkyl, such as methyl.
In a further embodiment of the compound of formula I, R’ is selected from hydrogen, halogen, cyano, Ci¢-alk(en/yn)yl, Ci-s-alk(en/yn)yloxy, Cis-alk(en/yn)ylsulfanyl, halo-Cj.¢-alk(en/yn)yl, or NR*RY wherein R* and RY are independently selected from . hydrogen, Ci.g-alk(en/yn)yl, cyano-Ci¢-alk(en/yn)yl, Csg-cycloalk(en)yl, Cis- cycloalk(en)yl-C.¢-alk(en/yn)yl, or NRR*-C,¢-alk(en/yn)yl, wherein R* and R" are ’ 30 independently selected from hydrogen, C;¢-alk(en/yn)yl, Cs.s-cycloalk(en)yl, or Cs.s- cycloalk(en)yl-Ci.¢-alk(en/yn)yl, provided that if one of R* and R’ is NR*R"-C)- alk(en/yn)yl then the other is selected from hydrogen, C;.s-alk(en/yn)yl, cyano-C.¢- alk(en/yn)yl, Csg-cycloalk(en)yl, or Csg-cycloalk(en)yl-Cis-alk(en/yn)yl; or R* and
R? together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom. In a further embodiment of the ’ compound of formula I R® is selected from hydrogen, halogen, cyano, Ci.- alk(en/yn)yl, C,-¢-alk(en/yn)yloxy, C,.¢-alk(en/yn)ylsulfanyl, halo-C;_¢-alk(en/yn)yl.
In a further embodiment R’ is NR*RY wherein R* and R” are independently selected from hydrogen, C;.¢-alk(en/yn)yl, cyano-C,.-alk(en/yn)yl, Cs.g-cycloalk(en)yl, Cs.g- cycloalk(en)yl-C,¢-alk(en/yn)yl, such as hydrogen, cyanomethyl, C,¢-alk(en/yn)yl. In a further embodiment R® is NR*RY wherein R* is NR*R"-C,.¢-alk(en/yn)yl, wherein R* and R" are independently selected from hydrogen, Cis-alk(en/yn)yl, Css- cycloalk(en)yl, or Cjs-cycloalk(en)yl-C;-alk(en/yn)yl, and R’ is selected from hydrogen, C;s4-alk(en/yn)yl, cyano-Ci¢-alk(en/yn)yl, Csg-cycloalk(en)yl, or Cs.s- cycloalk(en)yl-C;.¢-alk(en/yn)yl. In a further embodiment R’> is NR*R” wherein R* and RY” together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom, such as 1-morpholinyl, 1- piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1- pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or more selected from a C,g-alk(en/yn)yl, hydroxy, hydroxy-C,¢-alk(en/yn)yl, Ci.- alk(en/yn)yloxy-C, ¢-alk(en/yn)yl, e.g. one or two selected from hydroxy, hydroxy-C;. s-alkyl, Ci.s-alkyloxy-C;_¢-alkyl, C,¢-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl. Typically, R® is selected from hydrogen; halogen; cyano; Cj¢-alkyl; Ci_g-alkyloxy; Ci.s-alkylsulfanyl; halo-C,.¢-alkyl; NR*RY wherein
R* and RY are independently selected from hydrogen, C,¢-alkyl, cyanomethyl; NR*R” wherein RY is selected from hydrogen, or Ci¢-alkyl, and R* is NR’R"-C,- alk(en/yn)yl wherein R* and R" are independently selected from hydrogen, or Ci.- alkyl; 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1- imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or two selected from hydroxy, hydroxy-Ci¢-alkyl, C;¢-alkyloxy-C,.¢-alkyl, . Ci¢-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl.
To further illustrate without limiting the invention an embodiment of R’ is hydrogen; : 30 another embodiment of R® is Cy.¢-alkyl, such as methyl; a further embodiment of R’ is halogen, such as chloro, or fluoro.
In a further embodiment of the compound of formula I, R® is selected from hydrogen, halogen, C,.s-alk(en/yn)yl, halo-C;.¢-alk(en/yn)yl. Typically, R® is selected from hydrogen, halogen, Cy -alkyl, halo-C, alkyl. To further illustrate without limiting ) the invention an embodiment of R® is hydrogen; another embodiment of RC is halogen, such as fluoro.
In a further embodiment of the compound of formula I, R is selected from hydrogen, halogen, C,.¢-alk(en/yn)yl, halo-Cis-alk(en/yn)yl. Typically, R’ is selected from hydrogen, halogen, Ci.-alkyl, halo-C;¢-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, Ci¢-alk(en/yn)yl, halo-C_s-alk(en/yn)yl, or NR*RY wherein R* and RY are independently selected from hydrogen, C,.s-alk(en/yn)yl, cyano-C;_¢-alk(en/yn)yl, Cs. g-cycloalk(en)yl, Css-cycloalk(en)yl-C¢-alk(en/yn)yl, or NR’R™-C,.¢-alk(en/yn)yl, wherein R? and RY are independently selected from hydrogen, C,.s-alk(en/yn)yl, Cs.s- cycloalk(en)yl, or Cj.s-cycloalk(en)yl-C.s-alk(en/yn)yl, provided that if one of R* and
RY is NR*RY-C;¢-alk(en/yn)yl then the other is selected from hydrogen, Ci¢- alk(en/yn)yl, cyano-C,.s-alk(en/yn)yl, Cs.g-cycloalk(en)yl, or Cs.g-cycloalk(en)yl-C; ¢- alk(en/yn)yl; or R* and R” together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom. In a further embodiment of the compound of formula I, R®is selected from hydrogen, halogen, C;. s-alk(en/yn)yl, halo-C.¢-alk(en/yn)yl. In a further embodiment, R® is NR*RY wherein
R* and RY are independently selected from hydrogen, Ci.¢-alk(en/yn)yl, cyano-Ci4- alk(en/yn)yl, Cjs-cycloalk(en)yl, Csg-cycloalk(en)yl-Cis-alk(en/yn)yl, such as hydrogen, cyanomethyl, C;.¢-alk(en/yn)yl. In a further embodiment, R® is NR*'RY . wherein R* is NR’R"-C,.s-alk(en/yn)yl, wherein R* and R" are independently selected from hydrogen, Ci¢-alk(en/yn)yl, Cjs-cycloalk(en)yl, or Cjjg-cycloalk(en)yl-Cy- ) 30 alk(en/yn)yl, and R’ is selected from hydrogen, Ci¢-alk(en/yn)yl, cyano-Ci.q- alk(en/yn)yl, Csg-cycloalk(en)yl, or Cs.g-cycloalk(en)yl-C.¢-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 l-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1- homopiperazinyl, 1-imidazolyl, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrrolyl or pyrazolyl, optionally substituted with one or more selected from a C.¢-alk(en/yn)yl, hydroxy, hydroxy-C,¢-alk(en/yn)yl, Ci¢-alk(en/yn)yloxy-Ci.¢-alk(en/yn)yl, e.g. one or two selected from hydroxy, hydroxy-C,¢-alkyl, C;.s-alkyloxy-C;-alkyl, Cis-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl. Typically, R® is selected from hydrogen; halogen; cyano; Cie-alkyl; Ci—-alkyloxy; Ci.- alkylsulfanyl; halo-C,.s-alkyl; NR*R” wherein R* and RY are independently selected from hydrogen, Ci.s-alkyl, cyanomethyl; NR*R’ wherein R’ is selected from hydrogen, or C,¢-alkyl, and R* is NR’R"-C,.¢-alk(en/yn)yl wherein R* and R" are independently selected from hydrogen, or C,s-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-C,s-alkyl, Cis-alkyloxy-C,¢-alkyl, Ci¢-alkyl, in particular one or two selected from hydroxy, methoxy-methyl, methyl. To further illustrate without limiting the invention an embodiment of R® is hydrogen; another embodiment of R® is halogen, such as fluoro, or bromo; a further embodiment of R® is Ci¢-alkyl, such as methyl; another embodiment of R® is Ci_¢-alkyloxy, such as methoxy; a further embodiment of R® is halo-C;.¢-alkyl, such as CFs.
In a further embodiment of the compound of formula I, R’ is selected from hydrogen, halogen, Ci.¢-alk(en/yn)yl, halo-C,.s-alk(en/yn)yl. Typically, R’ is selected from hydrogen, halogen, C,-alkyl, halo-C;.¢-alkyl. To further illustrate without limiting the invention an embodiment of R’ is hydrogen; another embodiment of R® is halogen, such as fluoro.
Typically, the compound of formula I has at least one substituent in the phenyl . ring(s), selected from any one of R'-R’, which is different from hydrogen, such as 1, 2, 3, or 4 substituents in the phenyl ring(s), selected from any one of R!-R?, which : 30 is/are different from hydrogen, and the remaining substituents are hydrogen. Thus, in a further embodiment 1 substituent selected from any one of R!-R®, which is different from hydrogen, is present in either of the two phenyl rings, such as 1 substituent selected from R'-R’, or the substituent is selected from R°-R®. In a further
Claims (26)
1. A compound represented by the general formula I R* 3 2 s . R HN R Re rR’ R’ R® [ Wherein R!, RZ, rR? , RY, R® are independently selected from hydrogen, halogen, cyano, Ci.¢- alk(en/yn)yl, C,-alk(en/yn)yloxy, C,.¢-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C;¢- alk(en/yn)yl, halo-C, ¢-alk(en/yn)yl, halo-C;-alk(en/yn)yloxy, or NR*R” wherein R* and RY are independently selected from hydrogen, C.s-alk(en/yn)yl, cyano-C;.s- alk(en/yn)yl, Cs s-cycloalk(en)yl, Cs.g-cycloalk(en)yl-Cy.¢-alk(en/yn)yl, or NR'R"-C,. ¢-alk(en/yn)yl, wherein R* and RY are independently selected from hydrogen, C,.¢- alk(en/yn)yl, Csg-cycloalk(en)yl, or Cs.g-cycloalk(en)yl-C;.¢-alk(en/yn)yl; or R* and RY together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; R®, R, R®, R® are independently selected from hydrogen, halogen, Cy.¢-alk(en/yn)yl, C_s-alk(en/yn)yloxy, Cj.¢-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C;¢-alk(en/yn)yl, halo-C;.¢-alk(en/yn)yl, halo-C,¢-alk(en/yn)yloxy, or NR*R” wherein R* and R” are independently selected from hydrogen, C,.¢-alk(en/yn)yl, cyano-C,.¢-alk(en/yn)yl, Cs. g-cycloalk(en)yl, Cs.g-cycloalk(en)yl-C,¢-alk(en/yn)yl, or NR'R"-C,¢-alk(en/yn)yl, wherein R* and R" are independently selected from hydrogen, C,¢-alk(en/yn)yl, Cs.s- cycloalk(en)yl, Css-cycloalk(en)yl-Ci.¢-alk(en/yn)yl; or R* and R” together with the Amended sheet 12/01/2007 nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom; provided that at least one of R!, R?, R?, RY, R’, R®, R7, R8, and R’ is different from hydrogen, also provided that when R? is methyl, then at least one of R!, R% RY RS, RS, rR’, RS, R’ is different from hydrogen; or a salt thereof.
2. The compound of claim 1, wherein R! is selected from hydrogen, halogen, cyano, Ci¢-alk(en/yn)yl, C,¢-alk(en/yn)yloxy, C¢-alk(en/yn)ylsulfanyl, halo-Ci.c- alk(en/yn)yl, or NR*R” wherein R* and R” are independently selected from hydrogen, Cis-alk(en/yn)yl, cyano-C,¢-alk(en/yn)yl, C;.s-cycloalk(en)yl, Cs.s-cycloalk(en)yl-
C.s-alk(en/yn)yl, or NR’R"-C, ¢-alk(en/yn)yl, wherein R* and R" are independently selected from hydrogen, C,_¢-alk(en/yn)yl, C;_s-cycloalk(en)yl, or Cs.3-cycloalk(en)yl-
C,.¢-alk(en/yn)yl, provided that if one of R* and R” is NR*R"-C,¢-alk(en/yn)y! then the other is selected from hydrogen, C,¢-alk(en/yn)yl, cyano-C,¢-alk(en/yn)yl, Cs.s- cycloalk(en)yl, or Cs g-cycloalk(en)yl-C).¢-alk(en/yn)yl; or R* and R” together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom.
3. The compound according to claim 2, wherein R! is selected from hydrogen, C,.¢- alkyl, or halogen.
4. The compound of any one of claims 1-3, wherein R? is selected from hydrogen, halogen, cyano, Cj¢-alk(en/yn)yl, C,-alk(en/yn)yloxy, Ci¢-alk(en/yn)ylsulfanyl, halo-C,.¢-alk(en/yn)yl.
5. The compound according to claim 4, wherein R? is selected from hydrogen or C,.¢- alkoxy.
6. The compound of any one of claims 1-5, wherein R? is selected from hydrogen, halogen, cyano, C¢-alk(en/yn)yl, C,_¢-alk(en/yn)yloxy, Cie-alk(en/yn)ylsulfanyl, halo-C,.¢-alk(en/yn)yl. Amended sheet 12/01/2007
7. The compound according to claim 6, wherein R? is selected from hydrogen, C).4- alkyl, C,.¢-alkoxy, halogen, halo-C).¢-alkyl, hydroxy-C,-alkyl, NR*RY wherein R* is hydrogen and R’ is C,¢-alkyl, or C,6-alkenyl
8. The compound according to claim 6, wherein R’ is selected from hydrogen, halogen, cyano, C,.¢-alkyl, Ci¢-alkoxy, C,.¢-alkylsulfanyl or halo-C,_¢-alkyl.
9. The compound according to claim 6, wherein R? is selected from hydrogen, C- alkyl, C,¢-alkoxy or halogen.
10. The compound of any one of claims 1-9 wherein R* is selected from hydrogen, halogen, cyano, Cjg-alk(en/yn)yl, Ci-alk(en/yn)yloxy, C,.¢-alk(en/yn)ylsulfanyl, halo-C,.¢-alk(en/yn)yl.
11. The compound according to claim 10, wherein R! is selected from hydrogen or C,. ¢-alkoxy.
12. The compound of any one of claims 1-11 wherein R’ is selected from hydrogen, halogen, cyano, Ci ¢-alk(en/yn)yl, C,¢-alk(en/yn)yloxy, Ci¢-alk(en/yn)ylsulfanyl, halo-C).¢-alk(en/yn)yl, or NR*R’ wherein R* and R” are independently selected from hydrogen, Cs¢-alk(en/yn)yl, cyano-C,¢-alk(en/yn)yl, Css-cycloalk(en)yl, Cs.- cycloalk(en)yl-C;.¢-alk(en/yn)yl, or NR*R"-C)¢-alk(en/yn)yl, wherein R* and R" are independently selected from hydrogen, C,¢-alk(en/yn)yl, Css-cycloalk(en)yl, or Cs5- cycloalk(en)yl-C}.¢-alk(en/yn)yl, provided that if one of R* and R” is NR'R"-C.c- alk(en/yn)yl then the other is selected from hydrogen, C,.¢-alk(en/yn)yl, cyano-C.¢- alk(en/yn)yl, C;.s-cycloalk(en)yl, or Csg-cycloalk(en)yl-C,.¢-alk(en/yn)yl; or R* and RY together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom.
13. The compound according to claim 12, wherein R3 is selected from hydrogen, C,.¢- alkyl, or halogen.
14. The compound of any one of claims 1-13 wherein R® is selected from hydrogen, Amended sheet 12/01/2007 halogen, C;_¢-alk(en/yn)yl, halo-C,.¢-alk(en/yn)yl.
15. The compound according to claim 14, wherein R® is selected from hydrogen, or halogen.
16. The compound of any one of claims 1-15 wherein R’ is selected from hydrogen, halogen, C,¢-alk(en/yn)yl, halo-C;_¢-alk(en/yn)yl.
17. The compound according to claim 16, wherein R’ is selected from hydrogen, or halogen
18. The compound of any one of claims 1-17 wherein R® is selected from hydrogen, halogen, C¢-alk(en/yn)yl, halo-C,¢-alk(en/yn)yl, or NR*RY wherein R* and R” are independently selected from hydrogen, C,.¢-alk(en/yn)yl, cyano-C,¢-alk(en/yn)yl, Cs. g-cycloalk(en)yl, Csi.g-cycloalk(en)yl-Cj¢-alk(en/yn)yl, or NR’R"-C,¢-alk(en/yn)yl, wherein R”* and R" are independently selected from hydrogen, Cj.¢-alk(en/yn)yl, Cs.s- cycloalk(en)yl, or Cs.g-cycloalk(en)yl-C;.¢-alk(en/yn)yl, provided that if one of R* and RY is NRR"-C,¢-alk(en/yn)yl then the other is selected from hydrogen, Cj.- alk(en/yn)yl, cyano-C,.¢-alk(en/yn)yl, Cs.s-cycloalk(en)yl, or Cs_g-cycloalk(en)yl-C.¢- alk(en/yn)yl; or R* and R’ together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom.
19. The compound according to claim 18, wherein R® is selected from hydrogen, C).¢- alkyl, halo-C,s-alkyl, or halogen.
20. The compound of any one of claims 1-19 wherein R’ is selected from hydrogen, halogen, C,.¢-alk(en/yn)ylor halo-C,.¢-alk(en/yn)yl.
21. The compound according to claim 20, wherein R® is selected from hydrogen.
22. The compound of any one of claims 1-21 wherein the compound of formula I has 1-4 substituents in the phenyl ring(s), selected from any one of R'-R°, which are different from hydrogen, and the remaining substituents are hydrogen. Amended sheet 12/01/2007
23. The compound of claim 1, said compound being 4-[2-(4-Chloro-phenylsulfanyl)-5-trifluoromethyl-phenyl]-piperidine 4-[2-(4-Methoxy-phenylsulfanyl)-phenyl]-piperidine 4-[2-(2,4-Dimethyl-phenylsulfanyl)-5-trifluoromethyl-phenyl]-piperidine 4-[2-(4-Chloro-phenylsulfanyl)-4-fluoro-phenyl]-piperidine 4-[2-(4-Methoxy-phenylsulfanyl)-4-fluoro-phenyl]-piperidine 4-[2-(4-Methyl-phenylsulfanyl)-5-methyl-phenyl]-piperidine 4-[2-(2,4-Dimethyl-phenylsulfanyl)-5-methyl-phenyl]-piperidine 4-[2-(4-Methoxy-phenylsulfanyl)-5-methyl-phenyl]-piperidine 4-[2-(4-Chloro-phenylsulfanyl)-phenyl- piperidine 4-[2-(4-Methoxy-phenylsulfanyl)-5-fluoro-phenyl]-piperidine 4-[2-(4-Chloro-phenylsulfany!)-5-fluoro-phenyl]-piperidine or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition comprising a compound of any one of claims 1-23 or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.
25. The use of a compound of any one of claims 1 to 23 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders, such as depression, anxiety disorders including general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia.
26. A compound of any one of claims 1-23 for use as a medicament. Amended sheet 12/01/2007
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| Publication Number | Publication Date |
|---|---|
| ZA200507181B true ZA200507181B (en) | 2007-03-28 |
Family
ID=36091716
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200507181A ZA200507181B (en) | 2003-04-04 | 2004-04-02 | 4-(2-phenylsulfanyl-phenyl)-piperidine derivatives as serotonin reuptake inhibitors |
Country Status (10)
| Country | Link |
|---|---|
| KR (1) | KR101107536B1 (en) |
| CN (1) | CN1780622A (en) |
| AR (1) | AR043965A1 (en) |
| BR (1) | BRPI0408647A (en) |
| CL (1) | CL2004000725A1 (en) |
| EA (1) | EA010869B1 (en) |
| IS (1) | IS2676B (en) |
| NZ (1) | NZ541859A (en) |
| UA (1) | UA81472C2 (en) |
| ZA (1) | ZA200507181B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200932225A (en) * | 2007-12-14 | 2009-08-01 | Lundbeck & Co As H | 4-[2,3-difluoro-6-(2-fluoro-4-methyl-phenylsulfanyl)-phenyl]-piperidine |
| CN105348204B (en) * | 2015-11-18 | 2018-09-14 | 乳源瑶族自治县大众药品贸易有限公司 | 1- heterocycles -2- (Heteroarylthio) benzene derivatives and its application method and purposes |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4241071A (en) * | 1977-01-27 | 1980-12-23 | American Hoechst Corporation | Antidepressant (α-phenyl-2-tolyl)azacycloalkanes |
| US4198419A (en) * | 1979-01-10 | 1980-04-15 | American Hoechst Corporation | Phenylthiophenylpiperidines |
| SK4732002A3 (en) * | 1999-10-13 | 2002-12-03 | Pfizer Prod Inc | Biaryl ether derivatives useful as monoamine reuptake inhibitors |
| UA81749C2 (en) * | 2001-10-04 | 2008-02-11 | Х. Луннбек А/С | Derivated of phenylpiperazine as serotonin reuptake inhibitorS |
-
2004
- 2004-04-02 AR ARP040101131A patent/AR043965A1/en not_active Application Discontinuation
- 2004-04-02 ZA ZA200507181A patent/ZA200507181B/en unknown
- 2004-04-02 CL CL200400725A patent/CL2004000725A1/en unknown
- 2004-04-02 KR KR1020057018872A patent/KR101107536B1/en not_active IP Right Cessation
- 2004-04-02 NZ NZ541859A patent/NZ541859A/en not_active IP Right Cessation
- 2004-04-02 CN CNA2004800091749A patent/CN1780622A/en active Pending
- 2004-04-02 BR BRPI0408647-3A patent/BRPI0408647A/en not_active IP Right Cessation
- 2004-04-02 EA EA200501577A patent/EA010869B1/en not_active IP Right Cessation
- 2004-04-02 UA UAA200509599A patent/UA81472C2/en unknown
-
2005
- 2005-08-22 IS IS7996A patent/IS2676B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN1780622A (en) | 2006-05-31 |
| KR101107536B1 (en) | 2012-01-31 |
| BRPI0408647A (en) | 2006-03-07 |
| KR20050119681A (en) | 2005-12-21 |
| CL2004000725A1 (en) | 2005-02-18 |
| UA81472C2 (en) | 2008-01-10 |
| AR043965A1 (en) | 2005-08-17 |
| NZ541859A (en) | 2008-10-31 |
| IS7996A (en) | 2005-08-22 |
| EA010869B1 (en) | 2008-12-30 |
| EA200501577A1 (en) | 2006-04-28 |
| IS2676B (en) | 2010-09-15 |
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