MXPA02006591A - Novel heteroaryl derivatives, their preparation and use - Google Patents

Novel heteroaryl derivatives, their preparation and use

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Publication number
MXPA02006591A
MXPA02006591A MXPA/A/2002/006591A MXPA02006591A MXPA02006591A MX PA02006591 A MXPA02006591 A MX PA02006591A MX PA02006591 A MXPA02006591 A MX PA02006591A MX PA02006591 A MXPA02006591 A MX PA02006591A
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MX
Mexico
Prior art keywords
benzo
piperazine
dihydro
dioxin
propyl
Prior art date
Application number
MXPA/A/2002/006591A
Other languages
Spanish (es)
Inventor
Ejner Knud Moltzen
Mikkelsen Ivan
Christian Krogjensen
Mario Rottlander
Kim Andersen
Thomas Ruhland
Gitte Mikkelsen
Original Assignee
H Lundbeck A/S
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Publication of MXPA02006591A publication Critical patent/MXPA02006591A/en

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Abstract

A heteroaryl derivative having the formula (I) any of its enantiomers or any mixture thereof, or an acid addition salt thereof , wherein X is O, S, or CR4R5;and Y is CR6R7, CR6R7CR8R9, or CR6=CR7;or X and Y together form a group CR4=CR5, or CR4=CR5CR6R7;Z is O, or S;W is N, C, or CH;n is 2, 3, 4, 5, 6, 7, 8, 9 or 10;m is 2 or 3:A is O or S wherein the dotted lines mean an optional bond. The compounds of the invention are considered useful for the treatment of affective disorders such as general anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia and eating disorders, and neurological disorders such as psychosis.

Description

NEW HETEROYARL DERIVATIVES, THEIR PREPARATION AND USE The present invention relates to novel derivatives that bind with high potency to the 5-HT? A receptor, with pharmaceutical compositions containing these compounds and with the use thereof for the treatment Certain disorders psychiatric and neurological. The compounds of the present invention are also potent ligands of the dopamine D receptor and are considered especially useful for the treatment of depression and psychosis. Moreover, numerous compounds of the present invention have potent serotonin reuptake inhibition activity and / or effect on dopamine D3 receptors. Prior art Clinical and pharmacological studies have shown that 5-HTIA agonists and partial agonists are useful in the treatment of a variety of affective disorders such as generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, depression and aggression. ltAAÍ ^ »> j ^ Ía »Jfcj | iÍÍi > ifca < ^ toJldnBia ^ aaJfaM;; It has also been reported that 5-HTu ligands can be used for the treatment of ischemia. Schechter et al., Serotonm, 1997. Vol. 2. publication 7. present a general review of 5-HT antagonists ?? and propose potential therapeutic targets for these antagonists based on preclinical and clinical data. It is claimed that 5-HT ?A antagonists may be useful in the treatment of schizophrenia, senile dementia, dementia associated with Alzheimer's disease and, in combination with anti-SSRI agents are also useful in the treatment of depression. Inhibitors of 5-HT reabsorption are well-known drugs and serve for the treatment of panic disorders and social phobia. The effect of the combined administration of a compound that inhibits the reuptake of serotonin and a 5-HT? A receptor antagonist has been evaluated in several studies (Innis, RB et al., Eur. J. Pharmacol, 1987. 143. p. 195-204 and Gartside, SE, Br. J. Pharmacol., 1995. 115. pp. 1064-1070, Blier, P et al., Trends Pharmacol. Sci. 1994. 15. 220). In these studies, it has been found that the combination of 5-H T i A receptor antagonists and serotonin reuptake inhibitors will produce a more rapid advent of therapeutic action. The dopamine D4 receptors belong to the family of dopamine D2 receptors. which is considered responsible for the antipsychotic effects of neuroleptics. The dopamine D4 receptors are located mainly in areas of the brain other than the striatum, which suggests that the dopamine D4 receptor ligands have an antipsychotic effect and lack extrapyramidal activity. Accordingly, dopamine D4 receptor ligands are potential drugs for the treatment of psychosis and the positive symptoms of schizophrenia and compounds with combined effects on the dopamine D4 and serotonergic receptors may have the additional advantage of an improved effect about the negative symptoms of schizophrenia, such as anxiety and depression, alcohol abuse, impulse control disorders, aggression, side effects induced by psychotic agents with encionales, states «J¿dtAjaAa, 4« faM? ÉÍ «, ifefe & fa, - a ....? ÍA - .. of ischemic disease, migraine, senile dementia and cardiovascular disorders and in the improvement of sleep. Dopamine D3 receptors also belong to the family of D2 type receptors. The antagonistic properties of D3 of a drug could reduce negative symptoms and cognitive deficits and would result in an improved side effect profile with respect to EPS and hormonal changes. Accordingly, it is believed that agents that act on the 5-HT? A receptor, both agonists and antonics, are of potential use in the therapy of psychiatric and neurological disorders and, therefore, are highly convenient. In addition, antagonists which have at the same time potent serotonin reuptake inhibitory activity and / or D4 and / or D3 activity can be especially advantageous for the treatment of various psychiatric and neurological diseases. WO 95/04049 describes related compounds of the general formula wherein A is a phenyl group or a benzofuran or be n z odi oxa no. It is said that these compounds are antagonists of the oiA-adrenergic receptor and that they serve for the prevention Contractions of the prostate, the urethra and the lower urinary tract. Bart J van Steen and others, Structure-Affinity Relationship Studies on 5-HT? A receptor Ligands. 2. Heterocyclic Phe n and 1 p i pe r a z i ne s with N4-Aralkyl S ub s t i t ue n t s, J. I d. Ch em, 1994. 37 (17), 2761-73 describes certain benzofuran and benzodioxane derivatives related to affinity for the 5-H T iA receptor and, therefore, useful in the treatment of depression and anxiety. SUMMARY OF THE INVENTION It has now been found that compounds of a close class of heteroaryl derivatives bind to the 5-HT1A receptor with high affinities. In addition, the compounds also have an effect on the dopamine D receptors. Moreover, it has been found that many of the compounds have potent activity Í -.,? .. * i ?? MÁ * .Amt .. r jir- • - ".-A. ÍÚMÚ * iA»? -! ^% - rfßj ^^ A & amp; amp; amp; amp; amp; inhibitor of serotonin reuptake and / or effect on the dopamine D3 receptors Accordingly, the present invention relates to novel compounds of the general formula I: fl) in which: X is -0-, -S- or -CR 44 nR 5 - and Y is -CR6R7-, -CRdR7-CR8Rc or -CR6 = CR7- or X and Y together form a group -CR4 = CR5- or CR '= CR5-CR6R7-, Z is -0- or -S-; W is N, C or CH, n is 2. 3. 4. 5. 6. 7. 8. 9 or 10; m is 2 or 3; A is 0 or S. where the dotted lines mean an optional link; each of R.sub.1 R.sub.2 and R.sub.3 is independently selected from hydrogen, halogen, nitro, cyano, R.sub.1, or R.sub.1, or R.sub.1, R.sub.1, R.sub.1, C.sub.1, C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.-alkenyl, C.sub.3 -C.sub.3 cycloalkyl. iaüká.i C3-8 cycloalkyl. alkyl C? -6. C6-6 alkoxy. alkylthio C? -6. hydroxy, formyl, acyl, amino, Ci-eamino alkyl, di (Ci-j alkyl) araino, acylamino, C i -6 alkoxycarbonylamino, ami no carboni 1 ami no, C 1 6 alkylaminocarboni 1 ami no di (alkyl C i _ e) aminocarbonylamino; each of R 'R' R and R- are independently selected from hydrogen, halogen, trifluoromethyl, C 1-6 alkyl, and C 2-6 alkenyl. C2-6 alkynyl. C3_8 cycloalkyl. C3-8 cycloalkyl-Ci-e alkyl. C6-6 alkoxy. alkylthio C? _6. amino, C1-5 alkylamino. di (alkyl Ci-j) amino, phenylamino ofeni 1 to 1 qu i 1 ami no C? _6 where the phenyl group may be substituted, acylamino, hydroxy, -SH, cyano, nitro, -COOR18- -S02-R19 or alkyl C? -6 substituted with a substituent selected from halogen, CX-alkoxy. alkylthio C? -6. amino, alkylamino C? -6. di (C?-g) amino alkyl, acylamino hydroxy -SH c i to non-nitro -COOR 18 O S02-R19; R is hydrogen, C? _6 alkyl. alkenyl C2-s. C2-6 alkynyl. phenyl or phenylalkyl C? _6. wherein the phenyl groups may be substituted, amino, alkylamino Ci-s or di (C? 6 alkyl) amino and R 19 is hydrogen, C? _6 alkyl. amino, alkylamino C? _6. di (amino, phenyl or phenylalkyl) alkyl wherein the phenyl groups may be substituted, each of R 10 and R 11 is selected from hydrogen and alkyl C i, each of R 12. R 13 R 14 R 15 R 16 is independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trif 1 or r orne t or i, C 1 -C 6 alkyl, C 2-6 alkenyl, C 2 -3 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-a 1 qui 1. or C? -6 C.sub.1-6 alkyloxy C.sub.6-al to C.sub.1 to C.sub.1 to C.sub.1 or C.sub.6 -hydroxy, formyl, acyl, amino, acylamino, to 1 cox icar bon 11 ami no C? -6. ami no carb on i 1 ami no, a 1 qui 1 ami nocar bon i 1 ami no Ci-g di (alkyl C i _ < *) ami noca r bon i 1 ami noy NR20R Wherein R 20 21 and R independently represent hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl or phenyl, or R 2 and R 2 together with the nitrogen to which they are attached form a 5- or 6-membered carbocyclic ring which optionally it contains one more heteroatom; e that when X-Y-Z together with the phenyl ring form a ring of benzofuran or benzodioxane and A is 0, then at least one of R-R 13. R14. R 15 and R 16 n o s a h i d r o g e n o; any of its enantiomers or any mixture thereof, or an acid addition salt thereof. In one embodiment of the present invention, X is -O- and Y is -CR6R7"CR8 R9- and Z is -0- In a further embodiment of the invention, X is -CR4R5- Y is -CR6R7; and Z is -0- In a further embodiment of the invention, X and Y together form a group -CR4 = CR5- and Z is -S. In a further embodiment of the invention A is 0. In a further embodiment of the invention, A is S. In a further embodiment of the invention, W e s N In a further embodiment of the invention and R are hydrogen; In one embodiment of the invention e In a further embodiment of the invention R 12. R 13 -R 14 'R 15 and R 1 are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl. C2-6 alkenyl. C6-C6 alkoxy. cyano, C6-alkylsulfonyl acyl, nitro, trifluoromethyl and trifluoromethoxy.
In a further preferred embodiment of the invention, at least one of R? "R13 'R? 4 • R15 and Rlß is halogen In another preferred embodiment of the invention, at least one of R12' R13 'R14' R15 and R1 is halogen and the other substituents are selected from the group consisting of hydrogen , halogen, C6-6 alkoxy, C6-6 alkyl, C2-6 alkenyl, C6-6 alkylsulfonyl, acyl, nitro, cyano and trifluoromethyl The specific compounds of the present invention are compounds selected from: 1- [3 - (2-Chloro-phenoxy) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; l- [3- (2,6-Dichloro-phenoxy) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) - 4- [3- (2, 4, 6-trif luoro-f-enoxy) -propyl] -piperazam; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [3 - (4-fluoro-2-methoxy-phenoxy) -propyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [3 - (4-f luoro -2-methyl-phenoxy) -propyl] -piperazine; 1- [3- (4-chloro-phenoxy) -propyl] -4- (2,3-dihydro-benzo [1, 4] dioxin-5-yl) -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5? L) -4- [3 (4-trif luorao-ethyl-f-enoxy) -propyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] d? Oxin-5-yl) -4- [3 '(2-fluoro-phenoxy) -propyl] -piperazine; 2-. { 3- [4- (2,3-dihydro-benzo [1,4] d? Ox? N-5-yl) -p? Peraz? N-1-yl] -propoxy} -benzonitrile; 1-Benzo [b] thiofen-7-yl-4- [3- (2-chloro-4-f-luoro-phenylsulfonyl) -propyl] -piperazine; 1-Benzo [b] thiof en-7-yl-4- [4- (2-chloro-4-fluoro-phenylsulfanyl) -butyl] -piperazine; 1- [2- (3, 4-Dichloro-phenylsulfanyl) -ethyl] -4- (2,3-d? Hydro-benzo [1,4] dioxin-5? I) -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5? L) -4- [2 - (4-fluoro-phenylsulfanyl) -ethyl] -piperazine; 1- [2- (Bromo-trifluororaethyl-phenylsulfanyl) -ethyl] -4- (2,3-d? Hydro-benzo [1,4] d? Oxin-5-yl) -piperazine; 1- [2- (2,6-Dichloro-phenylsulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; l- (2,3-dihydro-benzo [1,4] dioxin-5? l) -4- (3-f-enylsulfanyl-propyl) -piperazine; 1- [3- (2-Bromo-4-f-luoro-phenoxy) -propyl] -4- (2,3-d? Hydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- [4- (2,6-Dichloro-phenylsulfanyl) -butyl] -4- (2,3-d? Hydro-benzo [1,4] dioxin-5? I) -piperazine; ? 1- 1- [3- (2-Chloro-4-fluoro-phenylsulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxm-5? I) -piperazine; 1-Benzo [b] thiof en-7-yl-4 - [3- (2-chloro-4-f luoro-f-enylsulfanyl) -propyl] -piperazine; 1-Benzo [b] thiof en-7-yl-4- [3- (2,6-d? Chloro-phenylsulfanyl) -propyl] -piperazine; 1-Benzo [b] thiof en-7-yl-4- [4- (2,6-dichloro-f-phenylsulfanyl) -butyl] -piperazine; l- [4- (3-Chloro-2-methoxy-phenylsulfan? l) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1-Benzo [b] thiof en-7-yl-4- [4- (3-chloro-2-methoxy-phenylsulfanyl) -butyl] -piperazine; l-Benzo [¿> ] thiophen-7-yl-4- [3- (2-chloro-4-f luoro-f-enylsulfanyl) -propyl] -piperazine; 1- [3- (2,6-Dibromo-4-fluoro-phenoxy) -propyl 4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1-Benzo [b] thiof en-7-yl-4- [3- (2,6-dibromo-4-fluoro-phenoxy) -propyl] -piperazine; 4-. { 3- [4- (2,3-dihydro-benzo [1,4] dioxin-5-l) -piperazin-1-yl] -proppoxy} -3, 5-diiodo-benzo-n 11 r i 1 o; kái &? iÁm, 3, 5-Di-tert-butyl-4-. { 3- [4- (2, 3-dihydro-b e n z or [1,4] dioxin-5-yl) -piperazin-1-yl] -propoxy} -benzonitrile; 1- [3- (2,6-Dichloro-4-methanesulfonyl-phenoxy) propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1-Benzo [ab] thiof en-7-yl-4 - [3- (2,6-d? Chloro-4-methanesulfonyl-phenoxy) -propyl] -piperazine; 1- [3- (Bromo-trifluoromethyl-phenylsulfanyl) propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1-Benzo []] thiof en-7-yl-4- [3- (bromo-trifluoromethyl-phenylsulfanyl) -propyl] -piperazine; 1-Benzo [b] thiof en-7-yl-4- [4- (2-chloro-6-methyl-phenylsulfanyl) -butyl] -piperazine; 1-Benzo [b] thiof en-7-yl-4- [4- (2-chloro-4-f luoro-f-enyl-sulfonyl) -butyl] -piperazine; 1- [3- (2,6-Dichloro-4-fluoro-phenoxy) -propyl 4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; l-Benzo [b] thiophen-7-yl-4- [3- (2,6-dichloro-4-fluoro-phenoxy) -propyl] -piperazine; 1- [4- (2-Chloro-6-methyl-phenylsulfanyl) -butyl] -4- (2,3-d? Hydro-benzo [l,] dioxin-5-yl) -piperazine; 1- [3- (2,6-Dichloro-phenylsulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5? I) -piperazm; 1- (5-Chloro-2,2-dimethyl-2,3-dihydro-benzo-furan-7-? L) -4- [4- (2-chloro-6-methyl-phenylsulfan? L) -butyl] -piperazine; 1- (5-Chloro-3, 3-dimethyl-2,3-dihydro-benzo-furan-7-yl) -4- [4- (2-chloro-6-methyl-phenylsulfanyl) -butyl] -piperazine; 1- (5-Chloro-2,2-dimethyl-2,3-dihydro-benzo-furan-7-yl) -4- [3- (2,6-dichloro-f-phenylsulfonyl) -propyl] -piperazine; 1- (5-Chloro-3, 3-dimethyl-2, 3-dihydro-benzo-furan-7-yl) -4- [3- (2,6-dichloro-phenylsulfanyl) -propyl] -piperazine; l- (5-Chloro-3,3-dimethyl-2,3-dihydro-benzo-furan-7-yl) -4- [3- (2-chloro-4-fluoro-phenylsulfanyl) -propyl] -piperazine; l-Benzo [b] thiophen-7-yl-4- [4- (2-chloro-4-fluoro-phenoxy) -butyl] -piperazine; l- (5-Chloro-2,2-dimethyl-l-2,3-dihydro-benzo-furan-7-yl) -4- [4- (2-chloro-4-fluoro-phenylsulfanyl) -butyl] - piperazine; 1- [4- (2-Bromo-4-fluoro-phenoxy) -butyl] -4- (2,3-d? Hydro-benzo [1,4] dioxin-5? I) -piperazine; fc-fc < ttn? < j, ia *** t- .. jaaa- ,. .- ^^^ • ^^^. «« ¿¿¿¿¿1-Benzo [b] thiof en-7-il-4- [4- (2-bromo-4-fluoro-phenoxy) -butyl ] -piperazine; 1- [4- (2-Bromo-4-fluoro-phenoxy) -butyl] -4- (5-chloro-2,2-d? -methyl-2,3-dihydro-benzofuran-7-yl) -piperazine; 1- (5-Chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl) -4- [3- (2,6-dichloro-4-methanesulfonyl-phenoxy) -propyl] - piperazine; 1- (5-Chloro-3, 3-dimethyl-2,3-dihydro-benzofuran-7-yl) -4- [3- (2,6-dichloro-4-methanesulfonyl-phenoxy) -propyl ] -piperazine; 1- (5-Chloro-3, 3-dimethyl-2,3-dihydro-benzofuran-7-yl) -4- [3- (3-chloro-2-methoxy-phenylsulfanyl) -butyl] -piperazine; l- (5-Chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl) -4- [3- (2,6-dichloro-4-fluoro-phenoxy) -propyl] - piperazine; 1- (5-Chloro-3, 3-dimethyl-2, 3-dihydro-benzofuran-7-yl) -4- [3- (2,6-dichloro-4-fluoro-phenoxy) -propyl] - piperazine; l- (4- { 4- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -butoxy.] -3,5-dif luoro-phenyl) -propan-1-one; 1- [2- (2-Bromo-4,6-difluoro-phenoxy) -ethyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- [3- (2-Bromo-4,6-difluoro-phenoxy?) -propyl] 4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- [4- (2,6-Dichloro-4-fluoro-phenoxy) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; l- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [3 (2, 4, 6-tribromo-f-enoxy) -propyl] -piperazine; 1- (4 - { 3- [4- (2, 3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -propoxy.] -3,5-dif luoro -f-enyl) -propan-1-one; l- (4- [4- (4-Benzo [j] thiophen-7-yl-piperazin-1-yl) -butoxy] -3,5-difluoro-phenyl} .propan-1-one; Benzo [b] thiophen-7-yl-4- [3- (2-bromo-4,6-difluoro-phenoxy) -propyl] -piperazine; 1-Benzo [b] thiof en-7-yl-4- [ 4- (2,6-dichloro-4-fluoro-phenoxy) -butyl] -piperazine; 1-Benzo [b] thiof en-7-yl-4- [3- (2, 4,6-tribromo-phenoxy) -propyl] -piperazine; 1- {4- [3- (4-Benzo [b] thiophen-7-yl-piperazin-1-yl) -propoxy] -3,5-difluoro-phenyl} - propan-l-one; 3,5 * -Dibromo-4- { 3- [4- (2,3-dihydro-benzo- [1,4] dioxin-5-yl) -piperazin-1? ] -propoxy.}. -benzonitrile; 1- [4- (2,6-Dibromo-4-fluoro-phenoxy) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-) il) -piperazine; iA-AJLéh * m-rí - «* mmHH ****. 1- [4- (4-Bromo-2,6-difluoro-phenoxy) -butyl] 4- (2,3-dihydro-benzo [1,4] diox? N-5-yl) -piperazine; 1-Benzo [b] thiofen-7-yl-4- [3- (2,6-d? Bromo-4-nitro-phenoxy) -propyl] -piperazine; 4- [3- (4-Benzo [jb] thiophen-7-? L-p? Perazin-l-11) -propoxy] -3,5-d? Bromo-benzon? Tr? Lo; 1-Benzo [b] thiof en-7-yl-4- [4- (4-bromo-2,6-difluoro-phenoxy) -butyl] -piperazine; 1- [3- (2-Chloro-phenylsulfan? I) -propyl] -4- (2,3-d? Hydro-benzo [1,4] dioxin-5? I) -piperazine; 1-Benzo [b] t? Ofen-7-? L-4- [3- (2-chloro-phenylsulfanyl) -propyl] -piperazine; 1- [3- (2, 4-Difluoro-phenoxy?) -propyl] -4- (2,3-d-hydro-benzo [1,4] dioxin-5-yl) -p? Perazma; l- [3- (4-Bromo-2,6-difluoro-phenoxy) -propyl 4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazm; l-Benzo [b] thiophen-7-yl-4- [2- (2-bromo-4,6-d? -fluoro-phenoxy?) ethyl-piperazine; 1-Benzo [b] thiof en-7-yl-4- [3- (2, 4-d? Uoro-phenoxy) -propyl] -piperazine; 1-Benzo [b] thiof-7-yl-4- [3- (4-bromo-2,6-d? -fluoro-phenoxy?) -propyl-piperazm; 8 -. { 4 - [3- (2-Chloro-4-fluorophenoxy?) -propyl] -p? Peraz? N-1-? L} -2, 3-dihydro-benzo [1,4] d? Ox? N-5-carbonitrile; ^ uwjfctfte- --- * • '- - • ffir ^ aasb 8 -. { 4 - [3- (2,6-Dichloro-phenoxy) -propyl] -p? Perazin-1-? L} -2,3-dihydro-benzo [1,4] d? Ox? N-5-carbonitrile; 8 -. { - [3- (4-Fluoro-2-met? L-phenoxy?) -propyl] -piperazin-1-? L} -2, 3-dihydro-benzo [1,4] dioxon-5-carbonitrile; 8 -. { 4 - [3- (2-Bromo-4-fluoro-phenoxy?) -propyl] -p? Peraz? N-1-? L} -2, 3-dihydro-benzo [1,4] d? Oxin-5-carbonitrile; 8-. { 4- [3- (2-Chloro-phenoxy) -propyl] -piperazin-1-yl} -2,3-dihydro-benzo [1,4] dioxin-5-carbonyl trile; 1- (2,3-dihydro-benzo [1,4] dioxin-5? I) -4- (2-phenylsulfanyl-ethyl) -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5? L) -4- [2- (2,6-dimethyl-f-enoxy) -ethyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [4- (2,6-dimethyl-phenylsulfanyl) -butyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) 4- [2- (2,4-dimethyl-phenylsulfanyl) -ethyl] -piperazine; l- (2,3-Dihydro-benzo [1,4] dioxin-5? l) -4- [2- (2-trifluoromethyl-phenoxy) -ethyl] -piperazm; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) 4- [2 - (2-trifluoromethyl] -phenylsulfanyl) -ethyl] -piperazine; 1- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -4- [2- (2-ethyl-phenoxy) -ethyl] -piperazine; 1- [2- (2, 3-Dichloro-phenylsulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- [2- (2-Allyl-β-chloro-phenoxy) -ethyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; l- (2,3-Dihydro-benzo [1,4] dioxin-5? l) -4- [3- (2,4-dimethyl-phenylsulfanyl) -propyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (2-trifluoromethyl-phenylsulfanyl) -propyl] -piperazine; 1- [3- (2, 3-Dichloro-phenylsulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- [3- (3, 4-Dichloro-phenylsulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5? I) -piperazine; 1- [4- (3,4-Dichloro-phenylsulfanyl) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; l- [4- (2-Chloro-5-methyl-phenoxy) -but? I] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- [2- (2,4-Dichloro-phenylsulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- (3-ffl-tolylsulfanyl-propyl) -piperazine; 1- [4- (2, 4-Dichloro-phenylsulfanyl) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [2- (2-ethyl-f-polysulfanyl) -ethyl] -piperazine; ^ Ah-A ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ A ^ A ^^^^^^^^^^ [2- (2, 5-Dichloro-phenylsulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,] dioxin-5-yl) -piperazine; 1- [2- (3-Chloro-phenylsulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; l- [2- (2-Chloro-phenylsulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [2- (2-fluoro-phenylsulfanyl) -ethyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (2-ethyl-f-polysulfanyl) -propyl) -piperazine; 1- [3- (2, 5-Dichloro-phenylsulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5? I) -piperazine; 1- [3- (3-Chloro-phenylsulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; l- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (2-fluoro-phenylsulfanyl) -propyl) -piperazine; 3-Chloro-4-. { 4- [4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -butoxy} -benzonitrile; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- (4-o-tolylsulfanyl-butyl) -piperazine; 1- [4- (2, 5-Dichloro-phenylsulfanyl) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- [4- (2-Chloro-phenylsulfanyl) -butyl] -4- (2, 3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- (2,3-dihydro-benzo [1,4] d? Oxin-5? L) -4- [4- (2-fluoro-phenylsulfanyl) -butyl] -piperazine; 1- (2, 3-d? Hydro-benzo [1,4] dioxin-5? L) -4- [2 (3,4-dimethoxy-phenylsulfanyl) -ethyl] -piperazm; 3-. { 4- [4- (2,3-dihydro-benzo [1,4] d? Oxm-5- 11) -piperazm-1-yl] -butoxy} -benzonitrile; 1- [4- (2-Chloro-4-fluoro-phenylsulfanyl) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; l- (2,3-Dihydro-benzo [1,4] dioxin-5? l) -4- [3- (4-trifluoromethoxy-phenylsulfanyl) -propyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5? L) -4- [3 - (2,5-d-methoxy-phenylsulfanyl) -propyl] -piperazine; l- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (3-bromo-phenylsulfanyl) -propyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [4 - (2-methoxy-phenylsulfanyl) -butyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [4- (2-isopropyl-phenylsulfanyl) -butyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- (2-o-tolylsulfanyl-ethyl) -piperazine; 1- [4- (2-Allyl-phenoxy) -butyl] -4- (2,3-dihydro-benzo [1,4] d? Ox? N-5-yl) -piperazine; an acid addition salt thereof. The invention also relates to a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or diluent. In another embodiment, the invention relates to the use of a compound of the formula (1) or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease that responds to the combined effect of 5-HTiA receptors and dopamine D4 receptors. In another of its embodiments, the invention relates to the use of a compound of the formula (I) or an pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease that responds to inhibition of serotonin uptake and antagonism of 5-HTlñ receptors. Specifically, the invention relates to the use of a compound according to the present invention or an acid addition salt The present invention provides a method for the treatment of affective disorders such as general anxiety disorder, panic disorder, obsessive-compulsive disorder, depression, social phobia as neurological disorders such as psychosis. In another of its embodiments, the present invention relates to a method for the treatment of a disorder or disease of a living animal body, including a human, that responds to the effect of the 5-HT? A and D4 receptors. which comprises administering to said living animal body, including a human, a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof. The compounds of the present invention have high affinity for the 5-HTiA and D4 receptors. Accordingly, the compounds of the present invention are considered useful for the treatment of affective disorders such as general anxiety disorder, panic disorder, obsessive-compulsive disorder, depression, social phobia and áJkáAÁJká ^ iiÁ. disorders of food, as well as neurological disorders such as psychosis. Due to their combined antagonism of 5-HTiA receptors and the inhibitory effect of serotonin reuptake, many of the compounds of the present invention are considered especially advantageous as fast-acting drugs for the treatment of depression. The compounds can also serve for the treatment of depression in patients who are resistant to treatment with the currently available p r e s.
Detailed Description Of The Invention Some of the compounds of the general formula I may exist in the form of optical isomers thereof and such optical isomers are also covered by the invention. The term C alquilo-d alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, -me ti 1 - 2 -pr op i lo and 2 -me ti 1 - 1 -pr op i 1 o.
Similarly, C2-6 alkenyl and C-6 alkynyl designate, in particular, groups having from two to six carbon atoms, inclusive. Halogen means fluoro, chromium, bromine or iodine. The term C3_8 cycloalkyl designates a monocyclic or bicyclic carbocycle with three to eight C atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The terms C 1-6 alkoxy C 1-6 alkylthio and C 1-6 alkylsulfonyl designate groups in which the alkyl group is C 1-6 alkyl according to the above defined. Acyl means -CO-alkyl, where the alkyl group is C 1-6 alkyl according to the above defined. Amino means NH2 Alkylamino C? -6 means -NH-alkyl and di (C? -d) alkyl amino means -N- (alkyl) 2 where the alkyl group is C1-0 alkyl according to the above defined. Acylamino means -NH-acyl where acyl is as defined above.
Alkoxycarbonylamino C i - & means alkyl-O-CO-NH- where the alkyl group is C 1-6 alkyl according to the above defined. Alkylcarbonylamino C? -D means alkyl-NH-CO-NH- where the alkyl group is C 1-6 alkyl according to the above defined. Di (Ci-β alkyl) aminocarbonylairuno means (alkyl) 2-N-CO-NH- where the alkyl group is Ci-g alkyl according to the above defined. As used herein, a phenyl group which may be substituted means a phenyl group which may be substituted one or more times with a substituent selected from halogen, trif 1 or orne 111, cyano, nitro, amino, alkylamino C? 6 di (CI-1-alkyl) amino, C-6-alkyl. Ci-g alkoxy and hydroxy. Examples of addition salts of organic acids according to the present invention are those prepared with maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bismethyl ester, 1,1-acetic acid, methanesulfonic acid, ethanolamine. co, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-ami nob e n z o i c o, glutamic, be n c e n n u u i n e c o n t i o f t i o f i i a c a t i c e, as well as 8-h a 1 o t e or f 111 n s, for example 8 - b r orno t o f 111 na. Examples of inorganic acid addition salts according to the present invention are those formed with hydrochloric, bromidic, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts of the present invention are preferably pharmaceutically acceptable salts formed with non-toxic acids. Moreover, the compounds of the present invention can exist in unsolvated forms as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and others. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention. Some of the compounds of the present invention contain chiral centers and such compounds exist in the form of isomers (e.g., enantiomers). The invention includes all such isomers and any mixture thereof, including racemic mixtures. The racemic forms can be resolved to obtain optical antipodes by methods * m 22 a * &? * J * & - fca »ala * jí j & &jj known, for example by separation of the diastereomeric salts thereof with an optically active acid and release of the optically active aminic compound by treatment with a base. Another method for resolving racemic mixtures in optical antipodes is based on chromatography in an optically active matrix. The racemic compounds of the present invention can thus be solved to obtain their optical antipodes, for example by fractional crystallization of d- or 1- (tartrates, mandelics or c a n f or r s u 1 f on a t) salts, for example. The compounds of the present invention can also be resolved by means of the formation of derivative d i a s t e r e or n e r co. Other methods can be used for the resolution of optical isomers, known to those skilled in the art. Such methods include those disclosed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates and Resolutions," John Wiley and Sons, New York (1981). The optically active compounds can also be prepared from optically active starting materials. The compounds of the present invention can be l? í? á < á- * L¡ **** - * - *** - *. *. ^? It is necessary to prepare by one of the following methods, which include: a) the reduction of carbonyl groups of a compound of the formula (H) where n = 0 - m = 2-3 and R R J 'R i or R 11 R 12 R 16 W, X, Y, Z, A and the dotted line are as defined above. b) the reduction of the carbonyl group of a compound of the formula (L?) in which p = 0-4. o '= 0-9 and R ^ R ^ R10, R11' R12-R16 'W, X, Y, Z, A, m, and the dotted line are as defined above. the alkylation of an amine of the f or rmu 1 a (IV) in which Rx-R3 R 1i0U, R 1i 1 W, X, Y, Z and the dotted line are as defined above with a formula reagent (V) in which R12-Rld A and n are as defined above and G is a suitable leaving group such as halogen, mesylate or tosylate. d) the reductive alkylation of an amine the f or rmu 1 a % ** "ahtÍÍÍÍÍ." * * * * * * * * * * * *. *., * ** ^. m, *, m ** tá *, * * .. ** Í -? *,. * ^. .- *. * .. **., OAj? JatA.it il.
(IV) in which Rx-R3 R 1i0U, R 11- W, X, Y, Z, m, and the dotted line are as defined above with a formula reagent (VI) in which R12-R16 'A and n are as defined above and B is an aldehyde or a carboxylic acid derivative. e) the reduction of the double bond of the cyclic unsaturated amines of the formula wherein R x -R 3 -R 10, R 11 R 12 -R 16 A, X, Y, Z, m and n are as defined above, to obtain the corresponding saturated derivatives; f) the treatment of a compound of the general formula (I), in which Y is -CR6 = CR7-, or in which X and Y together form a group -CR4 = CR5-, or -CR4 = CR5-CR6CR7 with a reducing agent in order to reduce the double bond, so as to obtain a corresponding reduced ring system; g) the reductive elimination of one or more of the compounds R ^ R3 or R12-R16 in a compound of the general formula (I) in which one or more of these compounds is selected from chlorine, bromine or iodine; h) the di a 1 qu 11 a c ón ion of an amine of the formula s? m * ^ lam? .J.m.m, in which Rx-R3 X, Y, Z, are as defined above with a reagent of the formula (OD in which R12-R16 A, m and n are as defined above and G is a suitable leaving group such as halogen, mesylate or tosylate i) the di a 1 qu 11 a c a ion of an amine of the formula (X) in which R12-Rld A and n are as defined above with a reagent of the formula (XI) in which R ^ R3 X, Y, Z, m, are as defined above and G is a suitable leaving group such as halogen, mesylate or tosylate. j) the reduction of sulfones or sulfoxides of the f o rmu 1 a (D) in which Rx-R3 R10, R11 R12-R16 W, X, Y, Z, m, n and the dotted line are as defined above and B 'is a sulphonyl or sulfinyl group; k) the alkylation of the compounds of the formula (xm) e n which R12-R 16 and A are as defined above, with a reagent of the formula (XIV) wherein R x -R 3 -R 10, R 11 W, X, Y, Z, m, n and the dotted line are as defined above and G is a suitable leaving group such as halogen, mesylate or tosylate; whereupon the compounds of the formula (I) are isolated in free base form or in the form of a pharmaceutically acceptable salt thereof. The reduction according to methods a and b) is preferably carried out in a solvent Itidá.? Éár ***** '»'» »*** -'- organic inert such as diethyl ether or tetrahydrofuran in the presence of aluminum hydride and lithium at reflux temperature. The alkylation according to method c) is conveniently carried out in an inert organic solvent such as an alcohol or ketone with a suitable boiling point, preferably in the presence of a base (potassium carbonate or triethylamine) at reflux temperature. The derivatives to r i 1 p i pe r a z i n of the formula (IV) can be obtained commercially, or they can be prepared from the arylamine known in the art according to the method described by Martin et al., J. Med. Chem. 1989. 32. 1052. or with the method described by Kruse et al., Rec. Tra v. Ch i m. Pa y s - B a s, 1988. 107. 303. The starting arylamines are commercially available or have been well described in the literature. The derivatives to r i 11 e t r a h i dr op i r i d i n of formula (IV) have been disclosed in the literature, refer to U.S. Patent No. 2,891,066; McElvain and others, J. Am e r. Ch em, S or c. 1959. 72. 3134. Conveniently, the corresponding arylbromide was lithiated with BuLi followed by the addition of 1 -be n ci 1-4-p ipe r i a. He Subsequent treatment with N-benzyl-a ry acid 11 e t r ah i d r op i r i di na. The benzyl group can be removed by catalytic hydrogenation or by treatment with, for example, ethyl chloroformate to give the corresponding ethyl carbamate followed by acid or alkaline hydrolysis. The starting aryl bromides can be purchased commercially or have been described in the literature. The reagents of the formula (V) can be purchased commercially or can be prepared by methods of the literature, for example from the corresponding carboxylic acid derivative by reduction to the 2-hydroxyethyl derivative and conversion of the hydroxy group to the group G by conventional methods or from the corresponding diha 1 or 1 qui 1 oo 1 - ha 1 or 1 c oh o 1. The reductive alkylation according to method d) is carried out by standard methods of the literature. The reaction can be carried out in two steps, ie coupling of (IV) and the reagent of formula (VI) by standard methods by means of carboxylic acid chloride or by the use of coupling reagents such as, for example, cc 1 or he x 11 car bodi imi da followed by reduction of the resulting amide with lithium aluminum hydride. The Jj **, &.: * I nü? Si-t * * - * & - • reaction can also be carried out by a standard procedure of a container. The carboxylic acids or aldehydes of the formula (VI) can be obtained commercially or have been described in the literature. The reduction of the double bonds according to the methods e) and f) is very conveniently carried out by hydrogenation in an alcohol in the presence of a noble metal catalyst such as, for example, platinum or palladium. The removal of the halogen substituents according to the method g) is carried out readily by catalytic hydrogenation in an alcohol in the presence of a palladium catalyst or by treatment with ammonium formate in an alcohol at elevated temperatures in the presence of a catalyst of palladium. The d i a 1 a tion of amines according to the methods h) and i) is carried out very advantageously at elevated temperatures in an inert solvent such as, for example, chlorobenzene, toluene, N-methylpyrrolidone, dimethylformamide or acetonitrile. The reaction can be carried out in the presence of a base such as, for example, potassium carbonate or triethylamine. The materials The starting materials for processes h) and i) can be purchased commercially or can be prepared from commercially available materials using conventional methods. The N-a 1 that is according to the method i) is carried out in an inert solvent such as for example an alcohol or ketone at elevated temperatures in the presence of a base, for example potassium carbonate or triethylamine at room temperature. Reflux. On the other hand, a phase transfer reagent can be used. The reduction of sulfones or sulfoxides according to method j) can be carried out using various commercially available reagents such as titanium tetrachloride and sodium borohydride at room temperature (S. Kano et al., Synthesis 1980, 9.695-697). . The alkylation of commercially available compounds corresponding to formula (XIII) using method k) is conveniently carried out using an alkylation reagent with the appropriate leaving group (eg, mesylate, halide) using a base (e.g. potassium or similar) in a polar aprotic solvent (for example methyl isobutyl ketone, dimethylformamide). The arylpiperazines employed in accordance with that described in the examples are prepared from the corresponding arylamine according to the method described by Martin et al., J. Med. Chem. 32 (1989) 1052. or by the method described by Kruse et al., Rec. Trav. Chim. Pays-Bas, 1988. 107. 303. The starting arylamines are available commercially or have been described in the literature as follows: The synthesis of 5-ami no-1.4-be nz od i oxa has not been described by Dauksas and others, Zh. Org. Khim. , 1967. 3. 1121. The corresponding chlorinated derivatives are prepared in a similar manner. The synthesis of 7-ami no-2, 3-di h i dr obe n z o f u r a has not been described in the United States patent application No. 4302592. The synthesis of 7 - ami no - b e n z o f u r a has not been described by Van Wijngaarden and others, J. Med. Chem., 1988. 31.1934. The synthesis of 7-ami no-be n z or [b] 11 or f e has not been described by Bos ell et al., J. Heterocycl. Chem. , 1968. 5. 69. lAJ ^ M »-á * AÉ ^ á ^. jfel »» «^» Jh¡ ^ fed ^ fr < "J,, The 7-ami no-2, 3-dime t i 1 b e n z o f u r a n o and the corresponding derivatives 5-chloro and 5-methyl are prepared according to Ger. Offen DE 3526510. 4-ami no-benzoti op ira was prepared not in accordance with the European patent application EP 79683. 8-ami no-6-c 1 gold-2, 2-dime ti 1 benz op ira was prepared not by conventional nitration of 6- c 1 gold - 2, 2 - dime ti 1 ebe nz op ir ano (prepared according to Bolzoni et al., An ge w Ch., 1978. 90, 727-) with subsequent reduction of the derivative 8-nitro thus obtained. Similarly, 7-amino-5- c 1 oro-3, 3-d ime ti lbe nzofura was obtained from 5-chloro-3, 3-d ime ti 1 benzofur ano (prepared according to the application European patent EP 7719 800206). The corresponding dechloro derivatives were obtained by treatment with hydrogen gas in the presence of a noble metal catalyst. The aryl tetrahydropyridine derivatives were disclosed in the literature (U.S. Patent No. 2,891,066 or McElvain et al., J. Am e r. Ch em. S o c., 1959. 72. 3134). Very soon, the corresponding arylbromide is subjected to lithiation with BuLi followed by the addition of 1-b e n c i 1 - 4 - p i p a n e a n a.
Subsequent treatment with mineral acid or trifluoroacetic acid gives N-benzyl-a r i 11 e t r a h i d r op i r i di n a. The benzyl group can be removed by catalytic hydrogenation or by treatment, for example, with ethyl chloroformate to give the corresponding ethyl carbamate followed by acid or alkaline hydrolysis. The corresponding piperidine derivatives can be prepared by the reductive elimination of the double bond of the ring of t e t r ah i dr op i r i di na. All these procedures are well known to those skilled in the art. The starting arylbromides have been extensively described in the literature. In this way, we obtain 4- (1,4-benz or ioxan-5-i 1) - 1.2.3.6 - tetrahi dr opidin, 4- (2,3-dihydro-2,2-dimethylbenzofuran-7-yl) - 1.2.3.6-tetrahydropyridine, 4- (2,3-dihydro-2,2-dihydrobenzofuran-7-yl) -1.2.3.6-tetrahydropyridine, 4 - (benzofuran - 7 - i 1) - 1.2.3.6 - tetrahi dr op iri di nay and the corresponding piperidines. The following examples illustrate the invention in more detail. However, they should not be considered as limiting. íá ^ ií Mtá i ^^? ^ i ^^^ ii E j ales The melting points were determined on a Buchi SMP-20 device and have not been corrected. The data from the LC-MS analyzes were obtained on a PE Sciex API 150EX instrument equipped with a lonSpray source (method D) or heated nebulizer (APCI, methods A and B) and a Shimadzu LC-8 A / S LC arrangement - 10 A LC. The CL conditions [30 x 4.6 mm YMC ODS-A with a particle size of 3.5 μm] consisted of the linear gradient elution with a trifluoroacetic acid (90:10: 0, 05) to w hen ce t on 11 r i 1 o / a c i do luoacetic tpf (10: 90: 0.03) in 4 min at 2 mL / min. The purity was determined by integration of the UV trace (254 nm). The retention times Rt are expressed in minutes. The table spectra were obtained by an alternate scan method to give molecular weight information. The molecular ion, MH +, was obtained at low orifice voltage (5-20V) and high-voltage orifice fragmentation (100 V). The preparation separation was performed by LC-MS in the same instrument. The LC conditions (50 x 20 mm YMS ODS-A with a particle size of 5 μm) consisted of linear gradient elution Í¿Í-f jJ, .J aJ¿.J », ¿a» tM j, ¿a?? TátJLlm-. -.TO . .. . ajfe. with a g u a a c e t on i t r i 1 o / a c i do trifluoroacetic (80: 20: 0.05) to water / acetonitrile / trifluoroacetic acid (10: 90: 0.03) in 7 min at 22.7 mL / min. Fractions were collected by split flow EM detection. The NMR: H spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument or at 250.13 MHz on a Bruker AC 250 instrument. The deuterated form chloroform (99.8% D) or dimethylsulfoxide (99.9% D) was used as solvents. TMS was used as an internal reference standard. The values of chemical shifts are expressed in ppm values. The following abbreviations were used for the multiplicity of NMR signals. s = smglete, d = doublet, t = triplet, q = quartet, qui = quintete, h = heptet, dd = double doublet, dt = double tpplete, dq = double quartet, tt = triplet of triplets, m = multiplet, b = broad singlet. In general, the NMR signals corresponding to the acid protons are omitted. The water content of the crystalline compounds was determined by Karl Fischer titration. The standard processing procedures refer to the extraction with the indicated organic solvent from aqueous solutions t - * t A.? .j ** "ttítMájLk * ... teafe». - 'appropriate, drying of the combined organic extracts (MgSO4 or anhydrous Na2SO4), filtering and evaporation of the solvent in vacuo. Silica gel of Kieselgel type 60, 230-400 mesh ASTM was used for the column chromatography. For ion exchange chromatography, (SCX, 1 g, Varian Mega Bond Elut®, Chrompack cat. No. 220776. Before use, the SCX columns were pr iodicted with a 10% solution of acetic acid in methanol (3 mL).
E j emplo 1 la. l- [3- (2-Chloro-phenoxy) -prop?] -4-! - (2,3-dihydro-benzo [1,4] dioxin-5-ll) -piperazine, oxalate. A solution of 2-chlorophenol (5 g) in tetrahydrofuran (25 mL) was added dropwise to a suspension of sodium hydride (47 mmol) in tetrahydrofuran (50 mL) at room temperature. The mixture was stirred for 30 min. The reaction mixture was then heated to reflux, after which 2-b rrno p r op a n 1 (3.5 mL) in tetrahydrofuran was added. (25 mL) in a period of 5 min. The mixture was refluxed overnight, one more equivalent of 3-b r omop r op a n 1 was added and the mixture was maintained at reflux for a further 12 hours. The í- üá < i *** AAA ÍAÁAlit **, *, ...-:, * ... j ** .. i ...., J.
The mixture was cooled, saline and ethyl acetate were added and washed using the standard procedure. The combined organic phases were dried and evaporated. It was dissolved in 3 - (2-c 1 or r or f e nox i) - 1 - crude p-no 1 in acetonitrile (500 mL) and carbon tetrabromide (38.7 g) was added. To the cooled mixture (0 ° C) triphenylphosphine was added in portions (25.5 g) in a lapse of 30 minutes. The reaction was allowed to proceed at room temperature for 3 hours, then evaporated to give an oily product. The crude product was purified using flash chromatography on silica gel (heptane: ethyl acetate: trie 111 amine / 70: 15: 5) to give 3- (2-chlorophenoxy?) -l-propyl bromide (10.7 g) . A mixture of 1 - (1,4-benz or ioxan-5-yl) piperazine (0.84 g), potassium carbonate (1.6 g), potassium iodide (cat.) And bromide of 3 - (2-c 1 orophen-oxy) ) - 1 - pr op i 1 o (1.0 g) in methyl of is obu ti 1 ketone / d ime ti 1 fo rmami da (1/1, 100 mL) was heated to 120 ° C. When the TLC indicated that the reaction had been completed (24 hours), the mixture was cooled, filtered and concentrated. The crude material was dissolved in ethyl acetate and washed using standard procedures, followed by drying, filtration and evaporation. The crude materials were purified using flash chromatography on silica gel (heptane: ethyl acetate: triet? Lamina / 55: 43: 2). The resulting oil was dissolved in acetone and then oxalic acid was added. Filtration gave the title compound as pure crystalline material (0.6 g). MP 163-166 ° C. XH NMR: 2.15 (m, 2H), 3.00-3.20 (m, 10H), 4.15 (t, 2H), 4.20 (m, 4H), 6.50 (d, ÍH), 6.55 (d, ÍH), 6.75 (dd) , ÍH), 6.95 (d, ÍH), 7.15 (d, ÍH), 7.30 (dd, ÍH), 7.40 (d, ÍH): MS: m / z: 389 (MH +), 218, 150. Anal. Cale. for C2? H25ClN203: C, 57.67; H, 5.69; N, 5.85. Found, C, 57.71; H, 5.74; N, 5.77. In an analogous manner, the following compounds were prepared: Ib. 1- [3- (2,6-Dichloro-phenoxy?) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine oxalate. Mp 179-181 ° C. 1N NMR: 2.15 (m, 2H), 3.00-3.20 (m, 10H), 4.05 (t, 2H), 4.20 (m, 4H), 6.50 (d, ÍH), 6.55 (d, ÍH), 6.75 (dd) , HH), 7.20 (dd, HH), 7.50 (d, 2H): MS: m / z: 423 (MH +), 247, 178. Anal. Cale, for C2? H24Cl2N203: C, 53.80; H, 5.11; N, 5.46. Found C, 53.73; H, 5.01; N, 5.40. lliÍ-? M.A? A-.lHS¿Alt? -.illK **** t. * A¿tm '.rJdts * íj ~.% X ?. ÍA lc. l- (2,3-Dihydro-benzo [1,4] dioxin-5? l) -4- [3- (2,4-, 6-tr? uoro-phenoxy) -propyl-piperazine, dihydrochloride. Mp 210-220 ° C. NMR lti: 2.10 (m, 2H), 3.05-3.25 (m, 10H), 3.80 (s, 3H), 4.00 (t, 2H), 4.25 (m, 4H), 6.50 (d, ÍH), 6.55 (d , ÍH), 6.65-6.80 (m, 2H), 6.85-7.00 (m, 2H) 11.25 (b, ÍH). MS: m / z: 409 (MH +), 232, 150. Anal. Cale. for C2? H23 F3N203: C, 52.39; H, 5.25; N, 5.82. Found C, 52.63; H, 5.40; N, 5.71. Id. 1- (2,3-dihydro-benzo [1,4] dioxm-5-yl) -4 - [3 - (4-fluoro-2-methoxy-phenoxy) -propyl-piperazine oxalate. Mp 141-142 ° C. XH NMR: 2.10 (m, 2H), 3.05- 3.25 (m, 10H), 3.80 (s, 3H), 4.00 (t, 2H), 4.25 (m, 4H), 6.50 (d, ÍH), 6.55 (d , ÍH), 6.65-6.80 (m, 2H), 6.85-7.00 (m, 2H). MS: m / z: 403 (MH +), 164. Anal. Cale, for C22 H27 FN20 ,? : C, 58.52; H, 5.95; N, 5.69. Found C, 58.53; H, 6.24; N, 5.22. you. l- (2,3-Dihydro-benzo [1,4] d? oxin-5? l) -4- [3- (4-fluoro-2-methyl-phenoxy) -propyl-piperazine, oxalate. Mp 139-150 ° C. XH NMR: 2.05-2.15 (m, 2H) 2.15 (s, 3H), 3.05-3.20 (m, 10H), 4.00 (t, 2H) 4.20-4.25 (m, 4H), 6.50 (d, ÍH), 6.75 (dd, 1 H) 6.95 (m, 2H), 7.00 (m, ÍH). MS: m / z: 387 (MH +), 218-164. Anal. Cale, for C22H27F 2? 3: C, 59.92; H, 6.19 N, 5.82. Found C, 59.82; H, 5.32; N, 5.49.
E j us 2 2a. l- [3- (4-Chloro-phenoxy?) -propyl] -4- (2,3-d? h? dro-benzo [1,4] d? ox? n-5-? l) - pe? na? na. A solution of 4-chlorophenol (5 g) in dimethylformamide (50 mL) was added dropwise to a suspension of sodium hydride (60%, 1.7 g) in dimethylammonium (50 mL) at room temperature in the course of 15 min. The mixture was stirred for 30 min. Then, the reaction mixture was added slowly (10 min) to a solution of 1,3-dibopropyl opy (78.5 g) in dιme 111 f or rmamide (25 mL) at room temperature. The final mixture was stirred for an additional 60 minutes at 70 ° C. The reaction was cooled by immersion by adding sufficient amounts of water to destroy the excess sodium hydride, acidified using ethereal hydrogen chloride followed by evaporation. The crude oil was purified using flash chromatography on silica gel (heptane: ethyl acetate: t r i e t i lamina / 95: 2.5: 2.5) to give 3- (4-chlorophenoxy?) -l-propyl bromide 4.5). A mixture of 1 - (1, 4-benz od io xa n - 5 -11) pi pe ratio (1.0 g), potassium carbonate (1.9 g), potassium iodide (cat.) And bromide of 3 - ( 4 - J-fci-aá iÉ mk ai- '- c 1 orofe nox i) - 1 - pr op i 1 o (1.13 g) in methyl isobutyl ketone / d ime ti 1 fo rmami da (1/1, 100 mL) was heated to 120 ° C. When the TLC indicated that the reaction had been completed (24 h) the mixture was cooled, filtered and evaporated. The crude material was dissolved in ethyl acetate and washed using standard procedures, followed by drying, filtration and concentration. The crude material was purified using chromatography on silica gel (heptane: ethyl acetate: ethanol: triethylamine / 85: 5: 25: 5). The collected oil was crystallized from ethanol. Filtration gave the title compound as a pure crystalline material (0.64 9). Mp. 116-119 ° C. X-ray NMR: 1.90 (q, 2H), 2.40-2.60 (m, 6H), 2.90-3.00 (m, 4H), 4.00 (t, 2H), 4.20 (m, 4H), 6.45 (m, 2H), 6.70 (t, ÍH), 6.95 (d, 2H), 7.30 (d, 2H). MS: m / z: 389 (MH +), 178. Anal. Cale. for C21H25C1N3N203: C, 64.86; H, 6.48; N, 7.20. Found C, 64.59; H, 6.49; N, 7.23. In an analogous manner, the following compounds were prepared: 2b. l- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (4-tr? fluoromethyl-phenoxy) -propyl-piperazine oxalate. Mp 148-150 ° C. XH NMR: 2.10 (m, 2H), 3.00-3.25 (m, 10H), 4.15 (t, 2H), 4.25 (m, 4H), 6.45-6.55 (m, 2H), 6.75 (t, ÍH), 7.15 (d, 2H), 7.60 (d, 2H). MS: m / z: 423 (MH +), 178. Anal. Cale. for C22H25F3N2O3: C, 56.25; H, 5.31; N, 5.47. Found C, 56.10; H, 5.34; N, 5.51. 2 C. l- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (2-f luoro-phenoxy) -propyl-piperazine, oxalate. Mp 167-169 ° C. 1 H NMR: 2.10 (m, 2H), 3.00-3.20 (m, 10H), 4.15 (t, 2H), 4.20 (m, 4H), 6.45-6.55 (m, 2H), 6.75 (t, ÍH), 7.10 -7.25 (m, 3H). MS: m / z: 373 (MH +), 178, 122. Anal. Cale, for C22H25FN203: C, 59.73; H, 5.88; N, 6.06. Found, C, 59.15; H, 5.99; N, 6.04. 2d. 2 - . { 3 - [4 - (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -propoxy} -benzonitrile, oxalate. Pf. 130 (amorphous) ° C. 1 H NMR: 2.15 (m, 2H) 3.00-3.20 (m, 10H), 4.20-4.30 (m, 6H), 6.50 (d, ÍH) 6.55 (d, 1H), 6.75 (t, ÍH), 7.10 (t , ÍH), 7.25 (d 1H), 7.65-7.75 (m, 2H). MS: m / z: 380 (MH +), 178 Anal. Cale. for C 22 H 25 N 3 O 3: C, 61.40; H, 5.80; N, 8.95. Found, C, 59.97; H, 6.02; N, 8.72. 2e. l-Benzo [b] thiophen-7-yl-4- [3- (2-chloro-4-f-luoro-phenylsulfonyl) -propyl] -piperazine, hydrochloride. Mp 216-219 ° C. 1N NMR: 2.06-2.17 (m, 2H), 3.10-3.18 (t, 2H), 3.21-3.35 (m, 6H), 3.58. 3.69 (d, 4H), 7.02 (d, ÍH), 7.27 (t, ÍH), 7.38 (t, AS .k ^ Á .ÍÍÍÍÍÍÍÍ ... * ¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡.. ..i .. ^ y ^ tí¡tt > «| * 4J ÍH), 7.48 (d, lH), 7.52-7.60 (m, 2H), 7.62 (d, 1H), 7.77 (d, ÍH), 11.0 (s, ÍH): MS: m / z: 421 (MH +), 299, 176. Anal. Cale. for C21H22CIFN2S2: C, 55.13; H, 5.08; N, 6.12. Found, C, 55.06; H, 5.09; N, 6.15. 2f. l-Benzo [jb] thiophen-7-? l-4- [4- (2-chloro-4-f 1 uo r o -f e no x i) -bu t i 1] -p i pe r a z i n a, hydrochloride. Mp. 193-105 ° C. XH NMR: 1.80-1.88 (m, 2H), 1.95-2.06 (m, 2H), 3.18-3.42 (m, 6H), 4.05-4.14 (m, 2H), 7.05 (d, ÍH), 7.20 (t, ÍH), 7.43 (m, 3H), 7.63 (d, 1 H); 7.77 (d, 1 H); 11.30 (s, ÍH). MS: m / z: 419 (MH +), 216, 134. Anal. Cale. for C22H24CIFN2OS: C, 58.01; H, 5.54; N, 6.15. Found, C, 57.89; H, 5.54; N, 6.19.
E j us 3 3a. 1- [2- (3, 4-Dichloro-phenylsulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine, oxalate. A solution of chloroacetyl chloride (0.72 g) in dry tetrahydrofuran (5 mL) was added dropwise to a mixture of 1- (1,4-benz or ioxan-5-yl) piperazine (1.28 g) and carbonate potassium (2.4 g) in dry tetrahydrofuran at room temperature. The reaction was allowed to stir for 30 minutes and 3,4-dichlorothiophenol (1.25 g) was added. ííL? * á.Á *?. & á á¡ * - *. ** & * «* & -. .. : .-- rlmm.Á ... * - m í. followed by the addition of potassium cyanide (1.49 g). The mixture was stirred for 30 minutes at room temperature and 30 minutes at reflux, after which it was cooled and concentrated. The crude mixture was washed using the standard procedure (ethyl acetate / saline), dried and evaporated to give 1 - [1,4-benzod? Oxan-5? L] -4- [3,4-d? Chlorophen ? lt? omet? l-carbon? l] peraz? na (2.54 g). Aluminum trichloride (0.4 g) was added dropwise in cold water (10 mL) to a suspension of lithium aluminum hydride (0.4 g) in water (20 mL) at 0 ° C. The mixture was stirred for 15 minutes and then warmed to about 10 ° C, after which a solution of the intermediate amide, previously prepared, was added in t e t r a h i d r o f u r a n (20 mL). The reaction was complete within 1 h and concentrated sodium hydroxide (2 mL) was added dropwise. A drying agent was added followed by filtration and evaporation to give the crude proposed base (1.94 g). Purification using flash chromatography on silica gel gave the pure base. The addition of oxalic acid in acetone followed by filtration gave the title compound as a pure white crystalline material tAitAÉ ^ jt fiíSjjií ^. ^. jj ^ trilfcj-a .. ^ ..njSg jttí. (1.26 g). X-ray NMR: 2.9-3.05 (s, 6H), 3.05-3.15 (s, 4H), 3.25-3.40 (t, 2H), 4.15-4.30 (m, 4H), 4.70-6.40 (b, ÍH), 6.45- 6.50 (d, ÍH), 6.50-6.55 (d, 1 H); 6.70-6.80 (t, ÍH), 7.30-7.40 (d, ÍH), 7.55-7.60 (d, ÍH), 7.65-7.67 (s, ÍH). MS: m / z: 425 (MH +), 177. Anal. Cale. for C2oH22Cl2N202S: C, 51.26; H, 4.70; N, 5.44. Found C, 51.41; H, 4.86; N, 5.44. The following compounds were prepared analogously: 3b 1 - (2, 3-d? H? Dro-benzo [1,4] d? O? N-5-lyl) -4- [2 - (4-fluoro -phen? sulfan? l) -e 111] -p ipe raz ina, oxalate. Pf. 200-202 ° C. XH NMR: 2.90-3.10 (m, 6H) 3.15-3.30 (s, 4H), 3.30-3.40 (t, 2H), 3.60-4.50 (b, ÍH), 6.35-6.40 (s, ÍH), 6.45-6.50 (d, 1H) 6.95-7.00 (t, ÍH), 7.05-7.10 (d, ÍH), 7.15-7.20 (s, ÍH), 7.25-7.30 (s, ÍH), 7.35-7.40 (d, ÍH), 7.55-7.60 (d, ÍH). MS: m / z: 375 (MH +), 177. Anal. Cale. for C20H23FN2O2S: C, 56.88; H, 5.44; N, 6.03. Found C, 56.88; H, 5.55; N, 5.96. 3c. l- [2- (Bromo-tr? fluoromet? l-phen? l-sulfan? l) -et? l] -4- (2,3-d? h? dro-benzo [l, 4] d? oxm -5-yl) -piperazm, oxalate. Pf. 196-197 ° C. 1 H NMR: 2.65-2.85 (m, 4 H); 2.85-2.95 (m, 2H) 2.95-3.15 (s, 4H), 3.15-3.35 (m, 2H), 4.15-4.40 (dd, 4H), 6.40-6.55 (m, 2H), 6.70 (t, ÍH) , 7.57 (d, ÍH), 7.73 (d, ÍH), 7.95 (s, ÍH). MS: m / z: 504 (MH +), 214. Anal Cale. for C2oH22BrF3N2? 2S: C, 45.51; H, 4.24; N, 4.62. Found C, 46.00; H, 4.25; N, 4.58. 3d 1 - [2 - (2,6-Dichloro-phenylsulfanyl) -etl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine, oxalate Pf -191 ° C is omp one RMN H 2. 85-3.0 (m, 6H) 3.00-3.15 (s, 4H), 3.20 (t, 2H), 4.15-4.25 (m, 4H), 5.00-6.00 (b, ÍH), 6.45 (d, ÍH), 6.50 (d, ÍH), 6.70 (t, ÍH), 7.40 (t, ÍH), 7.60 (d, 2H). MS: m / z: 425 (MH +), 170. Anal. Cale. for C 20 H 22 Cl 2 N 2 O 2 S: C, 51.27; H, 4.69; N, 5.44 '..
Found C, 51.17; H, 4.81; N, 5.46.
E xemplo 4 4a. l- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -4- (3-phenylsulfanyl-propi 1) -piperazine, di-1 or hydrated hydrate. To a stirred solution of concentrated sodium hydroxide (100 mL), dichloromethane (900 mL) and water (600 mL) was added thiophenol (56 g), 3-br omop r or n-1 - or 1 (111 g) and tetrabutylammonium sulfate (12 g). The mixture was kept under reflux for 42 h, slowly cooled, after which it was washed using dichloromethane / hydrochloric acid and water, dried and evaporated to give 3-phenylethyl opium or 1-crude oil, which was purified by atA ijiL i ijí? j & &- & SS! ^ * - í.mm ^ ..:. ¿ikA *, distillation (35 g, ie 1 O 2 - 15 ° C / O .15 mmHg. dissolved a portion (10 g) in diechloromethane (100 mL) and triethylamine (8.6 g) was added, followed by the dropwise addition of a solution in diechloromethane (100 mL) methanesulfonic acid chloride (9.3 g) at 2 ° C. The reaction was allowed to proceed at this temperature for 90 minutes and at 10 ° C for the same period, then the reaction was washed using dichloromethane and a dilute sodium carbonate solution and evaporated to give the crude mesylate (14.9 g). The mesylate (3.1 g) was treated directly with 1- (1,4-benz odi oxa n-5-11) piperazine, dic 1 orhi dr ato (3.22 g) and potassium carbonate (9.15 g) in methyl is The test was maintained at reflux for 48 h, cooled, evaporated and then washed using the standard procedure. on silica gel gave the sought base (0.56 g), which was crystallized as the hydrochloride by the addition of ethereal hydrogen chloride. Filtration gave the title compound (0.50 g). Mp. 185-206 ° C. NMR X: 2.00-2.16 (m, 2H), 3.03-3.30 (m, 8H), 3.34-3.55 (m, 4H), 4.18-4.25 (s, 4H), 5.80 (s, 4H), 6.48-6.61 ( m, 2H), 6.73 (t, ÍH), 7.14-7.25 (m, ÍH), 7.28-7.32 fe- ^ fe *. &! - & ».» ..,. ü & iat (m, 4H), 11.48 (s, ÍH). MS: m / z: 371 (MH +). Anal Cale. for C2iH26N202S: C, 54.73; H, 6.56; N, 6.08. Found C, 55.37; H, 6.65; N, 6.27.
Example 5 5aa. l- [3- (2-Bromo-4-fluoro-pheno?) -pr op 11] -4- (2, 3-d? h? dro-benzo [1,4] diox m-5-11) - p ipe raz ma. A solution of 2-b-rin-4-f-1 or o -f-no-1 (3.0 g) was added dropwise in t e t r a h i d r o f u r a no (50 mL) at room temperature to a suspension of sodium hydride (38.4 mmol) in ethanol (50 mL). The mixture was stirred for 30 more minutes once the generation of hydrogen ceased. Then it was dropped slowly to solution (0.3 ml / min) in a solution of 1, 3-d i b r omop r op a n o (159 g) in ethanol (300 mL) at 75 ° C and stirred for 16 h. The mixture was evaporated from the solvents and the residue extracted with ethyl acetate. The solution was washed with water and saline, dried, filtered and concentrated. The excess of 1, 3-d i b r omop r op a was not removed under vacuum (60 ° C, 0.01 mbar) and the oily residue was purified by flash chromatography on silica gel (eluent: heptane) to give bromide of 3 - (2 - b r omo - 4 - f 1 uo r or f e n ox i) - 1 - p r op 11 o (2.9 g, 60%) in the form of a colorless oily liquid. Cesium carbonate (108 mg) was added to a solution of bromide of 3 - (2-br omo-4-f 1 uo rofe nox i) -1-propyl (46 mg) and 1 - (1,4-benzodioxan-5) - i 1) Piperazine (26 mg) in acetonitrile (2 mL). The mixture was stirred at 70 ° C for 16 h. After 12 hours, polystyrene (75 mg) was added and the mixture was slowly cooled to room temperature. The resin was filtered and washed with methanol (1 x 1 mL) and dichloromethane (1 x 1 mL). The combined liquid phases were evaporated from the volatile solvents to give a dark brown oil. The crude product was dissolved in ethyl acetate (3 mL) and loaded on an ion exchange column pr e a c c o n d a n d a. The column was washed with methanol (4 mL) and acetonitrile (4 mL), after which the product was eluted with a 4 N solution of ammonia in methanol (4.5 mL). After evaporation of the volatile solvents, the product was purified by preparative reverse phase HPLC chromatography. The resulting solution was loaded once more into a column for ion exchange exchange. As described above, the column was washed with methanol 1 ^ A ^ l * saBfr¿ikft.a (4 mL) and acetonitrile (4 mL), after which the product was eluted with a 4 N solution of ammonia in methanol (4.5 mL). Evaporation of the volatile solvents afforded the title compound as a yellow oil (34 mg). LCMS (m / z) 451 (MH +), Rt = 6.0 (method A), purity: 95.6%. In an analogous manner, the following compounds were prepared: (me all A). 5ab. l- [4- (2,6-D? Chloro-phen? lsulfan? l) -but il] -4- (2,3-d? h? dro-benzo [l, 4] di ox m-5 - 11) -p ipe ratio LC / MS (m / z) 453 (MH +), Rt = 2.52 (method A), purity 96.1%. 5ac. 1 - [3- (2-Chloro-4-fluoro-phenylsulfanyl) -prop 11] -4- (2,3-d? H? Dro-benzo [1,4] d? Oxm-5-? L) - p íp erazi na. LCMS (m / z) 424 (MH +), R t = 5.75 (method A), purity 91.8%. 5ad *. 1-Benzo [b] t? Ofen-7 -? L-4- [3- (2-chloro-4-fluoro-phenylsulfanyl) -propylj-piperazm. LC / MS (m / z) 421 (MH +), Rt = 6.40 (method A), purity 73.2%. 5ae. l-Benzo [b] t? ofen-7-? l-4- [3- (2,6-dichloro-phenylsulfanyl) -prop il] -p ipe r az ma.
JjWa ?.
LCMS (m / z) 437 (MH +), Rt = 6.39 (method A), purity 84.1%. 5af. l-Benzo [b] t? ofen-7-? l-4- [4- (2,6-dichloro-phenylsulfanyl) -butyl] -p ipe r a z i na. LC / MS (m / z) 451 (MH +), Rt = 6.64 (method A), purity 87.6%. 5ag. 1 - [4 - (3-Chloro-2-methoxy-phenylsulfan-1) -butyl] -4- (2,3-dihydro-benzo [1,4] -di-ox-5-i-1) -pipe-ratio . LC / MS (m / z) 449 (MH +), Rt = 5.91 (method A), purity 90.8%. 5ah. l-Benzo [b] thiophen-7-yl-4- [4- (3-chloro-2-methoxy-phenylsulfanyl) -butyl] -piperazine. LC / MS (m / z) 447 (MH +), Rt = 6.54 (method A), purity 73.8%. 5ai. l-Benzo [b] thiophen-7-? l-4- [3- (2-chloro-4-f 1-uoro-phenylsulfanyl) -propi 1] -piperazine. LCMS (m / z) 422 (MH +), R t = 6.32 (method A), purity 94.2%. 5aj '. l- [3- (2,6-Dibromo-4-fluoro-phenoxy) -pr op 11] -4- (2,3-dihydro-benzo [1,4] diox in-5 -11) -p ip erazi na LC / MS (m / z) 531 (MH +), R t = 5.87 (method A), purity 96.4%. ia ^ éj¿, Jt -j ütea.g. ^ r &, 5ak. l-Benzo [b] t? ofen-7-? l-4- [3- (2,6-d? bromo-4-fluoro-phenoxy) -prop i 1] -p ipe ra z i n a. LC / MS (m / z) 529 (MH +), Rt = 6.98 (method A), purity 87.7%. 5al. 4 - . { 3- [4- (2, 3-d ih idr or -benz or [1, 4] dioxin-5-yl) -p iper az m-1-i 1] -propox i} - 3, 5-diiodo-benzoon i t r 11 o. LC / MS (m / z) 632 (MH +), Rt = 5.85 (method A), purity 86.0%. 5 am. 3, 5 - D i - t e r c - bu t i 1 - 4 -. { 3 - [4 - (2,3-Dihydro-benzo [1,4] diox in-5-i 1) -p iper az in-1-i 1] -propoxy} -be n z on i trilo. LC / MS (m / z) 492 (MH +), Rt = 6.74 (method A), purity 83.6%. 5an 1 - [3 - (2, 6-D ic 1 or ro-4-me tansu 1 foni 1-phenoxy) -prop 11] - 4 - (2,3-dihydrobenz [1,4] d? oxin-5- i 1) -piperazine. LC / MS (m / z) 503 (MH +), Rt = 5.06 (method A), purity 93.6%. 5ao l-Benzo [b] thiophen-7-yl-4- [3- (2,6-d-chloro-4-methanesulfonyl-phenoxy) -propyl] -p ipe ra z i na. LC / MS (m / z) 499 (MH +), R t = 5.82 (method A), purity 80.1%. 5ap. 1 - [3 - (B romo-tif 1 uorome ti 1-phenylsulfanyl) -prop i 1] -4- (2,3-d? Hydro-benzo [1,4] -dio-5-yl) -piperazine . LC / MS (m / z) 519 (MH +), Rt = 6.27 (method A), purity 86.5%. 5aq l-Benzo [b] t? ofen-7-yl-4- [3- (bromo-trifluoromethyl-phenylsulfanyl) -propyl] -piperazine. LC / MS (m / z) 517 (MH +), Rt = 6.86 (method A), purity 73.7%. 5ar 1-Ben z or [b] t io fen-7-i 1 - 4 - [4 - (2-c 1 or ro-6-methyl-phenylsulfanyl) -butyl] -p ipe r a zin. LC / MS (m / z) 431 (MH +), Rt = 6.66 (method A), purity 87.4%. 5as l-Benzo [b] thiophen-7-yl-4- [4- (2-chloro-4-fluoro-phenylsulfanyl) -butyl] -piperazine. LC / MS (m / z) 435 (MH +), Rt = 6.94 (method A), purity 83.0%. 5at. l- [3- (2,6-Dichloro-4-fluoro-phenoxy) -propyl] -4- (2,3-dihydro-benzo [1,4] d i or x in-5-11) -piperazine. LCMS (m / z) 441 (MH +), R t = 5.80 (method A), purity: 96.8%. 5au. l-Benzo [b] thiophen-7-yl-4- [3- (2,6-d-chloro-4-fluoro-phenoxy) -propi 1] -piperazine.
LC / MS (m / z) 439 (MH +), Rt = 6.49 (method A), purity 93.6%. 5av. 1 - [4 - (2-Chloro-6-meth? L-phen? Lsulfan? L) -butyl] -4- (2,3-d? H? Dro-benzo [1,4] d? Oxm-5 -? l) -p ipe raz ina. LCMS (m / z) 433 (MH +), Rt = 6.14 (method A), purity: 96.6%. 5a. l- [3- (2,6-D? Chloro-phen? lsulfan? l) -prop 11] -4- (2, 3-d? h? dro-benzo [1,4] diox m-5-11 ) -piperazma; LCMS (m / z) 439 (MH +), R t = 5.89 (method A), purity: 93.0%. 5ax. l- (5-Chloro-2,2-d? met? l-2, 3-d? h? dro-benzofuran-7-? l) - 4 - [4 - (2-chloro-6-met? l -fen? ls u 1 fa n 11) -bu 111] -p ipe ra z ina. LCMS (m / z) 479 (MH +), R t = 7.38 (method A), purity 91.3%. 5ay. l- (5-Chloro-3,3-d? met? l-2, 3-d? h? dro-benzofuran-7-? l) - 4 - [4 - (2-chloro-6-met? l -fen? ls u 1 f an 11) -b'ut 11] -p ipe raz ma. LCMS (m / z) 479 (MH +), R t = 7.38 (method A), purity 93.1%. 5az. 1 - (5-Chloro-2,2-d? Met? L-2, 3-d? H? Dro-benzofuran-7-? L) - 4 - [3 - (2,6-d? Chloro-phen ? lsulfan? l) -pr op 11] -p ip erazi na. llllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll M *.% Uk- * á * r! Tr-^ _ LC / MS (m / z) 488 (MH +), Rt = 6.92 (method A), purity 93.1%. 5ba l- (5-Chloro-3, 3-d? met? l-2, 3-d? h? dro-benzofuran-7-? l) -4- [3- (2,6-d? chloro-phen ? lsulfan? l) -pr op 11] -p ipe razi na. LCMS (m / z) 488 (MH +), Rt = 6.91 (method A), purity 88.7%. 5bb. l- (5-Chloro-3,3-d? met? l-2, 3-d? h? dro-benzofuran-7-? l) - 4 - [3 - (2-chloro-4-fluoro-phen ? ls u 1 fan 11) -prop 11] -piper az ma. LCMS (m / z) 469 (MH +), Rt = 6.84 (method A), purity 88.8%. 5bc. l-Benzo [b] t? ofen-7-? l-4- [4- (2-chloro-4-fluoro-phenoxy) -butyl] -piperaz ma. LC / MS (m / z) 419 (MH +), Rt = 6.44 (method A), purity 98.5%. 5bd. 1- (5-Chloro-2, 2-d? Met? L-2, 3-d? H? Dro-benzofuran-7-? L) - 4 - [4 - (2-chloro-4-fluoro-phenox ?) -bu 111] -p ipe ra z ma. LC / MS (m / z) 467 (MH +), Rt = 6.91 (method A), purity 94.2%. 5be. 1 - [4 - (2-Bromo-4-fluoro-phenoxy?) -but il] -4 - (2, 3 -a '.? Hi dr or -benz or [1, 4] d in -x - 5 - 11) -p ipe ra z ma. LC / MS (m / z) 467 (MH +), R t = 5.94 (method A), purity 99.3%.
A ^. 5bf. l -Benzo [b] thiophen-7-? l-4- [4- (2-bromo-4- f 1 or o-phenox i) -butyl] -p ipe ra z i na. LC / MS (m / z) 465 (MH +), Rt = 6.57 (method A), purity 99.7%. 5bg. 1 - [4- (2-Bromo-4-fluoro-phenoxy) -butyl] -4- (5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-? L) - pipera z ina LCMS (m / z) 514 (MH +), Rt = 7.02 (method A), purity 99.2%. 5bh. 1- (5-Chloro-2, 2-dimethyl-2, 3-dihydro-benzofuran-7-?) - 4 - [3 - (2,6-dichloro-4-methanesulfonyl-phenoxy) -propil] -p ipe ra z ma. LC / MS (m / z) 549 (MH +), Rt = 6.34 (method A), purity 88.6%. 5bi. 1 - (5-C lo ro-3, 3-dime ti 1-2, 3-dih-idro-benzofuran-7-yl) -4- [3 - (2,6-dichloro-4-methanesulfon-1-pheno) i) -prop 11] -piperazine. LC / MS (m / z) 549 (MH +), Rt = 6.43 (method A), purity 84.0%. 5bj. "1- (5-Chloro-3, 3-dimethyl-2, 3-dihydro-benzofuran-7-yl) -4- [4 - (3-chloro-2-methoxy? -phenyl-sulfanil ) -bu 111] -p ipe ra zi na LC / MS (m / z) 496 (MH +), Rt = 6.80 (method A), purity 78.9%. 5bk. 1- (5-Chloro-2, 2-d? Met? L-2, 3-d? H? Dro-benzofuran-7-? L) - 4 - [3 - (2,6-d? Clo? -4-fluoro-pheno ^?) -pr op 11] -p ipe ra zi na. LCMS (m / z) 487 (MH +), R t = 6.65 (method A), purity 98.5%. 5bl. l- (5-Chloro-3,3-d? met? l-2, 3-d? h? dro-benzofuran-7-? l) - 4 - [3 - (2,6-d? chloro-4) -fluoro-fenox?) -pr op 11] -p ipe razi na. LCMS (m / z) 488 (MH +), R t = 7.56 (method A), purity 88.2%. 5bm. l- (4- { 4- [4- (2,3-D? h? dro-benzo [1,4] -d? ox? n-5-? l) -pipera zm-1 - 11] -butoxy-3, 5-d? -fluoro-yl) -pr ope n-1 -one. LC / MS (m / z) 461 (MH +), Rt = 5.50 (method A), purity 72.9%. 5bn. l- [2- (2-Bromo-4,6-d? -fluoro-pheno?) -et 11] -4- (2,3-d? h? dro-benzo [1,4] d? ox? n-5-? l) -p iper az ma; LC / MS (m / z) 455 (MH +), Rt = 5.17 (method A), purity 77.3%. 5bo. l- [3- (2-Bromo-4,6-d? -fluoro-phenoxy?) ~ pr op 11] -4- (2,3-d? h? dro-benzo [1,4] gave xm-5 - 11) -p iper az ma; i * á. i ^ J ¿. ? ^. t, .iAi ii'l *. { -s,. ^!. *. * A.i, A -?,. * ... aifrfj LC / MS (m / z) 471 (MH +), Rt = 5.34 (method A), purity 98.9%. 5bp. l- [4- (2,6-Dichloro-4-fluoro-phenoxy) -butyl] -4- (2,3-dihydro-benzo [1,4] diox in 5-11) -piperazine. LC / MS (m / z) 455 (MH +), Rt = 5.73 (method A), purity 95.0%. 5bq 1 - (2,3-dihydro-benzo [1,4] dioxm-5-yl) -4- [3 - (2, 4, 6 -t r ib r omo-enoxi) -propi 1] -pipera z i na. LC / MS (m / z) 593 (MH +), Rt = 6.09 (method A), purity 99.7%. 5br. l- (4- { 3- [4- (2,3-Dihydro-benzo [1,4] -d? o in-5-yl) -p ipe ra z in-1-i 1] -propox i.) - 3, 5-difluoro-f in 11) -p clothing n-1 -one. LC / MS (m / z) 447 (MH +), Rt = 5.20 (method A), purity 99.2%. 5bs. l-. { 4- [4- (4-Benzo [b] thiophen-7-? L- p ipe r a z in-1-i 1) -butoxy] -3,5-difluoro-phenol} -propan-1-one. LC / MS (m / z) 459 (MH +), Rt = 6.11 (method A), purity 80.0%. 5bt. l-Benzo [b] thiophen-7-yl-4- [3- (2-bromo-4,6-difluoro-phenoxy) -pr op i 1] -piperazine. LC / MS (m / z) 467 (MH +), Rt = 6.05 (method A), purity 98.7%. 5bu. l-Benzo [b] t? ofen-7-? l-4- [4- (2, 6-d? chlor-4-fluoro-phenoxy?) -butyl] -p ipe ra z a n. LC / MS (m / z) 455 (MH +), Rt = 6.36 (method A), purity 96.7%. 5bv. 1-Benzo [b] t? Ofen-7 -? L-4- [3- (2, 4, 6-tribromo-phenoxy) -p rop i l] -p? Perazma; LC / MS (m / z) 591 (MH +), Rt = 6.71 (method A), purity 99.6%. 5b. l- (4- [3- (4-Ben? o [b] t? ofen-7-? l-p? perazm-1-? l) -propox i] -3,5-d? fluoro-phen? l.) .propan-1 -one LC / MS (m / z) 445 (MH +), Rt = 5.87 (method A), purity 98.4%, 5bx, 3,5-D? bromo-4-. { 3- [4- (2,3-d? H? Drobe nzo [1, 4] d? O. \ M-5-? L) -p? Perazm-1-? L] -pr opox i .}. - be nz on itr 11 o LC / MS (m / z) 538 (MH +), Rt = 5.37 (method A), purity 76.8% useful] -4- (2, 3-d? h Dro-benzo [l, 4] d? oxm-5? l) -p ipe razi na LC / MS (m / z) 545 (MH +), Rt = 5.91 (method A), purity 71.2%. 5bz 1 - [4 - (4-Br omo-2, 6-di f 'luo ro-f' eno xi) -but il] -4- (2, 3-d? Hydro-benzo [l, 4] d iox in 5 - i 1) -p ipe raz ina. LC / MS (m / z) 483 (MH +), R t = 5.76 (method A), purity 91.9%. 5ca l-Benzo [b] t? ofen-7-? l-4- [3- (2,6-d ibr omo-4-n i tro-phenoxy) -prop i 1] -piperazine; LCMS (m / z) 554 (MH +), R t = 6.24 (method A), purity 87.4%. 5cb. 4 - [3 - (4-Ben z or [b] t i or fen-7-11 -p ipe ra z i n-1-yl) -propox i] -3,5-dibromo-benzonitrile. LC / MS (m / z) 538 (MH +), R t = 6.05 (method A), purity 94.1%. 5cc. l-Benzo [b] thiophen-7-yl-4- [4- (4-bromo-2,6-difluoro-phenoxy) -butyl] -piperazine. LCMS (m / z) 481 (MH +), Rt = 6.34 (method A), purity 94.1%. 5cd. 1 - [3 - (2-Chloro-phenylsulfanyl) -propyl] -4 - (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine. LC / MS (m / z) 405 (MH +), Rt = 5.57 (method A), purity 99.5%. 5ce. l-Benzo [b] thiophen-7-yl-4- [3- (2-chloro-faith n 11 s u 1 fa n i 1) -propi 1] -pipera z i na; LC / MS (m / z) 403 (MH +), R t = 5.99 (method A), purity 100%. ta Áaba? A *? s¿ $ mÁÍM «, ¿. * s? r ... a;;? a,. 5cf. 1 - [3 - (2,4-Difluoro-phenoxy?) -propyl] -4- (2,3-dihydro-benzo [1,4] diox in-5-i 1) -p ipe ra z i na. LC / MS (m / z) 391 (MH +), R t = 7.66 (method A), purity 92.5%. 5cg. l- [3- (4-Bromo-2,6-difluoro-phenoxy) -propyl] -4- (2,3-dihydro-benzo [1,4] diox in-5-11) -piperazine. LCMS (m / z) 471 (MH +), Rt = 5.53 (method A), purity 97.9%. 5ch. l-Benzo [b] thiophen-7-yl-4- [2- (2-bromo-4,6-difluoro-phenoxy) ethyl-piperazm; LC / MS (m / z) 455 (MH +), Rt = 5.93 (method A), purity 92.0%. 5ci. l-Benzo [b] thiophen-7-yl-4- [3- (2, 4-difluoro-phenoxy) -pr op il -p iper az ma; LC / MS (m / z) 389 (MH +), R t = 5.76 (method A), purity 81.7%. 5cj. l-Benzo [b] thiophen-7-yl-4- [3- (4-bromo-2,6-difluoro-phenoxy) -propyl-p ipe r a zin. LC / MS (m / z) 469 (MH +), Rt = 6.20 (method A), purity 98.5%. 5ck. 8-. { 4- [3- (2-Chloro-4-fluorophenoxy) -propyl] -p ipe r a z m-1-i 1} - 2,3-dihydro-benzo [1,4] dioxin-5-carbonitrile.
LC / MS (m / z) 432 (MH +), Rt = 2.29 (method A), purity 75.0%. 5cl. 8-. { 4- [3- (2,6-Dichloro-phenoxy?) -prop il] -p ipe r a z in- 1 - 11} - 2,3-dihydro-benzo [1,4] diox m-5-ca rbon itril LC / MS (m / z) 464 (MH +), R t = 2.41 (method A), purity 67%.
Example 6 6a. 8-. { 4- [3- (4-Fl uo ro-2 -me t i-phenoxy) -prop 11] -piperazm-1-ylj-2,3-dihydro-benzo [1,4] -d? Oxm- 5-carbon? Trilo, oxalate. Ethyl acid 2, 3-d i hydroxide was dissolved (103 g) and 1,2-dibromoethane (250 mL) in ethanol (1.0 L); To this stirred mixture was added a solution of potassium tert-butoxide (316 g) in ethanol (1.5 L) by dripping over the course of 8 hours. The reaction was stirred for 16 hours. More 1,2-dibromoethane (100 mL) and also potassium tert-butoxide (126 g) in ethanol (700 mL) were added dropwise and once again, the reaction was stirred for 16 hours. After completion of the reaction, it was filtered and evaporated and then subjected to standard washing procedures of ethyl acetate. Raw dioxane (108 g) sufficiently pure to use was obtained directly in the subsequent reaction. It was dissolved in a mixture of ethanol: water (400 mL)., 1: 1) and sodium hydroxide (68 mL) was added dropwise at room temperature, followed by stirring for 16 hours. The reaction was evaporated, dissolved once more in ethyl acetate and the pH adjusted to 3, followed by washing using a standard procedure to give the free acid (86.5 g). The acid (229 g) was dissolved in thionyl chloride (2.0 L) and heated at reflux temperature for 3 hours and then cooled and evaporated. The remains were coevaporated 3 times with toluene. The crude chloride was dissolved in toluene and added dropwise to a solution of ammonium hydroxide (1.5 1) at 0 ° C. The subsequent stirring at room temperature for 30 minutes produced the total precipitation of the amido derivative. The precipitated product was filtered and washed (water and ethyl acetate) to give the pure amido derivative (267 g) containing some moisture. This compound was mixed with thionyl chloride (1.5 L) and heated to reflux temperature for 7 hours, cooled, evaporated and coevaporated with toluene (3 times) followed by standard washing to give the 5- c i a nob e n z od i o x a no (202 g) in the form of pure transparent oil. A part of this cyano derivative (25.5 g) was dissolved in acetic acid (120 mL) and heated to 60 ° C, after which a bromine solution (61 mL) was added dropwise in 15 min. acetic acid (70 mL). The mixture was heated at 80 ° C for 2.5 hours, cooled and filtered to give the 6.7-dibromo-5-cycloalkoxy in crystalline crude (24.7 g). The obtained dibromo derivative was added in portions to refrigerated nitric acid (steaming, 100 mL) at 0 ° C within 5 min. After 10 minutes at room temperature, the reaction was poured into ice water (800 mL) and stirred for 30 min; the precipitated product was filtered and dried (25.7 g). The obtained nitro compound was reduced by dissolving it together with potassium hydroxide (11.8 g) in methanol (600 mL). Palladium on charcoal (5%, 21.0 g) was added and the mixture was stirred under hydrogen pressure (3 bar) for 3 hours. When all the starting material had been consumed, water was added and the mixture was washed using standard procedures in ethyl acetate. Evaporation gave the 5-ami no-8-c i to nobe n z od i or xa not pure (12 g) which was dissolved in chlorobenzene (160 mL) and hydrochloride of b i s - (c 1 or r and e 111) amine was added I ???.? a- * ~ J? -tM ~ t ** -. Mt * Aát.m (12.3 g). The reaction mixture was heated at reflux temperature for 60 hours, cooled and the chlorobenzene was separated by decantation. The crude product was dissolved directly in tetrahydrofuran (500 mL) and water (500 mL) and potassium carbonate (92 g) were added, a solution of di-tert-butyl carbonate (46.8 g) in tetrahydrofuran ( 100 mL) to the stirred solution at room temperature. The reaction was stirred for 16 hours and washed using a standard procedure. The obtained crude product was purified using flash chromatography on silica gel to give the derivative tert-butylcarbamate (25 g). A part of this product (10.9 g) was deprotected by treatment with acid c 1 or r h i d r i co-t e r to give the pure crystalline amine (8.6 g) in the form of the hydrochloride salt. Treatment of this hydrochloride with ammonium hydroxide gave the free base, which was washed with ethyl acetate using a standard procedure. A part of l- [8-cyano-l, 4-benzodioxan-5-yl] -piperazine (0.44 g) was dissolved in a mixture of methyl i s obu t i 1 c e t on a and N, - dime t i 1 f o rmami da (6 + 6 mL) and then potassium carbonate (0.48 g) was added. This mixture was stirred for 15 minutes. HE added bromide of 3 - (2 - c 1 oro - 4 - f 1 uo rof in 11 - 1 - 11) -ox?] propyl (0.53 g) dissolved in methyl is ob uti 1 cet ona (4 mL) and warmed The reaction mixture was refluxed for 1.5 hours, cooled and evaporated to dryness and then washed with ethyl acetate using the standard procedure. The collected pure oil was dissolved in acetone to then add oxalic acid. Filtration gave the title compound as a pure crystalline material (0.14 g). Mp. 118-120 ° C. X H NMR (500 MHz): 2.18 (m, 5H), 2.75-3.00 (m, 6H), 3.35 (m, 4H), 4.00 (t, 2H), 4.35 (dd, 4H), 6.50 (d, ÍH) , 6.63 (m, ÍH), 6.72 (m, 2H), 7.08 (d, ÍH), 7.30 (dd, 1H), 7.50 (d, 2H). MS: m / z: 496 (MH +). Anal. Cale. for C23H26FN3O3: C, 58.19; H, 5.80; N, 8.15. Found C, 58.26; H, 5.55; N, 8.50. 6b. 8-. { 4- [3- (2-Bromo-4-fluoro-phenoxy?) -p rop 11] -p ipe ra z 1 n-1-i 1} - 2, 3-dihydro-benzo [1,4] -d? Ox? N-5-ca rbonitrile, oxalate. Mp. 152-154 ° C. X-ray NMR: 2.08 (t *, 2H), 3.00 (t, 2H), 3.05 (s, 4H), 3.25 (s, 4H), 4.09 (t, 2H), 4.35 (dd, 4H), 6.60 (d, ÍH), 7.18 (m, 3H), 7.55 (d, ÍH). MS: m / z: 476 (MH +), 397. 358. 149. Anal. Cale. for C22H23BrF 3? 3: C, 50.25; H, 4.54; N, 7.33. Found C, 50.31; H, 4.64; N, 6.85. 6c. 8-. { 4- [3- (2-Chloro-phenoxy?) -prop? L] -p per a z in- 1 - 11} - 2, 3-dihydro-benzo [1,4] diox m-5 -carbonitrile, oxalate. Mp. 96-98 ° C. NMR LH: 2.09 (m, 2H), 2.95-3.05 (m, 6-H), 3.28 (m, 4H), 4.12 (s, 2H), 4.38 (dd, 4H), 6.60 (d, ÍH), 6.95 (t, ÍH), 7.15-7.23 (m, 2H), 7.30 (t, ÍH), 7.43 (d, ÍH). MS: m / z: 414 (MH +), 258, 149. Anal. Cale. for C22 H: C 1 N 303: C, 56.28; H, 5.30; N, 8.21. Found, C, 56.22; H, 5.35; N, 8.21.
E j us 7 7aa. 1 - (2, 3 - d ih i d r o - b e n z o [1, 4] d i or x i n - 5 - 11) -4 - (2-phenylsulfanyl-ethyl) -piperaz ma. To a solution of thiophenol (176 mg, 1. Mmol) in DMF (1.6 mL) was added a solution of potassium tert-butoxide (1.6 mL, 1.6 mmol, 1.0 M in tert-buta no 1). ). The mixture was stirred for 5 minutes at room temperature. An aliquot of the resulting solution (850 μL) was added to a solution of 2-b as-1, 1-dimethoxyethane (59 mg, 0.35 mmol) in DMF (0.70 mL). The reaction mixture was heated to 80 ° C and stirred for 16 hours. After cooling to room temperature, ethyl acetate (6 mL) was added. The organic phase was washed with water (2 x 4 mL) and dried over sodium sulfate. After evaporation of the volatiles in vacuo, the resulting oil was dissolved in a mixture of dioxane and 3M HCl (4 mL, dioxane: 3M HCl 8: 1) and heated at 80 ° C for 1 hour. After cooling to room temperature, ethyl acetate (6 mL) was added. The organic phase was washed with water (2 x 4 mL) and dried over sodium sulfate. After evaporation of the volatiles in vacuo, the resulting oil was dissolved in 1, 2-d i c 1 or r o e t a no (1.80 mL). An aliquot of the produced solution (600 μL) was added to a solution of 1- (2, 3-d? H? Drobenzo [1,4] d? Ox? N) p? Perazma (22.4 μmol) in DMF (60 μL), followed by the addition of triacet ox i bo rohi dr uro (30 mg, 0.14 mmol). After stirring the mixture at room temperature for 2 hours, a mixture of methanol / water (600 μL, methanol: water 9: 1) was added and the resulting solution was loaded onto a pre-packed column. ion exchange The column was washed with acetonitrile (2.5 mL) and methanol (2.5 mL), followed by elution of the product with a 4 N solution of ammonia in methanol (4.5 mL). After removal of the solvents in vacuo, the title compound was obtained as a colorless oil (5.7 mg, 1 6, 9 μm or 1, 7 5%).
LCMS (m / z) 338 (MH +), Rt = 2.07 (method B), purity 89.3%. In an analogous manner, the following compounds were prepared: 7ab. 1 - (2,3-dihydr or -benzo [1,4] d? Oxm-5-yl) -4 - [2 - (2,6-d? Met? L-phenoxy?) - et 11] - pipera zin. LCMS (m / z) 369 (MH +), Rt = 2.34 (method B), purity 88.86%. 7ac. l- (2,3-d? h? dro-benzo [1,4] d? oxm-5-? l) ~ 4 - [2 - (2,6-d? meth? l-phen? lsulfan? l ) -but? l] -p? peraz? na. LC / MS (m / z) 413 (MH +), Rt = 2.54 (method B), purity 99.1%. 7ad. 1 - (2,3-d? H? Dro-benzo [1,4] d? O? M-5-? L) -4 - [2 - (2,4-d? Met? L-phen? Lsulfan ? l) -et? l] -p? perazma. LC / MS (m / z) 385 (MH +), Rt = 2.35 (method B), purity 96.14%. 7ae. 1- (2,3-d? H? Dro-benzo [1,4] diox m-5-11) -4 - [2 - (2-tpfluoromet? L-phenoxy?) - and 111] -pipera zi na . LC / MS (m / z) 409 (MH +), Rt = 2.31 (method B), purity 80.22%. 7af. l - (2,3-d? h? dro-benzo [l, 4] d? o m-5-? l) -4 - [2 - (2-tr? fluoromet? l-phen? lsulfan? l) - et 11] -pipera z ina. LC / MS (m / z) 425 (MH +), Rt = 2.33 (method B), purity 98.58%. 7ag. 1 - (2,3-d? H? Dro-benzo [l, 4] d? O? M-5-? L) -4 - [2 - (2-et? L-phenoxy?) - et i] -pipe zi na. LC / MS (m / z) 369 (MH +), Rt = 2.32 (method B), purity 75.61%. 7ah l- [2- (2,3-D? Chloro-phen? lsulfan? l) -e 111] -4- (2, 3-d? h? dro-benzo [1,4] d or x m-5 - 11) -pipe razma. LC / MS (m / z) 425 (MH +), Rt = 2.38 (method B), purity 97.58%. 7ai. l- [2- (2-Al? l-6-chloro-phenoxy?) -et? l] -4- (2, 3-d? h? dro-benzo [1,4] diox m-5-11 ) -p ipe ra z ma. LC / MS (m / z) 415 (MH +), Rt = 2.44 (method B), purity 91.16%. 7aj. 1 - (2,3-d? H? Dro-benzo [l, 4] d? O m-5-? L) -4 - [3 - (2,4-d? Meth? L-phen? Lsulfan? l) -propí 1] -p ipe ra zi na. LC / MS (m / z) 399 (MH +), R t = 2.43 (method B), purity 95.09%. 7ak. l- (2,3-d? h? dro-benzo [l, -4 - [3 - (2-tpfluoromet? l-phen? lsulfan? l) -pr op 11] -p ipe raz ina LC / MS (m / z) 439 (MH +), Rt = 2.4 (method B), purity 93.66%, 7al.l- [3- (2,3-D? Chloro-phen? lsulfan? l) -pr op 11] - 4 - (2, 3-d? H? Dro-benzo [1,4] diox m-5-11) -piperazm. ?gave?? ? -i .iM¿ákí * i * MÍA. * - m LC / MS (m / z) 439 (MH +), Rt = 2.47 (method B), purity 94.59%. 7 am. l- [3- (3,4-Dichloro-phenylsulfanyl) -p rop i 1] -4- (2,3-dihydro-benzo [1,4] diox in-5-yl) -piperazine. LC / MS (m / z) 439 (MH +), Rt = 2.52 (method B), purity 94.34%. 7an l- [4- (3, 4-Dichloro-phenylsulfanyl) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine. LC / MS (m / z) 453 (MH +), R t = 2.62 (method B), purity 72.11%. 7ao. 1- [4- (2-Chloro-5-methyl-phenoxy) -butyl] -4- (2,3-dihydro-benzo [1,4] diox in-5-yl) -piperazine. LC / MS (m / z) 417 (MH +), Rt = 2.27 (method C), purity 84.86%. 7ap. l- [2- (2,4-Dichloro-phenylsulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -p ipe ra z ine. LC / MS (m / z) 425 (MH +), Rt = 2.17 (method C), purity 93.15%. 7aq. 1 - (2,3-dihydro-benzo [1,4] gave in-5-yl) -4- (3-m-tolylsulfanyl -propi 1) -piperazine. LCMS (m / z) 385 (MH +), R t = 2.05 (method C), purity 75.1%. 7ar l - [4- (2, 4-D? Chloro-phen? lsulfan? l) -bu 111] -4- (2, 3-d? h? dro-benzo [1,4] diox m- 5 - 11 ) - p ipe r az ma. LC / MS (m / z) 453 (MH +), Rt = 2.37 (method C), purity 73.44%. 7th 1 - (2, 3 -dih idr or -benzo [1,4] dio-5-11) -4- [2 - (2-et? L-phen? Lsulfan? L) -et 11) -p ipe ra zi na LCMS (m / z) 385 (MH +), R t = 2.09 (method C), purity 96.15%. 7at. l- [2- (2,5-D? chlor-phen? lsulfan? l) ~ et il] -4- (2,3-d? h? dro-benzo [l, 4] d? oxm-5- ? l) - pipera z ma. LC / MS (m / z) 425 (MH +), Rt = 2.11 (method C), purity 96.58%. 7au. l- [2- (3-Chloro-phensulfan? l) -et? l] -4- (2,3-d? h? dro-benzo [1,4] diox m-5-11) -pipe r az LC / MS (m / z) 391 (MH +), R t = 1.99 (method C), purity 95.76%. 7av. 1- [2- (2-Chloro-phenylsulfanyl) -ethyl] -4- (2,3-d-hydrobenzo [1,4] dioxm-5-yl) -piperaz ma. LCMS (m / z) 391 (MH +), R t = 1.92 (method C), purity 97.93%. 7a. 1 - (2,3-d? H? Dro-benzo [1,4] d? O ^ m-5-? L) - 4 - [2 - (2-fluoro-phen? Lsulfan? L) -ethyl] -piperazma.
LCMS (m / z) 375 (MH +), R t = 1.82 (method C), purity 94.32%. 7ax. 1 - (2, 3 - d ih i d r o - b e n z o [1, 4] d i or m - 5 - 11) -4 - [3 - (2-et? L-phenylsulfanyl) -propi 1] -pipe ra z ma. LC / MS (m / z) 399 (MH +), Rt = 2.17 (method C), purity 83.64%. 7ay. l- [3- (2,5-Dichloro-phenylsulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,4] d i or x in -5-11) -pipe r a zin. LC / MS (m / z) 439 (MH +), Rt = 2.19 (method C), purity 89.61%. 7az 1 - [3 - (3-Chloro-phenylsulfanyl) -pr op 11] -4- (2,3-dihydro-benzo [1,4] d iox in-5-i 1) -piperazine. LC / MS (m / z) 405 (MH +), Rt = 2.09 (method C), purity 87.22%. 7ba 1- (2,3-dihydro-benzo [1,4] d? O: -: m-5-yl) -4 - [3 - (2-fluorophenylsulfanyl) -propyl] -pipe azine. LC / MS (m / z) 389 (MH +), R t = 1.91 (method C), purity 85.93%. 7bb. "3-Chloro-4 - (4- [4- (2, 3-dih? Dro-be nzo [1, 4] gave in- 5 - i 1) -p ipe ra z in - 1 - i 1 ] -butoxy.}. -benzonitrile LC / MS (m / z) 428 (MH +), Rt = 1.95 (method C), purity 76.61%. Íii-? J .- ^ A, i AÍ.á¿Í & Í.A¿..il¡? I¿i * S. ... aaa- * ií 7bc. l - (2,3-d? h? dro-benzo [1,4] d? o ^ m-5-? l) - 4 - (4-o-tol? lsulfan? l-but? l) -p ipe raz ma LC / MS (m / z) 399 (MH +), Rt = 2.13 (method C), purity 72.93%. 7bd. 1 - [4 - (2,5-Dichloro-phenoyl-phenyl) -butyl] -4- (2,3-d? -hydro-benzo [1,4] dioxm-5-11) - p ipe r az ma. LC / MS (m / z) 453 (MH +), Rt = 2.31 (method C), purity 77.14%. 7be. l- [4 ~ (2-Chloro-phensulfan? l) -but? l] -4- (2,3-d? h? dro-benzo [1,4] di ox m-5-11) - p ipe ra z ma. LC / MS (m / z) 419 (MH +), Rt = 2.14 (method C), purity 75.5%. 7bf. 1- (2,3-d? H? Dro-benzo [l, 4] d? O .m-5-? L) - 4 - [4 - (2-fluoro-phen? Lsulfan? L) -butyl] -pipe azma. LCMS (m / z) 403 (MH +), Rt = 2.03 (method C), purity 74.97%. 7bg. l- (2,3-d? h? dro-benzo [l, 4] d? o? m-5-? l) - 4 - [2 - (3,4-d? methox? -phen? lsulfan? l) - et 11] -piperazm. LC / MS (m / z) 417 (MH +), Rt = 1.7 (method D), purity 89.79%. 7bh. 3 - . { 4 - [4 - (2,3-d? H? Dro-benzo [1,4] d? Oxm-5-11) -pipera zm-l-? L] -butox ?} -benzon? LC / MS (m / z) 394 (MH +), R t = 1.85 (method D), purity 75.52%. 7bi. 1 - [4 - (2-Chloro-4-fluoro-phenylsulfanyl) -butyl] -4- (2,3-dihydro-benzo [1,4] gave x i n-5-i 1) -p ipe r a zin. LCMS (m / z) 437 (MH +), Rt = 2.23 (method D), purity 86.05%. 7bj. 1 - (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -4 - [3- (4-trifluoromethoxy-phenylsulfanyl) -propyl] -p ipe r a zin. LC / MS (m / z) 455 (MH +), R t = 2.29 (method D), purity 86.83%. 7bk. l- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -4- [3 - (2,5-dimethoxy-phenylsulfanyl) -prop i 1] -piperazine. LC / MS (m / z) 431 (MH +), Rt = 1.9 (method D), purity 74.89%. 7bl. l- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) ~ 4 - [3 - (3-bromo-phenylsulfanyl) -propyl] -p ipe r a zin. LC / MS (m / z) 449 (MH +), Rt = 2.13 (method D), purity 88.56%. 7bm. 1 - (2,3-dihydro-benzo [1,4] d? Oxin-5-yl) -4 - [4 - (2-methoxy-phenylsulfanyl) -butyl] -piperazine. LC / MS (m / z) 415 (MH +), Rt = 1.94 (method C), purity 94.04%. 7bn. 1 - (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [4- (2-is or p or p-1-phenylsulfanyl) -butyl] -piperazine. rARÁ & .? Í Í? S & *: l, &** i £ ** & * ü * A i. **.
LC / MS (m / z) 427 (MH +), Rt = 2.39 (method C), purity 73.56%. 7bo. 1- (2,3-dihydro-benzo [1,4] d IOX in 5-11) -4- (2-o-tolylsulfanyl-ethyl) -piperazine. LCMS (m / z) 371 (MH +), R t = 1.92 (method C), purity 93.93%. 7bp. l- [4- (2-Allyl-phenoxy) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine. LCMS (m / z) 409 (MH +), R t = 2.26 (method C), purity 91.57%.
Pharmacological Assays The affinity of the compounds of the present invention for 5-HT ?A receptors was determined by measuring the inhibition of binding of a radioactive ligand to the 5-HT 1A receptors therapeutically effective amount described in the following assay: Inhibition of the binding of 3H-5-CT to the 5-HT? A Human Receptors By this method, the inhibition by drugs of the 5-HTiA agonist of 3H-5-car box amidate tryptamine ( 3H-5-CT) to expressed cloned human 5-HTiA receptors , .4 »* a .m'í ..
Stably in transfected HeLa cells (HA7) (Fargin, A, et al., J. Biol. Chem., 1989. 264, 14848). The test was carried out as a modification of the method described by Harrington M.A. and others, J. Pharmacol. Exp. Ther. , 1994. 268. 1098. Human 5-HT? A receptors (40 μg of cell homogenate) were incubated for 15 minutes at 37 ° C in 50 mM Tris buffer at pH 7.7 in the presence of 3H-5-CT. The non-specific binding was determined including 10 μM of metergoline. The reaction was terminated by rapid filtration through Unifilter GF / B filters in a Tomtec Cell Harvester. The filters were counted in a Packard Top Counter counter. The results obtained are reported in Table 1. The compounds of the present invention have also been analyzed to determine their affinity for the dopamine D receptors in the following assay.
Inhibition of the binding of H-YM-09151-2 to human dopamine D receptors By this method the inhibition by drugs of the binding of [JH -YM-09151-2 0.06 nM membranes was determined in vitro human D4.2 dopamine receptors cloned expressed in CHO cells. Modified method from NEN Life Science Products, Inc., technical data certificate PC2533- 10/96. The following Table 1 presents the results in terms of IC50 values.
Table 1: Union data The compounds of the present invention were also analyzed for their effect on the reuptake of serotonin in the following assay: Inhibition of H-5-HT Absorption in Rat Brain Synaptosomes Using this method, the ability of drugs to inhibit the accumulation of 3H-5-HT in rat rat whole synaptosomes was determined in vitro. The assay was performed in accordance with that described by Hyttel, J. Psychopharmacology 1978. 60, 13. Moreover, the 5-HTiA antagonist activity of some of the compounds of the present invention in 5-HT1A receptors has been estimated in vitro. clones stably expressed in transfected HeLa cells (HA7). In this essay, the 5-HTiA antagonist activity is estimated by measuring the ability of the compounds to antagonize the 5-HT-induced inhibition of the cAMP accumulation induced by forskolin. The test was carried out as modification of the method described by Pauwels, P.J. and others, Biochem. Pharmacol. 1993. 45, 375. The compounds of the present invention were also analyzed for their affinity for the dopamine D3 receptors in the following assay.
Inhibition of [H] Spiperone binding to human D3 receptors. By this method, the inhibition, by drugs, of the binding of [3 H] E s p ipe r ona (0.3 nM) to membranes of D3 human dopamma receptors cloned expressed in CHO cells was determined. Modified method of R.G. MacKenzie et al., Eur. J. Pharm. Mol. Pharm. Sec., 1994, 266, 79-85. As seen from the above, the compounds of the present invention show affinity for 5-HTiA receptors and for dopamine D4 receptors. Moreover, many of the t-AiRiAlA. jfejg, a a £ &j. *.% * *? ^ ** compounds of the present invention possess valuable activity as inhibitors of serotonin reuptake and / or have an effect on D3 receptors. Accordingly, the compounds are considered to be useful for the treatment of psychiatric and neurological disorders as discussed above.
Pharmaceutical Formulation The pharmaceutical formulations of the present invention can be prepared by conventional methods in the art. For example: tablets can be prepared by mixing the active ingredient with ordinary adjuvants and / or diluents and then compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents include: corn starch, potato starch, talcum, magnesium stearate, gelatin, lactose, gums and so on. Any other adjuvant or additive can be used h a b i t u a lme n t used for purposes such as coloring, s a b or r i z ation, conservation, etc. As long as they are compatible with the active ingredients. Solutions for injections can be prepared by dissolving the active ingredient and the - ** I KNOW IF possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling in ampoules or ampoule bottles. Any additive can be added by employing a novel level in the art, such as tonicity agents, preservatives, n 11 ox i dations, etc. The pharmaceutical compositions of the present invention or those that can be made according to the present invention can be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally. in the form of injectable solutions. To prepare such compositions, methods well known in the art can be used and any vehicle, diluent, excipient or other pharmaceutically acceptable additive normally used in the art can be included. Advantageously, the compounds of the present invention are administered in the form of unit doses containing said compounds in an amount of about 0.01 to 1000 mg. The total daily dose is present in the range of a * .A? * A.rÉi a & áM * M **. > The amount of the compound of the present invention is about 0.05-500 mg, and most preferably about 0.1 to 50 mg of the active compound of the present invention.

Claims (19)

1. A heteroaryl derivative having the general Formula 1: (I) any of its enantiomers or any mixture thereof, or an acid addition salt thereof, wherein X is -0-, -S- or -CR4R5-; Y is -CR6R7- -CR6R7- CR8R9- or -CR6 = CR7- or X and Y together form a group -CR4 = CR5-, or -CR4 = CR5-CR6R7-; Z is -0-, or -S-; W is N, C or CH, n is 2, 3, 4, 5, 6, 7, 8, 9 or 10; m is 2 or 3: A is 0 or S where the dotted lines mean an optional link; each of R1, R 'and R are independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C6-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-B cycloalkyl, C -8 cycloalkyl -alkyl C? _6, alkoxy C? _e ,. alkylthio C? -6, hydroxy, formyl, acyl, amino, C? -6 alkylamino, di (CI-J? alkyl) amino, acylamino, a 1 c or x i c a r bon 11 ami no C? -6, ami n o c a r b o n 11 ami n, alkylaminocarbonylamino di (alkyl) C? -6) aminocarbonylamino; each of R, R 'R, R, R and R is independently selected from hydrogen, halogen, trifluoromethyl, C? -6 alkyl. C2-6 alkenyl. C 2-6 alkynyl C 3-8 cycloalkyl- Cycloalkyl Cjg-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, amino, C? -6 alkylamino, di (Ci-g alkyl) amino, phenylamino ofeni 1 a 1 qu i 1 ami no C? _6 Where the phenyl group may be substituted, acylamino, hydroxy, SH, cyano, nitro, -COOR18, -S02-R19 or C? _6 alkyl substituted with a substituent selected from halogen, C-alkoxy? _6, alkylthio C? -6? amino, alkylamino C? _6, di (Ci-s alkyl) amino, acylamino, hydroxy, -SH, cyano, nitro, -COOR18 or -S02-R19; R18 is hydrogen, C6-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl or phenylalkyl C1-, where phenyl groups may be substituted, amino, C1-6alkylamino or di (C6-6alkylamino) amino and R 19 is hydrogen, C 1-6 alkyl, amino, C 1-6 alkylamino, di (C 1-6 alkyl) amino, phenyl or phenyl-C 1-6 alkyl. wherein the phenyl groups may be substituted; each of R 10 and 1 are selected from hydrogen and C 1 -C 6 alkyl- and each of R 12, R 13, R 14, R 15 and R 16 are independently selected from hydrogen, halogen, nitro, cyano, tr 1 f 1 or orne ti 1, t r i f 1 uo r orne t ox i, C1-D alkyl. C? -6 alkenyl, C2 - alkynyl? , C-cycloalkyl, C3-cycloalkyl-Ci-g alkyl, Ci-e alkoxy, Ci-g alkylthio, at 1 qu i 1 su 1 f on 11 o C? -6, hydroxy, formyl, acyl, amino, acylamino, alkoxycarbonylamino Ci-g, ami no ca r bon 11 ami no, a 1 qu i 1 ami no carb on i 1 ami no C? -6, di (alkyl C i - ¿) ami noc arb on i 1 ami no and NR20R wherein R 2 and R "" 1 independently represent hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl or phenyl; or R20 and R2 together with the nitrogen to which they are attached form a 5- or 6-membered carbocyclic ring which optionally contains a further heteroatom; provided, when X-Y-Z together with the phenyl ring form a ring of benzofuran or benzodioxane; and A is 0, then at least one of R12, R13, R14, R15 and R 16 is not hydrogen
2. Compound according to claim 1, characterized in that X is -0-; and Y is -CR6R7-CR8R9 and Z is -0-.
C ompue s t o according to claim 1, characterized in that X is -CR R -; and Y is -CR ° R; and Z is - O -
4. Compound according to claim 1, characterized in that X and Y together form a group -CR4 = CR5-; and Z is -S-.
5. Composite according to any of claims 1-4, characterized in that W is N.
6. Compound according to any of claims 1-5, characterized in that R1, R2 and R3 are hydrogen.
7. Compound according to any of claims 1-6, characterized in that A is 0.
8. Compound according to any of claims 1-7, characterized by the fact that A is S.
9. Compound according to any of claims 1-8, characterized in that n is 2, 3, or 4.
10. Compound according to any of claims 1-9, characterized in that R 1 '2 ha? 1bM * t-iJ áito ± mbiát * .. R 1X 3X R 1X 4H, RiJ, and R are independently selected from the group consisting of hydrogen, halogen, alkyl CL-6 C2-6 alkenyl, C6-6 alkoxy. cyano, at 1 qui 1 s u 1 f on 11 o C? -6, acyl, nitro, t r i f 1 u o r orne 111 o y t r i f 1 uo r orne t ox i.
11. Compound according to any of claims 1-10, characterized in that at least one of R12, R13, R14, Ri5, and R16 is halogen.
12. Compound according to claim 11, characterized in that at least one of R12, R13, R14, R15, and R1 is halogen and the other substituents are selected from the group consisting of hydrogen, halogen, alkoxyCi-e , alkyl Ci-β, C2_6 alkenyl- to 1 qu 11 its 1 foni 1 or Ci-g, acyl, nitro, cyano and trifluoromethyl;
13. , Compound according to claim 1, characterized in that l- [3- (2-chloro-phenoxy) -propyl] -4- (2, 3-d? H? Drobenzo [1,4] d? Ox? n-5-? l) -p? peraz? na; 1 - [3 - (2,6-dichloro-phenoxy) -propyl] -4- (2,3-d? -hydrobenzene [1,4] d? Oxm-5-? L) -piperazine; 1- (2, 3-d? H? Dro- benzo [1,4] dioxin-5-yl) -4- [3- (2, 4.6-trifluoro-phenoxy) -propyl] -piperazine; l- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (4-fluoro-2-methoxy-phenoxy) -propyl] -piperazine; l- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (4-f luoro-2-methyl-phenoxy) -propyl] -piperazine; 1- [3- (4-Chloro-f-enoxy) -p'propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4 - [3- (4-trifluoromethyl-phenoxy) -propyl] -piperazine; 1 • (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (2-fluoro-phenoxy) -propyl] -piperazine; 2 - . { 3 - [4- (2, 3-dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -propoxy} -benzonitrile; 1-Benzo [b] thiof en-7-yl-4- [3- (2-chloro-4-fluoro-phenylsulfanyl) -propyl] -piperazine; 1-Benzo [b] thiof en-7-yl-4- [4- (2-chloro-4-fluoro-phenoxy) -butyl] -piperazine; 1- [2- (3,4-Dichloro-phenylsulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] d? Oxin-5-yl) -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4 - [2- (4-fluoro-phenylsulfanyl) -ethyl] -piperazine; 1- [2 - (Bromo-trifluoromethyl-phenylsulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- [2 - (2,6-Dichloro-phenylsulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] diox? N-5-yl) -piperazine; 1- (2,3-dihydro-benzo [1,4] diox? N-5-yl) 4- (3-phenylsulfanyl-propyl) -piperazine; 1- [3- (2-Bromo-4-f luoro-phenoxy) -propyl] - tj *% ití? ÉÉ '•' • •• 4 - (2, 3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- [4- (2,6-Dichloro-phenylsulfanyl) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- [3- (2-Chloro-4-fluoro-phenylsulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1-Benzo- [b] thiophen-7-yl-4- [3- (2-chloro-4-fluoro-phenyl-sulphonyl) -propyl] -piperazine; 1-Benzo [b] thiophen-7-yl-4- [3- (2,6-dichloro-phenylsulfanyl) -propyl] -piperazine; 1-Benzo [b] thiof en-7-yl-4- [4- (2,6-dichloro-phenyl-sulfanyl) -butyl] -piperazine; l- [4- (3-Chloro-2-methoxy-phenylsulfonyl) -butyl] -4- (2,3-dihydro-benzo [1,4] -dioxin-5-yl) -piperazine; 1-Benzo [b] thiof en-7-yl-4- [4 - (3-chloro-2-methoxy-phenylsulfanyl) -butyl] -piperazine; 1-Benzo [b] thiof en-7-yl-4- [3- (2-chloro-4-fluoro-phenylsulfanyl) -propyl] -piperazine; 1 - [3 - (2,6-D? Bromo-4-fluoro-phenoxy) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1-Benzo [b] thiophen-7-1-4-4- [3- (2,6-dibromo-4-f luoro-f-enoxy) -propyl] -piperazine; 4- . { 3- [4- (2, 3-dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -propoxy} 3, 5-diiodobenzonitrile; 3, 5-Di-tert-butyl-4- (3- [4- (2,3-dihydro-benzo [1,4] -dioxin-5-yl) -piperazin-1-yl] -propoxy. -benzonitrile; 1- [3- (2,6-Dichloro-4-methanesulfonyl-phenoxy) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5? I) -piperazma; 1-Benzo [b] thiof en-7-yl-4- [3- (2,6-dichloro-4-methanesulfonyl-f-enoxy) -propyl] -piperazine; 1- [3- (Bromo trifluoromethyl- phenylsulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1-Benzo- [b] thiof en-7-yl-4- [3- (bromo-trif luoroethyl-phenyl-sulfanyl) -propyl] -piperazine; 1-Benzo [b] thiof en-7-yl-4- [4- (2-chloro-6-methyl-phenylsulfanyl) -butyl] -piperazine; l-Benzo []] thiophen-7-yl-4- [4- (2-chloro-4-fluoro-phenylsulfanyl) -butyl] -piperazine; 1- [3- (2,6 -Dichloro-4-fluoro-phenoxy) -propyl] -4- (2,3-dihydro-benzo [1,4] d? Oxm-5-yl) -piperazine; 1-Benzo [b] thiophen-7-i 1 - 4 - [3- (2,6-dichloro-4-fluoro-phenoxy) -propyl] -piperazine; l- [4- (2-Chloro-6-methyl-phenylsulfanyl) -butyl] -4- (2,3-d? hydro-benzo [1,4] dioxin-5-yl) -piperazine; l- [3- (2,6-Dichloro-phenylsulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; l- (5-Chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl) -4- [4- (2-chloro-6-methyl-phenyl-sulfanyl) -butyl] -piperazine; 1- (5-Chloro-3, 3-dimethyl-2, 3-dihydro-benzofuran-7-yl) -4 - [4 - (2-chloro-6-methyl-phenylsulfanyl) -butyl] -piperazine; l- (5-Chloro-2,2-dimethyl-2, 3-dihydro-benzofuran-7-yl) -4- [3- (2,6-dichloro-f-phenylsulfanyl) -propyl] -piperazine; 1- (5-Chloro-3, 3-dimethyl-1,2-dihydro-benzofuran-7-yl) -4- [3- (2,6-dichloro-phenylsulfanyl) -propyl] -piperazine; 1 - (5-Chloro-3, 3-dimethyl-2,3-dihydro-benzofuran-7-yl) - 4 - i, AÍ.? * Í. MÜji. .. *.:. IjjhW-llM.J, ..r.i ..., m & ***. AÍte * r ..-.- ** i * ?, A * ....: í. I - ..:,,. . .,,. **,., A *. * T, * k., ... i "i [3- (2-Chloro-4-fluoro-phenylsulfanyl) -propyl] -piperazine; l-Benzo [b] thiophen-7-? l-4- [4- (2-chloro-4-fluoro-phenoxy) -butyl] -piperazine; 1- (5-Chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl) -4- [4- (2-chloro-4-fluoro-phenylsulfanyl) -butyl] -piperazine; 1 - [4 - (2 Bromo-4-f luoro-phenoxy) -butyl] -4- (2,3-dihydro-benzo- [1,4] dioxin-5-yl) -piperazine; 1-Benzo [b] t? Ofen-7-yl 4- [4- (2-bromo-4-fluoro-phenoxy) -butyl] -piperazine; 1 '[4- (2-Bromo-4-fluoro-phenoxy) -butyl] -4- (5-chloro-2,2-dimethyl-2,3-d-hydro-benzofuran-7-yl) -piperazine; 1 - (5-Chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl) -4- [3- (2,6-dichloro-4-methanesulfonyl-phenoxy) -propyl] -piperazine; l- (5-Chloro-3,3-dimet? l-2,3-dihydro-benzofuran-7-? l) -4- [3- (2,6-dichloro-4-methanesulfonyl-phenoxy) -propyl] -piperazine; 1- (5-Chloro-3, 3-dimethyl-2,3-dihydro-benzofuran-7-yl) -4 - [- (3-chloro-2-methoxy-phenylsulfanyl) -butyl] -piperazine; 1- (5-Chloro-2,2-dimethyl-2,3-d? Hydro-benzofuran-7-yl) -4- [3- (2,6-dichloro-4-fluoro-phenoxy) -propyl] - piperazine; 1- (5-Chloro-3, 3-dimethyl-2, 3-dihydro-benzofuran-7-yl) -4- [3 - (2,6-dichloro-4-fluoro-phenoxy) -propyl] -piperazine; 1 - (4 - { 4 - [4- (2, 3-Dihydro-benzo [1,4] dioxin-5-yl) -p [perazin-1-yl] -butoxy] -3.5 -difluoro-phenyl) -propan-1-one; 1- [2- (2-Bromo-4,6-difluoro-f-enoxy) -ethyl] -4- (2,3-d? Hydro-benzo [1,4] dioxin-5-? L) -piperaz ? na; 1 - [3- (2-Bromo-4,6-difluoro-f-enoxy) -propyl] -4- (2,3-d? H? Dro-benzo [1,4] dioxin-5-yl) -piperazine; 1 - [4 - (2,6-D? Chloro-4-fluoro-phenoxy) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- (2,3-dihydro-benzo [1,4] diox? N-5-yl) -4- [3- (2, 4, 6-tribromo-phenoxy) -propyl] -piperazine; l- (4- { 3- [4- (2,3-Dihydro-benzo- [1,4] dioxin-5-yl) -piperazin-1-yl] -propoxy.] -3,5 - dif luoro-phenyl) -propan-1-one; 1 - . { 4 - [4- (4-Benzo [b] -thiophen-7-yl-piperazin-1-yl) -butoxy] -3,5-difluoro-phenyl} -propan-l-one; l-Benzo [i] thiophen-7-? l-4- [3- (2-bromo-4,6-d? f luoro-phenoxy) -propyl] -piperazine; 1-Benzo [b] thiof en-7-yl4- [4- (2,6-dichloro-4-f-luoro-phenoxy) -butyl] -piperazine; 1-Benzo [b] thiof en-7-yl-4- [3- (2, 4, 6-tribromo-phenoxy) -propyl] -piperazine; 1 - . { 4 - [3- (4-Benzo [b] thiophen-7-yl-piperazin-1-yl) -propoxy] -3,5-difluoro-phenyl} -propan-l-one; 3, 5-D? Bromo-4-. { 3- [4- (2, 3-dihydro-benzo [1,4] dioxin-5-yl) -p [perazin-1-yl] -propoxy} -benzonitrile; l- [4- (2,6-Dibromo-4-fluoro-phenoxy) -butyl] -4- (2,3-dihydro-benzo [1,4] -d? ox? n-5-yl) -piperazine; 1- [4- (4-Bromo-2,6-difluoro-phenoxy) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; l-Benzo [¿> ] t? ofen-7-yl-4- [3- (2,6-d? bromo-4-nitro-phenoxy) -propyl] -piperazine; 4- [3- (4-Benzo [b] thiophen-7-yl-piperazin-1-yl) -propoxy] -3,5-dibromo-benzonitrile; 1-Benzo [b] thiof en-7-? L-4- [4- (4 - Í & á.iá. »& .Í íí? Át ** A * -lim * -. , ,, , *to-* .?. m, .--. bromo-2, 6-d? -uforophenoxy) -butyl] -piperazine; 1- [3 (2-Chloro-phenylsulfanyl) -propyl] -4- (2,3-d? -hydro-benzo [1,4] diox? N-5-yl) -piperazine; 1-Benzo [b] thiophen-7-1-4-4- [3- (2-chloro-phenylsulfanyl) -propyl] -piperazine; l- [3- (2,4-Difluoro-phenoxy?) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5? I) -piperazine; 1 - [3- (4-Bromo-2,6-difluoro-f-enoxy) -propyl] -4- (2,3-d? Hydro-benzo [1,4] dioxin-5-yl-piperazine; Benzo [b] thiof en-7-yl-4- [2- (2-bromo-4,6-difluoro-phenoxy) -ethyl-piperazine; 1-Benzo [b] thiof en-7-yl-4- [3 - (2,4-difluoro-phenoxy) -propyl-piperazine; 1-Benzo [b] thiof-7-yl-4- [3- (4-bromo-2,6-d? -fluoro-phenoxy) -prop? l] -piperazine; 8- (4- [3- (2-Chloro-4-fluorophenoxy) -propyl] -piperaz? n-1-yl) -2, 3-d? hydro-benzo [l, 4] dioxan-5-carbonitrile; 8- (4- [3- (2,6-dichloro-phenoxy) -propyl] -piperazin-1-yl.} -2, 3-dihydro-benzo [l, 4] dioxin-5-carbonitrile; 8- { 4- [3- (4-Fluoro-2-methyl-f-enoxy) -propyl] -piperazin-1-yl.} -2, 3-dihydro-benzo [1,4] dioxan-5-carbonitrile; 8 -. {4- [3- (2-Bromo-4-fluoro-phenoxy) -propyl] -piperaz? N-1-yl.} -2 , 3-d? Hydro-benzo [1,4] d? Oxin-5-carbonitrile; 8- { - [3- (2-Chloro-phenoxy) -propyl] -piperazin-1-yl}. 2, 3-dihydro-benzo [1,4] d? Oxin-5-carbonitrile; 1- (2,3-dihydro-benzo [1,4] d? Oxin-5-yl) -4- (2-phenylsulfanil -and til) -piperazine; l- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- * »A? A & m-i [2- (2,6-dimethyl-phenoxy) -ethyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [4- (2,6-dimethyl-f-phenylsulfonyl) -butyl] -piperazine; 1- (2,3-dihydrobenzo [1,4] dioxin-5-yl) -4- [2- (2, 4-dimethyl-f-polysulfanyl) -ethyl] -piperazine; 1- (2,3-dihydrobenzo [1,4] diox? N-5-yl) -4- [2- (2-trifluoromethyl-phenoxy) -ethyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4 - [2- (2-trifluoromethyl-phenylsulfanyl) -ethyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [2- (2-et? L-phenoxy) -ethyl] -piperazine; 1 - [2 • (2,3-Dichloro-phenylsulfanyl) -ethyl] -4- (2,3-dihydrobenzo [1,4] diox? N-5-yl) -piperazine; l- [2- (2-Allyl-6-chloro-phenoxy) -ethyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (2, 4-dimethyl-phenylsulfanyl) -propyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4 - [3- (2-trifluoromethyl-phenylsulfanyl) -propyl] -piperazine; l- [3- (2,3-Dichloro-phenylsulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; l- [3- (3,4-Dichloro-phenylsulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- [4- (3, 4-Dichloro-phenylsulfanyl) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1 - [4- (2-Chloro-5-methyl-phenoxy) -butyl] -4- (2,3-dihydrobenzo [1,4] dioxin-5-yl) -piperazine; 1 - [2 - (2, 4 - Dichloro-phenylsulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] diox? N-5-yl) -piperazine; 1- (2,3-dihydro-benzo [1,4] diox? N-5-yl) -4- (3-m-tolylsulfanyl-propyl) -piperazine; 1- [4- (2,4-Dichloro-phenylsulfanyl) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1 - (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [2- (2-ethyl-phenylsulfanyl) -ethyl) -piperazine; 1- [2- (2, 5-Dichloro-f-polysulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] -dioxin-5-yl) -piperazine; 1- [2- (3-Chloro-phenyl-sulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1- [2- (2-Chloro-phenylsulfanyl) -ethyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1 - (2,3-dihydro-benzo [1,4] dioxin-5-yl) 4- [2- (2-fluoro-phenylsulfanyl) -ethyl) -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (2-ethyl-f-enyl-sulfonyl) -propyl] -piperazine; l- [3- (2,5-Dichloro-phenol-sulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; l- [3- (3-Chloro-phenylsulfanyl) -propyl] -4- (2,3-dihydro-benzo [1,] dioxin-5-yl) -piperazine; l- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (2-fluoro-phenylsulfanyl) -propyl) -piperazine; 3 -Cloro-4-. { 4- [4- (2, 3-dihydro-benzo [1,4] diox? N-5-yl) -piperazin-1-yl] -butoxy} -benzonitrile; 1 - (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- (4-o-tol-lysulfanyl-butyl) -piperazine; l- [4- (2,5-Dichloro-phenylsulfan? l) - *. r ~ Ak * $ > . * £ -butyl] -4- (2, 3-dihydro-benzo [1,4] dioxin-5-l) -piperazine; 1- [4- (2-Chloro-phenylsulfanyl) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; 1 - (2,3-d? Hydro-benzo [1,4] dioxin-5? L) -4- [4- (2-fluoro-phenylsulfan I) -butyl] -piperazine; 1- (2,3-dihydrobenzo [1,4] diox? N-5-yl) -4- [2- (3,4-dimethoxy-phenylsulfanyl) -ethyl] -piperazine; 3-. { 4- [4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -butoxy-benzonitrile; 1- [4- (2-Chloro-4-f-luoro-phenylsulfanyl) -butyl] -4- (2,3-dihydro-benzo [1,4] -diox? N-5-yl) -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (4-trifluoromethoxy-phenylsulfanyl) -propyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -4- [3- (2, 5-dimethoxy-phenylsulfanyl) -propyl] -piperazine; 1- (2,3-dihydro-benzo [1,4] d? Ox? N-5-yl) -4 - [3- (3-bromo-phenylsulfanyl) -propyl] -piperazine; 1 - (2,3-dihydro-benzo [1,4] dioxin-5? L) -4- [4- (2-methoxy-phenylsulfanyl) -butyl] -piperazine; 1- (2,3-dihydrobenzo [1,4] diox? N-5-yl) -4- [4- (2-isopropyl-phenyl-sulfanyl) -butyl] -piperazine; 1- (2,3-dihydrobenzo [1,4] dioxm-5-yl) -4- (2-o-tol-lysulfanyl-ethyl) -piperazine; l- [4- (2-Allyl-phenoxy) -butyl] -4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazine; or an acid addition salt thereof.
14. A pharmaceutical composition comprising a compound according to claims 1 to 13 or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.
15. Use of a compound according to claims 1 to 13 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease that responds to the combined effect of the 5-HTiA receptors and the Dopamma D4 receptors.
16. Use of a compound according to claims 1 to 13 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease that responds to the inhibition of serotonin absorption and antagonism of 5-HTiA receptors.
17. Use of a compound according to any of claims 15 to 16 in which the medicament is for the treatment of affective disorders such as generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, depression, social phobia and eating disorders, as well as neurological disorders such as psychosis.
18. Method for the treatment of a disorder or disease of a living animal body, including a human being, which responds to the effect of the 5-HTiA and D receptors, which comprises administering to said living animal body, including a human, a therapeutically amount effective of a compound according to claims 1 to 15 or a pharmaceutically acceptable acid addition salt thereof.
19. Method of treatment according to claim 18 in which the disorder or disease is an affective disorder such as generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, depression, social phobia and eating disorders, as well as neurological disorders such as psychosis. t ^ AÜ.r? ¡^ ^ ^ mA ^^^^ i ^^ lti? ^ í ^? i • * -. ». ».ii ai-aS
MXPA/A/2002/006591A 1999-12-30 2002-06-28 Novel heteroaryl derivatives, their preparation and use MXPA02006591A (en)

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