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WO1994027992A1 - Piperidine derivatives, their preparation and use - Google Patents

Piperidine derivatives, their preparation and use Download PDF

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Publication number
WO1994027992A1
WO1994027992A1 PCT/DK1994/000199 DK9400199W WO9427992A1 WO 1994027992 A1 WO1994027992 A1 WO 1994027992A1 DK 9400199 W DK9400199 W DK 9400199W WO 9427992 A1 WO9427992 A1 WO 9427992A1
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WO
WIPO (PCT)
Prior art keywords
fluoro
compound
benzisoxazol
formula
piperidine
Prior art date
Application number
PCT/DK1994/000199
Other languages
French (fr)
Inventor
John Bondo Hansen
Frederik Christian GRØNVALD
John Patrick Mogensen
Original Assignee
Novo Nordisk A/S
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Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU69239/94A priority Critical patent/AU6923994A/en
Publication of WO1994027992A1 publication Critical patent/WO1994027992A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to piperidine derivatives which are useful for treating CNS-system, cardiovascular system and/or gastrointestinal dis- orders, methods for preparing such compounds and pharmaceutical compositions containing them.
  • DA dopamine
  • clozapine some neuroleptics (e.g. clozapine) show an atypical profile: the compounds are not only beneficial in treating patients, who respond poorly to classical neuroleptic therapy, but the compounds are also relatively devoid of extrapyrimidal side effects (EPS) commonly seen with classical neuroleptics (Ereshefsky et al., Clin.Pharm 8, 691-709, 1989).
  • EPS extrapyrimidal side effects
  • the antipsychotic effect of clozapine and related compounds might be due to its blockade of not only DA-receptors (D-1 , D-2, D-3, D-4, D-5) but also 5HT-receptor subtypes (5HT 2 -, 5HT 3 -, 5HT 1C -, 5HT 1A -), NA- ⁇ , -receptors, histamine and possibly other receptors.
  • 5HT 2 -blockade may also be important (Meltzer, Schizphr. Bull. 17: 263-87, 1991) to counteract the socalled negative symptoms of psycho ⁇ sis (delusions and social withdrawal) which are otherwise difficult to treat with conventional neuroleptics.
  • n and m independently are 0, 1 , 2, or 3;
  • A is cycloalkylene having 3-11 carbon atoms or cycloalkylidene having 3-8 carbon atoms;
  • X is O or NH
  • Y is O, S, NH, NCN, or N-alkyl
  • R 1 is 1 ,2-benzisoxazol-3-yl, 1 H-indazol-3-yl, or 1-methyl-1 H-indazol-3-yl, all of which may be substituted independently with halogen or alkyl in one, two, three or all of the 4-, 5-, 6- and 7-positions;
  • R 2 is hydrogen or alkyl
  • R 3 is phenyl optionally substituted with alkyl, halogen, alkoxy, or perhalome- thyl, or R 3 is
  • Z together with the double bond in the phenyl ring represents a 5- or 6-membered heterocyclic ring comprising one or more nitrogen-, oxy ⁇ gen-, or sulphur atoms; or
  • R 2 and R 3 together with the nitrogen atom form a fused heterocyclic ring system
  • Physiologically and pharmaceutically acceptable salts of the compounds of the invention include acid addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, nitrates, oxalates, phosphates, tartrates, citrates, fumarates, maleates, succinates, and sulphonates e.g. mesylates. If desirable, selected salts may be sub ⁇ jected to further purification by recrystallization.
  • the invention includes within its scope all optical isomers of compounds of the general formula I and their mixtures including racemic mixtures thereof.
  • the compound of the formula (I) includes all cis- and trans-isomers as well as mixtures thereof.
  • C ⁇ -alky refers to a straight or branched, saturated hydrocarbon chain having 1-6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, n-pentyl, neopentyl, n-hexyl and 2,2-dimethylpropyl.
  • cycloalkylene denotes a bivalent radical derived from a saturated monocyclic hydrocarbon by removal of two atoms of hydrogen from each of two different carbon atoms of the ring.
  • Preferred examples of cycloalkylenes having 3-11 carbon atoms are cyclopropylene, 1 ,2-cyclobutylene. 1 ,2-cyclopentylene, 1 ,3-cyclopentylene. 1 ,2-cyclohexyle- ne, 1 ,3-cyclohexylene, 1 ,3-cyclooctylene, 1 ,4-cycloundecylene.
  • cycloalkylidene denotes a bivalent radical derived from a saturated monocyclic hydrocarbon by removal of two atoms of hydrogen from the same carbon atom of the ring.
  • Examples of cycloalkyli- denes having 3-8 carbon atoms are cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene and cyclooctylidene.
  • alkoxy refers to a monovalent substituent comprising a lower alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen, e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy.
  • halogen means fluorine, chlorine, bromine and iodine.
  • perhalomethyl means -CF 3 , -CCI 3 , -CBr 3 and -Cl 3 .
  • 5- or 6-membered heterocyclic ring refers to a monocyclic unsaturated ring containing one or more hetero atoms selected from nitrogen, oxygen and sulphur and having 5 or 6 members, e.g. pyrrolo, imidazo, pyrazolo, piperido, piperazino, triazolo, pyrimido, pyridaz- o.oxazino, azino, isothiazolo, isoxazolo, oxazolo, oxadiazolo, thiadiazolo, thiazolo, 1 ,3-dioxolo, 1 ,4-dioxanyl.
  • pyrrolo imidazo, pyrazolo, piperido, piperazino, triazolo, pyrimido, pyridaz- o.oxazino, azino, isothiazolo, isoxazolo, oxazolo
  • fused heterocyclic ring system refers to a multiple heterocyclic ring system preferably having 2 or 3 fused unsaturated or saturated rings in a linear or branched arrangement.
  • the group -N(R 2 )(R 3 ) is preferably a group selected from 1 ,2.3,4-tetrahydro-quinolin-l -yl, 1 ,2,3,4-tetrahydro-5,6-methylenedioxy- quinolin-1-yl, 1 ,2,3,4-tetrahydro-6.7-methylenedioxy-quinolin-1 -yl, 1 ,2,3,4- tetrahydro-7.8-methylenedioxy-quinolin-1 -yl; 1 -indolinyl, 4,5-methylenedioxy- 1 -indolinyl, 5,6-methylenedioxy-1 -indolinyl, 6,7-methylenedioxy-1 -indolinyl; 1 ,2,3,4-tetrahydro-quinolin-l -yl substituted independently in one or more of the 5-, 6-, 7- or
  • halogen, C ⁇ -alkoxy or perhalo- methyl 1 -indolinyl substituted independently in one or more of the 4-, 5-, 6- or 7-positions with C ⁇ -alkyl, halogen, C- ⁇ -alkoxy or perhalomethyl; 3,4- dihydro-2H-1 ,4-benzoxapine substituted independently in one or more of the 4-, 5-, 6- or 7-positions with C ⁇ g -alkyl, halogen, C ⁇ -alkoxy or perhalo ⁇ methyl.
  • R 3 is selected from benzthia- zolyl, benzimidazolyl, benzisoxazol, 1 H-indazolyl, benzofuranyl, indolyl, 3H- indolyl, indolinyl, benzothiophenyl, quinolinyl, 1 ,2,3,4-tetrahydroquinolinyl, quinazolinyl and 3,4-methylenedioxyphenyl.
  • Z is selected from the group consisting of thiazolyl, imidazolyl, piperazinyl, morpholino, thiomor- pholino, 1 ,3-dioxolanyl, 1 ,4-dioxanyl, pyrrolidinyl, pyrazolyl, and pyrazinyl.
  • R 1 is 6-fluoro-1 H- indazol-3-yl, 6-fluoro-1 ,2-benzisoxazol-3-yl, or 6-fluoro-1 -methyl-1 H-indazol-3- yl;
  • X is O;
  • Y is O; and
  • -A- is cyclopropylene, cyclopropylidene or cyclohexyl- ene.
  • the substituent R 1 is preferably selected from 6-fluoro-1 ,2-benzisoxazol-3-yl, 6-fluoro-1 H-indazol-3-yl, and 6-fluoro-1 -methyl-1 H-indazol-3-yl.
  • Preferred compounds of the invention are:
  • the compounds of the present invention demonstrate high affinity for various receptor subtypes including the 5HT 2 -, the dopamine D and D 2 - receptors or a combination of these.
  • the invention relates to a compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of CNS-system disorders, cardiovascular disorders or gastrointestinal disorders.
  • the invention also relates to the use of the inventive com ⁇ pounds of formula (I) as medicaments useful for treating CNS-system, cardiovascular system and gastrointestinal disorders, such as treatment of anxiety, sleep disorders, depression, psychosis, schizophrenia, migraine, ischemic neuronal damage, asthma, hypertension, urticaria, analgesia and emesis.
  • the invention relates to a method of preparing the above mentioned compounds.
  • a compound of formula (II) a compound of formula (II)
  • N-ethyl-N-(3,4-methylenedioxyphenyl)carbamoyl chloride prepared by treatment of N-ethyl-3.4-methylenedioxyaniline with phosgene in the presence of triethylamine may be reacted with the desired aminoalkyi piperidine or hydroxyalkyi piperidine intermediate to obtain the desired urea or carbamate of formula I.
  • R 2 and R 3 have the meanings set forth above, prepared by the method described in R. Lee Webb and C.S. Labaw, J. Heterocyclic Chem. U9, 1205 (1982) from R 2 -NH 2 and N-cyanodiphenoxyimidocarbonate.
  • E is a suitable leaving group, e.g. CI-, Br-, I-, p-toluensulfonate-; R 12 is H or a protecting group, and A, n, m and X have the meaning set forth above.
  • compounds of formula (III) can be made by reacting a com- pound of formula (VIII) with one of the compounds of formula (XVa) or
  • p is an integer 1 ,2,3,4,5 or 6.
  • the compounds of the present invention have been tested for binding to various CNS receptor subtypes in vitro in mice.
  • TEST 1 In yjtro inhibition of DOPAMINE D2 receptor binding,
  • Radioactive-labelled ligand 3 H-Spiropehdol is incubated with isolated cell- membrane fragments at 37°C for a given period of time. Following complet- ed incubation, the incubate is filtered through GF/B filters which are rinsed following filtration to remove unspecifically adhered radioactivity. As opposed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters is indicative of the amount of ligand bound specifically as well as nonspecifically to the mem- branes.
  • the procedure is performed in ice bath. Polytron kinematica is rinsed with milli-Q-H 2 0 before and after use. Male Wistar rats, 150-200 g are decapitat- ed, striatum is removed quickly and weighed (approx. 50 mg). Striatum is transferred to a centrifuging vial containing 10 ml ice-cold D2 buffer. Homo- genization is performed applying polytron kinematica (homogenizer) setting 6 for 20 sec. The homogenizer is rinsed with 10 ml D2 buffer in another centrifuging vial. The 10 ml rinsing buffer is added to the tissue vial. Centri- fugation at 18,000 rpm for 10 min.
  • polytron kinematica homogenizer
  • the test result is shown in Table I as IC 50 indicating the concentration inhibiting specific binding by 50%.
  • Radioactive-labelled ligand 3 H-SCH 23390 is incubated with isolated cell- membrane fragments in incubation buffer at 30°C for a given period of time. Following completed incubation, the incubate is filtered through GF/B filters, which are rinsed following filtration to remove unspecifically adhered ra ⁇ dioactivity. As opposed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters indicates the amount of ligand bound specifically as well as nonspecifically to the membranes.
  • mice Male Wistar rats, 150-200 g are decapitated. Striatum is removed quickly, weighed (approx. 50 mg) and carefully homogenized in 100 x vol. of buffer I applying glass/teflon homogenizer 10 up/down strokes. Ex.: 50 mg striatum is homogenized in 5,000 ⁇ l buffer I. The homogenate is centrifuged at 18,000 rpm for 20 min. at 4°C, and the supernate is decanted. This step is performed three times, and each time the pellet is resuspended and homogenized in 100 x vol. of buffer I. Following the third centrifugation, the pellet is suspended in 100 x vol. of resuspension buffer and homogenized. The tissue is now ready for use. The tissue is stable at 0°C for 8 hours.
  • the test result is shown in Table I as IC 50 indicating the concentration inhibiting specific binding by 50%.
  • Radioactive-labelled ligand 3 H-Ketanserine is incubated with isolated cell membrane fragments at 37°C for a given period of time. Following complet ⁇ ed incubation, the incubate is filtered through GF/B filters, which are rinsed following filtration to remove unspecifically adhered radioactivity. As op ⁇ posed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters indicates the amount of ligand bound specifically as well as nonspecifically to the membranes.
  • the preparation is made in ice bath. Polytron kinematica is rinsed with milli- Q-H 2 0 before and after use. Male Wistar rats, 150-200 g are decapitated. Frontal cortex is removed quickly and weighed (approx. 200 mg). Frontal cortex is added to centrifuging vial containing 10 ml ice-cold D2 buffer. Homogenization applying polytron kinematica (homogenizer) setting 6 for 20 sec. The homogenizer is rinsed with 10 ml D2 buffer in another centrifug ⁇ ing vial. The 10 ml rinsing buffer is added to the tissue vial. Centrifuged at 18,000 rpm for 10 min. at 4°C. Final pellet is transferred to 125 x vol. of same buffer. (Ex 200 mg in 25 ml D2 buffer). Can be stored for approx. 30 min. at 0°C.
  • IC 50 i.e. the concentration inhibiting specific binding by 50%.
  • the compounds of the invention may be placed into the form of pharmaceutical composi ⁇ tions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, sus ⁇ pensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additio ⁇ nal active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
  • Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
  • Such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and digly- cerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvi- nylpyrrolidone.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Ampoules are convenient unit dosage forms.
  • tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or like can be used when a sweetened vehicle can be employed.
  • the compound of the invention is dis-claimedd in unit dosage form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • a typical tablet which may be prepared by conventional tabletting tech ⁇ niques contains:
  • trans-2,3- methylene-1 ,4-butanol 800 mg, 8 mmol
  • 3,4-methylenedi- oxyphenylisocyanate 1.3 g, 8 mmol
  • (+ trans-2,3-methylene-4-(3,4- methylenedioxyphenylcarbamoyloxy)butanol 750 mg, 28 mmol
  • MS/FAB (8 KV, 2mA): 584 (M + 1), 375, 233, 178, 166, 138.

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Abstract

Piperidine derivatives of formula (I) wherein n and m independently are 0, 1, 2, or 3; A is cycloalkylene or cycloalkylidenes; X is O or NH; Y is O, S, NH, NCN, or N-lower alkyl; R1 is 1,2-benzisoxazol-3-yl, 1H-indazol-3-yl, or 1-methyl-1H-indazol-3-yl, all of which may be substituted; R2 is H or alkyl; and R3 is phenyl optionally substituted, or R3 is (a) wherein Z together with the double bond in the phenyl ring represents a 5- or 6-membered heterocyclic ring; or R?2 and R3¿ together with the nitrogen atom form a fused heterocyclic ring system; or pharmaceutically acceptable salts thereof are useful in the treatment of indications related to the CNS-system, cardiovascular system or to gastrointestinal disorders.

Description

Piperidine Derivatives, their Preparation and Use
The present invention relates to piperidine derivatives which are useful for treating CNS-system, cardiovascular system and/or gastrointestinal dis- orders, methods for preparing such compounds and pharmaceutical compositions containing them.
Much evidence has accumulated to suggest that neuroleptics exert their antipsychotic action by blocking dopamine (DA) receptors in the brain. In recent years, it has become clear that some neuroleptics (e.g. clozapine) show an atypical profile: the compounds are not only beneficial in treating patients, who respond poorly to classical neuroleptic therapy, but the compounds are also relatively devoid of extrapyrimidal side effects (EPS) commonly seen with classical neuroleptics (Ereshefsky et al., Clin.Pharm 8, 691-709, 1989). In this respect it has been speculated that atypical neuro¬ leptics are working mainly by blocking socalled A10 mesolimbic DA systems (areas which are thought to be affected in psychosis), while the side effects of classical neuroleptics are produced by blockade of DA receptors in the motor areas of the brain (A9 DA system (Gudelsky, Psy- chopharmacology (Berl) 99: S13-S17, 1989)). The antipsychotic effect of clozapine and related compounds might be due to its blockade of not only DA-receptors (D-1 , D-2, D-3, D-4, D-5) but also 5HT-receptor subtypes (5HT2-, 5HT3-, 5HT1C-, 5HT1A-), NA-α, -receptors, histamine and possibly other receptors.
Furthermore, 5HT2-blockade may also be important (Meltzer, Schizphr. Bull. 17: 263-87, 1991) to counteract the socalled negative symptoms of psycho¬ sis (delusions and social withdrawal) which are otherwise difficult to treat with conventional neuroleptics.
Compounds reducing 5-HT neurotransmission have been suggested to be useful for the treatment of various neurological and psychiatric diseases.
More specifically, the present invention relates to piperidine derivatives of the general formula (I)
Figure imgf000004_0001
wherein n and m independently are 0, 1 , 2, or 3;
A is cycloalkylene having 3-11 carbon atoms or cycloalkylidene having 3-8 carbon atoms;
X is O or NH;
Y is O, S, NH, NCN, or N-alkyl;
R1 is 1 ,2-benzisoxazol-3-yl, 1 H-indazol-3-yl, or 1-methyl-1 H-indazol-3-yl, all of which may be substituted independently with halogen or alkyl in one, two, three or all of the 4-, 5-, 6- and 7-positions;
R2 is hydrogen or alkyl; and
R3 is phenyl optionally substituted with alkyl, halogen, alkoxy, or perhalome- thyl, or R3 is
Figure imgf000005_0001
wherein Z together with the double bond in the phenyl ring represents a 5- or 6-membered heterocyclic ring comprising one or more nitrogen-, oxy¬ gen-, or sulphur atoms; or
R2 and R3 together with the nitrogen atom form a fused heterocyclic ring system;
and pharmaceutically acceptable salts thereof.
Physiologically and pharmaceutically acceptable salts of the compounds of the invention include acid addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, nitrates, oxalates, phosphates, tartrates, citrates, fumarates, maleates, succinates, and sulphonates e.g. mesylates. If desirable, selected salts may be sub¬ jected to further purification by recrystallization.
The invention includes within its scope all optical isomers of compounds of the general formula I and their mixtures including racemic mixtures thereof.
It is to be understood that the compound of the formula (I) includes all cis- and trans-isomers as well as mixtures thereof.
Also, all enantiomers (+, -) as well as the racemic mixture of the compound of the general formula (I) are to be considered within the scope of the invention. The term "C^-alky." as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1-6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, n-pentyl, neopentyl, n-hexyl and 2,2-dimethylpropyl.
The term "cycloalkylene" as used herein denotes a bivalent radical derived from a saturated monocyclic hydrocarbon by removal of two atoms of hydrogen from each of two different carbon atoms of the ring. Preferred examples of cycloalkylenes having 3-11 carbon atoms are cyclopropylene, 1 ,2-cyclobutylene. 1 ,2-cyclopentylene, 1 ,3-cyclopentylene. 1 ,2-cyclohexyle- ne, 1 ,3-cyclohexylene, 1 ,3-cyclooctylene, 1 ,4-cycloundecylene.
The term "cycloalkylidene" as used herein denotes a bivalent radical derived from a saturated monocyclic hydrocarbon by removal of two atoms of hydrogen from the same carbon atom of the ring. Examples of cycloalkyli- denes having 3-8 carbon atoms are cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene and cyclooctylidene.
The term "alkoxy" as used herein, alone or in combination, refers to a monovalent substituent comprising a lower alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen, e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy.
The term "halogen" means fluorine, chlorine, bromine and iodine.
The term "perhalomethyl" means -CF3, -CCI3, -CBr3 and -Cl3.
The term "5- or 6-membered heterocyclic ring" as used herein refers to a monocyclic unsaturated ring containing one or more hetero atoms selected from nitrogen, oxygen and sulphur and having 5 or 6 members, e.g. pyrrolo, imidazo, pyrazolo, piperido, piperazino, triazolo, pyrimido, pyridaz- o.oxazino, azino, isothiazolo, isoxazolo, oxazolo, oxadiazolo, thiadiazolo, thiazolo, 1 ,3-dioxolo, 1 ,4-dioxanyl.
The term "fused heterocyclic ring system" as used herein refers to a multiple heterocyclic ring system preferably having 2 or 3 fused unsaturated or saturated rings in a linear or branched arrangement.
When R2 and R3 together with the nitrogen atom form a fused heterocyclic ring system, the group -N(R2)(R3) is preferably a group selected from 1 ,2.3,4-tetrahydro-quinolin-l -yl, 1 ,2,3,4-tetrahydro-5,6-methylenedioxy- quinolin-1-yl, 1 ,2,3,4-tetrahydro-6.7-methylenedioxy-quinolin-1 -yl, 1 ,2,3,4- tetrahydro-7.8-methylenedioxy-quinolin-1 -yl; 1 -indolinyl, 4,5-methylenedioxy- 1 -indolinyl, 5,6-methylenedioxy-1 -indolinyl, 6,7-methylenedioxy-1 -indolinyl; 1 ,2,3,4-tetrahydro-quinolin-l -yl substituted independently in one or more of the 5-, 6-, 7- or 8-positions with C^-alkyl. halogen, C^-alkoxy or perhalo- methyl; 1 -indolinyl substituted independently in one or more of the 4-, 5-, 6- or 7-positions with C^-alkyl, halogen, C-^-alkoxy or perhalomethyl; 3,4- dihydro-2H-1 ,4-benzoxapine substituted independently in one or more of the 4-, 5-, 6- or 7-positions with C^g-alkyl, halogen, C^-alkoxy or perhalo¬ methyl.
In a preferred embodiment of the invention, R3 is selected from benzthia- zolyl, benzimidazolyl, benzisoxazol, 1 H-indazolyl, benzofuranyl, indolyl, 3H- indolyl, indolinyl, benzothiophenyl, quinolinyl, 1 ,2,3,4-tetrahydroquinolinyl, quinazolinyl and 3,4-methylenedioxyphenyl.
In another preferred embodiment of the invention Z is selected from the group consisting of thiazolyl, imidazolyl, piperazinyl, morpholino, thiomor- pholino, 1 ,3-dioxolanyl, 1 ,4-dioxanyl, pyrrolidinyl, pyrazolyl, and pyrazinyl.
In yet another preferred embodiment of the invention, R1 is 6-fluoro-1 H- indazol-3-yl, 6-fluoro-1 ,2-benzisoxazol-3-yl, or 6-fluoro-1 -methyl-1 H-indazol-3- yl; X is O; Y is O; and -A- is cyclopropylene, cyclopropylidene or cyclohexyl- ene.
The substituent R1 is preferably selected from 6-fluoro-1 ,2-benzisoxazol-3-yl, 6-fluoro-1 H-indazol-3-yl, and 6-fluoro-1 -methyl-1 H-indazol-3-yl.
Preferred compounds of the invention are:
4-(6-Fluoro-1 H-indazol-3-yl)-1-(2-(3,4-methylenedioxyphenylcarbamoyloxy)- cyclohexyl) piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1-((2-(3,4-methylenedioxyphenylcarbamo- yloxymethyl)cyclopropyl)methyl)piperidine.
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1-((2-(6-benzothiazolylcarbamoyloxyme- thyl)cyclopropyl)methyl)piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1-((2-(3,4-ethylenedioxyphenylcarbamoyl- oxymethyl)cyclopropyl) methyl) piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -((2-(3,4,5-trimethoxyphenylcarbamoyl- oxy)methyl)cyclopropyl)methyl)piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -((2-((1 ,2,3,4-tetrahydroquinolin-1 -yl)car- bonyloxymethyl)cyclopropyl)methyl)piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -((2-((1.2,3.4-tetrahydro-6.7-methylenedi- oxyquinolin-1-yl)carbonyloxymethyl)cyclopropyl)methyl)piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1-((2-(N-methyl-N-(3.4-methyienedioxy- phenyl)carbamoyloxymethyl)cyclopropyl)methyl)-piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -((2-(1 -indolinylcarbonyloxymethyl)- cyclopropyl)methyl)piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -((1 -(3,4-methylenedioxyphenylcarbamo- yloxymethyl)cyclopropyl)methyl)piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1-((2-(3,4-methyienedioxyphenylcarbamo- yloxymethyl)cyclobutyl)methyl)piρeridine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1-((2-(3,4,5-trimethoxyphenylcarbamoyl- oxymethyl)cyclopentyl)methyl)piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1-((2-(N-methyl-N-phenylcarbamoyloxyme- thyl)cyclobutyl)methyl)piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -(5-(3,4-methylenedioxyphenylcarbamo- yloxy)-3,3-pentamethylen-pent-1-yl)piperidine,
4-(6-Fluoro-1 -methyl-1 H-indazol-3-yl)-1 -((1 -(1 ,2,3,4-tetrahydroquinolin-1 - yl)carbonyloxy)-2,2-trimethylen)propyl)piperidine,
4-(6-Fluoro-1 H-indazol-3-yl)-1 -(1 -(3.4-methylenedioxyphenylcarbamoyloxy)- cyclohex-2-yl)piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -(1 -(3,4-methylenedioxyphenylcarbamoyl- oxy)cyclohex-2-yl)piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -(2,2-(1 ,2-ethylene)-3-((6,7-methylene- dioxy-I ^.S^-tetrahydroquinolin-l-y carbonyloxyJpropyOpiperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -(2,2-(1 ,2-ethylene)-3-(indolin-1 -yl-carbo- nyloxy)propyl)piperidine, trans 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -((2,3-methylene)-4-((indolin-1 -yl)- carbonyloxy)butyl)piperidine,
trans 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -(2,3-methylene-4-(3,4-methylene- dioxyphenylcarbamoyloxy)butyl)piperidine,
4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -(1 -(3,4-methylenedioxophenylcarbamoyl- oxy)cyclohex-2-yl)piperidine,
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 (-5-(3,4,5-trimethoxyphenylcarbamoyl- oxy)-3,3-pentamethylen-pent-1-yl)piperidine
or pharmaceutically acceptable acid addition salts of these compounds.
The compounds of the present invention demonstrate high affinity for various receptor subtypes including the 5HT2-, the dopamine D and D2- receptors or a combination of these.
Accordingly, in another aspect the invention relates to a compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of CNS-system disorders, cardiovascular disorders or gastrointestinal disorders.
Furthermore, the invention also relates to the use of the inventive com¬ pounds of formula (I) as medicaments useful for treating CNS-system, cardiovascular system and gastrointestinal disorders, such as treatment of anxiety, sleep disorders, depression, psychosis, schizophrenia, migraine, ischemic neuronal damage, asthma, hypertension, urticaria, analgesia and emesis. ln yet another aspect, the invention relates to a method of preparing the above mentioned compounds. In a variant a) of the method of the inven¬ tion, a compound of formula (II)
Y
II Q-C-N-R2
I (II)
R3
wherein Y, R2 and R3have the meanings set forth above, and Q is a leaving group, is reacted with a compound of formula (III)
- (CH2 ) n-A- ( CH2 ) m-XH (III)
Figure imgf000011_0001
wherein A, X, n, m and R1 have the meanings set forth above to form a compound of formula I.
For instance the N-ethyl-N-(3,4-methylenedioxyphenyl)carbamoyl chloride prepared by treatment of N-ethyl-3.4-methylenedioxyaniline with phosgene in the presence of triethylamine may be reacted with the desired aminoalkyi piperidine or hydroxyalkyi piperidine intermediate to obtain the desired urea or carbamate of formula I.
Compounds of formula I, wherein X is -NH- and Y is =NH, =NCN or =N- C^-alkyl are prepared by standard procedures as described in e.g. H.J.
Petersen et al., J.Med.Chem. (1978) 21, 773-781 , and R. Lee Webb et al., J. Heterocyclic Chem. 24, 275 (1987). In a variant b) of the method of the invention a compound of formula (IV)
Figure imgf000012_0001
wherein A, n, m and R1 have the meanings set forth above, is reacted with a compound of formula (V)
Y
H. .CS-C-N-R2 (V)
5 /
R3
wherein R2 and R3 have the meanings set forth above, and Y is' =NH, =NCN or =N-C1.6-alkyl. and
in a variant c) of the method of the invention, a compound of formula (VI)
R3 1 2
N-R
( \ / »- ( CH Δ, ) n -A- ( CH λ, ) m -NH
wherein A, R1, R2, R3, n and m have the meanings set forth above, is reacted with NH3, NH^C^-alkyl or NH2CN by usual procedures to form a compound of formula (I), and
in a variant d) of the method of the invention, a compound of formula (III), wherein X is -NH- and A and R1 have the meanings set forth above, is reacted with a compound of formula (VII)
Figure imgf000013_0001
wherein R2 and R3 have the meanings set forth above, prepared by the method described in R. Lee Webb and C.S. Labaw, J. Heterocyclic Chem. U9, 1205 (1982) from R2-NH2 and N-cyanodiphenoxyimidocarbonate.
Compounds of formula (III), wherein R1, A and X have the meanings set forth above, have been prepared by alkylating the known piperidine deriva- tive (VIII) (J.T.Strupczewski et al., J.Med.Chem., 28, 761-769 (1985))
Figure imgf000013_0002
wherein R1 has the meaning set forth above, with a compound of formula (IX)
E-(CH2)n-A-(CH2)m-XR^ (IX)
wherein E is a suitable leaving group, e.g. CI-, Br-, I-, p-toluensulfonate-; R12 is H or a protecting group, and A, n, m and X have the meaning set forth above.
Compounds of the formula (IX) can be made by selective monoprotection of dihydroxy derivatives (XI) e.g. by using the procedures of P.C. McDougal et al.: J.Organic Chemistry (1986), 51, 3388-3390, followed by transform¬ ation of the hydroxy group of the compound of the formula (XI) into a leaving group using standard procedures:
HO-(CH2)n-A-(CH2)mOH (XI)
I HO-(CH2)n-A-(CH2)mOR12 (X)
the compound of formula (IX)
By a similar procedure compounds of formula XII
O / R2 E-(CH2)n-A-(CH2)m-X-C-N (XII)
\ R3
wherein A, E, n, m, R2, R3 and X have the meanings set forth above, which have been prepared by treatment of a compound of formula XIII with the carbamoyi chloride of XIV, followed by transformation of the hydroxy group to a suitable leaving group*. HO-(CH2)n-A-(CH2)m-XH (XIII)
HO-(C
Figure imgf000015_0001
XII
Alternatively, compounds of formula (III) can be made by reacting a com- pound of formula (VIII) with one of the compounds of formula (XVa) or
(XVb) to give a compound of formula (XVI) which can then be reduced by standard procedures to give a compound of the formula (III)
Figure imgf000015_0002
(XVa) (XVb)
Figure imgf000015_0003
wherein A, R1 ( n, m, E and R2 have the meanings set forth above.
Compounds of formula (III), wherein n = 0 and m = 0 can be prepared by reacting a compound of formula (VIII) with a compound of formula (XVII)
* ( CH9 ) -Λ 2 p
CH - - CH
(XVII)
wherein p is an integer 1 ,2,3,4,5 or 6.
The compounds of the present invention have been tested for binding to various CNS receptor subtypes in vitro in mice.
Detailed conditions for the in vitro assays are described below:
TEST 1 : In yjtro inhibition of DOPAMINE D2 receptor binding,
Method description
Principle:
Radioactive-labelled ligand 3H-Spiropehdol is incubated with isolated cell- membrane fragments at 37°C for a given period of time. Following complet- ed incubation, the incubate is filtered through GF/B filters which are rinsed following filtration to remove unspecifically adhered radioactivity. As opposed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters is indicative of the amount of ligand bound specifically as well as nonspecifically to the mem- branes. Tissue preparation:
The procedure is performed in ice bath. Polytron kinematica is rinsed with milli-Q-H20 before and after use. Male Wistar rats, 150-200 g are decapitat- ed, striatum is removed quickly and weighed (approx. 50 mg). Striatum is transferred to a centrifuging vial containing 10 ml ice-cold D2 buffer. Homo- genization is performed applying polytron kinematica (homogenizer) setting 6 for 20 sec. The homogenizer is rinsed with 10 ml D2 buffer in another centrifuging vial. The 10 ml rinsing buffer is added to the tissue vial. Centri- fugation at 18,000 rpm for 10 min. at 4°C. Final pellet is transferred to 1 ,000 x vol. of same buffer. (Ex. 50 mg striatum in 50 ml D2 buffer). Can be stored at 0°C for at least 4 hours. Note that the tissue must be monoge- neous (uniform) before use. If not, brief homogenization is performed.
Assay:
2,500 μl tissue (homogeneous) 25 μl 3H-Spiroperidol (0.05 nM) 25 μl test substance/H20/blind (Domperidone 0.2 μM)
Incubation for 20 min. at 37°C - 10 min. on ice bath.
10 ml ice-cold 0.9% NaCl is added to the tubes and filtered through GF/B filters (use gloves). This procedure is repeated. The filters are placed in counting vials and 4 ml opti-flour is added (perform in fume cupboard, use gloves). Counting is performed at window 0-19 of the beta-counter (Pachard). Note that receptor box and lid are rinsed thoroughly in H20 after use to avoid contamination. Further, the analytical site is cleaned carefully every day after use. Test substances:
Dissolved in H20, EtOH, MeOH or DMSO and further diluted in H20. The D2 binding will stand concentrations of up to approx. 20% of these solvents without affecting the binding. Most stock solutions are stable at 4°C, attention is, however, paid to any precipitation, change in colour etc. Test- substance dilutions are always made fresh every day. When weighing out test substances, it is attempted to weigh out approx. 1 mg of substance. Less than 0.8 mg must never be weighed out and only infrequently more than 2 mg (for economy reasons), dependent, however, on conc./assay.
Results:
The test result is shown in Table I as IC50 indicating the concentration inhibiting specific binding by 50%.
TEST 2: ID yjtro inhibition of DOPAMINE D1 receptor binding
Method description
Principle:
Radioactive-labelled ligand 3H-SCH 23390 is incubated with isolated cell- membrane fragments in incubation buffer at 30°C for a given period of time. Following completed incubation, the incubate is filtered through GF/B filters, which are rinsed following filtration to remove unspecifically adhered ra¬ dioactivity. As opposed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters indicates the amount of ligand bound specifically as well as nonspecifically to the membranes. Tissue preparation:
Male Wistar rats, 150-200 g are decapitated. Striatum is removed quickly, weighed (approx. 50 mg) and carefully homogenized in 100 x vol. of buffer I applying glass/teflon homogenizer 10 up/down strokes. Ex.: 50 mg striatum is homogenized in 5,000 μl buffer I. The homogenate is centrifuged at 18,000 rpm for 20 min. at 4°C, and the supernate is decanted. This step is performed three times, and each time the pellet is resuspended and homogenized in 100 x vol. of buffer I. Following the third centrifugation, the pellet is suspended in 100 x vol. of resuspension buffer and homogenized. The tissue is now ready for use. The tissue is stable at 0°C for 8 hours.
Assay:
600 μl incubation buffer 100 μl 3H-SCH 23390 (0.2 nM)
100 μl tissue 200 μl test substance/H20/blind (cis-flupentixol 2 μM)
Incubation for 60 min. at 30°C.
10 ml of ice-cold 0.9% NaCl is added to the tubes. Filtration is performed through GF/B filters (use gloves). This procedure is repeated. Filters are placed in counting vials and 4 ml opti-flour is added (perform in fume cupboard, use gloves) and counting is performed at window 0-19 of the beta-counter (Pachard). Note that receptor box and lid are rinsed thorough¬ ly in H20 after use to avoid contamination. Further, the analytical site is cleaned carefully every day after use.
Test substances:
Dissolved in H20, EtOH, MeOH or DMSO and further diluted in H20. The D1 binding will stand concentrations of up to approx. 20% of these solvents without affecting the binding. Most stock solutions are stable at 4°C. Attention should, however, be paid to any precipitation, change in colour etc. Test-substance dilutions are always made fresh every day. When weighing out test substances, it is attempted to weigh out approx. 1 mg of substance. Less than 0.8 mg must never be weighed out and only in¬ frequently more than 2 mg (for economy reasons), dependent, however, on conc./assay.
Results:
The test result is shown in Table I as IC50 indicating the concentration inhibiting specific binding by 50%.
TEST 3: ]n vitro inhibition of 5HT2-receptor binding
Method description
Principle:
Radioactive-labelled ligand 3H-Ketanserine is incubated with isolated cell membrane fragments at 37°C for a given period of time. Following complet¬ ed incubation, the incubate is filtered through GF/B filters, which are rinsed following filtration to remove unspecifically adhered radioactivity. As op¬ posed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters indicates the amount of ligand bound specifically as well as nonspecifically to the membranes.
Tissue preparation:
The preparation is made in ice bath. Polytron kinematica is rinsed with milli- Q-H20 before and after use. Male Wistar rats, 150-200 g are decapitated. Frontal cortex is removed quickly and weighed (approx. 200 mg). Frontal cortex is added to centrifuging vial containing 10 ml ice-cold D2 buffer. Homogenization applying polytron kinematica (homogenizer) setting 6 for 20 sec. The homogenizer is rinsed with 10 ml D2 buffer in another centrifug¬ ing vial. The 10 ml rinsing buffer is added to the tissue vial. Centrifuged at 18,000 rpm for 10 min. at 4°C. Final pellet is transferred to 125 x vol. of same buffer. (Ex 200 mg in 25 ml D2 buffer). Can be stored for approx. 30 min. at 0°C.
Assay:
1250 μl tissue 25 μl 3H-Ketanserine (0.4 nM) 25 μl test substance/H20/blind cyproheptadine (2 μM)
Incubation for 15 min. at 37°C.
10 ml ice-cold 0.9% NaCl is added to the tubes. Filtration is performed through GF/B filters (use gloves). This procedure is repeated. The filters are placed in counting vials and 4 ml opti-flour is added (prepare in fume cupboard, use gloves). Counting at window 0-19 of the beta-counter
(Pachard). Note that receptor box and lid are rinsed thoroughly in H20 after use to avoid contamination. Further, the analytical site is cleaned carefully every day.
Test substances:
Dissolved in H20, EtOH, MeOH or DMSO and further diluted in H20. The 5HT2 binding will stand concentrations of up to approx. 5% of these sol¬ vents without affecting the binding. Most stock solutions are stable at 4°C. Attention should, however, be paid to any precipitation, change in colour etc. Test-substance dilutions are always made fresh every day. When weighing out test substances, it is attempted to weigh out approx. 1 mg of substance. Less than 0.8 mg must never be weighed out and only in¬ frequently more than 2 mg (for economy reasons), dependent, however, on conc./assay.
Results:
The test result is shown in Table I as IC50 i.e. the concentration inhibiting specific binding by 50%.
TABLE I Results from in vitro tests
Compound of TEST 1 TEST 2 Example No. IC50 (nM) IC50 (nM)
4 13 429
5 15 72
The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, and if desired a pharmaceutically acceptable acid addi¬ tion salt thereof, may be placed into the form of pharmaceutical composi¬ tions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, sus¬ pensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additio¬ nal active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing one (1) milligram of active ingredient or, more broadly, one (1) to thirty (30) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and digly- cerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvi- nylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Ampoules are convenient unit dosage forms.
For oral application, particularly suitable are tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or like can be used when a sweetened vehicle can be employed. Generally, as to broader ranges, the compound of the invention is dis- pensed in unit dosage form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
A typical tablet which may be prepared by conventional tabletting tech¬ niques contains:
Active compound 1.0 mg
Lactosum 67.8 mg Ph. Eur.
Avicel® 31.4 mg
Amberlite® IRP 88 1.0 mg Magnesii stearas 0.25 mg Ph. Eur.
The following non-limitating examples illustrate the invention.
EXAMPLE 1
1 -(1 -(3,4-methylenedioxyphenylcarbamoyioxy)cyclohex-2-yl)-4-(6-fluoro-1 H- indazoi-3-yl) piperidine
A. A mixture of 4-(6-fluoro-1 H-indazol-3-yl)-piperidine (438 mg; 2 mmol) and 7-oxabicyclo[4.1.0]heptane (490 mg; 5 mmol) in 5 ml acetonitril was refluxed for 48 h. The cooled reaction mixture was concentrated in vacuo and purified by chromatography on silica gel 60 with ethyl acetate :methanol (9:1 , v/v) as eluent.
Concentration of the appropriate fractions gave 170 mg (26.8%) of 4-(6- fluoro-1 H-indazol-3-yl)-1 (1-hydroxycyclohex-2-yl)-piperidine as a foam. 1H-NMR (DMSO-d6) ppm: 1.15 (br., 4H); 1.6-1.95 (br., 8H); 2.2 (t, 1 H); 2_ 3. 8 (t, 1 H); 2.7 (br., 2H); 2.9-3.1 (br., 3H); 4.05 (s, 1 H); 6.9 (dt, 1 H); 7.22 (dd, 1 H); 7.91 (dt, 1 H); 12.7 (s, 1H).
B. To a solution of 4-(6-fluoro-1 H-indazol-3-yl)-1-(1-hydroxycyclohex-2-yl)- piperidine (170 mg; 0.54 mmol) in 5 ml dry DMF was added 3,4-methylene- dioxyphenylisocyanate (189 mg; 1.08 mmol) in 3 ml dry DMF. The reaction mixture was heated to 100°C for 2 h. The reaction was cooled to room temperature and added a mixture of 25 ml water and 150 ml ether, filtered and separated. The ether phase was washed with water, brine and dried with sodium sulphate and concentrated in vacuo. The crude product was purified by chromatography on silica gel 60 with ethyl acetate:methanol (9:1 , v/v) as eluent. Concentration of the appropriate fractions gave 15 mg (6%) of the title compound as an amorphous solid.
MS/EI (70 eV): m/z 480 (1%, M+), 299 (100%), 258, 232, 218, 189, 163, 137.
EXAMPLE 2
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -(1 -(3,4-methylenedioxyphenylcarbamoyl- oxy)cyclohex-2-yl)piperidine
A. Starting from 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-piperidine (1 g;
4.5 mmol) and 7-oxabicyclo[4.1.0]heptane (5 g; 51 mmol) using the pro¬ cedure described in example 1A was prepared in 1.1 g (76%) of 4-(6-fluoro- 1 ,2-benzisoxazol-3-yl)-1 -(1 -hydroxycyclohex-2-yl)-piperidine. M.p. 116-118°C.
MS/EI (70 eV): m/z 318 (57%, M+), 259, 180 (100%), 122, 108, 82, 55.
B. Starting from 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-(1-hydroxycyclo- hex-2-yl)-piperidine (500 mg; 1.57 mmol) and 3,4-methylenedioxyphenyliso- cyanate (500 mg; 3.06 mmol) using the procedure described in example 1 B was prepared 100 mg (13%) of the title compound. M.p. 121-122°C. 1H-NMR (DMSO-d6) ppm: 1.11-1.41 (br., 4H), 1.7 (br., 4H), 1.82-2.03 (br., 4H), 2.33 (t, 1 H), 2.48 (t, 1 H), 2.67 (t, 1 H), 2.78 (br., 1 H), 3.05 (br., 2H), 4.78 (m, 1 H), 5.98 (d, 2H), 6.82 (d, 1 H), 6.9-7.0 (br., 2H), 7.2 (d, 1 H), 7.65 (br.,
2H), 9.5 (s, 1 H).
EXAMPLE 3
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -(2,2-(1 ,2-ethylene)-3-((6,7-methylene- dioxy-1 ,2,3,4-tetrahydroquinolin-1 -yl)carbonyloxy)propyl)piperidine, oxalate
A. 3-(4,5-methylenedioxy-2-nitrophenyl)acrylic acid (10 g, 42 mmol) in 50 ml dry DMF, 450 ml absolute ethanol and 1.5 ml cone. HCI was reduced catalytically at 1 atm., 22°C, using 1.5 g 5% palladium on carbon to give 6.5 g 6,7-methylenedioxy-1 ,2,3,4-tetrahydro-2-oxoquinoline as light brown crystals, which was used without further purification.
B. To 6,7-methylenedioxy-1 ,2,3,4-tetrahydro-2-oxyquinoline (1.0 g, 5 mmol) suspended in 20 ml dioxane at 0°C was added NaBH4 (1.0 g, 25 mmol) whereupon a mixture of glacial acetic acid (1.4 ml, 25 mmol) in 25 ml dioxane was added dropwise over 10 min. After addition was completed the mixture was refluxed for 1.5 h, cooled to room temperature, concentrated in vacuo and taken up in H20 and methylene chloride.
The organic phase was dried over Na2S04 and evaporated to give 700 mg 6,7-methylenedioxy-1 ,2,3,4-tetrahydroquinoline as an oil. The oil was taken up in acetone and treated with 1 ml 5.5 M HCI in methanol to give 550 mg of the hydrochloride. M.p. 238-240°C.
C. To phosgene (7.9 ml, 1.9 M in toluene, 15 mmol) and methylene chloride (25 ml) stirred at 0°C was added, during 40 min., 6,7-methylene- dioxy-1 ,2,3,4-tetrahydroquinoline (1.8 g, 10 mmol) and triethylamine (1.5 ml, 10 mmol) in 25 ml methylene chloride. The mixture was stirred at 0°C for 1 h and concentrated in vacuo. The product was treated with E^O and filtered. The filtrate was concentrated jn vacuo to get 2.2 g 1-(6,6-methylene- dioxy-1 ,2,3,4-tetrahydroquinoline)carbonyl chloride. M.p. 86-87°C.
D. To 2,2-(1 ,2-ethylene)-1 ,3-dihydroxypropane (1.0 g, 10 mmol) in 20 ml dry THF, stirred under nitrogen, at 0°C, was added n butyllithium (5 ml, 16 M in hexane, 8 mmol). A solution of p-toluenesulfonyl chloride (1.5 g, 8 mmol) in 5 ml dry THF was added dropwise, whereupon the mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and taken up in H20 and CH2CI2. The organic phase was washed with saturated sodium chloride, dried over MgS04 and evaporated to give 900 mg 3-chloro-2-(1 ,2-ethylene)propanol as an oil.
E. 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)piperidine, hydrochloride (1.3 g, 5.4 mmol) and I^COg (740 mg, 5.4 mmol) was added to a mixture of 3- chloro-2,2-(1 ,2-ethylene)propanol (700 mg, 2.7 mmol) and Nal (410 mg, 2.7 mmol) in 10 ml dry acetone. The mixture was refluxed for 10 min., stirred at 50°C for 16 h and concentrated in vacuo. The product was taken up in H20 and ethyl acetate. The organic phase was dried over MgS04 and evapo¬ rated to give an oil, which was purified by column chromatography (Si02, CH2CI2, CHgOH (9:1 , V/V). Trituration with petroleum ether gave 430 mg of 2-(1 ,2-ethylene)-3-(4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidino)propanol. M.p. 95-96°C.
F. To 2,2-(1 ,2-ethylene)-3-(4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidino)- propanol (210 mg, 0.7 mmol) stirred under N2 in 20 ml dry THF at 0°C was added n-butyllithium (0.7 ml, 1.6 M in hexane, 1.1 mmol). The mixture was then stirred at room temperature for 1 h, cooled to 0°C whereupon 1 -(6,6- methylenedioxy-1 ,2,3,4-tetrahydroquinoline)carbonyl chloride (240 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 70 h, concentrated in vacuo and separated between H2O and methylene chloride. The organic fraction was purified by column chromatography (Si02, CH2C12, CHgOH (9:1 , V/V). The title compound was isolated by addition of oxalic acid to give 70 mg white crystals. M.p. 190-197°C. MS (70 eV): m/z 507 (M+, 60%), 287 (65), 259 (50), 233 (25), 177 (100).
EXAMPLE 4
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -(2,2-(1 ,2-ethylene)-3-(indolin-1 -yl-carbo- nyloxy)propyl) piperidine, oxalate
A. Indoline (4.8 g, 40 mmol) and triethylamine (6 ml, 40 mmol) in 50 ml dry methylene chloride was added to a solution of phosgene (32 ml of a 1.9 M solution in toluene) in ice cold methylene chloride (50 ml). After 1 h at 0°C the mixture was concentrated in vacuo. redissolved in dry ether and filtered through a short path of silica gel. By addition of petroleum ether, 6.7 g of indolin-1-carbonyl chloride crystallized out. M.p. 68°C.
B. To 2,2-(1 ,2-ethylene)propanediol (1.8 g, 17 mmol) in 20 ml dry THF, stirred at 0°C under N2, was added n-butyllithium (12.5 ml, 1.6 M in hexane, 20 mmol). After 10 min. at 0°C, the mixture was stirred at room temperature for 45 min. and cooled on ice, whereupon indolin-1-carbonylchloride (3.6 g, 20 mmol) in 10 ml dry THF was added. The reaction mixture was stirred for 1 h, concentrated jn vacuo and separated between water and ethyl acetate. The organic fraction was purified by column chromatography (Si02; methylene chloride, ethyl acetate (1 :1 , V)) to give 0.8 g of 2,2-(1 ,2- ethylene)-3-(1-indolincarbonyloxy)propanol. MS (70 eV): m/z 247 (M+, 35%), 163 (45), 132 (55), 119 (100).
C. 2,2-(1 ,2-Ethylene)-3-(1-indolin-carbonyloxy)propanol (460 mg, 1.8 mmol), p-toluenesulfonyl chloride (510 mg, 2.7 mmol) and pyridine (250 μl, 2.7 mmol) in 25 ml methylene chloride, was stirred for 4 h at 0°C, at room temperature for 16 h and at reflux for 4 h. The mixture was extracted with water and 1 N HCI, dried over N^SO,^ and concentrated in vacuo. The resulting oil was purified by column chromatography (Si02; methylene chloride, ethyl acetate (1 :1 , V/V)) to get 1-chloro-2,2-(1 ,2-ethylene)-3-(1- indolinecarbonyloxy) propane (180 mg) as an oil.
D. 1 -Chloro-2,2-(1 ,2-ethylene)-3-(1 -indolinecarbonyloxy) propane (180 mg, 0.7 mol), 4-(6-fluoro-1 ,2-benzisoxazol-3-yl) piperidine (240 mg, 1.1 mmol), Nal (160 mg, 1.1 mmol) and f ^COg (150 mg, 1.1 mmol) was stirred in 25 ml dry MIPK at 75°C for 20 h and at reflux for 8 h. The mixture was concentrated in vacuo and separated between water and ethyl acetate. The organic fraction was evaporated and redissolved in acetone. Addition of oxalic acid (100 mg) in 2 ml acetone precipitated the desired product, which was recrystallized from ethanol to give 240 mg. M.p. 203-205°C. MS (70 eV): m/z 449 (M+, 100%), 287 (42), 233 (30), 219 (35), 146 (50), 82 (98).
EXAMPLE 5
trans 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -((2,3-methylene)-4-((indolin-1 -yl)- carbonyloxy)butyl)piperidine, hydrochloride
A. By the same procedure described in example 4B indolin-1-carbo- nylchloride (1.4 g, 7.8 mmol) was reacted with trans 2,3-methylene-1 ,4- butanediol (0.8 g, 7.8 mmol) to give (±)trans 4-(1-indolincarbonyloxy)-2,3- methylene-butanol (1.0 g) as an oil. MS (70 eV): m/z 247 (M+, 75%) 163 (58, 119 (100).
B. By the same procedure described in example 4C, (+) trans-4-(1- indolinecarbonyloxy)-2,3-methylenebutanol (900 mg, 3.6 mmol) was reacted with p-toluenesulfonylchloride (1.3 g, 6.8 mmol) to give 0.9 g (+j-trans-1- chloro-4-(1-indoline-carbonyloxy)-2,3-methylenebutane as an oil. MS (70 eV): m/z 265 (M+, 43%), 132 (90), 118 (100). C. By the same procedure described in example 4D (+) -trans- 1- chloro-4-(1-indoline-carbonyloxy)-2,3-methylenebutane (900 mg, 3 mmol) was reacted with 4-(6-fluoro-1 ,2-benzisoxazol-3-yl) piperidine (550 mg, 2.5 mmol) to give 550 mg of the title compound. M.p. 213-214°C. MS (70 eV): m/z 449 (M+, 100%), 311 (25), 233 (20), 146 (40), 128 (42).
EXAMPLE 6
trans 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -(2,3-methylene-4-(3,4-methylene- dioxyphenylcarbamoyloxy) butyl) piperidine, oxalate
A. By the same procedure described in example 4B, trans-2,3- methylene-1 ,4-butanol (800 mg, 8 mmol) was reacted with 3,4-methylenedi- oxyphenylisocyanate (1.3 g, 8 mmol) to get (+ trans-2,3-methylene-4-(3,4- methylenedioxyphenylcarbamoyloxy)butanol (750 mg, 28 mmol). The product was treated with p-toluenesulfonyl chloride (570 mg, 3.0 mmol) in 2 ml pyridine and 10 ml dry CH2CI2 as described in example 4C, which in this case afforded 650 mg (±)-trans-2,3-methylene-1-(3,4-methylenedioxyphenyl- carbamoyloxy)-4-tosyloxybutane as an oil. M.p. 58-60°C.
B. By the same procedure described in example 4D (±)-trans-2,3- methylene-1-(3,4-methylenedioxyphenylcarbamoyloxy)-4-tosuloxybutane (420 mg, 1 mmol), 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidine (440 mg, 1 mmol) and KjCC^ (280 mg, 2 mmol) was stirred in 20 ml DMF at 100°C for 3 h and at room temperature. The mixture was separated between water and ether. The organic fraction was purified by column chromatography (Si02; CH2CI2> CH3OH (25:1), V/V) and treated with oxalic acid to get 25 mg of the desired product. M.p. 174-179°C. EXAMPLE 7
1 -(1 -(3,4-Methylenedioxophenylcarbamoyloxy)cyclohex-2-yl)-4-(6-fluoro-1 ,2- benzisoxazol-3-yl) piperidine
A. Starting from 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidine (1 g, 4.5 mmol) and 7-oxabicyclo [4.1.0] heptane (5 g, 51 mmol) using the procedure described in example 1A was prepared 1.1 g (76%) of 4-(6-fluoro-1 ,2- benzisoxazol-3-yl)-1 -(1 -hydroxycyclohex-2-yl)piperidine. M.p. 116-118°C. MS/EI (70 eV): m/z 318 (M+, 57%), 259, 180 (100%), 122, 108, 82, 55.
B. Starting from 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -(1 -hydroxycyclo- hex-2-yl) piperidine (500 mg, 1.57 mmol) and 3,4-methylenedioxyphenyliso- cyanate (500 mg, 3.06 mmol) using the procedure described in example 1 B was prepared 100 mg (13%) of the title compound. M.p. 121-122°C.
1 H-NMR (DMSO-d6) ppm: 1.11-1.41 (br., 4H), 1.7 (br., 4H), 1.82-2.03 (br., 4H), 2.33 (t, 1 H), 2.48 (t, 1 H), 2.67 (t, 1 H), 2.78 (br., 1 H), 3.05 (br., 2H), 4.78 (m, 1 H), 5.98 (d, 2H), 6.82 (d, 1 H), 6.9-7.0 (br., 2H), 7.2 (d, 1 H), 7.65 (br.,
2H), 9.5 (s, 1 H).
EXAMPLE 8
4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 (-5-(3,4,5-trimethoxyphenylcarbamoyl- oxy)-3,3-pentamethylen-pent-1-yl)piperidine
A. To a solution of 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidine hydrochloride (1.03 g, 4 mmol) and triethylamine (1.2 g, 12 mmol) in 20 ml dry THF was added 3,3-pentamethylenglutaric acid anhydride (728 mg, 4 mmol). The reaction mixture was heated to 60°C for 16 h and then cooled at room temp. Water (100 ml) was added and the mixture acidified with 1 N hydrochloride acid to pH 3 and extracted with ethyl acetate 200 ml washed with water, brine and dried with sodium sulphate and concentrated in vacuo. The crude product was recrystallized from methanol to give 1.1 g (64%) of 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-(4-carboxy-3,3-ρentamethylen- 1 -oxo-but-1 -yl)ρiperidine.
1H-NMR (CDCI3-ppm): 1.3 (br., 3H), 1.45-1.65 (br., 7H), 1.9 (m, 1 H), 2.08 (m, 1 H), 2.2 (br. 2H), 2.55 (br., 4H), 3.11 (dt, 1 H), 3.4 (m, 2H), 4.2 (d, 1 H), 4.65 (d, 1H), 7.1 (dt, 1H), 7.26 (dd, 1H), 7.6 (q, 1H).
B. A solution of 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-(4-carboxy-3,3- pentamethylen-1-oxo-but-1-yl)piperidine (1 g, 2.5 mmol) in THF (25 ml) was added sodium borohydride (0.27 g, 7.5 mmol) and cooled to 5°C, boron trifluoride etherate (1.44 g, 10.2 mmol) was added dropwise at 5°C. The temperature was maintained at 5°C for 4 h and then at room temperature for 16 h. The reaction mixture was added methanol (20 ml) and after 20 min. water (50 ml) was added and extracted with ethyl acetate (200 ml) washed with water, brine, dried with sodium sulphate and concentrated in vacuo. The crude product was purified by chromatography on silica gel 60 with ethyl acetate as eluent. Concentration of appropriate fractions gave 390 mg (41 %) of 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-(5-hydroxy-3,3-pentamethy- len-pent-1 -yl)piperidine.
MS/EI (70 eV): m/z 374 (55%, M+), 344, 233 (100%), 190, 109, 96, 82.
C. Starting from 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-(5-hydroxy-3,3- pentamethylen-pent-1-yl) piperidine (300 mg, 0.80 mmol) and 3,4,5-trime- thoxyphenylisocyanate (200 mg, 0.96 mmol) using the procedure described in example 1 B was prepared 110 mg (23%) of the title compound.
MS/FAB (8 KV, 2mA): 584 (M+1), 375, 233, 178, 166, 138.

Claims

!_. A compound of the general formula (I)
Figure imgf000033_0001
wherein n and m independently are 0, 1 , 2, or 3;
A is cycloalkylene having 3-11 carbon atoms or cycloalkylidene having 3-8 carbon atoms;
X is O or NH;
Y is O, S, NH, NCN, or N-C^-alkyl;
R1 is 1 ,2-benzisoxazol-3-yl, 1 H-indazol-3-yI, or 1 -methyl-1 H-indazol-3-yl, all of which may be substituted independently with halogen or C^-alkyl in one, two, three or all of the 4-, 5-, 6- and 7-positions;
R2 is hydrogen or C^-alkyl; and
R3 is phenyl optionally substituted with C^-alkyl, halogen, C^-alkoxy, or perhalomethyl, or R3 is
Figure imgf000033_0002
wherein Z together with the double bond in the phenyl ring represents a 5- or 6-membered heterocyclic ring comprising one or more nitrogen-, oxy¬ gen-, or sulphur atoms; or
R2 and R3 together with the nitrogen atom form a fused heterocyclic ring system;
or pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 , wherein R2 and R3 together with the nitrogen atom form a group selected from 1,2,3,4-tetrahydro-quinolin-1- yl, 1 ,2,3,4-tetrahydro-5,6-methylenedioxy-quinolin-1-yl, 1 ,2,3,4-tetrahydro-6,7- methylenedioxy-quinolin-1 -yl, 1 ,2,3,4-tetrahydro-7,8-methylenedioxy-quinolin- 1-yl; 1 -indolinyl, 4,5-methylenedioxy-1 -indolinyl, 5,6-methylenedioxy-1 - indolinyl, 6,7-methylenedioxy-1 -indolinyl; 1,2,3,4-tetrahydro-quinolin-1-yl substituted independently in one or more of the 5-, 6-, 7- and 8-positions with Cj.g-alkyl, halogen, C^-alkoxy or perhalomethyl; 1 -indolinyl substituted independently in one or more of the 4-, 5-, 6, or 7-positions with C^g-alkyl, halogen, C,_6-alkoxy or perhalomethyl; 3,4-dihydro-2H-1 ,4-benzoxapine substituted independently in one or more of the 4-, 5-, 6, or 7-positions with C^-alkyl, halogen, C^-alkoxy or perhalomethyl.
3i A compound according to claim 1 , wherein Z is selected from the group consisting of thiazolo, imidazolo, pyrazino, oxazino, thiazino, 1 ,3-dioxolo, 1 ,4-dioxino, pyrrolo and pyrazolo.
A compound according to claim 1 , wherein R1 is 6-fluoro-1 H- indazol-3-yl, 6-fluoro-1 ,2-benzisoxazol-3-yl, or 6-fluoro-1 -methyl-1 H-indazol-3- yl; X is 0; Y is 0; and -A- is cyclopropylene, cyclopropylidene or cyclohexyl- ene. 5. A compound according to any of the claims 1 -4 which is
1 -(1 -(3,4-methylenedioxyphenylcarbamoyloxy)cyclohex-2-yl)-4-(6-fluoro-1 H- indazol-3-yl)piperidine;
4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -(1 -(3,4-methylenedioxyphenylcarbamoyl- oxy)cyclohex-2-y I) piperidine;
4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -(2,2-(1 ,2-ethylene)-3-((6,7-methylene- dioxy-1 ,2,3,4-tetrahydroquinolin-1 -yl)carbonyloxy)propyl)piperidine, oxalate;
4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -(2,2-(1 ,2-ethylene)-3-(indolin-1 -yl-carbo- nyloxy)propyl) piperidine, oxalate;
trans 4-(6-fluoro-1 ,2-benzisoxazol-3<-yl)-1 -((2,3-methylene)-4-((indolin-1 -yl)- carbonyloxy) butyl) piperidine, hydrochloride;
trans 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -(2,3-methylene-4-(3,4-methylene- dioxyphenylcarbamoyloxy) butyl) piperidine, oxalate;
1 -(1 -(3,4-methylenedioxophenylcarbamoyloxy)cyclohex-2-yl)-4-(6-fluoro-1 ,2- benzisoxazol-3-yl) piperidine ;
4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 (-5-(3,4,5-trimethoxyphenylcarbamoyloxy)- 3,3-pentamethylen-pent-1 -yl) piperidine.
6;. A compound according to any of the claims 1 -5 or a pharmaceuti¬ cally acceptable salt thereof for use as a therapeutically acceptable sub¬ stance.
7. A compound according to any of the claims 1 -5 or a pharmaceuti¬ cally acceptable salt thereof for use as a therapeutically acceptable sub- stance in the treatment of CNS-system, cardiovascular system or gastrointestinal disorders.
8_. A method of preparing a compound according to any one of the claims 1-5, which comprises
a) reacting a compound of formula (II)
Y
II
Q-C- N-R2
I (II)
R3
wherein Y, R2 and R3 have the meanings set forth above and Q is a leaving group, with a compound of formula (III)
Figure imgf000036_0001
wherein A, X, n, m and R1 have the meanings set forth above , or
b) reacting a compound of formula (IV)
Figure imgf000036_0002
wherein A, n, m and R1 have the meanings set forth above, with a com¬ pound of formula (V) Y H3CS-C-N-R2 (V)
R3
wherein R2 and R3 have the meanings set forth above, and Y is =NH, =NCN or =N-C1.β-alkyl. or
c) reacting a compound of formula (VI)
Figure imgf000037_0001
wherein A, R1, R2, R3, n and m have the meanings set forth above, with NH3, NH^C^-alkyl or NH2CN to form a compound of formula (I), or
d) reacting a compound of formula (III), wherein X is -NH- and A, n, m and R1 have the meanings set forth above, with a compound of formula (VII)
Figure imgf000037_0002
wherein R2 and R3has the meaning set forth above to form a compound of formula (I) wherein X is -NH-. 9,. A pharmaceutical composition comprising a compound according to any one of the claims 1 -5 or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient, carrier or diluent.
10. A pharmaceutical composition for the treatment of CNS-system disorders, cardiovascular disorders or gastrointestinal disorders, which comprises a compound according to any of the claims 1 -5 or a pharma¬ ceutically acceptable salt thereof and a therapeutically inert excipient, carrier or diluent.
11. Use of a compound of formula I according to claim 1 or a pharma¬ ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of CNS-system disorders, cardiovascular disorders or gastrointestinal disorders.
12. A method of treating CNS-system disorders, cardiovascular dis¬ orders or gastrointestinal disorders in a subject in need thereof comprising administering an effective amount of a compound according to claim 1.
13. A method of treating CNS-system disorders, cardiovascular dis¬ orders or gastrointestinal disorders, in a subject in need thereof comprising administering a pharmaceutical composition according to claim 9.
14. A process for the manufacture of a medicament, particularly to be used in the treatment of CNS-system disorders, cardiovascular disorders or gastrointestinal disorders, which process comprises bringing a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof into a galenical dosage form.
PCT/DK1994/000199 1993-05-26 1994-05-25 Piperidine derivatives, their preparation and use WO1994027992A1 (en)

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US6444686B1 (en) 1998-12-18 2002-09-03 Brsitol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6605623B1 (en) 1998-12-18 2003-08-12 Bristol-Myers Squibb Pharma Co. N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6906066B2 (en) 1998-12-18 2005-06-14 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6897234B2 (en) 1999-12-17 2005-05-24 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US6949546B2 (en) 2000-06-30 2005-09-27 Bristol-Myers Squibb Pharma Company N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US20120040972A1 (en) * 2007-07-26 2012-02-16 Luca Gobbi Dual modulators of 5ht2a and d3 receptors
US20130165432A1 (en) * 2007-07-26 2013-06-27 Hoffmann-La Roche Inc. Dual Modulators of 5HT2A and D3 Receptors
US8829029B2 (en) 2007-07-26 2014-09-09 Hoffmann-La Roche Inc. Dual modulators of 5HT2A and D3 receptors
US8877778B2 (en) 2010-12-15 2014-11-04 Hoffmann-La Roche Inc. Benzofurane compounds
US8921397B2 (en) 2011-05-04 2014-12-30 Hoffmann-La Roche Inc. Benzofurane-piperidine compounds

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