WO1994027991A1 - Piperidine derivatives, their preparation and use - Google Patents

Piperidine derivatives, their preparation and use Download PDF

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Publication number
WO1994027991A1
WO1994027991A1 PCT/DK1994/000201 DK9400201W WO9427991A1 WO 1994027991 A1 WO1994027991 A1 WO 1994027991A1 DK 9400201 W DK9400201 W DK 9400201W WO 9427991 A1 WO9427991 A1 WO 9427991A1
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Prior art keywords
piperidine
ethyl
propyl
fluorobenzoyl
iodobenzoyl
Prior art date
Application number
PCT/DK1994/000201
Other languages
French (fr)
Inventor
John Bondo Hansen
Frederik Christian GRØNVALD
Original Assignee
Novo Nordisk A/S
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Publication of WO1994027991A1 publication Critical patent/WO1994027991A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • atypical neuroleptics 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 bloc ⁇ kade of DA receptors in the motor areas of the brain (A9 DA system (Gudelsky, Psychopharmacology (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-l, D-2, D-3, D-4) but also 5HT-receptor subtypes (5HT hinder-, 5HT 3 ⁇ , 5HT. -, 5HT. -), NA-alpha. -receptors, histamine and possibly other re- ceptors.
  • 5HT 5HT
  • 5HT 5HT
  • Meltzer Schizphr. Bull. 17: 263-87, 1991
  • Compounds reducing 5-HT neurotransmission have been suggested to be useful for the treatment of various neurological and psychiatric diseases.
  • 5-iT ⁇ -antagonists such as naftidrofuryl (Brain Res. 1989, 494(2) 387-90) are described to exhibit a pro ⁇ tective effect on ischemic neuronal damage in the ger- bil.
  • Ritanserin which is a potent and selective 5HT_- antagonist, has been shown to have anxiolytic-antide- pressant activities in humans (Barone et al., Drug
  • the piperidine derivative ketanserine which is a 5HT,-,-antagonist with weak() .-blocking properties has been shown to be useful for treatment of various car ⁇ diovascular disorders.
  • This invention relates to novel piperidine derivatives, methods for making them and pharmaceutical compositi ⁇ ons containing them.
  • the compounds of this invention demonstrate high affi ⁇ nity for various receptor subtypes including the 5HT--, the or a combination of these.
  • This invention relates to the use of said compounds as medicaments useful for treat- ing CNS-system, cardiovascular system and gastrointes ⁇ tinal disorders, such as treatment of anxiety, sleep disorders, depression, psychoses, schizophrenia, mi ⁇ graine, ischemic neuronal damage, astma, hypertension, urticaria, analgesia and emesis.
  • the present invention provides novel piperidine deri ⁇ vatives of the general formula (I):
  • A represents a straight or branched saturated or unsaturated hydrocarbon chain containing from 2 to 6 carbon atoms
  • R 3, R4, R5, R6 and R7 which may be identical or different, each is selected from the group consist ⁇ ing of hydrogen, halogen, C., ,-alkyl, C-_ R -cycloalkyl, cyano, nitrd and perhalomethyl;
  • X is -O- or
  • R is hydrogen, C., .--alkyl or C 3 _.-.-cycloalkyl
  • Z is hydrogen, C, g -alkyl or CN
  • R is selected from the group consisting of
  • R 9, R10, R11 and R12 which may be identical or different represent hydrogen, C 1 _ ⁇ -alkyl, halogen,
  • the compounds of formula I may be converted into any physiologically acceptable salt thereof.
  • the invention includes within its scope all optical isomers of compounds of the general formula I and their mixtures including racemic mixtures thereof.
  • Radioactive-labelled ligand H-Spiroperidol is incubat ⁇ ed with isolated cell-membrane fragments at 37°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 unspecifical- ly 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 membranes.
  • the procedure is performed in ice bath. Polytron kine- matica is rinsed with milli-Q-H 2 0 before and after use. Male Wistar rats, 150-200 g are decapitated, stri ⁇ atum is removed quickly and weighed (approx. 50 mg). Striatum is transferred to a centrifuging vial contain ⁇ ing 10 ml ice-cold D2 buffer. Homogenization is per- formed applying polytron kinematica (homogenizer) set ⁇ ting 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.
  • polytron kinematica homogenizer
  • test substance/HLO/blind Domperidone 0.2 ⁇ M
  • Test-substance dilutions are al- ways made fresh every day. When weighing out test sub ⁇ stances, 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 cone./assay.
  • test value is given as IC-.-. indicating the concen- tration inhibiting specific binding by 50%.
  • Radioactive-labelled ligand H-Prazosin is incubated with isolated cell-membrane fragments at 25 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 unspecifical- ly adhered radioactivity. 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.
  • Test-substance dilutions are al ⁇ ways prepared 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 cone./ass.
  • test value is given as IC-.-. indicating the concen- tration inhibiting specific binding by 50%. Cone.
  • Radioactive-labelled ligand 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 radioactivity. As oppos- ed 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 non-specifically to the mem ⁇ branes.
  • test value is given as IC.- n indicating the concen ⁇ tration inhibiting specific binding by 50%.
  • Radioactive-labelled ligand H-Ketanserine is incubat ⁇ ed with isolated cell-membrane fragments at 37 C for a given period of time. Following completed incubation,
  • the incubate is filtered through GF/B filters which are rinsed after filtration to remove unspecifically adhered radioactivity.
  • membrane fragments are not rinsed through the filters, the radioactivity bound to the filters
  • Test-substance diluti ⁇ ons are always made fresh every day. When weighing out test substance, it is attempted to weigh out approx. 1 mg of substance. Less than 0.8 mg must never be weigh ⁇ ed out and only infrequently more than 2 mg (for eco ⁇ nomy reasons) dependent, however, on cone./assay. Results :
  • test value is given as IC,- n , i.e. the concentra ⁇ tion inhibiting specific binding by 50%.
  • mice i.p. injection of acetic acid induces a writh ⁇ ing syndrome which is antagonized by analgesics (Sieg- mund et al. , 1957; Eckhardt et al., 1957).
  • Acetic acid 0.5 per cent is injected i.p. (0.15 ml/10 g body weight) to 6 mice (NMRI, either sex weighing 20-25 g) pretreated with physiological saline (con ⁇ trols) and to 6 mice pretreated with test substance.
  • acetic acid induces a syndrome chara ⁇ cterized by contraction of abdomen, turning of trunk and extension of hind limbs.
  • Saline and test substances are administered s.c. 30 min. before acetic acid. The number of writhings is counted 5- 15 min. after injec ⁇ tion of acetic acid. Results:
  • test substance is equivalent to 5- 10 per cent of LE) . if this dose decreases writh ⁇ ings, 3-5 dose levels are tested. The activity is ex ⁇ pressed as per cent protection:
  • the effect of active substances is evaluated by a dose response curve, log dose on the abscissa, and per cent protection on the ordinate.
  • the potency is expressed as the dose (ED.-.-, in mg/kg giving 50 per cent protec ⁇ tion against writhings.
  • Analgesics and various other drugs inhibit acetic acid- induced writhings in mice. This test is used as a screening test for analgesics. Additional results from other screening tests are required to exclude ac ⁇ tive anti-writhing substances without analgesic effect.
  • the compounds of the invention and physiologically ac ⁇ ceptable salts thereof may be prepared by a variety of synthetic routes, which indludes reacting a compound of formula II
  • an isocyanate or isothiocyanate of 3,4,5- trimethoxybenzene prepared by refluxing 3,4,5-trime- thoxyaniline and phosgene or thiophosgene respectively in toluene, may be reacted with the desired piperidine alkylamine or piperidine alkylhydroxy intermediate to obtain the desired urea or carbamate of formula I.
  • the procedure includes reacting a compound of formula IV
  • the purified reaction product may be converted into a physiologically acceptable salt.
  • salts include acid addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobromides, sul- phates, nitrates, oxalates, phosphates, tartrates, ci ⁇ trates, fumarates, maleates, succinates, and sulphona ⁇ tes e.g. mesylates.
  • selected salts may be subjected to fur- ther purification by recrystallization.
  • the compounds of the invention together with a con ⁇ ventional adjuvant, carrier, or diluent, and if desir ⁇ ed a pharmaceutically-acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or fil ⁇ led capsules, or liquids, such as solutions, suspen ⁇ sions, 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 subcu ⁇ taneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or with ⁇ out additional active compounds or principles, and such unit dosage forms may contain any suitable effec ⁇ tive central nervous system ailment alleviating amount of the active ingredient commensurate with the intend- ed daily dosage range to be employed.
  • Tablets contain ⁇ ing one (1) milligram of active ingredient or, more broadly, one (1) to thirty (30) milligrams, per tab- let, are accordingly suitable representative unit dos ⁇ age 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 in ⁇ cluding humans, in accordance with conventional me ⁇ thods of galenic pharmacy.
  • excipients are such pharmaceutically ac ⁇ ceptable organic or inorganic carrier substances suit ⁇ able for parenteral or oral application which do not delteriously react with the active compound.
  • Such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stea- rate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxilliary agents, such as lu ⁇ bricants, 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 compound.
  • auxilliary agents such as lu ⁇ bricants, 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 compound.
  • injectable solutions or suspensions preferably aqu ⁇ eous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Ampoules are convenient unit dosage forms.
  • 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 techniques contains:

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Piperidine derivatives represented by general formula (I) wherein A represents a straight or branched saturated or unsaturated hydrocarbon chain containing from 2 to 6 carbon atoms; R?1 and R2¿ represent various heterocycles, X is -O- or substituted nitrogen, Y is =O, =S or =NZ, wherein Z is hydrogen, C¿1-6?-alkyl or -CN; the compounds are useful in the treatment of indications related to the CNS-system, cardiovascular system or gastrointestinal disorders.

Description

Piperidine Derivatives, their Preparation and Use
Much evidence has accumulated to suggest that neurolep¬ tics exert their antipsychotic action by blocking do- pamine (DA) receptors in the brain. In recent years, it has become clear that some neuroleptics (e.g. clo¬ zapine) show an atypical profile: the compounds are not only beneficial in treating patients, who respond poorly to classical neuroleptic therapy, but the com- pounds are also relatively devoid of extrapyrimidal side effects (EPS) commonly seen with classical neuro¬ leptics (Ereshefsky et al., Clin.Pharm 8, 691-709, 1989). In this respect it has been speculated that atypical neuroleptics 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 bloc¬ kade of DA receptors in the motor areas of the brain (A9 DA system (Gudelsky, Psychopharmacology (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-l, D-2, D-3, D-4) but also 5HT-receptor subtypes (5HT„-, 5HT3~, 5HT. -, 5HT. -), NA-alpha. -receptors, histamine and possibly other re- ceptors.
Furthermore, 5HT„-blockade may also be important (Meltzer, Schizphr. Bull. 17: 263-87, 1991) to coun¬ teract the socalled negative symptoms of psychosis (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.
5-iT^-antagonists, such as naftidrofuryl (Brain Res. 1989, 494(2) 387-90), are described to exhibit a pro¬ tective effect on ischemic neuronal damage in the ger- bil. Ritanserin, which is a potent and selective 5HT_- antagonist, has been shown to have anxiolytic-antide- pressant activities in humans (Barone et al., Drug
Clin.Pharm. , 20 770 (1986)). Furthermore serotonergic mechanisms are described to be involved as active fac¬ tors, or inducing processes, in the organization of sleep (Neuropharmacology, 19, 163 (1980)).
The piperidine derivative ketanserine, which is a 5HT,-,-antagonist with weak() .-blocking properties has been shown to be useful for treatment of various car¬ diovascular disorders.
This invention relates to novel piperidine derivatives, methods for making them and pharmaceutical compositi¬ ons containing them.
The compounds of this invention demonstrate high affi¬ nity for various receptor subtypes including the 5HT--, the
Figure imgf000004_0001
or a combination of these. This invention relates to the use of said compounds as medicaments useful for treat- ing CNS-system, cardiovascular system and gastrointes¬ tinal disorders, such as treatment of anxiety, sleep disorders, depression, psychoses, schizophrenia, mi¬ graine, ischemic neuronal damage, astma, hypertension, urticaria, analgesia and emesis.
Related piperidine derivatives described in German Pa¬ tent 1930818, EP 0368 388, EP 377528, EP 184258 and EP 402644A .
The present invention provides novel piperidine deri¬ vatives of the general formula (I):
Figure imgf000005_0001
wherein A represents a straight or branched saturated or unsaturated hydrocarbon chain containing from 2 to 6 carbon atoms;
R1 is
Figure imgf000005_0002
wherein R 3, R4, R5, R6 and R7, which may be identical or different, each is selected from the group consist¬ ing of hydrogen, halogen, C., ,-alkyl, C-_R-cycloalkyl, cyano, nitrd and perhalomethyl;
X is -O- or
Figure imgf000005_0003
-N- Q wherein R is hydrogen, C., .--alkyl or C3_.-.-cycloalkyl;
Y is =0, =S or =NZ
wherein Z is hydrogen, C, g-alkyl or CN;
2
R is selected from the group consisting of
Figure imgf000006_0001
forms a 5- or 6-membered heterocyclic
Figure imgf000006_0002
ring containing one or more N-, 0- or S-atoms, and
wherein"R 9, R10, R11 and R12, which may be identical or different represent hydrogen, C1_β-alkyl, halogen,
C. ..-alkoxy or perhalomethyl;
The compounds of formula I may be converted into any physiologically acceptable salt thereof.
The invention includes within its scope all optical isomers of compounds of the general formula I and their mixtures including racemic mixtures thereof.
Among others the following compounds may be prepared according to the invention:
4-(4-Fluorobenzo 1)-1-[2-(4-indolinylcarbamoyloxy)- ethyl]piperidine, 4-(4-Fluorobenzoyl)-1-[2-(5-indolinylcarbamoyloxy)■ ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(6-indolinylcarbamoyloxy)■ ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(7-indolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(4-indolinylcarbamoyloxy)• propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(5-indolinylcarbamoyloxy)■ propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-(6-indolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-(7-indolinylcarbamoyloxy)■ propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(4-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-( 5-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(6-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(7-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(4-indolylcarbamoyloxy)- propyl]piperidine, 4-(4-Fluorobenzoyl)-1-[3-(5-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(6-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(7-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(4-isoindolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(5-isoindolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(4-isoindolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-(5-isoindolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(4-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(5-benzo[b]thienylcarbamoyl- oxy)ethyl] iperidine,
4-(4-Fluorobenzoyl)-1-[2-(6-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(7-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-(4-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine, 4-(4-Fluorobenzoyl)-l-[3-(5-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-( 6-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(7-benzo[b]thienylcarbamoyl- oxy) ropyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(4-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(5-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(6-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(7-benzo[b]f ranylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(4-benzo[b]furanylcarbamoyl- oxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-(5-benzo[b]furanylcarbamoyl- oxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-( 6-benzo[b]furanylcarbamoyl- oxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(7-benzo[b]furanylcarbamoyl- oxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(4-indazolylcarbamoyloxy)- ethyl]piperidine, 4-(4-Fluorobenzoyl)-1-[ 2-(5-indazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(6-indazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(7-indazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(4-indazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(5-indazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(6-indazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-(7-indazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(4-benzimidazolylcarbamoyloxy)■ ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(5-benzimidazolylcarbamoyloxy)■ ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(4-benzimidazolylcarbamoyloxy)■ propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(5-benzimidazolylcarbamoyloxy)■ propyl] iperidine,
4-(4-Fluorobenzoyl)-l-[2-(4-benzoxazolylcarbamoyloxy)- ethyl]piperidine, 4-(4-Fluorobenzoyl)-l-[2-(5-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(6-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(7-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(4-benzoxazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(5-benzoxazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-( 6-benzoxazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(7-benzoxazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(4-benzothiazolylcarbamoyloxy)• ethyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(5-benzothiazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(7-benzothiazolylcarbamoyloxy)■ ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(4-benzothiazolylcarbamoyloxy)• propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-(5-benzothiazolylcarbamoyloxy)■ propyl]piperidine, 4-(4-Fluorobenzoyl)-1-[3-(7-benzothiazolylcarbamoyloxy)• propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-( (1,2-benzisothiazol-4-yl)car- bamoyloxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-( (1,2-benzisothiazol-5-yl)- carbamoyloxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-( (1,2-benzisothiazol-6-yl)- carbamoyloxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-( (1, 2-benzisothiazol-7-yl)- carbamoyloxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-( (1,2-benzisothiazol-4-yl)- carbamoyloxy) ropyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-( (1, 2-benzisothiazol-5-yl)- carbamoyloxy)propyl]piperidine,
4-(4-Fluorobenzoyl )-1-[3-( ( 1,2-benzoisothiazol-6-yl)- carbamoyloxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-( (1,2-benzoisothiazol-7-yl)- carbamoyloxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-( (1, 2-benzoisoxazol-4-yl)car¬ bamoyloxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-( (1,2-benzisoxazol-5-yl)car- bamoyloxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-( (1,2-benzisoxazol-6-yl)car- bamoyloxy)ethyl]piperidine, 4-(4-Fluorobenzoyl)-1-[2-( (1,2-benzisoxazol-7-yl)car- bamoyloxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-( (1,2-benzisoxazol-4-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-( (1,2-benzisoxazol-5-yl)car- bamoyloxy)propyl] iperidine,
4-(4-Fluorobenzoyl)-1-[3-( (1,2-benzisoxazol-6-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-( ( 1,2-benzisoxazol-7-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(4-benzimidazolidinylcarba- moyloxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(5-benzimidazolidinylcarba- moyloxy)ethyl]piperidine,
4-(4-Fluorobenzoyl )-l-[3-(4-benzimidazolidinylcarba- moyloxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(5-benzimidazolidinylcarba- moyloxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(2,3-ethylenedioxyphenylcar- ba oyloxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(3,4-ethylenedioxyphenylcar- bamoyloxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(2,3-ethylenedioxyphenylcar- bamoyloxy)propyl]piperidine, 4-(4-Fluorobenzoyl)-1-[2-(2,3-methylenedioxyphenylcar- bamoyloxy)ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-(3,4-methylenedioxyphenylcar- bamoyloxy)ethyl]piperidine,
4_(4-Fluorobenzoyl)-l-[3-(2,3-methylenedioxyphenylcar- bamoyloxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(3,4-methylenedioxyphenyl)car- bamoyloxy)propyl]piperidine,
4_(4-Fluorobenzoyl)-l-[2-(5-quinoxalinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[2-( 6-quinoxalinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Fluorobenzoyl)-1-[3-(5-quinoxalinylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-( 6-quinoxalinylcarbamoyloxy)- propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[2-(5-quinolylcarbamoyloxy)ethyl]■ piperidine,
4-(4-Fluorobenzoyl)-l-[2-( 6-quinolylcarbamoyloxy)ethyl]• piperidine,
4-(4-Fluorobenzoyl)-1-[2-(7-quinolylcarbamoyloxy)ethyl]• piperidine,
4-(4-Fluorobenzoyl)-l-[2-(8-quinolylcarbamoyloxy)ethyl] piperidine, 4-(4-Fluorobenzoyl)-1-[3-(5-quinolylcarbamoyloxy)propyl]■ piperidine,
4-(4-Fluorobenzoyl)-l-[3-(6-quinolylcarbamoyloxy)propyl]■ piperidine,
4-(4-Fluorobenzoyl)-l-[3-(7-quinolylcarbamoyloxy)propyl]■ piperidine,
4-(4-Fluorobenzoyl)-1-[3-(8-quinolylcarbamoyloxy)propyl] piperidine,
4-(4-Fluorobenzoyl)-l-[2-(2,3,4-trimethoxyphenylcarba- moyloxy)ethyl]piperidine,
4-(4-Fluorobenzoyl )-1-[3-(2,3,4-trimethoxyphenylcarba- moyloxy)propyl]piperidine,
4-(4-Fluorobenzoyl)-l-[3-(3,4,5-trimethoxyphenylcarba- moyloxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-(4-indolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-(5-indolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-(6-indolinylcarbamoyloxy)- ethyl] iperidine,
4-(4-Chlorobenzoyl)-1-[2-(7-indolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(4-indolinylcarbamoyloxy)- propyl]piperidine, 4-(4-Chlorobenzoyl )-l-[3-(5-indolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-(6-indolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(7-indolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(4-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(5-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-( 6-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(7-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(4-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-(5-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-( 6-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoy1)-l-[3-(7-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-(4-isoindolinylcarbamoyloxy)- ethyl]piperidine, 4-(4-Chlorobenzoyl)-1-[2-(5-isoindolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(4-isoindolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-(5-isoindolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-(4-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(5-benzo[b]thienylcarbamoyl- oxy) thyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-( 6-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-(7-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(4-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-(5-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(6-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-(7-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(4-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine, 4-(4-Chlorobenzoyl)-l-[2-(5-benzo[b]f ranylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(6-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(7-benzo[b]f ranylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-(4-benzo[b]furanylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(5-benzo[b]furanylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-(6-benzo[b]furanylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(7-benzo[b]furanylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(4-indazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(5-indazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(6-indazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(7-indazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(4-indazolylcarbamoyloxy)- propyl]piperidine, 4-(4-Chlorobenzoyl)-1-[3-(5-indazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-(6-indazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(7-indazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(4-benzimidazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-( 5-benzimidazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(4-benzimidazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-( 5-benzimidazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(4-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-(5-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-( 6-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(7-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(4-benzoxazolylcarbamoyloxy)- propyl]piperidine, 4-(4-Chlorobenzoyl)-l-[3-(5-benzoxazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(6-benzoxazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(7-benzoxazolylcarbamoyloxy)- propyl] iperidine,
4-(4-Chlorobenzoyl)-1-[2-(4-benzothiazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(5-benzothiazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(6-benzothiazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(7-benzothiazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(4-benzothiazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(5-benzothiazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(6-benzothiazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(7-benzothiazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-((1,2-benzisothiazol-4-yl)- carbamoyloxy)ethyl]piperidine, 4-(4-Chlorobenzoyl)-1-[2-( (1, 2-benzisothiazol-5-yl)- carbamoyloxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-( ( 1,2-benzisothiazol-6-yl)- carbamoyloxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-( ( 1,2-benzisothiazol-7-yl)- carbamoyloxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-( (1, 2-benzisothiazol-4-yl)- carbamoyloxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-( ( 1, 2-benzisothiazol-5-yl)- carbamoyloxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-( ( 1,2-benzisothiazol-6-yl)- carbamoyloxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-( ( 1,2-benzisothiazol-7-yl)- carbamoyloxy) ropyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-( (1,2-benzisoxazol-4-yl)car- bamoyloxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-( (1,2-benzisoxazol-5-yl)car- bamoyloxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-( (1, 2-benzisoxazol-6-yl)car¬ bamoyloxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-( (1,2-benzisoxazol-7-yl)car- bamoyloxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-( ( 1,2-benzisoxazol-4-yl)car- bamoyloxy) ropyl]piperidine, 4-(4-Chlorobenzoyl)-l-[3-((1,2-benzisoxazol-5-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-( (1,2-benzisoxazol-6-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-( (1,2-benzisoxazol-7-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(4-benzimidazolidinylcarba- moyloxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(5-benzimidazolidinylcarba- moyloxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(4-benzimidazolidinylcarba- oyloxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(5-benzimidazolidinylcarba- moyloxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(2,3-ethylenedioxyphenylcar- bamoyloxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(3,4-ethylenedioxyphenylcar- bamoyloxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(2,3-ethylenedioxyphenylcar- bamoyloxy)propyl]piperidine,
4-(4-Chorobenzoyl)-1-[3-(3,4-ethylenedioxyphenylcarba- moyloxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-(2,3-methylenedioxyphenylcar- bamoyloxy)ethyl]piperidine, 4-(4-Chlorobenzoyl)-1-[2-(3,4-methylenedioxyphenylcar- bamoyloxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(2,3-methylenedioxyphenylcar- bamoyloxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(3,4-methylenedioxyphenylcar- bamoyloxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-(5-quinoxalinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(6-quinoxalinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-(5-quinoxalinylcarbamoyloxy)- propy1]piperidine,
4-(4-Chlorobenzoyl)-l-[3-( 6-quinoxalinylcarbamoyloxy)- propyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(5-quinolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(6-quinolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[2-(7-quinolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-(8-quinolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-(5-quinolylcarbamoyloxy)pro- pyl]piperidine, 4-(4-Chlorobenzoyl)-l-[3-(6-quinolylcarbamoyloxy)pro¬ pyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(7-quinolylcarbamoylox )pro- py1]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(8-quinolylcarbamoyloxy)pro- pyl]piperidine,
4-(4-Chlorobenzoyl)-l-[2-(2,3,4-trimethoxyphenylcarba- moyloxy)ethyl]piperidine,
4-(4-Chlorobenzoyl)-1-[3-(2,3,4-trimethoxyphenylcarba- moyloxy)propyl]piperidine,
4-(4-Chlorobenzoyl)-l-[3-(3,4,5-trimethoxyphenylcarba- moyloxy)propyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(4-indolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-(5-indolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-(6-indolinylcarbamoylox )- ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(7-indolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(4-indolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-(5-indolinylcarbamoyloxy)- propyl]piperidine, 4-(4-Bromobenzoyl)-1-[3-(6-indolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(7-indolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(4-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-( 5-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-( 6-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(7-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(4-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl )-1-[3-(5-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(6-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(7-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(4-isoindolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(5-isoindolinylcarbamoyloxy)- ethyl]piperidine, 4-(4-Bromobenzoyl )-l-[3-(4-isoindolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(5-isoindolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-("4-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-(5-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-( 6-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-(7-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-(4-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-(5-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Bromobenzoyl )-l-[3-( 6-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(7-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Bromobenzoy1)-1-[2-(4-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-( 5-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine, 4-(4-Bromobenzoyl)-l-[2-(6-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-(7-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(4-benzo[b]furanylcarbamoyl- oxy)propyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-(5-benzo[b]furanylcarbamoyl- oxy)propyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-( 6-benzo[b]furanylcarbamoyl- oxy)propyl] iperidine,
4-(4-Bromobenzoyl )-1-[3-(7-benzo[b]furanylcarbamoyl- oxy)propyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(4-indazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(5-indazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(6-indazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl )-1-[2-(7-indazolylcarbamoyloxy)- ethyl]piperidine,
4_(4-Bromobenzoyl)-l-[3-(4-indazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-( 5-indazolylcarbamoyloxy)- propyl]piperidine, 4-(4-Bromobenzoyl)-l-[3-(6-indazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-(7-indazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(4-benzimidazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(5-benzimidazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(4-benzimidazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-(5-benzimidazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-(4-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-(5-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-(6-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(7-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(4-benzoxazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(5-benzoxazolylcarbamoyloxy)- propyl]piperidine, 4-(4-Bromobenzoyl)-1-[3-( 6-benzoxazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(7-benzoxazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(4-benzothiazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-( 5-benzothiazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(6-benzothiazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-(7-benzothiazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(4-benzothiazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-( 5-benzothiazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-( 6-benzothiazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-(7-benzothiazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-( (1,2-benzisothiazol-4-yl)- carbamoyloxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-( (1, 2-benzisothiazol-5-yl)car- bamoyloxy)ethyl]piperidine, 4-(4-Bromobenzoyl)-l-[2-( (1,2-benzisothiazol-6-yl)car- bamoyloxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-( (l,2-benzisothiazol-7-yl)car- bamoyloxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-((1,2-benzisothiazol-4-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-( (1,2-benzisothiazol-5-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-( (1,2-benzisothiazol-6-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-( (1,2-benzisothiazol-7-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-( (1,2-benzisoxazol-4-yl)car- bamoyloxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-( (1,2-benzisoxazol-5-yl)car¬ bamoyloxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-( (1,2-benzisoxazol-6-yl)car¬ bamoyloxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-( (1,2-benzisoxazol-7-yl)car¬ bamoyloxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-( (1,2-benzisoxazol-4-yl)car¬ bamoyloxy)propyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-( (1,2-benzisoxazol-5-yl)car- bamoyloxy)propyl]piperidine, 4-(4-Bromobenzoyl)-1-[3-( (1,2-benzisoxazol-6-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-( (1, 2-benzisoxazol-7-yl)car- 5 bamoyloxy)propyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(4-benzimidazolidinylcarba- moyloxy)ethyl]piperidine,
10 4-(4-Bromobenzoyl)-1-[2-( 5-benzimidazolidinylcarba- moyloxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-(4-benzimidazolidinylcarba- moyloxy)propyl]piperidine, 15
4-(4-Bromobenzoy1)-1-[3-(5-benzimidazolidinylcarba- moyloxy)propyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(2,3-ethylenedioxyphenylcar- 20 bamoyloxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(3,4-ethylenedioxyphenylcar- bamoyloxy)ethyl]piperidine,
25 4-(4-Bromobenzoyl)-l-[3-(2,3-ethylenedioxyphenylcar- bamoyloxy)propyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-(3,4-ethylenedioxyphenylcar- bamoyloxy)propyl]piperidine, 30.
4-(4-Bromobenzoyl)-1-[2-(2,3-methylenedioxyphenylcar- bamoyloxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(3,4-methylenedioxyphenylcar- 35 bamoyloxy)ethyl]piperidine, 4-(4-Bromobenzoyl)-l-[3-(2,3-methylenedioxyphenylcar- bamoyloxy)propyl]piperidine,
4-(4-Bromobenzoy1)-1-[3-(3,4-methylenedioxyphenyl)car- bamoyloxy)propyl]piperidine, oalate
4-(4-Bromobenzoyl)-1-[2-(5-quinoxalinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(6-quinoxalinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoy1)-1-[3-(5-quinoxalinylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-( 6-quinoxalinylcarbamoyloxy)- propyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-( 5-quinolylcarbamoyloxy)- ethyl]piperidine,
4_(4-Bromobenzoy1)-l-[2-( 6-quinolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(7-quinolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-1-[2-(8-quinolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-(5-quinolylcarbamoyloxy)pro- pyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-(6-quinolylcarbamoyloxy)pro- pyl]piperidine, 4-(4-Bromobenzoyl)-1-[3-(7-quinolylcarbamoyloxy)pro¬ pyl]piperidine,
4-(4-Bromobenzoyl)-1-[3-(8-quinolylcarbamoyloxy)pro- pyl]piperidine,
4-(4-Bromobenzoyl)-l-[2-(2,3,4-trimethoxyphenylcarba- moyloxy)ethyl] iperidine,
4-(4-Bromobenzoyl)-l-[2-(3,4, 5-trimethoxyphenylcarba- moyloxy)ethyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-(2,3,4-trimethoxyphenylcarba- moyloxy)propyl]piperidine,
4-(4-Bromobenzoyl)-l-[3-(3,4, 5-trimethoxyphenylcarba- moyloxy)propyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(4-indolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(5-indolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(6-indolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(7-indolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(4-indolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(5-indolinylcarbamoyloxy)- propyl] iperidine, 4-(4-Iodobenzoyl)-1-[3-(6-indolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(7-indolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-(4-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(5-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(6-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(7-indolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(4-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-( 5-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-(6-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(7-indolylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-(4-isoindolinylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-(5-isoindolinylcarbamoyloxy)- ethyl]piperidine, 4-(4-Iodobenzoyl)-1-[3-(4-isoindolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-( 5-isoindolinylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(4-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(5-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(6-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl )-1-[2-(7-benzo[b]thienylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(4-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Iodobenzoyl )-l-[3-( 5-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-( 6-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-(7-benzo[b]thienylcarbamoyl- oxy)propyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-(4-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(5-benzo[b]furanylcarbamoyl- oxy)ethyl] iperidine, 4-(4-Iodobenzoyl)-l-[2-(6-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(7-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-(4-benzo[b]furanylcarbamoyl- oxy) ropyl] iperidine,
4-(4-Iodobenzoyl)-l-[3-(5-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-(6-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(7-benzo[b]furanylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-(4-indazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(5-indazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-(6-indazolylcarbamoyloxy)- ethyl] iperidine,
4-(4-Iodobenzoyl)-1-[2-(7-indazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(4-indazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(5-indazolylcarbamoyloxy)- propyl]piperidine, 4-(4-Iodobenzoyl)-1-[3-( 6-indazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(7-indazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(4-benzimidazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(5-benzimidazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(4-benzimidazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-( 5-benzimidazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-(4-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(5-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-(6-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(7-benzoxazolylcarbamoyloxy)- ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-(4-benzoxazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(5-benzoxazolylcarbamoyloxy)- propyl]piperidine, 4-(4-Iodobenzoyl)-l-[3-( 6-benzoxazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(7-benzoxazolylcarbamoyloxy)- propyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-(4-benzothiazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(5-benzothiazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-(6-benzothiazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-(7-benzothiazolylcarbamoyl- oxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(4-benzothiazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-( 5-benzothiazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-(6-benzothiazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(7-benzothiazolylcarbamoyl- oxy)propyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-( (1,2-benzisothiazol-4-yl)car- bamoyloxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-( ( 1, 2-benzisothiazol-5-yl)car- bamoyloxy)ethyl]piperidine, 4-(4-Iodobenzoyl)-l-[2-( (1,2-benzisothiazol-6-yl)car- bamoyloxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-( (1,2-benzisothiazol-7-yl)car- bamoyloxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-( (1,2-benzisothiazol-4-yl)car¬ bamoyloxy)propyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-( (1,2-benzisothiazol-5-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-( (1,2-benzisothiazol-6-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-( (1,2-benzisothiazol-7-yl)car- bamoyloxy)propyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-( (1,2-benzisoxazol-4-yl)carba- moyloxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-( (1,2-benzisoxazol-5-yl)carba¬ moyloxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-( (1,2-benzisoxazol-6-yl)carba¬ moyloxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-( (1,2-benzisoxazol-7-yl)carba- moyloxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-( (1,2-benzisoxazol-4-yl)carba- moyloxy)propyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-( (1,2-benzisoxazol-5-yl)carba- moyloxy)propyl]piperidine, 4-(4-Iodobenzoyl)-l-[3-( (1,2-benzisoxazol-6-yl-carba- moyloxy)propyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-( (1,2-benzisoxazol-7-yl)carba- moyloxy)propyl] iperidine,
4-(4-Iodobenzoyl)-1-[2-(4-benzimidazolidinylcarba- moyloxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-( 5-benzimidazolidinylcarba- moyloxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(4-benzimidazolidinylcarba- moyloxy)propyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-( 5-benzimidazolidinylcarba- moyloxy)propyl]piperidine,
4-(4-Iodobenzoyl )-l-[2-(2,3-ethylenedioxyphenylcar- bamoyloxy)ethyl]piperidine,
4-(4-lodobenzoyl)-1-[2-(3,4-ethylenedioχyphenylcar- bamoyloxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(2,3-ethylenedioxyphenylcar- bamoyloxy)propyl]piperidine,
4-(4-Iodobenzoyl )-l-[3-(3,4-ethylenedioxyphenylcarba- moyloxy)propyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(2,3-methylenedioxyphenylcar- bamoyloxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1-[2-(3,4-methylenedioxyphenylcar- bamoyloxy)ethyl]piperidine, 4-(4-Iodobenzoyl -l-[3-(2,3-methylenedioxyphenylcar- bamoyloxy)propyl piperidine,
4-(4-Iodobenzoyl -1-[3-(3,4-methylenedioxyphenylcar- bamoyloxy)propyl piperidine,
4-(4-Iodobenzoyl -1-[2-(5-quinoxalinylcarbamoyloxy)- ethyl]piperidine
4-(4-Iodobenzoyl -1-[2-(6-quinoxalinylcarbamoyloxy)- ethyl]piperidine
4-(4-Iodobenzoyl -1-[3-( 5-quinoxalinylcarbamoyloxy)- propyl]piperidine
4-(4-Iodobenzoyl -1-[3-(6-quinoxalinylcarbamoyloxy)- propyl]piperidine
4-(4-Iodobenzoyl -1-[2-(5-quinolylcarbamoyloxy)- ethyl]piperidine
4-(4-Iodobenzoyl -1-[2-(6-quinolylcarbamoyloxy)- ethyl]piperidine
4-(4-Iodobenzoyl •l-[2-(7-quinolylcarbamoyloxy)- ethyl]piperidine
4-(4-Iodobenzoyl -1-[2-(8-quinolylcarbamoyloxy)- ethyl]piperidine
4-(4-Iodobenzoyl -l-[3-(5-quinolylcarbamoyloxy)pro- py1]piperidine,
4-(4-Iodobenzoyl •1-[3-( 6-quinolylcarbamoyloxy)pro- pyl]piperidine, 4-(4-Iodobenzoyl)-l-[3-(7-quinolylcarbamoyloxy)pro¬ pyl]piperidine,
4-(4-Iodobenzoyl)-l-[3-(8-quinolylcarbamoyloxy)pro- pyl]piperidine,
4-(4-Iodobenzoyl)-l-[2-(2,3,4-trimethoxyphenylcarba- moyloxy)ethyl]piperidine,
4-(4-Iodobenzoyl)-1[2-(3,4,5-trimethoxyphenylcarba- moyloxy)ethyl]piperidine
4-(4-Iodobenzoyl)-l-[3-(2,3,4-trimethoxyphenylcarba- moyloxy)propyl]piperidine,
4-(4-Iodobenzoyl)-1-[3-(3,4,5-trimethoxyphenylcarba- moyloxy)propyl]piperidine,
Compounds of the general formula I were tested for binding to various CNS receptor subtypes as well as for analgesic activity in vivo in mice.
Detailed conditions for the in vitro and in vivo as- says are described below:
IN-VITRO inhibition of DOPAMINE D2 receptor binding,
Method description
Principle:
3 Radioactive-labelled ligand H-Spiroperidol is incubat¬ ed with isolated cell-membrane fragments at 37°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 unspecifical- ly 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 membranes.
Tissue preparation:
The procedure is performed in ice bath. Polytron kine- matica is rinsed with milli-Q-H20 before and after use. Male Wistar rats, 150-200 g are decapitated, stri¬ atum is removed quickly and weighed (approx. 50 mg). Striatum is transferred to a centrifuging vial contain¬ ing 10 ml ice-cold D2 buffer. Homogenization is per- formed applying polytron kinematica (homogenizer) set¬ ting 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. Centrifu¬ gation 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 ho¬ mogeneous (uniform) before use. If not, brief homoge¬ nization is performed.
Assay:
2,500 μl tissue (homogeneous)
25 μl 3H-Spiroperidol (0.05 nM)
25 μl test substance/HLO/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 fil- tered through GF/B filters (use gloves). This procedu¬ re is repeated. The filters are placed in counting vi¬ als and 4 ml opti-flour is added (perform in fume cup- board, use gloves). Counting is performed at window 0-19 of the beta- counter (Pachard). Note that recep¬ tor box and lid are rinsed thoroughly in H--0 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 dilut¬ ed in H„0. 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 al- ways made fresh every day. When weighing out test sub¬ stances, 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 cone./assay.
Results:
The test value is given as IC-.-. indicating the concen- tration inhibiting specific binding by 50%.
Cone.
Figure imgf000044_0001
100 "%control" " λ IN-VITRO inhibition of Alpha.. -receptor binding.
Method description
Principle:
3 Radioactive-labelled ligand H-Prazosin is incubated with isolated cell-membrane fragments at 25 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 unspecifical- ly adhered radioactivity. 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:
The procedure is performed in ice bath. Polytron kine- matica is rinsed with milli-Q-H^O before and after use. Male Wistar rats, 150-200 g are decapitated, cor¬ tex is removed quickly and weighed (approx. 500 mg). Cortex is transferred to a centrifuging vial contain- ing 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 centrifuging vial. The 10 ml rinsing buffer is added to the tissue vial. Centrifugation at 18,000 rpm for 12 min. at 4 C. This is repeated once. Final pel¬ let is added to 400 x vol. of same buffer. (Ex. 500 mg cortex in 200 ml D2 buffer). Can be stored for 30 min. at 0°C. Assay :
2,000 μl tissue 2 255 μμll 33HH--PPrraa:zosin (0.5 nM) 25 μl test substance/H20/blind Phentolamine (10 μM)
Incubation for 30 min. at 25 C.
10 ml of ice-cold 0.9% NaCl is added to the tubes and filtered through GF/B filters (use gloves). This pro- cedure is repeated. Filters are placed in counting vi¬ als and 4 ml opti-flour is added (perform in fume cup¬ board, use gloves). Counting is performed at window 0-19 of the beta- counter (Pachard). Note that recep¬ tor box and cover are rinsed thoroughly in H^O 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 dilut¬ ed in H-0. The binding will stand concentrations of up to approx. 5% of these solvents without affecting the binding. Most stock solutions are stable at 4 C. Atten¬ tion should, however, be paid to any precipitation, change in colour etc. Test-substance dilutions are al¬ ways prepared 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 cone./ass.
Results:
The test value is given as IC-.-. indicating the concen- tration inhibiting specific binding by 50%. Cone.
Figure imgf000047_0001
100
"%control" - 1
IN-VITRO inhibition of DOPAMINE DI receptor binding.
Method description
Principle:
3 Radioactive-labelled ligand 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 radioactivity. As oppos- ed 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 non-specifically to the mem¬ branes.
Tissue preparation:
Male Wistar rats, 150-200 g are decapitated. Striatum is removed quickly, weighed (approx. 50 mg) and care- fully 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 ul buffer I. The homogenate is centrifuged at 18,000 rpm for 20 min. at 4 C, and the supernate is decanted. This step is per- formed three times, and each time the pellet is resus- pended and homogenized in 100 x vol. of buffer I. Fol¬ lowing the third centrifugation, the pellet is suspend- ed in 100 x vol. of resuspension buffer and homogeniz¬ ed. The tissue is now ready for use. The tissue is stable at 0°C for 8 hours.
Assay:
600 ul incubation buffer
100 ul 3H-SCH 23390 (0.2 nM)
100 ul tissue
200 ul test substance/H20/blind (cis-flupentixol 2 uM)
Incubation for 60 min. at 30 C.
10 ml ice-cold 0.9% NaCl is added to the tubes. Filtra- tion is performed through GF/B filters (use gloves).
This procedure is repeated. Filters are placed in count¬ ing vials, 4 ml opti-flour is added (perform in fume cupboard, use gloves) and counting performed at window 0-19. of the beta-counter (Pachard). Note that receptor box and lid are rinsed thoroughly in H„0 after use to avoid contamination. Further, the analytical site is cleaned carefully every day after use.
Test substances:
Dissolved in H„0, EtOH, MeOH or. DMSO and further dilut¬ ed in H„0. The DI 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 precipitati¬ on, 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 the substance. Less than 0.8 mg must never be weigh- ed out and only infrequently more than 2 mg (for eco¬ nomy reasons) dependent, however, on cone./assay. .
47
Results :
The test value is given as IC.-n indicating the concen¬ tration inhibiting specific binding by 50%.
Cone. = IC50 (nM)
100
"%control" " 1
10
IN VITRO inhibition of 5HT2~receptor binding
Method description
15 Principle:
3 Radioactive-labelled ligand H-Ketanserine is incubat¬ ed with isolated cell-membrane fragments at 37 C for a given period of time. Following completed incubation,
20 the incubate is filtered through GF/B filters which are rinsed after 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
25 indicates the amount of ligand bound specifically as well as non-specifically to the membranes.
Tissue preparation:
30 The preparation is made in ice bath. Polytron kinema- tica 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 con-
35 taining 10 ml ice-cold D2 buffer. Homogenization apply¬ ing 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. 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 buf- fer). Can be stored for approx. 30 min. at 0°C.
Assay:
1250 μl tissue 2255 μμll 33HH--KKeettcanserine (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. Filtra¬ tion 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 (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 H.,0 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 dilut¬ ed in H20. The 5HT2 binding will stand concentrations of up to approx. 5% of these solvents without affect- ing the binding. Most stock solutions are stable at
4 C. Attention should, however, be paid to any preci¬ pitation, change in colour etc. Test-substance diluti¬ ons are always made fresh every day. When weighing out test substance, it is attempted to weigh out approx. 1 mg of substance. Less than 0.8 mg must never be weigh¬ ed out and only infrequently more than 2 mg (for eco¬ nomy reasons) dependent, however, on cone./assay. Results :
The test value is given as IC,-n, i.e. the concentra¬ tion inhibiting specific binding by 50%.
Cone.
Figure imgf000051_0001
100
"%control" " 1
Antagonism of acetic acid-induced writhings in mice
Principle:
In mice i.p. injection of acetic acid induces a writh¬ ing syndrome which is antagonized by analgesics (Sieg- mund et al. , 1957; Eckhardt et al., 1957).
Method:
Acetic acid 0.5 per cent is injected i.p. (0.15 ml/10 g body weight) to 6 mice (NMRI, either sex weighing 20-25 g) pretreated with physiological saline (con¬ trols) and to 6 mice pretreated with test substance. In the controls acetic acid induces a syndrome chara¬ cterized by contraction of abdomen, turning of trunk and extension of hind limbs. Saline and test substances are administered s.c. 30 min. before acetic acid. The number of writhings is counted 5- 15 min. after injec¬ tion of acetic acid. Results:
Initially, the dose of test substance is equivalent to 5- 10 per cent of LE) . if this dose decreases writh¬ ings, 3-5 dose levels are tested. The activity is ex¬ pressed as per cent protection:
100 average writhings of treated group . __ average writhings of daily control groups
The effect of active substances is evaluated by a dose response curve, log dose on the abscissa, and per cent protection on the ordinate. The potency is expressed as the dose (ED.-.-, in mg/kg giving 50 per cent protec¬ tion against writhings.
Specificity of test:
Analgesics and various other drugs inhibit acetic acid- induced writhings in mice. This test is used as a screening test for analgesics. Additional results from other screening tests are required to exclude ac¬ tive anti-writhing substances without analgesic effect.
References:
Eckhardt, E. et al.
Etiology of chemically induced writhing in mouse and rat. Proc. Soc. exp. Biol. £8, 186-188, 1958.
Siegmund, E. et al.
A method for evaluating both non-naracotic and narco¬ tic analgesics. Proc. Soc. exp. Biol. £5_, 729-731, 1957. The compounds of this invention were found active in the receptor binding assays, typically with IC,-n in the order of 0.1 nM to 500 nM. Furthermore the com¬ pounds were potent in the writhing test in mice with ED t--Λ in "the order of 0.1 mg/kg to 50 mg/kg.
The compounds of the invention and physiologically ac¬ ceptable salts thereof may be prepared by a variety of synthetic routes, which indludes reacting a compound of formula II
Y=C=N-R2 (II)
2 where Y and R have the meanings set forth above, with the compounds of formula III
1 /—\
R-( N-A-XH (HI)
1 wherein R , A and X have the meanings set forth above to form a compound of formula I.
For instance an isocyanate or isothiocyanate of 3,4,5- trimethoxybenzene, prepared by refluxing 3,4,5-trime- thoxyaniline and phosgene or thiophosgene respectively in toluene, may be reacted with the desired piperidine alkylamine or piperidine alkylhydroxy intermediate to obtain the desired urea or carbamate of formula I.
Compounds of formula I, wherein X is
Figure imgf000053_0001
-N- Q and Y is =NZ wherein R and Z have the meanings set forth above are prepared by standard procedures as des¬ cribed in e.g. H.J. Petersen et al., J. ed.Chem. (1978) 21, 773-781. 5
The procedure includes reacting a compound of formula IV
Figure imgf000054_0001
wherein R 1, A and R8 have the meanings set forth abo¬ ve, with a compound of formula V 15
i.
/
N
Figure imgf000054_0002
2 25 wherein R and Z have the meanings set forth above,
or reacting a compound of formula VI
Figure imgf000054_0003
prepared from a compound of formula VII
2
_ .. NH-R
35 \
( VII )
'• — ( N-A-NH wherein R1, A and R2 have the meanings set forth above and W is 0 or S, with NH„-Z, wherein Z has the meaning set forth above.
The purified reaction product may be converted into a physiologically acceptable salt. Such salts include acid addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobromides, sul- phates, nitrates, oxalates, phosphates, tartrates, ci¬ trates, fumarates, maleates, succinates, and sulphona¬ tes e.g. mesylates.
If desirable, selected salts may be subjected to fur- ther purification by recrystallization.
The compounds of the invention, together with a con¬ ventional adjuvant, carrier, or diluent, and if desir¬ ed a pharmaceutically-acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or fil¬ led capsules, or liquids, such as solutions, suspen¬ sions, 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 subcu¬ taneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or with¬ out additional active compounds or principles, and such unit dosage forms may contain any suitable effec¬ tive central nervous system ailment alleviating amount of the active ingredient commensurate with the intend- ed daily dosage range to be employed. Tablets contain¬ ing one (1) milligram of active ingredient or, more broadly, one (1) to thirty (30) milligrams, per tab- let, are accordingly suitable representative unit dos¬ age 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 in¬ cluding humans, in accordance with conventional me¬ thods of galenic pharmacy.
Conventional excipients are such pharmaceutically ac¬ ceptable organic or inorganic carrier substances suit¬ able for parenteral or oral application which do not delteriously react with the active compound.
Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stea- rate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxilliary agents, such as lu¬ bricants, 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 compound.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqu¬ eous solutions with the active compound dissolved in polyhydroxylated castor oil.
Ampoules are convenient unit dosage forms.
For oral application, particularly suitable are tab¬ lets, dragees, or capsules having talc and/or a carbo- hydrate carrier or binder or the like, the carrier pre¬ ferably 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 techniques contains:
Active compound 1.0 mg
Lactosum 67.9 mg ph.Eur.
Avicel ® 31.4 mg Amberlite ® IRP 88 1.0 mg
Magnesii stearas 0.25 mg Ph.Eur.
The following examples illustrate the specific methods employed in production of a representative number of compounds embraced by this invention.
The following examples serve to illustrate the present invention:
EXAMPLE 1
N-(3,4-Ethylenedioxyphenyl)-N'-3-[4-(4-fluorobenzoyl)- piperidino]propylthiourea, HCl
To a mixture of 1,4-benzodioxan-6-amine (15.1 g; 100 mmol) and triethylamine (20.2 g; 200 mmol) in toluene (350 ml) was added dropwise over 10 min thiophosgene
(11.5 g; 100 mmol) in toluene (50 ml). The mixture was stirred at 80°C for 30 min., cooled to room temperatu- re and filtered. The filtrate was evaporated. The pro¬ duct was redissolved in toluene and concentrated in vacuo. The resulting oil was taken up in warm petrole¬ um ether, which was filtered. The filtrate was concen- trated to a small volume, which afforded 7.2 g of 3,4- ethylenedioxyphenylisothiocyanate.
3,4-ethylenedioxyphenylisothiocyanate (0.26 g; 1.35 mmol) in dry dioxane (25 ml) was added to l-(3-amino- propyl)-4-(4-fluorobenzoyl)piperidine (0.35 g; 1.32 mmol) in dry dioxan (25 ml). The mixture was refluxed for 1.5 h, cooled to room temperature and concentrated in vacuo. The resulting oil was purified by flash chro¬ matography on silica gel 60 eluting with ethyl aceta- te, methanol (4:1, v/v) graduated to ethyl acetate, methanol (2:1, v/v). The product was dissolved in etha¬ nol and HCl in ether added to precipitate the desired product. Recrystallization from ethanol gave 100 mg white crystals. M.p. 183-5°C. MS (70 eV): m/z 457 (0.3%, M+), 306 (10), 220 (50), 193 (100), 151 (57).
EXAMPLE 2
N-Cyano-N'-(3,4-ethylenedioxyphenyl)-N' '-3-[4-(4-flu- orobenzoyl)piperidino]propylguanidine, oxalate
A mixture of S-methyl-N-3,4-ethylenedioxyphenyl-N'- cyanothiourea (1.0 g; 4 mmol) (produced by a method described in J.Med.Chem. (1978) 2^, 773-781 and in
J.Chem.Soc. (1948), p. 1630, from 3,4-ethylenedioxy- phenylisothiocyanate of example 1, cyanamide and me- thyliodide) and l-(3-aminopropyl)-4-(4-fluorobenzo¬ yl)piperidine (106 g; 4 mmol) in dry pyridine was stirred at room temperature for 13 days and then eva¬ porated. The product was purified by column chromato¬ graphy on silica gel 60 eluting with methylene chlori- de graduated to methylene chloride/methanol (9:1, v/v). The product was taken up in acetone (5 ml) and oxalic acid (0.5 g) in acetone (2 ml) added to preci¬ pitate the desired product as 0.52 g white crystals. M.p. 105-7°C (decomp.). MS (70 eV): m/z 465 (6%, M+; 220 (90), 151 (85), 95 (93), 70 (100).
EXAMPLE 3
1-[3-(6-Benzothiazolylcarbamoyloxy)propyl]-4-(4-fluo- robenzoyl)piperidine, oxalate
A mixture of 6-aminobenzothiazole (300 mg; 2 mmol) in toluene (40 ml) and phosgene (10 ml 20% in toluene, 20 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 6-benzothiazolyl- isocyanate. To the crude product was added 3-[4-(4- fluorobenzoyl)piperidino]propanol (400 mg, 15 mmol) in DMF (10 ml) . The mixture was stirred at 100°C for 2 h and then at room temperature for 16 h, whereupon it was taken up in ether and water. The organic phase was washed with water and saturated sodium chloride and concentrated in vacuo. The resulting oil was taken up in acetone/ethanol (4:1, v/v) and oxalic acid (150 mg) in acetone (2 ml) added to precipitate the desired pro¬ duct. The product was washed with ice cold ethanol giv¬ ing 500 mg. M.p. 87-89°C. MS (70 eV): m/z 44 (3%, M+), 220 (80), 176 (48), 150 (30), 123 (40), 114 (70), 70 (100). EXAMPLE 4
l- [3- ( 3 , 4-Ethylenedioxyphenylcarbamoyloxy ) propyl] -4- ( 4-fluorobenzoyl )piperidine, HCl
A mixture of l,4-benzodioxan-6-amine (300 mg; 2.0 mmol in toluene (20 ml) and phosgene (10 ml 20% in toluene; 19 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 3,4-ethylenedioxyphenylisocyanate.
To the crude product was added 3-[4-(4-fluorobenzoyl)- piperidino]propanol (530 mg; 20 mmol) in toluene (20 ml) was refluxed for 16 h. The reaction mixture was then concentrated in vacuo and submitted to flash chromatography on silica gel 60 eluting with toluene graduated to toluene/ethyl acetate (1:1). The product was taken up in ethanol and precipitated as the hydro- chloride by addition of hydrogen chloride in ether
(375 mg). M.p. 225-226°C. MS (70 eV): m/z 442 (4%, M+), 291 (9), 265 (9), 236 (14), 220 (83), 177 (66), 123 (32), 114 (61), 93 (28), 70 (100).
EXAMPLE 5
1-[2-(6-Benzothiazolylcarbamoyloxy)ethyl]-4-(4-fluo- robenzoyl)piperidine, oxalate
Starting from 6-benzothiazolylisocyanate (300 mg; 2 mmol) and 2-(4-(4-fluorobenzoyl)-piperidino)ethanol (400 mg; 1.5 mmol) using the procedure described in example 3 was prepared 0.5 g of the title compound, M.p. 182-184°C. MS (70 eV): m/z 427 (0.5%, M+), 23: (29), 220 (100), 177 (26), 176 (27), 123 (65). EXAMPLE 6
4-(4-Fluorobenzoyl)-l-[2-(3,4,5-trimethoxyphenylcarba- moyloxy)ethyl]piperidine, oxalate
Starting from 3,4,5-trimethoxyphenylisocyanate (600 mg, 3 mmol) and 2-[4-(4-fluorobenzoyl)-l-piperidyl]- ethanol (380 mg; 1.5 mmol) using the procedure describ- ed in example 3 was prepared 480 mg of the title com¬ pound. M.p. 165-167°C. MS (70 eV): m/z 460 (7%, M+), 233 (50), 220 (100), 209 (13).

Claims

1. Piperidine derivatives represented by formula I:
Figure imgf000062_0001
wherein A represents a straight or branched saturated or unsaturated hydrocarbon chain containing from 2 to 6 carbon atoms;
R1 is
Figure imgf000062_0002
wherein R 3, R4, R5, R6 and R7, which may be identical or different, each is selected from the group consist¬ ing of hydrogen, halogen, C1_f--alkyl, C3_g-cycloalkyl, cyano, nitro and perhalomethyl;
X is -0- or
Figure imgf000062_0003
-N- p wherein R is hydrogen, C.._g-alkyl or C-> -cycloalkylj
Y is =0, =S or =NZ
wherein Z is hydrogen, C-_,-alkyl or CN;
2
R is selected from the group consisting of
Figure imgf000063_0001
wherein forms a 5- or 6-membered heterocyclic
Figure imgf000063_0002
ring, containing one or more N-, 0- or S-atoms, and
wherein R 9, R10, R11 and R12, which may be identical or different represent hydrogen, C.,_g-alkyl, halogen,
C., ,-alkoxy or perhalomethyl, and pharmaceutically acceptable salts thereof.
2. A method of preparing compounds of formula I accord¬ ing to claim 1, which comprises
a) reacting a compound
Y=C=N-R2 (II)
2 wherein Y and R have the meanings set forth above, with the compounds of formula III
Figure imgf000064_0001
wherein R , A and X have the meanings set forth above, or
b) reacting a compound of formula IV
RiH- NN--AA--lNH-R8 (IV)
wherein R 1, A and R8 have the meanings set forth above, with a compound of formula V
Z
/
Figure imgf000064_0002
2 wherein R and Z have the meanings set forth above, or
c) reacting a compound of formula VI
Figure imgf000064_0003
prepared from a compound of formula VII
Figure imgf000065_0001
wherein R 1, A and R2 have the meanings set forth above and is 0 or S, with NH^-Z, wherein Z has the meaning set forth above, to form a compound of formula I.
3. A pharmaceutical composition comprising as active component a compound according to claim 1 or a pharma¬ ceutically acceptable salt thereof and a pharmaceuti¬ cally acceptable carrier or diluent.
4. A pharmaceutical composition according to claim 3 in the form of a dosage unit containing about 10-200 mg of the active compound.
5. A pharmaceutical composition suitable for use in the treatment of psychosis, which comprises as active component. a compound according to claim 1 or a pharma¬ ceutically acceptable salt thereof and a pharmaceuti¬ cally acceptable carrier or diluent.
6. A method of treating psychosis in a subject in need thereof, which comprises the step of administering to the said subject an effective amount of a compound re¬ presented by formula I (I)
Figure imgf000066_0001
wherein A represents a straight or branched saturated or unsaturated hydrocarbon chain containing from 2 to 6 carbon atoms;
R is
Figure imgf000066_0002
wherein R 3, R4, R5, R6 and R7, which may be identical or different, each is selected from the group consist¬ ing of hydrogen, halogen, C1_g-alkyl, C3_R-cycloalkyl, cyano, nitro and perhalomethyl;
X is -O- or
Figure imgf000066_0003
-N-
wherein R is hydrogen, C., ,-alkyl or C„ R-cycloalkyl;
Y is =0, =S or =NZ
wherein Z is hydrogen, C, g-alkyl or CN; 65
2
R is selected from the group consisting of
Figure imgf000067_0001
0 wherein i Het forms a 5- or 6-membered heterocyclic
wherein R 9, R10, R11 and R12, which may be identical or different represent hydrogen, C1 fi-alkyl, halogen, 5 C C--,,__gg--aallkkooxxyy oorr ppeerrhhaalloommeetth. yl, and pharmaceutically acceptable salts thereof.
0
5
0
5
PCT/DK1994/000201 1993-05-26 1994-05-25 Piperidine derivatives, their preparation and use WO1994027991A1 (en)

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WO2000035454A1 (en) * 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
WO2000035449A1 (en) * 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
WO2000035453A1 (en) * 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
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WO2000035452A1 (en) * 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6140344A (en) * 1998-11-17 2000-10-31 Syntex (U.S.A.) Inc. 4-aroylpiperidine derivatives-CCR-3 receptor antagonists
US6342509B1 (en) 1998-11-20 2002-01-29 Syntex (U.S.A.) Llc Piperidine quaternary salts- CCR- 3 receptor antagonists
US6521592B2 (en) 1998-12-18 2003-02-18 Bristol-Myers Squibb Pharma Co. N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
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US6140344A (en) * 1998-11-17 2000-10-31 Syntex (U.S.A.) Inc. 4-aroylpiperidine derivatives-CCR-3 receptor antagonists
US6342509B1 (en) 1998-11-20 2002-01-29 Syntex (U.S.A.) Llc Piperidine quaternary salts- CCR- 3 receptor antagonists
US6486180B1 (en) 1998-12-18 2002-11-26 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6525069B1 (en) 1998-12-18 2003-02-25 Bristol-Myers Squibb Pharma Co. N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
WO2000035452A1 (en) * 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
WO2000035453A1 (en) * 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
WO2000035449A1 (en) * 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6444686B1 (en) 1998-12-18 2002-09-03 Brsitol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
WO2000035454A1 (en) * 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6492400B1 (en) 1998-12-18 2002-12-10 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6521592B2 (en) 1998-12-18 2003-02-18 Bristol-Myers Squibb Pharma Co. N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
WO2000035451A1 (en) * 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6919368B2 (en) 1998-12-18 2005-07-19 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6780857B2 (en) 1998-12-18 2004-08-24 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6875776B2 (en) 1998-12-18 2005-04-05 Bristol-Myers Squibb Pharma Company 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

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