AU672182B2 - Piperidine derivatives and their use in treating psychosis - Google Patents

Description

CORRiECT'EDI Vi ISO revised abstract received by the international Biureau after P completion of tlie technical preparations for international0 PUl)Ohlicfltion 33 qp INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCi) (51) International Patent Classification 5 International Publication Number: WNO 93/10742 C07D) 413/0i41413/14,'40514 A A61K 31/445 A3 (43)International Publication Date: 10 June 1993 (10.06.93) (21) International Application Number: PCT/DK92/00348 (81) Designated States: AU, BG, CA, CS, FI, HU, JP, KR, NO, PL, PT, RO, RU, European patent (AT, BE, CH-, DE, (22) Initernational Filing Date: 25 November 1992 (25.11,92) DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).

Priority data: Published PCT/DK9I/00354 27 November 1991 (27.11.91I) WO With itnernatuinal search report.

('34)I Countries for wich the regional Before the exptration of the timte limit for amending the or international application claints and it) be republished in the even',t of the receipt of was filed: DK et al. antendments.

07 10/92 27 May 1992 (27.05.92) DK (88) Date ol publication ot the international search report: (71) Applicant: NOVO NORDISK A/S [DK/DK]; Novo A116, 22 J ulIy 199)3 (22 (17.93) (72) Inventors: HANSEN, John, Bondo Lang~sen 3, DK-4450 Jyderup JEPPESEN, Lone Malmmosevej 121,7i DK-2830 Virum GR0NVALD, Frederick, Chris-o tian Dronningeengen 19, DK-2950 Vedbamk (DK).

(54) Title: li.I.LCIPU fT1FA 2

NH-R

1>

Y--

2.

(II)

(57) Abstract The presenft invention relattes to therapeutically active piperidline derivatives a methiod of preparing the same an~ti plitirmaceutical compositions comprising the compounds. The compounds are useful in the treatment of indications related to the CNS-systern, caidiovascular system or to gastrointestinal disorders, wherein A represents a straight or branched saturated hydrocarbon chain containing from 2 to 6 carbon atoms; R' is WO 93/10742 PCr/DK92/00348( -1- Much evidence has accumulated to suggest that neuroleptics exert their antipsychotic action by blocking dopaminr. (DA) receptors in the brain. In recent years, it has become clear that some neuroleptics 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 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 blockade 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-2, D-3, D-4) but also 5HT-receptor subtypes (5HT 2 5HT3-, 5HTic-, 5HT 1 NA-a~ 1 -receptors, histamine and possibly other receptors.

Furthermore, 5HT 2 -blockade may also be important (Meltzer, Schizphr. Bull, 17: 263-87, 1991) to counteract 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.

i r' 1 J A WO8 93/10)742 PCT/DK92/00348 2 -antagonists, such as naftidrofuryl (Brain Res, 1989, 494(2) 387-90), are described to exhibit a protective effect on ischemic neuronal damage in the gerbil. Ritanserin, which is a potent and selective 5HT 2 -antagonist, has been shown to have anxiolytic-antidepressant activities in humans (Barone et al., Drug Clin. Pharm., 20 770 (1986)). Furthermore serotonergic mechanisms are described to be involved as active factors, or inducing processes, in the organization of sleep (Neuropharmacology, 19, 163 (1980)).

The piperidine derivative ketanserine, which is a 5HT 2 -antagonist with weak a,-blocking properties has been shown to be useful for treatment of various cardiovascular disorders.

Other similar piperidine derivatives are described in German Patent 1930818, EP 368388, EP 377528, EP 184258 and EP 402644.

This invention relates to piperidine derivatives, methods for making them and pharmaceutical compositions containing them.

The compounds of this invention demonstrate high affinity for various receptor subtypes including the 5HT 2 the NA-al-, the dopamine and

D

2 receptors or a combination of these. This invention relates to the use of said compounds 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 present invention provides piperidine derivatives of formula I: 2

NH-R

R -l-A-X (I) WO 93/10742 PC/DK92/0348 -3whe.ein A represents a straight or branched saturated hydrocarbon chain containing from 2 to 6 carbon atoms; R' is

R

3 47

N

R

R6 wherein R 3

R

4

R

5 and R 6 independently are hydrogen, halogen or C1alkyl; B is or -NH-; X is or -NH- Y is =S or wherein Z is hydrogen, C,.,-alkyl or -CN;

R

2 is selected from the group consisting of

R

7

R

D or wherein R 7

R

9 and R'O independently are hydrogen, C alkyi, halogen, WO 93/10742 PCT/DK92/00348 -4- C,--alkoxy or perhalomethyl; represents a 5- or 6-membered heterocycle containing one or more N-, O- or S-atoms, or a pharmaceutically acceptable salt thereof.

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, hydrobrcmides, sulphates, nitrates, oxalates, phosphates, tartrates, citrates, fumarates, maleates, succinates, and sulphonates e.g. mesylates. If desirable, selected salts may be subjected 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.

Specific compounds within the scope of the present invention include the following, or pharmaceutically acceptable salts thereof: 4-(6-Fluorr 'i ,2-benzisoxazol-3-yl)-1-[3-(6-indazolylcarbamoyloxy)propyl]piperidine, 4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-[3-(5-indazolylcarbamoyloxy)propyl]piperidine, 4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 piperidine, 4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -[2-(6-indazolylcarbamoyloxy)ethyl] piperidine, 4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -methylindazolyl)carbamoyloxy)ethyl]piperidine, WO 93/10742 WO 9310742PCT/DK9i2/00348 4-(6-Fluoro-1 ,2-benzisoxazol-3-y)-1 (1 -m ethyl in dazolyl) carbamoyloxy) ethyl] pi peri dine, 4- Flu oro- 1,2-benzisoxazol-3-y) -1 (6-indoiylcarbam oyl oxy) propy[] piperidine, 4-(6'-Fluoro-1 ,2-benzisoxazol-3-y)-1 (6-indolylcarbamoyloxy) ethyl] piperidine, 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-.1 piperidine, 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -[2-(5-indolylcarbamoyloxy) ethyl) piperidine, 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -methylindolyl)carbamoyloxy)ethyl] piperidine, 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -methylindolyl) carbamoyloxy) propyljpiperidine, 4-(6-Fluoro-1 ,2_benzisoxazol-3-yl)-1 (1 -methylindolyl) carbamoyloxy) propyl] piperidine, 4-(6-Fluoro- 1,2-benzisoxazol-3-yl)-1 -methylindolyl) carbamoyloxy)ethyl] piperidine, 1- [3-(6-Benzoxazolylcarbamoyloxy) propyl]-4- (6-fluoro-1 ,2-benzisoxazol-3-yl)piperidine, 1 (6-Benzoxazolylcarbamoyloxy) ethyl) (6-fluoro- 1,2-benzisoxazol-3yl)piperidine, WO 93/10742 WO 9310742PCT/DK92/00348 -6- 1- (5-Benzoxazolylcarbamoyloxy) propyl] (6-fluoro- 1 ,2-benzisoxazol-3yl) piperidine, 1- [2-(5-Benzoxazolylcarbamoyloxy) ethyl] (6-fluoro- 1 ,2-benzisoxazol-3yl)piperidine, 1 t2-(6-Benzothiazolylcarbamoyloxy) ethyl] (6-fluoro- 1 ,2-benzisaxazol-3yl)piperidine, 1- [2-(6-Benzothiazolylthic,-arbamoyloxy) ethyl] (6-fluoro- 1,2-benzisoxazol-3yl) piperidine, 1- (6-Berizothiazolylthiocarbamoyloxy) propyl] (6-fluoro- 1,2-benzisoxazol- 3-yl) piperidine, 4.(6-Fluoro-1 ,2-benzisoxazol-3-y)-1 (2-methyibenzothiazolyl) carbamoyloxy)propyl] piperidine, 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl) -1 -[2-(6-(2-methylbenzothiazolyl)carbamoyloxy) ethyl] piperidine, 1 -[3-(5-Benzothiazolylcarbamoyloxy) propyl]-4-(6-fluoro-1 ,2-benzisoxazol-3yI)piperidine, 1- (5-Benzothiazolylcarbamoyloxy) ethyl] (6-f luoro-1 ,2-benzisoxazol-3yl)piperidine, 1 -[3-(5-Benzothiazolylthiocarbamoyloxy) prop, i] 4. (6-f luoro-1 ,2-benzisoxazol- 3-yl) pipe rid ine, 1- (2-(5-Benzothiazolylthiocarbamoyloxy) ethyl)-4- (6-fluoro- 1,2-benzisoxazol-3yl) piperidine, WO 93/10742 WO 9310742PCr/DK92 /00348 -7- 4-(6-Fluoro-1 ,2-bP.-I-isoxazol-3-yl)-1 (3,4,5-trimethox'yphenylcarbamoyoxy) ethyl) pipe,, idiine, 4-(6-Fluoro-1 ,2-benzisoxazol-3-y)-1 -[2-(3,4,5-trimethoxyphenylthiocarbamoyloxy) ethyl] piperidine, 4-(6-Fluoro-1 ,2-benzisoxazol-3-y)-1 [3-(3,4,5-trimethoxyphenylthiocarbamoyloxy) propyl] piperidine, 1 (3,4-Dimethoxyphenylcarbamoyloxy) propyl] ilu oro-1 ,2-berizisoxazol-3-yl)piperidine, 1- (3,4-Dimethoxyphenylcarbamoyloxy) ethyl) (6-f luoro-1 ,2-benzisoxazol- 3-yl) pipe rid ine, 1 (3,4-Dimethoxyphenylthocarbamoyloxy) ethyl) -4 (6-fluoro-1 ,2-benzisoxazol-3-yl)piperidine, 1- [3-(3,4-Dimethoxyphenylthiocarbamoyloxy) propyl]-4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidine, 1 (3-Chloro-'4-methoxyphenylcarbamoyloxy) ethyl) (6-f luoro- 1,2-benzisoxazol-3-yl) piperidine, 1 (3-Chloro-4-methoxyphenylthocarbamoyloxy) ethyl) (6-f luoro-1 ,2benzisoxazol-3-yl) piperidine, 1 -[3-(3-Chloro-4-methoxyphenylthiocarbamoyloxy) propyl)-4-(6-fluoro-1 ,2benzisoxazol-3-yl)piperidine.

The invention also relates to methods of preparing the above mentioned compounds. These methods include reacting a compound of formula 11 WO 93/10742 PCI*/DK92/0348 -8-

Y=C=N-R

2

(II)

wherein Y and R 2 have the meanings set forth above, with a compound of formula III R N-A-XH (Ill) wherein A, X and R' 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-trimethoxyaniline 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 -NH- and Y is =NZ wherein Z has the meanings set forth above 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), The procedure includes reacting a compound of formula IV R--A-NH (IV) WO 93/10742 PCT/DK92/00348 -9wherein A and R 1 have the meanings set forth above, with a compound of formula V

N

II

H

3

CS-C-NH-R

2 wherein R 2 and Z have the meanings set forth above, or reacting a compound of formula VI prepared by standard procedures, from a compound of formula VII 2

NH-R

R

N-A-NH

(VII)

wherein A, R' and R 2 have the meanings set forth above and W is O or S, with NH 2 wherein Z has the meaning set forth above, to form a compound of formula I, or reacting a compound of formula III, wherein X is -NH- and A and R' have WO 93/10742 PCY/DK92/00348 the meanings set forth above, with a compound of formula VIII

CN

(VIII)

0 NH-R prepared by the method described in R. Lee Webb and C.S. Labaw, J.

Heterocyclic Chem. 19, 1205 (1982) from R 2

-NH

2 and N-cyanodiphenoxyimidocarbonate.

Compounds of formula ill, wherein A and X have the meanings set forth above, have been prepared by alkylating the known piperidine IX (J.T.Strupczewski et al., J.Med.Chem., 28, 761-769 (1985)) R NMH

(IX)

wherein R' has the meaning set forth above, using standard procedures.

The compounds of the present invention were tested for binding to various CNS receptor subtypes as well as for analgesic activity in vitro in mice.

Detailed conditions for the in vitro and in vivo assays are described below: IN-VITRO inhibition of DOPAMINE D2 receptor binding.

Method description Principle: WO 93/10742 PCI/DK92/00348 -11 Radioactive-labelled ligand "H-Spiroperidol is incubated with isolated cellmembrane fragments at 370C 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 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 kinematica is rinsed with milli-Q-H 2 0 before and after use. Male Wistar rats, 150-200 g are decapitated, striatum is removed quickly and weighed (approx. 50 mg). Striatum is transferred to a centrifuging vial containing 10 ml ice-cold D2 buffer. Homogenization 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. Centrifugation at 18,000 rpm for 10 min. at 40C. 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 monogeneous (uniform) before use. If not, brief homogenization is performed.

Assay: 2,500 pl tissue (homogeneous) .It 3 H-Spiroperidol (0.05 nM) gl test substance/HO0/blind (Domperidone 0.2 iM) Incubation for 20 min. at 370C 10 min. on ice bath.

ml ice-cold 0.9% NaCI is added to the tubes and filtered through GF/B WO 93/10742 PCr/DK92/00348 -12filters (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 ;d are rinsed thoroughly in H 2 0 after use to avoid contamination. Further, the analytical site is cleaned carefully every day after use.

Test substances: Dissolved in H 2 0, EtOH, MeOH or DMSO and further diluted in H0O. 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. Testsubstance 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 value is given as ICs indicating the concentration inhibiting specific binding by IN-VITRO inhibition of gl-receptor binding.

Method description Principle: Radioactive-labelled ligand 3 H-Prazosin is incubated with isolated cellmembrane fragments at 25°C for a given period of time. Following completed incubation, the incubate is filtered through GF/B filters, which are rinsed WO 93/10742 PCT/DM9/0348 13following filtration to remove unspecifically adhered radioactivity. As opposed to low-molecular compounds, membrane fragments .re 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 kinematica is rinsed with milli-Q-H 2 0 before and after use. Male Wistar rats, 150-200 g ae decapitated, cortex is removed quickly and weighed (approx. 500 mg). Cortex is transferred to a 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 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 pellet 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 .0C.

Assay: 2,000 Al tissue l 3H-Prazosin (0.5 nM) Ml test substance/H 2 0/blind Phentolamine (10 MM) Incubation for 30 min. at ml of ice-cold 0.9% NaCI is added to the tubes and filtered 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). Counting is performed at window 0-19 of the beta-counter (Pachard). Note that receptor box and cover are rinsed thoroughly in H0O after use to avoid contamination. Further, the analytical site is cleaned WO 93/10742 PCr/ DDK92/00348 -14carefully every day after use.

Test substances: Dissolved in H 2 0, EtOH, MeOH or DMSO and further diluted in H 2 0. The binding will stand concentrations of up to approx. 5% of these solvents without affecting the binding. Most stock solutions are stable at Attention is, however, paid to any precipitation, change in colour etc. Testsubstance 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 value is given as IC.o indicating the concentration inhibiting specific binding by IN-VITRO inhibition of DOPAMINE D1 receptor binding, Method description Principle: Radioactive-labelled ligand 3 H-SCH 23390 is incubated with isolated cellmembrane fragments in incubation buffer at 300C 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 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.

WO 93/10742 PCT/DK92/00348 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 ,l buffer I. The homogenate is centrifuged at 18,000 rpm for 20 miri. 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 p 1 incubation buffer 100 pl 3 H-SCH 23390 (0.2 nM) 100 gl tissue 200 p 1 test substance/H 2 0/blind (cis-flupentixol 2 M) Incubation for 60 min. at 300C.

ml of ice-cold 0.9% NaCI 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 lume cupboard, use gloves) and counting is performed at window 0-19 of the beta-counter (Pachard). Note that receptor box and lid are rinsed thoroughly in H 2 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 diluted in H 2 0. The WO 93/10742 PC/DK92/00348 16- 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 infrequently more than 2 mg (for economy reasons), dependent, however, on conc./assay.

Results: The test value is given as IC50 indicating the concentration inhibiting specific binding by IN VITRO inhibition of 5HT1-receptor binding Method description Principle: Radioactive-labelled ligand H-Ketanserine is incubated with isolated cell membrane fragments at 370C 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 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 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.

WO 93/10742 PCT/DK92/00348 -17 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 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 0 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. min. at 0 0

C.

Assay: 1250 tl tissue .i 3 H-Ketanserine (0.4 nM) pl test substance/H 2 0/blind cyproheptadine (2 pM) Incubation for 15 min. at 37 0

C.

ml ice-cold 0.9% NaCI 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 H 2 0 after use to avoid contamination. Further, the analytical site is cleaned carefully every day.

Test substances: Dissolved in H 2 0, EtOH, MeOH or DMSO and further diluted in H 2 0. The 2 binding will stand concentrations of up to approx. 5% of these solvents without affecting the binding. Most stock solutions are stable at 4 0

C.

Attention should, however, be paid to any precipitation, change in colour etc. Test-substance dilutions are always made fresh every day. When WYO 93/1 0742 PCT/DK92/00348 -18weighing 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 value is given as ICso i.e. the concentration inhibiting specific binding by Antagonism of acetic acid-induced writhings in micei Principle: In mice i.p. injection of acetic acid induces a writhing syndrome which is antagonized by analgesics (Siegmund 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 (controls) and to 6 mice pretreated with test substance. In the controls acetic acid induces a syndrome characterized 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 injection of acetic acid.

Results: Initially, the dose of test substance is equivalent to 5-10 per cent of LDs 0 If this dose decreases writhings, 3-5 dose levels are tested. The activity is WO 93/10742 PC/DK92/00348 19 expressed as per cent protection: 100 average writhings of treated group x 100 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 (EDso in mg/kg) giving 50 per cent protection 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 active anti-writhing substances without analgesic effect.

References: Eckhardt, E. et al.

Ethiology of chemically induced writhing in mouse and rat. Proc. Soc. exp.

Biol. 98, 186-188, 1958.

Siegmund, E. et al.

A method for evaluating both non-narcotic and narcotic analgesics. Proc.

Soc. exp. Biol. 95, 729-731, 1957.

The compounds of this invention typically binds to NA-a,, 5HT 2

DA-D,-,

and DA-D 2 -receptcrs, with ICo0 values in the order of 0.1 nM to 1 AM.

Furthermore the compounds are able to antagonize the acetic acid induced writhing in mice with EDso-values typically in the order of 0.1 mg/kg to 100 mg/kg.

WO 93/10742 PCT/DK92/00348 The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, and if desired 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 filled capsules, or liquids, such as solutions, suspensions, 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 additional 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 milligram of active ingredient or, more broadly, one 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 diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.

WO 93/10742 PCT/DK92/00348 -21 The pharmaceutical preparations can be sterilized and mixod, 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 org' 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 dispensed 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 67.8 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.

WO 93/10742 PCT/DK92/00348 -22- EXAMPLE 1 4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -[3-(3,4,5-trimethoxyphenylcarbamoyloxy)propyl]piperidine, oxalate A. 4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidine, hydrochloride (5.0 g, mmol), 3-bromopropanol (2.0 ml, 21.6 mmol) and potassium carbonate g, 47 mmol) in 300 ml dry acetone were refluxed for 16 h. The mixture was cooled to room temperature, filtered and concentrated in vacuo. The resulting compound was recrystallized from ethanol/water to give 4.3 g of the desired compound. M.p. 139-1410C.

B. A mixture of 3,4,5-trimethoxyaniline (365 mg; 2.0 mmol) in toluene (20 ml) and phosgene (6 mi 20% in toluene; 12 mmol) was refluxed for 6 h.

The solvent was removed under reduced pressure to give crude 3,4,5trimethoxyphenylisocyanate. To the crude product was added 3(4-(6-fluoro- 1,2-benzisoxazol-3-yl)-piperidino)propanol (420 mg; 1.5 mmol) in DMF 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 ethyl acetate and water. The organic phase was -rashed 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 2 ml acetone added to precipitate the desired product. The product was washed with ice cold ethanol giving 550 mg of the title compound. M.p. 77-8000. MS (70 eV): m/z 487 287 233 209 194 140 96 (100).

EXAMPLE 2 4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -[3-(3,4-ethylenedioxyphenylcarbamoyloxy)propyl]piperidine, oxalate A mixture of 1,4-benzodioxan-6-amine (300 mg; 2,0 mmol) in toluene WO 93/10742 PCT/DK92/00348 -23ml) and phosgene (10 ml 20% in toluene; 19 mmol) was refluxed for 6 h.

The solvent was removed under reduced pressure to give crude 3,4ethylenedioxyphenylisocyanate. To the crude product was added fluoro-1,2-benzisoxazol-3-yl)piperidino]propanol (420 mg; 1.5 mmol) in DMF (10 ml). The mixture was stirred at 10000 for 2 h and then at room temperature for 16 h, whereupon it was taken up in ethyl acetate 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 v/v) and oxalic acid (150 mg) in 2 ml acetone added to precipitate the desired product. The product was washed with ice cold ethanol to give 600 mg of the title compound. M.p. 109-110°C. MS (70 eV): m/z 455 278 233 177 140 121 96 (100).

EXAMPLE 3 1-[3-(6-Benzothiazolylcarbamoyloxy)propyl]-4-(6-fluoro-1,2-benzisoxazol-3yl)piperidine, oxalate A mixture of 6-amlnobenzothiazole (300 mg; 2 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 6-benzothiazolylisocyanate. Using the procedure of example 1 the crude 6-benzothiazolylisocyanate was combined with 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidino]propanol (410 mg; 1.5 mmol) in 10 ml DMF to give the 0.7 g of the title compound. M.p. 176-1770C. MS (70 eV): m/z 454 27 233 190 176 150 140 96 (100).

EXAMPLE 4 1-[3-(3,4-Ethylenedioxyphenylthiocarbamoyloxy)propyl]-4-(6-fluoro-1,2benzisoxazol-3-yl)piperidine, oxalate WO 93/10742 PCT/DK92/00348 -24- 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 min. thiophosgene (11.5 g; 100 mmol) in toluene (50 ml). The mixture was stirred at 800C for 30 min., cooled to room temperature and filtered. The filtrate was evaporated. The product was redissolved in toluene and concentrated in vacuo. The resulting oil was taken up in warm petroleum ether, which was filtered. The filtrate was concentrated to a small volume, which afforded 7.2 g of 3,4-ethylenedioxyphenylisothiocyanate.

Starting from 3,4-ethylenedioxyphenylisothiocyanate (390 mg; 2.0 mmol) and 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]propanol (420 mg; mmol) using the procedure described in example 1 was prepared 550 mg of the title compound: M.p. 101-104°C. MS (70 eV): m/z 471 278 233 193 (100), 151 140 EXAMPLE 4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-[2-(3,4,5-trimethoxyphenylcarbamoyloxy)ethyl]piperidine, oxalate A. 4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidine, hydrochloride (2.6 g, mmol), 2-bromoethanol (1.3 ml, 15 mmol) and potassium carbonate (4.1 g, mmol) in 25 ml dry acetone were refluxed for two hours and then stirred at 60°C for 16 h, whereupon extra 0.4 ml (5 mmol) 2-bromoethanol was added. The mixture was then refluxed for 4 h, cooled to room temperature, concentrated in vacuo and taken up in water and methylene chloride. The organic phase was washed with water and saturated sodium chloride, dried over MgSO 4 and concentrated in vacuo, Purification by column chromatography (silica gel; methylene chloride:methanol:conc. ammonium hydroxide (80:20:0.5, gave 2.2 g of 2-[4(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethanol. M.p. 119-1200C.

WO 93/10742 WO 930742PT/D K92/00348 25 B. Starting from 3,4,5-trimethoxyphenylisocyanate (600 mg, 3 mmol) and 2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-piperidino] ethanol (400 mg; mmol) using the procedure described in example 1 was prepared 450 mg of the title compound. M.p, 158-1 6000. MS (70 eV): m/z 473 246 233 (100), 209 (41).

EXAMPLE 6 1 '-,Benzthiazolylthiocarbamoyloxy) propyl)-4-(6-fluoro- 1,2-benzisoxazol-3yl)piperidine, oxalate Using the procedure described in example 4 starting from 3-[4-(6-fluoro.1 ,2benzisoxazol-3-yl)piperidino~propano (280 mg, 1.0 mmol) and 6-benzothiazolylisothocyanate (210 mg, 1.2 mmol), prepared from 6-aminobenzothiazole and thiophosgene, was prepared 280 mg of the title compound. M.p.

108-1120C, MS (70 eV): m/z 470 278, 233 192 (62), 150 140 98 (100).

EXAMPLE 7 4-(6-Fluoro-1 ,2-benzisoxazol-3-y)-1 (3,4-methylenedioxyphenylcarbamoyloxy) pro pyl) pipe rid ine, oxalate Using the procedure described in example 1 starting from 3.[4-(6.fluoro-1 ,2benzisoxazol-3-yl) pipe ridi no] pro panol (140 mg, 0.5 mmol) and 3,4-methylene dioxyphenylisocyan ate (240 mg, 1.5 mmol), prepared from 3,4-methylenedioxyaniline and phosgene, was prepared 210 mg of the title cornpound. M.p. 133.13600. MS (70 eV): m/z 441 303 278 (16), 233 163 140 96 (100).

WO 93/10742 PTD9/04 PCr/DK92/00348 26 EXAMPLE 8 1 Benzothiazolylcarbari ioyloxy) ethyl) (6-fl uo ro-1, ,2-benzisoxazol-3yI)piperidine, oxalate Using the procedure of example 3 crude 6-benzothiazolylisocyanate, prepared from 6-aminobenzothiazole (500 mg, 3.4 mmol), was combined with 2- (6-fluaro- 1,2-benzisoxazol-3-yl) piperid ino) ethanol (450 mg, 1.7 mmol) in 10 ml dry DMF to give 100 mg of the title compound. M.p. 130-1340C. MS eV): m/z 440 (1 264 233 150 (100).

EXAMPLE 9 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -[2-(3,4-methylenedioxyphenylcarbamoyloxy) ethyl) pi perid ine, hydrochloride Starting from 3,4-methylenedioxyphenylisocyanate (320 mg, 2 mmol) and 2luoro-1 ,2-benzisoxazol-3-yl) piperidino) ethanol (270 mg, 1 mmol) in ml dry DMF using the procedure described in example 1 was prepared 210 mg of the title compound as free base. This product was dissolved in 5 ml ethanol/acetone v/v) and ethanolic hydrochloric acid added to precipitate 180 mg of -the desired product as white crystals. M.p. 226-229 0

C.

MS (70 eV): m/z 428 246 233 (100), 208 190 163 EXAMPLE Flu oro- 1,2-benzisoxazol-3-yl) -1 (phe nylcarbamoyloxy) pro pyl) pipe ridine, hydrochloride Phenylisocyanate (0.36 g, 3 mmol) and 3-[4-(6-fluoro-1 ,2-benzisoxazol-3yl)piperidino~propanol (0.3 g, 1.1 mmol) was refluxed in toluene (25 ml) for WO, 93/10742 PC/DK92/00348 -27- 6 h. The mixture was cooled to room temperature and hydrochloric acid in ether was added. The resulting precipitate was recrystallized from ethanol/ether and isopropanol/ether to give 180 mg of the title compound as white crystals. M.p. 204.5-205.5°C. MS (70 eV): m/z 397 278 259 233 178 96 (100).

EXAMPLE 11 N-Cyano-N'-(3,4-methylenedioxyphenyl)-N"-3-((6-fluoro-1,2-benzisoxazol-3yl)piperidino)propyl)guanidine, oxalate A mixture of N-cyanodiphenoxyimidocarbonate (1.2 g, 5 mmol), 3,4-methylenedioxyaniline (0.7 g, 5 mmol) and 2-propanol (25 ml) was stirred at room temperature for 16 h. The formed precipitate was taken up in methylene chloride, treated with activated carbon. Evaporation of the solute and trituration with ether gave 1.2 g of N-cyano-N'-3,4-methylenedioxyphenyl-Ophenylisourea. M.p. 172-174oC.

1-(3-Aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (420 mg, 1.1 mmol), N-cyano-N'-3,4-methylenedioxyphenyl-O-phenylisourea (320 mg, 1.2 mmol), 0.4 ml triethyl amine and 25 ml 2-propanol were stirred at room temperature for 4 days. The mixture was concentrated in vacuo and then taken up in water and methylene chloride. The organic phase was washed with water and saturated sodium chloride, dried over magnesium sulphate and concentrated in vacuo. The product was purified by column chromatography (silica gel: ethyl acetate:methanol and then taken up in 2 ml dry acetone. Oxalic acid (50 mg) in 1 ml acetone was added precipitating 90 mg of the desired product as white crystals. M.p. 112-115°C. MS (70 eV): m/z 464 (M 422 233 220 137 (100).

WO 93/10742 PCT/DK92/00348 -28- EXAMPLE 12 1-[3-(3,4-Methylenedioxyphenylcarbamoyloxy)propyi]-4-(6-fluoro-1 H-indazol- 3-yl)piperidine A. To a mixture of 6-fluoro-3-(4-piperidinyl)-1 H-indazole (438 mg, 2 mmol) and dry potassium carbonate (1.1 g, 6 mmol) in 30 mi methyl isobutyl ketone was added 3-bromo-l-propanol (276 mg, 2 mmol). The mixture was refluxed for 48 h, cooled, filtered and concentrated in vacuo.

The crude product was purified by chromatography on silica gel 60 eluting with ethyl acetate:methanol viv). Concentration of the appropriate fractions afforded 300 mg of 3-[1-(1-hydroxyprop-3-yl)-4-piperidinyl]- 6-fluoro-1H-indazole as an oil.

'H-NMR (DMSO-d 6 1.62 2H), 1.7-2.1 8H), 2.39 2H), 2.95 (br., 3H), 3.48 2H), 6.90 (dt, 1H), 7.21 (dd, 1H), 7.78 1H), 12.70 1H).

B. A solution of 3-[1-(1-hydroxyprop-3-yl)-4-piperidinyl)-6-fluoro-1Hindazole (230 mg, 0.83 mmol) in 5 ml dry DMF was added 3,4-methylenedioxyphenylisocyanate (291 mg, 1.65 mmol) in 3 ml dry DMF. The reaction was heated to 100°C for 2 h and 16 h at 800C. The reaction was cooled to room temperature and added a mixture of 50 ml water and 200 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 eluting with ethyl acetate:methanol Concentration of the appropriate fractions afforded 50 mg of the title compound as an amorphous solid.

'H-NMR (DMSO-d 6 1.71-1.92 6H), 2.1 2H), 2.42 2H), 2.98 (br.d, 3H), 4.11 2H), 5.95 2H), 6.82 2H), 6.91 1H), 7.14 1H), 7.21 (dd, 1H), 7.80 (dt, 1H), 9.5 1H), 12.68 1H).

WO 93/10742 WO 9310742PCT/DK92/00348 29 Analysis: C 2

,H

25

N

4 0 4 F, 0.75 H 2 0: Calculated: C 60.85; H 5.88; N 12.34% Found: C 60.69; H 5.76; N 12.31 MS (70 eV): m/z 440 277 232 (100), 218 189 163 70 (16).

EXAMPLE 13 1 -[2-(3,4-Methylenedioxyphenylcarbamoyloxy)propyl] \(6-fluoro-1 H-indazol- 3-yI) piperidine A. A mixture of 6-fluo ro-3-(4-piperidinyl)-1 H-indazole (500 mg, 2.3 mmol) and propylene oxide (1 g, 17 mnmol) in 25 ml, toluene was heated to 5000 in an autoclave for 7 days. The cooled reaction was concentrated in vacuo and purified by chromatography or silica gel 60 eluting with ethyl acetate: meths,'iol Concentration of the appropriate fractions afforded 350 mg of 3- [1-(2-hydroxyprop- 1-yl)-4-piperidinyl) -6-f luoro- 1 H-indazde as a foam.

'H-NMR (DMSO-d., 1.04 3H), 1.87 (in, 4H), 2.18 (mn, 4H), 2.93 (br. d, 3H), 3.78 (mi, 1 4.25 1 6.91 (dt, 1 7.20 (dd, 1 7.78 1 H), 12.58 1 H).

B, Starting from 3-[1 -(2-hydroxyprop- 1 -yl)-4-piperidinyl)-6-fluoro-1 Hindazole (300 mng, 1 .1 minol) and 3,4-inethylenedioxyphenylisocyanate (380 mg, 2.2 minol) using the procedure described in example 12A was prepared 40 mng of the title compound as an amorphous solid.

'H-NMR (DMSO-d6, 1.21 3H), 1.85 (in, 4H), 2.20 (in, 2H), 2.4 (in, 1H), 2.55 (in, I1H), 3.0 (in, 2H), 3:11 (in, 1 4.9 (in, 1 5.98 2H), 6.8 1IH), 6.89 (in,2H), 7.14 7.19 (dd, 1H), 7.73 (dt, 1H), 9.51 1H), 12.68 (s, WO 93/10742 PCJT/DK92/00348 1 H).

MS (70 eV): m/z 441 (M 440 (M 259 232 (100), 218 189 163 137 EXAMPLE 14 1-[6-(3,4-Methylenedioxyphenylcarbamoyloxy)hexyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine A. A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (1 g, 3.9 mmol), lithium carbonate (865 mg, 1.7 mmol) and 6chloro-1-hexanol (534 mg, 3.9 mmol) in 5 ml dry DMF was heated at 100°C for 48 h. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water, brine, dried with sodium sulphate and concentrated in vacuo. The crude product was purified by chromatography on silica gel 60 eluting with ethyl acetate:methanol Concentration of the appropriate fractions afforded 310 mg of 3-[1-(1-hydroxyhex-6-yl)-4-piperidinyl]-6-fluoro- 1,2-benziscxazole as an oil, 'H-NMR (CDCI3, 1.39 4H), 1.58 4H), 2.10 6H), 2.41 2H), 3.09 (br.d, 3H), 3.65 2H), 7.04 (dt, 1H), 7.23 (dd, 1H), 7.75 1H).

MS (70 eV): m/z 320 (M 233 190 182 96 (100), 82 (100), 82 55 (23).

B. Starting from 3-[1-(1-hydroxyhex-6-yl]-4-piperidinyl]-6-fluoro-1,2benzisoxazole (270 mg, 0.84 mmol) and 3,4-methylenedioxyphenylisocyanate (297 mg, 1.69 mmol) using the procedure described in example 12B was prepared 210 mg of the title compound as an amorphous solid.

WO 93/10742 WO 9310742PCT/DK92/00348 31 'H-NMR (CDC13, 1.4 (in, 4H), 1.6 (in, 4H), 2.11 6H), 2.42 2H), 3.09 (br.d, 3H), 4.15 2H), 5.95 2H), 6.70 (in, 2H), 7.05 (in, 2H), 7.24 (in, 2H), 7.72 1 H).

MS (70 eV): mlz 483 320 233 182 163 (100), 130 96 77 EXAMPLE 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -(3-(2-bromo-4,5-methylenedioxyphenylcarbamoyloxy) propyl)piperidine, hydrochloride 4- Flu oro- 1 ,2-benzisoxazol-3-yl) -1 -(3-(3,4-methylenedioxyphenylcarbamoyloxy)propyl)piperidine (example 7) (220 mg, 0.5 mmol) vyas dissolved in 2 ml glacial acetic acid and the mixture stirred at room temperature under N 2 Br 2 (0.25 jpd, 0.5 inmol) dissolved in 1.0 ml glacial acetic acid was added.

The mixture was stirred for 2 h whereupon aqueous K 2 00 3 was added to neutralize the solution, which was then extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and concentrated in vacuo. The product was taken up in ecotone and HCI in ether added to crystallize the desired product as 40 mg white crystals. M.p. 21 5-21 800. MS eV): m/z 521 519 278 243 241 (34), 233 96 (100).

EXAMPLE 16 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)- 1 (3,4-methylenedioxyphenylthiocarbainoyloxy)propyl)piperidine, hydrochloride 3,4-Methylenedioxypherylisothiocyanate (360 mg, 2 inmol) and fluoro-1, ,2-be nzis oxazol-3-yI) pipe ridino) propanol (4.20 mg, 1.5 inmol) in 5 ml dry DMF were stirred~ at 10000 for 2 h and then at 6000 for 16 h. The WOT 93/ 107422 PC1'/DK92/00348 32mixture was cooled to room temperature and taken up between water and ether. The organic phase was washed with water and saturated sodium chloride, dried over magnesium sulphate and concentrated in vacuo.

Purification of the product by column chromatography (silicagel; ethyl acetate:methanol gave an oil, which was taken up in dry acetone.

HCI in ether was added to crystallize the desired product as 550 mg white crystals. M.p. 181-185°C. MS (70 eV): m/z 457 278 233 (56), 179 (100).

EXAMPLE 17 4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-(3-(2-methoxyphenyl carbamoyloxy)propyl)piperidine, hydrochloride 2-Methoxyphenylisocyanate (270 mg, 2 mmol) and 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]propanol (280 mg, 1 mmol) was dissolved in 100 ml dry toluene and refluxed for 16 h. 50 ml ethyl acetate was added to the cooled mixture, which was then washed with water and saturated sodium chloride. 2.5 ml (1.9 M) HCI in ethanol was added and the solution was concentrated to about 30 ml crystallizing 310 mg of the desired product.

Mp. 174-175 0 C. MS (70 eV): m/z 427 289 233 96 (100).

EXAMPLE 18 4-(6-Fluoro- ,2-benzisoxazol-3-yl)-1 -(3-(3-chloro-4-methoxypheny'l carbamoyloxy)propyl) hydrochloride Starting from 3-chloro-4-methoxyphenylisocyanate, prepared from 3-chloro- 4-methoxyaniline (470 mg, 3 mmol) and phosgene (7.5 mmol) as described in example 1, and 3-[4-(b-fluoro-1,2-benzisoxazol-3-yl)piperidino]propanol (560 mg, 2 mmol) using the procedure of example 1, was prepared 500 mg 11"^^r C WO 93/10742 PCT/DK92/00348 33mg of the desired product. M.p. 212-2150C, EXAMPLE 19 1- [2-(3,4-Methylenedioxyphenylcarbamoylox,) propyl] -4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidine, oxalate A. A mixture of 6-fluoro-3-(4-piperdinyl)-1 ,2-benzisoxazol (1.5 g, 6.8 mmol) and propylene oxide (2 g, 34.4 mmol) in 25 ml acetonitrile was heated to 5000 in an autoclave for 3 days. The cooled reaction was concentrated in vacuo and purified by chromatography on silica gel 60 eluting with ethyl acetate: methanol Concentration of the appropriate fraction afforded 1.3 g of 3-[1-(2-hydroxyprop-1-yl)-4-piperidinyl]-6fluoro-1,2-benzisoxazole. M.p. 45.4700. MS (70 eV): mlz 278 233 (100), 190 109 96 82 68 55 (22).

B. Starting from 3-ti -(2-hydroxyprop.1 -yl)-4-piperidinyl]-6-fluoro-l ,2benzisoxazole (500 mg, 1.1 mmol) and 3,4-methylenedioxyphenylisocyanate (500 mg, 2.2 mmol) using the procedure described in example 12B was prepared 100 mg of the title Compound. M,p. 163-16400. MS (70 eV): m/z 441 11 260 233 (100), 190 163 136 96 (56).

Analysis: C 2 5

H

2

,,N

3 F0 9 0.5 H 2 0 Calculated: C 55.55; H 5.03; N 7,77% Found: C 55,74;, H 4.91; N 7.39%

Claims (1)

1. 34- CLAIMS 1_ A compound of formula I 2 NH-R R -A-X wherein A represents a straight or branched saturated hydrocarbon chain containing from 2 to 6 carbon atoms; R 1 is wherein R 3 R 4 R 5 and R 6 independently are hydrogen, halogen or C 16 alkyl; B is or -NH-; X is or -NH- Y is =S or =NZ wherein Z is hydrogen, C, 4 -alkyl or -CN; WO 93/10742 WO 90742Prl D K92/00348 35 R 2 is selected from the group consisting of 8 or R9N R wherein R 7 R8, R 9 and R 1 0 independently are hydrogen, C 1 6 -alkyl, halogen, C 14 alkoxy or perhalomethyl; represents a 5- or 6-membered heterocycle containing one or more N-, 0- or S-atoms, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1 which is 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -[3-(3,4,5-trimethioxyphenylcarbamo- yloxy)propylj piperidine; 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -t3.(3,4-ethylenedioxyphenylcarbamo- yloxy) propyl] piperidine; 1 (6-Be nzothiazolylcarbamoyloxy) pro pyl (6-f luoro-1, ,2-benzlsoxazol-3- yI)piperidine; 1- [3-(3,4-Ethylenedioxyphenylthiocarbamoyloxy) propyl) -4-(6-fluoro-1 ,2- benzisoxazol-3-yl) piperidine; 4- Flu oro- 1,2-be nzisoxazol -3-yl) -1 -[2-(3,4,5-trimethoxyphenylcarbamoyl- oxy) ethyl] piperidine; 1 -(3-(6-Benzthiazolylthiocarbamoyloxy)propyl)-4-(6-fluoro-1 ,2-benzisoxazol-3- WO 93/10742 WO 9310742PCT/DK92/00348 36 yl) piperidine; 4-(6-Fluoro-1 ,2-benzisoxazol-3-y)-1 (3,4-m ethylene dioxyphenylcarbam oyl- oxy)propyl) piperidine; 1- (6-Benzothiazolylearbamoyloxy) ethyl) (6-fluoro- 1 ,2-benzisoxazol-3- yl)piperidine; 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl) -1 (3,4-m ethyl enedi oxyphenylcarbamoyl- oxy) ethyl) piperidine; 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-I -[3-(phenylcarbamoyloxy) propyl] piperi- dine; N-Cyano-N'-(3,4-methylenedioxyphenyl)-N"-3-((G-fluoro-i ,2-benzisoxazol-3- yl) piper!idino) propyl) guanidne; 1 -[3-(3,4-Methylenedioxyphenylcarbamoyloxy)propyl)-4-(6fluoro-1 H-Indazol- 3-yl)piperidine;, 1- [2-(3,4-Methylenedioxyphenylcarbamoyloxy) propyl) (6-f luoro-1 H-Indlazol- 3-yI) pipe ridine; 1 -[6-(3,4-Methylenedioxyphenylcarbamoyloxy)hexylJ -4-(6-fluoro-1 ,2-benz- isoxazol-3-yl)piperidine; 4-(6-(Fluoro-1 ,2-benzisoxazol-3-y)-1 (2-bromo-4,5-methylenedioxyphenyl- carbamoyloxy) propyl) piperidine; 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -(3-(3,4-methylenedioxyphenylthiocarba- moyloxy) propyl) piperldine;, 37 4-(6-Fluoro- 1,2-benzisoxazol-3-yD)-b(3-(2-niethioxyphenylcarbamioyloxy)propy1)- piperidine, 4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)- 1-(3-(3-chloro-4-methoxyphenylcarbamoyloxy)- propyl)piperidine 6 ,4-Methylenedioxyphenylcarbamoyloxy)propylj-4-(6-fluoro- 1,2-benz- isozazol-3-yl)piperidine; or a pharmaceutically acceptable salt thereof 3. A method of preparing a compound according to claim 1, which comprises a) reacting a compound of formula 11 Y=C=N-R 2 wherein Y and R 2 have the meanings as defined in claim 1, with a compound of formula III R N-A-XH(Il to 15 wherein A, X and R 1 have the meanings as defined in claim 1, or reacting a compound of formula IV 0a 0 so 0 0 000o0 I NAt.11)1-T'j(XW 1: mell WO 93/10742 PCT/DK92/00348 38 (IV) R N-A-NH, wherein A and R' have the meanings set forth above, with a compound of formula V Z N II H 3 CS-C-NH-R 2 (V) wherein R 2 and Z have the meanings set forth above, or c) reacting a compound of formula VI R N -A-N-C-NR (VI) prepared from a compound of formula VII 2 NH-R R N -VA-NH) wherein A, R' and R 2 have the meanings set forth above and W is O or S, 39 with NH 2 wherein Z has the meaning as defined in claim 1, to form a compound of formula I, or d) reacting a compound of formula III, wherein X is -NH- and A and R 1 have the meanings as defined in claim 1, with a compound of formula VIII CN, NI-I c N 0 NH-R 2 (Vlll) wherein R 2 has the meaning as defined in claim 1 to form a compound of formula I wherein X is -NH. 4. A pharmaceutical composition comprising as active component a compound o1 according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition according to claim 4 in the form of an oral dosage unit containing about 10-200 mg of the active compound. 6. A method of treating psychosis in a slubject in need thereof, comprising 15 administering an effective amount of a compound acccrding to claim 1. S7. A method of treating psychosis in a subject in need thereof, comprising administering a pharmaceutical composition according to claim 4 or 8. The compound prepared by the method of claim 3. 9. A method of preparing a pharmaceutical composition for treating psychosis, comprising mixing the compound of claim 8 with a pharmaceutical acceptable diluent carrier and/or adjuvant. 10. An anti-psychotic piperidine derivative substantially as hereinbefore described with reference to any one of the Examples. Dated 29 July, 1996 25 Novo Nordisk A/S Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [N:ALIBI3P1003 I:ANI INTERNATIONAL SEARCH REPORT A. CLASSIFICATION OF SUBJECT MATTER Internationln application No, PCT/DK 92/00348 IPC5: C07D 413/04, C07D 413/14, C07D 405/14 A61K 31/445 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) C07D, A61K Documentation searched other thali minimum documentation to the extent that such documents are included in the fields searched SE,DK,FI,NO classes as above Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No, A EP, A2, 0368388 (JANSSEN PHARMACEUTICA 1-6,9 16 May 1990 (16.05.90) A EP, Al, 0377528 (LIPHA, LYONNAISE INDUSTRIELLE 1-6,9 PHARMACEUTIQUE), 11 July 1990 (11.07.90) A EP, Al, 0402644 (HOECHST-ROUSSEL PHARMACEUTICALS 1-6,9 INCORPORATED), 19 December 1990 (19.12.90) A EP, Al, 0428437 (ADIR ET COMPAGNIE), 22 May 1991 1-6,9 (22.05.91) ,1- W Further documents are listed in the continuation of Box C. Z See patent family annex. Special categories of cited documents: "T later document published after the international filing date or pnonty date and not in conflict with the application but cted to understand document defining the general state of the an which is not considered the pnncipe orteory underlying the von to u n tan to be of particular relevance eriter document but published on or after the international fing date document of particular relevance: the claimed invention cannot be considered novel or cannot be considered to involve an inventive document which may throw doubts on pnonty claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other special reason (as specified) document of particular relevance: the claimed invention cannot be "O0 document referng to an tral disclosure, use, exhibition or other considered to involve an inventive Step when the document is means combined with one or more other such documents, such combination document published prior to the interntional filing date but later than being obvious to a person skilled in the art the pnonty datt claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 18 June 1993 2 -06- 1993 Name and mailing address of the ISAi Authorized officer Swedish Patent Office Box 5055, S-102 42 STOCKHOLM Gbran Karlsson Facsimile No. 46 8 666 02 86 Telephone No. +46 8 782 25 00 Form PCT/SA/210 (second sheet) (July 1992) INTERNATIONAL SEARCHI REI)OWI Iternational application No, PCT/DK 92/00348 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* I Citation or documecnt, with indication, where appropriate, or thc relevant passac ecanL to claim No, J. Med. Chem., Volume 29, 1986, Joseph P. Yevich et al, "Synthesis and Biological Evaluation of 1-(1,2-Benzisothiazol-3-yl)- and (1, 2-Benzisoxazol-3-yl)piperazine Derivatives as Potential Antipsychotic Agents", see page 359 1-6,9 Form PCTIISA,21ti (continuation of second shoot) (July 1992) I" INTERNATIONAL SEARCH REPORT I 'nllonal application No, PCT/DK 92/00348 Box I Observations where certain claims were found unsearchable (Continuation of item I of first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. [X Claims Nos.: 7-8 because they relate to subject matter not required to be searched by this Authority, namely. A method for treatment of the human or animal body by therapy, see Rule 39.1. 2. Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 Cf first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. 2. As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. D As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 4. No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest O The additional search fees were accompanied by the applicant's protest No protest ccompanied the payment of additional search fees. I~-I Form PCT/ISA/210 (continuation of first sheet (July 1992) INTERNATIONAL SEARCH REPORT Information on patent family members itrnational application No, 30/04/93 PCT/DK 92/00348 Patent document Publication Patent family Publication cited in search report I date Tmember(s) Tdate EP-A2- 0368388 16/05/90 AU-B- AU-A- CA-A- ~JP-A- US-A- 614437 4443689 2000786 2191276 5158952 29/08/91 10/05/90 07/05/90 27/07/90 27/10/92 EP-Al- 0377528 11/07/90 AU-A- CA-A- FR-AB- JP-A- US-A- EP-Al- 0402644 19/12/90 AU-A- CA-A- CN-A- JP-A- 4771390 2007127 2641278 2225465 5001134 5577090 2017193 1048037 3063263 631466 6581990 2029372 2654104 3188077 5100902 5134147 12/07/90 05/07/90 06/07/90 07/09/90 19/03/91 22/11/90 19/11/90 26/12/90 19/03/91 26/11/92 16/05/91 08/05/91 10/05/9 1 16/08/91 31/03/92 28/07/92 EP-Al- 0428437 22/05/91 AU-B- AU-A- CA-A- FR-A ,B- JP-A- US-A- US-A- Form PCT/JISA/21O (patent family annex) (July 1992)