WO1994027996A1

WO1994027996A1 - 1,2,5-thiadiazole derivatives, their preparation and use

Info

Publication number: WO1994027996A1
Application number: PCT/DK1994/000198
Authority: WO
Inventors: John Bondo Hansen; Frederik Christian GRØNVALD
Original assignee: Novo Nordisk A/S
Priority date: 1993-05-26
Filing date: 1994-05-25
Publication date: 1994-12-08
Also published as: AU6923894A; DK60493D0

Abstract

1,2,5-thiadiazole derivatives of formula (I) wherein A is a straight or branched, saturated acyclic hydrocarbon of 2-6 carbon atoms; Y is CH or N; X is O, S, NH, NCH3, or CH2; R1 is 1,2-benzisothiazol-3-yl, 1,2-benzisoxazol-3-yl, 1H-indazol-3-yl, or 1-methyl-1H-indazol-3-yl, all of which may be substituted; or R1 is 4-fluorobenzoyl or phenyl optionally substituted; R2 is optionally substituted aryl or heteroaryl; and pharmaceutically acceptable salts thereof are useful in the treatment of indications related to the CNS-system, cardiovascular system or to gastrointestinal disorders.

Description

1 ,2,5-Thiadiazole Derivatives, their Preparation and Use

The present invention relates to 1 ,2,5-thiadiazole derivatives which are useful for treating CNS-system, cardiovascular system and/or gastrointestinal disorders, methods for preparing such compounds and pharmaceutical compositions containing them.

Much evidence has accumulated to suggest that neuroleptics exert their antipsychotic action by blocking dopamine (DA) receptors in the brain. In recent years, it has become clear that some neuroleptics (e.g. clozapine) show an atypical profile: the compounds are not only beneficial in treating patients, who respond poorly to classical neuroleptic therapy, but the compounds are also relatively devoid of extrapyrimidal side effects (EPS) commonly seen with classical neuroleptics (Ereshefsky et al., Clin.Pharm 8, 691-709, 1989). In this respect it has been speculated that atypical neuro¬ leptics are working mainly by blocking socalled A10 mesolimbic DA systems (areas which are thought to be affected in psychosis), while the side effects of classical neuroleptics are produced by blockade of DA receptors in the motor areas of the brain (A9 DA system (Gudelsky, Psy- chopharmacology (Berl) 99: S13-S17, 1989)). The antipsychotic effect of clozapine and related compounds might be due to its blockade of not only DA-receptors (D-1 , D-2, D-3, D-4, D-5) but also 5HT-receptor subtypes (5HT₂-, 5HT₃-, 5HT_1C-, 5HT_1A-), NA-α receptors. histamine and possibly other receptors.

Furthermore, 5HT₂-blockade may also be important (Meltzer, Schizphr. Bull. 17: 263-87, 1991) to counteract the socalled negative symptoms of psycho¬ sis (delusions and social withdrawal) which are otherwise difficult to treat with conventional neuroleptics.

Compounds reducing 5-HT neurotransmission have been suggested to be useful for the treatment of various neurological and psychiatric diseases.

More specifically, the present invention relates to 1 ,2,5-thiadiazole deriva¬ tives of the general formula (I)

wherein

A is a straight or branched, saturated acyclic hydrocarbon of 2-6 carbon atoms;

Y is CH or N;

X is O, S, NH, NCH₃. or CH₂;

R¹ is 1 ,2-benzisothiazol-3-yl, 1 ,2-benzisoxazol-3-yl, 1 H-indazol-3-yl, or 1-methyl-1H-indazol-3-yl, all of which may be substituted independently with halogen or C,_₆-alkyl in one, two, three or all of the 4-, 5-, 6- and 7-posi- tions; or

R¹ is 4-fluorobenzoyl or phenyl optionally substituted with halogen or C,_₆- alkyl;

R² is optionally substituted any I or heteroaryl;

and pharmaceutically acceptable salts thereof. Physiologically and pharmaceutically acceptable salts of the compounds of the invention include acid addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, nitrates, oxalates, phosphates, tartrates, citrates, fumarates, maleates, succinates, and sulphonates e.g. mesylates. If desirable, selected salts may be sub¬ jected to further purification by recrystallization.

The invention includes within its scope all optical isomers of compounds of the general formula I and their mixtures including racemic mixtures thereof.

The term "C^-alkyl" as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1-6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, n-pentyl, neopentyl, n-hexyl and 2,2-dimethylpropyl.

The term "aryl" as used herein, either alone or in combination, denotes a phenyl group which optionally carries one or more substituents selected from halogen, 1 ,3-dioxolanyl and 1 ,4-dioxanyl, such as 2,3-methyleneoxy- phenyl, 4-chlorophenyl, 4-fluorophenyl.

The term "heteroaryl" as used herein denotes an univalent aromatic heterocyclic 5- or 6-membered ring containing one or more heteroatoms selected from oxygen, sulphur and nitrogen, such as pyridyl, pyrrolyl, thienyl, furanyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadia- zolyl, pyranyl, piperidyl, 1 ,4-dioxanyl, 1 ,3-dioxanyl, oxazinyl, thiazinyl, pipe- razinyl, pyrazinyl, pyrimidyl and pyrazinyl.

The term "halogen" means fluorine, chlorine, bromine and iodine.

In a preferred embodiment of the invention, R¹ is selected from benzisothia- zolyl, 6-fluoro-benzisoxazolyl, phenyl, 4-chlorophenyl, 4-fluorobenzoyl and 3,4-methy lenedioxyphenyl . ln another preferred embodiment of the invention, A is straight or branched C,.₆-alkyl, preferably ethyl or propyl; and X is O or S.

In yet another preferred embodiment of the invention, R² is selected from phenyl, 2,3-methyleneoxyphenyl, thienyl and pyridyl.

Preferred compounds of the invention are:

3-(2-(4-(6-fluorobenzisoxazol-3-yl)piperidino)ethoxy)-4-(3-pyridyl)-1 ,2,5- thiadiazol;

3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyloxy)-4-(3-pyridyl)-1 ,2,5-thiadia- zol;

3-(3-(4-(4-fluorobenzoyl)piperidino)propyloxy)-4-(3-pyridyl)-1 ,2,5-thiadiazol;

3-(3-(4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidino)propyloxy)-4-(3,4-methyl- enedioxyphenyl)-1 ,2,5-thiadiazole;

3-(3-(4-(1 ,2-benzisothiazol-3-yl)piperazin-1 -yl)propoxy)-4-(3-pyridyl)-1 ,2,5- thiadiazole;

3-(3-(4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidino)propoxy)-4-phenyl-1 ,2,5- thiadiazole; 3-(3-(4-(6-fluoro-1 ,2-benzisoxazole-3-yl)piperidino)propoxy)-4-(3-pyridyl)-

1,2,5-thiadiazole;

3-(4-(3-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidino)propylthio)-4-(3-thienyl)-

1 ,2,5-thiadiazol,

or pharmaceutically acceptable acid addition salts of these compounds.

The compounds of the present invention demonstrate high affinity for various receptor subtypes including the 5HT₂-, the dopamine D and D₂- receptors or a combination of these.

Accordingly, in another aspect the invention relates to a compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of CNS-system disorders, cardiovascular disorders or gastrointestinal disorders.

Furthermore, the invention also relates to the use of the inventive com¬ pounds of formula (I) as medicaments useful for treating CNS-system, cardiovascular system and gastrointestinal disorders, such as treatment of anxiety, sleep disorders, depression, psychosis, schizophrenia, migraine, ischemic neuronal damage, asthma, hypertension, urticaria, analgesia and emesis.

In yet another aspect, the invention relates to a method of preparing the above mentioned compounds wherein a compound of formula (II)

(N)

wherein R² has the meaning set forth above, and Q is a leaving group, e.g. halogen such as chloro, is reacted with a compound of formula (III)

(III)

wherein A, Y and R¹ have the meanings set forth above and W is O or S, to form a compound of formula (I) wherein X is O or S. The compounds of the present invention have been tested for binding to various CNS receptor subtypes jn vitro in mice.

Detailed conditions for the jn vitro assays are described below:

TEST 1: Jn yjtro inhibition of DOPAMINE D2 receptor binding,

Method description

Principle:

Radioactive-labelled ligand ³H-Spiroperidol is incubated with isolated cell- membrane fragments at 37°C for a given period of time. Following complet¬ ed incubation, the incubate is filtered through GF/B filters which are rinsed following filtration to remove unspecifically adhered radioactivity. As opposed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters is indicative of the amount of ligand bound specifically as well as nonspecifically to the mem¬ branes.

Tissue preparation:

The procedure is performed in ice bath. Polytron kinematica is rinsed with milli-Q-H₂0 before and after use. Male Wistar rats, 150-200 g are decapitat¬ ed, striatum is removed quickly and weighed (approx. 50 mg). Striatum is transferred to a centrifuging vial containing 10 ml ice-cold D2 buffer. Homo- genization is performed applying polytron kinematica (homogenizer) setting 6 for 20 sec. The homogenizer is rinsed with 10 ml D2 buffer in another centrifuging vial. The 10 ml rinsing buffer is added to the tissue vial. Centri- fugation at 18,000 rpm for 10 min. at 4°C. Final pellet is transferred to 1 ,000 x vol. of same buffer. (Ex. 50 mg striatum in 50 ml D2 buffer). Can be stored at 0°C for at least 4 hours. Note that the tissue must be monoge- neous (uniform) before use. If not, brief homogenization is performed.

Assay:

2,500 μl tissue (homogeneous) 25 μl ³H-Spiroperidol (0.05 nM) 25 μl test substance/H₂0/blind (Domperidone 0.2 μM)

Incubation for 20 min. at 37°C - 10 min. on ice bath.

10 ml ice-cold 0.9% NaCI is added to the tubes and filtered through GF/B filters (use gloves). This procedure is repeated. The filters are placed in counting vials and 4 ml opti-flour is added (perform in fume cupboard, use gloves). Counting is performed at window 0-19 of the beta-counter (Pachard). Note that receptor box and lid are rinsed thoroughly in H₂0 after use to avoid contamination. Further, the analytical site is cleaned carefully every day after use.

Test substances:

Dissolved in H₂0, EtOH, MeOH or DMSO and further diluted in H₂0. The D2 binding will stand concentrations of up to approx. 20% of these solvents without affecting the binding. Most stock solutions are stable at 4°C, attention is, however, paid to any precipitation, change in colour etc. Test- substance dilutions are always made fresh every day. When weighing out test substances, it is attempted to weigh out approx. 1 mg of substance. Less than 0.8 mg must never be weighed out and only infrequently more than 2 mg (for economy reasons), dependent, however, on conc./assay. Results:

The test result is shown in Table I as IC₅₀ indicating the concentration inhibiting specific binding by 50%.

TEST 2: jn yjtro inhibition of DOPAMINE D1 receptor binding

Method description

Principle:

Radioactive-labelled ligand ³H-SCH 23390 is incubated with isolated cell- membrane fragments in incubation buffer at 30°C for a given period of time. Following completed incubation, the incubate is filtered through GF/B filters, which are rinsed following filtration to remove unspecifically adhered ra¬ dioactivity. As opposed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters indicates the amount of ligand bound specifically as well as nonspecifically to the membranes.

Tissue preparation:

Male Wistar rats, 150-200 g are decapitated. Striatum is removed quickly, weighed (approx. 50 mg) and carefully homogenized in 100 x vol. of buffer I applying glass/teflon homogenizer 10 up/down strokes. Ex.: 50 mg striatum is homogenized in 5,000 μl buffer I. The homogenate is centrifuged at 18,000 rpm for 20 min. at 4°C, and the supernate is decanted. This step is performed three times, and each time the pellet is resuspended and homogenized in 100 x vol. of buffer I. Following the third centrifugation, the pellet is suspended in 100 x vol. of resuspension buffer and homogenized. The tissue is now ready for use. The tissue is stable at 0°C for 8 hours. Assav:

600 μl incubation buffer 100 μl ³H-SCH 23390 (0.2 nM) 100 μl tissue

200 μl test substance/H₂0/blind (cis-flupentixol 2 μM)

Incubation for 60 min. at 30°C.

10 ml of ice-cold 0.9% 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 fume cupboard, use gloves) and counting is performed at window 0-19 of the beta-counter (Pachard). Note that receptor box and lid are rinsed thorough- ly in H₂0 after use to avoid contamination. Further, the analytical site is cleaned carefully every day after use.

Test substances:

Dissolved in H₂0, EtOH, MeOH or DMSO and further diluted in H₂0. The

D1 binding will stand concentrations of up to approx. 20% of these solvents without affecting the binding. Most stock solutions are stable at 4°C. Attention should, however, be paid to any precipitation, change in colour etc. Test-substance dilutions are always made fresh every day. When weighing out test substances, it is attempted to weigh out approx. 1 mg of substance. Less than 0.8 mg must never be weighed out and only in¬ frequently more than 2 mg (for economy reasons), dependent, however, on conc./assay.

Results:

TEST 3: ]n vitro inhibition of 5HT₂-receptor binding

Method description

Principle:

Radioactive-labelled ligand ³H-Ketanserine is incubated with isolated cell membrane fragments at 37°C for a given period of time. Following complet¬ ed incubation, the incubate is filtered through GF/B filters, which are rinsed following filtration to remove unspecifically adhered radioactivity. As op¬ posed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters indicates the amount of ligand bound specifically as well as nonspecifically to the membranes.

Tissue preparation:

The preparation is made in ice bath. Polytron kinematica is rinsed with milli- Q-H₂0 before and after use. Male Wistar rats, 150-200 g are decapitated. Frontal cortex is removed quickly and weighed (approx. 200 mg). Frontal cortex is added to centrifuging vial containing 10 ml ice-cold D2 buffer. Homogenization applying polytron kinematica (homogenizer) setting 6 for 20 sec. The homogenizer is rinsed with 10 ml D2 buffer in another centrifug- ing vial. The 10 ml rinsing buffer is added to the tissue vial. Centrifuged at 18,000 rpm for 10 min. at 4°C. Final pellet is transferred to 125 x vol. of same buffer. (Ex 200 mg in 25 ml D2 buffer). Can be stored for approx. 30 min. at 0°C. Assay:

1250 μl tissue 25 μl ³H-Ketanserine (0.4 nM) 25 μl test substance/H₂0/blind cyproheptadine (2 μM)

Incubation for 15 min. at 37°C.

10 ml ice-cold 0.9% 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 H₂0 after use to avoid contamination. Further, the analytical site is cleaned carefully every day.

Test substances:

Dissolved in H₂0, EtOH, MeOH or DMSO and further diluted in H₂0. The 5HT₂ binding will stand concentrations of up to approx. 5% of these sol¬ vents without affecting the binding. Most stock solutions are stable at 4°C. Attention should, however, be paid to any precipitation, change in colour etc. Test-substance dilutions are always made fresh every day. When weighing out test substances, it is attempted to weigh out approx. 1 mg of substance. Less than 0.8 mg must never be weighed out and only in¬ frequently more than 2 mg (for economy reasons), dependent, however, on conc./assay.

Results:

The test result is shown in Table I as IC₅₀ i.e. the concentration inhibiting specific binding by 50%. TABLE I Results from in vitro tests

Compound of TEST 1 TEST 2 Example No. IC₅₀ (nM) IC₅₀ (nM)

5 4.5 300

7 3.7 61

The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, and if desired a pharmaceutically acceptable acid addi¬ tion salt thereof, may be placed into the form of pharmaceutical composi¬ tions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, sus- pensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additio- nal active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing one (1) milligram of active ingredient or, more broadly, one (1) to thirty (30) milligrams, per tablet, are accordingly suitable representative unit dosage forms.

The compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy. Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and digly- cerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvi- nylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

Ampoules are convenient unit dosage forms.

For oral application, particularly suitable are tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or like can be used when a sweetened vehicle can be employed. Generally, as to broader ranges, the compound of the invention is dis¬ pensed in unit dosage form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.

A typical tablet which may be prepared by conventional tabletting tech¬ niques contains: Active compound 1.0 mg

Lactosum 67.8 mg Ph.Eur.

Avicel® 31.4 mg

Amberlite® IRP 88 1.0 mg Magnesii stearas 0.25 mg Ph.Eur.

The following non-limitating examples illustrate the invention.

EXAMPLE 1

3- (2- (4- (6-Fluorobenzisoxazol-3-yl) piperidino) ethoxy) -4- (3-py ridyl) -1 ,2,5- thiadiazol, oxalate

To a stirred mixture of sodium hydride (50% in mineral oil) (100 mg,

2 mmol) in 10 ml dry DMF was added 3-chloro-4-pyridyl-1,2,5-thiadiazol (400 mg, 2 mmol). After 15 min. at room temperature 2-[4-(6-fluoro-1 ,2- benzisoxazol-3-yl) piperidino] ethanol (400 mg, 1.5 mmol) was added. This mixture was stirred at 60°C for 6 h, cooled to room temperature and taken up in water and ethyl acetate. The organic phase was washed with water and saturated sodium chloride and concentrated in vacuo. The resulting oil was purified by column chromatography (silica gel; methylene chloride, methanol (4:1 , v/v)) and then dissolved in 2 ml acetone and 0.5 ml abs. ethanol. Addition of oxalic acid (100 mg) in 1 ml acetone precipitated 180 mg of the title compound. M.p. 126-128°C.

MS (70 eV): m/z 425 (M⁺ 0.2%), 233 (1), 206 (2.5), 105 (45), 45 (100). EXAMPLE 2

3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyloxy)-4-(3-pyridyl)-1 ,2,5-thiadia- zol, oxalate

By following the same procedure as described in example 1 , 3-chloro-4- pyridyl-1 ,2,5-thiadiazol (400 mg, 2 mmol) was reacted with 3-(4-(4-chloro- phenyl)ρiperazin-1-yl)propanol (500 mg, 2 mmol) to give 300 mg of the title compound after recrystallization from ethanol. M.p. 205-206°C.

MS (70 eV): 417 (M⁺,8%) 415 (M⁺, 22%), 400 (15), 380 (1), 249 (40), 209 (15), 70 (100).

EXAMPLE 3

3-(3-(4-(4-Fluorobenzoyl)piperidino)propyloxy)-4-(3-pyridyl)-1 ,2,5-thiadiazol₎ oxalate

By following the same procedure as described in example 1 , 3-chloro-4- pyridyl-1 ,2,5-thiadiazol (0.56, 3 mmol) was reacted with 3-(4-(4-fluorobenzo- yl)piperidino)propanol (0.53 g, 2 mmol) to give 50 mg of the title com¬ pound. M.p. 112,3-130.8°C.

MS (70 eV): 426 (8), 275 (27), 220 (57), 123 (100).

EXAMPLE 4

3-(3-(4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)piperidino)propyloxy)-4-(3,4-methyl- enedioxyphenyl)-1 ,2,5-thiadiazole, oxalate

A. To KCN (2.7 g, 41 mmol) and NH₄CI (2.2 g, 41 mmol) in 10 ml water was added piperonal (5 g, 33 mmol) and 18-crown-6 (10 mg). The mixture was stirred at room temperature for 2 h and then kept at 0°C for 16 h. 4 N HCI was added until pH became less than 3. The aqueous solution was washed with ether, made alkaline with 4 N NaOH and extracted with ethyl acetate. The organic solution was dried over MgS0₄ and concentrated in vacuo giving 3.9 g amino-3,4-methylenedioxyphenyl- acetonitril as a brown oil. NMR (200 MHz, CDCI₃): δ: 7.0 (m,2H), 6.8 (d,1 H, 9.2 Hz), 5.97 (S.2H). 4.8 (bs,1 H), 1.95 (bs,2H).

B. To S₂CI₂ (5.3 ml, 66 mmol) in 5 ml DMF at 0°C was added amino-3,4-methylenedioxyphenyl-acetonitril (3.9 g, 22 mmol) in 5 ml DMF. The mixture was allowed to warm up to room temperature and stirred for 2 h and then taken up in H₂0 and ether. The aqueous phase was extracted twice with ether. The combined organic phases was then washed with H₂0 and saturated sodium chloride, dried over magnesium sulphate and con- centrated in vacuo. The resulting oil was purified by column chromatogra- phy (silica gel; ether, petroleum ether (1 :3, v/v)) giving 1.2 g of 3-chloro-4- (3,4-methylenedioxyphenyl)-1 ,2-5-thiadiazole.

C. By following the same procedure as described in example 1 , 3- chloro-4-(3,4-methylenedioxyphenyl)-1 ,2,5-thiadiazole (360 mg, 1.5 mmol) was reacted with 3-(4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-piperidino)propanol (280 mg, 1 mmol) to give 140 mg of the title compound. M.p. 127-128°C.

MS (70 eV): 482 (M⁺), 426 (50), 233 (52), 149 (75), 96 (100).

EXAMPLE 5

3-(3-(4-(1 ,2-Benzisothiazol-3-yI)piperazin-1 -yl)propoxy)-4-(3-pyridyl)-1 ,2,5- thiadiazole, oxalate

By following the same procedure as described in example 1 , 3-chloro-4- pyridyl-1 ,2,5-thiadiazole (0.56 g, 3 mmol) was reacted with 3-(4-(1 ,2-benz- isothiazol-3-yl)piperazin-1-yl)propanol (0.55 g, 2 mmol) to give 180 mg of the title compound. M.p. 206-210°C.

MS (70 eV): 438 (M⁺, 12), 423 (18), 304 (31), 288 (42), 275 (23), 263 (67), 220 (32), 163 (81), 70 (100).

EXAMPLE 6

3-(3-(4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)piperidino)propoxy)-4-phenyl-1 ,2,5- thiadiazole, hydrochloride

By following the same procedure as described in example 1 , 3-chloro-4- phenyl-1 ,2,5-thiadiazole (450 mg, 1.5 mmol) prepared as described in J.Oro.Chem. 32. 1967. p. 2829 was reacted with 3-(4-(6-fluoro-1 ,2-benzis- oxazol-3-yl) piperidino) propanol (280 mg, 1 mmol) to give 280 mg of the title compound. M.p. 193-194°C.

MS (70 eV): 438 (M⁺, 100%), 300 (90), 233 (85).

EXAMPLE 7

3-(3-(4-(6-Fluoro-1,2-benzisoxazole-3-yl)piperidino)propoxy)-4-(3-pyridyl)- 1 ,2,5-thiadiazole, hydrochloride

By following the same procedure as described in example 1 , 3-chloro-4- pyridyl-1 ,2,5-thiadiazole (560 mg, 3 mmol) was reacted with 3-(4-(6-fluoro- 1 ,2-benzisoxazol-3-yl) piperidino) propanol (560 mg, 2 mmol) to give 110 mg of the title compound by recrystallization from 2-propanol. M.p. 105-111°C.

MS (70 eV): 439 (M⁺, 60%), 301 (22), 233 (30), 96 (100). EXAMPLE 8

3- (4- (3- (6-Fluoro-1 ,2-benzisoxazol-3-yl) piperidino) propylthio) -4- (3-thienyl) -

1 ,2,5-thiadiazol, hydrochloride

A. To NaHS0₃ (5.2 g, 50 mmol) in 5 ml H₂0 was added thiophene- 2-carboxaldehyde (6.0 g, 50 mmol). After 30 min. at room temperature was added concentrated (13 M) aqueous ammonia (3.9 ml, 50 mmol). The mixture was cooled to 0°C and KCN (3.3 g, 50 mmol) was added over 30 min. After stirring at room temperature for 16 h the mixture was acidified and washed with ether. The aqueous phase was made alkaline with NaOH (4N) and extracted with ether. The ether phase was dried over Na₂S0₄ and concentrated jn vacuo to give a brown oil which was taken up in acetone (10 ml). Addition of HCI in ether crystallized 2.8 g of α-amino-α.-thien-2-yl- acetonitril, hydrochloride.

B. α.-Amino-α.-thien-2-yl-acetonitril (2.6 g, 15 mmol) was added during 10 min. to an ice-cold solution of S₂CI₂ (3.5 ml, 45 mmol) in DMF. The mixture was stirred at 0°C for 6 h and then at room temperature for 16 h, whereupon ice was added to quench excess S₂CI₂. The mixture was filtered and extracted three times with ether. The combined organic phases was washed with water and saturated NaCI, dried over MgS0₄ and concen¬ trated jn vacuo. The resulting oil was purified by column chromatography (silica gel; cyclohexane, methylene chloride (1 :1 , v/v)) giving 2.4 g of 3- chloro-4(2-thienyl)-1 ,2,5-thiadiazole. M.p. 47-50°C.

C. To 3-chloro-4-(2-thienyl)-1 ,2,5-thiadiazole (1.0 g, 5 mmol) dis¬ solved in DMF (5 ml) was added K-.CO₃ (700 mg, 5 mmol) and subsequently

NaSHΗ₂0 (740 mg, 10 mmol). The mixture was stirred at room tempera¬ ture for 2 h, whereupon 1 -bromo-3-chloropropan (1.0 ml, 10 mmol) was added. After 15 min. 40 ml water was added and the mixture was extracted with ether. The organic phase was washed with water and saturated NaCI, dried over MgS0₄ and concentrated in vacuo. The resulting oil was purified by column chromatography (silica gel; cyclohexane, methylene chloride (1 :1, v/v)) to give 1.1 g of 3-(3-chloropropylthio)-4-(2-thienyl)-1,2,5-thiadia- zole as an oil.

D. 4-(6-(Fluoro-1,2-benzisoxazol-3-yl)piperidine (270 mg, 1.2 mmol),

3-(3-chloropropylthio)-4-(2-thienyl)-1,2,5-thiadiazole (370 mg, 1.5 mmol), Nal (230 mg, 1.5 mmol) and I^CC^ (210 mg, 1.5 mmol) in 2-methyl-3-butanone (25 ml) was refluxed for 24 h. The mixture was concentrated in vacuo and taken up in water and ethyl acetate. The organic phase was washed with water and saturated NaCI, dried over MgS0₄ and concentrated jn vacuo. The resulting oil was taken up in acetone. HCI in ether was added which crystallized the title compound as 340 mg of white crystals. M.p. 177-179°C.

MS (70 eV): 460 (M⁺, 93%), 322 (37), 233 (50), 96 (100).

Claims

A 1 ,2,5-thiadiazole derivative of the general formula (I)

wherein

A is a straight or branched, saturated acyclic hydrocarbon of 2-6 carbon atoms;

Y is CH or N;

X is 0, S, NH, NCH_3> or CH₂;

R¹ is 1 ,2-benzisothiazol-3-yl, 1 ,

2-benzisoxazol-3-yl, 1 H-indazol-3-yl, or 1-methyl-1H-indazol-3-yl, all of which may be substituted independently with halogen or C,.₆-alkyl in one, two, three or all of the 4-, 5-, 6- and 7-posi- tions; or

R¹ is 4-fluorobenzoyl or phenyl optionally substituted with halogen or C_h¬ alky!;

R² is optionally substituted aryl or heteroaryl;

or pharmaceutically acceptable salts thereof.

A compound according to claim 1 , wherein R¹ is selected from benzisothiazolyl, 6-fluoro-benzisoxazolyl, phenyl, 4-chlorophenyl, 4-fluoro- benzoyl and 3,4-methylenedioxyphenyl.

3. A compound according to claim 1 , wherein R² is selected from 3,4-methylenedioxyphenyl, phenyl, thienyl and pyridyl.

4. A compound according to any of the claims 1-3, wherein A is straight or branched C^-alkyl, and X is O or S.

5i A compound according to any one of the claims 1-4 which is

3-(2-(4-(6-Fluorobenzisoxazol-3-yl)piperidino)ethoxy)-4-(3-pyridyl)-1 ,2,5- thiadiazol, oxalate;

3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyloxy)-4-(3-pyridyl)-1,2,5-thiadia- zol, oxalate;

3-(3-(4-(4-Fluorobenzoyl)piperidino)propyloxy)-4-(3-pyridyl)-1,2,5-thiadiazol, oxalate; 3-(3-(4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)piperidino)propyloxy)-4-(3,4-methyl- enedioxyphenyl)-1 ,2,5-thiadiazole, oxalate;

3-(3-(4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl)propoxy)-4-(3-pyridyl)-1 ,2,5- thiadiazole, oxalate;

3- (3-(4- (6-Fluoro- 1 ,2-benzisoxazol-3-y I) piperidino) propoxy) -4-phenyl-1 ,2,5- thiadiazole, hydrochloride;

3- (3- (4- (6-Fluoro-1 ,2-benzisoxazole-3-yl) piperidino) propoxy) -4-(3-py ridy I)-

1 ,2,5-thiadiazole, hydrochloride;

3-(4-(3-(6-Fluoro-1 ,2-benzisoxazol-3-yl)piperidino)propylthio)-4-(3-thienyl)-

1 ,2,

5-thiadiazol, hydrochloride.

6. A compound according to any of the claims 1 -5 or a pharma¬ ceutically acceptable salt thereof for use as a therapeutically acceptable substance.

~ A compound according to any of the claims 1-5 or a pharma¬ ceutically acceptable salt thereof for use as a therapeutically acceptable substance in the treatment of CNS-system, cardiovascular system or gastrointestinal disorders.

8. A method of preparing a compound according to any one of the claims 1-5, which comprises reacting a compound of formula (II)

wherein R² has the meaning set forth above and Q is a leaving group, with a compound of formula (III)

1 /~~^

R -Y N-A- H (III)

\ /

wherein A, Y and R¹ have the meanings set forth above and W is 0 or S, to form a compound of formula (I) wherein X is O or S.

∑L A pharmaceutical composition comprising a compound according to any one of the claims 1-5 or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient, carrier or diluent.

1 _. A pharmaceutical composition for the treatment of CNS-system disorders, cardiovascular disorders or gastrointestinal disorders, which comprises a compound according to any of the claims 1 -5 or a pharma- ceutically acceptable salt thereof and a therapeutically inert excipient, carrier or diluent.

11. Use of a compound of formula I according to claim 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of CNS-system disorders, cardiovascular disorders or gastrointestinal disorders.

12. A method of treating CNS-system disorders, cardiovascular disorders or gastrointestinal disorders in a subject in need thereof comprising admini¬ stering an effective amount of a compound according to claim 1.

13. A method of treating CNS-system disorders, cardiovascular disorders or gastrointestinal disorders, in a subject in need thereof comprising administering a pharmaceutical composition according to claim 9.

14. A process for the manufacture of a medicament, particularly to be used in the -treatment of CNS-system disorders, cardiovascular disorders or gastrointestinal disorders, which process comprises bringing a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof into a galenical dosage form.