AU722147B2

AU722147B2 - N-(benzothiazol-2-yl) piperidine-1-ethanamine derivatives, their preparation and application in therapeutics

Info

Publication number: AU722147B2
Application number: AU44638/97A
Authority: AU
Inventors: Gihad Dargazanli; Jonathan Frost; Pascal George; Patrick Lardenois; Pascale Magat; Maria-Carmen Renones; Johannes Schoemaker
Original assignee: Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1996-10-01
Filing date: 1997-09-26
Publication date: 2000-07-20
Anticipated expiration: 2017-09-26
Also published as: EE9900135A; CO4650030A1; KR20000048767A; ZA978772B; FR2753970A1; AR009105A1; CA2266510A1; TR199900634T2; WO1998014444A1; HUP9904091A2; IL128902A; BG103271A; HUP9904091A3; NO991581L; NZ334553A; JP2001501217A; IL128902A0; CN1230959A; NO991581D0; AU4463897A

Description

WO 98/14444 1 PCT/FR97/01692 N-(2-Benzothiazolyl)-1-piperidineethanamine derivatives, their preparation and their use in therapy.

The compounds of the invention correspond to the general formula (1) in n

R,

R

2 R3 which represents the number represents a hydrogen or methoxy group, represents a hydrogen represents a hydrogen atoms.

0, 1, 2 or 3, or halogen atom or a methyl atom or a methyl group, and atom or one or two halogen The compounds of the invention can exist in the free base state or in the state of addition salts with acids.

In accordance with the invention, the compounds of general formula may be prepared according to processes illustrated by the schemes which follow.

In the case of the compounds in which R 2 represents a hydrogen atom, and according to Scheme 1, a compound of general formula in which R, is as 2 defined above, is reacted with chloroacetyl chloride of formula (III) under conditions similar to the ones described in Bull. Soc. Chim. France (1962) 736-737, that is to say in an aprotic solvent, for example dioxane, at a temperature of 20 to 100 0

C.

An amide of general formula (IV) is obtained, which is reacted with a piperidine of general formula in which n and R 3 are as defined above, in an aprotic polar solvent, for example N,Ndimethylformamide, at a temperature of 50 to 80 0 C and in the presence of an inorganic base, for example potassium carbonate. An amide of general formula (VI) is obtained, which is finally reduced to an amine of general formula with R 2 by means of a simple or complex reducing agent such as an alkali metal hydride or other metal hydride, for example lithium aluminium hydride, boron hydride, the boron hydride/tetrahydrofuran or boron hydride/methyl sulphide complex or aluminium hydride, in an aromatic or ethereal inert solvent, for example toluene, xylene, diethyl ether, tetrahydrofuran or dioxane, at a temperature of 30 to 1400C depending on the solvent.

Scheme 1

NN

CICH

2

COCI

(IV)

(CHO)

HN9 a

(VI)

0I. R 2

=H)

In the case of the compounds in which R 2 represents a methyl group, and according to Scheme 2, a compound of general formula in which R, is as defined above, is reacted first with a mixture of acetic anhydride and formic acid under conditions similar to the ones described in Tetrahedron Letters (1982) 23 (33) 3315-3318 and in J. Med. Chem. (1966) 9 830-832, that is to say in an inert solvent, for example tetrahydrofuran, at a temperature of 20 to 40 0 C, and the N-formyl intermediate thereby obtained is then reduced as indicated above in relation to the compound of general formula (VI) to obtain an N-methyl- 2-benzothiazolamine of general formula (VII).

Separately, a piperidine of general formula in which n and R 3 are as defined above, is reacted with l-bromo-2-chloroethane under the standard conditions for a reaction of this kind, that is to say in a polar solvent, for example N,N-dimethylformamide, in the presence of an inorganic base, for example potassium carbonate, at a temperature of 50 to 80 0

C.

A chlorinated derivative of general formula (IX) is obtained, which is finally reacted with the N-methyl-2-benzothiazolamine of general formula (VII) in a polar solvent, for example N,N-dimethylformamide, in the presence of an inorganic base, for example potassium carbonate, at a temperature of 80 to 1000C, to obtain a compound of general formula R 2

=CH

3 Scheme 2 R >NH HNa 1) (CH 3

CO)

2 0 HCO g

H

BrCH 2

CH

2

CI

2) LAlH 4 i

(VIII)

jS CH 3 R/ -NH

N>

(ViI)

(XK)

R

2

=CH

3 The starting compounds of general formula (II) are available on the market.

The starting compounds of general formula (V) are available on the market or are described in Patent Applications EP-0109317 and EP-0524846.

The examples which follow illustrate in detail the preparation of a few compounds according to the invention. The elemental microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained.

6 The numbers of the compounds shown in brackets in the titles correspond to those in the table given later.

Example 1 (Compound No. 1) N-(2-Benzothiazolylyl)-4-phenyl-l-piperidineethanamine.

1.1. N-(2-Benzothiazolylyl)-2-chloroacetamide hydrochloride.

g (0.1 mol) of 2-benzothiazolamine and 200 ml of dioxane are introduced into a 1-1 roundbottomed flask, the mixture is stirred until dissolution is complete, a solution of 11.3 g (0.1 mol) of chloroacetyl chloride is added and the mixture is heated on an oil bath at 500C for 24 h.

A further 5.6 g (0.05 mol) of chloroacetyl chloride dissolved in 50 ml of dioxane are added and heating is continued at 500C overnight.

The mixture is allowed to cool, and the precipitate is separated by filtration, washed with a little dioxane and then with petroleum ether and dried in the presence of phosphorus pentoxide.

25.49 g of product are obtained, which product is used without further treatment in the next step.

1.2. N-(2-Benzothiazolylyl)-4-phenyl-lpiperidineacetamide.

2.63 g (0.01 mol) of N-(2-benzothiazolylyl)- 2-chloroacetamide hydrochloride, 1.61 g (0.01 mol) of 7 4-phenylpiperidine, 2.76 g of potassium carbonate and ml of N,N-dimethylformamide are introduced into a 500-ml round-bottomed flask, and the mixture is heated to 50 0 C for 3 h 30 min.

The mixture is allowed to cool, 160 ml of water are added, and the precipitate is collected by filtration and dried.

3.15 g of product are obtained, which product is used without further treatment in the next step.

1.3. N-(2-Benzothiazolylyl)-4-phenyl-lpiperidineethanamine.

430 mg (0.0112 mol) of lithium aluminium hydride and then 60 ml of tetrahydrofuran are introduced into a 500-ml round-bottomed flask, and the suspension is heated to reflux. 2 g (0.0056 mol) of N-(2-benzothiazolylyl)-4-phenyl-1-piperidineacetamide dissolved in 30 ml of tetrahydrofuran are added dropwise, and heating is maintained for a further min.

The mixture is cooled, 56 ml of ethyl acetate and 22 ml of water are added, the organic phase is separated after settling has taken place, the solvents are evaporated off under reduced pressure and the oily residue is dried under reduced pressure.

2.48 g of crude product are obtained, which product is purified by chromatography on a column of silica gel, eluting with a 9:1 mixture of 8 dichloromethane and methanol to obtain 1.6 g of a pale yellow oil which crystallizes.

After recrystallization in 2-propanol and drying under reduced pressure, 0.81 g of compound is finally isolated.

Melting point: 140-1410C.

Example 2 (Compound No. 3) N-(2-Benzothiazolylyl)-4-[(4-fluorophenyl)methyl]-1piperidineethanamine ethanedioate.

2.1. N-(2-Benzothiazolylyl)-4-[(4-fluorophenyl)methyl]- 1-piperidineacetamide.

2.26 g (0.0086 mol) of N-(2benzothiazolylyl)-2-chloroacetamide hydrochloride, 2.29 g (0.01 mol) of 4-[(4-fluorophenyl)methyl]piperidine hydrochloride, 4.14 g (0.03 mol) of potassium carbonate and 80 ml of N,N-dimethylformamide are introduced into a 500-ml round-bottomed flask, and the mixture is heated to 500C for 2 h 30 min.

The mixture is allowed to cool, 240 ml of water are added, the mixture is cooled in an ice bath, and the white precipitate is collected by filtration, washed copiously with water and dried in the presence of phosphorus pentoxide.

2.9 g of product are obtained, which product is recrystallized in 30 ml of ethanol. After drying, 2.42 g of compound are obtained.

Melting point: 141-1420C.

2.2. N-(2-Benzothiazolylyl)-4-[(4-fluorophenyl)methyl]l-piperidineethanamine ethanedioate.

1.3 g (0.00349 mol) of N-(2benzothiazolylyl)-4-[(4-fluorophenyl)methyl]-1piperidineacetamide dissolved in 25 ml of dry tetrahydrofuran are introduced under a nitrogen atmosphere into a 250-mi three-necked round-bottomed flask, 1.09 ml, that is to say 3 equivalents, of borane/methyl sulphide complex are added and the mixture is heated to reflux for 4 h. The mixture is allowed to cool to room temperature, a mixture of 53 ml of 2N hydrochloric acid and 25 ml of methanol is added, and the mixture is heated to reflux again for 1 h min and left standing overnight.

Concentrated sodium hydroxide is added to the mixture until the pH is alkaline and the mixture is extracted three times with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and filtered and the filtrate is evaporated under reduced pressure.

1.6 g of oily product are obtained, which product is purified by chromatography on a column of silica gel, eluting with a 95:5 mixture of dichloromethane and methanol.

0.83 g of opaque oil is obtained, which oil is dissolved in 2-propanol with one equivalent of oxalic acid.

After recrystallization, filtration and drying, 0.73 g of compound is finally isolated.

Melting point: 155-1560C.

Example 3 (Compound No. 4) N-(2-Benzothiazolyl)-N-methyl-4-(phenylmethyl)-1piperidineethanamine ethanedioate.

3.1. N-Methyl-2-benzothiazolamine.

10.2 ml of acetic anhydride are introduced into a round-bottomed flask, 4.3 ml of formic acid are added dropwise and while stirring and the mixture is then heated to 500C for 2 h. The mixture is cooled to room temperature, 10 ml of dry tetrahydrofuran are added, a solution of 11.25 g (0.075 mol) of 2-benzothiazolamine in 30 ml of dry tetrahydrofuran is then added dropwise and without the temperature exceeding 400C and the mixture is left standing for 2 days.

The solvent is evaporated off under reduced pressure, and the crystalline residue is washed twice with petroleum ether and dried in the presence of phosphorus pentoxide.

13 g of intermediate N-(2-benzothiazolyl)formamide are obtained.

A suspension of 0.854 g (0.0224 mol) of lithium aluminium hydride in 50 ml of tetrahydrofuran is prepared and heated to reflux, a solution of 2 g (0.0112 mol) of formyl intermediate in 100 ml of 11 tetrahydrofuran is added and heating is continued for min.

The mixture is cooled, 100 ml of ethyl acetate are added, 38 ml of water are added dropwise, the organic phase is separated after settling has taken place and evaporated under reduced pressure, and the crystallized residue is ground in petroleum ether, filtered off and dried in the presence of phosphorus pentoxide.

1.5 g of compound are obtained.

3.2. 1-(2-Chloroethyl)-4-(phenylmethyl)piperidine.

g (0.02 mol) of 4-(phenylmethyl)piperidine dissolved in 50 ml of N,Ndimethylformamide are introduced into a round-bottomed flask, 2.86 g (0.02 mol) of l-bromo-2-chloroethane and 2.76 g (0.02 mol) of potassium carbonate are added and the mixture is stirred vigorously at room temperature for 1 h.

The mixture is poured into 250 ml of ice-cold water and extracted with 2 times 150 ml of ethyl acetate. The organic phase is washed with saline solution and the solvent is evaporated off under reduced pressure. 7 g of oily product are obtained, which product is purified by chromatography on a column of silica gel, eluting with ethyl acetate.

2.1 g of purified product are obtained in the form of an oil.

3.3. N-(2-Benzothiazolyl)-N-methyl-4-(phenylmethyl)-1piperidineethanamine ethanedioate.

1 g (0.00421 mol) of l-(2-chloroethyl)-4- (phenylmethyl)piperidine is dissolved in 25 ml of N,Ndimethylformamide, 0.7 g (0.00426 mol) of N-methyl-2benzothiazolamine and 0.8 g of potassium carbonate are added and the mixture is heated to 100°C for 1 h.

It is cooled in an ice bath, 50 ml of water are added, the mixture is extracted with 2 times 100 ml of ethyl acetate, and the organic phase is washed with saline solution and evaporated. An oily residue is obtained, which is purified by two successive chromatographic runs on a column of silica gel, the first eluting with a 90:10 mixture of dichloromethane and methanol and the second eluting with ethyl acetate.

0.3 g of compound is obtained, 0.1 g of which is removed to form the oxalate in ethanol.

Melting point: 164-166 0

C.

Example 4 (Compound No. 11) N-(2-Benzothiazolyl)-4-[2-(4-fluorophenyl)ethyl]-1piperidineethanamine.

4.1. N-2-Benzothiazolyl)-4-[2-(4-fluorophenyl)ethyl]-lpiperidineacetamide.

2.63 g (0.01 mol) of N-(2-benzothiazolyl)-2chloroacetamide hydrochloride, 2.44 g (0.01 mol) of 4-[2-(4-fluorophenyl)ethyl]piperidine hydrochloride, 4.14 g (0.03 mol) of potassium carbonate and 80 ml of N,N-dimethylformamide are introduced into a 500-mi round-bottomed flask, and the mixture is heated to 50 0

C

for 3 h 30 min.

It is allowed to cool, 240 ml of water are added and the mixture is extracted with 300 ml of ethyl acetate.

The organic phase is washed with water and then with saturated sodium chloride solution, dried over sodium sulphate and filtered and the filtrate is concentrated under reduced pressure. A brown oily product is obtained, which is used without further treatment in the next step.

4.2. N-(2-Benzothiazolyl)-4-[2-(4-fluorophenyl)ethyl]- 1-piperidineethanamine.

0.96 g (0.025 mol) of lithium aluminium hydride and 140 ml of dry tetrahydrofuran are introduced under a nitrogen atmosphere into a 500-ml three-necked round-bottomed flask, the suspension is heated to reflux, 5.0 g (0.01 mol) of N-(2benzothiazolyl)-4-[2-(4-fluorophenyl)ethyl]-1piperidineacetamide dissolved in 60 ml of dry tetrahydrofuran are added dropwise and heating is continued for 30 min.

The mixture is cooled, 140 ml of ethyl acetate and 51 ml of water are added, the organic phase is separated, the solvents are evaporated off under 14 reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 9:1 mixture of dichloromethane and methanol. 1.6 g of an oil which crystallizes are obtained. After recrystallization in a mixture of ethanol and water, followed by drying under reduced pressure, 1.23 g of compound are isolated.

Melting point: 107-108 0

C.

The table which follows illustrates the chemical structures and the physical properties of a few compounds according to the invention. In the "salt" column, denotes a compound in the base state, "ox." denotes an oxalate or ethanedioate, and "fum." denotes a fumarate or (E)-2-butenedioate. The acid/base mole ratio is shown in brackets.

Table I II\ N 2 No. _n R, iR,. R, Salt M.P. 1 0 H H H -140-141 2 1 H jH H OX. (1.05:1) 141-142 O X. 155-156 3 1 H H 4-F fum. 150-151 4 1 H CM 3 H OX. (1.15:1) 164-166 1 H CM 3 4-F fum. 137-140 6 1 6-Cl H 4-F -118-119 7 1 6-CH 3 H 4-F -148-149 8 1 6-0CM 3 H H -123-124 9 1 6-OCH 3 H 4-F -107-108 2 H H H OX. 189-190 11 2 H H 4-F -107-108 12 2 6-0CM 3 H H -129-130 13 3 H H H OX. 179-180 14 2 H H 2-F fum. 159-160 2 H H 3-F fum. 168-169 16 2 H H 2,4-F fum. 156-158 17 2 H H 3,4-F fum. 100-138 isB 2 H H 3,5-F fum. 158-159 16 The compounds of the invention were subjected to tests which demonstrated their value as therapeutic active substances.

Thus, they were subjected to a study in relation to their neuroprotective activity in a model of permanent focal ischaemia produced by intraluminal occlusion of the middle cerebral artery in rats, according to a method similar to the one described in Stroke (1989) 20 84-91.

Under methohexitone sodium anaesthesia, the pterygopalatine artery, common carotid artery and the left external carotid artery are ligated, and a polyamide thread is introduced into the internal carotid artery over a length of approximately 18 mm, corresponding to the distance separating the point of origin of the internal carotid artery from that of the middle cerebral artery.

The compounds under study are administered intravenously after the occlusion.

24 h after occlusion of the middle cerebral artery, the animals are sacrificed and the brain is removed.

The volume of the cerebral infarction is evaluated from the measurement of the area of necrosis on 6 coronal sections stained with 2,3,5triphenyltetrazolium chloride. As an example, Compound No. 11 in the table above significantly reduces the volume of the infarction by approximately 48% at a dose 17 of 1 mg/kg administered intravenously at times 10 min, 1 h 30 min, 3 h and 6 h after occlusion.

The compounds of the invention were also subjected to the global cerebral ischaemia test in mice.

The ischaemia is due to a cardiac arrest induced by rapid intravenous injection of magnesium chloride. In this test, the "survival time", that is to say the interval between the time of injection of magnesium chloride and the last observable respiratory movement of each mouse, is measured. This last movement is considered to be the final sign of functioning of the central nervous system. Respiratory arrest occurs approximately 19 seconds after the injection of magnesium chloride.

Male mice (Charles River CDI) are studied in groups of 10. They are supplied with food and water ad libitum before the tests. The survival time is measured minutes after the intraperitoneal administration of the compounds of the invention. The results are given in the form of the difference between the survival time measured in a group of 10 mice which have received the compound, and the survival time measured in a group of mice which have received the vehicle liquid. The relationships between the modifications in the survival term and the dose of the compound are recorded graphically according to a semi-logarithmic curve.

This curve enables the "3-seconds effective dose" (ED 3 that is to say the dose (in mg/kg) which produces an increase of 3 seconds in the survival time relative to the control group of 10 untreated mice, to be calculated. An increase of 3 seconds in the survival time is both statistically significant and reproducible. The ED 3 of the most active compounds of the invention are less than 5 mg/kg via the intraperitoneal route.

The compounds according to the invention were also subjected to an in vitro study in relation to their affinity for the D 4 dopaminergic receptors, obtained by transfection of human D 4 4 receptors into CHO cells, essentially as described by Van Tol. et al., Nature (1991) 350 610-614 and Van Tol. et al., Nature (1992) 358 149-152.

On the day of the experiment, the membrane preparation (Receptor Biology, Inc., Glen Echo, MD20812, USA), stored at -80 0 C, is thawed rapidly and then diluted in 20 volumes of incubation buffer (50 mM Tris-HC1, 120 mM NaC1, 5 mM KC1, 2 mM CaC1 2 5 mM MgC1 2 pH The membrane suspension (100 gl, 78 gg of membrane) is incubated at 25 0 C for 60 min in the presence of 0.5 nM 3 H]spiperone (specific activity 17 to 20 Ci/mmol, New England Nuclear/Du Pont de Nemours, Boston, MA, USA) in a final volume of 1 ml of incubation buffer in the presence or absence of the test compound.

19 Incubation is completed by filtration, with the use of Whatman GF/B® filters treated beforehand with polyethylenimine Each reaction tube is rinsed three times with 3 ml of Tris-NaCl buffer (50 mM Tris- HC1, 120 mM NaCI, pH The filters are dried in an oven at 120 0 C for min. The radioactivity retained on the filters is determined by liquid scintigraphy. Non-specific binding is determined in the presence of 1 pM haloperidol.

For each concentration of compound under study, the percentage inhibition of the specific binding of 3 H]spiperone is calculated, and then the

IC

0 the concentration which inhibits 50% of the binding, is determined.

The ICs 5 values of the compounds of the invention are of the order of 3 to 30 nM.

The results of the tests show that, in vivo, the compounds according to the invention have neuroprotective properties, and that, in vitro, they displace the specific binding of [H]spiperone to human

D

4 4 dopaminergic receptors.

Consequently they may be used, on the one hand, for the treatment and prevention of cerebrovascular disorders of ischaemic or hypoxic origin (cerebral infarction, cranial or cord trauma, cardiac or respiratory arrest, transient ischaemic attack, perinatal asphyxia), glaucoma, progressive neurodegenerative disorders (senile dementia such as P:\Oper\l b\44(38-97 sp c.dnc-l April. 21H)0 Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, olivopontocerebellar atrophy, amyotrophic lateral sclerosis, neurodegenerative disorders of viral origin, and the like), and in the prevention of cerebral ischaemic accidents associated with cardiac and vascular surgery or with endovascular therapy.

They may be used, on the other hand, for the treatment of psychoses, especially schizophrenia (deficiency and productive forms) and the acute and chronic extrapyramidal symptoms induced by neuroleptics or resulting from Parkinson's disease, for the treatment of the various forms of anxiety, panic attacks, phobias, compulsive obsessional disorders, for the treatment of the different forms of depression, including psychotic depression, for the S* 15 treatment of narcotic and alcohol induced dependency and disorders of hypothalamohypophyseal function, and for the *0o treatment of cognitive disorders associated with age or Alzheimer's disease.

Accordingly, in another aspect, the invention provides 20 methods for the treatment and/or prevention of these 0** disorders comprising the administration of a compound of the invention to a patient in need thereof. There is also provided, the use of a compound of the invention in the manufacture of a medicament for the treatment and/or 0*0 25 prevention of these disorders.

The invention also provides pharmaceutical compositions comprising a compound of formula in combination with an excipient.

To this end, the compounds may be presented in all pharmaceutical dosage forms, in combination with suitable excipients, for enteral, parenteral or transdermal administration, for example in the form of tablets, drag6es, capsules including hard gelatin capsules, solutions or suspensions for oral administration or for injection, =-3 5 suppositories, patches, and the like, containing doses that P:.OCK.Adb\44638,7 sp-c.doc-IX Apdi]. 21 permit a daily administration of 1 to 500 mg of active substance.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

*a *a* *l *o o *a e

Claims

1. Compound corresponding to the general formula (1) ,(CH2)n Ra s (I) in which R, represents a hydrogen or halogen atom or a methyl or methoxy group, :R2 represents a hydrogen atom or a methyl group, and R 3 represents a hydrogen atom or one or two halogen 10 atoms, ooeQ:..in the free base state or in the state of an addition salt with an acid. Process for preparing a compound represents a hydrogen atom, a compound of general formula (II) RI NH 2 in which R, is as defined in Claim 1, is reacted with 23 chloroacetyl chloride to obtain an amide of general formula (IV) (IV) HC which is reacted with a piperidine of general formula (V) (CH2) t HNg ft 3 in which n and R 3 are as defined in Claim 1, to obtain an amide of general formula (VI) (CH2)n-^J R- NH (VI) which is finally reduced to an amine of general formula with R

2 =H) /-1/R 3 R 2 =H) or alternatively, to prepare a compound in the formula of which R 2 represents a methyl group, a compound of general formula (II) R I NH 2 (II) in which R, is as defined in Claim 1, is reacted first with a mixture of acetic anhydride and formic acid, and the N-formyl intermediate thereby obtained is then reduced to obtain an N-methyl-2-benzothiazolamine of general formula (VII) S C H3 R NH (VII) N and, separately, a a piperidine of general formula (V) (CH e) HNg a 3 (V) in which n and R 3 are as defined in Claim 1, is reacted with l-bromo-2-chloroethane to obtain a chlorinated derivative of general formula (IX) CI L( H)I- (IX which is finally reacted with the N-methyl-2- P:\OPER\PDB\44638-97 spec.doc-23A)5/ benzothiazolamine of general formula (VII) to obtain a compound of general formula with R 2 =CH 3 (CH 2 R3 S CH 3 R 2 =CH 3 R N N N

3. A pharmaceutical composition comprising a compound according to claim 1 in combinations with an excipient.

4. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment or prevention of cerebrovascular disorders of ischaemic or hypoxic origin, glaucoma and progressive neurodegenerative disorders.

Use according to claim 4 wherein the disorder is cerebral infarction, cranial or cord trauma, cardiac or respiratory arrest, transient ischaemic attacks, perinatal asphyxia, senile dementia, vascular dementia, Parkinson's disease, Huntington's disease, olivopontocerebellar atrophy, amyotrophic lateral sclerosis and neurodegenerative disorders of viral origin.

6. Use of a compound according to claim 1 in the manufacture of a medicament for the prevention of cerebral ischaemic accidents associated with cardiac and vascular surgery or with endovascular therapy.

7. Use of a compound according to claim 1 for the treatment of psychoses, acute and chronic extrapyramidal symptoms induced by neuroleptics or resulting from Parkinson's disease, forms of anxiety or panic attacks, phobias, compulsive obsessional disorders, depression, narcotic and alcohol induced dependency, disorders of hypothalamohypophyseal function and cognitive disorders associated with age or Alzheimer's disease. P.oper\pdh\4461X-97 spec doc-IX Apnl. 2(MII 26

8. Use according to claim 7 wherein the psychosis is schizophrenia.

9. A method for the treatment or for the prevention of cerebrovascular disorders of ischaemic or hypoxic origin, glaucoma and progressive neurodegenerative disorders, comprising the administration of a compound according to claim 1 to a subject thereof.

A method according to claim 9 wherein the disorder is cerebral infarction, cranial or cord trauma, cardiac or respiratory arrest, transient ischaemic attacks, perinatal asphyxia, senile dementia, vascular dementia, Parkinson's disease, Huntington's disease, olivopontocerebellar atrophy, amyotrophic lateral sclerosis and neurodegenerative disorders of viral origin.

11. A method for the prevention of cerebral ischaemic accidents associated with cardiac and vascular surgery or with endovascular therapy, comprising the administration of a compound according to claim 1 to a patient in need thereof. 20

12. A method for the treatment of psychoses, acute and chronic extrapyramidal symptoms induced by neuroleptics or resulting from Parkinson's disease, forms of anxiety or panic attacks, phobias, compulsive obsessional disorders, depression, narcotic and alcohol induced dependency, 25 disorders of hypothalamohypophyseal function and cognitive disorders associated with age or Alzheimer's disease, comprising the administration of a compound according to claim 1 to a patient in need thereof.

13. A method according to claim 12 wherein the psychosis is schizophrenia.

14. A compound of formula produced by the process of claim 2. An N-(2-benzothiazolyl)-1-piperidine ethanamine derivative or a composition comprising said derivative, 35 substantially as hereinbefore described. P \op~r\pdb44613X.97 April.

PPWr 27

16. A method of treatment or prevention using an N-(2- benzothiazolyl)-l-piperidine ethanamine derivative, or the use of said derivative in the manufacture of a medicamnent substantially as hereinbefore described. DATED this 1 8 th day of April 2000 Synthelabo By its Patent Attorneys DAVIES COLLISON CAVE too* go