WO2000069424A2

WO2000069424A2 - Method of treating psychotic disorders

Info

Publication number: WO2000069424A2
Application number: PCT/EP2000/003506
Authority: WO
Inventors: Roelof Van Hes; Johannes A. M. Van Der Heijden; Cornelis G. Kruse; Stephen K. Long
Original assignee: Solvay Pharmaceuticals B.V.
Priority date: 1999-05-12
Filing date: 2000-04-14
Publication date: 2000-11-23
Also published as: AU4552200A; JP2002544223A; EP1200072A2; CA2373855A1; WO2000069424A3

Abstract

The invention relates to the use of compounds having both dopamine D2-antagonistic activity and serotonin reuptake inhibitory (SRI) activity for the treatment of psychotic disorders such as schizophrenia. The invention further relates to a group of novel (1, 2, 3,6-tetrahydropyridin-4-yl) indole and -furan derivatives having these activities.

Description

Method of treating psychotic disorders

The invention relates to the use of compounds having combined dopamine D₂- antagonistic activity and serotonin reuptake inhibitory activity for the preparation of pharmaceutical compositions for the treatment of psychotic disorders such as schizophrenia.

It is described in J. Clin, Psychopharmacol, (1998) vol 18, no.1 , p. 2-9 and (1998), vol. 18, no.3, p.208-211 that there is considerable evidence that adding selective serotonin reuptake inhibitor (SSRI) to antipsychotic treatment improves negative symptoms of schizophrenia.

EP 0830864 describes a method for treating a patient suffering from or susceptible to psychosis, acute mania, mild anxiety states, or depression in combination with psychotic episodes by administering to said patient an effective amount of a first component which is an atypical antipsychotic, in combination with an effective amount of a second component which is a serotonin reuptake inhibitor.

It has now been found that compounds having affinity for both the dopamine D₂ receptor and the serotonin reuptake site are particularly useful for the treatment of psychotic disorders such as schizophrenia. Such compounds allow for a more complete treatment of all disease symptoms (e.g. positive symptoms and negative symptoms). Such compounds can be used also in patients suffering from mania, anxiety or depression in combination with psychotic episodes.

Such compounds show activity as antagonists at dopamine D₂ receptors as they potentially antagonize apomorphine-induced climbing behaviour in mice. The compounds also show activity as inhibitors of serotonin reuptake, as they potentiate 5-HTP induced behaviour in mice.

Preferably used compounds have hy-values of less than 10 nanomolair in the receptor binding assays for D₂ antagonistic activity and serotonin reuptake inhibitory activity.

These compounds are active in therapeutic models sensitive to clinically relevant antipsychotics (e.g. the conditioned avoidance response; Van der Heijden & Bradford, Behav. Brain Res., 1988, 31 :61-67) and antidepressants or anxiolytics (e.g. suppression of stress-induced vocalization; van der Poel et al., Psychopharmacology, 1989, 97: 147- 148).

in contrast to clinically relevant dopamine D₂ receptor antagonists these compounds have a low propensity to induce catalepsy in rodents and as such are likely to induce less extrapyramidal side effects than existing antipsychotic agents.

The inhibitory activity of serotonin reuptake inherent in these compounds may be responsible for the therapeutic effects observed in behavioural models sensitive to either antidepressants or anxiolytics.

The combination of two desired types of activity into one molecule has a number of advantages in view of combining two different active components in a composition: 1. constant ratio of both activities due to one kinetic behaviour

2. less burden for the body of the patient with chemical compounds

3. less possibilities for undesired side-effects

4. no interaction between active components.

The invention is illustrated by means of a group of 3-tetrahydropyridin 4-yl indoles having a combination of a high affinity for the dopamine D₂ receptor and the serotonin reuptake site, but is not restricted to the use of these compounds.

The group of 3-tetrahydropyridin-4-yl indole derivatives of the formula (I):

wherein:

- R, is halogen, CF₃, alkyl (1-3C), alkoxy (1-3C), CN or SCH₃ - m the value 0, 1 or 2

- R₂ is H or alkyl (1-3C)

- n has the value 3, 4, 5 or 6 - R₃ is halogen, alkyl (1-4C) or alkoxy (1-4C)

- p has the value 0, 1 , or 2 and salts thereof, show high affinity both for the dopamine D₂-receptor and the serotonin reuptake site. This group of compounds is described in patent application no. WO 99/EP/07912.

Preferred compounds of the invention are compounds having formula (I) wherein R, hydrogen (i.e. m=0) or F, Cl, CH₃ or CN, and m=1 , R₂ is H or CH₃, n=4, R₃ is hydrogen (i.e. p=0), or F or alkyl (1-4C), p=1, and the salts thereof.

The invention is further illustrated by means of a group of novel compounds having the general formula

wherein (R _m and R₂ have the above meanings, q has the value 2-4, and Q is a group of the formula

wherein R₄ represents H, C^-alkyl, C^-alkoxy or CN, R₅ is H, halogen, C^-alkyl, C^-alkoxy, CN, NH₂, SO₂-alkyl (1-3C), NO₂ or SO₂NH₂, and t has the value 1-3, or Q is a group of the formula ii-vi

iii iv v vι wherein Re is H or C^-alkyl, and R₇ is H or OH, or the general formula (lb)

wherein (R^)_m has the above meanings and Q^ represents a group of the formula (i)

and salts thereof.

A preferred compound of this group of novel compounds is the compound of formula (la) wherein (R₁)_rn=5-F, R₂=H, q=4 and Q is the group of the formula (iii), and the salts thereof.

Pharmacologically acceptable acids with which the compounds of the invention can form suitable acid addition salts are for example hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methanesulphonic acid and naphthalene sulphonic acid.

The compounds are their acid addition salts can be brought into forms suitable for administration by means of suitable processes using auxiliary substances such as liquid and solid carrier materials.

The compounds having formula (I) can be obtained as follows: a) by reaction of a compound of formula (II)

with a compound of the formula (III)

wherein the symbols have the above meanings and L is a so-called leaving group, for example bromo. This reaction is carried out in a solvent such as acetonitrile in the presence of triethylamine or K₂CO₃ and Kl at reflux temperature, or b) by (i) reduction of the cyano group in a compound of formula (IV)

wherein A represents the group -(CH₂)_n. CN, to the corresponding group -(CH₂)_π-NH₂; and

(ii) reacting the obtained amine with an optionally substituted phthalic anhydride of the formula (V)

in which formula the symbols have the meanings give above.

Reaction step b (i) can be carried out for example with LiAIH₄ in an organic solvent such as tetrahydrofuran at reflux temperature.

Reaction step b (ii) can be carried out for example in organic solvents such as tetrahydrofuran and toluene at reflux temperature. The starting compounds as used in method a) of the formula (II) can be obtained in a manner known per se by reacting an optionally substituted indole derivate with 4- piperidone.

The starting compounds used in method b) having formula (IV) can be obtained by reaction of a compound having formula (II) with a bromoalkyl nitrile of the formula Br-(CH₂)_n.₁-CN in a manner known per se.

The compounds having formula (la) wherein Q is the group of formula (a) can be obtained by reacting an amine obtainable according to the above method b (i) with the appropriate benzoyl chloride.

The compounds having formula (la) wherein Q represents a group of the formula i-vi can be prepared according to the above method a), i.e. reaction of a compound having formula (II) with a compound of the formula

L-(CH₂)_q-Q.

The preparation of the compounds having formula (I) and (la) will now be described in more detail in the following Examples.

Example I

Preparation of 1-methyl-3-(1 ,2,3,6-tetrahydropyridin-4-yl)indole.

To a solution of 4-piperidone.H₂O.HCI (50 g , 0.32 mol) in 100 ml of acetic acid and 150 ml of trifluoroacetic acid was added dropwise a solution of 1-methylindole (11.5 ml, 0.09 mol) in 100 ml of acetic acid at room temperature. After stirring for 1h the reaction mixture was concentrated (in vacuum , temp. ca. 30°C), water was added , the mixture was made basic with potassium carbonate and extracted with ethyl acetate. The organic layer was separated, dried and purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 84/15/1 ) to give 9 g (47%) of the title compound. Example 2

Preparation of 5-fiuoro-3-(1 ,2,3,6-tetrahydropyridin-4-yl)indole.

To a solution of sodium (60 g , 2.6 mol) in 1000 ml of methanol was added 5- fluoroindole (49 g, 0.36 mol) and 4-piperidone.H₂O.HCI (170 g , 1.11 mol). The mixture was heated under reflux for 18h , then concentrated , water was added and extracted with ethyl acetate. The combined organic layer was dried over sodium suifate and then concentrated. The resulting solid was dissolved in methanol (about 200 ml) and then diluted with water (about 1000-1500 ml). The precipitate was collected, washed with water and petroleum ether and then dried in a vacuum oven at 60°C. Yield 74 g (95%) of a yellow solid.

Example 3

Preparation of N-[4-[4-[(5-fluoro-1 H-indol-3-yl)-1 ,2,3,6-tetrahydropyridin-1-yl]butyl]- phthalimide.HCI (compound 1).

A solution of 5-fluoro-3-(1 ,2,3,6-tetrahydropyridin-4-yl)indole (7.5 g , 34.7 mmol) , N- (4-bromobutyl)phthalimide (10.8 g, 38.3 mmol) , triethylamine (4.5 ml) and potassium iodide (5.5 g) in 150 ml of acetonitrile was heated under reflux for 18h. The reaction mixture was concentrated and purified by silica gel column chromatografy

(dichloromethane/methanol /ammonium hydroxide= 92/7.5/0.5) to give 8.3 g of the title compound as a free base. Mp. 186°C. The hydrochloride was prepared by dissolving the above mentioned free base in 20 ml of 1M HCI in ethanol. The solution was concentrated and the resulting solid was washed with ether. Yield 8.4 g (54%) of compound 1 , mp. 224°C (dec).

Example 4

Preparation of 5-fluoro-3-[1-(3-cyanopropyl)-1 ,2,3,6-tetrahydropyridin-4-yl]indole.

A solution of 5-fluoro-3-(1 ,2,3,6-tetrahydropyridin-4-yl)indole (10 g , 46 mmol) , 4- bromobutyronitrile(5.6 ml , 56 mmol) , potassium carbonate (6.3 g) and potassium iodide (7.6 g) in 100 ml of acetonitrile was heated under reflux for 18h. The mixture was filtered and the residue on the filter was washed with dichloromethane/methanol/ammonium hydroxide = 84/15/1. The organic layer was concentrated to give 10.9 g (83%) of the title compound. M.p 152°C.

Example 5 Preparation of 5-fluoro-3-[1-(4-aminobutyl)-1 ,2,3,6-tetrahydropyridin-4-yl]indole.

To a solution of 5-fluoro-3-[1-(3-cyanopropyl)-1 ,2,3,6-tetrahydropyridin-4-yl]indole (10 g, 35 mmol) in 300 ml of dry THF was added slowly LiAIH₄ (2.0 g ). The mixture was stirred and heated to reflux for 2h. Then the reaction mixture was cooled and water (1.9 ml) in THF (10 ml) was added slowly, followed by 2N sodium hydroxide (1.9 ml) . This mixture was heated to reflux for 0.25h , filtered over hyflo and concentrated to give 8.76 g (88%) of the title compound.

Example 6 Preparation of N-[4-[4-(5-fluoro-1 H-indol-3-yl)-1 ,2,3,6-tetrahydropyridin-1 -yl]butyl]-4- fluorophthalimide (compound 19).

To a solution of 5-fluoro-3-[1-(4-aminobutyl)-1 ,2,3,6-tetrahydropyridin-4-yl]indole (1.46 g, 5 mmol) in 20 ml of THF was added 4-fluorophthalic anhydride and 50 ml of toluene. The THF was removed by distillation and the resulting mixture was heated to reflux for 18h, with azeotropic removal of water (Dean and Stark apparatus). The reaction mixture was concentrated and purified by silica gel column chromatografy (dichloromethane/methanol/amrnonium hydroxide =92/7.5/0.5) to give 1.52 g (69%) of the title compound 19. M.p. 197-199°C.

According to method a) as illustrated in Examples 1-3, or method b) as illustrated in Examples 4-6 the compounds listed in the following Table 1 have been prepared: Table 1

Example 7

Λ/-[2-[4-[(7-methyl-1 H-indol-3-yl)-1 ,2,3,6-tetrahydropyridin-1 -yl]ethyl]-4- chlorobenzamid (compound 34) To a stirred solution of 7-methyl-3-[1-(2-aminoethyl)-1 ,2,3,6-tetrahydropyridin-4-yl] indole (1.5g, 6 mmol) in 30 ml THF was added potassium carbonate (0.8g) and para- chloro-benzoyl chloride (0.8 ml). After stirring was continued for 30 minutes, dichloromethane (100 ml) and water (50 ml) were added. The organic layer was washed with water, dried and concentrated in vacuo to give the title compound as a yellow powder (1.3g, 56%). M.p. 176-181 °C

Example 8

a) 4-chlorobutyl-Λ/-4-(3H)-quinazolinon A mixture of isatoicacid anhydride (5g, 31 mmol), 4-hydroxy-butylamine (2.7g) and triethylformiate (5.6 ml) was heated at 130°C for 1 hour. The mixture was concentrated in vacuo to a dark brown oil, which could be used in the next step without further purification. The oil was dissolved in anhydrous acetonitril (50 ml) and to this solution was added thionylchloride (4.5ml, 61 mmol). The reaction mixture was heated at 80°C for two hours giving a light brown precipitate. The mixture was cooled to room temperature and the title compound was isolated by filtration in a yield of 6.3 g, 80%; m.p. 162°C

b) 3-[4-[4-(5-fluoro-1 H-indol-3-yl)-1 ,2,3,6-tetrahydropyridin-1 -yl]-butyl]-4-(3H)- quinazolinon (compound 38)

To a stirring solution of 5-fluoro-3-[1 ,2,3,6-tetrahydropyridin]-indole (1.5g, 7 mmol) in acetonitril (50 ml) was added potassium carbonate (1.0g), potassium iodide (1.2 g) and 4-chloro-butyl-4-(3H)-quinazolinon (1.8g, 7.6 mmol). The mixture was refluxed for 60 hours, after which time TLC showed complete conversion. The solution was concentrated in vacuo on silica gel and the title compound was obtained as a yellow solid after flash chromatography. Yield: 1.6g, 55%; m.p. 168-170°C.

The compounds 27 to 44 indicated in tables 2 and 3 were prepared in a similar manner: Table 2 (formula la)

Table 3 (formula lb^

Claims

1. Use of a compound having combined dopamine D₂-antagonistic activity and serotonin reuptake inhibitory activity for the preparation of pharmaceutical compositions for the treatment of psychotic disorders such as schizophrenia.

2. Use as claimed in claim 1 , characterised in that compounds having Ki-values of less than 10 nanomolair in the receptor binding assays for D₂-antagonistic activity and serotinin reuptake inhibitory activity are used.

3. Compounds having formula (la) or (lb)

wherein R is halogen, CF₃, alkyl (1-3C), alkoxy (1-3C), CN or SCH₃, m has the value 0, 1 or 2, R₂ is H or alkyl (1-3C), q has the value 2, 3 or 4, and Q is a group of the formula (a)

wherein R₄ is H, alkyl (1-3C), alkoxy (1-3C)₂ or CN, R₅ is H, halogen, alkyl (1-3C), alkoxy (1-3C), CN, NH₂, SO₂-alkyl (1-3C), NO₂ or SO₂NH₂₎ and t has the value 1 ,2 or 3, or Q is a group of the formula (ii-vi)

wherein R₆ is H or alkyl (1-3C), and R₇ is H or OH, and Q^ is a group of the formula (i),

I wherein R₆ has the above meaning, and salts thereof.

4. Compound as claimed in claim 3 having formula (la) wherein (R^^δ-F, R₂=H, q=4, and Q is the group (iii) wherein R₆=H, and salts thereof.

5. Pharmaceutical compositions which contain at least one compound as claimed in claim 3 as an active component.