JP2002544223A - How to treat psychotic disorders - Google Patents

Abstract

  (57) [Summary] The present 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 class of new (1,2,3,6-tetrahydropyridin-4-yl) indole and -furan derivatives having these activities.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound having combined dopamine D ₂ antagonistic activity and serotonin reuptake inhibitory activity for the manufacture of a pharmaceutical composition for the treatment of a psychiatric disorder such as schizophrenia. About use.

[0002] There is considerable evidence that the addition of selective serotonin reuptake inhibitors (SSRIs) to antipsychotic treatment ameliorates the negative symptoms of schizophrenia.
. Clin, Psychopharmacol, (1998) vol 18, n.
o. 1, p. 2-9 and (1998), vol. 18, no. 3, p. 208
−211.

[0003] EP 0 830 864 discloses that an effective amount of a first component, which is an atypical antipsychotic, is combined with an effective amount of a second component which is a serotonin reuptake inhibitor. By administering to patients with or suspected of having psychosis, acute mania, mild anxiety or depression in combination with manifestations
A method for treating the patient is described.

[0004] It has now been found that compounds having an affinity for both the dopamine D ₂ receptor and the serotonin reuptake site are particularly useful for treating psychiatric disorders such as schizophrenia. Such compounds allow for more complete treatment of all disease symptoms (eg, positive and negative symptoms). Such compounds can also be used in patients suffering from mania, anxiety or depression in combination with psychotic manifestations.

[0005] Such compounds exhibit activity as antagonists at the dopamine D ₂ receptor, as they potentially antagonize apomorphine-induced climbing behavior in mice. The compounds also show activity as inhibitors of serotonin reuptake because they enhance 5-HTP-induced behavior in mice.

[0006] Preferably, the compounds used have a K _i value of less than 10 nanomolar in a receptor binding assay for D ₂ antagonistic activity and serotonin reuptake inhibitory activity.

[0007] These compounds are known as clinically relevant antipsychotics (eg, the habituation avoidance response; Va
nd Heijden and Bradford, Behav. Brain R
es. Chem., 1988, 31: 61-67) and antidepressants or anxiolytics (eg, suppression of stress-induced vocalizations; van der Poel et al., Psycho).
Pharmacology, 1989, 97: 147-148).

[0008] In contrast to clinically relevant dopamine D ₂ receptor antagonists, these compounds have a lower propensity to induce catalepsy in rodents and themselves are less active than existing antipsychotics It is likely to induce extrapyramidal side effects.

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

[0010] The combination of two desired types of activity into one molecule has a number of advantages because of combining two different active ingredients in one composition. 1. a constant ratio of both activities due to one kinetic behavior; 2. Less burden on the patient's body with the compound. 3. Less chance of unwanted side effects. This is no interaction between the active ingredient invention is by a group of 3-tetrahydropyridin-4-yl indoles having a combination of high affinity dopamine D ₂ receptors and to serotonin reuptake sites are specifically described, but The use of these compounds is not limited.

Formula (I):

[0012]

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Wherein R ₁ is halogen, CF ₃ , alkyl (1-3C), alkoxy (1-3C), C
Is N or SCH _3, -m is a number 0, 1 or 2, -R ₂ is H or alkyl (l-3C), -n has a number 3, 4, 5 or 6, - R ₃ is halogen, alkyl (1-4C) or alkoxy (1-4C), and -p has a numerical value of 0, 1 or 2.] 3-tetrahydropyridin-4-ylindole derivatives and salts thereof Shows high affinity for both the dopamine D ₂ receptor and the serotonin reuptake site. Compounds of this group are described in the international patent application WO 99 / EP / 07912.

Preferred compounds of the present invention are those wherein R ₁ is hydrogen (ie, m = 0) or F, Cl,
CH3 or CN and,, m = 1, R ₂ is H or CH _3, n = 4,
Compounds having formula (I) wherein R ₃ is hydrogen (ie, p = 0), or F or alkyl (1-4C), and p = 1, and salts thereof.

The present invention provides a compound represented by the general formula

[0016]

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Wherein (R ₁ ) _m and R ₂ have the meanings above, q has the value 2-4, and Q is

[0018]

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Wherein R is_FourIs H, C_1-3-Alkyl, C_1-3Represents alkoxy or CN,
R_FiveIs H, halogen, C_1-3-Alkyl, C_1-3-Alkoxy, CN, NH_Two, SO _Two -Alkyl (1-3C), NO_TwoOr SO_TwoNH_TwoAnd t is the number 1
-3 or Q has the formula ii-vi

[0020]

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Wherein R ₆ is H or C _1-3 -alkyl, and R ₇ is H or OH] or a compound of the general formula (Ib)

[0022]

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Wherein (R ₁ ) _m has the meaning above and Q ₁ is of the formula (i)

[0024]

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A group of novel compounds having the formula: embedded image and salts thereof.

One of the preferred novel compounds of this group is (R ₁ ) _m = 5-F, R ₂ = H, q
= 4 and Q are a group of formula (iii): compounds of formula (Ia), and salts thereof.

The pharmacologically acceptable acids with which the compounds of the present invention can form suitable acid addition salts include, for example, hydrochloric, sulfuric, phosphoric, nitric, and citric, fumaric, maleic, tartaric, Organic acids such as acetic acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid and naphthalenesulfonic acid.

The compounds and their acid addition salts can be in a form suitable for administration by suitable methods using auxiliary substances such as liquid and solid carrier substances.

The compound having the formula (I) can be obtained as follows. A) Compound of formula (II)

[0030]

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A compound of formula (III)

[0032]

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Wherein the symbols have the above meanings and L is a so-called leaving group, for example bromo.

The reaction is carried out at reflux temperature in the presence of triethylamine or K ₂ CO ₃ and KI in a solvent such as acetonitrile. Or b) (i) a compound of formula (IV)

[0035]

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Wherein A represents the group — (CH ₂ ) _{n -1} —CN, in which the cyano group is reduced to the corresponding group — (CH ₂ ) _n —NH ₂ ; and (ii) obtaining The amine obtained is converted to a compound of formula (V)

[0037]

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Wherein the symbols have the meanings given above, by reacting with optionally substituted phthalic anhydride.

Reaction step b (i) can be carried out, for example, using LiAlH ₄ in an organic solvent such as tetrahydrofuran at the reflux temperature.

The reaction step b (ii) can be carried out, for example, at reflux temperature in an organic solvent such as tetrahydrofuran and toluene.

The starting compounds as used in process a) of the formula (II) can be obtained in a manner known per se by reacting an optionally substituted indole derivative with 4-piperidone.

The starting compounds used in process b) having the formula (IV) are of the formula (II) with bromoalkylnitrile of the formula Br— (CH ₂ ) _n-1 —CN in a manner known per se Can be obtained by the reaction of a compound having

Compounds having formula (Ia) wherein Q is a group of formula (a) can be obtained by reacting the amine obtainable according to method b (i) above with a suitable benzoyl chloride.

Compounds having the formula (Ia) in which Q represents a group of the formula i-vi can be prepared according to method a) above (ie of compounds having the formula (II), of the formula L- (CH ₂ ) _q -Q Reaction with compound).

The preparation of compounds having formulas (I) and (Ia) can now be described in more detail by the following examples.

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

4-Piperidone in 100 ml acetic acid and 150 ml trifluoroacetic acid.
H ₂ O. To a solution of HCl (50 g, 0.32 mol) at room temperature was added a solution of 1-methylindole (11.5 ml, 0.09 mol) in 100 ml of acetic acid dropwise. After stirring for 1 hour, the reaction mixture was concentrated (in vacuo, temperature about 30 ° C.).
Water was added, the mixture was basified 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 yield 9 g (47%) of the title compound.

Example 2 Preparation of 5-fluoro-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.
H ₂ O. HCl (170 g, 1.11 mol) was added. The mixture is refluxed for 1 hour.
Heated for 8 hours, then concentrated, added water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and then concentrated. The resulting solid is dissolved in methanol (about 200 ml) and then water (about 1000-15)
00 ml). The precipitate was collected, washed with water and petroleum ether, and then dried at 60 ° C. in a vacuum oven. This gives 74 g (95%) of a yellow solid.

Example 3 N- [4- [4-[(5-Fluoro-1H-indol-3-yl) -1,2,3
, 6-Tetrahydropyridin-1-] yl] butyl] phthalimide. Preparation of HCl (Compound 1).

5-fluoro-3- (1,2,3,6-tetrahydropyridin-4-yl) indole (7.5 g, 34.7 mmol) in 150 ml of acetonitrile, N
A solution of-(4-bromobutyl) phthalimide (10.8 g, 38.3 mmol), triethylamine (4.5 ml) and potassium iodide (5.5 g) was heated under reflux for 18 hours. The reaction mixture is concentrated and subjected to silica gel column chromatography (dichloromethane / methanol / ammonium hydroxide = 92 / 7.5 /
Purification by 0.5) yielded 8.3 g of the title compound as the free base. mp
. 186 ° C. The hydrochloride salt was prepared by dissolving the free base listed above in 20 ml of 1M HCl in ethanol. The solution was concentrated and the resulting solid was washed with ether. 8.4 g (54%) of compound 1, mp. 224 ° C (decomposition)
Is generated.

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

5-fluoro-3 (1,2,3,6-tetrahydropyridin-4-yl) indole (10 g, 46 mmol), 4-bromobutyronitrile (5.6 ml, 56 mmol) in 100 ml of acetonitrile, A solution of potassium carbonate (6.3 g) and potassium iodide (7.6 g) was heated under reflux for 18 hours. 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 yield 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.

5-Fluoro-3- [1- (3-cyanopropyl) -1,2,3,6-tetrahydropyridin-4-yl] indole in 300 ml of anhydrous THF (10 g,
LiAlH ₄ (2.0 g) was added slowly to the solution (35 mmol). The mixture was stirred and heated to reflux for 2 hours. Thereafter, 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). The mixture was heated to reflux for 0.25 hours, filtered over hyflo and concentrated to yield 8.76 g (88%) of the title compound.

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

5-fluoro-3- [1- (4-aminobutyl) -1,20 in 20 ml of THF
2,3,6-tetrahydropyridin-4-yl] indole (1.46 g, 5 m
mol) was added to 4-fluorophthalic anhydride and 50 ml of toluene. The THF was removed by distillation, and the resulting mixture was heated to reflux with azeotropic removal of water (Dean-Stark apparatus) for 18 hours. The reaction mixture is concentrated and subjected to silica gel column chromatography (dichloromethane / methanol /
Purification by ammonium hydroxide = 92 / 7.5 / 0.5) gave 1.52 g (6
9%) of the title compound 19. m. p. 197-199 ° C.

Following the methods a) as illustrated in Examples 1-3 or the methods b) as illustrated in Examples 4-6, the compounds listed in Table 1 below Manufactured:

[0059]

[Table 1]

Example 7 N- [2- [4-[(7-methyl-1H-indol-3-yl) -1,2,3,
6-Tetrahydropyridin-1-yl] ethyl] -4-chlorobenzamide (Compound 34) 7-Methyl-3- [1- (2-aminoethyl) -1,2 in 30 ml of THF.
, 3,6-tetrahydropyridin-4-yl] indole (1.5 g, 6 mmol
To the stirred solution of l) potassium carbonate (0.8 g) and parachlorobenzoyl chloride (0.8 ml) were added. 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 yield the title compound as a yellow powder (1.3g, 56%). m. p. 176-181 ° C.

Example 8 a) 4-Chlorobutyl-N-4- (3H) -quinazolinone isatoicacid anhydride (5 g, 31 mmol), 4-hydroxybutylamine (2.7 g) and triethylformate (triethylf)
(orimate) (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 acetonitrile (50 ml) and to this solution was added thionyl chloride (4.5 ml, 61 mmol). Reaction mixture at 80 ° C
For 2 hours to produce a light brown precipitate. The mixture was cooled to room temperature and the title compound was isolated by filtration in 6.3 g, 80% yield; m.p. p. 162 ° C. b) 3- [4- [4- (5-Fluoro-1H-indol-3-yl) -1,2,2;
3,6-Tetrahydropyridin-1-yl] butyl] -4- (3H) -quinazolinone (Compound 38) 5-Fluoro-3- [1,2,3,6-tetrahydropyridine] indole in acetonitrile (50 ml) (1.5 g, 7 mmol) to a stirred solution:
Potassium carbonate (1.0 g), potassium iodide (1.2 g) and 4-chlorobutyl-4- (3H) -quinazolinone (1.8 g, 7.6 mmol) were added. The mixture was refluxed for 60 hours, after which time TLC showed complete conversion. The solution was concentrated in vacuo over silica gel and the title compound was obtained after flash chromatography as a yellow solid. Yield: 1.6 g, 55%; p. 168-
170 ° C.

The compounds 27 to 44 shown in Tables 2 and 3 were prepared in a similar manner:

[0063]

[Table 2]

[0064]

[Table 3]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/519 A61K 31/519 A61P 25/18 A61P 25/18 43/00 114 43/00 114 C07D 209 / 14 C07D 209/14 209/46 209/46 209/48 401/14 401/14 403/08 403/08 513/04 355 513/04 355 209/48 Z (81) Designated country EP (AT, BE, CH , CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN) , GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU , LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Cruise, Comeris G. Netherlands, Nuel-1381 C.P.Wesp.・ Kay Holland Nuel-1381ピ ー ウ エ ス プ ス プ ス プ C C C C C ー C ー C ー C C C C C C C C C C ー C C C C ー ーBC46 CB29 GA07 MA01 MA04 NA14 ZA18 ZC14 4C204 CB03 DB13 EB02 FB01 GB01 GB03 GB24

Claims (5)

[Claims] 1. Use of a compound having a combined dopamine D ₂ antagonistic activity and serotonin reuptake inhibitory activity for the manufacture of a pharmaceutical composition for the treatment of a psychiatric disorder such as schizophrenia. 2. Use according to claim 1, characterized in that the compound has a Ki value of less than 10 nanomolar in a receptor binding assay for D ₂ antagonistic activity and serotonin reuptake inhibitory activity. 3. Formula (Ia) or (Ib): Wherein R ₁ is halogen, CF ₃ , alkyl (1-3C), alkoxy (1-3C
), Is CN or SCH _3, m has a numerical value 0, 1 or 2, R ₂ is H or alkyl (l-3C), q has a numerical value 2, 3 or 4, and Q is Formula (a) Wherein R ₄ is H, alkyl (1-3C), alkoxy (1-3C) ₂ or CN
And R ₅ is H, halogen, alkyl (1-3C), alkoxy (1-3C)
, CN, NH ₂ , SO ₂ -alkyl (1-3C), NO ₂ or SO ₂ NH ₂ , and t has the value 1, 2 or 3 or Q is of the formula (ii-vi) Chemical formula 3] Wherein R ₆ is H or alkyl (1-3C), and R ₇ is H or O
H and Q ₁ is of the formula (i) Wherein R ₆ has the above meanings, and salts thereof. 4. The method according to claim 3, wherein (R ₁ ) _m = 5-F, R ₂ = H, q = 4 and Q has the formula (Ia) wherein R ₆ = H is a group (iii). Compounds, and salts thereof. 5. A pharmaceutical composition comprising at least one compound according to claim 3 as an active ingredient.