EA006315B1 - Indole derivatives useful for the treatment of cns disorders - Google Patents

Abstract

The present invention relates to dopamine and serotonin receptor ligands having the general formula (I) wherein one of Y<1> and Y<2> is N, which is bound to Y<4>, Y<3> is Z-CH2, CH2-Z or CH2CH2 and the further meanings of Y<1>, Y<2>, Y<3>, Y<4>, Z, W, n, m, X, R<1>-R<9> and R<10> are as given in the claims and the description. The compounds of the invention are useful in the treatment of certain psychiatric and neurological disorders, i.e. schizophrenia, other psychoses, anxiety disorders, depression, migraine, cognitive disorders, ADHD and sleep improvement.

Description

Field of Invention

The present invention relates to a new class of indole derivatives having affinity for the dopamine receptor Ό ₄ . These compounds have an antagonistic effect on the dopamine receptor Ό ₄ and, thus, are suitable for the treatment of certain mental and neurological disorders, in particular psychoses. Some of these compounds also have affinity for the dopamine receptor Ό ₃ , the 5-HT _2a receptor and / or the 5-HT _2c receptor, and some of these compounds are serotonin reuptake inhibitors.

BACKGROUND OF THE INVENTION

До ₄ dopamine receptor ligands related to the compounds of the present invention are known from VO 98/28293. Derivatives of indane and dihydroindole described in this document have the general formula

where A represents an indole, and Υ represents a group terminating indan or dihydroindole, and other substituents defined in the application.

\ UO 00/23441 describes compounds of the general formula

where the substituents K ₁ , B ₂ . K ₃ , t, η and p are defined in the application.

It is said that these compounds show high affinity for dopamine receptors Ό ₂ , and also that they are serotonin reuptake inhibitors. It is claimed that these compounds are suitable for the treatment of schizophrenia and other mental disorders.

Other compounds structurally related to the compounds of the present invention are described in UO 99/58525. It is said that the compounds described in this document are 5-HT _{2 a} ligands and serotonin reuptake inhibitors and have the general formula

where the substituents are defined in the application. It is said that these compounds are suitable for the treatment of schizophrenia. \ UO 00/31074 relates to compounds of the general formula

where X represents CO or §O ₂ and Υ represents Ν-K ⁴ or CCM ⁵ , and the substituents are defined in the application. It is said that these compounds are active on the 5HT _2A receptor, have 5-HT reuptake inhibitory activity, and enhance 5-HT release.

Applications \\ 'O 94/18197, EP 329168, \\' O 93/16073, EP 732332, \\ 'O 98/37893 and \\' O 95/11680 describe ligands of dopamine receptors No. ₄ , which, like compounds of the present invention, are substituted derivatives of tetrahydroquinolinone and tetrahydroisoquinolinone. However, these compounds do not contain indole, as the compounds of the present invention. It is said that these compounds are ligands of dopamine receptors Ό ₄ , suitable as

- 1 006315 antipsychotic drugs. It is also claimed that the compounds described in XVO 93/16073 possess antagonistic activity against 5-HT ₂ receptors.

Dopamine receptors E ₄ belong to the subfamily of dopamine receptors E ₂ , which is considered responsible for the antipsychotic effect of antipsychotics. Side effects of antipsychotic drugs, which exert their effect primarily through antagonism towards receptors Ό ₂ , are known to arise as a result of antagonism towards receptors Ό ₂ in the striatal regions of the brain. However, dopamine receptors Ό ₄ are located primarily in other, rather than striatal, regions of the brain, which suggests that antagonists of dopamine receptor Ό ₄ will be deprived of extrapyramidal side effects. This shows the antipsychotic drug clozapine, which exhibits a higher affinity for E ₄ receptors. than e ₂ . and does not have extrapyramidal side effects (Wai To1 e! a1. No.! Ie 1991, 350, 610; Na61eu Me61C1ia1 Vekezat Ve \ ze 1996, 16, 507-526 and Baiyet Εχρ. Ορίη. Th. Ra! ei! K 1998, 8, 383-393).

It has been shown that a number of Ό ₄ ligands, which, as stated, are selective antagonists of the E ₄ receptor (L-745879 and I-101958), have antipsychotic potential (Maikbac e! A1. Rkucorbactosodu 1998, 135, 194-200). However, it has recently been reported that these compounds are partial agonists of Ό ₄ receptors in various antigen efficacy studies (Ca / ί e! A1. Vg. 1. Pagtaso1. 1998, 124, 889-896 and Οηζί e! A1. Vg. 1 Pbacto1. 1999, 128, 613-620). In addition, it was shown that clozapine, which is an effective antipsychotic drug, is a latent antagonist (Όηζί е! А1. Вg. 1. Рагтасо1. 1999, 128, 613-620).

Thus, ligands Ό ₄ , which are partial agonists or antagonists of receptors Ό ₄ , may have a beneficial effect in psychoses.

Antagonists of dopamine receptors Ό ₄ may also be suitable for the treatment of cognitive deficits (1e! Ksb e! A1. Rkusorbattasodu 1999, 142, 78-84).

In addition, data were published demonstrating the genetic relationship between the primary inattentive subtype ΑΌΗΌ and the tandem duplication polymorphism in the gene encoding the dopamine receptor E ₄ (Mssgaskey e! A1. Mo1. Rkusa !. 2000, 5, 531-536). This clearly indicates the relationship between the dopamine receptor Ό ₄ and ΑΌΗΌ, and ligands acting on the specified receptor may be suitable for the treatment of this particular disorder.

The dopamine receptors Ό ₃ also belong to the subfamily of dopamine receptors Ό ₂ , and they are located mainly in the limbic regions of the brain (Zok1oGG e! A1. No. Igry 1990, 347, 146-151), such as the blocker dopamine, where the dopamine blockade receptors associated with antipsychotic activity ^ 111iet 1i !. Syssa1 Rkusorbattasoodu 1997, 12, 297-308). In addition, an increase in receptor level ₃ in the limbic part of the brain of people with schizophrenia has been reported (Siguyu e! A1. Agc. Oey. Rkusyta 1997, 54, 225-32). Consequently, antagonists of receptors Ό ₃ can potentially be used for effective antipsychotic therapy without extrapyramidal side effects inherent in classical antipsychotic drugs, which exert their effect, primarily due to blockade of receptors E ₂ (8LaGet e! A1. Rkusorbactasoda 1998, 135, 1 -16 and 5> cb \\ wi e! A1. That time we have Bee1e \\ b 2000, 31, 277-287.

In addition, blockade of receptors No. ₃ causes mild stimulation of the prefrontal cortex of the brain (Mexibia! E! A1. Segeba1 Soiech 1996, 6, 561-570), which may be beneficial against negative symptoms and cognitive deficits associated with schizophrenia. In addition, antagonists of receptors могут ₃ can reverse the antagonist E ₂ EP8 induced (M111ai e! A1. Eig. 1. Pagtaco. 1997, 321, B7-B9), and do not cause changes in prolactin levels (Beacu e! A1. 1. Pagtaco1. Exp. Thy. 2000, 294, 1154-1165). Therefore, antagonistic with respect to Ό ₃ properties of an antipsychotic drug can reduce negative symptoms and cognitive deficits and lead to an improvement in the side effect profile in terms of EP8 and hormonal changes.

It is also believed that agonists of dopamine receptors пригод ₃ are suitable for the treatment of schizophrenia (^ I51o \\ · e! A1. Stew! Pagantaseis 1 Ee ^ di 1997, 3, 391-404).

Various effects are known associated with compounds that are ligands of various subtypes of serotonin receptors. Regarding the 5-HT _2A receptor, formerly called the 5-HT ₂ receptor, the following effects have been reported, for example:

Antidepressant effect and improved quality of sleep (Meey e! A1. Aegid Eyu. Century 1989, 18, 119), reduction of negative symptoms of schizophrenia and extrapyramidal side effects caused by treatment with classical antipsychotics in patients with schizophrenia (Ce16egr. 155 (kyr1. 50), 33). In addition, selective 5-HT _2A antagonists could be effective in the prevention and treatment of migraine (Zspr Vera; M1dgashe - Sztei!! Gay6k 1 and hekeages aib! Gea! Tei !; P1B PbSbayoik b! B, May 1991) and for treatment anxiety states (Coiray e! a1. Rkusorobactas lodu 1985, 86, 303-305 and Reggedaaa e! a1. Stew! Ortyui t Thégareis Ra! ei, 1993, 1, 101-128).

In some clinical studies, the 5-HT ₂ receptor subtype is credited with a role in aggressive behavior. In addition, atypical antipsychotics, which are antagonists of serotonin dopamine receptors, have a 5-HT ₂ receptor antagonistic effect, according to

- 2 006315 past their properties to block dopamine receptors, and have been reported to possess the properties of treating aggressive behavior (Soppog e! A1. Exp. Θρίη. Weaves. Ra1ep18 1998, 8 (4), 350-351). Recently, evidence has also been accumulated in favor of selective 5-HT _2A antagonists as drugs capable of treating the positive symptoms of psychosis (Losept e! A1. 2000, 2 (1), 22-24).

Compounds that are 5-HT reuptake inhibitors are well known as antidepressants.

5-HT _2c ligands have been found to enhance the effects of 5-HT reuptake inhibitors in microdialysis experiments and experimental animals, and compounds having a 5-HT reuptake inhibitory effect, in combination with affinity for the 5-HT _2c receptor may therefore be particularly suitable for the treatment of depression and other disorders treatable with serotonin reuptake inhibitors (PCT Application No. PCT / EC00 / 00671).

Accordingly, dopamine receptor ligands Ό ₄ are potential drugs for treating schizophrenia and other psychoses, and compounds with combined effects on the 5-HT transporter may have additional benefits in terms of improved effects on depressive and negative symptoms in patients with schizophrenia. Compounds with a combined effect on the dopamine receptor Ό ₄ and the 5-HT _2a receptor may have additional benefits in terms of improved effects on the positive and negative symptoms of schizophrenia, and additional benefits in terms of effects on depressive and anxiety symptoms. In addition, antipsychotic drug antagonistic properties of the Ό ₃ receptor Ό ₃ can reduce the negative symptoms and cognitive deficits of schizophrenia and cause an improvement in the side effect profile.

SUMMARY OF THE INVENTION

The aim of the present invention is to provide compounds that are partial agonists or antagonists of the dopamine receptor Ό ₄ , and similar compounds with combined effects on dopamine receptor Ό ₄ , receptor Ό ₃ , 5-HT _2A receptor, 5-HT _2c receptor and / or transporter 5-HT.

Another objective of the present invention is to provide compounds with the indicated properties, which have improved solubility compared to previously known prototype compounds.

Accordingly, the present invention relates to new compounds of formula I

where (a) one of Υ ¹ and Υ ² represents Ν, which is associated with Υ ⁴ , and the other of Υ ¹ and Υ ² represents CO, C8, 8O or 8O2, and Υ ⁴ represents CH2;

(b) one of Υ ¹ and Υ ² is Ν that is bonded to Υ ⁴ , and the other of Υ ¹ and Υ ² is CH2, and Υ ⁴ is CO, C8, 8O, or 8O2; or (c) one of Υ ¹ and Υ ² is Ν that is bonded to Υ ⁴ , and the other of Υ ¹ and Υ ² is CH2, and Υ ⁴ is CH2;

Υ ³ represents Ζ-ί.Ή _; . ί.Ή _; -Ζ or CH ₂ CH ₂ , and Ζ represents O or 8; provided that when Υ ¹ is Ν, Υ ³ may not be Ζ-SS;

represents a bond or a group of O, 8, CO, C8, 8O or 8O ₂ ;

n is 0-5, t is 0-5, and t + Ν is 1-10; provided that when it is O or 8, then n> 2, and m>1; when represents CO, C8, 8O or 8O ₂ , then n> 1, and m>1;

X represents C, CH or Ν; with the proviso that when X represents C, the dashed line indicates a bond, and when X represents Ν or CH, the dashed line is not a bond;

⁹ RS-K are independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, C 1 _-6 alkylamino, di-C 1 _-6 alkylamino, C1 _-6 -alkyl, C _2-6 -alkenyl, C _{2- 6} -alkynyl, C _1-6 alkoxy, C1 _-6 alkylthio, C1 _-6 alkyl substituted with a hydroxyl group or a thiol group, C _3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, an acyl group, thioacyl group, aryl group, trifluoromethyl group, trifluoromethylsulfonyl group and C1-6 alkylsulfonyl;

K ¹⁰ represents hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl substituted with a hydroxyl group or thiol group, C _3-8 cycloalkyl, C _{3 -8-} cycloalkyl-C _1-6 -alkyl, aryl

- 3 006315 group, an aryl-S1_ ₆ -alkyl acyl group tioatsilnuyu group, a C1. _6- alkylsulfonyl, trifluoromethylsulfonyl or arylsulfonyl group, or pharmaceutically acceptable acid addition salts thereof.

In a first specific embodiment of the present invention, the indole is linked to X at the 3 position of the indole.

In a second embodiment of the present invention, one of Υ ¹ and Υ ² is Ν, which is bonded to Υ ⁴ , and the other of Υ ¹ and Υ ² is CO, and Υ ⁴ is CH ₂ .

In a third embodiment of the present invention, one of Υ ¹ and Υ ² is Ν that is bonded to Υ ⁴ , and the other of Υ ¹ and Υ ² is CH2, and Υ ⁴ is CO.

In a fourth embodiment of the present invention, Υ ¹ is nitrogen, which is bonded to Υ ⁴ , and one of Υ ⁴ and Υ ² is CO and the other is CH2.

In a fifth embodiment of the present invention, Υ ¹ is nitrogen which is bonded to Υ ⁴ , Υ ² is CO, and Υ ⁴ is CH ₂ .

In a sixth embodiment of the present invention, Υ ¹ is nitrogen which is bound to Υ ⁴ , Υ ² is CH2, and Υ ⁴ is CO.

In a seventh embodiment of the present invention, Υ ² is nitrogen which is bonded to Υ ⁴ , and one of Υ ¹ and Υ ⁴ is CO and the other is CH2.

In an eighth embodiment of the present invention, Υ ² is nitrogen which is bound to Υ ⁴ , Υ ¹ is CH2, and Υ ⁴ is CO.

In a ninth embodiment of the present invention, Υ ² is nitrogen which is bound to Υ ⁴ , Υ ¹ is CO, and Υ ⁴ is CH2.

In a tenth embodiment of the present invention, one of Υ ¹ and Υ ² is Ν, which is associated with Υ ⁴ , and the other of Υ ¹ and Υ ² is CH2, and Υ ⁴ is CH2. These compounds are preferably in the form of their pharmaceutically acceptable double salts.

In yet another embodiment of the present invention, Υ ³ is CH ₂ CH ₂ or ΟΗ ₂ Ζ.

In still other embodiments, X is C, X is N, or X is CH.

The substituents ΚΖ-Κ ⁹ , in particular, are selected from hydrogen, halogen, cyano, nitro, amino, C1-6-alkylamine, di-C1-6-alkylamine, C1-6-alkyl, C3-8-cycloalkyl and trifluoromethyl groups, and Κ ¹⁰ represents hydrogen, a C1-6 alkyl or acyl group, and / or V represents a bond, and η + t is from 1 to 6, in particular from 3 to 6.

The compounds of the present invention are partial agonists or antagonists of the dopamine receptor Ό ₄ . Many compounds have a combined effect on dopamine receptor Ό ₄ and dopamine receptor Ό ₃ , 5-HT _2A receptor, 5-HT _2c receptor, and / or a 5-HT reuptake inhibitory effect.

Accordingly, the compounds of the present invention are considered useful for treating the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders such as generalized anxiety disorder, panic disorder and obsessive-compulsive disorder, depression, aggression, side effects induced by common antipsychotic agents, migraines, cognitive impairment, ΆΌΗΌ, and also to improve sleep.

In another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula I, as defined above, or a pharmaceutically acceptable acid addition salt thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.

In yet another aspect, the present invention relates to the use of a compound of formula I, as defined above, or an acid addition salt thereof, for the manufacture of a pharmaceutical preparation for the treatment of the above disorders.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of general formula I may exist as optical isomers, and these optical isomers are also included in the scope of the present invention.

The term “C _1-6 alkyl” refers to a branched or unbranched alkyl group having from one to six carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2methyl-2-propyl, 2-methyl-1-propyl, pentyl and hexyl.

Similarly, C _2-6 alkenyl or C _2-6 alkynyl, respectively, denote these groups having from two to six carbon atoms, including one double bond and a triple bond, respectively, such as ethenyl, propenyl, butenyl, ethynyl , propynyl and butynyl.

The terms C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfonyl, C _1-6 alkylamine, C _1-6 alkylcarbonyl, and the like. denote these groups in which the alkyl group is C _1-6 -alkyl, as defined above.

The term C _3-8 -cycloalkyl means a monocyclic or bicyclic carbocycle having from

- 4 006315 three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl and the like.

The term aryl refers to a carbocyclic aromatic group such as phenyl, naphthyl, in particular phenyl, including phenyl substituted with methyl, or naphthyl.

Halogen means fluoro, chloro, bromo or iodo. The term acyl as used herein refers to a formyl, a C1 _-6 alkylcarbonyl, arylcarbonyl, aryl-C1 _-6 alkylcarbonyl, _{C3-8-cycloalkylcarbonyl} or a _C3-8 -cycloalkyl-C _{1-b-alkylcarbonyl} group and the term thioacyl refers to the corresponding acyl group in which the carbonyl group is replaced by a thiocarbonyl group.

Acid addition salts of the compounds of the present invention are pharmaceutically acceptable salts formed with non-toxic acids. Examples of these organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylene salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, dairy, apple, almond, almond, zinc , stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as with 8-halogenophyophyllines, for example, 8bromteophylline. Examples of these inorganic salts are salts with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The pharmaceutical compositions of the present invention or compositions that are made in accordance with the present invention can be administered by any convenient route, for example, orally, in the form of tablets, capsules, powders, syrups and the like, or parenterally, in the form of injection solutions. For the manufacture of these compositions, methods well known to those skilled in the art and any pharmaceutically acceptable carriers, diluents, excipients or other excipients that are commonly used in the art can be used.

The compounds of the present invention are conveniently administered in the form of a dosage form containing the compounds in an amount of from about 0.01 to about 100 mg.

The total daily dose is usually in the range of about 0.05 to 500 mg, and most preferably about 0.1 to 50 mg of the active compound of the present invention.

The compounds of the present invention can be obtained as follows:

1) Alkylation of piperazine, piperidine or tetrahydropyridine of formula II with an alkylating derivative of formula III I *

(L) OY where Κ, '- Κ. ¹⁰ . X, Υ ¹ , Υ ² , Υ ³ , Υ ⁴ , η, t and the dashed line are as defined above, and b represents a leaving group such as halogen, mesylate or tosylate;

2) The reductive alkylation of an amine of formula II with a reagent of formula IV

where KZ-K ¹⁰ , X, Υ ¹ , Υ ² , Υ ³ , Υ ⁴ , η, t and the dashed line are defined above, and E represents an aldehyde or an activated carboxylic acid group;

3) Alkylation of a compound of formula V with an alkylating derivative of formula VI

- 5 006315

where K'-K ¹⁰ , X, Υ ³ , V. η, t and the dashed line are defined above, one of Υ ⁵ and Υ ⁶ is ΝΗ or Ν ^- , and the other of Υ ⁵ and Υ ⁶ is CO, C8 80, 8O ₂ or CH ₂ , and b represents a leaving group such as halogen, mesylate or tosylate; or

4) Reduction of the double bond in the tetrahydropyridinyl ring in derivatives of the following formula VII

where KZ-K ¹⁰ , Υ ¹ , Υ ² , Υ ³ , Υ ⁴ , V, η and m are defined above;

5) Reduction of carbonyl amide in the compound of formula VIII

where KZ-K ¹⁰ , Υ ¹ , Υ ² , Υ ³ , Υ ⁴ , η, t, V and the dashed line are defined above

6) Reduction of the amide group of compounds of formula IX

where KZ-K ¹⁰ , X, Υ ¹ , Υ ² , Υ ³ , η, t, V and the dashed line are defined above;

7) Reductive alkylation of a derivative of the formula να with an acylating derivative of the formula X:

- 6 006315

1103 78 where B-B, X, Υ, V. η, t and the dashed line are defined above, one of Υ and Υ is ΝΗ, and the other of Υ ⁷ and Υ ⁸ is CH ₂ , and E is aldehyde or activated carboxylic acid group;

8) Acylation of an amine of formula Wa with a reagent of formula X

1103 78 where BB, X, Υ, V, η, t and the dashed line are defined above, one of Υ and Υ is Υ, and the other of из ⁷ and Υ ⁸ is CH ₂ , and E is aldehyde or activated carboxylic acid group;

9) Cleavage of the polymer bond of the derivative of formula XI

where B ¹ -B ⁹ , Υ ¹ , Υ ² , Υ ³ , X, V, t and η are defined above, and B'OH is hydroxyethyl or hydroxymethyl polystyrene, resin \ Uapd or similar polyethylene glycol polystyrene resins; after which the compound of formula I is isolated in the form of a free base or its pharmaceutically acceptable acid addition salt.

Alkylation according to method 1) and 3) is conveniently carried out in an inert organic solvent, such as alcohol or a ketone with a suitable boiling point, preferably in the presence of an organic or inorganic base (potassium carbonate, diisopropylethylamine or triethylamine) at reflux temperature. Alternatively, the alkylation can be carried out at a fixed temperature, which differs from the boiling point, in one of the above solvents or in dimethylformamide (ΌΜΕ), dimethyl sulfoxide (ΌΜ8Ο) or Ν methylpyrrolidin-2-one (ΝΜΡ), preferably in the presence of a base.

The synthesis of amines of formula (II), 3- (piperidin-4-yl) -1H-indoles and 3- (3,6-dihydro-2H-pyridin-4-yl) 1H-indoles is described in the literature (see, for example, EP-A1-465398). Alkylating reagents of formula (III) are known from the literature (see Ochigo e! A1. I. Meb. Siet. 2000, 43, 177-189 and EP-B 1-512525) or they can be obtained by methods obvious to a specialist chemist ( see, for example, Κο \ ν; · ι151 <ί e! a1. 1. Non-Gosus11s Set. 2000, 37, 187-189, Mokgo5 / e! a1. Rkati-She 1997, 52, 423-428 and Μίκζίαΐ e! a1. Furniture. Suite. Century. 1992,

- 7 006315

2, 82-87). Alkylating reagents of formula (VI) can be obtained by methods obvious to a specialist chemist, and amines of formula (V) are commercially available or described in the literature.

Reductive alkylation according to methods 2) and 7) is carried out using conventional methods described in the literature. The reaction can be carried out in two stages, for example, by coupling derivatives of formula PAa and a reagent of formula ΐν / Χ using conventional methods, via carboxylic acid chloride, or using coupling reagents such as dicyclohexylcarbodiimide, followed by reduction of the resulting amide with lithium aluminum hydride or Alan. The reaction can be carried out using the usual procedure, in one vessel. Carboxylic acids or aldehydes of the formula ΐν / Χ can be obtained by methods obvious to a specialist chemist.

Alkylation according to method 3) can conveniently be carried out as described above, or by reacting a nitrogen anion V with VI. The nitrogen anion V can be obtained in an inert organic solvent, for example, in dimethylformamide (ΌΜΡ), dimethyl sulfoxide (ΌΜ8ΌΜ) or Y-methylpyrrolidin-2-one (ΝΜΡ), using a strong base, for example, ΝαΗ, before alkylation.

The double bond reduction according to method 4) is usually carried out by low pressure catalytic hydrogenation (<3 atm) in a Parr apparatus or using reducing agents, such as diborane or hydroboric derivatives, obtained from ίΐη δίΐιι from ΝαΒΗ ₄ in trifluoroacetic acid in inert solvents, such like tetrahydrofuran (TIR), dioxane or diethyl ether. The starting materials of formula (VII) can be obtained by methods 1), 3), 7) and 8).

The reduction of amide groups according to methods 5) and 6) is most conveniently carried out with lithium aluminum hydride or alan in an inert organic solvent, such as, for example, tetrahydrofuran (THP) or diethyl ether, at a temperature from 0 ° C to a boiling temperature under reflux . The starting materials of formula (VIII) can be obtained by methods 2) and 3), while the starting materials of formula (IX) can be obtained by methods 1), 7) and 8).

The interaction according to method 8) is conveniently carried out using interacting reagents, such as, for example, dicyclohexylcarbodiimide.

Derived structures (XI) are obtained by the following solid phase synthesis sequence shown in Scheme 1 below. The first building block (XII), obtained by methods obvious to the chemist, is usually attached to a resin (ethyl 4-nitrophenyl carbonate bonded to polystyrene) using a base, for example

Ν, Ν-dimethylaminopyridine and Ν, Ν-diisopropylethylamine, at an elevated temperature (e.g., 50-100 ° C.) in an aprotic solvent (e.g., ΌΜΡ or ΌΜ8Ο), to give (XIII). After deprotection of the amino group with trifluoroacetic acid (resin XIV), a second diversifying building block is introduced via alkylation. Alkylation is carried out at elevated temperature (50-100 ° C) in an aprotic solvent such as ΌΜΡ, acetone or acetonitrile, resulting in a resin (XV). After deprotection of the carboxylic acid ester with trifluoroacetic acid (resin XVI), by means of a standard sequence of amide-forming reactions, for example, conversion of the carboxylic acid to the corresponding acid chloride using thionyl chloride at low temperature in dichloromethane, acetonitrile or ΌΜΡ, followed by the action of an amine, a third diversifying construction substance is introduced block of the formula (V;). The final product is cleaved from the resin using dilute sodium methoxide in methanol / tetrahydrofuran at room temperature.

Scheme 1

- 8 006315

Experimental Section

The melting point was determined on a Visa B-540 apparatus and was not corrected. Mass spectra were obtained using the Oniigo M8-M8 system from the company US Vyu! Es, E18op8 1p8! Gitep! 8. Analytical data JS-M8 were obtained using the PE 8c1ex AP1 150EX tool equipped with a source of Sop8pgau and EC-8A / 8S-10A b-system 81itabhi. The bC conditions (50x4.6 mm ΥMS OE8-A with a particle size of 5 μm) were linear gradient elution with a mixture of water / acetonitrile / trifluoroacetic acid (90: 10: 0.05) to a mixture of water / acetonitrile / trifluoroacetic acid (10:90 : 0.03) in 7 minutes at a rate of 2 ml / min. Purity was determined by the integration of the U / F trace. (254 nm). The delay time K was expressed in minutes. Preparative L-M8 separation was carried out using the same tool. The bC conditions (50x20 mm ΥMS OE8-A with a particle size of 5 μm) were linear gradient elution with a mixture of water / acetonitrile / trifluoroacetic acid (80: 20: 0.05) to a mixture of water / acetonitrile / trifluoroacetic acid (5: 95: 0 , 03) for 7 minutes at a rate of 22.7 ml / min. The fractions were collected using M8 detection with separation by flow.

¹ H NMR spectra were recorded at 250.13 MHz using Vgikeg AC 250 or 500.13 MHz using Vgikeg ΌΡΧ 500. Deuterated chloroform (99.8% Ό) or dimethyl sulfoxide (99.9% Ό) were used as solvents. As an internal standard used TM8. Chemical shifts were expressed in parts per million. The following abbreviations were used for many NMR signals: 8 = singlet, b = doublet, ΐ = triplet, s. | = quartet, c | x = quintet, d = heptet, bb = double doublet, 6ΐ = double triplet, bs. | = double quartet, ίί = triplet of triplets, t = multiplet, d = wide. NMR signals corresponding to acid protons were omitted to some extent. The water content in crystalline compounds was determined by Karl Fischer titration. Silica gel of the K1e8e1de1 60 type, mesh 40-60 was used for column chromatography. The following material was used for ion-exchange chromatography: 8CX columns (1 g) from Uapap Meda Wopb E1i! ®, Sigotrask cat. No. 220776. Prior to use, the 8CX columns were pre-treated with a 10% solution of acetic acid in methanol (3 ml).

Examples

Preparation of Intermediates

A. Alkylating reagents

1- (2-chloroethyl) -3,4-dihydroquinolin-2 (1H) -one

A suspension of sodium hydride (3.0 g, 60% in mineral oil) and dimethylformamide (100 ml) was kept at 15-18 ° C, after which a solution of 3,4-dihydroquinolin-2 (1H) -one (10.0 g) was added. ) in dimethylformamide (150 ml). The resulting mixture was stirred at room temperature for 60 minutes, after which a solution of 2-chloroethyl acetate (10.0 g) in dimethylformamide (50 ml) was added at a temperature of 20 ° C. The resulting mixture was heated to 80 ° C for 24 hours, cooled and poured onto ice. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried (Md8O ₄₎ and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate / heptane 1: 1) to give crude 1- (2-acetoxyethyl) 3,4-dihydroquinoline-2 (1H) -one (10.2 g). A mixture of crude 1- (2-acetoxyethyl) -3,4-dihydroquinolin-2 (1H) -one, sodium methanolate (2.5 ml, 30% in methanol) and methanol (250 ml) was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / heptane 1: 1) to give the corresponding alcohol as a crystalline red compound (4.9 g). This alcohol was dissolved in tetrahydrofuran (100 ml), after which triethylamine (8.2 ml) was added. The resulting mixture was cooled to 5-6 ° C, after which a solution of methanesulfonic acid chloride (2 ml) in tetrahydrofuran (25 ml) was added. The mixture was filtered and evaporated to dryness under vacuum. The residue was dissolved in dimethylformamide (50 ml), after which lithium chloride (4.9 g) was added and the resulting mixture was heated to 70 ° C for 5 minutes. The mixture was poured into brine, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (Md8O ₄₎ filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / heptane 1: 1) to give the product as a red oil (2.9 g).

1- (3-bromoprolan-1-yl) -3,4-dihydroquinolin-2 (1H) -one

A suspension of sodium hydride (6.8 g, 60% in mineral oil) and dimethylformamide (200 ml) was kept at 20-25 ° C, after which a solution of 3,4-dihydroquinolin-2 (1H) -one (25.0 g) was added. ) in dimethylformamide (180 ml). The resulting mixture was stirred at room temperature for 10 minutes, after which a solution of 1,3-dibromopropane (172 g) in dimethylformamide (150 ml) was added at a temperature of 2035 ° C. The resulting mixture was stirred at 30 ° C for 20 minutes and concentrated in vacuo. The residue was poured onto ice and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried (MgO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate / heptane 1: 1) to give the product as a yellow oil (27 g).

- 9 006315

The following compounds were obtained in a similar manner:

1- (4-bromobutan-1-yl) -3,4-dihydroquinolin-2 (1H) -one of 3,4-dihydroquinolin-2 (1H) -one and 1,4-dibromobutane;

1- (5-bromopentan-1-yl) -3,4-dihydroquinolin-2 (1H) -one of 3,4-dihydroquinolin-2 (1H) -one and 1,5-dibromopentane;

4- (4-bromobutan-1-yl) -3,4-dihydro-2H-1,4-benzoxazin-3 (4H) -one of 3,4-dihydro-2H-1,4-benzoxazin-3 (4H ) -one and 1,4-dibromobutane;

2- (3-hydroxypropan-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one of 3,4-dihydroisoquinolin-1 (2H) -one and 3-bromopropanol;

2- (4-bromobutan-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one of 3,4-dihydroisoquinolin-1 (2H) -one and 1,4-dibromobutane

1- (3-bromopropan-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one.

The compound 2- (3-hydroxypropan-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one was dissolved in tetrahydrofuran (100 ml), after which triethylamine (5.2 ml) was added.

The resulting mixture was cooled to 6-11 ° C., after which a solution of methanesulfonic acid chloride (1.4 ml) in tetrahydrofuran (25 ml) was added. The mixture was stirred at 5 ° C for 10 min, filtered and concentrated in vacuo. The residue was dissolved in acetone (250 ml), after which lithium bromide (6.5 g) was added and the resulting mixture was refluxed for 2 hours. The mixture was poured into brine and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / heptane 1: 2) to give the product as a yellow oil (2.7 g).

3- chloro-1 - (3,4-dihydro-1H-isoquinolin-2-yl) propan-1-one

A solution of 3-chloropropanoyl chloride (10.5 g) in tetrahydrofuran (400 ml) was cooled to 6 ° C, after which a solution of 3,4-dihydro-1H-isoquinoline (10.0 g) was added. The resulting mixture was stirred at 10 ° C for 30 min, filtered and concentrated in vacuo. The residue was subjected to standard aqueous work-up, after which it was purified by flash chromatography on silica gel (eluent: ethyl acetate / heptane 1: 1) to give the product as a colorless oil (10 g).

The following compounds were obtained in a similar manner:

3-bromo-1 - (3,4-dihydro-1H-isoquinolin-2-yl) propan-1-one of 3,4-dihydro-1H-isoquinoline and 3-bromopropanoyl chloride;

4-chloro-1 - (3,4-dihydro-1H-isoquinolin-2-yl) butan-1-one of 3,4-dihydro-1H-isoquinoline and 4-chlorobutanoyl chloride;

4-chloro-1 - (3,4-dihydro-2H-quinolin-1-yl) butan-1-one of 3,4-dihydro-2H-quinoline and 4-chlorobutanoyl chloride

Preparation of Solid Intermediates

Preparation of 4-nitrophenyloxycarbonyloxyethyl polystyrene A round-bottomed flask was charged with hydroxyethyl polystyrene (62.9 g, 83 mmol, sold by Carr Ro1utege, Cat. No. 1 400 00), метил-methylmorpholine (20 ml, 183 mmol) and dry dichloromethane (900 ml ) The suspension was cooled in an ice bath and 4 nitrophenyl chloroformate dissolved in dry dichloromethane (400 ml) was added over 5 minutes. The mixture was stirred at room temperature for 16 hours. The resin was filtered and washed with dry dichloromethane (5x200 ml). The resin was dried under vacuum (20 ° C, 72 hours) to give the title resin (79.6 g).

Preparation of 7-chloro-3- (piperidin-4-yl) -1H-indole bound to a polymer

A 100 ml round bottom flask was charged with 4-nitrophenyloxycarbonyloxyethyl polystyrene (4.0 g, 4.3 mmol), 7-chloro-3- (1-tert-butoxycarbonylpiperidin-4-yl) -1H-indole (2.7 g, 8 , 1 mmol), diisopropylethylamine (3.5 ml, 20.2 mmol), 4-dimethylaminopyridine (0.5 g, 4 mmol) and dry dimethylformamide (50 ml). The mixture was stirred at 90 ° C for 72 hours. After cooling to room temperature, the resin was filtered and washed with dry dimethylformamide (3x25 ml), dry acetonitrile (3x25 ml) and dry dichloromethane (3x25 ml). The resin was transferred to a 250 ml glass cylinder with a frit and a triple adapter at the bottom. The resin was then acted on for 60 minutes with a 60 ml 1: 1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2% w / w) and methionine (0.2% w / w) using a nitrogen stream to mix resins (warning: carbon dioxide emission). The resin was filtered and washed with dry dichloromethane (25 ml), 1: 1 with a mixture of dichloromethane: triethylamine (3x25 ml) and dry dichloromethane (3x25 ml). The resin was dried under vacuum (20 ° C, 20 hours) to give the title resin (3.8 g).

The following polymer related compounds were prepared in a similar manner:

4-chloro-3 - (piperidin-4-yl) -1H-indole;

4-fluoro-3 - (piperidin-4-yl) -1H-indole;

5-chloro-3 - (piperidin-4-yl) -1H-indole;

5-fluoro-3 - (piperidin-4-yl) -1H-indole;

- 10 006315

6-chloro-3 - (piperidin-4-yl) -1H-indole.

Preparation of 3- [4- (7-chloro-1H-indol-3-yl) piperidin-1-yl] propionic acid bound to a polymer; ml round-bottom flask was charged with 7-chloro-3- (piperidin-4-yl) -1H-indole bound to the polymer (1.0 g, 0.98 mmol), triethylamine (80.2 ml), tert-butyl-3-bromopropionate and dry acetonitrile (5 ml). The mixture was stirred at 80 ° C for 3 hours. After cooling to room temperature, the resin was filtered and washed with dry acetonitrile (3x10 ml) and dry dichloromethane (3x10 ml). The resin was treated for 20 minutes with 8 ml of a 1: 1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2% w / w) and methionine (0.2% w / w) (warning: carbon dioxide evolution). The resin was filtered and washed with dry dichloromethane (10 ml), 1: 1 with a mixture of dichloromethane: triethylamine (3x10 ml) and dry dichloromethane (3x10 ml). The resin was dried under vacuum (20 ° C, 20 hours) to give the title resin (1.0 g).

The following polymer related compounds were prepared in a similar manner:

3- [4- (4-chloro-1H-indol-3-yl) piperidin-1-yl] propionic acid

3- [4- (4-fluoro-1H-indol-3-yl) piperidin-1-yl] propionic acid

3- [4- (5-fluoro-1H-indol-3-yl) piperidin-1-yl] propionic acid

3- [4- (6-chloro-1H-indol-3-yl) piperidin-1-yl] propionic acid

4- [4- (4-chloro-1H-indol-3-yl) piperidin-1-yl] butyric acid

4- [4- (4-fluoro-1H-indol-3-yl) piperidin-1-yl] butyric acid

4- [4- (5-chloro-1H-indol-3-yl) piperidin-1-yl] butyric acid

4- [4- (5-fluoro-1H-indol-3-yl) piperidin-1-yl] butyric acid

4- [4- (7-chloro-1H-indol-3-yl) piperidin-1-yl] butyric acid

5- [4- (4-chloro-1H-indol-3-yl) piperidin-1-yl] pentanoic acid

5- [4- (5-fluoro-1H-indol-3-yl) piperidin-1-yl] pentanoic acid

5- [4- (7-chloro-1H-indol-3-yl) piperidin-1-yl] pentanoic acid

6- [4- (4-fluoro-1H-indol-3-yl) piperidin-1-yl] hexanoic acid

6- [4- (4-chloro-1H-indol-3-yl) piperidin-1-yl] hexanoic acid

6- [4- (5-fluoro-1H-indol-3-yl) piperidin-1-yl] hexanoic acid

6- [4- (6-chloro-1H-indol-3-yl) piperidin-1-yl] hexanoic acid

6- [4- (7-chloro-1H-indol-3-yl) piperidin-1-yl] hexanoic acid

Obtaining compounds of the present invention

Example 1. 1a, 5-fluoro-3- {1- [2- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) ethyl] piperidin-4yl} -1H-indole hydrochloride

A mixture of 5-fluoro-3- (piperidin-4-yl) -1H-indole (0.3 g), 1- (2-chloroethyl) -3,4-dihydroquinolin-2 (1H) -one (0.41 g ) and triethylamine (0.75 g) in dimethylformamide (5 ml) and butanone (10 ml) were refluxed for 6 hours. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / ethanol / triethylamine 90: 10: 5) to obtain a crude product which was isolated from acetone in the form of a hydrochloride salt as a white crystalline compound (0.04 g). Ή NMR (DMSO- _4-6 ): 2.00-2.25 (m, 4H); 2.60 (t, 2H); 2.90 (t, 2H); 2.95-3.10 (m, 1H); 3.10-3.30 (m, 4H); 3.70 (d, 2H); 4.35 (t, 2H); 6.90 (t, 1H); 7.05 (t, 1H); 7.15-7.40 (m, 5H); 7.50 (d, 1H); 10.95 (br s, 1H); 11.05 (s, 1H), MS t / ζ: 392 (MH +), 174.

The following compounds were obtained in a similar manner:

lb, 5-fluoro-3- {1- [3- (1-oxo-3,4-dihydro-1H-quinolin-2-yl) propan-1-yl] piperidin-4-yl} -1indole oxalate -fluoro-3- (piperidin-4-yl) -1H-indole and 1- (3-bromopropan-1-yl) -3,4-dihydroisoquinoline1 (2H) one.

Ή NMR (DMSO-a ₆ ): 1.90-2.15 (m, 6H); 2.95-3.15 (m, 7H); 3.55-3.60 (m, 6H); 6.90 (t, 1H); 7.20 (s, 1H); 7.30 (d, 1H); 7.30-7.40 (m, 4H); 7.45-7.50 (m, 1H); 7.90 (d, 1H); 11.05 (s, 1H), MS t / ζ: 406 (MH +), 188.

lc, 5-fluoro-3- {1- [4- (1-oxo-3,4-dihydro-1H-quinolin-2-yl) butan-1-yl] piperidin-4-yl} 1 H-indole hydrochloride from 5-fluoro-3- (piperidin-4-yl) -1H-indole and 2- (4-bromobutan-1-yl) -3,4-dihydroisoquinolin-1 (2H) she. Ή NMR (DMSO-a ₆ ): 1.55-1.70 (m, 2H); 1.70-1.85 (m, 2H); 2.05 (d, 2H); 2.10-2.25 (m, 2H); 2.90-3.15 (7H); 3.40-3.65 (m, 6H); 6.90 (t, 1H); 7.20 (s, 1H); 7.30 (d, 1H); 7.30-7.40 (m, 2H); 7.40-7.55 (m, 2H); 7.90 (d, 1H);

10.75 (br s, 1H); 11.05 (s, 1H), MS t / ζ: 420 (MH +).

Example 2

2a, 5-fluoro-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4yl} -1H-indole hydrochloride

A mixture of 5-fluoro-3- (piperidin-4-yl) -1H-indole (5.0 g), 1- (3-bromopropan-1-yl) -3,4-dihydroquinoline2 (1H) -one (7, 7 g) and potassium carbonate (7.0 g) in dimethylformamide (40 ml) were heated to 100 ° C for 2.5 hours. The mixture was cooled, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate, then ethyl acetate / ethanol 90:10) to give the product as an orange oil (9.1 g). The title compound (1.8 g of the free base) was isolated in the form of a hydrochloride salt from tetrahydrofuran as a crystalline compound

- 11 006315 white (1.5 g). T. pl. 210-212 ° C. Ή NMR (DMSO-be): 2.00-2.20 (m, 6H); 2.60 (t, 2H); 2.90 (t, 2H); 2.95-3.10 (m, 3H); 3.10-3.20 (m, 2H); 3.55 (d, 2H); 3.95 (t, 2H); 6.90 (t, 1H); 7.05 (t, 1H); 7.15-7.30 (m, 4H); 7.30-7.40 (m, 1H); 7.50 (d, 1H); 10.55 (br s, 1H); 11.05 (s, 1H), MS t / ζ: 406 (MH +).

The following compounds were obtained in a similar manner:

2b, 5-fluoro-3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4yl} -1H-indole hydrochloride from 5 -fluoro-3- (piperidin-4-yl) -1H-indole and 1- (5-bromopentan-1-yl) -3,4-dihydroquinolin-2 (1H) -one. T. pl. 199-200 ° C. '11 NMR (DMSO-b ₆ ): 1.30-1.40 (m, 2H); 1.55-1.60 (m, 2H); 1.70-1.80 (m, 2H); 2.05-2.15 (m, 4H); 2.55 (t, 2H); 2.85 (t, 2H); 2.95-3.10 (m, 5H); 3.55 (d, 2H); 3.90 (t, 2H); 6.90 (t, 1H); 7.00 (t, 1H); 7.15 (d, 1H); 7.20-7.30 (m, 3H); 7.30-7.35 (m, 1H); 7.50 (d, 1H); 12.20 (br s, 1H); 11.05 (s, 1H), MS t / ζ: 434 (MH +).

2c, 5-chloro-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4yl} -1H-indole hydrochloride from 5 -chloro-3- (piperidin-4-yl) -1H-indole and 1- (3-bromopropan-1-yl) -3,4-dihydroquinolin-2 (1H) -one. T. pl. 142-146 ° C. Ή NMR (DMSO-b ₆ ): 1.95-2.15 (m, 6H); 2.60 (t, 2H); 2.90 (t, 2H); 2.95-3.15 (3H); 3.15-3.20 (m, 2H); 3.55 (d, 2H); 3.95 (t, 2H); 7.00-7.10 (m, 2H); 7.20-7.30 (m, 4H); 7.35 (d, 1H); 7.75 (s, 1H); 11.30 (br s, 1H); 11.15 (s, 1H), MS t / ζ: 422 (MH +), 188.

26, 5-chloro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} 1 H-indole hydrochloride from 5-chloro-3- (piperidin-4-yl) -1H-indole and 1- (4-bromobutan-1-yl) -3,4-dihydroquinolin-2 (1H) -one. T. pl. 229-231 ° C '11 NMR (DMSO-b ₆ ): 1.55-1.65 (m, 2H); 1.70-1.80 (m, 2H); 2.00-2.15 (m, 4H); 2.55 (t, 2H); 2.85 (t, 2H); 2.95-3.15 (m, 5H); 2.55 (d, 2H); 3.95 (t, 2H); 7.00 (t, 1H); 7.05 (d, 1H); 7.15 (d, 1H); 7.20-7.30 (m, 3H); 7.40 (d, 1H); 7.75 (s, 1H); 10.05 (br s, 1H); 11.10 (s, 1H), MS t / ζ: 436 (MH +).

2e, 5-chloro-3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4yl} -1H-indole hydrochloride from 5 -chloro-3- (piperidin-4-yl) -1H-indole and 1- (5-bromopentan-1-yl) -3,4-dihydroquinolin-2 (1H) -one. T. pl. 206-209 ° C. '11 NMR (DMSO-b ₆ ): 1.30-1.40 (m, 2H); 1.55-1.65 (m, 2H); 1.70-1.80 (m, 2H); 2.00-2.15 (m, 4H); 2.55 (t, 2H); 2.85 (t, 2H); 2.95-3.10 (m, 4H); 3.10-3.25 (m, 1H); 3.55 (d, 2H); 3.90 (t, 2H); 7.00 (t, 1H); 7.05 (d, 1H); 7.15 (d, 1H); 7.20-7.30 (m, 3H); 7.40 (d, 1H); 7.75 (s, 1H); 11.20 (br s, 1H); 11.15 (s, 1H), MS t / ζ: 450 (MH +), 299.

21, 7-chloro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} 1 H-indole hydrochloride from 7-chloro-3- (piperidin-4-yl) -1H-indole and 1- (4-bromobutan-1-yl) -3,4-dihydroquinolin-2 (1H) -one. T. pl. 253-254 ° C. Ή NMR (DMSO-b ₆ ); 1.55-1.65 (m, 2H); 1.75-1.85 (m, 2H); 2.05-2.25 (m, 4H); 2.55 (t, 2H); 2.90 (t, 2H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.95 (t, 2H); 6.95-7.05 (m, 2H); 7.15-7.30 (m, 5H); 7.70 (d, 1H); 10.60 (br s, 1H); 11.30 (s, 1H), MS t / ζ: 436 (MH +), 289.

2d, 5-fluoro-3- {1- [4- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} hydrochloride} -1H-indole from 5-fluoro-3- (piperidin-4-yl) -1H-indole and 4- (4-bromobutan-1-yl) -3,4-dihydro-2H-1,4-benzoxazin3 (4H )-she. T. pl. 83-92 ° C. '11 NMR (DMSO-be): 1.60-1.70 (m, 2H); 1.75-1.85 (m, 2H); 2.00-2.20 (m, 4H); 2,953.15 (m, 5H); 3.55 (d, 2H); 3.95 (t, 2H); 4.65 (s, 2H); 6.90 (t, 1H); 7.00-7.05 (m, 2H); 7.05-7.15 (m, 1H); 7.20 (s, 1H); 7.25 (d, 1H); 7.30-7.40 (m, 1H); 7.50 (d, 1H); 10.45 (br s, 1H); 11.05 (s, 1H), MS t / ζ: 422 (MH +), 273.

26, 5-chloro-3- {1- [4- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} hydrochloride} -1H-indole from 5-chloro-3- (piperidin-4-yl) -1H-indole and 4- (4-bromobutan-1-yl) -3,4-dihydro-2H-1,4-benzoxazine 3 (4H )-she. T. pl. 222-224 ° C. Ή NMR (DMSO-be): 1.60-1.7.0 (m, 2H); 1.75-1.85 (m, 2H); 2.05-2.15 (m, 4H); 3.00-3.15 (m, 5H); 3.55 (d, 2H); 3.95 (t, 2H); 4.65 (s, 2H); 7.00-7.10 (m, 4H); 7.20 (s, 1H); 7.25 (d, 1H); 7.40 (d, 1H); 7.75 (s, 1H); 10.30 (br s, 1H); 11.15 (s, 1H), MS t / ζ: 438 (MH +), 291, 204.

Example 3

3a, 5-fluoro-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] -3,6-dihydro-2Npyridin-4 oxalate -yl} -1H-indole

A mixture of 5-fluoro-3- (3,6-dihydro-2H-pyridin-4-yl) -1H-indole (3.0 g) and potassium carbonate (6.2 g) in butanone (250 ml) was heated to a temperature boiling under reflux, after which 1- (3bromopropan-1-yl) -3,4-dihydroquinolin-2 (1H) -one (5.0 g) in butanone (50 ml) was added. The resulting mixture was refluxed for 10 hours, filtered and concentrated in vacuo (7.7 g). The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / triethylamine 100: 5) to give a crude product which was crystallized from tetrahydrofuran / ethyl acetate. The title compound was isolated in the form of an oxalate salt as a yellowish crystalline compound (1.7 g). T. pl. 203-206 ° C. Ή NMR (DMSO-b ₆ ): 1.95-2.05 (m, 2H); 2.55 (t, 2H); 2.75 (s, 2H); 2.85 (t, 2H); 3.15 (t, 2H); 3.35 (s, 2H); 3.80 (s, 2H); 3.95 (t, 2H); 6.05 (s, 1H); 6.95-7.05 (m, 2H); 7.15-7.30 (m, 3H); 7.35-7.45 (m, 1H); 7.50-7.60 (m, 2H); 11.50 (s, 1H), MS t / ζ: 404 (MH +), 218.

- 12 006315

The following compounds were obtained in a similar manner:

3b, 5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] -3,6-dihydro-2Npyridin-4 hydrochloride -yl} -1 H-indole from 5-fluoro-3- (3,6-dihydro-2H-pyridin-4-yl) -1H-indole and 1- (4-bromobutan-1-yl) -3,4 -dihydroquinoline 2 (1H) -one. T. pl. 124-125 ° C. '11 NMR (DMSO- _6th ): 1.55-1.65 (m, 2H); 1.80 (q, 2H); 2.55 (t, 2H); 2.75 (d, 1H); 2,852.95 (m, 3H); 3.15-3.30 (m, 3H); 3.55-3.65 (m, 1H); 3.75 (d, 1H); 3.90-4.00 (m, 3H); 6.10 (s, 1H); 6.95-7.05 (m, 2H); 7.15 (d, 1H); 7.20-7.30 (m, 2H); 7.40-7.45 (m, 1H); 7.55-7.65 (m, 2H); 10.70 (br s, 1H); 11.50 (s, 1H), MS t / ζ: 418 (MH +), 231.

3c, 5-fluoro-3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] -3,6-dihydro-2Npyridin-4 oxalate -yl} -1 H-indole from 5-fluoro-3- (3,6-dihydro-2H-pyridin-4-yl) -1H-indole and 1- (5-bromopentan-1-yl) -3,4 -dihydroquinoline 2 (1H) -one. T. pl. 205-207 ° C. '11 NMR (DMSO-e): 1.35 (t, 2H); 1.55 (t, 2H); 1.75 (t, 2H); 2.55 (t, 2H); 2.75 (s, 2H); 2.85 (t, 2H); 3.10 (t, 2H); 3.35 (s, 2H); 3.80 (s, 2H); 3.90 (t, 2H); 6.10 (s, 1H); 6.95-7.05 (m, 2H); 7.15 (d, 1H); 7.20-7.30 (m, 2H); 7.40-7.45 (m, 1H); 7.55-7.60 (m, 2H); 11.50 (s, 1H), MS t / ζ: 432 (MH +), 245.

Example 4

4, 5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} 1 H-indole hydrochloride

Mixture of 5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] -3,6-dihydro-2H-pyridin4-yl } -1H-indole (3.5 g), ethanol (100 ml), acetic acid (100 ml) and platinum oxide (0.4 g) were shaken at 3 atm for 16 hours. The mixture was filtered, evaporated under vacuum under approximately to 100 ml, then it was poured onto ice and aqueous ammonia was added to the basic pH. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / triethylamine 100: 4) to give a crude product (2.0 g). The title compound was isolated from ethyl acetate in the form of a hydrochloride salt as a white crystalline compound (2.0 g). T. pl. 212-213 ° C. '11 NMR (DMSO- _6th ): 1.55-1.65 (m, 2H); 1.75-1.85 (m, 2H); 2.00-2.20 (m, 4H); 2.55 (t, 2H); 2.85 (t, 2H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.95 (t, 2H); 6.90 (t, 1H); 7.00 (t, 1H); 7.15-7.30 (m, 4H); 7.30-7.40 (m, 1H); 7.50 (d, 1H); 10.55 (br s, 1H); 11.05 (s, 1H), MS t / ζ: 420 (MH +), 273, 202.

Example 5

5a, 5-fluoro-1-methyl-3- {1- [3 - (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin4-yl} -1H oxalate indole

A suspension of sodium hydride (0.5 g, 60% in mineral oil) and dimethylformamide (60 ml) was kept at 22-24 ° C, after which a solution of 5-fluoro-3- {1- [3- (2-oxo- 3,4-dihydro-2H-quinolin-1-yl) propan1-yl] piperidin-4-yl} -1H-indole (4.9 g) in dimethylformamide (50 ml). The resulting mixture was stirred at room temperature for 25 minutes, after which a solution of methyl iodide (2.0 g) in dimethylformamide (15 ml) was added at a temperature of 22-27 ° C. The resulting mixture was stirred at 22 ° C for 1 h and poured onto ice. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate / heptane / triethylamine 50: 50: 5) to give the product as an orange oil (2.4 g). The title compound was isolated from acetone in the form of an oxalate salt as a white crystalline compound (0.6 g). T. pl. 188-189 ° C. '11 NMR (DMSO _6th ): 1.85-2.05 (m, 4H); 2.10 (d, 2H); 2.55 (t, 2H); 2.90 (t, 2H); 2.95-3.05 (m, 3H); 3.10 (t, 2H); 3.50 (d, 2H); 3.75 (s, 3H); 3.95 (t, 2H); 6.95-7.05 (m, 2H); 7.15-7.30 (m, 4H); 7.35-7.45 (m, 2H), MS t / ζ: 420 (MH +), 188.

The following compounds were obtained in a similar manner:

5b, 5-fluoro-1-methyl-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4yl} -1H hydrochloride -indole from 5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H-indole and methyl iodide. T. pl. 177-179 ° C. '11 NMR (DMSO- _6th ): 1.55-1.65 (m, 2H); 1.75-1.85 (m, 2H); 2.00-2.15 (m, 4H); 2.55 (t, 2H); 2.90 (t, 2H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.75 (s, 3H); 3.95 (t, 2H); 6.95-7.05 (m, 2H); 7.15 (d, 1H); 7.20-7.30 (m, 3H); 7.35-7.45 (m, 1H); 7.55 (d, 1H); 11.40 (br s, 1H), MS t / ζ: 434 (MH +).

5c, 1- (butan-1-yl) -5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] oxalate] -3,6-dihydro-2H-pyridin-4-yl} -1H-indole from 5-fluoro — 3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butane -1-yl] -3,6-dihydro-2H-pyridin-4yl} -1H-indole and butyl bromide. T. pl. 152-154 ° C. '11 NMR (DMSO _6th ): 0.90 (t, 3H); 1.20-1.30 (m, 2H); 1.55-1.65 (m, 2H); 1.65-1.80 (m, 4H); 2.55 (t, 2H); 2.75 (s, 2H); 2.85 (t, 2H); 3.10 (t, 2H); 3.35 (s, 2H); 3.80 (s, 2H); 3.95 (t, 2H); 4.15 (t, 2H); 6.10 (s, 1H); 6.95-7.05 (m, 2H); 7.15 (d, 1H); 7.20-7.30 (m, 2H); 7.50-7.55 (m, 1); 7.55-7.70 (m, 2H), MS t / ζ: 474 (MH +), 231.

- 13 006315

Example 6

6a, 5-fluoro-3- {1- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} 1 H-indole oxalate

A mixture of 5-fluoro-3- (piperidin-4-yl) -1H-indole (3.0 g), butanone (200 ml), tetrahydrofuran (100 ml), methanol (50 ml) and triethylamine (2.4 ml) heated to reflux, after which a solution of 3-chloro-1- (3,4-dihydro-1H-isoquinolin-2-yl) propan-1-one (3.5 g) in butanone (60 ml) was added . The mixture was refluxed for 30 hours, after which an additional amount of 3-chloro-1- (3,4-dihydro-1H-isoquinolin-2-yl) propan-1-one (2.0 g) and triethylamine ( 1.6 ml) in tetrahydrofuran (50 ml). The resulting mixture was refluxed for another 12 hours. The mixture was cooled, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / ethanol / triethylamine 100: 4: 4) to give a crude product. The title compound was isolated from acetone in the form of an oxalate salt as a white crystalline compound (0.75 g). T. pl. 206-209 ° C. ¹ H NMR (DMSO-b ₆ ): 1.95 (q, 2H); 2.05-2.15 (m, 2H); 2.80 (t, 0.8H); 2.90 (t, 1.2H); 2.90-3.10 (m, 5H); 3.30 (t, 2H); 3.55 (d, 2H); 3.70 (t, 2H); 4.65 (s, 1.20H); 4.70 (s, 0.8H); 6.85-6.95 (m, 1H); 7.15-7.25 (m, 5H); 7.30-7.40 (m, 1H); 7.40 (d, 1H); 11.05 (s, 1H), MS t / ζ: 406 (MH +), 231.

The following compounds were obtained in a similar manner:

6b, 1-chloro-3- {1- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin4-yl} -1H-indole hydrochloride from 7- chloro-3- (piperidin-4-yl) -1H-indole and 3-bromo-1- (3,4-dihydro-1H-isoquinolin-2-yl) propan-1one. Ή NMR (DMSO-b ₆ ): 2.05-2.25 (m, 4H); 2.80 (t, 0.8H); 2.95 (t, 1.2H); 3.00-3.20 (m, 5H); 3.30-3.45 (m, 2H); 3.55-3.65 (m, 2H); 3.65-3.75 (m, 2H); 4.65 (s, 1.2H); 4.75 (s, 0.8H); 7.00 (t, 1H); 7.15-7.25 (m, 6H); 7.70 (d, 1H); 10.70 (br s, 1H); 11.30 (s, 1H), MS t / ζ: 422 (MH +), 247.

6c, 5-chloro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} 1 H-indole hydrochloride from 5-chloro-3- (piperidin-4-yl) -1H-indole and 4-chloro-1- (3,4-dihydro-2H-quinolin-1-yl) butan-1-one. T. pl. 158-162 ° C. · Ή NMR (DMSO-b ₆ ): 1.85-1.95 (m, 2H); 1.95-2.20 (m, 6H); 2.60-2.75 (m, 4H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.70 (t, 2H); 7.05-7.25 (m, 6H); 7.40 (d, 1H); 7.75 (s, 1H); 10.45 (br s, 1H); 11.15 (s, 1H), MS t / ζ: 436 (MH +), 303.

Example 7

7, 5-fluoro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole

A mixture of 5-fluoro-3- (piperidin-4-yl) -1H-indole (3.0 g), butanone (200 ml), tetrahydrofuran (200 ml), methanol (30 ml), potassium iodide (11.4 g ) and triethylamine (7.6 ml) were heated to the boiling point under reflux, after which a solution of 4-chloro-1- (3,4-dihydro-1H-isoquinolin-2yl) butan-1-one (14.6 g) was added ) in butanone (50 ml). The mixture was refluxed for 2 hours, filtered hot and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / ethanol / triethylamine 100: 5: 5) to give a crude product. The title compound was isolated from ethyl acetate in the form of the free base as a white crystalline compound (0.9 g). T. pl. 146-148 ° C. ¹ H NMR (DMSO-b ₆ ): 1.55-1.70 (m, 2H); 1.70-1.80 (m, 2H); 1.85-1.95 (m, 2H); 2.00 (q, 2H); 2.30 (q, 2H); 2.35-2.45 (m, 2H); 2.60-2.70 (m, 1H);

2.75 (t, 0.8H); 2.80-3.00 (m, 3.2H); 3.65 (t, 2H); 4.60 (s, 1.2H); 4.70 (s, 0.8H); 6.85-6.95 (m, 1H); 7.10-7.20 (m, 5H); 7.25 (d, 1H); 7.30-7.35 (m, 1H); 10.85 (s, 1H), MS t / ζ: 420 (MH +), 202.

Example 8

8, 5-chloro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole

A mixture of 5-fluoro-3- (piperidin-4-yl) -1H-indole (3.0 g), butanone (200 ml) and triethylamine (8.9 ml) was heated to reflux, after which a solution was added 4-chloro-1 (3,4-dihydro-1H-isoquinolin-2-yl) butan-1-one (15.2 g) in butanone (80 ml). The mixture was refluxed for 6 hours. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / ethanol / triethylamine 100: 4: 4) to give a crude product. The title compound was isolated from acetone in the form of the free base as a white crystalline compound (0.6 g). T. pl. 172-175 ° C. ¹ H NMR (DMSO-b ₆ ): 1.55-1.65 (m, 2H); 1.65-1.75 (m, 2H); 1.90 (s, 2H); 2.00 (q, 2H); 2.30 (q, 2H); 2.40 (q, 2H); 2.652.80 (m, 1.8H); 2.80-3.00 (m, 3.2H); 3.70 (t, 2H); 4.60 (s, 1.2H); 4.70 (s, 0.8H); 7.05 (d, 1H); 7.10-7.25 (m, 5H); 7.35 (d, 1H); 7.55 (s, 1H); 11.00 (s, 1H), MS t / ζ: 436 (MH +), 202.

Example 9

9a, 5-fluoro-3- {1- [3- (3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4-yl} 1 H-indole dihydrochloride

A suspension of lithium aluminum hydride (0.94 g) in tetrahydrofuran (40 ml) was stirred at 5 ° C, after which concentrated sulfuric acid (1.2 g) in tetrahydrofuran (20 ml) was added. The mixture was stirred at 7 ° C. for 60 minutes, after which 5-fluoro-3- {1- [3- (2-oxo-3,4-dihydro-2Hquinolin-1-yl) propan-1-yl] piperidine was added -4-yl} -1H-indole (2.0 g) in tetrahydrofuran (60 ml). The resulting mixture was stirred at 5 ° C for 60 minutes, after which it was processed in a standard manner. The remainder

- 14 006315 was purified by flash chromatography on silica gel (eluent: ethyl acetate) to give the crude product as a colorless oil. The title compound was isolated from tetrahydrofuran in the form of a dihydrochloride salt as a white crystalline compound (1.0 g). Mp 230-236 ° C ' ¹ H NMR (DMSO-b ₆ ): 1.95 (t, 2H); 2.00-2.30 (m, 4H); 2.75 (t, 2H); 2.95-3.20 (m, 5H); 3.30 (t, 2H); 3.40 (t, 2H); 3.55 (d, 2H); 6.20 (br s, 1H); 6.70 (br s, 1H); 6.95 (m, 2H); 7.00 (d, 1H); 7.10 (t, 1H); 7.20 (s, 1H); 7.30-7.40 (m, 1H); 7.50 (d, 1H); 10.95 (br s, 1H); 11.05 (s, 1H), ΜC t / ζ: 392 (ΜΗ +), 259.

The following compounds were obtained in a similar manner:

9b, 5-fluoro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1-indole from 5-fluoro-3 dihydrochloride - {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H-indole. Mp 207-212 ° C. Ή NMR (DMSO-6 ₆ ): 1.65 (s, 2H); 1.80-1.90 (m, 2H); 1.95 (s, 2H); 2.05 (d, 2H); 2.20 (q, 2H); 2.65-2.80 (m, 2H); 2.95-3.25 (m, 4H); 3.15-3.25 (m, 1H); 3.35 (s, 4H); 3.55 (d, 2H); 4.65 (br s); 5.55-6.95 (m, 3H); 7.00 (s, 1H); 7.10 (s, 1H); 7.20 (s, 1H); 7.30-7.40 (m, 1H); 7.55 (d, 1H); 11.75 (br s, 1H); 11.05 (s, 1H), ΜC t / ζ: 406 (MH +), 274.

9c, 5-fluoro-3- {1- [5- (3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1-indindol from 5-fluoro-3 dihydrochloride - {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1H-indole. T. pl. 155-158 ° C. Ή NMR (DMSO-6 ₆ ): 1.30-1.45 (m, 2H); 1.65 (s, 2H); 1.75-1.80 (m, 2H); 1.95 (s, 2H); 2.20 (q, 2H); 2.75 (s, 2H); 2.95-3.10 (m, 5H); 3.35 (s, 4H); 3.55 (d, 2H); 5.05 (br s); 6.70-7.15 (m, 4H); 6.90 (t, 1H); 7.20 (s, 1H); 7.30-7.40 (m, 1H); 7.50 (d, 1H); 10.75 (br s, 1H); 11.05 (s, 1H), ΜC t / ζ: 420 (MH +), 287.

96, 5-chloro-3- {1- [3- (3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4-yl} -1-indole from 5-chloro-3 dihydrochloride - {1- [3 - (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4-yl} -1H-indole. T. pl. 201-204 ° C. Ή NMR (DMSO-6 ₆ ): 1.95 (t, 2H); 2.00-2.25 (m, 6H); 2.75 (t, 2H); 3.00-3.20 (m, 5H); 3.30 (t, 2H); 3.40 (t, 2H); 3.55 (d, 2H); 6.40 (br s); 6.65 (s, 1H); 6.85 (s, 1H); 6.95 (d, 1H); 7.00-7.10 (m, 2H); 7.20 (s, 1H); 7.40 (d, 1H); 7.75 (s, 1H); 10.85 (br s, 1H); 11.20 (s, 1H), ΜC t / ζ: 408 (MH +), 275.

9e, 5-chloro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1-indole from 5-chloro-3 dihydrochloride - {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H-indole. Mp 140-145 ° C. Ή NMR (DMSO-6 ₆ ): 1.65 (s, 2H); 1.80-1.90 (m, 2H); 1.95 (s, 2H); 2.00-2.25 (m, 4H); 2.75 (s, 2H); 2.95-3.25 (m, 5H); 3.35 (s, 4H); 3.55 (d, 2H); 6.75 (br s, 1H); 6.90 (br s, 1H); 7.00 (s, 1H); 7.05-7.15 (m, 2H); 7.20 (s, 1H); 7.40 (d, 1H); 7.80 (s, 1H); 10.70 (br s, 1H); 11.20 (s, 1H), MS t / ζ: 422 (MH +), 289.188.

9 £, 5-chloro-3- {1- [5- (3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1-indole from 5-chloro- dihydrochloride 3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1H-indole. Mp 101-106 ° C. Ή NMR (DMSO-6 ₆ ): 1.30-1.45 (m, 2H); 1.65 (s, 2H); 1.70-1.85 (m, 2H); 1.95 (s, 2H); 2,00-

2.25 (m, 4H); 2.75 (s, 2H); 2.95-3.25 (m, 5H); 3.35 (s, 4H); 3.55 (d, 2H); 6.80 (br s, 1H); 6.90-7.15 (m, 4H); 7.20 (s, 1H); 7.35 (d, 1H); 7.75 (s, 1H); 10.70 (br s, 1H); 11.20 (s, 1H), MS t / ζ: 436 (MH +), 303.

9d, 7-chloro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1-indindi from 7-chloro-3 dihydrochloride - {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H-indole. Mp 214-219 ° C. Ή NMR (DMSO-6 ₆ ): 1.65 (s, 2H); 1.80-1.90 (m, 2H); 1.95 (s, 2H); 2.00-2.15 (m, 2H); 2.152.30 (m, 2H); 2.70 (s, 2H); 2.95-3.15 (m, 5H); 3.35 (s, 4H); 3.55 (d, 2H); 6.70 (br s, 1H); 6.85 (br s, 1H); 6.95-7.05 (m, 2H); 7.10 (s, 1H); 7.15-7.25 (m, 2H); 7.70 (d, 1H); 10.80 (br s, 1H); 11.30 (s, 1H), MS t / ζ: 422 (MH +), 289.188.

911. 5-fluoro-1-methyl-3- {1- [3- (3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin4-yl} -1H-indole dihydrochloride from 5 -fluoro-1-methyl-3- {1- [3 - (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4-yl} -1Nindole. T. pl. 202-206 ° C. Ή NMR (DMSO-6 ₆ ): 1.85-1.95 (m, 2H); 2.00-2.10 (m, 4H); 2.10-2.25 (m, 2H); 2.65-

2.75 (m, 2H); 2.95-3.15 (m, 5H); 3.25-3.35 (m, 2H); 3.35-3.40 (m, 2H); 3.55 (d, 2H); 3.75 (s, 3H); 6.65 (br s, 1H); 6.80 (br s, 1H); 6.90-7.10 (m, 3H); 7.20 (s, 1H); 7.35-7.45 (m, 1H); 7.55 (d, 1H); 10.90 (br s, 1H), MS t / ζ: 406 (MH +), 273.

91, 5-fluoro-1-methyl-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1-indole oxalate 5 of 5 -fluoro-1-methyl-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1Nindole. T. pl. 123-125 ° C. Ή NMR (DMSO-6 ₆ ): 1.50-1.60 (m, 2H); 1.65-1.75 (m, 2H); 1.80-1.90 (m, 2H); 1,902.00 (m, 2H); 2.10 (d, 2H); 2.60-2.70 (m, 2H); 2.95-3.10 (m, 5H); 3.20-3.30 (m, 4H); 3.50 (d, 2H); 3.75 (s, 3H); 6.45 (t, 1H); 6.60 (d, 1H); 6.85 (d, 1H); 6.95-7.05 (m, 2H); 7.20 (s, 1H); 7.40-7.45 (m, 2H), ΜC t / ζ: 420 (MH +), 287.

- 15 006315

9), 5-fluoro-3- {1- [4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4yl} -1H-indole dihydrochloride from 5-fluoro-3- {1- [4- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} -1Nindole. T. pl. 179-186 ° C. Ή NMR (DMSO-b ₆ ): 1.55-1.65 (m, 2H); 1.75-1.90 (m, 2H); 2.00-2.10 (m, 2H); 2.15-

2.25 (m, 2H); 2.95-3.25 (m, 5H); 3.25-3.40 (m, 4H); 3.55 (d, 2H); 4.15-4.25 (m, 2H); 6.55 (t, 1H); 6.65 (d, 1H);

6.70-6.80 (m, 2H); 6.90 (t, 1H); 7.20 (s, 1H); 7.30-7.40 (m, 1H); 7.55 (d, 1H); 10.80 (br s, 1H); 11.05 (s, 1H), MS t / ζ: 408 (MH +), 273, 190.

9k, 5-chloro-3- {1- [4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4yl} -1H-indole dihydrochloride from 5 -chloro-3- {1- [4- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} -1 Nindole. T. pl. 186-190 ° C. Ή NMR (DMSO-b ₆ ): 1.55-1.65 (m, 2H); 1.70-1.85 (m, 2H); 2.00-2.20 (m, 4H); 2.95-

3.25 (m, 5H); 3.25-3.40 (m, 4H); 3.55 (d, 2H); 4.15-4.20 (m, 2H); 6.55 (t, 1H); 6.65 (d, 1H); 6.70-6.80 (m, 2H); 7.05 (d, 1H); 7.20 (s, 1H); 7.40 (d, 1H); 7.75 (s, 1H); 10.50 (br s, 1H); 11.15 (s, 1H), MS t / ζ: 424 (MH +), 289, 190.

91, 5-fluoro-3- {1- [3- (3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] -3,6-dihydro-2Npyridin-4-yl dihydrochloride} - 1 H-indole from 5-fluoro-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] -3,6-dihydro-2H -pyridin-4yl} -1H-indole. T. pl. 220-223 ° C. Ή NMR (DMSO-b ₆ ): 1.85-2.00 (m, 2H); 2.05-2.10 (m, 2H); 2.70-2.80 (m, 4H); 2.90-3.00 (m, 1H); 3.15-3.30 (m, 2H); 3.30-3.35 (m, 2H); 3.40 (t, 2H); 3.55-3.65 (m, 1H); 3.70-3.80 (m, 1H); 4.00 (d, 1H); 6.10 (s, 1H); 6.70 (br s, 1H); 6.90 (br s, 1H); 6.95-7.05 (m, 2H); 7.05-7.10 (m, 1H); 7.40-7.45 (m, 1H); 7.55-7.65 (m, 2H); 11.10 (br s, 1H); 11.60 (s, 1H), MS t / ζ: 390 (MH +), 203, 146.

9t, 5-fluoro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] -3,6-dihydro-2Npyridin-4-yl dihydrochloride} - 1H-indole from 5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] -3,6-dihydro-2H- pyridin-4yl} -1H-indole. T. pl. 198-200 ° C Ή NMR (DMSO-b ₆ ): 1.60-1.75 (m, 2H); 1.80-1.90 (m, 2H); 1.95 (s, 2H);

2.70-2.80 (m, 4H); 2.85-3.00 (m, 1H); 3.15-3.30 (m, 4H); 3.30-3.40 (m, 2H); 3.55-3.65 (m, 1H); 3.70-3.80 (m, 1H); 3.95 (d, 1H); 6.10 (s, 1H); 6.80 (br s, 1H); 6.90-7.20 (m, 3H); 7.00 (t, 1H); 7.40-7.45 (m, 1H); 7.55-7.65 (m, 2H); 10.95 (br s, 1H); 11.55 (s, 1H), MS t / ζ: 404 (MH +), 271, 217.

9p, 5-fluoro-3- {1- [5- (3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] -3,6-dihydro-2Npyridin-4-yl dihydrochloride - - 1 H-indole from 5-fluoro-3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] -3,6-dihydro-2H -pyridin-4yl} -1H-indole. T. pl. 167-169 ° C. Ή NMR (DMSO-b ₆ ): 1.30-1.45 (m, 2H); 1.70 (s, 2H); 1.75-1.90 (m, 2H); 2.00 (s, 2H); 2.70-2.85 (m, 3H); 2.85-3.00 (m, 1H); 3.05-3.20 (m, 2H); 3.20-3.30 (m, 1H); 3.35 (s, 2H); 3.55-3.65 (m, 1H); 3.70-3.80 (m, 1H); 3.95 (d, 1H); 6.10 (s, 1H); 6.80-7.25 (m, 4H); 7.00 (t, 1H); 7.40-7.45 (m, 1H); 7.557.65 (m, 2H); 11.00 (s, br s, 1H); 11.60 (s, 1H), MS t / ζ: 418 (MH +), 231, 188.

Example 10

10a, 4-fluoro-3- {1- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1Nindol

3- [1- (4-fluoro-1H-indol-3-yl) piperidin-1-yl) propionic acid bound to the polymer (0.1 g, 0.08 mmol) and dry dichloromethane (1 ml) were stirred in a chemical test tube. The mixture was cooled to 0 ° C and treated for 2 hours with a 2M solution of thionyl chloride (0.4 ml, 0.8 mmol) in dichloromethane. The resin was filtered and washed with dry dichloromethane (3x1 ml), resuspended in dichloromethane (1 ml) and treated at room temperature for 3 hours with 3,4-dihydro-1H-isoquinoline (0.05 g, 0.4 mmol). The resin was filtered and washed with dichloromethane (3x1 ml), 1: 1 with a mixture of dichloromethane: triethylamine (3x1 ml) and dry dichloromethane (3x1 ml). The resin was treated for 1 h with 1 ml of a mixture of sodium methoxide (2 ml, 5N solution of sodium methoxide in methanol), methanol (50 ml) and tetrahydrofuran (50 ml). After filtration, the resin was washed with methanol (1 ml). The combined filtrates were loaded into a pretreated ion exchange column (500 mg §CX column, sold by Apa1uIsa1 ShbtiteShk, lot no. 1210-2040), washed with acetonitrile (1 ml) and methanol (1 ml). The product was eluted with 4M ammonia in methanol. After evaporation of the volatile solvents, the crude product was purified by preparative reverse phase HPLC. The resulting solution was then loaded into a pre-treated ion exchange column, washed with acetonitrile (1 ml) and methanol (1 ml). The product was eluted with 4M ammonia in methanol. After evaporation of the volatile solvents, the title compound was obtained as a yellow oil (5 mg, 12 μmol). BC ^ C (t / z) 406 (MH +), BT = 3.61, purity 66%.

The following compounds were obtained in a similar manner (10b-10t) or using 3,4-dihydro-2H-quinoline (10η-10ζ):

10b, 4-fluoro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1Nindol

LMSC (t / ζ) 420 (MH +), BT = 3.69, purity: 93%.

10c, 4-fluoro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1Nindol

- 16 006315

L / MS (t / z) 448 (MH +), ΚΤ = 3.81, purity 97%.

10th, 4-chloro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1Nindol

L / MS (t / z) 436 (MH +), ΚΤ = 3.86, purity 97%.

10e, 4-chloro-3- {1- [5- (3,4-dihydro-1H-isoquinolin-2-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1Nindol

L / MS (t / z) 450 (MH +), ΚΤ = 3.87, purity 81%.

10 £, 4-chloro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1Nindol

L / MS (t / z) 464 (MH +), ΚΤ = 3.97, purity 86%.

10d, 5-fluoro-3- {1- [5- (3,4-dihydro-1H-isoquinolin-2-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1Nindol

L / MS (t / z) 434 (MH +), ΚΤ = 3.67, purity 93%.

1011. 5-fluoro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1Nindol

L / MS (t / z) 448 (MH +), ΚΤ = 3.79, purity 89%.

101, 6-chloro-3- {1- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1Nindol

L / MS (t / z) 422 (MH +), ΚΤ = 3.80, 85% purity.

10_), 6-chloro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1Nindol

L / MS (t / z) 464 (MH +), ΚΤ = 3.98, purity 87%.

10k, 7-chloro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1Nindol

L / MS (t / z) 436 (MH +), ΚΤ = 3.85, purity 98%.

101, 7-chloro-3- {1- [5- (3,4-dihydro-1H-isoquinolin-2-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1Nindol

L / MS (t / ζ) 450 (MH +), ΚΤ = 3.85, purity 96%.

10t, 7-chloro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1Nindol

L / MS (t / z) 464 (MH +), ΚΤ = 3.96, purity 97%.

10η, 4-fluoro-3- {1- [3- (3,4-dihydro-2H-quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1H-indole

L / MS (t / z) 406 (MH +), ΚΤ = 3.67, purity 82%.

100, 4-fluoro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole

BC / MS (t / z) 420 (MH +), ΚΤ = 3.78, purity 84%.

10p, 4-chloro-3- {1- [3- (3,4-dihydro-2H-quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1H-indole

BC / MS (t / z) 422 (MH +), ΚΤ = 3.85, purity 97%.

10c, 4-chloro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole

L / MS (t / z) 436 (MH +), ΚΤ = 3.97, purity 92%.

10g, 5-fluoro-3- {1- [3 - (3,4-dihydro-2H-quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1H-indole

L / MS (t / z) 406 (MH +), ΚΤ = 3.63, purity 97%.

108, 5-fluoro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole

L / MS (t / z) 420 (MH +), ΚΤ = 3.73, 96% purity.

101, 5-fluoro-3- {1- [5- (3,4-dihydro-2H-quinolin-1-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1H-indole

L / MS (t / z) 434 (MH +), ΚΤ = 3.76, purity 97%.

10i, 5-fluoro-3- {1- [6- (3,4-dihydro-2H-quinolin-1-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole

L / MS (t / z) 448 (MH +), ΚΤ = 3.88, purity 97%.

10ν, 6-chloro-3- {1- [3 - (3,4-dihydro-2H-quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1H-indole

L / MS (t / z) 422 (MH +), ΚΤ = 3.88, purity 90%.

10 ^, 6-chloro-3- {1- [6- (3,4-dihydro-2H-quinolin-1-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole

L / MS (t / z) 464 (MH +), ΚΤ = 4.09, purity 96%.

10x, 7-chloro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole

L / MS (t / z) 436 (MH +), ΚΤ = 3.91, purity 98%.

10y, 7-chloro-3- {1- [5- (3,4-dihydro-2H-quinolin-1-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1H-indole

L / MS (t / z) 450 (MH +), ΚΤ = 3.93, purity 96%.

10ζ, 7-chloro-3- {1- [6- (3,4-dihydro-2H-quinolin-1-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole

L / MS (t / z) 464 (MH +), ΚΤ = 4.05, purity 97%.

Example 11

11a, 5-fluoro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) butan-1-yl] piperidin-4-yl} -1indole dioxalate

A mixture of 5-fluoro-3- (piperidin-4-yl) -1H-indole (5.0 g), triethylamine (6.35 ml) and tetrahydrofuran (500 ml) was cooled to 7 ° C, and then a mixture of succinic anhydride was added (2.5 g) in tetrahydrofuran (50

- 17 006315 ml). The mixture was stirred at 8-10 ° C for 2 hours and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate and the organic phase was washed with a cold 2N aqueous hydrochloride solution and brine. The organic phase was dried (Mg _{4 4} ), filtered and concentrated in vacuo (6.4 g). The residue (1.5 g) and 3,4-dihydro-1H-isoquinoline (0.63 g) were dissolved in a mixture of acetonitrile (25 ml) and dimethylformamide (10 ml) and the resulting mixture was cooled (5 ° C), and then added 1,3-dicyclohexylcarbodiimide (1.0 g). The mixture was stirred at room temperature for 16 hours, filtered and poured into brine. The aqueous phase was extracted with ethyl acetate and tetrahydrofuran, and the combined organic phase was washed with brine, dried (Mg _{4 4} ) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate) to give a white solid (1.0 g), which was then added to a mixture of alan in tetrahydrofuran (100 ml) at 5-10 ° C. Alan was prepared from lithium aluminum hydride (0.55 g) and concentrated sulfuric acid (0.72 g). The mixture was quenched by the addition of water (1 ml), 15% aqueous sodium hydroxide solution (0.5 ml) and water (2.5 ml), and the resulting mixture was dried (Mg _{4 4} ), filtered and concentrated in vacuo. The title compounds were crystallized from acetone in the form of a dioxalate salt (0.8 g). T. pl. 105-111 ° C. ¹ H NMR (DMSOb ₆ ): 1.75 (s, 4H); 1.85-2.05 (m, 2H); 2.10 (d, 2H); 2.90-3.20 (m, 9H); 3.25 (t, 2H); 3.50 (d, 2H); 4.15 (s, 2H); 6.85-6.95 (m, 1H); 7.10-7.25 (m, 5H); 7.30-7.45 (m, 2H); 11.05 (s, 1H), MS t / ζ: 406 (MH +), 273, 188.

The following compound was obtained in a similar manner:

11b, 5-fluoro-3- {1- [4- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) butan-1-yl] piperidin-4yl} -1H-indole dioxalate from 5-fluoro-3- (piperidin-4-yl) -1H-indole and 6,7-dimethoxy-3,4-dihydro-1H-isoquinoline. Mp 98105 ° C. ^! H NMR (DMSO-b ₆ ): 1.75 (s, 4H); 1.85-2.00 (m, 2H); 2.10 (d, 2H); 2.90-3.15 (m, 9H); 3.30 (s, 2H); 3.50 (d, 2H); 3.75 (d, 6H); 4.10 (s, 2H); 6.75 (s, 1H); 6.80 (s, 1H); 6.90-6.95 (m, 1H); 7.20 (s, 1H); 7.30-7.45 (m, 2H); 11.05 (s, 1H), MS t / ζ: 466 (MH +), 273, 248.

Pharmacological studies

The compounds of the present invention were studied using well-known and reliable tests. These tests were as follows:

Inhibition of binding of [ ³ H] UM-09152-2 to dopamine receptors Ό ₄ people

Using this method, ίη νίΐτο inhibition of binding of [ ³ H] UM-09152-2 (0.06 nM) to membranes of cloned dopamine receptors Ό _{4> 2} , expressed in CHO cells, is determined by drugs. Method modified from ΝΕΝ ΝΕΝ г е Р г ис ис ис й. 1ps., Certificate of technical data RS2533-10 / 96.

In the table. Table 1 below shows the test results: __________________________________________

Soy l · No. Linking with Ό ₄ Connection No. Binding to β ₄ Soel · " Linking to 1a 92% Per 0, 71 10th 25% 1b 97% B fifty SOUTH 17% 1s 95% Ss fifteen Yud 65% 2a 0.58 4 4.8 1011 fifty% 2b 12 91 0, 51 ΙΟί 94% 2a 0, 69 9t 17 103 70% 26 thirty 9p 53 Yuk 95% 2c 12 Yua 93% 101 82% 2 £ 78% yu 81% Ut 69% 2d 7.5 Jus 21% 2b 10 yua 86%

Table 1: Binding data (1C ₅₀ values in nM or% inhibition of binding at 50 nM) (ηΐ means not tested)

The compounds of the present invention have been shown to potently inhibit the binding of tritiated UM-09152-2 to Ό ₄ dopamine receptors.

Compounds were also tested in the functional assay described by Ca / ί c1 a1. in ΒτίΙίδΗ ίοιίΓηαΙ оГ Р11агтасодод 1999, 128, 613-620. In this test, the compounds have been shown to be partial agonists or antagonists for dopamine receptors Ό ₄ .

The compounds of the present invention were also tested in the following tests:

Inhibition of the binding of [ ³ H] spiperone to receptors ϋ ₂

The compounds of the present invention were studied for affinity for the dopamine I ₂ receptor by determining their ability to inhibit the binding of [ ³ H] spiperone to I ₂ receptors, according to the method described by Nouye1 s1 a1. Mr. No. 1985, 44, 1615.

- 18 006315

Inhibition of binding of [ ³ H] spiperone to receptors ϋ ₃

Using this method, ίη νίίτο drug inhibition of the binding of [ ³ H] spiperone (0.3 nM) to the membranes of cloned dopamine receptors Ό ₃ expressed by CHO cells was determined. The method is modified according to MasKep / 1e e1 a1. Eig. ί. P11Act.-Mo1. Ryagt. Zes. 1994, 266, 79-85.

Inhibition of capture of [ ³ N] serotonin in synaptosomes of rat intact brain

Compounds were tested for their inhibitory effect on 5HT reuptake by measuring their ability to inhibit [ ³ H] serotonin uptake into synaptosomes of the rat intact brain ίη ν интτο. This analysis was carried out as described by Nuje1 in Rkusjoryagtasodu 1978, 60, 13.

Inhibition of the binding of [ ³ H] ketanserin to 5-HT _2A receptors

Compounds were examined for affinity for 5-HT _2a receptors by determining their ability to inhibit the binding of [ ³ H] ketanserin (0.50 nM) to membranes from the rat brain (cortex) ίη νίίτο. This method is described Zapsyekh e1 a1. Aegis Eet. Ke8. 1991, 22, 239-250.

Efficiency against receptors 5-HT _2C according to the results of fluorometry

Compounds were examined for their efficacy against CHO cells expressing 5-HT _2C receptors using fluorometric imaging plate reader (EYRK) assay. This study was carried out according to the instructions of Mo1eci1ag Ee \ '1ce5 1ps. for their ЕЫРК Sa1ssht Lkkau Ky and with the modification according to Royeg e1 a1. ΒπίΜι 1oita1 o £ Ryagtasoodu 1999, 128: 13.

It was found that these compounds do not possess or have a very weak affinity for the dopamine receptor E ₂ .

It has been found that many compounds inhibit the binding of [ ³ H] spiperone to the Ό ₃ dopamine receptor, some of the compounds inhibit serotonin reuptake, and some of the compounds are 5-HT _2A receptor ligands and / or 5-HT _2c receptor ligands.

As mentioned above, the compounds of the present invention are highly soluble in water compared to the related compounds described in UO 98/28293. Accordingly, these compounds are expected to have improved bioavailability.

Thus, the compounds of the present invention are considered useful for treating the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders such as generalized anxiety disorder, panic disorder and obsessive-compulsive disorder, depression, side effects induced by common antipsychotic agents, migraines, ΆΌΗΌ as well as to improve sleep. In particular, the compounds of the present invention are considered useful in treating the positive and negative symptoms of schizophrenia without causing extrapyramidal side effects.

Examples of compositions

The pharmaceutical compositions of the present invention can be prepared by conventional methods known in the art.

For example, tablets can be made by mixing the active ingredient with conventional excipients and / or diluents, followed by compressing the mixture on conventional tabletting equipment. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, and the like. You can also use any other auxiliary substances or additives that are usually used for these purposes, such as dyes, flavors, preservatives, etc., provided that they are compatible with the active ingredients.

Injectable solutions can be prepared by dissolving the active ingredient and possible additives in part of the injection solvent, preferably in sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling it into suitable ampoules or vials. Any suitable additional agent that is commonly used in the art can be added, such as toning agents, preservatives, antioxidants, and the like.

Typical examples of prescriptions for the compositions of the present invention are as follows:

1) Tablets containing 5.0 mg of the compound of the present invention based on the free base:

Compound 5.0 mg Lactose 60 mg Corn starch 30 mg Hydroxypropyl cellulose 2.4 mg Microcrystalline cellulose 19.2 mg Type A croscarmellose sodium 2.4 mg Magnesium stearate 0.84 mg

- 19 006315

2) Tablets containing 0.5 mg of the compound of the present invention based on the free base:

Compound Lactose Corn starch Povidone Microcrystalline Cellulose Sodium Croscarmellose Type A Magnesium Stearate 3) Syrup containing in a milliliter: 0.5 mg 46.9 mg 23.5 mg 1.8 mg 14.4 mg 1.8 mg 0.63 mg Compound Sorbitol Hydroxypropyl cellulose Glycerol Methylparaben Propylparaben Ethanol Corrigent Saccharinum Water 25 mg 500 mg 15 mg 50 mg 1 mg 0.1 mg 0.005 ml 0.05 mg 0.5 mg to 1 ml

4) Injection solution containing in a milliliter:

Compound Sorbitol Acetic acid Saccharinum Water 0.5 mg 5.1 mg 0.05 mg 0.5 mg to 1 ml

CLAIM

Claims (22)

CLAIM 1. A substituted indole derivative of formula I where (a) one of Υ ¹ and Υ ² represents Ν, which is associated with Υ ⁴ , and the other of Υ ¹ and Υ ² represents CO, C8, 80 or 8O2 and Υ ⁴ represents CH2; (b) one of Υ ¹ and Υ ² is Ν, which is associated with Υ ⁴ , and the other of Υ ¹ and Υ ² is CH2 and Υ ⁴ is CO, C8, 80 or 8O2; or (c) one of Υ ¹ and Υ ² represents Ν, which is associated with Υ ⁴ , and the other of Υ ¹ and Υ ² represents CH2 and Υ ⁴ represents CH2; Υ ³ represents Ζ-ΟΗ2, ί.'Η2-Ζ or CH2CH2, and Ζ represents O or 8; provided that when Υ ¹ is Ν, Υ ³ may not be Ζ-ΟΗ2; V represents a bond or a group of O, 8, CO, C8, 80 or 8O ₂ ; η is 0-5, t is 0-5, and t + η is 1-10; provided that when V represents O or 8, then η> 2, and m>1; when V is CO, C8, 80 or 8O ₂ , then η> 1, and m>1; X represents C, CH or Ν; provided that when X represents C, the dashed line denotes a bond, and when X represents Ν or CH, the dashed line is not a bond; K ¹ -R ⁹ are independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, C 1 _-6 alkylamino, di-C 1 _-6 alkylamino, C1 _-6 -alkyl, C _2-6 -alkenyl, C _{2 -6-} alkynyl, C ₁ . ₆ alkoxy, C _1-6 alkylthio, C _1-6 alkyl substituted with a hydroxyl group or thiol group, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-6 alkyl, acyl group, thioacyl group, aryl group, a trifluoromethyl group, trifluoromethylsulphonyl groups and C1 _-6 alkylsulfonyl; To ¹⁰ represents hydrogen, C1 _-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C1 _-6 alkyl substituted by a hydroxyl group or a thiol group, C 3-8 cycloalkyl, C 3-8 cycloalkyl -S1-6 alkyl, aryl, aryl-C1 _-6 -alkyl, acyl group, tioatsilnuyu group, C1 _-6 alkylsulfonyl, trifluoromethylsulfonyl or arylsulfonyl group, or a pharmaceutically acceptable acid addition salt thereof. 2. The compound according to claim 1, in which the indole is linked to X at position 3 of the indole. 3. The compound according to claim 1 or 2, in which one of Υ ¹ and Υ ² represents Ν, which is associated with Υ ⁴ , and - 20 006315 the other of Υ ¹ and Υ ² represents CO and Υ ⁴ represents CH ₂ . 4. The compound according to claim 1 or 2, in which one of Υ ¹ and Υ ² represents Ν, which is associated with Υ ⁴ , and the other of Υ ¹ and Υ ² represents CH2 and Υ ⁴ represents CO. 5. The compound according to claim 1 or 2, in which Υ ¹ is nitrogen, which is associated with Υ ⁴ , and one of Υ ⁴ and Υ ² is CO, and the other is CH2. 6. The compound according to claim 3 or 5, in which Υ ¹ represents nitrogen, which is associated with Υ ⁴ , Υ ² represents CO, and Υ ⁴ represents CH ₂ . 7. The compound according to claim 4 or 5, in which Υ ¹ represents nitrogen, which is associated with Υ ⁴ , Υ ² represents CH2, and Υ ⁴ represents CO. 8. The compound according to claim 1 or 2, in which Υ ² represents nitrogen, which is associated with Υ ⁴ , and one of Υ ¹ and Υ ⁴ represents CO, and the other represents CH2. 9. The compound according to claim 4 or 8, in which Υ ² represents a nitrogen atom that is bonded to Υ ⁴ , Υ ¹ represents CH2, and Υ ⁴ represents CO. 10. The compound according to claim 3 or 8, in which Υ ² represents a nitrogen atom that is bonded to Υ ⁴ , Υ ¹ represents CO, and Υ ⁴ represents CH2. 11. The compound according to claim 1 or 2, in which one of Υ ¹ and Υ ² represents Ν, which is associated with Υ ⁴ , and the other of Υ ¹ and Υ ² represents CH2 and Υ ⁴ represents CH2. 12. The compound according to any one of claims 1 to 11, in which Υ ³ represents CH ₂ CH ₂ or ΟΗ ₂ Ζ. 13. The compound according to any one of claims 1 to 12, in which X represents C. 14. The compound according to any one of claims 1 to 12, in which X represents Ν. 15. The compound according to any one of claims 1 to 12, in which X represents CH. 16. The compound according to any one of claims ^{1 to 15} , in which K ¹ -K ^{9 are} independently selected from hydrogen, halogen, cyano group, nitro group, amino group, C1-6 alkylamine, di-C1-6 alkylamine, C1-6- alkyl, C3-8 cycloalkyl and trifluoromethyl groups, and K. ¹⁰ represents hydrogen, a C1-6 alkyl or acyl group, and / or its pharmaceutically acceptable acid addition salt. 17. The compound according to any one of claims 1 to 16, in which V represents a bond, and η + t is 1-6. 18. The compound according to 17, in which η + t is 3-6. 19. The compound according to claim 1, selected from 5-fluoro-3- {1- [2- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) ethyl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [3- (1-oxo-3,4-dihydro-1H-quinolin-2-yl) propan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1 - [4- (1-oxo-3,4-dihydro-1H-quinolin-2-yl) butan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [ 3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1H-indole, 5-chloro-3- {1- [3 - (2 -oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4-yl} -1H-indole, 5-chloro-3- {1- [4- (2-oxo -3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H-indole, 5-chloro-3- {1- [5- (2-ok o-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1H-indole, 7-chloro-3- {1- [4- (2-oxo- 3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [4- (3-oxo-3, 4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} -1Nindole, 5-chloro-3- {1- [4- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} -1Nindole, 5-fluoro-3- {1- [3 - (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] -3,6-dihydro-2H-pyridin-4- silt} 1H-indole, 5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] -3,6-dihydro-2H-pyridin-4- silt} 1H-indole, 5-fluoro-3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] -3,6-dihydro-2H-pyridin-4- silt} 1 H-indole, 5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H-indole, 5- fluoro-1-methyl-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4-yl} -1Nindole, 5-fluoro-1-methyl-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1Nindole, 1- (butan-1-yl) -5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] -3, 6-dihydro-2Npyridin-4-yl} -1H-indole, 5-fluoro-3- {1- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1H-indole, 7-chloro-3- {1- [3 - (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1H-indole, 5-chloro -3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole, 5-chloro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [3- (3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [4- (3,4-dihydro -2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [5- (3,4-dihydro-2H-quinolin-1 -yl) pentan-1-yl] piperidin-4-yl} -1H-indole, - 21 006315 5-chloro-3- {1- [3 - (3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4-yl} -1H-indole, 5-chloro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H-indole, 5-chloro-3- {1- [5- (3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1H-indole, 7-chloro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-1-methyl-3- {1 - [3- (3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-1-methyl-3- {1- [ 4- (3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [4- (3,4 -dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} -1H-indole, 5-chloro-3- {1- [4- (3,4-dihydro -2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [3 - (3,4-dihydro-2H -quinolin-1-yl) propan-1-yl] 3,6-dihydro-2H-pyridin-4-yl} -1Nindole, 5-fluoro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] -3,6-dihydro-2H-pyridin-4-yl} -1Nindole , 5-fluoro-3- {1- [5- (3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] 3,6-dihydro-2H-pyridin-4-yl} -1Nindole, 4-fluoro-3- {1- [3 - (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1H-indole, 4-fluoro -3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole, 4-fluoro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole, 4-chloro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole, 4-chloro-3- {1- [5- (3,4-dihydro-1H-isoquinolin-2-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1H-indole, 4- chloro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [5- (3,4-dihydro-1H-isoquinolin-2-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole, 6- chloro-3- {1- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1H-indole, 6- chloro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole, 7- chloro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole, 7-chloro -3- {1- [5- (3,4-dihydro-1H-isoquinolin-2-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1H-indole, 7-chloro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole, 4-fluoro-3- {1- [3 - (3,4-dihydro-2H-quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1H-indole, 4-fluoro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole, 4-chloro-3- {1- [3 - (3, 4-dihydro-2H-quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1H-indole, 4- chloro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [3- (3,4-dihydro-2H-quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro -3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [5- (3,4-dihydro-2H-quinolin-1-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [6- (3,4-dihydro-2H-quinolin-1-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole, 6- chloro-3- {1- [3 - (3,4-dihydro-2H-quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1H-indole, 6- chloro-3- {1- [6- (3,4-dihydro-2H-quinolin-1-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole, 7- chloro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole, 7-chloro -3- {1- [5- (3,4-dihydro-2H-quinolin-1-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1H-indole, 7-chloro-3- {1- [6- (3,4-dihydro-2H-quinolin-1-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) butan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- {1- [4- (6, 7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) butan-1-yl] piperidin-4-yl} -1H-indole or pharmaceutically acceptable salts thereof. 20. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 19 in combination with one or more pharmaceutically acceptable carriers or diluents. 21. The use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament suitable for the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders such as generalized anxiety disorder, panic disorder and obsessive-compulsive disorder, depression, aggression, side effects induced by conventional antipsychotic agents, migraines, cognitive impairment, ΑΌΗΌ, as well as to improve sleep. 22. A method for treating the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders such as generalized anxiety disorder, panic disorder and obsessive-compulsive disorder, depression, aggression, side effects induced by conventional antipsychotic agents, migraines, cognitive disorders, ΑΌΗΌ, a also improving sleep, comprising administering a therapeutically effective amount of a compound according to any one of claims 1-19.