PL172692B1 - Condensed derivatives of indole - Google Patents

Abstract

1. Condensed indole derivatives with the formula (I) or their pharmaceutically-acceptable salts with the formula IMAGE> where X refers to O, S, SO, SO2>, CH2>, CH or NR, where R refers to hydrogen or C1-6alkyl; A refers to saturated or non-saturated polymethylene chain with 2-4 atoms of carbon; R1 and R2 refer to a hydrogen atom or C1-6alkyl; R3 refers to hydrogen, a halogen, C1-6alkyl, an amino group, a nitro group or C1-6alkoxyl; R4 refers to hydrogen, a halogen, C1-6alkyl or C1-6alkoxyl; Y refers to O or NH; Z refers to a group with the formula (a), (b) or (c); (a) (b) (c) where n1> is equal to 1, 2, 3 or 4; n2> is equal to 0, 1, 2, 3 or 4; n3> is equal to 2, 3, 4 or 5; q is equal to 0, 1, 2 or 3; p is equal to 0, 1 or 2; m is equal to 0, 1 or 2; R5 refers to hydrogen, C1-12alkyl, arylalkyl or R5 refers to (CH2)2-R10, where z is equal to 2 or 3, while R10 is matched from the set of groups: cyanic, hydroxyl, C1-6alkoxyl, phenoxyl, C(O)C1-6alkyl, COC6H5, -CONR11R12, NR11COR12, SO2NR11R12 or NR11SO2R12, where R11 and R12 refer to hydrogen or C1-6alkyl; while R6 R7 and R8 independently of each other refer to C1-6alkyl; while R9 refers to hydrogen or C1-10alkyl, which act as an antagonist of the 5-HT4 receptor.

Description

The subject of the invention is novel fused indole derivatives with pharmacological activity.

EP-A-429984 (Nisshin Flour Milling Co., Ltd) describes indole derivatives having 5-HT3 receptor antagonist activity.

In European Journal of Pharmacology 146 (1988), 187-188 and Naunyn-Schmiedeberg's Arch. Pharmacol. (1989) 340: 403-410 describes the non-classical 5-hydroxytryptamine receptor, now referred to as the 5-HT4 receptor, and that ICS 205-930, which is also an antagonist of the 5-HT3 receptor, acts as an antagonist of this receptor.

WO91 / 16045 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT4 receptor antagonists in the treatment of atrial arrhythmias and apoplexy. ,

EP-A-501322 (Glaxo Group Limited) describes indole derivatives with 5-HT4 antagonist activity.

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A new class of structurally different compounds has now been discovered. These compounds are derivatives of the 1,2-disubstituted alkyleneoxy indole with an azacyclic, conjugated azabicyclic or aminoalkyl moiety. These compounds have 5-HT4 receptor antagonistic activity.

Thus, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

X is O, S, SO, SO2, CH2, CH or NR, wherein R is hydrogen or C1-4alkyl;

A is a saturated or unsaturated polymethylene chain with 2 to 4 carbon atoms;

Ri and R2 are hydrogen or C1-4alkyl;

R 3 is hydrogen, halogen, C 1-4 alkyl, amino, nitro or C 1-4 alkoxy;

R4 is hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy;

Y is O or NH;

Z is a group of formula (a), (b) or (c);

- (CH ₂ ) _n 3 -N 6 ( _C ) ^R 9 wherein n ¹ is equal to 1, 2, 3 or 4; n ^z is 0, 1, 2, 3 or 4; n ³ is equal to 2, 3, 4 or 5; q is 0, 1, 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2;

Rs is hydrogen, Ci-ualkyl, aralkyl, or R5 is (CH2) _with -Rio, where z is equal to 2 or 3, and R10 is selected from cyano, hydroxyl,

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C 1-6 alkoxy, phenoxy, C 1-4 alkyl, COC 6 H 5, -CONR 11 R 12, NR _n CORi 2, SO 2 NR 11 R 12, or NR 11 SO 2 R 12, wherein R 11 and R 12 are hydrogen or C 1-4 alkyl; and

R 6, R 7 and R 8 are each independently hydrogen or C 1-4 alkyl; while

R9 is hydrogen or C1-10alkyl;

5-HT4 receptor antagonist.

Examples of alkyl or alkyl-containing groups include C1, C2, C3, C4, C5, C6 C7, Cs, C9, C10, C11, and C12 straight chain, branched or cyclic groups, respectively. C 1-4 alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec-, and tert-butyl. Cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

Aryl includes phenyl and naphthyl, optionally substituted with one or more substituents selected from halogen, C 1 -alkyl, and C 1-6d12, C, 3, 4, and 3.

Halogen includes fluorine, chlorine, bromine, and iodine.

X often stands for O.

The meanings of A include -CH ₂ - (CH2) r-CH2-, where r is 0, and or 2; -CH2-CH = CH-; -C (CH3) = CH- or when X is CH or N, A may be - (CH2) ₂ -CH = or -CH = CH-CH =. Other examples of A are as described in the examples.

Ri and R2 are often hydrogen or Ri and R2 are gem-dimethyl. r often means and.

R3 is preferably hydrogen.

R4 is preferably hydrogen or a halogen such as fluoro.

Y is preferably O or NH.

When Z is a group of formula (a), ni is preferably 2, 3 or 4 when the azacyclic is attached at the nitrogen atom and ni is preferably equal to and when the azacyclic is attached to carbon such as at position 4, when q is equal to 2.

When Z is a group of formula (b), n preferably is such that the number of carbon atoms between the ester or amide linkages is 2 to 4 carbon atoms.

The respective values for p and m are p = m = i, p = 0, p = i, m = 2, p = 2, m = i.

When Z is a group of formula (c), n is preferably 2, 3 or 4.

R9 and R10 are preferably both alkyl, especially one of R9 and R10 is C4 or higher alkyl.

The following individual meanings of Z are of particular interest:

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The invention also covers novel compounds of formula (I) with side chains (i), (ii), (iii), (iv), (v), (vi) or (vii). In a further aspect, the piperidine ring in (i), (ii) or (iii) may be replaced with pyrrolidinyl or azetidinyl and / or the N-substituent in (i) or (ii) may be replaced with C3 alkyl or greater or optionally substituted benzyl.

In an alternative aspect, the N-substituent in formula (i) or (ii) may be replaced by _(CH2) ^nR4 as defined in formula (I) and the compound of the specific examples of EP-A-501322.

Pharmaceutically acceptable salts of the compounds of formula (I) include addition salts with traditional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulfuric acids, and pharmaceutically acceptable organic acids such as acetic, tartaric, milionic, citric, umstyin, benoic, ascorbic acids. , methanesulfonic, α-ketoglutaric, α-glycerophosphate and glucose-1-phosphoric.

Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I), such as compounds czwaΓtorzędowaye by compounds Rx-T wherein _Rx is Ci-alkyl or Cs-feyylorClrsalkil Ycykoalkil and T is a radical corresponding to the anion of the acid. Suitable examples of Rx include methyl, ethyl, and n- and isopropyl: as well as benzyl and phenylethyl. Suitable examples of T include halide such as chloride, bromide and iodide.

Examples of pharmaceutically acceptable salts also include inner salts such as N-oxides.

Compounds of formula (I), their pharmaceutically acceptable salts (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable sonatates, such as hydrates, which are included, wherever compounds of formula (I) or a salt thereof are mentioned herein. .

It should be noted that the group (CH ₂₎ n2 in the compound of formula (I) wherein Z is (b) may be in a or β configuration with respect to the coupled portion of the azabicyclic.

Compounds of formula (I) can be prepared by conventional coupling of the indole portion with Z. Suitable methods are described in GB 2125398A (Sandoz Limited), GB 1593146A and EP-A-36269 (Beecham Group plc), EP-A-429984 (Niss ^ hin Flour Milling Co.) and EP-A-328200 (Merck Sharp & Dohme Limited). A reference is also found in EP-A-5-01322 (Glaxo Group Limited). It should be noted that the introduction-modification of the clamping ring (CH2) o-O or R3 / R4 may be performed before or after the coupling.

The aza (bi) cckliczyy side chain intermediates are known compounds or can be prepared according to the method described in PCT / GB92 / 01519 and / 01612 (SmithKlne Beecham p. L. C.).

The compounds of the invention are antagonists of the 5-HT4 receptor and therefore are expected to be generally used in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and disorders of the central nervous system.

They are potentially of interest in the treatment of irritable bowel symptoms (IBS), especially IBS-related diarrhea, ie, these compounds block the ability of 5-HT to stimulate bowel movement by activating intestinal neurons. In animal models of IBS, this can conveniently be measured as a reduction in defecation. Potentially, they can also be used to treat urinary metastasis, which is often associated with IBS.

They can also be used for other gastrointestinal disorders such as disorders associated with upper bowel movements and as anti-emetic agents. In particular, they have potential utility in the treatment of nausea and gastric symptoms, regurgitation and dyspepsia. The antiemetic effect is determined in known animal models by cytotoxic / radiation induced emesis.

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It would also be expected that specific cardiac 5-HT4 receptor antagonists which prevent atrial fibrillation and other 5-HT associated atrial arrhythmias would reduce the incidence of apoplexy (see AJ Kaufman 1990, Naumyn-Scłuniedeberg's Arch. Pharmacol. 342, 619-622, for appropriate animal test methods).

Platelet-derived 5-HT is believed to induce atrial arrhythmias that promote atrial fibrillation and atrial disturbances associated with symptomatic cerebral and systemic embolism. Cerebral embolism is the most common cause of ischemic stroke and the heart is the most common source of embolic material. This is especially true of the frequency of embolism associated with atrial fibrillation.

The anxiety activity is probably induced by the hippocampus (Dumuis et al. 1988, Mol Pharmacol., 34, 880-887). Activity can be demonstrated in standard animal models, the social interaction test and the X-maze test.

Migraine sufferers are often subject to anxiety and emotional stress situations that precede the onset of a headache (Sachs, 1985, Migraine. Pan Books, London). It has also been observed that during or within the 48 hours of a migraine attack, cyclic AMP levels in the cerebrospinal fluid increase markedly (Welch et al., 1976, Headache 16, 160-167). Migraine, including the precursor phase and associated increased cyclic AMP levels, is believed to be associated with stimulation of 5-HT4 receptors, and thus, a potential benefit of administering a 5-HT4 antagonist is to eliminate the migraine attack.

The pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

Such compositions are prepared by admixing the ingredients and are typically adapted for enteral administration such as oral, nasal or rectal, or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, powders for oral administration. dissolution, nasal sprays, suppositories, injection and infusion solutions or suspensions. Sublingual or transdermal administration may also be considered. Orally administrable compositions are preferred as they are more convenient for general administration.

Tablets and capsules for oral administration are usually made in the form of single doses and contain conventional excipients such as joining agents, fillers, diluents, tabletting agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents. The tablets may be coated by well known techniques, for example enteric coatings.

Suitable fillers include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants are starch, polyvinylpyrrolidone and starch derivatives! such as sodium starch glycolate. Suitable lubricants are, for example, magnesium stearate.

Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate. Oral liquid pharmaceutical preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methylcellulose, gelatin, hydroxyethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitol monooleate or acacia; non-aqueous vehicles (which may include edible oils) for example almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol or ethyl alcohol;

Preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and optionally traditional flavoring or coloring agents.

Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or are presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavoring or coloring agents.

Oral compositions can be prepared by mixing, filling, or tabletting. Repeated mixing operations can be used to distribute the active ingredient throughout the composition using large amounts of fillers. Such operations are, of course, traditional activities.

For parenteral administration, fluid unit doses are prepared containing a compound of the invention and a sterile vehicle. The compound, depending on the vehicle and concentration, can either be suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilizing before filling into vials or ampoules and sealing. Preferably, auxiliary substances such as local anesthetics, preservatives and buffering agents are also dissolved in the carrier. To increase stability, the composition can be frozen after filling into vials and the water removed in vacuo.

Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of dissolving, and sterilized by exposure to ethylene oxide prior to suspension in the sterile vehicle. Preferably, a surfactant or wetting agent is added to the composition to facilitate uniform distribution of the compound of the invention.

For the treatment of symptoms of intestinal irritation, gastrointestinal regurgitation, dyspepsia, atrial arrhythmia and apoplexy, anxiety and / or migraine in mammals such as humans, administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is used. In particular, this applies to the treatment of IBS or atrial arrhythmia and apoplexy.

The amount effective to treat the disorders described above depends on the relative efficacy of the compounds of the invention, the nature and severity of the disorder being treated, and the weight of the mammal. However, a single dose for a 70 kg adult will normally contain 0.05 to 1000 mg, for example 0.5 to 500 mg of a compound of the invention. Single doses may be administered one or more times daily, for example 2, 3 or 4 times daily, typically 1 to 3 times daily, i.e. in the range of approximately 0.0001 to 50 mg / kg / day, typically 0.0002 to 25 mg / kg / day.

In the range of the above-mentioned doses, no harmful toxicological effects were observed.

The invention also includes a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active drug substance, especially for use as an inhibitor of the 5-HT4 receptor in the treatment of the disorders listed above.

The following examples illustrate the preparation of compounds of Formula (I); the following recipes illustrate the production of intermediate products.

Examples

..... ^R !

E1 H.

E2 H r ^r 4

With (i) (vi)

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ra H. H. 1 H. H. ABOUT NH (and) Μ H. H. 1 H. H. 0 0 (iii) E5 H. H. 1 H. H. ABOUT NH (iii) ra H. H. 0 H. H. 0 0 (and) E7 3- ^(CH3 ) ² 1 H. H. ABOUT 0 (and) ra H. H. 1 H. H. S. 0 (and) ra H. H. 2 H. H. ABOUT 0 (and) E10 H. H. 1 H. H. ^CH 2 0 (and) E11 H. H. 0 H. H. ^CH 2 0 (and) E12 H. H. 2 H. H. ^CH 2 0 (and) E13 H. H. 0 H. H. CH ² NN (and) E14 H. H. 0 H. ABOUT 2 NH () E15 H. H. 1 H. H. ABOUT ABOUT Bzppm E16 H. H. 1 H. H. SO ABOUT (and) E17 - Δ - H. H. CH 0 (and) E18 - Γ - H. H. C2 0 (and) E19 H. H. 1 H. H. S. NH (and) rao H. H. and H. H. ABOUT NH Bzppm E21 H. H. 1 H. H. ABOUT NH ppm E22 H. H. 1 H. H. ABOUT NN nCg ^ PP * E23 H. H. 1 H. H. 0 NH (ii) £? 2 H. H. 1 H. H. 0 fH Etppm races H. H. 1 H. R 0 UH ΜβΕ ^ λ, εΕΓρριη E2S H. H. 1 H. H. 0 iffi Cvi) E27 H. H. 1 8-F H. 0 0 (and) E28 H. H. 1 8-F H. 0 NH (and) E29 H. H. 1 H. H. NMte 0 (and)

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E30 - π 1 Η E31 Η H. 0 Η E32 - 0 - H. E33 - Λ - Η KJ4 H. H. 0 H. E35 - Φ - Η E36 Η H. 1 Η E33 H. Η 0 Η E39 H. H. 2 Η E39 Η Η Γ Η E30 Η Η 0 Η 41 H. H. 0 Η E42 - Φ - Η E43 - Φ - Η E44 H. H. 1 Η E35 - Γ 1 Η E36 Η Η 0 H. E47 H. H. 1 H.

Η S. 0 (and) Η S. 0 (and) H. S. ABOUT (and) Η Ν 0 (and) H. S. NH (and) Η S. NH (and) Η NHI 0 (!) Η 0 0 (IN) Η 0 NH (and) Η Ν 0 (and) Η S. 0 (iii) Η S. 1H0 (vi) Η S. 0 (vi) Η S. JW1 (vi) Η S. 0 (v () Η KH1 IH1 (and) Η Ν iH1 ii) H. ABOUT NH Phprppm

^{Δ Γ - π} ♦ ^{- ΑΚ} Λ ^{Λ - ar} i ^r 2

means - (CB ^ ig-CB® Bz - tenzyil is -CH = CH-CH = ppm - 4-piperidylmethyl oziKU2zą - ^ (CH ^ i ^ CH- a £ t - suninoethyl means -CH = CH- P pr - 3 phenoxypropyl mark. -C (CBg) = CB-C (CH ₃ ) =

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Example 1.

3.4- Dihydro-2H- [1,3] oxazine [3,2-a] indole-10-carboxylate (1-n-butyl-4-pipydyl] methyl (E1).

(a) A suspension of indole-3-carboxylic acid (500 mg, 0.003 mol) in dichloromethane (50 ml) was treated with oxalyl chloride (0.635 g, 0.005 mol) and two drops of dimethylformamide. The mixture was then stirred at room temperature for one and a half hours after which the solvent was removed in vacuo leaving the acid chloride.

A solution of 1-butyl-4-piperidinomethanol, D6, (513 mg, 0.003 mol) in dry THF (10 ml) under nitrogen atmosphere, was cooled in an ice bath. N-Butyllithium (1.88 mL of a 1.6 M solution in hexane, 0.003 mol) was added dropwise and the resulting solution was stirred at 0 ° C for 15 minutes.

The acid chloride was dissolved in dry THF (20 ml) and the solution was added dropwise to the lithium alkoxide solution at 0 ° C.

The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The solvent was removed in vacuo and the residue was partitioned between the chloroform and water phase. Chloroform was separated, washed several times with water, dried, and concentrated to give (1-butyl-4-piperidyl) methyl 1H-indole-3-carboxylate as a pale brown gum.

'* H MR (250 MHz) CDCl ₃ ;

δ: 9.90 (br. s, 1H), 8.10-8.18 (m, 1H), 7.78 (d, 1H), 7.37-7.46 (m, 1H), 7, 16-7.28 (m, 2H), 4.19 (d, 2H), 3.05-3.15 (br.s, 2H), 2.40-2.49 (m, 2H), 0, 90 (t, 3H), 1.20-2.18 (m, 11H).

. (b) A suspension of N-chlorotoxycin Pg (57 mg, 0.48 mmol) in chloroform (2 ml) was treated with a solution of molol-3-carboxylate (1-n-bgtyl-4-piperidyl) methylg (100 mg, 0.32 mmol) in chloroform (2 ml) and the mixture was stirred at room temperature for 2 hours. The pale yellow solution was treated with 5-bromo-1-propanol (0.03 ml, 0.32 mmol), stirred at room temperature for 16 hours; then basified with 10% Na 2 CO ₃ solution and extracted with chloroform. The extract was dried and concentrated to give a yellow gum which was dissolved in acetone (6 ml), treated with anhydrous potassium carbonate (130 mg, 0.94 mmol) and stirred at room temperature for 18 hours. The mixture was quenched with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried and concentrated to give a brown oil which was chromatographed first on silica gel eluting with chloroform / methanol (97: 3) then on basic alumina eluting with ethyl acetate to give a colorless oil which crystallized from ether / pentane to give the title compound (E1) in as a white solid (11 mg), mp 11-119 ° C.

1 H NMR (CDCl ₃ );

δ: 7.97 (d, 1H), 7.10-7.30 (m, 3H), 4.55 (t, 2H), 4.20 (d, 2H), 4.11 (t, 2H) , 2.90-3.03 (m, 2H), 2.25-2.40 (m, 4H), 1.75-2.00 (m, 5H), 1.22-1.55 (m, 6H), 0.91 (t, 3H).

MS (E1) M ⁺ 370.

Example 2.

Eqquinolizidin-2-ylmethyl 3.4- dihydro-2H- [1,3] oxazine [3,2-a] molo-10-carboxylate (E2).

(a) eq-2-Hqd2oHlmethylceinolihidynz (NJ (οϊοηι ^ and wrp., in Org. (Orem., ie57, 22, 1445) was reacted with indole-carboxylic acid chloride as described in example 1a to give 1-hinPol-3. - eq-quinoiiidin-2-ylmethyl carboxylate, mp 154-157 ° C.

1 H NMR (CDCl ₃ );

δ: 9.40 (br.s, 1H), 8.10-8.20 (m, 1H), 7.87 (d, 1H), 7.35-7.45 (m, 1H), 7, 20-7.30 (m, 2H), 4.20 (d 2H), 2.80-2.97 (m, 2H), 1.43-2.20 (m, 11H), 1.10-1 . 40 (m, 3H).

(B) Eq-quinolizidin-2-ylmethyl 1HIndcdo-3-carboxylate was initially treated with N-chlorosuccinimide (1.5 eq.) For 2 hours followed by 3-bromo-1-propanol (2 eq.) For 16 hours and then anhydrous potassium carbonate in acetone as described in Example 1b. The crude product was purified using the same chromatography conditions as in Example 1b to give the title compound as a colorless oil (51%) which was converted into the hydrochloride salt and crystallized from acetone, m.p. 164-167 ° C.

1 H NMR (HCl salt) (d * DMSO);

δ: 10.35 (br.s, 1H), 7.85 (d, 1H), 7.32 (d, 1H), 7.07-7.20 (m, 2H), 4.54 (t, 2H), 4.13 (t, 2H), 4.05 (d, 2H), 3.25-3.43 (m, 2H), 2.74-3.15 (m, 3H), 2.20 -2.33 (m, 2H), 2.00-2.15 (m, 1H), 1.35-1.95 (m, 10H).

Example 3.

N - [(1-n-butyl-4-piperidyl) methyl] -3,4-dihydro-2H- [1,3] oxazine [3,2-a] indole-10-carboxamide (E3).

Method 1: A mixed solution of N-chlorosuccinimide (57 mg, 0.48 mmol) in chloroform (3 ml) was treated with a solution of N - [(1-n-butyl-4-piperidyl) methyl] indole-3-carboxamide, D1, ( 100 mg, 0.32 mmol) in chloroform (8 ml) and kept at room temperature for 2 hours, then quenched with 3-bromo-1-propanol (0.03 ml, 0.32 mmol). After stirring for 16 hours, more 3-bromo-1-propanol (0.03 mL, 0.32 mmol) was added. The mixture was stirred at room temperature for a further 3 hours, then quenched with excess 10% Na ₂ CO ₃ solution and extracted with chloroform. The extract was dried (Na ₂ SO 4) and concentrated in vacuo to give a yellow oil which was dissolved in acetone (10 mL), treated with anhydrous potassium carbonate (130 mg, 0.96 mmol) and stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, the residue was treated with 10% Na ₂ CO ₃ solution (10 ml) and extracted with chloroform. The extract was dried (Na2SO4) and concentrated in vacuo to give a yellow oil which was chromatographed initially on silica gel eluting with chloroform / methanol (181) then on basic alumina eluting with ethyl acetate. The resulting colorless oil was crystallized from ether to give the title compound (E3) as a white solid (20 mg, 17%), mp 110-113 ° C.

NMR (CDCE);

<5: 8.34 (d, 1H), 7.05-7.30 (m, 3H), 6.55 (t, 1H), 4.53 (t, 2H), 4.10 (t, 2H ), 3.33 (t, 2H), 2.90-3.05 (m, 2H), 2.25-2.45 (m, 4H), 1.90-2.25 (m, 2H), 1.20-1.85 (m, 9H), 0.92 (t, 3H).

MS (Cl) MH + 370.

Method 2: A stirred suspension of N - [(1-n-butyl-4-piperidyl) methyl] mol-3-carboxamide (D1, 120 g, 0.38 mol) in chloroform (21) under nitrogen atmosphere at room temperature was freshly quenched. distilled 3-bromo-1-propanol (69 mL, 0.77 mol,) then dry N-chlorosuccinimide (55 g, 0.42 mol) was added portionwise over 5 minutes. The resulting yellow solution was stirred 2.5 hours then quenched with 1M HCl in ether (15 mL, 0.015 mol). A moderate exotherm occurred and the color of the reaction mixture turned orange. After a further 2 hours, 10% Na2CO3 solution (700 mL) was added and the chloroform layer was separated, dried (Na2SO4) and concentrated in vacuo to give a thick red oil which was treated with acetone (1.5 L) and anhydrous potassium carbonate (130 g, 0.15 g). 95 mol) and then stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was quenched with water (11) and extracted with ethyl acetate (1t). Upon standing from the ethyl acetate extract, a solid began to crystallize. After 2 hours at 8 ° C, they were filtered off and dried to give 51.7 g of the title compound (E3) as a beige solid. The mother liquor was extracted with 1M HCl acid (800 ml), the acid extract was then basified with K2CO3 and extracted with chloroform (2 x 700 ml). The combined chloroform extracts were dried (Na ₂ SO 4) and concentrated in vacuo and the residue was

The 172,692 was chromatographed on silica gel, eluting with chloroform / methanol (96: 4). A yellow oil was obtained which on trituration with ether gave a further 21.3 g of the title compound (E3) as a white solid. Conversion to the hydrochloride salt and recrystallization from ethanol / 60-80 petroleum ether gave a white solid; mp 254-256 ° C with decomposition.

HCl salt - ¹ H NMR (DO);

δ: 7.90 (d, 1H), 6.88-7.20 (m, 3H), 4.35 (br.t, 2H), 3.70 (br.t, 2H), 3.40 ( br. d, 2H), 3.20 (br. d, 2H), 2.9 (br. t, 2H), 2.65 (br. t, 2H), 2.12 (br. t, 2H) , 1.20-1.90 (m, 9H), 0.87 (t, 3H).

The elemental analysis results were as follows:

Theoretical Marked Carbon 65.09 64.76 64.75 Hydrogen 7.95 7.73 7.77 Nitrogen 1035 10.35 1036

Example 4.

2- (1-piperidyl) ethyl 3,4-dihydro-2H- [1,3] oxazine [3,2-ajindole-10-carboxylate (E4).

(a) 1-Piperidineethanol was reacted with 1H-indole-3-carboxylic acid chloride as described in Example 1a to give 2- (1-piperidyl) ethyl 1H-indole-3-carboxylate.

Ή NMR (CDCls);

δ: 9.6 (br. s, 1H), 8.03-8.12 (m, 1H), 7.73 (d, 1H), 7.30-7.40 (m, 1H), 7, 13-7.25 (m, 2H), 4.48 (t, 2H), 2.82 (t, 2H), 2.50-2.65 (m, 4H), 1.35-1.70 ( m, 6H).

(b) 2- (1-piperidyl) ethyl 1H-indole-3-carboxylate was initially treated with N-chlorosuccinimide (1.5 eq.) for 2 hours followed by 3-bromo-1-propanol (3 eq.) for 21 hours. followed by anhydrous potassium carbonate in acetone as described in Example 1b. The crude product was purified using the same conditions as in Example 1b to give the title compound (E4) as a pale yellow oil (15%) which was converted to the oxalate salt and crystallized from acetone; mp 174-177 ° C.

Free base: ^X H NMR (CDCl3);

δ: 8.02 (d, 1H), 7.07-7.30 (m, 3H), 4.40-4.55 (m, 4H), 4.08 (t, 2H), 2.78 ( t, 2H), 2.45-2.65 (m, 4H), 2.25-2.38 (m, 2H), 1.54-1.66 (m, 4H), 1.35-1. 50 (m, 2H).

MS (Cl) MH + 329.

Example 5.

N- [2- (1-piperidyl) ethyl] -3,4-dihydro-2- [1,3-oxazine [3,2-a] indole-1-carboxamide (E5).

N- [2 - ('1-piperidyl) ethyl] 1H-indole-3-carboxamide (D2) was first treated with N-chlorosuccinimide, then with 3-bromo-1-propanol, then with potassium carbonate in acetone and the procedure described in Example 3. The crude product was chromatographed on silica gel eluting with chloroform / methanol (19: 1) to give a pale yellow oil which crystallized from ether to give the title compound (E5) as a white solid (29%), m.p. 124-127 ° C.

Tl NMR (CDCl3);

δ: 8.33 (d, 1H), 7.06-7.28 (m, 3H), 7.02 (br t, NH), 4.51 (t, 2H), 4.08 (t, 2H ), 3.50-3.60 (m, 2H), 2.54 (t, 2H), 2.30-2.60 (m, 6H), 1.40-1.65 (m, 6H).

MS (Cl) MH + 328.

172 692

Example 6.

(1-n-butyl-4-piperidyl) methyl dihydrooxazolo [3,2-a] indole-9-carboxylate.

Methyl (1-n-butyl-4-piperidyl) 3-carboxylate (Ela) was first treated with

N-chlorosuccinimide (1.5 eq.) For 4 hours followed by 2-bromoethanol (2 eq.) For 18 hours followed by anhydrous potassium carbonate in acetone (18 hours) as described in Example 1b. The crude product was purified using the same chromatography conditions as in Example 1b to give a colorless oil (26%) which crystallized from ether to afford compound (E6) as a white solid, mp 128-130 ° C.

^! 11 NMR (CDCls);

δ: 7.95-8.02 (m, 1H), 7.07-7.27 (m, 3H), 5.18-5.27 (m, 2H), 4.24-4.33 (m , 2H), 4.19 (d, 2H), 2.92-3.04 (m, 2H), 2.27-2.38 (m, 2H), 1.75-2.05 (m, 5H ), 1.25-1.66 (m, 6H), 0.91 (t, 3H).

MS (E1) M + 356.

Example 7.

(1-n-butyl-4-piperidyl) methyl 3.3-dimethyl-3,4-dihydro-2H- [1,3] oxazine [3,2-a] indole-1-carboxylate (E7).

Methyl 1H-indole-3-carboxylate (E1a) was first treated with N-chlorosuccinimide (1.5 eq) for 2 hours and then with 3-bromo-2,2-dimethyl -1-propanol (2 eq.) For 20 hours then anhydrous potassium carbonate in acetone (2 1/2 days) was added using the method described in Example 1b. The crude product was chromatographed on silica gel eluting with chloroform / methanol (95: 5) to afford the title compound (E7) as a white solid (10%), m.p. 134-135 ° C.

Ή NMR (CDCl ₃ );

δ: 7.98 (d, 1H), 7.08-7.30 (m, 3H), 4.21 (d, 2H), 4.15 (s, 2H), 3.77 (s, 2H) , 2.95-3.07 (m, 2H), 2.32-2.42 (m, 2H), 1.80-2.10 (m, 5H), 1.25-1.60 (m, 6H), 1.20 (s, 6H), 0.93 (t, 3H).

MS (Cl) MH. + 399.

Example 8.

(1-n-butyl-4-piperidyl) methyl 3.4- dihydro-2H- [1,3] thiazino [3,2-a] indole-10-carboxylate (E8).

Methyl 1H-Indole-3-carboxylate, E1a, (314 mg, 0.0010 mol) was first treated with N-chlorosuccinimide (180 mg, 0.0015 mol) for 2 hours and then 3-chloro-1-propanethiol (0.20 ml, 0.0020 mol) for 5 days using the method described in Example 1b. The resulting solution was basified with 10% Na2CO3 solution and extracted with chloroform. The extract was dried (Na2SO4) and concentrated in vacuo to leave a dark oil which was chromatographed on silica gel eluting with chloroform / methanol (95: 5) to afford 2- (3-chloropropyl mercapto) -1H-indole-3-carboxylate (1-n-butyl-4). -piperidyl) methyl as a gray oil (220 mg) which was dissolved in acetone (50 ml) and treated with anhydrous potassium carbonate (220 mg, 0.0015 mol) and sodium iodide (390 mg, 0.0026 mol) and heated in reflux for 8 hours. The mixture was concentrated in vacuo and the residue was taken up in 10% Na 2 CO 3 solution then extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated. The residue was chromatographed on basic alumina, eluting with ethyl acetate. The obtained colorless oil was crystallized from ether to afford the title compound (E8) as a white solid (80 mg, 21%); ŁŁ 99-100 ° C.

1 H NMR (CDCl 3);

δ: 7.97-8.04 (m, 1H), 7.14-7.30 (m, 3H), 4.22 (d, 2H), 4.15 (t, 2H), 3.05- 3.15 (m, 2H), 2.92-3.02 (m, 2H), 2.38-2.5 (m, 2H), 2.27-2.37 (m, 2H), 1. 75-2.02 (m, 5H), 1.20-1.55 (m, 6H), 0.91 (t, 3H).

MS (E1) M + 386.

172 692

Example 9.

(1-n-butyl-4-piperidyl) methyl 2,3,4,5-tetrahydro [1,3] azepino [3,2-a] indole-11-carboxylate.

Methyl lH-Indole-3-carbocaclay (1-γ-butyl-4-pipetidClk) (E1a) was first treated with N-chloro-succinimidebm (1.5 eq.) for 2 hours followed by 4-chloro-1-butanol (2 eq. for 18 hours by the method of Example 1b and the product was extracted as in Example 8a to give 2- (4-chlorobuyocac) -1'Hrlndolor-3-cathboxyl (1-yrbutyl-4-pipercdoclo) methyl as a yellow oil. The acetone solution was treated with anhydrous potassium carbonate and sodium iodide and refluxed for 30 hours, then purified as in Example 8 to give the title compound (E9) as a pale yellow oil (31) which was converted to its oxalate salt and crystallized from acetone to give a white solid; mp 161-164 ° C.

Oxalate salt: ^X H HMR (d ⁶ DMSQ);

δ: 7.85-7.95 (m, 1H), 7.45-7.55 (m, 1H), 7.10-7.25 (m, 2H), 445-4.30 (ni,

4.10 ((, 2IH, 3.33-, 45 (nm 2H), ^ 8) -3.25-m, 4H), 1.80-2, 10 (nm 7H), 1.57-1 , 75 (m, 4H), 1.20-1.40 (m, 2H), 0.89 (t, 3H).

MS (E1) M + 384.

Example 10.

Methyl (1-n-butyl-4-piperidyl) [12a] indole-10-carboxylate.

A solution of 6,7,8,9-tetrahydrropitido [1,2 r] iydolor10carbkxclic acid, D3, (400 mg, 0.00186 mol) in dichloromethane (20 ml) was treated with oxalyl chloride (0.20 ml, 0.0023 mol) and 2 drops of DMF and stirred at room temperature for 2 hours then concentrated in vacuo to give the acid chloride as an orange solid.

A solution of (ln-bu1ylo-4-pipercdy ^{o) me} 'tanolu (D6) 0.32 g, 0.00186 mol) in dry THF (25 ml) at 5 ° C under nitrogen, treated with 1.5 m methyllithium in ether (1.24 ml, 0.00186 mol) and allowed to stir for 15 minutes, then quenched with a solution of the above acid chloride in dry THF (15 ml). After 16 hours at room temperature, the mixture was quenched with saturated K2CO3 solution (50 mL) and extracted with ethyl acetate (2 x 75 mL), dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with chloroform / ethanol (95: 5). The title compound (E10) was obtained as a yellow oil which was converted into its hydrochloride to give a white solid; mp 230-232 ° Ο

HCl salt: NMR (D 6 O O);

e: 10.3 (br. s, 1H), 7.92-8.03 (m, 1H), 7.43-7.53 (m, 1H), 7.16-7.26 (m, 2H ), 4.18 (d, 2H), 4.11 (t, 2H), 3.43-3.56 (m, 2H), 3.23 (t, 2H), 2.82-5.05 ( m, 4H), 1.85-2.12 (m, 7H), 160-1.80 (m, 4H), 1.25-1.40 (m, 2H), 0.90 (t, 3H) .

MS (E1) M + 368.

Example 11.

Methyl (1-n-butyl-4-pipeiyidyl) 2,3-dihydro-1H-pyrrolo [1 _& gt _; 2-a] indole-9-carboxylate (E11).

The title compound (E11) was prepared from 2,5-dihydro-1H-pyrrolo [1,2ra] indcto-1-carboxylic acid (D4) by the method of Example 10 and isolated as a pale orange solid (24%); mp 100-102 ° C.

Ή NMR (CDCl3);

δ: 8.03-8.12 (m, 1H), 7.13r7, m5 (m, 3H), 4.17 (d, 2H), 4.11 (t, 2H), 3.29 (t, 2H), 2.95-3.08 (m, 2H), 2.57-2.72 (m, 2H), 2.30-2.41 (m, 2H), 1.92-2.07 ( m, 2H), 1.73-1.90 (m, 3H), 1.40-1.60 (m, 4H), 1.22-1.39 (m, 2H), 0.92 (t, 3H).

MS (E1) M + 354.

172 692

Example 12.

Methyl (l-n-butyl-4-piperidyl) tetrahydro-6H-azepino [1,2-a] indole-11-carboxylate (E12).

The title compound (E12) was prepared from the acid 7.8, ^< ^, N ^ O - <stt ^ r ^ l ^^ ch-o- (6b ^^^^: ^ t ^; pi ^ o [1.2 -a] indole-11-carboxylic acid (D5) as in Example 10. The crude product was purified by chromatography on silica gel eluting with chloroform / ethanol (98: 2) to give a yellow oil which was converted to its hydrochloride to give a beige solid (20%) mp 196-198 ° C.

NMR (D ⁶ DMSO) - HCl salt;

δ: 10.52 (br.s, 1H), 7.93-8.00 (m, 1H), 7.55-7.62 (m, 1H), 7.13-7.25 (m, 2H ), 4.25-4.40 (m, 2H), 4.17 (d, 2H), 3.35-3.55 (m, 4H), 2.80, -3.10 (m, 4H) , 1.55-2.15 (m, 13H), 1.24-1.40 (m, 2H), 0.88 (t, 3H).

MS (Cl) MH + 383.

Example 13.

N - [(1-n-butyl-4-piperidyl) methyl] -2,3-dihydro-1H-pyrrolo [1,2-a] indole-9-carboxamide (E13).

A solution of 2,3-dihydro-1H-pyrrolo [1,2-a] indole-9-carboxylic acid, D4, (180 mg, 0.89 mmol) in dichloromethane (20 mL) was treated with oxalyl chloride (0.096 mL, 1 1 mmol) and 2 drops of DMF and stirred at room temperature for 1 hour then concentrated in vacuo to give the acid chloride as a yellow solid.

A solution of (1-n-butyl-4-piperidyl) methylamine, D8 (150 mg, 0.89 mmol) and triethylamine (0.15 ml, 1.1 mmol) in dichloromethane (20 ml) under nitrogen atmosphere was quenched with a solution of the above acid chloride in dichloromethane (5 ml) and stirred at room temperature for 3 hours. The solution was quenched with a 10% Na ₂ CO _{3 solution} and the organic layer was separated, dried (Na ₂ SO 4) and concentrated in vacuo to give a beige solid which was recrystallized from ethyl acetate to give the title compound (E13) as a white solid (180mg, 55 %); mp 152-154 ° C.

^l H NMR (CDCl?);

δ: 7.75-7.84 (m, 1H), 7.13-7.33 (m, 3H), 5.93 (br.t, NH), 4.10 (t, 2H), 3, 38 (t, 2H), 3.31 (t, 2H), 2.90-3.02 (m, 2H), 2.65 (quintet, 2H), 2.28-2.36 (m, 2H) , 1.60-2.10 (m, 6H), 1.22-1.55 (m, 5H), 0.90 (t, 3H).

MS (Cl) MH + 354.

Example 14.

N - [(1-n-buyo-4-piperidyl) methyl] -2,3-dihydrooxazolo [3,2-a] idolo-9-carboxamide (E14).

N - [(1-n-butyl-4-piperidyl) methyl] indole-3-carboxamide (D1) was first treated with N-ch-Yorosuccinimide (1.5 eq.) For 2 hours followed by 2-bromoethanol (2 eq.) For 16 hours, then with potassium carbonate (3 eq.) in acetone for 68 hours by the method of Example 1b.

The crude product was purified by chromatography on silica gel eluting with chloroform / ethanol (19: 1) to give the title compound (E14) as a white solid after recrystallization from chloroform / ether (14%); mp 156-158 ° C.

^X H NMR (CDCl ₃ );

δ: 8.19 (d, 1H), 7.00-7.30 (m, 3H), 6.00 (t, NH), 5.15 (t, 2H), 3.32 (t, 2H) , 2.90-3.15 (m, 2H), 2.25-2.42 (m, 2H), 1.20-2.05 (m, 11H), 0.90 (t, 3H).

MS (Cl) MH + 356.

Example 15.

3,4-Dihydrd2H- [1,3] oxazind [3 _^ 2-a] inddlo ^ 10-carboxylate (1-benzene> A-piperidide) methyhu (a) Indoto-3-carboxylic acid pvekpzzalcono as its clergide to acids, o then reacted with 1-benzyl-4-pipelineidine methanol (D7) as indicated

172 172 in Example 1a. The resulting orange oil was chromatographed on silica gel, eluting with chloroform / ethanol (9: 1) to give methyl indole-3-carboxylate as a yellow oil (88%).

Ή NMR (CDCls);

δ: 9.24 (s, 1H), 8.12-8.20 (m, 1H), 7.81 (d, 1H), 7.20-7.45 (m, 8H), 4.20 ( d, 2H),

3.53 (s, 1H), 2.93-3.04 (m, 2H), 1.73-2.10 (m, 5H), 1.36-1.58 (m, 2H).

(b) Methyl indole-3-oaobocaflate (ilbet-L1-4-piperipic>) with N-chlorosuccinimide (1.5 eq.) for 2 hours followed by 3-bromo-1-propanol (2 eq.) for 16 hours followed by with anhydrous potassium carbonate in acetone as described in Example 1b. The crude product was purified by chromatography on silica gel eluting with chloroform / ethanol (19: 1) to give the title compound (E15) as a beige solid after recrystallization from chloroform / ether (47%); mp 158-160 ° C.

Ή NMR (CDCls);

δ: 7.94-8.00 (m, 1H), 7.10-7.38 (m, 8H), 4.48-4.56 (m, 2H), 4.19 (d, 2H), 4.05-4.12 (m, 2H), 3.50 (s, 2H), 2.88-2.98 (m, 2H), 2.28-2.39 (m, 2H) 1.75 -2.08 (m, 5H), 1.35-1.55 (m, 2H).

MS (Cl) MH + 405.

Example 16.

Methyl (1-n-butyl-4-piperidyl) 3,4-dihydro-1-oxo-2H- [1,3] thiazino [3,2-a] indole-10-carboxylate (E16).

3,4-Nihydro-2H- [1,3] thiazino [3,2-a] indole-1-carboxyl for3 (1-n-autyl-1-piperdnyl) methyl solution (E8, 80 mg, 0.21 mmol) in acetone (5 ml) and water (5 ml) were treated with sodium nanionate (100 mg, 0.46 mmol) and stirred at room temperature for 24 hours. The solution was then quenched with saturated K2CO3 solution (10 mL) and extracted using ethyl acetate (2x25 mL). The extract was dried (Na2SO4) and concentrated in vacuo to yield a yellow oil which was chromatographed on silica gel eluting with 5% methanol / chloroform. The obtained colorless oil was crystallized from ether to afford the title compound (E16) as a white solid (27 mg, 32%); mp 130-135 ° C.

'ii NMR (CDCls);

δ: 8.24 (d, 1H), 7.30-7.50 (m, 3H), 4.54 (dd, 1H), 4.22-4.38 (m, 2H), 4.05 ( dt, 1H), 3.40 (dd, 1H), 3.21 (dq, 1H), 2.86-3.08 (m, 3H), 2.30-2.45 (m, 3H) 1, 80-2.10 (m, 5H), 1.40-1.65 (m, 4H), 1.20-1.40 (m, 2H), 0.90 (t, 3H).

MS (Cl) MH + 403.

Example 17.

Methyl (1-n-butyl-piperidyl) 7-dihydropyrido [1,2-a] indole-10-carboxylate (E17).

The title compound was prepared from 6,7-nihydropicdno [1,2-a] indole-10-carboxylic acid (D8) by the method of Example 10 and chromatographed on silica gel eluting with ethyl acetate to give a yellow solid (18%); mp 62-62 ° C (n-pentane).

Ή NMR (CDCls);

δ: 8.10-8.17 (m, 1H), 7.42 (dt, 1H), 7.18-7.33 (m, 3H), 6.25-6.35 (m, 1Ή), 4.22 (d, 2H), 4.15 (t, 2H), 2.90-3.05 (m, 2H), 2.63-2.75 (m, 2H), 2.29-2. 38 (m, 2H), 1.75-2.04 (m, 5H), 1.25-1.55 (m, 6H), 0.91 (t, 3H).

MS (E1) M + 366.

Example 18.

(1-n-butyl-4-piperidyl) methyl pyrido [1,2-a] indole-10-carboxylate.

The title compound was prepared from pyrino [1,2-aiienol-10-carboxylic acid (D9) as in Example 10 and chromatographed on silica gel, eluting with ethyl acetate to give a yellow solid (10%); mp 57-59 ° C (n-pentane).

I72 692 ^x H NMR (CDO3);

δ: 8.35-8.50 (m, 3H), 7.88 (p 1H), 7.48-7.56 (m, 1H), 7.28-7.40 (m, 2H), 6 , 78-6.86 (m, 1H), 4.30 (p 2H), 2.95-3.05 (m, 2H), 2.30-2.40 (m, 2H), 1.85- 2.05 (m, 5H), 1.43-1.60 (m, 4H), 1.25-1.40 (m, 2H), 0.92 (t, 3H).

MS (E1) M + 364.

Example 19.

N - [(1-n-butyl-4-piperid ^] ^) imethyl] -3 ₎ 4-hydroxy ^ ^ 2] H- [1,3] thiazino [3,2-a] indole-10-carboxamide ( E19).

The title compound was prepared from N - [(1-n-butyl-4-piperidyl) methyl] indole-3-carboxyamide (D1b) by the method of Example 8 as a white solid (7%); mp 141-142 ° C.

1 H NMR (CDCl 3);

δ: 7.70 (P, 1H), 7.13-7.30 (m, 3H), 6.07 (t, 2H), 3.38 (t, 2H), 3.08 (t, 2H) , 2.90-3.02 (m, 2H), 2.38-2.50 (m, 2H), 2.25-2.36 (m, 2H), 1.60-2.00 (m, 5H), 1.23-1.56 (m, 6H), 0.91 (t, 3H).

MS (E1) M + 385.

Example 20.

N - [(1-benzyl-4-piperidylmethyl] -3,4-dihydro-1H- [1,3] oxazine [3,2-a] indole-10-carboxamide (E20).

(a) The indole-M-carboxylic acid was converted to the acid chloride and then reacted with (1-benzyl-4-piperidyl) methylamine (D10) as in recipe 1b to give N - [(1-benzyl-4-piperidyl) methyl] molar -3-carboxylamP as a white solid (6o%).

Ή NMR (CDCl3);

δ: 9.90 (s, 1H), 7.85-7.95 (m, 1H), 7.64 (d, 1H), 7.15-7.43 (m, 8H), 6.17 ( t, 1H),

3.48 (s, 2H), 3.37 (t, 2H), 2.83-2.98 (m, 2H), 1.87-2.08 (m, 2H), 1.54-1. 82 (m, 3H)

1.23-1.50 (m, 2H).

(b) A stirred suspension of N - [(1-benzyl-4-piperPylmethyl] inPol-3-carboxamide (17.5 g, 0.050 mol) in chloroform (250 ml) was treated with 3-bromo-1-propanol (10.1 ml 0.11 mol) and N-chlorosuccinimide (8.7 g, 0.065 mol) at room temperature and a clear solution was obtained after 15 minutes.After 1 hour the reaction mixture turned pale yellow to orange and the temperature rose after 38 ° C. for a further 1 hour the reaction mixture was quenched with 10% NaHCO3 solution and the chloroform layer was separated, dried (Na2SO4) and concentrated in vacuo to give a yellow oil which was chromatographed on silica gel eluting with 3% methanol / chloroform. Intermediate 2- (3-bromopropoxy) inPol was dissolved. in acetone (400 ml), quenched with anhydrous potassium carbonate (11 g, 0.80 mol) and stirred at room temperature for 20 hours The reaction mixture was concentrated in vacuo and the residue was taken up in water (200 ml) and extracted with chloroform (2 × 250 ml) The combined extracts were dried (Na2SO4), concentrated in vacuo and remained Chromatograph on silica gel eluting with 5% methanol / chloroform to give the title compound (E20) as a pale yellow oil (31 g. 15%) that was converted to the oxalate and crystallized from acetone as a white solid; mp 169-170 ° C.

Free base: - 1 H NMR (CDC3);

δ: 8.32 (p 1H), 7.05-7.38 (m, 8H), 6.53 (t, 1H), 4.50 (t, 2H), 4.08 (t, 2H), 3.48 (s, 2H), 3.31 (t, 2H), 2.83-2.97 (m, 2H), 2.27-2.41 (m, 2H), 1.54-2. 6 (m, 5H), 1.25-1.45 (m, 2H).

Example 21.

N- (4-piper ^ (d ^^ inethyl) -3,4- <iihydr <^ -: 2H- [1 ₎ 3] oxazine [3,2-a] indole-10-carboxamide (E21), 'Mixed suspension of N - [(1-benzyl-'4-piperidyl) methyl] 3,4-dihydro2H- [13] oxalate [3,2-a] molol-10-carboxamide (E20, 2.25 g, 0 0.0046 mol) in ethanol (100 ml) and glacial acetic acid (4 ml) were hydrogenated over 10% Pd-C (0.8 g) at atmospheric pressure and 45 ° C for 18 hours. The mixture was filtered and the filtrate was concentrated in vacuo. Most of the product was a solid which was filtered off. The material was shaken with a concentrated solution of potassium carbonate (50 ml) and chloroform (50 ml) along with the rest of the filtrate. The mixture was filtered, the chloroform layer separated and filtered (NaSO 4) then concentrated in vacuo to give the title compound as a white solid (1.52 g, 100%) which was recrystallized from chloroform / 60-80 petroleum ether; mp 139-141 ° C.

NMR (CDCl 3);

δ: 8.32 (d, 1H), 7.03-7.30 (m, 3H), 6.53 (t, 1H), 4.48 (t, 2H), 4.05 (t, 2H) , 3.30 (t, 2H), 3.02-3.15 (m, 2H), 2.52-2.70 (m, 2H), 2.27-2.40 (m, 2H), 1 . 65-1.90 (m, 4H),

1.10-1.30 (m, 2H).

MS (E1) M + 313.

Example 22.

N - [(1-n-hexyl-4-piper ^ (d ^ ^ ^ ethyl] -3,4-dihydro-2H- [1,3] ^ x ^ c ^ 2 y ^ n ^ [^ 2 ^ - a ^] indole-10-carboxy ^^^ and d (E22).

A solution of N- (4-piperidylmethyl) 3,4-dihydro-2H- [1,3] oxazine [3,2-a] indole-10-carboxamide (E21, 250 mg, 0.70 mmol) in acetone (12 mL) was added 1-bromohexane (0.14 ml, 1.0 mmol) and anhydrous potassium carbonate (280 mg, 2.0 mmol) and stirred at room temperature for 70 hours. The mixture was concentrated in vacuo and the residue was treated with 10% Na2CO3 solution and extracted with chloroform. The extract was dried (Na2SO4), concentrated in vacuo and the residue was chromatographed on silica gel eluting with 5% methanol / chloroform to give a yellow oil which was passed through a short plug of basic alumina eluting with ethyl acetate. The title compound (E22) was obtained as a colorless oil (150 mg, 54%) which was converted to its hydrochloride and crystallized from acetone / ether as a white solid; mp 170-171 ° C.

Free base: - Tl NMR (CDCls);

δ: 8.32 (d, 1H), 7.03-7.30 (m, 3H), 6.53 (t, 1H), 4.48 (t, 2H), 4.04 (t, 2H) , 3.32 (t, 2H), 2.90-3.00 (m, 2H), 2.25-2.38 (m, 4H), 1.83-1.96 (m, 2H), 1 , 20-1.81 (m, 13H). 0.88 (t, 3H).

MS (E1) M + 397.

Example 23.

N- [(-cyldohexylethyl-4-pperidyl) methyl] -3,4-dihydro-2H- [1,3] oxazine [3,2-a] and n-ol-10-carboxylic acid (E23).

N- (4-piperidylmethyl) -3,4-dihydro-2H- [1,3] oxazine [3,2-a] indole-10-carboxamide (E21) was alkylated with cyclohexylmethyl bromide as in Example 22 for 70 hours at at room temperature and then 8 hours at reflux. The title compound (E23) was obtained as a white solid (31%) which was converted to the hydrochloride salt and crystallized from acetone / ether as a white solid; mp 209-210 ° C.

HCl salt: - Tl NMR (CD ₃ OD);

δ: 8.03-8.09 (m, 1H), 7.20-7.28 (m, 1H), 7.10-7.17 (m, 2H), 4.60 (t, 2H), 4.15 (t, 2H), 3.53-3.65 (m, 2H), 3.36 (d, 2H), 2.85-3.05 (m, 4H), 2.30-2. 43 (m, 2H), 1.50-2.07 (m, 11H), 1.18-1.46 (m, 3H), 0.95-1.13 (m, 2H).

MS (E1) M + 409.

1.72692

Example 24.

N- [(1-Ethyl-4-piper- and 6-rnr) -methyl] -3 ₎ 4-dihydro-2H- [1,3-Ioxazine [3,2-ajindole-10-carboxamide (24).

N- (4-piperidylmethyl) -3,4-dihydro-2H- [1,3] oxazine [3,2-a] indole-10-carboxamide (E21) was alkylated with iodoethane as in Example 22. The title compound was obtained as a white a solid (27%) that was converted to its hydrochloride and crystallized from acetone / ethanol / ether as a white solid; mp 243-245 ° C.

Free base: NMR (CDCl3);

δ: 8.34 (d, 1H), 7.05-7.28 (m, 3H), 6.55 (t, 1H), 4.52 (t, 2H), 4.07 (t, 2H) , 3.33 (t, 2H), 2.90-3.02 (m, 2H), 2.30-2.40 (m, 4H), 1.55-1.98 (m, 5H), 1 , 25-1.45 (m, 2H), 1.08 (t, 3H).

MS (E1) M + 341.

Example 25.

N - [(1- (2-melanesulfonamidoethyl) -4-pipelydyl)) methyl] -3,4-dihydro-2H- [1,3] oxazine [3,2-a] indole-10-carboxamide ( E25).

A mixed solution of N- (4-pipeydylmethyl) 3,4-dihydro-2H- [1,3] oxazine [3,2-a] indole-10-carboxamide (E21, 220 mg, 0.70 mmol) in acetonitrile (8 mL) was treated with diisopropylethylamine (0.24 mL, 1.4 mmol), and N- (2-bromoethyl) methanesulfonamide (D14, 160 mg, 0.77 mmol) and the mixture was refluxed for 2.5 hours . The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel eluting with dichloromethane / methanol / 0.88 ammonia solution (200: 10: 1). The resulting colorless oil was dissolved in chloroform (30 mL) and washed with water (2 x 20 mL) then dried (Na2SO4) and concentrated in vacuo. The residue was passed through a short plug of basic alumina eluting with ethyl acetate. The title compound was obtained as a colorless oil (34 mg, -11%) which was converted to its oxalate and crystallized from acetone to give a white solid; mp 80-85 ° C.

Free base: - ^1H NMR (CDCl3);

δ: 8.32 (d, 1H), 7.05-7.30 (m, 3H), 6.56 (t, 1H), 4.53 (t, 2H), 4.08 (t, 2H) , 3.33 (t, 2H), 3.17 (t, 2H), 2.95 (s, 3H), 2.78-2.92 (m, 2H), 2.50 (t, 2H), 2.28-2.44 (m, 2H),

1.55-2.10 (m, 6H), 1.20H, 45 (m, 2H).

Example 26.

N- (eq-cinolizidin-2-ylmethyl) -3,4-dihydro-2H- [1,3] oxazine [3,2-a] indole-10-carboxamide (E 26).

(a) eq-Quinolizidin-2-ylmethylamine (D12) was reacted with indole-3-carboxylic acid chloride as described in recipe 1b to give N- (eq-quinolysin-2-ylmethyl) indole-3-carboxamide (55%) .

Ή NMR (CD3OD);

δ: 8.06-8.15 (m, 1H), 7.89 (s, 1H), 7.39-7.46 (m, 1H), 7.10-7.22 (m, 2H), 3.27 (d, 2H), 2.80-2.95 (m, 2H), 2.04-2.23 (m, 2H), 1.53-1.98 (m, 8H), 1. 22-1.48 (m, 3H), 0.96-1.15 (m, 1H).

(b) A stirred suspension of N- (eq -cholizidin-2-ylmethyl) indole-3-carboxamide (300 mg, 0.94 mmol) in chloroform (16 ml) was treated with 3-bromo-1-propanol (0.17 ml, 1.9 mmol) followed by N-chlorosuccinimide (140 mg, 1.05 mmol) to give a clear solution within 30 minutes. After 2 hours, the mixture was quenched with 1M HCl / ether (3 drops) to give a yellow color, then after 1.5 hours, the mixture was quenched with excess 10% NaHCO3 solution and the chloroform layer was separated, dried (Na2SO4) and concentrated in vacuo to give a yellow oil. which was dissolved in acetone (20 ml), quenched with anhydrous potassium carbonate (400 mg, 2.9 mmol) and stirred at room temperature for 24 hours then concentrated in vacuo. Residue

172,692 was treated with 10% Na2CO3 solution and extracted with chloroform. The extract was dried (Na2SO4) and concentrated to leave a yellow oil which was chromatographed on silica gel eluting with 10% methanol / chloroform. The resulting oil was passed through a short plug of basic alumina eluting with ethyl acetate. The title compound (E26) was obtained as a colorless oil (110 mg, 32%) which was converted into its hydrochloride and crystallized from methanol / ether as a white solid; mp 243-247 ° C.

Free base: - 1H NMR (CDCl3);

δ: 8.30 (d, 1H), 6.98-7.25 (m, 3H), 6.51 (t, 1H), 4.45 (t, 2H), 3.96 (t, 2H) , 3.20-3.27 (m, 2H), 2.78-2.92 (m, 2H), 2.202.35 '(m, 2H), 1.94-2.14 (m, 2H), 0.98-1.85 (m, 12H).

MS (Cl) MH + 368.

Example 27.

Methyl (1-n-butyl-4-piperidyl) 8-fluoro-3,4-dihydro-2H- [1,3] oxazine [32-a] indole-10-carboxylate (E27).

(a) 5-Fluoroindole-3-carboxylic acid chloride was reacted with (1-n-butyl-4-piperiddoomethanol (D6) according to example 1a to give 5-fluoroindole-3-carboxylate (1-n-butyl-4-). piperidyl) methyl as an orange oil (30%) after flash chromatography on silica gel eluting with 10% ethanol / chloroform.

NMR (CDCl3);

δ: 9.95 (br.s, 1H), 7.82 (s, 1H), 7.78 (dd, 1H), 7.00 (dt, 1H), 4.22 (d, 2H), 3 .00-3.15 (m, 2H), 2.33-2.47 (m, 2H), 1.95-2.10 (m, 2H), 1.75-1.93 (m, 3H) , 1.22-1.65 (m, 6H), 0.92 (t, 3H).

(b) Methyl (1-n-butyl-4-piperidyl) 5-fluoroindole-3-carboxylate was reacted with N-chlorosuccinimide and 3-bromo-1-propanol and then with potassium carbonate in acetone as in Example 26b to give a pale an oil that was flash chromatographed on silica gel, eluting with 10% ethanol / chloroform. This gave the title compound (E27) as a pale yellow oil (8%) that was converted to its oxalate to give a beige solid, mp 118-119 ° C.

Free base: - 1 H NMR (CDCl 3);

δ: 7.64 (dd, 1H), 7.04 (dd, 1H), 6.87 (dt, 1H), 4.55 (t, 1H), 4.20 (d, 2H), 4.10 (t, 2H), 2.96-3.10 (m, 2H), 2.28-2.46 (m, 4H), 1.77-2.14 (m, 5H), 1.25-1 . 65 (m, 6H). 0.92 (t, 3H).

MS (Cl) MH + 389.

Example 28.

N - [(1-n-butyl-4-piperidyl) methyl] -8-fluoro-3,4-dihydro-2H- [1,3] oxazine [3,2-a] indole-10-carboxamide (E28) .

(a) 5-Fluoroindole-3-carboxylic acid chloride was reacted with (1-n-butyl-4-piperidyl) methylamine (D1a) according to recipe 1b to give N - [(1n-butyl-4-piperycypyl) methyl] 5 -fluoroindole-3-carboxamide as an off-white solid (64%).

Ή NMR (CD3OD);

δ: 7.92 (s, 1H), 7.78 (dd, 1H), 7.38 (dd, 1H), 6.95 (dt, 1H), 3.28 (d, 2H), 2.93 -3.07 (m, 2H), 2.30-2.42 (m, 2H), 1.60-1.87 (m, 3H), 1.22-1.60 (m, 6H), 0 . 94 (t, 3H).

(b) N - [(1-n-butyl-4-piperidyl) methyl] -5-fluoroindole-3-carboxamide was reacted with 3-bromo-1-propanol and N-chlorosuccinimide and then with potassium carbonate in acetone in the manner Example 26b to give a yellow oil which was flash chromatographed on silica gel eluting with 20% ethanol / chloroform. The title compound was obtained as a pale yellow oil (8%) which was converted to the hydrochloride salt to give a beige solid; mp 90 ° C with decomposition.

Free base: - 11 ¹ HMR (CDCF);

172,692 -: 7.98 (dd, 1H), 6.98 (dd, 1H), 6.83 (dt, 1H), 6.56 (t, 1H), 4.56 (d, 2H), 4 . 08 (t, 2H), 3.33 (t, 2H), 3.05-3.20 (m, 2H), 2.30-2.58 (m, 4H), 2.10-2.26 (m, 2H), 1.25-1.90 (m, 9H), 0.92 (t, 3H).

MS (Cl) MH + 388.

Example 29.

(1-n-Butyl-4-plperidylmethyl-methyl-1,2,3,4-tetrahydropyrimido [1,2-a] indole-10-carboxylate (E29).

A solution of (1-n-butyl-4-pipetidyl) methanol (D 6.1.7 g, 0.010 mol) in dry THF (20 ml) under argon at 10 ° C was treated with 1.5 m methyllithium in ether (2 7 ml, 0.004 mol) and stirred for 15 minutes, then a solution of methyl 1-methyl-1,2,3,4-tetrahydropyrimido [1,1 ma] indcl-10-carbocarbonate (D11, 0.5 g, 0.002 mol) in THF (5 ml) and the reaction mixture was heated under reflux for 24 hours. The mixture was allowed to cool, then quenched with 10% Na ₂ CO ₃ solution (50 ml) and extracted with ethyl acetate (2x40 ml). The combined extracts were dried (Na ₂ SO 4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 2% meyayol / clnrofotm to give the title compound (E29) as a colorless oil (0.58g, 74%). This compound was converted to the oxalate and rectified from methanol to give a white solid; mp. 186-187 °

Free base: - ^X H NMR (CDCl 3);

δ: 7.92 (d, 1H), 7.00-7.20 (m, 3H), 4.17 (d, 2H), 3.95 (t, 2H), 3.37 (t, 2H) , 3.28 (s, 3H), 2.92-3.03 (m, 2H), 2.28-2.38 (m, 2H), 2.12-2.24 (m, 2H), 1 . 80-2.03 (m, 5H).

1.23-1.57 (m, 6H). 0.92 (t, 3H).

MS (E1) M + 383.

Example 30.

Methyl (1-n-butyl-4-piperidyl) methyl 3-methylthiazolo [3,2-a] indole-9-carboxylate (E30).

The title compound (E30) was prepared from 3-methylthiazolo [3,2-a] indolor-9-carboxitic acid (D13) by the method of Example 10. The crude product was chromatographed on silica gel, eluting with chloroform / methanol (95: 5) and then passed through short plug of basic alumina, eluting with ether. A pale yellow oil (35%) was obtained which was converted to its oxalate and crystallized from methanol to give a white solid; mp 224-226 ° C.

Free base: - ⁷ H NMR (CDCl3);

δ: 8.18 (d, 1H), 7.77 (d, 1H), 7.14-7.42 (m, 2H), 6.40 (s, 1H), 4.25 (d, 2H) , 2.92-3.08 (m, 2H), 2.73 (s, 3H), 2.28-2.40 (m, 2H), 1.75-2.05 (m, 5H), 120 -1.62 (m, 6H), 0.92 (t, 3H).

MS (Cl) MH + 388.

Example 31.

(1-n-Butylpiperidyl) -nethyl 2,3-dihydrothiazolo [3,2-a] indole-9-carboxylate (E31).

The title compound was prepared from 2,3-dihydrothiazolo [3,2-a] rndole-9-carboxylic acid (D15) as in Example 10. The crude product was purified by chromatography on silica gel eluting with 5% methanol / chloroform to give a yellow oil which was passed through to the crude product. through a basic alumina plug eluting with ethyl acetate. The title compound was obtained as a pale yellow oil (31%) that was converted to oxalate and crystallized from acetone as an off-white solid; mp 212-215 ° C.

Free base: - 1 H NMR (CDCl 3);

δ: 7.98 (d, 1H), 7.09-7.26 (m, 3H), 4.26 (t, 2H), 4.20 (d, 2H), 3.80 (t, 2H) , 2.94-3.06 (m, 2H), 2.30-2.40 (m, 2H), 1.73-2.06 (m, 5H), 1.24-1.60 (m, 6H), 0.92 (t, 3H).

Example 32.

(.1.-n-butyl-4-piperidyl) methyl thiosol [1,2-o] molol-9-carboxylate (E32).

The title compound was prepared from thiozolo [3,9-a] indole-9oCarbaCoylic acid (D16) as in Example 10. The crude product was purified by silicon dioxide gel chromatography eluting with 3% methanol / chloroform to give a pale purple solid (70%) which was converted into oxalate and re-crystallized from methanol to give a light blue solid; mp 217-218 ° C.

Free base: - 1 H NMR (CDCl ₃ );

δ: 8.18 (d, 1H), 7.79 (d, 1H), 1.6 (d, 1H), 7.30l7.13 (m1 1H), 7.20-7.30 (m, 1H ), 6.91 (d, 1H), 4.27 (d, 2¾ 2.95 - .00 (m 2H), 2.30-2.40 (m, ^ 1.79-0.08 (m , 5H), 1.40-1.62 (m, 4H), 1. ^^ (se ^ et, 2H), 0.92 (t, 3H).

Example 33.

24 Dimethidpyrimidide [1,2-a] inddld-10-dtbdxylate (1-n-buoylF4-prryl) methyl (E33).

The title compound was prepared from methyl 2 < 4-dimethylpyrimido [1,9-o] indole-.10-corboxylate (D17) by the method of Example 29. The crude product was chromatographed on silica gel eluting with ethyl acetate to give an orange oil (21%). which was converted to the oxalate to give an orange solid; mp 195-198 ° C.

Oxalate salt: - ¹ H NMR (d ⁶ DMSO);

δ: 8.45 (d, IH), 8.33 - <(IH), 7.59 -t, IH), 7.7-4 (t, 1H), 6.97 (s, Uf)

4.90 - (br, -s, 2H), 4.27 2HH 3.38-3.30 (m, 2HH 3.14 4-, -H (m, 44),

2.61 (s, 3H), 9.01-9.97 (m, 3H), 1 <59o 1.34 (m, 4H) <1.37 (sextet 2)), 0.97 3H).

Example 34.

N - [(1-n-butyl-4-piperidyl) methyl] -2,3-dihydrothiazole- [3,2-a / inddld-9-carboxamide.

The title compound (E34) was prepared from 2 < 3-dihydrothiozolo [3,2-o] molo-9CorboCSylowege acid (D15) via its acid chloride according to the method of Example 13. The crude product was chromatographed on silica gel eluting with 5% methanal / chloroform to give yellow solid (63% which was converted to oxalate and re-crystallized from acetone to give a beige solid, mp 203-904 ° C).

Oxalate salt: - ^1H NMR (d6-DMSO);

δ: 7 <83o7.92 (π, Π1), 7.333-, 44 (u, 2H), 7.00-7.18 (m 2H), 4.35- (t, 2H), W (t ^ 9H ) &Lt; 3.39-3.50 (m, 211). 2.18-3.30 (m, 2H), 2.25-3.05-m, 4H), 1 M ^ (m 33Γ),

8.40o8.10 (m, 4h), 1.30 (sextet, 2)), 0.97 (t, 3H).

Example 35.

N - [(1-n-butyl-4-piperidyl) methyl] thiazolo [3,2-a] indd1d-9-carboxamide (E35).

The title compound (&lt; 35 &gt;) was prepared from thiazolo [3,2-a] indole-9-carboxylic acid (D16) via its Cwaoony chloride as in Example 13. The crude product was chromatographed on silica gel eluting with 5% methanol / chloroform to give a purple solid (73% which was converted to oxalate and recrystallized from acetone. A purple gave a solid, mp 259-901 ° C.

The oxalate salt - ¹ H NMR (d6-DMSO);

δ: 8.49 (d, TH), 8.14 (d, H), ą— (d, H), (t, 1H), 7 <90-7.40 (m, 3H) <

1.38-1.95 (m, 2H), 3.24-3.35 (m, 21), 9.79-3.05 (m, 4H), 1.80-9.00 (m, 3H), 8 , 40-1 < 70 (m, 4H), 1.70 (sextet, TH), O < 38 (t, 3H).

Example 36.

(1-n-butyl-4-piperidyl) methyl tetrahydropyrmido [1,2-a] inddlo-10-carboxylate (E36).

The title compound (E36) was prepared from 1,2,3, 4-tetrapyrimido [1,9-a] indal-10-carboCsylone-methyl by the method of example 29 under refluxing conditions.

172 172 reflux for 140 hours. The crude product was purified by chromatography on silica gel eluting first with ethyl acetate then 10% methanol / ethyl acetate to give a yellow solid which was passed through a basic alumina plug eluting with ethyl acetate. The title compound was obtained as a beige solid (23%) which was converted to oxalate and crystallized from acetone to give a beige solid; mp 190-194 ° C.

Free base: - 1 H NMR (CDCl 3);

δ: 7.71 (br, d, 1H), 6.98-7.18 (m, 3H), 7.0 (br. s, 1H), 4.17 (d, 2H), 3.98 ( t, 2H), 3.46-3.57 (m, 2H), 2.92-3.06 (m, 2H), 2.30-2.40 (m, 2H), 2.22 (quintet, 2H), 1.75-2.08 (m, 5H), 1.23-1.60 (m, 5H), 0.92 (t, 3H).

Example 37.

E-Quinolizidin-2-ylmethyl 2,3-dihydrooxazolo [3,2-a] indole-9-carboxylate (E37).

A stirred suspension of 1H-iedole-3-carbox (for eu eq-quinolizddn-2-dlomethyl (E2a, 280 mg, 0.94 mmol) in chloroform (10 ml) was treated with 2-bromoethanol (0.13 ml) followed by N- chlorosuccinimide (135 mg, 1.0 mmol) and kept at room temperature for 2 hrs The mixture was then quenched with 1M HCl in ether (0.05 ml, 0.05 mmol) and after 2 h the resulting yellow solution was slightly reduced by the addition of 10% Na2CO3 solution (10 mL) and extracted with chloroform (2x15 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give an orange oil. This oil was dissolved in acetone (20 mL), treated with anhydrous potassium carbonate (410 mg, 3.0 mmol). ) and stirred at room temperature for 22 hours, then concentrated in vacuo and the residue was treated with 10% Na2CO3 solution (20 ml) and extracted with ethyl acetate (2x20 ml) The combined extracts were dried (Na2SO4), concentrated in vacuo and the residue was chromatographed on gel silica eluting with 3% methanol / chloroform. A yellow oil obtained (145 mg, 44%) pass through a plug of basic alumina eluting with ethyl acetate to afford the title compound (E37) which crystallized as a white solid from ethyl acetate / ether; mp 153-155 ° C.

* H NMR (CDCls);

δ: 7.95 (d, 1H), 7.00-7.25 (m, 3H), 5.14 (t, 2H), 4.18 (t, 2H), 4.15 (d, 2H) , 2.78-2.96 (m, 2H), 1.02-2.18 (t, 14H).

Example 38.

N- [(1-n-butyl-4-piperidylmethyl] -2,3,4,5-tetrahydro [1,3] oxazepino [3,2-a] indole-11-carboxamide (E38).

(a) A stirred suspension of N - [(1-e-autyl-4-piperdinyl) methylindole-3-kb) boxdamide (D1b, 1.0 g, 0.0032 mol) in chloroform (25 ml) was treated with 4-chlorobutanol ( 0.69 ml, 0.0064 mol) followed by N-chlorosuccinimide (470 mg, 0.0035 mol) and a yellow solution was formed within 5 minutes. After a further 40 minutes, the color darkened to orange. The mixture was kept at room temperature for a further 1 hour then quenched with 10% Na2CO3 solution (30 ml) and extracted with chloroform (2 x 30 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give an orange oil which I chromatographed on silica gel eluting with 5% methanol / chloroform to give N - [(1-e-autdl-4-piperddl) methyl & 2- (r-chlorobutoxd) ienole-3-carboxydbmide (0.67 g, 50%) as a yellow oil.

* H NMR (CDCls);

δ: 10.7 (br s, 1H), 8.23 (d, 1H), 7.00-7.32 (m, 3H), 6.88 (t, 1H), 4.43 (t, 2H ),

3.48 (t, 2H), 3.34 (t, 2H), 2.86-3.02 (m, 2H), 2.25-2.40 (m, 2H), 1.18-2. 00 (m, 15H), 0.90 (t, 3H).

(b) A solution of N- [1-n-butyl-4-piperdnyl) methdloi-2- (4-tetrhhorobutoxy) innole-3-carboxdamide (0.67 g, 0.0016 mol) in acetone (25 ml) was added with anhydrous potassium carbonate (0.74 g, 0.0054 mol) and sodium iodide (1.34 g, 0.0089 mol) and heated under reflux for 24 hours. The mixture was concentrated in vacuo,

692 I72 and the residue was quenched with 10% Na 2 CO ₃ solution (25 mL) and extracted with chloroform (2x30 mL). The combined extracts were dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 5% methanol / chloroform. The resulting colorless oil was passed through a basic alumina plug eluting with ethyl acetate to afford the title compound (E38) as a white solid (370 mg, 60%) which was converted to oxalate and crystallized from acetone to give a white solid; mp 210-211 ° C.

Free base: - ^X H NMR (CDCM);

δ: 8.36-8.44 (m, 1N), 7.17-7.25 (m, 3N), 6.94 (t, 1H), 4.30 (t, 2H), 4.11- 4.20 (m, 2H), 3.35 (t, 2H), 2.90-3.00 (m, 2N), 2.25-2.35 (m, 2H), 2.18 (quintet, 2H), 1.55-2.02 (m, 7H), 1.23-1.55 (m, 6H), 0.92 (t, 3H).

Example 39.

(1-n-buyo-4-piperidyl) methyl pyrinido [1,2-a] indole-10-carboxylate (E39).

The title compound was prepared from methyl pyrimido [1,2-a] mdolo-, 10-carboxylate methyl (D19) by the method of Example 29. The crude product was washed at -78 ° C with n-pentane and the residue was chromatographed on silica gel eluting with 5% methanol / with chloroform to give an orange oil.

Ή NMR (CDCl ₃ );

δ: 8.68-8.78 (m, 2H), 8.45 (d, 1H), 7.87 (p, 1H), 7.59 (t, 1N), 7.45 (t, 1H) , 6.77-6.89 (m, 1H), 4.37 (P, 2H), 2.90-3.12 (m, 2N), 2.25-2.48 (m, 2H), 1 , 75-2.13 (m, 5H), 1.19-1.70 (m, 6H), 0.92 (t, 3H).

The following compounds were also made:

2.3-Dihydrothiazolo [3,2-a] inPol-9-carboxylate eq-quinolysisPyn-2-ylmethylg (E40).

2,3-Pihydrothiazolo [3,2-a] inPol-9-carboxylic acid was converted to the acid chloride and reacted with eq-2-hydroxymethylquinolysisPine by a method analogous to Po described in Example 10.

Free base: - 1 NMR (CDCl 3);

δ: 8.00 (d, 1N), 7.15-7.30 (m, 3H), 4.34 (t, 2H), 4.10-4.25 (m, 2H), 3.87 ( t, 2H), 2.80-3.00 (m, 2H), 1.05-2.20 (m, 14N).

dq-Quinolizidin-2-ylmethyl-23-dihydrothiazolo [3,2-a] Indole-9-carboctyamide (E41).

2,3-Dihydrothiazolo [3,2-a] inPol-9-carboxylic acid was converted to the acid chloride and reacted with eq-chymolysisPyn-2-ylmethylamine (D13) in analogy to the procedure described in Example 10.

Thiazolo ^^ - ajindole ^ -carboxylate eq-quinosePyn-2-ylmethyl (E42).

Thiazolo [3,2-a] inPol-9-carboxylic acid was converted into Po with its acid chloride and reacted with eq-hydroxymethylcinolizidine in an analogous manner to the procedure described in example Pzid 10 to afford the title compound as a white solid; mp 129-131C (ether).

1 H NMR (CDCl 3);

δ: 8.16 (P, - 1H), 7.75 (P, 1H), 7.61 (P, 1H), 7.33-7.42 (m, 1N), 7.19-7.30 (m, 1H), 6.87 (p 1H), 4.15-4.32 (m, 2H), 2.80-3.00 (m, 2H), 1.40-2.18 (m, 11H), 1.08-1.40 (m, 3H).

dq-QuinolysisPyn-2-ylmethyl-thiazolo [3,2-a] indole-9-caroctyamide (E43).

Thiazolo [3,2-a] inPol-9-carbolcyl acid was converted to Po with its acid chloride and reacted with eq-quinolizidin-2-ylmethylamine using the same procedure as Po described in preparation 1b.

3.4- Dihydro-2H- [1,3] thiazino [3,2-a] inPol-10-carboxylate eq-quinolysisPyn-2-ylmethyl (E44).

3,4-Dihydro-2H- [1,3] thiazino [3,2-a] indole-10-carboxylic acid was prepared from thioxinPol in a manner analogous to that described in recipe 15. The acid was converted into acid chloride and reacted with eq -2-hyProcymethylquinolysidine

172 692 following a procedure analogous to that described in Example 10. Oxalate salt, m.p. 130-132 ° C.

Free base ¹ H NMR (CDCl?);

δ: 7.96-8.04 (m, 1H), 7.13-7.30 (m, 3H), 4.05-4.30 (m, 4H), 2.90-3.20 (m , 4H), 2.35-2.51 (m, 2H), 1.20-2.32 (m, 14H).

(1-n-butyl-4-piperidyl) methyl-pyrimido [1,2-a] indole-10-carboxamide (E45).

(a) Benzyl pyrimido [1,2-a] indole-10-carboxylate was prepared using a procedure analogous to that described in preparation 19, followed by hydrogenation over 10% Pd / C in ethanol to give pyrimido [1,2-a] indole acid. 10-carboxylic acid.

(b) Pyrimido [1,2-a] indole-10-carboxylic acid was converted to the acid chloride and reacted with (1-n-butyl-4-piperidyl) methylamine (D1) using the procedure of recipe 1b.

(1-n-butyl-4-piperidyl) methyl-1,2,3,4-tetrahydropyrimido [1,2-a] indole-10-carboxamide (E46).

(a) 2-Chloroindole-3-carboxylic acid (L. Marchetti and A. Andreani, Ann. Chim. (Rome), 1973, 63, 681) was converted to its acid chloride and reacted with N- (1-n- butyl-4-piperidyl) methylamine (D1) using the procedure of recipe 1b to give N - [(1-n-butyl-4-piperidyl) methyl] -2-chloroindole-3-carboxamide.

(b) N - [(1-n-butyl-4-piperidyl) methyl] -2-chloroindole-3-carboxamide was reacted with 3-chloropropylamine using the procedure analogous to that described in preparation 18.

Example 47.

(a) While stirring, a solution of isonipecotamide (30.1 g, 0.23 mol) and benzyl bromide (27.9 ml, 0.23 mol) in ethanol (250 ml) was treated with anhydrous potassium carbonate (64.9 g, 0.18 mol). 47 mol) and heated under reflux for 3 hours. The mixture was allowed to cool, then filtered and the filtrate was concentrated in vacuo. The oil residue was dissolved in chloroform (200 ml) and washed with water (1x150 ml) then dried (Na2 O4) and concentrated in vacuo to give the substance a yellow constant (41.0 g). The resulting material is mixed thoroughly with phosphorus pentoxide (38.3 g, 0.27 mol) and the mixture is heated at 180 ° C under a nitrogen atmosphere for 2.5 hours with gentle agitation. The reaction mixture was allowed to cool, then quenched with water (300 ml). After dissolving the solid, the solution was basified with solid K2CO3 and extracted with ethyl acetate (2x250 ml). The combined extracts are dried (Na2SO4) and concentrated in vacuo to a brown oil (35.3 g). The resulting material was dissolved in anhydrous ether (250 mL) and added dropwise over 30 minutes to a stirred suspension of lithium aluminum hydride (10.1 g, 0.26 mol) in ether (150 mL) at 0 ° C under nitrogen. . After the dropwise addition, the mixture was allowed to warm to room temperature and stirred for 1.5 hours. After cooling back to 0 ° C, it was treated carefully with water (10 ml), 10% NaOH solution (15 ml) and again with water (25 ml). The mixture is filtered through silica gel and the filtrate is concentrated in vacuo to a brown oil which is distilled in vacuo to give (1-benzyl-4-piperidinyl) methylamine, after distillation as a colorless oil (27.8 g, 67%) boiling point 106 ° C at a pressure of 33.333 Pa (0.25 mm Hg).

1 H NMR (CDCl 3);

δ: 7.20-7.37 (m, 5H), 3.48 (s, 2H), 2.85-2.95 (m, 2H), 2.55 (d, 2H), 1.87- 2.00 (m, 2H), 1.60-1.75 (m, 2H), 1.10-1.40 (m, 5H).

(b) To a stirred solution of indole-3-carboxylic acid (15 g, 0.093 mol) in dichloromethane (250 ml) under nitrogen atmosphere was added oxalyl chloride (8.7 ml, 0.10 mol) and anhydrous dimethylformamide (6 drops of ). After 2 hours, the solvent was evaporated under reduced pressure. The remaining acid chloride (0.093 mol) was dissolved in dichloromethane (100 ml) and added dropwise to the stirred solution

N- (1-beyzyl-4-pipettedcyclo) methylamyc (D1, 16.4 g, 0.093 mol) and ytieylkyc (15.5 ml, 0.11 mol) in dichloromethane (150 ml) at 5 ° C. After stirring at room temperature overnight, the reaction mixture was washed with 10% Na2CO3 and the organic phase was dried (NazSOf). The solvent was evaporated under reduced pressure and the solid residue was crystallized from ethyl acetate to give N - [(1-benzoclo-4-piperidyl) methyl] indol-5-carboxamide as a white solid (17.5 g, 60%).

1 H NMR (CDC3);

δ: 9.90 (s, 1H), 7.8 (r7.95 (m, 1H), 7.64 (d, 1H), 7.15-7.43 (m, 8H), 6.17 ( t, 1H),

3.48 (s, 2H), 3.37 (t, 2H), 2.83rm, 95 (m, 2H), 1.87-2.08 (m, 2H), 1.54-1.82 ( m, 3H),

1.23-1.50 (m, 2H).

(c) While stirring, a suspension of N - [(1 -beyzclo-4-pipetidcyyl) methyl] Indole-5-catboka Camld (17.5 g, 0.050 mol) in chloroform (250 ml) was treated with 3-bromk-1-propanol (10.1 ml). , 0.11 mol) and N-chloroaccimide (8.7 g, 0.065 mol) at room temperature and a clear solution was obtained within 15 minutes. After 1 hour, the mixture turns from light yellow to orange in color and the temperature rises to 38 ° C. After a further 1 hour, the mixture is quenched with 10% NaHCO3 solution and the chloroform layer is separated, dried (Na2SO4) and concentrated in vacuo to give a yellow oil which is chromatographed on silica gel, eluting with 3% metayol / chloroform. The intermediate 2- (3-bromopropac) idol was dissolved in acetone (400 ml), treated with anhydrous potassium carbonate (11 g, 0.08 mol) and stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, and the residue was treated with water (200 ml) and extracted with chloroform (2 × 250 ml). The combined extracts are dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 5% methanol / chloroform to give N - [(1-bbnzyl-4-pipercdyclo) methyl] -3,4-dihydro-2H- [1 , 3] oxazyyo [3,2-a] mdoSco10-k ^ u · boxamld as a light yellow oil (3.1 g, 15%). After conversion to the oxalate salt and crystallization from acetone, a white solid is obtained, m.p. 169-170 ° C.

Free base: 1 H NMR (CDC3);

δ: 8.32 (d, 1H), 7.05-7.38 (m, 8H), 6.53 (t, 1H), 4.50 (t, 2H), 4.08 (t, 2H) , 3.48 (s, 2H), 3.31 (t, 2H), 2.83-2.97 (m, 2H), 2.27-2.41 (m, 2H), 1.54-2 . 06 (m, 5H), 1.25-1.45 (m, 2H). '(d) While stirring, a suspension of N - [(1-beyzylor-4-piρetidcyyl) methyl] 3,4-dihydro-2Hr [1,5] ocaseyo [3.2ra] iydol-10-catbocacamld (2.25 g, 0, 0046 mol) in ethanol (100 ml) and glacial acetic acid (4 ml) are hydrogenated over 10% PdC (0.8 g) at atmospheric pressure at 45 ° C for 18 hours. The mixture is filtered and the filtrate is concentrated in vacuo. Most of the solid product was filtered off. This material was shaken with concentrated potassium carbonate solution (50 ml) and chloroform (50 ml) along with the filtrate residue. The mixture is filtered, the chloroform layer separated, dried (Na2SO4) then concentrated in vacuo to give N- (4-pipetidcyclomethyl) 3,4-dihycdo-2Hr [1,5] oxazine [3,2-a] mtoSlk10k ^ α-boxamide [ E 11] as a solid white (1.52 g, 100%). The substance after recrystallization from chlorofkrm / 60-80 gasoline has the t. 1. 139-141 ° C.

1 H NMR (CDCl 3);

δ: 8.32 (d, 1H), 7.03-7.30 (m, 3H), 6.53 (t, 1H), 4.48 (t, 2H), 4.05 (t, 2H) , 3.30 (t, 2H), 3, -02-3.15 (m, 2H), 2.52-2.70 (m, 2H), 2.27-2.40 (m, 2H), 1.65-1.90 (m, 4H),

1.10-1.30, (m, 2H).

(e) While stirring a solution of N- (4-piperidcyylmethyl) 5,4-dihydro-2H- | 1,31-caazine [3,2-a] indole-10-carboxamide (E 211) 2253 mag, 0.83 mmol) and trieClcon Inm3 ( 0.25 mL, 1.8 mmol) in a mixture of aceyonittyl (15 mL) and N, N-dimethylformamide (10 mL) was treated with 3-phenoxcpropylene bromide (0.13 mL, 0.88 mmol) and the solution was heated while keeping at reflux for 48 hours. The mixture was allowed to cool then concentrated in vacuo and the residue was dissolved in ethyl acetate (25 ml) and washed with water (20 ml). The organic solution is dried (MgSO4), concentrated in vacuo and the residue is purified by flash chromatography on silica gel, eluting with 0-20% methanol / ethyl acetate. N - [(1- (3-phenokaypropylρ) -4-pipesidine) o) meSlP ^o ] 3,4-dώ.ydro-2H- [1,3] ocaza [3,2-a] indole-10- carboxamide (E 77) in the form of a soft orange color, o-o-o-o-o-o-o-o-u and terecm (42 mg) with a mp of 120-126 ° C.

1H NMR (CDC3);

δ: 8.30 (d, 1H), 7.07-7.37 (m, 5H), 6.96 (t, 1H), 6.88 (d, 2H), 6.64 (t, 1H) . 4.57 (t, 2H), 4.13 (t, 2H), 4.30 (t, 2H), 3.22-3.43 (m, 4H), 2.78-3.00 ( m, 2H), 2.13-2.57 (m, 6H), 1.59-2.03 (m, 5H).

P r z e p i s y:

Recipe 1 (intermediates to examples 3,13,14,19 and 28).

(a) N- (1-n-butyl-4-pipeaydylethylamiab.

A mixed solution of CoonipekotbmCdu (70 g, 0.55 mol) and 1- ^ 01 ^^^ 11 (58.8 ml, 0.55 mol) in ethanol (700 ml) was treated with anhydrous potassium carbonate (152 g, 1.10 mol). ), and refluxed under reflux for 3 hours. The mixture was allowed to cool, then it was filtered and the filtrate was concentrated in vacuo. The oily residue was dissolved in chloroform (400 ml) and washed with water (1 x 300 ml) followed by oauoooo (Na2SO47 and concentrated in vacuo to give a yellow oil (77.5 g). This atbraaie oil was mixed with phosphorus pentoxide (75 g) and Mieaobaine was heated at 160-180 ° C under nitrogen for 2.5 hours with gentle agitation. The reaction mixture was allowed to cool and then quenched with water (500 ml). When the solids had dissolved, the solution was digested by adding K 2 CO 3 and extracted. ethyl acetate (2 x 400 ml) The combined extracts were dried (Nb2SO4) and concentrated in vacuo to give a brown oil (78 g). This oil was dissolved in dry ether (400 ml) and added dropwise over 30 'minutes to a stirring lithium hydride (25 g). , 0.66 mol) in ether (200 mL) at 0 ° C under a nitrogen atmosphere After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 18 hours. It was then re-cooled to 0 ° C and carefully. The mixture was treated with water (25 ml), 10% NaOH solution (25 ml) and again with water (75 ml). The mixture was filtered through diatomaceous earth and the filtrate concentrated in vacuo to give a brown oil which was distilled in vacuo to afford the title compound as a colorless oil (66 g, 71%): mp. 96-99 ° C at 3 mmHg (0.4 kPa).

NMR (CDCl3);

δ: 2.90-3.02 (m, 2H), 2.58 (d, 2H), 2.25-2.38 (m, 2H), 1.65-2.00 (m, 2H), 1.08-1.58 (m, 9H), 0.92 (t, 3H).

(b) N - [(1-α-butyl-4-piperidylmethylp] adplo-3-kbrb () xybmide.

To a stirred solution of iadolβ-3-carboxylic acid (1 g) in dichloromethane (20 ml) at 0 ° under nitrogen was added oxalyl chloride (0.81 ml) and dry dimethylformamide (3 drops). After 3 hours, the solvents were evaporated under reduced pressure. Part of the acid chloride residue (420 mg) was dissolved in dichloromethane (12 ml) and added dropwise to a solution of N - [(1-n-butyl-4-piperidyl) methyl] amiay (400 mg) in dichloromethane (12 ml) followed by triethylamine (0.36 ml). After stirring overnight at ambient temperature, the reaction mixture was washed with NaHCO3 nbayapym and the organic phase with oausha r (Nb2SO4i. The solvent was evaporated under reduced pressure and the residue recrystallized from ethyl acetate to give the title compound (D1) (467mg, 64%).

^X H NMR (CDClb) 250 MHz;

δ: 9.29 (br. s, 1H), 8.05-7.9 (m, 1H), 7.81 (d, 1H), 7.55-7.4 (m, 1H), 7, 39-7.2 (m, 2H), 6.28 (br. S, 1H), 3.39 (t, 2H), 3.0 (br d, 2H), 2.45-2.25 (m , 2H), 2.1-1.1 (m, UH), 0.9 (t, 3H).

172 692

Recipe 2 (intermediate product to example 5).

N- [2- (1-piperidyl) ethyl] -1H-indole-3-carboxamide.

1-Piperidineethylamine is reacted with 1H-indole-3-carboxylic acid chloride as described in Preparation 1 to give the title compound (D2) as a beige solid.

¹ H NMR (CDCl3);

δ: 9.90 (br. s, 1H), 7.97-8.07 (m, 1H), 7.78 (d, 1H), 7.36-7.50 (m, 1H), 7, 15-7.30 (m, 2H), 7.13 (br. T, NH), 2.40-2.55 (m, 4H), 1.40-1.73 (m, 6H).

Recipe 3 (intermediate product for example 10).

(a) ethyl 2-aminophenylacetate. '

A solution of ethyl 2-nitrophenylacetate (13.6 g, 0.065 mol) in ethanol (150 ml) was hydrogenated over a 10% Pd / C catalyst (1 g) at room temperature and pressure for 18 hours. The reaction mixture was filtered through diatomaceous earth and concentrated in vacuo to provide the title compound as a clear oil which on standing solidified (10 g, 93%).

1 H NMR (CDCl 3);

δ: 7.05-7.15 (m, 2H), 6.68-6.80 (m, 2H), 4.13 (q, 2H), 4.05 (br s, 2H), 3.55 (s, 2H), 1.25 (t, 3H).

(b) 2- (5-C5H1 ^] row: a ^ i ^] r ^ "l (^^ mino) phenyl ^ ^ and ^^ ethyl citane.

A solution of ethyl 2-amine phenylacetate (5.60 g, 0.031 mol) and diisopropylethylamine (7.08 ml, 0.042 mol) in dry THF (75 ml) was treated with 5-chloravaleryl chloride (4.00 ml, 0.031 mol) and left to stand. for mixing for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 ml) and washed with 1M HCl (100 ml), dried (Na 2 O 4) and concentrated in vacuo to give a beige solid which was washed with n-pentane / ether (1: 1) and dried to afford the title compound as a light beige solid (8.1 g, 91%).

Ή NMR (CDCl3);

δ: 8.90 (br. s, 1H), 7.88 (d, 1H), 7.05-7.37 (m, 3H), 4.17 (q, 2H), 3.60 (s, 2H), 3.45-3.65 (m, 2H), 2.35-2.55 (m, 2H), 1.68-1.98 (m, 4H), 1.28 (t, 3H) .

(c) Ethyl 6,7,8,9-tetrahydropyridine [1,2-a] mole-10-carboxylate.

A solution of ethyl 2- (5-chlorovalerylamino) phenylacetate (8.10 g, 0.027 mol in dry THF (50 ml) was added to a stirred suspension of potassium t-butoxide (7.62 g, 0.068 mol) in dry THF (200 ml) in room temperature under nitrogen atmosphere After 1 hour, the purple solution formed was quenched with water (10 mL) and concentrated in vacuo. The residue was shaken with ethyl acetate (200 mL) and saturated ammonium chloride solution (150 mL), then the organic layer was separated, dried ( Na2SO4) and concentrated in vacuo to yield an orange oil which was chromatographed on silica gel eluting with ether to afford the title compound as a yellow solid (1.25g, 20%).

NMR (CDCl3);

δ: 8.07-8.17 (m, 1H), 7.13-7.30 (m, 3H), 4.38 (q, 2H), 4.00 (t, 2H), 3.30 ( t, 2H), 1.82-2.12 (m, 4H), 1.43 (t, 3H).

(d) 6,7,8,9-etrahydropyridine [1,2-a] molol-10-carboxylic acid.

A solution of ethyl 6,7,8,9-etrahydro-1H-pyrido [1,2-a] indole-10-carboxylate (1.20 g, 0.0047 mol) in ethanol (50 ml) and 10% NaOH solution (50 ml) was heated to reflux for 4 hours. The reaction mixture was then acidified with 1M HCl acid (50 ml) and extracted with ethyl acetate (50 ml). The organic layer was separated and extracted with 10% Na2CO3 solution (120 ml) and the aqueous solution was re-acidified with 5M HCl acid and extracted into ethyl acetate (2x75 ml). The organic extracts were combined, dried (N2SO4) and concentrated in. vacuo to afford the title compound (D3) as a white solid (400 mg, 40%).

1H NMR (CDCl3);

172 692 δ: 8.23 (d, 1H), 7.20-7.35 (m, 3H), 4.10 (t, 2H), 3.40 (t, 2H), 2.00-2, 15 (m, 2H), 1.85-2.00 (m, 2H).

Recipe 4 (intermediate product to examples 11 and 13).

(a) ethyl 2- (4-chlorobutd) ylbmino) phenylacetate.

The title compound was prepared from ethyl bminophenylacetate using the method of recipe 3b and isolated as a beige solid, (100%).

Ή NMR (CDCls);

δ: 8.90 (br. s, 1H), 7.85 (d, 1), 7.05-7.35 (m, 3H), 4.15 (q, 2H), 3.68 (t, 2H), 3.60 (s, 2H), 2.60 (t, 2H), 2.10-2.30 (m, 2H), 1.26 (t, 3H).

(b) 2,3-Dihdro-1H-picolo [1,2-biidole-9-ka) side (for e-ethyl.

The title compound was prepared from ethyl 2-t4-chloroautrylamino) -phenylacetic acid according to recipe 3c and isolated as an orange oil which crystallized on standing (15%).

'Il NMR (CDCfe);

δ: 8.05-8.15 (m, 1H), 7.15-7.30 (m, 3H), 4.35 (q, 2H), 4.06 (t, 2H), 3.28 ( t, 2H),

2.55-2.72 (m, 2H), 1.40 (t, 3H).

(c) 2,3-Dihydro-1H-pyrrolo [1,2-bi-3-dole-9-carboxylic acid.

The title compound (D4) was prepared from ethyl 2,3- ^^^^ o-1H-p ^ olo [1,2- ^! A] ^^ ol ^ -9-] ^ i-ethyl carboxylate according to recipe 3d and isolated as an off-white solid (42%).

Ή NMR (d ⁶ DMSO);

δ: 11.85 (br, s, 1H), 7.90-8.02 (m, 1H), 7.32-7.47 (m, HI), 0-0-7.25 (m, 2H ),

4.15 (mp 2H), 3.20 (tt 2H),? 2.70 (m, 22Γ).

Recipe 5 (intermediate product for example 12).

(a) ethyl 2- (6-chlorohek (anoylamino) fendloacetate.

The title compound was prepared from ethyl 2-aminohexylacetate and 6-O-chromohexboyl chloride according to recipe 3b and isolated as a beige solid (100%).

^J H NMR (CDCl3);

δ: 8.90 (br. s, 1H), 7.90 (d, 1H), 7.05-7.35 (m, 3H), 4.17 (q, 2H), 3.60 ((, 2H), 3.42 '(t, 2H), 2.45 ((, 2H), 1.45-2.0 (m, OH), 1.28 (t, 3H).

(b)), 8,9,10-Tetrahynro-1H-pyrrolo [1,2-biindole-β-kb) side (for ethyl.

The title compound was prepared from ethyl 2- (6-chlorohexb3oylammo) feedlooc'tb3 according to recipe 3c and purified by chromatography on silica gel, eluting with 60-80 petroleum ether / ether. (9: 1) to give a white solid (16%).

Ή HMR (CDCls);

δ: 8.07-8.19 (m, 1H), 7.15-7.35 (m, 3H), 4.40 (q, 2H), 4.15-4.25 (m, 2H), 3.45-3.60 (m, 2H), 1.67-2.00 (m, 6H), 1.45 (t, 3H).

(c) 7,8,9,10-Tetrahdro-1H-pyrrolo [1,2-biinole-11-cbralxic acid.

The title compound was prepared from ethyl 7,8,9,10-tetrahalo-1H-pyrrolo [1,2-αiindole-11-carboxylate by hydrolysis with sodium hydroxide as in preparation 3d. After 4 hours of heating under reflux (the mixture was acidified dropwise with 5M HCl, the formed white solid was filtered off and dried (82%).

Ή NMR (CDCls);

δ: 12.05 (s, 1H), 7.94-8.04 (m, 1H), 7.48-7.60 (m, -1H), 7.05-7.30 (m, 2H) , 4.24-4.36 (m, 2H), 3.38-3.53 (m, 2H), 1.54-1.90 (m, 6H).

Recipe 6 (intermediates for examples 1, 10, 27 and 29).

(1-3-autdlo-4-piperdddedlo) meta3ol.

A mixture of ethyl isoeipekotae (102 g, 0.65 mol) and 1-bromobutae (72 ml, 0.67 mol) in ethanol (1.2 L) was treated with anhydrous potassium carbonate (180 g, 1.3 mol)

172,692 and heated to reflux for 2 hours. The mixture was allowed to cool and then filtered through silicon dioxide. The filtrate was concentrated in vacuo to give a yellow oil which was dissolved in ether (300 mL) and dropped over 20 minutes into a stirred suspension of lithium aluminum hydride (50 g, 1.3 mol) in ether (500 mL) at 0 ° C at nitrogen atmosphere. The mixture was stirred at room temperature for 18 hours, then cooled to 0 ° C and quenched with water (50 ml), 10% NaOH solution (50 ml) and water (150 ml). The mixture was filtered through diatomaceous earth and the filtrate concentrated in vacuo to give a pale yellow oil which was distilled to give the title compound as a colorless oil (33 < 5% < 30) < 8090-108 ° C at 0 < 8 mmHg (83 < 3 Pa).

Ή NMR (CDCl3); .

δ: 3.48 (d, 2H), 2.83-3.03 (m, 2H), 2 <95-2.18 (m, 2H) <(br s, 1H), 1 <66-2 < 55 (m, 4H). 1 < 17-1.60 (m, 7H). 0 < 50 (t, 31).

Recipe 7 (intermediate product for example 15).

Ethyl isonipectonate was initially alkylonated with benzyl bromide and then the product was reduced with lithium aluminum hydride using the method of Preparation 6 to give the title compound (D7) as a colorless oil (100%).

1H NMR (CDCl3);

δ: 7 <25-7.39 (m, 5H), 3 <59 (s, 21), 3.48 (d, 21), 2.36-3.55 (m, 2H), 8.90-2 < 59 (m, 81).

Recipe 8 (intermediate product for examples 13 and 17).

6,1olihy acid; hropyridine [1,9-a] mole-10-carbo-Coylone.

Mixed solution of methyl 6 <7-dihydropyrid [1 <9-a] indole-15-kαrboCsylate (T. Teitei and LK Dalton, Australian J. Chem. 1969, 22, 997) (1.0 g <0.0044 mol) in methanol (40 ml) was treated with a solution of potassium hydroxide (3.0 g <0.594 mol) in water (50 ml) and heated under reflux for 3 hours. The solution was allowed to cool then acidified with HCl acid and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to give the title compound (D8) as a yellow solid (600 mg, 64%).

Ή NMR (CDCl3);

δ: 8 <13-8 <29 (m, 8H) <7.50 (d, 1H), 7.20-7 <35 (, 31), 6 <91-6.38 (m, 1H), 4 . 15 (1 ^ 21), 2 < 69-9.78 (m 21).

Recipe 9 (intermediate product for example 18).

Pyrido [8.9a] indole-10-CarboCoyl acid The title compound (D6) was prepared from methyl pyrido [1-9-o] indo] o-1 () - CarboCoylate (T. Teitei and LK Dalton, Australian J. Chem. 1969, 22.997) using recipe 8 as a brilliant yellow solid (76%).

Ή NMR (CDCl3 + CD3OD);

δ: 3.56 (d, 1H), 3.34o3 < 46 (m, 2H), (d, H), 7 < 32o7.57 (m, 31), 6.87 (t, 11).

Recipe 10 (intermediate product for example 20).

(8-Benzyl-, 4-pyridyl) methylaminα (D10).

Iseniketomide first alkylated with benzyl bromide, then the amide with phosphorus pentoxide and the obtained nitrile was reduced with lithium aluminum hydride according to recipe 1a to give the title compound as a colorless oil after distillation (67%), m.p. 106 ° C at 0.29 mmHg (3 <3 Pa).

^X 1 NMR (CDCl 3);

δ: 7.90-7.37 (m, 5H) <3.43 (s, 21), 2 <85-2.99 (m, 21), (d, 9H) <1.87-2.00 (s, 21), 865o1.79 (m, 21), 1.10o8.40 (m, 51).

172 692

Recipe 11 (intermediate product for example 29).

(a) Methyl 2-chloroindole-3-carboxylate.

A stirred suspension of methyl indole-3-carboxylate (6.0 g, 0.034 mol) in chloroform (200 ml) was treated with N-chlorosuccinimide (5.04 g, 0.038 mol) to give a clear solution over 15 minutes. After 2 hours at room temperature it was quenched. 1M HCl / ether (34 mL, 0.034 mol) and allowed to stir for a further hour then quenched with excess 10% Na 2 CO 3 solution and the chloroform layer was separated, dried (Na ₂ SO 4) and concentrated in vacuo. The remaining yellow solid was recrystallized from chloroform / 60-80 petroleum ether to afford the title compound (D11a) as a beige solid (3.4 g, 48%).

¹ H NMR (CDCWDMSO);

δ: 11.3 (br. s, 1H), 8.02-8.12 (m, 1H), 7.30-7.40 (m, 1H), 7.18-7.26 (m, 2H ). 3.95 (s, 3H).

MS (E1) M ⁺ 209 and 211.

(b) Methyl 1-methyl-1,2,3,4-tetrahydropyrimido [1,2-a] indole-10-carboxylate.

A solution of methyl 2-chloroindole-3-carboxylate (3.4 g, 0.016 mol) in dry THF (70 ml) at 5 ° C under nitrogen was added portionwise with sodium hydride (480 mg, 80% slurry, 0.016 mol). and then stirred at room temperature for 30 minutes. The resulting solution was treated with a solution of 3,3-dimethylaminopropyl chloride (0.020 mol) in toluene (30 ml) and refluxed for 48 hours, then concentrated in vacuo and the residue treated with 10% Na2CO3 solution (50 ml) and extracted. ethyl acetate (2x70 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give a yellow oil which was chromatographed on silica gel eluting with ether / 60-80 petroleum ether (1: 1). The title compound (D11) was obtained as a beige solid (1.95 g, 50%).

&lt; 1 &gt; H NMR (CDCl3);

δ: 7.92 (d, 1H), 6.97-7.19 (m, 3H), 3.92 (t, 2H), 3.88 (s, 3H), 3.36 (t, 2H) , 3.27 (s, 3H), 2.10-2.22 (m, 2H).

Recipe 12 (intermediate product for example 26). eq-Quinolizidin-2-ylmethylamine.

A stirred suspension of lithium aluminum hydride (400 mg, 0.010 mol) in THF (20 ml) at room temperature under nitrogen was treated with a solution of eq-2-cyanoquinolysidine (E. Koshinaka et al., Yakugaku Zasshi 1980, 100, 88) in THF (3 mL) and the mixture was then heated under reflux for 20 minutes. After the mixture was allowed to cool, it was carefully quenched with water (0.4 mL), 10% NaOH solution (0.4 mL), and water (1.2 mL). The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was distilled on a Kugelrohr apparatus to afford the title compound (D13) as a colorless oil (700 mg, 97%).

Ή NMR (CDCl 3);

δ: 2.80-2.92 (m, 2H), 2.57 (d, 2H), 1.94-2.12 (m, 2H), 1.20-1.80 (m, 13H), 0.88-1.05 (m, 1H).

Recipe 13 (intermediate product of example 30).

3-Methyl-thiazolo [3,2-a] indole-9-carboxylic acid.

(a) A mixed solution of 3-methylthiayolυ [3.2 [m2o] (A. Kiprianov -V. Khilya, Zh. Organ. 1966, 2, 1474) (270 mg, 0.0014 mol) in DMF (3 ml ) cooled to 5 ° C under argon and quenched with trifluoroacetic anhydride (0.23 ml, 0.0017 mol), then allowed to warm to room temperature over 3 hours. The solution was poured into water (25 ml) and the mixture was extracted with ethyl acetate (2 × 20 ml). The combined extracts were dried (Na2SO4) then concentrated in vacuo to give 3-methyl-9-trifluoroacetylthiazolo [3,2-a] indole (370 mg, 90%) as a tan solid.

172 692 '1F NMR (CDCl3);

δ: 8.10 (br.s, 1H), 7.85 (d, 1H), 7.39-7.47 (m, 1H), 7.25-7.35 (m, 1H), 6, 69 (s, 1H), 2.83 (s, 3H).

(b) 3-Meίyl-9-lrP'luoroacprylottazlPojZ, 2-a [indole -Soo (37.0013 mol) pabaπo with 20% NaOH solution (15 ml) and ethanol (15 ml) and refluxed condensate for 6 hours. The mixture was concentrated in vacuo to half of its volume and the residue was acidified with 2M HCl acid then extracted with ethyl acetate (2x30ml). The combined pausooao extracts (Nb2SO4i and concentrated in vacuo) gave the title compound (D13) as a tan solid (300 mg, 100%).

Ή NMR (d 2 MSO);

δ: 12.3 (br. s, 1H), 7.93-8.08 (m, 2H), 7.16-7.40 (m, 2H), 6.95 (s, 1H), 2, 59 (s, 3H7.

Recipe 14 (intermediate product of example 25).

N- (2-bromρetsl) methanesulfonamide.

To a mixed solution of 2-bromoethylamine hydrobromide (5.10 g, 0.025 mole) and triethylamine (6.96 g, 0.050 mole) in dichloromethane (200 ml) at vcoplon ice bath temperature, methanesulfonyl chloride (1.96 ml, 0.025 mole) ). The mixture was allowed to warm to room temperature and stirred for 16 hours then washed with water and 5M HCl acid, dried (Na2SO4) and concentrated in vacuo to give the title compound (D14) as a colorless oil which solidified on standing to white solid (3.5 g, 69).

1 H NMR (CDCl 3);

δ: 4.92 (s, 1H), 3.62-3.48 (m, 4H), 3.05 (s, 3H).

Recipe 15 (intermediate product for example 31).

(a) 2,3-Dihydrothiazolo [3,2-b] indole.

A solution of thioxindole (400 mg, 0.0027 mol) and 1,2-dibromoethbene (0.24 ml, 0.0027 mol) in dry THF (10 ml) was added to a stirred solution of potassium t-butoxide (760 mg, 0.0068 mol) in dry THF (40 ml) at room temperature under argon. After stirring for 3 hours, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (2x70 mL). The combined extracts were dried (Nb2SO4i and concentrated in vacuo to give an orange oil which was chromatographed over silica gel eluting with 10% ether / 60-80 petroleum ether. The title compound was obtained as a white solid (135 mg, 29%).

'1-1 NMR (CDCl3);

δ: 7.42-7.23 (m, HT), 7.00-7.25 (m, 3H), 6.20 (s 1H), 4.23 (t, 2H), 3.79 (t , 2H).

(b) 2,3-Dihydrothiaoplo [3,2-b] indole-9-carboxylic acid.

2,3-Dihydrothiazplo [3,2-a] indole was treated with trifluproacetic anhydride using the method of recipe 13a to give 9-trifluoroacetylthiaoolo [3,2-a] indp1 as a purple solid (85%).

Ή NMR (CDCl3);

δ: 7.93 (br. s, 1H), 7.07-7.30 (311), 4.30 (t, 2H), 3.85 (t, 211).

The title compound (D15b) was prepared from 9-trifluoroalpha, tyllP-, 3-dihydrotibzolp [3,2-b] indole by the method of preparation 13b to give a purple solid (95%) that was used without purification.

Recipe 16.

(a) Thiaoolo [3,2-a] indole.

A mixed solution of thiocaCndol (3.8 g, 0.025 mol) and bromobcetaldehyde diethyl acetal (3.9 ml, 0.026 mol) in acetone (200 ml) was treated with anhydrous potassium carbonate (6.9 g, 0.050 mol) and the mixture was refluxed at under reflux for 2 hours, then 12 hours at room temperature. The mixture was concentrated in vacuo and the residue was taken up in water (100 ml) and extracted

Was extracted with ethyl acetate (2x100 ml). The combined extracts were dried (N2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 10% ether / 60-80 petroleum ether to afford 2- (2,2-diethoxyethyl mercapto) mdol (3.0 g, 44%) as yellow oil.

1 H NMR (CDCl 3);

δ: 9.30 (br.s, 1H), 7.52 (d, 1H), 7.04-7.20 (m, 2H), 6.58 (s, 1H), 4.72 (t, 1H),

3.55-3.85 (m, 4H), 3.05 (d, 2H), 1.31 (t, 6H).

A well-stirred mixture of 2- (2,2-diethylmercaptondol (1.5 g, 0.0057 mol) in polyphosphoric acid (30 g) was heated to 130 ° C for 20 minutes, then allowed to cool to room temperature and the mixture was diluted with water (300 mL). The resulting aqueous solution was basified by the addition of solid potassium carbonate and then extracted with ethyl acetate (2 x 120 mL). The combined extracts were dried (Na2SO4, concentrated in vacuo and the residue chromatographed on silica gel, eluting with 10% ether) 60- 80 with petroleum ether to afford the title compound as a white solid (0.56 g, 57%).

1.1. NMR (CDCl3);

δ: 7.60-7.70 (m, 3H), 7.11-7.28 (m, 2H), 6.60 (d, 1H), 6.53 (s, 1H).

(b) Thiazolo [3,2-a] indole-9-carboxylic acid.

The thiazole [3,2-a] indole was treated with trifluoroacetic anhydride using the method of Example 3a to afford 9-trifluoroacetylthiazolo [3,2-a] indole as a beige solid (95%).

Ή NMR (CDCl3);

δ: 8.06 (br s, 1H), 7.94 (d, 1H), 7.69 (d, 1H), 7.39-7.48 (m, 1H), 7.30-7, 37 (m, 1H), 7.18 (d, 1H).

The title compound (D16b) was prepared from 9-trifluoroacetylthiazolo [3,2-a] indole using the method of recipe 13b and isolated as a light purple solid (84%).

Ή NMR (CDCl3);

δ: 7.98-8.08 (m, 2H), 7.73 (d, 1H), 7.10-7.31 (m, 2H), 7.00 (d, 1H).

Recipe 17.

Methyl 2.4-dimethylpyrimido [1,2-a] indole-10-carboxylate.

A mixed solution of methyl 2-aminoindole-3-carboxylate (I. Forbes et al., J. Chem. Soc. Perkin I, 1992, 275) (0.25 g, 0.0013 mol) in xylene (5 ml) was treated with 2 , 4-pentanedione (0.13 g, 0.0013 mol) and several crystals of 4-toluenesulfonic acid and refluxed for 2 hours. The mixture was concentrated in vacuo and the residue was dissolved in chloroform (20 ml), washed with water (2x20 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as a tan solid (0.25 g, 75%).

Ή NMR (CDCl3);

δ: 8.58 (d, 1H), 8.09 (d, 1H), 7.52 (dt, 1H), 7.34 (dt, 1H), 6.53 (s, 1H), 4.06 (s, 3H), 3.03 (s, 3H), 2.68 (s, 3H).

Recipe 18.

1.2.3.4- Methyl tetrahydropyrimido [1,2-a] indole-10-carboxylate.

A solution of methyl 2-chloro-3-carboxylate (D11a, 1.5 g, 0.0071 mol) in THF (30 ml) under argon was treated with sodium hydride (2.15 mg of an 80% oil dispersion, 0.0071 mol) and stirred for 20 minutes. The resulting solution was treated with a solution of 3-bromopropylamine (0.0093 mol) in toluene (15 ml) and a white gelatinous precipitate formed. This mixture was diluted with more THF (30 ml) and refluxed for 18 hours, then concentrated in vacuo and the residue was shaken well with ethyl acetate (40 ml) and a 10% Na2CO3 solution (30 ml). The organic layer was separated, dried (Na2SO4), and concentrated in vacuo to a beige solid.

1.72692 which was chromatographed on silica gel eluting with eyer / 60r80 petroleum ether (1: 1) to give mept-reacted starting material (600 mg) and the title compound (D18) as a white solid (110 mg, 6%).

1 H NMR (d ⁶ DMSO);

δ: 7.58 (d, 1H), 7.26 (br.s, 1H), 7.12 (d, 1H), 6.85r7.05 (m, 2H), 3.98 (t, 2H) , 3.73 (s, 3H), 3.38-3.46 (m, 2H), 2.08 (quintet, 2H).

Recipe 19.

Pircmido [1,2ra1iydnlor10rkatbs ^ methyl kaclay.

A mixed solution of methyl m-aminoidol-3-carboxclane (I. Forbes et al., J. Chem. Soc. Perkin I, 1992, 275) (0.5 g, 0.0026 mol) in xylene (10 ml) was quenched with 1 , 2,3,3-tetrambtnkaypropay (0.43 g, 0.0026 mol) and a few crystals of 4-toluene sulfkyic acid and refluxed for 2.5 hours. The mixture was concentrated in vacuo and the residue was diluted with chloroform (25 ml), washed with water (2 x 10 ml), dried (MgSO4) and concentrated in vacuo to give a dark orange solid which was purified by silica gel chromatography eluting with ethyl acetate to give compound ( D19) as an orange solid (0.23 g, 35%).

1 H NMR (CDCty);

δ: (m, 2H), 8.57 (d, 1H), 7.89 (d, 1H), 7.59 (dt, 1H), 7.45 (dt, IH),

6.80-6.90 (m, 1H), 4.08 (s, 3H).

Activity of the aytaggyist towards the 5-HT4 receptor

1) Guinea pig colon.

The tests were carried out on male guinea pigs weighing 250-400 g. Preparations from the longitudinal muscle-muscular plexus of the intestine were obtained from the distal region of the colon. The preparations were suspended under a load of 0.5 g in an isolated tissue bath containing a Krebs solution through which 5% CO ₂ in O _{2 was} bubbled and kept at 37 ° C. In all experiments the Krebs solution also contains 10 ^-7 mol Methiothepin and 10 mol * to block the action of 5-HT1 receptors, 5-HT ₂ and 5-HT3.

After constructing the normal curve of concentration - response of 5-HT at the time of contact 30 seconds and 15 minutes dosing cycle, the concentration of 5-HT is chosen so as to obtain a contraction of the muscle approximately 40-70% maximum (approximately 10 ^"9 mol). The tissue was then alternately dosed every 15 minutes with this concentration of 5-HT, followed by approximately the same concentration of the nicotinic receptor stimulant, dimethylphenylpiperazine (DMPP). Then, after obtaining consistent responses to both 5-HT and DMPP, increasing concentrations of the 5-HT4 receptor antagonist to be tested were added to the bath solution. The effects of this compound were then determined as the% reduction in contraction induced by 5-HT or DMPP. From these data, pICo values were determined, which are defined as the -log concentration of the antagonist that reduces contraction by 50%. A compound that reduces a 5-HT response rather than a DMPP response is believed to act as a 5-HT4 receptor antagonist.

In general, the compounds were active in a concentration range of pICo = 7 or more, E1, E2, E4, E6, E8, E15 and E27 showed particularly good activity when Y is O and E3, E20, E23 and E28 showed particularly good activity when Y is NH.

2) Piglet vestibules.

The compounds were tested in piglets on a spontaneous beating screen (Nauycy-Schmiedeberg's Arch. Pharmacol 342, 619-622). The pKn (-logoKs) value for the compound of Example 3 was 10.05.

i72 692

3) Rat esophagus.

The mucosa of the rat esophagus muscle was prepared according to Baxter et al. Naunyn-Schmiedeberg's Arch. Pharmacol., 343, 439-446 (1991). The inner tube of the smooth muscle of the muscle mucosa was isolated and mounted to record the isometric tension in an oxygenated (95% O25% CO2) solution of Tyrola at 37 ° C. All trials were performed with pargilline pretreated formulations (100 µmol for 15 minutes followed by washout) and in the presence of cocaine (30 µmol). A 5-Nt relaxing reaction was obtained after initial contraction of the esophageal tissue with carbachol (3 µmol).

4) 5-NT-induced mobility in oPPziernl kg of the dog's stomach.

The compounds were tested for in vivo inhibition by the method described in Stimulation of canine motility by BRL 24924, a new gastric prokinetic agent, Bermułez et al., And J. Gastrointestinal Motility, 1990, 2 (4), 281-286.

In vivo study for anxiolytic effects Herd interaction test in the rat

Rats (male, Spraque Dawleys, Charles River, 250-300 g) were grouped eight and housed in a common room for 5 days. They were then placed individually in the adjacent room of the experimental room for 4 days during the trial. During the trial, rats were administered vehicle, test compound, or the anxiolytic benzopiazepine, chlorine-piazepoxide, in pairs (n = 846) at 15-minute intervals starting at 10.00 am. 30 minutes later, the collected, incandescent pairs (first encountered) were placed by weight in a herd interaction in a separate room in the box. The box is made of white plastic 54 cm x 37 cm x 26 cm with a transparent front wall and without a cover. The floor is divided into 24 squares and the booth is brightly lit (115 lux). Active gregarious behavior (cleaning, sniffing, climbing up and down, walking behind each other, hitting, seating and boxing) were blind scored for the next 15 minutes by remote video monitoring for a total interaction score. The number of squares crossed by each rat was also scored and summed. The box was carefully wiped clean at the end of each attempt.

E3 increased the total dose interaction score from 0.01-10 mg / kg p. O.

Publishing Department of the UP RP. Circulation of 90 copies. Price PLN 6.00

Claims (12)

Patent claims 1. Condensed indole derivatives of formula (I), or pharmaceutically acceptable salts thereof of formula wherein X is O, S, SO, SO _2, CH _2, CH or NR wherein R is hydrogen or Ci-6alldl; A is a saturated or unsaturated polymethylene chain with 2 - 4 carbon atoms; Ri and R ₂ represent hydrogen or alkyl; R 3 is hydrogen, halogen, C 1-4 alkyl, amino, nitro or C 1-4 alkoxy; R 4 is hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy; Y is O or NH; Z is a group of formula (a), (b) or (c); (a) (b) - {CH ^ a —N (c) 172 692 wherein n ¹ is equal to 1, 2, 3, or 4; n ² is equal to 0, 1, 2, 3 or 4; n ³ is equal to 2, 1, 4 or 5; q is 0, 1, 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2; R5 is hydrogen, C1-4alkyl, aralkyl or R5 is (CH2) 2-Rio where z is equal to 2 or 3, and R10 is selected from cyano, hydroxy, Ci6alkoxy, phenoxy, C (O) Ci6alkyl, COC5H5, - CONR11R12, NR11COR12, SO2NR11R12 or NR11SO2R12, wherein R11 and R12 are hydrogen or Ciealkyl; and Rs, R7 and Re are independently of each other hydrogen or C1-8alkyl; while R9 is hydrogen or Cuoalkyl; having 5-HT4 receptor antagonist activity. 2. The compound according to claim 1, wherein X is O. 3. Relationship according to claim 1 or 2, wherein A - (CH1. 4. Zwd2i ^ (^ 1 and according to claim 1, 2 or 3, wherein R 1 and R _{2 are} independently of each other hydrogen or methyl. 5. The compound according to p. 1, 2, 3 or 4, wherein R3 is hydrogen, and R ₄ is hydrogen or halogen. 6. The compound according to p. 5, wherein Y is NH. 7. The compound of claim 1 Wherein W is a group of formula (a) and (CH ₂ ) _n 1 is attached to the azacyclic carbon atom. 8. The compound of claim 1 The compound of claim 7, wherein W is an N-substituted 4-piperidylmethyl group. 9. The compound of claim 1 8. The compound of claim 8, wherein the N-substituent is C2-12alkyl or benzyl, optionally substituted with one or more substituents such as halogen, C1-6alkyl and C1-6alkoxy. 10. The compound of claim 1 1 selected from compounds E1 through E46 including pharmaceutically acceptable salts thereof 172 692 R1 R2 r R3 R4 X Y WITH E1 H. H. 1 H. H. 0 ABOUT 0) E2 H. H. 1 H. H. 0 ABOUT <vi) E3 H. H. 1 H. H. 0 NH (and) E4 H. H. 1 H. H. 0 ABOUT (Hi) E5 H. H. 1 H. H. 0 NH (in) E6 H. H. 0 H. H. 0 ABOUT 0) E7 (CH ₃ ) 2 1 H. H. ABOUT ABOUT ω E8 H. H. 1 H. H. s ABOUT ω E9 H. H. 2 H. H. 0 ABOUT 0) E10 H. H. 1 H. H. ΟΪ2 ABOUT 0) E11 H. H. 0 H. H. ΟΪ2 ABOUT 0) E12 H. H. 2 H. H. CH2 ABOUT (and) E13 H. H. 0 H. H. Οϊ ₂ NH 0) E14 H. H. 0 H. H. 0 NH 0) E15 H. H. 1 H. H. ABOUT ABOUT Bzppm E16 H. H. 1 H. H. SO ABOUT (and) 172 692 Ri R2 Γ R3 R4 X Y WITH E17 Η Η Δ H. Η CH ABOUT (and) E18 Η Η Γ H. Η CH ABOUT (and) E19 Η Η 1 H. Η S. NH (and) E20 Η Η 1 H. Η ABOUT NH Bippmi E21 Η Η 1 H. Η ABOUT NH ppm E22 Η Η 1 H. Η ABOUT NH CH13Ppm E23 Η Η 1 H. Η ABOUT NH (ii) E24 Η Η 1 H. Η ABOUT NH Eppm E25 Η Η 1 H. Η ABOUT NH MeSCfytEtpipm E26 Η Η 1 H. Η ABOUT NH (vi) E27 Η Η 1 8-F Η ABOUT ABOUT (and) E28 Η Η 1 8-F Η ABOUT NH (and) E29 Η Η 1 H. Η NMe ABOUT (and) E30 - π - H. Η S. ABOUT (and) E31 Η Η 0 H. Η S. ABOUT (and) E32 - ύ - H. Η S. ABOUT (and) E33 Μ * Λ H. Η N ABOUT (and) 172 692 Rl R2 T. R3 ®4 X Y WITH E34 H. H. 0 H. H. s NH (and) E35 - ύ - H. H. s NH ω E36 H. H. 1 H. H. NH ABOUT (and) E37 H. H. 0 H. H. ABOUT ABOUT (vi) £ 38 H. H. 2 H. H. ABOUT NH (and) E39 H. H. Γ H. H. N ABOUT (and) E40 H. H. 0 H. H. S. ABOUT (vi) E41 H. H. 0 H. H. s NH (\ ii) E42 - ϋ - H. H. s ABOUT (vi) E43 - ύ - H. H. s NH (vi) E44 H. H. 1 H. H. s ABOUT Shhh) E45 - Γ - H. H. NH NH (and) E46 H. H. 1 H. H. N NH (and) in which 172 692 (iii) Ν (vi) Δ = ARjR2 is - (CH2) 2 * CHΓ = AR1R2 is -CH = CH- <CH = π = AR1R2 is -C (CH3) = CHύ- ARjR2 is -CH = CHBz - benzyl ppm - 4-piperidylmethyl aEt - aminoethyl . 11. N - [(1-n-butyl-4-piperidyl) methyl] -3,4-dihydro-2H- [1,3] oxazine [3,2-a] indole-10-carboxamide or a pharmaceutically acceptable salt thereof. 12. N - [(1-n-Butyl-4-piperidyl) methyl] -3,4-dihydro-2H- [1,3] oxazine [3,2-a] indole-10-carboxamide hydrochloride.