Heterocyclic compound as antagonists of 5-ht4receptor, the method of preparation and pharmaceutical composition

 

(57) Abstract:

Heterocyclic compound of the formula I, where X1-(CH2)x-X2form a 5-7 membered cycle; X1-O; X2Is O, NR or NRCO, where R is hydrogen or alkyl; x = 1,2 or 3; R1is a hydrogen atom, halogen or amino group; R2and R3is a hydrogen atom or halogen; R4and R5-M; y is o or NH4 Z is a group of the formula R1a-alkyl or benzyl, possibly substituted by a halogen atom or alkoxygroup. The compounds I can be used in the production of pharmaceuticals for the treatment of gastrointestinal and cardiovascular disorders and disorders of the Central nervous system. 3 S. and 12 C.p. f-crystals, 1 table.

The invention relates to the use of compounds as antagonists of 5-HT4receptors in the treatment of diseases of the gastrointestinal tract, Central nervous system (CNS) and/or cardiovascular diseases, as well as some new compounds with antagonistic activity against 5-HT4-receptors.

In magazines aigeria Tvicrnol Parmacol. 146 (1988), 187-188 and Naunyn-Schmiedebergis Arch Parmacol (1989) 340:403-410 described non-classical 5-hydroxytryptamine receptor, now called 5-HT4-ptx2">

Some antagonists of 5-HT3-receptor open as a possible means to treat certain types of syndrome intestinal irritation (see EP-A-189002 (Sandoz Limited) and EP-A-201165 (Beecham Group p.l.sec.)

Interaction of 5-HT3receptors, which can be used in the treatment of the syndrome of the colon, associated with either internal pain and pathological aspects of the sensations of the disease, or they refer to the ability of some antagonists of 5-HT-receptor to cause higher among volunteers.

Some antagonists of the receptor 5-HT open as a means of treatment of gastrointestinal disorders associated with mobility of the upper intestine [see EP-A-226266 (Glaxo Group Ltd) and EP-A-189002 (Sandoz Limited)]. Antagonists of the receptor 5-HT are also well known antiemetic means, such as ondansetron (oudansetron), granisetron (granisetron and tropisetron (tropisetron) (see Drags of the Future 1989, 14(9) p. 875 F. D. King and G. J. sanger).

In the application PCT/GB91/00650 (Smithkline and French Laboratories - Limited) described the use of orbitonasal antagonists of the receptor 5-HT4in the treatment of atrial arrhythmias and seizures.

In the application EP-A-36269 (Beecham Group p.l.c.) describes a group of compounds for potential use as tools for Leisti receptor 5-HT4derivatives of 2,3-disubstituted-alkyladamantanes acid.

Currently, it is found that some compounds, the prisoners in the General formula proposed in this invention, and their derivatives compounds possess properties of receptor antagonists of 5-HT4and, therefore, likely their use in the treatment of irritable syndrome bowel or atrial arrhythmias and seizures.

It is also possible to use compounds of this invention in the treatment of disorders of the Central nervous system such as anxiety and/or migraine, the treatment of movement disorders of the upper intestine and as antiemetics.

Used herein, the term "treatment" includes preventing, if possible.

Thus, the invention provides the use of compounds of General formula I or pharmaceutically acceptable salt of this compound

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in which

X1-(CH2)x- X2forms a 5-7-membered cycle, where

X1Is O or S;

X2Is O, S, NR or NRCO, where R is hydrogen or C1-6-alkyl;

x is 1, 2 or 3;

R1is hydrogen, amino, halogen, C1-6-alkyl, hydroxy or C1-6-R>
R3is hydrogen, halogen, C1-6-alkyl, C1-6-alkoxy or amino;

R4and R5- independently hydrogen or C1-6-alkyl;

y is O or NH;

Z corresponds to the subformulas (a), (b) or (C)

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where

-(CH2)1nconnected to the carbon atom or nitrogen and

n1- 1, 2, 3 or 4; n2is 1 or 2; n3- 2, 3, 4, or 5; q is 0, 1, 2 or 3; p is 0 or 2; m is 0, 1 or 2;

Ra is hydrogen or a lipophilic group, such as C1-12is alkyl or aralkyl;

R6, R7and R8- independently hydrogen or C1-6-alkyl; and

R9is hydrogen or C1-10-alkyl;

or the compound of formula I, where CO-Y bond substituted heterocyclic bioisosteres

in the manufacture of medicaments for use as an antagonist of 5-HT4-receptor.

Examples of alkyl or alkalmazasa groups include C1C3C4C5C6C7C8C9C10C11or C12branched or straight chain or cyclic alkyl, as necessary. C1-4- alkyl groups include methyl, ethyl, n - and ISO-propyl, n-, ISO-, sec - and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, qi is Mascitelli, selected from halogen, C1-6-alkyl and C1-6-alkoxy, corresponding to Ra is benzyl.

The halogen includes fluorine, chlorine, bromine and iodine, preferably chlorine.

Appropriate bioisosterism for amide or ether links containing Y in formula I is a compound of formula (g)

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where the dashed cycle represents one or two double bonds in any position in the 5-membered cycle; H, J and I is independently oxygen, sulfur, nitrogen or carbon, provided that at least one of H, J and I is other than carbon; U is nitrogen or carbon.

Relevant examples (g) described for X, Y and X in EP-A-328200 (Mersk Sharp & Dohme Ltd), such as oxadiazolyl fragment.

Examples of fragment X1-(CH2)x-X2include O-(CH2)2-O, O-(CH2)3-O, O-(CH2)2NR4, O-(CH2)2-S or O-CH2-CONR4where any methylene linkages are optional mono - and disubstituted C1-6-alkyl groups such as methyl. A preferred group of X1-(CH2)2-X2is O-(CH2)2-O. R1preferably hydrogen or amino.

R2preferably hydrogen or halogen.

beam, when R4/R5C1-6is alkyl, it is often - methyl. In particular, when R4and R5are metelli, diametrical containing X1and X2- O-C(CH3)2-O.

Y is preferably o

When Z corresponds to Podgornoe (a), n1is preferably 2, 3 or 4 in the case when Azazel attached to the nitrogen atom, and n1is preferably 1, when Azazel attached to the carbon atom, such as in position 4 when q is equal to 2.

When Z corresponds to Podgornoe (b), n2is preferably such that the number of carbon atoms between ether or amide bond is from 2 to 4 carbon atoms.

Corresponding values for p and m include P = m = 1; p = 0, m = 1, m = 2, p = 1.

When Z corresponds to Podgornoe (in), n3is preferably 2, 3 or 4.

R8and R9preferably both alkali, in particular one of R8, R9is C4or more alkyl.

Of particular interest are the following values:

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The invention also provides obtaining new compounds included in formula (I) , in particular with the side chains Foy, in particular, those in which the side chain of the formula (I) or (II) replaced by the corresponding side chain alkyl or optionally substituted benzene N-substituent and/or in which 4-piperideine group substituted 3-pyrrolidinyl or 3-azetidinol.

The invention also provides new compounds included in formula (I) in which X1-(CH2)x- X2has the structure of O-(CH2)2- Oh, especially compounds in which the side chain Z has the structure corresponding to Podgornoe (a) or (b).

Pharmaceutically acceptable salts of compounds of formula (I) include salts attached acids with appropriate acids such as hydrochloric, Hydrobromic, boric, phosphoric, sulphuric acid, and pharmaceutically acceptable salts of organic acids such as acetic, tartaric, maleic, citric, succinea, benzoic, ascorbic, methansulfonate, -Ketoglutarate, -2-glycerolphosphate and glucose-1-phosphoric acid.

Examples of pharmaceutically acceptable salts include Quaternary derivatives of the compounds of formula (I), such as Quaternary derivatives with compounds of formula Rx- T, where Rx- C1-6-alkyl, phenyl-C1-6-alkyl Il is methyl, ethyl and n - and ISO-propyl; benzyl and phenetyl. Examples't include halide such as chloride, bromide and iodide.

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

The compounds of formula (I), their pharmaceutically acceptable salts (including Quaternary derivatives and N-oxides) can also form pharmaceutically acceptable solvate such as a hydrate, which always include a compound of formula (I) or its salt as defined above.

It will be shown that (CH2)2n- a fragment of the compounds of formula (I), where Z corresponds to the structure (b) may accept or configuration relative to the condensed azabicycles fragment.

The compound of formula (I), where CO-Y is an ether or an amide bond, to receive a corresponding interaction of fragment Z with the corresponding acid. Corresponding methods are described in GB 212538A (Sandoz Limited) GB 1593146A, EP-A-36269 and WO 92/05174 (Beecham Group p. l. c.). For the case when CO-Y substituted heterocyclic bioisosteres, the methods described in EP-A-328200 (Merck Sharp & Dohme Limited).

The invention also includes a method of obtaining new compounds of the formula (I) that the PTO. The method involves reacting a derivative of benzoic acid, in which the aromatic substituents are such as required at the end of compounds of formula (I) or substituents can be converted to such deputies with alcohol or amine containing Z or a group which is convertible to him, and then, if necessary, conversion of the substituents derivatives of benzoic acid and/or Z, and the optional formation of a pharmaceutically acceptable salt.

Examples of conversions in the aromatic substituents include chlorine, hydrogen chlorine, restoration of nitro group to amino group, dehydrohalogenation, such as dibromononane and/or the reaction of 2,3-disubstituted benzoic acid with ethylene glycol education benzodioxane.

Examples of conversions in the Z-containing fragment include conversion modification of the N-substituent replacing and/or removing protection or when at the end of the required 2-, 3 - or 4-substituted piperidyl, the restoration of the relevant pyridylketone.

Any interaction of X and/or Z, however, is primarily for education ether or amide linkages.

Intermediate products azabicyclic compounds or can be obtained from ketones of formula (II):

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in accordance with suitable methods.

The compounds of this invention are antagonists of 5-HT4-receptor and are thought to be used in the treatment and prevention of gastrointestinal diseases, cardiovascular disorders and diseases of the Central nervous system.

They represent a potential interest in the treatment of inflammatory syndrome colon (WSTC), especially species STK associated with diarrhea, i.e., these compounds block the ability of 5-HT to stimulate the motility of the intestine through the activation of enteric neurons. In experiments in WSTC on animals that can be measured as a reduction in the rate of defecation. It is also possible their use in the treatment of urinary incontinence, which often accompanies STK.

They can also be potentially used for treatment of other gastrointestinal disorders associated with the motility of the upper intestine and as antiemetics. In particular, they can be used in the treatment of nausea and gastric symptoms of gastro-esophageal regurgitation disorders and dyspepsia. Antiemetic activity determined in a known animal with induzione the agonists 5-HT4receptors, which prevent atrial fibrillation and other atrial arrhythmias associated with 5-HT-receptor, have, as expected, to reduce the occurrence of attacks (see A. T. Kanmann 1990, Naunyn-Schmiedebergis Arch Pharmacol 342, 619 - 622 appropriate method for testing on animals).

Calming effect, probably through effects on the mediated (Dumuis et al., 1988, Mol Pharmacol 34, 880 - 887). The activity can be demonstrated in experiments on standard animal models in the test, social interaction test and X-maze.

Migraine sufferers are often exposed to situations associated with fear and emotional stress that precede the headache (Sach, 1985, Migraine, Pau Books, London). It was observed that during and for 48 hours after migrainebuy attack the content of cyclic adenosine monophosphate (AMP) in cerebral fluid is significantly increased. I believe that migraine, including prodromal phase and the associated increase in the content of cyclic AMP, is associated with stimulant receptors 5-HT4and , therefore, the introduction of an antagonist of 5-HT4is potentially favourable to reflect migrainebuy attack.

Such compositions are offset and are usually used inside the oral, nasal or rectal, or parenterally introduction and they can be in the form of tablets, capsules, oral liquid preparations, powders, granules, pellets, composite powders, nasal solutions for injections, suppositories, solutions and suspensions for injection and infusion. Oral introduction of the compositions is preferred because it is more suitable for General use.

Tablets and capsules for oral administration, usually issued in a single dose and contain appropriate eccipienti, such as binding agents, fillers, diluents, tabletiruemye agents, binding agents, disintegrant, dyes, corrigentov and wetting agents. Tablets may be coated according to well known methods, for example, intersolubility the floor.

Appropriate fillers for applications include cellulose, mannitol, lactose, and other similar agents. Relevant disintegrant include starch, polyvinylpolypyrrolidone and derivatives of starch such as sodium starch glycollate. Appropriate lubricating agents include, for example, sodium stearate. Liquid preparations for oral administration can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or made in the form of a dry product for mixing with water or other component before use. Such liquid preparations may contain suitable additives such as suspendresume agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, gel, aluminum stearate or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate or Arabian gum; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol or ethyl alcohol; preservance, for example, methyl or propyl ester of p-hydroxybenzoic acid or sorbic acid, and, if necessary, appropriate corrective or coloring agents.

Liquid preparations for oral administration are usually made in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or are in the form of a dry product for compounds with water or drugima as suspendresume agents, emulsifying agents, non-aqueous vehicles (which may include edible fatty oil), preservance and correcting or coloring agents.

Compositions for oral administration can be prepared using appropriate methods of binding, filling or tableting. Re-bind operation can be used to distribute the active agent in these compositions containing significant amounts of fillers. Such operations, of course, are available for implementation.

For parenterale the introduction of the prepared liquid form containing a unit dose of a compound of this invention and a sterile carrier. Connection, depending on the form and concentration, can be either suspended or dissolved. Solutions for parenterale introduction usually prepared by dissolving in media and filter sterilized before application to the appropriate vessel or ampoule and sealing. It is also useful to dissolve in the carrier adjuvants such as local anasthesiologie substances, preservance and buferiruemoi agents. To increase the stability of the composition can be frozen after filling her vessel, and the water removed under vacuumcleaner, that connection is suspended in the carrier instead of dissolving and sterilized by exposure to ethylene oxide before suspendirovanie in sterile media. It is useful to include in the composition of a surfactant or wetting agent to enhance the uniformity of distribution of the compounds of this invention.

The invention also provides a method of treatment or prophylaxis of an inflammatory syndrome, colon cancer, dispersion, atrial fibrillation and attacks, fear, and/or migraine in mammals, such as man, which comprises introducing an effective amount of the compounds of formula (I) or pharmaceutically acceptable salts thereof.

The amount needed for effective treatment of the disorders described above, depends on the relative effectiveness of the compounds of the present invention, the nature and severity of the disease, which is treatable and weight of the mammal. Nevertheless, the single dose for an adult weighing 70 mg will typically contain from 0.05 to 1000 mg, for example, from 0.5 to 500 mg of the compounds of this invention. A single dose can be injected once or more per day, for example, 2, 3 or 4 times a day, more acceptable 1-3 times a day, which is approximately from 0.0001 to 50 mg/kg/day, balearian within the above doses.

The invention also provides the use of compounds of formula (I) or its pharmaceutically acceptable salt as an active therapeutic agent, in particular for the treatment of inflammatory syndrome colon, gastro-esophageal regurgitation disorders, dyspepsia, atrial fibrillation and attacks, fear, and/or migraine.

The following examples ( see end of text) illustrate the formation of compounds of formula (I); the following descriptions refer to intermediate products (descriptions 1-3 and 11 are examples of the introduction of intermediate products containing fragment X1-(CH2)x-X2; description 4-9 and 10 - side-chain-containing intermediate products and a description of the 12 - piperidine intermediate products obtained from the corresponding compounds in which Z corresponds to Podgornoe (a) and which is derived in turn from the corresponding pyridyl-derived.

Example 1

8-Amino-7-chloro-/1-butyl-4-piperidyl/methyl-1,4-benzodioxan-5-carboxylate (P1)

A suspension of 8-amino-7-chloro-1,4-benzodioxan-5-carboxylic acid (obtained from the corresponding 7-H acid by chlorination protected form) (720 mg) was dissolved in acetonitrile (10 ml). Bis-kabakumba and the residue is dried. A solution of 1-butyl-4-piperidinemethanol (510 mg) in dry tetrahydrofuran (THF) (20 ml) is added dropwise to a solution of n-utility (1,88 ml of 1.6 M solution in hexane) at 0oC and the resulting solution was stirred for 15 minutes. Imidazole obtained as described above was dissolved in dry THF (25 ml) and the resulting solution is added dropwise to a solution of lithium alcoholate in dry THF. The reaction mixture was stirred at room temperature overnight. After removal of solvent the residue is distributed between ethyl acetate (EA) and H2O, the ethyl acetate layer is separated. The solution is washed several times with water and dried (MgO4). In the solvent evaporation receives a yellow gum, which was purified by the method of column chromatography on SiO2using as eluent a mixture containing 95% CHCl3and 5% MeOH. The product is isolated in the form of a hydrochloric salt, etc., 243-244oC.

TMR 250 MHZ(CDCl3) (free base)

: 7,49 (s, 1H), 4,48 (ush.S., 2H), 4.26 deaths - of 4.38 (m, 4H), 4,08 (d, 2H), 2,93 - 3,05 (ush.D., 2H), 2,30 - to 2.40 (m, 2H), 1,20 - of 2.05 (m, 11H), of 0.90 (t, 3H).

Examples 2 to 12

The following connections get the same way:

8-Amino-(1-butyl-4-piperidyl/methyl-1,4-benzodioxan-5 - carboxylate (P2)

TMR 250 MHZ

7-Bromo-5-(1-butyl-4-piperidyl)methyl-1,4(benzodioxan-5-carboxylate (P3)

so pl. 205-206oC (florodora salt)

TMR 250 MHZ(CDCl3) (free base)

: 7.5 (d, 1H), 7,12 (d, 1H), 4,3 was 4.42 (m, 4H), of 4.12 (d, 2H), 2,90 - 3,05 (ush.D., 2H), 2.3 to 2.4 (m, 2H), 1,22 - of 2.05 (m, 11H), to 0.92 (t, 3H).

1-Butyl-4-piperidyl/methyl-1,4-benzodioxan-5-carboxylate (A4)

so pl. 144-146oC (florodora salt)

TMR 250 MHZ(CDCl3) (free base)

: 7,38 (D. D., 1H), 7,0 (D. D., 1H), PC 6.82 (t, 1H), 4,28 - 4,4 (m, 4H), of 4.12 (d, 2H), 2,9 - 3,05 (ush.D., 2H), 2.3 to 2.4 (m, 2H), 1,22 - of 2.05 (m, 11H), to 0.92 (t, 3H).

7-Chloro-(1-butyl-4-piperidyl)methyl-1,4-benzodioxan-5 - carboxylate (P5)

so pl. 185-186oC (hydrochloric salt)

TMR 250 MHZ(CDCl3) (free base)

: 7,37 (d, 1H), 7,02 (d, 1H), 4,25 - and 4.40 (m, 4H), 4,14 (d, 2H), 2,98 (ush.D., 2H), 2,28 - of 2.38 (m, 2H), 1,24 is 2.00 (m, 11H), to 0.92 (t, 3H).

8-Amino-6,7-dichloro-(1-butyl-4-piperidyl)methyl-1,4- (benzodioxan-5-carboxylate (P6)

so pl. 168-169oC (florodora salt)

TMR 250 MHZ(CDCl3) (free base).

: 4,39 (s, 2H), 4,28 - 4,37 (m, 4H), to 4.15 (d, 2H), 2,9 - 3,05 (ush.D., 2H), 2.3 to 2.4 (m, 2H), 1,22 - to 1.98 (m, 11H), to 0.92 (t, 3H).

8-Amino-7-iodine-(1-cyclohexylmethyl-4-piperidyl/methyl-1,4 - benzodioxan-5-carboxylate (A7)

TMR 250 MH30 (m, 20H).

8-Amino-7-chloro-1,4-benzodioxan-(s-3-Hino-libidinal)methylcarbazole (P8)

so pl. 139-140oC

TMR 250 MHZ(CDCl3) (free base)

: 7,42 (s, 1H), 4,19 to 4.5 (m, 8H), 2,72 (D. D., 1H), 2,60 (ush.D., 1H), 1,10 - 2,11 (m, 14H).

8-Amino-7-chloro-1,4-benzodioxan-(EQ. -3-finalizedin) methylcarbazole (P9)

TMR 250 MHZ(CDCl3) (free base)

: 7,49 (s, 1H), 4,48 (ush.S., 2H), 4,28 - to 4.38 (m, 4H), 3.95 to to 4.15 (m, 2H), 3,0 (ush.D., 1H), 2,83 (ush.D., 1H), 1,01 - of 2.20 (m, 14H).

8-Amino-7-chloro-(1-cyclohexylmethyl-4-piperidyl)methyl-1,4 - benzodioxan-5-carboxylate (P10)

so pl. 185-186oC (hydrochloric salt)

TMR 250 MHZ(CDCl3) (free base).

: 7,49 (s, 1H), 4,48 (ush.S., 2H), 4,30 - to 4.38 (m, 4H), 4,08 (d, 2H), 2,82 - 2.91 in (ush.D., 2H), 2,10 (d, 2H), 0,80 - of 1.95 (m, 18H).

EQ.-Finalisation-2-ylmethyl-7-chloro-1,4-benzodioxan-5 - carboxylate (A11)

so pl. 191-192oC (florodora salt)

PMR (d6DMSO) (HCl salt)

: 7,24 (d, 1H), 7,20 (m, 1H), 4,28 is 4.36 (m, 4H), 4,11 (d, 2H), 3.25 to to 3.36 (m, 2H), was 2.76 - 3,11 (m, 1H), 2,01 and 2.13 (m, 1H), 1,36 - of 1.92 (m, 10H).

EQ.-Finalisation-2-ylmethyl-8-amino-7-chloro-1,4-benzodioxan-5 - carboxylate (A12)

so pl. 173-175oC.

TMR 250 MHZ(CDCl3) (free base)

: of 7.48 (s, 1H), 4,45 (ush.S., 2H), 4,28 - and 4.40 (m, 4H), 4,07 (d, 2H), basamid (A13)

A solution of 8-amino-7-chloro-1,4-benzodioxan-5-carboxylic acid (see example 1) (500 mg, 0,0022 mol) in acetonitrile (30 ml) is treated with bicarbonato (356 mg, 0,0022 mol). The mixture is stirred at room temperature for 2 hours.

To the resulting mixture add a solution of 1-ethyl-4-amino-methylpiperidine (312 mg, 0,0022 mol) in acetonitrile (25 ml) and the reaction mass stirred at room temperature overnight. The solvent is removed under vacuum and the residue distributed between ethyl acetate and water. The ethyl acetate layer is separated, washed several times with water, dried (MgSO4) and evaporated to obtain an orange gum, which was purified by the method of column chromatography on SiO2using chloroform with increasing proportions of methanol as eluent. Get the product in the form of a slightly coloured gum.

TMR 250 MHZ(CDCl3) (free base).

: 7,79 (s, 1H), 7,50 (ush.S., 1H), 4,29 - 4,39 (m, 6H), of 3.25 (t, 2H), 2,94 (ush. D., 2H), 2,38 (D. D., 2H), 1,20 - of 1.95 (m, 7H), is 1.01 (t, 3H).

Examples 14 and 15

The following compounds were obtained by the method described in example 13.

8-Amino-7-chloro-/1-butyl-4-piperidyl/methyl-1,4-benzodioxan-5-carboxamid (A14)

so pl. 75 - 76oC

TMR 250 M (m, 2H), 2,0 - 2,14 (ush. so, 2H), 1,20 - to 1.82 (m, 9H), to 0.92 (t, 3H).

8-Amino-7-chloro-(1-cyclohexylmethyl-4-piperidyl/methyl-1,4 - benzodioxan-5-carboxamid (p)

TMR 250 MHZ(CDCl3) (free base)

: 7,72 (s, 1H), 7,55 (ush. so, 1H), 4,30 - to 4.41 (m, 6H), 3,3 (t, 4H), 2,82 - 2,95 (ush. D., 2H), 2,10 (D., 2H), 0,78 - 1,9 (m, 18H).

Example 16

8-Amino-7-chloro-(4-piperidinylmethyl)-1,4-benzodioxan-5-carboxylate hydrochloride (A16)

a) To a solution of 8-amino-7-chloro-1,4-benzodioxan-5-carboxylic acid (1.10 g) in acetonitrile was added with stirring bicarbonated (0,77 g). The reaction mixture was stirred at room temperature for 1.5 hours. The solvent is removed under vacuum, resulting in a technical 8-amino-7-chloro-1,4-benzodioxan-5-imidazole.

b) To a solution of N-tert an butoxycarbonyl-4-hydroxyethylpiperazine (0.25 g) in dry THF (10 ml) is added at a temperature of 0oC and under nitrogen atmosphere motility (1.5 M in diethyl ether; 0,78 ml). Stirring is continued at ambient temperature for 10 minutes. The reaction mixture was added 8-amino-7-chloro-1,4-benzodioxan-5-imidazole (0.33 g) in THF (10 ml) and the resulting mass is stirred for 2 hours. After that the reaction mixture is cooled to 0oC and add water. Vaut water (three times), dried (Na2SO4), filtered and evaporated under vacuum. By thin layer chromatography on silica using as eluent chloroform and ethanol obtain the above compound (0.26 g).

TMR 250 MHZ(CDCl3)

: 7,47 (s, 1H) of 4.49 (s, 2H), 4,08 - 4,22 (m, 4H), 2,64 is 2.80 (m, 2H), 1,84 is 2.01 (m, 1H), 1.70 to to 1.83 (m, 2H), of 1.46 (s, 9H), 1.18 to to 1.38 (m, 2H).

C) HCl (gas) is bubbled into the cold solution of 8-amino-7-chloro-(N-tert-butoxycarbonyl-4-piperidinyl)-1,4 - benzodioxan-5-carboxylate (0.26 g) in dioxane (50 ml) for 25 minutes. The solvent is evaporated under vacuum and the residue planted diethyl ether to obtain the above compound (0.12 g)

so pl. 249 - 251oC

TMR 250 MHZ(DMSO)

: 8,99 - 9,10 (m, 1H), 8,59 - 8,78 (m, 1H), 7,29 (s, 1H), 5,73 (s, 2H), 4,25 - 4,34 (s, 4H), a 4.03 (d, 2H), 3,20 - of 3.42 (m, 2H), 2,75 - of 2.97 (m, 2H), 1,76 - to 2.06 (m, 3H), 1,48 - of 1.57 (m, 2H).

Example 17

5/3-Piperidino propyl/-3-/benzo-1,4-dioxane-5-yl/-1,2,4-oxadiazol (A17)

1,4-Benzodioxan-5-carboxamid the oxime (3) (0,300 g, 1.55 mmol) dissolved in dry THF (10 ml) with stirring and treated with molecular sieves sizes 4A (1 g) in a nitrogen atmosphere. After 30 minutes, add sodium hydride (80% dispersion in mineral oil) (0,051 g, 1,71 mmol). Then reactionable ethyl-4-(piperidino)butyrate (0,340 g, 1,71 mmol). After that the reaction mixture is heated to boiling and boiled for 2.5 hours, then allowed to cool, and then filtered. The filter cake was washed with two portions of THF. The filtrate is evaporated under vacuum. The residue is purified by chromatography on silica gel, using as eluent a mixture of pentane : ethyl acetate with proportion of 1:1 to 2:3 to obtain the above compound as a pale yellow oil, which turned into chlorodrol salt so pl. 175 - 176oC.

TMR 250 MHZ(CDCl3)

: 12,20 to 12.5 (ush. S., 1H), 7,52 (D. D., 1H), 6.90 to - was 7.08 (m, 2H), 4,45 (m, 2H), 4,35 (m, 2H), of 3.5 - 3.7 (m, 2H), 2,97 - 3,20 (m, 4H), 2,47 is 2.80 (m, 4H), of 2.15 - 2.45 (m, 2H), 1,74 is 2.00 (m, 3H), 1.30 and of 1.54 (m, 1H).

Example 18

(1-Butyl-4-piperidyl)methyl-1,3-benzodioxol-4-carboxylate hydrochloride (P)

The method described in example 1 is used for the conversion of 1,3-benzodioxol-4-carboxylic acid (D II) (705 mg) in the above-mentioned compound (393 mg, 29% yield) with so pl. 168 - 169oC.

TMR 250 MHZ(CDCl3)

: to 7.4 (d, 1H), 6,98 (d, 1H), 6,86 (t, 1H), 6,10 (s, 2H), 4,20 (d, 2H), 3.04 from (ush.D., 2H), 2,45 - 2,3 (m, 2H), 2,1 - 1,2 (m, 11H), were 0.94 (t, 3H).

Examples 19 to 21

Obtaining a source of acid for examples 19 to 21 described in applications EP-A-407137 and 313393 (Yoshitomi).

(1-Butyl-4-piperidin the HZ(CD3SOCD3) (HCl salt)

: 11,17 (s, 1H), 10,34 - 10,10 (s, 1H), 7,41 (d, 1H), 7,21 (d, 1H), 4,80 (s, 2H), 4,22 (d, 2H), only 3.57 (m, 2H), 3,20 - to 2.85 (m, 4H), 2,12 - of 1.95 (m, 3H), 1,90 - to 1.60 (m, 4H), of 1.40 (m, 2H), and 1.00 (t, 3H).

(1-Butyl-4-piperidyl)methyl-6-chloro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-8-carboxylate (P)

so pl. 87 - 88oC

TMR 250 MHZ(CDCl3)

: 7,49 (d, 1H), 7,10 (d, 1H), 4,18 (d, 1H), 3,38 (s, 3H), 3.00 and (d, 2H), 2,33 (t, 2H), 1,97 (t, 2H), 1,78 (m, 3H), 1,54 - 1,25 (m, 6H), to 0.92 (t, 3H).

(1-Butyl-4-piperidyl)methyl-6-chloro-3,4-dihydro-2H-1,4-benzoxazin-8-carboxylate (A21)

so pl. 177 - 178oC (HCl salt)

TMR 250 MHZ(CD3SOCl3) (HCl salt)

: 10,28 (s, 1H), 6,85 (m, 2H), return of 6.58 (s, 1H), 4,23 (t, 2H), 4,15 (d, 1H), to 3.67 (d, 2H), 3.45 points (m, 3H), 3,10 - 2,90 (m, 3H), 2,15 - of 1.92 (m, 3H), 1,88 is 1.60 (m, 4H), of 1.40 (m, 2H), and 1.00 (t, 3H).

Example 22

8-Amino-7-chloro-5-/1-methyl-4-piperidinylmethyl/1,4-benzodioxan carboxylate hydrochloride (A22)

To a solution of 8-amino-7-chloro-5-(1H-4-piperidinylmethyl)-1,4-benzodioxan of carboxylate (p) (100 mg) and trimethylamine (70 l) in acetone (15 ml) add iodomethane (20 l). The reaction mixture was stirred at room temperature for 64 hours. The solvent is distilled off under vacuum and the residue partitioned between chloroform and water. The organic phase is dried (Na2SO4), filtered and evaporated under vacuum. Prduct. Processing ethereal HCl leads to obtain the title compound (40 mg).

TMR 250 MHZ(CDCl3) (free base)

: 7,49 (s, 1H), 4.53-in (ush.S., 2H), or 4.31 - of 4.44 (m, 4H), 4,19 (d, 2H), 3,49 (d, 2H), 2,69 - to 2.85 (m, 5H), 1,97 - of 2.15 (m, 5H).

Examples 23 to 43

The method described in example 22, based on the compound obtained in example 16, to obtain the following compounds:

8-Amino-7-chloro-5-/1-ethyl-4-piperidyl/methyl-1,4-benzodioxan carboxylate hydrochloride (A23)

TMR 250 MHZ(CDCl3) (free base)

: 7,47 (s, 1H), 4.53-in (ush. S., 2H), 4,29 - to 4.46 (m, 4H), 4,17 (d, 2H), 3,44 (d, 2H), 2.95 and (q, 2H), of 2.51 - 2,69 (m, 2H), 1,90 - 2,12 (m, 5H), of 1.40 (t, 3H).

8-Amino-7-chloro-5-(1-propyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate hydrochloride (P)

TMR 250 MHZ(CD3OD)

: 7,44 (s, 1H), 4,27 - to 4.38 (m, 4H), 4.16 the (d, 2H), 3,64 (d, 2H), 2,94 - 3,13 (m, 4H), 2,03 - 2,17 (m, 3H), 1,59 - of 1.88 (m, 4H), of 1.03 (t, 3H).

8-Amino-7-chloro-5-(1-isobutyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate hydrochloride (A25)

TMR 250 MHZ(CDCl3) (free base)

: 7,50 (s, 1H), 4,48 (ush, S., 2H), or 4.31 - 4,39 (m, 4H), 4.09 to (d, 2H), 2,89 (d, 2H), 2,08 (d, 2H), 1,69 - of 1.95 (m, 6H), 1,31 - 1,49 (m, 2H), of 0.91 (d, 6H).

8-Amino-7-chloro-5-(1-cyclopropylmethyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate hydrochloride (A26)

TMR 250 MHZ(CDCl3

8-Amino-7-chloro-5-/1-pentyl-4-piperidinyl/methyl-1,4-benzodioxan carboxylate hydrochloride (P)

TMR 250 MHZ(CD3OD)

: the 7.43 (s, 1H), or 4.31 - to 4.41 (m, 4H), 4,17 (d, 2H), 3,65 (d, 2H), 2.95 and - 3,17 (m, 4H), 2,01 - to 2.18 (m, 3H), 1,61 is 1.86 (m, 4H), 1,29 - 1,49 (m, 4H), of 0.95 (t, 3H).

8-Amino-7-chloro-5-(2-methylbutyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate hydrochloride (P)

TMR 250 MHZ(CD3OD)

: 7,43 (c, 1H), 4,28 - 4,43 (m, 4H), 4,18 (d, 2H), 3,65 (d, 2H), 2.95 and - 3,19 (m, 4H), 2,02 - 2,19 (m, 3H), 1,59 - of 1.78 (m, 5H), of 0.97 (d, 6H).

8-Amino-7-chloro-5-/2-methoxyethyl-4-piperidyl/methyl-1,4-benzodioxan carboxylate hydrochloride (A23)

TMR 250 MHZ(CDCl3) (free base)

: 7,49 (s, 1H), 4,49 (ush. S., 2H), 4,30 was 4.42 (m, 4H), 4,11 (d, 2H), 3,52 (t, 4H), to 3.35 (s, 3H), 3,01 (d, 2H), 2,60 (t, 2H), 2,03 (t, 2H), 1,73 - of 1.84 (m, 3H), 1,38 - of 1.57 (m, 2H).

8-Amino-7-chloro-5-(1-benzyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate hydrochloride (PPP)

TMR 250 MHZ(CDCl3) (free base)

: 7,49 (s, 1H), 7,22 - 7,40 (m, 5H), 4,49 (ush.S., 2H), 4,28 - to 4.52 (m, 4H), 4,10 (d, 2H), 3,50 (c, 2H), 2,94 (d, 2H), 2,00 (t, 2H), 1.70 to 1.85 to (m, 3H), 1,33 - is 1.51 (m, 2H).

8-Amino-7-chloro-5-(2-cyclohexylethyl-4-piperidinyl)methyl-1,4-benzodioxan carboxylate hydrochloride (P)

TMR 250 MHZ(CDCl3) (free base)

: 7,49 (s, 1H), 4,47 (ush.S., 2H)PR-5-(1-hexyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate hydrochloride (P)

TMR 250 MHZ(CDCl3) (free base)

: of 7.48 (s, 1H), 4,46 (ush. S., 2H), 4,30 - 4,39 (m, 4H), of 4.12 (d, 2H), 3,11 (d, 2H), 2,47 (t, 2H), 2,04 (t, 2H), 1,79 - 1,90 (m, 3H), 1,52 was 1.69 (m, 4H), 1,29 - of 1.45 (m, 7H), 0,83 - of 0.91 (m, 3H).

8-Amino-7-chloro-5-(1-octyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate hydrochloride (P)

TMR 250 MHZ(CDCl3) (free base)

: 7,50 (s, 1H), 4,46 (m, 2H), or 4.31 - 4,39 (m, 4H), of 4.12 (d, 2H), 3.04 from - 3,13 (m, 2H), 2,38 - 2,48 (m, 2H), 2,01 - of 2.16 (m, 2H), 1.77 in - a 1.88 (m, 3H), 1,51 - of 1.65 (m, 4H), 1,24 - of 1.32 (m, 10H), 0,85 - of 0.91 (m, 3H).

8-Amino-7-chloro-5-(1-nonyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate hydrochloride (P)

TMR 250 MHZ(CDCl3) (free base)

: 7,47 (s, 1H), 4,51 (ush., 2H), or 4.31 - and 4.40 (m, 4H), 4,14 (d, 2H), up 3.22 (d, 2H), 2,59 (t, 2H), 2,31 (t, 2H), 1,62 - of 1.94 (m, 7H), to 1.21 and 1.35 (m, 12H), 0,85 with 0.93 (m, 3H).

8-Amino-7-chloro-5-/1-decyl-4-piperidyl/methyl-1,4-benzodioxan carboxylate hydrochloride (P36)

TMR 250 MHZ(CDCl3) (free base)

: 7,41 (s, 1H), of 4.44 (ush.S., 2H), 4,24 - 4,32 (m, 4H), 4,08 (d, 2H), 3.15 in (d, 2H), 2,48 - to 2.57 (m, 2H), 2,24 (d, 2H), 1,57 - of 1.88 (m, 7H), 1,13 - of 1.28 (m, 14H), 0,79 is 0.84 (m, 3H).

8-Amino-7-chloro-5-(1-undecyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate hydrochloride (P)

TMR 250 MHZ(CDCl3) (free base

: 7,49 (s, 1H), 4,50 (ush.S., 2H), 4,32 - to 4.41 (m, 4H), to 4.15 (d, 2H), 3,19 (d, 2H), 2,50 - of 2.58 (m, 2H), 2,17 - to 2.29 (m, sodickson carboxylate hydrochloride (P)

TMR 250 MHZCDCl3) (free base)

: 7,49 (s, 1H), 4,49 (ush.s, 2H), 4,33-to 4.41 (m, 4H), 4,14 (d, 2H), 3,18 (d, 2H), 2,49-to 2.57 (m, 3H), 2,22 (t, 2H), 1,80-of 1.94 (m, 3H), of 1.57 to 1.76 (m, 4H), to 1.22 and 1.33 (m, 18H), 0,85-of 0.91 (m, 3H).

8-Amino-7-chloro-5-(1-(4-terbisil)-4-piperidyl)methyl-1,4-benzodioxan carboxylate hydrochloride (P39)

TMR 250 MHZ(CDCl3) (free base)

: of 7.48 (s, 1H), 7,27-7,38 (m, 2H), 7,01 (t, 2H), 4,49 (ush.S., 2H), 4,30-4,39 (m, 4H), 4,11 (d, 2H) 3,53 (s, 2H), 2,94 (d, 2H), 3,53 (s, 2H), 2,94 (d, 2H), 2,04 (t, 2H) 1,72-of 1.84 (m, 3H), 1,39-of 1.52 (m, 2H).

8-Amino-7-chloro-5-/1-/4-methoxybenzyl/-4-piperidyl/methyl/1,4-benzodioxan carboxylate hydrochloride (P)

TMR 250 MHZ(CDCl3) (free base)

: of 7.48 (s, 1H), 7,22 (d, 2H), 6,85 (d, 2H), 4,49 (ush.S., 2H), 4,29 is 4.36 (m, 4H), 4.09 to (d, 2H), of 3.78 (s, 3H), 3,47 (s, 2H), 2.91 in (d, 2H), 1,96 (t, 2H), 1,70-1,80 (m, 3H), 1,29 to 1.47 (m, 2H).

8-Amino-7-chloro-5-/1-/4-methylbenzyl/-4-piperidyl/methyl-1,4 - benzodioxan carboxylate hydrochloride (P)

TMR 250 MHZ(CDCl3) (free base)

: of 7.48 (m, 1H), 7,22 (d, 2H), 7,12 (d, 2H), 4,45 (ush.S., 2H), 4,30 is 5.38 (m, 4H), 4,10 (d, 2H), 3,47 (s, 2H), 2,92 (d, 2H), 2,33 (s, 3H), 2,00 (t, 2H), 1.70 to is 1.81 (m, 3H), 1.32 to 1,50 (m, 2H).

8-Amino-7-chloro-5-/1-phenetyl-4-piperidyl/methyl-1,4-benzodioxan carboxylate hydrochloride (P)

TMR 250 MHZ(CDCl3) (free base)

: 7,50 (s, 1H), 7,15-7,34 (m, 5H), 4,49 (ush.S., 2H), 4,2-7-chloro-1,4-benzodioxan-5-(1-pentyl-4-piperidyl)methyl carboxamide hydrochloride (P)

A solution of 8-acetamido-7-chlorobenzoyloxy-5-(1-pentyl-4 - piperazinecarboxamide (d13) (60 mg) in ethanol (10 ml) is treated with 10% aqueous NaOH solution (110 l). The resulting mixture is boiled for 5 hours. The solvent is distilled off under vacuum and the residue partitioned between water and chloroform. The organic phase is dried (Na2SO4), filtered and evaporated under vacuum to obtain oil. Processing ethereal HCl gives the pure title compound (39 mg).

TMR 250 MHZ(CDCl3) (free base)

: of 7.70 (s, 1H), 7,42-7,53 (m, 1H), 4,24-of 4.49 (m, 6H), of 3.27 (t, 2H), 2,88 (d, 2H), 2,18-of 2.28 (m, 2H), 1,84 (t, 2H), 1,13-1,71 (m, 11H), or 0.83 (t, 3H).

Examples 44-46

The method described in example 43, receive the following connections:

8-Amino-7-chloro-1,4-benzodioxan-5-/1-cyclohexyl-4-piperidinyl/methyl carboxamide hydrochloride (P44)

TMR 250 MHZ(CDCl3) (free base)

: of 7.69 (s, 1H), 7,42-7,53 (m, 1H), 4,22-to 4.38 (m, 6H), 3,24 (t, 2H), 2,85 (d, 2H), 2,18-2,31 (m, 2H), 1,81 (t, 2H), 0,95-1,72 (m, 16H), 0,70-0,93 (m, 2H).

8-Amino-7-chloro-1,4-benzodioxan-5-/1-isobutyl-4-piperidyl/methyl carboxamide hydrochloride (P)

TMR 250 MHZ(CDCl3) (free base)

: for 7.78 (s, 1H), 7,49-to 7.59 (m, 1H), 4,32 is 4.45 (m, 6H), to 3.34 (t, 2H), 2,88 (d, 2H), 2,07 (d, 2H), 1,52 is 1.91 (m, 6H), 1,23-of 1.40 (m, 2H), 0,89 (d, 6H).

8-Amino-7SUB>3
) (free base)

: of 7.70 (s, 1H), 7,44-7,53 (m, 1H), 4,24-4,37 (6H), of 3.28 (t, 2H), 2,87 (d, 2H), 2,19-to 2.29 (m, 2H), 1,75-1,90 (m, 2H), 1,42-1,71 (m, 4H), 1,5-of 1.37 (m, 4H), or 0.83 (d, 6H).

Example 47

8-Amino-7-chloro-1,4-benzodioxan-5-/4-piperidyl/methyl carboxamide hydrochloride (P)

A solution of 8-acetamido-7-chloro-1,4-benzodioxan-5-(4-piperidyl)-methyl carboxamide (12) (1.65 g) in ethanol (50 ml) is treated with 10% aqueous solution of sodium hydroxide (4,58 ml) and the resulting mixture is boiled overnight. The solvent is distilled off under vacuum, the residue storeroot K2CO3and extracted with chloroform. The organic phase is dried (NaSO4), filtered and evaporated under vacuum of the solvent, resulting in a gain of 8-amino-7-chloro-1,1-benzodioxan-5-/4-piperidyl/methyl carboxamide (0,89 g). Processing ethereal HCl gives the title compound.

TMR 250 MHZ(CDCl3) (free base)

: 7,74 (s, 1H), 6.48 in-rate of 7.54 (m, 1H), 4.26 deaths-4,48 (m, 6H), of 3.32 (t, 2H), 3,09 (d, 2H), 2,59 (d, t, 2H), 2,03 (ush.S., 1H), 1,62-of 1.81 (m, 3H), 1,08 of 1.28 (m, 2H).

Examples 48-50

The method described in example 13, to obtain the following compounds:

8-Amino-7-chloro-1,4-benzodioxan-5-/1-methyl-4-piperidyl/methyl carboxamide hydrochloride (P)

TMR 250 MHZ(CD3OD) (free base)

: 8,15 is 8.25 (m, 1H), 7,15 (s, 1H), or 4.31-4,48 (sawdust-4-piperidyl/methyl carboxamide hydrochloride (p)

TMR 250 MHZ(CD3CD) (free base)

: 7,53 (s, 1H), to 4.38-of 4.54 (m, 4H), 3,57 (d, 2H), 3.27 to to 3.41 (m, 2H), 2,83 is 3.15 (m, 4H), 1,54-2,12 (m, 7H), of 1.03 (t, 3H).

8-Amino-7-chloro-1,4-benzodioxan-5-/1-benzil-4-piperidyl/methyl carboxamide hydrochloride (P)

TMR 250 MHZ(CDCD3)

: 7,75 (c, 1H), of 7.48-of 7.60 (m, 1H), 7,17-7,38 (m, 6H), 3,49 (s, 2H), and 3.31 (t, 2H), 2.91 in (d, 2H), 1,98 (t, 2H), 1,52-of 1.78 (m, 3H), 1,23-of 1.42 (m, 2H).

M+ (EI) 359

Example 51

8-Amino-7-chloro-(1-butyl-1-methyl-4-piperidyl)methyl-1,4-benzodioxan-5-carboxylate iodide (P)

A solution of 8-amino-7-chloro-(1-butyl-4-piperidyl)methyl-1,4-benzodioxan-5-carboxylate hydrochloride (P1) (75 mg) is converted to free base is then dissolved in acetone (10 ml). Iodomethane (20 ml) is added and the mixture is boiled for 3 hours. The solvent is distilled off under vacuum, the residue is dried to obtain a pale yellow solid (70 mg). The product exists in two isomeric forms.

TMR 250 MHZ(DMSO)

: 7,28 (c, 1H), 5,72 (ush. S., 2H), 4,28 (ush.S., 4H), 4,08 (d, 2H), 3,38-3,5 (m, 2H), 3,2-3,37 (m, 4H), to 3.00 (m, 3H), 1,20-2,05 (m, 9H), to 0.92 (t, 3H).

Example 52

8-Amino-7-iodide-1,4-benzodioxan-5-(1-butyl-4-piperidyl)methyl carboxylate hydrochloride (P)

The title compound is obtained from 8-amino-7-iodide-1,4-benzodioxan-5-carboxylic acid (I) by the method described in paragraph (m, 2H), 1,89-of 2.08 (m, 2H), 1,69-of 1.88 (m, 3H), 1,28-to 1.60 (6H), of 0.93 (t, 3H).

Example 53

(1-Butyl-4-piperidyl)methyl-8-chloro-1,4-benzodioxan-5-carboxylate (P)

The title compound is obtained from 8-amino-1,4-benzodioxan-5-carboxylic acid (I) by the method described in example 1

so pl. 153-154oC (hydrochloric salt)

TMR 250 MHZ(CDCl3) (free base)

: 7,38 (d, 1H), of 6.96 (d, 1H), to 4.41 (m, 4H), 4,13 (d, 2H), 2,98 (d, 2H) 2,32 (t, 2H), 1.93 and (t, 2H), 1,84-of 1.65 (m, 3H), 1,54-of 1.20 (m, 6H), to 0.92 (t, 3H).

Example 54

(1-Butyl-4-piperidyl)methyl-6,7-dibromo-1,4-benzodioxan-5-carboxylate (P)

The title compound is obtained from 6,7-dibromo-1,4-benzodioxan-5-carboxylic acid by the method described in example 1

so pl. 175-177 (florodora salt)

TMR 250 MHZ(CDCl3) (free base)

: 7,20 (s, 1H), 4,30 (s, 4H), 4,20 (d, 2H), to 3.02 (d, 2H), of 2.38 (t, 2H), 2,00 (t, 2H), 1,87-of 1.65 (m, 3H), 1,55 of 1.28 (m, 6H), 1,55 of 1.28 (m, 6H), were 0.94 (t, 3H).

Description

(intermediate products)

Description 1 (the intermediate product of example 7)

8-Amino-7-iodide-1,4-benzodioxan-5-carboxylic acid

A solution of 3-amino-1,4-benzodioxan-5-carboxylic acid (500 mg, 0,0025 m) in AcOH (50 ml) is treated with a solution of chloride of iodine (0,423 g, 0,0026) in AcOH (10 ml). The reaction mixture was stirred at Connaught solid red, which is filtered and washed with water. The output is 0.60,

PMR (250 MHZ) DMSO

: of 7.69 (s, 1H), 5-5,5 (ush., 1H), 4,3 (s, 6H).

Description 2 (intermediate example 6)

8-Amino-6,7-dichloro-1,4-benzodioxan-5-carboxylic acid

8-Amino-1,4-benzodioxan-5-carboxylic acid1(6,14 g 0,029 m) suspended in AcOH (200 ml) and add a solution of C2in AcOH (52 ml of a solution of 9.6 g per 100 ml). The reaction mixture was stirred at room temperature overnight. The solution is distilled off under vacuum, the residue is planted by the water. Planted solid allocate filtration, washed with water and dried to obtain 6.20 g of product.

PMR (250 MHZ) DMSO

: 12,4-12,5 (ush., 1H), 9,3 (ush.s, 1H), 4,35 (s, 4H), 2,07 (s, 3H).

Description 3 (the intermediate product of example 17)

1,4-Benzodioxan-5-carboxamid the oxime

Sodium (determined as 0.720 g, 0,031 mol) is dissolved with stirring in methanol (8 ml). A solution of hydroxylamine hydrochloride (2,18 g 0,031 mol) in methanol (40 ml), then added dropwise. After that, the mixture was stirred at room temperature for 1/2 hour. Next, the reaction mixture is filtered and the filter cake washed with methanol. Then the filtrate is treated with 1,4-benzodioxan-5-nitrile2(2,52 g 0,016 MESI allow to cool and evaporated under vacuum to obtain a brown oily solid. Recrystallization of the residue from methanol gives the title compound in the form of cream-coloured crystals (to 2.57 g), so pl. 147-148oC.

PMR (250 MHZ) DMSO

: 8,42 (s, 1H), 6.75 in-of 6.96 (m, 3H), 5,62 (s, 2H), 4,25 (s, 4H).

Description 4 (Z corresponds to Podgornoe (i), Y = 0)

1-Butyl-4-piperidine methanol

A mixture of ethyl ether isonipecotic acid (31,4 g, 0.2 mol), K2CO3(54 g, 0.4 mol) and n-butylbromide (27.4 g, 0.2 mol) in ethanol (400 ml) is stirred at boiling for 3 hours. Next, the reaction mixture is allowed to cool, filtered through kieselguhr and the filtrate evaporated to obtain a pale yellow oil. The oil was dissolved in dry diethyl ether (200 ml) and added dropwise to a suspension of LiAlH4(20 g, 0.26 mol) in dry diethyl ether. The reaction mixture was stirred at room temperature overnight, and then cooled in an ice bath. Carefully add water (20 ml), then 20% aqueous NaOH solution (20 ml), then water (60 ml). The mixture is stirred at room temperature for 30 minutes, then filtered through diatomaceous earth. The filtrate is evaporated under vacuum to obtain a colorless oil (0.25 g).

TMR 250 MHZ(CDCl3)

: 3,48 (d, 2H), 2,93-2,99 (ush.D., 2H), 1,18-2,4 (m, 14H), and 0.9 (t, 3H).

About get method, see 4 from ethyl ether isonipecotic acid and cyclohexylethylamine.

TMR 250 MHZ(CDCl3)

: 3,48 (d, 2H), 2,84-2,94 (ush.D., 2H), 0,78-2,4 (m, 21H UGT.D., 2H).

Description 6 (Z corresponds to Podgornoe (ii), Y = NH2)

4-Aminomethyl-1-cyclohexylpiperidine

The solution isonicotinamide (7 g, 0,0055 mol) in ethanol (150 ml) is treated with K2CO3(13.8 g, 0.1 mol) and cyclohexylamine (12.4 g, 0.07 mol) and the reaction mixture is boiled for the night. Next, the mixture is allowed to cool, the solid is removed by filtration through kieselguhr and the filtrate evaporated under vacuum to obtain solid pink color (7,3 g). This amide is suspended in dry THF (30 ml) and the suspension is brought to a boil. BH3Me2S (4.8 ml) is added dropwise within 15 minutes, the mixture is then heated to boiling and boiled for 1 hour. Me2S removed from the mixture using a ratio of reflux distilled upper fraction. The mixture is heated continuously during the night, and then the reaction mass is allowed to cool down. 5NHCl (6 ml) is added, after which the reaction mixture is heated to boiling and boiled for the night. Next, the solution is cooled, alkalinized 40% NaOH and extracted with CHC. Drying and evaporation of the races of the sh.D., 2H), by 2.55 (d, 2H), 1,09 (d, 2H), of 0.75 to 1.9 (m, 20H).

Description 7 (Z corresponds to Podgornoe (i), Y is - NH)

4-Aminomethyl-1-butylpiperazine

The title compound is obtained by the method described in description 6, isonipecotamide and butylbromide.

TMR 250 MHZ(CDCl3)

: 2,88-3,0 (ush.D., 2H), 2,56 (d, 2H), 1.18 to 1,95 (m, 15H), to 0.92 (t, 3H).

Description 8 (Z corresponds to the epm Y = NH)

4-Aminomethyl-1-ethylpiperidine

The title compound is obtained by the method described in description 6, isonipecotamide and ethyliodide.

TMR 250 MHZ(CDCl3)

: 2,9-3,0 (ush.D., 2H), 2,56 (d, 2H), 2,48 (D. D., 2H), 1,1-of 1.95 (m, 9H), of 1.05 (t, 3H).

Description 9 (Z corresponds to the epm, Y = O)

N-tert-Butoxycarbonyl-4-hydroxyethylpiperazine

To a suspension of LiAlH4(14, 48mm g) in diethyl ether (200 ml) with stirring, add dropwise a solution of utilisedictated (19.3 ml) in diethyl ether (100 ml) at 0oC under nitrogen atmosphere. Stirring is continued at room temperature overnight. The mixture is cooled and successively added water (14,5 ml), 10% aqueous NaOH (to 21.8 ml) and again water (36.2 ml). The mixture is stirred at room temperature for 1 hour. The precipitate is removed by filtration through kieselguhr and the filtrate evaporated under vacuum, d is the solution of 4-hydroxyethylpiperazine (4.71 g) in 50% aqueous THF. Solid K2CO3add the reaction mixture to achieve a pH of 9, the mixture is stirred at room temperature overnight. The solvent is distilled off under vacuum and the residue versionyou between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried (Na2SO4), filtered and evaporated under vacuum, resulting in a gain of the title compound as a pale yellow solid (6,12 g).

TMR 250 MHZ(CDCl3)

: 4,08-4,2 (ush. D. , 2H), 3,45-3,52 (ush.T., 2H), 2,6-2,78 (m, 2H), 1,58-1,9 (m, 4H), of 1.46 (s, 9H), 1,03-1,22 (m, 2H).

Description 10

EQ. - 2-Hydroxyethylhydrazine get method N. I.Leonard and others (T.Org. Chem, 1957, 22, 1445)

the coding gain. - 3-Hydroxyethylhydrazine get method, Davis and North Shoppe (T. Chem. Soc. 1956, 313).

Description 11 (the intermediate product of example 18)

a) Ethyl-1,3-benzodioxol-4-carboxylate

The method proposed by J. G. Clarke and others (Tetraderon Letters N 38, 3361, 1976), ethyl-2,3-dihydroxybenzoate (4.5 g) is transformed into the title compound (2,21 g, 46%).

TMR 250 MHZ(CDCl3)

: for 7.12 (d, 1H), 6,98 (d, 1H), 6,86 (t, 1H), 6,11 (s, 2H), and 4.40 (q, 2H), 1,4 (t, 3H).

b) 1,3-Benzodioxol-4-carboxylic acid

A solution of ethyl-1,3-benzodiox the ml) and heated to boiling for 30 minutes. After cooling, the reaction mixture is acidified with diluted hydrochloric acid, the precipitate filtered and washed with water to obtain the title compound (D 13) (0.71 g, 84%).

TMR 250 MHZ(d6DMSO)

: 13,01 (ush. S., 1H), 7,29 (d, 1H), 7,13 (d, 1H), 6.90 to (t, 1H), 6,13 (s, 2H).

Description 12 (the intermediate product of example 47)

a) 8-Acetamido-1,4-benzodioxan-5-/4-pyridyl/methyl carboxamide

8-Acetamido-1,4-benzodioxan-5-carboxylic acid (2.5 g) is suspended in acetonitrile (100 ml) and N,N-carbonyldiimidazole (1.7 g) is added to the resulting suspension. The reaction mixture is stirred gently heating under nitrogen atmosphere for 1 hour. The mixture is cooled to room temperature and the solvent evaporated under vacuum. The oil is passed through a layer of silica using as eluent chloroform and ethanol. The oil was dissolved in dichloromethane (100 ml) and treated with 4-(aminomethyl)pyridine (1,17 ml). The resulting mixture is boiled overnight. The solution is cooled to room temperature and the solvent is distilled off under vacuum. The remainder chromatographic on silicon dioxide, elwira a mixture of etano/chloroform, resulting in the pure title compound as a solid (1.47 g).

TMR 250 .

b) 8-Acetamido-1,4-benzodioxan-5-(4-piperidyl)methyl carboxamide

A solution of 8-acetamido-1,4-benzodioxan-5-(4-piperidyl)methyl carboxamide (3.0 g) in acetic acid (200 ml) gidrogenit at a pressure of 50 psi on platinum oxide (IV). After the expiration of 4 hours, the catalyst was removed by filtration through kieselguhr, the filtrate is evaporated under vacuum. The residue is placed in water, alkalinized K2CO3and extracted with chloroform. The organic phase is dried, filtered and evaporated under vacuum, resulting in getting the title compound (2.85 g)

TMR 250 MHZ(CDCl3)

: 8,03 (d, 1H), 7,70-7,80 (m, 2H), 7,55 - 7,63 (m, 1H), 4,35 (m, 4H), 3,24 (t, 2H), 3,10 (d, 2H), 2,59 (t, 2H), 2,12 (s, 3H), 2,09 (ush. S., 1H), 1,68 and 1.80 (m, 3H), 1,11-of 1.29 (m, 2H).

in) 8-Acetamido-7-chloro-1,4-benzodioxan-5-(4-piperidyl)methyl carboxamide

A solution of 8-acetamido-1,4-benzodioxan-5-(4-piperidyl)methyl carboxamide (2,56 g) in acetic acid (100 ml) is treated with a chlorine solution (0.55 g) in acetic acid (18 ml). The reaction mixture was stirred at room temperature overnight. The solvent is distilled under vacuum, resulting in getting the title compound in the form of gum (D12).

TMR 250 MHZ(CD3CD)

: 7,47 (s, 1H), 4,29 - to 4.46 (m, 4H), 3,29 - to 3.49 (m, 4H), 3,01 (t, 2H), 2,12-of 2.21 (m, 3H), of 1.99 (s, 3H), EN-5-/1-pentyl-4-piperidyl/-methyl carboxamide

To a solution of 8-acetamido-7-chloro-1,4-benzodioxan-5-/4-piperidinomethyl/ carboxamide (150 ml) in acetone (15 ml) is added potassium carbonate (100 mg) and 1-bromopentane (60 l). The resulting mixture was stirred at room temperature overnight. The solvent is distilled off under vacuum, the residue chromatographic on silica using chloroform and ethanol as the eluent, resulting in a pure product (D13) (60 mg).

TMR 250 MHZ(CDCl3)

: 7,72-7,79 (s, 1H), 7,55-the 7.65 (m, 1H), 7,21-7,34 (m, 1H), 4,32-4,50 (m, 4H), of 3.45 (t, 2H), 3,03 (d, 2H), 2,43 is 2.55 (t, 2H), 2,15-to 2.29 (m, 3H), 2,01 (t, 2H), 1,21-to 1.82 (m, 11H), of 0.91 (t, 3H).

Description from 14 to 16 (intermediate products for examples 44-46)

Using the method given in description 13 receive the following connections:

8-Acetamido-7-chloro-1,4-benzodioxan-5-(1-cyclohexylethyl-4-piperidyl)methyl carboxamide (D14)

TMR 250 MHZ(CDCl3)

: of 7.70 (s, 1H), 7,47-of 7.55 (m, 2H), 4,30-4,47 (m, 4H), 3.46 in (t, 2H), 3,01 (d, 2H), 2,34 at 2.45 (m, 2H), 2,21 (ush. C., 3H), 1,99 (t, 2H), 1,57-to 1.82 (m, 8H), 1,09-for 1.49 (m, 8H), or 0.83 to 1.00 (m, 2H).

8-Acetamido-7-chloro-1,4-benzodioxan-5-/1-isobutyl-4-piperidyl/methyl carboxamide (D15)

TMR 250 MHZ(CDCl3)

: 7,73 (s, 1H), 7,52-to 7.61 (m, 1H), 7,22-7,32 (m, 1H), 4,32 figure-4.49 (m, 4H), to 3.34 (t, 2H), 2.91 in (d, 2H), 2,18 (ush. C., 3H), 2,10 (d, 2H), 1,52-of 1.97 (m, 6H), 1,25-1,45 (m, 2H), 0,89 (mid (D16)

TMR 250 MHZ(CDCl3)

: of 7.75 (s, 1H), 7,55-the 7.65 (m, 1H), 7,19-7,30 (m, 1H), 4,33-4,51 (m, 4H), to 3.33 (t, 2H), to 3.02 (d, 2H), 2,33 is 2.44 (m, 2H), 2,19 (ush. C., 3H), 2,01 (t, 2H), 1,37-of 1.81 (m, 8H), of 0.90 (d, 6H).

Links:

1. U. K. Patent 1571278.

2. R. C. Fuson, R. Gaertner, A. D. H. chadwick, J. Org. chem. 1948, 13, 489.

Antagonistic activity against 5-HT4receptor

1) the large intestine of the Guinea pig

Use of male Guinea pigs weighing 250-400 g drugs Longitudinal muscle bundles of the inner lining of the intestine length 3 cm (approximately) receive from the distal region of the colon. They are suspended under a load of 0.5 g in isolated bathrooms are medium containing Krebs solution, through which barotiwala 5% CO2in O2, incubated at 37oC. In all experiments, the Krebs solution also contains methiothepin at a concentration of 10-7M and granisetron at a concentration of 10-6M for blocking action on the receptors 5-HT1, 5-HT2and 5-HT3.

After building a simple curve concentration-response with 5-HT at time of contact, is equal to 30 seconds, and a 15-minute dosing cycle, the concentration of 5-HT is chosen so to obtain muscle contraction by approximately 40-70% of the maximum is approximately equieffective concentration of nicotinic receptor stimulus - dimethylphenylpiperazinium (DMPP). After receiving successive responses of 5-HT and DMPP increasing concentrations of the test antagonist of 5-HT4-receptor type in the solution bath. The action of this compound is estimated as the percentage reduction in concentration caused by 5-HT or DMPP. Based on these data to determine the magnitude pIC50represented as the logarithm of the concentration of antagonist that reduces a reduction of 50%. Compound that reduces the response to 5-HT, but not DMPP, as I believe, acts as an antagonist of 5-HT-receptor.

Typically, compounds were active in the area of concentration about pIC50= 7 or more compounds of examples 1, 2, 3, 5, 6, 9, 11, 12, 21, 22, 25, 26, 27, 28, 30, 31, 32, 33, 35, 39, 40, 41, 42, 44, 49, 53 and showed particularly good activity.

2) Atrium pig

Compounds of experience in the protection of spontaneously cutting the pig Atria (Naunyn - Schmiedebergis Arch Pharmacol, 342, 619-622). pKB(-lig 10KBfor compounds of examples 1, 2, 5, 10, 13, 52, 53 and 55 lies in the region from 7 to 10.

3) Esophagus rats

The mucous membrane of the muscle membrane of the esophagus in rats isolated in accordance with methods Baxter and others (Naunyn - Schmiedebergis Arch Pharmacol 343, 439-446, 1991). Internal agenia in the oxidation solution Tyrode (95% O2/5% CO2) at a temperature of 37oC. All experiments are performed on preparations pretreated with pargyline (pargyline) 100 M for 15 minutes followed by rinsing) and in the presence of cocaine (30 M). Reduced response to 5-HT get after first reducing environment of the esophagus Carballo (3 M).

The compound of example 1 operates as a not-surmountable antagonist of 5-MT in the rat esophagus, and as causing a decrease of the maximum response, without significant right shift of the curves of the concentration steps.

4) Mobility, caused by 5-HT in the ventricle of the dog

Join explore experience in vivo by the method described in "Ltimulation of canine motility by BRL 24924, a new gastric prokinetic ogent" by Bermuder et al, F. Gastrointestinal Motility 1990, 2(4), 281-286. The compounds showed inhibition at 10 g/kg, and the connection of experiment 1 showed inhibition at 1 g/kg

Test in vivo on irritable syndrome bowel

In General terms, the method described in F. discrimination, 1958, 141, page 14P-15P.

Male mice (line: CDI; weight ranging from 25 to 35 g) is placed in a high boxes with a hole on the bottom and the top for 20 minutes prior to the introduction of substances. Then animals injected with either control solution, or 5-HTP (10 mg/kg) subcutaneously. Antagonists injected after 5 minutes after centuries the item for 15 minutes (total time = 75 minutes). Value and standard error of the cumulative number of pellets counted.

The compound of example 1 at a dose of 10 g/kg does not change femalee the removal of the pellets compared to the control solution; i.e., the connection does not cause constipation. 5-HTP significantly increases the rate of excretion of the pellets, but at a dose of 10 g/kg causes wetting of the pellets without causing diarrhea.

The dose of a compound of example 1, the dependent affecting 5 HTP applied in a dose of from 0.1 to 1 g/ha, is 1 g/kg 100 g/kg, and the rate of defecation is reduced to a normal level, which is shown in the experiments with the control solution.

Test in vivo on anxiolytic activity

1) Social interaction

Rats (male, Sprague Dawleys, charles Biver weighing 250-300 g) are placed in groups of eight pieces in the room content within 5 days. Then they are placed one by one into the room adjacent to the experimental room and contain within 4 days that precede the day of the experiment. On the day of the experiment rats injected solution connection P1 or benzodiazepine anxiolytic - chlordiazepoxide - subcutaneously in pairs (n = 8-16) with an interval of 15 minutes, starting at 10.00. After 30 minutes they are placed to the weighted sparing-partner (see arachnoi front wall and without a lid, dimensions 54 cm x 36 cm x 26 see Floor is divided into 24 squares and Boxing well enough lit (Suite 115). The behavior of active social interaction (courtship, Obrucheva, climbing over and under, adherence, biting, charge separation) concealed fix in the next 15 minutes, using remote video and still obtaining a General picture of the interaction. The number of squares crossed each rat also noticed and counted. At the end of each experience Boxing carefully wipe.

The compound of example 1 increased the total interaction in doses of 0.001-1.0 mg/kg subcutaneous injection. The results of the counting of movement differed slightly, although the decreasing trend in the movement observed at 10.0 mg/kg (subcutaneously). This result corresponds to the action of anxiolytic.

2) X-labyrinth

X-maze is placed at a height of 50 cm from the floor, it consists of two closed sleeves 45 cm (length) x 10 cm (width) x 10 cm (height) and two open sleeves, arranged in such a way that the two arms of each type were placed opposite each other. Rats are placed in the center of the X-maze and watch them for 5 minutes, during which notice the following indicators: 1) number of prhovo g) closed sleeves; 2) the number of cross-sections. Suppression of fear in open sleeves surpasses fear in closed sleeves, and rats typically show a clear preference for open sleeves closed. Anxiolytic drugs increase the number of traversed inputs, and the time spent on it, the remote parts of the open sleeves, and finished percentage of entries and time spent in General, all open sleeves. These four dimensions of fear, as well as the total number of cells crossed by the rats, calculated for each animal.

In doses of from 0.01 to 1.0 mg/kg (subcutaneously) compound of example 1 increases the dimension of fear (the time taken to open the sleeve, the passage to the open end of the sleeve, % time on open arm and % of inputs into the open sleeve) without affecting movement within a 5-minute period. Most significantly changed is the % of time on the open sleeve. This picture, follow anxiolysis and confirmed positive control hlordiazepoksida (5 mg/kg subcutaneously).

1. Heterocyclic compound of the formula I and its pharmaceutically acceptable salt

< / BR>
where X1- (CH2)x- X2form a 5-7 membered cycle;

X1- ON;

X what kind amino group, halogen atom;

R2is a hydrogen atom or halogen;

R3is a hydrogen atom or halogen;

R4and R5is a hydrogen atom;

Y is O or NH;

Z is a group of the formula

< / BR>
where R1a- C1- C12-alkyl or benzyl, unsubstituted or substituted by a halogen atom or C1- C6-alkoxygroup.

2. Connection on p. 1, where R1is a hydrogen atom or amino group.

3. Connection under item 1 or 2, where R2is a hydrogen atom or a halogen.

4. Connection PP.1, 2 or 3, where R3is a hydrogen atom or a halogen.

5. The compound according to any one of paragraphs.1 to 4, where diametrical X1-(CH2)x-X2is a group O-(CH2)2-O,O-(CH2)3-O,O-CH2-O, -O-(CH2)2-NR or O-CH2CONR, or substituted R4and R5methyl group and a represents a group of formula O-C-(CH3)2-O.

6. Connection on p. 5, where disabilities is a group O-(CH2)2-O.

7. The compound according to any one of paragraphs.1 - 6, where Y = NH.

8. The compound according to any one of paragraphs.1 to 7, where R1ais cyclohexylmethyl.

9. Connection PP.1 to 7, where R1is possessing a n-butyl.

11. Connection PP. 1 to 7, where R1arepresents benzyl, unsubstituted or substituted by a halogen atom, and C1- C6-alkoxygroup.

12. The compound of formula I and its pharmaceutically acceptable salt PP.1 - 10 with the properties of antagonists of the receptor 5-HT4.

13. Connection on p. 1, selected from the group which includes:

7-bromo-5-(1-butyl-4-piperidyl)methyl-1,4-benzodioxan-5-carboxylate,

(1-butyl-4-piperidyl)methyl-1,4-benzodioxan-5-carboxylate, (1-butyl-4-piperidyl)methyl-6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-8-carboxylate, (1-butyl-4-piperidyl)methyl-6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-8-carboxylate, (1-butyl-4-piperidyl)methyl-6-chloro-3,4-dihydro-2H-1,4-benzoxazin-8-carboxylate, 8-amino-7-chloro-5-(1-methyl-4-piperidinylmethyl)-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-ethyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-propyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-undecyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-dodecyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-(4-terbisil)-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-(4-methoxybenzyl)-4-piperidyl)IU which-amino-7-chloro-1,4-benzodioxan-5-(1-pentyl-4-piperidyl)methyl carboxamide,

8-amino-7-chloro-1,4-benzodioxan-5-(1-isobutyl-4-piperidyl)methyl carboxamide,

8-amino-7-chloro-1,4-benzodioxan-5-(1-(2-methylbutyl)-4-piperidyl)methyl carboxamide,

8-amino-7-chloro-1,4-benzodioxan-5-(1-methyl-4-piperidyl)methyl carboxamide, 8-amino-7-chloro-(1-isobutyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-cyclopropylmethyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-pentyl-4-piperidinyl)methyl-1,1-benzodioxan carboxylate, 8-amino-7-chloro-5-(2-methylbutyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-benzyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-hexyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-heptane-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-octyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-nonyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-5-(1-decyl-4-piperidyl)methyl-1,4-benzodioxan carboxylate, 8-amino-7-chloro-1,3-benzodioxan-5-(1-n-propyl-4-piperidyl)methyl carboxamide,

8-amino-7-chloro-1,4-benzodioxan-5-(1-benzyl-4-piperidyl)methyl carboxamide, 8-amino-7-iodine-1,4-benzodioxan-5-(1-butyl-4-piperidyl)methyl carboxylate, (1-butyl-4-piperidyl)methyl-8-chloro-1,4-benzodioxan-5 is)methyl-1,4-benzodioxan-5-carboxylate, 8-amino-(1-butyl-4-piperidyl)methyl-1,4-benzodioxan-5-carboxylate, 7-chloro-(1-butyl-4-piperidyl)methyl-1,4-benzodioxan-5-carboxylate, 8-amino-6,7-dichloro-(1-butyl-4-piperidyl)methyl-1,4-benzodioxan-5-carboxylate, 8-amino-7-iodine-(1-cyclohexylmethyl-4-piperidyl)-1,4-benzodioxan-5-carboxylate, 8-amino-7-chloro-(1-cyclohexylmethyl-4-piperidyl)methyl-1,4-benzodioxan-5-carboxylate, 8-amino-7-chloro-(1-ethyl-4-piperidyl)methyl-1,4-benzodioxan-5-carboxamide, 8-amino-7-chloro-(1-butyl-4-piperidyl)methyl-1,4-benzodioxan-5-carboxamide, 8-amino-7-chloro-(1-cyclohexylmethyl-4-piperidyl)methyl-1,4-benzodioxan-5-carboxamide.

14. The method of obtaining the compounds of formula I on p. 1, characterized in that it includes the interaction of the compounds of formula II or its reactive derivative

< / BR>
where X1-(CH2)x-X2, R1, R2, R3, R4and R5defined under item 1,

with the compound of the formula

HDZ or H2NZ,

where Z has the meanings given in paragraph 1.

15. The pharmaceutical composition exhibiting antagonistic activity against T4receptors comprising an effective amount of the compounds of formula I according to any one of paragraphs.1 to 12 and a pharmaceutically acceptable carrier.

 

Same patents:

The invention relates to new chemical compounds with valuable properties, in particular to derive hinolan and naphthyridinone acid of General formula

< / BR>
in which

A is CH, CF, CCl, C-OCH3C-CH3N;

X1hydrogen, halogen, NH2CH3;

R1alkyl containing 1 to 3 carbon atoms, FCH2CH2- cyclopropyl, phenyl, which can be from one to three times substituted by halogen, or

A and R1together can mean the bridge structure C-O-CH2-CH(CH)3,

R2hydrogen, not substituted or substituted by a hydroxy-group, halogen or amino alkyl containing 1 to 3 carbon atoms, or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl;

B balance formulas

< / BR>
where

Y is O or CH2;

R3oxaalkyl containing 2 to 5 carbon atoms, CH2-CO-C6H5CH2CH2CO2R', R O2C-CH=-CO2R', -CH=CH-CO2R' or CH2CH2-CN, where R' denotes hydrogen or alkyl containing 1 to 3 carbon atoms;

R4hydrogen, alkyl containing 1 to 3 carbon atoms, окMG SRC="http://www.fips.ru/fullimg2/rupat3/19981/010.dwl/2105770-6t.gif" ALIGN="ABSMIDDLE">CH=CH-CO2-R' or CH2CH2-CN or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, where R' denotes hydrogen or alkyl containing 1 to 3 carbon atom,

in the form of mixtures of isomers or individual isomers, pharmaceutically applicable hydrates and salts, for example acid additive salts and alkaline, alkaline earth, silver and guanidinium salts of the corresponding carboxylic acids

The invention relates to pharmaceutically active bicyclic heterocyclic amines (XXX) and can be used as pharmaceuticals for the treatment of diseases and injuries

The invention relates to new Amida 4 - oxoazetidin-2-sulphonic acids and their salts, to a process of obtaining

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to a method for producing derivatives taxane General formula (I) by esterification of protected baccatin III or protected 10-desacetyl-baccatin III using the acid of General formula (II)

The invention relates to a new method of obtaining derivatives taxane General formula

< / BR>
which have valuable protivoanemicakimi and antitumor properties

The invention relates to endothelin antagonists, used inter alia for the treatment of hypertension

The invention relates to novel 1,2,4-oxalatotetraaminecobalt, to the way they are received, to the containing compositions and methods for their use as antiviral agents

The invention relates to vasoconstrictor /(benzodioxan, benzofuran and benzopyran)-alkylamino/-alkyl-substituted guanidine formula I, their pharmaceutically acceptable salts, or their stereochemical isomers, where X = O, CH2or a direct bond; R1= H, C1-C4alkyl, R2= H, C1-C6alkyl, C3-C6alkenyl, C3-C6quinil, R3= H, C1-C4alkyl; or R2and R1taken together, may form a bivalent radical of the formula/CH2/m-, where m = 4 or 5; or R1and R2taken together may form a bivalent radical of formula-CH=CH -, or the formula/CH2/n-, where n = 2, 3 or 4; or R3may indicate a relationship when R1and R2taken together form a bivalent radical of formula-CH=CH-CH= -, -CH= CH-N= or-CH=N-CH=; where one or two hydrogen atom substituted by a halogen atom, a C1-C6alkoxygroup, C1-C6the alkyl, CN, NH, mono - or di(C1-C6alkyl) amino group, aminocarbonyl, C1-C6alkylaminocarbonyl, R4-H or C1-C6-alkyl; Alk1denotes a divalent C1-C3-ascandilwy radical, A denotes dwuhvalentny a radical of the formula /, lk2represents C2-C15-alcander or C5-C7-cycloalkenyl, and each "R" represents 0, 1, 2, R7and R8each independently is H, a halogen atom, a C1-C6by alkyl, hydroxyl, C1-C6allyloxycarbonyl, C1-C6alkoxygroup, cyano, amino, C1-C6the alkyl, carboxyla, nitro or amino group, aminocarbonyl, C1-C6alkylcarboxylic or mono - or di-(C1-C6)alkylamino, provided that excluded /2-/ (2,3-dihydro-1,4-benzodioxin-2-yl)-methyl/-amino/-ethyl-guanidine

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to new derivatives of hinoklidilkarbinola General formula where n is an integer 1, 2, 3, R1-halogen or trihalomethyl, R2is hydrogen, R3-furanyl, tetrahydrofuranyl, DIOXOLANYL, pyranyl, tetrahydropyranyl, optionally substituted by 1, 2 or 3 substituents selected from the group comprising oxoprop and C1-C3-alkyl

The invention relates to new derivatives of N-(3-hydroxy-4-piperidinyl) (dihydro-2H-benzopyran or dihydrobenzoic) carboxamide, having valuable pharmaceutical properties, namely activity to stimulate gastrointestinal peristalsis
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