RU2110517C1 - N,n-dimethyl-2-(5-(2-oxo-1,3-oxazolidine-4-yl-methyl)-1h-indo- -le-3-yl)-ethylamine, its physiologically acceptable salt or solvate, method of its synthesis, drug used as an agonist of "5-ht1-like" receptor in mammals, method of drug agent preparing - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: N,N-dimethyl-2-[5-(2-oxo-1,3-oxazolidine-4-yl-methyl)-1H-indo- -le-3-yl] -ethylamine of the formula (I) HT•001 as its (S)- or (R)-form or their mixture or its physiologically acceptable salt or solvate. Method of synthesis involves interaction of compound of the formula (II) HT₁ with compound of the formula (III) or its carbonyl-protected form where L - suitable group that can be removed or protective amino-group that under conditions in situ can be converted to dimethylamino-group, or group

where

and -NR¹R², - methyl. Invention proposes a drug agent containing an effective amount of compound (I) R¹, method of its preparing, prophylaxis and treatment of mammals required for intake of agonist of "5-R²-like" receptor by administration of compound (I) -HT₁- in mammal organism at the dose 0.01-5 mg/kg body weight as measured for free base. In part, proposed drug can be used for migraine treatment. EFFECT: improved method of synthesis, enhanced effectiveness of prophylaxis and treatment. 14 cl

Description

 The invention relates to new chemical compounds, their preparation, pharmaceutical compositions containing them, and use in medicine, in particular the prevention and treatment of migraine.

Receptors that mediate 5-hydroxytryptamine (5-HT) actions have been identified in mammals both in the periphery and in the brain. According to the classification and nomenclature proposed in a recent article (Bradleyetat. Neuropharmac, 25, 563 (1986)), these receptors can be classified in three main types, namely, “5-HT ₁ -like”, 5-HT ₂ and 5 -HT ₃ . Various classes of compounds have been proposed as 5-HT agonists (substances having an affinity for the receptor) or antagonists for therapeutic use, but they are not always specific for a particular type of 5-HT receptor. European patent specification 0313397 describes a class of 5-HT agonists that are specific for a particular type of 5-HT ₁ -like receptor and are effective drugs for treating clinical conditions in which a selective agonist for this type of receptor is indicative (required) . For example, the receptor in question is an intermediate link (mediates in) vasoconstriction (narrowing of blood vessels) in the carotid vascular bed and thereby measures blood flow in it. Therefore, the compounds described in the description of the invention of the European patent are beneficial in the treatment or prevention of conditions in which vasoconstriction in the carotid vascular bed is indicative (required), for example, migraine, a condition associated with excessive dilatation (expansion) of the carotid vasculature. However, within the scope of the early application is that the “target tissue” can be any tissue in which the action binds to the mediation of “5-HT ₁ -like” receptors of the type mentioned above.

We have now discovered an additional class of compounds with unusual agonism for “5-HT ₁ -like” receptors and excellent absorption (absorption) after an oral dose. These properties make the compounds particularly useful for certain medicinal applications, especially the prevention and treatment of migraine, histamine headache and headache associated with vascular disorders, hereinafter collectively referred to as "migraine".

в которой
n является целым числом от 0 до 3;
w является группой формулой (i), (ii) или (iii)
Группы формул (i), (ii) и (iii)

в которой R является водородом, или C_1-4 алкилом, X является -O-, -S-, -NH- или -CH₂-, W является кислородом или серой, а хиральный центр ^* в формуле (i) или (ii) находится в своей (S)- или (R)-форме или является их смесью в любых пропорциях, а
Z является группой формулы (iv), (v) или (vi)
Группа формул

в которой R¹ и R² независимо выбираются из водорода и C_1-4 алкила, а R³ является водородом или C_1-4-алкилом, и соли, сольваты и физиологически функциональные производные его. Соединения формулы (I), имеющие особенно желательные свойства для лечения и профилактики мигрени, включают соединения, в которых n является 1, W является группой формулы (i), а Z является группой формулы (iv) или (vi). Из них особенно предпочтительными являются соединения формулы (I), в которой n является 1, W является группой формулы (I), в которой R является водородом, X является -O-, а Y является кислородом и Z является группой формулы (iv) или (vi), в которой R¹=R²=водород или метил.Therefore, according to a first aspect of the present invention, there is provided a compound of formula (I)
Formula (I) on p. 2

wherein
n is an integer from 0 to 3;
w is a group of formula (i), (ii) or (iii)
Groups of formulas (i), (ii) and (iii)

in which R is hydrogen, or C _1-4 alkyl, X is —O—, —S—, —NH— or —CH ₂ -, W is oxygen or sulfur, and the chiral center ^* in formula (i) or (ii ) is in its (S) - or (R) -form or is a mixture of them in any proportions, and
Z is a group of formula (iv), (v) or (vi)
Group of formulas

in which R ¹ and R ^{2 are} independently selected from hydrogen and C _1-4 alkyl, and R ³ is hydrogen or C _1-4 alkyl, and salts, solvates and physiologically functional derivatives thereof. Compounds of formula (I) having particularly desirable properties for the treatment and prevention of migraine include compounds in which n is 1, W is a group of formula (i), and Z is a group of formula (iv) or (vi). Of these, compounds of formula (I) in which n is 1 are particularly preferred, W is a group of formula (I) in which R is hydrogen, X is —O— and Y is oxygen and Z is a group of formula (iv) or (vi) in which R ¹ = R ² = hydrogen or methyl.

 Two compounds of formula (I) having exceptional properties for the treatment and prevention of migraine are N, N-dimethyl-2- [5- (2-oxo-1,3-oxazolidin-4-yl-methyl) -1H-indole- 3-yl] ethylamine and 3- (1-methyl-4-piperidyl) -5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indole either in their (S) - or (R ) -form, or as a mixture of them in any ratio. Salts and solvates of these compounds, for example, maleate hydrates, are particularly preferred.

 Physiologically acceptable salts are especially suitable for medicinal use because of their higher solubility in water compared to related ones, i.e. basic compounds. Such salts should definitely have a physiologically acceptable anion. Suitable physiologically acceptable salts of the compounds of the present invention include salts derived from acetic, hydrochloric, hydrobromic, phosphoric, malic, maleic, fumaric, citric, sulfuric, lactic or tartaric acids. Succinate or chloride salts are especially preferred for medicinal purposes. Salts having a physiologically unacceptable anion are within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and / or for use in non-therapeutic, for example, in vitro (in a laboratory vessel) situations.

According to a second aspect of the present invention, there is provided a compound of formula (I) or a physiologically acceptable salt, solvate or physiologically functional derivative thereof for use as a therapeutic agent, in particular as an agonist for a “5-HT ₁ -like” receptor, for example, as a carotid vasocostrictor in the prevention and treatment of migraine. However, as shown, the "target organs" for the presented compounds, in addition to the carotid vasculature, are within the scope of the present invention.

 The amount of a compound of formula (I) or a salt or solvate thereof that is required to achieve an appropriate biological effect depends on a number of factors, such as the particular compound, the use for which it is intended, the methods of use and the recipient. A typical daily dose for the treatment of migraine, as you can assume, lies in the range from 0.01 to 5 mg per kg of live weight. Unit doses may contain from 1 to 100 mg of the compound of formula (I), for example, ampoules for injection may contain from 1 to 10 mg, and orally administered unit dosage forms, such as tablets or capsules, may contain from 1 to 100 mg. Such unit doses may be applied one or more times a day, alone or in formulations thereof. The intravenous dose is believed to be in the range of 0.01 to 0.15 mg / kg and is usually administered as an infusion of 0.0003 to 0.15 mg per kg per minute. Infusion solutions suitable for this purpose may contain from 0.01 to 10 mg / ml.

 When the active compound is a salt or solvate of a compound of formula (I), the dose is based on a cation (for salts) or an unsolvated compound.

 Further references to “compound (s) of formula (I)” are intended to include physiologically acceptable salts and solvates thereof.

According to a third aspect of the present invention, pharmaceutical compositions are therefore provided comprising, as an active ingredient, at least one compound of formula (I) and / or a pharmacologically acceptable salt or solvate thereof together with at least one pharmaceutical carrier or excipient. These pharmaceutical compositions can be used in the prophylaxis or treatment of clinical conditions for which an agonist for the 5-HT ₁ -like receptor is indicative of, for example, migraine. The carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a harmful effect (on) other (e) ingredients (s) in the composition. The carrier may be solid or liquid, and is preferably included with at least one compound of formula (I) in unit dosage form, for example, a tablet, which may contain from 0.05 to 95% by weight of the active ingredient. If desired, other physiologically active ingredients may also be incorporated into the pharmaceutical compositions of the invention.

 Possible dosage forms include those suitable for oral, sublingual, buccal (intraoral), parenteral (e.g., subcutaneous, intramuscular or intravenous), rectal, external and intranasal (intranasal) use. The most suitable route of administration for a particular patient depends on the nature and severity of the condition to be treated and on the nature of the active compound, but where possible, oral administration is preferred.

 Dosage forms suitable for oral administration can be formulated as separate dosage forms, such as tablets, capsules, starch capsules or lozenges, each containing a predetermined amount of the active compound, in the form of powders or granules, in the form of solutions or suspensions in aqueous or non-aqueous liquids or in the form of emulsions such as oil in water or water in oil.

 Dosage forms suitable for sublingual or buccal administration include lozenges containing the active compound and usually a flavoring and aromatic base such as sugar and acacia or tragacanth and pastilles containing the active compound in an inert basis such as gelatin and glycerin or sucrose and acacia.

 Dosage forms suitable for parenteral administration usually include sterile aqueous solutions containing a predetermined concentration of the active compound, the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intravenously, they can also be administered by subcutaneous or intramuscular injection.

 Dosage forms suitable for rectal administration are preferably formulated as unit dose suppositories comprising the active ingredient and one or more solid carriers which form the basis for the suppository, for example cocoa butter.

 Dosage forms suitable for external or intranasal use include ointments, creams, lotions, pastes, gels, aerosols and oils. Suitable carriers for such dosage forms are petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof. The active ingredient is usually contained in such dosage forms at a concentration of from 0.1 to 15 wt.%.

 Dosage forms of the invention can be prepared by any suitable method, usually by uniformly and uniformly mixing the active compound (s) with liquid or finely ground solid carriers, or with both carriers, in the required proportions, and then, if necessary, molding the resulting mixtures in the target form.

 For example, a tablet may be prepared by compressing a homogeneous mixture comprising a powder or granules of an active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent or surfactant dispersant, or by molding a homogeneous mixture of a powdered active ingredient and an inert liquid diluent.

 Parenteral aqueous solutions are usually prepared by dissolving the active compound in a sufficient amount of water to obtain the desired concentration, and then converting the resulting solution into a sterile and isotonic solution.

Thus, according to a fourth aspect of the present invention, there is provided the use of a compound of formula (I) in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which an agonist for a “5-HT ₁ -like” receptor, for example, migraine, is indicated.

According to a fifth aspect of the invention, there is provided a method for the prophylaxis or treatment of a clinical condition in mammals, for example, humans, for which an agonist for a “5-HT ₁ -like” receptor, for example, migraine, is shown, which (method) comprises administering to said mammal a therapeutically effective amount of a compound of the formula (I) or a physiologically acceptable salt, solvate or physiologically functional derivative thereof.

 According to a sixth aspect of the invention, compounds of formula (I) in which Z is formula (iv) can be prepared by reacting a compound of formula (II) (isolated or in situ (see) - see below).

в которой n и w имеют определенные выше значения, с соединением формулы (III)

или с карбонил-замещенной формой его, такой как диметил- или диэтил-ацеталем, в которой L является подходящей уходящей группой, такой как хлор, или замещенной амино-группой, любая из которых может быть превращена ин ситу в амино-группу или является группой - NR¹R², где R¹ и R² имеют определенные выше значения. Реакция обычно проводится кипячением с обратным холодильником соединений в системе полярных растворителей, например, этанол/вода, разбавленная уксусная кислота или вода в присутствии кислотной ионообменной смолы, например "Амберлита 15".Formula (II)

in which n and w are as defined above, with a compound of formula (III)

or with a carbonyl substituted form thereof, such as dimethyl or diethyl acetal, in which L is a suitable leaving group, such as chlorine, or a substituted amino group, any of which can be converted into an amino group or is a group - NR ¹ R ² where R ¹ and R ² are as defined above. The reaction is usually carried out by refluxing the compounds in a polar solvent system, for example, ethanol / water, diluted acetic acid or water in the presence of an acidic ion exchange resin, for example, Amberlite 15.

Standard N-alkylation methods can be used to convert compounds of formula (I) in which Z is a group of formula (iv) and R ¹ and / or R ² are hydrogen, into the corresponding compounds in which R ¹ and / or R ² are C _1-4 alkyl.

Compounds of formula (I) in which Z = (iv) and R ¹ = R ² = C _1-4 -alkyl can be obtained from the corresponding compound in which R ¹ = R ² = H, using methods N, N-dialkylations well known to those skilled in the art, for example, by treatment with the appropriate aldehyde in the presence of a reducing system, for example, sodium cyanoborohydride / acetic acid, in a polar solvent such as methanol.

The compounds of formula (I) in which Z = (iv) and R ¹ mlm R ² = C _1-4 -alkyl can be obtained from the corresponding compound in which R ¹ = R ² = H, by N-benzylation, using benzaldehyde and a suitable reducing agent, for example sodium borohydride, in a polar solvent such as ethanol followed by N-alkylation using a suitable agent such as the corresponding dialkyl sulfate, usually in the presence of a base, for example, anhydrous potassium carbonate, in a polar aprotic solvent such as DMF, and finally, N-debenzylation, usually Uteem catalytic hydrogenation using e.g., Pd / C in a polar solvent such as ethanol.

в которой n и w имеют определенные выше значения, путем диазотирования, за которым следует восстановление. Диазотирование обычно проводят путем использования нитрита натрия / концентрированная HCl и получающееся диазо-соединение восстанавливают ин ситу, используя, например, хлорид олова (II) / концентрированная HCl. Получающийся гидразин может быть выделен или превращен в соединение формулы (I) ин ситу.Hydrazines of formula (II) can be obtained from the corresponding aniline of formula (IV)
Formula (IV)

in which n and w are as defined above, by diazotization, followed by recovery. Diazotization is usually carried out using sodium nitrite / concentrated HCl and the resulting diazo compound is reduced in situ using, for example, tin (II) chloride / concentrated HCl. The resulting hydrazine can be isolated or converted into a compound of formula (I) in situ.

в которой n и W имеют определенные выше значения, обычно путем каталитического гидрирования, используя, например, Pd/C в системе полярных растворителей, такой как подкисленная смесь этанола, воды и этилацетата.Anilines of formula (IV) can be prepared by reducing the corresponding para-nitro compound of formula (V)
Formula (V)

in which n and W are as defined above, usually by catalytic hydrogenation, using, for example, Pd / C in a polar solvent system such as an acidified mixture of ethanol, water and ethyl acetate.

или (XXXIV)
Формула (XXXIV)

в которых n и X имеют определенные выше значения, а R⁴ является группой -COOR⁵, где R⁵ является C_1-4-алкилом, обычно путем нагревания в присутствии основания, такого как метоксид натрия.Anilines of the formula (IV) in which W is a group of the formula (i) or (ii) can also be obtained by cyclization of a compound of the formula (XXXIII)
Formula (XXXIII)

or (XXXIV)
Formula (XXXIV)

in which n and X are as defined above, and R ⁴ is a —COOR ⁵ group, where R ⁵ is C _1-4 alkyl, usually by heating in the presence of a base such as sodium methoxide.

Compounds of formula (XXXIII), where X is oxygen, can be prepared by reducing the corresponding C _1-4 alkyl ester using, for example, sodium borohydride in a polar solvent system such as ethanol / water at 0 ^° C. The ester can be obtained by esterification of the corresponding carboxylic acid, using, for example, the corresponding alcohol and / or by reducing the corresponding para-nitro compound, for example, by catalytic hydrogenation. Both the acid and the para-nitro compound can be obtained from the corresponding para-nitro amino acid, the acid by N-alkoxycarbonylation using, for example, R ⁵ OCOCl, where R ⁵ has the meanings given above, followed by reduction of the nitro group, for example, by catalytic hydrogenation or by reduction of the nitro group, followed by N-alkoxycarbonylation, and the para-nitro compound by N-alkoxycarbonylation (with respect to acid), followed by esterification, using, for example, the appropriate Peart and HCl, or by esterification followed by N-alkoxycarbonylation. p-Nitroamino acid can be obtained commercially or obtained from readily available starting materials according to methods known to those skilled in the art or obtained from the chemical literature, for example, by para-nitration of the corresponding amino acid using, for example, concentrated H ₂ SO ₄ / concentrated HNO ₃ at 0 ^o C.

Compounds of formula (XXXIV) in which X is oxygen can be prepared by reducing the corresponding dinitro compound, usually by catalytic hydrogenation, using, for example, Pd / C in a polar solvent such as ethanol. A dinitro compound can be prepared by reacting the corresponding aldehyde with nitromethane, usually in the presence of a base, for example sodium methoxide, in a polar solvent such as methanol, followed by para-nitration, using, for example, concentrated H ₂ SO ₄ / concentrated HNO ₃ or para-nitration of the corresponding aldehyde, followed by a reaction with nitromethane. The aldehyde can be obtained commercially or obtained from readily available starting materials according to methods known to specialists in this field of technology, or obtained from the chemical literature.

в которой n, R и X имеют определенные выше значения, с соединением формулы (VII)

в которой Y имеет определенные выше значения, а L и L' которые могут быть одинаковыми или различными, являются подходящими уходящими группами, например, хлором, этокси, трихлорметилом, трихлорметокси-группой или имидазолилом, например, в случае когда L=L'-хлор, в неполярном растворителе, таком как толуол, в присутствии основания, например, гидроокиси калия;
б) в случае, когда W является группой формулы (ii), в которой Y является кислородом или серой, реакцией соединения формулы (VIII)
Формула (VIII)

в которой n, R и X имеют определенные выше значения, с соединением формулы (VII), в которой Y, L, L' имеют определенные выше значения, используя обычно условия реакции, описанные в (a);
b) в случае, когда W является группой формулы (iii), реакцией соединения формулы (IX)
Формула (IX)

в которой R имеет определенные выше значения, с соединением формулы (X).para-Nitro compounds of formula (V) can be prepared:
a) in the case where W is a group of formula (i) in which Y is oxygen or sulfur, by reaction of a compound of formula (VI)
Formula (VI)

in which n, R and X are as defined above, with a compound of formula (VII)

in which Y has the meanings defined above, and L and L 'which may be the same or different, are suitable leaving groups, for example, chlorine, ethoxy, trichloromethyl, trichloromethoxy or imidazolyl, for example, in the case where L = L'-chlorine , in a non-polar solvent, such as toluene, in the presence of a base, for example potassium hydroxide;
b) in the case where W is a group of formula (ii) in which Y is oxygen or sulfur, by the reaction of a compound of formula (VIII)
Formula (VIII)

in which n, R and X are as defined above, with a compound of formula (VII), in which Y, L, L 'are as defined above, usually using the reaction conditions described in (a);
b) in the case where W is a group of formula (iii), by reacting a compound of formula (IX)
Formula (IX)

in which R has the meanings defined above, with a compound of formula (X).

в которой R имеет определенные выше значения, обычно в полярном апротонном растворителе, таком как ДМФА, в присутствии диэтилового эфира азодикарбоновой кислоты и Ph₃P (ДЭАД/Ph₃P).Formula (X)

in which R is as defined above, usually in a polar aprotic solvent such as DMF, in the presence of diethyl ether of azodicarboxylic acid and Ph ₃ P (DEAD / Ph ₃ P).

 Compounds of formula (VI) can be prepared by a ring opening reaction of a compound of formula (V) in which n is as defined above and W is a group of formula (i) in which R, X and Y are as defined above, for example, by boiling under reflux in 2 N aqueous KOH.

Compounds of formula (VI) in which X is oxygen can be prepared by esterification of the corresponding carboxylic acid, usually by treatment with thionyl chloride and the corresponding alcohol at -10 ^° C, followed by reduction of the ester using, for example, sodium borohydride in the system polar solvents such as ethanol / water, at 0 ^o C. The acid may be obtained commercially or prepared from readily available starting materials by methods known to those skilled in the art or obtainable from the chemical iteratury, for example, by p-nitration of the corresponding aminoacid using, e.g., concentrated H ₂ SO ₄ / HNO ₃ conc at 0 ^o C.

 Compounds of formula (VIII) can be prepared by a ring opening reaction of a compound of formula (V) in which n is as defined above and W is a group of formula (ii) in which R, X and Y are as defined above, for example, by boiling with reflux in 2N aqueous KOH.

 The compounds of formulas (III), (VII), (IX) and (X) can be obtained commercially or obtained from readily available starting materials by methods known to those skilled in the art or obtained from the chemical literature.

 para-Nitro compounds of formula (V) in which W is a group of formula (i) and (ii) can also be prepared by para-nitration of a compound of formula (XXXVI).

в которой n и W имеют определенные выше значения, используя, например, концентрированную H₂SO₄/концентрированную HNO₃ при 0^oC.Formula (XXXVI)

in which n and W are as defined above, using, for example, concentrated H ₂ SO ₄ / concentrated HNO ₃ at 0 ^o C.

 Compounds of formula (XXXVI) can be prepared by reaction of a compound of formula (XXXVII).

или ((XXXVIII)
Формула (XXXVIII)

в которой n, R и X имеют определенные выше значения с соединением формулы (VII), в которой Y, L и L' имеют определенные выше значения, обычно в присутствии основания, например, гидроокиси калия в неполярном растворителе, таком как толуол.Formula (XXXVII)

or ((XXXVIII)
Formula (XXXVIII)

in which n, R and X are as defined above with a compound of formula (VII), in which Y, L and L 'are as defined above, usually in the presence of a base, for example, potassium hydroxide in a non-polar solvent such as toluene.

 Compounds of formulas (XXXVII) and (XXXVIII) can be prepared by reduction of the corresponding nitro compounds, usually by catalytic hydrogenation, using, for example, Pd / C in a polar solvent such as ethanol. A nitro compound corresponding to a compound of formula (XXXVII) can be prepared by reacting a compound of formula (XXIV).

в которой n имеет определенные выше значения, с пара-формальдегидом в полярном апротонном растворителе, таком как ДМФА, в присутствии основания, например, метоксида натрия, при 0^oC, или этерификацией соответствующей карбоновой кислоты, обычно обработкой с хлористым тионилом и соответствующим спиртом при -10^oC, за которой следует восстановление сложноэфирной группы, используя, например, борогидрид натрия, в системе полярных растворителей, такой как этанол/вода, при 0^oC. Нитро-соединение, соответствующее соединению формулы (XXXVIII), может быть получено реакцией соответствующего альдегида с нитрометаном, обычно в присутствии основания, например, метоксида натрия, в полярном растворителе, таком как метанол. Соединение формулы (XXIV), кислота и альдегид могут быть получены коммерческим путем или получены из легко доступных исходных веществ по методам, известным специалистам в данной области техники или получаемым их химической литературы.Formula (XXIV)

in which n is as defined above, with para-formaldehyde in a polar aprotic solvent such as DMF, in the presence of a base, for example sodium methoxide, at 0 ^° C, or by esterification of the corresponding carboxylic acid, usually by treatment with thionyl chloride and the corresponding alcohol at -10 ^o C, followed by reduction of the ester group using, for example, sodium borohydride, in a polar solvent system such as ethanol / water, at 0 ^o C. Nitro-compound corresponding to the compound of formula (XXXVIII), n may be lucheno reacting the appropriate aldehyde with nitromethane, typically in the presence of a base, for example sodium methoxide, in a polar solvent such as methanol. The compound of formula (XXIV), acid and aldehyde can be obtained commercially or obtained from readily available starting materials by methods known to specialists in this field of technology or obtained from their chemical literature.

para-Nitro compounds of formula (V) in which W is a group of formula (i), (ii) and (iii) in which R is C _1-4 alkyl can be prepared from the corresponding compound of formula (V), in which R is hydrogen, by N-alkylation using a suitable reagent, such as the corresponding dialkyl sulfate, usually in the presence of a base, for example sodium hydride, in a non-polar solvent such as THF.

 Compounds of formula (I) in which W is a group of formula (i) or (ii) can also be prepared by reaction of a compound of formula (XV).

или (XXV)
Формула (XXV)

в которой n, R, X и Z имеют определенные выше значения, с соединением формулы (VII), в которой Y, L и L' имеют определенные выше значения, например, в случае, когда L = L' этокси, путем нагревания в присутствии основания, например, карбоната калия.Formula (XV)

or (xxv)
Formula (XXV)

in which n, R, X and Z are as defined above, with a compound of formula (VII), in which Y, L and L 'are as defined above, for example, in the case where L = L' is ethoxy, by heating in the presence of bases, for example, potassium carbonate.

 Compounds of formula (XV) can be prepared by a ring opening reaction of a compound of formula (I) in which n and Z are as defined above and W is a group of formula (i) in which R, X and Y are as defined above, for example, by refluxing in 2N aqueous KOH.

Compounds of formula (XV) in which X is oxygen can be prepared by esterification of the corresponding carboxylic acid, usually by treatment with thionyl chloride and the corresponding alcohol at -10 ^° C, followed by reduction of the ester using, for example, sodium borohydride in the system polar solvents, such as ethanol-water, at 0 ^° C. The acid can be obtained by a ring opening reaction of a compound of formula (XVI).

в которой n, R и Z имеют определенные выше значения, а R⁶ является водородом или бензилом, обычно путем кипячения с обратным холодильником в воде в присутствии основания, например, гидроокиси бария.Formula (XVI)

in which n, R and Z are as defined above, and R ⁶ is hydrogen or benzyl, usually by boiling under reflux in water in the presence of a base, for example, barium hydroxide.

в которой n, R, R⁶ и Z имеют определенные выше значения, обычно путем каталитического гидрирования, используя, например, Pd/C в системе полярных растворителей, такой как этанол/вода. Наоборот, чтобы восстановить двойную связь и тем самым ввести хиральный центр в положение 4 диоксоимидазольного цикла, может быть использован энантиоселективный восстановитель, такой как Rh (код) (дипамп)⁺ BF $\genfrac{}{}{0ex}{}{\text{-}}{\text{4}}$ (JCS. Chem. Comm., 275, 1991)). Стадия восстановления может быть использована, чтобы превратить соединение формулы (XVII), в которой Z является группой формулы (vi), в соединение формулы (XVI), в которой Z является группой формулы (vi).Compounds of formula (XVI) in which n ≠ 0 can be prepared by reduction of a compound of formula (XVII)
Formula (XVII)

in which n, R, R ⁶ and Z are as defined above, usually by catalytic hydrogenation, using, for example, Pd / C in a polar solvent system such as ethanol / water. Conversely, to restore the double bond and thereby introduce the chiral center at position 4 of the dioxoimidazole ring, an enantioselective reducing agent such as Rh (code) (dipump) ⁺ BF can be used $\genfrac{}{}{0ex}{}{\text{-}}{\text{4}}$ (JCS. Chem. Comm., 275, 1991)). The reduction step can be used to convert a compound of formula (XVII) in which Z is a group of formula (vi) into a compound of formula (XVI) in which Z is a group of formula (vi).

 Compounds of formula (XVII) can be prepared by reaction of a compound of formula (XVIII).

в которой n и Z имеют определенные выше значения, в случае, когда R⁶ должен быть водородом, с соединением формулы (X), в которой R имеет определенные выше значения, обычно путем нагревания в ледяной уксусной кислоте в присутствии ацетата аммония.Formula (XVIII)

in which n and Z are as defined above, in the case where R ⁶ must be hydrogen, with a compound of formula (X) in which R is as defined above, usually by heating in glacial acetic acid in the presence of ammonium acetate.

 The compound of formula (XVIII) can be obtained by reductive hydrolysis of the corresponding nitrile, usually using Raney nickel and sodium hypophosphite in a mixture of water, acetic acid and pyridine. Nitrile can be obtained by the reaction of a compound of formula (XIX).

в которой n имеет определенные выше значения, с соответствующим соединением формулы (XXVIII), в случае, когда Z должен быть группой формулы (V) или (vi),

в которой R³ имеет определенные выше значения, обычно путем кипячения с обратным холодильником в полярном растворителе, таком как метанол, в присутствии основания, например, гидроокиси калия.Formula (XIX)

in which n has the meanings defined above, with the corresponding compound of formula (XXVIII), in the case when Z must be a group of formula (V) or (vi),

in which R ³ has the meanings defined above, usually by refluxing in a polar solvent such as methanol in the presence of a base, for example, potassium hydroxide.

 The compounds of formulas (XIX) and (XXVIII) can be obtained commercially or obtained from readily available starting materials according to methods known to specialists in this field of technology or obtained from the chemical literature. Compounds of formula (XVI) in which n = 0 can be prepared in the same manner.

в которой n и R имеют определенные выше значения, с соединением формулы (III), в которой Z имеет определенное выше значение, используя обычно условия реакции, описанные выше для реакции соединения (II) с (III).Compounds of formula (XVI) in which R ⁶ is benzyl and Z is a group of formula (iv) can be prepared by the reaction of a compound of formula (XXXV)
Formula (XXXV)

in which n and R are as defined above, with a compound of formula (III), in which Z is as defined above, usually using the reaction conditions described above for the reaction of compound (II) with (III).

Hydrazines of formula (XXXV) can be obtained from the corresponding aniline, usually using the reaction conditions described above to convert compound (IV) to (II). Aniline can be prepared by reducing the corresponding para-nitro compound, usually using the reaction conditions described above to convert compound (V) to (IV). The para-nitro compound can be prepared by reacting the corresponding para-nitro amino acid with a benzyl isocyanate in the presence of a base, for example potassium hydroxide, in a polar solvent such as water. Para-nitroamino acid can be obtained commercially or obtained from readily available starting materials according to methods known to those skilled in the art or obtained from the chemical literature, for example, by para-nitration of the corresponding amino acid, using, for example, concentrated H ₂ SO ₄ / concentrated HNO ₃ at 0 ^o C.

в которой n, X и Z имеют определенные выше значения, обычно каталитическим гидрированием, используя, например, Pd/C в полярном растворителе, таком как этанол. Подобная стадия может быть использована, чтобы превратить соединение формулы (XX), в которой Z является группой формулы (V), в соединение формулы (XV), в которой Z является группой формулы (vi).Compounds of formula (XV) in which R is hydrogen can be prepared by reducing a compound of formula (XX)
Formula (XX)

in which n, X and Z are as defined above, usually by catalytic hydrogenation, using, for example, Pd / C in a polar solvent such as ethanol. A similar step can be used to convert a compound of formula (XX) in which Z is a group of formula (V) into a compound of formula (XV) in which Z is a group of formula (vi).

 Compounds of formula (XX) in which X is oxygen can be prepared by reaction of a compound of formula (XXI).

в которой n и Z имеют определенные выше значения, с пара-формальдегидом в полярном апротонном растворителе, таком как ДМФА, в присутствии основания, например, метоксида натрия, при 0^oC.Formula (XXI)

in which n and Z are as defined above, with para-formaldehyde in a polar aprotic solvent such as DMF, in the presence of a base, for example sodium methoxide, at 0 ^° C.

 Compounds of formula (XXI) can be prepared by reaction of a compound of formula (XXII).

в которой n имеет определенные выше значения, в случае, когда Z должен быть группой формулы (V) или (vi) с соответствующим соединением формулы (XXVIII), в которой R³ имеет определенные выше значения, обычно путем нагревания в ледяной уксусной кислоте.Formulas (XXII)

in which n has the meanings defined above, in the case where Z must be a group of formula (V) or (vi) with the corresponding compound of formula (XXVIII) in which R ³ has the meanings defined above, usually by heating in glacial acetic acid.

 Compounds of formula (XXII) in which n ≠ 0 can be prepared by reducing a compound of formula (XXIII).

в которой n имеет определенные выше значения, используя, например, борогидрид натрия и 40 мас.%/объем водную NaOH в полярном апротонном растворителе, таком как ацетонитрил, при 0^oC.Formula (XXIII)

in which n is as defined above, using, for example, sodium borohydride and 40 wt.% / volume aqueous NaOH in a polar aprotic solvent such as acetonitrile, at 0 ^o C.

 Compounds of formula (XXIII) can be prepared by heating the corresponding aldehyde with nitromethane in the presence of ammonium acetate. The aldehyde can be obtained from a compound of formula (XIX) in which n is as defined above, using the reaction conditions described above to obtain a compound of formula (XVIII) from the corresponding nitrile.

 Compounds of formula (XXII) in which n = 0 can be obtained commercially or obtained from readily available starting materials by methods known to those skilled in the art or obtained from the chemical literature.

 Compounds of formula (XXI) in which n ≠ 0 can also be prepared from compounds of formula (XXXIX).

в которой n и Z имеют определенные выше значения, используя условия реакции, аналогичные используемым при превращении (XXIII) в (XXII). Соединения формулы (XXXIX), в которой n и Z имеют определенные выше значения, используя условия реакции, аналогичные используемым при получении (XXIII) из соответствующего альдегида и нитрометана.Formula (XXXIX)

in which n and Z have the meanings given above, using reaction conditions similar to those used in the conversion of (XXIII) to (XXII). Compounds of formula (XXXIX) in which n and Z are as defined above using reaction conditions similar to those used in the preparation of (XXIII) from the corresponding aldehyde and nitromethane.

 Compounds of formula (XX) in which X is not oxygen can be obtained commercially or obtained from readily available starting materials by methods known to those skilled in the art or obtained from the chemical literature.

 Compounds of formula (XXV) can be prepared by a ring opening reaction of a compound of formula (I) in which n and Z are as defined above and W is a group of formula (ii) in which R, X and Y are as defined above, for example, by refluxing in 2 N aqueous KOH.

 Compounds of formula (I) in which W is a group of formula (i) wherein Y is sulfur can be prepared by refluxing a compound of formula (XV) in which n, R and X are as defined above, with a compound of formula (VII) in which Y is sulfur and L and L ′ are as defined above, for example, N, N′-thiocarbonylimidazole, usually in an aprotic solvent such as THF.

 Compounds of formula (I) in which W is a group of formula (ii) in which Y is sulfur can be prepared by refluxing a compound of formula (XXV) in which n, R and X are as defined above, with a compound formula (VII), in which Y is sulfur, and L and L 'have the meanings defined above, for example, N-N'-thiocarbonylimidazole, usually in an aprotic solvent such as THF.

в которой
n и R имеют определенные выше значения, является группой формулы (V) или (vi), а R⁷ является C_1-4-алкилом, обычно путем нагревания в водной кислоте, например, 2 N HCl.Compounds of formula (I) in which W is a group of formula (iii) and Z is a group of formula (V) or (vi) can also be prepared by cyclization of a compound of formula (XXVI)
Formula (XXVI)

wherein
n and R are as defined above, is a group of formula (V) or (vi), and R ⁷ is C _1-4 alkyl, usually by heating in aqueous acid, for example, 2 N HCl.

 Compounds of formula (XXVI) in which Z is a group of formula (V) can be prepared by reacting a compound of formula (XXVII).

в которой
n, R и R⁷ имеют определенные выше значения, с соединением формулы (XXVIII), в которой R³ имеет определенные выше значения, обычно путем нагревания в неводной кислоте, например ледяной уксусной кислоте.Formula (XXVII)

wherein
n, R and R ⁷ are as defined above, with a compound of formula (XXVIII) wherein R ³ is as defined above, usually by heating in non-aqueous acid, for example glacial acetic acid.

 Compounds of formula (XXVI) in which Z is a group of formula (vi) can be prepared by reducing a compound of formula (XXVI) in which Z is a group of formula (V), usually by catalytic hydrogenation, using, for example, Pd / C in a polar solvent system such as acidified methanol / water.

в которой
n имеет определенные выше значения, с соединением формулы (XXX)

в которой
R⁷ имеет определенные выше значения, обычно в апротонном растворителе, таком как ДСМ (хлористый метилен).Compounds of formula (XXVII) can be prepared by reaction of a compound of formula (XXIX)
Formula (XXIX)

wherein
n is as defined above, with a compound of formula (XXX)

wherein
R ⁷ is as defined above, usually in an aprotic solvent such as DSM (methylene chloride).

 Compounds of formulas (XXIX) and (XXX) can be obtained commercially or obtained from readily available starting materials by methods known to those skilled in the art or obtained from the chemical literature.

в которой
n и W имеют определенные выше значения, по методам, известным специалистам в данной области техники или получаемым из химической литературы, например, обработкой с (COL)₂, где L является подходящей уходящей группой, например, хлором, чтобы получить соответствующее соединение 3-COOOL, которое может быть обработано затем с HNR¹R², где R¹ и R² имеют определенные выше значения, и восстановлено, используя, например, литийалюминийгидрид. Или же соединение формулы (XXXI) может быть обработано смесью CH₂O/KCN, чтобы получить соответствующее 3-цианометильное соединение, которое затем может быть подвергнуто каталитическому гидрированию над никелем Ренея в присутствии HNR¹R², который определен выше.Compounds of formula (I) in which Z is a group of formula (iv) can also be prepared from a compound of formula (XXXI)
Formula (XXXI)

wherein
n and W have the meanings given above, by methods known to those skilled in the art or obtained from the chemical literature, for example, treatment with (COL) ₂ , where L is a suitable leaving group, for example, chlorine, to obtain the corresponding compound 3-COOOL which can then be treated with HNR ¹ R ² , where R ¹ and R ² are as defined above, and reduced using, for example, lithium aluminum hydride. Alternatively, the compound of formula (XXXI) can be treated with a mixture of CH ₂ O / KCN to obtain the corresponding 3-cyanomethyl compound, which can then be subjected to catalytic hydrogenation over Raney nickel in the presence of HNR ¹ R ² as defined above.

 The above 3-cyanomethyl compound can also be obtained by cyclization of a compound of formula (XXXX).

в которой n и W имеют определенные выше значения, обычно путем кипячения с обратным холодильником в апротонном растворителе, таком как хлороформ, в присутствии полифосфатного сложного эфира.Formula (XXXX)

in which n and W are as defined above, usually by refluxing in an aprotic solvent such as chloroform in the presence of a polyphosphate ester.

 Compounds of formula (XXXX) can be prepared by reacting a compound of formula (II) in which n and W are as defined above, with a 3-cyanopropanal, or with a carbonyl protected form thereof, such as diethyl acetal, usually in aqueous acid, for example, diluted HCl.

Compounds of formula (I) in which Z is a group of formula (V) can also be prepared by reaction of compound (XXXI) in which n and W are as defined above, with a compound of formula (XXVIII) in which R ³ is as defined above values, usually, but by heating in glacial acetic acid.

в которой n и W имеют определенные выше значения, обычно путем нагревания с никелем Ренея в полярном растворителе, таком как IPA (изопропиловый спирт).Compounds of formula (XXXI) can be prepared by reducing a compound of formula (XXXII)
Formula (XXXII)

in which n and W are as defined above, usually by heating with Raney nickel in a polar solvent such as IPA (isopropyl alcohol).

 Compounds of formula (XXXII) can be prepared by reacting hydrazine of formula (II) in which n and W are as defined above, with phenylthioacetaldehyde, or with a carbonyl protected form thereof, for example diethyl acetal, in a polar solvent such as acidified ethanol.

 Compounds of formula (I) in which Z is a group of formula (vi) can also be prepared by reducing a compound of formula (I) in which Z is a group of formula (V), usually by catalytic hydrogenation, using, for example, Pd / C in a polar solvent system such as acidified methanol / water.

Synthetic Examples
Synthetic Example 1
Preparation of (S) -2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl] -ethylamine
(a) (S) -4-nitrophenylalanine methyl ester hydrochloride
Methanol (110 ml) was treated dropwise with thionyl chloride (26.3 g) at -10 ^° C, and 1-4-nitrophenylalanine (Fluka 21.7 g) was added as a solid. The mixture was stirred overnight at room temperature, and methanol was removed in vacuo to give the desired reaction product as a pale yellow solid (21.2 g).

(b) (S) -2-amino-3- (4-nitrophenyl) propanol
The reaction product from step (a), (21.2 g) was dissolved in ethanol / water (190 ml), (100/90 in volume ratio), and the solution was added dropwise at 0 ^° C. to a stirred solution of sodium borohydride (13 , 0 g) in a mixture of ethanol / water (190 ml, 100/90 in volume ratio). The resulting mixture was refluxed for 2.5 hours, cooled, and the precipitate was filtered off. Ethanol was partially removed from the filtrate in vacuo, and the resulting precipitate was filtered off and dried to obtain the desired reaction product as a pale yellow solid (7.5 g).

(c) (5 -) - 4- (4-nitrobenzyl) -1,3-oxazolidin-2-one
The reaction product from step (b) (4.9 g) was suspended in toluene, the suspension was cooled to 0 ^° C., and a solution of potassium hydroxide (7.0 g) in water (56 ml) was added dropwise. A phosgene solution (62.5 ml of a 12% w / v solution in toluene) was added dropwise to the resulting solution over 30 minutes and stirring for 1 hour. The mixture was extracted with ethyl acetate and the extracts washed with brine, dried and evaporated in vacuo. to get yellow oil. Crystallization from ethyl acetate gives the desired reaction product as pale yellow crystals (2.3 g).

(d) (S) -4- (4-aminobenzyl) -1,3-oxazolidin-2-one hydrochloride
A suspension of the reaction product from step (c) (0.79 g) and 10% palladium-carbon (0.26 g) in a mixture of ethanol (15 ml) and water (11 ml), ethyl acetate (2.0 ml) and aqueous 2N HCl (2.3 ml) was stirred at 1 atm hydrogen pressure until hydrogen uptake ceased. The mixture was filtered through Hytlo and the filtrate was evaporated in vacuo to give the desired reaction product as a pale yellow foamy substance (0.79 g).

e) (S) -4- (4-hydrazinobenzyl) -1,3-oxazolidin-2-one hydrochloride
The reaction product from step (g) (0.79 g) was suspended in water (4.8 ml) and concentrated HCl (8.1 ml) was added dropwise. The resulting mixture was cooled to -5 ^° C, and a solution of sodium nitrite (0.24 g) in water (2.4 ml) was added dropwise to the stirred mixture over 15 minutes, followed by 30 minutes stirring at a temperature of from -5 ^o C to 0 ^o C. Then the solution is added at 0 ^o C for 15 minutes to a stirred solution of tin (II) chloride (3.8 g) in concentrated HCl (6.9 ml), followed by 3 hours stirring at room temperature. The solution was evaporated in vacuo and the residue was triturated with ether to give the desired reaction product as a pale yellow solid (0.96 g).

(e) (S) -2- [5- (2-oxo-1,3-oxazolidin-1-yl-methyl) -1H-indol-3-yl] ethylamine
The reaction product from step (e) (0.84 g) was dissolved in ethanol / water (125 ml, 5: 1), and the solution was treated with 4-chlorobutanaldehyde dimethyl acetal (JA CS1365 (1951) (0.52 g). The mixture was boiled. reflux for 2 h, the solvent was removed in vacuo, and the residue was eluted through a silica gel column using a EtOH / NH ₄ OH methylene chloride mixture (30: 8: 1) as an eluent. The expected reaction product was obtained as a colorless oil (0 21 g).

Salt of synthetic example 1
Maleate (maleic acid salt)
An ethanol solution of maleic acid (1.0 eq) was added dropwise to the free base (0.21 g), and ethanol was evaporated in vacuo. The resulting resin is dried at a temperature below 0 ^o C to get rid of water and get the target reaction product in the form of a white lyophilization product (lyophilate) (0.22 g) [α] $\genfrac{}{}{0ex}{}{\text{21}}{\text{D}}$ - 5.92 (s = 0.3 - MeOH). ( ¹ H-NMR (DMCO-d ₆ δ): 2.7-3.5 (6H, multiplet, CH ₂ ), 3.35 (2H, singlet, NH ₂ ), 4.05 (2H, multiplet, CH ₂ ), 4.25 (1H, multiplet, CH), 6.05 (2H, singlet, maleic acid), 6.98 (1H, doublet, Ar), 7.2 (1H, singlet, Ar), 7, 3 (1H, doublet, Ar), 7.4 (1H, singlet, Ar), 7.75 (1H, singlet, NH) and 10.9 (1H, singlet, NH).

 Microanalysis: C 55.03 (54.96), H 5.54 (5.85), N 10.30 (10.68).

Synthetic Example 2
Preparation of 0.9 isopropanolate 0.5 (S) -N, N-dimethyl-2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl-ethylamine hydrate
A solution of formaldehyde (0.03 g) in methanol (1.8 ml) is added to a solution of the free base from step (e) of Synthetic example 1 (0.12 g) and sodium cyanoborohydride (0.04 g) in a mixture of methanol (5, 5 ml) and glacial acetic acid (0.14 g), and the resulting mixture was stirred overnight at room temperature. The pH was adjusted to 8.0 using aqueous K ₂ CO ₃ and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried and evaporated to give a colorless oil (0.14 g), which was crystallized from isopropyl alcohol to obtain the desired reaction product as a white crystalline solid (0.10 g), mp. 139-141 ^o C.

¹ H-NMR (DMCO-d ₆ δ): 2.2 (6H, singlet, NMe ₂ ), 2.5 (2H, multiplet, CHAr), 2.7-3.0 (multiplet, CH ₂ ), 4 , 1 (2H, multiplet, CH ₂ O), 4.3 (1H, multiplet, CH), 6.9 (1H, doublet, Ar), 7.1 (1H, singlet, Ar), 7.3 (1H doublet, Ar), 7.4 (1H, singlet, Ar), 7.7 (1H, singlet, NHCO) and 10.7 (1H, singlet, NH).

Microanalysis: C 64.26 (64.11), H 8.28 (8.34), N 12.02 (12.00). [α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{D}}$ - 5.79 (C = 0.5 MeOH).

Salts of Synthetic Example 2
Maleate
A solution of maleic acid (0.17 g) in ethanol (5 ml) was added to a solution of the free base (0.5 g) in ethanol (5 ml). The mixture was evaporated in vacuo and the resulting oil was triturated with ether and methanol to give the maleate salt as a white solid, which was crystallized from ethanol (0.45 g), mp. 151-152 ^o C.

Hydrochloride
An ethereal HCl solution (1.1 eq) was added dropwise to a stirred solution of the free base (0.35 g) in methanol (1 ml) at 0 ^° C. The hydrochloride salt precipitated as an oil. The mixture was evaporated in vacuo and the resulting foamy substance was crystallized from isopropyl alcohol to obtain the desired reaction product as a white solid (0.36 g), mp. 118-120 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ - 9.35 (C = 0.31, water).

Succinate (succinic acid salt)
A solution of succinic acid (0.36 g) in ethanol (10 ml) was added to a solution of the free base (1.0 g) in ethanol (10 ml). The mixture was evaporated in vacuo, and the resulting foamy substance was triturated with isopropyl alcohol to obtain a sectioned salt as a white solid (1.0 g), mp. 122-123 ^o C.

Benzoate
A solution of benzoic acid (0.37 g) in ethanol (10 ml) is added to a solution of the free base (1.0 g) in ethanol (10 ml). The mixture was evaporated in vacuo and the resulting foamy substance was crystallized from ethyl acetate to give the benzoate salt as a white solid (0.74 g), mp. 90-92 ^o C.

Synthetic Example 3
Another method for producing 0.9 isopropanolate 0.5 of the (S) -N, N-dimethyl-2- [5- (2-oxo-1,3-oxazolidinylmethyl) -1H-indol-3-yl] ethylamine hydrate
4-Dimethylaminobutanaldehyde diethyl acetal (Croatica Chemica Acta, 36, 103 (1964) (3.9 g) was added to a solution of the reaction product from step (e) of Synthetic Example 1 (10.4 g) in a mixture of acetic acid (50 ml) and water (150 ml), and the resulting mixture was refluxed for 4.5 hours. The mixture was cooled, evaporated in vacuo, and the residue was eluted through a silica column using a mixture of methylene chloride / EtoH / NH ₄ OH (50: 8: 1 ) as an eluent to obtain the desired reaction product as a pale yellow oil, which crystallizes from isopropyl alcohol as a white crystalline solid (3.5 g), mp 138-140 ^o C.

¹ H-NMR, microanalysis and [α] _D are the same as the reaction product of Synthetic Example 2.

Synthetic Example 4
Preparation of (±) -3- (1-methyl-4-piperidyl) -5- (2-oxo-1,3-oxazolidin-4-yl methyl) -1H-indole
(a) 3- (1-methyl-1,2,3,6-tetrahydro-4-pyridyl) -1H-indole-5-carbonitrile
5-cyanoindole (Aldrich, 20.0 g) was added to a solution of KOH (22.4 g) in methanol (200 ml). Then, N-methyl-4-piperidone (Aldrich, 40.4 g) was added dropwise, and the resulting mixture was refluxed for 4 hours, then cooled and poured into water. The resulting precipitate was filtered off and dried to obtain the desired reaction product as a pale pink crystalline solid (32.6 g).

(b) 3- (1-methyl-1,2,3,5-tetrahydro-4-pyridyl) -1H-indole-5-carbaldehyde
Raney Nickel (approximately 10 g) is added to a solution of the reaction product from stage (a) (5.0 g) and sodium hypophosphite (6.0 g) in a mixture of water (25 ml), glacial acetic acid (25 ml) and pyridine ( 25 ml) at 45 ^o C.

The resulting mixture was stirred at 45 ^o C for 1 h, cooled and basified to pH 9 with 0.88 NH ₄ OH. The mixture was filtered through Hytlo and the filtrate was extracted with chloroform. The combined extracts were dried and evaporated in vacuo to give the desired reaction product as an off-white solid, which was recrystallized from ethanol (2.4 g).

(c) 5- [3- (1-methyl-1,2,3,6-tetrahydro-4-pyridyl) -1H-indol-5-ylmethylene] - 2,4-imidazolidinedione
A mixture of the reaction product from step (b) (2.4 g), hydantoin (Aldrich 0.98 g) and ammonium acetate (0.74 g) in glacial acetic acid (2.4 ml) is heated at 120 ^° C. for 4 hours. The mixture is cooled, and the resulting precipitate is filtered off and dried to obtain the desired reaction product as a yellow solid (2.4 g).

(g) (±) -5- (2,5-dioxo-4-imidazolidinylmethyl) -3- (1-methyl-4-piperidyl) - 1H-indole
The reaction product from step (c) (2.4 g) is suspended in a mixture of water (100 ml) and ethanol (200 ml) and 10% by weight of Pd / C (0.25 g) is added. The mixture was stirred at a hydrogen pressure of 1 atm for 17 hours when absorption was complete. The mixture was filtered through Hytlo and the filtrate was evaporated in vacuo to give the desired reaction product as a colorless solid (2.4 g).

(e) (±) -3- [3- (1-methyl-4-piperidyl) -1H-indol-5-yl] alanine
A solution of the reaction product from step (g) (2.4 g) and barium hydroxide hydrate (8.4 g) in water (50 ml) was refluxed for 72 hours, then cooled and evaporated in vacuo. The residue was taken up in hot methanol and filtered to remove barium salts. The filtrate was evaporated in vacuo, the residue was dissolved in water and dry ice was added to precipitate barium carbonate. The latter was filtered off and the filtrate was evaporated in vacuo to give the desired reaction product as a yellow foamy substance (1.3 g).

(f) (±) -3- [3- (1-methyl-4-piperidyl) -1H-indol-5-yl] alanine methyl ester
A solution of the reaction product from step (e) (6.2 g) in methanol (40 ml) was added dropwise to a solution of thionyl chloride (2.9 ml) in methanol (35 ml) at -10 ^° C. The resulting mixture was stirred for overnight at room temperature, then evaporated in vacuo, and the residue was eluted through a column of silica using a mixture of methylene chloride EtoH / NH ₄ OH (30: 8: 1) as an eluent. The eluate was evaporated in vacuo to give the desired reaction product as a yellow foamy substance (4.8 g).

(g) (±) -3- [3- (1-methyl-4-piperidyl) -1H-indol-5-yl] -2-amino-1-propanol
A solution of the reaction product from step (e) (4.8 g) in water (20 ml) and ethanol (20 ml) is added dropwise to a suspension of sodium borohydride (0.61 g) in a mixture of water (20 ml) and ethanol (20 ml) at 0 ^° C. The resulting mixture was refluxed for 3 hours, then evaporated in vacuo and the residue was eluted through a column of silica using a mixture of methylene chloride EtoH / NH ₄ OH (30: 8: 1) as an eluent. The eluate was evaporated in vacuo and the residue was recrystallized from isopropyl alcohol / ether to give the desired reaction product as a colorless crystalline solid (1.1 g), mp. 191-192 ^o C.

¹ H-NMR (DMCO-d ₆ δ): 1.6-1.8 (2H, 2x CHNMe), 1.8-2.1 (4H, 2x CH ₂ ), 2.2 (3H, singlet, NMe ), 2.6-3.0 (2H, 2x CHNMe), 1H, CH, 2H, CH ₂ Ar), 3.9-4.1 (2H, multiplet, CH ₂ O), 4.2-4, 4 (1H, multiplet, CHII), 6.9 (1H, doublet, Ar), 7.1 (1H, doublet, Ar), 7.3 (Doublet, Ar), 7.4 (1H, singlet, Ar) 7.8 (singlet, NHCO); and 10.7 (H, singlet, NH).

Salt of synthetic example 4
Hydrochloride
To a stirred solution of the free base (1.1 g) in ethanol (5 ml), concentrated HCl (1.0 equiv) was added dropwise at 5 ^° C. Adding ether to the resulting mixture precipitates the desired reaction product as a white solid (1.1 g), mp 235-236 ^o C (decomposition).

Synthetic Example 5
Another method for producing (±) -3- (1-methyl-4-piperidyl) -5- (1,3-oxazolidin-4-ylmethyl) -1H-indole
(a) 1H-indole-5-carbaldehyde
Raney Nickel (6.7 g) is added to a solution of 5-cyanoindole (aldrich, 10.0 g) and sodium hypophosphite (20.0 g) in a mixture of water (73 ml), glacial acetic acid (73 ml) and pyridine (145 ml) at 45 ^° C. The resulting mixture was stirred at 45 ^° C. for 2 hours, then cooled and filtered through Hytlo. The filtrate was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, 10% aqueous citric acid, N aqueous HCl, water and brine, dried and evaporated in vacuo to give the desired reaction product as a dull yellow solid, which was recrystallized from chloroform (7.5 g )

(b) 5- (2-nitroethenyl) -1H-indole
A mixture of the reaction product from step (a) (7.5 g) of ammonium acetate (1.5 g) and nitromethane (77 ml) is heated at 110 ^° C. for 2 hours, then cooled and evaporated in vacuo. The residue was triturated with water to obtain the desired reaction product as a yellow solid, which was filtered off and dried (9.2 g).

(c) 5- (2-nitroethyl) -1H-indole
A solution of sodium borohydride (2.0 g) and 40% wt./about. aqueous NaOH was added dropwise to a solution of the reaction product from step (b) (1.9 g) in acetonitrile (55 ml) at 0 ^° C. The pH was maintained at 3-6 by periodic additions of 2N aqueous HCl. The resulting solution was stirred at 0 ^° C. for 2 hours, then diluted with water and extracted with methylene chloride. The combined extracts were washed with brine, dried and evaporated in vacuo to give a yellow oil, which was eluted through a column of silica using chloroform as an eluent to give the desired reaction product as a pale yellow oil (0.78 g).

(g) 3- (1-methyl-1,2,3,6-tetrahydro-4-pyridyl) -5- (2-nitroethyl) -1H-indole
N-methyl-4-piperidone (Aldrich 4.2 g) was added to a solution of the reaction product from step (c) (2.3 g) in glacial acetic acid (35 ml) at 100 ^° C. The resulting solution was heated at 100 ^° C. for 1 h, cooled and poured into a mixture of 0.88 NH ₄ OH (61 ml) and ice (61 g). The resulting solid was filtered off, dried and recrystallized from ethanol to give the desired reaction product as a white solid (1.6 g).

(e) (±) -3- [3- (1-methyl-1,2,3,6-tetrahydro-4-pyridyl) -1H-indol-5-yl] -2-amino-1-propanol
Sodium methoxide (0.30 g) was added to a solution of the reaction product from step (g) (1.5 g) in DMF (15 ml) at 0 ^° C. A suspension of para-formaldehyde (0.19 g) was added dropwise to the resulting solution. ) in DMF (20 ml). The resulting mixture was stirred at 0 ^° C. for 1.5 hours, then poured into water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and evaporated in vacuo to give a yellow oil, which was eluted through a silica column using a mixture of methylene chloride EtoH / NH ₄ OH (50: 8: 1) as an eluent to obtain the desired product reactions in the form of an off-white solid (0.85 g), which is recrystallized from ethanol.

 (e) (±) -3- [3- (1-methyl-4-piperidyl) -1H-indol-5-yl] -2-amino-1-propanol.

The reaction product from step (e) (0.08 g) was dissolved in ethanol (25 ml) and 10% in a weight ratio of Pd / C (0.23 g) was added. The mixture is stirred at a hydrogen pressure of 1 atm for 7 hours when the absorption of hydrogen is complete. The mixture was filtered through celite and filtered evaporated in vacuo to give the desired reaction product as a colorless oil, which was eluted through a silica column using a mixture of methylene chloride EtoH / NH ₄ OH (50: 8: 1) as an eluent.

(g) (±) -3- (1-methyl-4-piperidyl) -5- (1,3-oxazolidin-4-ylmethyl) -1H-indole
A mixture of the reaction product from step (e) (1.6 g) diethyl carbonate (0.71 g) and potassium carbonate (0.08 g) is heated at 130 ^° C. for 5 hours. The mixture is cooled, transferred to methanol, and insoluble carbonate potassium is filtered off. The filtrate was evaporated in vacuo and the residue was eluted through a column of silica using a mixture of methylene chloride EtoH / NH ₄ OH (30: 8: 1) as an eluent to obtain a colorless foamy substance which crystallized from a mixture of isopropyl alcohol / ether to to obtain the target reaction product in the form of a colorless crystalline solid (1.1 g), so pl. 191-192 ^o C.

¹ H-NMR and microanalysis are the same as for the reaction product of Synthetic Example 4.

Synthetic Example 6
Preparation of (R) -2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl) ethylamine
(a) (R) -4- (4-nitrobenzyl) -1,3-oxazolidin-2-one
A solution of D-4-nitrophenylalanine (Fduka, 53 g) and dimethoxyethane (250 ml) was heated to 67 ^° C and BF ₃ • Et ₂ O (Aldrich, 37 ml) was added over 1 hour. The resulting solution was stirred at 67 ^o C for 1 h, then heated to 80 ^o C and added for 1 h at 80-85 ^o C (Aldrich, 40 ml). The resulting solution was heated at 85 ^° C. for 4 hours, then cooled and methanol (40 ml) was added. The solution was heated to 85 ^° C. and the solvents were removed by distillation to 1/3 of the original volume. 6 N aqueous NaOH (136 ml) was added to the hot solution, which was then heated at 85 ^° C. for 1/2 hour, cooled and methylene chloride (100 ml) was added. The solution was cooled to -15 ^° C to -20 ^° C, and a solution of trichloromethyl ester of chloroformic acid (Aldrich, 18.2 ml) in methylene chloride (23 ml) was added at a temperature below -10 ^o C. The pH was maintained at 9-11 by periodic additions of 6 N aqueous NaOH. The resulting solution was stirred at room temperature for 1 h, then diluted with water and extracted with methylene chloride. The combined extracts were washed with water and brine, dried and evaporated in vacuo to give the desired reaction product as a pale brown solid, which was recrystallized from ethyl acetate to give a pale yellow solid (35 g), mp. 113-115 ^o C.

[[α] $\genfrac{}{}{0ex}{}{\text{21}}{\text{D}}$ + 46.47 (C = 0.56 MeOH).

(b) Hydrochloride (R) -4- (4-aminobenzyl) -1,3-oxazolidin-2-one
The reaction product from stage (a) (10.0 g) is suspended in a mixture of water (120 ml), ethanol (60 ml) and 2 N aqueous HCl (22.5 ml), and 10 wt.% Pd / C is added (1, 0 g). The mixture is stirred at a hydrogen pressure of 1 atm for 8 hours when the absorption of hydrogen is complete. The mixture was filtered through Hytlo and the filtrate was evaporated in vacuo to give the desired reaction product as a colorless glassy substance (10.3 g).

(c) Hydrochloride (R) -4- (4-hydrazinobenzyl) -1,3-oxazolidin-2-one
The reaction product from step (b) (10.3 g) was suspended in water (53 ml) and concentrated HCl (106 ml) was added dropwise. The resulting mixture was cooled to -5 ^° C and a solution of sodium nitrite (3.2 g) in water (30 ml) was added dropwise to the stirred mixture over 15 minutes, followed by 30 minutes stirring at a temperature of from -5 ^° C to 0 ^° C. The solution was then added at 0 ^° C. over 15 minutes to a stirred solution of tin (II) chloride (51 g) in concentrated HCl (91 ml), followed by 3 hours stirring at room temperature. The solution was evaporated in vacuo and the residue was triturated with ether to give the desired reaction product as a pale yellow solid (11 g).

(g) (R) -2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl] ethylamine
The reaction product from step (c) (8.8 g) was dissolved in ethanol / water (500 ml, 5: 1 in volume ratio), and the solution was treated with dimethylacetal-4-chlorobutanaldehyde (J. Amer. Chem. Soc., 1365 , (1951), (5.5 g) The mixture was refluxed for 2 hours, the solvent was removed in vacuo and the residue was eluted through a silica column using a mixture of methylene chloride (EtoH / NH ₄ OH) (30: 8 : 1 (v / v) as eluent: The expected reaction product is obtained as a pale yellow oil (0.60 g).

Salt Synthetic Example 6
Hydrochloride
Concentrated HCl (0.06 ml) was added dropwise to a stirred solution of the free base (0.16 g) in ethanol (2 ml) at 0 ^° C. The hydrochloride salt precipitates as a tan solid, mp. 269-271 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{21}}{\text{D}}$ + 5.88 (C = 0.27 MeOH).

Synthetic Example 7
Preparation of (R) -N, N-dimethyl-2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl) ethylamine
The solution is 35% weight / vol. aqueous pharmacaldehyde (0.3 ml) in methanol (2.0 ml) is added to a solution of the reaction product from step (g) of Synthetic Example 6 (0.44 g) and sodium cyanoborohydride (0.13 g) in a mixture of methanol (8, 5 ml) and glacial acetic acid (0.51 g) at 10 ^° C., and the resulting mixture was stirred at room temperature for 2.5 hours. 2 N aqueous NaOH (1.3 ml) was added, followed by sodium borohydride (0, 19 g), followed by 2N aqueous HCl (1.3 ml). Methanol was evaporated in vacuo and the remaining solution was diluted with water, adjusted to pH 7 with solid potassium carbonate and washed with ethyl acetate. Additional potassium carbonate was added to pH 11, and the solution was extracted with ethyl acetate. The combined extracts were evaporated in vacuo to give the desired reaction product as a white foamy substance (0.45 g).

Salt of synthetic example 7
Hydrochloride
Concentrated HCl (0.16 ml) was added dropwise at 0 ^° C. to a stirred solution of the free base (0.45 g) in ethanol (4.5 ml). The mixture was evaporated in vacuo and the resulting foamy substance was triturated with ethyl acetate to obtain the desired reaction product as a white solid, mp. 130 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{21}}{\text{D}}$ + 5.15 (c = 0.77 MeOH).

Synthetic Example 8
Preparation of (S) -N, N, dimethyl-2- [5- (2-thia-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl] ethylamine hydrochloride
(a) (S) -N, N-Dimethyl-2- [5- (2-amino-1-propanol) -1H-indol-3-yl] ethylamine
A solution of the hydrochloride salt of the reaction product from Synthetic Example 2 (0.33 g) in 2 N aqueous KON (10 ml) was refluxed for 4 hours, then cooled and extracted with ethyl acetate. The combined extracts were dried and evaporated in vacuo to give the desired reaction product as a colorless oil (0.25 g).

(b) (S) -N, N-dimethyl-2- [5- (2-thia-1,3-oxazolidin-4-yl-methyl) -1H-indol-2-yl] -ethylamine hydrochloride
A solution of N, N-thiocarbonylimidazole (Aldrich, 0.21 g) in THF (4 ml) was added dropwise to a stirred solution of the reaction product from step (A) (0.31 g) in THF (4 ml), and the mixture was boiled with reflux for 23 hours, then cooled in vacuo. The residue was chromatographed over a silica column using a mixture of methylene chloride EtoH / NH ₄ OH (20: 8: 1) as an eluent to obtain the desired reaction product as a colorless oil.

Salt of synthetic example 8
Hydrochloride
A 1 M ethanolic HCl solution (1.0 eq) was added dropwise to the free base, and ethanol was evaporated in vacuo. The resulting resin is dried at a temperature below 0 ^o C to remove water and get the target reaction product in the form of a white solid (0.17 g), so pl. 133-136 ^o C, (softens at 128 ^o C).

[α] $\genfrac{}{}{0ex}{}{\text{24.5}}{\text{D}}$ - 29.8 (c = 0.5 water).

Synthetic Example 9
Preparation of (S) -2- [5- (3-methyl-2-oxo-1,3-oxazolidin-4-yl-methyl) -1H-indol-3-yl] - ethylamine bromide
(a) (S) -2-methyl-4- (4-nitrobenzyl) -2-oxazolidinone
Sodium hydride (0.80 g as a 60% by weight dispersion in oil) is added at room temperature to a stirred solution of the reaction product from step (c) of Synthetic Example 1 (4.4 g) in dry THF (150 ml) . The mixture was stirred for 1.5 hours, then dimethyl sulfate (2.1 ml) was added and stirring was continued for an additional 16 hours. An additional 0.40 g of sodium hydride was added and stirring was continued for another 2 hours. The mixture was evaporated in vacuo and the residue was suspended in ethyl acetate and filtered. The filtrate was evaporated in vacuo, and the residue was crystallized from ethyl acetate / hexane to give the desired reaction product as yellow crystals (3.7 g), mp. 146-147 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ + 64.5 (c = 1.0 MeOH).

(b) (S) -3-methyl-4- (4-aminobenzyl) -2-oxazolidinone hydrochloride
A suspension of the reaction product from step (a) (4.0 g) and 10 wt.% Pd / C (0.20 g) in a mixture of ethanol (70 ml) and dilute HCl (2 N aqueous HCl (12 ml) + water ( 55 ml)) is hydrogenated at a pressure of 45 psi (3.16 atm) for 1 h. The mixture is filtered through Hytlo and the filtrate is evaporated in vacuo to obtain the desired reaction product as a foamy substance.

(c) (S) -3-methyl-4- (4-hydrazinobenzyl) -2-oxazolidinone hydrochloride
A solution of the reaction product from step (b) (4.1 g) in water (24 ml) was cooled to −5 ^° C. and concentrated HCl was added. A solution of sodium nitrite (1.2 g) in water (12 ml) is added, and then stirring is continued for 0.5 h. The resulting solution is added dropwise at -5 ^° C to a stirred solution of tin (II) chloride dihydrate (18, 8 g) in concentrated HCl (34 ml). The resulting mixture was stirred at 0 ^° C. for 2.5 hours, then evaporated in vacuo. The residue was taken up in water, adjusted to pH 2.5 using 10 N aqueous NaOH, and filtered. The filtrate was evaporated in vacuo and the residue was triturated with ethanol and filtered. The filtrate was evaporated in vacuo to give the desired reaction product as a foamy substance.

(d) Hydrobromide (S) -2- [5- (3-methyl-2-oxo-1,3-oxazolidin-4-yl-methyl) -1H-indol-3-yl] -ethylamine
4-Chlorobutanaldehyde dimethyl acetal (J. Amer. Chem. Soc., 1365 (1951) (2.3 g) was added to a stirred solution of the reaction product from step (c) (4.4 g) in an ethanol / water mixture (150 ml / 30 ml), and the mixture was refluxed for 2 hours. The cooled mixture was evaporated in vacuo and the residue was eluted through a silica column using a mixture of methylene chloride (MeOH) NH ₄ OH (60: 8: 1) as an eluent, to obtain brown oil (1.7 g) A portion of this oil (0.25 g) was dissolved in ethanol and treated with excess HBr in acetic acid (approximately 45% w / v). the solution was evaporated in vacuo and the residue was triturated with ether, then crystallized from ethanol / hexane to give the desired reaction product as pale yellow crystals (0.14 g), mp 203-205 ^° C .

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 29.9 (c = 0.5 MeOH). Elemental analysis and H-NMR are consistent with the proposed structure.

Synthetic Example 10
Preparation of 0.75 (S) -N, N-dimethyl-2- [5- (3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl] ethylamine maleate
Sodium cyanoborohydride (0.14 g), followed by glacial acetic acid (0.54 ml), is added at room temperature to a stirred solution of the free base (0.52 g) from step (g) of Synthetic Example 9 in methanol (9, 0 ml). When rapid evolution of gas is complete, a solution of 37% w / v aqueous formaldehyde (0.16 g) in methanol (2.0 ml) is added and the mixture is stirred for 1 h, then diluted with water, saturated with potassium carbonate and extracted with ethyl acetate. The combined extracts were evaporated in vacuo, and the residue was eluted through a column of silica using a MeOH / NH ₄ OH methylene chloride mixture (60: 8: 1) as an eluent to obtain the free base of the desired reaction product as a colorless oil (0.25 g ) The latter was dissolved in ethanol (10 ml), treated with a solution of maleic acid (0.09 g) in ethanol (1 ml), and the resulting solution was evaporated in vacuo to obtain an oil, which was triturated with ether, dried at a temperature below 0 ^o C to get rid of water and get the target reaction product in the form of a colorless glassy substance.

[α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{D}}$ + 24.5 (c = 0.5 MeOH). Elemental analysis, ¹ H-NMR and mass spectrometry are consistent with the intended structure.

Synthetic Example 11
Preparation of 0.75 (S) -N-benzyl-2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl] ethylamine maleate hydrate
Benzaldehyde (0.70 g) was added at room temperature and to a stirred solution of the compound of Synthetic Example 1 (1.7 g) in ethanol (20 ml). The solution was stirred for 36 hours, then sodium borohydride (0.25 g) was added in portions, and stirring was continued for another 2 hours. The solution was evaporated in vacuo and the residue was cooled, acidified with 2N aqueous HCl, made basic with sodium bicarbonate, saturated potassium carbonate and extracted with ethyl acetate. The combined extracts were evaporated in vacuo to give an oil which was eluted through a column of silica using a mixture of methylene chloride EtoH / NH ₄ OH (100: 8: 1) as an eluent to obtain the free base of the desired reaction product as a yellow foamy substance ( 1.6 g). A part of this substance (0.13 g) was dissolved in ethanol (10 ml), treated with a solution of maleic acid (43 mg) in ethanol (1 ml), and the resulting solution was evaporated in vacuo. The residue is dried at a temperature below 0 ^o C to get rid of water and get the target reaction product in the form of a pale yellow powder (0.16 g).

[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ + 1.4 (c = 0.5 MeOH). Elemental analysis, ¹ H-NMR and mass spectrometry are consistent with the proposed structure.

Synthetic Example 12
Preparation of (S) -N-benzyl-N-methyl-2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl) ethylamine maleate hydrate
Anhydrous potassium carbonate (0.34 g) was added at room temperature to a solution of the free base of Synthetic Example 11 (0.45 g) in DMF (8.0 ml). The suspension was stirred for 0.5 h, then a solution of dimethyl sulfate (0.17 g) in DMF (2.0 ml) was added and stirring was continued for another 3 hours. Water (40 ml) was added and the mixture was extracted with ethyl acetate. The combined extracts were evaporated in vacuo to give a yellow oil, which was eluted through a silica column using a mixture of methylene chloride (EtoH / NH ₄ OH 100: 8: 1) as an eluent to obtain the free base of the desired reaction product as a colorless oil ( 0.32 g). A portion of this oil (73 g) was dissolved in ethanol (10 ml), treated with a solution of maleic acid (23 g) in ethanol (1 ml), and the resulting solution was evaporated in vacuo. The residue is dried at a temperature below 0 ^o C to get rid of water and get the target reaction product in the form of a pale yellow powder.

[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ + 3.1 (c = 0.5 MeOH). Elemental analysis, ¹ H-NMR and mass spectrometry are consistent with the proposed structure.

Synthetic Example 13
Preparation of 0.5 (S) -N-methyl-2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl] ethylamine maleate hydrate
A suspension of the free base of the reaction product from Synthetic Example 12 (0.25 g) and 10 wt.% Pd / C (0.10 g) in ethanol (25 ml) was hydrogenated for 16 hours. The mixture was filtered through Hytlo and the filtrate was evaporated to vacuum. The residue was eluted through a column of silica using a mixture of methylene chloride EtoH / NH ₄ OH (30: 8: 1) as an eluent to obtain the free base of the desired reaction product (0.14 g). The latter was dissolved in ethanol (10 ml), treated with a solution of maleic acid (0.06 g) in ethanol (1 ml), and the resulting solution was evaporated in vacuo. The residue is dried at a temperature below 0 ^o C to get rid of water and get the target reaction product in the form of a hygroscopic solid.

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ - 5.4 (c = 0.5 MeOH), elemental analysis and H-NMR consistent with the proposed structure.

Synthetic Example 14
Obtaining 0.33 methanol 0.75 hydrate (S) -3- (1-methyl-1,2,3,6-tetrahydro-4-pyridyl) -5- (2-oxo-1,3-oxazolidin-4- ilmethyl) -1H-indole
(a) (S) -3-phenylthio-5- (2-oxo-1,3-oxazolidin-4-ylmethyl-1H-indole
Phenylthioacetaldehyde diethyl acetal (JCS Chem. Conm., 924 (1978) (9.1 g) was added to a stirred solution of the reaction product from step (e) of Synthetic Example 1 (9.8 g) in a mixture of ethanol (150 ml) and water (100 ml). Concentrated HCl (5 drops) was added and the mixture was stirred at room temperature for 2 days, then partially evaporated in vacuo. The resulting aqueous suspension was extracted with ethyl acetate, and the combined extracts were washed with water and evaporated in vacuo to give brown oil. last elute h Res a silica column using DCM EtOH / NH ₄ OH (150: 8: 1) as eluent to give the desired product as a pale yellow oil (5.0 g).

 (b) (S) -5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indole.

 Raney Nickel (3.0 g) is added to a solution of the reaction product from step (a) (3.1 g) in isopropyl alcohol (150 ml), and the suspension is refluxed for 1 hour. An additional 2.0 g of nickel is added. Raney and refluxing were continued for an additional 2 hours. The suspension was filtered while hot through Hytlo and the filtrate was evaporated in vacuo to give an oil. The latter is eluted through a silica column using ethyl acetate as an eluent to obtain the desired reaction product as a foamy substance (1.3 g).

¹ P-NMR and mass spectrometry are consistent with the proposed structure.

(c) 0.33 Methanolate 0.75 hydrate (5) -3- (1-methyl-1,2,3,6-tetrahydro-4-pyridyl) -5- (2-oxo-1,3-oxazolidine- 4-ylmethyl) -1H-indole
1-methyl-4-piperidone (0.74 g) (Aldrich) was added to a stirred solution of the reaction product from step (b) (0.30 g) in glacial acetic acid (2.0 ml), and the mixture was stirred at 100 ^° C for 2 hours. The cooled mixture was poured onto a mixture of ice NH ₄ OH (20 ml) and the resulting solid was filtered. The latter was eluted through a silica column using a mixture of methylene chloride (EtOH / NH ₄ OH (60: 8: 1) as an eluent and crystallized from ethyl acetate to obtain the desired reaction product as a colorless solid (0.11 g), t pl. 225 - 227 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ - 45.4 (c = 0.5 1N aqueous HCl). Elemental analysis and ¹ H-NMR are consistent with the proposed structure.

Synthetic Example 15
Preparation of (S) -3- (1-methyl-4-piperidyl) -5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indole hydrobromide
A suspension of the reaction product from Synthetic Example 14 (0.35 g) and 10 wt. % Pd / C (0.10 g) in a mixture of methanol (10 ml), water (10 ml) and 1N aqueous HCl was hydrogenated for 5 hours. The mixture was filtered through Hytlo and the filtrate was evaporated in vacuo. The residue was basified with NH ₄ OH, evaporated in vacuo and eluted through a column of silica using a mixture of methylene chloride (EtOH / NH ₄ OH (45: 8: 1) as an eluent to obtain an oil. The latter was dissolved in ethanol (5, 0 ml) and treated with an excess of HBr in acetic acid (approximately 45% w / v) to obtain the desired reaction product as colorless crystals (0.20 g), mp 260-261 ^° C.

[α] $\genfrac{}{}{0ex}{}{\text{21}}{\text{D}}$ - 5.2 (s = 0.5 water). Elemental analysis and ¹ H-NMR are consistent with the proposed structure.

Synthetic Example 16
Preparation of (R) -3- (1-methyl-1,2,3,6-tetrahydro-4-pyridyl) -5- (2-oxo-1,3-oxazolidin-5-ylmethyl) -1H-indole hydrate
(a) (R) -4- (4-hydrazinobenzyl) -1,3-oxazolidin-2-one hydrochloride
In steps identical with steps (a) to (c) of Synthetic Example 6, D-4-nitrophenylalanine is converted to (R) -4- (4-hydrazinobenzyl) -2-oxazolidinone hydrochloride.

(b) Hydrate (R) -3- (1-methyl-1,2,3,6-tetrahydro-4-pyridyl) -5- (2-oxo-1,3-oxazolidin-4-yl) -1H- indole
In steps analogous to steps (a) to (c) of Synthetic Example 14, the reaction product from step (a) is converted to the hydrate (R) -3- (1-methyl-1,2,3,6-tetrahydro-4 -pyridyl) -5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indole, m.p. 229-231 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{18}}{\text{D}}$ + 24.9 (c = 0.5 1N aqueous HCl). Elemental analysis and H-NMR are consistent with the proposed structure.

Synthetic Example 17
Preparation of (R) -3- (1-methyl-4-piperidyl) -5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indole bromide
By a method analogous to Synthetic Example 15, the reaction product from synthetic Example 16 was converted to (R) -3- (1-methyl-4-piperidyl) -5- (2-oxo-1,3-osazolidin-4-ylmethyl bromide ) -1H-indole, m.p. 260-261 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{19}}{\text{D}}$ + 4.6 (C = 0.5 water). Elemental analysis and ¹ H-NMR are consistent with the proposed structure.

Synthetic Example 18
Preparation of (R) -3- (1-benzyl-1,2,3,6-tetrahydro-4-pyridyl) -5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indole hydrate
1-benzyl-4-piperidone (Aldrich, 2.8 g) was added to a stirred suspension of (R) -5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indole (1.0 g) , an intermediate precursor (starting material) of the reaction product of Synthetic Example 16, in glacial acetic acid (20 ml) and stirred at 100 ^° C. for 3 hours. The cooled mixture was evaporated in vacuo and the residue was dissolved in methanol, made basic with NH ₄ OH and evaporated in vacuo to obtain a dark tar. The latter is eluted through a column of silica using a mixture of methylene chloride EtoH / NH ₄ OH (100: 8: 1) as an eluent and treated with methylene chloride. The resulting precipitate was filtered off to obtain the desired reaction product as yellow crystals (0.25 g), mp. 169-170.5 ^o C.

 Elemental analysis and H-NMR are consistent with the proposed structure.

Synthetic Example 19
Preparation of (R) -3- (4-piperidyl) -5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indole bromide
A suspension of the reaction product from Synthetic Example 18 (0.25 g) and 10 wt. % Pd / C (0.10 g) in methanol (25 ml) was hydrogenated at a pressure of 90 psi (6.32 atm) for 20 hours when hydrogen uptake ceased. The mixture was filtered through Hytlo and the filtrate was evaporated in vacuo. The residue was eluted through a silica column using a mixture of methylene chloride EtOH / NH ₄ OH (30: 8: 1) as an eluent to give an oil. The latter is dissolved in isopropyl alcohol and treated with an excess of HBr in acetic acid (approximately 45% w / v) to obtain a hygroscopic solid which is dried at a temperature below 0 ^° C to remove water and obtain the desired reaction product as a pale brown powder . Elemental analysis and ^I H-NMR are consistent with the proposed structure.

Synthetic Example 20
Preparation of (±) -N, N-dimethyl-2- [5- (1-thio-2-thia-3-oxazolidin-4-ylmethyl) -1H-indol-3-yl) ethylamine acetate
Carbon disulphide (90 μl) was added to a stirred solution of the reaction product from step (a) of Synthetic Example 8 (0.31 g) and potassium hydroxide (0.08 g) in ethanol (3.8 ml), and the mixture was refluxed, then evaporated in vacuo. The residue is extracted with ether, acidified and chromatographed using a reversible phase HPLC column with silica and eluting with a mixture of 10-> 90 vol. % water / acetonitrile together with 0.1 M aqueous ammonium acetate buffer at pH 4.0 for 20 minutes to obtain the desired reaction product (0.01 g) and, after treatment with HCl, the reaction product from Synthetic Example 8 (0, 11 g). Both products are dried at a temperature below 0 ^o C to remove water and obtain H-NMR and mass spectrometry, which are consistent with the proposed structure.

Synthetic Example 21
Preparation of (±) -N, N, dimethyl-2- [5- (2-oxo-1,3-oxazolidin-5-ylmethyl) -1H-indol-3-yl] ethyl-amine hydrochloride

(a) (±) -1-nitromethyl-2-phenylethanol
Sodium methoxide (1.1 g) was added to a stirred solution of nitromethane (Aldrich 12.2 g) in methanol (100 ml) at 0 ^° C, and the mixture was stirred for 10 minutes. A solution of phenylacetaldehyde (Aldrich, 24.0 g) in methanol (50 ml) was added dropwise over 15 minutes, and the mixture was stirred for 45 minutes at 0 ^° C., then brought to room temperature over 1 hour and stirred overnight. . The mixture was evaporated in vacuo and the residue was dissolved in water and extracted with ether. The combined extracts were washed with water and brine and evaporated in vacuo to give the desired reaction product as a yellow oil (20.0 g).

(b) Hydrochloride- (±) -1-aminomethyl-2-phenylethanol
A suspension of the reaction product from step (a) (10.0 g) and 10 wt.% Pd / C (1.0 g) in ethanol (250 ml) is hydrogenated until hydrogen uptake has ceased. The mixture was filtered through Hytlo, and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate and extracted with 2N aqueous HCl. The combined extracts were washed with ethyl acetate, then evaporated in vacuo to give the desired reaction product as a pinkish-white solid (6.8 g).

(c) (±) -5-Benzyl-1,3-oxazolidin-2-one
A solution of KOH (9.4 g) in water (85 ml) was added to a stirred solution of the reaction product from step (b) (5.1 g) in toluene (150 ml) at 0 ^° C. A phosgene solution (9.8 g) in toluene (78.4 ml = 12.5 w / v) was added dropwise over 15 minutes, and the mixture was brought to room temperature, then stirred overnight. The aqueous phase is separated and extracted with ethyl acetate. The combined extracts were evaporated in vacuo to give the desired reaction product as a white solid (2.2 g), mp. 106-108 ^o C. Elementary analysis is consistent with the proposed structure.

(g) (±) - 5- (4-nitrobenzyl) -1,3-oxazolidin-2-one
Concentrated H ₂ SO ₄ (1.6 ml) was added to the reaction product from step (c) at 0 ^° C, followed by concentrated HNO ₃ (0.33 ml), approximately 0.05 ml in 5 minutes) also at 0 ^o C. The mixture was stirred for 0.5 h at 0 ^° C. and then for 0.5 h at room temperature. A water / ice mixture (100 ml) was added and the reaction mixture was extracted with ethyl acetate. The combined extracts were evaporated in vacuo to give a yellow oil, which was recrystallized from ethyl acetate to give the desired reaction product as a white powder (0.4 g), mp. 143-146 ^o C.

(e) (±) -5- (4-aminobenzyl) -1,3-oxazolidin-2-one hydrochloride
A suspension of the reaction product from step (g) (1.4 g) and 10 wt.% Pd / C (0.14 g) in a mixture of water (21 ml), ethanol (28 ml) and 2N aqueous HCl (3.2 ml) ) hydrogenate for 2 hours when the absorption of hydrogen ceases. The mixture was filtered through Hytlo and the filtrate was evaporated in vacuo to give the desired reaction product as a pale yellow foamy substance (1.4 g).

(e) (±) -N, N-Dimethyl -2- [5- (2-oxo-1,3-oxazolidin-5-ylmethyl) -1H-indol-3-yl) ethylamine hydrochloride
Concentrated HCl (14.5 ml) was added to a stirred solution of the reaction product from step (e) (1.4 g) in water (8.5 ml) at 0 ^° C. A solution of sodium nitrite (0.43 g) in water (4.3 ml) was added dropwise over 15 minutes at 0 ^° C. and the mixture was stirred for 0.5 hours at 0 ^° C. The mixture was then added dropwise to the stirred a solution of tin (II) chloride (6.8 g) in concentrated HCl (12.4 ml) at 0 ^o C for 15 minutes The mixture was brought to room temperature over 1 h, then evaporated in vacuo. The residue was dissolved in water (30 ml), adjusted to pH 2.5 using 10N aqueous NaOH, and the precipitated salts were filtered off. Diethyl acetal-4-dimethylaminobutanaldehyde (Croatica Chemica Acta, 36, 103 (1964) (1.1 g), followed by an Amberlit 15 ion exchange resin (Aldrich, 3.0 g), was added to the filtrate and the mixture was heated to 3 hours at 100 ^° C., filtered and the filtrate evaporated in vacuo. The residue is taken up in hot ethanol, filtered and the filtrate is evaporated in vacuo. The residue is triturated with ethyl acetate, filtered and the filtrate is evaporated in vacuo. The residue is recrystallized from ethanol to to obtain the desired reaction product as a pale yellow solid VA (0.75 g), mp 280-281 ^o C. H-NMR and mass spectrometry are consistent with the proposed structure.

Synthetic Example 22
Preparation of (S) -N, N, dimethyl-2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl)] - (1H-indol-3-yl) ethylamine
(a) (S) -5- (4-nitrobenzyl) -1,3-imidazolidine-2,4-dinon
Benzyl azocyanate (Aldrich, 3.2 g) is added to a solution of 1-4-nitrophenylalanine (Aldrich, 4.2 g) and potassium hydroxide (1.3 g) in water (40 ml) at 0 ^o C. The mixture is heated at 60- 70 ^° C. for 2 hours, filtered, and the filtrate was acidified with concentrated HCl to give an off-white solid, which was filtered, suspended in 2N aqueous HCl (20 ml) and refluxed for 2 hours. Chilled mixture diluted with water and filtered to obtain the desired reaction product as a white solid (5.6 g).

(b) (S) -N, N-Dimethyl-2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl] ethylamine
In steps similar to steps (d) to (e) of Synthetic Example 1 and Synthetic Example 2 or steps (g) and (e) of Synthetic Example 1 and Synthetic Example 3 and steps (e) to (h) of Synthetic Example 4, converting the reaction product from step (a) to (S) -N, N-dimethyl-2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl] ethylamine .

Synthetic Example 23
Preparation of (S) -N, N-dimethyl-2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl) ethylamine
a) Hydrochloride (S) -4- (4-hydrazinobenzyl) -1,3-oxazolidin-2-one
In steps analogous to steps (a) to (c) of Synthetic Example 6, 1-4-nitrophenylalanine is converted to (S) -4- (4-hydrazinobenzyl) -1,3-oxazolidin-2-one hydrochloride.

(b) (S) - [4- [4-2- (3-cyanopropylidene) -hydrazino] benzyl] - 1,3-oxazolidin-2-one
1 M aqueous HCl (4.0 ml) was added to a solution of the reaction product from step (a) (2.4 g) in water (35 ml). Diethyl acetal-3-cyanopropanaldehyde (Aldrich, 1.7 g) was added at room temperature and the mixture was stirred for 2 hours. An additional 0.20 g of acetal was added and the mixture was stirred for an additional 20 minutes. The aqueous phase is decanted from the resulting resin and extracted with ethyl acetate. The extracts were combined with the resin and evaporated in vacuo to give the desired reaction product (2.5 g).

(c) (S) -3-cyanomethyl-5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indole
A solution of the reaction product from step (b) (2.5 g) and a polyphosphate ester (20.0 g) in chloroform (40 ml) are refluxed for 20 minutes. Ice was added to the cooled mixture and the chloroform was evaporated in vacuo. The remaining aqueous phase was extracted with ethyl acetate, and the combined extracts were evaporated in vacuo to give the desired reaction product as a pale yellow oil (1.8 g).

(g) (S) -N, N-dimethyl-2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl] ethylamine
A suspension of the reaction product from step (c) (1.3 g) t 10 wt.% Pd / C (1.0 g) in 30 wt.% Ethanol dimethylamine (25 ml) is hydrogenated for 24 hours and filtered through Hytlo. Freshly prepared Pd / C (0.7 g) and ethanol dimethylamine (5 ml) were added to the filtrate, and hydrogenation was continued for another 16 hours. The mixture was filtered through a column of silica using a mixture of methylene chloride EtOH / NH ₄ OH (40: 8 : 1) as an eluent, to obtain the desired reaction product as a colorless foamy substance (0.3 g). Elemental analysis and ¹ H-NMR are consistent with the proposed structure.

Synthetic Examples 24 to 31
By methods similar to those described in Synthetic Examples 1 to 23, the following compounds of formula (I) are prepared. NMR and microanalysis for each compound are consistent with the proposed structure.

24) 0.75 2- [5- (3-methyl-2-oxoimidazolidin-4-ylmethyl) -1H-indol-3-yl] ethylamine maleate hydrate, mp 94 - 98 ^o C;
25) 0.95 2- [5- (3-methyl-2-oxoimidazolidin-4-ylmethyl) -1H-indol-3-yl) -N, N-dimethylethylamine maleate hydrate (freeze-dried white product);
26) 2- [5-2- (2,5-dioxoimidazolidinyl) ethyl-1H-indol-3-yl] ethylamine hydrochloride hydrate, mp 83 - 85 ^o C;
27) 2- [5- [2- (2,5-dioxoimidazolidinyl) ethyl] -1H-indol-3-yl] -N, N-dimethylethylamine maleate hydrate (pale yellow lyophilized product);
28) 5- [2- (2,5-dioxoimidazolidinyl) ethyl-3- (1-methyl-4-piperidinyl) -1H-indole hydrochloride, m.p. 320 - 322 ^o C (decomposition);
29) 2- [5- (5-methyl-2-oxoimidazolidin-4-yl-ethyl) -1H-indol-3-yl] -ethylamine maleate hydrate, m.p. 99 ^o C (softens at 88 ^o C);
30) 1,4- 5- [3- (4-piperidyl) -1H-indol-5-ylmethyl] - 2,4-imidazolidinedione acetate hydrate, m.p. 92 - 93 ^o C (softens at 86 ^o C) and
31) 2.75 2- [5- (1-methyl-2-oxo-4-imidazolidinylmethyl) -1H-indol-3-yl] ethylamine diacetate hydrate (pale yellow lyophilized product).

Examples of the preparation of medicines
In the following examples, the “active ingredient” may be any compound of formula (I) and / or a physiologically acceptable salt, solvate or physiologically functional derivative thereof.

(I) Preparation of dosage forms in tablets
(i) Oral form - the results are presented in table. 1.

 (ii) Sublingual form - the results are presented in table. 2.

 Dosage forms A to E can be prepared by wet granulating the first six ingredients with povidone, followed by the addition of magnesium stearate and compression into a tablet.

(iii) Buccal mg / tablet
Active ingredient - 25
Hydroxypropyl methylcellulose (HPMC) - 25
Polycarbophil - 39
Magnesium Stearate - 1 - 90
A dosage form can be prepared by directly compressing the mixed ingredients.

(2) Dosage Forms in Capsules
(i) Powder - the results are presented in table. 3.

 Dosage forms F and G can be prepared by mixing the ingredients and filling the double-sided hard gelatin capsules with the resulting mixture.

 (ii) Liquid filling - the results are presented in table. 4.

 Dosage Form H can be prepared by melting Macrogol 400 BP, dispersing the active ingredient in the melt and filling the double-sided hard gelatin capsules with the melt mixture. Dosage form 1 can be prepared by dispersing the active ingredient in decitin and peanut butter and filling soft, elastic gelatin capsules with the dispersion obtained.

(iii) Controlled release, mg / capsule:
Active ingredient - 25
Avicel - 123
Lactose - 62
Triethyl citrate (triethyl ether of citric acid) - 3
Ethylcellulose - 12 - 225
A dosage form can be prepared by mixing and extruding the first four ingredients and transforming into a spherical form and drying the extrudate. The dried beads are coated with ethyl cellulose as a release control membrane and filled into bilateral, hard gelatin capsules.

(3) Dosage form for intravenous injection, wt.%:
Active ingredient - 2
Hydrochloric acid - The amount of solution is adjusted to pH 7
Citrate buffer - The amount of solution is adjusted to pH 7
Water for injection - Up to 100%
The active ingredient is mixed in citrate buffer and a sufficient amount of hydrochloric acid is added to affect dissolution and bring the pH to 7. The resulting solution is brought to volume and filtered through a microporous filter into sterile glass ampoules, which are sealed and sealed.

(4) Intranasal dosage form, wt%:
Active ingredient - 0.5
Hydrochloric acid - The amount of solution is adjusted to pH 7
Citrate buffer - The amount of solution is adjusted to pH 7
Oxybenzoic acid methyl ester - 0.2
Oxybenzoic acid propyl ester - 0.02
Water for injection - Bring to 100
The active ingredient is absorbed in a mixture of oxybenzoates and citrate buffer and a sufficient amount of hydrochloric acid is added to affect the dissolution and bring the pH to 7. The resulting solution is brought to volume and filtered through a microporous filter into sterilized glass ampoules, which are sealed and sealed.

(5) Dosage form for intramuscular injection, g:
Active ingredient - 0.05
Benzyl alcohol - 0.10
Glycofurol 75 - 1.45
Water for injection - The amount of solution is adjusted to 3.00 ml
The active ingredient is soluble in glycofurol.

 Benzyl alcohol is added, which dissolves, and water up to 3 ml is added. The mixture is filtered through a microporous filter into sterilized glass ampoules, which are sealed and sealed.

(6) Syrup-like dosage form, g:
Active ingredient - 0.05
Sorbitol solution - 1.50
Glycerin - 1.00
Sodium Benzoate - 0.005
Flavoring and flavoring substances - 0.0125 ml
Sodium benzoate is dissolved in part of the purified water and a solution of sorbitol is added. The active ingredient is added and dissolved. The resulting solution is mixed with glycerin and brought to the desired volume using purified water.

 (7) Dosage form in the form of a suppository, mg / suppository.

Active ingredient (63 microns) ^w - 50
Solid fat, BP (Witeipsol H15-Dynamite Nobel) - 1950 - 2000
g) The active ingredient is used in the form of a powder in which at least 90% of the particles have a diameter of 63 μm or less.

One fifth of Witeipsol H15 is melted in a vessel with a steam jacket at a maximum temperature of 45 ^o C. The active ingredient is sieved through a sieve with a hole size of 20 μm and mixed with the molten base using a Silverson mixer equipped with a cutting head until a uniform head is reached until a uniform dispersion. Maintaining the mixture at 45 ^° C, the rest of Witeipsol H15 is added to the suspension, which is mixed to ensure a homogeneous mixture. The whole suspension is then passed through a stainless steel sieve and aperture size of 250 μm, and left to cool to 40 ^° C with continuous stirring. At a temperature of 38-40 ^° C, 2 g aliquots of the mixture are filled into suitable plastic molds and the suppositories are allowed to cool to room temperature .

(8) Dosage form in the form of a pessary (vaginal suppository, mg / pessary:
Active ingredient (63 microns) - 50
Anhydrous Dextrose - 470
Potato Starch - 473
Magnesium Stearate - 473 - 1000
The above ingredients are directly mixed, and pessaries are obtained by compressing the resulting mixture.

Biological test
The compounds of formula (I) obtained in Synthetic Examples 1 to 17 are each tested for their activity as agonists for the “5-HT ₁ -like" receptor mediating smooth muscle contraction, according to the following method.

The saphenous veins of the right and left legs are obtained from New Zealand white male rabbits (2.4 - 2.7 kg), which were slaughtered by intravenous injection of pentobarbitone sodium (60 mg / kg). Ring segments (3-5 mm wide) obtained from each vessel (vein) are suspended between two wire hooks and immersed in 20 ml organ baths containing Krebs solution (pH 7.4) of the following composition, mM: NaCl 118, 41 n; NaHCO ₃ 25.00; KCl 4.75; K ₂ HPO ₄ 1.19; MgSO ₄ 1.19; glucose 11.10 and CaCl ₂ 2.50. Cocaine (30 μM) is contained in the Krebs solution throughout the experiment to prevent the absorption of amines by sympathetic neurons (nerve cells). The solution was maintained at 37 ^° C. and continuously purged (aerated) with a mixture of 95% oxygen / 5% carbon dioxide. Increases in the isometric strength of the tissue are measured using Grass FN03C type force mixing sensors and recorded on a Gould VD-212 type recorder.

A strength of 1.0 g is applied to each preparation and is reinstalled twice over the next 30 minute period of time. During this time period, the tissues are exposed to pargyline (500 μM) to irreversibly inhibit monoamine oxidase and to phenoxybenzamine (0.1 μm) to inactivate α ₁ -adrenoceptors. At the end of 30 minutes, the inhibitors are removed by several changes in the Krebs solution in the organ baths.

The activity of agonists is evaluated by cumulative additions of the test compound, and its concentration increases in 0.5 log ₁₀ units of increase until additional additions cause further changes in the strength (mixing) of the tissue. In each experiment, the activity of the test compound is compared with the activity of 5-HT. Activity is expressed as p [A ₅₀ ] (-log ₁₀ [M], where m is the molar concentration of the agonist required to produce half the maximum effect). The results obtained for the compounds of Synthetic examples 2/3 and 4/5 are presented in table. 5.

Toxicity data
The hydrochloride salt of the compound from Synthetic Examples 2/3 is orally administered by feeding through a gastric tube to Wistar rats in the form of a solution in distilled water at doses of 25, 100 and 200 mg / kg in the main form and to Beagle dogs (bloodhounds?) At doses of 0.25 , 0.50, 1.0 and 2.0 mg / kg in the main form once a day for 14 days. In a separate study, dogs within 30 days, the dosage of the free base was increased from 2 mg / kg on the first day to 100 mg / kg on the 30th day. The free base is also orally administered to dog-like (Cynomolgus) monkeys at a dose of 50 mg / kg once a day for 15 days.

 There is a lack of evidence of toxicity in any of the above studies at any dosages used.

Claims (14)

 1. N, N-dimethyl-2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl] ethylamine in its (S) - or (R) - form or in the form of a mixture thereof, or a physiologically acceptable salt or solvate thereof.  2. The compound according to claim 1, which is (S) -N, N-dimethyl-2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl] - ethylamine, or a physiologically acceptable salt thereof, or a solvate. 3. The compound according to claim 1 or 2, or a physiologically acceptable salt or solvate thereof, for use in the prophylaxis or treatment of a clinical condition for which a “5-HT ₁ -like” receptor agonist is indicated.  4. The compound according to claim 1 or 2, or its physiologically acceptable salt, or MES for use in the prevention or treatment of migraine. 5. The compound according to claim 1 or 2, or a physiologically acceptable salt or solvate thereof, used in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a 5-HT ₁ -like receptor agonist is indicated.  6. The compound according to claim 1 or 2, or a physiologically acceptable salt or solvate thereof, used in the manufacture of a medicament for the prevention or treatment of migraine. 7. A medicine for the treatment or prevention of clinical conditions for which a 5-HT ₁ -like receptor agonist is indicated containing an active ingredient including an indole derivative and a physiologically acceptable additive or additives, characterized in that it is an active ingredient contains an effective amount of a compound according to claim 1 or 2, or a physiologically acceptable salt or solvate thereof.  8. The tool according to claim 7, characterized in that in addition to the compound according to claim 1 or 2, or its physiologically acceptable salt, or solvate contains one or more other physiologically acceptable agent.  9. The tool according to claim 7 or 8 in the form of tablets or capsules. 10. A method for the prevention or treatment of a clinical condition in mammals for which an “5-HT ₁ -like" receptor agonist is shown, comprising administering to the mammal a drug containing an indole derivative as an active ingredient, characterized in that it is used as a medicine the compound of formula I according to claim 1 or 2, or a physiologically acceptable salt or solvate thereof in a dose of 0.01-5 mg / kg body weight, based on the free base. 11. Method for the preparation of N, N-dimethyl-2- [5- (2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indol-3-yl] ethylamine in its (S) - or (R ) -form or mixtures thereof, characterized in that the reaction of the compounds of formula II

where W is a group of the formula

where the chiral center * represents (S) - or (R) -form or a mixture thereof,
with a compound of formula III

or with a carbonyl protected form thereof,
where L is a suitable leaving group or amino protecting group that can be converted into a dimethylamino group or is a group
-NR ¹ R ² ,
where R ¹ and R ² each is methyl.  12. A method of obtaining a medicine by mixing the active ingredient containing an indole derivative with a pharmaceutically acceptable additive or additives, characterized in that N, N-dimethyl-2- [5- (2-oxo-1,3-) is used as the active ingredient oxazolidin-4-ylmethyl) -1H-indol-3-yl] ethylamine in its (S) - or (R) -form or mixtures thereof, or its physiologically acceptable salt or solvate, obtained by the method according to claim 11.  13. The method according to p. 12, characterized in that it further mixes the active ingredient, or its physiologically acceptable salt, or MES with one or more other physiologically active agents.  14. The method according to p. 12 or 13, characterized in that the resulting mixture is further molded in the form of tablets or capsules. Priority on points:
06/07/90 according to claims 1 - 4, 6 - 14;
06/06/91 according to claim 5.

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