Derivatives of bicyclic amides, pharmaceutical composition and method for the treatment of pathological and inflammatory conditions

 

(57) Abstract:

Describes new derivatives of bicyclic amides of General formula I, where R1, R2, R3and R4selected (each) of hydrogen and fluorine and at least one and not more than two of them are fluorine, R5selected from hydrogen and C1-C4-alkyl, R6selected from hydrogen, C1-C4-alkyl and hydroxy-group, or R5and R6together with the carbon ring form a carbonyl group, R7selected from hydrogen and a hydroxy-group, R8and R9selected, each of hydrogen WITH1-C4-alkyl, cyclo (C3or4)alkyl or together with the nitrogen form morpholinopropan, their salts and solvate. Also describes pharmaceutical compositions based on compounds of the formula I, which are used in medicine, in particular, as the main muscle relaxants. Also described is a method of treatment of pathological and inflammatory conditions. The compounds of formula I possess a significantly reduced ability to cause sedation and loss of coordination in comparison with the known means. 10 C. and 21 C.p. f-crystals, 7 PL.

The invention relates to amide compounds, and the x compounds and compositions in medicine and therapy, in particular, as the main muscle relaxants.

The main limiting side effects of many clinically effective Central muscle relaxants and anticonvulsants are the induction of sedation and impaired coordination of movements in the body, which seriously limits their applicability. Such side effects found in drugs used in the treatment of anxiety, such as benzodiazepines. Although these effects may be transient, patients with such therapy often can not drive a car or engage in a particular kind of practice.

Now unexpectedly found that amides of the formula (I) are strong Central muscle relaxants and have a significantly reduced ability to cause sedation and loss of coordination in comparison with the known means.

In one aspect this invention relates to new compounds of the formula (I)

< / BR>
where R1, R2, R3and R4selected, each of hydrogen and fluorine, and at least one and not more than two of them are fluorine,

R5selected from hydrogen and C1-C4-alkyl, what herodom rings form a carbonyl group,

R7selected from hydrogen and hydroxy,

R8and R9selected (each) of hydrogen, C1-C4-alkyl, cyclo(C3or C4) alkyl or together with the nitrogen form morpholinopropan, and X is selected from communication, and methylene-O - and is always a bond or-O-, if any of R5, R6and R7is not hydrogen, and is always a link, if R5and R6together with the carbon ring form a carbonyl group,

and their salts and solvate.

As here used, "C1-C4-alkyl" denotes a linear or branched alkyl group having 1, 2, 3 or 4 carbon atom,

"cyclo(C3or C4)alkyl" denotes cycloalkyl group having 3 or 4 carbon atom,

"salt" refers to basic salts formed when in the formula (I) one of the radicals R8and R9is hydrogen, and "solvate" refers to a combination of certain ratios of the compounds of formula (I) and its solvent.

It must be considered that the compounds of formula (I) can exist in different geometrical isomeric forms and mixtures thereof in any ratio. The present invention includes within its scope such geometrically isomerase these isomers in any ratio.

In the formula (I) includes compounds where one or more carbon centers are chiral. The present invention includes within its scope each of the possible optical isomers, containing no, i.e., having less than 5%, any other optical isomer (isomers) and mixtures of one or more optical isomers in any proportion, including racemic mixtures.

Expert it is clear that some of the compounds of formula (I) can exist in enantiomeric forms in accordance with the direction of rotation of plane polarized light passing through a sample of this compound. The individual optical isomers and mixtures thereof in any ratio are included in the scope of this invention.

Be aware that the structural formula (I) represents only a two-dimensional image of these compounds. A separate group of compounds of formula (I) include those where:

(i) one of R1, R2, R3and R4denotes fluorine,

(ii) two of R1, R2, R3and R4denote fluorine,

(iii) R1denotes fluorine,

(iv) R2denotes fluorine,

(v) R3denotes fluorine,

(vi) R4denotes fluorine,

(vii) R5about the carbon atom, and, more preferably, methyl or ethyl,

(ix) R6denotes hydrogen,

(x) R6represents C1-C4-alkyl, preferably alkyl having 1, 2 or 3 carbon atoms and, more preferably, methyl or ethyl,

(xi) R6denotes a hydroxy-group,

(xii) R5and R6together with the carbon ring form a carbonyl group,

(xiii) R7denotes hydrogen,

(xiv) R7denotes hydroxy,

(xv) R8denotes hydrogen,

(xvi) R8represents C1-C4-alkyl, preferably alkyl having 1, 2 or 3 carbon atoms and, more preferably, methyl, ethyl or isopropyl,

(xvii) R8means cyclo(C3or C4) alkyl, preferably cyclopropyl,

(xviii) R9denotes hydrogen,

(xix) R9represents C1-C4-alkyl, preferably alkyl having 1, 2 or 3 carbon atoms and, more preferably, methyl, ethyl or isopropyl,

(xx) R9means cyclo(C3or C4) alkyl, preferably cyclopropyl,

(xxi) R8and R9together with the nitrogen form morpholinopropan,

(xxii) X denotes a bond,

(xxiii) X denotes methylene,

(xxiv) X denotes-O-,

and their salts and SOLV is located on the opposite sides of the Exo-double bond, and their salts and solvate.

Individual preferred compounds of formula (I) are

(E)-2-(6-fluoro-3-methyl-1-inderide)ndimethylacetamide,

(E)-N-cyclopropyl-2-(6-fluoro-3-methyl-1-inderide)ndimethylacetamide,

(E)-2-(6-fluoro-3,3-dimethyl-1-Indonesien)-N-methylacetamide,

(E)-N-cyclopropyl-2-(6-fluoro-3-ethyl-1-inderide)ndimethylacetamide,

(E)-N-cyclopropyl-2-(5,6-debtor-1-inderide)ndimethylacetamide,

(E)-2-(5,6-debtor-1-Indonesien)-N-methylacetamide,

(E)-2-(5,6-debtor-1-inderide)ndimethylacetamide,

(E)-2-(5,7-debtor-1-inderide)ndimethylacetamide,

(E)-N-cyclopropyl-2-(4,6-debtor-1-inderide)ndimethylacetamide,

(E)-2-(4,6-debtor-1-Indonesien)-N-isopropylacetate,

(E)-2-(4,6-debtor-1-Indonesien)-N,N-dimethylacetamide,

(Z)-2-(4,6-debtor-2-hydroxy-1-inderide)ndimethylacetamide,

(E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthalide)ndimethylacetamide,

(E)-N-cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthalide)-ndimethylacetamide,

(E)-N-cyclopropyl-2-(6-fluoro-3,4-dihydro-2H-1-benzopyran-4 - ilidene)ndimethylacetamide,

(E)-2-(4,6-debtor-1-inderide)ndimethylacetamide,

(E)-2-(6-fluoro-1-inderide)ndimethylacetamide,

(Z)-2-(6-fluoro-2-hydroxy-1-inderide)ndimethylacetamide,

(E)-2-(6-fluoro-3,3-dimethyl-1-inderide)ndimethylacetamide,

(E)-2-(6-fluoro-3-ethyl-1-Indonesien)-N,N-dimethylacetamide,

(E)-2-(6-fluoro-3-hydroxy-1-inderide)are cetamide, together with its salts and solvate.

The preferred salt and a solvate, which is pharmaceutically acceptable.

In addition, the present invention relates to the compound of formula (I) or its pharmaceutically acceptable salt or MES for use in the treatment of a mammal, including man.

This invention relates also to the use of compounds of formula (I) or its pharmaceutically acceptable salt or MES for obtaining a medicinal product for the treatment of a mammal, including man.

Pharmaceutically acceptable salts include ammonium salts, alkali metal salts, e.g. sodium and potassium salts, and salts of alkaline earth metals such as magnesium salt and calcium.

Salts that are not pharmaceutically acceptable are used in obtaining and/or purification of the compounds and/or their salts, which are useful and/or non-therapeutic use, for example, in vitro.

The compounds of formula (I) together with their pharmaceutically acceptable salts and solvate applicable in medicine as a Central muscle relaxant and can therefore be used in the treatment of conditions asso skeletal muscles in spastic, hypertensive and hyperkinetic States. In particular, they can be used in treating and relieving symptoms caused by physical stress spasm of skeletal muscles, for example, in the case of pain in the lower back. They can also be used in such conditions as spinal cord injury, Parkinson's disease, chorea, arthritis, Atmos, epilepsy and tetanus, and especially to ease muscle spasm under such conditions as muscle spasticity, myositis, spondylitis, cerebral (cortical) paralysis, cerebrovascular disease and multiple sclerosis. They can also be used as a preoperative muscle relaxants.

The compounds of formula (I) together with their pharmaceutically acceptable salts and solvate can also be applied to the treatment in cases of convulsive state, for example, which is the consequence of having epileptic, small epileptic seizures, psychomotor epileptic seizure or focal epileptic seizure.

The compounds of formula (I) together with their pharmaceutically acceptable salts and solvate are also applicable in the treatment of anxiety, as used here, this term should be understood as disorders with symptom is, 987, published. The American Psychiatric Association, Washington, D. C., USA, see the pages 235-253) as a psychiatric condition, with symptoms of anxiety and avoidance as characteristic features. In such States include generalized anxiety, simple phobia and panic.

Anxiety may also occur as a symptom associated with other psychiatric disorders, for example, obsessive compulsive States, post-traumatic stress, schizophrenia depression and major depression, and organic clinical conditions such as Parkinson's disease, multiple sclerosis, and other infringing physical disability disorders.

The compounds of formula (I) together with their pharmaceutically acceptable salts and solvate are also applicable in the treatment of pain, for example, is associated with inflammation and/or trauma, and are used as soft and strong analgesics.

The compounds of formula (I) together with their pharmaceutically acceptable salts and solvate are also applicable to the treatment of inflammatory conditions such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and gouty and is it the intervertebral disc, bursitis, tendonitis, tendosynovitis, fibromyalgia syndrome and other inflammatory conditions associated with ligamentous and regional deformation of skeletal muscles. Especially it should be noted that these compounds are less elsergany than other anti-inflammatory drugs such as ibuprofen, naproxen etc.

Thus, the present invention relates also to method of treatment

a) state associated with pathologically increased tone of skeletal muscles

b) state associated with convulsions,

c) alarm,

d) pain, or

e) inflammatory condition

at a mammal, including man, introducing him therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or MES.

The compounds of formula (I) and their pharmaceutically acceptable salt and solvate can be associated with other therapeutic means to treat the above conditions. For conditions associated with pathologically increased tone of skeletal muscles, such other means can be analgesics, such as codeine, acetaminophen, phenacetin and ibuprofen. For inflammatory conditions (aminofen, phenacetin and ibuprofen, antiarthritis tools, such as methotrexate and azathioprine, and decongestants such as ephedrine and pseudoephedrine.

The compound, salt or MES (hereinafter referred to as the active ingredients) may be administered by any route including oral, rectal, nazalnam, topical (including buccal and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous and intradermal) and percutaneous. It should be clear that the preferred route of administration will be determined, for example, the condition and age of the recipient and the state which is subject to treatment.

The number of the desired active ingredient depends on a number of factors, including the type of condition and its severity, the identity of the recipient and the route of administration, and is determined ultimately by the treating physician.

As a rule, for each of these States a suitable dose of the active ingredient (estimated in the calculation of the original compound) is in the range of 0.05-100 mg per kg of body weight of the recipient per day, preferably in the range of 0.1-50 mg per kg of body weight per day, most preferably in the range of 0.5-20 mg per kg of body weight per day and optimally 1-10 mg on its subdot, entered at appropriate intervals throughout the day.

Although the active ingredient can be entered individually, it is preferable to provide it in the form of a pharmaceutical composition containing an active ingredient listed above, together with an acceptable carrier. Each carrier must be "acceptable" in the sense that it is compatible with other ingredients of the composition and harmless for the recipient.

The compositions include compositions suitable for oral, rectal, nasal, external (including buccal and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous and intradermal) or percutaneous administration. The compositions may be presented for convenience in the form of a standard single dose and can be prepared by any means well known to the expert in the field of pharmacy. Such methods include the stage of connection of the active ingredient with a carrier consisting of one or more additional ingredients. Typically, these compositions are prepared homogeneous and tight binding of the active ingredient with liquid carriers or finely ground solid carriers or both types of media, pokerenlinea introduction, can be represented in the form of separate units, such as capsules, starch wafers or tablets, each of which contains a defined amount of the active ingredient, as a powder or granules; as solution or suspension in aqueous or non-aqueous liquid, or in the form of a liquid emulsion of the type oil-in-water or a liquid emulsion of the type water-in-oil. The active ingredient may also be presented in the form of a bolus, paste or electuary (medicinal porridge).

Tablets may be prepared by compressing or molding, sometimes with one or more additional ingredients. Compressed tablets may be prepared by compressing in a suitable tablet press machine the active ingredient in free-free-flowing form such as powder or granules, sometimes mixed with a binder (e.g. povidone, gelatin, hypromellose), lubricant, inert diluent, preservative, loosening means (for example, a sodium salt of glycolate starch, cross-linked povidone, sodium salt of cross-linked carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made formula etki sometimes may be covered or may have grooves and can be shaped so to provide slow or controlled allocation of the contained active ingredient, for example, using hydroxypropylmethylcellulose in varying proportions to provide the desired release profile. Tablets can be sometimes protected intersolubility coating to ensure the selection in parts of the gut other than the stomach.

Compositions suitable for oral administration described above, may also contain buferiruemoi the agents to neutralize acidity in the stomach. Such buffers can be selected from a variety of organic and inorganic agents, such as weak acids or bases mixed with their conjugated salts.

Compositions for topical introduction in the mouth include tablets containing the active ingredient on a flavored basis, usually sucrose and Arabian gum or tragakant, lozenges, containing the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and Arabian gum, and liquid mouth rinse containing the active ingredient and a suitable carrier liquid.

Compositions for rectal injection can be presented in the form of spinaloga introduction can be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to active ingredient, such carriers known that they are suitable for this application.

Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostatic agents and dissolved substances, which make the compositions isotonic with blood recipient, and aqueous and non-aqueous sterile suspensions, which may contain suspendresume agents and thickening agents, such as liposomes or other consisting of microparticles systems intended for the direction of these compounds to blood components or one or more organs. Songs can be submitted in sealed containers for a single dose or multiple doses, e.g., in ampoules or vials, and can be stored in a lyophilized condition requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use.

Not prepared solutions and suspensions for injection can be obtained from sterile powders, granules and tablets opisannyh patches, adapted to remain in close contact with the epidermis of the recipient for a long period of time. Such patches for facilities contain the active ingredient in the form, sometimes buffered, aqueous solution, for example, with a concentration of 0.1-0.2 M active compounds. In a particular embodiment, the active ingredient may be delivered from the patch by iontophoresis as described in General terms in Pharmaceutical Research, 3(6), 318 (1986).

Preferred compositions with standard doses containing a daily dose or unit, daily divided dose or convenient part of the active ingredient, for example, 1-1500 mg, preferably 5-1000 mg, and most preferably 10-700 mg of active ingredient, based on the original connection.

It should be clear that, except as specifically mentioned ingredients, the compositions of this invention may include other agents conventional in this field, corresponding to the type of composition, for example, compositions for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.

Thus, this invention relates also to pharmaceutical compositions, the content is m

The compounds, salts and solvate can be prepared by the method including the interaction of the compounds of formula (II)

< / BR>
where R1-R7and X have the above meanings and Z represents tsepliaeva group, with an amine NR8R9or a suitable derivative. Suitable otsepleniya group include halogen atoms such as chlorine or bromine, activated esters (for example, N-hydroxysuccinimide, pentafluorophenyl, nitrophenyl, 1-hydroxybenzotriazole), mixed anhydrides (for example, ethoxycarbonyl) or C1-C6-alkoxy (for example, ethoxy). The reaction is conveniently carried out in an inert organic solvent (e.g. dichloromethane) at a temperature of approximately-20-120oC and conveniently at about 0-25oC. Suitable amine derivatives are hydrated or cleaners containing hydrochloride derivatives, for example, NH4OH, NH4Cl.

When R8and R9denote H, the compounds of formula (I) can be obtained by the interaction of the compounds of the formula (II), where X denotes a halogen atom such as chlorine or bromine, with an amine in the hydrated form, for example, with NH4OH, in a suitable organic solvent (e.g. dichloromethane) at a temperature of approximately 0-25o1-C6-alkoxy, for example, ethoxypropan, and the hydroxy-group is protected, for example, SiMe2-tert-Bu with the amine represented in the form of hydrochloride, for example, NH4Cl, in the presence of Me3Al in neutral conditions, followed by removal of the protective group in the neutral conditions, for example, p-toluensulfonate pyridinium (ppts).

Alternatively, the compounds of formula (I), where R6or R7denote a hydroxy-group, can be obtained from compounds of formula (I), where R6or R7denote H, halogenoalkanes, for example, N-bromosuccinimide (NBS), followed by hydrolysis, for example, silver carbonate (Ag2CO3). The compounds of formula (I), where R6or R7denote the allylic hydroxy-group, can be obtained from compounds of formula (I) in which R6or R7denote H, by oxidation, for example, selenium dioxide.

The compounds of formula (II), where Z represents a halogen atom, can be obtained from compounds of formula (III)

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in which R1- R7and X have the above values, by interacting with a halogenation agent (for example, oxalylamino or thionyl chloride) in a suitable organicheskoi a temperature of from about -20oC to the boiling temperature under reflux.

The compounds of formula (II), where Z represents alkoxygroup (for example, ethoxypropan), can be obtained from compounds of formula (III) interaction with a suitable polar solvent (e.g., an organic alcohol, such as ethanol) sometimes in the presence of catalytic amount of acid (e.g. p-toluenesulfonic acid) at a temperature of approximately 0oC to the temperature of distillation.

The compounds of formula (II), where Z is an activated ester (described above), can be obtained from compounds of formula (III) interaction with phenol or N-hydroxidealuminum and a carbodiimide (for example, dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3 - ethylcarbodiimide) in a solvent such as dimethylformamide (DMF) or dichloromethane, at 0-50oC.

The compounds of formula (III) can be obtained by dehydration of compounds of formula (IV)

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where R1- R7and X have the above values, the interaction with a suitable dehydrating agent (e.g. acid, such as triperoxonane acid) in a suitable organic solvent (e.g. dichloromethane) at a temperature of from Lenium corresponding C1-C6-Olkiluoto ester base (e.g. sodium hydroxide) in a suitable polar solvent (e.g. ethanol) at a temperature of from about 0oC to the temperature of the distillation or aqueous acid (e.g. hydrochloric acid) at a temperature of from about 0oC to the temperature of distillation.

Esters of compounds of the formula (IV) with R6or R7protected hydroxy groups, for example, secure SiMe2-tert-Bu, can be digidrirovanny in neutral conditions (e.g., Sulfureum Martin, bis [a, a - bis(trifluoromethyl)- benzoimidazole] diphenylether) to obtain the corresponding protected hydroxycodone formula (II), where Z represents a C1-C6-alkoxy (for example, ethoxy).

Esters of compounds of the formula (IV) can be obtained from compounds of formula (V)

< / BR>
where R1-R7and X have the above values interaction with halCH2CO2R, where hal denotes a halogen atom such as chlorine, bromine or iodine, preferably bromine, R represents a C1-6-alkyl (e.g. ethyl), in the presence of a metal (e.g. zinc, preferably activated zinc) and catalytic amounts of halogen (e.g. iodine) is the temperature of the distillation or interaction with the lithium salt of ethyl acetate in a suitable solvent (for example, tetrahydrofuran) at a temperature between -100oC and room temperature (for example, -80 to -70oC).

The compounds of formula (V) with R6or R7protected hydroxy groups, as described above, can be obtained from the corresponding unprotected hydroxycodone formula (V) with a suitable protection under neutral conditions, for example, t-butyldimethylsilyl, in the presence of a base such as imidazole.

The compounds of formula (V) with R6or R7in the form of hydroxyl groups, can be obtained from the corresponding halogen (e.g. bromine) compounds by hydrolysis in neutral conditions, for example, silver carbonate (Ag2CO3).

The compounds of formula (V) with R6or R7as allyl alkyl (e.g. methyl), can be obtained from corresponding compounds of formula (V) in which R6and/or R7represent H, interaction with a base (e.g. sodium hydride) followed by alkylation, for example, methyliodide (MeI).

The compounds of formula (V) can be obtained from compounds of formula (VI).

< / BR>
where R1-R7, X and Z have the above values, predpochtitelnei aluminum in a suitable solvent (for example, dichloromethane) at a temperature of from about 0oC to the temperature of distillation.

The compounds of formula (VI), where Z represents a halogen atom (e.g. chlorine or bromine), can be obtained from the corresponding carboxylic acid by interaction with a halogenation agent (for example, oxalylamino or thionyl chloride) either in pure form or in a suitable organic solvent (e.g. methylene chloride or N,N-dimethylformamide) at a temperature of from about 0oC to the temperature of distillation.

The compounds of formula (VI), where Z represents alkoxygroup (for example, ethoxypropan), can be obtained from compounds of formula (VII)

< / BR>
where R1-R7and X have the above values by interaction with a suitable organic alcohol (e.g. ethanol) sometimes in the presence of catalytic amount of acid (e.g. p-toluenesulfonic acid) at a temperature of from about 0oC to the temperature of distillation.

Carboxylic acids can be obtained by saponification of the corresponding C1-6-alilovic ethers base (e.g. sodium hydroxide) in a suitable polar solvent, e.g. water or ethanol) at a temperature of arr is E. from about 0oC to the temperature of distillation.

Carboxylic acid, where X is oxygen, can be obtained from compounds of formula (VIII)

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where R and R1-R6have the above values, and n denotes 0 or 1, mono deesterification strong base (such as aqueous potassium hydroxide) at a temperature of distillation.

The compounds of formula (VIII) can be obtained by reaction of compounds of formula (IX) with the compound of the formula (X)

< / BR>
where R, R1-R6and n have the above meanings and Hal denotes Cl, Br or I (preferably Br), in an organic solvent (e.g. anhydrous diethyl ether) and sometimes in the presence of copper halide (e.g. iodide copper (I)) at temperatures between -50oC and distillation temperature.

The compounds of formula (IX) can be obtained by reaction of compounds of formula (XI) with the compound of the formula (XII)

< / BR>
where R, R5and R6have the above meanings and m denotes 1 or 2, in an organic solvent (e.g. ethyl ether or dichloromethane) at a temperature between room temperature and the distillation temperature.

The compounds of formula (X) can be obtained from the corresponding halogenated compounds (halogenoalkane can be obtained from commercially available means, well-known experts in the field or taken from the chemical literature.

Alternatively, the compounds of formula (IX) can be obtained according to method E. Z. Eliel, R. O. Hutchins, and Sr.M. Knoeber, Organis Synthesis Coll. Vol. VI, 442, 1988 with modifications, readily apparent to experts in this field.

Compounds of formulas (XI) and (XII) may be commercially available or obtained by methods well known to specialists in this field or taken from the chemical literature.

Alternative these esters can be obtained from compounds of formula (XIII)

< / BR>
where R, R1-R4, R6and R7have the above values by restoring the double bond, for example, by catalytic regeneration, for example, platinum oxide (PtO2) and hydrogen in a suitable organic solvent (e.g. ethanol) at a temperature of approximately 20-60oC.

If X represents oxygen, esters can be obtained by reaction of compounds of formula (XIV) with the compound of the formula (XV)

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where R, R1-R6and Z have the above meanings, in a suitable organic solvent in the presence of a base (e.g. sodium hydride).

Compounds of formula (XIV) or taken from the chemical literature.

The compounds of formula (XIII) can be obtained from compounds of formula (XVI)

< / BR>
where R1-R4, R6and R7have the above values, by the esterification of a suitable organic alcohol (e.g. ethanol), optionally in the presence of catalytic amount of acid (e.g., HCl, p-toluenesulfonic acid, thionyl chloride) at a temperature of approximately 20-60oC.

The compounds of formula (XVI) can also be used to directly obtain the corresponding unsaturated acids by restoring the double bond, i.e., catalyst recovery, for example, palladium or platinum oxide (PtO2and hydrogen, in a suitable organic solvent (e.g. ethanol) at a temperature of from about 0oC to the temperature of distillation.

The compounds of formula (XVI) can be obtained from compounds of formula (XVII)

< / BR>
where R1-R4and R6have the above values, interaction with HOOCCHR7COOH in an organic base (e.g. pyridine), optionally in an organic solvent (e.g. dichloromethane), optionally with a catalytic amount of base (e.g., piperidine) at a temperature of approximately the ski available or obtained by means well-known experts in this field or described in the chemical literature.

Alternatively, the compounds of formula (I) can be obtained by the interaction of R8R9NCOCH2PO(OR)2(where R, R8, R9have the values indicated above) with a base (such as NaH) in a suitable organic solvent (such as THF or DMSO) and the interaction of the obtained anionic sample with the compound of the formula (VI) or formula (VIa), respectively, at a temperature of from about 0oC to the temperature of distillation. The reaction is facilitated by the addition of anionic stabilizing reagent (for example, hexamethyldisilazane potassium or crown ether (15-crown-5).

Connection R8R9NCOCH2PO(OR)2maybe, depending on R, R8and R9to be commercially available or obtained by methods well known in the art or described in the chemical literature. Alternatively, these compounds can be obtained by the interaction of a suitable R8R9NCOCH2Z (where Z has the above meaning) with a suitable P(OR)3in an organic solvent (such as THF) at a temperature of approximately 0-50oC.

Connection R8Rwho administers an organic solvent (for example, diethyl ether) at a temperature of from about 0oC to the temperature of distillation.

Connection R8R9NH may be commercially available or obtained by methods well known to experts in the field of production of amines or described in the chemical literature. Connection ZCH2COZ may be obtained commercially or by methods known to experts in the field of production of such compounds or described in the chemical literature.

Alternatively, the compounds of formula (I) can be obtained by the interaction of R8R9NCOCH2P(+)(Ph))3Cl(-) (where R8, R9and Z have the values indicated above) with a suitable base (such as NaH) in a suitable organic solvent (for example, dimethoxyethane) at a temperature of approximately 0-50oC and cooperation received anionic product with the compound of the formula (V) at a temperature of from about 0oC to the temperature of distillation.

Connection R8R9NCOCH2P(+)(Ph)3Cl(-) can be obtained by reaction of a suitable R8R9NCOCH2Z with a 50% molar excess of P(Ph)3(triphenylphosphine) in a suitable organic solution is UP>R9NCOCH2Z can be obtained as described earlier.

Alternatively, the compounds of formula (I) can also be obtained directly from compounds of formula (III) interaction of a suitable binding agent (for example, dicyclohexylcarbodiimide (DCC) or ethylchloride) with subsequent interaction educated thus activated ester with a suitable amine, HNR8R9.

Alternatively, the compounds of formula (I), where R5represents hydrogen, a R6represents a hydroxy-group, can be obtained from compounds of formula (I) in which R5and R6together form a carbonyl group, by restoring this carbonyl group using a suitable reducing agent, e.g. sodium borohydride, in a suitable solvent, such as alkanol (e.g., ethanol).

The compounds of formula (I), as well as any of the intermediate products, used in obtaining these compounds can be subjected to one or more of the following optional conversions:

(i) converting the compounds of formula (I) or intermediates in their salt,

(ii) in the formation of salts of the compounds of CNY product.

The following examples illustrate the invention but do not restrict it.

Example 1

Obtaining (E)-2-(6-fluoro-1-inderide)ndimethylacetamide

a) Obtaining 3-(4-forfinal)propionic acid

A mixture of 4-tortorice acid (300,0 g, 1.8 mol, Aldrich) and 5% palladium on coal (9.0 g) in ethanol (3 l) was first made at atmospheric pressure and room temperature for 4.5 hours, the Mixture was filtered through celite (diatomaceous earth) and the filtrate was concentrated in vacuum, obtaining 275,1 g (91%) of 3-(4-forfinal)propionic acid as a white solid, so square 86-88oC.

b) Obtaining 3-(4-forfinal)propionitrile

A mixture of 3-(4-forfinal)propionic acid (275,1 g of 1.6 mol) and thionyl chloride (300 ml, of 4.1 mol) was heated under reflux for 3 hours, cooled to room temperature and distilled in a water jet vacuum pump, receiving 287,6 g (96%) of 3-(4-forfinal)propionitrile in the form of a pale pink oil, so Kip. 120-122oC/15 mm Hg.

C) Obtaining 6-fluoro-1-indanone

A solution of 3-(4-forfinal)propionitrile (287,6 g, a 1.5 mol) in dichloromethane (1.4 l) was added dropwise over 3 h to a cooled on ice mechanically stirred suspension of aluminium chloride (226,0 g to 1.7 mol, Aldrich) in dij is within 5 h and gave it to cool to room temperature.

The solution was washed successively with water (2 l), 1 N. sodium hydroxide (2 l), water (2 l) and brine (2 l). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a reddish-brown liquid (229,1 g, 99%). The liquid was recrystallized from a mixture of dichloromethane-hexane, obtaining 215,7 g (93%) of 6-fluoro-1-indanone in the form of crystals custom white color, so pl. 57-59oC.

d) Obtaining ethyl-2-(6-fluoro-1-hydroxy-1-indanyl)acetate

(i) a Mixture of 6-fluoro-1-indanone (5.0 g, a 33.3 mmole), ethylbromoacetate (8,3 g, 50.0 mmol, Aldrich), activated powdered zinc (3.2 g, 50.0 mmol, Mallinckrodt; Org. Synth., Coll. Vol. 6, 290, 1988) and a few crystals of iodine in a mixture of diethyl ether-benzene (1:1, 100 ml) was heated under reflux in nitrogen atmosphere for 24 hours. The mixture was filtered and the filtrate was concentrated in vacuum. The residue in diethyl ether was intensively stirred with excess dilute aluminum hydroxide, dried and concentrated, obtaining ethyl-2-(6-fluoro-1-indanyl)acetate in the form of an amber oil (7.6 g, 97%).

(ii) Acetate (1.8 g, 20 mmol) was added in drops to a stirred cooled (in a bath of acetone with dry ice) 1 H. to a solution of bis(trimethylsilyl)amide lithium in tetrahydrofuran (20 ml) and the resulting mixture was stirred for 1 hour in a bath with a dry ice-acetone). Added 1N hydrochloric acid (20 ml) and the mixture was allowed to warm to room temperature. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to a pale yellow oil (5.3g). The mixture was chromatographically on silica gel 60 using a linear gradient of dichloromethane-hexane (1:1) - dichloromethane as eluent. The fractions containing only the ethyl-2-(6-fluoro-1-hydroxy-1-indanyl)acetate were combined and concentrated in vacuum, obtaining 3.1 g (65%) of colorless oil.

e) Obtaining 2-(6-fluoro-1-hydroxy-1-indanyl)acetic acid

A mixture of ethyl-2-(6-fluoro-1-hydroxy-1-indanyl)acetate (44,0 g of 0.18 mol), 1 n sodium hydroxide (180 ml) and absolute ethanol (280 ml) was stirred for 18 hours at room temperature. The mixture was concentrated in vacuo, added an H2O and was extracted with diethyl ether. A layer of diethyl ether was washed with saline, dried over sodium sulfate and concentrated in vacuum, obtaining 2-(6-fluoro-1-hydroxy-1-indanyl)acetic acid as an amber oil (37,7 g, 100% note: this connection spontaneously dehydratases upon standing at room temperature to a mixture of olefins, if it is not immediately exposed to interaction with Tr-fluoro-1-hydroxy-1-indanyl)acetate (2.0 g, 8.4 mmole) of 1 n lithium hydroxide (8,4 ml) and absolute ethanol (13,0 ml) was stirred for 18 hours at room temperature. The mixture was concentrated in vacuum, diluted with H2O and was extracted with diethyl ether. The aqueous phase was concentrated in vacuum, diluted with toluene (100 ml) and concentrated in vacuum, obtaining 2-(6-fluoro-1-hydroxy-1-indenyl)lithium acetate as a white solid (1.4 g, 77%)

g) Obtaining (E)-2-(6-fluoro-1-inderide)acetic acid

Triperoxonane acid (1.5 ml) was added to a stirred cooled (bath with ice and methanol) suspension of 2-(6-fluoro-1 - hydroxy-1-indanyl)of lithium acetate (0.5 g, 2.3 mmole) in dichloromethane (13.5 ml). After 15 minutes the mixture was concentrated in vacuo and the resulting white solid was recrystallized from aqueous acetone, obtaining (E)-2-(6-fluoro-1-inderide)acetic acid as white crystals (0.32 g, 73%), identical to the compound of example 1i in so pl. mixture 203-205oC and NMR.

h) Obtaining (E)-2-(6-fluoro-1-inderide)acetic acid

Triperoxonane acid (100 ml) was added to a stirred cooled (bath with ice and methanol) solution of 2-(6-fluoro-1-hydroxy-1-indanyl)acetic acid (37.5 g, 0,18 mol) in dichloromethane (900 ml). After 15 minutes the mixture is newago solids (33,0 g, 95%), so pl. 203-205oC.

i) Obtaining (E)-2-(6-fluoro-1-inderide)acetylchloride

Chilled on ice stir a suspension of (E)-2-(6-fluoro-1-inderide)acetic acid (384 mg, 2 mmole) in benzene was treated with oxalylamino (761 mg, 6 mmol) and allowed it to warm to room temperature for 1.5 hours. The obtained yellow solution was concentrated in vacuum, obtaining (E)-2-(6-fluoro-1-inderide)acetylchloride in the form of a pale yellow solid (421 mg, 100%), so pl. 97-99oC.

j) Obtaining (E)-2-(6-fluoro-1-inderide)ndimethylacetamide

29,6% aqueous ammonium hydroxide solution (17.6 ml, 134 mmole) was added dropwise to a stirred, cooled (bath with ice) solution of (E)-2-(6-fluoro-1-inderide)acetylchloride (14.1 g, 67 mmol) in dichloromethane (165 ml). After 1 hour, the obtained white precipitate was collected by filtration, dissolved in ethyl acetate (600 ml) and washed with water (I ml). The ethyl acetate layer was dried over sodium sulfate and concentrated in vacuum. The obtained solid is not completely white washed with hexane, obtaining 11.6 g (91%) of (E)-2-(6-fluoro-1-inderide)ndimethylacetamide, so pl. 180-183oC.

Example 2

Obtaining (E)-2-(6-fluoro-1-inderide)ndimethylacetamide

Stir a suspension of (E)-2-(6-fluoro-1-indan is the NML etelcharge.com (0.3 g, 2.6 mmole, Aldrich) and triethylamine (0.3 g, 2.6 mmole, Eastman). The mixture was stirred at -20oC for 2 hours was Added anhydrous ammonia in dichloromethane (0.8 M, 12 ml) (note: when using aqueous ammonium hydroxide mixed anhydride partially hydrolizable to acid), the mixture was stirred for 16 hours at room temperature and then washed successively with water, sodium bicarbonate solution, water and brine. The dichloromethane layer was dried over sodium sulfate, filtered and concentrated in vacuum, obtaining 0.18 g of a mixture of 6: 1 (E)-2-(6-fluoro-1-inderide)ndimethylacetamide and 2-(5-fluoro-1H-inden-3-yl)ndimethylacetamide.

Example 3

Obtaining (E)-N-ethyl-2-(6-fluoro-1-inderide)ndimethylacetamide

This compound was obtained analogously to receive in example 5, with the substitution used in example 5 cyclopropylamine ethylamine (70 wt.% in water). Obtained by chromatography solutions, the content of (E)-N-ethyl-2-(6-fluoro-1-inderide)ndimethylacetamide, concentrated on a rotary evaporator under vacuum. Recrystallization of the residue from a mixture of dichloromethane-hexane gave 1.7 g (68%) of (E)-N-ethyl-2-(6-fluoro-1-indolenine)ndimethylacetamide, so pl. 125-126oC.

Example 4

Obtaining (E)-N-cyclopropyl-2-(6-fluoro-1-inderide)ndimethylacetamide

To a chilled on ice is in (1.65 g, 28,86 mmole) and the reaction mixture was heated to room temperature over night. The mixture is evaporated in vacuo to a solid residue. The residue was dissolved in ethyl acetate (300 ml), washed with water (75 ml) and the organic layer was concentrated by rotary evaporation under vacuum. The residue was chromatographically on silica gel using a mixture of ETHYLACETYLENE (0:1 to 1:1 gradient) as eluent. The fractions containing only the reaction product, were combined and concentrated by rotary evaporation under vacuum. Recrystallization of the residue from a mixture of dichloromethane-hexane gave 1.6 g (76%) of (E)-N-cyclopropyl-2-(6-fluoro-1-inderide)ndimethylacetamide in the form of a white powdered solid substance, so pl. 124-127oC.

(E)-N-ethyl-2-(6-fluoro-1-Indonesien)-N-methylacetamide was obtained similarly by replacing cyclopropylamine N-ethylmethylamine (3.5 ml, 0,025 mol, Aldrich). The residue was chromatographically on silica gel using a mixture of ethyl acetate-hexane (gradient 1: 5 to 1:2) as eluent. Chromatographic fractions containing (E)-N-ethyl-2-(6-fluoro-1-Indonesien)-N - methylacetamide, concentrated by rotary evaporation under vacuum. Recrystallization of the residue from a mixture of ethyl acetate-hexane gave 1,32 g (61%) of (E)-N-ethyl-2-(6-fluoro-1-Indonesien)-N-methylacetamide den)ndimethylacetamide

a) Obtaining 3-(2,4-differenl)propanoic acid

A mixture of 2,4-deformational acid (30.0 g, 0,16 mol, Aldrich) and hydrate platinum oxide (0.5 g, EM Scientific ) in 95% ethanol (140 ml) was placed in a Parr apparatus for hydrogenation. After absorbing a certain amount of hydrogen the catalyst was filtered and the filtrate was concentrated in vacuum, obtaining and 29.7 g (98%) of 3-(2,4-differenl)propanoic acid as a white solid. Recrystallization 1.0 g of mixtures of acetonitrile:water gave 0.61 g of 3-(2,4-differenl)propanoic acid as a white solid, so pl. 104-106oC NMR (DMSO-d6): d 12,2 (width, 1H), 6,98-7,40 (m, 3H), of 2.81 (t, 2H), of 2.51 (t, 2H).

Anal.calculated for C9H8F2O2(mol. weight 186,15): C 58,06, H of 4.38.

Found: C 57,94, H 4,36.

b) Obtaining 4,6-debtor-1-indanone

To a mixture of 3-(2,4-differenl)propanoic acid (28,7 g to 0.15 mole) and dimethylformamide (5 drops) at ambient temperature was added dropwise oxalicacid (50 ml, Aldrich). The mixture was stirred at ambient temperature for 18 hours. Excess oxalicacid was removed by distillation in vacuum, obtaining 3-(2,4-differenl)propionate. A solution of 3-(2,4-differenl) propionitrile in dichloromethane (300 ml) was added papaverine added, the mixture boiled under reflux for 3.5 hours and allowed it to warm to ambient temperature overnight. The reaction mixture was poured into ice water (1500 ml), the two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed sequentially with 0.1 N. aqueous sodium hydroxide and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuum, obtaining of 21.7 g of the crude 4,6-debtor-1-indanone. Chromatography on silica gel using a mixture of hexane: dichloromethane (3: 1) as eluent gave 10.1 g of light yellow solid. Recrystallization 0.5 g from mixtures of acetone:water gave 0.2 g of 4,6-debtor-1-indanone as a white solid, so pl. 97-99oC NMR (CDCl3d 7,02-7,27 (m, 2H), 3,12 (t, 2H), was 2.76 (m, 2H).

Anal. calculated for C9H6F2O (mol. weight 168,14): C 64,29, H 3,60.

Found: C 64,18, H 3.61.

c) Obtaining ethyl-2-(4,6-debtor-1-hydroxy-1-indanyl)acetate

A mixture of 4,6-debtor-1-indanone (12,6 g of 0.08 mol), ethyl-bromoacetate (19,0 g of 0.11 mol, Aldrich) of activated zinc powder (7.5 g, of 0.11 mol, Aldrich, Org. Syn. Coll. Vol. 6, 290, 1988) and a few crystals of iodine in diethyl ether: toluene (1: 1, 300 ml) was heated at 30-35oC in nitrogen atmosphere for 24 hours. Added a little crystal of iodine is added, the temperature was brought up to 40-45oC and the mixture vyd was treated with a mixture of diethyl ether (450 ml), concentrated ammonium hydroxide (135 ml) and water (135 ml). The aqueous phase was separated and was extracted with diethyl ether. The combined organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuum, obtaining an increase of 22.7 g of the crude ethyl-2-(4,6-debtor-1-hydroxy-1-indanyl)acetate, which was chromatographically on silica gel using a mixture of dichloromethane:hexane (9:1) as eluent, receiving 12.7 g (66%) of yellow oil, NMR (CDCl3); d 6,67-to 6.88 (m, 2H), 4,22 (K, 2H), to 3.02 (m, 1H), 2,75 (2m, 3H), 2,31 (m, 2H), 1.28 (in t, 3H).

Anal. calculated for C13H14F2O3(mol. weight 256,24): C 60,93, H 5,51.

Found: C 60,68, H 5,50.

d) Obtaining 2-(4,6-debtor-1-hydroxy-1-indanyl)acetic acid

A mixture of ethyl-2-(4,6-debtor-1-hydroxy-1-indanyl)acetate (12.0 g, 0,147 mole) and 1.0 n sodium hydroxide (48 ml, 0,048 mole, Universal Scientific Supply Co. ) in ethanol (75 ml) was stirred for 18 hours at ambient temperature. The reaction mixture was concentrated in vacuum, diluted with water and washed with diethyl ether. The aqueous phase was neutralized with 1.0 G. hydrochloric acid (48 ml, 0,048 mole, Universal Scientific Supply Co.) and was extracted with diethyl ether. Extract diethyl ether was dried debtor-1-hydroxy-1-indanyl)acetic acid. This material was used immediately without further purification.

e) Obtaining (E)-2-(4,6-debtor-1-inderide)acetic acid

Triperoxonane acid (39.9 g, of 0.35 mol) was added dropwise to a stirred, cooled (bath of methanol with ice) mixture of 2-(4,6-debtor-1-hydroxy-1-indanyl)acetic acid (11.3 g, 0.05 m) in dichloromethane (250 ml). After 35 minutes, the mixture was concentrated in vacuum. To the residue was added dichloromethane and the mixture was concentrated in vacuum. This procedure was repeated once more, gaining 6.4 g of crude (E)-2-(4,6-debtor-1-inderide)acetic acid. Recrystallization 0.9 g of a mixture of acetone:water gave 0.15 g (E)-2-(4,6-debtor-1-inderide)acetic acid as a white solid, so pl. 238-239oC NMR (DMSO-d6): d 12,25 (width, 1H), 7.23 percent-of 7.65 (m, 2H), 6,46 (t, 1H), 3,20-3,28, 2,97-3,20 (2m, 4H), AEO (nuclear Overhauser effect) in the steady state: lighting. when 6,46 d observed AAO to 21.6% at 7,63 d.

Anal. calculated for C11H8F2O2(mol. weight 210,17): C 62,86, H 3,84.

Found: 62,76, H 3,86.

f) Obtaining (E)-2-(4,6-debtor-1-inderide)acetylchloride

A suspension of (E)-2-(4,6-debtor-1-inderide)acetic acid (5.49 g, was 0.026 mole) in a mixture of dichloromethane:dimethylformamide (50 ml: 5 drops) was treated with oxal Astor was concentrated in vacuo and the residue used without further purification.

g) Obtaining (E)-2-(4,6-debtor-1-inderide)ndimethylacetamide

30% aqueous ammonium hydroxide solution (1.7 ml, was 0.026 mol) was added dropwise to a stirred, cooled (ice bath) solution of (E)-2-(4,6-debtor-1-inderide)acetylchloride (2,97 g of 0.013 mol) in dichloromethane (50 ml). After 4.5 hours the mixture was concentrated in vacuo and the residue was distributed between 5% solution in water of sodium bicarbonate and ethyl acetate. The ethyl acetate was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuum. Chromatography on silica gel using a mixture of ethyl acetate: hexane (7:3) as eluent and kneading the obtained solid with pentane gave 1.63 g (60%) of (E)-2-(4,6-debtor-1-inderide)ndimethylacetamide in the form of a white solid substance, so pl. 178-180oC NMR (DMSO-d6): d 6,04 was 7.45 (m, 4H), 6,46 (s, 1H), 2,94-3,00, 3,21-3,27 (2m, 4H): AEO stationary state: lighting. when 6,46 d, the observed AAO 19% at 7,26 d.

Anal. calculated for C11H9F2NO (mol. weight 209,19): C 63,15, H 4,34, N 6,70.

Found: C 63,07, H 4,36, N 6,67.

h) Obtaining (E)-2-(4-chloro-1-inderide)acetic acid

Triperoxonane acid (25.1 ml) was added to a stirred, cooled (bath with methanol and ice) solution of 2-(4-Chlo in vacuum. To the residue was added dichloromethane and the mixture was concentrated in vacuum, obtaining 6.5 g (68%) of white solids. Recrystallization 0,98 g from mixtures of acetonitrile: 2-propanol gave of 0.62 g of a white solid substance, so pl. 233-234oC NMR (DMSO-d6): d 12,15 (width, 1H, COOH), 7,30-for 6.81 (m, 3H, A), 6,41 (s, 1H, =CH), 3,00-3,06, 3,19-3,22 (2m, 4H, HSN2), AEO stationary state: lighting. when 6,41 d, the observed AAO of 19.7% at 7,79 d.

i) Obtaining (E)-2-(4-chloro-1-inderide)acetylchloride

A suspension of (E)-2-(4-chloro-1-inderide)acetic acid (5.5 g, of 0.03 mole) in a mixture of dimethylformamide: dichloromethane (5 drops: 50 ml) was treated with oxalylamino (6.6 g, 0.05 m) and stirred at room temperature for 16 hours. The resulting solution was concentrated in vacuo and the residue used without further purification.

j) Obtaining (E)-2-(4-chloro-1-Indonesien)-N-cyclopropylacetic

Chilled on ice, a solution of (E)-2-(4-chloro-1-inderide)acetylchloride (2,95 g of 0.013 mol) in dichloromethane (30 ml) was treated with cyclopropylamine (1.48 g, 0,026 mol, Aldrich) and the mixture was stirred for 4 hours. The mixture was concentrated in vacuo and the residue was collected with a mixture of ethyl acetate and 5% aqueous sodium bicarbonate. The ethyl acetate phase washed with 5% aqueous sodium bicarbonate, saturated the product. Chromatography on silica gel using a mixture of ethyl acetate:hexane (1:1) as eluent and kneading the obtained solid from hexane gave 2.46 g (76%) of (E)-2-(4-chloro-1-Indonesien)-N-cyclopropylacetic in the form of solids non-standard white: so pl. 140-142oC NMR (DMSO-d6): d is 8.16 (d, 1H, NH), 7,29-7,51 (m, 3H, Ar), 6,34 (t, 1H, = CH), 2,93-3,07, 3,18-3,31 (2m, 4H, HSN2), of 2.72 (m, 1H, CH), 0,62-0,72, 0,39-0,47 (2m, HSN2), AEO stationary state: lighting. when 6,34 d observed 20,3% AAA when 7,46 d.

Anal. calculated for C14H14ClNO (mol. weight 247,72): C 67,88, H 5,70, N 5,65.

Found: C 67,86, H 5,74, N 5,58.

Example 6

Obtaining (E)-N-cyclopropyl-2-(4,6-debtor-1-Indonesien)- ndimethylacetamide

Chilled on ice, a solution of (E)-2-(4,6-debtor-1-Indonesien)- acetylchloride (2,97 g of 0.013 mol) in dichloromethane (30 ml) was treated with cyclopropylamine (1.48 g, 0,026 mol, Aldrich) and the mixture was stirred for 4 hours. The mixture was concentrated in vacuo and the residue was collected with a mixture of ethyl acetate and 5% aqueous sodium bicarbonate. An ethyl acetate phase is washed with 5% aqueous sodium bicarbonate, saturated aqueous NaCl and dried over sodium sulfate. Chromatography on silica gel using a mixture of ethyl acetate:hexane (1:1) as eluent and rubbing receiving the th solids: I. pl. 156-158oC.

Example 7

Obtaining (E)-2-(4-fluoro-1-inderide)ndimethylacetamide

a) Obtaining ethyl-2-vertinamte

A solution of 2-tortorice acid (48,4 g of 0.29 mol, Aldrich) and thionyl chloride (5 ml) in ethanol (650 ml) was heated under reflux for 48 hours. The mixture was concentrated in vacuum. The residue was absorbed with ethyl acetate, washed sequentially with 5% aqueous sodium bicarbonate solution, water and brine and dried over sodium sulfate. Filtration and concentration gave 54,25 g (96%) of crude ethyl-2-vertinamte. This material was used without further purification.

b) Obtaining ethyl-3-(2-forfinal)propionate

A mixture of ethyl-2-vertinamte (29,25 g, 0,176 mol) and hydrate oxide of palladium (0.25 g, EM Scientific) in 95% ethanol (150 ml) was placed in a Parr apparatus for hydrogenation and rocked under pressure 2-4 bar of hydrogen. After the consumption of a sufficient amount of hydrogen the catalyst was removed by filtration and the filtrate was concentrated in vacuum, obtaining 29,39 g (99%) of crude ethyl-3-(2-forfinal)propionate. This material was used without further purification.

c) Obtaining 3-(2-forfinal)propionic acid

A mixture of ethyl-3-(2-forgeryproof (25,54 g, 0,130 mole) and 50% aqueous RA is placed and the mixture was washed with diethyl ether (CH ml). The aqueous phase was cooled in a bath of ice and the pH was set equal to 3 using hydrochloric acid. The resulting white precipitate was collected by filtration, washed several times with water and dried in vacuum at 60oC for 18 hours, getting 18,66 g (85%) of 3-(2-forfinal)propionic acid as a white solid, so pl. 72-74oC. This material was used without further purification.

d) Obtaining 4-fluoro-1-indanone

To a mixture of 3-(2-forfinal)propionic acid (18,64 g, 0,111 mole) and dimethylformamide (5 drops) at room temperature was added dropwise oxalicacid (60 ml). The mixture was stirred at room temperature until gas evolution stops. Excess oxalicacid was removed by distillation, obtaining 3-(2-forfinal)propionate. A solution of 3-(2-forfinal)propionitrile in dichloromethane (230 ml) was added dropwise to a mixture of aluminium chloride (16,25 g, 0.12 moles) in dichloromethane (230 ml) and the mixture was delegirovali for 3.5 hours. The reaction mixture was poured into ice water (1200 ml) and was divided in two phases. The dichloromethane phase was washed sequentially with 0.1 N. aqueous sodium hydroxide (CH ml), water (200 ml) and brine (200 ml), dried over sodium sulfate, filtered and concentrated in vacuum. Residual is 4-fluoro-1-indanone as a yellow solid. Recrystallization from mixtures of acetone:water gave 8,02 g (48%) of 4-fluoro-1-indanone as a pale yellow solid: so pl. 71-72oC NMR (DMSO-d6): d 7,51 (m, 3H, Ar), of 3.13 (t, 2H, CH2), is 2.74 (t, 2H, CH2).

Anal. calculated for C9H7FO (mol. weight 150, 152): C 71,99, H 4,70.

Found: C 71,86, H 4,79.

e) Obtaining ethyl-2-(4-fluoro-1-hydroxy-1-indanyl)acetate

This compound was obtained in a manner analogous to the one described in example 5C for ethyl-2-(4,6-debtor-1-hydroxy-1-indanyl)acetate, replacing 4-fluoro-1-indanone (15,53 g, 0,103 mole) of 4,6-debtor-1 - indanone. Chromatography on silica gel with a mixture of ethyl acetate:hexane (19:1) as eluent gave 19,11 g (78%) of ethyl-2-(4-fluoro-1 - hydroxy-1-indanyl)acetate which was used without further purification.

f) Obtaining 2-(4-fluoro-1-hydroxy-1-indanyl)acetic acid

This compound was obtained in a manner similar to that described for 2-(4,6-debtor-1-hydroxy-1-indanyl)acetic acid in example 5d, substituting ethyl-2-(4-fluoro-1-hydroxy-1-indanyl) acetate (of 17.35 g, 0,0728 mole) ethyl-2-(4,6-debtor-1-hydroxy-1 - indanyl)acetate and getting quantitative yield of the crude 2-(4-fluoro-1-hydroxy-1-indanyl)acetic acid. This material was used directly without further purification.

isonomy for (E)-2-(4,6-debtor-1-inderide)acetic acid in example 5e, substituting 2-(4-fluoro-1-hydroxy-1-indanyl)acetic acid (14.6 g, 0,069 mole) of 2-(4,6-fluoro-1-hydroxy-1-indanyl)acetic acid and receiving crude (E)-2-(4-fluoro-1-inderide)acetic acid. Recrystallization from mixtures of acetonitrile: 2-propanol gave 6.85 g (52%) of (E)-2-(4-fluoro-1-inderide)acetic acid as a white solid, so pl. 249-251oC.

h) Obtaining (E)-2-(4-fluoro-1-inderide)acetylchloride

This compound was obtained in a manner similar to that described for (E)-2-(4,6-debtor-1-inderide)acetylchloride in example 5f, replacing (E)-2-(4-fluoro-1-inderide)acetic acid (5,77 g of 0.03 mol) of (E)-2-(4,6-debtor-1-inderide)acetic acid. The resulting solution was concentrated in vacuo and the residue used without further purification.

i) Obtaining (E)-2-(4-fluoro-1-inderide)ndimethylacetamide

Chilled on ice, a solution of (E)-2-(4-fluoro-1-indaniel) acetylchloride (2,11 g of 0.01 mol) in dichloromethane (65 ml) was treated with 30% aqueous ammonium hydroxide solution (2,63 ml of 0.02 mol) and the mixture was stirred for 18 hours. Hexane was added to the mixture and the solid material was collected by filtration, getting 1.63 g of the crude product. Recrystallization from mixtures of acetonitrile: water gave 1,11 g (58%) of (E)-2-(4-fluoro-1-inderide)ndimethylacetamide in the form of a white is n)ndimethylacetamide

Chilled on ice, a solution of (E)-2-(4-fluoro-1-inderide) acetylchloride (2,11 g 0,010 mol) in dichloromethane (65 ml) was treated with cyclopropylamine (1.39 ml of 0.02 mol) and the mixture was stirred for 18 hours. Hexane was added to the mixture and the solid material was collected by filtration and washed successively with water and hexane, obtaining 1.22 g of the crude product. Recrystallization from mixtures of acetonitrile:water gave 0,83 g (36%) of (E)-2-N-cyclopropyl-(4-fluoro-1-inderide)ndimethylacetamide in the form of a white solid substance, so pl. 121-122oC.

Example 9

Obtaining (E)-2-(5-fluoro-1-inderide)ndimethylacetamide

a) Obtaining ethyl-2-(5-fluoro-1-hydroxy-1-indanyl)acetate

This compound was obtained in a manner analogous to the one described in example 5C for ethyl-2-(4,6-debtor-1-hydroxy-1-indanyl)acetate, substituting 5-fluoro-1-indanone (14,77 g, 0,098 mole, Fairfield) of 4,6-debtor-1-indanone. Chromatography on silica gel with a mixture of ethyl acetate:hexane (9:1) as eluent gave 19,56 g (83%) of analytically pure ethyl-2-(5-fluoro-1-hydroxy-1-indanyl)acetate as a pale yellow oil, NMR (CDCl3): d 6,88-7,30 (m, 3H, Ar), and 5.30 (s, 1H, OH), 4,20 (K, 2H, CH2CH3), 2,66-is 3.08 (m, 4H, 2CH2), is 2.30 (t, 2H, CH2Ar) of 1.28 (t, 3H, CH3).

Anal. calculated for C13H15FO3(mol. weight is the notes

This compound was obtained in a manner analogous to that described for 2-(4,6-debtor-1-hydroxy-1-indanyl)acetic acid in example 5d, substituting ethyl-2-(5-fluoro-1-hydroxy-1-indanyl)acetate (19,55 g, 0,082 mole) ethyl-2-(4,6-debtor-1-hydroxy-1-indanyl)acetate and receiving 14,70 g (84%) of crude 2-(5-fluoro-1-hydroxy-1-indanyl)acetic acid as a white solid. This material was used immediately without further purification.

C) Obtaining (E)-2-(5-fluoro-1-inderide)acetic acid

This compound was obtained in a manner analogous to that described for (E)-2-(4,6-debtor-1-inderide)acetic acid in example 5e, substituting 2-(5-fluoro-1-hydroxy-1-indanyl)acetic acid (14,70 g, 0,069 mole) of 2-(4,6-debtor-1-hydroxy-1-indanyl)acetic acid. Recrystallization from mixtures of acetonitrile: 2-propanol gave 9,05 g (68%) of (E)-2-(5-fluoro-1-inderide)acetic acid as a white solid, so pl. 240-242oC.

d) Obtaining (E)-2-(5-fluoro-1-inderide)acetylchloride

This compound was obtained in a manner analogous to that described for (E)-2-(4,6-debtor-1-inderide)acetylchloride in example 5f, replacing (E)-2-(5-fluoro-1-inderide)acetic acid (5,77 g of 0.03 mol) of (E)-2-(4,6-debtor-1-inderide)acetic acid. The resulting solution was concentrated in vacuo>/BR>This compound was obtained in a manner analogous to that described for (E)-2-(6-fluoro-1-inderide)ndimethylacetamide in example 1k, substituting (E)-2-(5-fluoro-1-inderide)acetylchloride (3,16 g 0,015 mol) of (E)-2-(6-fluoro-1-inderide)acetylchloride. Recrystallization from mixtures of acetonitrile:water gave 1.28 g (44%) of (E)-2-(5-fluoro-1-inderide)ndimethylacetamide in the form of a white solid substance, so pl. 191-193oC.

Example 10

Obtaining (E)-N-cyclopropyl-2-(5-fluoro-1-inderide)ndimethylacetamide

A solution of (E)-2-(5-fluoro-1-inderide)acetic acid (0.97 g, of 0.005 mol), 1-hydroxybenzotriazole (0.68 g, 0,005 mol, Fluka), cyclopropylamine (0,35 ml of 0.005 mol, Aldrich) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.96 g, 0,005 mol, Sigma), which was added last, in dimethylformamide (15 ml) was stirred at room temperature for 18 hours and the solution was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed sequentially with 5% aqueous citric acid solution (g ml), saturated aqueous sodium bicarbonate (g ml) and brine and was dried over sodium sulfate. The solution was concentrated in vacuum, obtaining the crude (E)-N-cyclopropyl-2-(5-fluoro-1-inderide)ndimethylacetamide. Chromatography on silica gel with elution by the mixture hexane:ethyl acetate (1:1) CLASS="ptx2">

Example 11

Alternative obtaining (E)-2-(6-fluoro-1-inderide)ndimethylacetamide

To ice stirred suspension of NaH (60% dispersion in mineral oil, 12,41, y, 60,25 mmole, Aldrich) in tetrahydrofuran (30 ml) with 15-crown-5 (3,96 g, 17,98 mmole, Aldrich) was added under nitrogen diethylcarbamazine (11,7 g, 59,97 mmole, K&K-IC) and 6-fluoro-1-indanone (9.0 g, 59,96 mmole) in tetrahydrofuran (80 ml). This mixture was poured into 200 ml of ice water and was extracted 3 times with 600 ml of diethyl ether. One organic phase is washed successively with 200 ml portions of aqueous sodium bisulfite (10%) and a saturated solution of sodium chloride. The organic phase is dried over potassium carbonate, filtered, concentrated on a rotary evaporator under vacuum and re-subjected to rotary evaporation with 200 ml dichloromethane, getting sticky solid residue. This residue was chromatographically on Silica gel 60 with a mixture of ethyl acetate:hexane (2:1) as eluent. The fractions containing (E)-2-(6-fluoro-1-inderide)ndimethylacetamide, were combined and concentrated by rotary evaporation in vacuum, obtaining of 2.38 g of yellow solid. The dilution solution in dichloromethane crude material hexane gave 2.16 g (18,8%) (E)-2-(6-fluoro-1-inderide)ndimethylacetamide, so pl. 178-182). AEO stationary state: lighting. when d 6,37, significant observed AEO d 7,33-7,28.

Anal. calculated for C11H10FNO: C 69,10, H 5,27, N 7,33.

Found: C 69,01, H Of 5.29, N 7,28.

Example 12

Obtaining (E)-N-cyclopropyl-2-(5-fluoro-1,2,3,4-tetrahydro-1 - naphthalide)ndimethylacetamide

a) Obtaining 2-(2-forfinal)ethylbromide

To a mixture of aqueous Hydrobromic acid (48%, 360 ml) and concentrated sulfuric acid (103,6 ml) at room temperature was added dropwise 2-(2-forfinal)ethanol (250 ml) of 1.78 mol, Aldrich). The reaction mixture is boiled under reflux for 7 hours, then poured into 600 ml of ice and the mixture was extracted with diethyl ether. Extracts in diethyl ether, washed sequentially with a saturated solution of sodium carbonate and brine. The organic phase was dried (MgSO4) and concentrated in vacuo, getting to 359.9 g (99%) 2-(2-forfinal)ethylbromide in the form of a brown oil. This product was used without further purification. NMR (CDCl3): d of 7.6 to 6.9 (m, 4H, ArH), and 3.6 (t, 2H, CH2), and 3.2 (t, 2H, CH2).

b) Obtaining diethyl-2-(2-(2-forfinal)ethylmalonate

To absolute ethanol (1.5 l) at room temperature under nitrogen atmosphere was added sodium metal (61,1 g of 2.66 mol) in the ur and the mixture was heated to 40oC was added dropwise diethylmalonate (525,4 g of 3.28 mol) followed by addition of 2-(2-forfinal)ethylbromide (to 359.9 g, or 1.77 mol). The mixture was delegirovali within 8 hours. The crude material was purified by vacuum distillation at 85-130oC and 0,60 mm Hg, getting 312,6 g (62%) of diethyl-2-(2-(2-forfinal)ethyl) malonate in the form of a clear oil. NMR (CDCl3): d of 7.6 to 7.0 (m, 4H, ArH), 4,2 (K, 4H, HSN2), and 3.4 (t, 1H, CH), and 2.6 (2H, CH2), 2,2 (t, 2H, CH2), 1,2 (t, 6H, HSN3).

c) Obtaining 2-[2-(2-forfinal)ethyl]malonic acid

A mixture of diethyl-2-(2-(2-forfinal) ethyl) malonate (381,8 g of 1.35 mol) and potassium hydroxide (227,3 g of 4.1 mol) in ethanol (500 ml) and water (500 ml) was heated under reflux for 24 hours. The reaction mixture was placed in an ice bath was added hydrochloric acid (6N, 442 ml). The ethanol was removed in vacuo and the aqueous residue was extracted with diethyl ether. The extracts were dried (MgSO4) and concentrated in vacuum, obtaining 309,3 g(100 %) 2-[2-(2-forfinal)ethyl]malonic acid in the form of solids non-standard white color. This product was used without further purification. NMR (DMSO-d6): d of 6.8 to 6.2 (m, 4H, ArH), 2,4 (t, 1H, CH), 1,9 (K, 2H, CH2), 1,3 (t, 2H, CH2), IR (KBr) 1691 cm-1.

d) Obtaining 4-(2-forfinal) butyric acid 2,5 hours. When cooled 4-(2-forfinal) butyric acid (117.3 g, 99%) was crystallized in the form of a reddish-brown solid. This product was used without further purification. NMR (CDCl3): d of 7.6 to 7.0 (m, 4H, ArH), of 3.0 to 1.8 (m, 6H, HSN2). IR (pure) 1709 cm-1.

e) Receiving 5-verticalone

A mixture of 4-(2-forfinal)butyric acid (100 g, of 0.55 mol) and thionyl chloride (418,8 g, 3,51 mole) was heated under reflux for 3 hours. The excess thionyl chloride was removed in vacuum, obtaining 110,1 g (100%) 4-(2-forfinal)butyrylcholine.

To 4-(2-forfinal)butyrylcholine in carbon disulfide (1.0 l) at -78oC was added aluminium chloride (93,2 g to 0.7 mol) in portions over a period of 30 minutes. The mixture was heated to room temperature for 30 minutes, then was delegirovali within 2 hours. The reaction mixture was poured into a mixture of ice (500 ml) and HCl (6 N. , 500 ml). Serouglerode layer was separated, washed with saturated sodium bicarbonate solution and was extracted with ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated in vacuum, obtaining 84,2 g (93%) 5-verticalone in the form of a solid reddish-brown color. NMR (CDCl3): d to 7.7 (m, 1H, ArH), and 7.1 (m, 2H, ArH), 2,9 (t, 2H, CH2), and 2.6 (t is etamide

To a stirred suspension of NaH (60% dispersion in mineral oil, Aldrich) in dimethyl sulfoxide at room temperature under nitrogen was added diethyl(cyclopropanecarboxylate)phosphonate (21,5 g, and 0.09 mole). The reaction was slightly exothermic. To the resulting solution was added 5-torterolo (13,7 g of 0.08 mole) in dimethyl sulfoxide. The mixture was stirred over night at room temperature. The reaction mixture was poured into ice water (800 ml) and was extracted 4 times with portions of 500 ml of water, filtered and evaporated in a rotary evaporator under vacuum.

Chromatography on silica gel using a mixture of ethyl acetate:hexane (35% : 50%) as eluent, followed by kneading the obtained solid with pentane at room temperature gave 5,07 g (25%) (E)-N-cyclopropyl-2-(5-fluoro - 1,2,3,4-tetrahydro-1-naphthalide)ndimethylacetamide, so pl. 148-149oC.

Example 13

Obtaining (E)-N-cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1 - naphthalide)ndimethylacetamide

a) Obtaining 3-(4-perbenzoic)propionic acid

A mixture of Forasol (104,4 g of 1.09 mol, Aldrich) and succinic anhydride (93,5 g of 0.93 mol) in 1,2-dichlorobenzene (530 ml) was heated to 50oC. was Added in portions aluminium chloride (245 g of 1.84 mol), maintaining the temperature of MES concentrated HCl (200 ml) and ice water (2 l). The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was dried and concentrated in vacuum. The residue was poured into hexane (2 l) and the resulting solid was filtered and washed with pentane, getting 164,1 g (89%) of 3-(4-perbenzoic)propionic acid as a white solid. So pl. 102-104,5oC (in the literature, J. Org. Chem. 26, 2667, 1961, so pl. 102,5-103,5oC).

b) Obtaining 4-(4-forfinal)butyric acid

A mixture of 3-(4-perbenzoic)propanoic acid (42,3 g and 0.22 mol) and palladium on coal (10%, 3 g) in acetic acid (250 ml) was first made at 50 psi (344737,85 PA) and 25oC for 6 hours. The mixture was filtered and concentrated in vacuum. The residue was distilled at 0.02 mm Hg and the product has led, receiving 4-(4-forfinal)butyric acid as a white solid (97%), so pl. 44-46,2oC (in the literature, J. Am. Chem. Soc. 89, 386, 1967, I. pl. 45,5-46,5oC).

C) Obtaining 7-fluoro-1-tetralone

A mixture of 4-(4-forfinal)butyric acid (68,2 g of 0.37 mole) and thionyl chloride (155 g of 1.3 mol) was heated under reflux for 1.25 hours. The mixture was concentrated in vacuum, obtaining 75,3 g (100%) 4-(4-forfinal)butyrylcholine.

To a mixture of aluminium chloride (66 g of 0.5% mol) in carbon disulfide (600 ml) is Rennie temperature below 10oC. After heating under reflux for 0.5 hour, the reaction mixture was poured into a mixture of concentrated HCl (50 ml) and ice water (800 ml). The mixture was filtered and was extracted with diethyl ether. Extracts in diethyl ether was dried and concentrated in vacuum, obtaining the crude 7-fluoro-1-tetralone. Vacuum distillation gave pure 7-fluoro-1-tetralone, so Kip. 83oC at 0.3 mm Hg, which was utverjdala to white solid (94%), so pl. 62-64oC (in the literature, J. Am. Chem. Soc., 89, 386, 1967, I. pl. 63,5-65,0oC.

d) Obtaining (E)-N-cyclopropyl-2-(7-fluoro-1,2,3,4 - tetrahydro-1-naphthalide)ndimethylacetamide

This compound was obtained in a manner analogous to the one described in example 12f, replacing 5-fluoro-1-tetralone and diethyl(cyclopropanecarbonyl)methylphosphonate 7-fluoro-1-tetralone (7,76 g, 0.05 m) and diethyl(cyclopropanecarbonyl)methylphosphonate (11.1 g, 0.05 m). Chromatography on silica gel using a mixture of ethyl acetate:hexane (1:2) as eluent gave of 4.38 g (37%) of (E)-N-cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthalide)ndimethylacetamide, so pl. 122,8-123,3oC NMR (DMSO-d6): d 8,00 (d, J = 4.0 Hz, 1H), 7,32 (DD, J = 11.2 Hz, 1H),? 7.04 baby mortality-of 7.23 (m, 2H), 6,33 (s, 1H), 3,06 (m, 2H), 2,69 (m, 3H), of 1.70 (m, 2H), 0,66 (m, 2H), and 0.40 (m, 2H), AEO stationary state: lighting. when 6,39 d observed significant is prohibited: C 73,38, H 6,64, N 5,67.

Example 14

Obtaining (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthalide) -N, N-dimethylacetamide

a) Obtaining ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-hydroxy-1 - naphthyl)acetate

Ethyl acetate (5.4 g, 61 mmol) was added dropwise to a stirred cooled (bath with acetone - dry ice) to a solution of 1 M bis(trimethylsilyl)amide lithium in tetrahydrofuran (61 ml, 0,061 mol, Aldrich) under nitrogen. After 15 minutes, was added dropwise a solution of 7-fluoro-1-tetralone (10.0 g, 61 mmol) in tetrahydrofuran (25 ml) and the resulting mixture was stirred for 1 hour in a bath of dry ice and acetone). Added 1 n hydrochloric acid (61 ml) and the mixture was allowed to warm to room temperature. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to a pale yellow oil (15.0 g, 100%). An analytical sample was obtained by chromatography of a portion of 1.5 g silica gel 60 using a mixture of dichloromethane-hexane (1:1) as eluent. The fractions containing only the ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-hydroxy-1-naphthyl)acetate were combined and concentrated in vacuum, obtaining 1.2 g (80%) of colorless oil, NMR (DMSO-d6): d 6,93-7,31 (m, 3H, Ar), 5,28 (s, 1H, OH), 3,98 (m, 2H, CH2OOC), 2,60-2,87 (m, 4H, CH2CO, CH2), 2,12-of 2.28 (m, 1H, CH), the

Triperoxonane acid (20 ml) was added to a stirred cooled (bath with dry ice and methanol) solution of the crude ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-hydroxy-1-naphthyl)acetate (10.0 g, 35,8 mol) in dichloromethane (180 ml). After 4 hours the mixture was concentrated in vacuo to a clear oil (8,3 g, 100%). NMR (DMSO-d6): d 6,94-the 7.65 (m, 3H, Ar), 6,45 (Shir. C, 0,2 H, =CH/E), 6,10 (t, 0,8 H, =CH/endo), 4,08 (m, 2H, CH2OOC), 3,67, 3,51 (SS, 2, 2H, H2O, CH2/endo), 3,08, 2,70, 2,25, 1,77 (m, 4,4 H, HSN2), of 1.26 (t, 0,6 H, CH3/E) of 1.17 (t, 2,4 H, CH3/endo).

Part of the mixture obtained above E and endo-ester (2.3 g, 10 mmol), hydrate hypophosphite sodium (1.8 g, 20 mmol, Aldrich) and 10% palladium on coal (0.2 g) in 75% aqueous ethanol (20 ml) was heated under reflux for 2 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuum. The residue in dichloromethane was washed successively with water (100 ml) and brine (50 ml), dried over anhydrous sodium sulfate, concentrated in vacuo and was chromatographically on silica gel 60 using a mixture of ethyl acetate-hexane (3: 97) as eluent. The fractions containing only the ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthyl)acetate were combined and concentrated in vacuum, obtaining 1.9 g (78%) of pale yellow oil, NMR (DMSO-d6).

c) Obtaining ethyl-2-bromo-2-(7-fluoro-1,2,3,4 - tetrahydro-1-naphthyl)acetate

To a stirred cooled (bath with dry ice and acetone) solution of Diisopropylamine (0.3 ml, 1.9 mmole, Aldrich) in tetrahydrofuran (3 ml) under nitrogen was consistently added 2.5 n-utility in hexane (0.8 ml, Aldrich) chlorotrimethylsilane (0.2 ml, 1.8 mmole, Aldrich) and ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthyl)acetate (236 mg, 1.0 mmol). The obtained clear solution was stirred for 1 hour, and treated with N-bromo-succinimide (180 mg, 1.0 mmol, Aldrich) and stirred for 0.5 hour before removing bath with dry ice and acetone. Reddish cloudy solution was stirred for 2 hours at room temperature, was treated with dilute aqueous hydrochloric acid (4 mEq) and was extracted with diethyl ether (30 ml). The ether layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and was chromatographically on silica gel 60 using a mixture of dichloromethane-hexane (1:9) as eluent. The fractions containing only the ethyl-2-bromo-2-(7-fluoro - 1,2,3,4-tetrahydro-1-naphthyl)acetate in a 1:4 isomeric mixture were combined and concentrated in vacuo to a clear oil (171 mg, 54%), NMR (DMSO-d6): d 7,00-to 7.18 (m, 3H, Ar), 5,20 (d, J = 6.2 Hz, and 0.8 H, CHCO), to 5.17 (d, J = 6,2 is to 1.67 (m, 1H, CH), 1,21 (t, 0,4 H, CH3), with 1.07 (t, 0,6 H, CH3).

g) Obtaining (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1 - naphthalide)acetic acid

A mixture of ethyl-2-bromo-2-(7-fluoro-1,2,3,4-tetrahydro-1 - naphthyl)acetate (2.2 g, 7.0 mmol), 1 H. tert-butoxide potassium in tetrahydrofuran (14 ml, Aldrich) and tert-butanol (140 ml) was stirred for 5 hours at room temperature. The resulting suspension was concentrated in vacuo, diluted with water (200 ml) and washed with diethyl ether. The aqueous layer was acidified by addition of 1 N. hydrochloric acid (14 ml) and was extracted with diethyl ether. The ether extract was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and was chromatographically on Silica gel 60 using a mixture of ethyl acetate-hexane (1:1) as eluent. The fractions containing only the (E)-2-(7-fluoro-1,2,3,4 - tetrahydro-1-naphthalide)acetic acid were combined and concentrated in vacuum, obtaining white solid (0.8 g, 55%), NMR (DMSO-d6): d 12,22 (Shir.S., 1H, COOH), EUR 7.57 (DD, Jm= 2,6 Hz), Jo= to 11.0 Hz, 1H, Ar), 7,12-7,28 (m, 2H, Ar), 6,36 (s, 1H, = CH/E), totaling 3.04 (t, 2H, ArCH2), is 2.74 (t, 2H, CH2), of 1.74 (m, 2H, CH2), AEO stationary state: lighting. when 6,36 observed 25% AAA when EUR 7.57.

e) Obtaining (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthalide)- acetylchloride acid (2,03 g, 0,01 mol) in toluene (35 ml) at 0oC, protect from humidity atmosphere of nitrogen. Stir the mixture was allowed to warm to 25oC and the mixture was stirred for 1.5 hours. Concentration in vacuo gave (E)-2-(7-fluoro-1,2,3,4-tetrahydro - 1-naphthalide)acetylchloride, which was dissolved in dichloromethane and used without purification.

f) Obtaining (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthalide)- N,N-dimethylacetamide

Dimethylamine (3 ml of 0.045 mol, Kodak) was added to a chilled (ice bath) solution of (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1 - naphthalide)acetylchloride (2.3 g, 0,010 mol) in dichloromethane (35 ml). The reaction mixture was heated to 25oC and was stirred for 1.5 hours. Volatile components were removed by rotary evaporation under vacuum, obtaining a beige residue. It was dissolved in ethyl acetate (200 ml), washed with deionized water (50 ml) and the organic layer was concentrated by rotary evaporation under vacuum. The residue was chromatographically on Silica gel 60 using a stepwise gradient from ethyl acetate-hexane/1: 5 to ethyl acetate. The fractions containing (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthalide)-N, N - dimethylacetamide, were combined and concentrated by rotary evaporation in vacuo to a white solid. Recrystallization from a mixture of dihalides solids, so pl. 66-70oC.

Anal. calculated for C14H16FNO (mol. weight 233,278): C 72,08, H 6,91, N 6,00.

Found: C 71,97, H 6,94, N 5,95.

Example 15

Obtaining (E)-2-(6-fluoro-3,3-dimethyl-1-inderide)ndimethylacetamide

a) Obtaining diethylazodicarboxylate

Diethylazodicarboxylate received by way E. Z. Eliel, R. O. Hutehins and Sr. M. Knoeber, Organic Synthesis Coll. Vol. VI, 442, 1988, with the following modifications. A mixture of acetone (54 g of 0.93 mol, Mallinckrodt), diethylmalonate (100 g, of 0.62 mol, Aldrich), acetic anhydride (80 g, 0,78 mol, Mallinckrodt) and zinc chloride (12.5 g, 0,78 mol, Aldrich) was delegirovali (90oC, oil bath) for 18 hours, protecting from moisture. The reaction solution was diluted with dichloromethane (500 ml) and washed with cold water (I ml). Water washing were combined and extracted with dichloromethane. All dichloromethane layers were combined and concentrated by rotary evaporation under vacuum. The remaining oil was distilled under vacuum and the fraction boiling at 102-138oC with 12 Top, combined with the sediment tank and heated for 6 hours at 200oC in an oil bath. The dark oil was distilled, getting to 40.1 g (32%) of diethylazodicarboxylate in the form of a clear oil, so Kip. 110-115oC/12 mm Hg.

b) Obtaining diethyl-2-(2-(4-forfinal)iodide copper (I) (0,310 mg, 1,63 mmole, Aldrich) was stirred for 15 minutes at -10oC under nitrogen. To this mixture was added a solution of diethylazodicarboxylate (29,6 g, 0,148 mol) in anhydrous diethyl ether (250 ml) in a thin stream with rapid stirring. The resulting solution was stirred at -10oC for 2 hours, at 25oC for 30 minutes and then poured with rapid stirring in 0.5 kg of crushed ice containing 30 ml 12 N. hydrochloric acid. Separated the layers and the aqueous layer was extracted with ethyl ether (3x400 ml). All ether layers were combined and washed with deionised water (I ml), saturated solution in water of sodium bicarbonate (25 ml) and deionised water (25 ml). This ether layer was concentrated by rotary evaporation in vacuo and the residue was distilled, obtaining of 25.9 g (59%) of diethyl-2-(2-(4-forfinal)-2-methylethyl)malonate in the form of a clear oil (so Kip. 140-145oC/0.01 mm Hg).

C) Obtaining 3-(4-forfinal)-3-methylmalonic acid

A solution of diethyl-2-(2-(4-forfinal)-2-methylethyl)malonate (41 g, was 0.138 mole) potassium hydroxide (85%, 18,25 g, 0,277 mol, Mallinckrodt) in 250 ml of deionized water was intensively delegirovali for 4 hours with an oil bath at 150oC. After cooling in an ice bath, the solution was neutralized 18 called sarnali, washed with water and concentrated by rotary evaporation under vacuum. The residue is suspended with water and the crystalline product was collected by filtration, getting 24,3 g (90%) of 3-(4-forfinal)-3-methylmalonic acid, so pl. 45-47oC.

d) Obtaining 3-(4-forfinal)-3-methylbutyraldehyde

Oxalicacid (46,5 g, 0,367 mol, Aldrich) was added to a solution of 3-(4-forfinal)-3-methylmalonic acid (24 g, 0,122 mol) at -10oC, protect from moisture atmosphere of nitrogen. Stir the mixture was allowed to warm to 25oC and the mixture was stirred for 2 hours. Fractional distillation gave to 26.6 g (76%) of 3-(4-forfinal)-3 - methylbutyraldehyde in the form of a clear oil, so Kip. 132-138oC.

e) Receiving 6-fluoro-3,3-dimethyl-1-indanone

A solution of 3-(4-forfinal)-3-methylbutyraldehyde (19,0 g, 0,0815 mol) in dichloromethane (100 ml) was added dropwise over 2.5 hours to peremestivsheesya mixture of aluminium chloride (13,57 g is 0.102 mol, Aldrich) in dichloromethane (200 ml), protect from moisture atmosphere of nitrogen. After stirring for 18 hours at 25oC the reaction solution was poured into ice (400 g) and the resulting solution was extracted with dichloromethane (I ml). Layers of dichloromethane were combined, washed with deionised water (50 ml) and concentrated by rotary ispravlyali portion of ethyl acetate. Removal of volatile components from the United leaching by rotary evaporation in vacuo gave 15.2 g (99%) 6-fluoro-3,3-dimethyl-1-indanone as a pale yellow oil that crystallized upon standing, so pl. 57-62oC.

f) Obtaining ethyl-2-(6-fluoro-1-hydroxy-3,3-dimethyl-1 - indanyl)acetate

This compound was obtained in a manner similar to that described for ethyl-2-(6-fluoro-1-hydroxy-1-indanyl)acetate in example 1d, substituting 6-fluoro-3,3-dimethyl-1-indanone 6-fluoro-1-indanone and getting activated zinc heating zinc dust (Aldrich) and iodine (Aldrich) without solvent. Removal of volatile components from the working solution by rotary evaporation in vacuo gave 16.2 g (82%) of ethyl-2-(6-fluoro-1-hydroxy-3,3-dimethyl-1-indanyl)acetate as a pale yellow oil.

g) Obtaining (E)-2-(6-fluoro-3,3-dimethyl-1-inderide)acetic acid

A solution of ethyl-2-(6-fluoro-1-hydroxy-3,3-dimethyl-1-indanyl)acetate (16 g, 0,0601 mol) in 1 N. the sodium hydroxide (60,1 ml, 0,0601 mol) in ethanol (60 ml) was stirred for 20 hours. The solution was concentrated to a small volume by rotary evaporation in vacuo, diluted with deionized water (100 ml) and acidified to pH 3 1 N. hydrochloric acid. This biphasic solution was extracted with dichloromethane (h m). The extracts were combined, promisewe. The residue was dissolved in dichloromethane (30 ml), cooled to 0oC and diluted to 400 ml of cold (0oC) solution triperoxonane acid (45 g, Aldrich) in dichloromethane (400 ml). After 15 minutes the solution was concentrated by rotary evaporation in vacuo and the residue was led by addition of hexane, getting 9,23 g (70%) of (E)-2-(6-fluoro-3,3-dimethyl-1-inderide)acetic acid as a white crystalline solid, so pl. 202-203oC.

h) Obtaining (E)-2-(6-fluoro-3,3-dimethyl-1-inderide)acetylchloride

To a chilled on ice, stirred suspension of (E)-2-(6-fluoro-3,3-dimethyl-1-inderide)acetic acid (9.0 g, 0,0409 mol) in dichloromethane (200 ml) was added oxalicacid (15.6 g, 0,123 mol, Aldrich). Stir the suspension was allowed to warm to 25oC for 2 hours. The resulting solution was concentrated by rotary evaporation under vacuum with the addition of dichloromethane (I ml) to give (E)-2-(6-fluoro-3,3-dimethyl-1-inderide)acetylchloride in the form of non-characterized oil. Dichloromethane (about 70 g) was added to dissolve this remaining oil and the resulting solution was divided equally and used without further purification in the examples 15i, 16 and 17.

i) Obtaining (E)-2-(6-fluoro-3,3-dimethyl-1-inderide)acetamido-inderide)acetylchloride (0,01363 mol), obtained from example 41h, was diluted with dichloromethane (200 ml) and cooled to 0oC. the Biphasic solution was rapidly stirred and gave it to warm to room temperature for 18 hours. The reaction solution was concentrated by rotary evaporation in vacuo, diluted with dichloromethane (200 ml) and washed with 1 N. aqueous hydrochloric acid (Mejntosh) a solution of 5% aqueous sodium bicarbonate (Mallinckrodt), dried with magnesium sulfate (Mallinckrodt) and concentrated by rotary evaporation under vacuum. The residue was chromatographically on Silica gel 60 using a mixture of ethyl acetate-hexane (1:1) and then ethyl acetate. The fractions containing (E)-2-(6-fluoro-3,3-dimethyl-1-inderide)ndimethylacetamide, were combined and concentrated by rotary evaporation under vacuum. Recrystallization from a mixture of dichloromethane-hexane gave 2.85 g (95%) of (E)-2-(6-fluoro-3,3-dimethyl-1-inderide)ndimethylacetamide in the form of a white crystalline solid, so pl. 167-168oC.

Example 16

Obtaining (E)-2-(6-fluoro-3,3-dimethyl-1-Indonesien)-N-methylacetamide

This compound was obtained in a manner analogous to the one described in example 15i replacement solution of 30% aqueous ammonium hydroxide 40% aqueous solution of methylamine (10 ml, Aldrich). Recrystallization from a mixture of dichloromethane-hexane gave 2,89 g (91%) of (E)-2-(6 o
C.

Example 17

Obtaining (E)-N-cyclopropyl-2-(6-fluoro-3,3-dimethyl-1 - inderide)ndimethylacetamide

This compound was obtained in a manner analogous to the one described in example 15i replacement solution of 30% aqueous ammonium hydroxide by cyclopropylamine (4 ml, Aldrich). Recrystallization from a mixture of dichloromethane-hexane gave 2.86 g (81%) of (E)-N-cyclopropyl-2-(6-fluoro-3,3-dimethyl-1-inderide)ndimethylacetamide in the form of a white crystalline solid, so pl. 149-150oC.

Example 18

Obtaining (E)-2-(6-fluoro-3-methyl-1-inderide)ndimethylacetamide

a) Obtaining ethyl-4-vertinamte

The solution of utility, 2.5 M in hexano (159 ml, 0,3975 mol, Aldrich) was added dropwise over 0.25 hour with rapid stirring to a solution of triethylphosphate (89.2 g, 0,389 mol, Aldrich) in tetrahydrofuran (800 ml, anhydrous, Aldrich) in less than 5oC in nitrogen atmosphere. This solution was stirred for another of 0.25 hours and was cooled to 0oC in the bath with ice, after which the solution was added 4-fortetienne (50 g, 0,362 mol, Aldrich) in tetrahydrofuran (50 ml) in one portion. Stirring was continued for 18 hours without further cooling. Then the solution was concentrated to about 100 ml by rotary evaporation in vacuo and diluted to 500 MIEM in vacuum. Distillation under reduced pressure gave 48 g (63%) of ethyl-4-vertinamte in the form of a mixture of (E) - (Z) isomers (ratio 3:1) mixed with 16% of triethylphosphate in the form of a clear oil, so Kip. 138-143oC at 14 mm Hg.

b) Obtaining ethyl-3-(4-forfinal)butyrate

A mixture of ethyl-4-vertinamte (47,5 g, 0,228 mol) and 10% palladium on coal (0.85 grams, Aldrich) in 95% ethanol was shaken in hydrogenator Parra at 2-3 ATM of H2-pressure for 1 hour. The mixture was filtered and concentrated by rotary evaporation under vacuum. Fractional distillation gave a 46.5 g (97%) of ethyl-3-(4-forfinal)butyrate in the form of a clear oil, so Kip. 122-128oC.

C) Obtaining 3-(4-forfinal)butane acid

A solution of ethyl-3-(4-forfinal)butyrate (45,3 g, 0,215 mole), 85% potassium hydroxide (14,22 g, 0,215 mol, Mallinckrodt) in 200 ml of deionized water were delegirovali for 2 hours, concentrated by rotary evaporation in vacuo, acidified to pH 3 12 N hydrochloric acid (Mallinckrodt) and was extracted with dichloromethane (I ml). Layers of dichloromethane were combined, washed with deionised water (50 ml) and concentrated by rotary evaporation under vacuum. The residue was led from a mixture of dichloromethane-hexane, obtaining of 34.5 g (88%) of 3-(4-forfinal)butyric acid as a white kristallicheskogo, Aldrich) was added to a mixture of 3-(4-forfinal)butyric acid (34 g, 0,187 mol) in 200 ml of dichloromethane at 5oC. After stirring for 20 minutes at this temperature, the solution was allowed to warm to 25oC and stirring was continued for 2 hours. Volatile components were removed by rotary evaporation under vacuum with the addition of dichloromethane (4) during concentration, receiving of 35.1 g (94%) of 3-(4-forfinal)butyrylcholine in the form of a light yellow oil.

e) Receiving 6-fluoro-3-methyl-1-indanone

This compound was obtained in a manner analogous to the one described in example 15th, with the replacement of 3-(4-forfinal)-3-methylbutylamine 3-(4-forfinal)botrylloides (35.1 g, 174,9 mmole). Removal of volatile components from the United leaching by rotary evaporation in vacuo gave 26,3 g (92%) of 6-fluoro-3-methyl-1-indanone in the form of oil, forming melting at a low temperature crystals upon standing.

f) Obtaining ethyl-2-(6-fluoro-1-hydroxy-3-methyl-1-indanyl)acetate

This compound was obtained in a manner analogous to the one described in example 15f, with the replacement of the 6-fluoro-3,3-dimethyl-1-indanone 6-fluoro-3-methyl-1-indanone (25 g, 140 mmol). Removal of volatile components from the treated solution gave 15.0 g (45%) ethyl-2-(6-fluoro-1-hydroxy-3-methyl-1-indanyl)acetate in the lots

This compound was obtained in a manner analogous to the one described in example 15g, replacing ethyl-2-(6-fluoro-1-hydroxy-3,3 - dimethyl-1-indanyl)acetate ethyl-2-(6-fluoro-1-hydroxy-3-methyl - 1-indanyl)acetate (15 g, 59,5 mmole). Removal of volatile components from the treated solution gave 9.3 g (76%) of (E)-2-(6-fluoro-3-methyl-1-inderide)acetic acid as a tan solid, so pl. 175-177oC.

h) Obtaining (E)-2-(6-fluoro-3-methyl-1-inderide)acetylchloride

This compound was obtained in a manner analogous to the one described in example 15h , with the replacement of (E)-2-(6-fluoro-3,3-dimethyl-1-inderide)acetic acid (E)-2-(6-fluoro-3-methyl-1-inderide)acetic acid (9 g, 43.6 mmole). The residue product was dissolved in dichloromethane and used without purification in examples 17, 18 and 19.

i) Obtaining (E)-2-(6-fluoro-3-methyl-1-inderide)ndimethylacetamide

This compound was obtained in a manner analogous to example 15i, with the replacement of (E)-2-(6-fluoro-3,3-dimethyl-1-inderide)acetylchloride (E)-2-(6-fluoro-3-methyl-1-inderide)acetylchloride (3,26 g, 14.5 mmole). Recrystallization from a mixture of dichloromethane-hexane gave 2,39 g (77%) of (E)-2-(6-fluoro-3-methyl-1-inderide)ndimethylacetamide in the form of a white crystalline solid, so pl. 149-151oC.

Example 19

Obtaining (E)in example 16, with the replacement of (E)-2-(6-fluoro-3,3-dimethyl-1-inderide)acetylchloride (E)-2-(6-fluoro-3-methyl-1-inderide)acetylchloride (3,26 g, 14.5 mmole). Recrystallization from a mixture of dichloromethane-hexane gave of 2.27 g (71%) of (E)-2-(6-fluoro-3-methyl-1-Indonesien)-N-methylacetamide in the form of a white crystalline solid, so pl. 168-169oC.

Example 20

Obtaining (E)-N-cyclopropyl-2-(6-fluoro-3-methyl-1 - inderide)ndimethylacetamide

This compound was obtained in a manner analogous to the one described in example 17, with the replacement of (E)-2-(6-fluoro-3,3-dimethyl-1-inderide) acetylchloride (E)-2-(6-fluoro-3-methyl-1-inderide)acetylchloride (3,26 g, 14.5 mmole). Recrystallization from a mixture of dichloromethane-hexane gave 2.30 g (67%) of (E)-N-cyclopropyl-2-(6-fluoro-3-methyl-1 - inderide)ndimethylacetamide in the form of a white crystalline solid, so pl. 132-134oC.

Example 21

Obtain (Z)-2-(6-fluoro-2-hydroxy-1-inderide)ndimethylacetamide (Method A)

a) Obtain (Z)-2-(2-bromo-6-fluoro-1-inderide)ndimethylacetamide

N-bromosuccinimide (22,57 g to 126.8 mmole, Aldrich) and benzoyl peroxide (1.89 g, 7,8 mol, Aldrich) was added to a suspension of (E)-2-(6-fluoro-1-inderide)ndimethylacetamide (21,00 g, 109,8 mmole) in carbon tetrachloride (400 ml) and benzene (400 ml). The mixture was heated under reflux under a drying tube with chloride cal is on and the light was removed and the solution was stirred at ambient temperature for 18 hours. The mixture was filtered and the solids washed with ethyl acetate. The washing and the filtrate were combined and evaporated in vacuum. The residue was dissolved in ethyl acetate (800 ml) and washed with water (I ml) and brine (200 ml), dried over sodium sulfate, filtered and evaporated in vacuum. The residue was chromatographically on silica gel, elwira first with a mixture of hexane:ethyl acetate (2:1) gradually increasing the polarity to hexane:ethyl acetate (1:1). The fractions containing the main spot were combined and evaporated in vacuum, obtaining a yellow solid, which was dried in vacuum at 70oC for 18 hours, getting 1,022 g (3%) of (Z)-2-(2-bromo-6-fluoro-1-inderide)ndimethylacetamide in the form of a yellow solid, so pl. 162-163oC.1H-NMR.

b) a Mixture of (Z)-2-(2-bromo/6-fluoro-1-inderide)ndimethylacetamide (5.30 g, 19,25 mmole) and silver nitrate (the 10.40 g, 61,18 mmole, Aldrich) in dimethoxyethane (265 ml) and water (100 ml) was heated under reflux for 18 hours. The mixture was filtered and the filtrate was diluted with water (700 ml) and was extracted with ethyl acetate (CH ml). The combined extracts were washed with water (200 ml) and brine (200 ml), dried over magnesium sulfate, filtered and evaporated in vacuum. The residue was chromatographically on silica gel, elwira a mixture hexaethylene with Rf=0,18, were combined and evaporated in a vacuum, getting 1.13 g (28%) of the crude (Z)-2-(6-fluoro-2-hydroxy-1 - inderide)ndimethylacetamide as an orange solid. Recrystallization from mixtures of ethyl acetate:hexane gave 0,49 g (12%) of (Z)-2-(6-fluoro-2-hydroxy-1-inderide)ndimethylacetamide, in the form of solids non-standard white, so pl. 201-202oC.

c) Obtain (Z)-2-(6-fluoro-2-hydroxy-1-inderide)ndimethylacetamide (Method B)

A suspension of (E)-2-(6-fluoro-1-inderide)ndimethylacetamide (12.00 g, 62.8 mmole) in dichloromethane (250 ml) was added to a solution of selenium dioxide (5.20 g, 46,9 mmole, Aldrich) and tert-butylhydroperoxide (25 ml, 260,8 mmole, Aldrich) in dichloromethane (500 ml). The suspension was stirred at ambient temperature for 3 days. Added additional amount of tert-butylhydroperoxide (10 ml, 104,3 mmole) and the mixture was stirred at ambient temperature for 18 hours. Added additional amount of selenium dioxide (5,00 g, 45,1 mmole) and the mixture was stirred at ambient temperature for 18 hours. Added additional amount of tert-butylhydroperoxide (15 ml, 156,5 mmole) and the mixture was stirred at ambient temperature for 18 hours. The mixture was filtered to remove approximately 1 Gali additional amount of selenium dioxide (5,00 g, 45,1 mmole) and the mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo to 300 ml, was added hexane and the precipitate was collected by filtration, washed with hexane and combined with the solid material collected previously. The combined solid material was dissolved in ethyl acetate (700 ml), washed successively with water (I ml), brine (100 ml), concentrated in vacuo to 100 ml and cooled in an ice bath. The solid is collected by filtration and the filtrate was concentrated in vacuum, obtaining a second portion of solids. All solids were combined and were chromatographically on silica gel, elwira a mixture of hexane:ethyl acetate (1:1). The fractions containing the main spot were combined and evaporated in a vacuum, getting 5,80 g solids non-standard white, which was washed with chloroform (CH ml), receiving 5,43 g (42%) of (Z)-2-(6-fluoro-2-hydroxy-1 - inderide)ndimethylacetamide in the form of a white solid substance, so pl. 202-204oC.

Example 22

Obtain (Z)-2-(4,6-debtor-2-hydroxy-1-inderide)ndimethylacetamide

A suspension of (E)-2-(4,6-debtor-1-inderide)ndimethylacetamide (10.0 g, 0.05 m) in dichloromethane (250 ml), obtained as described in example 5g was added in portions during 10 minutes to a mixture of 70% in at ambient temperature. After 18 hours added additional tert-butylhydroperoxide (10 ml, 5.0 M solution in 2,2,4-trimethylpentane, 0.05 m, Aldrich) and selenium dioxide (1.8 g, of 0.02 mol) and the mixture was stirred at room temperature. After 18 hours added additional tert-butylhydroperoxide (10 ml 70% aqueous solution of 0.08 mole) and selenium dioxide (3.7 g, 0.05 m) and the mixture was stirred at ambient temperature for 8 days. The obtained solid material was filtered and washed with dichloromethane, receiving of 5.85 g of crude (Z)-2-(4,6-debtor-2 - hydroxy-1-inderide)ndimethylacetamide. After 7 days at ambient temperature, the second part of the crude (Z)-2-(4,6-debtor-2 - hydroxy-1-inderide)ndimethylacetamide was obtained from the filtrate. Column chromatography on silica gel using ethyl acetate as eluent, followed a second column chromatography on silica gel using a mixture of ethyl acetate:hexane (3: 2) as eluent and kneading the obtained solid with pentane gave 2.38 g (Z)-2-(4,6-debtor-2-hydroxy-1 - inderide)ndimethylacetamide with the form of a pink solid, so pl. 235-237oC.

Example 23

Obtaining (E)-2-(6-fluoro-3-hydroxy-1-inderide)ndimethylacetamide

a) Obtaining 3-bromo-6-fluoro-1-indanone

A mixture of N-bromosuccinic the carbon (20 ml) was heated under reflux in nitrogen atmosphere for 2 hours. The mixture was cooled to ambient temperature, filtered and the solids washed with dichloromethane. The washing and the filtrate were combined, washed sequentially with 1.0 N. sodium hydroxide (CH ml), water (I ml) and brine (30 ml) and evaporated in vacuo. The residue was chromatographically on silica gel, elwira first with hexane gradually increasing polarity to hexane:ethyl acetate (95:5). The fractions containing the main spot were combined and evaporated in a vacuum, getting 2.30 g (66%) of 3-bromo-6 - fluoro-1-indanone as a yellow oil which was used without further purification.

b) Obtaining 3-hydroxy-6-fluoro-1-indanone

A mixture of 3-bromo-6-fluoro-1-indanone (2.50 g, 10.0 mmole) and silver carbonate (4,19 g, 15.2 mmole, Aldrich) in dimethoxyethane (85 ml) and water (65 ml) was stirred overnight at ambient temperature. The mixture was filtered through a pad celite and the filtrate was diluted with water (500 ml) and was extracted with ethyl acetate (4x100 ml). The combined extracts were washed with water (100 ml) and brine (75 ml), dried over sodium sulfate, filtered and evaporated in vacuum, obtaining 2,80 g (quantitative yield) of the crude 3-hydroxy-6-fluoro-1-indanone which was used without further purification. Chromatography of 0.41 g have reddish-brown solid, so pl. 73-76oC.

c) Obtaining 3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanone

A solution of 3-hydroxy-6-fluoro-1-indanone (4.09 g, of 24.6 mmole) in dimethylformamide (10 ml) was added to a solution of tert-butyldimethylsilyloxy (4,60 g, 30.5 mmole, Aldrich) and imidazole (4,22 g, 62,0 mmole, Aldrich) in dimethylformamide (20 ml). The solution was stirred at ambient temperature for 18 hours and evaporated in vacuum. The residue was dissolved in dichloromethane (200 ml) and washed with water (I ml) and brine (100 ml), dried over magnesium sulfate, filtered and evaporated in vacuum. The residue was chromatographically on silica gel, elwira a mixture of hexane:ethyl acetate (95:5). The fractions containing the main spot were combined and evaporated in vacuo, and the residue was dried in vacuum at ambient temperature for 18 hours, getting to 4.14 g (60%) of 3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanone as a white solid, so pl. 56-58oC.

d) Obtaining ethyl-2-(3-((tert-butyldimethylsilyl)oxy) -6-fluoro-1-hydroxy-1-indanyl)acetate

A solution of ethyl acetate (1,00 ml, 10.3 mmole) and Diisopropylamine lithium (This salt was obtained from Diisopropylamine (1,41 ml, 10.0 mmol, Aldrich) and n-utility (4,00 ml, 1.5 M solution of hexane, 10.0 mmol, Aldrich) in tetrahydrofuran (15 Danon (2,80 g, 10.0 mmol) in tetrahydrofuran (15 ml) was added dropwise over 7 minutes and the solution was stirred at -78oC under nitrogen for 1.5 hours. A solution of ammonium chloride (1.60 g, 30.0 mmol) in water (9 ml) was added and the resulting suspension was allowed to warm to ambient temperature. The layers were separated and the aqueous layer was extracted with ether (CH ml). The organic extracts were combined and washed successively with water (100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and evaporated in vacuum. The residue was chromatographically on silica gel, elwira a mixture of hexane-ethyl acetate (98:2), gradually increasing the polarity to hexane:ethyl acetate (4:1). The fractions containing the main spot were combined and evaporated in vacuum. The residue was dried in vacuum at ambient temperature for 18 hours at 60oC, receiving 2.86 g (78%) of ethyl-2-(3-((3- tert-butyldimethylsilyl)oxy)-6-fluoro-1-hydroxy-1-indanyl)acetate as a clear oil.

e) Obtaining (E)-ethyl-2-(3-((tert-butyldimethylsilyl)oxy)-6 - fluoro-1-inderide)acetate

A solution of ethyl-2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1 - hydroxy-1-indanyl)acetate (2,80 g, 7.6 mmole) was added to a solution of bis[2,2,2-Cryptor-1-phenyl-1-(trifluoromethyl)-ethoxy] - diphenylsulfone environment for 35 minutes and was poured into water (500 ml). The organic layer was separated, washed with brine (250 ml), dried over magnesium sulfate, filtered and evaporated in vacuum. The residue was chromatographically on silica gel with elution by the mixture hexane:ethyl acetate (99:1). The fractions containing the main spot (and also small impurity) were combined and evaporated in vacuum, obtaining of 2.68 g (quantitative yield) of the crude (E)-ethyl-2-(3-((tert - butyldimethylsilyl)oxy)-6-fluoro-1-inderide)acetate as a yellow oil which was used without further purification.

f) Obtaining (E)-2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro - 1-inderide)ndimethylacetamide

A solution of amide dimethylaluminum was obtained by adding trimethylaluminum (6.5 ml, 1.0 M solution in toluene, 13.0 mmol, Aldrich) to a solution of aluminium chloride (0,695 g, 13.0 mmol) in dichloromethane (25 ml) under nitrogen atmosphere and stirring for 45 minutes at the temperature of the surrounding environment. This solution of amide dimethylaluminum (13.0 mmol) was added to a solution of (E)-ethyl-2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-inderide)acetate (1,190 g, 3.4 mmole) in dichloromethane (60 ml) under nitrogen. The mixture was stirred at ambient temperature for 30 minutes and was delegirovali for 18 hours. After cooling at ambient temperature and SSTaR was diluted with water (50 ml), the layers were separated and the aqueous layer was extracted with dichloromethane (75 ml). The organic layers were combined, washed successively with water (75 ml) and brine (75 ml), dried over magnesium sulfate, filtered and evaporated in vacuum. The residue was recrystallized from mixtures of dichloromethane:hexane, getting 0,321 g (29%) of (E)-2-(3-((tert - butyldimethylsilyl)oxy)-6-fluoro-1-inderide)ndimethylacetamide in the form of a white solid substance, so pl. 160-165oC.

g) Obtaining (E)-2-(6-fluoro-3-hydroxy-1-inderide)ndimethylacetamide

A solution of (E)-2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro - 1-inderide)ndimethylacetamide (1.80 g, 5.6 mmole) and p-toluensulfonate pyridinium of 0.85 g, 3.4 mmole, Aldrich) in ethanol (65 ml) was heated at 55-68oC for 3.5 hours under nitrogen atmosphere and evaporated in vacuum. The residue was dissolved in ethyl acetate (150 ml) and washed successively with water (I ml) and brine (150 ml), dried over magnesium sulfate, filtered and evaporated in vacuum. The residue was chromatographically on silica gel with elution by ethyl acetate, gradually increasing the polarity to ethyl acetate:ethanol (95:5). The fractions containing the main spot were combined and evaporated in vacuum. The residue was dried in vacuum at 80oC for 18 hours, getting to 0.72 g (62%) of (E)-2-(6-fluoro-3-hydroxy-1-and the(Z)-2-(2,3-dihydroxy-6-fluoro-1-inderide) ndimethylacetamide

a) Obtain (Z)-2-(2,3-dibromo-6-fluoro-1-inderide)ndimethylacetamide

N-bromosuccinimide (49,37 g, 277,4 mmole, Aldrich) and benzoyl peroxide (1.60 g, 6.6 mmole, Aldrich) was added to a suspension of (E)-2-(6-fluoro-1-inderide)ndimethylacetamide (17,68 g, 92,5 mmole) in carbon tetrachloride (335 ml) and benzene (335 ml). The mixture was heated under reflux under a drying tube with calcium chloride for 4 hours, then formed an orange solution. Heating was removed and the solution was stirred at ambient temperature for 18 hours. The mixture was filtered and the solids washed with ethyl acetate. The washing and the filtrate were combined and evaporated in vacuum. The residue was dissolved in ethyl acetate (800 ml) and washed with water (I ml) and brine (200 ml), dried over sodium sulfate, filtered and evaporated in vacuum. The residue was chromatographically on silica gel with elution by the mixture hexane:ethyl acetate (2:1). The fractions containing the compound with Rf= 0.4 V mixture of hexane: ethyl acetate (1: 1), were combined and evaporated in vacuum, obtaining a solid, which was washed with hexane and dried in vacuum at 50oC for 18 hours, receiving 1.35 g (4%) of (Z)-2-(2,3-dibromo-6-fluoro-1-inderide)ndimethylacetamide in the form of a yellow solid, so pl. 158-163oC.

b) CME is cetane (15 ml) and water (30 ml) was delegirovali within 6 hours. The mixture was stirred overnight at ambient temperature and was again delegirovali within 6 hours. The mixture was diluted with water (100 ml) and was extracted with ethyl acetate (CH ml). The combined extracts were washed with water (100 ml) and brine (100 ml) and evaporated in vacuo. The residue was chromatographically on silica gel with elution by the mixture hexane:ethyl acetate (2:1). The fractions containing the compound with Rf= 0,15, with elution by ethyl acetate were combined and evaporated in vacuum, obtaining 0.12 g (35%) of the crude (Z)-2-(2,3-dihydroxy-6-fluoro-1-inderide)ndimethylacetamide in the form of a beige solid. Recrystallization from mixtures of ethyl acetate: hexane gave 0.037 g (11%) of (Z)-2-(2,3-dihydroxy-6-fluoro-1-indaniel)ndimethylacetamide in the form of solids non-standard white color, which, as was shown by1H-NMR, was a mixture (85:15) diastereomers, so pl. 212-220oC.1H-NMR (DMSO-d6): d of 7.82 (d, 2H), 7,28-7,76 (m, 3H), of 6.96 (s, 1H), 6,80 (C 0,15 H), is 6.54 (s, 0,85 H), 6,51 and 6,12 (m, 0,3 H) of 5.92 (d, 1H), 4,81 (m, 1,7 H), AEO stationary state: lighting. when 6,47 d, the observed 20% AAA when 7,38 d.

Example 25

Obtaining (E)-2-(6-fluoro-3-oxo-1-inderide)ndimethylacetamide.

a) Obtaining (E)-ethyl-3-vertinamte

This compound was obtained in a manner analogous to the described Il-3-vertinamte in 5 fractions (so the TRC. 140-155oC for 15 Top) containing the same amount, approximately 13%, triethylphosphate in the form of impurities. This material was used without additional purification.1H-NMR (DMSO-d6); d 7,66-7,47 (m, 2H), 7,45-7,40 (m, 1H), 7,27-7,20 (m, 1H), 6,70 (d, 1H, JHH= 16 Hz), 4,18 (K, 2H, JHH= 7,2 Hz), 4,10-of 3.96 (m, 0,78 H) of 3.77 (d, 0,26 H, JPH= 21,3 Hz) of 1.24 (t, 3H, JHH= 7,0 Hz), 1,24-1,14 (m, 1,17 H).

b) Obtaining diethyl-2-carbethoxy-3-(3-forfinal)glutarate

Sodium metal (0,388 g, 0,0169 mol) was stirred in diethylmalonate (15,28 g, 0,0953 mol, Aldrich) under nitrogen atmosphere at 120oC for 0.33 hour. To the obtained solution was added (E)-ethyl-3-pertinent (16.4 g, 0,0845 mol) and stirring was continued for 7 hours at the same temperature. The dark solution was cooled, dissolved in dichloromethane (500 ml) and acidified with 30 ml of 1 N. aqueous hydrochloric acid (Macintosh). Volatile components were removed from the resulting foam by rotary evaporation in vacuo and the residue was dissolved in ethyl acetate. This solution is washed with 5% aqueous sodium bicarbonate until neutral, water and volatile components were removed by rotary evaporation under vacuum. Distillation gave 20 g of the material so boiling between 130 and 185oC when 0,150 Top. Repeated distillation gave 14,72 g (44%) of diethyl-2-carbethoxy-3-(who phenyl)glutaric acid

To a hot solution of sodium hydroxide (19,15 g, 0,479 mol) in water (50 ml) was added a solution of diethyl-2-carbethoxy - 3-(3-forfinal)glutarate (18,8 g, 0,0532 mol) and ethanol (36 ml). The resulting suspension was heated under reflux for 5 hours. The mixture was poured into ice water and the ethanol was removed by rotary evaporation under vacuum. The remaining aqueous solution was acidified with concentrated hydrochloric acid (12 BC) and a solution (200 ml) were extracted with ethyl acetate (CH ml). An ethyl acetate layers were combined, washed with water (50 ml) and the volatile components were removed by rotary evaporation under vacuum, obtaining a solid, which was recrystallized from dichloromethane and hexane, obtaining 9.3 g (77%) of 3-(3-forfinal)glutaric acid in the form of a white solid substance, so pl. 126-127,5oC.

d) Obtaining 2-(6-fluoro-3-oxo-1-indanyl)acetic acid

Connected polyphosphoric acid (39,6 g, Aldrich) and 3-(3-forfinal)glutaric acid (6.6 g, 0,0292 mol) and this mixture was heated with an oil bath at 120oC for 10 minutes. Became red solution was cooled to approximately 60oC and approximately 100 ml of water was added dropwise with intensive stirring. The precipitate was collected and washed with water. Recrystallization from dichloro who-(6-fluoro-3-oxo-1-indanyl)acetylchloride

Oxalicacid (4.5 g, a 0.035 mol, Aldrich) was added to a chilled on ice peremestivsheesya a mixture of 2-(6-fluoro-3-oxo-1 - indanyl)acetic acid (5.0 g, 0,024 mol) in dichloromethane (200 ml) under nitrogen atmosphere. The mixture was allowed to warm to room temperature and stirring was continued for 48 hours. Volatile components were removed from the solution by rotary evaporation under vacuum with the addition of dichloromethane (I ml) to give 2-(6-fluoro-3-oxo-1-indanyl)acetylchloride, which was used without purification or analysis.

f) Obtaining 2-(6-fluoro-3-oxo-1-indanyl)ndimethylacetamide

A solution of 2-(6-fluoro-3-oxo-1-indanyl)acetylchloride (obtained from 0,024 mole of 2-(6-fluoro-3-oxo-1-indanyl)acetic acid) in dichloromethane (150 ml) was cooled to 0oC and stirred quickly, adding 50 ml of ammonium hydroxide (28-30%). The resulting mixture was allowed to warm to room temperature and stirring continued for 18 hours. Volatile components of the mixture were removed by rotary evaporation in vacuo and the residue was dissolved in dichloromethane (250 ml) and washed with water (I ml). The dichloromethane phase is then suspended with Silica gel 60 and volatile components were removed by rotary evaporation under vacuum. This slurry is then applied on a column of Silica gel 60 (h mm) moistened with recommendations from methanol, 2.4 g (48%) of 2-(6-fluoro-3-oxo-1-indanyl)ndimethylacetamide in the form of a yellow solid, so pl. 150-152oC.

g) Obtaining (E)-2-(6-fluoro-3-oxo-1-inderide)ndimethylacetamide

A mixture of 2-(6-fluoro-3-oxo-1-indanyl)ndimethylacetamide (0,750 g, 0,0036 mol), N-bromosuccinimide (0,750 g, 0,0042 mol, Aldrich), benzoyl peroxide (0,270 g, 0,0011 mol, Aldrich) in carbon tetrachloride (37 ml) and benzene (37 ml) was stirred under heating at an oil bath at 120oC for 20 minutes. This reaction combined with similarly-reaching reaction (except for the scale of the reaction - 0.0024 mol). The resulting solution was added with Silica gel 60 and volatile components were removed by rotary evaporation under vacuum. This silica gel is then applied on a column of Silica gel 60 (h mm) moistened with dichloromethane, and the product was obtained by elution with a mixture of methanol:dichloromethane (3:97). After removal of volatile components from the combined fractions containing the product by rotary evaporation in vacuo the residue was recrystallized from methanol, getting 0.810 g (58%) of (E)-2-(6-fluoro-3-oxo-1-inderide)ndimethylacetamide, so pl. 235oC (decomposition).

Example 26

Obtaining (E)-N-cyclopropyl-2-(6-fluoro-3-ethyl-1-inderide)ndimethylacetamide

a) Obtaining ethyl-3-(4-forfinal)pentanoate

The solution of utility, 1.6 M in hexane (230 ml, 0 and (78,9 g, 0,351 mol, Aldrich) in tetrahydrofuran (800 ml, anhydrous, Aldrich) at a temperature below 5oC in nitrogen atmosphere. This solution was stirred for 0.25 hour, and cooled to -5oC in a bath with methanol and ice, and then in one portion was added a solution of 4'-forpromotion (50 g, 0,328 mol, Aldrich) in tetrahydrofuran (50 ml). Stirring was continued for 18 hours without further cooling. The solution was concentrated to a Golden yellow slime rotary evaporation in vacuo and the slurry was diluted to 1000 ml with ethyl acetate. After washing with deionized water (I ml) this solution was concentrated by rotary evaporation under vacuum. Distillation under reduced pressure gave 45,65 g (63%) of ethyl-3-(4-forfinal)pentanoate in the form of a mixture of (E) and (Z) isomers (ratio 1:1) with 30% impurities in the form of triethylphosphate in the form of a transparent liquid, so Kip. 140-146oC when the pressure of the suction device.

b) Obtaining ethyl-3-(4-forfinal)valerate

A mixture of ethyl-3-(4-forfinal)pentanoate (45,65 g, 0,137 mol) and 10% palladium on coal (0,86 g, Aldrich) in 95% ethanol was shaken under 4 atmospheres pressure of hydrogen in hydrogenator Parra for 1.5 hours. The mixture was filtered and concentrated by rotary evaporation under vacuum. Fractional distillation gave 38>
C at 17 mm Hg.

C) Obtaining 3-(4-forfinal)valerianic acid

This compound was obtained in a manner analogous to the one described in example 18C, with the replacement of 3-(4-forfinal)butyrate ethyl-3-(4-forfinal)valerate (38,05 g, 0,144 mol, containing 29% of triethylphosphate) and the use of excess of 85% potassium hydroxide (18,05, 0,273 mol, Mallinckrodt). Dichloromethane layers were combined, washed with deionised water (50 ml) and concentrated by rotary evaporation under vacuum. The residue was led from hexanol getting 23,47 g (83%) of 3-(4-forfinal)valerianic acid as a white crystalline solid; NMR (DMSO-d6); d 12 (s, 1H), 7,28-7,24 (m, 2H), 7,14-was 7.08 (m, 2H), 2.91 in-2,89 (m, 1H), 2,64-to 2.41 (m, 2H), 1,66-of 1.62 (m, 1H), 1.56 to a rate of 1.51 (m, 1H), of 0.71 (t, 3H, J = 7,3 Hz).

a) Obtaining 3-(4-forfinal)valerylchloride

This compound was obtained in a manner analogous to the one described in example 18d, with the replacement of 3-(4-forfinal)butyrate 3-(4-forfinal)- valerianic acid (23,47 g, 0,120 mol). Volatile components were removed by rotary evaporation under vacuum with the addition of dichloromethane (I ml) during concentration, getting 25,25 g (98%) of 3-(4-forfinal)valerylchloride in the form of Golden yellow liquid : NMR (DMSO-d6): d 7,3-7,22 (m, 2H), 7,15-7,06 (m, 2H), 2,98-by 2.73 (m, 1H), 2,66-of 2.38 (m, 2H), 1,74 to 1.37 (m, 2H), 0,70 (t, 3H, J= 7.2 Hz).mu in example 18E, with the replacement of 3-(4-forfinal)butyrylcholine 3-(4-forfinal)valerolactam (25,27 g, amount of 0.118 mol). The dichloromethane extracts were combined, washed with deionised water (100 ml) and concentrated by rotary evaporation under vacuum. The residue was chromatographically on Silica gel 60 using a stepwise gradient from hexanol to a mixture of ethyl acetate:hexane (1:1). The fractions containing 3-ethyl-6-fluoro-1-indanone, were combined and concentrated by rotary evaporation under vacuum with dichloromethane (h) added during the concentration, getting 17,48 g (83%) of 3-ethyl-6-fluoro-1-indanone as Canary yellow syrup: NMR (DMSO-d6): d 7,74-in 7.7 (DD, 1H, JHF= 8,4 Hz, JHH= 4,8 Hz), 7,6-7,53 (DDD, 1H, JHF= 9,0 Hz, JHH= 9,0 Hz and 2.7 Hz), 7,37 (DD, 1H, JHF= 7.8 Hz, JHH= 2,4 Hz), ~ 3,3 (m, 1H, partially obscured by water), is 2.88 (DD, 1H, Jheme= 19.2 Hz), 2,39 (DD, 1H, Jheme= 19.2 Hz, J = 2.4 Hz), 1,98-1,90 (m, 1H), 1,54-of 1.44 (m, 1H), from 0.90 (t, 3H, J = 7,3 Hz).

f) obtaining the CIS and TRANS ethyl-2-(3-ethyl-6-fluoro-1-hydroxy-1 - indanyl)acetate

This compound was obtained in a manner analogous to the one described in example 18f, with the replacement of the 6-fluoro-3-methyl-1-indanone 3-ethyl-6-fluoro-1-indanone (17.3 g, 0,097 mol). Removal of volatile components from the treated solution gave 25,17 g (97%) of CIS and TRANS ethyl-2-(3-ethyl-6-f is), 4,0 (, 2H, J = 7,2 Hz), 2,90-2,82 (m, 1H), 2,80-by 2.73 (m, 1H), 2,70 is 2.55 (m, 2H), 2,04-1,9 (m, 1H), 1,83-to 1.67 (m, 1H), 1,46 of 1.28 (m, 1H), 1,11 (t, 3H, J = 7,1 Hz) of 0.95 (t, 3H, J = 7,3 Hz).

g) Obtaining (E)-2-(3-ethyl-6-fluoro-1-inderide)acetic acid

This compound was obtained in a manner analogous to the one described in example 18g, with the substitution of ethyl-2-(6-fluoro-1-hydroxy-3-methyl-1-indanyl)acetate ethyl-2-(3-ethyl-6-fluoro-1-hydroxy-1-indanyl)acetate (24,85 g, 0,093 mol). Removal of volatile components from the treated solution gave a beige residue. Recrystallization from a mixture of dichloromethane-hexane gave 12,91 g (63%) of (E)-2-(3-ethyl-6-fluoro-1-inderide)acetic acid as a white crystalline solid, so pl. 145-148oC.

h) Obtaining (E)-2-(3-ethyl-6-fluoro-1-inderide)acetylchloride

This compound was obtained in a manner analogous to the one described in example 18h, with the replacement of (E)-2-(6-fluoro-3-methyl-1-inderide) acetic acid (E)-2-(3-ethyl-6-fluoro-1-inderide)acetic acid (5.7 g, 25,88 mmole). The product residue was dissolved in dichloromethane and used without purification in example 26.

i) Obtaining (E)-N-cyclopropyl-2-(6-fluoro-3-ethyl-1 - inderide)ndimethylacetamide

This compound was obtained by a method similar to that described in example 20, with the replacement of (E)-2-(6-fluoro-3-methyl-1-Indonesien)- acetylchloride (E)-2-(who and 2.24 g (65%) of (E)-N-cyclopropyl-2-(6-fluoro-3-ethyl-1 - inderide)ndimethylacetamide in the form of a white crystalline solid, so pl. 143-147oC.

Example 27

Obtaining (E)-N-cyclopropyl-2-(6-fluoro-3-propyl-1 - inderide)ndimethylacetamide

Aluminium chloride (139 g, the 1.04 mol) was added to a solution of butyrylcholine (55,45, 0,520 mol, Aldrich) in dichloromethane (500 ml) with stirring in a nitrogen atmosphere at 25oC. Solution of Forasol (50,1 g, 0,521 mol, Aldrich) in dichloromethane was added and stirring continued for 18 hours.

The reaction solution was poured into ice and was extracted with dichloromethane (3x400 ml). The combined dichloromethane extracts were washed in deionised water (I ml), and 1.0 G. hydrochloric acid (500 ml), saturated sodium bicarbonate solution (2x500 stretch-forming press ml) and deionised water (I ml), concentrated by rotary evaporation under vacuum. This material was combined with material from such receipt (with the use of 0.26 mol of fervently) for distillation. Distillation under reduced pressure gave 69,27 g (53%) of 4'-verbalisation in the form of a pale yellow liquid, which later partially crystallized, so Kip. 108-112oC for 30 millitorr, NMR (DMSO-d6): d 8,03 (K, 2H, J = 9,0 Hz and 5.6 Hz), 7,31 (t, 2H, J = 8,9 Hz), of 2.97 (t, 2H, J = 7.0 Hz), 1,65-of 1.55 (m, 2H), of 0.91 (t, 3H, J = 7,3 Hz).

b) Obtaining ethyl-3-(4-forfinal)hexanoate

The solution of utility, 2.5 M in hexane (166 Ethylphosphonate (93,2 g, 0,416 mol, Aldrich) in tetrahydrofuran (700 ml, anhydrous, Aldrich) at a temperature below 5oC in nitrogen atmosphere. This solution was stirred for 0.25 hour, and cooled to -5oC in the bath with methanol and ice and then added in one portion a solution of 4'-verbalization (69 g, 0,415 mol, Aldrich) in tetrahydrofuran (150 ml). Stirring was continued for 18 hours without further cooling. The solution was concentrated to a slurry dark camel color rotary evaporation in vacuo and diluted to 600 ml of deionized water. The aqueous solution was extracted with dichloromethane (I ml) and dichloromethane was concentrated by rotary evaporation under vacuum. Distillation under reduced pressure gave 58.5 g (60%) of ethyl-3-(4 - forfinal)hexanoate in the form of a mixture of (E) and (Z) isomers (compound 1: 1) in the form of a transparent liquid, so Kip. 140-150oC when the pressure of the suction device.

C) Obtaining ethyl-3-(4-forfinal)hexanoate

A mixture of ethyl-3-(4-forfinal)hexanoate (58, 12 g, 0,246 mol) and 10% palladium on coal (1.1 g, Aldrich) in 95% ethanol was shaken in hydrogenator Parra at a pressure of 2-4 ATM of hydrogen for 0.75 hour. The mixture was filtered and concentrated by rotary evaporation in a vacuum, getting 58,4 g (99.6%) ethyl-3-(4-forfinal)hexanoate in vestice shaded DMSO), 1,59 of 1.46 (m, 2H), 1,13-of 1.07 (m, 2H), of 1.02 (t, 3H, J = 7.2 Hz), to 0.78 (t, 3H, J = 7.5 Hz).

d) Obtaining 3-(4-forfinal)hexanoic acid

This compound was obtained in a manner analogous to the one described in example 65s, with the replacement of 3-(4-forfinal)valerate ethyl-3-(4 - torvenyesseget (58 g, 0,243 mol). Dichloromethane layers were combined, washed with deionised water (250 ml) and concentrated by rotary evaporation under vacuum. The residue is evaporated with hexane (200 ml), receiving 46.81 / bbl g (92%) of 3-(4-forfinal)hexanoic acid as a yellow oil.

e) Obtaining 3-(4-forfinal)hexanophenone

This compound was obtained in a manner analogous to the one described in example 18d, with the replacement of 3-(4-forfinal)butyric acid 3-(4-forfinal)hexanoic acid (46,5 g, 0,222 mol). Volatile components were removed by rotary evaporation under vacuum with the addition of dichloromethane (I ml) during concentration, getting repossessed a 50.01 g (99%) 3-(4-forfinal)hexanophenone in the form of a Golden yellow liquid.

f) Receiving 6-fluoro-3-propyl-1-indanone

This compound was obtained in a manner analogous to the one described in example 18E, with the replacement of 3-(4-forfinal)butyrylcholine 3-(4-forfinal)hexanolactam (49,95 g, 0,218 mol). The dichloromethane extracts were combined, washed Denisovicha 41,26 g (98%) of 6-fluoro-3-propyl-1 - indanone in the form of Golden yellow syrup.

g) obtaining the CIS and TRANS ethyl-2-(6-fluoro-1-hydroxy-3-propyl-1 - indanyl)acetate

This compound was obtained in a manner analogous to the one described in example 18f, with the replacement of the 6-fluoro-3-methyl-1-indanone 6-fluoro-3-propyl - 1-indanone (40,75 g, 0,212 mol). Removal of volatile components from the treated solution gave 57,48 g (97%) of CIS and TRANS ethyl-2-(6-fluoro-1-hydroxy-3-propyl-1-indanyl)acetate in the form of a Golden-yellow oil.

h) Obtaining (E)-2-(6-fluoro-3-propyl-1-inderide)acetic acid

This compound was obtained in a manner analogous to the one described in example 18g, with the substitution of ethyl-2-(6-fluoro-1-hydroxy-3-methyl - 1-indanyl)acetate ethyl-2-(6-fluoro-1-hydroxy-3-propyl-1 - indanyl)acetate (57,12 g, 0,204 mol). Removal of volatile components from the working solution gave a Golden-yellow residue. The residue is suspended in hexano getting 24,49 g (51%) of (E)-2-(6-fluoro-3-propyl-1-inderide)acetic acid as white crystalline solids, so pl. 141-144oC NMR (DMSO-d6).

i) Obtaining (E)-2-(6-fluoro-3-propyl-1-inderide)acetylchloride

This compound was obtained in a manner analogous to the one described in example 18h, with the replacement of (E)-2-(6-fluoro-3-methyl-1-Indonesien)- acetic acid (E)-2-(6-fluoro-3-propyl-1-inderide)acetic acid (15,01 g, 64,x2">

j) Obtaining (E)-N-cyclopropyl-2-(6-fluoro-3-propyl-1 - inderide)ndimethylacetamide

This compound was obtained by a method similar to that described in example 20, with the replacement of (E)-2-(6-fluoro-3-methyl-1-Indonesien)- acetylchloride (E)-2-(6-fluoro-3-propyl-1-inderide)acetylchloride (3,26 g of 0.013 mol). Volatile components were removed by rotary evaporation under vacuum, receiving a Golden-yellow oil. The oil was chromatographically on Silica gel 60 with step gradient hexane - acetate-hexane (1: 1). The fractions containing (E)-N-cyclopropyl-2-(6-fluoro-3 - propyl-1-inderide)ndimethylacetamide, were combined and concentrated by rotary evaporation under vacuum with hexane (h ml), added during the concentration, getting 2,09 g (59%) of (E)-N-cyclopropyl-2-(6-fluoro-3-propyl-1-inderide)ndimethylacetamide in the form of a white powdered solid substance, so pl. 94-97oC.

Example 28

Obtain (Z)-2-(6-fluoro-1-inderide)ndimethylacetamide

A solution of (E)-2-(6-fluoro-1-inderide)ndimethylacetamide (20 g, 104,6 mmole) in a mixture of dichloromethane:methanol (3:1) (1000 ml) was covered quartz photochemical immersion lamp with mercury vapor Canrad-Hanovia, 450 watts (Ace Jlass, 7825-35) for 0.5 hours. Volatile components were removed by rotary evaporation under vacuum, obtaining a beige residue. The residue was chromatographically Forces on The Faction, containing (Z)-2-(6-fluoro-1-inderide)ndimethylacetamide, were combined and concentrated by rotary evaporation under vacuum. The obtained solid is suspended in hexane, getting 7,52 g (37%) of (Z)-2-(6-fluoro-1 - inderide)ndimethylacetamide in the form of a white crystalline solid, so pl. 175-177oC.

Example 29

Obtaining (E)-2-(4,6-debtor-3-oxo-1-inderide)ndimethylacetamide

a) Obtaining 2,4-dicarbamate-3-(3,5-differenl)-5 - hydroxy-5-methyl-1-cyclohexanone

Slightly warm liquid 3,5-differentally (5.0 g, 0,0352 mol, Aldrich), 95% ethanol (1.75 ml) and piperidine (0.7 ml) was added to ethylacetoacetate (9.2 grams, 0,0704 mol, Aldrich). The solution was stirred to homogeneity and then placed in a water bath to control the slightly exothermic reaction. After 4 hours the crystalline mass was dissolved in warm dichloromethane (100 ml). When diluted with hexane (300 ml) formed a cloudy solution. After standing for 24 hours, the crystalline product was collected by filtration and washed with hexane, obtaining 8.0 g (59%) of 2,4-dicarbamate-3-(3,5-differenl)-5-hydroxy-5-methyl-1 - cyclohexanone, T. pl. 185-186oC.

b) Obtaining 3-(3,5-differenl)glutaric acid

To a hot (95oC) the solution prepared from sodium hydroxide (322 is xenon (43 g, 0,112 mol) in ethanol (322 ml) with rapid stirring. The resulting mixture was heated under reflux for 4 hours using an oil bath at 140oC. the Ethanol was removed by rotary evaporation under vacuum and the resulting suspension was cooled in an ice bath and concentrated hydrochloric acid (12 BC) was added to bring the pH to about 1. The precipitate was dissolved by addition of water and the aqueous solution was extracted with ethyl acetate (total volume of 1500 ml). An ethyl acetate extracts were combined, washed with water, dried with MgSO4and volatile components were removed by rotary evaporation under vacuum. Recrystallization of the residue from dichloromethane gave 9,10 g (33%) of 3-(3,5-differenl)glutaric acid, so pl. 170-172oC.

C) Obtaining 2-(4,6-debtor-3-oxo-1-indanyl)acetic acid

This compound was obtained in a manner analogous to the one described in example 25d, with the replacement of 3-(3-forfinal)glutaric acid 3-(3,5-differenl)glutaric acid (9,02 g, 36,9 mmole) and increasing time of heating from 10 minutes to 30 minutes. Chromatography of the collected product on a column of Silica gel 60 (h mm) with elution with a mixture of methanol:dichloromethane (4:96) gave material which was recrystallized from water, receiving of 1.93 g (23%) of 2-(4,6-debtor-3-oxo-1-indanyl)vinegar is inania received by way similar to that described in example 25th, replacing 2-(6-fluoro-3-oxo-1-indanyl)acetic acid 2-(4,6-debtor-3-oxo-1-indanyl)acetic acid (3,85 g of 0.017 mol). Thus obtained 2-(4,6-debtor-3-oxo-1-indanyl) acetylchloride used without further purification or analysis.

e) Obtaining 2-(4,6-debtor-3-oxo-1-indanyl)ndimethylacetamide

This compound was obtained in a manner analogous to the one described in example 25f, replacing 2-(3-fluoro-3-oxo-1-indanyl)acetylchloride 2-(4,6-debtor-3-oxo-1-indanyl)acetic acid (4,2 g, 17 mmol). After chromatography, recrystallization twice from a mixture of dichloromethane:hexane gave 2.8 g (77%) of 2-(4,6-debtor-3-oxo-1-indanyl)ndimethylacetamide, so pl. 155-157oC.

f) Obtaining (E)-2-(4,6-debtor-3-oxo-1-inderide)ndimethylacetamide

A mixture of 2-(4,6-debtor-3-oxo-1-indanyl)ndimethylacetamide (1.0 g, 0,0044 mol), N-bromosuccinimide (0,950 g, 0,00533 mole), 2,2-azobis(2 - methylpropionitrile) (0,350 g, 0,00213 mole, Kodak), carbon tetrachloride (50 ml) and benzene (50 ml) was heated with an oil bath at 120oC for 1 hour. The reaction solution was diluted with dichloromethane, added with Silica gel 60 and volatile components were removed by rotary evaporation under vacuum. This silicon dioxide is then applied on a column of Silica gel 60 (h mm) soaked in dichloromethane what begins in a vacuum, getting 0,613 g of residue. The residue was recrystallized from methanol, getting 0,302 g (31%) of (E)-2-(4,6-debtor-3-oxo-1-inderide)ndimethylacetamide, so pl. 250oC (decomposition).

Example 30

Obtaining (E)-N-ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1 - naphthalide)ndimethylacetamide

a) Obtaining 2-chloro-N-ethylacetamide

Chlorocatechol (45 g, 398 mmol, Aldrich) was added dropwise to aqueous ethylamine (70%, of 30.7 g of 0.48 mol) in 100 ml of deionized water source at -20oC, with stirring. The reaction temperature was raised to 0oC and stirring continued until the reaction is no longer exothermic. The resulting solution was acidified with concentrated hydrochloric acid (7 ml) and was extracted with dichloromethane (I ml). The organic layer was washed with deionized water (150 ml), filtered through glass wool and concentrated by rotary evaporation in vacuum, obtaining a pale yellow liquid residue. The residue was concentrated with hexane (200 ml) and dichloromethane (600 ml), receiving 16,01 g (59%) of 2-chloro-N-ethylacetamide. The spectrum of this compound was consistent with the proposed structure and the compound was used without further purification.

b) Obtaining diethyl-N-ethylcarbamate)methyl)phosphonate

2-chloro-N-ethylacetamide (15.5 g, 127,5 mmole) was added the/SUP>C for 30 minutes, cooled to 125oC and volatile components were removed by distillation in a water-jet pump vacuum (15 mm Hg) at this temperature. Fractional distillation gave 25,06 g (88%) of diethyl((N-ethylcarbamate)methyl)phosphonate, so Kip. 135-147oC at 0.50 mm Hg. This compound is used without further analysis.

C) Obtaining (E)-N-ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1 - naphthalide)ndimethylacetamide

To a stirred suspension of NaH (80% dispersion in mineral oil, of 0.91 g, 0,030 mol, Aldrich) in dimethyl sulfoxide (150 ml) at room temperature under nitrogen atmosphere was added a solution of diethyl((N-ethylcarbamate)methyl)phosphonate (6.8 g, being 0.030 mole) in dimethyl sulfoxide (50 ml). The reaction was slightly exothermic. The reaction mixture was stirred for 0.75 in hours. A solution of 7-fluoro-1-tetralone (5,00 g, being 0.030 mole) in dimethyl sulfoxide (50 ml) was added and the reaction was stirred for 1 hour. The reaction was poured into ice water (300 ml) and was extracted with diethyl ether (3x250 ml). The combined ether phases were washed with water (100 ml) and concentrated by rotary evaporation under vacuum, receiving Golden yellow syrup. This residue was chromatographically on Silica gel 60 using a stepwise gradient from a mixture of ethyl acetate: hexane/1: 3 to see what and concentrated by rotary evaporation under vacuum, getting 3,74 g of a white solid. Recrystallization from a mixture of dichloromethane:hexane gave 3.28 g (46%) of (E)-N-ethyl-2-(7-fluoro - 1,2,3,4-tetrahydro-1-naphthalide)ndimethylacetamide in the form of a fluffy white solid, so pl. 87-89oC.

Anal. calculated for C14H16FNO (mol. weight 233,278): 72,08, H 6,91, N 6,00.

Found: C 72,05, H 6,91, N 6,05.

Example 31

Obtain (Z)-N-ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1 - naphthalide)ndimethylacetamide

Fractions from the chromatographic purification described in example 30, containing (Z)-N-ethyl-2-(7-fluoro-1,2,3,4-tetrahydro - 1-naphthalide)ndimethylacetamide, were combined and concentrated in vacuum, obtaining 1.07 g (20%) of (Z)-N-ethyl-2-(7-fluoro-1,2,3,4-tetrahydro - 1-naphthalide)ndimethylacetamide in the form of a white solid substance, so pl. 117-118oC.

Anal. calculated for C14H16FNO (mol. weight 233,278): 72,08, H 6,91, N 6,00.

Found: C 71,99, H 6,89, N 6,01.

Example 32

Obtaining (E)-2-(4,6-debtor-3-hydroxy-1-inderide)ndimethylacetamide

A suspension of (E)-2-(4,6-debtor-3-oxo-1-inderide)ndimethylacetamide (0,100 g, 0.45 mmole) and sodium borohydride (0,017 g, 0.45 mmole) in 95% ethanol was stirred at ambient temperature for 2 hours. The mixture was cooled in an ice bath and extinguished 0.1 G. of hydrochloric acid (3 ml). The ethanol evaporated in ACML), was dried over sodium sulfate, filtered and evaporated in vacuum. The residue was washed successively with cold ethyl acetate, hexane, diethyl ether, receiving 0,046 g (45%) of (E)-2-(4,6-debtor-3-hydroxy-1-inderide)ndimethylacetamide in the form of a white solid substance, so pl. 232-237oC (decomposition). 1H-NMR (DMSO-d6): 7,06-7,42 (m, 4H), of 6.49 (s, 1H), 5,52 (d, 1H), and 5.30 (m, 1H), 3,44 (m, 1H), 3,03 (1H).

Connection (see tab. 1) was obtained by methods similar to those described in these examples.

Pharmaceutical compositions

In the following examples, 73-78 "Active ingredient" is a compound of formula (I) or a pharmaceutically acceptable salt or MES.

Example 73

Composition for tablets

Composition A (see table. 2) B (see tab. 3), and C were prepared by wet granulation of the ingredients with a solution of povidone followed by addition of magnesium stearate and pressed.

Composition C - mg/tablet

Active ingredient - 100

Lactose - 200

Starch - 50

Povidone - 5

Magnesium stearate - 4 - 359

The following compositions D and E were prepared by direct pressing of the mixed ingredients. Lactose in the composition E is lactose type direct extrusion (Dairy-Crest - "Zeparox").

Composition D - mg/tab the E - mg/tablet

Active ingredient: 250

Lactose - 150

Avriel - 100 - 500

Composition F (preparation with controlled release of active ingredient)

The composition was prepared by wet granulation of the ingredients (see below) with a solution of povidone followed by the addition of magnesium stearate and compression. mg/tablet

(a) Active ingredient: 500

(b) Hypromellose (Methocel K4M Premium) - 112

(C) Lactose C. R. - 53

(d) Povidone C. R. - 28

(e) magnesium Stearate - 7 - 700

Example 74

Composition for capsules

Composition A

Composition for capsules were prepared by mixing the ingredients of the composition D in example 73 and filled with a mixture of hard gelatin capsules. Composition (nifra) is prepared in a similar fashion.

Composition mg/capsule

(a) Active ingredient 250

(b) Lactose C. R. - 143

(C) the Sodium salt of glycolate starch - 25

(a) magnesium Stearate - 2 - 420

Composition C - mg/capsule

(a) Active ingredient 250

(b) Macrogol 4000 C. P. - 350 - 600

Composition D - mg/capsule

Active ingredient: 250

Lecithin - 100

Peanut butter - 100 - 450

Capsule compositions D were prepared by dispersing the active ingredient in the lecithin and Arachis is psula

(a) Active ingredient - 100

(b) Lactose - 300

(C) magnesium Stearate - 2

(d) sodium dodecyl sulfate - 2

(e) the Sodium salt of glycolate starch - 50

(f) Talc, USP - 25 - 479

Composition for capsules prepared micronsize (microasperities) of the active ingredient with the help of GEM-T Type 1047 Jet Mill and mixing with the remaining ingredients of the composition E. the resulting mixture was filled solid with two-piece gelatin capsules.

Composition F (capsule with controlled release)

The following composition for capsules with controlled release of active ingredient were prepared by extrusion of the ingredients a, b and c using an extruder, followed by the formation of spherical particles of the extrudate and drying. The dried precipitates were then coated controlling the allocation of the membrane (d) and fill them two-part hard gelatin capsule. mg/capsule

(a) Active ingredient 250

(b) Microcrystalline cellulose - 125

(C) Lactose C. R. - 125

(a) Ethylcellulose - 13 - 513

Example 75

Composition for injection

Active ingredient - 0,200 g

95% ethanol and PEG 400, 1:1

Sterile water - q.s. to 10 ml

The active ingredient was dissolved in 95% economically filter into a sterile vial (type 1) amber glass 10 ml, which was covered with a sterile cover, and outer cover.

Example 76

Syrup

Active ingredient - 0.25 grams

The sorbitol solution of 1.50 g

Glycerin - 2,00 g

Sodium benzoate - 0,005 grams

Flavoring, Peach 17,42.3169 - of 0.0125 ml

Purified water - q.s to 5.00 ml

The active ingredient was dissolved in a mixture of glycerin and most of purified water. An aqueous solution of sodium benzoate was added to the solution followed by the addition of a solution of sorbitol and finally, flavoring. The volume was brought purified water and well stirred.

Example 77

Suppository - mg/suppository

Active ingredient: 250

Tallow, W. R. (Witepsol H15-Dynamit Nobel) - 1770 - 2020

1/5 Witepsol H15 was melted in a tank with a steam jacket at 45oC (maximum). The active ingredient was sieved through a 200 μm sieve and added to the molten base with mixing, using Silverson fitted with a cutting head, until it formed a smooth dispersion. While maintaining the mixture at 45oC the remaining Witepsol H15 was added to the suspension and stirred, providing a homogeneous mixture. The entire suspension was passed through a stainless steel sieve of 250 μm and with continuous stirring, allowed it to cool to 40oC. P to cool to room temperature.

Example 78

Pessaries - mg/pessary

Active ingredient: 250

Anhydrous dextrose - 380

Potato starch - 363

Magnesium stearate - 7 - 1000

These ingredients were mixed directly with each other and pessaries were prepared by direct pressing of the mixture.

Example 79

Central muscle relaxant activity

Central muscle relaxant activity of the compounds of formula (I) was determined using the test Straub-tails on the basis of the method described by K. O. Ellis, J. F. Carpenter, Neuropharm. 13, 211 (1974).

The test result Straub-tails grow as ED50in mg/kg ED50defined as the dose introduced compounds that prevent Straub-tails 50% of mice. Connection enter the sensing 60 minutes prior to evaluation.

Possible side effects of these compounds were determined using rodorod test in mice (rotating cylinder) described H. D. Novak, and J. M. Zwolshei, J. Pharmacologocl Methods, 10, 175 (1983). The result rodorod test in mice were expressed as ED50in mg/kg ED50is the dose that causes 50% of the animals can't stay on the cylinder rotating at 11 rpm

Antagonism towards induced by morphine Straub-tail reflects effective poor coordination.

Determination of the relationship of adverse outcome in rodorod test for antagonism against induced by morphine Straub-tails is a measure of the ability to side effects of the underlying muscle relaxants (J. D. Novak, Drug Del. Res. 2, 383 (1982) (see tab. 4).

Example 80

Anticonvulsant activity

Anticonvulsant activity of the compounds of formula (I) was determined using the method described by Mehta et al., J. Med. Chem., 24, 465 (1981).

Anticonvulsant activity was expressed as ED50in mg/kg ED50for maximum protection against induced by electroshock seizures was the dose that prevented the straightening of the back leg in 50% of animals. ED50to protect against induced Metrazol seizures was the dose that prevented convulsions in 50% of animals (see table. 5).

Example 81

Anxiolytic activity

Anxiolytic activity of the compounds of formula (I) was measured using the method Geller and Seifter, J. Psycho-pharmacologia, 1, 482 (1960) modified Pollard and Howard, Psychopharmacology, 62, 117 (1979). Clinically effective anxiolytics increase suppressed response. Anxiolytic activity of the compounds is expressed as the lowest dose required for significant SS="ptx2">

MED - minimum effective dose.

Example 82

Anti-inflammatory activity

The compounds of formula (I) have anti-inflammatory activity, as shown by the modification of the standard test-induced carrageenan pleurisy described Vinegar R., J. F. Traux and J. Z. Selph (Pro. Soc. Exp. Biol. Med. 143:711-714, 1973). In these experiments used Zewis male rats weighing 160-180 g, divided into groups consisting of 5 animals. Test compounds were given to the hungry rats by feeding through a stomach tube for 0.5 hour before intrapleural injection 50 mg carrageenan. After 4 hours the pleural exudate was collected and determined the amount of swelling and the number of cells. ED50values were determined by linear regression analysis and these values represented the dose at which you entered the drug gave 50% inhibition induced carrageenan accumulation of cells and the formation of edema in the pleural cavity of rats (see table. 6).

Example 83

Caused by the adjuvant arthritis

The compounds of formula (I) also exhibit chronic anti-inflammatory activity, as shown by the inhibition induced adjuvant arthritis in rats. The procedure for this test was detailed product description product the Rys with the original weight, 19010 Arthritic rats were divided into groups consisting of 6 animals. Receiving food rats were dosed out by sensing through the mouth of the test compound, starting from the 21st day after the injection of adjuvant therapy was continued until the 28th day. The frequency and severity of arthritic damage was assessed using a modification of procedures described by H. Z. F. Currey and M. Ziff (J. Exp. Med. 121: 185-203, 1968). Briefly, bilateral joints were evaluated for swelling, erythema and ankylosis, as shown in table. 7.

The maximum possible score for the rat was 40. Experimental results were analyzed by one-factor ANOVA with subsequent post hoc comparisons of therapeutic effects compared to untreated arthritic controls using test Newman-Keuls. The percentage inhibition of each of the processed medicines group was calculated from the average value with respect to arthritic control. Compound of example No. 5 significantly (p < 0,01) was downgraded points of arthritis on the 22nd, 25th and 27th days in rats with induced adjuvant arthritis at doses of b.i.d.c 50 mg/kg Weight of the spleen and plasma fibrinogen was measured after the death on the 27th day, and these scores were significantly reduced (p < 0,01).

Example 84

Easy analgesia

The compounds of formula is another hyperalgesia of the hind limbs of rats, described Vinegar R., J. F. Truax, J. Z. Selph and P. R. Johuston (J. Pharmacol. Meth. 23: 51-61, 1990). These studies used Zewis males weighing 160-180 g were divided into groups consisting of 5-6 animals. Test compounds were given receiving food to rats by intubation through the mouth for 0.5 hour before subplantar injection of 250 mg of trypsin in one hind limb. An hour later rats were assessed on hyperalgesia with F-shaped clamp metatarsalgia area injected hind limbs. Determined latent state (seconds) pain response (voice or contacting the flight), and the maximum latent period was 4 seconds. The magnitude of the ED50was evaluated using linear regression analysis, and they represented the dose at which this drug gave 50% inhibition, using the formula: (4 sec control latent period) - (4 sec - test latent period)/4 sec control the latent period x 100.

The compound of example N - R. O. ED50mg/kg

5 - 4,0

Example 85

Strong analgesia

The compounds of formula (I) possess strong analgesic activity, as shown by the painful test for phalanges (modification test induced by trypsin was hyperlipoidemia males Zewis rats weighing 160-180 g, which was divided into groups of 5-6 animals. Pain test for phalanges is pain test (without hyperalgesia), in which test compounds give get food to rats by intubation through the mouth. After 1 hour F-shaped mechanical clamps were put on the knuckle of one hind limb, which initiated the pain response (voice or contacting the flight). The latent period (in seconds) before the pain response was defined with 3 seconds maximum permitted period of time. ED50values were determined by linear regression analysis, and they represented the dose at which this compound increased the latent period, giving 50% inhibition, using the formula: (3 sec control latent period) - (3 s - test latent period)/3 sec - control latent period x 100.

The compound of example N - R. O. ED50mg/kg

5 - 20

Example 86

Toxicity data

(i) Compound of example 1

A single dose (15, 45, or 250 mg/kg) was administered by intubation through the mouth of the 4 groups receiving food male CD-1 mice (Charles River). The maximum tolerated dose was 250 mg/kg, so as not watched the animal's death within 7 days after dosing.

(ii) Connection PRH food male CD-1 mice (Charles River). The maximum tolerated dose was more than 1000 mg/kg, as there was no death of animals within 7 days after dosing.

1. Derivatives of bicyclic amides of the formula I

< / BR>
where R1, R2, R3and R4selected, each of hydrogen and fluorine, and at least one and not more than two of them are fluorine;

R5selected from hydrogen and C1-C4-alkyl;

R6selected from hydrogen, C1-C4-alkyl and hydroxy-group

or R5and R6together with the carbon ring form a carbonyl group;

R7selected from hydrogen and hydroxy-group;

R8and R9selected, each from hydrogen, C1-C4-alkyl, cyclo(C3or C4)alkyl or together with the nitrogen form morpholinopropan.

2. Connection on p. 1, wherein R1- hydrogen.

3. Connection under item 1 or 2, wherein R2- fluoride.

4. Connection PP.1, 2 or 3, wherein R3- hydrogen.

5. Connection PP.1 to 4, wherein R4- fluoride.

6. Connection PP.1 to 5, wherein R5- hydrogen.

7. Connection PP.1 to 6, wherein Ror hydroxy-group.

9. Connection on p. 8, wherein R8and R9both hydrogen.

10. Connection on p. 9, wherein R3and R4both fluorine.

11. Connection on p. 1, selected from the group including:

1. (E)-2-(6-fluoro-3-methyl-1-inderide)ndimethylacetamide,

2. (E)-N-cyclopropyl-2-(6-fluoro-3-methyl-1-inderide) ndimethylacetamide,

3. (E)-2-(6-fluoro-3,3-dimethyl-1-Indonesien)-N-methylacetamide,

4. (E)-N-cyclopropyl-2-(6-fluoro-3-ethyl-1-inderide)ndimethylacetamide,

5. (E)-N-cyclopropyl-2-(5,6-debtor-1-inderide)ndimethylacetamide,

6. (E)-2-(5,6-debtor-1-Indonesien)-N-methylacetamide,

7. (E)-2-(5,7-debtor-1-Indonesien)-ndimethylacetamide,

8. (E)-N-cyclopropyl-2-(4,6-debtor-1-inderide)ndimethylacetamide,

9. (E)-2-(4,6-debtor-1-Indonesien)-N-isopropylacetate,

10. (E)-2-(4,6-debtor-1-Indonesien)-N,N-dimethylacetamide,

11. (Z)-2-(4,6-debtor-2-hydroxy-1-inderide)ndimethylacetamide,

12. (E)-2-(4,6-debtor-1-inderide)ndimethylacetamide,

13. (E)-2-(6-fluoro-1-inderide)ndimethylacetamide,

14. (Z)-2-(6-fluoro-2-hydroxy-1-inderide)ndimethylacetamide,

15. (E)-2-(6-fluoro-3,3-dimethyl-1-inderide)ndimethylacetamide,

16. (E)-2-(6-fluoro-3-ethyl-1-Indonesien)-N,N-dimethylacetamide,

17. (E)-2-(6-fluoro-3-hydroxy-1-inderide)ndimethylacetamide or its salt or solvate.

12. (E)-2-(6-fluoro-1-inderide)acetone the foreign Ministry.

15. (Z)-2-(6-fluoro-2-hydroxy-1-inderide)ndimethylacetamide.

16. (Z)-2-(4,6-debtor-2-hydroxy-1-inderide)ndimethylacetamide.

17. (E)-2-(6-fluoro-3-hydroxy-1-inderide)ndimethylacetamide.

18. The compound according to any one of paragraphs.1 - 17, or its pharmaceutically acceptable salt, or MES for the treatment of pathological States in mammals selected from the group comprising pathologically increased tone of skeletal muscles, convulsions, anxiety, pain or inflammation.

19. The compound according to any one of paragraphs.1 - 17, or its pharmaceutically acceptable salt, or MES to obtain drugs for the treatment of pathological conditions in mammals selected from the group including the increased tone of skeletal muscles, convulsions, anxiety, pain or inflammation.

20. The pharmaceutical composition exhibiting muscle relaxant, anticonvulsant, anti-anxiety and anti-inflammatory effects, including the active ingredient with a pharmaceutically acceptable carrier, characterized in that it comprises a compound according to any one of paragraphs.1 - 17, or its salt, or MES as specified active component.

21. The method of treatment of pathological conditions in mammals, which shows the introduction of C is the Vogue, the pain, the introduction of an effective amount of an active compound, characterized in that, as specified connection, use the connection formula I on PP.1 - 17, or its pharmaceutically acceptable salt, or MES.

22. The method according to p. 21, characterized in that the pathologically increased tone of skeletal muscles is a state of spasm, tonic tension or hyperkinesis.

23. The method according to p. 21, characterized in that the pathologically increased tone of skeletal muscles is a spasm of skeletal muscles.

24. The method according to p. 23, characterized in that the spasm of skeletal muscles associated with lumbar pain.

25. The method according to p. 23, characterized in that the spasm of skeletal muscles associated with spasticity, spinal disease, cerebral palsy, cerebrovascular disease and multiple sclerosis.

26. The method according to p. 21, wherein the condition is damage to the spinal cord, horey, Atmos, tehnicheskie and epileptic seizures.

27. A method of treating inflammatory conditions in mammals by introduction of an effective amount of an active compound, characterized in that, as specified connection is used with the notable that inflammation associated with arthritis.

29. The method according to p. 27, wherein the inflammatory condition is a rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gout arthritis.

30. The method according to p. 17, wherein the inflammatory condition is not associated with the joints.

31. The method according to p. 27, characterized in that neustannoe inflammatory condition is a syndrome formed the herniated (ruptured) dropped out of the intervertebral disc, bursitis, tendonitis, tenosynovitis, fibromyalgia syndrome and other inflammatory conditions associated with ligamentous and regional deformation of skeletal muscles.

 

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The invention relates to methods for new nitrogen-containing compounds of General formula I

Rwhere R1is hydroxy, lower alkanoyloxy, OCOT1Y2where: Y1, Y2is hydrogen, lower alkyl when X = CH2; R2group of the formula

ororor< / BR>
ororwhere n' is 0,1,2,3; n = 2,1,0, where: Y3Y4is hydrogen, lower alkyl, Y5- phenyl-lower alkoxy, hydrogen, lower alkoxy when X is - S R2group

CHY5ororwhere Y3, Y5have the specified values;

R3lowest alkoxyl, lower alkyl, hydrogen, halogen, trifluoromethyl, lower alkylsulfonyl, R
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