Compounds, method for preparing compound, pharmaceutical composition

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 3 tbl, 35 ex

 

The present invention relates to organic compounds, their reception and their use as pharmaceuticals.

One of the objects of the invention is a compound of the formula

in free form or in salt form or MES, where

AG denotes a group of the formula

R1denotes hydrogen, hydroxy or alkoxy,

R2and R3each independently of one another denotes hydrogen or alkyl,

R4, R5, R6and R7each independently of one another denotes hydrogen, halogen, cyano, hydroxy, alkoxy, aryl, alkyl, alkyl substituted by one or more halogen atoms or by one or more hydroxy or alkoxygroup, alkyl comprising one or more heteroatoms, alkenyl, trialkylsilyl, carboxy, alkoxy-carbonyl or-CONR11R12where R11and R12each independently of one another denotes hydrogen or alkyl, or R4and R5, R5and R6or R6and R7together with the carbon atoms to which they are attached, denote a carbocyclic or heterocyclic ring,

R8denotes halogen, -OR13, -CH2OR13or other13where R13denotes hydrogen, alkyl, alkyl comprising one or more heteroatom is in, -COR14where R14denotes hydrogen, -N(R15R16, alkyl or alkyl comprising one or more heteroatoms, or aryl and R15and R16each independently of one another denotes hydrogen, alkyl or alkyl comprising one or more heteroatoms, or R13denotes-C(=NH)R17, -SOR17or-SO2R17where R17denotes alkyl or alkyl comprising one or more heteroatoms, and R9denotes hydrogen, or R8means-other18where is the other18and R9together with the carbon atoms to which they are attached, represent a 5 - or 6-membered heterocycle,

R10means-OR19or other19where R19denotes hydrogen, alkyl, alkyl comprising one or more heteroatoms, or-COR20where R20represents-N(R21R22, alkyl or alkyl comprising one or more heteroatoms, or aryl, and R21and R22each independently of one another denotes hydrogen, alkyl or alkyl comprising one or more heteroatoms,

X denotes halogen or halomethyl or alkyl,

Y represents carbon or nitrogen,

n is 1 or 2,

p is zero when Y represents nitrogen, or 1 when Y represents carbon,

q and r are each zero or 1, the sum of q+r is 1 or 2; and the carbon atom marked with an asterisk *is in the R - or S-is configuratie, or their mixture, when R1denotes a hydroxy or alkoxy.

Terms used in this description have the following meanings:

“Alkyl” refers to alkyl straight or branched chain, which may represent, for example, C1-C10alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl with straight or branched chain hexyl straight or branched chain heptyl straight or branched chain, nonyl straight or branched chain or decyl straight or branched chain. Preferably denotes alkyl With1-C4alkyl. Alkyl, substituted by one or more halogen atoms or by one or more hydroxy or alkoxygroup, can be any of the above C1-C10alkyl groups substituted by one or more halogen atoms, preferably fluorine atoms or chlorine, one or more hydroxy groups or one or more C1-C10preferably1-C4alkoxygroup.

“Alkyl comprising one or more heteroatoms” refers to alkyl straight or branched chain, for example, C1-C10alkyl, in which one or more pairs of carbon atoms linked by-O-, -NR-, -S-, -S(=O) or-SO2-where R stands in the location or C 1-C10(preferably1-C4) alkyl. Such preferred groups are alkoxyalkyl group, preferably C1-C4alkoxy-C1-C4alkyl groups.

“Alkoxy” refers to alkoxygroup straight or branched chain and may constitute, for example, C1-C10alkoxygroup, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, or intoxi, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy straight or branched chain. Preferably alkoxy represents a C1-C4alkoxy.

“Alkenyl” means an alkenyl straight or branched chain, which may be unsubstituted or may be substituted, for example, by one or more halogen atoms or one or more alkoxygroup and can represent, for example, C2-C10alkenyl, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, Isobutanol or pentenyl, hexenyl, heptenyl, octenyl, nonanol or decenyl straight or branched chain. Preferably alkenyl represents a C2-C4alkenyl.

“Aryl” means unsubstituted or substituted aryl, for example, unsubstituted phenyl or naphthyl or phenyl or naphthyl substituted by one or more, for example 1-4 for what estately, selected from the group comprising From1-C4alkyl, hydroxy, C1-C4alkoxy, halogen or Gialos1-C4alkyl. Preferably the aryl represents unsubstituted phenyl or phenyl substituted with 1-2 substituents selected from the group comprising From1-C4alkyl or halogen.

“Alkylene” means alkylene straight or branched chain, which may represent, for example, C1-C10alkylene, such as methylene, ethylene, 1,2-propylene, 1,3-propylene, butylene, pentile, hexylen, reptile, octiles, Nonlin or deciles. Preferably alkylene stands With1-C4alkylen.

“Albaniles” means albaniles straight or branched chain, which may represent, for example, C2-C10albaniles, such as vinile, propylen, butylen, penttinen, hexenlini, heptenyl, hoktanyan, nonpenile or decoiler. Preferably albaniles stands With2-C4albaniles.

In formula I, n is 1 or 2, i.e. in a ring condensed with the indicated benzene ring, there are 2 or 4 CH2groups, therefore, the ring represents a 5-membered, or 7-membered ring.

Group AG in the formula II, in which R8means-other18and-other18and R9together represent a 5 - or 6-membered heterocycle may be with the Oh, for example, a group in which Y denotes a carbon atom, R8means-other18and-other18and R9together denote a group of formula-NH-CO-R23-where R23denotes alkylene, albaniles or accelerograph, a group of the formula-NH-SO2-R24where R24denotes accelerograph, a group of the formula-NH-R25(COOR26)-, where R25denotes alkylene or albaniles and R26denotes alkyl, or a group of the formula-NH-CO-NH or-NH-CO-S-,

R10means-OR19where R19has the above values, X represents alkyl, p is 1, q is 1 and r is zero or 1.

Allenova, Alcanena and accelerometry preferably have 1-4 carbon atoms.

A preferred group AG formula II in which R8means-other18and-other18and R9together represent a 5 - or 6-membered heterocycle include groups in which

Y represents carbon, R8means-other18and-other18and R9together denote a group of formula-NH-CO-C(R27)=C(R28or-NH-CO-CH2-O-, or-NH-CO-CH2-, or-NH-SO2-CH2-O-, or-NH-C(COOR26)=CH-, or-NH-CO-NH-, or-NH-CO-S-, where R27and R28each independently of one another denotes hydrogen or C1-C4alkyl, and R26stands With1-C4alkyl, R10means-HE, X denotes a1-C4 alkyl, p is 1, q is 1 and r is zero or 1.

A more preferred group AG formula II, where R8means-other18and-other18and R9together represent a 5 - or 6-membered heterocycle, include groups of the formula

in which R29, R30and R31each independently of one another denotes hydrogen or C1-C4alkyl,

in which Z denotes-O-, -NH-or-S-.

Group AG formula II in which R8denotes halogen and R9denotes hydrogen, can represent, for example, a group of the formula II in which Y represents carbon, R8denotes halogen, preferably chlorine, R9denotes hydrogen, R10means-other18where R18denotes hydrogen or C1-C4alkyl, preferably hydrogen or methyl, X denotes a halogen or halomethyl, preferably chlorine or trifluoromethyl, and p, q and r each is 1. Among these groups, preferred group AG include groups of the formula

Group AG formula II in which R8means-OR13and R9denotes hydrogen, can represent, for example, a group of the formula II in which Y represents carbon, R8means-OR13where R13denotes hydrogen, C1-C4alkyl, the 1-C4alkoxy-C1-C4alkyl, -COR14where R14stands With1-C4alkyl, C6-C10aryl or-N(R15R16where R15and R16each independently of one another denotes hydrogen or C1-C4alkyl, R10means-OR19or other19where R19denotes hydrogen, C1-C4alkyl, C1-C4alkoxy-C1-C4alkyl, or-COR20where R20represents-N(R21R22With1-C4alkyl, C1-C4alkoxy-C1-C4alkyl or C6-C10aryl and R21and R22each independently of one another denotes hydrogen or C1-C4alkyl, p and q each is 1 and r is zero. Among these groups, preferred group AG include groups of the formula

Group AG formula II in which R8denotes-CH2OR13may represent, for example, a group of the formula II in which Y represents carbon, R8denotes-CH2OR13where R13denotes hydrogen, C1-C4alkyl or C1-C4alkoxy-C1-C4alkyl, R9denotes hydrogen, R10means-OR19where R19denotes hydrogen, C1-C4alkyl or C1-C4alkoxy-C1-C4alkyl, or R10 means-other19where R19denotes hydrogen, C1-C4alkyl, or-COR20where R20stands With1-C4alkyl, C6-C10aryl or-N(R21R22where R21and R22each independently of one another denotes hydrogen or C1-C4alkyl, p and q each is 1 and r is zero; or a group of the formula in which Y denotes a nitrogen, R8denotes-CH2OR13where R13denotes hydrogen, C1-C4alkyl or C1-C4alkoxy-C1-C4alkyl, R10means-OR19where R19denotes hydrogen, C1-C4alkyl or C1-C4alkoxy-C1-C4alkyl, R and r are zero and q is 1. Among these groups, preferred group AG include groups of the formula

Group AG formula II in which R8means-other13may represent, for example, a group of the formula II in which Y represents carbon, R8means-other13where R13denotes hydrogen, C1-C10alkyl, C1-C10alkyl comprising 1-3 heteroatoms, -COR14where R14denotes hydrogen, C1-C10alkyl or C1-C10alkyl comprising 1-3 heteroatoms, or R13denotes-C(=NH)R17, -SOR17or-SO2R17where R17putting the AET C 1-C10alkyl or C1-C10alkyl comprising 1-3 heteroatoms, R9denotes hydrogen, R10means-OR18where R18denotes hydrogen, C1-C4alkyl or C1-C4alkoxy-C1-C4alkyl, p and q each is 1 and r is zero. Among these groups, preferred group AG include groups of the formula

first of all group, where R13denotes hydrogen, C1-C4alkyl, -COR14where R14denotes hydrogen or C1-C4alkyl, or R13means-SO2R17where R17stands With1-C4alkyl.

The most preferred group AG are groups of the above formulas III, IV, V, XII and XV.

The group R1in the formula I may represent, for example, hydrogen, hydroxy or C1-C4alkoxygroup, such as methoxy, ethoxy, ISO-propoxy, n-butoxy or tert-butoxy. Preferably R1represents hydroxy.

When R1represents hydroxy or alkoxy, the carbon atom in formula I, are marked with an asterisk *, is preferably in the R-configuration.

Group R2and R3in the formula I may, for example, each independently of one another denote hydrogen or C1-C4alkyl, for example methyl or ethyl. Most preferably, R2 3denotes hydrogen or methyl.

Group R4, R5, R6and R7in the formula I may, for example, each independently of one another denote hydrogen, chlorine, fluorine, chloromethyl, trifluoromethyl, hydroxy, C1-C10alkoxy, C1-C10alkyl, C1-C10alkyl comprising one or more oxygen atoms or sulfur, or one or more NH groups, SO or SO2With2-C4alkenyl, trimethylsilyl, triethylsilyl, phenyl, carboxy, C1-C4alkoxycarbonyl, -ONR11R12(where R11and R12each independently of one another denotes hydrogen or C1-C4alkyl), or R4and R5, R5and R6or R6and R7together with the carbon atoms to which they are attached, can denote a 5 - or 6-membered carbocyclic ring, which preferably represents a cycloaliphatic ring, preferably a saturated, or 5 - or 6-membered O-heterocyclic ring containing one or two oxygen atom. Preferably R4, R5, R6and R7each independently of one another denotes hydrogen or represent such groups that the benzene ring to which they are attached, is symmetrically substituted, i.e. either (a) R4and R7are the same and R5and R6are the same is passed or together denote a symmetric ring, or (b) R4and R5together and R6and R7together represent the same ring. More preferably R4and R7are the same and each represents hydrogen, C1-C4alkyl or C1-C4alkoxy and either R5and R6are the same and each represents hydrogen, C1-C4alkyl, C1-C4alkoxy or C1-C4alkoxy-C1-C4alkyl, or R5and R6together represent -(CH2)s- or-O(CH2)tO-, where s is 3 or 4 and t is 1 or 2.

The most preferred compounds according to the invention include compounds of formula I, where AG denotes a group of formula III, IV, V, XII or XV, R1denotes hydroxy, R2and R3represent hydrogen and R4and R7are the same and each represents hydrogen, C1-C4alkyl or C1-C4alkoxy and either R5and R6are the same and each represents hydrogen, C1-C4alkyl, C1-C4alkoxy or1-C4alkoxy-C1-C4alkyl, or R5and R6together represent -(CH2)4- or-O(CH2)2O-, in free form or in salt form or MES. In such compounds the carbon atom in formula I, is indicated by an asterisk *, is preferably in the R-configuration. oncrete the most preferred compound is described below in the examples.

The compounds of formula (I) can form acid additive salts, especially pharmaceutically acceptable acid salt additive. Pharmaceutically acceptable acid additive salts of the compounds of formula I include salts of inorganic acids, for example, halogen acids such as hydrofluoric acid, hydrochloric acid: Hydrobromic acid or uudistoodetena acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, ortho-hydroxybenzoic acid, para-hydroxybenzoic acid, para-chlorbenzene acid, diphenyloxy acid, triphenylarsine acid, 1-hydroxynaphthalene-2-carboxylic acid, 3-hydroxynaphthalene-2-carboxylic acid, aliphatic hydroxy acid such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as fumaric acid, maleic acid or succinic acid, and sulfonic acids such as methanesulfonate acid or benzolsulfonat acid. Such salts can be formed from compounds of formula I by known methods of obtaining salt.

Suitable solvate are pharmaceutically acceptable solvate, preferably hydrates.

p> In the present invention is also a method for obtaining compounds of formula I in free form or in salt form or MES. They can be obtained by the method, which is that: (a) to obtain compounds where R1denotes hydroxy, or

(I) subject to the interaction of the compound of the formula

with the compound of the formula

where AG1denotes AG, as defined above in the present description, or a protected form, R2, R3, R4, R5, R6, R7and n have the above meanings and R32denotes hydrogen or aminosidine group, or (II) restore the connection of the formula

where Ar1, R2, R3, R4, R5, R6and R7have the above values, the transformation specified ketogroup in group-CH(OH)-; or

(b) to obtain compounds where R1denotes hydrogen, restore the corresponding compound of formula I, where R1represents hydroxy; or

(C) to obtain the compounds of formula I, where R1denotes alkoxy, either (I) carry out the O-alkylation of the corresponding compounds of formula I, where R1denotes hydroxy, or (II) is subjected to the interaction of the corresponding connection, the soda is relevant instead of R 1a leaving group, with an alcohol of formula R1H, where R1denotes alkoxy;

not necessarily make the resulting compound of formula I in protected form in the appropriate connection in unprotected form;

and allocate the resulting compound of formula I in free form or in salt form or MES.

Option (a)(I) of the method can be carried out using known methods of conducting reactions between the epoxide and the amine. Typically, the interaction is carried out without solvent or in an inert solvent, for example hydrocarbons, such as toluene, or alcohol, such as n-butanol. The reaction temperature is usually in the range from 25 to 200°C, preferably from 80 to 150°C. the Temperature may be achieved by conventional heating or microwave radiation.

Option (a)(II) of the method can be carried out using known methods, for example, by reacting with sodium borohydride under standard conditions.

Option (b) of the method can be carried out using known techniques used for recovery of secondary alcohols to hydrocarbons. Option (C)(I) of the method can be carried out using known methods for O-alkylation, for example, by reacting with an alkylating agent such as haloalkyl, in standard conditions is H. Option (C)(II) of the method can be carried out using known methods of conducting reactions of benzyl substitution, while this group may represent, for example, tosylate, mesilate, halogen or hydroxy-group.

The compounds of formula I in free form can be converted to the standard method in the form of salt or MES and Vice versa.

Compounds according to the invention can be isolated from the reaction mixture and purified by a standard method. Isomers, such as enantiomers can be obtained by a standard method, for example, fractionated crystallization or by asymmetric synthesis of the corresponding asymmetrically substituted, for example, optically active, original products.

The compounds of formula XVI are known compounds or can be obtained by methods similar to those used for known compounds, for example, the methods described in Journal of Medicinal Chemistry, 30, 1563-1566, 1987. The compounds of formula XVI, in which the carbon atom marked with an asterisk *is chiral, can be obtained from compounds of formula

where AG1and R2have the abovementioned meanings and L represents a leaving group or a group described in WO 95/25104.

Alternatively, the compounds of formula XVI can be obtained by epoxidase the project for the compounds of formula

where AG1and R2have the above values, using standard methods such as the methods described below in the examples.

The compounds of formula XX are known or can be obtained using methods similar to the methods used to obtain the known compounds, for example, the methods described below in the examples.

The compounds of formula XVII are known or can be obtained by methods similar to the methods used to obtain the known compounds. R32denoting aminosidine group of the formula XVII can be a well-known group, for example as described in Protective Groups in Organic Synthesis, T.W.Greene, P.G.M.Wuts, John Wiley & Sons Inc, 2nd edition, 1991, preferably benzyl or TRIFLUOROACETYL.

The compounds of formula XVII, where R3denotes hydrogen, can be obtained, for example, by the reduction of oxime of the formula

where R4, R5, R6, R7and n have the above values. The recovery may be carried out by standard methods of recovery Asimov to amines. For example, the recovery may be carried out by catalytic hydrogenation, preferably using as a catalyst of palladium on coal. The hydrogenation can be carried out using known is the shaft of the methods for example, according to the methods described in R.D.Sindelar etc., J. Med. Chem., 25(7), 858-864 (1982). Oximes of formula XXI can be obtained according to the methods described in Sindelar, and others (see above), or similar methods.

The compounds of formula XVII, where R4and R7denote hydrogen, can be obtained by reacting the compounds of formula

with the compound of the formula

where R3, R5, R6, R32and n have the above values. The reaction can be carried out in the presence of a catalyst, such as chloride, Tris(triphenylphosphine)rhodium. The reaction temperature may be, for example, from 60 to 120°C. the Reaction is generally carried out in an inert solvent, for example ethanol, and the reaction temperature, usually close to the temperature of reflux distilled solvent. The reaction can be carried out using known methods, for example according to the methods described in WO 96/23760. If R5and R6denote trialkylsilyl, the interaction between the compounds of formulas XXII and XXIII can be carried out in the presence of a catalyst based on a complex metal-carbonyl, for example, using the method described in ...Vollhardt and R.Hillard, J.Am.Chem. Soc., 99(12), 4058, 1977 or a similar method. The compounds of formula XXII can be obtained according to the method described in WO 96/2760 or similar methods. The compounds of formula XXIII are known or can be obtained by known methods.

The compounds of formula XVII, where R3denotes alkyl, especially methyl, and n is 1, can be obtained by amination of the corresponding 2-alkyliden-1-it using ammonia and Ka3FeCN6for example, using the method described in Fornum and Carlson, Synthesis, 191,1972.

The above compounds of formula XVII, where R4, R5, R6and R7are such groups that the benzene ring to which they are attached, is symmetrically substituted, are new in contrast to compounds, where R4, R5, R6, R7and R30each denotes hydrogen, where R4and R7denote methyl or methoxy, when R5, R6and R30each denotes a hydrogen, and where R4, R7and R30represent hydrogen when R5and R6each represents hydroxy, fluorine or chlorine. In particular, the new ones are preferred intermediates of formula XVII, where (I) R4and R7each denotes hydrogen, or R5and R6each stands With2-C4alkyl, C2-C4alkoxy, C1-C4alkoxy-C1-C4alkyl, or R5and R6together represent -(CH2)s- or-O(CH2)tO-, where s is 1-4 and t is 1 or 2; or (II) R4and R7each stands With2-C4alkyl or C2-C4alkoxy and either R5and R6each represents hydrogen, C1-C4alkyl, C1-C4alkoxy and either R5and R6each represents hydrogen, C1-C4alkyl, C1-C4alkoxy or1-C4alkoxy-C1-C4alkyl, or R5and R6together represent -(CH2)s- or-O(CH2)tO-, where s is 1-4 and t is 1 or 2.

The compounds of formula XVIII are new compounds which can be obtained by reacting the compounds of formula

where AG1has the above meanings and Hal denotes a halogen atom, preferably chlorine or bromine, with a compound of the above formula XVII. The reaction can be carried out using standard methods, for example using the methods described in Yoshizaki, etc., J. Med. Chem, 19(9), 1138-42 (1976).

If necessary, at any appropriate stage of the above-described processes can be implemented to protect any reactive groups. As a protective group generally used usually used in this field the group, and it can be introduced and removed using the standard method. For example, if the hydroxy-group in AG1protect with benzyl groups may be removed by catalytic hydrogenation in the presence of palladium on coal by using standard methods, such as the methods described in the examples.

The compounds of formula I in free form, in salt form or MES can be used as medicines. Thus, the invention also relates to the compound of formula I in free form, in salt form or MES, intended for use as a drug. The compounds of formula I in free form, in salt form or MES can be used as medicines. Thus, the invention also relates to the compound of formula I in free form, in salt form or MES, intended for use as a drug. The compounds of formula I in free form, in salt form or MES, referred to below in the present description as “agents according to the invention have a pronounced activity as agonists (β2-adrenergic receptors. Activity as β2-agonists, onset of action and duration of action of the agents according to the invention can be studied using in vitro assays using strips of trachea of Guinea pigs according to the method described in R.A.Coleman and ..Nials, J.Pharmacol. Methods, 21(1), 71-86 (1989). The ability to bind and selectivity against β2-adrenergic receptors compared with β1-adrenergic receptors can be estimated using the classical analysis of the binding used is the Finance filtration according to the method described in Current Protocols in Pharmacology (S.J.Enna (editor) et al, John Wiley & Son, Inc., 1998), or by assessing the level of camp in cells expressing β2 or β1-adrenergic receptors according to the method described in B. January and others, British J. Pharmacol. 123: 701-711 (1998).

The agents according to the invention are generally characterized by a rapid onset of action and they have long lasting stimulant β2-adrenergic receptors, communication from below in the present description examples have Ki values (β2) about 0.1-1000 nm, have a duration of from about 1 to more than 12 hours and have a selectivity in relation to β2-adrenergic receptors compared with β1-adrenergic receptors from 1.5 to 500. For example, the compounds of examples 1, 2, 4, 5, 6, 8 and 27 are characterized by activities associate with β2 and β1, which was determined on the basis of measurement of camp levels in cells expressing β2 and β1-adrenergic receptors, which are expressed as values EU50(β2/β1) (in nm), components 0,92/9,52, 0,23/1,25, 6,07/14,5, 0,79/6,10, 0,3/3,60, 0,57/8,46 and 0,012/0,5 respectively. The compounds of examples 2, 4, 5, 27 and 29 on the results of the analysis using strips of trachea of Guinea pigs have times T(50%) (in minutes)that are >400 at a concentration of nm, 82 at 100nm, 444 at 100nm, 222 1,nm and 279 at 10Nm, respectively, where T(50%) indicates the time required is for the inhibition of voltage, want to transition from contraction to relaxation at 50% of its maximum value.

Thanks to its β2-agonistic activity of the agents according to the invention can be used to treat any condition that can be prevented or facilitated by activating β2-adrenergic receptors. Because they have the electoral β2-agonistic activity, characterized by prolonged action, the agents according to the invention can be used for relaxation of smooth muscles of the bronchi and weakening bronchostenosis. The weakening of bronchostenosis can be evaluated on models, for example, by in vivo studies on plethysmographically models, described by Chong and others, J. Pharmacol.Toxicol. Methods, 39, 163-168 1998, Hammelmann, and others, Am. J. Respir. Crit. Care Med., 156, 766-775, 1997, as well as similar models. Thus, the agents according to the invention can be used in the treatment of obstructive or inflammatory diseases of the respiratory tract. Taking into account their long-lasting effects in the treatment of such diseases, it is possible to introduce the agents according to the invention once a day. According to another object of the agents according to the invention are characterized in that they have little side effects, characteristic β2-agonists, causing, for example, tachycardia, tremor and to the excited state, resulting in that they can p imeetsya for urgent (emergency) treatment, and for the preventive treatment of obstructive or inflammatory diseases of the respiratory tract.

Treatment of diseases according to the invention may be symptomatic or preventive. Inflammatory or obstructive Airways disease, for which treatment can be used in the present invention include asthma of any type and origin, including hereditary (endogenous) and acquired (exogenous) asthma. The term “asthma treatment” also refers to the treatment of patients under the age of 4 or 5 years of age who have symptoms of stridor and in respect of which diagnosed or may be diagnosed as suffering from stridor child”, i.e. patients related to having great medical value patients, which currently often referred to as asthmatics with an initial or early stage of asthma. (For simplicity, this specific asthmatic condition called “syndrome suffering from stridor child”).

The effectiveness of preventive treatment of asthma can be identified to reduce the frequency or severity of symptomatic episodes, for example, acute asthma attacks or attacks bronchostenosis, improve lung function or reduce the increased reactivity of the Airways. In addition, it can be estimated reduction is often what s the use of other means of symptomatic treatment, i.e. treatment intended to limit or eliminate symptomatic seizures if they occur, for example, use of anti-inflammatory drugs (such as corticosteroids or bronchodilators. Prophylactic efficacy in asthma is most evident for patients who are prone to the so-called “morning dipping”. “Morning dipping” is an asthmatic syndrome that affects a certain percentage of asthmatics, characterized by asthma attack, for example, approximately between 4 and 6 a.m., i.e. in the period of time sufficiently distant from the time when a previously produced any symptomatic treatment of asthma.

Other inflammatory or obstructive disease or condition of the respiratory tract, for which treatment can be used in the present invention include respiratory distress syndrome, adult (rdsw), chronic obstructive pulmonary disease or respiratory (COPD or HSDP), including chronic bronchitis or associated shortness of breath, emphysema, and increased airway responsiveness as a result of treatment with other drugs, in particular, treatment with other drugs, administered by inhalation. The invention also mo is should be used for the treatment of bronchitis of any type or origin, for example, acute, arachidonic, catarrhal, lobar, or chronic purulent tuberculous bronchitis. Other inflammatory or obstructive Airways disease, for which treatment can be applied to the present invention, include pneumoconiosis (an inflammatory, usually an occupational disease of the lungs, frequently accompanied by airway obstruction, which may be chronic or acute and is linked to the constant inhalation of dust of any kind and origin, including, for example, aluminas, antraks, asbestosis, helicos, Philos, sideros, silicosis, tabacos and bissines.

Thanks to its β2-agonistic activity of the agents according to the invention can also be used to treat a condition that requires relaxation of smooth muscles of the uterus or the vascular system. So, they can be applied to prevent or relieve premature contractions during pregnancy. They can also be used for the treatment of chronic and acute urticaria, psoriasis, allergic conjunctivitis, actinica, hay fever and mastocytosis.

The agents according to the invention can also be used as an auxiliary therapeutic agents in combination with anti-inflammatory or bronchodilator drugs primarily for the treatment of specified who's above obstructive or inflammatory diseases of the respiratory tract, for example, as a potential means to enhance therapeutic activity of such drugs or as a means to reduce the required doses or possible side effects of such medicines. The agent according to the invention can be blended with anti-inflammatory or bronchodilator drug with obtaining certain pharmaceutical composition or it may be entered individually before, concurrently or after administration of anti-inflammatory or bronchodilator medicines. Such anti-inflammatory drugs include steroids, especially corticosteroids, such as budesonide, beclamethasone, fluticasone or mometazon and agonists of the dopamine receptor, such as cabergoline, parlodel or ropinirole. Such bronchodilatory drugs include anticholinergic or antimuskarinovoe act occurs agents, in particular ipratropium bromide, bromide oxytrope and Tiotropium bromide.

Combinations of agents according to the invention and steroids can be used, for example, for the treatment of COPD or, in particular, asthma. Combinations of agents according to the invention and anticholinergic antimuskarinovoe act occurs or agents or agonists of dopamine receptor can be used, for example, for the treatment of asthma or, in particular, COPD.

In accordance with either the described present invention also relates to a method for treatment of obstructive or inflammatory Airways disease, which provides for the introduction of the patient, especially a human in need of such treatment, the above-described compounds of formula I or its pharmaceutically acceptable salt or MES. Another object of the invention is the above compound of formula I or its pharmaceutically acceptable salt or MES, intended for the preparation of drugs for the treatment of obstructive or inflammatory Airways disease.

The agents according to the invention can be administered by any suitable route, e.g. orally, e.g. in the form of a tablet or capsule; parenterally, for example intravenously; topically to the skin, for example, in the treatment of psoriasis; intranasally, for example, in the treatment of hay fever; or preferably by inhalation, especially in the treatment of obstructive or inflammatory diseases of the respiratory tract.

Another object of the invention is a pharmaceutical composition comprising a compound of formula I in free form or in the form of its pharmaceutically acceptable salt or MES, optionally in combination with a pharmaceutically acceptable diluent or carrier. Such compositions can be prepared using conventional diluents or excipients known in the field of manufacturing of herbal forms. So, forms for oral introduced what I can include tablets and capsules. Compositions for topical application may include creams, ointments, gels and transdermal delivery systems, such as plaques. Compositions for inhalation may be an aerosol or other spray composition or composition based on the dry powder.

Thus, the object of the invention is (a) compound of formula I, as described above, in free form or in the form of its pharmaceutically acceptability of salt or MES, suitable for administration by inhalation; (B) intended for inhalation drug comprising such a compound in a form suitable for inhalation, in combination with a pharmaceutically acceptable carrier in a form suitable for inhalation; (C) a pharmaceutical product comprising such a compound in a form suitable for inhalation, in combination with a device for inhalation; and (G) a device for inhalation containing such a connection in a form suitable for inhalation.

Doses used in the practical implementation of the invention should, of course, vary depending, for example, on the particular condition to be treated, the expected action and route of administration. In General, a suitable daily dose with the introduction by inhalation of approximately from 1 to 5000 mcg.

Below the invention is illustrated in the examples. The compounds used in p is imarah, get as follows:

The intermediate product 1: Hydrochloride 5,6-ditelindjen-2-ylamine

Stage a 1: 3-Chloro-1-(3,4-diethylphenyl)-1-propanone

1,2-Diethylbenzene (10,9 g, 74,6 mmole) and propionitrile (9.7 g, 74,6 mmole) is added dropwise within 30 min to ll3(22,3 g, 167,8 mmole) in nitromethane (75 ml). The reaction mixture was stirred at room temperature for 2 h, then add 70 g of ice and 14 ml of concentrated sulfuric acid. The aqueous phase is extracted with simple ether and the combined organic phases are extracted with 2n. HCl and saturated aqueous NaCl. Then the organic phase is treated with activated charcoal, magnesium sulfate and filtered, after which the solvent is removed in vacuum.

1H-NMR (CDCl3) part./million: 7,8 (1H, s, AG), and 7.7 (1H, d, AG); to 7.2 (1H, d, AG); 3,9 (2H, t, CH2); 3,4 (2H, t, CH2); and 2.8 (4H, q, CH2CH3); 1,2 (6N, m, CH3).

Stage receiving 2: 2,3-Dihydro-5,6-diethyl-1H-inden-1-he

3-Chloro-1-(3,4-diethylphenyl)-1-propanone (15.5 g) was dissolved in 66 ml of concentrated sulfuric acid and heated to 90°C for 4 hours

The reaction mixture is cooled, add ice (70 g) and the aqueous solution extracted twice with toluene. The organic layer is washed with sodium bicarbonate, saturated aqueous NaCl and treated with activated charcoal and magnesium sulfate. After filtering, RA is the solvent removed in vacuum. The product was then purified using the rapid chromatography on a column (silica gel, hexane/ethyl acetate 10:1) and then subjected to crystallization in hexane.

1H-NMR (CDCl3) part./million, a 7.6 (1H, s, AG); and 7.3 (1H, d, Ar); and 3.1 (2H, m, (CH2); 2,7 (6N, m, CH2+CH2CH3); 1,2 (6N, m, CH3).

The stage of obtaining 3: 5,6-Diethyl-3-oxime-1H-inden-1,2-(3H)-dione

2,3-Dihydro-5,6-diethyl-1H-inden-1-he (5 g, 26 mmol) in methanol (75 ml) is heated to 40°With added dropwise n-butylnitrite (3.0 g, 28.6 mmole), and then add concentrated Hcl (1.25 ml). After 1 h, the reaction mixture is brought to room temperature and filtered usageprice product, washed with chilled on ice with methanol and dried.

1H-NMR ((d6-DMSO) ppm million: 12,6 (1H, s, OH); AND 7.4 (1H, s, AG); and 7.3 (1H, d, AG); 3,6 (2H, s, CH2); to 2.6 (4H, m, CH2CH3); 1,1 (6N, m, CH3).

Stage 4: Hydrochloride 5,6-dietlinde-2-ylamine

5,6-Diethyl-3-oxime-1H-inden-1,2-(3H)-dione (4.5 g) is added to a mixture of acetic acid (150 ml) and concentrated sulfuric acid (4.5 ml). Add 5%Pd/C (1.5 g), the reaction mixture Tegaserod with nitrogen and hydronaut for 5 hours and Then the catalyst was removed by filtration, the pH value was adjusted to 10 using 4M NaOH and the solution extracted with chloroform. The organic phase is dried over magnesium sulfate and the solvent is removed in vacuum. The remainder of the process is Aut in a minimum number of simple ether and add a simple ester, saturated Hcl. Filter the precipitate is white and dry, receiving hydrochloride 5,6-dietlinde-2-ylamine, i.e. the compound of formula XVII, where R3, R4and R7denote N, R5and R6each represents CH2CH3-, R30means and n is 1.

1H-NMR (d6-DMSO) ppm million: 8,7 (3H, bd s, NH3); and 7.3 (2H, s, AG); 4,2 (1H, bd s, CH); 3,5 (2H, dd, CH2); 3,3 (2H, dd, CH2); and 2.8 (4H, q, CH2CH3); 1,4(6N, t,CH3).

Other compounds of formula XVII to be made by methods similar to the methods of obtaining the intermediate product 1, or by using methods similar to the methods of obtaining 3 and 4, using the appropriate starting compound. Such compounds of formula XVII are presented in the table below, with all connections R3denotes hydrogen and n is 1.

The intermediate productR4R5R6R7
2CH3CH2HHCH3CH2
3N-(CH2)4-N
4N-O(CH2)2O-N
5the CH3(CH2)3CH3(CH2)3N
6NCH3(CH2)2CH3(CH2)2N
7NCH3AboutCH3AboutN

The intermediate product 2: ES + MS m/e (MH+): 204

The intermediate product 3:1H-NMR (d6-DMSO) ppm million: 8,1 (3H, bd s, NH3); 6,9 (2H, s, Ar); 3,9 (1H, bd s, CH); 3,2 (2H, dd, CH2); 2,8 (2H, dd, CH2); and 2.7 (4H, m, CH2AG); 1,7 (6N, t, CH2).

The intermediate product 4:1H-NMR (d6-DMSO) ppm million: 8,3 (3H, bd s, NH3); 6,85 (2H, s, Ar); to 4.2 (4H, s, 2CH2); and 3.1 (2H, dd, CH2); to 2.85 (2H, dd, CH2).

The intermediate product 5:1H-NMR (d6-DMSO) ppm million: 6,9 (2H, s, AG); and 3.8 (1H, m, CH); 3,1 (2H, dd, CH2); 2,6 (2H, dd, CH2); 2,5 (4H, t, 2CH2); of 1.65 (2H, bd s, NH2); of 1.55 (4H, m, 2CH2); 1,4 (4H, m, 2CH2); 0,95 (6N, t, 2CH3).

The intermediate product 6:1H-NMR (d6-DMSO) ppm million: 8,1 (3H, bd s, NH3); 7,0 (2H, s, Ar); 3,9 (1H, bd s, CH); 3,2 (2H, dd, CH2); 2,8 (2H, dd, CH2); 2,5 (4H, q, EtCH2Ar); 1,6 (4H, q, CH2), and 0.9 (6N, t, CH3).

The intermediate product 7:1H-NMR (d6-MCO) part./million: 8,3 (3H, bd s, NH3)and 6.9 (2H, s, H-AG), a 3.9 (1H, bd m, CHN), 3,7 (6N, s, CH3About), and 3.2 (2H, dd, CH2), 2,9 (2H, dd, CH2).

Sub the full product 8: 2-(Triptorelin)-5,6-bis(methoxymethyl)indan

In accordance with the method described in Magnus and others, (Tetrahed. Lett., 34, 23-26 (1993)) solution of commercially available 1,4-dimethoxy-2-butene (1,32 g, 11.5 mmole) in degassed with nitrogen ethanol is heated under stirring to 80°C in nitrogen atmosphere. Within 2 h portions add chloride, Tris(triphenylphosphine)rhodium (64 mg, 0.07 mmole) and a solution of 2,2,2-Cryptor-N-[1-(2-PROPYNYL)-3-butenyl]ndimethylacetamide (470 mg, 2,32 mmole; obtaining, according to the literature method (see Romero, Arthur G.; Leiby, Jeffrey A., PCT WO 9623760). The mixture is stirred under nitrogen atmosphere at 80°even within 3 hours the Solvent is removed in vacuo and the residue purified using the rapid chromatography on silica gel, using as eluent hexane/ethyl acetate (2:1).

1H-NMR (CDCl3) part./million, or 2.9 (2H, dd), to 3.35 (2H, dd), 3.45 points (6N, s), of 4.57 (4H, s), is 4.85 (1H, m), 6,4 (1H, br s), 7,30 (2H, s).

The intermediate product 9: 2-Amino-5,6-bis(methoxymethyl)indan

A solution of potassium hydroxide (150 mg, 2,60 mmole) in water (0.5 ml) are added to a solution of 2-(triptorelin)-5,6-bis(methoxymethyl)indane (240 mg, 0.75 mmole) in methanol (3 ml) and the mixture was kept at the temperature of reflux distilled for 2.5 hours the Solvent is removed in vacuo and the residue partitioned between aqueous sodium hydroxide solution (10 ml) and ethyl acetate (20 ml). The organic extract is dried (MgSO4and rastitel removed in vacuum, obtaining the product as a dark oil.

1H-NMR (CDCl3) part./million: 2,60 (2H, dd), 3,10 (2H, dd), 3,33 (6N, s in), 3.75 (1H, m), 4,42 (4H, s), 7,17 (2H, s).

The intermediate product 10: 8-Hydroxy-5-[(indan-2-ylamino)acetyl]-1H-quinoline-2-he

5-(Chloroacetyl)-8-hydroxy-2-(1H)-chinoline (25 mg, 0,105 mmole), obtained as described in the literature method (Yoshizaki, Shiro; Tanimura, Kaoru; Tamada, Shigeharu; Yabuuchi, Youichi; Nakagawa, Kazuyuki., J. Med. Chem., 19(9), 1138-11342 (1976)), is subjected to the interaction with indan-2-aluminum (205 mg, 1,21 mmole) at 25°C for 2 h, the Reaction mixture was purified using a rapid-chromatography (silica gel, CH2CL2/methanol 9:1). ES+MC m/e 335 (MH+).

The intermediate product 11

This compound of formula XVIII, where AG denotes a group of formula III, R27, R28and R29denote hydrogen, R2, R3, R4and R7represent hydrogen and R5and R6each represents methoxy, produced by the method similar to the methods of obtaining the intermediate product 10. ES+MC m/e (MH+): 395.

The intermediate product 12: 8-Benzyloxy-3-methyl-5-oxiranyl-1H-quinoline-2-he

8-Hydroxy-3-methyl-1H-quinoline-2-he will get according to the method described by Wang and others, (So-.Wang, Y.-L.Chen, K.-H.Lee, C.-C.Izeng Synthesis 1997, 87-90.).

1H-NMR (d4-CH3HE frequent./mn: and 2.14 (s, 3H), at 6.84-6.89 in (m, 1H), 6,95-7,03 (m, 2H), 6.90 to (s, 1H), 7,71 (s, 1H).

8-Benzyloxy-3-methyl-1H-quinoline-2-he

Benzylbromide (1,28 ml) are added to a suspension of potassium carbonate (2.9 g) in a solution of 8-hydroxy-3-methyl-1H-quinoline-2-it (1.26 g) in acetone (36 ml) at room temperature. The reaction mixture was refluxed for 18 h, filtered and purified using the rapid chromatography on a column of silica gel, using as eluent 2%methanol in dichloromethane.

1H-NMR (CDCl3) part./million: 2,11 (s, 3H), 5,13 (s, 2H), 6,92-6,98 (m, 1H), 7,02-was 7.08 (m, 2H), 7,29-7,40 (m, 5H), EUR 7.57 (s, 1H), 9,23 (s, 1H).

8-Benzyloxy-5-bromo-3-methyl-1H-quinoline-2-he

A solution of bromine (0,57 g) in acetic acid (2 ml) is added dropwise to a solution of 8-benzyloxy-3-methyl-1H-quinoline-2-it (0,94 g) and sodium acetate (0.96 g) in acetic acid (12 ml) at room temperature. The reaction mixture was stirred at room temperature for 3 h, evaporated, the residue partitioned between water (5 ml) and ethyl acetate (5 ml), then extracted twice more with ethyl acetate (5 ml). The combined organic extracts are dried over magnesium sulfate and purified using the rapid chromatography on a column of silica gel, using as eluent 2%methanol in dichloromethane.

1H-NMR (CDCl3) part./million: of 2.27 (s, 3H), by 5.18 (s, 2H), 6,83 (d, 1H), 7,39 (d, 1H), 7,37-7,41 (m, 5H), to $ 7.91 (s, 1H), remaining 9.08 (s, 1H).

8-Benzyloxy-3-methyl-5-vinyl-1 H-quinoline-2-he

Tetrakis(triphenylphosphine)palladium (30 mg) are added to a solution of 8-benzyloxy-5-bromo-3-methyl-1H-quinoline-2-she (239 mg) and tributyltinhydride (203 μl) in toluene (7 ml) at room temperature. The reaction mixture was incubated for 2 h with 10° C, cooled to room temperature and the product was then purified using the rapid chromatography on silica gel, using as eluent 2%ethyl acetate in dichloromethane.

1H-NMR (l3) part./million: 2,24 (s, 3H), by 5.18 (s, 2H), 5,32 of 5.39 (m, 1H), 5,61-of 5.68 (m, 1H), 6,95 (d, 1H), 7,09-7,20 (m, 1H), 7,21-7,26 (m, 2H), 7,31-the 7.43 (m, 4H), 7,89 (s, 1H), 9,20 (s, 1H).

8-Benzyloxy-3-methyl-5-oxiranyl-1H-quinoline-2-he

8-benzyloxy-3-methyl-5-vinyl-1H-quinoline-2-ONU (300 mg) add 0,1M solution dimethyldioxirane in acetone (12,4 ml). After stirring at room temperature for 2 h the solvent is removed in vacuum, obtaining the product.

1H-NMR (Dl3) part./million: of 2.23 (s, 3H), 2.77-to of 2.81 (m, 1H), 3,18 is 3.23 (m, 1H), 4,17-is 4.21 (m, 1H), 5,18 (s, 2H), 6,91 (d, 1H), 7,01 (d, 1H), to 7.93 (s, 1H), 9,10 (s, 1H).

Intermediate 13: 8-Benzyloxy-5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-3-methyl-1H-quinoline-2-he

A solution of intermediate 12 (65 mg) and 5,6-dietlinde-2-ylamine (120 mg) in DMSO (1.5 ml) was incubated for 18 h at 90°C. the Solvent is removed in vacuum and the product was then purified using the rapid chromatography on silica gel, using as eluent 10%methanol in dichloromethane.

13C-NMR (d4-CH3HE frequent./million: 15,96, 17,14, 26,33, 36,77, 53,34, 59,82, 67,33, 71,73, 112,09, 118,98, 121,73, 125,42, 128,74, 129,24, 129,47, 129,61, 131,84, 134,56, 137,52, 137,64, 142,29, 145,94, 164,02.

The intermediate product 14: 8 Methoxyethoxy-6-methyl-5-oxiranyl-1 N-China is n-2-he

8-Hydroxy-6-methyl-1H-quinoline-2-he will get according to the method described by Wang and others, (So-.Wang, Y.-L.Chen, K.-H.Lee, C.-C.Izeng Synthesis 1997, 87-90.).

1H-NMR (d6-DMSO) ppm mn: and 2.26 (s, 3H), of 6.45 (d, 1H), 6,79 (s, 1H), 6.90 to (s, 1H), 7,78 (d, 1H).

5-Bromo-8-hydroxy-6-methyl-1H-quinoline-2-he

45%solution of Hydrobromic acid in acetic acid (324 μl) is added dropwise to a solution of 8-hydroxy-6-methyl-1H-quinoline-2-she(316 mg) in dimethyl sulfoxide (9 ml) at room temperature. The reaction mixture is allowed to stand for 18h at room temperature and the solvent is removed in vacuum.

1H-NMR (d6-DMSO) ppm million: of 2.33 (s, 3H), return of 6.58 (d, 1H), 6,92 (s, 1H), 8,03 (d, 1H), 10,44 (s, 1H), 10,67 (s, br, 1H).

5-Bromo-8-methoxyethoxy-6-methyl-1 H-quinoline-2-he

Methoxymethane (410 μl) are added to a suspension of potassium carbonate (1.24 g) in a solution of 5-bromo-8-hydroxy-6-methyl-1H-quinoline-2-she (480 mg) in dimethylformamide (9 ml) at 0°C. the Reaction mixture was stirred for 18 h at room temperature, filtered, the solvent is removed in vacuum and the product was then purified using the rapid chromatography on silica gel, using as eluent 2%methanol in dichloromethane.

13C-NMR (CDCl3) part./million: 23,42, 56,52, 95,07, 115,78, 116,19, 119,32, 123,30, 128,13, 132,14, 139,78, 141,78, 161,32.

8 Methoxyethoxy-6-methyl-5-vinyl-1H-quinoline-2-he

Chloride bis(triphenylphosphine)palladium(II) (98 mg) are added to the Astaro 5-bromo-8-methoxyethoxy-6-methyl-1H-quinoline-2-she (410 mg) and tributyltinhydride (603 μl) in dimethylformamide (14 ml) at room temperature. The reaction mixture was incubated for 24 h at 90°, evaporated and purified using the rapid chromatography on a column, using as eluent 2%methanol in dichloromethane.

1H-NMR (CDCl3) part./million: 2,19 (s, 3H), 3,41 (s, 3H), by 5.18 (d, 1H), 5,20 (s, 2H), ceiling of 5.60 (d, 1H), of 6.52 (d, 1H), 6,63-6,69 (m, 1H), of 6.96 (s, 1H), 7,95 (d, 1H),9,78(s, 1H).

8 Methoxyethoxy-6-methyl-5-oxiranyl-1H-quinoline-2-it is obtained from 8-methoxyethoxy-6-methyl-5-vinyl-1H-quinoline-2-she (186 mg) according to the method described in the last stage of the process of obtaining the intermediate product 12.

1H-NMR (CDCl3) part./million: of 2.38 (s, 3H), 2,68-of 2.72 (m, 1H), 3,19 is 3.23 (m, 1H), 3.43 points (s, 3H), 3,97-4,01 (m, 1H), total of 5.21 (s, 2H), 6.60 (d, 1H), 6,98 (s, 1H), they were 8.22 (d, 1H), which is 9.09 (s, 1H).

Intermediate 15: (R)-2-(4-benzyloxy-3-nitrophenyl)oxirane receive according to the method described in R.Hett and others, Tetrahedron Lett., 38(7), 1125-1128 (1997).

The intermediate product 16: (S)-8-Benzyloxy-5-oxiranyl-1H-quinoline-2-he

8-Benzyloxy-5-((S)-2-chloro-1-hydroxyethyl)-1H-quinoline-2-he

(S)-2-methyl-CBS-oxazaborolidine, 1M solution in toluene (of 0.30 ml, 0.30 mmole) is added to anhydrous THF (tetrahydrofuran) (10 ml), located in kiln dried flask. Then added dropwise complex, borane-THF, 1M solution in THF (3,05 ml) and the solution stirred at room temperature for 15 min, then cooled to 0°C. in Small portions over 30 min add 8-benzyloxy-5-chlorate is -1 H-quinoline-2-he (1,00 g), obtained according to the method described in WO 95/25104. The reaction mixture was stirred at 0°C. According to the analysis by TLC (thin layer chromatography), the reaction is finished after 15 minutes the Reaction is stopped by adding methanol (1 ml), the solvent is removed in vacuo and the residue partitioned between 0.2 M solution of H2SO4(100 ml) and l3(100 ml). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuum. Carry out crystallization from ethyl acetate. According to TLC (silica gel, dichloromethane/methanol 25:1) retention time is Rf=0,30).

(S)-8-Benzyloxy-5-oxiranyl-1H-quinoline-2-he

8-Benzyloxy-5-((S)-2-chloro-1-hydroxyethyl)-1H-quinoline-2-he (0.55 g) was dissolved in acetone (20 ml). Add To2CO3(0,58 g) and the reaction mixture is refluxed. According to the analysis by TLC, the reaction is finished after 18 hours the Solvent is removed in vacuo and the residue distributed between ethyl acetate (100 ml) and water (100 ml). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuum. The product is triturated with diethyl ether, filtered and dried. According to TLC (silica gel, dichloromethane/methanol 25:1) retention time is Rf=0,45.

The intermediate product 17: 6,7,8,9-Tetrahydro-5H-benzocycloheptene-7-ylamine

Benzyl-(6,7,8,9-tetrahydro-5H-benzonalogi the ten-7-yl)Amin

5,6,8,9-tetrahydrobenzaldehyde-7-he (3.00 g) and benzylamine (2.00 g) resturaunt in ethanol (50 ml). Add a catalytic amount of 10%palladium on coal and the reaction mixture is placed in an atmosphere of hydrogen. The reaction mixture was stirred at K.T. (room temperature). According to the analysis by TLC, the reaction is finished after 24 hours the Catalyst is filtered off and the solvent is removed in vacuum. The product is not subjected to additional purification. According to TLC (silica gel, n-hexane/ethyl acetate 1:2) retention time is Rf=0,50).

6,7,8,9-Tetrahydro-5H-benzocycloheptene-7-ylamine

Benzyl-(6,7,8,9-tetrahydro-5H-benzocycloheptene-7-yl)amine (2,80 g) dissolved in methanol (100 ml) and the connection remove the protective group by adding a catalytic amount of 10%palladium on coal and placing the solution in an atmosphere of hydrogen. According to the analysis by TLC, the reaction is finished after 24 hours the Catalyst is filtered off and the solvent is removed in vacuum. The product is not subjected to additional purification. According to TLC (silica gel, diclomelan/methanol 25:1) retention time is Rf=0,15).

Intermediate 18: Benzyl(5.6-dietlinde-2-yl)Amin

N-(5,6-Dietlinde-2-yl)benzamid

5,6-Dietlinde-2-ylamine (4,10 g) dissolved in dichloromethane (DHM) (150 ml) and add triethylamine (2,41 g). Then added dropwise b is soilgard (3,20 g) and the reaction mixture was stirred at room temperature. According to the analysis by TLC, the reaction is finished after 1 h the Solution was washed with 0.2m Hcl solution (100 ml), water (100 ml) and with brine (100 ml). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuum. Carry out crystallization from ethyl acetate. According to TLC (silica gel, diclomelan/methanol 10:1) retention time is Rf=0,85).

Benzyl-(5,6-dietlinde-2-yl)Amin

N-(5,6-Dietlinde-2-yl)benzamide (3,30 g) dissolved in anhydrous THF (100 ml). Then added dropwise to alumoweld lithium, 1M solution in THF (22,52 ml). The reaction mixture was stirred at 50°C. According to the analysis by TLC, the reaction is finished after 6 hours the Reaction mixture is allowed to cool, it is slowly poured into a mixture of ice-water (200 ml) and extracted with diethyl ether (2×150 ml). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuum. The product is not subjected to additional purification. According to TLC (silica gel, n-hexane/ethyl acetate 2:1) retention time is Rf=0,20).

The intermediate product 19: (R)-1-(3-Amino-4-benzyloxyphenyl)-2-[benzyl-(5,6-dietlinde-2-yl)amino]ethanol

(R)-2-[Benzyl-(5,6-dietlinde-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)ethanol)

Specified in the title compound is obtained from intermediate 15 (3,01 g) and intermediate 18 (3,10 g) by a method similar to IU the ode to obtain (S)-8-benzyloxy-5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-1H-quinoline-2-she's from example 19. According to the analysis by TLC, the reaction is finished after 24 hours the Product was then purified using the rapid chromatography on a column (silica gel, n-hexane/ethyl acetate 4:1). According to TLC (silica gel, n-hexane/ethyl acetate 4:1) retention time is Rf=0,25).

(R)-1-(3-Amino-4-benzyloxyphenyl)-2-[benzyl-(5,6-dietlinde-2-yl)amino] ethanol

(R)-2-[Benzyl-(5,6-dietlinde-2-yl)amino]-1-(4-benzyloxy-3-nitrophenyl)ethanol (3.00 g) was dissolved in THF (50 ml) and toluene (50 ml).

Add a catalytic amount PtO2and the solution is stirred in an atmosphere of H2. According to the analysis by TLC, the reaction is finished after 6 hours the Catalyst is filtered off and the solvent is removed in vacuum. The product is not subjected to additional purification. According to TLC (silica gel, n-hexane/ethyl acetate 1:1) retention time is Rf=0,75).

The intermediate product 20: 1-(3-Amino-4-benzyloxyphenyl)-2-[benzyl-(5,6-dietlinde-2-yl)amino]alanon

2-[Benzyl-(5,6-dietlinde-2-yl)amino]-1-(4-benzyloxy-3-nitrophenyl)alanon

1-(4-Benzyloxy-3-nitrophenyl)-2-brometane (2.00 g) (obtained according to the method described in Hett, Robert; Fang, Qun Kevin; Gao, Yun; Hong, Yaping; Butler, Hal T.; Nie, Xiaoyi; Wald, Stephen A. Tetrahedron Lett., 38, 1125-1128, 1997) dissolved in methylethylketone (100 ml). Add triethylamine (0.64 g), and then benzyl-(5,6-dietlinde-2-yl)amine (1.60 g). After that the reaction mixture is boiled with a back hall is dildocam. According to the analysis by TLC, the reaction is finished after 3 hours the Solvent is removed in vacuum and the product was then purified using the rapid chromatography on a column (silica gel, n-hexane/ethyl acetate 4:1). According to TLC (silica gel, n-hexane/ethyl acetate 2:1) retention time is Rf=0,75).

1-(3-Amino-4-benzyloxyphenyl)-2-[benzyl-(5,6-dietlinde-2-yl)amino]alanon obtained from 2-[benzyl-(5,6-dietlinde-2-yl)amino]-1-(4-benzyloxy-3-nitrophenyl)ethanone (1.50 g) by a method similar to the method used to obtain (R)-1-(3-amino-4-benzyloxyphenyl)-2-[benzyl-(5,6-dietlinde-2-yl)amino]ethanol in example 19. According to the analysis by TLC, the reaction is finished after 48 hours the Catalyst is filtered off and the solvent is removed in vacuum. The product was then purified using the rapid chromatography on a column (silica gel, n-hexane /ethyl acetate 4:1). According to TLC (silica gel, n-hexane/ethyl acetate 2:1) retention time is Rf=0,70).

1H NMR [CDCl3, 400 MHz] d 1,20 (6N, t)to 1.60 (2H, broad), 2,60 (4H, q)of 3.00 (4H, m), 3,90 (6N, m), of 5.15 (2H, s), to 6.80 (1H, d), to 6.95 (2H, s), 7,30 (M, m).

Intermediate 21: Benzyl-(4,5,6,7-tetramethylene-2-yl)Amin

3-Chloro-1-(2,3,4,5-tetramethylene)propane-1-it is obtained from 1,2,3,4-tetramethylbenzene and 3-chloropropionitrile method similar to the method of obtaining the product 1.

1H NMR (CD3OD) part./million: 7,5 (1H, s); of 4.2 (2H, t); 3,6 (2H, t); ,6 (3H, s); to 2.57 (3H, s); 2,52 (3H, s); 2,5 (3H, s).

4,5,6,7-Tetramethylene-1-it is obtained from 3-chloro-1-(2,3,4,5-tetramethylene)propane-1-it is a method similar to the method of obtaining the product 2.

1H NMR (CD3OD) part./million, a 3.2 (2H, t); 2,9 (2H, t); 2,85 (3H, s); 2,6 (3H, s); to 2.55 (3H, s); 2,5 (3H, s).

4,5,6,7-Tetramethylene-1,2-dione 2-oxime is obtained from 4,5,6,7-tetramethylene-1-it is a method similar to the method of obtaining the product 3.

1H NMR (d6-DMSO) ppm million: 12,4 (1H, s); the 3.65 (2H, s); 2,7 (3H, s); 2,4 (3H, s); 2,3 (6N, s).

Hydrochloride of 2-amino-4,5,6,7-tetramethylene-1-get it from 4,5,6,7-tetramethylene-1,2-dione-2-oxime method similar to the method of obtaining the product 4.

1H-NMR (d6-DMSO) ppm million: 9,0 (3H, bd s); 4,5 (1H, bd t); 3,7 (1H, dd); 3,2 (1H, dd); 2,8 (3H, s); 2,6 (3H, s); 2,5 (6N, 2 s).

N-(4,5,6,7-tetramethyl-1-oxonian-2-yl)benzamid

The benzoyl chloride (1,635 g) is added dropwise to 4,5,6,7-tetramethylene-1,2-dione-2-oxime (2,53 g) and triethylamine (2.25 g) in anhydrous dichloromethane (60 ml) at 0°C. the Reaction mixture was stirred at room temperature for 1.5 h, after which the solid product is filtered, mixed with water (150 ml), re-filtered and dried. The organic filtrate was washed with 1 M Hcl solution, 10%salt solution, saturated sodium bicarbonate solution and treated with magnesium sulfate. After filtration the solvent is removed in vacuo and the product triturated with IER the silt ether, filtered and dried.

1H-NMR (CDCl3) part./million: 7,8 (2H, d); 7,45 (1H, m), and 7.4 (2H, m); 6,8 (1H, bd (d); 4,6 (1H, m); and 3.8 (1H, dd); 2,8 (1H, dd); to 2.55 (3H, s); of 2.25 (3H, s); 2,15 (6N, 2 s).

N-(1-Hydroxy-4,5,6,7-tetramethylene-2-yl)benzamid

Borohydride sodium (213 mg) are added to N-(4,5,6,7-tetramethyl-1-oxonian-2-yl)benzamide (495 mg) in chloroform (20 ml) and methanol (20 ml). The reaction mixture was stirred at room temperature for 2 h, then water (50 ml) and add chloroform (20 ml). The aqueous phase is washed with chloroform (x2), organic layers combined is treated with magnesium sulfate, filtered and the solvent is removed in vacuum.

1H-NMR (CDCl3) part./million: the 7.65 (2H, d); and 7.4 (1H, m), 7,35 (2H, m); and 6.3 (1H, bd (d); 5.15 (1H, d); 4,5 (1H, m); 3,7 (1H, bd s); 3,5 (1H, dd); to 2.65 (1H, dd); to 2.25 (3H, s); 2,15 (N, 3 s).

N-(4,5,6,7-Tetramethylene-2-yl)benzamide obtained from N-(1-hydroxy-4,5,6,7-tetramethylene-2-yl)benzamide method similar to the method of obtaining the product 4.

1H-NMR (CDCl3) part./million: the 7.65 (2H, d); and 7.4 (1H, m), and 7.3 (2H, m); and 6.25 (1H, bd (d); is 4.85 (1H, m); at 3.35 (1H, dd); 2,80 (1H, dd); 2,1 (12H, 2s).

Benzyl-(4,5,6,7-tetramethylene-2-yl)Amin

1M solution alumoweld lithium (2.4 ml) in tetrahydrofuran is added dropwise to a solution of N-(4,5,6,7-tetramethylene-2-yl)benzamide (352 mg) in anhydrous THF (10 ml) under nitrogen atmosphere at room temperature. The reaction mixture is stirred for 20 h at 50°C. After 4 h, add another portion 1M of the races is the thief of lithium aluminum hydride (1.2 ml, 1.20 mmole) in THF. The reaction is stopped by adding ice-cold water. The aqueous phase is washed with diethyl ether (X3), organic layers combined is treated with magnesium sulfate, filtered and the solvent is removed in vacuum.

1H-NMR (CDCl3) part./million: of 7.25 (4H, m); to 7.15 (1H, m); 3,8 (2H, s); 3,55 (1H, m); 3,1 (2H, dd); 2,7 (2H, dd); 2,1 (12H, 2s).

The intermediate product 22: Benzyl-(2,3,5,6,7,8-hexahydro-1H-cyclopent[b]naphthalene-2-yl)Amin

According to the method described in A.F.Abdel-Magid and others, J.Org.Chem., 61, 3849-3862 1996, triethylamine (0,87 ml of 6.17 mmole) is added under stirring in nitrogen atmosphere at room temperature to a suspension of 2,3,5,6,7,8-hexahydro-1H-cyclopent[b]naphthalene-2-ylamino in 1,2-dichloroethane (30 ml). After that add benzaldehyde (0,52 ml, 5,14 mmole), and then triacetoxyborohydride sodium (1.64 g, 7.7 mmole) and acetic acid (of 0.44 ml, 7.7 mmole). The reaction mixture was stirred at room temperature for 18 hours After dilution with dichloromethane, the mixture is washed with aqueous NaOH solution (50 ml, 1M)and then with brine. After removal of the solvent and implementation chromatography (silica gel, ethyl acetate/hexane, 2:1) receive the product in the form of oil.

1H-NMR (CDCl3) part./million: to 1.70 (m, 4H), to 2.65 (m, 4H), 2,68 (dd, 2H), 3,05 (dd, 2H), to 3.58 (m, 1H), 3,78 (s, 2H), 6,83 (s, 2H), 7,25 (m, 5H).

Intermediate 23: 2-Methylinden-2-ylamine

2-Amino-2-methylinden-1-he

According to the method of description is nomu from Farnum and others, (Synthesis, 191-192, 1972), water (1.35 l) was stirred at 80°and Tegaserod by periodic evacuation and purging with nitrogen (3x). Add K3FeCN6(202 g, 615 mmol) and 2-methylinden-1-he (20 g, 137 mmol). The mixture is intensively stirred in nitrogen atmosphere at 80°and within 30 min add aqueous concentrated ammonia solution (105 ml). Stirring is continued for 20 h at 80°C. After cooling, the solution is alkalinized by adding sodium hydroxide (2 g) and extracted with ethyl acetate (2×200 ml). The organic extract was concentrated to a volume of 200 ml and the product is extracted with aqueous solution of Hcl (200 ml, 1M). Separate the acidic aqueous phase is alkalinized with sodium hydroxide and extracted with ethyl acetate (2×100 ml). The organic layer is separated, dried (Na2SO4) and the solvent is removed, getting the product in the form of an orange oil.

1H-NMR (CDCl3) part./million: to 1.38 (s, 3H), 1.8 m (br, s, 2H), of 3.07 (d, 1H), 3,25 (d, 1H), of 3.45 (m, 2H), 7,65 (t, 1H), 7,80 (d, 1H).

2,2,2-Cryptor-N-(2-methyl-1-oxonian-2-yl)ndimethylacetamide

2-Amino-2-methylinden-1-he (to 16.4 g) in THF (100 ml) cooled to 0°C in nitrogen atmosphere. Add triethylamine (21 ml), and then slowly add triperoxonane anhydride (18.5 ml). The reaction mixture was stirred at room temperature overnight, then remove the solvents. The residue is dissolved in dichlor is Tanya and washed with aqueous solution of Hcl, and then an aqueous solution of NaOH. The organic extract is dried (MgSO4) and remove the solvent. The product was then purified via chromatography (silica gel, ethyl acetate)to give a solid cream color.

1H-NMR (CDCl3) part./million: of 1.52 (s, 3H), 3,44 (d, 1H), 3,55 (d, 1H), 7,05 (br, s, 1H), 7,43 (m, 2H), of 7.70 (t, 1H), 7,87 (d, 1H).

2,2,2-Cryptor-N-(2-methylindol-2-yl)ndimethylacetamide

2,2,2-Cryptor-N-(2-methyl-1-oxonian-2-yl)ndimethylacetamide (3,41 g) in acetic acid (25 ml) and H2SO4(0.5 ml) was stirred at room temperature in hydrogen atmosphere in the presence of 10%Pd/C for 18 hours the Mixture is filtered through celite and the filtrate concentrated in vacuo. After dilution with water the mixture is extracted with diethyl ether. The organic phase is separated, washed several times with an aqueous solution of sodium bicarbonate and dried (Na2SO4). The solvent is removed, getting the product in the form of oil, which hardens.

1H-NMR (CDCl3) part./million: of 1.55 (s, 3H), 3,05 (d, 2H), or 3.28 (d, 2H), 6,28 (br, s, 1H), 7,12 (s, 4H).

2-Methylinden-2-ylamine

A solution of 2,2,2-Cryptor-N-(2-methylindol-2-yl)ndimethylacetamide (6,70 g) and NaOH (4.0 g) in methanol (100 ml) and water (1 ml) was incubated for 2 h with stirring at 70°C. the Solvent is removed and the residue partitioned between aqueous Hcl solution (100 ml, 2M) and ethyl acetate (100 ml). The aqueous extract is separated, alkalinized with ethyl acetate. The organic phase is separated from, dried (MgSO4) and remove the solvent, obtaining a product in the form of an orange oil, which hardens.

1H-NMR (CDCl3) part./million: 1,19 (s, 3H), 1.5 a (br, s, 2H), 2,65 (d, 2H), and 2.79 (d, 2H), 6,97 (m, 4H).

Intermediate 24: 2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopent[b]naphthalene-2-ylamine

1-(5,6,7,8-Tetrahydronaphthalen-2-yl)propane-1-he

Propionate (17.5 ml) and 1,2,3,3-tetrahydronaphthalen (27.5 ml) slowly over 1 h added under stirring at 0°With the solution ll3(61,3 g) in nitromethane (200 ml). After stirring for 18 h at room temperature the reaction mixture is carefully added to a mixture of ice and concentrated Hcl. The product is extracted with ethyl acetate, washed with brine and dried (Na2SO4).

1H-NMR (Dl3) part./million: to 1.15 (t, 3H), 1,72 (m, 4H), of 2.72 (m, 4H), 2,88 (q, 2H),? 7.04 baby mortality (d, 1H), 7,60 (m, 1H).

2-Methyl-2,3,5,6,7,8-hexahydrotriazine [b]naphthalene-1-he

According to the method described by Bhattacharya and others, (Synth. Commit, 26, 1775-1784, 1996) a mixture of 1-(5,6,7,8-tetrahydronaphthalen-2-yl)propane-1-it (37.6 g), hexamethylenetetramine (44,9 g) and acetic anhydride (38,8 ml) incubated under stirring at 80°C for 23 hours the Mixture is allowed to cool and added slowly with stirring to a mixture of ethyl acetate (200 ml) and aqueous sodium hydroxide (200 ml, 2M). The organic layer is separated, washed with aqueous solution of Hcl, hydrochloric who m solution and dried (Na 2SO4). The solvent is removed, getting the product in the form of a brown oil. Carefully add concentrated sulfuric acid (120 ml) and the resulting mixture was incubated for 5 h at 55°and then for 18 h at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. After drying (Na2SO4) the solvent is removed, getting the product in the form of oil. The product was then purified via chromatography (silica gel, ethyl acetate/hexane)to give a geometric mixture of isomers containing 2-methyl-1,2,6,7,8,9-hexahydrotriazine[a]naphthalene-3-one and specified in the header of the connection.

1H-NMR (CDCl3) part./million (mixture): 1,4 (m, 3H), and 1.9 (m, 4H), of 2.5-3.0 (m, 6H), to 3.35 (m, 1H), 7,15 (m, 1H), 7,55 (m, 1H).

2,2,2-Cryptor-N-(2-methyl-1-oxo-2,3,5,6,7,8-hexahydro-1H-cyclopent[b]naphthalene-2-yl)ndimethylacetamide

This compound is prepared from a mixture of isomers containing 2-methyl-2,3,5,6,7,8-hexahydrotriazine[b]naphthalene-1-he, according to the method used to obtain 2,2,2-Cryptor-N-(2-methyl-1-oxonian-2-yl)ndimethylacetamide. The mixture of isomers is recrystallized from ethyl acetate/hexane, obtaining a mixture of 4:1, where the main component is a specified in the header of the connection.

1H-NMR (CDCl3) part./million (the main component): 1.55V (s, 3H), of 1.85 (m, 4H), 2,87 (m, 4H), to 6.88 (br, s, 1H), 7,18 (s, 1H), EUR 7.57 (s, 1H). PF MC ES-m/e 310 (MH-).

A mixture of 4:1 geometric isomers, containing mainly 2,2,2-Cryptor-N-(2-methyl-1-oxo-2,3,5,6,7,8-hexahydro-1H-cyclopent[b]naphthalene-2-yl)acetamide", she is subjected to hydrogenation over Pd/C in a mixture of acetic acid /H2SO4and the products are subjected to saponification with NaOH according to the methods described for obtaining 2-methylinden-2-ylamine. The resulting mixture of products again recrystallized from hexane, obtaining specified in the title compound in the form of an individual isomer.

1H-NMR (CDCl3) part./million: of 1.40 (s, 3H), 1,6 (br, s, NH2), a 1.75 (m, 4H), of 3.75 (m, 4H), 2,78 (d, 2H), 2,94 (d, 2H), 6,93 (s, 2H).

Intermediate 25: 2-Atienden-2-ylamine

2-Atienden-1-it is obtained from benzene according to methods similar to the methods used to obtain 2-methyl-2,3,5,6,7,8-hexahydrotriazine[b]naphthalene-1-it.

1H-NMR (CDCl3) part./million: of 0.97 (t, 3H), 1,50 (m, 1H), 1,90 (m, 1H), to 2.55 (m, 1H), 2,75 (dd, 1H), 3,25 (q, 1H), 7,29 (t, 1H), 7,39 (d, 1H), 7,50 (t, 1H), 7,69 (d, 1H).

2-Atienden-2-ylamine is obtained from 2-atienden-1-it methods similar to the methods used to obtain the intermediate product 23.

1H-NMR (CDCl3) part./million: of 1.05 (t, 3H), 1,5 (br.s, NH2), 2,70 (q, 2H), 2,75 (d, 2H), 3,01 (d,2H), 7,20 (m, 4H).

Intermediate 26: 2,5,6-Trimethylene-2-ylamine

2,5,6-Trimethylene-2-ylamine is obtained from 1,2-xylene methods similar to the methods used for p is obtaining 2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopent[b]naphthalene-2-ylamine.

1H-NMR (CDCl3) part./million: of 1.29 (s, 3H), of 2.16 (s, 6H), 2,69 (d, 2H), 2,84 (d, 2H), 2,89 (s, 2H).

Intermediate 27: (R)-1-(3-Amino-4-benzyloxyphenyl)-2-[benzyl-(2-methylindol-2-yl)amino]ethyl ester of acetic acid

(R)-2-[Benzyl-(2-methylindol-2-yl)amino]-1-(4-benzyloxy-3-nitrophenyl)ethanol

Specified in the title compound is obtained from (R)-2-(4-benzyloxy-3-nitrophenyl)oxirane (2,52 g) and benzyl(2-methylindol-2-yl)amine (2.20 g) methods similar to the methods used to obtain (S)-8-benzyloxy-5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-1H-quinoline-2-she in example 19. According to the analysis by TLC, the reaction is finished after 24 hours the Product was then purified using the rapid chromatography on a column (silica gel, n-hexane /ethyl acetate 4:1). TLC (silica gel, n-hexane/etelaat 4:1, Rf=0,30).

1H-NMR [CDCl3, 400 MHz] d of 1.20 (3H, s), 2,65 (1H, m), a 2.75 (1H, m), 2,90 (2H, m), of 3.25 (2H, m), 3,60 (1H, d), 3,70 (1H, broad), 3,80 (1H, dd), 4,10 (1H, d), 5,20 (2H, s), 7,00 (1H, d), 7,20 (4H, m), 7,35 (11H, m), 7,60 (1H, d).

(R)-2-[benzyl-(2-methylindol-2-yl)amino]-1-(4-benzyloxy-3-nitrophenyl)ethyl ester of acetic acid

(R)-2-[Benzyl-(2-methylindol-2-yl)amino]-1-(4-benzyloxy-3-nitrophenyl)ethanol (2,75 g) dissolved in pyridine (15 ml). Add acetic anhydride (1.66 g) and the reaction mixture was stirred at room temperature. According to the analysis by TLC, the reaction is finished after 18 hours To terminate the reaction, doba is given in water (10 ml). Add ethyl acetate (250 ml) and the solution washed with 1M KHSO4(3×100 ml), saturated solution Panso3(100 ml), water (100 ml) and with brine (100 ml). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuum. The product is not subjected to additional purification. TLC (silica gel, n-hexane/ethyl acetate 4:1, Rf=0,40).

1H-NMR [CDCl3, 400 MHz] d of 1.20 (3H, s), 1,90 (3H, s), 2,80 (3H, m)of 3.00 (1H, d), 3,10 (1H, m), 3,20 (1H, d), of 3.75 (1H, d), 3,90 (1H, d), 5,20 (2H, s), a 5.25 (1H, m), to 6.95 (1H, d), 7,10 (4H, m), 7,30 (11H, m), 7,55 (1H, d).

(R)-1-(3-amino-4-benzyloxyphenyl)-2-[benzyl-(2-methylindol-2-yl)amino] ethyl ester of acetic acid

Specified in the title compound is obtained from (R)-2-[benzyl-(2-methylindol-2-yl)amino]-1-(4-benzyloxy-3-nitrophenyl)ethyl ester of acetic acid (2,90 g) by a method similar to the method for producing (R)-1-(3-amino-4-benzyloxyphenyl)-2-[benzyl-(5,6-dietlinde-2-yl)amino]ethanol in example 19. According to the analysis by TLC, the reaction is finished after 6 hours the Catalyst is filtered off and the solvent is removed in vacuum. The product is not subjected to additional purification. TLC (silica gel, n-hexane/ethyl acetate 2:1, Rf=0,60).

1H-NMR [CDCl3, 400 MHz] d of 1.10 (3H, s), of 1.80 (3H, s), 2,70 (3H, m), 3,05 (2H, m)and 3.15 (1H, d), the 3.65 (2H, broad in), 3.75 (1H, d), 3,90 (1H, d), of 4.95 (2H, s), 5,20 (1H, m), 6,40 (2H, m), of 6.65 (1H, d), 7,20 (14H, m).

Intermediate 28: Benzyl-(2,5,6-trimethylene-2-yl)Amin

N-(2,5,6-Three is yilinda-2-yl)benzamid

The intermediate product 26 is treated with benzoyl chloride in a mixture of dichloromethane/triethylamine for 1 h the Mixture was washed with 1N. HCl, then with saturated solution of NaHCO3, dried (Na2SO4) and evaporated. The residue is triturated with a mixture of simple ether/hexane, getting the product in the form of white crystals.

1H-NMR (CDCl3) part./mn: 1,60 (s, 3H), of 2.18 (s, 6H), to 3.02 (d, 2H), 3,30 (d, 2H), 6,17 (br.s, NH), 6.90 to (s, 2H), 7,34 (m, 2H), 7,40 (m, 1H), 7,63 (d, 1H).

Benzyl-(2,5,6-trimethylene-2-yl)Amin

To a solution of N-(2,5,6-trimethylene-2-yl)benzamide in THF under nitrogen atmosphere add LiAlH4and the mixture is refluxed for 48 hours the Reaction is terminated by 0°using a mixture of ice/water, the product extracted with simple ether, dried (Na2SO4) and the solvent is removed in vacuum. By purification via chromatography (silica gel, ethyl acetate/hexane 1:4) to give the product as a colourless oil.

1H-NMR (CDCl3) part./mn: was 1.58 (s, 3H), 1,79 (br.s., NH), 2.40 a (s, 6H), 3.00 and (d, 2H), 3,20 (d, 2H), 3,99 (s, 2H), 7,15 (s, 2H), 7,37-7,53 (m, 5H).

Intermediate 29: (R)-1-(3-Amino-4-benzyloxyphenyl)-2-[benzyl-(2,5,6-trimethylene-2-yl)amino]ethyl ester of acetic acid

(R)-1-(4-Benzyloxy-3-nitrophenyl)-2-[benzyl-(2,5,6-trimethylene-2-yl)amino]ethanol

A mixture of 2-(4-methyl-3-nitrophenyl)oxirane and benzyl-(2,5,6-trimethylene-2-yl)amine is maintained at 110°C for 48 hours Product which t is used without additional purification. ES+MS m/e 538 (MH+).

(R)-1-(4-Benzyloxy-3-nitrophenyl)-2-[benzyl-(2,5,6-trimethylene-2-yl)amino] ethyl ester of acetic acid

To a solution of (R)-1-(4-benzyloxy-3-nitrophenyl)-2-[benzyl-(2,5,6-trimethylene-2-yl)amino]ethanol in pyridine add acetic anhydride and the mixture is stirred for 18 hours the Reaction is stopped by addition of water and after adding ethyl acetate washed twice with an aqueous solution KHSO4double-aqueous solution Panso3and once with brine. The product was then purified via chromatography (silica gel, ethyl acetate/hexane 1:4). ES+MS m/e 579 (MN+).

(R)-1-(3-Amino-4-benzyloxyphenyl)-2-[benzyl-(2,5,6-trimethylene-2-yl)amino] ethyl ester of acetic acid

(R)-1-(4-Benzyloxy-3-nitrophenyl)-2-[benzyl-(2,5,6-trimethylene-2-yl)amino]ethyl ester of acetic acid in a mixture of THF and toluene is stirred in hydrogen atmosphere in the presence of PtO2at room temperature for 15 hours the Mixture is filtered through celite and the filtrate concentrated in vacuo. ES+MS m/e 549 (MN+).

Intermediate 30: 5.6-Diethyl-2-methylinden-2-ylamine

N-(5-acetyl-2-methylindol-2-yl)benzamid

Aluminium chloride (3.7 g) dissolved in nitromethane (12 ml) under nitrogen atmosphere, and then at 0°add N-(2-methylindol-2-yl)benzamide (3.0 g). Dropwise within 30 min add acetylchloride of 0.85 ml). After you remove the air traffic management the mixture for 4 h at room temperature the reaction is stopped by adding ice and concentrated Hcl and extracted with DHM. The organic layers are washed with dilute Hcl and with brine. After evaporation of the solvent to obtain the desired product. ES+MS m/e 294 (MN+).

N-(5-Ethyl-2-methylindol-2-yl)benzamid

A solution of N-(5-acetyl-2-methylindol-2-yl)benzamide (3.4 g) in ethanol (200 ml) and concentrated HCl (2 ml) is stirred in hydrogen atmosphere in the presence of 10%Pd/C at room temperature for 48 hours the Mixture is filtered through celite and the filtrate was concentrated in vacuo, obtaining specified in the header of the connection.

1H-NMR (CDCl3) part./million: of 1.20 (t, 3H), 1,60 (s, 3H), by 2.55 (q, 2H), 3,05 (d, 2H), 3,35 (d, 2H), 6.35mm (br.s, NH), 6.90 to-7,10 (m, 3H), 7,39 (d, 2H), 7,65 (s, 2H)

N-(5-Acetyl-6-ethyl-2-methylindol-2-yl)benzamide obtained from N-(5-ethyl-2-methylindol-2-yl)benzamide (2.6 g) according to the method used to obtain N-(5-acetyl-2-methylindol-2-yl)benzamide. The product was then purified via chromatography (silica gel, hexane/ethyl acetate, 4:1), obtaining specified in the header connection. ES+MS m/e 322 (MN+).

N-(5,6-Diethyl-2-methylindol-2-yl)benzamide obtained from N-(5-acetyl-6-ethyl-2-methylindol-2-yl)benzamide (1.1 g) according to the method used to obtain N-(5-ethyl-2-methylindol-2-yl)benzamide. ES+MS m/e 308 (MN+).

Benzyl(5,6-diethyl-2-methylindol-2-yl)amine is obtained from N-(5,6-diethyl-2-methylindol-2-yl)benzamide according to the method similar to the method used for proceduresin(5,6-dietlinde-2-yl)amine, which is described in “Obtaining the intermediate product 18”. ES+MS m/e 294 (MN+).

5,6-Diethyl-2-methylinden-2-ylamine

A solution of benzyl(5,6-diethyl-2-methylindol-2-yl)amine (0,48 g) in methanol (10 ml) is stirred in hydrogen atmosphere in the presence of 10%Pd/C at room temperature for 18 hours the Mixture is filtered through celite and the filtrate was concentrated in vacuo, obtaining specified in the header connection. ES+MS m/e 204 (MN+).

Example 1

(R)-8-Benzyloxy-5-[2-(4,7-dimethoxyindole-2-ylamino)-1-hydroxyethyl]-1H-quinoline-2-he

(R)-8-Benzyloxy-5-oxiranylmethyl (100 mg, 0.34 in mmole), obtained as described in the literature method (Beeley, Lee James; Dean, David Kenneth, PCT Int. Appl. WO 95/25104), and 4.7-dimethoxyindole-2-ylamine (66 mg, 0.34 in mmole), obtained as described in the literature method (Sindelar, R.D.; Mott J.; Barflcnecht c.f.nielsen (Denmark); Arneric SP; Flynn J.R.; Long J.P.; R.K. Bhatnagar, J. Med. Chem., 25(7), 858-64 (1982)), was dissolved in toluene (1 ml). The reaction mixture is heated to 110°and allow to evaporate the solvent. Then the residue is stirred for 4 h at 110°C. Analysis by TLC indicates complete reaction. The product was then purified using the rapid chromatography on a column (silica gel, dichloromethane/methanol 20:1). TLC (silica gel, dichloromethane/methanol 25:1, Rf=0,10). ES+MS m/e 487 (MN+).

Hydrochloride (R)-8-hydroxy-5-[2-(4,7-dimethoxyindole-2-ylamino)-1-hydroxyethyl]-1H-quinoline-2-on the Sabbath.

(R)-8-Benzyloxy-5-[2-(4,7-dimethoxyindole-2-ylamino)-1-hydroxyethyl]-1H-quinoline-2-he (37 mg, 0.08 mmole) was dissolved in methanol (10 ml) and the connection remove the protective group by adding a catalytic amount of 10%palladium on coal and placing the solution in an atmosphere of hydrogen. According to the analysis by TLC, the reaction is finished after 4 hours the Catalyst is filtered off, add a mixture of 1M HCl/diethyl ether (1.1 EQ.) and the solvent is removed in vacuum.

TLC (silica gel, dichloromethane/methanol 10:1, Rf=0,15). ES+MS m/e 397 (MN+).

Using methods similar to the method described in example 1 from (R)-8-benzyloxy-5-oxiranylmethyl ((R)-2-(4-benzyloxy-3-nitrophenyl)oxirane (intermediate 15) in example 11) and the corresponding compounds of formula XVII is given to the compounds of formula I. These compounds, in which R1IT denotes, R2and R3denote N, AG denotes a group of formula III in which R29, R30and R31denote N (except for example 11, where AG denotes a group of the formula XV, in which R13denotes N) and n is equal to 1 (with the exception of example 9, where n is equal to 2), are presented in the following table 1.

Table 1
ExampleR4R5R 6R7ES+MC m/e (MH+)
2NCH3CH2CH3CH2N393
3NCH3CH3N365
4CH3CH2NNCH3CH2393
5N-(CH2)4-N391
6N-O(CH2)2O-N395
7NCH3(CH2)3CH3(CH2)3N449
8NCH3(CH2)2CH3(CH2)2N421
9NNNN365
10NCH3Och2CH3Och2N 
11NCH3CH2CH3 CH2N341

Example 10:1H-NMR (d4-MeOH) part./million: 2,78 (2H, m), 2,9 (2H, m)and 3.15 (2H, m), 3,28 (6N, s), and 3.7 (1H, m), 4,55 (1H, br s), of 5.15 (1H, m), to 6.58 (1H, d), 6,9 (1H, d), 7,11 (2H, s), to 7.15 (1H, s), of 8.25 (1H, s).

Example 12

8-Hydroxy-5-[1-hydroxy-2-(indan-2-ylamino)ethyl]-1H-quinoline-2-he

The intermediate product 10 (18 mg, 0,054 mmole) is dissolved in methanol (2 ml) and cooled on ice. Within 2 h add borohydride sodium (6 mg, 0.12 mmole). Then add concentrated Hcl to achieve pH 1 and the reaction mixture is filtered. The filtrate is washed with methanol. The combined liquid phase twice evaporated and re-dissolved in methanol. After removal of methanol in vacuo, the residue re-dissolved in water and the pH adjusted to 12 with 1N. the solution of KOH. The solvent is removed in vacuo and the residue together twice evaporated with toluene. The residue is purified via Express chromatography (silica gel, CH2CL2/methanol 8:2). ES+MS m/e 337 (MH+).

Example 13

5-[2-(5,6-Dimethoxyindole-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-he

This compound is obtained from the intermediate product 11 by a method similar to the method described in example 12. ES+MC m/e 397 (MN+).

Example 14

5-[2-(5,6-Dietlinde-2-ylamino)-1-hydroxyethyl]-8-hydroxy-3-methyl-1H-quinoline-2-he

This compound is obtained from the intermediate p is oduct 13 (21 mg) using the process of hydrogenation to remove the benzyl group, described in example 1.

1H-NMR (d4-CH3HE frequent./million of 1.11 (t, 6H), 2,11 (s, 3H), 2,58 (q, 4H), 3,01-3,37 (m, 6H), 4,10-4,16 (m, 1H), 5,31 is 5.38 (m, 1H), 6,91 (d, 1H), 7,00 (s, 2H), 7,21 (d, 1H), 8,13 (s, 1H).

Example 15

5-[2-(5,6-Dietlinde-2-ylamino)-1-hydroxyethyl]-8-methoxyethoxy-6-methyl-1H-quinoline-2-he

This compound is obtained from an intermediate product 14 (20 mg) and 5,6-dietlinde-2-ylamine (72 mg) according to the method used to obtain the intermediate product 13.

1H-NMR (CDCl3) part./million: 1.14 in (t, 6H), is 2.30 (s, 3H), of 2.51 (q, 4H), 2,64-and 3.16 (m, 6H), to 3.41 (s, 3H), 3,60-3,68 (m, 1H), 5,18-a 5.25 (m, 3H), of 6.50 (d, 1H), 7,89-7,94 (m, 3H), 8,68 (d, 2H), 9,15 (s, br, 1H).

5-[2-(5,6-Dietlinde-2-ylamino)-1-hydroxyethyl]-8-hydroxy-6-methyl-1H-quinoline-2-he

To a solution of 5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-8-methoxyethoxy-6-methyl-1H-quinoline-2-it (12 mg) in isopropanol (1 ml) and tetrahydrofuran (1 ml) at room temperature add 3h. hydrochloric acid (1 ml) and the reaction mixture was incubated for 18 h at 40°C. the Solvent is removed in vacuo and the product purified using preparative GHUR on the type column C8, using elution gradient of water/acetonitrile/triperoxonane acid.

1H-NMR (d4-CH3HE frequent./million: 15,97, 20,09, 26,34, 36,87, 51,75, 59,72, 67,33, 118,41, 119,12, 121,21, 125,45, 126,11, 128,60, 133,35, 137,52, 137,55, 142,32, 142,50, 145,69, 163,24.

Example 16

8-Hydroxy-5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-3,4-dig the DRO-1H-quinoline-2-he

By hydrogenation of a solution of 8-hydroxy-5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-1H-quinoline-2-it (example 2) in a mixture of methanol/ethanol in the presence as catalyst of 10%palladium on coal in an atmosphere of hydrogen at 30°C for 48 h, followed by filtration and evaporation receive specified in the header connection. Further purification is carried out using preparative GHUR (column: Phenomenex Luna 10 μm, 150 mm × 50 mm, eluent: gradient from 10% to 95% acetonitrile in water with addition of 0.1% triperoxonane acid, UV detection at 254 nm).

13C-NMR (d6-DMSO) ppm million: 15,77, 21,42, 25,01, 30,37, 37,73, 37,83, 53,88, 58,68, 67,37, 113,28, 120,21, 122,08, 124,31, 124,34, 131,01, 138,46, 138,52, 139,58, 143,12, 169,44.

Example 17

(a) (R)-1-(4-benzyloxy-3-formylamino)-2-[benzyl-(2,5,6-trimethylene-2-yl)amino]ethyl ester of acetic acid

To the intermediate product 29 in a mixture of toluene/THF is added slowly sustained a mixture of formic acid and acetic anhydride and the reaction mixture is stirred for 5 h at room temperature. Add ethyl acetate and washed with a saturated solution Panso3. After purification by chromatography (silica gel, ethyl acetate/hexane 1:2) and trituration with simple ether get the product in the form of whitish crystals. ES+MS m/e 577 (MH+).

(b) (N)-(2-Benzyloxy-5-{(R)-2-[benzyl-(2,5,6-trimethylene-2-yl)amine is]-1-hydroxyethyl}phenyl)formamide

The product from example 17(a) is suspended in ethanol and added a catalytic amount of N3in methanol. After incubation for 2 h at 70°the solvent is removed and the residue purified via chromatography (silica gel, ethyl acetate/hexane 2:3)to give product as white crystals. ES+MS m/e 535 (MN+).

(C) N-{2-Hydroxy-5-[(R)-1-hydroxy-2-(2,5,6-trimethylene-2-ylamino)ethyl]phenyl}formamide obtained from the product of example 17(b) according to the method similar to the method described in example 34(b). ES+MS m/e 355 (MN+).

Example 18

(a) 8 Benzylamino-5-[(R)-2-(5,6-diethyl-2-methylinden-2-ylamino)-1-hydroxyethyl]-1H-quinoline-2-he

A mixture containing 5,6-diethyl-2-methylinden-2-ylamine (0.28 g) and 8-benzyloxy-5-oxiranyl-1H-quinoline-2-he (0,42 g) in n-butanol (0.7 ml), placed on a 75 min in a microwave type Prolabo at 100°C. the Product was then purified via chromatography (silica gel, DHM/ethanol 5:1)to give the desired product. ES+MS m/e 497 (MN+).

5-[(R)-2-(5,6-diethyl-2-methylinden-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-he

A solution of the product from example 18(a) (0.20 g) in methanol (20 ml) is stirred in hydrogen atmosphere in the presence of 10%Pd/C at room temperature for 2 hours the Mixture is filtered through celite and the filtrate concentrated in vacuo. After trituration with diethyl ether get demand the product. ES+MS m/e 407 (MN+).

Example 19

(a) (S)-8-Benzyloxy-5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-1H-quinoline-2-it is obtained from the intermediate product 16 (152 mg) and intermediate 1 (100 mg) according to the method similar to the method described in example 1(a). TLC (silica gel, dichloromethane/methanol 10:1, Rf=0,25).

(b) Hydrochloride (S)-5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-it is obtained from the product of example 19(a) according to the method similar to the method described in example 1(b). TLC (silica gel, dichloromethane/methanol 10:1, Rf=0,05).

Example 20

(a) 8-Benzyloxy-5-[(R)-1-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzocycloheptene-7-ylamino)ethyl]-1H-quinoline-2-it is obtained from (R)-8-benzyloxy-5-oxiranylmethyl (203 mg) and intermediate 17(110 mg) according to the method similar to the method described in example 1(a). TLC (silica gel, dichloromethane/methanol 10:1, Rf=0,30).

(b) Hydrochloride 5-[(R)-1-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzocycloheptene-7-ylamino)ethyl]-8-hydroxy-1H-quinoline-2-it is obtained from the product of example 20(a) according to the method similar to the method described in example 1(b). TLC (silica gel, dichloromethane/methanol 10:1, Rf=0,05).

Example 21

(a) (R)-8-Benzyloxy-5-{(S)-2-[benzyl-(5,6-dietlinde-2-yl)amino]-1-hydroxyethyl}-1H-quinoline-2-he

A solution containing (K.)-8-benzyloxy-5-oxiranylmethyl(5,00 g) and 2-amino-5,6-dietlinde (a 3.87 g) in n-butanol, incubated for 4 h at 110°C. After cooling to room temperature, add toluene (100 ml) and the organic phase washed with water (3×25 ml), bring in a chromatographic column filled with silica gel and elute with toluene, and then with a mixture of toluene:ethanol:ethyl acetate:concentrated ammonia solution(45:10:45:2), getting listed at the beginning of the connection.

(b) Maleate (R)-5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-it

(R)-8-benzyloxy-5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-1H-quinoline-2-he (360 mg) was dissolved in methanol (10 ml) and the connection remove the protective group, adding a catalytic amount of 10%palladium on coal and placing the solution in an atmosphere of hydrogen. According to the analysis by TLC after 4 h the reaction is finished. The catalyst is filtered off and the solvent is removed in vacuum. The product is dissolved in isopropanol and add a solution of maleic acid in isopropanol. After recrystallization from ethanol specified in the header connection. TLC (silica gel, dichloromethane/methanol 10:1, Rf=0,05). ES+MS m/e 393 (MN+).

Example 22

(a) N-(5-{(R)-2-[Benzyl-(5,6-dietlinde-2-yl)amino]-1-hydroxyethyl}-2-benzyloxyphenyl)formamide obtained from intermediate 19 (1,00 g), formic acid (155 mg) and acetic anhydride (226 mg) according to the method similar IU the ode, described in example 21 (a). TLC (silica gel, n-hexane/ethyl acetate 2:1, Rf=0,20).

(b) N-{5-[(R)-2-(5,6-Dietlinde-2-ylamino)-1-hydroxyethyl]-2-hydroxyphenyl}formalin is obtained from the product of example 22(a) according to the method similar to the method described in example 1(b). TLC (silica gel, n-hexane/ethyl acetate 2:1, Rf=0,05).

Example 23

(a) (R)-2-[Benzyl-(5,6-dietlinde-2-yl)amino]-1-(4-benzyloxy-3-dimethylaminophenyl)ethanol

The intermediate product 19 (0,37 g) dissolved in CH3HE (50 ml) and added formaldehyde, 37%in water (5 ml), dissolved in water (10 ml). Add a catalytic amount PtO2and the solution is stirred in an atmosphere of H2. According to the analysis by TLC after 24 h the reaction is finished. The catalyst is filtered off, the solvent is removed in vacuo and the residue distributed between ethyl acetate (100 ml) and water (100 ml). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuum. The product was then purified using the rapid chromatography on a column (silica gel, n-hexane/ethyl acetate 4:1). TLC (silica gel, n-hexane/ethyl acetate 2:1, Rf=0,65).

(b) Hydrochloride of 4-[(R)-2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-2-dimethylaminophenol obtained from the product of example 23(a) according to the method similar to the method described in example 1(b).

1H-NMR [DMSO, 400 MHz] δ of 1.10(6H,t), to 2.55 (4H, q), of 3.05(2H,m), 3,10 (6N, s), 20 (4H, m)4,00 (1H, m), of 4.95 (1H, m), 7,00 (2H, s), to 7.15 (1H, d), 7,35 (1H, d), 7.80 (1H, s), 9,20 (1H, broad), of 9.75 (1H, broad), 11,40 (1H, broad).

Example 24

(a) (R)-2-[Benzyl-(5,6-dietlinde-2-yl)amino)-1-(4-benzyloxy-3-methylaminophenol)ethanol

The product from example 22 (260 mg) was dissolved in dioxane (20 ml). Add borohydride sodium (90 mg), and then added dropwise acetic anhydride (142 mg). The reaction mixture was stirred at 90°C. According to the analysis by TLC after 4 h the reaction is finished. The solvent is removed in vacuo and the residue distributed between ethyl acetate (100 ml) and water (100 ml). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuum. The product was then purified using the rapid chromatography on a column (silica gel, n-hexane/ethyl acetate 4:1). TLC (silica gel, n-hexane/ethyl acetate 2:1, Rf=0,65).

(b) Hydrochloride of 4-[(R)-2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-2-methylaminophenol obtained from the product of example 24(a) according to the method similar to the method described in example 1(b).

1H-NMR [DMSO, 400 MHz] δ of 1.10 (6H,t), to 2.55 (4H, q), 2,85 (3H, s), 3,10 (6N, m)4,00 (1H, m), the 4.90 (1H, m)to 7.00 (3H, m), to 7.15 (1H, m), 7,40 (1H, m), 9,10 (1H, broad), 9,60 (1H, broad), 10,80 (1H, broad).

Example 25

(a) N-(5-{[Benzyl-(5,6-dietlinde-2-yl)amino]acetyl}-2-benzyloxy-phenyl)methanesulfonamide

The intermediate product 20 (240 mg) was dissolved in dichloromethane (10 ml). Add triethylamine (56 mg), and ZAT is m methanesulfonanilide (58 mg). The reaction mixture was stirred at room temperature. According to the analysis by TLC after 24 h the reaction is finished. The solvent is removed in vacuum and the product was then purified using the rapid chromatography on a column (silica gel, n-hexane/ethyl acetate 4:1). TLC (silica gel, n-hexane/ethyl acetate 2:1, Rf=0,40).

(b) N-(5-{2-[Benzyl-(5,6-dietlinde-2-yl)amino]-1-hydroxyethyl}-2-benzyloxyphenyl)methanesulfonamide

The product from example 25(a) (120 mg) dissolved in ethanol (10 ml). Add borohydride sodium (9 mg) and the reaction mixture was stirred at room temperature. According to the analysis by TLC after 3 h the reaction is finished. The reaction is stopped by adding 2M Hcl (1 ml), the solvent is removed in vacuo and the residue distributed between ethyl acetate (50 ml) and saturated aqueous NaHCO3(50 ml). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuum. The product is not subjected to additional purification. TLC (silica gel, n-hexane/ethyl acetate 2:1, Rf=0,45).

(b) Hydrochloride of N-{5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide obtained from the product of example 25(b) according to the method similar to the method described in example 1(b).

1H-NMR [CDCl3, 400 MHz] δ 1,15 (6N, t)to 2.55 (4H, q) 2,95 (3H, s), 3,10 (6N, m)4,00 (1H, m), is 4.85 (1H, m), 6,10 (1H, broad), of 6.90 (2H, d), 7,00 (2H, s), 7,10 (1H, dd), 7,25 (1, d)is 8.75 (1H, s), of 8.95 (1H, broad), the 9.25 (1H, broad), 10,00 (1H, s).

Example 26

(a) (R)-8-Benzyloxy-5-{(S)-2-[benzyl-(4,5,6,7-tetramethylene-2-yl)amino]-1-hydroxyethyl}-1H-quinoline-2-he

(R)-8-Benzyloxy-5-oxiranylmethyl (204 mg) and intermediate product 21 (194 mg) dissolved in n-butanol (0.5 ml) in nitrogen atmosphere. The reaction mixture was kept at 110°C for 22 hours, After cooling the solvent is removed in vacuum. The product was then purified using the rapid chromatography on a column (silica gel, ethyl acetate/hexane 50:50). ES+MC m/e 573 (MN+).

(b) (R)-8-Hydroxy-5-[(S)-1-hydroxy-2-(4,5,6,7-tetramethylene-2-ylamino)ethyl]-1H-quinoline-2-it is obtained from the product of example 26(a) according to the method similar to the method described in example 1(b).

1H-NMR (CD3OD) part./million: 8,55 (1H, d); and 7.5 (1H, d); of 7.25 (1H, d); 6,9 (1H, d); 5,6 (1H, m); 4,3 (1H, m); 3,7 (2H, q); 3,6 (2H, dd); 3,3 (2H, dd); 2,4 (N, s)

Example 27

(a) 8-Benzyloxy-5-[(R)-1-hydroxy-2-(2-methylinden-2-ylamino)ethyl]-1H-quinoline-2-it.

A mixture containing 8-benzyloxy-5-(R)-oxiranyl-1H-quinoline-2-he (500 mg) and 2-methylinden-2-ylamine (276 mg) in n-butanol (1 ml), subjected to within 90 min of microwave irradiation on the device type Prolabo Synthewave 402 110°C. the Balance adsorb on silica gel and the product was then purified using the rapid-chromatography (silica gel, chloroform/ethanol 4:1).

1H-NMR (CDCl3) part./million: of 1.30 (s, 3H), 2,65 (s, 1H), 2,95 (dd, 2H), of 3.07(m, 3H), of 5.15 (m, 1H), 5,18 (s, 2H), 6,66 (d, 1H), 7,17 (m, 4H), 7,26 (d, 1H), 7,45 (m, 5H), 8,07 (d, 1H), 8,8-9,5 (br.d, 1H)

(b) 8-Hydroxy-5-[(R)-1-hydroxy-2-(2-methylinden-2-ylamino)ethyl]-1H-quinoline-2-he

The product from example 27(a) (100 mg, 0.22 mmole) was dissolved in methanol (20 ml), and he removes the protective group, adding a catalytic amount of 10%palladium on coal and stirring for 1 h in hydrogen atmosphere. The catalyst was removed and the solvent is evaporated, receiving the product in a solid yellow color.

1H-NMR (d4-CH3OH) ppm million: of 1.20 (s, 3H), of 2.75 (m, 4H), 2.95 and (d, 2H), to 5.03 (m, 1H), 6,60 (d, 1H), PC 6.82 (d, 1H), 7,0 (m, 4H), was 7.08 (d, 1H), to 8.20 (d, 1H).

Example 28

5-[2-(5,6-Dietlinde-2-ylamino)ethyl]-8-hydroxy-1H-quinoline-2-he

This compound is obtained from the product of example 2 according to the method described by Temple and others, J. Med. Chem., 19, 626-633 (1976).

1H-NMR (d4-CH3OH) ppm million: a 1.08 (t, 3H), by 2.55 (q, 4H), 2,96 (dd, 2H), 3,18 (m, 4H), of 3.28 (dd, 2H), 3,99 (m, 1H), 6,60 (d, 1H), 6.90 to (d, 1H), 6,97 (d, 1H), 6,00 (s, 2H), 8,07 (d, 1H).

Example 29

(a) 8-Benzyloxy-5-[(R)-1-hydroxy-2-(2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopent[b]naphthalene-2-ylamino)util-1H-quinoline-2-it is obtained from 8-benzyloxy-5-(R)-oxiranyl-1H-quinoline-2-she (220 mg) and intermediate 24 (150 mg) according to the method similar to the method described in example 27(a).

1H-NMR (CDCl3) part./million: 1,37 (s, 1H), 1,78 (m, 4H), 2,1 (br.s, 2H), 2,72 (m, 5H), 2,80 (dd, 2H), 2.95 and (m, 3H), 5,08 (m, 1H), 5,17 (s, 2H), of 6.65 (d, 1H), to 6.88 (s, 2H) 7,02 (d, 2H), 7,26 (d, 1H), and 7.4 (m, 5H), 8.05 (d, 1H).

(b) 8-Hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopent[b] naphthalene-2-ylamino)ethyl]-1H-quinoline-2-it is produced by hydrogenation of the product of example 29(a) according to the method similar to the method described in example 27(b). The product was then purified using GHUR (H2O, CH3SP, CF3COOH, elution with a gradient of solvent).

1H-NMR (d4-CH3OH) ppm million (TFA salt): 1,65 (s, 3H), of 1.85 (m, 4H), 2,85 (m, 4H), 3.15 in (m, 2H), 3,4 (m, 4H), of 5.48 (t, 1H), 6,83 (d, 1H), 7,03 (s, 2H), 7,15 (d, 1H), 7,45 (d, 1H), 8,40 (d, 1H).

Example 30

(a) 5-{(S)-2-[Benzyl-(2,3,5,6,7,8-hexahydro-1H-cyclopent[b]naphthalene-2-yl)amino]-1-hydroxy-ethyl}-8-benzyloxy-1H-quinoline-2-he

A mixture of intermediate 16 (150 mg) and benzyl(2,3,5,6,7,8-hexahydro-1H-cyclopent[b]naphthalene-2-yl)amine (142 mg) in toluene (1 ml) was kept at 80°within 36 hours the Residue purified via chromatography (silica gel, l3/tOH, 20:1)to give the product as a yellow foam.

1H-NMR (l3) part./mn: or 1.77 (m, 4H), of 2.72 (m, 6H), 3,01 (m, 4H), 3,70 (d, 1H), 3,88 (d, 1H), 4,82 (m, 1H), further 5.15 (s, 2H), 6,50 (d, 1H), 6,8-8 (m, 13H), 9,05 (br.s, 1H)

(b) 5-[(S)-2-(2,3,5,6,7,8-Hexahydro-1H-cyclopent[b]naphthalene-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-he

A solution of the product from example 30(a) (150 mg) in methanol (20 ml) is stirred for 5 hours in a hydrogen atmosphere in the presence of 10%Pd/C (20 mg) at room t is mperature. The reaction mixture is filtered and the product purified via chromatography (silica gel, l3/tO, 20:1), and then by crystallization (CH3IT).

1H-NMR (d4-CH3OH) ppm million: of 1.65 (m, 4H), 2.57 m (m, 4H), of 2.86 (dd, 2H), 3,1 (m, 4H), 3,82 (m, 1H), 5.25 in (m, 1H), 6,55 (d, 1H), 6,78 (s, 2H), 6,91 (d, 1H), 7,19 (d, 1H), 8,27 (d, 1H).

Example 31

(a) (R)-2-[Benzyl-(2-methylindol-2-yl)amino]-1-(4-benzyloxy-3-methanesulfonylaminoethyl)ethyl ester of acetic acid produced from the intermediate product 27 (476 mg), triethylamine (231 mg) and methane sulphonylchloride (210 mg) according to the method similar to the method described in example 25(b). TLC (silica gel, n-hexane/ethyl acetate 2:1, Rf=0,45).

(b) N-(5-{(R)-2-[Benzyl-(2-methylindol-2-yl)amino]-1-hydroxyethyl)-2-benzyloxyphenyl)methanesulfonamide

The product from example 31(a) (200 mg) was dissolved in CH3HE (8 ml). Add To2CO3(138 mg), and then added dropwise water (2 ml). The reaction mixture was stirred at room temperature. According to the analysis by TLC after 24 h the reaction is finished. Add ethyl acetate (100 ml) and the solution washed with water (50 ml) and with brine (50 ml). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuum. The product was then purified using the rapid-chromatography (silica gel, n-hexane/ethyl acetate 3:1). TLC (silica gel, n-hexane/ethyl acetate 2:1, Rf=0,35).

(C) N-{2-Hydroxy-5-[()-1-hydroxy-2-(2-methylinden-2-ylamino)ethyl] phenyl) methanesulfonamide obtained from the product of example 31(b) according to the method similar to the method described in example 1(b). TLC (silica gel, dichloromethane/methanol 10:1, Rf=0,10).

Example 32

(a) (R)-2-[Benzyl-(2-methylindol-2-yl)amino]-1-(4-benzyloxy-3-ethanolgasoline)ethyl ester of acetic acid produced from the intermediate product 27, triethylamine (242 mg) and acanaloniidae (247 mg) according to the method similar to the method described in example 25(b). TLC (silica gel, n-hexane/ethyl acetate 2:1, Rf=0,50).

(b) (5-{(R)-2-[Benzyl-(2-methylindol-2-yl)amino]-1-hydroxyethyl}-2-benzyloxyphenyl)amide econsultancy acid is obtained from the product of example 32(a) according to the method similar to the method described in example 31(b). TLC (silica gel, n-hexane/ethyl acetate 2:1, Rf=0,40).

(in) {2-Hydroxy-5-[(R)-1-hydroxy-2-(2-methylinden-2-ylamino)ethyl]phenyl}amide econsultancy acid is obtained from the product of example 32(b) according to the method similar to the method described in example 1(b). TLC (silica gel, dichloromethane/methanol 10:1, Rf=0,10).

Example 33

(a) (R)-2-[Benzyl-(2-methylindol-2-yl)amino]-1-[4-benzyloxy-3-(propane-1-sulfonylamino)phenyl]ethyl ester of acetic acid produced from the intermediate product 27 (525 mg), triethylamine (255 mg) and 1-propanesulfonate (288 mg) according to the method similar to the method described in example 25(a). TLC (silica gel, n-hexane/ethyl acetate 4:1, Rf=0,25).

(b) (5-{(R)-2-[Benzyl-(2-IU is Ilinden-2-yl)amino]-1-hydroxyethyl}-2-benzyloxyphenyl)amide propane-1-sulfonic acid obtained from the product of example 33(a) according to the method similar to the method described in example 31(b). TLC (silica gel, n-hexane/ethyl acetate 4:1, Rf=0,15).

(in) {2-Hydroxy-5-[(R)-1-hydroxy-2-(2-methylinden-2-ylamino)ethyl]phenyl}amide propane-1-sulfonic acid obtained from the product of example 33(b) according to the method similar to the method described in example 1(b). TLC (silica gel, dichloromethane/methanol 10:1, Rf=0,05).

Example 34

(a) N-{2-Benzyloxy-5-[(2-atienden-2-ylamino)acetyl]phenyl}methanesulfonamide

A mixture of 2-atienden-2-ylamine and N-(2-benzyloxy-5-bromoacetyl)methanesulfonamide stirred in acetonitrile at room temperature for 20 hours the Product emit filtering. ES+MS m/e 479 (MN+).

(b) N-{2-Benzyloxy-5-[2-(2-atienden-2-ylamino)-1-hydroxyethyl]phenyl} methanesulfonamide

The product from example 34(a) is suspended in a mixture of ethanol and dichloromethane. Add at 0°borohydride sodium and the mixture is stirred at room temperature for 3 h, then filtered and chromatographic (silica gel, ethyl acetate/ethanol 4:1)to give the product as a white foam. ES+MS m/e 480 (MN+).

(C) N-{5-[2-(2-Atienden-2-ylamino)-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide

The product from example 34(b) (0,29 g) in methanol (20 ml) is stirred for 18 h at room temperature in a hydrogen atmosphere in the presence of 10%Pd/C. the Mixture is filtered through celite the filtrate was concentrated in vacuo, then chromatographic (silica gel, ethyl acetate/ethanol 2:1). After trituration with a mixture of simple ether/ethyl acetate to obtain the product in the form of whitish crystals (100 mg).

1H-NMR (d4-CH3HE frequent./million: of 0.85 (t, 3H), of 1.65 (m, 2H), 2,75 (m, 2H), 2,85 (s, 3H), 2.95 and (m, 4H), to 6.80 (d, 1H), 7,05 (m, 5H), 7,30 (s, 1H). ES+MC m/e 491 (MN+).

Example 35

(a) (R)-1-(4-Benzyloxy-3-methanesulfonylaminoethyl)-2-[benzyl-(2,5,6-trimethylene-2-yl)amino] ethyl ester of acetic acid

To a solution of intermediate 29 in dichloromethane and triethylamine at room temperature add methanesulfonanilide and the mixture is stirred for 18 hours Then washed with 0,2n. HCl, a saturated solution Panso3and salt solution. The product was then purified by chromatography (silica gel, ethyl acetate/hexane 1:4). ES-MS m/e 625 (MH-).

(b) N-(2-Benzyloxy-5-{(R)-2-[benzyl-(2,5,6-trimethylene-2-yl)amino]-1-hydroxyethyl}phenyl)methanesulfonamide

The product from example 35(a) is stirred in a mixture of methanol/water with K2CO3within 3 days, after which the solvent is removed in vacuum. The product was then purified via chromatography (silica gel, ethyl acetate/hexane 1:2).

1H-NMR (l3) part./million: to 1.21 (s, 3H), 2,22 (s, 6H), 2,63-2,82 (m, 4H), 2,84 (s, 3H), 3,20 (br.d, 2H), 3,61 (d, 1H), 3,64 (br.s., 1H), 3,83 (m, 1H), 4,08 (d, 1H), 5,09 (s, 2H), 6.75 in (br.s, NH), 6.90 to-7,05 (m, 4H), 7,25 was 7.45 (11H).

(C) N-{2-Hydroxy-5-[(R)-1-hydroxy-2-(2,5-trimethylene-2-ylamino)ethyl] phenyl} methanesulfonamide obtained from the product of example 35(b) according to the method similar to the method described in example 34(b). ES+MS m/e 405 (MN+).

Pharmacological report

The ability to bind against β2-adrenergic receptors and β1-adrenergic receptors for a number of claimed compounds was determined using the classical analysis of binding using a filter according to the method described in Current Protocols in Pharmacology, John Wiley 1998 (see page 18 for details). The results obtained are presented in table 2

Table 2
Exampleβ2-adrenergic receptors Ki(nm)β1-adrenergic receptors

Ki (nm)
1647226
24(b)4072397
25 (C)133851
28261478
31 (b)41465
32 (b)772139
33 (C)2523725
34 (C)2703928
35 (C)13121

The duration of action in relation to β2-adrenergic receptors of a number of claimed compounds was studied using in vitro assays using strips of tracheae marine light is OK according to the method described by Coleman and Nials (see page 18 for details). Metric Tons(50%) indicates the time required for inhibition of voltage that is required for the transition from contraction to relaxation at 50% of its maximum value. The results obtained are presented in table 3

Table 3
ExampleT (50%), minutes
16143 at a concentration of 10 nm
25 (C)608 at a concentration of 10 nm
31 (b)175 at a concentration of 100 nm
32 (b)476 at a concentration of 1000 nm
35 (C)286 at a concentration of 100 nm

1. The compound of the formula

in free form or in salt form, where

AG denotes a group of the formula

R1denotes hydrogen or hydroxy,

R2and R3each independently of one another denotes hydrogen or C1-C4alkyl,

R4, R5, R6and R7each independently of one another denotes hydrogen, C1-C4alkoxy, C1-C4alkyl or C1-C4alkyl, substituted C1-C4alkoxygroup, or R5 and R6together with the carbon atoms to which they are attached represent a 6-membered cycloaliphatic ring or 6-membered heterocyclic ring containing two oxygen atoms

R8means-other13where R13denotes hydrogen, C1-C4alkyl, or-COR14where R14denotes hydrogen, or R13means-SO2R17where R17stands With1-C4alkyl, and R9denotes hydrogen, or R8means-other18where is the other18and R9together with the carbon atoms to which they are attached represent a 6-membered heterocycle,

R10means-HE,

X denotes a1-C4alkyl,

Y represents carbon,

n is 1 or 2,

p is 1,

q is 1,

r is 0 or 1; and

the carbon atom marked with an asterisk *is in the R - or S-configuration, or a mixture, if R1denotes a hydroxy-group.

2. The compound according to claim 1, where AG denotes a group of formula II in which R8means-other18and-other18and R9together denote a group of formula-NH-CO-R23-where R23stands With1-C4alkylen or2-C4albaniles.

3. The compound according to claim 2, where AG denotes a group of the formula III or IIIa

in which R29, R30and R31each independently of one another denotes hydrogen or C1-C4alkyl.

4. The compound according to claim 1, where AG denotes a group of formula II in which R8means-other13where R13denotes hydrogen, C1-C4alkyl, or-COR14where R14denotes hydrogen, or R13means-SO2R17where R17stands With1-C4alkyl, R9denotes hydrogen, p and q is 1 and r is 0.

5. The compound according to claim 4, where AG denotes a group of the formula XV

where R13matter specified in paragraph 4.

6. The compound according to any one of the preceding paragraphs, in which R4and R7are the same and each represents hydrogen, C1-C4alkyl or C1-C4alkoxy and either R5and R6are the same and each represents hydrogen, C1-C4alkyl, C1-C4alkoxy or1-C4alkoxy-C1-C4alkyl, or R5and R6together represent -(CH2)s- or-O(CH2)tO-, where s is equal to 4 and t is 2.

7. The compound according to claim 1, where AG denotes a group of the formula III or IIIA according to claim 3, or formula XV according to claim 5, R1denotes hydroxy, R2and R3additional who are hydrogen and R 4and R7are the same and each represents hydrogen, C1-C4alkyl or C1-C4alkoxy and either R5and R6are the same and each represents hydrogen, C1-C4alkyl, C1-C4alkoxy or1-C4alkoxy-C1-C4alkyl, or R5and R6together represent -(CH2)4- or-O(CH2)2O-, in free form or in salt form.

8. The compound according to any one of the preceding paragraphs, in which R1denotes hydroxy, and the carbon atom in formula I, is indicated by an asterisk *is in the R-configuration.

9. The compound according to claim 1 of the formula

in free form or in salt form,

(A) where AG denotes a group of the formula

in which R29, R30and R31each represents H, R1IT denotes, R2and R3each denotes H and

(I) n represents 1 and R4and R7each represents CH3O - and R5and R6each represents H; or

(II) n is 1 and R4and R7each denotes H and each R5and R6denotes CH3CH2-; or

(III) n is 1 and R4and R7each represents H and R5and R6each represents CH3-; or

(IV, n is 1 and R 4and R7each represents CH3CH2and R5and R6each represents H; or

(V) n is 1 and R4and R7each represents H and R5and R6together represent -(CH2)4-; or

(VI) n is 1 and R4and R7each represents H and R5and R6together represent-O(CH2)2O-; or

(VII) n is 1 and R4and R7each represents H and R5and R6each represents CH3(CH2)3-; or

(VIII) n is 1 and R4and R7each represents H and R5and R6each represents CH3(CH2)2-; or

(IX) n is 1, R4, R5, R6and R7each represents H; or

(X) n is 1 and R4and R7each represents H and R5and R6each represents CH3Och2-; or

(B) where AG denotes a group of the formula

in which R13denotes H, R1IT denotes, R2and R3each represents H, R4and R7each represents H and R5and R6each denotes H and n is 1; or

(C) is a compound selected from a range that includes

8-hydroxy-5-[1-hydroxy-2-(indan-2-ylamino)ethyl]-1H-quinoline-2-it,

5-[2-(5,6-dimethoxyindole-2-ylamino)-1-HYDR shall xitil]-8-hydroxy-1H-quinoline-2-it,

5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-8-hydroxy-3-methyl-1H-quinoline-2-it,

5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-8-methoxyethoxy-6-methyl-1H-quinoline-2-it,

5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-8-hydroxy-6-methyl-1H-quinoline-2-it,

8-hydroxy-5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-3,4-dihydro-1H-quinoline-2-it,

N-{2-hydroxy-5-[(R)-1-hydroxy-2-(2,5,6-trimethylene-2-ylamino)ethyl]phenyl}formamide,

5-[(R)-2-(5,6-diethyl-2-methylinden-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-it,

hydrochloride (S)-5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-it,

hydrochloride 5-[(R)-1-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzocycloheptene-7-ylamino)ethyl]-8-hydroxy-1H-quinoline-2-it,

maleate (R)-5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-it,

hydrochloride (R)-5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-it,

N-{5-[(R)-2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-2-hydroxyphenyl}formamide,

hydrochloride 4-[(R)-2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-2-dimethylaminophenol,

hydrochloride 4-[(R)-2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-2-methylaminophenol,

the hydrochloride of N-{5-[2-(5,6-dietlinde-2-ylamino)-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide,

(R)-8-hydroxy-5-[(S)-1-hydroxy-(4,5,6,7-tetramethylene-2-ylamino)ethyl]-1H-quinoline-2-it,

8-hydroxy-5-[(R)-1-hydroxy-2-(2-methylinden-2-ylamino)ethyl]-1H-quinoline-2-it,

5-[2-(5,6-dietlinde-2-ylamino)ethyl]-8-hydroxy-1H-quinoline-2-it,

8-hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopent[b]naphthalene-2-ylamino)ethyl]-1H-quinoline-2-it,

5-[(S)-2-(2,3,5,6,7,8-hexahydro-1H-cyclopent[b]naphthalene-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-it,

N-{2-hydroxy-5-[(R)-1-hydroxy-2-(2-methylinden-2-ylamino)ethyl]phenyl}methanesulfonamide,

{2-hydroxy-5-[(R)-1-hydroxy-2-(2-methylinden-2-ylamino)ethyl]phenyl}amide econsultancy acid,

{2-hydroxy-5-[(R)-1-hydroxy-2-(2-methylinden-2-ylamino)ethyl]phenyl}amide propane-1-sulfonic acid,

N-{5-[2-(2-atienden-2-ylamino)-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide and

N-{2-hydroxy-5-[(R)-1-hydroxy-2-(2,5,6-trimethylene-2-ylamino)ethyl]phenyl}methanesulfonamide.

10. The pharmaceutical composition exhibiting the properties of agonist β2-adrenergic receptors and including a connection according to any one of the preceding paragraphs optionally in combination with a pharmaceutically acceptable carrier.

11. The method of obtaining the compounds of formula I, where R1denotes hydroxy, in free form or in salt form, which consists in the fact that they are subjected to the interaction of the compound of the formula

connection fo the mules

where AG1denotes AG as defined in claim 1, or a protected form, R2, R3, R4, R5, R6, R7and n have the meanings indicated in claim 1, and R32denotes hydrogen or aminosidine group;

not necessarily make the resulting compound of formula I in protected form in the appropriate connection in unprotected form;

and allocate the resulting compounds of formula I in free form or in salt form.

12. The compound of formula XVII

where R3, R4, R5, R6, R7and n have the meanings indicated in claim 1, and R4, R5, R6and R7are such groups that the benzene ring to which they are attached, is symmetrically substituted, and R32denotes hydrogen or aminosidine group, with the exception of compounds where R4, R5, R6, R7and R32each denotes hydrogen, where R4and R7denote methyl or methoxy, when R5, R6and R32each denotes hydrogen.



 

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