RU2449991C2 - Quinolinone derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula l

in the form of a salt wherein W means a group of formula

and A means acetate or xinafoate, as well as to based pharmaceutical compositions which may be used for treating the diseases accompanied by bronchospasms.

EFFECT: what is offered is a new effective bronchial spasmolytic.

7 cl, 23 ex, 4 tbl, 8 dwg

Description

The present invention relates to new salts, to a method for their preparation and to their use in pharmaceutical compositions.

An object of the present invention is a compound of formula I

in salt or solvate form,

in which W denotes a group of the formula

R ^x and R ^{y are} both —CH ₂ - or - (CH ₂ ) ₂ -;

R ¹ is hydrogen, a hydroxy group or a C ₁ -C ₁₀ alkoxy group;

R ² and R ^{3 are} each independently hydrogen or C ₁ -C ₁₀ alkyl;

R ⁴ , R ⁵ , R ⁶ and R ^{7 are} each independently hydrogen, halogen, cyano, hydroxy, C ₁ -C ₁₀ alkoxy, C ₆ -C ₁₀ -aryl, C ₁ -C ₁₀ -alkyl, C ₁ -C _10- alkyl substituted with one or more halogen atoms or one or more hydroxy groups or C ₁ -C ₁₀ alkoxy groups, C ₁ -C ₁₀ alkyl, which includes one or more heteroatoms, C ₂ -C ₁₀ alkenyl , trialkylsilyl, carboxy, C ₁ -C ₁₀ alkoxycarbonyl or -CONR ¹¹ R ¹² , where R ¹¹ and R ^{12 are} each independently hydrogen or C ₁ -C ₁₀ alkyl, or R ⁴ and R ⁵ , R ⁵ and R ⁶ or R ⁶ and R ⁷ together with the atoms uglero and to which they are attached denote a 5-, 6- or 7-membered carbocyclic ring or 4-10 membered heterocyclic ring;

R ⁸ , R ⁹ and R ^{10 are} each independently hydrogen or C ₁ -C ₄ alkyl; and

And selected from the group comprising hydrosuccinate, fumarate, hippurate, mesylate, hydrosulfate, hydrotartrate, hydrochloride, hydrobromide, formate, esylate, tosylate, glycolate, acetate, xinafoate and hydro malalon.

The terms used in the present description have the following meanings:

“Halogen” when used in the present invention means an element of group 17 (formerly group VII) of the Periodic system of elements, which may be, for example, fluorine, chlorine, bromine or iodine. Preferred halogen is fluorine or chlorine.

“C ₁ -C ₁₀ -alkyl” as used in the present invention means a linear or branched chain alkyl that contains from 1 to 10 carbon atoms. A preferred C ₁ -C ₁₀ alkyl is C ₁ -C ₄ alkyl.

“Alkyl in which one or more heteroatoms are included” means a straight or branched chain alkyl, for example C ₂ -C ₁₀ -alkyl, in which one or more carbon atom pairs are bonded via -O-, -NR-, - S-, -S (= O) - or -SO ₂ -, where R is hydrogen or C ₁ -C ₁₀ - (preferably C ₁ -C ₄ ) -alkyl. Preferred such groups are alkoxyalkyl groups, more preferably C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl groups.

“C ₂ -C ₁₀ alkenyl” as used in the present invention means straight or branched chain hydrocarbon chains that contain from 2 to 10 carbon atoms and one or more carbon-carbon double bonds. A preferred “C ₂ -C ₁₀ alkenyl” is “C ₂ -C ₄ alkenyl."

“5-, 6- or 7-membered carbocyclic ring" as used in the present invention means a carbocyclic group containing from 5 to 7 ring carbon atoms, cycloaliphatic, such as C ₅ -C ₇ -cycloalkyl, or aromatic, such as phenyl, which may be substituted by one or more, usually one or two C ₁ -C ₄ alkyl groups.

“C ₅ -C ₇ cycloalkyl” as used in the present invention means cycloalkyl containing from 5 to 7 ring carbon atoms, for example cyclopentyl, cyclohexyl or cycloheptyl, any of which may be substituted by one or more, usually one or two C ₁ -C ₄ -alkyl groups.

“C ₁ -C ₁₀ alkoxy group” as used in the present invention means a straight or branched chain alkoxy group which contains from 1 to 10 carbon atoms. A preferred C ₁ -C ₁₀ alkoxy group is a C ₁ -C ₄ alkoxy group.

“C ₁ -C ₁₀ -alkoxycarbonyl” as used in the present invention means a C ₁ -C ₁₀ alkoxy group as defined above in the present invention, via its oxygen atom, bonded to a carbonyl group.

“C ₆ -C ₁₀ Aryl” as used in the present invention means a monovalent carbocyclic aromatic group which contains from 6 to 10 carbon atoms and which may be, for example, a monocyclic group such as phenyl or a bicyclic group such as naphthyl . A preferred C ₆ -C ₁₀ aryl is C ₆ -C ₈ aryl, more preferably phenyl.

A “4-10 membered heterocyclic ring containing at least one ring atom of nitrogen, oxygen or sulfur” when used in the present invention may be, for example, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, tetrazole, thiadiazole, oxazole, isoxazole , thiophene, thiazole, isothiazole, oxadiazole, pyridine, pyrazine, pyridazine, pyrimidine, piperidine, piperazine, triazine, oxazine, morpholine, quinoline, isoquinoline, naphthyridine, indane or indene. Preferred heterocyclic rings include thiazole, pyrrolidine, piperidine, azacyclopentane and isoxazole.

In the present description and the following claims, unless the context indicates otherwise, the word “includes” or its variants, such as “including”, should be understood as including the indicated integer or stage, or a group of integers or stages, but not an exception any other integer or stage, or group of integers or stages.

Preferred compounds of formula I include those in which

R ⁸ , R ⁹ and R ^{10 are} all H, R ¹ is OH, R ² and R ^{3 are} all H and

(i) R ^x and R ^{y are} both —CH ₂ -, and R ⁴ and R ^{7 are} all CH ₃ O—, and R ⁵ and R ^{6 are} all H;

(ii) R ^x and R ^{y are} both —CH ₂ -, and R ⁴ and R ^{7 are} all H, and R ⁵ and R ^{6 are} all CH ₃ CH ₂ -;

(iii) R ^x and R ^{y are} both —CH ₂ -, and R ⁴ and R ^{7 are} all H, and R ⁵ and R ^{6 are} all CH ₃ -;

(iv) R ^x and R ^{y are} both —CH ₂ -, and R ⁴ and R ^{7 are} all CH ₃ CH ₂ -, and R ⁵ and R ^{6 are} all H;

(v) R ^x and R ^{y are} both —CH ₂ -, and R ⁴ and R ^{7 are} all H, and R ⁵ and R ^{6 are} together

- (CH ₂ ) ₄ -;

(vi) R ^x and R ^{y are} both —CH ₂ -, and R ⁴ and R ^{7 are} all H, and R ⁵ and R ^{6 are} together

-O (CH ₂ ) ₂ O-;

(vii) R ^x and R ^{y are} both —CH ₂ -, and R ⁴ and R ^{7 are} all H, and R ⁵ and R ^{6 are} all CH ₃ (CH ₂ ) ₃ -;

(viii) R ^x and R ^{y are} both —CH ₂ -, and R ⁴ and R ^{7 are} all H, and R ⁵ and R ^{6 are} all CH ₃ (CH ₂ ) ₂ -;

(ix) R ^x and R ^{y are} both - (CH ₂ ) ₂ -, R ⁴ , R ⁵ , R ⁶ and R ^{7 are} all H; or

(x) R ^x and R ^{y are} both —CH ₂ -, and R ⁴ and R ^{7 are} all H, and R ⁵ and R ^{6 are} all CH ₃ OCH ₂ -.

Preferred compounds of formula I include the following:

8-hydroxy-5- [1-hydroxy-2- (indan-2-ylamino) ethyl] -1H-quinolin-2-onglycolate, 5- [2- (5,6-dimethoxyindan-2-ylamino) -1 -hydroxyethyl] -8-hydroxy-1H-quinolin-2-onglycolate, 5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-3-methyl-1H-quinoline- 2-onglycolate, 5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-methoxymethoxy-6-methyl-1H-quinolin-2-onglycolate, 5- [2- (5, 6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-6-methyl-1H-quinolin-2-onglycolate, 8-hydroxy-5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -3,4-dihydro-1H-quinolin-2-onglycolate, 5 - [(R) -2- (5,6-diethyl-2-methylindan-2-ylamino) -1-hydroxyethyl ] -8-hydroxy-1H-quinolin-2-onglycolate, (S) -5- [2- (4,7-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2- onhydrochloride glycolate; 5 - [(R) -1-hydroxy-2- (6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino) ethyl] -8-hydroxy-1H-quinolin-2-onhydrochloride glycolate, (R ) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onmaleate glycolate, (R) -5- [2- (5,6- diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onhydrochloride glycolate, (R) -8-hydroxy-5 - [(S) -1-hydroxy-2- (4,5, 6,7-tetramethylindan-2-ylamino) -ethyl] -1H-quinolin-2-onglycolate, 8-hydroxy-5 - [(R) -1-hydroxy-2- (2-methylindan-2-ylamino) ethyl ] -1H-quinolin-2-onglycolate, 5- [2- (5,6-diethylindan-2-ylamino) ethyl] -8-hydroxy-1H-quinolin-2-onglycolate, 8-hydroxy-5 - [( R) -1-hydrox -2- (2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] naphthalene-2-ylamino) ethyl] -1H-quinolin-2-glycolate, 5 - [( S) -2- (2,3,5,6,7,8-hexahydro-1H-cyclopenta- [b] naphthalene-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onglycolate , 8-hydroxy-5- [1-hydroxy-2- (indan-2-ylamino) ethyl] -1H-quinolin-2-one-acetate, 5- [2- (5,6-dimethoxyindan-2-ylamino) - 1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one-acetate, 5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-3-methyl-1H-quinoline -2-onacetate, 5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-methoxymethoxy-6-methyl-1H-quinolin-2-oneacetate, 5- [2- (5 , 6-diethylindan-2-ylamino) -1-hydr xyethyl] -8-hydroxy-6-methyl-1H-quinolin-2-one-acetate, 8-hydroxy-5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -3,4-dihydro -1H-quinolin-2-one-acetate, 5 - [(R) -2- (5,6-diethyl-2-methylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one-acetate , (S) -5- [2- (4,7-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onhydrochloride acetate, 5 - [(R) -1-hydroxy- 2- (6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino) ethyl] -8-hydroxy-1H-quinolin-2-onhydrochloride acetate, (R) -5- [2- (5.6 -diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onmaleate acetate, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl ] -8-hydroxy-1H-quinolin-2-onhydrochloride acetate, (R) -8-hydroxy-5 - [(8) -1-hydroxy-2- (4,5,6,7-tetramethylindan-2-ylamino) - ethyl] -1H-quinolin-2-one-acetate, 8-hydroxy-5 - [(R) -1-hydroxy-2- (2-methylindan-2-ylamino) -ethyl] -1H-quinolin-2-one-acetate, 5 - [2- (5,6-diethylindan-2-ylamino) ethyl] -8-hydroxy-1H-quinolin-2-one-acetate, 8-hydroxy-5 - [(R) -1-hydroxy-2- (2 -methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] naphthalene-2-ylamino) ethyl] -1H-quinolin-2-one-acetate, 5 - [(S) -2- (2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] naphthalene-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one-acetate, 8-hydroxy-5 - [1-hydroxy-2- (indan-2-ylamino) ethyl] -1H-quinolin-2-one xinafoate, 5- [2- (5,6-dimethoxyindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onxsinafoate, 5- [2- (5,6-diethylindane-2- ilamino) -1-hydroxyethyl] -8-hydroxy-3-methyl-1H-quinolin-2-onxsinafoate, 5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-methoxymethoxy- 6-methyl-1H-quinolin-2-onxsinafoate, 5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-6-methyl-1H-quinolin-2-onxsinafoate, 8-hydroxy-5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -3,4-dihydro-1H-quinolin-2-onxsinafoate, 5 - [(R) -2- ( 5,6-diethyl-2-methylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onxsinafoate, (S) -5- [2- (4,7-diethyl dan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onhydrochloridexynafoate, 5 - [(R) -1-hydroxy-2- (6,7,8,9-tetrahydro-5H- benzocyclohepten-7-ylamino) ethyl] -8-hydroxy-1H-quinolin-2-onhydrochloridexynafoate, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8- hydroxy-1H-quinolin-2-onmaleatexynafoate, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onhydrochloridexynafoate, (R ) -8-hydroxy-5 - [(S) -1-hydroxy-2- (4,5,6,7-tetramethylindan-2-ylamino) ethyl] -1H-quinolin-2-onxsinafoate, 8-hydroxy- 5 - [(R) -1-hydroxy-2- (2-methylindan-2-ylamino) ethyl] -1H-quinolin-2-onxsinafoate, 5- [2- (5,6-die tilindan-2-ylamino) ethyl] -8-hydroxy-1H-quinolin-2-onxsinafoate, 8-hydroxy-5 - [(R) -1-hydroxy-2- (2-methyl-2,3,5, 6,7,8-hexahydro-1H-cyclopenta [b] naphthalene-2-ylamino) ethyl] -1H-quinolin-2-onxsinafoate, 5 - [(S) -2- (2,3,5,6, 7,8-hexahydro-1H-cyclopenta [b] naphthalen-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onxsinafoate, 8-hydroxy-5- [1-hydroxy-2- ( indan-2-ylamino) ethyl] -1H-quinolin-2-onhydromalonate, 5- [2- (5,6-dimethoxyindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2- onhydromalonate, 5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-3-methyl-1H-quinolin-2-onhydromalonate, 5- [2- (5,6- diethylindane -2-ylamino) -1-hydroxyethyl] -8-methoxymethoxy-6-methyl-1H-quinolin-2-onhydromalonate, 5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8 -hydroxy-6-methyl-1H-quinolin-2-onhydromalonate, 8-hydroxy-5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -3,4-dihydro-1H-quinoline -2-onhydromalonate, 5 - [(R) -2- (5,6-diethyl-2-methylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onhydromalonate, (S) -5- [2- (4,7-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onhydrochloride hydromalonate, 5 - [(R) -1-hydroxy-2- (6 , 7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino) ethyl] -8-hydroxy-1H-quinolin-2-onhydrochloride dihydromalonate, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onmaleate hydromalonate, (R) -5- [2- ( 5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onhydrochloridehydromalonate, (R) -8-hydroxy-5 - [(S) -1-hydroxy-2- ( 4,5,6,7-tetramethylindan-2-ylamino) ethyl] -1H-quinolin-2-onhydromalonate, 8-hydroxy-5 - [(R) -1-hydroxy-2- (2-methylindan-2- amylamino) ethyl] -1H-quinolin-2-onhydromalonate, 5- [2- (5,6-diethylindan-2-ylamino) ethyl] -8-hydroxy-1H-quinolin-2-onhydromalonate, 8-hydroxy- 5 - [(R) -1-hydroxy-2- (2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] naphthalene-2-ylamino) ethyl] -1H- quinol n-2-onhydromalonate and 5 - [(S) -2- (2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] naphthalene-2-ylamino) -1-hydroxyethyl] -8- hydroxy-1H-quinolin-2-onhydromalonate.

Particularly preferred compounds of formula I are compounds of formula II

in which A is selected from the group consisting of hydrosuccinate, fumarate, hippurate, mesylate, hydrosulfate, hydrotartrate, hydrochloride, hydrobromide, formate, esylate, tosylate, glycolate, acetate, xinafoate and hydromalonate, namely (R) -5- [2- ( 5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onhydrosuccinate, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1 -hydroxyethyl] -8-hydroxy-1H-quinolin-2-onfumarate, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin- 2-hippurate, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onmesylate, (R) -5- [2 - (5,6-die tilindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onhydrosulfate, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] - 8-hydroxy-1H-quinolin-2-onhydrotartrate, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onhydrochloride, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onhydrobromide, (R) -5- [2- (5, 6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onformate, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl ] -8-hydroxy-1H-quinolin-2-oneesylate, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2- ont osilate, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-glycolate, (R) -5- [2- ( 5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one-acetate, (R) -5- [2- (5,6-diethylindan-2-ylamino) -1 -hydroxyethyl] -8-hydroxy-1H-quinolin-2-onxsinafoate and (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin- 2-onhydromalonate.

The free form of the compounds of formula I can be obtained by the methods described in the application WO 2000/075114, the contents of which are incorporated into this invention by reference. Compounds of formula I are prepared by reacting the free base with an appropriate acid or by a similar procedure as described in the examples, by methods known in the art for preparing addition salts with acids from secondary amines. If A is hydrosuccinate, fumarate, hippurate, mesylate, hydrosulfate, hydrotartrate, hydrochloride, hydrobromide, formate, esylate or tosylate, then the corresponding acid is succinic acid, fumaric acid, hippuric acid, methanesulfonic acid, sulfuric acid, (+) - L- tartaric acid, hydrochloric acid, hydrobromic acid, formic acid, ethanesulfonic acid and p-toluenesulfonic acid, respectively. If A is glycolate, then the glycolates of the present invention are prepared by reacting the free base with glycolic acid or by a similar procedure as described in the examples, by methods known in the art for preparing addition salts with glycolic acid from secondary amines. If A denotes acetate, then the acetates of the present invention are prepared by reacting the free base with acetic acid or by a similar procedure as described in the examples, by methods known in the art for the preparation of acetic acid addition salts from secondary amines. If A denotes xinafoate, then the xinafoates of the present invention are prepared by reacting the free base with 1-hydroxy-2-naphthoic acid or by a similar procedure as described in the examples, by methods known in the art for preparing addition salts with 1-hydroxy-2-naphthoic acid from secondary amines. If A denotes hydromalonate, the tohydromalonates of the present invention are prepared by reacting the free base with malonic acid or by a similar procedure as described in the examples, by methods known in the art for preparing addition salts with malonic acid from secondary amines.

A second aspect of the present invention is a pharmaceutical composition comprising, as an active ingredient, an effective amount of a compound of formula I, optionally together with a pharmaceutically acceptable carrier. Preferably, the composition is in a respirable form.

A third aspect of the present invention is the use of a compound of formula I for the preparation of a medicament for the treatment of inflammatory or obstructive airway disease.

A fourth aspect of the present invention is a process for preparing a compound of formula I, comprising reacting the free base with an appropriate acid.

In accordance with this, the method proposed in the present invention includes:

(i) to obtain compounds of formula I, in which A denotes hydrosuccinate, the interaction of the free base with succinic acid;

(ii) to obtain compounds of formula I, in which A denotes a fumarate, the interaction of the free base with fumaric acid;

(iii) to obtain compounds of formula I in which A is hippurate, the interaction of the free base with hippuric acid;

(iv) to obtain compounds of formula I, in which A denotes a mesylate, the interaction of the free base with methanesulfonic acid;

(v) for the preparation of compounds of formula I, wherein A is hydrosulfate, reacting the free base with sulfuric acid;

(vi) to obtain compounds of formula I, in which A denotes hydrotartrate, the interaction of the free base with (+) - L-tartaric acid;

(vii) to obtain compounds of formula I, in which a denotes hydrochloride, the interaction of the free base with hydrochloric acid;

(viii) to prepare compounds of formula I in which A is hydrobromide, reacting the free base with hydrobromic acid;

(ix) to obtain compounds of formula I, in which A denotes formate, the interaction of the free base with formic acid;

(x) for the preparation of compounds of formula I in which A is an esilate, reacting the free base with ethanesulfonic acid;

(xi) to obtain compounds of formula I in which A is tosylate, the interaction of the free base with p-toluenesulfonic acid;

(xii) to obtain compounds of formula I, in which A denotes glycolate, the interaction of the free base with glycolic acid;

(xiii) to obtain compounds of formula I, in which a denotes acetate, the interaction of the free base with acetic acid;

(xiv) to obtain compounds of formula I in which A is xinafoate, reacting the free base with 1-hydroxy-2-naphthoic acid; or

(xv) to obtain compounds of formula I, in which A denotes hydromalonate, the interaction of the free base with malonic acid.

The compounds of formula I below in the present invention are alternatively referred to as “the agents of the present invention”, have good agonistic activity towards the β ₂ -adrenoreceptor and are useful as medicaments. Agonistic activity against β ₂ , the onset of exposure, and the duration of exposure of the agents of the present invention can be investigated in vitro using a guinea pig trachea strip according to the procedure described in RAColeman and A.T. Nials, J. Pharmacol. Methods (1989), 21 (1), 71-86. The ability to bind and selectivity for β ₂ -adrenoreceptor compared to β ₁ -adrenoreceptor can be studied by the classical method for studying the degree of binding to a membrane filter described in Current Protocols in Pharmacology (SJEnna (editor-in-chief) et al. John Wiley & Son, Inc, 1998), or by determining cAMP (cyclic adenosine monophosphate) in cells expressing a β ₂ or β ₁ adrenergic receptor according to the procedure described in publication by B. January et al, British J. Pharmacol. 123: 701-711 (1998).

The funds proposed in the present invention are usually characterized by a rapid onset of exposure and have a long-term stimulating effect on the β ₂ -adrenoreceptor. Typically, they have Ki (β ₂ ) values of about 0.1 to 1000 nM, a duration of exposure of about 1 to more than 12 hours, or even 24 hours, and have a selectivity for binding to the β ₂ -adrenoreceptor that exceeds binding selectivity for β ₁ -adrenoreceptor 1.5-500 times.

Given their agonistic activity against β ₂ agents proposed in the present invention are suitable for use in the treatment of any pathological condition that is prevented or alleviated by activation of β ₂ -adrenoreceptor. Due to their prolonged selective agonistic activity with respect to β ₂ , the agents of the present invention are useful for relaxing the smooth muscles of the bronchi and weakening bronchostenosis. The attenuation of bronchostenosis can be investigated using models such as plethysmographic in vivo models described in publications by Chong et al, J. Pharmacol. Toxicol. Methods 1998, 39, 163-168, Hammelmann et al, Am. J. Respir. Crit. Care Med., 1997, 156, 766-775, and similar models. Therefore, the agents of the present invention are useful for treating obstructive or inflammatory diseases of the respiratory tract. Due to their prolonged exposure, the agents of the present invention can be administered once a day in the treatment of such diseases. In another aspect, the agents of the present invention typically exhibit characteristics indicative of a low incidence of side effects commonly associated with β ₂ agonists, such as tachycardia, tremor and dysphoria, therefore such agents are suitable for use on demand treatment ( emergency), as well as prophylactic treatments for obstructive or inflammatory diseases of the respiratory tract.

The corresponding maleate of the compound of formula II, namely (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onmaleate, has been successfully studied in Clinic for the treatment of asthma and chronic obstructive pulmonary disease.

Other salts have been studied to solve these problems associated with the preparation of a compound for administration by inhalation, or at least to find a suitable alternative to maleates.

According to the invention, it was unexpectedly found that the compounds of formula I have good crystallinity and retain a minimal residual amount of solvent. They are poorly soluble in ethanol, which is especially useful for inhalation preparations containing ethanol. The agents of the present invention can prevent or minimize coughing that occurs in some patients after administration, especially the first administration of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1- hydroxyethyl] -8-hydroxy-1H-quinolin-2-onmaleate. The glycolates of formula I, including (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onglycolate, are found to have good crystallinity and are waterless. They are mostly non-hygroscopic and have a clear melting peak at 140-250 ° C. They are especially stable before and after micronization, with and without the use of inert fillers and with and without the use of wetting. They are poorly soluble in ethanol, which is especially useful for inhalation preparations containing ethanol. They are also characterized by a clear melting onset temperature, do not contain residual solvents, have good crystallinity and their crystalline form does not change after equilibration for 1 day at 25 ° C in water, ethanol and isopropanol. The acetates of formula I, including (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one acetate, are found to have good crystallinity and keep the minimum residual amount of solvent. They are mostly non-hygroscopic and have a clear melting peak at 140-250 ° C. They are especially stable before and after micronization, with and without the use of inert fillers and with and without the use of wetting. They are poorly soluble in ethanol, which is especially useful for inhalation preparations containing ethanol. They are also characterized by a clear melting onset temperature, do not contain residual solvents and their crystalline form does not change after equilibration for 1 day at 25 ° C in water, ethanol and isopropanol. The xinafoates of formula I, including (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onxsinafoate, are found to have good crystallinity and keep the minimum residual amount of solvent. They are mostly non-hygroscopic and have a clear melting peak at 140-250 ° C. They are especially stable before and after micronization, with and without the use of inert fillers and with and without the use of wetting. They are poorly soluble in ethanol, which is especially useful for inhalation preparations containing ethanol. They are also characterized by a clear melting onset temperature, do not contain residual solvents and their crystalline form does not change after equilibration for 1 day at 25 ° C in water, ethanol and isopropanol. The malonates of formula I, including (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-onhydromalonate, have been found to have good crystallinity and keep the minimum residual amount of solvent. They are mostly non-hygroscopic and have a clear melting peak at 140-250 ° C. They are especially stable before and after micronization, with and without the use of inert fillers and with and without the use of wetting. They are poorly soluble in ethanol, which is especially useful for inhalation preparations containing ethanol. They are also characterized by a clear melting onset temperature, do not contain residual solvents and their crystalline form does not change after equilibration for 1 day at 25 ° C in water, ethanol and isopropanol.

Due to their anti-inflammatory activity, the agents of the present invention are useful for the treatment of inflammatory pathological conditions, preferably inflammatory or obstructive respiratory diseases. Treatment in the context of the present invention may be symptomatic or prophylactic.

Inflammatory or obstructive respiratory diseases to which the present invention is applicable include asthma of any type or genesis, including hereditary asthma (non-allergic) and acquired (allergic) asthma, mild, moderate, severe asthma, bronchial asthma, tension asthma, occupational asthma and asthma, caused by a bacterial infection. Asthma treatment should also be understood as including treatment of subjects, for example, under 4 or 5 years of age who have wheezing and are diagnosed or can be diagnosed with “infant bronchitis,” an established category of patients of great concern to physicians who currently often referred to as suffering from incipient asthma or early asthma. (For convenience, this particular asthmatic condition is often referred to as “infant bronchitis syndrome”).

Prophylactic effectiveness in the treatment of asthma is manifested in the form of a reduced frequency or severity of a symptomatic attack, for example, an acute asthmatic or bronchoconstrictive attack, improved lung function, or improved airway hyperresponsiveness. It can also manifest itself as a decrease in the need for another, symptomatic, treatment, i.e. in the treatment of a symptomatic attack or intended to limit or suppress a symptomatic attack when it occurs, for example, anti-inflammatory (e.g., corticosteroids) or bronchodilator. Prophylactic efficacy in the treatment of asthma, in particular, may occur in subjects prone to “morning attacks”. A “morning attack” is an established asthmatic syndrome, common in a significant proportion of asthma sufferers and characterized by an asthma attack, occurring, for example, from about 4 to 6 in the morning, i.e. in a period of time significantly removed from the moment of the previous administration of a symptomatic anti-asthma agent.

Other inflammatory or obstructive pathological conditions and diseases of the respiratory tract to which the present invention is applicable include acute lung injury (ARS), acute respiratory distress syndrome of adults (ARDS), chronic obstructive pulmonary disease, respiratory or lung disease (COPD, CHD, COPD) , including chronic bronchitis or associated dyspnea, emphysema, as well as an exacerbation of airway hyperresponsiveness resulting from treatment with another drug, in particular , Other means of inhalation therapy. The present invention also relates to the treatment of bronchitis of any type or genesis, including, for example, acute, peanut, catarrhal, croupous, chronic or purulent tuberculous bronchitis. Other inflammatory or obstructive airway diseases to which the present invention relates include pneumoconiosis (inflammatory, usually occupational, lung disease, often accompanied by airway obstruction, chronic or acute, and caused by repeated inhalation of dust) of any type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, poultry, siderosis, silicosis, tobaccoosis and byssinosis.

As regards their anti-inflammatory activity, in particular with respect to inhibiting the activation of eosinophils, the agents of the present invention are also useful for treating eosinophil-related disorders, for example eosinophilia, in particular respiratory tract related eosinophils (e.g., involving painful infiltration of tissue eosinophils lungs), including hypereosinophilia, because it affects the airways and / or lungs, as well as, for example, respiratory problems associated with eosinophils of diseases following or simultaneously with Leffler's syndrome, eosinophilic pneumonia, infection (in particular, multicellular) with parasites (including tropical eosinophilia), bronchopulmonary aspergillosis, nodose polyarteritis (including Cherge-Stros syndrome), eosinophilic granuloma and eosinophil-related disorders to the respiratory tract caused by a reaction to the drug.

The agents of the present invention are also useful for treating inflammatory pathological conditions of the skin, for example, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetiform dermatitis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigloid, bullous pemphigloid, , congenital bullous epidermolysis and other inflammatory pathological conditions of the skin.

The agents of the present invention can also be used to treat other diseases or pathological conditions, in particular diseases or pathological conditions including an inflammatory component, for example, to treat diseases and pathological conditions of the eyes, such as conjunctivitis, dry keratoconjunctivitis and spring conjunctivitis, diseases, affecting the nose, including allergic rhinitis, joint diseases such as rheumatoid arthritis, and inflammatory bowel diseases such as ulcerative coli t and Crohn's disease.

In addition, the agents of the present invention can also be used to treat cystic fibrosis, pulmonary hypertension and pulmonary fibrosis.

The agents of the present invention are also useful as jointly used therapeutic agents for use in conjunction with other medicinal substances for treating respiratory diseases, preferably anti-inflammatory, bronchodilating, antihistamines / anti-allergic or antitussive drugs, preferably for treating obstructive or inflammatory diseases of the respiratory tract, such as those indicated in above in the present invention, for example, as agents that enhance the therapeutic activity of such drugs, or as agents that reduce the required dose or weaken the possible side effects of such drugs. The agents of the present invention may be mixed with one, two, three or more other drugs in a fixed pharmaceutical composition or may be administered separately, before, simultaneously or after another drug substance (s).

Such anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, cyclesonide, dexamethasone, flunisolide, mometasonefuroate and triamcinolone, as well as the compounds described in WO 02/006166, WO 02/006166 WO 02/100879 or WO 02/00679, especially as described in Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99, and 101 (including salts or derivatives thereof, such as sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates, and, if possible, hydrates), and non-steroidal steroid agonists, such as those described in WO 00/00531, WO 02/10143, WO 03/082280, WO 03/082787, WO 03/104195, WO 04/005229 ; dopamine agonists such as bromocriptine, carbegolin, alpha-dihydroergocriptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, thalipexole, terguride and viosan (including their pharmaceutically acceptable salts, such as hydrochloric acid, hydrochloric acid, hydrobromic acid, hydrobromic acid methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid); LTB4 antagonists such as BIIL 284, CP-195543, DPC11870, LTB4 ethanolamide, LY 293111, LY 255283, CGS025019C, CP-195543, ONO-4057, SB 209247, SC-53228 and described in US 5451700 and WO 04/1087; LTD4 antagonists such as montelukast, pranlukast, zafirlukast, accolate, SR2640, Wy-48,252, ICI 198615, MK-571, LY-171883, Ro 24-5913 and L-648051; dopamine receptor agonists such as cabergoline, bromocriptine, ropinirole and 4-hydroxy-7- [2 - [[2 - [[3- (2-phenylethoxy) propyl] sulfonyl] ethyl] amino] ethyl] -2 (3H ) -benzothiazolone and its pharmaceutically acceptable salts (hydrochloride is Viozan® - AstraZeneca);

PDE4 inhibitors such as cilomilast (ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plow), arophylline (Almirall Prodesfarma), PD18965 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID (TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW- 4490 (Kyowa Hakko Kogyo), GRC 3886 (Oglemilast, Glenmark), WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/39544, WO 03/104204, WO 03/104205, WO 04/000814, WO 04/000839 and WO 04/005258 (Merck), WO 04/018450, WO 04/018451, WO 04/018457, WO 04 / 018465, WO 04/018431, WO 04/018449, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607, WO 04 / 037805, WO 04/063197, WO 04/103998, WO 04/111044, WO 05/012252, WO 05012253, WO 05/013995, WO 05/030212, WO 05/030725, WO 05/087744, WO 05/087745 WO 05/087749 and WO 05 / 090345 (including their physiologically acceptable acid addition salts, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid ); A2a agonists, such as those described in EP 409595A2, EP 1052264, EP 1241176, WO 94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451 , WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399 , WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462, WO 03/086408, WO 04/039762, WO 04/039766 WO 04/045618 and WO 04/046083; and A _2B adenosine receptor antagonists, such as those described in WO 02/42298 and WO 03/042214.

Such bronchodilator drugs include anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxytropium bromide, tiotropium salts, glycopyrrolate, CHF 4226 (Chiesi) and SVT-40776, as well as described in EP 424021, US 37143547, US 511717, US 511717 US 2005/182091, WO 01/04118, WO 02/00652, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/18422, WO 04/05285, WO 04/96800, WO 05/77361 and WO 06/48225.

Suitable bronchodilator drugs also include beta-2-adrenoreceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, prouterol and, preferably, formoterol, carmoterol, TA-2005, GSK159797 and their pharmaceutically acceptable salts the compounds described in EP 147719, EP 1440966, EP 1460064, EP 1477167, EP 1574501, JP 05025045, JP 2005187357, US 2002/0055651, US 2004/0242622, US 2004/0229904, US 2005/0133417, US 2005/5159448, US 2005/5159448, US 2005/171147, US 2005/182091, US 2005/182092, US 2005/209227, US 2005/256115, US 2005/277632, US 2005/272769, US 2005/239778, US 2005/215542, US 2005/215590, US 2006/19991, US 2006/58530, WO 93/18007, WO 99 / 64035, WO 01/42193, WO 01/83462, WO 02/66422, WO 02/70490, WO 02/76933, WO 03/24439, WO 03/42160, WO 03/42164, WO 03/72539, WO 03 / 91204, WO 03/99764, WO 04/16578, WO 04/16601, WO 04/22547, WO 04/32921, WO 04/33412, WO 04/37768, WO 04/37773, WO 04/37807, WO 04 / 39762, WO 04/39766, WO 04/45618 WO 04/46083, WO 04/80964, WO 04/087142, WO 04/89892, WO 04/108675, WO 04/108676, WO 05/33121, WO 05 / 40103, WO 05/44787, WO 05/58867, WO 05/65650, WO 05/66140, WO 05/70908, WO 05/74924, WO 05/77361, WO 05/90288, WO 05/92860, WO 05 / 92887, WO 05/90287, WO 05/95328, WO 05/102350, WO 06/56471, WO 06/74897 or WO 06/8173.

Suitable dual-acting anti-inflammatory and bronchodilator drugs include dual-acting beta-2 adrenergic receptor agonists / muscarinic antagonists, such as disclosed in US 2004/0167167, US 2004/0242622, US 2005/182092, US 2005/256114, US 2006 / 35933, WO 04/74246, WO 04/74812, WO 04/89892 and WO 06/23475.

Suitable antihistaminic / anti-allergic drug substances include acetaminophen, activastine, astemizole, azelastin, bamipin, cetirizine hydrochloride, dekskhlorferniramin, hlorfenoksamin, klemastinfumarat, desloratidine, dimenhydrinate, diphenhydramine, doxylamine, ebastine, emedastin, epinastine, feksofenadingidrohlorid, ketotifen, levotsetiridin, loratidine, meclizine, mizolastine , ferniramine, promethazine and tefenadine, as well as disclosed in JP 2004107299, WO 03/099807 and WO 04/026841 (including any pharmacologically acceptable acid addition salts thereof otami that may exist).

Combinations of the agents of the present invention with steroids, PDE4 inhibitors, or LTD4 antagonists are particularly suitable for use in treating asthma. While combinations of the agents of the present invention with anticholinergic or antimuscarinic agents, PDE4 inhibitors, LTB4 antagonists are particularly suitable for use in the treatment of COPD.

In accordance with the above, the present invention relates to a method for treating an inflammatory pathological condition, preferably an inflammatory or obstructive airway disease, which comprises administering to a subject in need thereof, preferably a human, an effective amount of a compound of formula I described above in the present invention. The present invention also relates to the use of a compound of formula I described above in the present invention for the manufacture of a medicament for the treatment of an inflammatory pathological condition, preferably an inflammatory or obstructive airway disease.

The agents of the present invention can be administered by any suitable route, for example, orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example, for the treatment of inflammatory or obstructive airways disease; nasal, for example, for the treatment of allergic rhinitis; topically on the skin, for example, for the treatment of atopic dermatitis; or rectally, for example, for the treatment of inflammatory bowel disease.

Accordingly, the present invention relates to a pharmaceutical composition comprising, as an active ingredient, a compound of formula I, optionally together with a pharmaceutically acceptable diluent or carrier. The present invention also relates to a pharmaceutical composition comprising, as an active ingredient, a compound of formula I and 1, 2, 3 or more anti-inflammatory, bronchodilating, antihistamines / anti-allergic or antitussive drugs, optionally together with a pharmaceutically acceptable diluent or carrier. Such compositions can be prepared using conventional diluents or inert fillers and techniques known in the art of preparing herbal preparations.

Suitable tablets can be obtained, for example, by mixing the active substance (s) with known inert excipients, for example, inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or delayed release agents such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also contain several layers.

Coated tablets can be prepared by coating onto cores prepared analogously to tablets, coating from substances commonly used to coat tablets, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core may also contain several layers to provide sustained release or to prevent incompatibilities. Similarly, to provide sustained release, a tablet coating may consist of several layers, possibly using the inert fillers mentioned above for tablets.

Syrups or elixirs containing the active substances or combinations thereof of the present invention may further comprise a sweetener, such as saccharin, cyclamate, glycerin or sugar, and a flavor enhancer, for example, a flavoring agent, such as vanillin or orange extract. They may also contain suspending agents or thickeners, such as sodium carboxymethyl cellulose, wetting agents, such as, for example, condensation products of fatty alcohols with ethylene rxide, or preservatives, such as p-hydroxybenzoates.

Capsules containing one or more active substances or combinations of active substances can, for example, be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packaging them in gelatin capsules.

Suitable suppositories can be prepared, for example, by mixing with carriers used for this purpose, such as neutral fats or polyethylene glycol or their derivatives.

Suitable inert excipients may be, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (e.g., oil fractions), vegetable oils (e.g., peanut or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerol), carriers such as, for example, powdered natural minerals (e.g. kaolin, clays, talc, chalk), powdered synthetic minerals (e.g. finely divided silicic acid and silicates), sugar (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulfite liquors, methyl cellulose, starch and polyvinyl pyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

If the composition is an aerosol preparation, it preferably contains, as a propellant, for example, hydrofluoroalkane (HFA), such as HFA134a or HFA227, or a mixture thereof, and may contain one or more cosolvents known in the art, such as ethanol ( up to 20 wt.%); and / or one or more surfactants, such as oleic acid or sorbitan trioleate; and / or one or more excipients, such as lactose. If the composition is a dry powder preparation, it preferably contains, for example, an agent of the present invention having particles up to 10 μm in diameter, optionally together with a diluent or carrier, such as lactose, having the desired particle size distribution, and a compound, which helps protect against degradation of the product due to moisture, for example magnesium stearate, usually 0.05-2.0% magnesium stearate. If the composition is a spray preparation, it preferably contains, for example, the agent of the present invention, dissolved or suspended in a diluent containing water, a co-solvent such as ethanol or propylene glycol, and a stabilizer, which may be a surfactant.

The present invention includes (A) the agent of the present invention in a respirable form, for example in the form of an aerosol or other sprayable composition, or in the form of an inhaled ground substance, for example in a micronized form, (B) a medication for inhalation, including the agent of the present invention in a respirable form; (C) a pharmaceutical product comprising the agent of the present invention in a respirable form instead of with an inhalation device; and (D) an inhalation device comprising the agent of the present invention in a respirable form.

A suitable device for the delivery of dry powder in capsule form is described in US 3991761 (including the AEROLIZER ™ device) or WO 05/113042, and suitable NDISP devices (a multi-dose dry powder inhalation device) include those described in WO 97/20589 (including the device CERTIHALER ™), WO 97/30743 (including the TWISTHALER ™ device) and WO 05/37353 (including the GYROHALER ™ device).

Dosages of the agents of the invention used in the practice of the invention will, of course, vary depending on, for example, the particular condition being treated, the desired effect and route of administration. Typically, daily doses suitable for administration by inhalation are from about 0.005 to 10 mg, and for oral administration, suitable daily doses are usually from about 0.05 to 100 mg.

The following examples illustrate the present invention.

EXAMPLES

Example 1

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one hydrosuccinate

Suspension of 2.312 g of the free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (5.890 mmol) and 0.695 g of amber acids (5.890 mmol) in 50 ml of isopropanol are heated to 80 ° C. The resulting almost clear solution was stirred at 80 ° C. After about 5 minutes, spontaneous crystallization occurs. The suspensions were allowed to cool slowly and it was stirred at room temperature for 18 hours. The salt was collected by filtration and washed with 7 ml of isopropanol. The crystals are dried at 70 ° C and about 10 mbar for 20 hours

Yield: 2.89 g of a white powder (96.3%)

Elemental analysis:

Calculated: 65.87% C; 6.71% H; 5.49% N; 21.93% O

Found: 65.49% C; 6.75% H; 5.56% N; 21.86% About

Example 2

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one fumarate

Suspension of 2.208 g of the free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (5.625 mmol) in 20 ml of methanol heated to 50 ° C. A solution of 0.326 g of fumaric acid (2.81 mmol) in 5 ml of methanol is added dropwise to the suspension over 10 minutes at a constant speed. The resulting solution was stirred at 50 ° C. Then, after about 10 minutes, spontaneous crystallization occurs. The suspension was allowed to cool and was stirred for 3 hours at room temperature. The mixture is filtered. The crystals are washed with 7 ml of methanol and dried first at 60 ° C and about 10 mbar for 20 hours and then at 60 ° C and about 1 mbar for 2 hours. Yield: 2.19 g of a white powder (86.4% )

Elemental analysis:

Calculated: 69.31% C; 6.71% H; 6.22% N; 17.76% About

Found: 67.69% C; 6.62% H; 6.35% N; 19.00% About

Example 3

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one hippurate

A suspension of 1.95 g of the free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (4.968 mmol) in 28 5 ml of methanol are heated to 45 ° C. At 45-50 ° C, 0.89 g of hippuric acid (4.968 mmol) are added in portions over 5 minutes. Then the resulting solution, almost free of undissolved substances, is stirred at 50 ° C. After about 5 minutes, spontaneous crystallization occurs. 15 ml of methanol are added to a very thick mixture. The suspension was allowed to cool and it was stirred at room temperature for 4 hours. The suspension was filtered and the salt was washed with 10 ml of methanol. The crystals are dried first at 70 ° C and about 10 mbar for 20 hours and then at 60 ° C and about 1 mbar for 4 hours. Yield: 2.15 g of a white powder (75.7%)

Elemental analysis:

Calculated: 69.33% C; 6.52% H; 7.35% N; 16.79% O

Found: 69.20% C; 6.67% H; 7.35% N; 16.85% About

Example 4

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one mesylate monohydrate

Suspension of 2.139 g of the free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (5.45 mmol) in 20 ml of water is heated to 70 ° C. A solution of 0.524 g of methanesulfonic acid (5.45 mmol) in 5 ml of water is added dropwise over about 2 minutes. At the end of the addition, the undissolved solid consists of aggregates. Then, at about 70 ° C. after about 10 minutes, a white suspension forms, which lends itself well to stirring. The mixture was slowly cooled to 25 ° C and stirred at room temperature for 20 hours. After filtration, the solid was washed with 5 ml of water and 10 ml of acetone and dried at 70 ° C and about 10 mbar for 20 hours. Yield: 2, 40 g of white powder (86.9%)

Elemental analysis:

Calculated: 59.27% C; 6.76% H; 5.53% N; 6.33% S; 22.11% O

Found: 59.24% C; 6.74% H; 5.46% N; 6.33% S; 22.36% O

Amount of water: 3.7% (w / w)

Example 5

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one hydrosulfate

2.063 g of the Free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (5.256 mmol) is dissolved at 50 ° C in 12 ml of acetic acid. A solution of 0.526 g of sulfuric acid 98% (5.256 mmol) in 4 ml of acetic acid is added dropwise over 5 minutes at a constant speed. The clear solution is allowed to cool. At about 35 ° C, spontaneous crystallization occurs. The suspension was stirred at room temperature for 18 hours and then filtered. The crystals are washed with 4 ml of acetic acid and 10 ml of ethyl acetate. The salt is dried first at 70 ° C and about 10 mbar for 20 hours and then at 60 ° C and about 1 mbar for 2 hours. Yield: 2.31 g of white powder (86.9%)

Elemental analysis:

Calculated: 58.76% C; 6.16% H; 5.71% N; 6.54% S; 22.83% O

Found: 57.22% C; 6.05% H; 5.31% N; 6.69% S; 24.55% O

Example 6

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one hydrotartrate

Suspension 2.0 g of the free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (5.10 mmol) in 14 ml of isopropanol is heated to 50 ° C. Then, a solution of 0.77 g of L (+) - tartaric acid (5.10 mmol) in 7.7 ml of isopropanol is added dropwise over about 2 minutes. The suspension was stirred at 50 ° C. for 15 hours. The white suspension was cooled to about 25 ° C. and filtered. The salt is washed with 10 ml of isopropanol and dried at 50 ° C / about 10 mbar for 18 hours and at 60 ° C / about 1 mbar for 2 hours. Yield: 2.33 g of white powder (84.27%)

Elemental analysis:

Calculated: 61.98% C; 6.32% H; 5.16% N; 26.54% O

Found: 59.02% C; 6.41% H; 5.47% N; 23.30% O

Example 7

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one hydrochloride

Suspension 3.78 g of the free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (9.63 mmol) in 36.5 ml of methanol is heated to 50 ° C. A solution of 0.949 g of hydrochloric acid 37% (9.63 mmol) in 10 ml of methanol is added dropwise over 15 minutes. The resulting clear solution was allowed to cool. At 40 ° C, spontaneous crystallization begins. The suspension was stirred at room temperature for 17 hours. After filtration, the salt was washed with 7 ml of methanol. The crystals are dried at 50 ° C / about 10 mbar for 16 hours and at 50 ° C and about 1 mbar for 2 hours. Yield: 2.33 g of a white powder (84.27%)

Elemental analysis:

Calculated: 67.20% C; 6.81% H; 6.53% N; 8.26% C1; 11.19% O

Found: 66.79% C; 6.88% H; 6.55% N; 7.99% CI; 11.81% O

Example 8

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one hydrobromide

Suspension 1.93 g of the free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (4.92 mmol) in 13.5 ml of methanol is heated to 50 ° C. A solution of 0.829 g of hydrobromic acid 48% (4.92 mmol) in 5 ml of methanol is added dropwise over 15 minutes. The resulting very thick suspension was diluted with 43 ml of methanol and allowed to cool. After stirring at room temperature for 3 hours, the precipitate was filtered off. The filtered precipitate was washed with 5 ml of methanol. The crystals are dried at 50 ° C / about 10 mbar for 16 hours at 50 ° C and about 1 mbar for 2 hours. Yield: 2.33 g of a white powder (84.27%)

Elemental analysis:

Calculated: 60.89% C; 6.17% H; 5.92% N; 16.88% Br; 10.14% O

Found: 60.55% C; 6.09% H; 6.00% N; 16.37% Br; 10.43% O

Example 9

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one formate

Suspension 2.00 g of the free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (5.1 mmol) in 15 ml of methanol is heated to 50 ° C. 0.24 g of formic acid (5.2 mmol) are added dropwise. The dropping funnel is washed with 5 ml of methanol. The resulting clear solution was allowed to cool slowly. At about 47 ° C, spontaneous crystallization begins. The mixture was stirred at about 25 ° C. for 15 hours and filtered. The filtered precipitate was washed with 4 ml of methanol. The salt is dried at 50 ° C / about 10 mbar for 20 hours and at 70 ° C and about 1 mbar for 3 hours. Yield: 1.77 g of a white powder (79.37%)

Elemental analysis:

Calculated: 68.47% C; 6.90% H; 6.39% N; 18.24% O

Found: 68.30% C; 6.96% H; 6.38% N; 18.46% O

Example 10

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one esilate

2.00 g of the Free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (5.1 mmol) at 50 ° C is dissolved in 8 ml of dimethyl sulfoxide. The solution is cooled to 25 ° C. 0.595 g of ethanesulfonic acid (5.4 mmol) is added dropwise over 5 minutes and the dropping funnel is washed with 1 ml of DMSO (dimethyl sulfoxide). Then, over about 30 minutes, 18 ml of water are added at a constant rate. The resulting thick suspension was diluted with 8 ml of water and stirred at room temperature overnight. The mixture was filtered and the solid was washed with 10 ml of water. The product is dried at 50 ° C / about 10 mbar for 3 hours and at 70 ° C and about 1 mbar for 3 hours

Yield: 1.56 g of a white powder, according to Karl Fischer: 3.2% w / w. H ₂ O

Elemental analysis: (in terms of monohydrate)

Calculated: 59.98% C; 6.97% H; 5.38% N; 6.16% S; 21.51% O

Found: 61.70% C; 6.73% H; 5.69% N; 6.36% S; 19.13% O

Example 11

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one tosylate

A mixture of 2.00 g of the free base (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (5.1 mmol) and 0.98 g of p-toluenesulfonic acid monohydrate (5.1 mmol) in 30 ml of ethyl acetate is heated to 60 ° C. During heating, the viscous yellow amorphous mass first turns into a white suspension, which lends itself well to stirring. The suspension was allowed to cool and was stirred at room temperature overnight. The crystals were collected by filtration and washed with ethyl acetate. The salt is dried at 50 ° C and about 10 mbar for about 20 hours. Yield: 2.73 g of an almost white powder (94.8%)

Elemental analysis:

Calculated: 65.94% C; 6.43% H; 4.96% N; 5.68% S; 17.00% About

Found: 64.51% C; 6.42% H; 5.01% N; 5.60% S; 18.60% About

Example 12

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one glycolate

A suspension of 2.075 g of the free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (5.286 mmol) in 25 ml of methanol heated to 50 ° C. A solution of 0.402 g of glycolic acid (5.286 mmol) in 5 ml of methanol is added dropwise over 7 minutes. The resulting clear solution was stirred at 50 ° C. After about 15 minutes, spontaneous crystallization occurs. The white suspension was allowed to cool to room temperature and was stirred overnight at about 25 ° C. After 18 hours, the salt is filtered off. The filtered precipitate was washed with 7 ml of methanol and dried first at 60 ° C and about 10 mbar for 20 hours and then at 60 ° C and about 1 mbar for 2 hours. Yield: 1.77 g of white powder (71.37 %).

Elemental analysis:

Calculated: 66.65% C; 6.88% H; 5.98% N; 20.49% O

Found: 66.46% C; 6.80% H; 6.19% N; 20.33% O

Example 13

X-ray Powder Examination of Salt

An X-ray diffraction pattern of the glycolate (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one obtained in accordance with Example 12 was obtained using SCINTAG ™ X-ray diffractometer with CuK alpha radiation source. The X-ray diffraction pattern thus obtained is shown in FIG. 1 and the following table I presents data for the reflection lines and the intensities of the most important lines.

TABLE I Diffraction lines and intensities for glycolates 2θ (°) Interplanar distances (Å) Relative intensity 2,8 31.28 S 5.7 15.39 m 12,2 7.22 m 14.5 6.10 m 15,2 5.84 L 16.8 5.27 L 17.4 5.08 L 18.3 4.82 L 19.2 4.62 L 19.7 4,51 L 20,4 4.35 L 21,4 4.14 L 23.3 3.82 M 25,4 3,50 L 26,4 3.38 L

An intense diffraction peak is observed in the PRRG spectrum at 2.8 °.

Example 14

Salt analysis using IR spectroscopy

The infrared Fourier spectrum of the glycolate (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one, obtained in accordance with example 12, removed in transmission using KBr (in a KBr tablet about 1.1 mm thick and weighing 302 mg) using a BRUKER OPTICS IFS-55 ™ infrared Fourier spectrometer (Fourier-X). The infrared Fourier spectrum thus obtained is shown in FIG. 2. The main IR bands are registered. The main bands of the infrared spectrum: 3169; 2965; 1657; 1599; 1552; 1491; 1431; 1390; 1298; 1226; 1088; 1061; 875; 829; 742; 699; 543 cm ^-1 .

Example 15

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one acetate

2.168 g of the Free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (5.523 mmol) and 1.17 g acetic acid (19.48 mmol) at 80 ° C is dissolved in 60 ml of isopropanol. The clear solution is allowed to cool slowly. At 35 ° C, spontaneous crystallization occurs. The suspension was stirred at room temperature for 17 hours and then filtered. The filtered precipitate was washed with 10 ml of isopropanol and dried at 60 ° C / about 10 mbar for 20 hours.

Yield: 2.123 g of white crystals (84.9%)

Elemental analysis:

Calculated: 69.01% C; 7.13% H; 6.19% N; 17.68% O

Found: 68.92% C; 6.98% H; 6.12% N; 17.67% O

Example 16

X-ray Powder Examination of Salt

An X-ray diffraction pattern of the (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one acetate obtained in accordance with Example 15 was obtained using SCINTAG ™ X-ray diffractometer with CuK alpha radiation source. The X-ray diffraction pattern thus obtained is shown in FIG. 3 and the table II below presents data for the reflection lines and the intensities of the most important lines.

TABLE II Diffraction lines and intensities for acetates 2θ (°) Interplanar distances (Å) Relative intensity 4.3 20.36 S 8.4 10.48 m 11,4 7.78 m 15.1 5.88 S 17.0 5.21 L 18.6 4.76 L 19.1 4.64 L 19.7 4.49 L 20.5 4.32 L

2θ (°) Interplanar distances (Å) Relative intensity 22.9 3.87 L 23.3 3.82 L 23.5 3.78 M 24.6 3.61 L 25.6 3.48 L 28.9 3.09 L 30.5 2.93 L

An intense diffraction peak is observed in the PRRG spectrum at 4.3 °.

Example 17

Salt analysis using IR spectroscopy

The infrared Fourier spectrum of the acetate (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one, obtained in accordance with example 15, removed in transmission using KBr (in a KBr tablet about 1.1 mm thick and 300 mg in weight) using a BRUKER OPTICS IFS-55 ™ infrared Fourier spectrometer (Fourier-X). The infrared Fourier spectrum obtained in this way is shown in Fig.4. The main bands of the IR spectrum are recorded. The main bands of the infrared spectrum: 3409; 2964; 1663; 1613; 1546; 1491; 1417; 1396; 1293; 1231; 1165; 1029; 873; 838; 816; 663 cm ^-1 .

Example 18

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one xinafoate

5.0 g of the free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (12.738 mmol) and 2, 40 g of 1-hydroxy-2-naphthoic acid (12.626 mmol) at 100 ° C are dissolved in 60 ml of n-butanol. The solution was allowed to cool. At 25 ° C, seed crystals are added and crystallization slowly occurs. The suspension was stirred at room temperature for 17 hours and then filtered. The crystals are washed with 10 ml of n-butanol and dried at 70 ° C and about 10 mbar for 20 hours.

Yield: 5.57 g of beige powder (76%).

Elemental analysis:

Calculated: 72.40% C; 6.25% H; 4.82% N; 16.53% O

Found: 72.16% C; 6.18% H; 4.81% N; 16.47% O

Example 19

X-ray powder analysis of the salt X-ray diffraction pattern of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one xenaphoate obtained in accordance with Example 18 was prepared using a SCINTAG ™ X-ray diffractometer with a CuK alpha radiation source. The X-ray diffraction pattern thus obtained is shown in FIG. 5 and Table III below presents data for reflection lines and intensities of the most important lines.

TABLE III X-ray diffraction lines and intensities 2θ (°) Interplanar distances (Å) Relative intensity 4.1 21.72 S 10.0 8.87 M 12,2 7.25 M 12.9 6.85 M 18.2 4.86 L 20.9 4.25 L 25.9 3.43 L

An intense diffraction peak is observed in the PRRG spectrum at 4.1 °.

Example 20

Salt analysis using IR spectroscopy

Infrared Fourier spectrum of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one xinafoate obtained in accordance with Example 18, removed in transmission using KBr (in a KBr tablet about 1.2 mm thick and weighing 305 mg) using a BRUKER OPTICS IFS-55 ™ infrared Fourier spectrometer (Fourier-X). The infrared Fourier spectrum obtained in this way is shown in Fig.6. The main bands of the IR spectrum: 2964; 1661; 1611; 1582; 1467; 1435; 1404; 1303; 1255; 1172; 1079; 1054; 829; 795; 773; 624; 537 cm ^-1 .

Example 21

Preparation of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one hydromalonate

Suspension 2.172 g of the free base of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one (5.533 mmol) and 0.576 g of malonic acids (5.533 mmol) in 25 ml of n-butanol are heated to 80 ° C. Upon heating, an oil is first formed, which crystallizes upon prolonged heating. The mixture was stirred at 80 ° C. for 15 minutes and then allowed to cool to room temperature. The suspension was stirred at room temperature for 18 hours. After filtration, the crystals were washed with 5 ml of n-butanol and 10 ml of acetone. The product was dried at 70 ° C and about 10 mbar for 20 hours. Yield: 2.62 g of white powder (95.28%)

Elemental analysis:

Calculated: 65.31% C; 6.50% H; 5.64% N; 22.55% O

Found: 65.21% C; 6.50% H; 5.75% N; 22.49% O

Example 22

X-ray Powder Examination of Salt

An X-ray diffraction pattern of the hydromalonate (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one obtained in accordance with Example 21 was obtained using SCINTAG ™ X-ray diffractometer with CuK alpha radiation source. The X-ray diffraction pattern thus obtained is shown in FIG. 7 and the table IV below presents data for the reflection lines and the intensities of the most important lines.

TABLE IV Diffraction lines and intensities for hydromalonates 2θ (°) Interplanar distances (Å) Relative intensity 5.2 17.03 S 10,4 8.53 L 13.3 6.67 S 14.2 6.21 m

2θ (°) Interplanar distances (Å) Relative intensity 15.7 5.64 M 16,0 5.54 L 16.7 5.31 L 19.3 4.60 M 20.3 4.36 L 21.0 4.23 M 21,4 4.15 L 21.7 4.09 L 22.6 3.92 M 25,4 3,50 L 25.8 3.45 L 26.3 3.38 M 26.7 3.33 L 28.7 3.11 L 29.8 2.99 L 32,4 2.76 L

An intense diffraction peak is observed in the PRRG spectrum at 13.3 °.

Example 23

Salt analysis using IR spectroscopy

The infrared Fourier spectrum of the hydromalonate of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one, obtained in accordance with example 21, removed using transmission using KBr (in a KBr tablet about 1.3 mm thick and weighing 303 mg) using a BRUKER OPTICS IFS-55 ™ infrared Fourier spectrometer (Fourier-X). The infrared Fourier spectrum thus obtained is shown in FIG. 8. The main bands of the infrared spectrum: 3306; 2964; 1644; 1604; 1563; 1484; 1426; 1387; 1317; 1272; 1154; 1051; 826; 758; 689 cm ^-1 .

Claims (7)

1. The compound of formula I

in the form of a salt in which W is a group of the formula

and A is acetate or xinafoate. 2. The compound according to claim 1 in crystalline form. 3. The compound according to claim 2, where the compound is a crystalline form of the acetate (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2 -one, which has a strong diffraction peak (2θ) when radiographing the sample at 4.3 °. 4. The compound according to claim 3, characterized by diffraction lines (2θ) during radiography of the sample at 4.3 °, 8.4 °, 11.4 °, 15.1 °, 17.0 °, 18.6 °, 19, 1 °, 19.7 °, 20.5 °, 22.9 °, 23.3 °, 23.5 °, 24.6 °, 25.6 °, 28.9 ° and 30.5 °. 5. The compound according to claim 2, where the compound is a crystalline form of (R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2 xinafoate -one, which has a strong diffraction peak (2θ) when radiographing the sample at 4.1 °. 6. The compound according to claim 5, characterized by diffraction lines (2θ) during radiography of the sample at 4.1 °, 10.0 °, 12.2 °, 12.9 °, 18.2 °, 20.9 ° and 25, 9 °. 7. A pharmaceutical composition having bronchodilator activity, comprising as an active ingredient the compound of claim 1 in an effective amount, optionally together with a pharmaceutically acceptable carrier.

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