KR20070017542A - Combinations comprising antimuscarinic agents and pde4 inhibitors - Google Patents

Abstract

in the form of (a) a PDE4 inhibitor and (b) a salt having an anion X which is a pharmaceutically acceptable anion of a monovalent or polyhydric acid, wherein (3R) -1-phenethyl-3- (9H-xanthene-9-carr A combination comprising an antagonist of M3 muscarinic receptor that is carbonyl) -1-azoniabicyclo [2.2.2] octane.

PDE4 inhibitors, anions, M3 muscarinic receptors, antimuscarinic agents, antagonists, silomilast, roflumilast, denbuphylline, tetomilast.

Description

COMBINATIONS COMPRISING ANTIMUSCARINIC AGENTS AND PDE4 INHIBITORS}

This application is incorporated by reference in Spanish Patent Application No. P200401312, filed May 31, 2004, PCT Patent Application No. PCT / EP2005 / 001969, filed February 24, 2005 and PCT patent, filed February 25, 2005 Priority is claimed from application numbers PCT / GB2005 / 000722 and PCT / GB2005 / 000740.

The present invention relates to novel combinations of certain antimuscarinic and PDE4 inhibitors and their use in respiratory disorders.

PDE4 inhibitors and antimuscarinic agents, particularly antagonists of the M3 muscarinic receptor, are two classes of drugs useful for the treatment of respiratory disorders such as asthma or chronic obstructive pulmonary disease (COPD).

Although PDE4 inhibitors and antimuscarin can be effective therapies, there is a clinical need for asthma and COPD therapies with a profile of potent, selective and beneficial actions.

It is known that both classes of drugs can be used in combination.

Combinations of drugs in which the active ingredient works through different physiological pathways are known to be useful for treatment. Frequently, therapeutic benefits arise because the combination can achieve a useful therapeutic effect using lower concentrations of each active ingredient. This can minimize the side effects of the drug. Thus, combinations may be formulated such that each active ingredient is present in subclinical concentrations in cells other than target disease cells. The combination is nonetheless effective for treatment in target cells that respond to both components.

Surprisingly, when one or more PDE4 inhibitors are used in combination with antimuscarin of formula (I), unexpected beneficial therapeutic effects can be observed in the treatment of inflammation or obstructive diseases of the airways. In view of this effect, the pharmaceutical combinations according to the invention can be used in smaller doses than in the case of the individual compounds used for monotherapy in a conventional manner. This reduces unwanted side effects such as may occur when PDE4 inhibitors or antimuscarin of formula (I) are administered alone.

The present invention thus comprises (a) a PDE4 inhibitor and (b) optionally an antagonist of the M3 muscarinic receptor of formula (I), in the form of their racemic compounds, their enantiomers, their diastereomers and mixtures thereof Provide a combination

Where:

B is a phenyl ring, a 5 to 10 membered heteroaromatic group containing one or more heteroatoms or naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo [1,3] dioxyl or biphenyl group ego;

R ¹ , R ² and R ³ are each independently a hydrogen atom or a halogen atom, or a hydroxy group, or phenyl, -OR ⁴ , -SR ⁴ , -NR ⁴ R ⁵ , -NHCOR ⁴ , -CONR ⁴ R ⁵ , A -CN, -N0 ₂ , -COOR ⁴ or -CF ₃ group, or a straight or branched lower alkyl group, which may be optionally substituted, for example with a hydroxy or alkoxy group, wherein R ⁴ and R ⁵ are each independently Or a hydrogen atom, a straight chain or branched lower alkyl group, or together an alicyclic ring; Or R ¹ and R ² together form an aromatic, alicyclic or heterocyclic ring,

n is an integer of 0 to 4;

A is -CH ₂ -,-CH = CR ⁶ -,-CR ⁶ = CH-, -CR ⁶ R ⁷ -,-CO-, -O-,-S-, -S (O)-, -S0 ₂ -Or -NR ⁶ -group, wherein R ⁶ and R ⁷ each independently represent a hydrogen atom, a straight chain or branched lower alkyl group or R ⁶ and R ⁷ together form an alicyclic ring;

m is an integer from 0 to 8, provided that m = 0 and A is not -CH _2- ;

p is an integer from 1 to 2 and the substitution at the azonia dicyclic (bicyclic) ring can be at the 2,3 or 4 position, including all possible configurations of asymmetric carbons;

D represents a group of formula i) or ii):

In which R ¹⁰ represents a hydrogen atom, a hydroxy or methyl group or a —CH ₂ 0H group;

R ⁸ is

를 나타내고

Indicates

R ⁹ is selected from alkyl groups of 1 to 7 carbon atoms, alkenyl groups containing 2 to 7 carbon atoms, alkynyl groups containing 2 to 7 carbon atoms, cycloalkyl groups of 3 to 7 carbon atoms, or Represents a group:

Wherein R ¹¹ represents a hydrogen or halogen atom, a straight or branched substituted or unsubstituted lower alkyl group, a hydroxy group, an alkoxy group, a nitro group, a cyano group, -CO ₂ R ¹² , -NR ¹² R ¹³ R ¹² and R ¹³ are the same or different and are selected from hydrogen and a straight or branched lower alkyl group

Q represents a single bond, -CH _2- , -CH ₂ -CH _2- , -0-, -0-CH _2- , -S-,-S-CH ₂ -or -CH = CH-;

X represents a pharmaceutically acceptable anion of monovalent or polyvalent acid.

Compounds of the present invention represented by formula (I) above, which may have one or more asymmetric carbons, include all possible stereoisomers. Single isomers and mixtures of isomers are within the scope of the present invention.

As used herein, an alkyl group is typically a lower alkyl group. Lower alkyl groups preferably contain 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon atoms. In particular such alkyl groups are preferably represented by propyl comprising methyl, ethyl, i-propyl or butyl comprising n-butyl, sec-butyl and tert-butyl groups. 1 to 7 carbon atoms-containing alkyl as referred to herein group may be group C _{1 -4} alkyl group or a straight-chain or branched pentyl, hexyl or heptyl, as described above.

Alkenyl groups having 2 to 7 carbon atoms as referred to herein are ethenyl or straight or branched groups such as straight or branched propenyl, butenyl, pentenyl, hexenyl or heptenyl. The double bond can be at any position in the alkenyl group, as in the terminal bond.

Alkynyl groups having 2 to 7 carbon atoms as referred to herein are straight or branched groups such as ethynyl, propynyl or straight chain or branched butynyl, pentynyl, hexynyl or heptynyl. The triple bond can be at any position in the alkynyl group as in the terminal bond.

The alkoxy groups mentioned herein are typically lower alkoxy groups, groups containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and the hydrocarbon chain is branched or straight chain. Preferred alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy and t-butoxy.

Alicyclic groups or rings referred to herein typically contain 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms, unless otherwise specified. Alicyclic rings of 3 to 6 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Aromatic rings as mentioned herein typically contain 5 to 14, preferably 5 to 10 carbon atoms. Examples of aromatic groups include cyclopentadienyl, phenyl and naphthalenyl.

The heterocyclic or heteroaromatic group referred to herein is a 5-10 membered group, such as a 5,6 or 7 membered group, typically containing one or more heteroatoms selected from N, S and O. Typically, there are 1, 2, 3 or 4 heteroatoms, preferably 1 or 2 heteroatoms. The heterocyclic or heteroaromatic group can be a single ring or two or more conjugated rings in which at least one ring contains heteroatoms. Examples of heterocyclic groups include piperidyl, pyrrolidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, imidazolyl, imidazolidinyl, pyrazolinyl, indolinyl, isoindolinyl , Pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, isoindolyl, indolyl, indazolyl, furinyl, quinolinyl, isoquinolyl, quinolyl, quinoxalinyl, quinazolinyl , Cynolinyl, putridinyl, quinuclidinyl, triazolyl, pyrazolyl, tetrazolyl and thienyl. Examples of heteroaromatic groups are pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, benzothiazolyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, furinyl , Quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cynolinyl, triazolyl and pyrazolyl.

As used herein, halogen atoms include fluorine, chlorine, bromine or iodine atoms, typically fluorine, chlorine or bromine atoms.

Examples of pharmaceutically acceptable anions of monovalent or polyvalent acids are anions derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or organic acids such as methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid or maleic acid. . Moreover, mixtures of the aforementioned acids can be used.

Preferably, the M3 antagonists according to the invention are those having the formula I, optionally in the form of their racemic compounds, their enantiomers, their diastereoisomers and mixtures thereof.

Where:

B is a phenyl ring, C ₄ to C ₈ containing one or more heteroatoms Heteroaromatic group or naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group;

Each of R ¹ , R ² and R ³ is independently a hydrogen atom or a halogen atom, or a hydroxy group, or phenyl, -OR ⁴ , -SR ⁴ , -NR ⁴ R ⁵ , -NHCOR ⁴ , -CONR ⁴ R ⁵ , —CN, —N0 ₂ , —COOR ⁴ or —CF ₃ group, or a straight or branched lower alkyl group, which may be optionally substituted with, for example, a hydroxy or alkoxy group, wherein R ⁴ and R ⁵ are each Independently represent a hydrogen atom, a straight or branched lower alkyl group or together form an alicyclic ring; Or R ¹ and R ² together form an aromatic, alicyclic or heterocyclic ring,

N is an integer from 0 to 4;

A is -CH ₂ -,-CH = CR ^6- , -CR ⁶ = CH-,-CR ⁶ R ⁷ -,-CO-, -O-,-S-, -S (O)-, -S0 _{A 2} -or -NR ⁶ -group, wherein R ⁶ and R ⁷ each independently represent a hydrogen atom, a straight chain or branched lower alkyl group, or R ⁶ and R ⁷ together form an alicyclic ring;

M is an integer from 0 to 8, provided that m = 0 and A is not -CH _2- ;

P is an integer from 1 to 2 and the substitution in the azonia dicyclic ring can be at the 2,3 or 4 position, including all possible configurations of the asymmetric carbon;

D represents a group of formula i) or ii):

In which R ¹⁰ represents a hydrogen atom, a hydroxy or a methyl group; R ⁸ and R ⁹ each independently represent

Wherein R ¹¹ represents hydrogen or a halogen atom or a straight or branched lower alkyl group and Q represents a single bond, -CH _2- , -CH ₂ -CH _2- , -0-,-O-CH _2- , -S-,- S-CH ₂ -or -CH = CH-;

X represents a pharmaceutically acceptable anion of a monovalent or polyvalent acid.

 Combinations comprising (a) PDE4 inhibitors and (b) antagonists of the M3 muscarinic receptor of Formula (I), optionally in the form of their racemic compounds, their enantiomers, their diastereomers and mixtures thereof Preferred embodiments of the invention.

Where:

B represents a phenyl group;

R ¹ , R ² and R ³ Represents a hydrogen atom

m is an integer from 1 to 3;

n is 0;

A is a group selected from -0- and -CH _2- ;

p is an integer from 1 to 2; Substitution in the azonia dicyclic ring may be at the 2,3 or 4 position, including all possible configurations of the asymmetric carbon;

-OC (O) D is 2-hydroxy-2,2-dithien-2-ylacetoxy, 9H-xanthene-9carbonyloxy and (2S) -2-cyclopentyl-2-hydroxy-2 -Thien-2-ylacetoxy;

X represents a pharmaceutically acceptable anion of monovalent or polyvalent acid.

More preferably, the M3 antagonists according to the invention are those having the formula (I), optionally in the form of their racemic compounds, their enantiomers, their diastereomers and mixtures thereof:

Wherein X represents a pharmaceutically acceptable anion of a monovalent or polyvalent acid.

The M3 antagonists of the present invention represented by formula (I) above, which may have one or more asymmetric carbons, include all possible stereoisomers. Single isomers and mixtures of isomers are within the scope of the present invention.

Of particular interest in accordance with the invention are enantiomers of formula 1a.

In the formula, X ⁻ may have the meaning mentioned above in the present application.

Particular preference is given to M3 antagonists in which the ester group, —OC (O) D, is attached to a ring containing a quaternary nitrogen atom at the 3 position.

The M3 antagonists described may optionally be used in the form of their pure enantiomers, mixtures thereof or their racemic compounds. Typically the carbon atoms carrying the -OC (O) D group have a (R) configuration.

3 (R)-(2-hydroxy-2,2-dithien-2-ylacetoxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane bromide, (3R) -1-Phenyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide and (3R) -3-[(2S)- One of 2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (2-phenoxyethyl) -1-azoniabicyclo [2.2.2] octane bromide Particular preference is given to being used as the M3 antagonist.

The present invention therefore provides (3R) in the form of (a) PDE4 inhibitors and (b) antagonists of M3 muscarinic receptors of formula (I), in particular in the form of salts with anions X, which are pharmaceutically acceptable anions of monovalent or polyvalent acids. A combination comprising an antagonist of M3 muscarinic receptor, which is -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane, is provided. Typically the antagonist of the M3 muscarinic receptor is (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide.

Typically the composition contains the active ingredients (a) and (b) which form part of a single pharmaceutical composition.

For the avoidance of doubt, the formula and term (3R) -1- phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane shown above dissociate Intact, partially dissociated or undissociated form, for example, salts of aqueous solutions. Other salts of the compound may exist in the form of solvates, ie hydrates, all of which are also within the scope of the present invention. Moreover, other salts and solvates of the compounds may exist in amorphous form or in the form of other polymorphs within the scope of the present invention.

(3R) -1-Pe in the form of (a) PDE4 inhibitors and (b) antagonists of M3 muscarinic receptors of formula (I) and in particular salts with anion X, which are pharmaceutically acceptable anions of monovalent or polyvalent acids Netyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane (especially (3R) -1-phenethyl-3- (9H-xanthene-9) Also provided is a product comprising an antagonist which is -carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide) and a combination for use simultaneously, separately or sequentially in the treatment of a human or animal patient. Formulation. Typically the product is for use simultaneously, separately or sequentially in the treatment of respiratory diseases that respond to M3 antagonism in human or animal patients.

The present invention further provides (a) PDE4 inhibitors and (b) for the manufacture of a medicament for use simultaneously, synergistically, or sequentially in the treatment of respiratory diseases in response to M3 antagonism in human or animal patients. (3R) -1-phenethyl-3- (9H-xanthene) in the form of a salt having an anion X, which is an antagonist of the M3 muscarinic receptor of formula (I) and in particular a pharmaceutically acceptable anion of monovalent or polyvalent acids -9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane (especially (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-a Antagonist of M3 muscarinic receptor, which is zonabicyclo [2.2.2] octane bromide).

(A) for the preparation of a medicament for use simultaneously, synergistically, individually or sequentially in combination with a PDE4 inhibitor for the treatment of a respiratory disease responsive to M3 antagonism in human or animal patients. (3R) -1-phenethyl-3- (9H-xanthene-9-car) in the form of an antagonist of the M3 muscarinic receptor of) and in particular a salt having an anion X which is a pharmaceutically acceptable anion of a monovalent or polyvalent acid. Bonyloxy) -1-azoniabicyclo [2.2.2] octane (especially (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [ Octene bromide) The use of antagonists of the M3 muscarinic receptor is also provided.

(b) (3R) -1-phenethyl-3- (9H) in the form of a antagonist of the M3 muscarinic receptor of formula (I) and in particular a salt with anion X, which is a pharmaceutically acceptable anion of monovalent or polyvalent acids Xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane (particularly (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy)- Concurrently with the antagonist of the M3 muscarinic receptor, 1-azoniabicyclo [2.2.2] octane bromide), in response to M3 antagonism in human or animal patients, in synergy, by individual or sequential co-administration Also provided is the use of (a) a PDE4 inhibitor for the manufacture of a medicament for use in the treatment of a respiratory disease.

The present invention also provides for the manufacture of a medicament for use in the treatment of a respiratory disease in response to M3 antagonism in human or animal patients by (a) co-administration, simultaneously or separately, with a PDE4 inhibitor, b) (3R) -1-phenethyl-3- (9H) in the form of a salt with an anion X, which is an antagonist of the M3 muscarinic receptor of formula (I) and in particular a pharmaceutically acceptable anion of monovalent or polyvalent acids Xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octene (especially (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy)- Provided is the use of an antagonist of M3 muscarinic receptor, 1-azoniabicyclo [2.2.2] octane bromide).

The present invention further provides a method of treating a human or animal patient suffering from or susceptible to respiratory disease responsive to M3 antagonism, wherein the method simultaneously, synergistically, individually or sequentially with an effective amount of (b) (3R) -1-phenethyl-3- (9H-xanthene) in the form of an antagonist of the M3 muscarinic receptor of formula (I) and in particular a salt with anion X, which is a pharmaceutically acceptable anion of monovalent or polyvalent acids -9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane (especially (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-a Administering an antagonist of the M3 muscarinic receptor, which is zona bicyclo [2.2.2] octane bromide, and (a) a PDE4 inhibitor.

Typically the respiratory disease is asthma, acute or chronic bronchitis, (lung) emphysema, chronic obstructive pulmonary disease (COPD), bronchial hypersensitivity or rhinitis, especially asthma or chronic obstructive pulmonary disease (COPD).

Preferably the patient is a human.

And (c) in association with a pharmaceutically acceptable carrier or diluent, comprising: (a) a PDE4 inhibitor; And (b) (3R) -1-phenethyl-3- () in the form of an antagonist of the M3 muscarinic receptor of formula (I) and in particular a salt with anion X, which is a pharmaceutically acceptable anion of monovalent or polyvalent acids. 9H-Xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane (especially (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) A pharmaceutical composition is provided comprising an antagonist of M3 muscarinic receptor, which is -1-azoniabicyclo [2.2.2] octane bromide).

The present invention also provides instructions for use simultaneously, synergistically, individually or sequentially in combination with (a) PDE4 inhibitors for the treatment of human or animal patients suffering from or susceptible to respiratory diseases responsive to M3 antagonism. (b) (3R) -1-phenethyl-3- (9H- in the form of an antagonist of the M3 muscarinic receptor of formula (I), in particular in the form of a salt having an anion X which is a pharmaceutically acceptable anion of a monovalent or polyvalent acid. Xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octene (particularly (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1 Some kits are provided that contain an antagonist of M3 muscarinic receptor, which is azoniabicyclo [2.2.2] octane bromide).

(b) (3R) -1-phenethyl-3- (9H-), which is in the form of a salt having an anion X, which is an antagonist of the M3 muscarinic receptor of formula (I), in particular pharmaceutically acceptable anions of monovalent or polyvalent acids. Xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octene (particularly (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1 Antagonist of M3 muscarinic receptor, azoniabicyclo [2.2.2] octane bromide, and for use in the treatment of respiratory diseases responsive to M3 antagonism simultaneously, in synergy, individually or sequentially (a) further provides a package comprising a PDE4 inhibitor.

Further provided are combinations, products, parts of kits or packages as described above, wherein such combinations, products, parts of kits or packages are intended for use simultaneously, individually or sequentially: (a) β2 agents, (b) Another active compound (c) selected from corticosteroids, (c) leukotriene D4 antagonists, (d) inhibitors of egfr-kinase, (e) p38 kinase inhibitors, and (f) NK1 receptor agonists. Typically the additional active compound (c) is selected from the group consisting of (a) β2 agonists and (b) corticosteroids.

The combination, product, part of the kit or package is (3R)-in the form of a salt with an anion X which is (b) an antagonist of the M3 muscarinic receptor of formula (I), in particular a pharmaceutically acceptable anion of a monovalent or polyvalent acid. 1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane (particularly (3R) -1-phenethyl-3- (9H-ch) An antagonist of M3 muscarinic receptor, which is santen-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide), and (a) a PDE4 inhibitor as an active compound alone It is an example.

B) M3 mousse of formula (I) without any other active compound, for the manufacture of a medicament for simultaneous or synergistic, separate or sequential use in the treatment of respiratory diseases that respond to M3 antagonism in human or animal patients. (3R) -1-Phenyl-3- (9H-xanthene-9-carbonyloxy)-, in the form of a salt with an anion X, which is an antagonist of a carin receptor, in particular a pharmaceutically acceptable anion of monovalent or polyvalent acids. 1-azoniabicyclo [2.2.2] Octane (particularly (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] The use of antagonists of M3 muscarinic receptors (octane bromide) and (a) PDE4 inhibitors is an embodiment of the invention.

Examples of PDE4 inhibitors to be used in the combination of the present invention are theophylline, drotaberine hydrochloride, silomilast, roflumilast, denbuphylline, rolipram, tetomilast, enpropylin, arophylline, sifamphylline, toffeill Last, filaminast, piclamyllast, (R)-(+)-4- [2- (3-cyclopentyloxy-4-methoxyphenyl) -2-phenylethyl] pyridine, mesopram, N- (3,5-dichloro-4-pyridinyl) -2- [1- (4-fluorobenzyl) -5-hydroxy-1H-indol-3-yl] -2-oxoacetamide, CDC-801 ( ex.Celgene), CC-1088 (ex. Celgene), Lilimilast, ONO-6126 (ex. Ono), CC-10004 (ex. Celgene), MN-001 (ex. Kyorin), KW-4490 (ex Kyowa Hakko), benafenthrin dimaleate, zardaverin, tolapentrin, 3- [3- (cyclopentyloxy) -4-methoxybenzyl] -6- (ethylamino) -8-isopropyl-3H -Purine hydrochloride, N- (3,5-dichloro-4-pyridinyl) -8-methoxyquinoline-5-carboxamide, 4- (3-chlorophenyl) -1,7-diethylpyrido [2 , 3-d] Rimidin-2 (1H) -one, N- [9-methyl-4-oxo-1 -phenyl-3,4,6,7-tetrahydropyrrolo [3,2,1-jk] [1,4 ] Benzodiazepin-3 (R) -yl] pyridine-4-carboxamide, 3,5-dichloro-4- [8-methoxy-2- (trifluoromethyl) quinolin-5-ylcarboxamido] pyridine -1-oxide, NIK-616 (ex. Nikken Chemicals), CDC-998 (ex. Celgene), Project PDE 4 (ex. Celltech), EHT-0202 (ex. ExonHit Therapeutics), 5 (S)-[3 -(Cyclopentyloxy) -4-methoxyphenyl] -3 (S)-(3-methylbenzyl) piperidin-2-one, ND-1251 (ex. Neuro3d), GRC-3886 (ex. Glenmark Pharmaceuticals ), Atizoram, fumapentrin, 4- [6,7-diethoxy-2,3-bis (hydroxymethyl) naphthalen-1-yl] -1- (2-methoxyethyl) pyridine-2 (1H ) -One, 2- [4- [6,7-diethoxy-2,3-bis (hydroxymethyl) naphthalen-1-yl] pyridin-2-yl] -4- (3-pyridyl) phthala Jin-1 (2H) -one hydrochloride, 1-ethyl-8-methoxy-3-methyl-5-propylimidazo [1,5-a] pyrido [3,2-e] pyrazine-4 (5H ) -One, 4- (3-bromophenyl) -1-ethyl-7-methyl-1,8 -Naphthyridin-2 (1H) -one, N- [9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo [3,2,1-jk] [1, 4] benzodiazepine-3 (R) -yl] pyridine-3-carboxamide, hydroxyfumapentrine and PCT Patent Application Nos. WO 03/097613, WO, 2004/058729 and WO 2005 / Selected from the group.

Preferred PDE4 inhibitors under the present invention are: theophylline, drotaberine hydrochloride, silomilast, roflumilast, denbuphylline, rolipram, tetomilalast, enpropyline, arophylline, sifamphylline, topimilast, pila Minast, picclamilast, (R)-(+)-4- [2- (3-cyclopentyloxy-4-methoxyphenyl) -2-phenylethyl] pyridine, mesopram, N- (3, 5-dichloro-4-pyridinyl) -2- [1- (4-fluorobenzyl) -5-hydroxy-1H-indol-3-yl] -2-oxoacetamide, CDC-801 (ex. Celgene ), CC-1088 (ex. Celgene), Lilimast, ONO-6126 (ex. Ono), CC-10004 (ex. Celgene), MN-001 (ex. Kyorin) and PCT Patent Application No. WO 03/097613 , WO, 2004/058729 and WO 2005 /.

More preferred PDE4 inhibitors under the present invention are: theophylline, drotaberine hydrochloride, silomilast, roflumilast, denbuphylline, rolipram, tetomilalast, N- (3,5-dichloro-4-pyridinyl) -2- [1- (4-fluorobenzyl) -5-hydroxy-1H-indol-3-yl] -2-oxoacetamide, enpropylin, arophylline and PCT Patent Application No. WO03 / 097613, WO , 2004/058729 and WO 2005 /. Most preferred PDE4 inhibitors are cilillolasts, roflumilasts, denbuphylline, tetomilasts and compounds exemplified in PCT patent applications Nos. WO 03/097613, WO, 2004/058729 and WO 2005 /, in particular silomilast, loaf Rumillasts, denbuphylline, and tetomilasts and most preferably loflumilasts and silomilasts.

Pharmaceutically acceptable salt forms of the combinations of the compounds of this invention are prepared in large part by conventional means. When the component compound contains a carboxylic acid group, a suitable salt thereof can be formed by reacting the compound with an appropriate base to provide the corresponding base addition salt. Examples of such bases include alkali metal hydroxides including potassium hydroxide, sodium hydroxide, and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alkoxides such as potassium ethanolate and sodium propanolate, and various organic bases such as piperidine, diethanolamine, and N-methylglutamine. Component Also included are aluminum salts of the compounds of the present invention.

For certain component compounds, the compounds may be used as pharmaceutically acceptable organic and inorganic acids such as hydrohalides such as hydrochloride, hydrobromide, hydroiodide; Other inorganic acids and their corresponding salts such as sulfates, nitrates, phosphates, and the like; And alkyl- and monoarylsulfonates such as ethanesulfonate, toluenesulfonate, and benzenesulfonate; And acid addition salts can be formed by treatment with other organic acids and their corresponding salts such as acetates, tartrates, maleates, succinates, citrates, benzoates, salicylates, ascorbates, and the like.

Thus, the pharmaceutically acceptable acid addition salts of the compounds of the present invention are not limited to this: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate ), Bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, di Nitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galactate (from slime acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisul Pate, Heptanoate, Hexanoate, Hyporate, Hydrochloride, Hydrobromide, Hydroioda Id, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, maleate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzo Ate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, And phthalates.

Particularly preferred examples of pharmacologically acceptable acid addition salts of PDE4 inhibitors are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid Pharmaceutically acceptable salts selected from acids, or salts of maleic acid. If necessary, mixtures of the above-mentioned acids can be used to prepare salts of PDE4 inhibitors.

In the pharmaceutical compositions according to the invention, PDE4 inhibitors may be present in the form of their racemic compounds, enantiomers or mixtures thereof. Separation of the enantiomer from the racemic compound can be carried out using methods known in the art (eg, by chromatography on chiral or the like).

Preferred embodiments of the invention are (3R) -1-phenethyl-3- in the form of a salt with an anion X, which is an antagonist of the M3 muscarinic receptor of formula (I), in particular mono or polyvalent acid. (9H-Xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octene (especially (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy Antagonist of M3 muscarinic receptor, which is) -1-azoniabicyclo [2.2.2] octein bromide, and a PDE4 inhibitor selected from silomilast, roflumilast, denbuphylline, and tetomilast. to be. (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabi in the form of a salt having an anion X which is a pharmaceutically acceptable anion of monovalent or polyvalent acid With cyclo [2.2.2] octane (particularly (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide) (3R) -1-Phenyl-3- (9H-xanthene-9-carbonyloxy in the form of a salt with anion X, in combination with silomilast and a pharmaceutically acceptable anion of monovalent or polyvalent acid ) -1-azoniabicyclo [2.2.2] octane (particularly (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2. 2] a combination of octane bromide) and roflumilast is more preferred.

Particularly preferred embodiments of the invention are (3R) -1-phenethyl- in the form of salts with anion X, which are antagonists of the M3 muscarinic receptor of formula (I), in particular pharmaceutically acceptable anions of monovalent or polyvalent acids. 3- (9H-Xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octene (especially (3R) -1-phenethyl-3- (9H-xanthene-9-carbox Antagonist of M3 muscarinic receptor, which is carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide), and a PDE4 inhibitor selected from cilillolast, roflumilast, denbuphylline, and tetomilalast It is a combination.

Another embodiment of the invention is 3 (R)-(2-hydroxy-2,2-dithien-2-ylacetoxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [ 2.2.2] octane bromide, (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide, and (3R ) -3-[(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (2-phenoxyethyl) -1-azoniabicyclo [2.2.2 ] M3 antagonist selected from the group consisting of octane bromide and PDE4 inhibitors selected from silomilast, roflumilast, denbuphylline, and tetomilast.

According to one embodiment of the invention the antagonist of the M3 muscarinic receptor is (3R) -1-phenethyl in the form of a salt having an anion X which is a pharmaceutically acceptable anion of the compound of formula (I), in particular monovalent or polyvalent acid -3- (9H-Xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octene (especially (3R) -1-phenethyl-3- (9H-xanthene-9-) Carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide) and the PDE4 inhibitor is roflumilast.

According to another embodiment of the invention the antagonist of the M3 muscarinic receptor (3R) -1- is in the form of a salt having an anion X, which is a pharmaceutically acceptable anion of the compound of formula (I), in particular monovalent or polyvalent acid. Phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octene (especially (3R) -1-phenethyl-3- (9H-xanthene-) 9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide) and the PDE4 inhibitor is silomylast.

The combination of the present invention is one or more additional active substances known to be useful for the treatment of respiratory disorders, such as β2 agonists, corticosteroids or glucocorticoids, leukotriene D4 inhibitors, egfr-kinase inhibitors, p38 kinase inhibitors and / or NK1-receptor antagonists. It may optionally include.

Examples of suitable β2-agents that may be used in the combination of the present invention are optionally in the form of their racemic compounds, their enantiomers, their diastereoisomers, and mixtures thereof, and optionally their pharmacologically-compatible acid addition salts. Furo: Arformoterol, bambuterol, bitolterol, broxetherol, carbuterol, clenbuterol, dopexamine, phenoterol, formoterol, hexoprelinin, ibuterol, isoetarin, isoprenin, Levosalbutamol, mabuterol, meluadrin, metaprotenerol, nolomyrol, orsiprelinin, pirbuterol, procaterol, leproterol, ritodrin, limotrol, salbutamol, salmephamol, Salmeterol, Sibenabyan, Sothenerot, Sulfonterol, Terbutalin, Tiaramid, Tulobuterol, GSK-597901, GSK-159797, GSK-678007, GSK-642444, GSK-159802, HOKU-81, ( -)-2- [7 (S)-[2 (R) -hydroxy-2- (4-hydroxyphenyl) ethylamino] -5,6,7,8- Trahydro-2-naphthyloxy] -N, N-dimethylacetamide hydrochloride monohydrate, caroterol, QAB-149 and 5- [2- (5,6-diethylindan-2-ylamino)- l-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7- [2-{[2-{[3- (2-phenylethoxy) propyl] sulfonyl} Ethyl] amino} ethyl] -2 (3H)-benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2- Butylamino] ethanol, 1- [3- (4-methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2 -Propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl 2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl ) -2-methyl-2-propylamino] Ol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2, 4-triazol-3-yl] -2-methyl-2-butylamino} ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazine 3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol and 1- (4-ethoxycarbonylamino-3- Cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol.

Suitable corticosteroids and glucocorticoids that can be combined with M3 antagonists and PDE4 inhibitors are prednisolone, methylprednisolone, dexamethasone, naflocorte, deplazacort, halopredone acetate, budesonide, beclomethasone dipropionate, Hydrocortisone, triamcinolone acetonide, fluorinolone acetonide, fluorinoneide, clocortolone pivalate, methylprednisoloneacenateate; Dexamethasone palmitoate, thipredine, hydrocortisone acenate, prednicarbate, alclomethasone dipropionate, halomethasone, methylprednisolone sulphtanate, mometasone fluorate, limexolone, prednisolone farnesyl Latex, ciclesonide, deprodone propionate, fluticasone propionate, halobetasol propionate, loteprednol etabonate, betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate , Triamcinolone, betamethasone 17-valorate, betamethasone, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate and hydrocortisone probutate.

Examples of suitable LTD4 antagonists that may be combined with M3 antagonists and PDE4 inhibitors include tomellukast, ibudilast, pobilicast, franlukast hydrate, zafirlukast, ritlukast, burlukast, sulcastast, sinal Luccast, rallucast sodium, montelukast sodium, 4- [4- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylsulfonyl] phenyl] -4-oxobutyric acid, [ [5-[[3- (4-acetyl-3-hydroxy-2-propylphenoxy) propyl] thio] -1,3,4-thiadiazol-2-yl] thio] acetic acid, 9-[( 4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl] -3- (H-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-4-one , 5- [3- [2- (7-chloroquinolin-2-yl) vinyl] phenyl] -8- (N, N-dimethylcarbamoyl) -4,6-dithiaoctanoate sodium salt; 3- [1- [3- [2- (7-chloroquinolin-2-yl) vinyl] phenyl] -1- [3- (dimethylamino) -3-oxopropylsulfanyl] methylsulfanyl] sodium propionate , 6- (2-cyclohexylethyl)-[1,3,4] thiadiazolo [3,2-a] -1,2,3-triazolo [4,5-d] pyrimidine-9 (1H ) -One, 4- [6-acetyl-3- [3- (4-acetyl-3-hydroxy-2-propylphenylthio) propoxy] -2-propylphenoxy] butyric acid, (R) -3- Methoxy-4- [1-methyl-5- [N- (2-methyl-4,4,4-trifluorobutyl) carbamoyl] indol-3-ylmethyl] -N- (2-methylphenylsulfonyl ) Benzamide, (R) -3- [2-methoxy-4- [N- (2-methylphenylsulfonyl) carbamoyl] benzyl] -1-methyl-N- (4,4,4-trifluoro 2-methylbutyl) indole-5-carboxamide, (+)-4 (S)-(4-carboxyphenylthio) -7- [4- (4-phenoxybutoxy) phenyl] -5 (Z) -Heptenic acid and compounds claimed in PCT Patent Application No. PCT / EP03 / 12581.

 Examples of suitable inhibitors of egfr-kinase that can be combined with M3 antagonists and PDE4 inhibitors are palippermin, cetuximab, gefitinib, lepifermin, allertinib hydrochloride, canertinib dihydrochloride, la Patinib, and N- [4- (3-chloro-4-fluorophenylamino) -3-cyano-7-ethoxyquinolin-6-yl] -4- (dimethylamino) -2 (E)- Butenamide.

Examples of suitable p38 kinase inhibitors that may be combined with M3 antagonists and PDE4 inhibitors are chlormethazole edylate, doramatimod, 5- (2,6-dichlorophenyl) -2- (2,4-difluorophenyl Sulfanyl) -6H-pyrimido [3,4-b] pyridazin-6-one, 4-acetamido-N- (tert-butyl) benzamide, (Clin Pharmacol Ther 2004, 75 (2): AbstPII SCIO-469 and Circulation 2003, 108 (17, Suppl. 4): VX-702, described in Abst 882).

Examples of suitable NK1-receptor antagonists that may be combined with M3 antagonists and PDE4 inhibitors include nolpittanium besylate, dapitant, lanepitant, bopopitant hydrochloride, aprepitant, ezelopitant, N- [ 3- (2-pentylphenyl) propionyl] -threonyl-N-methyl-2,3-dehydrotyrosyl-leucil-D-phenylalanyl-allo-threonyl-asparaginyl-serine C-1.7 -0-3.1 lactone, 1-methylindol-3-ylcarbonyl- [4 (R) -hydroxy] -L-prolyl- [3- (2-naphthyl)]-L-alanine N-benzyl- N-methylamide, (+)-(2S, 3S) -3- [2-methoxy-5- (trifluoromethoxy) benzylamino] -2-phenylpiperidine, (2R, 4S) -N- [1- [3,5-bis (trifluoromethyl) benzoyl] -2- (4-chlorobenzyl) piperidin-4-yl] quinoline-4-carboxamide, 3- [2 (R)- [1 (R)-[3,5-bis (trifluoromethyl) phenyl] ethoxy] -3 (S)-(4-fluorophenyl) morpholin-4-ylmethyl] -5-oxo-4 , 5-dihydro-1H-1,2,4-triazole-1-phosphinic acid bis (N-methyl-D-gluka ) Salt; [3- [2 (R)-[1 (R)-[3,5-bis (trifluoromethyl) phenyl] ethoxy] -3 (S)-(4-fluorophenyl) -4-morpholi Nylmethyl] -2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl] phosphonic acid 1-deoxy-1- (methylamino) -D-glucitol ( 1: 2) salt, 1 '-[2- [2 (R)-(3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl] Spiro [benzo [c] thiophene-1 (3H) -4'-piperidine] 2 (S) -oxide and Eur Respir J 2003, 22 (Suppl. 45): Compound CS-003 as described in Abst P2664 .

The combination of the present invention can be used for the treatment of any disorder that is sensitive to simultaneous, simultaneous or sequential antagonism of M3 muscarinic receptors and improvement by inhibition of phosphodiesterase 4. Thus, the present application encompasses the use of the combination of the invention in the manufacture of a medicament for the treatment of these disorders, as well as methods of treating these disorders.

Preferred examples of disorders in which the use of airway dilators are expected to have a beneficial effect are respiratory diseases such as asthma, acute or chronic bronchitis, (lung) emphysema, or chronic obstructive pulmonary disease (COPD).

In combination the active compounds, ie the M3 antagonists, PDE4 inhibitors and any other selected active compounds of the invention, are administered together in the same pharmaceutical composition or in different compositions intended to be administered separately, simultaneously, simultaneously or sequentially by the same or different routes. Can be.

In one embodiment the invention relates to a M3 muscarinic receptor of formula (I) with instructions for simultaneous, synergistic, separate or sequential use in combination with PDE4 inhibitors for the treatment of respiratory diseases that respond to M3 antagonism. Some kits containing an antagonist are provided.

In a preferred embodiment the invention relates to pharmaceuticals of monovalent or polyvalent acids in combination with PDE4 inhibitors for the treatment of respiratory diseases responsive to M3 antagonism, simultaneously with synergistic, separate or sequential use instructions. (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane, in the form of a salt having an anion X which is an acceptable anion. An antagonist of the M3 muscarinic receptor (particularly (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide) Some kits are included.

In another embodiment the invention provides a package comprising an antagonist of an M3 muscarinic receptor of formula (I) and a PDE4 inhibitor for use simultaneously, synergistically, or sequentially in the treatment of a respiratory disease in response to M3 antagonism. To provide.

In another embodiment the invention relates to (3R) -1-phenethyl-3 in the form of a salt with an anion X, which is an antagonist of the M3 muscarinic receptor of formula (I), in particular a monovalent or polyvalent acid. -(9H-Xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane (especially (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyl Antagonist of M3 muscarinic receptor, oxy) -1-azoniabicyclo [2.2.2] octane bromide), used simultaneously, synergistically, individually or sequentially in the treatment of respiratory diseases that respond to M3 antagonism It consists of a package containing a PDE4 inhibitor for.

In a preferred embodiment of the invention the active compounds in combination are administered by inhalation via conventional delivery devices, where they can be formulated in the same or different pharmaceutical compositions.

In the most preferred embodiment both the M3 antagonist and the PDE4 inhibitor of the present invention are present in the same pharmaceutical composition and are administered by inhalation via conventional delivery devices.

In one aspect the invention provides a combination as defined herein, wherein the active ingredients (a) and (b) form part of a single pharmaceutical composition.

In another embodiment the invention provides a pharmaceutical composition as defined herein, characterized in that the antagonist of the M3 muscarinic receptor, PDE4 inhibitor and optionally other additives and / or carriers are mixed and processed by the original known methods. Provide a course for

The active compounds in combination, ie the M3 antagonists, PDE4 inhibitors and any other optional active compounds of the invention, may be, for example, orally (syrups, tablets, capsules, lozenges) by any suitable route depending on the nature of the disorder to be treated. Paper, controlled-release preparations, quick-dissolving preparations, lozenges, and the like); Topically (as creams, ointments, lotions, nasal sprays or aerosols, etc.); It can be administered by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.) or by inhalation (as a dry powder, solution, dispersion, etc.).

Pharmaceutical formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient (s) with the carrier. Generally, formulations are prepared by uniformly and directly bringing the active ingredient into association with the liquid carrier or the finely divided solid carrier or both, and if necessary, then shaping the product into the desired formulation.

Formulations of the invention suitable for oral administration may be presented as discrete units, such as capsules, cachets or tablets, each containing a predetermined amount of active ingredient; Such as powder or particulates; As a solution or a suspension in an aqueous liquid or a non-aqueous liquid; Or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be presented as a large pill, soft or paste.

Syrup formulations will generally consist of a suspension or solution of a compound or salt in a liquid carrier such as ethanol, natural, synthetic or semisynthetic oils, such as peanut oil and olive oil, glycerin or water together with flavors, sweeteners and / or colorants.

When the composition is in the form of a tablet, any form of pharmaceutical carrier commonly used to prepare solid dosage forms can be used. Examples of such carriers include stearates such as cellulose, magnesium stearate or stearic acid, talc, gelatin, acacia, starch, lactose and sucrose.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredients in a free-flowing form, such as powders or particulates, optionally mixed with a binder, lubricant, inert diluent, lubrication, surface active or dispersant in a suitable machine. Molded tablets can be made by molding in a suitable machine a mixture of the powdered blend comprising the active compound wetted with an inert liquid diluent and optionally dried and sieved. Tablets may be optionally coated or scored and formulated to provide modified (ie, slow or controlled) release of the active ingredient therein.

When the composition is in the form of a capsule, it is appropriate for any routine encapsulation to use a carrier as mentioned, for example, prior to hard gelatin capsules. When the composition is a soft gelatin capsule, any form of pharmaceutical carrier routinely used to prepare dispersions or suspensions, such as aqueous rubbers, celluloses, silicates or oils, may be considered and incorporated into soft gelatin capsules.

Dry powder compositions for topical delivery to the lungs by inhalation are for example used in inhalers or blowers, for example in other major packaging systems (such as eg capsules and cartridges of laminated aluminum foil, eg gelatin or foam). It can be presented as.

Packaging of the formulation may be suitable for unit dose or multi-dose delivery. In the case of multi-dose delivery, the formulation may be pre-metered or metered in use. Dry powder inhalers are thus classified into three groups: (a) single dose, (b) multi unit dose and (c) multiple dose device.

The formulations generally contain a powder mix for inhalation of the compounds of the invention and a suitable powder base (carrier material) such as lactose or starch. The use of lactose is preferred. Each capsule or cartridge may generally contain between 2 μg and 400 μg of active ingredient in each treatment. As an alternative, the active ingredient (s) can be presented without excipients.

For a single dose inhaler of the first type, a single dose is weighed by the manufacturer into a small container, which is mostly a hard gelatin capsule. Capsules must be taken from individual boxes or containers and inserted into the reservoir area of the inhaler. The capsule must then be opened or punctured with a pin or cutting blade to pass a portion of the inspiratory air stream through the capsule for powder loading or to release the powder from the capsule through these perforations by centrifugal force during inhalation. . After inhalation, the empty capsule must be removed from the inhaler again. In most cases, disassembly of the inhaler is required to insert and remove capsules, which is a difficult and burdensome operation for some patients. Other disadvantages associated with the use of hard gelatin capsules for inhalation powders include: (a) poor protection against moisture absorption from the ambient air, (b) problems with openings or perforations after the capsule has been previously exposed to extreme relative humidity, which may lead to fracture or Causing a nick, and (c) possible inhalation of the capsule fragment. Moreover, for many capsule inhalers, incomplete exclusion has been reported (eg Nielsen et al, 1997).

Some capsule inhalers, as described in WO 92/03175, have a magazine in which individual capsules can be moved to a receiving chamber where perforation and emptying occur. Other capsule inhalers have an accompanying magazine with capsule chambers that can be lined up with air conduits for dose release (eg, W091 / 02558 and GB 2242134). They include a type of multi unit dose inhaler with a blowing agent inhaler, which has a limited number of unit doses in the supply in the disc or strip.

Blowing agent inhalers provide better moisture protection of the medicine than capsule inhalers. As well as blowing agent foil, access to the powder is obtained by perforating the cover or by peeling off the cover foil. When using a foam strip instead of the disc, the number of doses can be increased, but it is inconvenient for the patient to replace the empty strip. Thus, such devices are often disposable with the incorporated dosing system, including the technique used to move the strip and open the foam pocket.

Multi-dose inhalers may contain a pre-measured amount of powder formulation. They consist of a relatively large container and the principle of dose measurement, which should be operated by the patient. The vessel has multiple doses that are individually separated from the bulk of the powder by volumetric substitution. Rotatable membranes (eg EP0069715) or discs (eg GB 2041763; EP 0424790; DE 4239402 and EP 0674533), rotatable cylinders (eg EP 0166294; GB 2165159 and WO 92/09322) and Various dose measuring principles exist, including rotatable frustums (eg WO 92/00771), all having cavities that must be filled with powder from the container. Another multi-dose device has a measuring slide (eg US 5201308 and WO 97/00703) or a measuring plunger (eg US 5201308 and WO 97/00703) which has a local or peripheral recess for transferring a certain volume of powder from a container to a delivery chamber or air conduit. EP 0505321, WO 92/04068 and WO 92/04928).

Reproducible dose measurements are one of the major concerns for multiple dose inhaler devices.

Since filling the dose measuring cups or cavities is mostly under the influence of gravity, the powder formulation should exhibit good and stable flow.

For reloaded single dose and multi unit dose inhalers, dose measurement accuracy and reproducibility can be assured by the manufacturer. On the other hand, multi-dose inhalers may contain a much higher number of doses, while the number of handling to prepare the dose is generally lower.

Since the inspiratory airflow in a multi-dose device is often straight across the volumetric cavity, and because the bulk precise volumetric system of the multidose inhaler cannot be disturbed by this inspiratory airflow, the powder material is simply Accompanying and little deagglomeration is achieved during release.

As a result, separate decomposition means are required. But in reality, they are not always part of the inhaler design. Because of the high number of capacities in the multi-dose device, the means for powder attachment and de-agglomeration over the inner wall of the air conduit should be minimized and / or allow regular cleaning of these parts without affecting the remaining capacity in the device. Some multi-dose inhalers have a disposable drug container that can be removed after a prescribed number of doses have been taken (eg WO 97/000703). For such semi-permanent multiple dose inhalers with disposable drug containers, the requirements to prevent drug accumulation are more stringent.

Apart from application via a dry powder inhaler, the composition of the present invention can be administered as an aerosol, operating through a propellant gas or by a so-called nebulizer, through which a solution of pharmacologically-active substance is produced by the mist of inhalable particles. May be sprayed under high pressure to produce. The advantage of these nebulizers is that the use of propellant gas can be completely unnecessary.

Such nebulizers are described, for example, in PCT patent application No. WO 91/14468 and International Patent Application No. Described in WO 97/12687, reference is made to its contents.

Spray compositions for topical delivery to the lungs by inhalation can be formulated with an aerosol derived from a pressurized pack, such as, for example, an aqueous solution or suspension, or with a metered dose inhaler, using the appropriate liquefied propellant. Aerosol compositions suitable for inhalation can be either suspensions or solutions and are generally fluorocarbons or hydrogen-containing chlorofluorocarbons or mixtures thereof, in particular hydrofluoroalkanes such as dichlorodifluoromethane, Trichlorofluoromethane, dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane Or active ingredient (s) such as mixtures thereof and appropriate propellants. Carbon dioxide or other suitable gas may also be used as propellant. The aerosol composition may be free from excipients other than propellants or may optionally contain additional formulations well known in the art such as surfactants such as oleic acid or lecithin and cosolvents such as ethanol. The pressurized formulation will generally be held in a canister (for example an aluminum canister) fitted to an actuator provided with a blockage (eg metering valve) and a mouthpiece provided.

Medicines for administration by inhalation preferably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1-10 μ, preferably 2-5 μ. Particles with a size of 20 μ or larger are generally too large to reach a small airway when inhaled. Particles of the active ingredient as produced to achieve these particle sizes can be reduced in size by conventional means, for example by micronized or supercritical fluid techniques. The desired small portion can be separated by air fractionation or sieving. Preferably, the particles will be crystalline.

It is difficult to achieve high capacity regeneration with micronized powders because of their poor fluidity and extreme tendency to agglomerate. To improve the efficiency of the dry powder composition, the particles should be large while in the inhaler, but small when released into the airways. Thus, excipients such as lactose, mannitol or glucose are generally adopted. The particle size of the excipient will usually be much larger than the inhaled medicament within the present invention. When the excipient is lactose it will typically be presented as processed lactose, preferably crystalline alpha lactose monohydrate.

The pressurized aerosol composition will generally be filled in a canister with a valve, in particular a metering valve. The canister may optionally be coated with a plastic material, for example, a fluorocarbon polymer as described in WO96 / 32150. The canister will be fitted with an actuator adapted for ball delivery.

Typical compositions for nasal delivery include those mentioned above for inhalation and in combination with conventional excipients such as buffers, antimicrobials, mucoadhesives, tonicity modifiers and viscosity modifiers, which may optionally be administered by a nasal pump, It further comprises a non-pressurizing composition in the form of a solution or suspension in an inert vehicle such as water.

Typical skin and transdermal formulations are in the form of plasters, patches or membranes containing conventional aqueous or non-aqueous media such as creams, ointments, lotions or pastes or mixed with drugs.

The proportion in which (a) PDE4 inhibitors and (b) antagonists of M3 muscarinic receptors can be used in accordance with the present invention is variable. The active substances (a) and (b) may possibly be present in the form of their solvates or hydrates. Depending on the choice of compounds (a) and (b), the weight ratios that can be used within the scope of the invention vary based on the different molecular weights of the various salt forms. Pharmaceutical combinations according to the invention may contain (a) and (b) in a weight ratio (b) :( a), generally in the range from 1: 5 to 500: 1, preferably from 1:10 to 400: 1. .

The weight ratios specified below are represented by (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide (b) And the particularly preferred PDE4 inhibitors roflumilast and silomylast according to the invention.

The pharmaceutical combination according to the invention is in the case of roflumilast, for example 1:10 to 300: 1, preferably 1: 5 to 200: 1, preferably 1: 3 to 150: 1, more preferably Preferably it may contain (a) and (b) in the weight ratio (b) :( a) in the range of 1: 2 to 100: 1.

Pharmaceutical compositions according to the invention containing a combination of (a) and (b) are typically (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabi Cyclo [2.2.2] octane bromide and roflumilast are administered such that they are present together in a dose of 0.5 to 5000 μg, preferably 1 to 2000 μg, more preferably 5 to 1000 μg, even 10 to 800 μg per single dose.

For example, the scope of the invention is defined as (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide (b) Without limiting to the combination used and used as roflumilast as (a), the composition according to the invention is for example 20 to 1000 μg of (3R) -1-phenethyl-3- (9H-xanthene-9). -Carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide and 5 to 500 μg of roflumilast.

For example, the active substance combination according to the invention is (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide And (a) in the case of silomilast, from about 1:30 to 400: 1, preferably from 1:25 to 200: 1, preferably from 1:20 to 100: 1, most preferably from 1:15 to It may be contained in the weight ratio (b) :( a) in the range of 50: 1.

Pharmaceutical compositions according to the invention containing a combination of (a) and (b) are usually (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] Octane bromide and beclomethasone dipropionate are dosed at a dosage of 1 to 10000 μg, preferably 5 to 5000 μg, more preferably 10 to 2000 μg, more preferably 20 to 800 μg per single dose. To be present together.

For example, the scope of the invention is defined as (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide (b) The composition according to the invention is not limited to the combinations used in the present invention, and silomilast is used in (a), for example, 5 to 5000 μg of (3R) -1-phenethyl-3- (9H-xanthene-9- Carbonyloxy) -1-azoniabicyclo [2.2.2] octane bromide and from 15 to 300 μg of silomyllast.

It is understood that the foregoing examples of possible doses applicable for the combination according to the invention refer to doses per single application. However, these examples are not to be understood as excluding the possibility of administering the combination according to the invention multiple times. Depending on the medical need, the patient may also receive multiple inhalation applications. By way of example, a patient may receive a combination according to the invention for example 2 or 3 times (eg 2 or 3 puffs with a powder inhaler, MDI, etc.) in the morning of each treatment day. Since the aforementioned dosage examples are only understood as dosage examples per single application (ie per puff), multiple applications of the combination according to the invention result in multiple dosages of the aforementioned examples. Application of the compositions according to the invention can be carried out, for example, once a day, or twice a day, or once every two or three days or even on a "when needed" basis (sometimes a day, depending on the duration of the action of the anticholinergic) 3 or more).

Preferably the composition is in unit dosage form, such as a tablet, capsule or metered aerosol dose, so that the patient can administer a single dose.

Each dosage unit suitably contains 20 μg to 1000 μg and preferably 50 μg to 300 μg of the M3 antagonist according to the present invention or a pharmaceutically acceptable salt thereof and 1 μg to 300 μg, and preferably 5 μg to 100 μg of the PDE4 inhibitor according to the present invention. It contains.

The amount of each activity required to achieve a therapeutic effect will of course vary depending on the specific activity, the route of administration, the subject to be treated, and the particular disorder or disease being treated.

The active ingredient may be administered 1 to 6 times per day, sufficient to exhibit the desired activity. Preferably, the active ingredient is administered once or twice a day.

It is envisioned that all active agents will be administered at the same time, or very close time. Alternatively, one or two actives can be taken in the morning and the rest later in the day. Or in another scenario, one or two actives may be taken twice a day, the remainder at the same time or separately, two times a day during which dosing occurs. Preferably at least two times, more preferably both active agents will be taken together at the same time. Preferably at least two times, more preferably all active agents will be administered as a mixture.

The active substance composition according to the invention is preferably administered in the form of a composition for inhalation delivered with the aid of an inhaler, in particular a dry powder inhaler, but any other form or parenteral or oral application is possible. The application of the inhaled compositions herein specifies the preferred form of application, particularly in the treatment of obstructive pulmonary disease or for the treatment of asthma.

The following formulation forms are cited as formulation examples:

Pharmacological activity

Surprisingly, if antimuscarin of formula (I) is used in combination with one or more PDE4 inhibitors, unexpected beneficial therapeutic effects can be observed in the treatment of inflammation or obstructive diseases of the airways. In view of this effect, the pharmaceutical combinations according to the invention can be used in smaller doses than in the case of the individual compounds used in monotherapy in a conventional manner. This reduces unwanted side effects such as may occur when, for example, a PDE4 inhibitor is administered.

As a result, the combination of the present invention has properties that are beneficial to the treatment which makes it suitable for the treatment of respiratory diseases, especially in all kinds of patients.

Claims (17)

in the form of (a) a PDE4 inhibitor and (b) a salt having an anion X, which is a pharmaceutically acceptable anion of a monovalent or polyvalent acid, (3R) -1-phenethyl-3- (9H-xanthene-9- A combination comprising an antagonist of M3 muscarinic receptor that is carbonyloxy) -1-azoniabicyclo [2.2.2] octane. The method of claim 1, wherein (b) the antagonist of the M3 muscarinic receptor is (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2 ] Octane bromide. The combination according to claim 1 or 2, wherein the active ingredients (a) and (b) form part of a single pharmaceutical composition. In the treatment of a patient suffering from or susceptible to a respiratory disease responsive to M3 antagonism, at the same time, in a synergistic, combined formulation for use individually or sequentially, a combination of (a) PDE4 inhibitors and (b) 1 or 2 A product comprising an antagonist of the M3 muscarinic receptor as defined in the paragraph. For the treatment of patients suffering from or susceptible to respiratory disease responsive to M3 antagonism, (a) in combination with PDE4 inhibitors simultaneously, in combination, with instructions for use individually or sequentially, (b) first Some kits comprising an antagonist of the M3 muscarinic receptor as defined in claim 2. (B) antagonists of the M3 muscarinic receptor as defined in claim 1 or 2 and (a) PDE4 inhibitors for simultaneous, synergistic, separate or sequential use in the treatment of respiratory diseases in response to M3 antagonism. Package containing. (A) for the preparation of a medicament for use simultaneously, synergistically, individually or sequentially in combination with a PDE4 inhibitor for the treatment of a respiratory disease that responds to M3 antagonism in a patient, (b) Use of antagonists of the M3 muscarinic receptor as defined in. For the treatment of respiratory diseases responsive to M3 antagonism in a patient (b) for use simultaneously, synergistically, individually or sequentially in combination with an antagonist of the M3 muscarinic receptor as defined in claim 1 or 2. (A) Use of PDE4 inhibitors for the manufacture of a medicament. (A) PDE4 inhibitors and (b) as defined in claims 1 or 2, for the manufacture of a medicament for use simultaneously or synergistically, individually or sequentially in the treatment of respiratory diseases in response to M3 antagonism in a patient. Use of the antagonist of the M3 muscarinic receptor as shown. (b) administering to the patient an effective amount of an antagonist of an M3 muscarinic receptor as defined in claim 1 or (a) a PDE4 inhibitor simultaneously, synergistically, individually or sequentially. A method of treating a patient suffering from or susceptible to respiratory disease or condition that responds to M3 antagonism. A product according to claim 4, a kit according to claim 5, a use according to claims 7 to 9 or a method according to claim 10, characterized in that the respiratory disease is asthma or chronic obstructive pulmonary disease (COPD). PDE4 inhibitors may optionally be used in the form of their racemic compounds, their enantiomers, their diastereoisomers, and mixtures thereof, and optionally in the form of their pharmacologically-compatible acid addition salts, theophylline, drotaberine hydrochloride, silomilast, Loflumilast, denbuphylline, lolifram, tetomilast, enpropyl, arophylline, cifamphylline, topimillast, pilaminest, picclamilast, (R)-(+)-4- [2 -(3-cyclopentyloxy-4-methoxyphenyl) -2-phenylethyl] pyridine, mesopram, N- (3,5-dichloro-4-pyridinyl) -2- [1- (4-fluoro Lovenzyl) -5-hydroxy-1H-indol-3-yl] -2-oxoacetamide, CDC-801 (ex. Celgene), CC-1088 (ex. Celgene), lirimilast, ONO-6126 ( exo Ono), CC-10004 (ex. Celgene) and MN-001 (ex. Kyorin) combinations, products according to any one of claims 1 to 11, characterized in that , Part of Tree, package, use or method. PDE4 inhibitors are optionally in the form of their racemic compounds, their enantiomers, their diastereoisomers, and mixtures thereof, and optionally their pharmacologically-compatible acid addition salts, silomylast, roflumilast, denbuphylline And a combination, product, part of a kit, package, use or method according to any one of claims 1 to 12, characterized in that it is selected from the group comprising tetomillast. The combination, product, or part of a kit, package, use or method according to any one of claims 1 to 13, characterized in that the PDE4 inhibitor is roflumilast. Combination, part kit, package, use or method according to any one of claims 1 to 13, characterized in that the PDE4 inhibitor is silomilast. (C) For combinations, products, and some kits or packages to be used simultaneously, individually or sequentially: Another active compound selected from (a) β2 agonists, (b) corticosteroids, (c) leukotriene D4 antagonists, (d) inhibitors of egfr-kinase, (e) p38 kinase inhibitors, and (f) NK1 receptor agonists A combination according to any one of claims 1 to 3, a product according to claim 4, a kit according to claim 5 or a package according to claim 6, further comprising. 17. The combination, product, or part of a kit or package of claim 16, wherein the active compound (c) is selected from the group consisting of (a) β2 agonists and (b) corticosteroids.