EP1521580A1

EP1521580A1 - Novel pharmaceutical compositions comprising novel anticholinergic agents and nk1-receptor antagonists

Info

Publication number: EP1521580A1
Application number: EP03762508A
Authority: EP
Inventors: Michel Pairet; Christopher John Montague Meade; Michael P. Pieper; Birgit Jung
Original assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2002-07-09
Filing date: 2003-06-25
Publication date: 2005-04-13
Also published as: AU2003242754A1; WO2004004724A1; CA2491451A1; DE10230750A1; JP2005532378A

Abstract

The invention relates to novel pharmaceutical compositions comprising novel anticholinergic agents and NK1-receptor antagonists, method for production and use thereof in the treatment of respiratory diseases.

Description

New drug compositions based on new anticholinergics and NK- _j receptor antagonists

The present invention relates to novel pharmaceutical compositions based on new anticholinergics and NK-i receptor antagonists, methods for their

Production and their use in the therapy of respiratory diseases.

DESCRIPTION OF THE INVENTION The present invention relates to novel pharmaceutical compositions based on new anticholinergics and NK-j receptor antagonists, and processes for their use

Production and their use in the therapy of respiratory diseases.

Surprisingly, an unexpectedly advantageous therapeutic effect, in particular a synergistic effect in the treatment of inflammatory and / or obstructive respiratory diseases, can be observed if one or more, preferably a new anticholinergic of formula 1 together with one or more, preferably an NK-j receptor Antagonists 2 are used. Because of this synergistic effect, the pharmaceutical combinations according to the invention can be used in lower doses than is the case with the otherwise customary monotherapy of the individual compounds. is.

The active compound combinations according to the invention are surprisingly characterized both by a rapid onset of action and by a long duration of action. This is of great importance for the well-being of the patient, since on the one hand he quickly after application of the combination

Noticeable improvement in his condition and, on the other hand, application once a day is sufficient due to the long duration of action. The above-mentioned effects are observed both with simultaneous application within a single active substance formulation and with successive application of the two active substances in separate formulations. According to the invention, the simultaneous application of the two active ingredient components in a single formulation is preferred.

In the context of the present invention, the salts of formula 1 are used as anticholinergic wherein

X 'is a single negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate,

Fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate means use.

The salts of formula 1 are preferably used, in which X ^{_ is} a simply negatively charged anion selected from the group

Chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide.

The salts of the formula I are particularly preferably used in which X "is a simply negatively charged anion selected from the group

Chloride, bromide and methanesulfonate, preferably bromide.

According to the invention, the salt of formula 1 in which X "represents bromide is particularly preferred.

Fromel salts! are known from the international patent application WO 02/32899.

Within the scope of the present patent application there is an explicit reference to the pharmacologically active cation of the formula recognized by using the designation V. A reference to compounds 1 naturally includes a reference to the cation V.

A reference in the context of the present invention to the salts which can be used according to the invention includes optionally available hydrates and solvates of these compounds.

In the context of the present invention, NK- | receptor antagonists (hereinafter 2) are understood to mean compounds which are selected from the group consisting of N- [2- (3,5-bis-trifluoromethylphenyl) ethyl] - 2- {4-cyclopropylmethyl-piperazin-1-yl} -N-methyl-2-phenyl-acetamide (BIIF 1149), CP-122721, FK-888, NKP 608C, NKP 608A, CGP 60829, SR 48968 (Saredutant) , SR 140333 (Nolpitantium besilate / chloride), LY 303 870 (Lanepitant), MEN-11420 (Nepadutant), SB 223412, MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, SR-144190, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, Aprepitant (MK-869), L-754030, CJ-11974, L-758298, DNK -33A, 6b-1, CJ-11974, TAK-637, GR 205171 and the arylglycinamide derivatives of the general formula 3

wherein

R ^"1 and R ² together with the N to which they are attached form a ring of the formula

form where r and s are 2 or 3;

R ⁶ H, -Cη-Cs-alkyl, C3-C5-alkenyl, propynyl, hydroxy (C2-C4) alkyl, methoxy (C2-C-4) alkyl, di (Cι-C3) alkylamino (C2-C4) alkyl , Amino (C2-C4) alkyl, amino, di (C- | -C3) alkylamino, monofluoro- to perfluoro (C- | - C2) alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,

R ^{7 has} one of the meanings (a) to (d),

(a) Hydroxy

(b) 4-piperidinopiperidyl, (c)

R ¹⁶

-N

\ s 17

R

in which R ^ ⁶ and R ¹⁷ independently of one another are H, (-C-C4) alkyl, (C3-C6) cycloalkyl, hydroxy (C2-C4) alkyl, dihydroxy (C2-C4) alkyl, (Cι -C3) alkoxy (C2- C4) alkyl, phenyl (C-ι- C4) alkyl or di (C- | -C3) alkylamino (C2-C4) alkyl,

R ⁸ denotes H, optionally in the form of their enantiomers and mixtures of

Enantiomers, optionally in the form of their racemates.

The abovementioned compounds of the formula 3 are known, for example, from international patent applications WO 96/32386, WO 97/32865 and WO 02/32865, to which reference is made here in full. Compound 2 is preferably selected from the group consisting of BIIF 1149, CP-122721, CGP 60829, MK-869, CJ-11974, GR 205171 and the arylglycinamide derivatives of the general formula 3, in which R1 and R ² together with the N they are bound, a ring of the formula

form where s is 2 or 3;

R ⁷ for a group

R ¹⁶

/

-N

^R stands

where R ¹⁶ and R ^ ⁷ independently of one another are H, (C-ι-C4) alkyl, (C3-C6) cycloalkyl, hydroxy (C2-C4) alkyl, dihydroxy (C2-C4) alkyl, (Cι-C3) alkoxy ( C2-C4) alkyl, phenyl (Cj-C4) alkyl or di (C- | -C3) alkylamino (C2-C4) alkyl,

R ⁸ denotes H, optionally in the form of their enantiomers and mixtures of the enantiomers, and optionally in the form of their racemates.

The compound 2 is particularly preferably selected from BIIF1149 and the arylglycinamide derivatives of the general formula 3, in which R ¹ and R ² together with the N to which they are attached form a ring of the formula

form where s is 2 and R ⁷ for a group

R .16

/

-N

\

R ¹⁷ stands,

wherein R ¹⁶ and R ^{17 are} independent of one another

H, (C-ι-C4) alkyl, (C3-C6) cycloalkyl, hydroxy (C2-C4) alkyl or

Are dihydroxy (C-2-C-4) alkyl,

R ⁸ denotes H, optionally in the form of their enantiomers and mixtures of the enantiomers, and optionally in the form of their

Racemates.

2 N- [2- (3,5-bis-trifluoromethylphenyl) ethyl] -2- {4 - [(3-hydroxypropyl) methylamino] piperidine-1- are very particularly preferred as compounds. yl} -N-methyl-2-phenyl-acetamide, N- [2- (3,5-bis-trifluoromethyl-phenyl) -ethyl] -2- [4- (2-hydroxy-1 - hydroxymethyl-ethylamino) - piperidin-1 -yl] -N-methyl-2-phenylacetamide, N- [2- (3,5-bis-trifluoromethyl-phenyl) -ethyl] -2- [4- (cyclopropylmethyl-methyl-amino) -piperidine- 1-yl] -N-methyl-2-phenyl-acetamide, N- [2- (3,5-bis-trifluoromethyl-ρhenyl) -ethyl] -2- {4 - [(2-hydroxy-ethyl) - ( 3-hydroxypropyl) amino] piperidin-1-yl} -N-methyl-2-phenyl-acetamide and N- [2- (3,5-bis-trifluoromethyl-phenyl) -ethyl] -2- { 4- [cyclopropylmethyl- (3-hydroxypropyl) amino] piperidin-1-yl} -N-methyl-2-phenyl-acetamide, optionally in the form of their enantiomers and mixtures of the enantiomers, and optionally in the form of their racemates.

Of particular importance is the N- [2- (3,5-bis-trifluoromethyl-phenyl) -ethyl] -2- [4- (2-hydroxy-1-hydroxymethyl-ethylamino) -piperidin-1-yl] -N -methyl-2-phenylacetamide, optionally in the form of its enantiomers, preferably in the form of its (S) -enantiomer, optionally in the form of the mixtures of the enantiomers, and optionally in the form of its racemates.

Unless otherwise defined, branched and unbranched alkyl groups with ibis 5 carbon atoms are considered as alkyl groups (also insofar as they are part of other radicals). Examples include: methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl (tert-butyl), etc. Here, from the definitions propyl, Butyl and pentyl die respective isomeric residues always included. Hydroxy or dihydroxyalkyl groups are alkyl groups which are substituted by one or two hydroxy groups.

Alkenyl groups (also insofar as they are part of other radicals) are branched and unbranched alkenyl groups with 3 to 5 carbon atoms, provided that they have at least one double bond, such as propenyl, isopropenyl, butenyl etc.

Cycloalkyl generally represents a saturated cyclic hydrocarbon radical having 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl etc.

Alkyloxy, which may also be referred to as alkoxy, stands for a straight-chain or branched alkyl group bonded via an oxygen atom. The methoxy group is particularly preferred.

In the context of the present invention, a reference to the aforementioned NK-j receptor antagonists 2 includes a reference to their pharmacologically acceptable acid addition salts which may exist.

According to the invention, the physiologically compatible acid addition salts which can be formed by 2 are understood to be pharmaceutically compatible salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid , According to the invention, preference is given to the salts of the compounds 2 which are selected from the group consisting of acetate, hydrochloride, hydrobromide, sulfate, phosphate, maleic acid and methanesulfonate.

The pharmaceutical combinations according to the invention from 1 and 2 are preferably administered by inhalation. Suitable inhalable powders, which are filled into suitable capsules (inhalettes) and applied by means of appropriate powder inhalers, can be used. As an alternative to this, inhalative use can also be carried out by applying more suitable ones

Inhalation aerosols take place. This also includes powdered inhalation aerosols, which contain, for example, HFA134a, HFA227 or their mixture as propellant. Inhalation can also be carried out using suitable solutions of the drug combination consisting of 1 and 2. One aspect of the present invention accordingly relates to a medicament which contains a combination of 1 and 2.

Another aspect of the present invention relates to a medicament which contains one or more salts i and one or more compounds 2, optionally in the form of their solvates or hydrates. Here too, the active substances can either be contained together in a single dosage form or in two separate dosage forms. According to the invention, preference is given to medicaments which contain the active compounds 1 and 2 in a single administration form.

Another aspect of the present invention relates to a medicament which, in addition to therapeutically effective amounts of 1 and 2, contains a pharmaceutically acceptable carrier or auxiliary. Another aspect of the present invention relates to a medicament which, in addition to therapeutically effective amounts of I and 2, contains no pharmaceutically acceptable carrier or auxiliary.

The present invention further relates to the use of 1 and 2 for the production of a therapeutically effective amount of medicament containing 1 and 2 for the treatment of inflammatory or obstructive respiratory diseases, in particular asthma or chronic obstructive pulmonary diseases (COPD), and their complications such as, for example, pulmonary hypertension , also allergic and non-allergic rhinitis, provided treatment with NKι ~ receptor antagonists is not contraindicated from a therapeutic point of view, by simultaneous or successive application.

The present invention further aims at the simultaneous or successive use of therapeutically effective doses of the combination of the above medicinal products 1 and 2 for the treatment of inflammatory and / or obstructive respiratory diseases, in particular asthma or chronic obstructive pulmonary disease (COPD), and their complications such as, for example, pulmonary hypertension, in addition, allergic and non-allergic rhinitis, provided treatment with NK -] receptor antagonists is not contraindicated from a therapeutic point of view, by simultaneous or successive application.

In the active compound combinations according to the invention from 1 and 2, constituents 1 and 2 can be present in the form of their enantiomers, mixtures of the enantiomers or in the form of the racemates. The ratios in which the two active ingredients 1 and 2 can be used in the active ingredient combinations according to the invention are variable. The active ingredients 1 and 2 can optionally be in the form of their solvates or hydrates. Depending on the choice of compounds 1 and 2, the weight ratios which can be used in the context of the present invention vary on account of the different molecular weight of the different compounds and on the basis of their different potency. As a rule, the pharmaceutical combinations according to the invention can contain the compounds 1 and 2 in weight ratios which are in a range from 1: 100 to 100: 1, preferably from 1:80 to 80: 1. In the particularly preferred pharmaceutical combinations which, in addition to a compound of the formula 1_, a compound selected from the group consisting of BIIF 1149, CGP 60829, MK-869, CJ-11974, GR 205171, N- [2- (3,5-bis- trifluoromethyl-phenyl) -ethyl] -2- {4 - [(3-hydroxypropyl) methylamino] piperidin-1-yl} -N-methyl-2-phenyl-acetamide, N- [2- ( 3,5-bis-trifluoromethyl-phenyl) -ethyl] -2- [4- (2-hydroxy-1-hydroxymethyl-ethylamino) -piperidin-1-yl] -N-methyl-2-phenylacetami, N- [2 - (3,5-bis-trifluoromethyl-phenyl) -ethyl3-2- [4- (cyclopropylmethyl-methyl-amino) - piperidin-1-yl] -N-methyl-2-phenyl-acetamide, N- [2- (3,5-bis-trifluoromethyl-phenyl) ethyl] -2- {4 - [(2-hydroxyethyl) - (3-hydroxypropyl) amino] piperidin-1-yl} -N-methyl -2-phenyl-acetamide and N- [2- (3,5-bis-trifluoromethyl-phenyl) -ethyl3-2- {4- [cyclopropylmethyl- (3-hydroxypropyl) amino] piperidin-1-yl } -N-methyl-2-phenyl-acetamide and the arylglycinamide derivatives of formula 3 as NK-j receptor antagonist 2, the weight ratios are from 1 to 2 particularly preferably in a range in which V and 2 are contained in ratios of 1:50 to 50: 1, further preferably from 1:20 to 20: 1.

For example and without restricting the scope of the invention thereto, preferred combinations according to the invention of 1 and 2 can contain the cation V and NK-j receptor antagonist 2 in the following weight ratios: 1:50; 1:49; 1:48; 1:47; 1:46; 1:45; 1:44; 1:43; 1:42; 1:41; 1:40; 1:39; 1:38; 1:37; 1:36; 1:35; 1:34; 1:33; 1:32; 1:31; 1:30; 1:29; 1:28; 1:27; 1:26; 1:25; 1:24; 1:23; 1:22; 1:21; 1:20; 1:19; 1:18; 1:17; 1:16; 1:15; 1:14; 1:13; 1:12; 1:11; 1:10; 1: 9; 1: 8; 1: 7; 1: 6; 1: 5; 1: 4; 1: 3; 1: 2; 1: 1; 2: 1; 3: 1; 4: 1; 5: 1; 6: 1; 7: 1; 8: 1; 9: 1; 10: 1; 11: 1; 12: 1; 13: 1; 14: 1; 15: 1; 16: 1; 17: 1; 18: 1; 19: 1; 20: 1.

The pharmaceutical compositions according to the invention containing the combinations of ₁ and 2 are normally administered so that 1 and 2 g together in dosages of 0.01 to 10000, preferably from 0.1 to 2000 g, more preferably from 1 to 1500μg, further preferably from 50 to 1200 / g per single dose are included. For example, combinations of ± and 2 according to the invention contain such a combination Amount of V and NKi receptor antagonist 2 that the total dose per single dose is 100 / yg, 105 / yg, 110 / yg, 115 / yg, 120 / yg, 125 / yg, 130 / yg, 135 / g, 140 / yg, 145 / yg, 150 / yg, 155 / yg, 160 / tg, 165 / yg, 170 / ^y g, 175 / ^y g, 180 / ^y g, 185 // g, 190 / yg, 195 / yg, 200 / yg, 205 / yg, 210 / yg, 215 / yg, 220 / yg, 225 / ^y g, 230 / ^y g, 235 // g, 240 / yg, 245 / g, 250 / yg, 255 / yg , 260 / yg, 265 / yg, 270 / yg, 275 / yg, 280 / ^y g, 285 / g, 290 / g, 295 / yg, 300 / yg, 305 / yg, 310 / yg, 315 / yg, 320 / yg, 325 / g, 330 / yg, 335μg, 340 / g, 345 / g, 350 / g, 355 / yg, 360 / yg, 365 / yg, 370 / yg, 375 / yg, 380 / yg, 385 / vg, 390 / yg, 395 / yg, 400 / g, 405 / yg, 410 / yg, 415 / yg, 420 / g, 425 / ^y g, 430 // g, 435 / yg, 440 / yg, 445 / ^y g, 450 / g, 455 / ^y g, 460 / g, 465 / g, 470 / yg, 475 / yg, 480 / yg, 485 / yg, 490 / yg, 495 / yg, 500 / g, 505 / ^y g, 510 / ^y g, 515 // g, 520 // g, 525 / yg, 530 // g, 535 / yg, 540 // g, 545 / vg, 550 / yg, 555 / ^y g , 560 / ^y g, 565 / ^y g, 570yg, 575 / vg, 580 / yg, 585 / yg, 590 / yg, 595 / g, 600 / yg, 605 / yg, 610 / ^y g, 615 g, 620 / g, 625 / yg, 630 / yg, 635 / yg, 640 / yg, 645 / yg, 650 / yg, 655 / yg, 660 / yg, 6 65 / ^y g, 670 / ^y g, 675 / ^y g, 680 / yg, 685 / yg, 690 / yg, 695yg, 700 / tg, 705 / yg, 710 / yg, 715 / yg, 720 / ^y g, 725 / ^y g, 730 / ^y g, 735 / yg, 740 / g, 745 / g, 750 / yg, 755 // g, 760 // g, 765 g, 770 / yg, 775 / yg, 780 / g , 785 / yg, 790 // g, 795 // g, 800 / yg, 805 / yg, 810 / yg, 815 / g, 820 / yg, 825 / yg, 830 / ^y g, 835 / vg, 840 / yg, 845 / yg, 850 / yg, 855 / yg, 860yg, 865 / yg, 870 / g, 875yg, 880yg, 885yg, 890 / g, 895yg, 900 / g, 905 / yg, 910 / yg, 915yg, 920yg, 925yg, 930yg, 935yg, 940yg, 945yg, 950 / g, 955 / g, 960 / yg, 965 / yg, 970 / yg, 975 / yg, 980yg, 985 // g, 990 / yg, 995 / yg , 1000 / vg, 1005 / yg, 1010 / yg, 1015 / yg, 1020 / yg, 1025yg, 1030 / yg, 1035yg, 1040 / yg, 1045 / g, 1050 / yg, 1055 / yg, 1060 / yg, 1065 / g, 1070 / g, 1075 // g, 1080yg, 1085 / vg, 1090 / yg, 1095 / yg, 1100 / yg or the like. The above-mentioned dosage suggestions per single dose are not to be regarded as limited to the explicitly stated numerical values, but only serve as dosage examples disclosed. Of course, dosages that fluctuate around the above-mentioned numerical values in a range of approximately +/- 2.5yg are of course also included in the presently explained values. In these dosage ranges, the active ingredients V and 2 can be contained in the weight ratios described above.

For example and without restricting the scope of the invention thereto, the combinations according to the invention from 1 and 2 may contain such an amount of V and NKi receptor antagonist 2 that 16.5 / yg V and 25 / yg 2, 16, 5 / ^y g V and 50yg 2, 16.5 / yg V and 100yg 2, 16.5yg V and 200yg 2, 16.5 / g V and 300 ^y g 2, 16.5yg V and 400 / yg 2, 16 , 5 ^y g V and 500 / yg 2, 16.5 / ^y g V and 600 / yg 2, 16.5 / ^y g V and 700 / yg 2, 16.5yg and 800 / yg 2, 16.5 / yg JT and 900yg 2, 16.5 / yg V and 1000 / yg 2, 33, 1 g and 25 / ^y g 2, 33, 1 / yg and 50yg 2, 33, 1 gr and 100 / yg 2, 33, 1 / g V and 200 // g 2, 33.1 ^y g V and 300 / yg 2, 33.1 // g V and 400yg 2, 33.1 yg V and 500 / yg 2, 33.1 / yg r and 600 / ^y g 2, 33.1 / yg V and 700 / yg 2, 33.1 yg V and 800 / yg 2, 33.1 / ^y g V and 900 // g 2, 33.1 ^y g V and 1000 / yg 2, 49.5 / g V and 25 / yg 2, 49.5 / yg V and 50 / ^y g 2, 49.5yg V and 100 ^y g 2, 49.5 / g V and 200 // g 2, 49.5 ^y g V and 300 / yg 2, 49.5 / yg V and 400 / yg 2, 49.5 / yg V and 500 / yg 2, 49.5 / yg V and 600 / yg 2, 49.5 / yg V and 700 / yg 2, 49, 5 / yg V and 800 yg 2, 49.5 / yg V and 900 / yg 2, 49.5 / yg V and 1000 / yg 2, 82.6 / yg V and 25 // g 2, 82.6 / yg V and 50 / yg 2, 82.6 / yg V and 100 / g 2, 82.6 yg V and 200 yg 2, 82.6 yg V and 300 // g 2, 82.6 / yg V and 400 // g 2, 82.6 / yg V and 500 / yg 2, 82.6 / yg r and 600 yg 2, 82.6 / yg r and 700 / yg 2, 82.6 ^y g V and 800 / yg 2, 82.6 / yg r and 900 / yg 2, 82.6 // gr and 1000 / yg 2, 165.1 / yg r and 25 / yg 2, 165.1 / yg V and 50 / yg 2, 165.1 / yg V and 100 yg 2, 165.1 / yg and 200 / yg 2, 165.1 / yg V and 300 / yg 2, 165.1 / yg r and 400 / yg 2, 165.1 / yg r and 500 / yg 2, 165, 1 / yg r and 600 / yg 2, 165.1 / yg r and 700 / yg 2, 165.1 yg V and 800 / yg 2, 165.1 / yg V and 900 / yg 2, 165.1 // g V and 1000 / yg 2, 206.4 yg and 25 / yg 2, 206.4 / yg V and 50 / yg 2, 206.4 / yg r and 100 / yg 2, 206.4 yg V and 200 / yg 2, 206.4 / yg r and 300 / yg 2, 206.4 / yg and 400 / yg 2, 206.4 / yg r and 500 / yg 2 or 206, 4 / yg r and 600 / yg 2, 206.4 / yg r and 700 / yg 2, 206.4 / yg and 800 / yg 2, 206.4 // gr and 900 / yg 2, 206.4 // gr and 1000 / g 2, 412.8 / yg V and 25 / yg 2, 412.8 / yg and 50 / yg 2, 412.8 / yg V and 100 / yg 2, 412.8 / yg r and 200 / yg 2, 412.8 / yg V and 300 / yg 2, 412.8 yg r and 400 / yg 2, 412.8 / yg V and 500 / yg 2 or 412.8 / yg r and 600 yg 2, 412.8 / yg V and 700 / g 2, 412.8 / yg V and 800 yg 2, 412.8 // gr and 900 / yg 2, 412.8 / yg V and 1000 / yg 2 can be applied.

If the combination of active ingredients in which 1 represents the bromide is used as the combination of 1 and 2 preferred according to the invention, the active ingredient amounts of r and 2 given above by way of example correspond to the subsequent amounts of 1 and 2: 20 / yg 1 and applied per single administration 25 // g 2, 20 / yg 1 and 50 / yg 2, 20 / yg 1 and 100 / yg 2, 20 / yg 1 and 200 / yg 2, 20 / yg 1 and 300 // g 2, 20 / yg 1 and 400 / yg 2, 20 / g 1 and 500 / yg 2, 20 yg 1 and 600 / yg 2, 20 / yg 1 and 700 / yg 2, 20 / yg 1 and 800 / yg 2, 20 / yg 1 and 900 / yg 2, 20 / yg 1 and

1000 / yg 2, 40 / yg 1 and 25 / yg 2, 40 / yg 1 and 50 / yg 2, 40 / yg 1 and 100 / yg 2, 40 / yg 1 and 200 / yg 2, 40 / yg 1 and 300 yg 2, 40 yg 1 and 400 / yg 2, 40 yg 1 and 500 / yg 2, 40 / yg 1 and 600 / yg 2, 40 / yg I and 700 / yg 2, 40 yg 1 and 800 / yg 2 , 40 / ^y g 1 and 900 / yg 2, 40 / yg 1 and 1000 / yg 2, 60 / yg 1 and 25 / ^y g 2, 60 // g 1 and 50 / g 2, 60 / ^y g 1 and 100 / yg 2, 60 // g 1 and 200 yg 2, 60 / yg 1 and 300 / ^y g 2, 60 / yg 1 and 400 // g 2, 60 / ^y g 1 and 500 / yg 2, 60 / yg 1 and 600 / yg 2, 60 ^y g 1 and 700 / yg 2, 60 / yg 1 and 800 / ^y g 2, 60 / yg 1 and 900 / yg 2, 60 / yg 1 and 1000 / yg 2, 100 / ^y g 1 and 25 / yg 2, 100 / yg 1 and 50 / ^y g 2, 100 / yg 1 and 100 / yg 2, 100 yg 1 and 200 / yg 2, 100 / yg I and 300 // g 2 , 100 // g 1 and 400 / yg 2, 100 / yg 1 and 500 / yg 2, 100 / yg 1 and 600 ^y g 2, 100 / yg I and 700 / ^y g 2, 100 // g 1 and 800 / yg 2, 100 / yg 1 and 900 / yg 2, 100 ^y g 1 and 1000 / yg 2, 200 / yg 1 and 25 / ^y g 2, 200 / yg 1 and 50 / yg 2, 200 / yg 1 and 100 / ^y g 2, 200 / ^y g 1 and 200 / yg 2, 200 // g 1 and 300 / yg 2, 200 yg 1 and 400 / yg 2, 200 / yg 1 and 500 / ^y g 2, 200 / yg 1 and 600 / ^y g 2, 200 / ^y g 1 and 700 / yg 2, 200 / yg 1 and 800 / yg 2, 200 / ^y g 1 and 900 / yg 2, 200 / yg 1 and 1000 / ^y g 2, 250 / yg 1 and 25 / yg 2, 250 yg 1 and 50 ^y g 2, 250 / yg 1 and 100 / yg 2, 250 / yg 1 and 200 / yg 2, 250 / yg 1 and 300 / yg 2, 250 / yg 1 and 400 // g 2, 250 / yg 1 and 500 / ^y g 2, 250 / yg I and 600 / yg 2, 250 / yg 1 and 700 / yg 2, 250 / yg 1 and 800 / yg 2, 250 / ^y g 1 and 900 / yg 2, 250 // g 1 and 1000 / yg 2, 500 / yg I and 25 / yg 2, 500 / yg 1 and 50 / yg 2, 500 / yg 1 and 100 / yg 2, 500 / yg 1 and 200 yg 2, 500 / yg 1 and 300 / yg 2, 500 / yg I and 400 / yg 2, 500 / yg 1 and 500 // g 2, 500 / yg 1 and 600 / yg 2, 500 / yg 1 and 700 / yg 2, 500 / yg 1 and 800 / yg 2, 500 yg 1 and 900 / yg 2 or 500 / yg 1 and 1000 / yg 2.

The active ingredient combinations according to the invention from 1 and 2 are preferably administered by inhalation. For this purpose, components 1 and 2 must be provided in inhalable dosage forms.

Inhalable dosage forms are inhalable powders, metered-dose aerosols containing propellant gas, or propellant-free inhalation solutions. Inhalable powders according to the invention containing the combination of active substances 1 and 2 can consist solely of the active substances mentioned or of a mixture of the active substances mentioned with physiologically compatible auxiliaries. In the context of the present invention, the term propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions. The dosage forms according to the invention can contain the active ingredient combination from 1 and 2 either together in one or in two separate dosage forms. These dosage forms which can be used in the context of the present invention are described in detail in the following part of the description.

A) Inhalation powder containing the active compound combinations according to the invention from 1 and 2:

The inhalable powders according to the invention can contain ± and 2 either alone or in a mixture with suitable physiologically acceptable excipients.

If the active ingredients 1 and 2 are contained in a mixture with physiologically acceptable auxiliaries, the following physiologically acceptable auxiliaries can be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose, trehalose), oligo and polysaccharides (for example dextrans), polyalcohols (for example sorbitol, mannitol, xylitol), salts (for example sodium chloride, calcium carbonate) or mixtures of these auxiliaries with one another. Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, in particular, but not exclusively, in the form of their hydrates. Lactose, most preferably lactose monohydrate, is used as an auxiliary as particularly preferred in the sense of the invention. In the context of the inhalable powders according to the invention, the auxiliaries have a maximum average particle size of up to 250 / ym, preferably between 10 and 150 / ym, particularly preferably between 15 and 80 / ym. If necessary, it may seem sensible to finer the above-mentioned auxiliary substances

Add auxiliary fractions with an average particle size of 1 to 9 / ym. The latter finer excipients are also selected from the group of excipients that can be used. Finally, to produce the inhalable powders according to the invention, micronized active ingredients 1 and 2, preferably with an average particle size of 0.5 to 10 / ym, particularly preferably 1 to 6 / ym, are admixed with the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronizing and by finally mixing the constituents are known from the prior art. The inhalable powders according to the invention can be provided and applied either in the form of a single powder mixture which contains both 1 and 2 or in the form of separate inhalable powders which contain only 1 and 2.

The inhalable powders according to the invention can be applied using inhalers known from the prior art.

Inhalation powders according to the invention, which in addition to ± and 2 also contain a physiologically acceptable auxiliary, can be applied, for example, by means of inhalers, which take a single dose from a supply by means of a measuring chamber, as described in US Pat. No. 4,570,630A, or via other apparatus, such as the one described are described in DE 3625 685 A, meter. The inhalable powders according to the invention, which in addition to 1 and 2 contain physiologically acceptable excipients, are preferably filled into capsules (for so-called inhalers), which are used in inhalers as described, for example, in WO 94/28958.

An inhaler which is particularly preferred for use of the pharmaceutical combination according to the invention in inhalettes can be seen in FIG. 1. This inhaler (handihaler) for inhaling powdered pharmaceuticals from capsules is characterized by a housing 1, containing two windows 2, a deck 3, in which there are air inlet openings and which is provided with a sieve 5 fastened via a sieve housing 4, one with a deck 3 connected inhalation chamber 6, on which a pusher 9 provided with two ground needles 7 and movable against a spring 8 is provided, and a pusher connected to the housing 1, the deck 3 and a cap 11 via an axis 10 Mouthpiece 12, and Lutdurchlaßlöcher 13 for adjusting the flow resistance.

If the inhalable powders according to the invention are to be filled into capsules (inhalettes) in the sense of the preferred use mentioned above, fill quantities of 1 to 30 mg, preferably 3 to 20 mg, preferably 5 to 10 mg inhalable powder per capsule are appropriate. According to the invention, these contain either together or in each case the doses per single dose already mentioned above for V and 2.

B) Inhalation aerosols containing propellant gas containing the active compound combinations according to the invention from 1 and 2:

Inhalation aerosols containing propellant gas according to the invention can contain Λ and 2 dissolved in the propellant gas or in dispersed form. Here, 1 and 2 can be contained in separate dosage forms or in a common dosage form, where 1 and 2 can either be both dissolved, both dispersed or in each case only one component dissolved and the other dispersed. The propellant gases which can be used to produce the inhalation aerosols according to the invention are known from the prior art. Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as chlorinated and / or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellant gases are halogenated alkane derivatives selected from the group consisting of TG11, TG 12, TG 134a and TG227. Of the above-mentioned halogenated hydrocarbons, the TG 134a (1,1, 1, 2-tetrafluoroethane) and the TG227 (1, 1, 1, 2,3,3,3-heptafluoropropane) and mixtures thereof are preferred according to the invention.

The inhalation aerosols containing propellant gas according to the invention can furthermore contain further constituents such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and agents for adjusting the pH. All of these components are known in the art.

The inhalation aerosols containing propellant gas according to the invention can contain up to 5% by weight of active ingredient 1 and / or 2. Aerosols according to the invention contain, for example, 0.002 to 5% by weight, 0.01 to 3% by weight, 0.015 to 2% by weight, 0.1 to 2% by weight, 0.5 to 2% by weight or 0.5 to 1 % By weight of active ingredient 1 and / or 2. If the active ingredients 1 and / or 2 are in dispersed form, the active ingredient particles preferably have an average particle size of up to 10 μm, preferably from 0.1 to 5 μm, particularly preferably from 1 to 5 μm.

The above-mentioned inhalation aerosols containing propellant gas according to the invention can be administered by means of inhalers known in the art (MDIs = metered dose inhalers). Accordingly, a further aspect of the present invention relates to medicaments in the form of propellant-containing aerosols as described above in connection with one or more inhalers suitable for the administration of these aerosols. The present invention further relates to inhalers, characterized in that they contain propellant-containing aerosols according to the invention described above. The present invention further relates to cartridges which can be used with a suitable valve in a suitable inhaler and which contain one of the above-mentioned inhalation aerosols containing propellant gas according to the invention. Suitable cartridges and methods for filling these cartridges with the inhalation aerosols containing propellant gas according to the invention are known from the prior art.

C) propellant-free inhalable solutions or suspensions containing the active compound combinations according to the invention from I and 2:

The active compound combination according to the invention is particularly preferably applied in the form of propellant-free inhalation solutions and inhalation suspensions. Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic, solutions. The solvent can only be water or it is a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70 percent by volume, in particular up to 60 percent by volume and particularly preferably up to 30 percent by volume. The remaining volume percentages are filled up with water. The solutions and suspensions containing 1 and 2, separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. Acids selected from inorganic or organic acids can be used to adjust this pH. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or Propionic acid and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active ingredients. Ascorbic acid, fumaric acid and citric acid are preferred among the organic acids. If appropriate, mixtures of the acids mentioned can also be used, in particular in cases of acids which, in addition to their acidifying properties, also have other properties, for example as flavorings, antioxidants or complexing agents, such as, for example, citric acid or ascorbic acid. According to the invention, hydrochloric acid is particularly preferably used to adjust the pH.

70

According to the invention, the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as a stabilizer or complexing agent can be dispensed with in the present formulation. Other embodiments include this connection (s). In such a preferred embodiment, the content based on sodium edetate is less than 100 mg / 100 ml, preferably less than 50 mg / 100 ml, particularly preferably less than 20 mg / 100 ml.

Inhalation solutions in which the sodium edetate content is 0 to 10 mg / 100 ml are generally preferred.

20th

Co-solvents and / or further auxiliaries can be added to the propellant-free inhalation solutions according to the invention.

Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols

25 - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. In this context, auxiliary substances and additives are understood to mean any pharmacologically acceptable substance which is not an active substance, but together with the active substance (s) in the pharmacologically suitable one

30 solvents can be formulated to match the qualitative properties of the

Improve drug formulation. These substances preferably have no or no significant or at least no undesirable pharmacological effect in the context of the desired therapy. The auxiliaries and additives include e.g. surfactants such as Soy lecithin, oleic acid, sorbitan esters, such as

35 polysorbates, polyvinylpyrrolidone other stabilizers, complexing agents,

Antioxidants and / or preservatives that ensure or extend the useful life of the finished pharmaceutical formulation, flavors. Vitamins and / or other additives known in the art. To The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.

The preferred auxiliary substances include antioxidants, such as, for example, ascorbic acid, unless already used for adjusting the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human organism.

Preservatives can be used to protect the formulation from contamination with germs. Suitable preservatives are those known from the prior art, in particular cetylpyridinium chloride,

Benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. The preservatives mentioned above are preferably present in concentrations of up to 50 mg / 100 ml, particularly preferably between 5 and 20 mg / 100 ml.

In addition to the solvent water and the active substance combination of X and 2, preferred formulations only contain benzalkonium chloride and sodium edetate. In another preferred embodiment, sodium edetate is dispensed with.

For the application of the propellant-free inhalation solutions according to the invention, there are particularly those inhalers which can nebulize a small amount of a liquid formulation in the therapeutically necessary dosage within a few seconds into an aerosol suitable for therapeutic inhalation. In the context of the present invention, those nebulizers are preferred in which an amount of less than 100 μL, preferably less than 50 μL, particularly preferably between 20 and 30 μL of active ingredient solution, preferably with a stroke to an aerosol with an average particle size of less than 20 μm, preferably less than 10 μm, can be atomized in such a way that the inhalable portion of the aerosol already corresponds to the therapeutically effective amount.

Such a device for propellant-free administration of a metered amount of a liquid medicinal product for inhalation use is described in detail, for example, in international patent application WO 91/14468 and also in WO 97/12687 (there in particular FIGS. 6a and 6b). The nebulizers described there are also known under the name Respimat ^® .

This nebuliser (Respimat ^®) may be advantageous to produce the inhalable aerosols according to the invention containing the combination of active substances and are used. 2 Because of its cylinder-like shape and a Handy size of less than 9 to 15 cm in length and 2 to 4 cm in width, this device can be carried by the patient at any time. The nebulizer sprays a defined volume of the drug formulation using high pressures through small nozzles, so that inhalable aerosols are formed.

Essentially, the preferred atomizer consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a storage container, characterized by a pump housing which is fastened in the upper housing part and which has a nozzle body with the nozzle at one end or nozzle arrangement carries, a hollow piston with valve body, an output flange in which the hollow piston is fastened, and which is in the

Upper housing part is - a locking mechanism, which is located in the upper housing part, a spring housing with the spring therein, which is rotatably mounted on the upper housing part by means of a rotary bearing, a lower housing part which is attached to the spring housing in the axial direction.

The hollow piston with valve body corresponds to a device disclosed in WO 97/12687. It projects partially into the cylinder of the pump housing and is arranged axially displaceably in the cylinder. In particular, reference is made to FIGS. 1-4 - in particular FIG. 3 - and the associated parts of the description. The hollow piston with valve body exerts a pressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured active ingredient solution on its high pressure side at the time the spring is triggered. Volumes of 10 to 50 microliters are preferred, volumes of 10 to 20 microliters are particularly preferred, and a volume of 15 microliters per stroke is very particularly preferred.

The valve body is preferably attached to the end of the hollow piston which faces the nozzle body.

The nozzle in the nozzle body is preferably microstructured, that is to say manufactured by micro technology. Microstructured nozzle bodies are disclosed, for example, in WO-94/07607; reference is hereby made to this document, in particular to FIG. 1 disclosed there and its description. The nozzle body consists, for example, of two firmly connected plates made of glass and / or silicon, of which at least one plate has one or more microstructured channels which connect the nozzle inlet side to the nozzle outlet side. On the nozzle outlet side there is at least one round or non-round opening of 2 to 10 micrometers deep and 5 to 15 micrometers wide, the depth preferably being 4.5 to 6.5 micrometers and the length being 7 to 9 micrometers.

In the case of a plurality of nozzle openings, preferably two, the jet directions of the nozzles in the nozzle body can run parallel to one another or they are inclined towards one another in the direction of the nozzle opening. In the case of a nozzle body with at least two nozzle openings on the outlet side, the jet directions can be inclined at an angle of 20 degrees to 160 degrees, an angle of 60 to 150 degrees is preferred, particularly preferably 80 to 100 °. The nozzle openings are preferably arranged at a distance of 10 to 200 micrometers, more preferably at a distance of 10 to 100 micrometers, particularly preferably 30 to 70 micrometers. Most preferred are 50 microns.

Accordingly, the jet directions meet in the vicinity of the nozzle openings.

The liquid pharmaceutical preparation hits the nozzle body at an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is atomized into an inhalable aerosol via the nozzle openings. The preferred particles. Droplet sizes of the aerosol are up to 20 micrometers, preferably 3 to 10 micrometers.

The locking mechanism contains a spring, preferably a cylindrical helical compression spring, as a store for the mechanical energy. The spring acts on the output flange as a jumping piece, the movement of which is determined by the position of a locking element. The path of the output flange is precisely limited by an upper and a lower stop. The spring is preferably via a force-transmitting gear, e.g. a screw-type thrust gear, tensioned by an external torque generated when the upper housing part is turned against the spring housing in the lower housing part. In this case, the upper part of the housing and the output flange contain a single or multi-speed wedge gear.

The locking member with engaging locking surfaces is arranged in a ring around the output flange. It consists, for example, of a radially elastically deformable ring made of plastic or metal. The ring is perpendicular to the plane Atomizer axis arranged. After tensioning the spring, the locking surfaces of the locking member slide into the path of the output flange and prevent the spring from relaxing. The locking element is triggered by a button. The trigger button is connected or coupled to the locking member. To release the locking mechanism, the release button is moved parallel to the ring plane, and preferably into the atomizer; the deformable ring is deformed in the plane of the ring. Structural details of the locking mechanism are described in WO 97/20590.

The lower part of the housing is pushed in the axial direction over the spring housing and covers the bearing, the drive of the spindle and the reservoir for the fluid.

When the atomizer is actuated, the upper housing part is rotated against the lower housing part, the lower housing part taking the spring housing with it. The spring is compressed and tensioned via the screw-type thrust gear, and the locking mechanism engages automatically. The angle of rotation is preferably an integer fraction of 360 degrees, e.g. 180 degrees. Simultaneously with the tensioning of the spring, the driven part in the upper part of the housing is shifted by a predetermined distance, the hollow piston is withdrawn inside the cylinder in the pump housing, whereby a part of the fluid is sucked out of the reservoir into the high-pressure space in front of the nozzle.

If necessary, a number of interchangeable storage containers containing the fluid to be atomized can be inserted and used in the atomizer. The storage container contains the aqueous aerosol preparation according to the invention.

The atomization process is initiated by gently pressing the trigger button. The barrage clears the way for the stripping section. The tensioned spring pushes the piston into the cylinder of the pump housing. The fluid exits the atomizer nozzle in atomized form.

Further structural details are disclosed in PCT applications WO 97/12683 and WO 97/20590, to which reference is hereby made.

The components of the atomizer (nebulizer) are made of a material that is suitable for their function. The housing of the atomizer and - as far as the function allows - other parts are preferably made of plastic, for example in the Injection molding process. Physiologically harmless materials are used for medical purposes.

FIGS. 6 a / b of WO 97/12687, to which reference is explicitly made at this point, describe the nebulizer (Respimat ©) with which the aqueous aerosol preparations according to the invention can advantageously be inhaled. Figure 6a of WO 97/12687 shows a longitudinal section through the atomizer with the spring under tension. Figure 6b of WO 97/12687 shows a longitudinal section through the atomizer with the spring relaxed. The upper housing part (51) contains the pump housing (52), at the end of which the holder (53) for the atomizer nozzle is attached. The nozzle body (54) and a filter (55) are located in the holder. The hollow piston (57) fastened in the output flange (56) of the locking tension mechanism partially projects into the cylinder of the pump housing. The hollow piston carries the valve body (58) at its end. The hollow piston is sealed by means of the seal (59). Inside the upper part of the housing is the stop (60), against which the output flange rests when the spring is relaxed. The stop (61) is located on the output flange, against which the output flange rests when the spring is tensioned. After tensioning the spring, the locking member (62) slides between the stop (61) and a support (63) in the upper part of the housing. The release button (64) is connected to the locking member. The upper housing part ends in the mouthpiece (65) and is closed with the clip-on protective cap (66).

The spring housing (67) with compression spring (68) is rotatably mounted on the upper part of the housing by means of the snap lugs (69) and rotary bearings. The lower housing part (70) is pushed over the spring housing. The exchangeable storage container (71) for the fluid (72) to be atomized is located within the spring housing. The storage container is closed with the stopper (73) through which the hollow piston protrudes into the storage container and with its end is immersed in the fluid (supply of active substance solution).

The spindle (74) for the mechanical counter is mounted in the outer surface of the spring housing. The drive pinion (75) is located at the end of the spindle which faces the upper housing part. The rider (76) sits on the spindle.

The nebulizer described above is suitable, the invention

Nebulize aerosol preparations into an aerosol suitable for inhalation.

If the formulation according to the invention nebulised using the method described above (Respimat ^®), the mass expelled, in at least 97%, preferably at least 98% of all actuations of the inhaler (hub) correspond to a defined amount with a tolerance range of at most 25%, preferably 20% of this amount. Between 5 and 30 mg of formulation are preferably applied as a defined mass per stroke, particularly preferably between 5 and 20 mg.

However, the formulation according to the invention can also be nebulized using inhalers other than those described above, for example jet stream inhalers.

Accordingly, a further aspect of the present invention relates to medicaments in the form of above-described propellant-free inhalable solutions or suspensions in combination with a suitable device for administering these formulations, preferably in conjunction with the Respimat ^®. Preferably the present invention to propellant-free inhalable solutions or suspensions characterized by the aims of the invention combination of active substances 1 and 2 in connection with the known under the name Respimat ^® device. Further, the present invention relates to the abovementioned devices for inhalation preferred Respimat ^®, in the fact that they contain according to the invention the propellant-free inhalable solutions or suspensions as described above.

The propellant-free inhalation solutions or suspensions according to the invention can, in addition to the solutions and suspensions intended for application in the Respimat, also be present as concentrates or sterile, ready-to-use inhalation solutions or suspensions. Ready-to-use formulations can be generated from the concentrates, for example, by adding isotonic saline solutions. Sterile, ready-to-use formulations can be applied using energy-operated stand-up or portable nebulisers that generate inhalable aerosols using ultrasound or compressed air according to the Venturi principle or other principles.

Accordingly, a further aspect of the present invention relates to medicaments in the form of propellant-free inhalable solutions or suspensions as described above, which are present as concentrates or sterile, ready-to-use formulations, in conjunction with a

Administration of these solutions suitable device, characterized in that it is an energy-operated standing or portable nebulizer that generates inhalable aerosols by means of ultrasound or compressed air according to the Venturi principle or other principles. The following examples serve to explain the present invention in more detail without, however, restricting the scope of the invention to the following exemplary embodiments.

Formulierunqsbeispiele

Inhalable powder: 1)

)

3)

4)

Claims

Patent claims

1) Medicinal products characterized by a content of one or more

Formula 1 anticholinergics

wherein

^" means in combination with one or more NK1 receptor antagonists (2), optionally in the form of their enantiomers, mixtures of the enantiomers or in the form of the racemates, optionally in the form of the solvates or hydrates and optionally together with a pharmaceutically acceptable

Excipient.

2) Medicament according to claim 1, characterized in that the active ingredients X and 2 are contained either together in a single dosage form or in two separate dosage forms.

3) Medicament according to one of claims 1 or 2, characterized in that in the compounds of the formula ¹

4) Medicament according to one of claims 1 to 3, characterized in that in the compounds of the formula XX ^" stands for bromide. ) Medicament according to one of claims 1 to 4, characterized in that 2 is selected from the group consisting of BIIF 1149, GP-122721,

FK-888, NKP 608C, NKP 608A, CGP 60829, SR 48968(Saredutant), SR

140333 (Nolpitantium besilate/chloride), LY 303 870 (Lanepitant), MEN-

11420 (Nepadutant), SB 223412, MDL-105172A, MDL-103896, MEN-11149,

MEN-11467, DNK 333A, SR-144190, YM-49244, YM-44778, ZM-274773,

MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030,

CJ-11974, L-758298, DNK-33A, 6b-l, CJ-11974, TAK-637, GR 205171 , N-[2-

(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(3-hydroxy-propyl)-methyl-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide , N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2 -phenylacetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-

(cyclopropylmethyl-methyl-amino)-piperidin-1-yl]-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4- [(2-hydroxy-ethyl)-

(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide, N-[2-

(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide and the

Arylglycinamide derivatives of the general formula 3

wherein

R ¹ and R ² together with the N to which they are attached form a ring of the formula

(CH ₂ ) ₂ \^

/

R° - N

\N-

/

^' (Cl-L 2h)

where r and s are 2 or 3; R ⁸ H, -Cι-C5-alkyl, C3-C5-alkenyl, propynyl, hydroxy(C2-C4)alkyl, methoxy(C2-C4)alkyl, di(Cι -C3)alkylamino(C2-C4)alkyl, amino (C2-C4)alkyl, amino, di(C-|-C-3)alkylannino, monofluoro to perfluoro

(C-|-C2)alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl means,

R ⁷ has one of the meanings (a) to (d), (a) hydroxy

(b) 4-piperidinopiperidyl, (c)

16

R

/

-N

\ 17

R

where R ^"18 and R ¹⁷ are independent of each other

H, (Cι-C4)alkyl, (C3-C6)cycloalkyl, hydroxy^-C^alkyl, dihydroxy(C2-C4)alkyl, (Ci -C3)alkoxy(C2-C4)alkyl, phenyl(Cι-C4) alkyl or di(Cι-C-3)alkylamino(C-2-C4)alkyl,

R ⁸ means H, optionally in the form of their enantiomers and mixtures

Enantiomers, optionally in the form of their racemates.

Medicament according to one of claims 1 to 5, characterized in that 2 is selected from the group consisting of BIIF 1149, CP-122721, CGP 60829, MK-869, CJ-11974, GR 205171, N-[2-(3, 5-Bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(3-hydroxy-propyl)-methyl-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide, N- [2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide, N-[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(cyclopropylmethyl-methyl-amino)-piperidin-1-yl]-N-methyl-2-phenyl-acetamide, N-[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidin-1-yl }-N-methyl-2-phenylacetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[cyclopropylimethyl-(3-hydroxy-propyl)-amino] -piperidin-1-yl}-N-methyl-2-phenylacetamide and den Arylglycinamide derivatives of the general formula 3, in which R ¹ and R ² together with the N to which they are bonded form a ring of the formula

R ⁷ / (CH ₂ ) ₂ \

N-a/ ^C

R (CH ₂ ) /

'2 p/'sS

form where s is 2 or 3;

^R7 for a group

^R16 /

-N,17

^R " stands,

wherein R ¹⁸ and R ¹⁷ are independently H, (C-ι-C4)alkyl, (C3-C6)cycloalkyl, hydroxy(C2-C4)alkyl, dihydroxy(C2-C-4)alkyl, (C-|-C3 )alkoxy(C2-C-4)alkyl,

are phenyl(Cι-C4)alkyl or di(C-|-C3)alkylamino(C-2-C4)alkyl,

R ⁸ means H, optionally in the form of their enantiomers and mixtures of the enantiomers, and optionally in the form of their racemates.

7) Medicament according to one of claims 1 to 6, characterized in that 2 (S)-N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy- 1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide or an acid addition salt thereof.

8) Medicament according to one of claims 1 to 7, characterized in that the weight ratios of X to 2 are in a range from 1:100 to 100:1, preferably from 1:80 to 80:1.

9) Medicament according to one of claims 1 to 8, characterized in that a single application corresponds to a dosage of the active ingredient combination 1 and 2 of 0.01 to 10,000/yg, preferably from 0.1 to 2,000/yg. 10) Medicament according to one of claims 1 to 9, characterized in that it is in the form of a dosage form suitable for inhalation.

11) Medicament according to claim 10, characterized in that it is a dosage form selected from the group of inhalation powders, propellant-containing metered aerosols and propellant-free inhalation solutions or suspensions.

12) Medicament according to claim 11, characterized in that it is an inhalation powder which contains contains together.

13) Inhalation powder according to claim 12, characterized in that the excipient has a maximum average particle size of up to 250 / ym, preferably between 10 and 150 / ym.

14) Capsules characterized by a content of ingestion powder according to claim 12 or 13.

15) Medicament according to claim 11, characterized in that it is an inhalation powder which only contains active ingredients 1 and 2 as components.

16) Medicament according to claim 11, characterized in that it is an inhalation aerosol containing propellant gas which contains 1 and 2 in dissolved or dispersed form.

17) Inhalation aerosol containing propellant gas according to claim 16, characterized in that it contains hydrocarbons such as n-propane, n-butane or isobutane or halogenated hydrocarbons such as chlorinated and / or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane as propellant gas. 18) Inhalation aerosol containing propellant gas according to claim 17, characterized in that the propellant gas represents TG11, TG 12, TG 134a, TG227 or mixtures thereof, preferably TG134a, TG227 or a mixture thereof.

19) Inhalation aerosol containing propellant gas according to claim 16, 1 or 18, characterized in that it optionally contains one or more further components selected from the group consisting of cosolvents, stabilizers, surface-active agents (surfactants), antioxidants, lubricants and agents for adjusting the pH value contains.

20) Inhalation aerosol containing propellant gas according to one of claims 16 to 19, characterized in that it can contain up to 5% by weight of active ingredient 1 and / or 2.

21) Medicament according to claim 11, characterized in that it is a propellant-free inhalation solution or suspension which contains water, ethanol or a mixture of water and ethanol as a solvent.

22) Inhalation solution or suspension according to claim 21, characterized in that the pH is 2 - 7, preferably 2 - 5.

23) Infusion solution or suspension according to claim 22, characterized in that the pH is adjusted by means of an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid or mixtures thereof.

24) Inhalation solution or suspension according to one of claims 21 to 23, characterized in that it optionally contains further co-solvents and / or auxiliary substances. 25) Inhalation solution or suspension according to claim 24, characterized in that it contains, as co-solvents, components which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol,

Polyoxyethylene alcohols and polyoxyethylene fatty acid esters.

26) Inhalation solution or suspension according to one of claims 24 or 25, characterized in that it contains surface-active substances, stabilizers, complexing agents, antioxidants and / or as auxiliary substances

Contains preservatives, flavorings, pharmacologically harmless salts and/or vitamins.

27) Inhalation solution or suspension according to claim 26, characterized in that it contains editic acid or a salt of the complexing agent

Editic acid, preferably sodium edetate, contains.

28) Inhalation solution or suspension according to claim 26 or 27, characterized in that they are antioxidant compounds selected from the group consisting of ascorbic acid, vitamin A, vitamin E and

Contains tocopherols.

29) Inhalation solution or suspension according to claim 26, 27 or 28, characterized in that it contains compounds selected from cetylpyridinium chloride, benzalkonium chloride, benzoic acid and

Contains benzoates.

30) Inhalation solution or suspension according to one of claims 24 to 29, characterized in that, in addition to the active ingredients 1 and 2 and the solvent, it only contains bezalkonium chloride and sodium edetate.

31) Inhalation solution or suspension according to one of claims 24 to 29, characterized in that, in addition to the active ingredients 1 and 2 and the solvent, it only contains benzalkonium chloride.

32) Inhalation solution or suspension according to one of claims 21 to 31, characterized in that it is a concentrate or a sterile, ready-to-use inhalation solution or suspension. 33) Use of a capsule according to claim 14 in an inhaler, preferably in a handihaler.

34) Use of an inhalation solution according to one of claims 21 to 31 for nebulization in an inhaler according to WO 91/14468 or an inhaler as described in Figures 6a and 6b of WO 97/12687.

35) Use of an inhalation solution according to claim 32 for nebulization in an energy-operated standing or transportable nebulizer, which produces inhalable aerosols using ultrasound or compressed air

Venturi principle or other principles generated.

36) Use of a composition according to one of claims 1 to 32 for the production of a medicament for the treatment of inflammatory or obstructive respiratory diseases.