MRP IV INHIBITORS FOR THE TREATMENT OF RESPIRATORY DISEASES

• US 20060286041A1
• Filed: 06/16/2006
• Published: 12/21/2006
• Est. Priority Date: 06/17/2005
• Status: Abandoned Application

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Goeggel, Rolf, Cui, Yunhai
• Application Number:
  US11/424,596
• Publication Number:
  US 20060286041A1
• Time in Patent Office: Days
• US Class Current: 424/46
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics

Abstract

The present invention relates to the use of MRP4 inhibitors for the treatment of respiratory diseases, pharmaceutical compositions containing them and processes for the preparation thereof.

Claims

1. A method for treating a respiratory disease in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one MRP 4 inhibitor 1.

2. The method according to claim 1, wherein the MRP 4 inhibitor 1 is selected from the group consisting of N-Acetyl-dinitrophenyl-Cysteine (1.1), cGMP (1.2), Cholate (1.3), Diclofenac (1.4), Dehydroepiandrosterone 3-glucuronide (1.5), Dehydroepiandrosterone 3-sulphate (1.6), Dilazep (1.7), Dinitrophenyl-S-glutathione (1.8), Estradiol 17-O-glucuronide (1.9), Estradiol 3,17-disulphate (1.10), Estradiol 3-glucuronide (1.1), Estradiol 3-sulphate (1.12), Estrone 3-sulphate (113), Flurbiprofen (1.14), Folate (1.15), N5-formyl-tetrahydrofolate (1.16), Glycocholate (1.17), Glycolithocholic acid sulphate (1.18), Ibuprofen (1.19), Indomethacin (1.20), Indoprofen (1.21), Ketoprofen (22), Lithocholic acid sulphate (23), Methotrexate (1.24), MK571 ((E)-3-[[[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid;

1.25), α

-Naphthyl-β

-D-glucuronide (1.26), Nitrobenzyl mercaptopurine riboside (27), Probenecid (1.28), PSC833 (1.29), Sildenafil (1.30), Sulfinpyrazone (1.31), Taurochenodeoxycholate (1.32), Taurocholate (33), Taurodeoxycholate (1.34), Taurolithocholate (0.35), Taurolithocholic acid sulphate (1.36), Topotecan (1.37), Trequinsin (1.38) and Zaprinast (1.39), optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts and the hydrates thereof.

3. A pharmaceutical composition comprising at least one MRP 4 inhibitor 1 wherein the pharmaceutical composition is a formulation suitable for inhalation.

4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is selected from the group consisting of inhalable powders, propellant-driven metered-dose aerosols and propellant-free inhalable solutions or suspensions.

5. The pharmaceutical composition according to claim 3, wherein the MRP 4 inhibitor 1 is selected from the group consisting of N-Acetyl-dinitrophenyl-Cysteine (1.1), cGMP (1.2), Cholate (1.3), Diclofenac (1.4), Dehydroepiandrosterone 3-glucuronide (1.5), Dehydroepiandrosterone 3-sulphate (1.6), Dilazep (1.7), Dinitrophenyl-S-glutathione (1.8), Estradiol 17-β

-glucuronide (1.9), Estradiol 3,17-disulphate (1.10), Estradiol 3-glucuronide (1.11), Estradiol 3-sulphate (1.12), Estrone 3-sulphate (1.13), Flurbiprofen (1.14), Folate (1.15), N5-formyl-tetrahydrofolate (1.16), Glycocholate (1.17), Glycolithocholic acid sulphate (1.18), Ibuprofen (1.19), Indomethacin (1.20), Indoprofen (1.21), Ketoprofen (1.22), Lithocholic acid sulphate (1.23), Methotrexate (1.24), MK571 ((E)-3-[[[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid;

1.25), α

-Naphthyl-β

-D-glucuronide (1.26), Nitrobenzyl mercaptopurine riboside (1.27), Probenecid (1.28), PSC833 (1.29), Sildenafil (0.30), Sulfinpyrazone (1.31), Taurochenodeoxycholate (1.32), Taurocholate (1.33), Taurodeoxycholate (1.34), Taurolithocholate (1.35), Taurolithocholic acid sulphate (1.36), Topotecan (1.37), Trequinsin (1.38) and Zaprinast (1.39), optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts and the hydrates thereof.

6. The pharmaceutical composition according to claim 3, further comprising a second active ingredient selected from the group consisting of betamimetics 2a, anticholinergics 2b, PDEIV-inhibitors 2c, steroids 2d, and LTD4 antagonists 2e, optionally together with a pharmaceutically acceptable excipient.

7. The pharmaceutical composition according to claim 6, wherein the betamimetic 2a is selected from the group consisting of albuterol (2a.1), bambuterol (2a.2), bitolterol (2a.3), broxaterol (2a.4), carbuterol (2a.5), clenbuterol (2a.6), fenoterol (2a.7), formoterol (2a.8), hexoprenaline (2a.9), ibuterol (2a.0), isoetharine (2a.11), isoprenaline (2a.12), levosalbutamol (2a.13), mabuterol (2a.14), meluadrine (2a.15), metaproterenol (2a.16), orciprenaline (2a.17), pirbuterol (2a.18), procaterol (2a.19), reproterol (2a.20), TD 3327 (2a.21), ritodrine (2a.22), salmeterol (2a.23), salmefamol (2a.24), soterenot (2a.25), sulphonterol (2a.26), tiaramide (2a.27), terbutaline (2a.28, tolubuterol (2a.29), CHF-4226 (=TA 2005 or carmoterol;

2a.30), HOKU-81 (2a.31), KUL-1248 (2a.32), 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfoneamide (2a.33), 5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (2a.34), 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone (2a.35), 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol (2a.36), 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol (2a.37), 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol (2a.38), 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol (2a.39), 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol (2a.40), 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 (2a.41), 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one (2a.42), 1-(4-amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)ethanol (2a.43), 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol (2a.44), and N-[2-Hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide (2a.45), optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts and the hydrates thereof.

8. The pharmaceutical composition according to claim 6, wherein the anticholinergic (2b) is selected from the group consisting of tiotropium salts (2b.1), oxitropium salts (2b.2), flutropium salts (0.3, ipratropium salts (0.4, glycopyrronium salts (2b.5), trospium salts (2b.6), an anticholinergic of formula 2b.7

wherein

X⁻

denotes an anion with a single negative charge, optionally in the form of the racemates, enantiomers or hydrates thereof,

and an anticholinergic of formula 2b.8

wherein R denotes either methyl (2b.8.1) or ethyl (2b.8.2) and wherein X⁻

has the meaning above, optionally in the form of the racemates, enantiomers or hydrates thereof.

9. The pharmaceutical composition according to claim 6, wherein the anticholinergic (2b) is selected from anticholinergics of formula 2b.9

wherein

A denotes a double-bonded group selected from the groups

X⁻

denotes an anion with a single negative charge;

R¹ and R² which may be identical or different denote a group selected from methyl, ethyl, n-propyl and iso-propyl, optionally substituted by hydroxy or fluorine;

R³, R⁴, R⁵ and R⁶, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF₃ or NO₂;

R⁷ denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, —

CH₂—

F, —

CH₂—

CH₂—

F, —

O—

CH₂—

F, —

O—

CH₂—

CH₂—

F, —

CH₂—

OH, —

CH₂—

CH₂—

OH, CF₃, —

CH₂—

OMe, —

CH₂—

CH₂—

OMe, —

CH₂—

OEt, —

CH₂—

CH₂—

OEt, —

O—

COMe, —

O—

COEt, —

O—

COCF₃, —

O—

COCF₃, fluorine, chlorine or bromine,

optionally in the form of the racemates, enantiomers or hydrates thereof.

10. The pharmaceutical composition according to claim 6, wherein the anticholinergic (2b) is selected from the compounds of formula 2b.10

wherein

A, X⁻

, R¹ and R² have the meanings given in claim 9, and wherein

R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R², which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF₃ or NO₂, while at least one of the groups R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are not hydrogen, optionally in the form of the racemates, enantiomers or hydrates thereof.

11. The pharmaceutical composition according to claim 6, wherein the anticholinergic (2b) is selected from the compounds of formula 2b.11

wherein

A and X⁻

have the meanings given in claim 9 and wherein

R¹⁵ denotes hydrogen, hydroxy, methyl, ethyl, —

CF₃, CHF₂ or fluorine;

R^1′

and R^2′

which may be identical or different, denote C₁-C₅-alkyl, optionally substituted by C₃-C₆-cycloalkyl, hydroxy or halogen,

or

R^1′

and R^2′

together denote a —

C₃-C₅-alkylene bridge;

R¹³, R¹⁴, R^13′

and R^14′

which may be identical or different, denote hydrogen, —

C₁-C₄-alkyl, —

C₁-C₄-alkyloxy, hydroxy, —

CF₃, —

CHF₂, CN, NO₂ or halogen,

optionally in the form of the racemates, enantiomers or hydrates thereof.

12. The pharmaceutical composition according to claim 6, wherein the anticholinergic (2b) is selected from anticholinergics of formula 2b.12

wherein X⁻

has the meaning given in claim 9, and wherein

D and B which may be identical or different, preferably identical, denote O, S, NH, CH₂, CH═

CH or N(C₁-C₄-alkyl);

R¹⁶ denotes hydrogen, hydroxy, —

C₁-C₄-alkyl, —

C₁-C₄-alkyloxy, —

C₁-C₄-alkylene-halogen, —

O—

C₁-C₄-alkylene-halogen, —

C₁-C₄-alkylene-OH, —

CF₃, CHF₂, —

C₁-C₄-alkylene-C₁-C₄-alkyloxy, —

O—

COC₁-C₄-alkyl, —

O—

COC₁-C₄-alkylene-halogen, —

C₁-C₄-alkylene-C₃-C₆-cycloalkyl, —

O—

COCF₃ or halogen;

R^1″

and R^2″

which may be identical or different, denote —

C₁-C₅-alkyl, optionally substituted by —

C₃-C₆-cycloalkyl, hydroxy or halogen,

or

R^1″

and R^2″

together denote a —

C₃-C₅-alkylene bridge;

R¹⁷, K¹⁸, R^17′

and R^18′

, which may be identical or different, denote hydrogen, —

C₁-C₄-alkyl, —

C₁-C₄-alkyloxy, hydroxy, —

CF₃, —

CHF₂, CN, NO₂ or halogen;

R^x and R^x′

which may be identical or different, denote hydrogen, —

C₁-C₄-alkyl, —

C₁-C₄-alkyloxy, hydroxy, —

CF₃, —

CHF₂, CN, NO₂ or halogen,

or

R^x and R^x′

together denote a single bond or one of the double-bonded groups O, S, NH, CH₂, CH₂—

CH₂, N(C₁-C₄-alkyl), CH(C₁-C₄-alkyl) and —

C(C₁-C₄-alkyl)₂,

optionally in the form of the racemates, enantiomers or hydrates thereof.

13. The pharmaceutical compositions according to claim 6, wherein the anticholinergic (2b) is selected from anticholinergics of formula 2b.13

wherein X⁻

has the meaning given in claim 9 and wherein

A′

denotes a double-bonded group selected from

R¹⁹ denotes hydroxy, methyl, hydroxymethyl, ethyl, —

CF₃, CHF₂ or fluorine;

R<sup>1′

″</sup>

and R<sup>2′

″</sup>

which may be identical or different, denote C₁-C₅-alkyl, optionally substituted by C₃-C₆-cycloalkyl, hydroxy or halogen,

or

R<sup>1′

″</sup>

and R<sup>2′

″</sup>

together denote a —

C₃-C₅-alkylene bridge;

R²⁰, R²¹R^20′

and R^21′

which may be identical or different, denote hydrogen, —

C₁-C₄-alkyl, —

C₁-C₄-alkyloxy, hydroxy, —

CF₃, —

CHF₂, CN, NO₂ or halogen,

optionally in the form of the racemates, enantiomers or hydrates thereof.

14. The pharmaceutical composition according to claim 6, comprising as the PDE IV-inhibitor 2c a compound selected from among enprofyllin (2c.1), theophyllin (2c.2), roflumilast (2c.3), ariflo (Cilomilast, 2c.4)), CP-325,366 (2c.5, BY343 (2c.6), D-4396 (Sch-351591, 2c.7), AWD-12-281 (GW-842470, 2c.8)), N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide (2c.9), NCS-613 (2c.10), pumafentine (2c.11), (−

)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide (2c.12), (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone (2c.13), 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′

-[N-2-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone (2c.14), cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid] (2e.15), 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one (2c.16), cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol] (2c.17), (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate (2c.18), (S)-(−

)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate (2e.19), 4-(3-cyclopentyloxy-4-methoxy-phenyl)-3-(1-hydroxy-ethyl)-3-methyl-pyrrolidine-1-carboxylic acid methyl ester (═

IC 485, 2c.20), CDP840 (2c.21), Bay-198004 (2c.22), D-4418 (2c.23), PD-168787 (2e.24), T-440 (2e.25), T-2585 (2c.26), arofyllin (2c.27), atizoram (2.28), V-11294A (2c.29), C1-1018 (2c.30), CDC-801 (2.31), CDC-3052 (2c.32), D-22888 (2c.33), YM-58997 (2c.34), Z-15370 (2c.35), 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine (2c.36), 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine (2c.37), and tetomilast (2c.38), optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.

15. The pharmaceutical composition according to claim 6, comprising as the steroid 2d a compound selected from the group consisting of prednisolone (2d.1), prednisone (2d.2), butixocortpropionate (2d.3), RPR-106541 (2d.4), flunisolide (2d.5), beclomethasone (2d.6), triamcinolone (2d.7), budesonide (2d.8), fluticasone (2d.9, mometasone (2d.10), ciclesonide (2d.11), rofleponide (2d.12), ST-126 (2d.13, dexamethasone (2d.14), (S)-fluoromethyl 6α

,9α

-difluoro-17α

-[(2-furanylcarbonyl)oxy]-11β

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothionate (2d.15), (S)-(2-oxo-tetrahydro-furan-3S-yl)6α

,9α

-difluoro-11β

-hydroxy-16α

-methyl-3-oxo-17α

-propionyloxy-androsta-1,4-diene-17β

-carbothionate (2d.16) and etiprednol-dichloroacetate (BNP-166, 2d.17), optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof.

16. The pharmaceutical composition according to claim 6, comprising as the LTD4 antagonist 2e a compound selected from among montelukast (2e.1), 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid (2e.2), 1-(((1 (R)-3 (3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropanacetic acid (2e.3), pranlukast (2e.4), zafirlukast (2e.5), [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]-phenyl]acetic acid (2e.6), MCC-847 (ZD-3523) (2e.7), MN-001 (2e.8), MEN-91507 (LM-1507) (2e.9), VUF-5078 (2e.10), VUF-K-8707 (2e.11) and L-733321 (2e.12), optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts thereof as well as optionally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof.