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WO2001011933A2 - Pharmaceutical compositions comprising a 7-(2-aminoethyl)-benzothiazolone and a pde4 inhibitor - Google Patents

Pharmaceutical compositions comprising a 7-(2-aminoethyl)-benzothiazolone and a pde4 inhibitor Download PDF

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Publication number
WO2001011933A2
WO2001011933A2 PCT/GB2000/003114 GB0003114W WO0111933A2 WO 2001011933 A2 WO2001011933 A2 WO 2001011933A2 GB 0003114 W GB0003114 W GB 0003114W WO 0111933 A2 WO0111933 A2 WO 0111933A2
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WO
WIPO (PCT)
Prior art keywords
active ingredient
methyl
methoxyphenyl
dihydro
cyclopentyloxy
Prior art date
Application number
PCT/GB2000/003114
Other languages
French (fr)
Other versions
WO2001011933A3 (en
Inventor
Francis Ince
John Dixon
Philip Holt
Original Assignee
Astrazeneca Uk Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Astrazeneca Uk Limited filed Critical Astrazeneca Uk Limited
Priority to AU64602/00A priority Critical patent/AU6460200A/en
Publication of WO2001011933A2 publication Critical patent/WO2001011933A2/en
Publication of WO2001011933A3 publication Critical patent/WO2001011933A3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention relates to combinations of pharmaceutically active substances for use in the treatment of obstructive airways diseases.
  • a pharmaceutical composition comprising, in admixture, a first active ingredient (A) being 4-hydroxy-7-[2-
  • the invention also provides a pharmaceutical product comprising, in combination, a preparation of a first active ingredient (A) being 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]- propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, and a preparation of a second active ingredient (B) being a PDE4 inhibitor for sequential or separate use in therapy.
  • A a preparation of a first active ingredient (A) being 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]- propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof
  • B a preparation of a second active ingredient (B) being a PDE4 inhibitor for sequential or separate use in therapy.
  • the invention provides a kit comprising a preparation of a first active ingredient (A) being 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]propylsulphonyl]- ethylamino] ethyl]- 1 ,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, a preparation of a second active ingredient (B) being a PDE4 inhibitor, and instructions for the sequential or separate administration of the preparations to a patient in need thereof.
  • A being 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]propylsulphonyl]- ethylamino] ethyl]- 1 ,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof
  • B being a PDE4 inhibitor
  • the combination of active ingredients according to the invention is advantageous because it is beneficial in the treatment of obstructive airways diseases including chronic obstructive pulmonary disease (COPD); and asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness).
  • COPD chronic obstructive pulmonary disease
  • asthma such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness).
  • COPD chronic obstructive pulmonary disease
  • asthma such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness).
  • the active ingredient (A) is most preferably 4-hydroxy-7-[2-[2-[3-[2- phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one hydrochloride.
  • a PDE4 inhibitor is a compound that is capable of inhibiting the enzymatic activity of cyclic nucleotide phosphodiesterase 4 (PDE4) isozyme which is responsible for breakdown of cyclic adenosine monophosphate (cAMP) in airway smooth muscle and inflammatory cells.
  • PDE4 cyclic nucleotide phosphodiesterase 4
  • Methods for assaying phosphodiesterase activity are described, for example, by M.S. Barnette et al in J. Pharmacol. Exp. Ther., 273(2), 674-679 (1995), by TJ. Torphy and L.B. Cieslinski in Mol. Pharmacol, 37(2), 206 to 214 (1990) and by S. Jacobitz et al in Mol. Pharmacol, 51(6), 999 to 1006 (1997).
  • Examples of the active ingredient (B) which are PDE4 inhibitors include: cis-4-Cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylic acid, (SB 207499, Ariflo);
  • PDE4 inhibitors are known from WO 99/20280 whose disclosures are incorporated herein by reference.
  • the pharmaceutical composition of the invention may be prepared by mixing the first active ingredient (A) with the second active ingredient (B). Therefore, in another aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition which comprises mixing a first active ingredient (A) being 4-hydroxy-7-[2-[2- [3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]- 1 ,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, with a second active ingredient (B) being a PDE4 inhibitor.
  • the pharmaceutical composition of the invention will typically comprise a total amount of first active ingredient (A) and second active ingredient (B) in the range from 0.05 to 99 %w (per cent by weight), more preferably in the range from 0.10 to 70 %w, and even more preferably in the range from 0.10 to 50 %w, all percentages by weight being based on total composition.
  • the first and second active ingredients (A) and (B) may alternatively be administered sequentially or separately in any suitable order to treat obstructive airways diseases.
  • sequential is meant that the first and second active ingredients are administered one immediately after the other. They still have the desired effect if they are administered separately but less than about 4 hours apart, preferably less than about 2 hours apart, more preferably less than about 30 minutes apart.
  • the active ingredients may, and indeed usually will, be used in admixture with one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
  • pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
  • the dosages administered will, of course, vary with the first and second active ingredients (A) and (B) employed, the mode of administration, the treatment desired and the disorder indicated.
  • the total daily dosage of first active ingredient (A) is preferably in the range from 5 to 1500 ⁇ g, e.g. from 10 to 1450 ⁇ g or from 20 to 1400 ⁇ g
  • the second active ingredient (B) is administered orally
  • the total daily dosage of second active ingredient (B) is preferably in the range from 1 to 50 mg, particularly from 1, 2, 3, 4 or 5 to 40, preferably to 30 mg.
  • the pharmaceutical composition, pharmaceutical product or kit according to the invention may be administered as divided doses from 1 to 4 times a day, and preferably once or twice a day.
  • the first and second active ingredients (A) and (B) may be administered topically (to the lung and/or airways) in the form of solutions, suspensions, aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions.
  • metered dose inhaler devices may be used to administer the active ingredient(s), dispersed in a suitable propellant and with or without additional excipients such as ethanol, surfactants, lubricants or stabilising agents.
  • Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane
  • propellants e.g. heptafluoroalkane
  • propellants e.g. HFA-134a and HFA-227, each of which may be used alone or in combination with other propellants and/or surfactants and/or other excipients.
  • Nebulised aqueous suspensions or, preferably, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulations.
  • Dry powder inhalers may be used to administer the active ingredient(s), alone or in combination with a pharmaceutically-acceptable carrier, in the latter case either as a finely divided powder or as an ordered mixture.
  • the dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.
  • Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.
  • Tablets and gelatin capsules, which may be coated if desired, containing the active ingredient(s) may, for example, also include one or more diluents, carriers, binders, lubricants or stabilising agents.
  • I ⁇ jectable solutions of the active ingredient(s) may also contain, for example, one or more preservatives, stabilising agents, viscosity-regulating agents, emulsifying agents or buffering agents.
  • the present invention further provides the use of a pharmaceutical composition, pharmaceutical product or kit according to the invention in the manufacture of a medicament for the treatment of an obstructive airways disease.
  • the present invention provides a method of treating, or reducing the risk of, an obstructive airways disease in a patient suffering from, or at risk of, the disease, which comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition of the invention.
  • the present invention provides a method of treating, or reducing the risk of, an obstructive airways disease which comprises sequentially or separately administering (in any suitable order) to a patient suffering from, or at risk of, the disease
  • mice Female CR/CD rats weighing 250-300g were dosed orally at lml.kg "1 with either distilled water (DI ⁇ 2 0) or Ariflo (active ingredient (B)) (see table 2). Sixty (60) minutes later they were placed into open fronted holding cones that were attached to a cylindrical metal aerosol chamber.
  • DI ⁇ 2 0 distilled water
  • Ariflo active ingredient
  • the lavages were centrifuged at 1800 m for 10 min at 4°C.
  • the supernatant from tube A was kept for future mediator analysis, and the remaining supernatant poured away into Trigene.
  • the cell pellets from the remaining two tubes were resuspended in a total of lml HBSS.
  • a 1 in 10 dilution of the lavage suspension was made in Kimura's stain and using an improved Neubauer counting chamber, the number of neutrophils counted.
  • PDE4 inhibitors such as Ariflo are known to have anti-inflammatory properties and as the above data clearly demonstrate, such compounds in combination with the active ingredient (A) show an advantageous synergistic improvement in these properties.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides a pharmaceutical composition, pharmaceutical product or kit comprising a first active ingredient (A) being 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]-1,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, and a second active ingredient (B) being a PDE4 inhibitor, for use in the treatment of obstructive airways diseases.

Description

PHARMACEUTICAL COMPOSITIONS
The present invention relates to combinations of pharmaceutically active substances for use in the treatment of obstructive airways diseases.
In accordance with the present invention, there is therefore provided a pharmaceutical composition comprising, in admixture, a first active ingredient (A) being 4-hydroxy-7-[2-
[2-[3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, and a second active ingredient (B) being a PDE4 inhibitor.
The invention also provides a pharmaceutical product comprising, in combination, a preparation of a first active ingredient (A) being 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]- propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, and a preparation of a second active ingredient (B) being a PDE4 inhibitor for sequential or separate use in therapy.
In another aspect, the invention provides a kit comprising a preparation of a first active ingredient (A) being 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]propylsulphonyl]- ethylamino] ethyl]- 1 ,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, a preparation of a second active ingredient (B) being a PDE4 inhibitor, and instructions for the sequential or separate administration of the preparations to a patient in need thereof.
The combination of active ingredients according to the invention is advantageous because it is beneficial in the treatment of obstructive airways diseases including chronic obstructive pulmonary disease (COPD); and asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness). 4-Hydroxy-7-[2-[2-[3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l,3- benzothiazol-2(3H)-one and pharmaceutically acceptable salts thereof are described in WO 93/24473. The active ingredient (A) is most preferably 4-hydroxy-7-[2-[2-[3-[2- phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one hydrochloride.
A PDE4 inhibitor is a compound that is capable of inhibiting the enzymatic activity of cyclic nucleotide phosphodiesterase 4 (PDE4) isozyme which is responsible for breakdown of cyclic adenosine monophosphate (cAMP) in airway smooth muscle and inflammatory cells. Methods for assaying phosphodiesterase activity are described, for example, by M.S. Barnette et al in J. Pharmacol. Exp. Ther., 273(2), 674-679 (1995), by TJ. Torphy and L.B. Cieslinski in Mol. Pharmacol, 37(2), 206 to 214 (1990) and by S. Jacobitz et al in Mol. Pharmacol, 51(6), 999 to 1006 (1997).
Examples of the active ingredient (B) which are PDE4 inhibitors include: cis-4-Cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylic acid, (SB 207499, Ariflo);
4-[(3-Butoxy-4-methoxyphenyl)methyl] -2-imidazolidinone, (RO 20- 1724) ;
3-(3,4-Dihydro-2,4-dioxo-3-(phenylmethyl)pyrido[2,3-d]pyrimidin-l(2Η)-yl)-benzoic acid, methyl ester, (CP 77059);
5-[3-[( \S,2S,4R)- icyc\o[2.2.1 ]hept-2-yloxy]-4-methoxyphenyl]tetrahydro-2( 1H)- pyrimidinone, (CP 80633);
4-[(2R)-2-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]pyridine, (CDP 840);
3-(Cyclopentyloxy)-N-(3 ,5-dichloro-4-pyridinyl)-4-methoxybenzamide, (RP 73401 ) ; 8-Amino-l,3-bis(cyclopropylmethyl)-3,7-dihydro-lH-purine-2,6-dione, (BRL 61063); l-[3,5-Bis(2-methoxyethoxy)phenyl]-6,7-dimethoxy-3-methylisoquinoline, (MNS 949);
6-(3-Methyl-2-butenyl)-8-(3-nitrophenyl)pyrido[2,3-d]pyridazin-5(6H)-one, (RS 33793); (R)-N-Cyano-N-methyl-N"-[4-(l,4,5,6-tetrahydro-4-methyl-6-oxo-3- pyridazinyl)phenyl]guanidine, (SB 94836);
3-(4-Chlorophenyl)-3 ,7-dihydro- 1 -propyl- 1 H-purine-2,6-dione, (arofylline);
4-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidinone, (rolipram); 3,7-Dihydro-l,3-dimethyl-lH-purine-2,6-dione, (theophylline);
3,7-Dihydro-l,3-dimethyl-lH-purine-2,6-dione with 1,2-ethanediamine (2: 1), (aminophylline); l,3-Dibutyl-3,7-dihydro-7-(2-oxopropyl)-lH-purine-2,6-dione, (denbufylline);
3,7-Dihydro-3,7-dimethyl-l-(5-oxohexyl)-lH-purine-2,6-dione, (pentoxifylline); and 3,7-Dihydro-l-methyl-3-(2-methylpropyl)-lH-purine-2,6-dione, (EBMX).
Further PDE4 inhibitors are known from WO 99/20280 whose disclosures are incorporated herein by reference.
The pharmaceutical composition of the invention may be prepared by mixing the first active ingredient (A) with the second active ingredient (B). Therefore, in another aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition which comprises mixing a first active ingredient (A) being 4-hydroxy-7-[2-[2- [3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]- 1 ,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, with a second active ingredient (B) being a PDE4 inhibitor. The pharmaceutical composition of the invention will typically comprise a total amount of first active ingredient (A) and second active ingredient (B) in the range from 0.05 to 99 %w (per cent by weight), more preferably in the range from 0.10 to 70 %w, and even more preferably in the range from 0.10 to 50 %w, all percentages by weight being based on total composition.
The first and second active ingredients (A) and (B) may alternatively be administered sequentially or separately in any suitable order to treat obstructive airways diseases. By sequential is meant that the first and second active ingredients are administered one immediately after the other. They still have the desired effect if they are administered separately but less than about 4 hours apart, preferably less than about 2 hours apart, more preferably less than about 30 minutes apart.
The active ingredients may, and indeed usually will, be used in admixture with one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
For the above-mentioned therapeutic uses the dosages administered will, of course, vary with the first and second active ingredients (A) and (B) employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the first active ingredient (A) is administered by inhalation, the total daily dosage of first active ingredient (A) is preferably in the range from 5 to 1500 μg, e.g. from 10 to 1450 μg or from 20 to 1400 μg, and the second active ingredient (B) is administered orally, the total daily dosage of second active ingredient (B) is preferably in the range from 1 to 50 mg, particularly from 1, 2, 3, 4 or 5 to 40, preferably to 30 mg.
The pharmaceutical composition, pharmaceutical product or kit according to the invention may be administered as divided doses from 1 to 4 times a day, and preferably once or twice a day.
The first and second active ingredients (A) and (B) may be administered topically (to the lung and/or airways) in the form of solutions, suspensions, aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions. For example metered dose inhaler devices may be used to administer the active ingredient(s), dispersed in a suitable propellant and with or without additional excipients such as ethanol, surfactants, lubricants or stabilising agents.
Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane
(e.g. heptafluoroalkane) propellants, or mixtures of any such propellants. Especially preferred propellants are HFA-134a and HFA-227, each of which may be used alone or in combination with other propellants and/or surfactants and/or other excipients.
Nebulised aqueous suspensions or, preferably, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulations.
Dry powder inhalers may be used to administer the active ingredient(s), alone or in combination with a pharmaceutically-acceptable carrier, in the latter case either as a finely divided powder or as an ordered mixture. The dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.
Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.
Tablets and gelatin capsules, which may be coated if desired, containing the active ingredient(s) may, for example, also include one or more diluents, carriers, binders, lubricants or stabilising agents.
Iηjectable solutions of the active ingredient(s) may also contain, for example, one or more preservatives, stabilising agents, viscosity-regulating agents, emulsifying agents or buffering agents. The present invention further provides the use of a pharmaceutical composition, pharmaceutical product or kit according to the invention in the manufacture of a medicament for the treatment of an obstructive airways disease.
Also, the present invention provides a method of treating, or reducing the risk of, an obstructive airways disease in a patient suffering from, or at risk of, the disease, which comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition of the invention.
Still further, the present invention provides a method of treating, or reducing the risk of, an obstructive airways disease which comprises sequentially or separately administering (in any suitable order) to a patient suffering from, or at risk of, the disease
(a) a (therapeutically effective) dose of a first active ingredient (A) being 4-hydroxy-7-[2- [2-[3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof; and
(b) a (therapeutically effective) dose of a second active ingredient (B) being a PDE4 inhibitor.
The present invention will now be further described with reference to the following illustrative example.
Example 1 Pharmacological Analysis
Female CR/CD rats weighing 250-300g were dosed orally at lml.kg"1 with either distilled water (DIΗ20) or Ariflo (active ingredient (B)) (see table 2). Sixty (60) minutes later they were placed into open fronted holding cones that were attached to a cylindrical metal aerosol chamber. Their noses were exposed to an aerosol of either saline or 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l,3- benzothiazol-2(3H)-one hydrochloride (active ingredient (A)) (see table 2) for 30 minutes before being exposed, for another 30 min, to an aerosol of O.lmg.mf1 lipopolysaccharide (LPS). Aerosols were generated using two jet nebulisers to each column with airflow of 12 l.min"1 (6 l.min"1 per nebuliser). 10 ml of agent was placed into each nebuliser at the beginning of the aerosol challenge and after 15 min aerosolisation the solution was removed and replaced with fresh.
Table 2 Experimental groups
Figure imgf000008_0001
End points
Six hours after LPS exposure the rats from each group were terminally anaesthetised with 0.5ml Euthatal and blood samples taken from the dorsal vena cava for analysis in Clinical Pathology. Following exsanguination, the trachea was exposed and cannulated, the lungs were lavaged with 3 x 3ml aliquots of Hanks Buffered Salt Solution (HBSS). Each 3ml was gently pushed in and, while gently massaging the chest, withdrawn 10 seconds later. The first wash was placed into a 15ml conical polypropylene centrifuge tube A while the second and third washes were pooled in similar tubes. Samples were kept on ice at all times. The lavages were centrifuged at 1800 m for 10 min at 4°C. The supernatant from tube A was kept for future mediator analysis, and the remaining supernatant poured away into Trigene. The cell pellets from the remaining two tubes were resuspended in a total of lml HBSS. A 1 in 10 dilution of the lavage suspension was made in Kimura's stain and using an improved Neubauer counting chamber, the number of neutrophils counted. The number of cells found for each rat was calculated using the following formula: Number of cells x dilution (10) x volume (lml) = total cell count per rat (xlO6).
All results are expressed as percentage inhibition of the vehicle LPS treated group. Statistical significance was evaluated using a Mann-Whitney U-test following a Kruskal- Wallis (non-parametric ANOVA) and significance was accepted when p<0.05.
Results
Figure imgf000009_0001
* p<0.05 using a Mann- Whitney U-test following a Kruskal-Wallis
PDE4 inhibitors such as Ariflo are known to have anti-inflammatory properties and as the above data clearly demonstrate, such compounds in combination with the active ingredient (A) show an advantageous synergistic improvement in these properties.

Claims

C L A I M S
1. A pharmaceutical composition comprising, in admixture, a first active ingredient (A) being 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]- 1,3- benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, and a second active ingredient (B) being a PDE4 inhibitor.
2. A composition according to claim 1, wherein, as first active ingredient (A), 4-hydroxy- 7-[2-[2-[3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)- one hydrochloride is used.
3. A composition according to claim 1 or claim 2, wherein the second active ingredient (B) is: cw-4-Cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylic acid, 4-[(3-Butoxy-4-methoxyphenyl)methyl]-2-imidazolidinone,
3-(3,4-Dihydro-2,4-dioxo-3-(phenylmethyl)pyrido[2,3-d]pyrimidin-l(2Η)-yl)-benzoic acid, methyl ester,
5-[3-[(l.S,25,4R)-Bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl]tetrahydro-2(lH)- pyrimidinone, 4-[(2R)-2-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]pyridine,
3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridinyl)-4-methoxybenzamide, 8-Amino-l,3-bis(cyclopropylmethyl)-3,7-dihydro-lH-purine-2,6-dione, l-[3,5-Bis(2-methoxyethoxy)phenyl]-6,7-dimethoxy-3-methylisoquinoline, 6-(3-Methyl-2-butenyl)-8-(3-nitrophenyl)pyrido[2,3-d]pyridazin-5(6H)-one, (R)-N-Cyano-N,-methyl-N"-[4-( 1 ,4,5,6-tetrahydro-4-methyl-6-oxo-3- pyridazinyl)phenyl] guanidine,
3,7-Dihydro- 1 -methyl-3-(2-methylpropyl)- 1 H-purine-2,6-dione, arofylline, rolipram, theophylline, aminophylline, denbufylline or pentoxifylline.
4. A process for the preparation of a pharmaceutical composition as defined in claim 1 which comprises mixing a first active ingredient (A) being 4-hydroxy-7-[2-[2-[3-[2- phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, with a second active ingredient (B) being a PDE4 inhibitor.
5. Use of a pharmaceutical composition as claimed in any one of claims 1 to 3 in the manufacture of a medicament for the treatment of an obstructive airways disease.
6. Use according to claim 5 wherein the obstructive airways disease is chronic obstructive pulmonary disease or asthma.
7. A method of treating, or reducing the risk of, an obstructive airways disease in a patient suffering from, or at risk of, the disease, which comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition as defined in any one of claims 1 to 3.
8. A method according to claim 7, wherein the obstructive airways disease is chronic obstructive pulmonary disease or asthma.
9. A pharmaceutical product comprising, in combination, a preparation of a first active ingredient (A) being 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]propylsulphonyl]- ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, and a preparation of a second active ingredient (B) being a PDE4 inhibitor for sequential or separate use in therapy.
10. A product according to claim 9, wherein, as first active ingredient (A), 4-hydroxy-7-[2- [2-[3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one hydrochloride is used.
11. A product according to claim 9 or claim 10, wherein the second active ingredient (B) is: cw-4-Cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylic acid, 4-[(3-Butoxy-4-methoxyphenyl)methyl]-2-imidazolidinone, 3-(3,4-Dihydro-2,4-dioxo-3-(phenylmethyl)pyrido[2,3-d]pyrimidin-l(2H)-yl)-benzoic acid, methyl ester,
5-[3-[(15,2_ ,4R)-Bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl]tetrahydro-2(lH)- pyrimidinone,
4-[(2R)-2-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]pyridine, 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridinyl)-4-methoxybenzamide,
8-Amino-l,3-bis(cyclopropylmethyl)-3,7-dihydro-lH-purine-2,6-dione, l-[3,5-Bis(2-methoxyethoxy)phenyl]-6,7-dimethoxy-3-methylisoquinoline, 6-(3-Methyl-2-butenyl)-8-(3-nitrophenyl)pyrido[2,3-d]pyridazin-5(6H)-one, (R)-N-Cyano-N,-methyl-N"-[4-(l,4,5,6-tetrahydro-4-methyl-6-oxo-3- pyridazinyl)phenyl]guanidine,
3,7-Dihydro- 1 -methyl-3-(2-methylpropyl)- 1 H-purine-2,6-dione, arofylline, rolipram, theophylline, aminophylline, denbufylline or pentoxifylline.
12. Use of a product as claimed in any one of claims 9 to 11 in the manufacture of a medicament for the treatment of an obstructive airways disease.
13. Use according to claim 12 wherein the obstructive airways disease is chronic obstructive pulmonary disease or asthma.
14. A kit comprising a preparation of a first active ingredient (A) being 4-hydroxy-7-[2-[2- [3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l ,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof, a preparation of a second active ingredient (B) being a PDE4 inhibitor, and instructions for the sequential or separate administration of the preparations to a patient in need thereof.
15. A kit according to claim 14, wherein, as first active ingredient (A), 4-hydroxy-7-[2-[2- [3-[2-phenylethoxy]propylsulphonyl]ethylamino]ethyl]-l,3-benzothiazol-2(3H)-one hydrochloride is used.
16. A kit according to claim 14 or claim 15, wherein the second active ingredient (B) is: i'-4-Cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylic acid, 4-[(3-Butoxy-4-methoxyphenyl)methyl]-2-imidazolidinone,
3-(3,4-Dihydro-2,4-dioxo-3-(phenylmethyl)pyrido[2,3-d]pyrimidin- l (2Η)-yl)-benzoic acid, methyl ester, 5-[3-[(15,25,4R)-Bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl]tetrahydro-2(lH)- pyrimidinone,
4-[(2R)-2-[3-(Cyclopentyloxy)-4-methoxyρhenyl]-2-phenylethyl]pyridine, 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridinyl)-4-methoxybenzamide, 8-Amino-l ,3-bis(cyclopropylmethyl)-3,7-dihydro-lH-purine-2,6-dione, l-[3,5-Bis(2-methoxyethoxy)phenyl]-6,7-dimethoxy-3-methylisoquinoline,
6-(3-Methyl-2-butenyl)-8-(3-nitrophenyl)pyrido[2,3-d]pyridazin-5(6H)-one, (R)-N-Cyano-N'-methyl-N"- [4-( 1 ,4,5 ,6-tetrahydro-4-methyl-6-oxo-3- pyridazinyl)phenyl]guanidine,
3 ,7-Dihydro- 1 -methy l-3-(2-methylpropyl)- 1 H-purine-2,6-dione, arofylline, rolipram, theophylline, aminophylline, denbufylline or pentoxifylline.
17. A method of treating, or reducing the risk of, an obstructive airways disease which comprises sequentially or separately administering to a patient suffering from, or at risk of, the disease (a) a dose of a first active ingredient (A) being 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]- propylsulphonyl]ethylamino]ethyl]-l ,3-benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof; and (b) a dose of a second active ingredient (B) being a PDE4 inhibitor.
PCT/GB2000/003114 1999-08-18 2000-08-14 Pharmaceutical compositions comprising a 7-(2-aminoethyl)-benzothiazolone and a pde4 inhibitor WO2001011933A2 (en)

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US8058294B2 (en) 2007-02-08 2011-11-15 Astrazeneca Ab Pharmaceutical salts of N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-napthyl)ethoxy]propanamide
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US7345060B2 (en) 2003-11-21 2008-03-18 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US7838535B2 (en) 2003-11-21 2010-11-23 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US7842704B2 (en) 2003-11-21 2010-11-30 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US8247564B2 (en) 2003-11-21 2012-08-21 Theravance, Inc. Compounds having BETA2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US7709511B2 (en) 2005-08-09 2010-05-04 Astrazeneca Ab Benzothiazolone derivatives
US7951954B2 (en) 2006-03-14 2011-05-31 Astrazeneca Ab Bezothiazol derivatives as Beta2 adrenoreceptor agonists
US7700782B2 (en) 2006-12-20 2010-04-20 Astrazeneca Ab Compounds 569
US8058294B2 (en) 2007-02-08 2011-11-15 Astrazeneca Ab Pharmaceutical salts of N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-napthyl)ethoxy]propanamide
EP2255189A4 (en) * 2008-02-07 2012-05-02 Philadelphia Children Hospital COMPOSITIONS AND METHODS FOR MODULATING G-PROTEIN SIGNALING IN THE TREATMENT OF ASTHMA
US8569229B2 (en) 2008-02-07 2013-10-29 The Children's Hospital Of Philadelphia Compositions and methods which modulate G-protein signaling for the treatment of inflammatory disorders such as asthma and allergic conjunctivitis
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