WO1997015298A1 - Combination of ltd, receptor antagonists with glucocorticosteroids - Google Patents

Combination of ltd, receptor antagonists with glucocorticosteroids Download PDF

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Publication number
WO1997015298A1
WO1997015298A1 PCT/EP1996/004391 EP9604391W WO9715298A1 WO 1997015298 A1 WO1997015298 A1 WO 1997015298A1 EP 9604391 W EP9604391 W EP 9604391W WO 9715298 A1 WO9715298 A1 WO 9715298A1
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Prior art keywords
hydrocortisone
acetate
betamethasone
sodium phosphate
prednisolone
Prior art date
Application number
PCT/EP1996/004391
Other languages
French (fr)
Inventor
Elmar-Reinhold Burchardt
Reiner Müller-Peddinghaus
Trevor S. Abram
Original Assignee
Bayer Aktiengesellschaft
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Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU72891/96A priority Critical patent/AU7289196A/en
Publication of WO1997015298A1 publication Critical patent/WO1997015298A1/en

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone

Definitions

  • the present invention relates to the combination of LTD 4 receptor antagonists with glucocorticosteroids (GCSs), in particular for the treatment of acute and chronic inflarnmatory disorders.
  • GCSs glucocorticosteroids
  • GCSs are used, because of their potent antiinflammatory effect, in the treatment of a large number of widely different inflammatory disorders.
  • GCSs modulate protein biosynthesis and are described as selective regulators of gene transcription. GCSs suppress the synthesis of cytokines and growth factors in inflammatory cells and the expression of adhesion molecules on their surface. It is likewise known that protein biosynthesis of orther gene products such as, for example, of lipocortin and of IL-6 ist induced.
  • Lipocortins are described as proteins regulating the activity of phospholipase A 2 , which is responsible for the release of free fatty acids from phospholipid- containing membranes. Lipocortins show an antiinflammatory effect in vitro and in vivo. One of the most important free fatty acids, arachidonic acid, is metabolized by the enzymatic action of cyclooxygenases and lipoxygenases, especially 5-lipoxygenase, and converted into a variety of proinflammatory mediators.
  • LTD 4 receptor antagonists are used for the treatment of inflammatory, especially of allergic asthma.
  • GCS represents the customary glucocortico ⁇ steroids such as, for example, amcinonide, beclomethasone dipropionate, betamethasone, betamethasone acetate, betamethasone benzoate, betamethasone di ⁇ propionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, carbenoxolone sodium, clocortolone acetate, clocortolone pivalate, cloprednol, corticotropin (injection), corticotropin (repository), corticotropin zinc hydroxide, cortisone acetate, cortivazole, descinolone acetonide, dexamethasone, dexa- methasone sodium phosphate, diflucortolone, diflucortolone pivalate, flucloronide, flumethasone, flumethasone pivalate, flunisolide, fluocinolone acetonide, fluocinomid
  • GCSs which are preferably mentioned are beclomethasone dipropionate, betamethasone, betamethasone acetate, betamethasone benzoate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, cortisone acetate, dexamethasone, dexamethasone sodium phosphate, diflucortolone, deflucortolone pivalate, flumethasone, flumethasone pivalate, hydrocortisone, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone cypionate, hydrocortisone sodium phosphate, fluticasone, hydrocortisone sodium succinate, hydrocortisone valerate, methylprednisilone, methylprednisiline acetate, methylprednisolone sodium phosphate, methyl ⁇ prednisolone sodium succinate, para
  • LTD 4 receptor antagonists within the scope of the invention are all substances which block the biological effect of the cysteinyl-leukotrienes LTC 4 and LTD 4 at their receptor (CysLTl).
  • preferred compounds are those of the gereral formula
  • X and Y denote, identically or differently, sulphur, sulphoxide, sulphone, an alkylene chain, -SCH 2 - or oxygen or a direct linkage,
  • o denotes a number from 1 to 5
  • a and B denote, identically or differently, carboxyl, carboxymethyl , tetrazolyl or tetrazolylmethyl or -CO 2 R 9 or -CH 2 CO 2 R 9 or -CONR 10 R n or cyano,
  • n denotes a number from 1 to 10
  • n denotes a number from 0 to 7
  • T and Z denote, identically or differently, oxygen or a direct linkage
  • R , R , R denote, identically or differently, hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano or nitro, R 9 denotes lower alkyl and
  • R 10 and R 11 denote hydrogen, lower alkyl, alkylsulphonyl or arylsulphonyl, or they form together an alkylene chain to form a ring,
  • Particularly preferred LTD 4 receptor antagonists are compounds of the formula (I) in which
  • X denotes sulphur, sulphone or a methylene group
  • Y denotes sulphur, a methylene group, -SCH-,- or a direct linkage
  • R 8 and R 3 denote H
  • R 2 is H or F
  • o is a number from 1, 2, 3 or 4,
  • n is a number from 2, 3, 4, 5 or 6,
  • n is a number from 0, 1 or 2
  • T denotes oxygen or a direct linkage
  • Z denotes oxygen or a direct linkage
  • A denotes carboxyl or an ester thereof
  • Very particularly preferred LTD 4 receptor antagonists are those of the formula (Ia) in which
  • R 1 and R 2 are identical or different and
  • glucocorticosteroids with the LTD 4 receptor antagonists can be used, on account of its specific properties, for the treatment of acute, chronic, autoimmune or non-autoimmune inflammations
  • GCS and LTD 4 receptor antagonists in the combination can be combined in one or second ratio depending on the action potency of the individual substances
  • Suitable indications are the treatment and prevention of inflammatory disorders of the airwagy such as allergies/asthma, bronchitis, emphysema, shock lung, pulmonary hypertension, and of the liver, intestine, kidney, pancreas, heart, nose, mouth, ears, eyes, central nervous system, muscles, connective tissue and joints, inflammations/rheumatism and oedemas, thromboses and thromboembolisms, ischaemias (disturbances of peripheral, cardiac and cerebral blood flow), infarcts (myocardial, cerebral, intestinal and other tissues), angina pectoris, inflammatory vascular disorders, arteriosclerosis, in tissue transplants, postoperative inflammations as well as vasodilatation, vessel transplant, dermatoses such as psoriasis, inflammatory dermatoses and inflammatory processes during infectious diseases (parasites, viruses, bacteria, fungi and oncoses).
  • inflammatory disorders of the airwagy such as allergies/asth
  • novel combination can be converted in a manner known per se, using inert, non-toxic, pharmaceutically suitable vehicles or solvents, into the customary perenteral formulations such as, for example, lyophilisates and solutions
  • the therapeutically effective combination should in each case be present in a concentration of about 0,5 to 90 % by weight, preferably from 5 to 70 % by weight, which is sufficient to reach the stated range of dosage
  • the combination can be used orally, subcutaneously, intramuscularly, intra ⁇ venously or topically as aerosol (lung), ointment/cream (skin) or solution (mucous membranes)
  • compositions can be produced in a conventional way by known methods, for example with the ancillary substance(s) or vehicle(s).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a combination of glucocorticosteroids with LTD4 receptor antagonists in medicaments for the treatment of inflammatory disorders, especially of the airways.

Description

Combination of LTD. receptor antagonists with glucocorticosteroids
The present invention relates to the combination of LTD4 receptor antagonists with glucocorticosteroids (GCSs), in particular for the treatment of acute and chronic inflarnmatory disorders.
It is known that GCSs are used, because of their potent antiinflammatory effect, in the treatment of a large number of widely different inflammatory disorders.
GCSs modulate protein biosynthesis and are described as selective regulators of gene transcription. GCSs suppress the synthesis of cytokines and growth factors in inflammatory cells and the expression of adhesion molecules on their surface. It is likewise known that protein biosynthesis of orther gene products such as, for example, of lipocortin and of IL-6 ist induced.
Lipocortins are described as proteins regulating the activity of phospholipase A2, which is responsible for the release of free fatty acids from phospholipid- containing membranes. Lipocortins show an antiinflammatory effect in vitro and in vivo. One of the most important free fatty acids, arachidonic acid, is metabolized by the enzymatic action of cyclooxygenases and lipoxygenases, especially 5-lipoxygenase, and converted into a variety of proinflammatory mediators.
This is why it has been assumed hitherto that the antiinflammatory effect of GCSs derives indirectly from the PLA2-inhibitory effect of lipocortins which are induced by GCSs.
It is additionaloly known that LTD4 receptor antagonists are used for the treatment of inflammatory, especially of allergic asthma.
On account of the mode of action hitherto described for the GCSs on eicosanoid release and the effect reported to date of the LTD4 receptor antagonists on in¬ flammations mediated by cysteinyl-leukotrienes, the additive effects of the combi¬ nation of the two substances were completely surprising.
It has been found that the combination of LTD4 receptor antagonists with GCSs is particularly suitable, on account of their surprising synergistic effect or for the treatment of acute and chronic inflammatory processes, in particular for the treatment of inflammatory airway disorders such as asthma.
Within the scope of the invention, GCS represents the customary glucocortico¬ steroids such as, for example, amcinonide, beclomethasone dipropionate, betamethasone, betamethasone acetate, betamethasone benzoate, betamethasone di¬ propionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, carbenoxolone sodium, clocortolone acetate, clocortolone pivalate, cloprednol, corticotropin (injection), corticotropin (repository), corticotropin zinc hydroxide, cortisone acetate, cortivazole, descinolone acetonide, dexamethasone, dexa- methasone sodium phosphate, diflucortolone, diflucortolone pivalate, flucloronide, flumethasone, flumethasone pivalate, flunisolide, fluocinolone acetonide, fluocinomide, fluocortolone, fluocortolone caproate, fluorometholone, fluperolone acetate, fluprednisolone, fluprednisolone valerate, flurandrenolide, formocortal, fluticasone, hydrocortisone, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone valerate, medrysone, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium phosphate, methylprednisolone sodium succinate, nivazole, paramethasone acetate, predni carb ate, prednisolone, prednisilone acetate, prednisolone hemisuccinate, prednisoline sodium phosphate, prednisolone sodium succinate, prednisiline tebutate, prednisone, prednival, ticabesone propionate, tralonide, triamcinolone, triamcinolone acetonide, triamcinolone acetonide sodium phosphate, triamcinolone diacetate and triamcinolone hexacetonide.
GCSs which are preferably mentioned are beclomethasone dipropionate, betamethasone, betamethasone acetate, betamethasone benzoate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, cortisone acetate, dexamethasone, dexamethasone sodium phosphate, diflucortolone, deflucortolone pivalate, flumethasone, flumethasone pivalate, hydrocortisone, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone cypionate, hydrocortisone sodium phosphate, fluticasone, hydrocortisone sodium succinate, hydrocortisone valerate, methylprednisilone, methylprednisiline acetate, methylprednisolone sodium phosphate, methyl¬ prednisolone sodium succinate, paramethasone acetate, prednisolone, prednisolone acetate, prednisolone hemisuccinate, prednisolone sodium phosphate, prednisolone sodium succinate, prednisolone tebutate, prednisone and triamcinolone. Beclo¬ methasone and budesonide are particilarly preferred.
LTD4 receptor antagonists within the scope of the invention are all substances which block the biological effect of the cysteinyl-leukotrienes LTC4 and LTD4 at their receptor (CysLTl).
In this connection, preferred compounds are those of the gereral formula
(CH2)m-
Figure imgf000005_0001
Figure imgf000005_0002
in which
X and Y denote, identically or differently, sulphur, sulphoxide, sulphone, an alkylene chain, -SCH2- or oxygen or a direct linkage,
W denotes -CH=CH- or -CH2-CH2-,
o denotes a number from 1 to 5,
A and B denote, identically or differently, carboxyl, carboxymethyl , tetrazolyl or tetrazolylmethyl or -CO2R9 or -CH2CO2R9 or -CONR10Rn or cyano,
n denotes a number from 1 to 10,
m denotes a number from 0 to 7,
T and Z denote, identically or differently, oxygen or a direct linkage, and
"? " ft
R , R , R denote, identically or differently, hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano or nitro, R9 denotes lower alkyl and
R10 and R11 denote hydrogen, lower alkyl, alkylsulphonyl or arylsulphonyl, or they form together an alkylene chain to form a ring,
and the salts thereof.
Particularly preferred LTD4 receptor antagonists are compounds of the formula (I) in which
X denotes sulphur, sulphone or a methylene group,
Y denotes sulphur, a methylene group, -SCH-,- or a direct linkage,
W is -CH=CH-,
R8 and R3 denote H,
R2 is H or F,
o is a number from 1, 2, 3 or 4,
n is a number from 2, 3, 4, 5 or 6,
m is a number from 0, 1 or 2,
T denotes oxygen or a direct linkage,
Z denotes oxygen or a direct linkage,
A denotes carboxyl or an ester thereof,
B denotes para-carboxyl or an ester thereof,
and the salts thereof.
Very particularly preferred LTD4 receptor antagonists are those of the formula (Ia)
Figure imgf000007_0001
in which
R1 and R2 are identical or different and
represent hydrogen, a branched or straight-chain C ,_( -alkyl or a benzyl radical, appropriate isomers thereof, and salts thereof
In view of the effect of GCSs an eicosanoid release and the effects of LTD4 receptor antagonists on inflammation reaction mediated by cysteinylleukotriene, it is completely suφrising to find a superadditive effect of the combinations according to the invention.
The compound of the formula (I), the processes for preparing it are descirbed in the publications EP 494 621 and Bioorg Med Chem Lett (1993), 3(8), 1517-22
The combination according to the invention of glucocorticosteroids with the LTD4 receptor antagonists can be used, on account of its specific properties, for the treatment of acute, chronic, autoimmune or non-autoimmune inflammations
The combination according to the invention furthermore opens up the possibility of a significant reduction in the effective dose of the glucocorticosteroids This makes it possible to achieve a reduction in the dosedependent unwanted effects of the medicament
GCS and LTD4 receptor antagonists in the combination can be combined in one or second ratio depending on the action potency of the individual substances
The combination according to the invention can be used both in human medicine and in veterinary medicine Suitable indications are the treatment and prevention of inflammatory disorders of the airwagy such as allergies/asthma, bronchitis, emphysema, shock lung, pulmonary hypertension, and of the liver, intestine, kidney, pancreas, heart, nose, mouth, ears, eyes, central nervous system, muscles, connective tissue and joints, inflammations/rheumatism and oedemas, thromboses and thromboembolisms, ischaemias (disturbances of peripheral, cardiac and cerebral blood flow), infarcts (myocardial, cerebral, intestinal and other tissues), angina pectoris, inflammatory vascular disorders, arteriosclerosis, in tissue transplants, postoperative inflammations as well as vasodilatation, vessel transplant, dermatoses such as psoriasis, inflammatory dermatoses and inflammatory processes during infectious diseases (parasites, viruses, bacteria, fungi and oncoses).
The novel combination can be converted in a manner known per se, using inert, non-toxic, pharmaceutically suitable vehicles or solvents, into the customary perenteral formulations such as, for example, lyophilisates and solutions In these, the therapeutically effective combination should in each case be present in a concentration of about 0,5 to 90 % by weight, preferably from 5 to 70 % by weight, which is sufficient to reach the stated range of dosage
The combination can be used orally, subcutaneously, intramuscularly, intra¬ venously or topically as aerosol (lung), ointment/cream (skin) or solution (mucous membranes)
The abovementioned pharmaceutical compositions can be produced in a conventional way by known methods, for example with the ancillary substance(s) or vehicle(s).
However, it may, where appropriate, be advantageous to deviate from the stated amounts, in particular depending on the body weight and on the mode of administration, or on the individual behaviour towards the medicament, the type of formulation thereof and the time or interval over which administration takes place Thus, it may be sufficient in some cases to deal with less than the abovementioned minimum amount, whereas in other cases the stated upper limit must be exceeded. When larger amounts are administered, it may be advisable to distribute these in several individual doses throughout the day.

Claims

Patent Claims
1. Combination of LTD4 receptor antagonists with glucocorticosteroids (GCSs).
2. Combination according to Claim 1, characterized in that compounds of the group consisting of amcinonide, beclomethasone dipropionate, betamethasone, betamethasone acetate, betamethasone benzoate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, carbenoxolone sodium, clocortolone acetate, clocortolone pivalate, cloprednol, corticotropin (injection), corticotropin (repository), corticotropin zinc hydroxide, cortisone acetate, cortivazole, descinolone acetonide, dexamethasone, dexamethasone sodium phosphate, diflucortolone, diflucortolone pivalate, flucloronide, flumethasone, flumethasone pivalate, flunisolide, fluocinolone acetonide, fluocinomide, fluocortolone, fluocortolone caproate, fluorometholone, fluperolone acetate, fluprednisolone, fluprednisolone val erate, flurandrenolide, formocortal, fluticasone, hydrocortisone, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone valerate, medrysone, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium phosphate, methylprednisolone sodium succinate, nivazole, paramethasone acetate, prednicarbate, prednisolone, prednisilone acetate, prednisolone hemisuccinate, prednisoline sodium phosphate, prednisolone sodium succinate, prednisiline tebutate, prednisone, prednival, ticabesone propionate, tralonide, triamcinolone, triamcinolone acetonide, triamcinolone acetonide sodium phosphate, triamcinolone diacetate and triamcinolone hexacetonide, aare empoyed as clucocorticosteroids.
3. Combination according to Claim 1, characterized in that compounds of the series consisting of beclomethasone dipropionate, betamethasone, beta- methasone acetate, betamethasone benzoate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, cortisone acetate, dexamethasone, dexamethasone sodium phosphate, diflucortolone, deflucortolone pivalate, flumethasone, flumethasone pivalate, hydrocortisone, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone cypionate, hydrocortisone sodium phosphate, fluticasone, hydrocortisone sodium succinate, hydrocortisone valerate, methylprednisilone, methylprednisiline acetate, methylprednisolone sodium phosphate, methylprednisolone sodium succinate, paramethasone acetate, prednisolone, prednisolone acetate, prednisolone hemisuccinate, prednisolone sodium phosphate, prednisolone sodium succinate, prednisolone tebutate, prednisone and triamcinolone, are employed as glucocorticosteroids.
4. Combination according to Claim 1, characterized in that beclomethasone or budesonide are employed as glucocorticosteroids.
5. Combination according to Claim 1 to 4, characterized in that compounds of the general formula
Figure imgf000010_0001
in which
X and Y denote, identically or differently, sulphur, sulphoxide, sulphone, an alkylene chain, -SCH2- or oxygen or a direct linkage,
W denotes -CH=CH- or -CH2-CH2-,
o denotes a number from 1 to 5,
A and B denote, identically or differently, carboxyl, carboxymethyl, tetrazolyl or tetrazolylmethyl or -CO2R9 or -CH2CO2R9 or
-CONR10Rn or cyano,
n denotes a number from 1 to 10, m denotes a number from 0 to 7,
T and Z denote, identically or differently, oxygen or a direct linkage, and
R2, R2, R8 denote, identically or differently, hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano or nitro,
R9 denotes lower alkyl and
R10 and R11 denote hydrogen, lower alkyl, alkylsulphonyl or arylsulphonyl, or they form together an alkylene chain to form a ring,
and the salts thereof,
are employed as LTD4 receptor antagonists
Combination according to Claim 1 to 4, characterized in that a compound of the formula
Figure imgf000011_0001
in which
1
R and R are identical or different.
is employed as LTD4 receptor antagonist
Combination according to Claim 1 to 6, characterized in that the ratio of glucocorticosteroid to LTD4 receptor antagonist can be combined in another ratio depending on the action potency of the individual substances
Medicament containing the combinations according to Claim 1 to 7 9. Use of combinations according to Claims 1 to 7 for producing medicaments.
PCT/EP1996/004391 1995-10-23 1996-10-10 Combination of ltd, receptor antagonists with glucocorticosteroids WO1997015298A1 (en)

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US6750210B2 (en) 2000-08-05 2004-06-15 Smithkline Beecham Corporation Formulation containing novel anti-inflammatory androstane derivative
US6759398B2 (en) 2000-08-05 2004-07-06 Smithkline Beecham Corporation Anti-inflammatory androstane derivative
US6777400B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6777399B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6787532B2 (en) 2000-08-05 2004-09-07 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivatives
US6858593B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6878698B2 (en) 2001-04-07 2005-04-12 Glaxo Group Limited Anti-inflammatory androstane derivatives
WO2006099591A1 (en) * 2005-03-16 2006-09-21 Elan Pharma International Limited Nanoparticulate leukotriene receptor antagonist/corticosteroid formulations
US7125985B2 (en) 2000-08-05 2006-10-24 Glaxo Group Limited Compounds useful in the manufacture of an anti-inflammatory androstane derivative
US8048918B2 (en) 2000-08-17 2011-11-01 Vampex Limited Treatment of hyperproliferative diseases
US8933060B2 (en) 2002-06-14 2015-01-13 Cipla Limited Combination of azelastine and ciclesonide for nasal administration

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7125985B2 (en) 2000-08-05 2006-10-24 Glaxo Group Limited Compounds useful in the manufacture of an anti-inflammatory androstane derivative
US6787532B2 (en) 2000-08-05 2004-09-07 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivatives
US6750210B2 (en) 2000-08-05 2004-06-15 Smithkline Beecham Corporation Formulation containing novel anti-inflammatory androstane derivative
US6777399B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US7132532B2 (en) 2000-08-05 2006-11-07 Glaxo Group Limited Compounds useful in the manufacture of an anti-inflammatory androstane derivative
US6858593B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6759398B2 (en) 2000-08-05 2004-07-06 Smithkline Beecham Corporation Anti-inflammatory androstane derivative
US7144845B2 (en) 2000-08-05 2006-12-05 Glaxo Group Limited Compounds useful in the manufacture of an anti-inflammatory androstane derivative
US6777400B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US8048918B2 (en) 2000-08-17 2011-11-01 Vampex Limited Treatment of hyperproliferative diseases
US6878698B2 (en) 2001-04-07 2005-04-12 Glaxo Group Limited Anti-inflammatory androstane derivatives
US7592329B2 (en) 2002-02-04 2009-09-22 Glaxo Group Limited Crystalline complexes of fluticasone-2-furoate
US8933060B2 (en) 2002-06-14 2015-01-13 Cipla Limited Combination of azelastine and ciclesonide for nasal administration
US8937057B2 (en) 2002-06-14 2015-01-20 Cipla Limited Combination of azelastine and mometasone for nasal administration
US9259428B2 (en) 2002-06-14 2016-02-16 Cipla Limited Combination of azelastine and fluticasone for nasal administration
US9901585B2 (en) 2002-06-14 2018-02-27 Cipla Limited Combination of azelastine and fluticasone for nasal administration
WO2006099591A1 (en) * 2005-03-16 2006-09-21 Elan Pharma International Limited Nanoparticulate leukotriene receptor antagonist/corticosteroid formulations

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