WO2004098606A1 - Composition comprenant un inhibiteur de la pde4 et shuil-1r ii - Google Patents

Composition comprenant un inhibiteur de la pde4 et shuil-1r ii Download PDF

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WO2004098606A1
WO2004098606A1 PCT/EP2004/050749 EP2004050749W WO2004098606A1 WO 2004098606 A1 WO2004098606 A1 WO 2004098606A1 EP 2004050749 W EP2004050749 W EP 2004050749W WO 2004098606 A1 WO2004098606 A1 WO 2004098606A1
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phthalazin
tetrahydro
piperidin
pde4
disease
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PCT/EP2004/050749
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English (en)
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Johannes Barsig
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Altana Pharma Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Composition comprising a PDE4 inhibitor and shuIL-1 R II
  • the invention relates to the combination of certain known active compounds for therapeutic purposes.
  • the substances used in the combination according to the invention are known active compounds from the PDE4 inhibitor class and known active compounds from the interleukin-1 (IL-1 ) antagonist class. Their combined use in the sense according to the invention for therapeutic purposes has not yet been described in the prior art.
  • IL-1 interleukin-1
  • the invention relates to pharmaceutical compositions and methods for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental.
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • the Invention relates in a first aspect to a method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental by administering to a patient in need thereof simultaneously an effective amount of (1) a PDE4 inhibitor and (2) shulL-1 R II.
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • the invention in a second aspect relates to a method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin- 1 (IL-1) activity is detrimental by administering to a patient in need thereof in succession, close in time or remote in time, in any order whatever an effective amount of (1) a PDE4 inhibitor and (2) shuIL-1 R
  • the invention also relates to a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or i ⁇ terleukin-1 (IL-1) activity is detrimental, comprising as a fixed combination an effective amount of
  • the invention additionally relates to a method for preparing a pharmaceutical composition which is effective for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, which method comprises mixing an effective amount of a PDE4 inhibitor and shulL-1 II with a pharmaceutically acceptable carrier.
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • the invention furthermore relates to the use of a combination of a PDE4 inhibitor and shulL-1 R II for the preparation of a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin- 1 (IL-1) activity is detrimental.
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • the combination therapy which is the subject matter of this invention comprises administering a PDE4 inhibitor with shulL-1 R II to prevent onset of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental or to treat such an existing condition.
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • the invention thus relates to the combined use of a PDE4 inhibitor and shulL-1R II in preventing the symptoms of, or treating a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental.
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • the PDE4 inhibitors useful in this invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which is only or essentially only a PDE4 inhibitor, not compounds which inhibit to a degree of exhibiting a therapeutic effect other members of the PDE family as well as PDE4.
  • PDE4 INHIBITORS One group of PDE4 inhibitors that may be usefully employed in the present invention [hereinafter referred to as "SELECTED PDE4 INHIBITORS”] include a compound of formula (1 )
  • R1 and R2 are both hydrogen or together form an additional bond
  • R3 represents a benzene derivative of formula (a) or (b)
  • R4 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine
  • R5 is 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine
  • R6 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkyImethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine, R7 is 1 ⁇ 4C-alkyl and R8 is hydrogen or 1 -4C-alkyl, or wherein
  • R7 and R8 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen or sulphur atom,
  • R9 is 1-4C-Alkyl, -S(O) 2 -R10, -S(0) 2 -(CH 2 )n-R11 , -(CH 2 ) m -S(0) 2 -R12, -C(0)R13, -C(0)-(CH 2 ) n -R14, -(CH 2 ) m -C(0)-R15, Hetaryl, Aryl1 or Aryl2-(1 -4C)-alkyl,
  • R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1 -yl, -N(R16)R17, phenyl or phenyl substituted by R18 and/or R19,
  • R11 is -N(R16)R17
  • R12 is -N(R16)R17
  • R13 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl, 4-ethyl-piperazin-2,3-dion-1-yl or -N(R16)R17,
  • R14 is -N(R16)R17
  • R15 is -N(R16)R17, phenyl, phenyl substituted by R18 and/or R19 and/or R20,
  • R16 and R17 are independent from each other hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl- ethyl, phenyl or phenyl substituted by R18 and/or R19 and/or R20, or R16 and R17 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyr- rolidinyl-, 1-piperidinyl-, 1 -hexahydroazepino- or a 1-piperazinyl-ring of formula (c)
  • R21 is pyrid-4-yl, pyrid-4-ylmethyl, 1-4C-alkyl-dimethylamino, dimethylaminocarbonylmethyl,
  • R18 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, amino, mono-or di-1 -4C-alkylamino, aminocarbonyl, 1-4G-alkylcarbonylamino or mono-or di-
  • R19 is halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy
  • R20 is halogen
  • Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl, 1-methyl-1 H-pyrazolo-[3,4-d]pyrimidin-4-yl, thia- zolyl, imidazolyl or furanyl
  • AryH is pyridyl, phenyl or phenyl substituted by R18 and/or R19
  • Aryl2 is pyridyl, phenyl, phenyl substituted by R18 and/or R19, 2-oxo-2H-chromen-7-yl or 4-(1 ,2,3- thiadiazol-4-yl)phenyl
  • n is an integer from 1 to 4
  • m is an integer from 1 to 4 or a pharmaceutically acceptable salt or a N-oxide thereof or
  • 1-4C-Alkyl is a straight -chain or branched alkyl radical having 1 to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert -butyl, propyl, isopropyl, ethyl and methyl radicals.
  • 1-4C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight -chain or branched alkyl radical having 1 to 4 carbon atoms.
  • Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned in this context are, for example, the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.
  • 1-8C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight -chain or branched alkyl radical having 1 to 8 carbon atoms.
  • Alkoxy radicals having 1 to 8 carbon atoms which may be mentioned in this context are, for example, the octyloxy, heptyloxy, isoheptyloxy (5-methy I hexyloxy), hexyloxy, isohexyloxy (4-methylpentyloxy), neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy (3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.
  • 1-4C-Alkoxy which is completely or predominantly substituted by fluorine is, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy and in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxy radical, of which the difluoromethoxy radical is preferred.
  • "Predominantly" in this connection means that more than half of the hydrogen atoms of the 1-4C-alkoxy group are replaced by fluorine atoms.
  • 3-7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cyclo- heptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
  • 3-7G-Cycloalkylmeth ⁇ xy stands for cyelopropylmethoxy, cyclobutylmethoxy, cyclopentyl ethoxy, cy- clohexylmethoxy or cycloheptyl methoxy, of which cyelopropylmethoxy, cyclobutylmethoxy and cyclo- pentylmethoxy are preferred.
  • 3-5C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.
  • 3-5C-Cycloalkylmethoxy stands for cyelopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy.
  • Halogen within the meaning of the present invention is bromine, chlorine or fluorine.
  • spiro-linked 5-, 6- or 7-membered hydrocarbon rings optionally interrupted by an oxygen or sulphur atom
  • the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahy- dropyran and the tetrahydrothiophen ring may be mentioned the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahy- dropyran and the tetrahydrothiophen ring.
  • 1-4C-Alkoxycarbonyl is a carbonyl group to which one of the abovementioned 1-4G-alkoxy radicals is bonded.
  • Examples are the methoxycarbonyl [CH 3 0-C(0)-] and the ethoxycarbonyl [CH 3 CH 2 ⁇ -C(0)-] radical.
  • An 1-4C-Alkylcarbonylamino radical is, for example, the propionylamino [C 3 H 7 C(0)NH-] and the ace- tylamino radical [CH 3 C(0)NH-].
  • Mono- or Di-1-4C-alkylamino radicals contain in addition to the nitrogen atom, one or two of the abovementioned 1-4C-alkyl radicals.
  • Mono- or Di-1-4C-alkylaminocarbonyl radicals contain in addition to the carbonyl group one of the abovementioned mono- or di-1-4C-alkylamino radicals. Examples which may be mentioned are the N-methyl- the N.IM-dimethyl-, the N-ethyl-, the N-propyh the N,N-diethyl- and the Misopropylamino- carbonyl radical.
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds which are generally prepared by reacting a free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. Particular mention may be made of the pharmaceutically acceptable inorganic and organic acids customarily used in pharmacy.
  • Those suitable are in particular water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic aci d, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic d, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, the acids bei ng employed in salt preparation - depending on whether it is a mono- or polybasic acid and depending on which salt is desired - in an equimolar quantitative ratio or one differing therefrom.
  • acids such as, for example, hydrochloric acid, hydrobro
  • salts with bases are mentioned the lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, meglumine or guanidinium salts, here, too, the bases being employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
  • active compounds and their pharmaceutically acceptable salts mentioned can also be present, for example, in the form of their pharmaceutically acceptable solvates, in particular in the form of their hydrates.
  • SELECTED PDE4 INHIBITORS which are to be emphasized include a compound of formula (1), in which
  • R3 represents a benzene derivative of formula (a) or (b)
  • R4 is 1-4G-alkoxy
  • R5 is 1-4C-alkoxy
  • R6 is 1-2C-alkoxy
  • R7 is methyl
  • R8 is hydrogen, R9 is 1-4C-alkyl, -S(O) 2 -R10, -C(0)R13, -C(0)-(CH 2 ) n -R14, -(CH 2 ) m -C(0)-R15, Hetaryl, AryH or
  • Aryl2-(1-2C-)alkyl R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1 -yl, phenyl or phenyl substituted by R18, R13 is 1-4G-alkyl, hydroxycarbonyl-1-4C-alkyl, pyridyl, 4-ethyl-piperazin-2,3-dion-1-yl or
  • R14 is -N(R16)R17
  • R15 is -N(R16)R17
  • R16 and R17 are independent from each other hydrogen, 1-4C-alkyl, phenyl or phenyl substituted by R18 and/or R19 and/or R20, or R16 and R17 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl ring or a 1-piperazinyl ring of formula (c)
  • R21 is dimethylamino-1 -4C-alkyl
  • R18 is halogen, nitro, 1-4C-alkyl or 1-4C-alkoxycarbonyl
  • R19 is amino
  • R20 is halogen
  • Hetaryl is pyrimidin-2-yl, thieno-[2,3- ]pyrimidin-4-yl or 1-methyl-1 H-pyrazolo-[3,4-d]pyrimidin-4-yl, AryH is phenyl or phenyl substituted by R18,
  • Aryl2 is pyridyl, phenyl, 2-oxo-2H-chromen-7-yl or 4-(1 ,2,3-thiadiazol-4-yl)phenyl, n is 1 or 2, m is 1 or 2, or a pharmaceutically acceptable salt or a N-oxide thereof or a pharmaceutically acceptable salt of the latter.
  • SELECTED PDE4 INHIBITORS which are preferred include a compound selected from
  • SELECTED PDE4 INHIBITORS which are particularly preferred include a compound selected from
  • PDE4 inhibitors that may be usefully employed in the present invention include a compound selected from
  • shuIL-1 R II is understood to represent a soluble human Type II interleukin-1 receptor of Immunex.
  • the preparation and use of soluble human Type II interleukin-1 receptors is described in USP5,767,064.
  • the pharmaceutical compositions according to the invention can furthermore be used in the treatment of conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease or multiinfarct dementia; in the treatment of malignancies to inhibit tumor growth, or metastasis, and/or to alleviate cachexia secondary to malignancy; in the treatment of infectious diseases like bacterial meningitis, cachexia or cerebral malaria; and in the treatment of diseases like inflammatory bone disease, bone resorption disease, hepatitis, viral hepatitis, reperfusion injury, scar tissue formation, pyrexia, periodontal disease and radiation toxicity.
  • the pharmaceutical compositions according to the invention can as well be used in the treatment of chronic fever syndromes, metabolic syndrome and sequalae, e.g. type 2 diabetes.
  • combined use (or “combination”) embraces the administration of a PDE4 inhibitor and shuIL-1 R II as part of a specific treatment regimen intended to provide a beneficial effect from the co- action of these therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually, minutes, hours, days or weeks depending upon the combination selected).
  • Combined use generally is not intended to encompass the administration of two of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
  • Combined use or “combination” within the meaning of the present Invention is to be understood as meaning that the individual components can be administered simultaneously (in the form of a combination medicament - fixed combination) or more or less simultaneously, respectively in succession (from separate pack units - free combination; directly in succession or else alternatively at a relatively large time interval).
  • one therapeutic agent could be taken in the morning and one later in the day.
  • one therapeutic agent could be taken once daily and the other once daily or once weekly.
  • Simultaneous administration preferably is accomplished by administering to the subject in need thereof, for example, a single intravenous injection having a fixed ratio of each therapeutic agent. More or less simultaneous administration or administration in succession of each therapeutic agent can be effected by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and by infusion techniques.
  • the therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous or subcutaneous injection while the other therapeutic agent of the combination may be administered orally.
  • the sequence in which the therapeutic agents are administered is not narrowly critical.
  • the therapeutic agent(s) according to the invention may be administered in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., inject- able and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposo es or suppositories.
  • liquid solutions e.g., inject- able and infusible solutions
  • dispersions or suspensions e.g., tablets, pills, powders, liposo es or suppositories.
  • the preferred form depends on the intended mode of administration and therapeutic application.
  • PDE4 inhibitor is oral.
  • the PDE4 inhibitor is administered by intravenous infusion or injection.
  • the PDE4 inhibitor is administered by intramuscular or subcutaneous injection.
  • Other routes of administration are also contemplated, including intranasal and transdermal routes, and by inhalation.
  • Purified soluble type II IL-1 R protein compositions preferably are administered by bolus injection, continuous infusion, sustained release from implants.
  • a soluble type II IL-1 R therapeutic agent will be administered in the form of a composition comprising purified protein in conjunction with physiologically acceptable carriers, excipients or diluents. Such carriers will be ⁇ ontoxic to recipients at the dosages and concentrations employed.
  • compositions entails combining the type II 1L-1 R with buffers, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, sucrose or dextrins, chelating agents such as EDTA, glutathione and other stabilizers and excipients.
  • antioxidants such as ascorbic acid
  • chelating agents such as EDTA, glutathione and other stabilizers
  • excipients Neutral buffered saline or saline mixed with conspecific serum albumin are exemplary appropriate diluents.
  • product is formulated as a lyophilizate using appropriate excipient solutions (e.g., sucrose) as diluents.
  • compositions typically must be sterile and stable under the condition of manufacture and storage.
  • the composition can be formulated, for example, as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
  • the therapeutic agent(s) of the present invention can be administered by a variety of methods known in the art, although for many therapeutic applications, the preferred route of administration for a fixed combination of a PDE4 inhibitor and the shulL-1 R II according to the invention is intravenous injection or infusion.
  • the therapeutic agent(s) may be prepared with a carrier that will protect the agent against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and poylactic acid. Many methods for the preparation of such formulations are generally known to those skilled in the art.
  • the therapeutic agent(s) of the invention may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the therapeutic agent(s) may also be enclosed in a hard or soft shell gelatine capsule or compressed into tablets.
  • the therapeutic agent(s) may be incorporated with excipients and used in the form of ingesta- ble tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • To administer the therapeutic agent(s) according to the invention it may be necessary to coat the therapeutic agent(s) with, or co-administer with the therapeutic agent(s) with, a material to prevent its inac- tivation.
  • the therapeutic agent(s) are dosed in an order of magnitude customary for the individual dose, it more likely being possible, on account of the individual actions, which are mutually positively influencing and reinforcing, to reduce the respective doses on the combined administration of the therapeutic agent(s) with the norm.
  • the daily dose will be in the range from 0.001 to 3 mg/kg body weight of the subject to be treated, preferably by once daily administration.
  • the adult dose of Cilomilast is between 5 mg and 20 mg twice a day, preferably between 10 mg and 15 mg twice a day.

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Abstract

L'invention concerne l'administration combinée d'un inhibiteur de la PDE4 et de shuIL-1 R II pour le traitement d'une maladie dans laquelle l'activité de la phosphodiestérase 4 (PDE4) et/ou de l'interleukine-1 (IL-1) est néfaste.
PCT/EP2004/050749 2003-05-12 2004-05-10 Composition comprenant un inhibiteur de la pde4 et shuil-1r ii WO2004098606A1 (fr)

Applications Claiming Priority (2)

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EP03010596.9 2003-05-12
EP03010596 2003-05-12

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WO2004098606A1 true WO2004098606A1 (fr) 2004-11-18

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019749A1 (fr) * 1992-04-02 1993-10-14 Smithkline Beecham Corporation Composes destines a traiter les maladies allergiques et inflammatoires
US5767064A (en) * 1990-06-05 1998-06-16 Immunex Corporation Soluble type II interleukin-1 receptors and methods
WO1999055696A1 (fr) * 1998-04-28 1999-11-04 Arzneimittelwerk Dresden Gmbh Nouveaux hydroxyindoles, leur utilisation comme inhibiteurs de la phosphodiesterase 4 et leur procede de preparation
WO2002064584A1 (fr) * 2001-02-15 2002-08-22 Altana Pharma Ag Derives de phtalazinone-piperidine en tant qu'inhibiteurs de pde4

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5767064A (en) * 1990-06-05 1998-06-16 Immunex Corporation Soluble type II interleukin-1 receptors and methods
WO1993019749A1 (fr) * 1992-04-02 1993-10-14 Smithkline Beecham Corporation Composes destines a traiter les maladies allergiques et inflammatoires
WO1999055696A1 (fr) * 1998-04-28 1999-11-04 Arzneimittelwerk Dresden Gmbh Nouveaux hydroxyindoles, leur utilisation comme inhibiteurs de la phosphodiesterase 4 et leur procede de preparation
WO2002064584A1 (fr) * 2001-02-15 2002-08-22 Altana Pharma Ag Derives de phtalazinone-piperidine en tant qu'inhibiteurs de pde4

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WOLDA S L: "PDE4 INHIBITORS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE", EMERGING DRUGS, ASHLEY PUBLICATIONS, LONDON, GB, vol. 5, no. 3, 2000, pages 309 - 319, XP008016335, ISSN: 1361-9195 *

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