Classifications

• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • 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
• • 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
• • 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
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates compositions and methods for preventing or reducing the onset of symptoms of pulmonary diseases, or treating or reducing the severity of pulmonary diseases.
• compositions and methods for treating pulmonary diseases mediated by phosphodiesterase 4 (PDE4) by administering a PDE4 inhibitor with other pharmaceutically active agents which affect pulmonary function.
• cAMP adenosine cyclic 3 ',5 - monophosphate
• Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973].
• adenylate cyclase is activated, which converts Mg + --ATP to cAMP at an accelerated rate.
• Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma.
• an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation.
• compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.
• the principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
• PDE IV cyclic nucleotide phosphodiesterase
• this invention relates to a method for treating a pulmonary disease by administering to a patient in need thereof an effective amount of a PDE 4 inhibitor and a long-acting beta adrenergic bronchodilator either in a single combined form, separately, or separately and sequentially where the sequential administration is close in time, or remote in time.
• this invention relates to a composition for treating a pulmonary disease comprising an effective amount of a PDE4 inhibitor, an effective amount of a long-acting beta adrenergic bronchodilator and a pharmaceutically acceptable excipient.
• this invention relates to a method for preparing a composition which is effective for preventing the symptoms of treating a pulmonary disease which method comprises mixing an effective amount of a PDE4 inhibitor and a long-acting beta adrenergic bronchodilator with a pharmaceutically acceptable excipient.
• the combination therapy contemplated by this invention comprises administering a PDE4 inhibitor with a long-acting beta adrenergic bronchodilator to prevent onset of a pulmonary disease event or to treat an existing condition.
• the compounds may be administered together in a single dosage form. Or they may be administered in different dosage forms. They may be administered at the same time. Or they may be administered either close in time or remotely, such as where one drug is administered in the morning and the second drug is administered in the evening.
• the combination may be used prophylactically or after the onset of symptoms has occurred. In some instances the combination(s) may be used to prevent the progression of a pulmonary disease or to arrest the decline of a function such as lung function.
• the PDE4 inhibitor useful in this invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act in as PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4.
• a PDE4 antagonists which has an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE IV catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.
• PDE inhibitors used in treating inflammation and as bronchodilators drugs like theophylline and pentoxyfyllin, inhibit PDE isozymes indiscriminently in all tissues. These compounds exhibit side effects, apparently because they non- selectively inhibit all 5 PDE isozyme classes in all tissues.
• the targeted disease state may be effectively treated by such compounds, but unwanted secondary effects may be exhibited which, if they could be avoided or minimized, would increase the overall therapeutic effect of this approach to treating certain disease states.
• clinical studies with the selective PDE 4 inhibitor rolipram which was being developed as an antidepressant, indicate it has psychotropic activity and produces gastrointestinal effects, e.g., pyrosis, nausea and emesis.
• hPDE 4 human monocyte recombinant PDE 4
• the preferred PDE4 inhibitors of for use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity.
• the preferred compounds will have an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE 4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.
• Examples of such compounds are:
• Papaverine l-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline; Trequinsin -- 2,3,6,7-tetrahydro-2-(mesitylimino)-9,10-dimethoxy-3-methyl- 4H-primido[6, 1 - ⁇ ]isoquinoline-4-one;
• Dipyrimadole the generic name for 2,2',2",2"'-[(4,8- dipiperidinopyrimido[5,4-d]pyrimidine-2-6-diyl)dinitrilo]tetraethanol; (R)-(+)-l-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2- pyrrolidone;
• PDE4 inhibitors which have an IC50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0.
• Preferred compounds are trequinsin, dipyridamole, and papaverine.
• Compounds such as cis-[cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylate], 2- carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l- one, and cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan- 1 - ol] are examples of structures which bind preferentially to the low affinity binding site and which have an IC50 rano °f 0.1 or greyer- Reference is made to co-pending U.S.
• resorcinols such as metaproterenol, terbutaline, and fenoterol can be combined with a PDE4 inhibitor in the practice of this invention.
• beta adrenergic bronchodilators is the likes of two structurally related compounds, albuterol ⁇ racemic ( ⁇ -[(t- butylamino)methyl]-4-hydroxy-m-xylene-°c,°c'-diol) ⁇ and formoterol ⁇ (R*, R*)-( ⁇ )- N-[2-hydroxy-5-[ 1 -hydroxy-2-[[2-(4-methoxyphenyl)- 1 - methylethyl]ethyl]phenyl]formamide ⁇ .
• Metaproterenol is the subject of U.S. patent 3,341,594 and is commercially available under the trade names of Alotec, Alupent, Metaprel or Novasmasol.
• Terbutaline is described in U.S. patent 3.938,838 and is available commercially as Brethine from Novartis.
• the preparation of fenoterol is described in U.S. patent 4,341,593. It is sold under several trade names, including Airum, Berotec, Dosberotec and Partusisten.
• Albuterol is sold under the trademark Proventil® by Schering Corporation.
• Formoterol is described in U.S. patent 3,994,974 and is available commercially under the names Atock and Foradil.
• a preferred combination therapy is that of formoterol and cis-[cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -carboxylate] .
• These drugs, the beta agonists are usually administered as an oral or nasal spray or aerosol, or as an inhaled powder. Usually these drugs are not administered systemically or by injection.
• the PDE4 inhibitors can be administered orally or by inhalation (orally or internasally) This invention contemplates either co- administering both drugs in one delivery form such as an inhaler, that is putting both drugs in the same inhaler. Alternatively one can put the PDE4 inhibitor into pills and package them with an inhaler that contains the beta agonist. Formulations are within the skill of the art.
• both active agents would be administered at the same time, or very close in time.
• one drug could be taken in the morning and one later in the day.
• one drug could be taken twice daily and the other once daily, either at the same time as one of the twice-a-day dosing occurred, or separately.
• both drugs would be taken together at the same time.

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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pulmonology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1999
  • 1999-08-24 BR BR9913152-8A patent/BR9913152A/pt not_active IP Right Cessation
  • 1999-08-24 MY MYPI99003615A patent/MY126544A/en unknown
  • 1999-08-24 DZ DZ990176A patent/DZ2876A1/xx active
  • 1999-08-24 WO PCT/US1999/019332 patent/WO2000012078A1/en not_active Ceased
  • 1999-08-24 NZ NZ527232A patent/NZ527232A/en unknown
  • 1999-08-24 TR TR2001/00500T patent/TR200100500T2/xx unknown
  • 1999-08-24 CA CA002341488A patent/CA2341488A1/en not_active Abandoned
  • 1999-08-24 AU AU54939/99A patent/AU754379B2/en not_active Ceased
  • 1999-08-24 JP JP2000567196A patent/JP2002523452A/ja active Pending
  • 1999-08-24 HU HU0103160A patent/HUP0103160A3/hu unknown
  • 1999-08-24 US US09/763,516 patent/US6288118B1/en not_active Expired - Fee Related
  • 1999-08-24 KR KR1020017002358A patent/KR20010072931A/ko not_active Ceased
  • 1999-08-24 PL PL99346271A patent/PL346271A1/xx unknown
  • 1999-08-24 IL IL14133599A patent/IL141335A0/xx unknown
  • 1999-08-24 EP EP99941248A patent/EP1107747A4/en not_active Withdrawn
  • 1999-08-24 CN CN99810111A patent/CN1314811A/zh active Pending
  • 1999-08-24 CZ CZ2001692A patent/CZ293735B6/cs not_active IP Right Cessation
  • 1999-08-25 PE PE1999000856A patent/PE20001032A1/es not_active Application Discontinuation
  • 1999-08-25 MA MA25745A patent/MA26302A1/fr unknown
  • 1999-09-03 AR ARP990104234A patent/AR022072A1/es not_active Application Discontinuation
• 2001
  • 2001-02-21 NO NO20010882A patent/NO20010882D0/no not_active Application Discontinuation
  • 2001-08-20 US US09/933,455 patent/US6555583B2/en not_active Expired - Fee Related

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