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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/18—Sulfonamides
• • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• • 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
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
• • 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
• • 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

Definitions

• This invention relates to a new combination use of FK506 derivatives and j32-agonist, which is useful in a medical field.
• asthma Despite recent advances in the awareness of asthma and the introduction of powerful and effective anti-asthma drugs, asthma remains a poorly understood and frequently poorly treated disease. There have been recent advances in the treatment of the disease which result from the recognition that asthma is a chronic inflammatory disease. Therapy is now aimed at both controlling the symptoms and reducing the inflammation. The symptoms may be controlled by 32-agonists such as terbutaline, salbutamol, for oterol and salmeterol . Prophylactic therapy is typically provided by steroids such as beclomethasone dipropionate, fluticasone propionate,mometasone furoate and budesonide.
• steroids such as beclomethasone dipropionate, fluticasone propionate,mometasone furoate and budesonide.
• FK506 derivatives such as tacrolimus and its related compounds, are known to have preventing or treating reversible obstructive airways disease, such as asthma (USP 5,519,049) .
• reversible obstructive airways disease such as asthma (USP 5,519,049) .
• aerosol formulation comprising FK506 derivatives are also known by USP 6,361,760.
• This invention relates to a new use of FK506 derivatives and ⁇ 2-agonist for manufacturing a medicament for simultaneous, separate or sequential use for treating or preventing acute or chronic asthma.
• this invention also relates to a method for treating or preventing acute or chronic asthma , by administering an effective amount of FK506 derivatives and j3 2-agonist, simultaneously, separately or sequentially, to a human being or an animal .
• a further object of this invention is to provide a composition comprising FK506 derivatives and j32-agonist as a combined preparation for treating and preventing acute or chronic asthma .
• FK506 derivatives for manufacturing a medicament for treating or preventing acute or chronic asthma with j32-agonist, simultaneously, separately or sequentially.
• a composition comprising FK506 derivatives for treating or preventing acute or chronic asthma with j32-agonist, simultaneously, separately or sequentially.
• a composition comprising ⁇ 2-agonist for treating or preventing acute or chronic asthma with FK506 derivatives, simultaneously, separately or sequentially.
• the " 2-agonist” should not be limited and be considered to mean any compounds which can stimulate ⁇ 2 receptor.
• long-acting 02-agonists such as, salmeterol, formoterol, etc
• short-acting ]32-agonists such asalbuterol, bitolterol, fenoterol, isoetharine, metaproterenol, pirbuterol, terbutaline, salbutamol, etc
• More preferable one is long-acting ⁇ 2-agonists, such as, salmeterol, or formoterol.
• FK506 derivatives means tricyclic compounds shown in EP-0184162, WO89/05303, WO93/05058, W096/31514, and so on, the disclosure of which is incorporated herein by reference. It is well known that those tricyclic compounds have strong immunosuppressive activity.
• the tricyclic compound of the following formula (I) can be exemplified.
• R 2 is two adjacent hydrogen atoms, but R 2 may also be an alkyl group or
• (b) may form another bond formed between the carbon atoms to which they are attached;
• R 7 is a hydrogen atom, a hydroxy group, a protected hydroxy group, or an alkoxy group, or an oxo group together with
• R 1 ; R 8 and R 9 are independently a hydrogen atom or a hydroxy group
• R 10 is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups, or an alkyl group substituted by an oxo group
• X is an oxo group, (a hydrogen atom and a hydroxy group) , (a hydrogen atom and a hydrogen atom) , or a group represented by the formula -CH 2 0-
• Y is an oxo group, (a hydrogen atom and a hydroxy group) ,
• R 11 and R 12 are independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group
• R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 22 and R 23 are independently a hydrogen atom or an alkyl group
• R 24 is an optionally substituted ring system which may contain one or more heteroatoms
• n is an integer of 1 or 2
• Y, R 10 and R 23 together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkoxy, a benzyl, a group of the formula -CH
• lower means, unless otherwise indicated, a group having 1 to 6 carbon atoms .
• alkyl groups and an alkyl moiety of the "alkoxy group” include a straight or branched chain aliphatic hydrocarbon residue, forexample, a lower alkyl group suchasmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl and hexyl .
• alkenyl groups include a straight or branched chain aliphatic hydrocarbon residue having one double-bond, for example, a lower alkenyl group such as vinyl, propenyl (e.g., allyl group), butenyl, methylpropenyl, pentenyl and hexenyl.
• a lower alkenyl group such as vinyl, propenyl (e.g., allyl group), butenyl, methylpropenyl, pentenyl and hexenyl.
• aryl groups include phenyl, tolyl, xylyl, cumenyl, mesityl and naphthyl.
• protective groups in the "protected hydroxy groups” and the “protected amino” are l-( lower alkylthio)-
• acyl group such as an aliphatic, aromatic acyl group or an aliphatic acyl group substituted by an aromatic group, which are derived from a carboxylic acid, sulfonic acid or carbamic acid.
• aliphatic acyl groups include a lower alkanoyl group optionally having one or more suitable substituents such as carboxy, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl, etc.; a cyclo (lower) alkoxy (lower) alkanoyl group optionally having one or more suitable substituents such as lower alkyl, e.g., cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentanoyl, menthyloxyhexanoyl
• aromatic acyl groups include an aroyl group optionally having one or more suitable substituents such as nitro, e.g., benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl, etc.; and an arenesulfonyl group optionally having one or more suitable substituents such as halogen, e.g., benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl, etc.
• suitable substituents such as nitro, e.g., benzoyl, toluoyl, xy
• Examples of the aliphatic acyl groups substituted by an aromatic group include ar (lower) alkanoyl group optionally having one or more suitable substituents such as lower alkoxy or trihalo (lower) alkyl, e.g., phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethy1-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl-2-propoxy-2-phenylacetyl, etc.
• ar (lower) alkanoyl group optionally having one or more suitable substituents such as lower alkoxy or trihalo (lower) alkyl, e.g., phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethy1-2-trifluoromethyl-2-
• More preferable acyl groups among the aforesaid acyl groups are C ⁇ C 4 alkanoyl group optionally having carboxy, cyclo (C 5 -C 6 ) alkoxy (C ⁇ -C 4 ) alkanoyl group having two (C ⁇ -C 4 ) alkyls at the cycloalkyl moiety, camphorsulfonyl group, carboxy- (C ⁇ -C 4 ) alkylcarbamoyl group, tri (C ⁇ -C 4 ) alkylsilyl (C ⁇ C 4 ) alkoxycarbonyl (C 1 -C 4 ) - alkylcarbamoyl group, benzoyl group optionally having one or two nitro groups, benzenesulfonyl group having halogen, or phenyl (C ⁇ -C 4 ) alkanoyl group having C ⁇ -C 4 alkoxy and trihalo (C ⁇ C 4 ) alkyl group.
• the most preferable ones areacetyl, carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2-trifluoromethy1-2-methoxy-2-phenylacetyl .
• Preferable examples of the "5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring" include a pyrrolyl group and a tetrahydrofuryl group.
• R 24 is an optionally substituted ring system which may contain one or more heteroatoms, Preferable R 24 may be cyclo (Cs- ) alkyl group optionally having suitable substituents, and the following ones can be exemplified.
• a heteroaryl which may be substituted by suitable substituents moiety of the "heteroaryloxy which may be substituted by suitable substituents” may be the ones exemplified for R 1 of the compound of the formula of EP-A-532, 088 , with preference given to l-hydroxyethylindol-5-yl, the disclosure of which is incorporated herein by reference.
• the preferred examples of the tricyclic compounds (I) are the ones, wherein each of adjacent pairs of R 3 and R 4 or R 5 and R 6 independently form another bond formed between the carbon atoms to which they are attached; each of R 8 and R 23 is independently a hydrogen atom; R 9 is a hydroxy group; R 10 is a methyl group, an ethyl group, a propyl group or an allyl group; X is (a hydrogen atom and a hydrogen atom) or an oxo group; Y is an oxo group; each of R > 14 , R .15 , R , 16 , R .1 1 7' , R iB , R > 19 , and R 2" 2 is a methyl group ; R 24 is a 3-R 20 -4 -R 21 -cyclohexyl group, in which R 20 is hydroxy, an alkoxy group, an oxo group, or a -OCH 2 OCH 2 CH 2 OCH 3 group, and
• tricyclic compounds (I) is, in addition to FK506, ascomycin derivatives such as halogenated-ascomycin (e.g., 33-epi-chloro-33-desoxyascomycin) , which is disclosed in EP 427,680, example 66a.
• ascomycin derivatives such as halogenated-ascomycin (e.g., 33-epi-chloro-33-desoxyascomycin) , which is disclosed in EP 427,680, example 66a.
• the tricyclic compounds (I) may be in a form of its salt, which includes conventional non-toxic and pharmaceutically acceptable salt such as the salt with inorganic or organic bases, specifically, an alkali metal salt such as sodium salt and potassium salt, an alkali earth metal salt such as calcium salt and magnesium salt, an ammonium salt and an amine salt such as triethylamine salt and N-benzyl-N-methylamine salt.
• an alkali metal salt such as sodium salt and potassium salt
• an alkali earth metal salt such as calcium salt and magnesium salt
• an ammonium salt and an amine salt such as triethylamine salt and N-benzyl-N-methylamine salt.
• a daily dose thereof is about from 0.001 to lOOOO ⁇ g, preferably from 0.01 to 1000 ⁇ g, and more preferably, from 0.1 to 500 ⁇ g for therapeutic purposes.
• the average unit dose may be generally about 0.1 ⁇ g, 0.5 ⁇ q, l ⁇ g, 5 ⁇ g, 10 ⁇ g, 50 ⁇ q, 100 ⁇ g, 250 ⁇ q, or 500 ⁇ g.
• a suitable unit dose of ⁇ 2-agonist is in the range of from 0.1 ⁇ q to 500 ⁇ q, preferably from 0 . 5 ⁇ q to 250 ⁇ q, and more preferably between l ⁇ g to 100 ⁇ q .
• the daily dose of ]32-agonist, such as formoterol (as fumarate dihydrate) , including maintenance therapy, should be in the range of from 0.1 ⁇ g to 1000 ⁇ g, preferably from 0.5 ⁇ g to 500 ⁇ g, and more preferably from l ⁇ g to 200 ⁇ g.
• the particular dose regimen will depend on the patient (age, sex, weight etc. ) and the severity of the disease (mild, moderate, severe asthma etc.).
• One or more of the ingredients of the mixture may be in the form of dry powder, more preferably a small particle dry powder, most preferably an agglomerated small particle dry powder.
• one or more of the active ingredients are in the form of an ordered mixture with diluent, additive or carrier.
• the ingredients used in the invention can be obtained in these preferred forms using methods known to those skilled in the art.
• the particle size of the active ingredients is preferably less than 10 ⁇ m.
• the ingredients of the system are preferably adapted to be administered from a dry powder inhaler, a pressurized metered dose inhaler, or a nebulizer.
• a pressurized inhaler When the ingredients of the system are adapted to be administered from a pressurized inhaler, they are preferably in a small particle form. They are dissolved, or, preferably, suspended in a liquid propellant mixture.
• the propellants which can be used include chlorofluorocarbons, hydrocarbons or liquefied hydrofluoroalkane .
• Especially preferred propellants are HFA-134a (tetrafluoroethane) and HFA-227, each of which may be used alone or in combination.
• ingredients of the systemof the invention are adapted to be administered via a nebulizer they may be in the form of a nebulized aqueous suspension or solution, with or without suitable pH or tonicity adjustment, either as a unit dose or multidose formulation.
• 2-agonist can be mixed with the FK506 derivatives prior to its use. So, the composition comprising the said ⁇ 2-agonist of the present invention may further comprise the FK506 derivatives . And optionally, it comprises further additional active ingredients.
• Ovalbumin (OA) -sensitized guinea pigs were prepared in a similar manner to that of Am. J. Respir. Crit . Care Med. 160(2) : 663-671(1999) .
• Drugs can be given to animals placed in a plastic chamber by puffing aerosol of the drugs. Then, aerosolized OA solution is introduced in the chamber. Antigen-induced immediate increase in airway resistance can be monitored in a similar manner to that of Eur J Pharmacol (1996) Apr 11; 300 (3) : 215-9.
• mice On the next day, the airway responsiveness to acetylcholine can be determined in mice in a similar manner to that of J. Exp. Med. (1998) 188: 157-167.
• BAL bronchoalveolar lavage
• Hartley guinea pigs weighing approximately 300 g were injected with saline solution of egg albumin (EA, 5mg/mL) intraperitoneally and subcutaneously . The same procedure was repeated 7 days after the first immunization.
• EA egg albumin
• EA solution 1% in saline
• Saline instead of EA solution was used for the negative control group. All animals received 10 mg/kg of pyriramine maleate intraperitoneally 35 min before the antigen challenge .
• FK506 aerosol (2 puffs) identified below, its placebo (4 puffs), Serevent® (salmeterol xinafoate) inhalation aerosol (2 puffs) identified below, or FK506 + Serevent® (each 2 puffs) was given once, 30 min before the antigen challenge. Animals were placed in the double chambered box, puffed aerosol, and kept for 2 min.
• FK506 aerosol (0.1%) : FK506 (5 mg) in a mixture of HFA-134a and Miglyol 812, which was prepared in a similar manner to Example 1 of US6,361,760.
• Serevent® salmeterol xinafoate (36.25 ⁇ g/ 1 puff) in a mixture of 2 chlorofluorocarbon propellants
• Immediate bronchoconstriction was assessed by measurement of enhanced pause (Penh) as described in Reference 1) . After measurement of basal value of Penh for 5 min, animals were challenged with EA or saline, and then measured Penh for 10 min.
• BAL bronchoalveolar lavage
• BALF BAL fluid
• the BALF cells were obtained by centrifugation, suspended with saline, the total cell number counted, and the cell suspension was smeared on a slide glass. The cells were stained and differentially counted intoneutrophils, eosinophils, macrophages, lymphocytes and others under a microscope. To obtain the absolute number of each cell type in the BALF, the percentages of each cell type were multiplied by the total numbers of cells recovered from the BALF.
• Antigen inhalation caused an immediate bronchoconstriction and a late response (airway inflammation) .
• the combinatory use of FK506 aerosol and Serevent® inhalation aerosol suppressed both the immediate response and the late response.
• the combination use of FK506 derivatives and ⁇ 2-agonist shows a remarkable and/or synergistic prevention of asthmatic attack upon antigen exposure, relief of on-going bronchospasm, reduction of airway hyper-responsiveness and reduction of airway inflammation, which leads to better control of the condition of asthma patients.
• the combination use is also useful for decreasing side effects of FK506 derivatives and/or ⁇ 2-agonist by providing a better control and thus by decreasing the total amount of each drug.
• the present invention also provides the following inventions. i) An article of manufacture, comprising packaging material and FK506 derivatives and ⁇ 2-agonist contained within said packagingmaterial, wherein said FK506 derivatives and 2-agonist is therapeutically effective for treating and preventing acute or chronic asthma, and wherein said packaging material comprises a label or a written material which indicates that FK506 derivatives and 2-agonist can be used for treating and preventing acute or chronic asthma.
• An article of manufacture comprising packaging material and FK506 derivatives and ⁇ 2-agonist contained within said packaging material, wherein said FK506 derivatives and ⁇ 2-agonist is therapeutically effective for treating and preventing acute or chronic asthma, and wherein said packaging material comprises a label or a written material which indicates that said FK506 derivatives and ⁇ 2-agonist can be used for treating and preventing acute or chronic asthma.

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