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WO1998042650A2 - Antagonistes de leucotriene utilises dans le traitement de la mucoviscidose - Google Patents

Antagonistes de leucotriene utilises dans le traitement de la mucoviscidose Download PDF

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Publication number
WO1998042650A2
WO1998042650A2 PCT/US1998/005455 US9805455W WO9842650A2 WO 1998042650 A2 WO1998042650 A2 WO 1998042650A2 US 9805455 W US9805455 W US 9805455W WO 9842650 A2 WO9842650 A2 WO 9842650A2
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Prior art keywords
alkyl
ethyl
pharmaceutically acceptable
solvate
acceptable salt
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Application number
PCT/US1998/005455
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English (en)
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WO1998042650A3 (fr
Inventor
Jerome H. Fleisch
William T. Jackson
Jason S. Sawyer
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Eli Lilly And Company
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Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to AU67647/98A priority Critical patent/AU6764798A/en
Publication of WO1998042650A2 publication Critical patent/WO1998042650A2/fr
Publication of WO1998042650A3 publication Critical patent/WO1998042650A3/fr

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Definitions

  • Cystic fibrosis is an inherited disease that usually manifests itself in early childhood. Increasing numbers of children with cystic fibrosis are now surviving into young adulthood: the median age of survival currently exceeds 30 years. Some patients have a variant form of the disease in which symptoms first appear during adolescence or adulthood.
  • CFTR cystic fibrosis transmembrane conduct and regulator
  • Involved glands fall into 3 types: (1) those that become obstructed by viscid or solid eosinophilic material in the lumen (pancreas, intestinal glands, intrahepatic bile ducts, gallbladder, submaxillary glands) ; (2) those that produce an excess of histologically normal secretions ( tracheobronchial and Brunner ' s glands); and (3) those that are normal histologically but secrete excessive Na and Cl (sweat, parotid, and small salivary glands) .
  • Duodenal secretions are viscid and contain an abnormal mucopolysaccharide .
  • Insulin-requiring diabetes develops in 2 to 3% of patients, and multinodular biliary cirrhosis with varices and portal hypertension develops in 4 to 5% of adolescents and adults.
  • Chronic and/or recurrent abdominal pain may be related to intussusception, peptic ulcer disease, periappendiceal abscess, pancreatitis, gastroesophageal reflux, esophagitis, gallbladder disease, or episodes of partial intestinal obstruction secondary to abnormally viscid fecal contents.
  • the chest radiograph may strongly suggest the diagnosis of cystic fibrosis.
  • Extrapulmonary manifestations may also suggest the diagnosis of cystic fibrosis.
  • pancreatic insufficiency with consequent steatorrhea recurrent partial intestinal obstruction caused by abnormal fecal accumulation (so-called meconium ileus equivalent) , heat prostration, hepatic cirrhosis, and aspermia in males .
  • a sweat test with pilocarpine iontophoresis performed in an experienced laboratory is highly sensitive and specific for cystic fibrosis. Sweat chloride concentrations exceeding 60 mEq/L are found in 98 percent of patients with cystic fibrosis. Although sweat chloride concentrations increase with age, values greater than 80 mEq/L are not found in normal persons or in patients with any other respiratory illness.
  • Treatment of cystic fibrosis includes management of infections and use of respiratory therapy modalities designed to mobilize secretions, including regular percussion and postural drainage.
  • arachidonic acid derivatives formed by the action of lipoxygenases are related to various disease states.
  • Some of these arachidonic acid metabolites have been classified as members of a family of eicosatetraenoic acids termed leukotrienes .
  • Three of these substances are currently thought to be major components of what has been previously called slow reacting substance of anaphylaxis (SRS-A) and have been designated leukotrienes C 4 , D4, and E 4 (LTC 4 , LTD 4 , and LTE 4 , respectively) .
  • SRS-A slow reacting substance of anaphylaxis
  • LTB4 Another arachidonic acid metabolite, leukotriene B4 (LTB4), is a proinflammatory lipid which has been implicated in the pathogenesis of psoriasis, arthritis, chronic lung diseases, acute respiratory distress syndrome, shock, asthma, inflammatory bowel diseases, and other inflammatory states characterized by the infiltration and activation of polymorphonuclear leukocytes and other proinflammatory cells. Thus activated, the polymorphonuclear leukocytes liberate tissue-degrading enzymes and reactive chemicals causing the inflammation. Antagonism of LTB4 should therefore provide a novel therapeutic approach to treatment of these and other LTB4 mediated conditions. Because of the debilitating effects of cystic fibrosis there continues to exist a need for effective treatment.
  • Rl is C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl,
  • each R2 and R3 are each independently hydrogen, halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, (C1-C4 alkyl) -S (O)q-, trifluoromethyl , or di- (C1-C3 alkyl) amino;
  • Y is -0- or -CH2-
  • Z is a straight or branched chain C1-C10 alkylidenyl ;
  • each R ⁇ is independently -COOH, 5-tetrazolyl, -CON ( Rg ) 2, or -CONHSO2R10;
  • each R7 is hydrogen, C1-C4 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, benzyl, methoxy, -W-R6 , -T-G-R6, (C1-C4 alkyl) -T- (C1-C4 alkylidenyl ) -0- , or hydroxy ;
  • R8 is hydrogen or halo; each Rg is independently hydrogen, phenyl, or C1-C4 alkyl, or when taken together with the nitrogen atom form a morpholino, piperidino, piperazino, or pyrrolidino group;
  • RlO is C1-C4 alkyl or phenyl
  • Rll is R2, -W-R6, or -T-G-R6;
  • each W is a bond or straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms
  • each G is a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms
  • each q is independently 0, 1, or 2;
  • p is 0 or 1
  • t is 0 or 1;
  • X is -O- or -S-, Y is not -0- ;
  • A is -0- or -S-, R4 is not R ⁇ ;
  • A is -O- or -S- and Z is a bond, Y is not -0-;
  • W is not a bond when p is 0; or a pharmaceutically acceptable salt or solvate thereof.
  • C1-C5 alkyl refers to the straight and branched aliphatic radicals of 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, n-pentyl, 2 , 2-dimethylpropyl , and the like. Included within this definition are the terms “C1-C3 alkyl” and "C1-C4 alkyl”.
  • C2-C5 alkynyl refers to straight and branched aliphatic residues of 2 to 5 carbon atoms containing one triple bond, such as -C ⁇ CH, -CH2-C ⁇ CH, -CH 2 CH 2 C ⁇ CH, -CH 2 CH(CH 3 )C ⁇ CH, -CH 2 C ⁇ CCH 3 , and the like.
  • C1-C4 alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and tert-butoxy.
  • halo refers to fluoro, chloro, bromo, and iodo.
  • C 1 -C 10 alkylidenyl refers to a divalent radical derived from a Ci-Cio alkane such as -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(C 2 H 5 )-, -CH 2 CH 2 -, -CH 2 CH (CH 3 ) - ,
  • C4-C8 cycloalkyl refers to a cycloalkyl ring of four to eight carbon atoms, such as cyclobutyl, cyclopentyl, cyclohexyl, 4, 4-dimethylcyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • straight or branched chain divalent hydrocarbyl residue of one to eight carbon atoms refers to a divalent radical derived from a straight or branched alkane, alkene, or alkyne of one to eight carbon atoms.
  • such a moiety can contain one, two or three double or triple bonds, or combinations of both.
  • this term can be considered an alkylidene group as defined above containing from 1 to 8 carbon atoms optionally containing one to three double or triple bonds, or combinations of the two, limited as noted in the preceding sentence.
  • This invention includes the pharmaceutically acceptable base addition salts of the compounds of Formula I.
  • Such salts include those derived from inorganic bases, such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines, such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkylamines, and the like.
  • bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methyl amine, diethyl amine, ethylene diamine, cyclohexylamine, ethanolamine, and the like.
  • the potassium and sodium salt forms are particularly preferred.
  • This invention includes both mono-salt forms, i.e., a 1:1 ratio of a compound of Formula I with a base as previously described, as well as di-salt forms in those instances where a compound of Formula I has two acidic groups.
  • this invention includes any solvate forms of the compounds of Formula I or salts thereof, such as ethanol solvates, hydrates, and the like.
  • a most preferred group of compounds employed in the methods of the present invention are those compounds of Formula la:
  • R2 is halo, particularly fluoro.
  • Preferred Ri substituents are propyl and especially ethyl.
  • Preferred Z substituents include C2-C4 alkylidene, particularly -CH2CH2- and -CH2CH2CH2CH2- .
  • Preferred A groups include -0-, -CH2-, -CH (R 7 -substituted phenyl)-, and -
  • R4 groups include -COOH, 5-tetrazolyl, or a mono-, di-, or tri-cyclic group as drawn above wherein there is at least one acidic group attached to a ring, such as -W-COOH, -T-G-COOH, or the corresponding tetrazole derivatives .
  • the preferred W moiety is that of a bond or straight chain C1-C4 alkylidene; preferred G moieties are straight chain C1-C4 alkylidene.
  • R5 or R7 be C1-C4 alkyl, especially n-propyl .
  • Particularly preferred groups are those wherein A is -CH(R7-substituted phenyl)- and R4 is -COOH or 5- tetrazolyl. Also preferred are those compounds wherein A is -0- and R4 is
  • Preferred aspects of this substructure are those wherein R 7 is C 1 -C 4 alkyl, especially n-propyl , and R ⁇ is -W-COOH. Particularly preferred are those compounds wherein T is -O- or -S- and W is a bond.
  • Particularly preferred compounds of the instant invention include 2- [2-propyl-3- [3- [2-ethyl-4- (4- fluorophenyl ) -5-hydroxyphenoxy] propoxy] phenoxy] benzoic acid; 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5- hydroxyphenoxy) propoxy) -6- (4-carboxy- phenoxy) phenyl )propionic acid; 1- (4- (carboxy- methoxy) phenyl) -1- (lH-tetrazol-5-yl) -6- (2-ethyl-4- (4- fluorophenyl) -5-hydroxyphenoxy) hexane ; 3- [4- [7-carboxy-9- oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] - propoxy] -9H-xanthene] ]propanoic acid; 5- [3- [2-
  • LTB4 leukotriene B4
  • the leukotriene B4 (LTB4) antagonists employed in the methods of the present invention may be synthesized essentially as described in US Patent No. 5,462,954 issued October 31, 1995, the entire contents of which are herein incorporated by reference.
  • the following examples further illustrate the preparation of the intermediates and compounds employed in this invention. The examples are illustrative only and are not intended to limit the scope of the invention. Melting points were determined on a Thomas-Hoover apparatus and are uncorrected. NMR spectra were determined on a GE QE-300 spectrometer. All chemical shifts are reported in parts per million (_) relative to tetramethylsilane . Chemical shifts of aromatic protons of quinoline species in DMS0-d are concentration dependent.
  • the methods of the present invention describe the use of leukotriene antagonists for the treatment or inhibition of cystic fibrosis which is characterized by the excessive release of leukotriene B4.
  • leukotriene release refers to an amount of the leukotriene sufficient to exacerbate the symptoms of cystic fibrosis.
  • the amount of leukotriene which is considered to be excessive will depend on a variety of factors, including the amount of leukotriene required to cause the symptoms of disease, and the species of the mammal involved. As will be appreciated by those skilled in the art, the success of treating a mammal suffering from cystic fibrosis characterized by an excessive release of leukotriene with a compound of Formula I will be measured by the regression or prevention of the symptoms of the condition.
  • Cystic fibrosis is a multi-organ disease arising from an abnormality of the chloride ion channel that regulates transportation of chloride ions across fluid- transporting epithelial cells.
  • the defect leads to altered secretions, blocked ducts and reduced mucosal defenses to infections.
  • patients become hosts for chronic, recurring infections such as Pseudomonas aeruginosa in the lung. Once the infection persists in this organ, a chronic inflammatory response ensues with massive infiltration of neutrophils. The sputum becomes extremely viscous due to accumulation of DNA from degraded neutrophils.
  • much of the tissue damage in the lung is a result of proteases and reactive oxidants released by these granulocytes .
  • [ 3 H]-LTB 4 (196-200 Ci/mmole) was purchased from New England Nuclear (Boston, MA) . All other materials were purchased from Sigma (St. Louis, MO). Incubations (555 mL) were performed in polypropylene minitubes for 45 minutes at 30°C and contained 25 mg of guinea pig lung membrane protein (Silbaugh, e al..
  • Retained radioactivity was determined by liquid scintillation counting at 50% counting efficiency using Ready Protein Plus cocktail (Beckman, Fullerton, CA) .
  • Nondisplaceable binding was determined in the presence of 1 mM LTB 4 and was usually less than 10% of total binding.
  • Data were analyzed using linear regression analysis of log-logit plots of the values between 10% and 90% of control binding to calculate IC5 0 S and slope factors (pseudo-Hill coefficients) .
  • IC50 values thus obtained were corrected for radioligand concentration (Cheng and Prusoff, Biochem. Pharmacol . , 22. 3099 (1973)) to calculate Ki values.
  • pKi is the mean -log Ki for n experiments . Compounds of the instant invention tested in the above assay were found to have a pKi of between 7 and 11.
  • a chronic endobronchial infection in rats serves as a good model of the inflammatory response associated with cystic fibrosis (Konstan, et al . , Am. Rev. Respir . Pis . , 141, 186-92, 1990) .
  • a slurry of agarose beads containing 10 ⁇ colony-forming units per ml of P. aeruginosa , strain 3064 (a mucoid isolate from a cystic fibrosis patient) is prepared.
  • Young adult male rats weighing 150 grams are lightly anesthetized with ether and inoculated in the left lung with 60 ⁇ l of the slurry using a bead-tipped 20 gauge needle inserted through a tracheal incision.
  • Control groups are injected with sterile untreated beads. Animals are housed in hanging cages and allowed free access to rat chow and water. Oral dosing with a compound of formula I or vehicle is done twice daily for a period of 14 days. Daily weights of each animal are recorded.
  • the rats are sacrificed by exsanquination .
  • Lungs from half of the animals in each treatment group are used to make histological examinations; lungs from the other half are used for quantitative bacteriologic counts.
  • the lungs used for histologic examination are initially fixed in 10% formalin in phosphate-buffered saline (PBS) .
  • PBS phosphate-buffered saline
  • the left lungs are then cut sagitally into 3 slices, 3 mm thick, and the entire medial, central and lateral surfaces embedded in paraffin, then sectioned at 5 ⁇ m thickness and stained with hematoxylin-eosin.
  • a midsagittal slice of the right lung is also similarly processed.
  • Stained sections are viewed at 160-fold magnification. Each section is divided into units of 0.75 mm square size and each square scored for the presence or absence of inflammation. Inflammatory foci consist of inflammatory cells as well as areas of necrosis and fibrosis. Six hundred squares are counted in the left lung and 300 in the right lung. For bacteriologic examination, lungs are removed aseptically and homogenized in 50 ml of PBS. Serial dilutions are spread on replicate tryptic soy agar plates and colony-forming units counted after 20 hours incubation at 37°C. Dose-response effects are obtained by dividing the animals into 4 experimental groups of 20 rats each.
  • Animals in these groups are treated with either vehicle, or 10, 25 or 50 mg/kg doses of a compound of formula I.
  • the effectiveness of a treatment is mainly assessed by comparing the percentage of left lung involved in inflammation of the treated group to that of the vehicle control. Comparisons of weight gain and lung bacteriologic counts between the groups serve as secondary parameters of interest .
  • the therapeutic and prophylactic treatments provided by this invention are practiced by administering to a mammal in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, that is effective to inhibit or treat the symptoms of cystic fibrosis.
  • inhibitor includes its generally accepted meaning which includes prohibiting, preventing, restraining and slowing, stopping or reversing progression, severity or a resultant symptom.
  • the present method includes both medical therapeutic and/or prophylactic administration as appropriate.
  • the compounds are usually administered in the form of pharmaceutical formulation comprising a pharmaceutically acceptable excipient and at least one compound of the present invention.
  • the compounds or for ulations of the present invention may be administered by the oral and rectal routes, topically, parenterally, e.g., by injection and by continuous or discontinuous intra- arterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, cachets, elixirs, gels, suspensions, aerosols, ointments, for example, containing from 0.01 to 90% by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injectable solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injectable solutions.
  • Such formulations are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g. ,
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • Suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragacanth, gelatin, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates ; sweetening agents; and flavoring agents.
  • compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art .
  • the compounds of this invention may be delivered transdermally using known transdermal delivery systems and excipients .
  • a compound of this invention is admixed with permeation enhancers including, but not limited to, propylene glycol, polyethylene glycol monolaurate, and azacycloalkan-2-ones, and incorporated into a patch or similar delivery system. Additional excipients including gelling agents, emulsifiers, and buffers may be added to the transdermal formulation as desired.
  • a compound of this invention ideally can be admixed with any variety of excipients in order to form a viscous liquid or cream-like preparation.
  • a compound of this invention ideally can be admixed with carriers and diluents and molded into tablets or enclosed in gelatin capsules.
  • a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tableting machine.
  • a lubricant may be employed for instance aluminum, magnesium or calcium stearates, talc or mineral oil.
  • Preferred pharmaceutical forms of the present invention include capsules, tablets and aerosols.
  • the therapeutic and prophylactic treatments provided by this invention are practiced by administering to a mammal in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof that is effective to inhibit or treat the symptoms of cystic fibrosis .
  • formulations may be provided in unit dosage form, preferably each dosage unit containing from about 5 to about 500 mg (from about 5 to 50 mg in the case of parenteral or inhalation administration, and from about 25 to 500 mg in the case of oral or rectal administration) of a compound of Formula I.
  • Dosages from about 0.5 to about 300 mg/kg per day, preferably 0.5 to 20 mg/kg, of active ingredient may be administered although it will, of course, readily be understood that the amount of the compound or compounds of Formula I actually to be administered will be determined by a physician, in the light of all the relevant circumstances including the condition to be treated, the choice of compound to be administered and the choice of route of administration and therefore the above preferred dosage range is not intended to limit the scope of the present invention in any way.
  • the specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the route of administration the age, weight and response of the individual patient, the condition being treated and the severity of the patient's symptoms.
  • the compounds of the invention are most desirably administered at a concentration that will generally afford effective results without causing any serious side effects and can be administered either as a single unit dose, or if desired, the dosage may be divided into convenient subunits administered at suitable times throughout the day.
  • Hard gelatin capsules are prepared using the following ingredients :
  • the above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
  • a tablet is prepared using the ingredients below:
  • Magnesium stearate 5 The components are blended and compressed to form tablets each weighing 665 mg.
  • An aerosol solution is prepared containing the following components:
  • Propellant 114 29.75 (Dichlorotetrafluoroethane)
  • the active compound is dissolved in the ethanol and the solution is added to the propellant 11, cooled to -30°C. and transferred to a filling device. The required amount is then fed to a container and further filled with the pre-mixed propellants 12 and 114 by means of the cold-filled method or pressure-filled method. The valve units are then fitted to the container.
  • Tablets each containing 60 mg of active ingredient are made up as follows:
  • the active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No . 14 mesh U.S. sieve.
  • the granules so produced are dried at 50-60° and passed through a No . 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No . 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Capsules each containing 80 mg of medicament are made s follows:
  • the active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No . 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities .
  • Suppositories each containing 225 mg of active ingredient are made as follows:
  • the active ingredient is passed through a No . 60 mesh
  • the medicament is passed through a No . 45 mesh U.S. sieve and mixed with the sodium carboxymethylcellulose, sugar, and a portion of the water to form a suspension.
  • the parabens, flavor and color are dissolved and diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
  • Formulation 8 An intravenous formulation may be prepared as follows :
  • the solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.

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Abstract

La présente invention concerne des procédés de traitement ou d'inhibition des symptômes de mucoviscidose consistant à administrer, à un mammifère qui en a besoin, une quantité efficace d'un composé présentant une activité d'antagoniste de leucotriène B4.
PCT/US1998/005455 1997-03-21 1998-03-19 Antagonistes de leucotriene utilises dans le traitement de la mucoviscidose WO1998042650A2 (fr)

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AU67647/98A AU6764798A (en) 1997-03-21 1998-03-19 Leukotriene antagonists useful for treating cystic fibrosis

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US4087097P 1997-03-21 1997-03-21
US60/040,870 1997-03-21

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WO1998042650A3 WO1998042650A3 (fr) 1998-12-23

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Cited By (8)

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US6441015B2 (en) 2000-01-25 2002-08-27 Pfizer Inc. Tetrazole compounds as thyroid receptor ligands
US6667337B2 (en) 2000-03-03 2003-12-23 Cancer Research Technology Limited Combination therapy for cancer
US7462642B2 (en) 2002-03-22 2008-12-09 Cancer Research Technology Limited Anti-cancer combinations
US7510830B2 (en) 2000-07-28 2009-03-31 Cancer Research Technology Limited Cancer treatment by combination therapy
US7585893B2 (en) 2002-11-01 2009-09-08 Cancer Research Technology Limited Anti-cancer composition comprising DMXAA or related compound
US7863322B2 (en) 2001-09-03 2011-01-04 Cancer Research Technology Limited Anti-cancer combinations
US8044236B2 (en) 2006-10-12 2011-10-25 Institute Of Medicinal Molecular Design, Inc. Carboxilic acid derivatives
US8633245B2 (en) 2008-04-11 2014-01-21 Institute Of Medicinal Molecular Design, Inc. PAI-1 inhibitor

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PH30449A (en) * 1991-11-25 1997-05-28 Lilly Co Eli Substituted phenyl phenol leukotriene antagonists
US5324743A (en) * 1992-12-10 1994-06-28 Eli Lilly And Company Leukotriene B4 antagonists
US5478857A (en) * 1993-12-23 1995-12-26 Eli Lilly And Company Use of PLA2 inhibitors as treatment for alzheimer's disease
US5543428A (en) * 1994-08-31 1996-08-06 Eli Lilly And Company Method for treating resistant tumors

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6441015B2 (en) 2000-01-25 2002-08-27 Pfizer Inc. Tetrazole compounds as thyroid receptor ligands
US6667337B2 (en) 2000-03-03 2003-12-23 Cancer Research Technology Limited Combination therapy for cancer
US7510830B2 (en) 2000-07-28 2009-03-31 Cancer Research Technology Limited Cancer treatment by combination therapy
US7863322B2 (en) 2001-09-03 2011-01-04 Cancer Research Technology Limited Anti-cancer combinations
US7863321B2 (en) 2001-09-03 2011-01-04 Cancer Research Technology Limited Anti-cancer combinations
US7863320B2 (en) 2001-09-03 2011-01-04 Cancer Research Technology Limited Anti-cancer combinations
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