EP0873311A1 - Derives d'ethane tri-aryle utilises comme inhibiteurs de pde iv - Google Patents

Derives d'ethane tri-aryle utilises comme inhibiteurs de pde iv

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Publication number
EP0873311A1
EP0873311A1 EP96940967A EP96940967A EP0873311A1 EP 0873311 A1 EP0873311 A1 EP 0873311A1 EP 96940967 A EP96940967 A EP 96940967A EP 96940967 A EP96940967 A EP 96940967A EP 0873311 A1 EP0873311 A1 EP 0873311A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
independently selected
ethyl
pyridyl
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96940967A
Other languages
German (de)
English (en)
Inventor
Daniel Guay
Yves Girard
Yves Ducharme
Marc Blouin
Pierre Hamel
Mario Girard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Frosst Canada and Co
Original Assignee
Merck Frosst Canada and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9606377.1A external-priority patent/GB9606377D0/en
Application filed by Merck Frosst Canada and Co filed Critical Merck Frosst Canada and Co
Publication of EP0873311A1 publication Critical patent/EP0873311A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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 to compounds and pharmaceutical compositions for the treatment of diseases by raising the level of cyclic adenosine-3',5'-monophosphate (cAMP) through the inhibition of phosphodiesterase IV (PDE IV).
  • cAMP cyclic adenosine-3',5'-monophosphate
  • PDE IV phosphodiesterase IV
  • cAMP 3', 5 '-cyclic adenosine monophosphate
  • the cellular levels of cAMP are regulated by mechanisms which control synthesis and breakdown.
  • the synthesis of cAMP is controlled by adenyl cyclase which may be directly activated by agents such as forskolin or indirectly activated by the binding of specific agonists to cell surface receptors which are coupled to adenyl cyclase.
  • the breakdown of cAMP is controlled by a family of phosphodiesterase (PDE) isoenzymes, which also control the breakdown of guanosine 3',5'-cyclic monophosphate (cGMP).
  • PDE phosphodiesterase
  • PDE I-VII the distribution of which varies from tissue to tissue. This suggests that specific inhibitors of PDE isoenzymes could achieve differential elevation of cAMP in different tissues, [for reviews of PDE distribution, structure, function and regulation, see Beavo & Reifsnyder (1990) TIPS, ⁇ : 150- 155 and Nicholson et al (1991) TIPS, 12: 19-27].
  • the availability of PDE isotype selective inhibitors has enabled the role of PDEs in a variety of cell types to be investigated. In particular it has been established that PDE IV controls the breakdown of cAMP in many inflammatory cells, for example, basophils (Peachell P.T.
  • PDE IV inhibitors for the treatment of inflammatory diseases such as asthma, has met with limited success to date. Many of the PDE IV inhibitors which have been synthesised have lacked potency and/or inhibit more than one type of PDE isoenzyme in a non-selective manner. PDE IV inhibitors that are relatively potent and selective for PDE IV, are reported to be emetic as well. Indeed this side effect has been so universal that experts have expressed their belief that the emesis experienced upon administration of a PDE IV inhibitor, may be mechanism based.
  • compounds according to the invention have good oral activity and at orally effective doses exhibit little or none of the side-effects associated with known PDE IV inhibitors, such as rolipram.
  • the compounds of the invention are therefore of use in medicine, especially in the prophylaxis and treatment of asthma and other inflammatory conditions.
  • the invention encompasses novel compounds of Formula I useful in the treatment of disease by inhibition of PDE IV, resulting in an elevation of cAMP.
  • the invention also encompasses certain pharmaceutical compositions and methods for treatment of diseases by inhibition of PDE IV, resulting in an elevation of cAMP, comprising the use of compounds of Formula I.
  • the invention encompasses the novel compound of Formula I useful in the treatment of disease by inhibition of PDE IV, resulting in an elevation of cAMP,
  • R is selected from (a) hydrogen,
  • Rl is selected from
  • R2 and R3 are independently selected from (a) C ⁇ _7alkyl, (b) substituted Cl-7 alkyl, wherein the substituent is F, Cl, Br or I,
  • R4 is selected from
  • R5, R8 and Rl 1 are each independently selected from (a) -CF3, (b) Cl -6alkyl, (c) phenyl, benzyl or 2-phenethyl, optionally mono or di ⁇ substituted, wherein the substituents on the benzene ring are independently selected from the group consisting of (1) halo, (2) Cl-6alkoxy,
  • R6, R7, R9 an( j R10 are eacn independently selected from (a) hydrogen, and (b) Cl-6alkyl, or
  • R6 and R may be joined to form a saturated 5, 6 or 7 membered heterocycle, said heterocycle containing a heteroatom which is nitrogen and optionally containing an additional hetero atom which is an O or an S atom or NR4 , and optionally containing a carbonyl group;
  • HET is selected from pyridyl and imidazolyl, optionally mono-, or disubstituted, wherein the substituents are independently selected from halo, Cl-6alkyl, Cl- 6alkoxy, Cl-6alkylthio, benzyl, 2- ⁇ henethyl, NHCOR8, NR9R10, NHS(0)2 1 1 ' OH, CN, or CF3, and the N-oxides thereof; and X is selected from N, N ⁇ O or CH.
  • R is selected from (a) hydrogen, (b) Cl-4alkyl,
  • R2 is cyclopentyl
  • R3 is methyl
  • R4 is selected from
  • R5, R and R 1 are each independently selected from (a) -CF3, (b) Cl-6alkyl, (c) phenyl, benzyl or 2-phenethyl, optionally mono or di ⁇ substituted, wherein the substituents on the benzene ring are independently selected from the group consisting of
  • HET is selected from pyridyl and imidazolyl, optionally mono-, or disubstituted, wherein the substituents are independently selected from halo, Cl-6alkyl, Cl- ⁇ alkoxy, Cl-6alkylthio, benzyl, 2-phenethyl, NHCOR 8 , NR ⁇ RlO, NHS(0)2R! *' OH, CN, or CF3, and the N-oxides thereof; and X is selected from N, N ⁇ O or CH.
  • Rl is selected from
  • R2 is cyclopentyl
  • R3 is methyl
  • R4 is selected from
  • R6 and R7 may be joined to form a saturated 5, 6 or 7 membered heterocycle, said heterocycle containing a heteroatom which is nitrogen and optionally containing an additional hetero atom which is an O or an S atom or NR4 , and optionally containing a carbonyl group;
  • HET is selected from pyridyl, optionally mono-, or disubstituted, wherein the substituents are independently selected from halo, Cl-6alkyl, Cl-6alkoxy, Cl- 6alkylthio, benzyl, 2-phenethyl, NHCOR8, NR9R10, NHS(0)2R U ' OH, CN, or CF3, and the N-oxides thereof; and X is CH.
  • Halo is intended to include F, Cl, Br, and I.
  • alkyl is defined to include linear, branched, and cyclic structures, with Ci-6alkyl including including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Cl-6alkoxy is intended to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration.
  • alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
  • C 1 -6alkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration. Examples of alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies -SCH2CH2CH3.
  • C 1 -6haloalkyl means an alkyl group in which two or more hydrogen atoms have been replaced by halogen atoms.
  • Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
  • the invention encompasses pharmaceutical compositions for treatment of disease by inhibition of PDE IV, as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of formula I as described above.
  • compositions for treatment of disease by inhibition of PDE IV, resulting in an elevation of cAMP comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of formula I as described above.
  • a compound is said to selectively inhibit PDE IV in preference to other PDE's if the ratio of the IC50 concentration for all other PDE inhibition to PDE IV inhibition is 100 or greater.
  • compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N_- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as arg
  • references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
  • Compounds according to the invention are selective and potent inhibitors of PDE IV. The ability of the compounds to act in this way may be simply determined by the tests described in the Examples hereinafter.
  • the compounds according to the invention are thus of particular use in the prophylaxis and treatment of human diseases where an unwanted inflammatory response or muscular spasm (for example bladder or alimentary smooth muscle spasm) is present and where the elevation of c AMP levels may be expected to prevent or alleviate the inflammation and relax muscle.
  • an unwanted inflammatory response or muscular spasm for example bladder or alimentary smooth muscle spasm
  • the elevation of c AMP levels may be expected to prevent or alleviate the inflammation and relax muscle.
  • Particular uses to which the compounds of the invention may be put include the prophylaxis and treatment of asthma, especially inflamed lung associated with asthma, cystic fibrosis, or in the treatment of inflammatory airway disease, chronic bronchitis, eosinophilic granuloma, psoriasis and other benign and malignant proliferative skin diseases, endotoxic shock, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis and artherosclerosis.
  • Compounds of the invention also suppress neurogenic inflammation through elevation of cAMP in sensory neurones. They are, therefore, analgesic, anti-tussive and anti-hyperalgesic in inflammatory diseases associated with irritation and pain. Compounds according to the invention may also elevate cAMP in lymphocytes and thereby suppress unwanted lymphocyte activation in immune-based diseases such as rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease.
  • Compounds according to the invention have also been found to reduce gastric acid secretion and therefore can be used to treat conditions associated with hypersecretion of gastric acid.
  • Compounds of the invention suppress cytokine synthesis by inflammatory cells in response to immune or infectious stimulation. They are, therefore, useful in the treatment of bacterial, fungal or viral induced sepsis and septic shock in which cytokines such as tumour necrosis factor (TNF) are key mediators. Also compounds of the invention suppress inflammation and pyrexia due to cytokines and are, therefore, useful in the treatment of inflammation and cytokine- mediated chronic tissue degeneration which occurs in diseases such as rheumatoid or osteo-arthritis. Over-production of cytokines such as TNF in bacterial, fungal or viral infections or in diseases such as cancer, leads to cachexia and muscle wasting. Compounds of the invention ameliorate these symptoms with a consequent enhancement of quality of life.
  • TNF tumour necrosis factor
  • Compounds of the invention also elevate cAMP in certain areas of the brain and thereby counteract depression and memory impairment.
  • Compounds of the invention suppress cell proliferation in certain tumour cells and can be used, therefore, to prevent tumour growth and invasion of normal tissues.
  • the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • compounds of formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non- toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the compound of the invention is effective in the treatment of humans.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxy- propylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compounds of formula I may also be administered in the form of a suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day.
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
  • the compounds of the present invention can be prepared according to W094/14742, published on 7 July 1994, or according to WO 95/17386, published on 29 June 1995, which are hereby incorporated by reference or by the methods described below. It will be apparent to one skilled in the art that similar methodology could be used to prepare the enantiomers or the racemates of the illustrated compounds.
  • Carboxylic acid derivatives were prepared by the method presented in Scheme 1. The diastereoselective addition of Grignard reagents derived from suitable bromoaryl-l,3-dioxolanes to acylsultam Michael acceptor II afforded triarylpropanoylsultam intermediates. Removal of the chiral auxiliary, subsequent decarboxylation and aldehyde deprotection were then performed in a one-pot fashion by successive treatment with a suitable lithium thiolate followed by a saponification with aqueous hydroxide and then by an aqueous acidic treatment. In this way, carboxaldehyde intermediates were obtained.
  • Arenesulfonamide derivatives were prepared by the method presented in Scheme 3. Condensation of a suitable arenecarboxaldehyde with diphenyl l-chloro-l-(heteroaryl)methanephosphonate (J. Org. Chem., 1992, 57, 1622) afforded the corresponding diarylalkynes. Acid catalized addition of hydrogen iodide followed by palladium catalyzed stannylation gave access to vinyltin intermediates. These were submitted to palladium catalyzed coupling with N,N-bis-(p-methoxybenzyl)-4- bromobenzenenesulfonamide to yield the corresponding triarylethylene derivatives.
  • the chloride XII was condensed with the a-anion of ethyl 4-pyridyl acetate, affording the intermediate ester derivative XIII, which on hydrolysis with lithium hydroxide in a THF-methanol- water medium, followed by acidification with aqueous ammonium chloride afforded the decarboxylated intermediate XIV. Removal of the SEM protecting group was effected using TBAF in THF, leading to the final compound XV.
  • the compound XV was oxidized with m-chloroperoxy benzoic acid to afford the N-oxide XVI.
  • CHO-Kl cells stably expressing the prostacyclin receptor and grown under G418 selection as described previously (Y. Boie, et al. J. Biol. Chem.: 269, 12173-12178, 1994) were plated at a density of 1.75 x 10° cells/175cm 2 in a T-175 flask (Gibco, Burlington, VT) containing alpha MEM media; 10% heat inactivated fetal bovine serum (FBS); 1 % (v/v) penicillin/streptomycin; 25 mM Hepes, pH 7.4; and 500 ⁇ g/ml G418 (complete media). The cells were placed in an incubator for 24 hr at 37°C and 5% C0 2 .
  • the cells were then washed with warmed sterile phosphate buffered saline (PBS) and incubated with 2 ⁇ g/ml DNA, and 9 ⁇ g/ml lipofectamine reagent in Opti-MEM for 7 hr. At 37°C and 5% C0 2 .
  • the incubation solution was diluted 1 :2 with Opti-MEM containing 20% FBS and incubated overnight. Following the overnight incubation, the media was replaced by complete media containing 500 ⁇ g/ml hygromycin B. Colonies were identified and grown in T-175 flasks for further characterization.
  • CHO-Kl cells were plated at a density of 10 6 cells/175 cm 2 containing complete media with 500 ⁇ g/ml hygromycin. The flasks were maintained in an incubator at 37°C with 5.0% C0 2 for 72 hr. The media was changed and the cells were allowed to grow overnight. The cells were washed and dissociated from the plate with PBS containing 0.5 mM EDTA. Cellular cAMP content was measured by centrifuging the cell suspension at 150 g x 10 min. And resuspending the cells in a Hanks buffered salt solution at a density of 0.2 x 10 6 cells/ml. The cells were preincubated at room temperature for 15 min.
  • PGI 2 prostaglandin I 2
  • Basal cAMP levels were determined by incubating the cells in 0.1 % DMSO. The incubations were terminated by the addition of HCl (0.1 N final) and the cells measured for cAMP as described below.
  • Determinations of whole-cell cAMP content were performed by incubating 100 ⁇ l reconstituted rabbit anti-succinyl cAMP serum with 100 ⁇ l of the whole-cell reaction or known cAMP standard and 30 pmol of 12 T-cAMP TME in a ScintiStripTM well (300 ⁇ l final volume) at room temperature for 18 h. Total cpm (B 0 ) was determined in the absence of sample of cAMP standard. The reaction mixture was then aspirated out of the well, and the individual wells were counted in a Beckman LS 6000SC with the window open from 10-999 for 1 min.
  • %B/B 0 [(standard or sample cpm - non-specific cpm) / (B 0 cpm - non-specific cpm)] x 100.
  • Non-specific cpm were determined by incubating only the ,25 I-cAMP TME with assay buffer (50 nM acetate; pH 5.8) in the ScintiStripTM well. All determinations were performed in triplicate.
  • CHO-Kl cells were lysed by sonication for 10 sees at a power setting of 50% (Braunsonic Model 2000) in an ice cold solution containing 50 mM Tris, pH 7.5; ImM EDTA; and 200 ⁇ M ⁇ -mercaptoethanol.
  • the soluble and particulate fractions of the cell were obtained by centrifuging the sonicate for 90 min. at 100,000 x g at 4°C.
  • PDE activity was measured in a solution containing 50 mM Tris, pH 7.5; lOmM MgCl 2 ; 1 mM EDTA; and 100 nM (or indicated) 3 H-cAMP (100 ⁇ l final volume) in the presence of varying concentrations of inhibitor.
  • the reaction mixture containing enzyme was incubated for 10 min. at 30°C in 96-well View Plates (Packard), and terminated by the addition of 50 ⁇ l Phosphodiesterase Scintillation Proximity Assay (SPA) Beads (Amersham) containing 18 mM ZnS0 4 .
  • SPA Phosphodiesterase Scintillation Proximity Assay
  • Beads Amersham
  • the amount of 3 H-cAMP hydrolysis was determined by counting the plates in a Wallac 1450 ⁇ Beta LSC counter.
  • the most potent compounds according to the Examples induced a concentration -dependent elevation of cAMP in neutrophils and/or eosinophils at concentrations of O. lnM to l ⁇ M.
  • LPS Lipopolysaccharide
  • TNF tumour necrosis factor
  • PBM peripheral blood monocytes
  • the effects of compounds of the invention on guinea-pig isolated tracheal smooth muscle were investigated. Isolated tracheal rings were suspended in organ baths and immersed in oxygenated Krebs' solution. The smooth muscle was contracted with sub-maximal concentrations of histamine or carbachol prior to the addition of increasing concentrations of test compound to the organ baths. The most potent compounds of the Examples caused a concentration- dependent reversal of both histamine and carbachol-induced contractions at concentrations of InM to lOO ⁇ M. The compounds were generally more potent in reversing histamine-induced tone than carbachol-induced tone.
  • Interleukin-5 (IL-5)-induced pleural eosinophilia in the rat is inhibited by compounds of the Examples given orally at doses of 0.0001 to lO.Omg/kg.
  • the most potent compounds cause a dose-dependent reduction in migrating eosinophils with ED 50 S of 0.003 to 0.03mg/kg p.o.
  • Compounds of the invention also reduce the inflammatory responses induced in rats by platelet activating factor (PAF). Anti-allergic Activity in vivo
  • BAL bronchial alveolar lavages
  • Examples (0.001 -lOmg/kg i.p. or p.o.), up to three times during the 48h following antigen challenge, lead to a significant reduction in the eosinophilia and the accumulation of other inflammatory leukocytes. There was also less inflammatory damage in the lungs of animals treated with compounds of the Examples.
  • Compounds of the invention (0.001 -lOmg/kg by oral or other route of aministration) reduce the allergic bronchoconstruction caused by antigen in sensitized guinea pigs.
  • Compounds of the invention are free from adverse effects following repeated overdosage to rats or dogs. For example, over administration of 125mg/kg/day of active compounds of the Examples to rats for 30 days is not associated with adverse toxicity.
  • potent compounds of the invention are 20-30 times less active than rolipram in inducing behavioural changes, sedation or emesis in rats, ferrets or dogs.
  • test compound dissolved in 2 ul DMSO
  • substrate buffer containing [2,8- 3 H] adenosine 3 ',5 '-cyclic phosphate (cAMP, 100 nM to 50 ⁇ M)
  • cAMP adenosine 3 ',5 '-cyclic phosphate
  • the reaction was initiated by the addition of 10 ml of human recombinant PDE-IV
  • IC50 values shown in Table 4 were determined with 100 nM cAMP using the purified GST fusion protein of the human recombinant phosphodiesterase IVa (met-248) produced from a baculovirus/Sf-9 expression system.
  • n-Butyllithium (2.4 M solution in hexane; 92.7 mL, 0.222 mol) was added dropwise (20 min) to a solution of -dibromobenzene (50.0 g, 0.212 mol) in Et2 ⁇ (1.2 L) at -60 °C. After completion of the addition, the reaction was left at -50 °C for 30 min and hexafluoroacetone (42.2 g, 0.254 mol) was bubbled through the heterogeneous mixture, at the same temperature. The resulting solution was allowed to warm to -30 °C over 30 min before saturated aqueous NH4CI was added.
  • Step 2 2-(4-Bromophenyl)-2-[2-(trimethylsilyl)ethoxymethoxy]- 1,1,1 ,3,3,3-hexafluoropropane
  • Step 3 (1/?, 55)-N- ⁇ (3/?)-3-(3-Cyclopentyloxy-4-methoxyphenyl)-3-[4- (2-(2-(trimethylsilyl)ethoxymethoxy)- 1 ,1, 1 ,3,3, 3-hexafluoropropan-2- yl)phenyl]-2-(4-pyridyl)propanoyl ⁇ - 10, 10-dimethy l-3-thia-4- azatricyclo[5.2.1. ⁇ l'5]decane-3,3-dioxide
  • Step 4 (R)-4- ⁇ 2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-[4-(2-(2- (trimethylsilyl)ethoxymethoxy)- 1,1,1 ,3,3,3-hexafluoropropan-2- yl)phenyl]ethyl ⁇ pyridine
  • n-Butyllithium (2.4 M solution in hexane; 7.76 mL, 18.6 mmol) was added dropwise to a solution of 1-propanethiol (2.06 mL, 22.8 mmol) in THF (100 mL) at 0 °C.
  • the reaction was then quenched by the addition of 25% aqueous NH4OAC buffer.
  • the aqueous layer was extracted with EtOAc (2x), and the combined organics were washed successively with 25% aqueous NH4OAC buffer and brine, dried (MgS04) and concentrated.
  • the residue was dissolved in EtOH (170 mL) and water (57 mL), lithium hydroxide monohydrate (2.20 g, 52.0 mmol) was added and the mixture heated to reflux for 2.5 h.
  • the reaction mixture was cooled to room temperature before the addition of AcOH (3.56 mL, 62.1 mmol). After 30 min., 25% aqueous NH4OAC buffer was added and the aqueous layer extracted with EtOAc (2x).
  • Step 5 ( )-4- ⁇ 2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-[4- (1,1,1 ,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]ethyl ⁇ pyridine
  • Tetrabutylammonium fluoride (1.0 M in THF; 30.4 mL, 30.4 mmol) was added dropwise to a solution of (R)- ⁇ - ⁇ 2-(3- cyclopentyloxy-4-methoxy ⁇ henyl)-2-[4-(2-(2- (trimethylsilyl)ethoxymethoxy)- 1,1, 1,3,3, 3-hexafluoro ⁇ ropan-2- yl)phenyl]ethyl ⁇ pyridine from Step 4 (4.08 g, 6.09 mmol) in THF (50 mL) at room temperature, and the resulting solution was heated to the reflux temperature for 2.5 h, allowed to cool, and 25% aqueous NH4OAC buffer was added.
  • Step 1 (3-Cyclopentyloxy-4-methoxyphenyl)(4-pyridyl)acetylene
  • Step 2 l-(3-Cyclopentyloxy-4-methoxyphenyl)-l-iodo-2-(4- pyridyl)ethylene
  • Step 3 l-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)-l- (trimethylstannyl)ethylene
  • Step 4 N,/V-Bis-(p-methoxybenzyl)-4-[l-(3-cyclo ⁇ entyloxy-4- methoxyphenyl)-2-(4-pyridyl)ethenyl]benzenenesulfonamide
  • Step 5 N,N-Bis-(p-methoxybenzyl)-4-[l-(3-cyclopentyloxy-4- methoxyphenyl)-2-(4-pyridyl)ethyl]benzenenesulfonamide
  • Step 6 4-[l-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4- pyridyl)ethyl]benzenenesulfonamide
  • Trifluoroacetic acid (0.5 mL) was added to a 0°C solution of protected sulfonamide from Step 5 (98 mg, 0.14 mmol) in CH2CI2 (3 mL) and the reaction mixture was stirred at room temperature for 24 h. EtOAc was then added and the organic phase was washed successively with 25% aqueous NH4OAC buffer, water and brine, dried (MgS ⁇ 4) and concentrated. The residue was purified by flash-chromatography (silica gel, EtOAc) to afford the title compound as an off-white solid (46 mg, 72%).
  • Step 7 N-( ⁇ -Toluoyl)-4-[l-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4- pyridyl)ethyl]benzenenesulfonamide
  • Step 2 r3.4-Bis(difluoromethoxy)phenyll-(4-r2-(2-trimethylsilyl ethoxy )methoxy1- 1.1.1.3.3.3-hexafluoropropan-2-yl phenyl) methanol
  • 2-(4-bromophenyl)-2-[2-(trimethylsilyl) ethoxy methoxy]- 1,1,1, 3,3, 3-hexafluoro propane from Example 7, Step 2 (2.44 g, 5.4 mmol) in THF (15 mL) at -78 ⁇ C was added n- butyllithium in hexanes (1.25 M, 4 mL, 5 mmol), and the resulting solution was kept at -78 ⁇ C for 20 minutes.
  • Step 3 [3.4-Bis(difluoromethoxy)phenvn-(4-r2-(2-trimethylsilyl ethoxy )methoxyl-l .1.1.3.3.3-hexafluoro propan-2-yl phenyl ⁇ chloromethane
  • Step 4 4-( l-Carbethoxy-2-(3.4-bis(difluoromethoxy)phenyn-2-r4-
  • Step 5 4- ⁇ 2-r3.4-Bis(difluoromethoxyl-2-r4-(2-(2-trimethylsilyl) ethoxymethoxy)- 1.1.1.3.3.3-hexafluoropropan-2- yllphenyllethyl ⁇ pyridine
  • the crude product from Step 4 was refluxed in a mixture of methanol (10 mL), THF (10 mL) and water (5 mL) containing lithium hydroxyde hydrate (168 mg, 4 mmol) for 1.5 hours. After cooling, sat'd aq. ammonium chloride (25 mL) was added and heating was resumed for 20 minutes.
  • Step 6 4- ( 2-(3.4-Difluoromethoxy)phenyl-2-r4-(l .1.1.3.3.3- hexafluoro-2-hvdroxypropan-2-yl)phenyllethyl ) pyridine
  • the procedure for the removal of the SEM protecting group described in Example 7, Step 5 was applied using the product of
  • Step 1 3.5-Dichloro-4-f 2-r3.4-bisfdifluoromethoxyl-2-r4-(2-(2- trimethylsilyl) ethoxymethoxy)- 1.1.1.3.3.3- hexafluoropropan-2-yl)phenyl1ethyl i pyridine To freshly prepared lithium diisopropylamide in THF (0.3
  • Step 2 (IR, 55')-N- ⁇ (3 ⁇ )-3-(3-Cyclopentyloxy-4-methoxyphenyl)-3-[4- ( 1 ,3-dioxolan-2-yl)phenyl]-2-(4-pyridyl) ⁇ ropanoyl ⁇ - 10, 10-dimethyl-3- thia-4-azatricyclo[5.2.1. ⁇ l ' ⁇ ]decane-3,3-dioxide
  • Step 3 (#)-4-[l-(3-Cyclopentyloxy-4-methoxy ⁇ henyl)-2-(4- pyridyl)ethyl]benzaldehyde
  • n-Butyllithium (2.4 M solution in hexane; 10.6 mL, 25 mmol) was added dropwise to a 0°C solution of propanethiol (4.6 mL, 51 mmol) in THF (150 mL).
  • Step 4 (/?)-4-[l-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4- pyridyl)ethyl]benzoic acid
  • Step 3 (1R, 5S)-N- ⁇ (3 ⁇ )-3-(3-Cyclopentyloxy-4-methoxyphenyl)-3-[4- ( 1 ,3-dioxolan-2-ylmethyl)phenyl]-2-(4-pyridyI)propanoyl ⁇ - 10, 10- dimethyl-3-thia-4-azatricyclo[5.2.1. ⁇ l ' 5] ( ⁇ ecane . 3 ) 3_ ( jio ⁇ ide
  • the reaction mixture was stirred at room temperature for 16 h and quenched by the addition of saturated aqueous NH4CI.
  • the organic layer was concentrated and diluted with EtOAc, and the aqueous phase extracted with EtOAc (2x).
  • the combined organics were washed successively with 25% aqueous NH4OAC buffer, water and brine, dried (MgS ⁇ 4) and evaporated.
  • the residue was recrystallized in EtOH (a minimum of CHCI3 was necessary to insure dissolution) to afford the title compound as a white solid (12.2 g, 46%).
  • Step 4 (7 )-4-[l-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4- pyridyl)ethyl]phenylacetaldehyde diethyl acetal
  • n-Butyllithium (2.4 M solution in hexane; 13.2 mL, 31.3 mmol) was added dropwise to a solution of 1-propanethiol (3.47 mL, 38.3 mmol) in THF (160 mL) at 0 °C.
  • Step 5 ( ⁇ )-4-[l-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4- pyridyl)ethyl]phenylacetaldehyde
  • Step 6 ( ?)-4-[l-(3-Cyclo ⁇ entyloxy-4-methoxyphenyl)-2-(4- pyridyl)ethyl]phenylacetic acid
  • reaction mixture was stirred at room temperature for 1.5 h before 25% aqueous NH4OAC buffer was added (a few drops of acetic acid were necessary to bring the pH at 7).
  • the mixture was then extracted with EtOAc (2x), and the combined organics were washed successively with 25% aqueous NH4OAC buffer, water and brine, dried (MgS ⁇ 4) and concentrated.
  • the residue was purified by column chromatography on silica (EtOAc containing 0.5% AcOH). Residual AcOH was co-evaporated with toluene (2x) to afford the title compound as a white foam (319 mg, 83%).

Abstract

Nouveau composé de formule (I) utilisé pour traiter des maladies, y compris l'asthme, par augmentation du niveau d'adénosine-3',5'-monophosphate cyclique (cAMP), cette augmentation étant obtenue par l'inhibition de la phosphodiestérase IV (PDE IV). L'invention se rapporte également à certaines compositions pharmaceutiques et à des méthodes de traitement des maladies par inhibition de la PDE IV, entraînant une augmentation de cAMP, ces méthodes consistant à utiliser des composés de la formule (I).
EP96940967A 1995-12-15 1996-12-11 Derives d'ethane tri-aryle utilises comme inhibiteurs de pde iv Withdrawn EP0873311A1 (fr)

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US870495P 1995-12-15 1995-12-15
US8704P 1995-12-15
GBGB9606377.1A GB9606377D0 (en) 1996-03-26 1996-03-26 Tri-aryl ethane derivatives as PDE IV inhibitors
GB9606377 1996-03-26
PCT/CA1996/000839 WO1997022586A1 (fr) 1995-12-15 1996-12-11 Derives d'ethane tri-aryle utilises comme inhibiteurs de pde iv

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US6180650B1 (en) * 1999-04-23 2001-01-30 Merck Frosst Canada & Co. Heterosubstituted pyridine derivatives as PDE 4 inhibitors
US6200993B1 (en) * 1999-05-05 2001-03-13 Merck Frosst Canada & Co. Heterosubstituted pyridine derivatives as PDE4 inhibitors
JP5038568B2 (ja) 1999-08-21 2012-10-03 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング 協力剤の組合せ物
WO2002045718A1 (fr) * 2000-12-08 2002-06-13 Institut Pasteur De Lille Utilisation de composes actifs capables de moduler la voie intracellulaire declenchee par le recepteur de dp dans des cellules de langerhans
MXPA03010679A (es) 2001-05-23 2004-03-02 Tanabe Seiyaku Co Una composicion para acelerar la cicatrizacion de fractura osea.
KR20040007583A (ko) 2001-05-23 2004-01-24 다나베 세이야꾸 가부시키가이샤 연골 질환의 재생치료용 조성물
NZ540138A (en) * 2002-11-19 2008-07-31 Memory Pharm Corp Pyridine n-oxide compounds as phosphodiesterase 4 inhibitors
CN112250627B (zh) 2014-10-06 2024-02-02 弗特克斯药品有限公司 囊性纤维化跨膜转导调节因子调节剂
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EP3634402A1 (fr) 2017-06-08 2020-04-15 Vertex Pharmaceuticals Incorporated Méthodes de traitement de la fibrose kystique
AU2018304168B2 (en) 2017-07-17 2023-05-04 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
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EP3774825A1 (fr) 2018-04-13 2021-02-17 Vertex Pharmaceuticals Incorporated Modulateurs du régulateur de la conductance transmembranaire de la fibrose kystique, compositions pharmaceutiques, procédés de traitement et procédé de fabrication du modulateur

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AU707574B2 (en) 1999-07-15
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