WO2009037302A1 - 1,4-benzodiazépines 5-substituées en tant qu'inhibiteurs de phosphodiestérase - Google Patents

1,4-benzodiazépines 5-substituées en tant qu'inhibiteurs de phosphodiestérase Download PDF

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WO2009037302A1
WO2009037302A1 PCT/EP2008/062425 EP2008062425W WO2009037302A1 WO 2009037302 A1 WO2009037302 A1 WO 2009037302A1 EP 2008062425 W EP2008062425 W EP 2008062425W WO 2009037302 A1 WO2009037302 A1 WO 2009037302A1
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phenyl
benzodiazepine
compound
benzo
diethoxy
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Mustapha Abarghaz
Said Oumouch
Yan Lagouge
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Via Pharmaceuticals, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the field of this invention relates to novel 5-(substituted alkylene-phenyl)-i,4- benzodiazepines which are inhibitors of phosphodiesterase type-IV (PDE-4) making them active as anti-inflammatory agents.
  • Phosphodiesterase type-IV belongs to a complex superfamily of at least 11 isozymes that regulates the intracellular level of cyclic adenosine-3',5'- monophosphate (cAMP) and/or cyclic guanylate-3',5'- monophosphate (cGMP) ubiquitous second messengers involved in regulating many cellular activities.
  • PDE-4 is characterized by its selective, high affinity hydrolytic degradation of the second messenger cyclic nucleotide, adenosine 3',5'-cyclic monophosphate (cAMP), and by its sensitivity to inhibition by rolipram.
  • PDE-4 i n pathological conditions, diseases and disorders associated with these tissues suggests pharmacological intervention in a variety of disorders involving inflammatory states such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), vascular disorders, autoimmune pathology and neurological disorders such as depression, Parkinson's disease and Alzheimer's disease.
  • COPD chronic obstructive pulmonary disease
  • RA rheumatoid arthritis
  • vascular disorders vascular disorders
  • autoimmune pathology and neurological disorders such as depression, Parkinson's disease and Alzheimer's disease.
  • COPD chronic obstructive pulmonary disease
  • RA rheumatoid arthritis
  • vascular disorders vascular disorders
  • autoimmune pathology and neurological disorders such as depression, Parkinson's disease and Alzheimer's disease.
  • autoimmune pathology autoimmune pathology
  • neurological disorders such as depression, Parkinson's disease and Alzheimer's disease.
  • COPD chronic obstructive pulmonary disease
  • RA rheumato
  • Rolipram® (ZK 62711, Schering AG) is active in the central nervous system and is suggested as an antidepressant. It was also found that this PDE-4 inhibitor improves memory in both long-term potential and contextual learning.
  • Other examples of PDE-4 inhibitors include cipamfylline, arofyline, cilomilast, roflumilast, mesopram and pumafentrine.
  • PDE-4 inhibitors provide therapeutic potential through selective elevation of intracellular cAMP and therefore can be potent antidepressant, neuroprotective, neuroregenerative and anti-inflammatory agents.
  • inhibition of PDE-4 leads to an elevation of the intracellular cAMP and produces a variety of biological effects, including, for example :t he relaxation of airway smooth muscle, inhibition of the activation of inflammatory cells and modulation of the activity of pulmonary nerves.
  • Torphy et al. Environ. Health Perspect. 102 Suppl. 10, 79-84, 1994
  • Ri and R 2 are lower alkoxy; n is an integer from i to 5; R 3 is hydrogen or lower alkyl; R 4 is hydrogen or lower alkyl; R 5 is lower alkyl,
  • ⁇ - ⁇ is a ring selected from the group consisting of phenyl, a 3 to 10 membered cycloalkyl ring and a 4 to 7 membered heterocycloalkyl or a 5 or 6 membered heteroaromatic ring with said hetero rings containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen: or R 4 and R 5 can also be taken together with their attached nitrogen atom to form a nitrogen containing ring of the formula:
  • ri is a nitrogen containing 5 to 7 membered heterocycloaiicyi ring containing from 0 to 2 additional hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen;
  • Re is lower alkyl;
  • R 7 is hydrogen, lower alley! , hydroxy, lower alkoxy, halogen or trifluoromethyl;
  • Rg is hydrogen, hydroxy, lower alkoxy , halogen, trifluoromethyl or lower alkyl;
  • R 9 is hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, trifluoromethyl,
  • the compounds of formula I and its pharmaceutically-acceptable salts inhibit the activity of PDE-4. Therefore these compounds may be used in therapeutic treatment, prevention or suppression of pathological conditions, diseases and disorders associated with PDE-4 activation such as that produced by inflammation.
  • the compounds and the compositions of the invention are of particular interest as anti-inflammatory agents for use in therapy, especially in the treatment of pathological conditions, diseases and disorder in the inhibition of inflammatory pathology of the central nervous system or neuroinflammation. Therefore the compounds of this invention may be useful in treating inflammatory conditions in various diseases which include asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), vascular disorders, autoimmune pathology and neurological disorders such as depression, Parkinson's disease and Alzheimer's disease.
  • COPD chronic obstructive pulmonary disease
  • RA rheumatoid arthritis
  • halogen includes the four halogens chlorine, fluorine, bromine and iodine.
  • lower alkyl means a monovalent straight or branched-chain saturated hydrocarbon alkyl group containing from one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like.
  • cycloalkyl unless otherwise indicated, means a cycloalkyl substituent which is a monovalent unsubstituted 3- to 10-membered monocyclic bicyclic or tricyclic saturated carbocylic hydrocarbon ring.
  • cycloalkyl substituents are cyclopropyl, cyclobutyl, cyclohexyl, adamantanyl.
  • the cycloalkyl substituent forms the outer fused ring i,e. when Rs and R 9 taken together or when Ri 0 and R n are taken together with their attached carbon atoms to form a cycloalkyl ring, the cycloalkyl ring so formed contains from 5 to 10 carbon atoms.
  • lower alkoxy means a straight-chain or branched- chain alkoxy group formed from lower alkyl containing from one to six carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.
  • heterocycloalkyl refers to a monovalent 4 to 7 membered monocyclic saturated ring containing 3 to 5 carbon atoms and one or two hetero atoms selected from the group consisting of oxygen, sulfur or nitrogen.
  • heterocyclic alkyl groups are included mopholinyl, piperidinyl, piperazinyl.
  • heteromatic ring refers to a monovalent 5 on 6 membered monocyclic heteroaromatic ring containing from 3 to 5 carbon atoms and from 1 to 2 hetero atoms selected from the group consisting of oxygen, nitrogen or sulfur.
  • heteroaromatic groups include pyridinyl, pyrimidinyl, furanyl, and the like.
  • lower alkylene designates a divalent saturated straight or branch chain hydrocarbon substituent containing from one to six carbon atoms.
  • n, y, , R 1 , R 21 R 3 , and R 7 are as above; or pharmaceutically acceptable salts thereof; compounds of the formula:
  • n, Ri, R 2 , R 3 are as above, and R's and R' 9 are individually hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, trifluoromethyl, or when R's and R' 9 are substituted on adjacent carbon, atoms, they can also be taken together with said attached carbon atoms to form a ring selected from the group consisting of phenyl, cycloalkyl containing 5 to 10 carbon atoms, or a 4 to 7 membered heterocyclic or a 5 or 6 membered heteroaromatic ring, with said hetero rings containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; or when R's and R 9 are substituted on the same carbon atom of a heterocycloalkyl ring, they can also form oxo or be taken together with their attached carbon atom to form a ring selected from the group consisting of phenyl, a 5 to IO membered cycloalkyl
  • Ri, R 2 , R 3 , Ri 0 , R ⁇ ? n, v and y are as above and R"s is hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen or trifloromethyl; or pharmaceutically acceptable salts thereof; or compounds of the formula:
  • n,x,Ri, R 2 , R 3 , R 4 and Re are as above; or pharmaceutically acceptable salts thereof.
  • n is an integer from 1-3 when R 4 and R 5 are taken together with their attached nitrogen atom form the nitrogen containing ring i.e. such as in the compounds of Formula IA- 1.
  • compounds of Formula I when n is an integer of from 1-5 are preferred in the case when R 4 and R 5 are other than being taken together with their attached nitrogen atom to form the nitrogen containing ring.
  • pharmaceutically-acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient.
  • Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically- acceptable inorganic or organic acids.
  • Salts derived from pharmaceutically-acceptable acids include acetic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic (i-hydroxy-2-naphthoic acid) and the like.
  • Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occuring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethyl enediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • arginine betaine
  • caffeine choline
  • pharmaceutically acceptable salt also comprises solvates.
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, i.e. a compound of the invention or a pharmaceutically-acceptable salt thereof, and one or more molecules of a solvent.
  • solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent.
  • Representative solvents include by way of example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.
  • the present invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • R 2 and R 1 each independently represent an ethoxy or methoxy group, preferably both Ri and R 2 represent an ethoxy group.
  • the compounds of the invention may be prepared from commercially available starting materials, by using a sequence of chemical reactions known to those skilled in the art.
  • a reaction scheme outlining the synthesis of the compounds of the invention from a common intermediate A is given below.
  • the intermediate A is obtained from commercially available starting materials through benzoylation of 1,2-diethoxybenzene with the appropriate benzoyl chloride. Nitration followed by reduction of the nitro compound to the corresponding aniline and then acylation and reaction with ammonia gave the intermediate B which was transformed into the final products in the number of steps shown in the Scheme depending on the nature of the substituent X.
  • a further object of this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula (I), as defined above, and a pharmaceutically acceptable vehicle or support, optionally in association with another active agent.
  • the compounds and the compositions of the invention are of particular interest as active agents for use in therapy, especially in the treatment of pathological conditions, diseases and disorders associated with PDE-4 activation.
  • the compounds are useful for the treatment of a pathological condition or disorder susceptible to amelioration by inhibition of PDE-4 such as treatment of an inflammatory pathology of the central nervous system or neuroinflammation.
  • the compounds and the pharmaceutical composition of the invention are more particularly intended to treat the inflammatory states in diseases such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), vascular disorders, autoimmune pathology and/or neurological disorders such as depression, Parkinson's disease, Alzheimer's disease, and also to improve memory in both long-term potential and contextual learning, or to treat obesity.
  • COPD chronic obstructive pulmonary disease
  • RA rheumatoid arthritis
  • vascular disorders vascular disorders
  • autoimmune pathology and/or neurological disorders such as depression, Parkinson's disease, Alzheimer's disease, and also to improve memory in both long-term potential and contextual learning, or to treat obesity.
  • the compounds may be formulated in various forms, including solid and liquid forms, such as tablets, gels, syrups, powders, aerosols, etc.
  • compositions of this invention may contain physiologically acceptable diluents, fillers, lubricants, excipients, solvents, binders, stabilizers, and the like.
  • Diluents that may be used in the compositions include but are not limited to dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar and for prolonged release tablet, hydroxypropyl methyl cellulose (HPMC).
  • the binders that may be used in the compositions include but are not limited to starch, gelatin and fillers such as sucrose, glucose, dextrose and lactose.
  • Natural and synthetic gums that may be used in the compositions include but are not limited to sodium alginate, ghatti gum, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone and veegum.
  • Excipients that may be used in the compositions include but are not limited to microcrystalline cellulose, calcium sulfate, dicalcium phosphate, starch, magnesium stearate, lactose, and sucrose.
  • Stabilizers that may be used include but are not limited to polysaccharides such as acacia, agar, alginic acid, guar gum and tragacanth, amphotsics such as gelatin and synthetic and semi-synthetic polymers such as carbomer resins, cellulose ethers and carboxymethyl chitin.
  • Solvents that may be used include but are not limited to Ringers solution, water, distilled water, dimethyl sulfoxide to 50% in water, propylene glycol (neat or in water), phosphate buffered saline, balanced salt solution, glycol and other conventional fluids.
  • the dosages and dosage regimen in which the compounds of formula (I) are administered will vary according to the dosage form, mode of administration, the condition being treated and particulars of the patient being treated. Accordingly, optimal therapeutic concentrations will be best determined at the time and place through experimentation.
  • the compounds according to the invention can be used enterally.
  • suitable forms are, for example, tablets, gel, aerosols, pills, dragees, syrups, suspensions, emulsions, solutions, powders and granules; a preferred method of administration consists in using a suitable form containing from i mg to about 500 mg of active substance.
  • the compounds according to the invention can also be administered parenterally, for instance in the form of solutions or suspensions for intravenous or intramuscular perfusions or injections.
  • compositions comprising the same, or treatment can be implemented alone or in combination with other active ingredients, compositions or treatments. Moreover, it can correspond to treatment of chronic or acute disorders. Further aspects and advantages of this invention will be disclosed in the following examples, which should be regarded as illustrative and not limiting the scope of this application.
  • the melting points were performed using a capillary melting point apparatus, 7SMP3-0 Bibby. PHARMACOLOGICAL ACTIVITY
  • PDE-4 activity was measured by a radio-enzymatic assay as described in Keravis TM, Wells JNand Hardman JG. "Cyclic nucleotide phosphodiesterase activities from pig coronary arteries:lackof interconvertibility of major forms";. Biochim. Biophys. Acta. 1980; 613: 116-129. The procedure is as follows: A. Isolation of phosphodiesterases from smooth muscle
  • a 3g segment of bovine aortic media cut into pieces ⁇ vith scissors was homogenized with an ultra-turrax then a potter glass/glass homogenizer in 7 volumes by weight of buffer A containing a protease inhibitor cocktail (20 mM Tris-HCI, G.25 M saccharose, 2 mM magnesium acetate, 1 mM dithiothreitol, 5 mM EGTA, 2000 U/ml aprotinin, 10 mg/1 leupeptin and 10 mg/i soya typsic inhibitor). The homogenate was centrifuged at 105,000 g for 1 hour.
  • the supernatant was loaded on a DKAE-Sephacel column (15 x 1.6 cm) pre-equilibrated with buffer B (buffer A without the saccharose, EGTA and protease inhibitors). The column was washed until there was no detectable absorption at 280 nm, then eluted with a linear gradient of NaCl (0-0,5 M) in buffer B. 3-ml fractions were collected described hereinafter to localize the different enzymes PDEi, PDE3, PDE4 and PDE5, which were aliquoted and frozen at -80 0 C. (Lugnier et al., Biochem, PhamacoL, 35 (1986) 1746-1751).
  • PDE2 was isolated from human platelets, provided by Etablatorium Fran ⁇ ais du Sang-Alsace (French establishment of blood in Alsace). It was purified according to Kameni Tcheudji JF et al. ⁇ Kameni Tcheudji JF, Lebeau L, Virmaux N, Maftei CG, Cote RH, Lugnier C and S:hultz P. Molecular organisation of bovine rod cGMP-phosphodiesterase 6. J. MoI Biol. 2001; 3io:i8i-ygi.), and stored until use at -80 0 C in small aliquots.
  • Cyclic nucleotide phosphodiesterase activity was determined in vitro by a radio enzymatic assay as described by Lugnier et al., 1986.
  • PDE2, PDE ⁇ , PDE4 activities were measured at a substrate concentration of 1 ⁇ M of cyclic AMP in the presence of 15,000 cpm [sH]-cyclic AMP (as a tracer).
  • PDEi and PDE5 activities were measured at a substrate concentration of 1 ⁇ M of cyclic GMP in the presence of 15,000 cpm [3B]-cyclic GMP (as a tracer).
  • the activity of the PDE enzyme was assessed by a two -step radio enzymatic assay by measuring the amount of radiolabeled 5 '-nucleotide product resulting from the hydrolysis of the radiolabelled substrate after separation from the non-hydrolysed substrate by an anion-exchange chromatography.
  • Phosphodiesterase enzymes were first incubated in the presence or in the absence of increasing concentrations of test substance. The reactions were stopped by the addition of Phosphodiesterase-stopping buffer. During this first step, both radiolabelled and non-radiolabelled cyclic nucleotides are hydrolyzed into nucleotide monophosphate. The second step performed in the presence of 1.5 mg/ml of 5'- nucleotidase snake venom results in the formation of nucleoside. The products resulting from the enzymatic reaction are separated by anion- exchange chromatography (QAE- sephadex A-25 column).
  • Anion-exchange chromatography allows the separation of the dephosphorylated products (nucleoside) from the non-hydrolyzed cyclic nucleotide, Nucleoside radioactivity was determined by liquid scintillation counting. Enzymatic incubations were carried out under conditions allowing no more than 15% hydrolysis of the substrate, each point was performed in duplicate.
  • the concentration of substance which inhibits enzymatic activity by 50% (IC 50 ) at 1 ⁇ M cyclic AMP was calculated by nonlinear regressions (Prism, GraphPad).
  • cytosolic PDE4 was isolated from media layer of bovine aorta (Lugnier C, Schoeffter P 3 Le Bee A, Strouthou E and Stoclet JC. Selective inhibition of cyclic nucleotide phosphodiesterases of human, bovine and rat aorta. Biochem. Pharmacol. 1986; 35: 1743-1751). PDE activities were measured as described in section B. PDE assays were performed in the absence or in the presence of increasing concentrations of PDE inhibitor in order to determine the IC 50 for each PDE isoform. The PDE concentration is adjusted to hydrolyze less than 15 % of the total substrate. The concentration of drug that produced 50% inhibition of substrate hydrolysis (IC 50 ) values was calculated by non-linear regression analysis from concentration-response curves (Prism software).
  • CNP hydrolyzed cyclic nucleotide phosphate
  • the compound 8 (lg, 2.7mmo ⁇ ) was dissolved in THF C2 ⁇ mL). Then N-methyl- morpholine Co.3rnL, ieq) and isobutylchloroformate Co.37mL, l.ieq) were added. The mixture was cooled at O 0 C and then with stirring, NaBH 4 (o.6ig, 6eq) in water CiomL) was added to the mixture. After lh ethyl acetate (lOomL) was added and the organic layer was separated and then dried over Na 2 SO 4 .
  • Compounds synthesized by this method include:
  • Compounds synthesized by this method include:
  • the compound 23 (33.3 g, 0.069 m °0 dissolved in ethyl acetate (40OmL) was charged with 10% Pd/C (3.4 g) and hydrogenated with H 2 at atmospheric pressure at room temperature for 24L The reaction mixture was then filtered through a celite pad which was washed with methanol. The filtrate was concentrated in vaccuo to give an oily residue partially reduced. The residue was again dissolved in ethyl acetate (400 ml), charged with fresh 10% Pd/C (3.4 g) and hydrogenated at atmospheric atmosphere for an additional 24 ⁇ 1 for complete reaction. The reaction mixture was filtered over a celite pad which was rinsed with methanol.

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Abstract

L'invention porte sur de nouvelles 7,8-dialcoxy-5-(aminoalkylphényl)-1,4-benzodiazépines représentées par la formule I, ledit amino étant substitué ou formant un noyau alkyle hétérocyclique contenant de l'azote, lesquelles 1,4-benzodiazépines sont des inhibiteurs de phosphodiestérase du type IV (PDE-4), les rendant actives en tant qu'agents anti-inflammatoires.
PCT/EP2008/062425 2007-09-18 2008-09-18 1,4-benzodiazépines 5-substituées en tant qu'inhibiteurs de phosphodiestérase WO2009037302A1 (fr)

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US60/994,219 2007-09-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017089347A1 (fr) 2015-11-25 2017-06-01 Inserm (Institut National De La Sante Et De La Recherche Medicale) Procédés et compositions pharmaceutiques pour le traitement de mélanomes résistant aux inhibiteurs de braf

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098865A2 (fr) * 2001-06-07 2002-12-12 Neuro3D Inhibiteurs des phosphodiesterases des nucleotides cycliques, preparation et utilisations de ces inhibiteurs
EP1548011A1 (fr) * 2003-12-23 2005-06-29 Neuro3D Dérivés de 1,4-benzodiazépine-2-one comme inhibiteurs de PDE2 phosphodiesterase, leurs préparation et utilisation thérapeutique
EP1749824A1 (fr) * 2005-08-03 2007-02-07 Neuro3D Derivés de la benzodiazepine, préparation et utlisations thérapeutiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098865A2 (fr) * 2001-06-07 2002-12-12 Neuro3D Inhibiteurs des phosphodiesterases des nucleotides cycliques, preparation et utilisations de ces inhibiteurs
EP1548011A1 (fr) * 2003-12-23 2005-06-29 Neuro3D Dérivés de 1,4-benzodiazépine-2-one comme inhibiteurs de PDE2 phosphodiesterase, leurs préparation et utilisation thérapeutique
EP1749824A1 (fr) * 2005-08-03 2007-02-07 Neuro3D Derivés de la benzodiazepine, préparation et utlisations thérapeutiques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017089347A1 (fr) 2015-11-25 2017-06-01 Inserm (Institut National De La Sante Et De La Recherche Medicale) Procédés et compositions pharmaceutiques pour le traitement de mélanomes résistant aux inhibiteurs de braf

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