WO2001081312A2 - Method of treatment using phenyl and biaryl derivatives as prostaglandin e inhibitors and compounds useful therefore - Google Patents
Method of treatment using phenyl and biaryl derivatives as prostaglandin e inhibitors and compounds useful therefore Download PDFInfo
- Publication number
- WO2001081312A2 WO2001081312A2 PCT/CA2001/000563 CA0100563W WO0181312A2 WO 2001081312 A2 WO2001081312 A2 WO 2001081312A2 CA 0100563 W CA0100563 W CA 0100563W WO 0181312 A2 WO0181312 A2 WO 0181312A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- prostaglandin
- compound
- pain
- substituted
- mediated disease
- Prior art date
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- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title description 16
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- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
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- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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- 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
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- This invention relates to methods for treating prostaglandin mediated diseases. More particularly, the compounds are antagonists of the pain and inflammatory effects of E-type prostaglandins. Additionally preferred compounds are included.
- Two review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists: Eicosanoids: From Biotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf, and Nelo eds, Plenum Press, New York, 1996, chap. 14, 137-154 and Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87.
- PGE2 Prostaglandin E2
- selective prostaglandin ligands, agonists or antagonists have anti- inflammatory, antipyretic and analgesic properties similar to a conventional non- steroidal anti-inflammatory drug, and in addition, inhibit hormone-induced uterine contractions and have anti-cancer effects.
- These compounds have a diminished ability to induce some of the mechanism-based side effects of NSALDs which are indiscriminate cyclooxygenase inhibitors.
- the compounds have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
- a method of treating or preventing a prostaglandin E mediated disease comprises administering to a mammalian patient in need of such treatment or prevention a compound of formula I:
- R is a group Ar as defined hereinafter;
- Rl is hydrogen, hydroxy, Ci-6 " alkyl, Ci-6alkoxy, X(CH2)pAr, or a methylenedioxy group attached to two adjacent ring carbon atoms;
- R2 is -(CH 2 ) x C(O)N(R4)S(O) y R5, -(CH 2 ) ⁇ S(O) y N(R4)C(O)R5, -(CH 2 ) ⁇ C(O)N(R4)C(O)R5, -(CH2) x S(O) y N(R4)S(O) y R5, -(CH2) ⁇ C ⁇ 2 4 , or tetrazol-5-yl optionally substituted by C ⁇ _6alkyl;
- R3 is X(CH2)pAr or X(CH2)pR 4 or a group of formula (a):
- Ar is a group of formula (b) or (c):
- Ar is naphthyl, indolyl, pyridyl, thienyl, furyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thriazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, mo ⁇ holinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidinyl, all of which may be unsubstituted or substituted by one or more R ⁇ or R8 groups;
- each B is independently -CH2- or -O-;
- R4 is hydrogen or Ci-6alkyl
- R is hydrogen or Ci-ioalkyl or Ar, both of which may be unsubstituted or substituted by one or two Cl, F, Br, hydroxy, XC ⁇ _5alkyl, C ⁇ _5alkyl, NO2, tetrazol-5- yl optionally substituted by Ci-6alkyl, or R5 is N(R4)2;
- R6 is hydrogen, RlO, CO2R 11 , C ⁇ 2C(Rl0) 2 O(CO)XRH, P ⁇ 3(RH)2, SO2NRHRIO, NRHSO2R 10 , CONRHSO2R 10 , SO3RH, S(O) q Rl l, S(O) q N(Rl l)C(O)Rl0, S(O) q N(RH)S(O) q Rl0, C(O)N(RH)C(O)R10, N(Rl l)C(O)Rl0, N(Rll)2, N(RH)C(0)NRH , P(O)(ORll)Rll, CN, - C ⁇ 2(CH2)mC(O)N(R4) 2 , C(R10) 2 N(RH)2, C(0)N(R4) 2 , OR4 or tetrazolyl optionally substituted by C 1-6 alkyl;
- R7 and R9 are independently hydrogen, RlO, OH, Ci-8 alkoxy, S(O)qRl0, N(R4)2, Br, F, I, Cl, CF3, NO2, NHCOR4, Rl2c ⁇ 2RU, -X-R13-Y, -X(CR4) p OR4, S(CH2) p C ⁇ 2H, (CH2)pX-R 13 , -X(CH2) p CONRl lS ⁇ 2R 1 0, (CH2)pXCONRl lSO2R 10 or X(CH2) p R 6 wherein each methylene group within - X(CH2)qR6 may be unsubstituted or substituted by one or two -(CH2)pAr groups; R8 is hydrogen, RlO, OH, Ci -5alkoxy, S(O) q Rl0, N(R4) 2 , Br, F, I, Cl or NHCOR4 wherein the Ci-5 alkoxy may be unsubstituted or substituted
- RlO is hydrogen, Ar, Ci-ioalkyl, C2-10alke n yl > C2-10alkynyl, all of which may be unsubstituted or substituted by one or more OH,.CH2OH, N(R4)2 or halogen; or RlO is N(R4) 2 ;
- RU is independently hydrogen, Ci-ioalkyl, C2-10alkenyl or C2-8alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R4)2, CO2R1 , halogen or XCi-5alkyl; or RU is (CH2)pAr;
- Rl2 is divalent Ar, Ci-ioalkylene, Ci-ioalkylidene, C2-10 a lk en yl ene > C2-10 alkynylene, all of which may be unsubstituted or substituted by one or more of OH, CH2OH, N(R4)2 or halogen;
- Rl3 is a bond, Ci-ioalkylene, Ci-ioalkenylene, Ci-ioalkylidene, Ci-ioalkynylene, all of which may be linear or branched, or phenylene, all of which may be unsubstituted or substituted by one or more OH, N(R4)2, COOH or halogen;
- Rl4 is hydrogen, Ci-6 alkyl, C2-6 alkenyl or C2-7 alkynyl;
- X is (CH2)p, O, NR4 or S(O) p ;
- Y is CH3 or X(CH2) p Ar
- a method of treating or preventing a prostaglandin E mediated disease comprises administering to a mammalian patient in need of such treatment or prevention a compound of formula I:
- R is a group Ar as defined hereinafter;
- Rl is hydrogen, hydroxy, Ci-6alkyl, C ⁇ _6alkoxy, X(CH2)pAr, or a methylenedioxy group attached to two adjacent ring carbon atoms;
- R2 is -(CH2) x C(O)N(R4)S(O) y R5, -(CH2) ⁇ S(O) y N(R4)C(O)R5, -(CH 2 ) x C(O)N(R4)C(O)R5, -(CH 2 ) ⁇ S(O) y N(R4)S(O) y R5, -(CH2) ⁇ C02R4, or tetrazol-5-yl optionally substituted by Ci-6alkyl;
- R3 is X(CH2) p Ar or X(CH2) p R 4 or a group of formula (a):
- Ar is a group of formula (b) or (c):
- Ar is naphthyl, indolyl, pyridyl, thienyl, furyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thriazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, mo ⁇ holinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidinyl, all of which may be unsubstituted or substituted by one or more R7 or R8 groups;
- each B is independently -CH2- or -O-;
- R4 is hydrogen or Ci- ⁇ alkyl
- R5 is hydrogen or Ci-ioalkyl or Ar, both of which may be unsubstituted or substituted by one or two Cl, F, Br, hydroxy, XCi-5alkyl, Ci-5alkyl, NO2, tetrazol-5- yl optionally substituted by Ci-6alkyl, or R5 is N(R4)2;
- R6 is hydrogen, RlO, CO2RU, C ⁇ 2C(RlO) 2 O(CO)XRH, P ⁇ 3(RH)2, SO2NRHRIO, NRHSO2RIO, CONRHSO2RIO, SO3RH, S(O) q Rl l, S(O) q N(Rl l)C(O)Rl0, S(O) q N(RH)S(O) q RlO, C(O)N(RH)C(O)Rl0, N(Rl l)C(O)Rl0, N(Rll)2, N(RH)C(0)NRH, P(O)(ORl l)Rl l, CN, - C ⁇ 2(CH2) m C(O)N(R4) 2 , C(RlO) 2 N(RH)2, C(O)N(R4) 2I OR4 or tetrazolyl optionally substituted by Cl-6 alkyl;
- R7 and R9 are independently hydrogen, RlO, OH, C1 -8 alkoxy, S(O)qRl0, N(R4)2, Br, F, I, Cl, CF3, NO2, NHCOR4, Rl2c ⁇ 2RU, -X-R13-Y, -X(CR4) p OR4, S(CH 2 ) p C ⁇ 2H, (CH2) p X-Rl3, -X(CH2) p CONRl lSO2Rl°, (CH2) p XCONRl lS ⁇ 2Rl° or X(CH2) p R 6 wherein each methylene group within - X(CH2)qR6 may be unsubstituted or substituted by one or two -(CH2)pAr groups; R8 is hydrogen, RlO, OH, Ci-Salkoxy, S(O) q Rl0, N(R4) 2 , Br, F, I, Cl or NHCOR4 wherein the Ci-5 alkoxy may be
- RlO is hydrogen, Ar, Ci-ioalkyl, C2-10 a lkenyl, C2-10 a lkynyl, all of which may be unsubstituted or substituted by one or more OH,.CH2OH, N(R4)2 or halogen; or RlO is N(R4) 2 ;
- R 1 is independently hydrogen, Ci-ioalkyl, C2-10 a lkenyl or C2-8 a lkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R4)2, CO2R14, halogen or XCi-5alkyl; or Rl 1 is (CH2)pAr;
- Rl2 is divalent Ar, Ci-ioalkylene, C -ioalkylidene, C2-10 a lkenylene, C2-10 alkynylene, all of which may be unsubstituted or substituted by one or more of OH, CH2OH, N(R4)2 or halogen;
- Rl3 is a bond, Ci-ioalkylene, Ci-ioalkenylene, Ci-ioalkylidene, Ci-ioalkynylene, all of which may be linear or branched, or phenylene, all of which may be unsubstituted or substituted by one or more OH, N(R4)2, COOH or halogen;
- Rl4 is hydrogen, Ci-6 alkyl, C2-6 alkenyl or C2-7 alkynyl;
- X is (CH2) p , O, NR4 or S(O) p ;
- Y is CH3 or X(CH2)pAr
- An embodiment of the invention that is of particular interest relates to a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the prostaglandin mediated disease is selected from the group consisting of:
- coagulation disorders selected from hypoprothrombinemia, haemophilia and other bleeding problems;
- kidney disease (14) kidney disease; (15) thrombosis;
- Another embodiment of the invention is a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the prostaglandin mediated disease is selected from the group consisting of: pain, fever or inflammation associated with rheumatic fever, influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures as well as immune and autoimmune diseases.
- the prostaglandin mediated disease is selected from the group
- Another embodiment of the invention is a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the prostaglandin mediated disease is pain, fever or inflammation associated with dysmenorrhea.
- Another embodiment of the invention is a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the compound is co-administered with other agents or ingredients.
- Another embodiment of the invention is a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the compound is co-administered with another agent or ingredient selected from the group consisting of:
- an analgesic selected from acetaminophen, phenacetin, aspirin, a narcotic;
- a decongestant selected from phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine;
- an antiitussive selected from codeine, hydrocodone, caramiphen, carbetapentane and dextrametho ⁇ han;
- prostaglandin ligand selected from misoprostol, enprostil, rioprostil, ornoprostol and rosaprostol; a diuretic; and
- COX-2 inhibitors are disclosed in U.S. Patent Nos. 5,474,995; 5,633,272; and 5,466,823; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691, and WO 95/0051.
- Another embodiment of the invention is a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the compound is co-administered with a cyclooxygenase-2 selective nonsteroidal anti- inflammatory drug or a conventional nonsteroidal anti-inflammatory drug.
- Another embodiment of the invention is a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the compound is co-administered with a conventional nonsteroidal anti-inflammatory drug selected from the group consisting of: aspirin, ibuprofen, naproxen, and ketoprofen.
- a conventional nonsteroidal anti-inflammatory drug selected from the group consisting of: aspirin, ibuprofen, naproxen, and ketoprofen.
- Another embodiment of the invention is a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the compound is co-administered with a cyclooxygenase-2 selective nonsteroidal anti- inflammatory drug selected from rofecoxib and celecoxib.
- a cyclooxygenase-2 selective nonsteroidal anti- inflammatory drug selected from rofecoxib and celecoxib.
- Additional preferred species for use in treating prostaglandin mediated diseases or conditions include the following:
- AT-BN 2,2 -azobisisobutyronitrile
- Bn benzyl
- DL3AL diisobutyl aluminum hydride
- DIPHOS 1 ,2-bis(diphenylphosphino)ethane
- EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
- HBBS Hanks balanced salt solution
- HEPES N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid]
- KHMDS potassium hexamethyldisilazane
- LPS lipopolysaccharide
- m-CPBA metachloroperbenzoic acid
- PCC pyridinium chlorochromate
- Ph phenyl
- PPTS pyridinium p-toluenesulfonate
- pTSA p-toluenesulfonic acid
- r.t. room temperature
- rac. racemic
- THF tetrahydrofuran
- alkyl, alkenyl, and alkynyl mean linear, branched, and cyclic structures and combinations thereof.
- alkyl includes “cycloalkyl” and “lower alkyl” and extends to cover carbon fragments having up to 20 carbon atoms.
- alkyl groups include octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7- diethyl-2,2-dimethyl-4-propylnonyl, and the like.
- Lower alkyl includes “lower cycloalkyl” and means alkyl groups of from 1 to 7 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, heptyl, and the like.
- Cycloalkyl includes “lower cycloalkyl” and means a hydrocarbon, containing one or more rings of from 3 to 12 carbon atoms, with the hydrocarbon having up to a total of 20 carbon atoms.
- Examples of cycloalkyl groups are cyclopropyl, cyclopentyl, cyclo-heptyl, aldamantyl, cyclododecylmethyl, 2-ethyl-l- bicyclo[4.4.0]decyl, and the like.
- Lower cycloalkyl means a hydrocarbon containing one or more rings of from 3 to 7 carbon atoms, with the hydrocarbon having up to a total of 7 carbon atoms.
- lower cycloalkyl groups are cyclopropyl, cyclopropylmethyl, cyclobutyl, 2-cyclopentylethyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, and the like.
- alkenyl includes “cycloalkenyl” and “lower alkenyl” and means alkenyl groups of 2 to 20 carbon atoms. Examples of alkenyl groups include allyl, 5-decen-l-yl, 2-dodecen-l-yl, and the like.
- “Lower alkenyl” includes “lower cycloalkenyl” and means alkenyl groups of 2 to 7 carbon atoms. Examples of lower alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
- “Cycloalkenyl” includes “lower cycloalkenyl” and means alkenyl groups of 3 to 20 carbon atoms, which include a ring of 3 to 12 carbon atoms, and in which the alkenyl double bond may be located anywhere in the structure.
- cycloalkenyl groups are cyclopropen-1-yl, cyclohexen-3-yl, 2-vinyladamant-l-yl, 5- methylene-dodec-1-yl, and the like.
- “Lower cycloalkenyl” means alkenyl groups of 3 to 7 carbon atoms, which include a ring of 3 to 7 carbon atoms and in which the double bond may be located anywhere in the structure.
- lower cycloalkenyl groups are cyclopropen-1-yl, cyclohexen-3-yl, 2-cyclopentylethen-l-yl, and the like.
- alkynyl includes “cycloalkynyl” and “lower alkynyl” and means alkynyl groups of 2 to 20 carbon atoms. Examples of alkynyl groups are ethynyl, 2-pentadecyn-l-yl, 1-eicosyn-l-yl, and the like.
- “Lower alkynyl” includes “lower cycloalkynyl” and means alkynyl groups of 2 to 7 carbon atoms. Examples of lower alkynyl groups include ethynyl, propargyl, 3 -methyl- 1-pentynyl, 2-heptynyl and the like.
- “Cycloalkynyl” includes “lower cycloalkynyl” and means alkynyl groups of 5 to 20 carbon atoms, which include a ring of 3 to 20 carbon atoms.
- the alkynyl triple bond may be located anywhere in the group, with the proviso that if it is within a ring, such a ring must be of 10 members or greater.
- cycloalkynyl examples include cyclododecyn-3-yl, 3-cyclohexyl-l-propyn-l-yl, and the like.
- “Lower cycloalkynyl” means alkynyl groups of 5 to 7 carbon atoms which include a ring of 3 to 5 carbon atoms.
- Examples of lower cycloalkynyl are cyclopropylethynyl, 3-(cyclobutyl)-l-propynyl, and the like.
- Halogen includes F, Cl, Br, and I.
- 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.
- 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- ethyl-mo ⁇ holine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, mo ⁇ holine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
- basic ion exchange resins
- salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
- Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
- prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases.
- 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 2 g 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.
- 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, flavouring agents, colouring 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 abso ⁇ tion 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-miscible solvents such as propylene glycol, PEGs and ethanol, 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
- water-miscible solvents such as propylene glycol, PEGs and ethanol
- 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 carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, 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 heptadecaethyleneoxycetanol, 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 sorbitan monoole
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more 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 flavouring 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.
- a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
- the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
- 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 flavouring and colouring 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.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this pu ⁇ ose 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.
- compositions may also be administered in the form of 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 ambient 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 ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non-irritating excipient which is solid at ambient 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, gels, solutions or suspensions, etc., containing the compound of formula I are employed.
- Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
- prostaglandin receptors The ability of the compounds of formula I to interact with prostaglandin receptors makes them useful for preventing or reversing undesirable symptoms caused by prostaglandins in a mammalian, especially human subject.
- This mimicking or antagonism of the actions of prostaglandins indicates that the compounds and pharmaceutical compositions thereof are useful to treat, prevent, or ameliorate in mammals and especially in humans: Pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post- partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures as well
- Such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer.
- Compounds of formula I may also be of use in the treatment and/or prevention prostaglandin-mediated proliferation disorders such as may occur in diabetic retinopathy and tumor angiogenesis.
- Compounds of formula I will also inhibit prostanoid-induced smooth muscle contraction by antagonizing contractile prostanoids or mimicking relaxing prostanoids and hence may be use in the treatment of dysmenorrhea, premature labor, asthma and eosinophil related disorders.
- a compound of formula I will prove useful as an alternative to conventional nonsteroidal anti-inflammatory drugs (NS AID'S) particularly where such non-steroidal anti-inflammatory drugs may be contraindicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems; kidney disease; thrombosis, occlusive vascular diseases; those prior to surgery or taking anti- coagulants.
- Compounds of formula I will also be useful as a cytoprotective agent for patients under chemotherapy.
- the invention encompasses pharmaceutical compositions for treating prostaglandin E2 mediated diseases as defined above comprising a non-toxic therapeutically effective amount of the compound of formula I as defined above and one or more ingredients such as another pain reliever including acetaminophen or phenacetin; a COX-2 selective inhibiting agent; a conventional NSAID; a potentiator including caffeine; an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antiitussive including codeine, hydro
- the invention encompasses a method of treating prostaglandin E2 mediated diseases comprising: administration to a patient in need of such treatment a non-toxic therapeutically effective amount of the compound of formula I, optionally co- administered with one or more of such ingredients as listed immediately above.
- the acid group (AC(O)B) is introduce by Horner- Emmons (or Wittig) condensation. Suzuki' s coupling between the boronic acid 11 and the aryl dihalide 1 led to the aldehyde 12 under previously described conditions.
- the acid unit is introduce by a Homer-Emmons reaction to afford the diaryl halide 13 followed by cross coupling with the boronic acid 1 to give the desired ester 9.
- coupling between 12 and 2 followed by a Homer-Emmons reaction on the resulting aldehyde 14, can also afford the ester 9.
- the compounds were purified by flash chromatography on silica gel, recrystallization and/or swish (suspension in a solvent followed by filtration of the solid); The course of reactions was followed by thin layer chromatography
- Step 4 3-r2-(3-Bromophenyl)phenyllpropanoic acid:
- Step 5 Methyl 3-f 2-r3-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)phenyllphenyll propanoate: After esterification of the previous acid (1.72 g, 5.64 mmol) in ether
- Step 7 Methyl 3-(2-(3-r5-chloro-2-(phenylmethoxy)-3-pyridyl1phenyl)phenyl) propanoate:
- Step 8 3-(2-(3-r5-Chloro-2-(phenyImethoxy)-3-pyridyl1phenyl)phenyl)propanoic acid :
- Step 1 Ethyl (E)-3-(2- ( 3-r2-(PH ⁇ NYLM ⁇ THOXY)PH ⁇ NYLlPH ⁇ NYL)PH ⁇ NYL) PROP-2-ENOIC ACID (7)
- Step 1 Ethyl (E)-3-(2-
- Step 2 (E)-3-(2- ⁇ 3-r2-(Phenylmethoxy)phenyl]phenyl ⁇ phenyl)prop-2-enoic acid :
- Step 2 2- ⁇ 5-r2-(Phenylmethoxy)phenyl1-3-pyridyllbenzaldehyde:
- step 1 a mixture of the previous bromide (507 mg, 1.93 mmol, stepl), 2-(phenylmethoxy)benzeneboronic acid (638 mg, 2.80 mmol), 2M Na 2 CO 3 (3.5 mL) and (Ph 3 P) 4 Pd (102 mg, 0.09 mmol) in DME (10 mL) was heated to 80 °C for 6 h. Purification by flash chromatography (To EtOAc, 9:1) provided the desired material as a yellow oil (642 mg, 91%).
- Step 3 (E)- 3-(2-
- step 2 a mixture of the previous aldehyde (640 mg, 1.75 mmol, step 2), triethyl phosphonoacetate (420 uL, 2.12 mmol) and NaH (2.7 mmol) in Tol (6 mL) was stirred at it for 6 h.
- the crude material was not purified.
- the crude ester was hydrolyzed in THF:MeOH:2N LiOH (6 mL:3 mL:3 mL).
- Step 2 l-Bromo-4-r3-(3-methylphenoxy)propoxylbenzene :
- Step 3 7ert-butyl 3-(2-f4-r3-(3-methylphenoxy)propoxy1phenyl jphenyl) propanoate
- Step 4 Tert-butyl 2-methyl-3-(2- ⁇ 4-r3-(3-methylphenoxy)propoxy1phenyl) phenyl )propanoate :
- a solution of the previous ester (2.76 g, 6.17 mmol) in THF (10 mL) was added to a solution of lithium N-isopropylcyclohexylamide (56 mL; 0.14 M; 7.8 mmol) in THF at -78 °C then 30 min later, iodomethane (1.3 mL, 21 mmol).
- the solution was warmed slowly (1.5 h) at 0 °C, then poured in IN HCl and extracted with EtOAc (2x).
- Step 5 2-Methyl-3-(2- ⁇ 4-r3-(3-methylphenoxy)propoxy1phenyl ⁇ phenyl)propanoic acid:
- Step 2 (3-r3-(3-Bromophenoxy)propoxy]phenyl ⁇ methan-l-ol :
- Step 4 7ert-butyl 3-[2-(3- ⁇ 3-r3-(hydroxymethyl)phenoxy1propoxy)phenyl) phenyl] propanoate :
- Step 5 7ert-butyl 3-(2-(3-r3-(3-formylphenoxy)propoxy1phenyl
- Step 6 Tert-butyl (E)-3-(2-r3-(3- ⁇ 3-r2-(7-chloro-2- ⁇ uinolyl)vinyl1phenoxyl propoxy) phenyll phenyl) propanoate : To a suspension of (7-chloroquinolin-2-yl)methyl triphenylphosponium bromide (1.71 g; 3.3 mmol) in 15 mL THF at -78°C was added dropwise t-BuOK (3.6 mL; 1.0 M; 3.6mmol). The mixture was stirred at -78°C for 15 min, at 0 °C for 30 min then was cooled down to -78 °C.
- Step 7 (E)-3-(2-r3-(3-f 3-r2-(7-chloro-2-quinolyl)vinyl1phenoxy ⁇ propoxy) phenyll phenyl ⁇ propanoic acid :
- Step 8 (E)-3-(2-r3-(3- ⁇ 3-r2-(7-chloro(2-quinolyl))vinyl1phenoxylpropoxy) phenyllphenyl ) -N-(2-thienylsulfonyl)propanamide:
- Step 1 (E)-3-(2-(3-r2-(7-CHLORO(2-OUINOLYL))VINYL1PHENYL)PHENYL)-N-(2- THIE ⁇ YLSULFO ⁇ YL)PROP-2-E ⁇ AMIDE (103)
- Step 1 (E)-2-
- Step 2 Ethyl (E)-3-(2- ⁇ 3-r2-(7-chloro-2-quinolyl)vinyl1phenyl)phenyl)prop-2- enoate:
- Step 3 (E)-3-(2-f 3-r2-(7-chloro-2-quinolyl)vinyl1phenyl
- 1,4-dioxane was added 4 mL of NaOH (10 M). The mixture was stirred at 90°C for 12h, cooled down and acidified using HCl 10%. The residual precipitate ( HCl salt of the quinoline) was filtered, washed with ⁇ t 2 O and dried in vacuo to yield the title compound (3.5 g; 97%) which was used without further purification.
- 1H NMR (dmso-d ⁇ ) ⁇ 6.49 (IH, d), 7.28 (IH, d), 7.4-8.0 (14H, m), 8.38 (IH, d).
- Step 4 (E)-3-(2-(3-r2-(7-chloro(2-quinolyl))vinvnphenyl ⁇ phenyl)-N-(2-thienyl sulfonyl) prop-2-enamide:
- the compounds of Formula I can be tested using the following assays to determine their prostanoid antagonist or agonist activity in vitro and in vivo and their selectivity.
- the prostaglandin receptors investigated were DP, EP 1 ; EP 2 , EP 3 , EP 4 , FP, IP and TP.
- HEK 293(ebna) cell line Prostanoid receptor cDNAs corresponding to full length coding sequences were subcloned into the appropriate sites of mammalian expression vectors and transfected into HEK 293(ebna) cells.
- HEK 293(ebna) cells expressing the individual cDNAs were grown under selection and individual colonies were isolated after 2-3 weeks of growth using the cloning ring method and subsequently expanded into clonal cell lines.
- HEK 293(ebna) cells are maintained in culture, harvested and membranes are prepared by differential centrifugation, following lysis of the cells in the presence of protease inhibitors, for use in receptor binding assays.
- Prostanoid receptor binding assays are performed in 10 mM MES/KOH (pH 6.0) (EPs, FP and TP) or 10 mM HEPES/KOH (pH 7.4) (DP and IP), containing 1 mM EDTA, 10 mM divalent cation and the appropriate radioligand.
- the reaction is initiated by addition of membrane protein.
- Ligands are added in dimethylsulfoxide which is kept constant at 1 % (v/v) in all incubations.
- Non-specific binding is determined in the presence of 1 ⁇ M of the corresponding non-radioactive prostanoid. Incubations are conducted for 60 min at room temperature or 30 °C and terminated by rapid filtration. Specific binding is calculated by subtracting non specific binding from total binding. The residual specific binding at each ligand concentration is calculated and expressed as a function of ligand concentration in order to construct sigmoidal concentration- response curves for determination of ligand affinity.
- Prostanoid receptor agonist and antagonist assays Whole cell second messenger assays measuring stimulation (EP 2 , EP , DP and
- IP in HEK 293(ebna) cells) or inhibition (EP 3 in human erythroleukemia (HEL) cells) of intracellular cAMP accumulation or mobilization of intracellular calcium (EPi, FP and TP in HEK 293(ebna) cells stably transfected with apo-aequorin) are performed to determine whether receptor ligands are agonists or antagonists.
- cAMP assays cells are harvested and resuspended in HBSS containing 25 mM HEPES, pH 7.4.
- Incubations contain 100 ⁇ M RO-20174 (phosphodiesterase type IN inhibitor, available from Biomol) and, in the case of the EP 3 inhibition assay only, 15 ⁇ M forskolin to stimulate cAMP production. Samples are incubated at 37°C for 10 min, the reaction is terminated and cAMP levels are then measured.
- For calcium mobilization assays cells are charged with the co-factors reduced glutathione and coelenterazine, harvested and resuspended in Ham's F12 medium. Calcium mobilization is measured by monitoring luminescence provoked by calcium binding to the intracellular photoprotein aequorin. Ligands are added in dimethylsulfoxide which is kept constant at 1 % (v/v) in all incubations.
- second messenger responses are expressed as a function of ligand concentration and both EC 50 values and the maximum response as compared to a prostanoid standard are calculated.
- the ability of a ligand to inhibit an agonist response is determined by Schild analysis and both K B and slope values are calculated.
- mice Female Lewis rats (body weight -146-170 g) were weighed, ear marked, and assigned to groups (a negative control group in which arthritis was not induced, a vehicle control group, a positive control group administered indomethacin at a total daily dose of 1 mg/kg and four groups administered with a test compound at total daily doses of 0.10-3.0 mg/kg) such that the body weights were equivalent within each group.
- Six groups of 10 rats each were injected into a hind paw with 0.5 mg of Mycobacte ⁇ um butyricum in 0.1 mL of light mineral oil (adjuvant), and a negative control group of 10 rats was not injected with adjuvant.
- Body weights, contralateral paw volumes (determined by mercury displacement plethysmography) and lateral radiographs (obtained under Ketamine and Xylazine anesthesia) were determined before (day -1) and 21 days following adjuvant injection, and primary paw volumes were determined before (day -1) and on days 4 and 21 following adjuvant injection.
- the rats were anesthetized with an intramuscular injection of 0.03 - 0.1 mL of a combination of Ketamine (87 mg/kg) and Xylazine (13 mg/kg) for radiographs and injection of adjuvant.
- radiographs were made of both hind paws on day 0 and day 21 using the Faxitron (45 kVp, 30 seconds) and Kodak X-OMAT TL film, and were developed in an automatic processor. Radiographs were evaluated for changes in the soft and hard tissues by an investigator who was blinded to experimental treatment. The following radiographic changes were graded numerically according to severity: increased soft issue volume (0-4), narrowing or widening of joint spaces (0-5) subchondral erosion (0-3), periosteal reaction (0-4), osteolysis (0-4) subluxation (0-3), and degenerative joint changes (0-3). Specific criteria were used to establish the numerical grade of severity for each radiographic change. The maximum possible score per foot was 26.
- test compound at total daily doses of 0.1, 0.3, 1, and 3 mg/kg/day, indomethacin at a total daily dose of 1 mg/kg/day, or vehicle (0.5% methocel in sterile water) were administered per os b.i.d. beginning post injection of adjuvant and continuing for 21 days.
- the compounds were prepared weekly, refrigerated in the dark until used, and vortex mixed immediately prior to administration.
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01927526A EP1278734A2 (en) | 2000-04-24 | 2001-04-23 | Method of treatment using phenyl and biaryl derivatives as prostaglandin e inhibitors and compounds useful therefore |
JP2001578407A JP2003531194A (en) | 2000-04-24 | 2001-04-23 | Therapeutic methods using phenyl and biaryl derivatives as prostaglandin E inhibitors and compounds useful in the methods |
AU2001254555A AU2001254555A1 (en) | 2000-04-24 | 2001-04-23 | Method of treatment using phenyl and biaryl derivatives as prostaglandin E inhibitors and compounds useful therefore |
CA002405170A CA2405170A1 (en) | 2000-04-24 | 2001-04-23 | Method of treatment using phenyl and biaryl derivatives as prostaglandin e inhibitors and compounds useful therefore |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US19929900P | 2000-04-24 | 2000-04-24 | |
US60/199,299 | 2000-04-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2001081312A2 true WO2001081312A2 (en) | 2001-11-01 |
WO2001081312A3 WO2001081312A3 (en) | 2002-08-08 |
Family
ID=22736988
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CA2001/000563 WO2001081312A2 (en) | 2000-04-24 | 2001-04-23 | Method of treatment using phenyl and biaryl derivatives as prostaglandin e inhibitors and compounds useful therefore |
Country Status (6)
Country | Link |
---|---|
US (1) | US6627656B2 (en) |
EP (1) | EP1278734A2 (en) |
JP (1) | JP2003531194A (en) |
AU (1) | AU2001254555A1 (en) |
CA (1) | CA2405170A1 (en) |
WO (1) | WO2001081312A2 (en) |
Cited By (25)
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WO2004084824A3 (en) * | 2003-03-24 | 2005-03-31 | Merck & Co Inc | Biaryl substituted 6-membered heterocyles as sodium channel blockers |
WO2005115990A1 (en) * | 2004-05-26 | 2005-12-08 | Eisai R & D Management Co., Ltd. | Cinnamide compound |
WO2006037982A2 (en) * | 2004-10-05 | 2006-04-13 | Astrazeneca Ab | Modulators of crth2 receptor activity for the treatment of prostaglandin d2 mediated diseases |
FR2878522A1 (en) * | 2004-12-01 | 2006-06-02 | Merck Sante Soc Par Actions Si | Use of new and known biphenyl derivatives as caspase-10 inhibitors in preparation of a drug to prevent and/or treat retinopathy |
EP1847524A1 (en) | 2006-04-21 | 2007-10-24 | Cellzome (UK) Ltd. | Terphenyl derivatives for treatment of Alzheimer's disease |
WO2009064250A1 (en) * | 2007-11-15 | 2009-05-22 | Astrazeneca Ab | Bis-(sulfonylamino) derivatives in therapy 065 |
WO2009064251A1 (en) * | 2007-11-15 | 2009-05-22 | Astrazeneca Ab | Bis-(sulfonylamino) derivatives in therapy 066 |
US7618960B2 (en) | 2005-11-24 | 2009-11-17 | Eisai R&D Management Co., Ltd. | Morpholine type cinnamide compound |
US7713993B2 (en) | 2006-03-09 | 2010-05-11 | Eisai R&D Management Co., Ltd. | Multi-cycle cinnamide derivatives |
US7737141B2 (en) | 2006-07-28 | 2010-06-15 | Eisai R&D Management Co., Ltd. | Prodrug of cinnamide compound |
US7737135B2 (en) | 2004-08-24 | 2010-06-15 | Astrazeneca Ab | Biphenyloxyacetic acid derivatives for the treatment of respiratory disease |
US7923563B2 (en) | 2004-10-26 | 2011-04-12 | Eisai R&D Management Co., Ltd. | Amorphous object of cinnamide compound |
US7935815B2 (en) | 2007-08-31 | 2011-05-03 | Eisai R&D Management Co., Ltd. | Imidazoyl pyridine compounds and salts thereof |
US8003703B2 (en) | 2003-08-21 | 2011-08-23 | Astrazeneca Ab | Phenoxiacetic acid derivatives |
US8008350B2 (en) | 2005-10-06 | 2011-08-30 | Astrazeneca Ab | Biphenyloxyacetic acid derivatives for the treatment of respiratory disease |
US8022248B2 (en) | 2004-07-08 | 2011-09-20 | Astrazeneca Ab | Substituted acids for the treatment of respiratory diseases |
US8048878B2 (en) | 2005-11-24 | 2011-11-01 | Eisai R&D Management Co., Ltd. | Two cyclic cinnamide compound |
US8148421B2 (en) | 2006-09-11 | 2012-04-03 | Fuji Yakuhin Co., Ltd. | Phenylacetic acid derivative |
US8148572B2 (en) | 2005-10-06 | 2012-04-03 | Astrazeneca Ab | Compounds |
US8158820B2 (en) | 2003-04-07 | 2012-04-17 | Astrazeneca Ab | Compounds |
CN1972916B (en) * | 2004-05-26 | 2013-03-27 | 卫材R&D管理有限公司 | Cinnamide compound |
US8507544B2 (en) | 2007-07-05 | 2013-08-13 | Astrazeneca Ab | Bi-aryl amide compounds as CRTh2 receptor modulators |
US8524715B2 (en) | 2004-11-23 | 2013-09-03 | Astrazeneca Ab | Phenoxyacetic acid derivatives useful for treating respiratory diseases |
US9145380B2 (en) | 2007-12-20 | 2015-09-29 | Astrazeneca Ab | Bis-(sulfonylamino) derivatives for use in therapy |
US9453000B2 (en) | 2007-08-31 | 2016-09-27 | Eisai R&D Management Co., Ltd. | Polycyclic compound |
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WO1994002474A1 (en) * | 1992-07-17 | 1994-02-03 | Smithkline Beecham Corporation | Endothelin receptor antagonists |
WO1995003295A1 (en) * | 1993-07-20 | 1995-02-02 | Merck & Co., Inc. | Endothelin antagonists |
WO1996030358A1 (en) * | 1995-03-27 | 1996-10-03 | Smithkline Beecham Plc | Phenyl derivatives useful as endothelin receptor antagonists |
WO1999047497A2 (en) * | 1998-03-13 | 1999-09-23 | Merck Frosst Canada & Co. | Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment |
WO2000020371A1 (en) * | 1998-10-07 | 2000-04-13 | Merck Frosst Canada & Co. | Prostaglandin receptor ligands |
Family Cites Families (1)
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US6242493B1 (en) * | 1998-03-13 | 2001-06-05 | Merck Frosst Canada & Co. | Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment |
-
2001
- 2001-04-23 JP JP2001578407A patent/JP2003531194A/en not_active Withdrawn
- 2001-04-23 WO PCT/CA2001/000563 patent/WO2001081312A2/en not_active Application Discontinuation
- 2001-04-23 AU AU2001254555A patent/AU2001254555A1/en not_active Abandoned
- 2001-04-23 CA CA002405170A patent/CA2405170A1/en not_active Abandoned
- 2001-04-23 EP EP01927526A patent/EP1278734A2/en not_active Withdrawn
- 2001-04-24 US US09/840,942 patent/US6627656B2/en not_active Expired - Fee Related
Patent Citations (5)
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WO1994002474A1 (en) * | 1992-07-17 | 1994-02-03 | Smithkline Beecham Corporation | Endothelin receptor antagonists |
WO1995003295A1 (en) * | 1993-07-20 | 1995-02-02 | Merck & Co., Inc. | Endothelin antagonists |
WO1996030358A1 (en) * | 1995-03-27 | 1996-10-03 | Smithkline Beecham Plc | Phenyl derivatives useful as endothelin receptor antagonists |
WO1999047497A2 (en) * | 1998-03-13 | 1999-09-23 | Merck Frosst Canada & Co. | Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment |
WO2000020371A1 (en) * | 1998-10-07 | 2000-04-13 | Merck Frosst Canada & Co. | Prostaglandin receptor ligands |
Cited By (43)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004084824A3 (en) * | 2003-03-24 | 2005-03-31 | Merck & Co Inc | Biaryl substituted 6-membered heterocyles as sodium channel blockers |
US8158820B2 (en) | 2003-04-07 | 2012-04-17 | Astrazeneca Ab | Compounds |
US8003703B2 (en) | 2003-08-21 | 2011-08-23 | Astrazeneca Ab | Phenoxiacetic acid derivatives |
US8394986B2 (en) | 2003-08-21 | 2013-03-12 | Astrazeneca Ab | Phenoxiacetic acid derivatives |
US7667041B2 (en) | 2004-05-26 | 2010-02-23 | Eisai R&D Management Co., Ltd. | Cinnamide compound |
WO2005115990A1 (en) * | 2004-05-26 | 2005-12-08 | Eisai R & D Management Co., Ltd. | Cinnamide compound |
US7880009B2 (en) | 2004-05-26 | 2011-02-01 | Eisai R&D Management Co., Ltd. | Cinnamide compound |
US7687640B2 (en) | 2004-05-26 | 2010-03-30 | Eisai R&D Management Co., Ltd. | Cinnamide compound |
CN1972916B (en) * | 2004-05-26 | 2013-03-27 | 卫材R&D管理有限公司 | Cinnamide compound |
US8022248B2 (en) | 2004-07-08 | 2011-09-20 | Astrazeneca Ab | Substituted acids for the treatment of respiratory diseases |
US7737135B2 (en) | 2004-08-24 | 2010-06-15 | Astrazeneca Ab | Biphenyloxyacetic acid derivatives for the treatment of respiratory disease |
US8163727B2 (en) | 2004-08-24 | 2012-04-24 | Astrazeneca Ab | Biphenyloxyacetic acid derivatives for the treatment of respiratory disease |
US8722741B2 (en) | 2004-08-24 | 2014-05-13 | Astrazeneca Ab | Biphenyloxyacetic acid derivatives for the treatment of respiratory disease |
WO2006037982A3 (en) * | 2004-10-05 | 2006-08-17 | Astrazeneca Ab | Modulators of crth2 receptor activity for the treatment of prostaglandin d2 mediated diseases |
WO2006037982A2 (en) * | 2004-10-05 | 2006-04-13 | Astrazeneca Ab | Modulators of crth2 receptor activity for the treatment of prostaglandin d2 mediated diseases |
US7923563B2 (en) | 2004-10-26 | 2011-04-12 | Eisai R&D Management Co., Ltd. | Amorphous object of cinnamide compound |
US8524715B2 (en) | 2004-11-23 | 2013-09-03 | Astrazeneca Ab | Phenoxyacetic acid derivatives useful for treating respiratory diseases |
US7829721B2 (en) | 2004-12-01 | 2010-11-09 | Merck Patent Gmbh | Specific caspase-10 inhibitors |
WO2006058592A1 (en) * | 2004-12-01 | 2006-06-08 | Merck Patent Gmbh | Novel specific caspase-10 inhibitors |
FR2878522A1 (en) * | 2004-12-01 | 2006-06-02 | Merck Sante Soc Par Actions Si | Use of new and known biphenyl derivatives as caspase-10 inhibitors in preparation of a drug to prevent and/or treat retinopathy |
US8148572B2 (en) | 2005-10-06 | 2012-04-03 | Astrazeneca Ab | Compounds |
US8415394B2 (en) | 2005-10-06 | 2013-04-09 | Astrazeneca Ab | Biphenyloxyacetic acid derivatives for the treatment of respiratory disease |
US8008350B2 (en) | 2005-10-06 | 2011-08-30 | Astrazeneca Ab | Biphenyloxyacetic acid derivatives for the treatment of respiratory disease |
US8349897B2 (en) | 2005-10-06 | 2013-01-08 | Astrazeneca Ab | Biphenyloxyacetic acid derivatives for the treatment of respiratory disease |
US8048878B2 (en) | 2005-11-24 | 2011-11-01 | Eisai R&D Management Co., Ltd. | Two cyclic cinnamide compound |
US7618960B2 (en) | 2005-11-24 | 2009-11-17 | Eisai R&D Management Co., Ltd. | Morpholine type cinnamide compound |
US7713993B2 (en) | 2006-03-09 | 2010-05-11 | Eisai R&D Management Co., Ltd. | Multi-cycle cinnamide derivatives |
US7973033B2 (en) | 2006-03-09 | 2011-07-05 | Eisai R&D Management Co., Ltd. | Multi-cyclic cinnamide derivatives |
US7897632B2 (en) | 2006-03-09 | 2011-03-01 | Eisai R&D Management Co., Ltd. | Multi-cyclic cinnamide derivatives |
EA016908B1 (en) * | 2006-04-21 | 2012-08-30 | Орто-Макнил-Дженссен Фармасьютикэлз, Инк. | Terphenyl derivatives for treatment of alzheimer's disease |
US8106236B2 (en) | 2006-04-21 | 2012-01-31 | Ortho-Mcneil Pharmaceutical, Inc. | Triaryl compounds and derivates thereof |
EP1847524A1 (en) | 2006-04-21 | 2007-10-24 | Cellzome (UK) Ltd. | Terphenyl derivatives for treatment of Alzheimer's disease |
WO2007124351A1 (en) | 2006-04-21 | 2007-11-01 | Ortho-Mcneil Pharmaceutical, Inc. | Terphenyl derivatives for treatment of alzheimer' s disease |
US7737141B2 (en) | 2006-07-28 | 2010-06-15 | Eisai R&D Management Co., Ltd. | Prodrug of cinnamide compound |
US8148421B2 (en) | 2006-09-11 | 2012-04-03 | Fuji Yakuhin Co., Ltd. | Phenylacetic acid derivative |
US8507544B2 (en) | 2007-07-05 | 2013-08-13 | Astrazeneca Ab | Bi-aryl amide compounds as CRTh2 receptor modulators |
US7935815B2 (en) | 2007-08-31 | 2011-05-03 | Eisai R&D Management Co., Ltd. | Imidazoyl pyridine compounds and salts thereof |
US9453000B2 (en) | 2007-08-31 | 2016-09-27 | Eisai R&D Management Co., Ltd. | Polycyclic compound |
CN101910121A (en) * | 2007-11-15 | 2010-12-08 | 阿斯利康(瑞典)有限公司 | Bis-(sulfonylamino) derivatives in therapy 066 |
WO2009064250A1 (en) * | 2007-11-15 | 2009-05-22 | Astrazeneca Ab | Bis-(sulfonylamino) derivatives in therapy 065 |
WO2009064251A1 (en) * | 2007-11-15 | 2009-05-22 | Astrazeneca Ab | Bis-(sulfonylamino) derivatives in therapy 066 |
AU2008321577B2 (en) * | 2007-11-15 | 2011-05-26 | Astrazeneca Ab | Bis-(sulfonylamino) derivatives in therapy 066 |
US9145380B2 (en) | 2007-12-20 | 2015-09-29 | Astrazeneca Ab | Bis-(sulfonylamino) derivatives for use in therapy |
Also Published As
Publication number | Publication date |
---|---|
US20020082266A1 (en) | 2002-06-27 |
AU2001254555A1 (en) | 2001-11-07 |
CA2405170A1 (en) | 2001-11-01 |
US6627656B2 (en) | 2003-09-30 |
EP1278734A2 (en) | 2003-01-29 |
WO2001081312A3 (en) | 2002-08-08 |
JP2003531194A (en) | 2003-10-21 |
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