EP1259488A1 - Ortho-sulfonamido-aryl-hydroxamsäuren, verfahren zu ihrer herstellung und ihre anwendung als matrix metalloproteinase-inhibitoren - Google Patents
Ortho-sulfonamido-aryl-hydroxamsäuren, verfahren zu ihrer herstellung und ihre anwendung als matrix metalloproteinase-inhibitorenInfo
- Publication number
- EP1259488A1 EP1259488A1 EP01912836A EP01912836A EP1259488A1 EP 1259488 A1 EP1259488 A1 EP 1259488A1 EP 01912836 A EP01912836 A EP 01912836A EP 01912836 A EP01912836 A EP 01912836A EP 1259488 A1 EP1259488 A1 EP 1259488A1
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- Prior art keywords
- heteroaryl
- aryl
- phenyl
- alkenyl
- alkynyl
- Prior art date
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- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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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- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
Definitions
- the present invention relates to novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) which are useful for the treatment of diseases in which these enzymes
- matrix metalloproteinases e.g. gelatinases, stromelysins and collagenases
- this invention provides orthosulfonamido aryl hydroxamine
- MMPs Matrix metalloproteinases
- Angiogenesis required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology [Crawford, H.C; Matrisian, L.M. Invasion Metast. 1994-95, 14, 234; Ray, J.M.; Stetler-Stevenson, W.G. Exp. Opin. Invest. Drugs, 1996, 5, 323.].
- MMPs diseases mediated by MMPs
- Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization and corneal graft rejection.
- MMPs are important mediators of the tissue destruction that occurs in arthritis.
- these enzymes are capable of degrading collagens and proteoglycans which are the ajor structural components of cartilage [Sapolsky, A.I.; Keiser, H.; Howell, D.S.; Woessner, J.F., Jr.; J. Clin. Invest. 1976, 58, 1030; Pelletier, J.-P.; Martel-Pelletier, J.; Howell, D.S.; Ghandur-Mnaymneh, L.; Enis, J.E.; Woessner, J.F., Jr., Arthritis Rheum.
- MMP-13 collagenase-3
- MMP-13 is produced by chondrocytes, and elevated levels of MMP-13 has been found in human osteoarthritic tissues [Reboul, P.; Pelletier, J-P.; Hambor, J.; Magna, H.; Tardif, G.; Cloutier, J-M.; Martel-Pelletier, J. Arthritis Rheum. 1995, 38 (Suppl. 9), S268;Shlopov, B.V.; Mainardi, C.L.; Hasty, K.A. Arthritis Rheum. 1995, 38 (Suppl.
- patents 5,455,258, 5,506,242 and 5,552,419, as well as European patent application EP606,046A1 and WIPO international publications WO96/00214 and WO97/22587 disclose non-peptide matrix metalloproteinase inhibitors of which the compound CGS27023A is representative. The discovery of this type of MMP inhibitor is further detailed by MacPherson, et. al. in J. Med. Chem., (1997),40, 2525.
- German patent application DEI 9,542, 189-A1 discloses additional examples of cylic sulfonamides as MMP inhibitors.
- the sulfonamide- containing ring is fused to a phenyl ring to form an isoquinoline.
- the MMP inhibiting ortho-sulfonamido aryl hydroxamic acids of the present invention are represented by formula I
- A is aryl, heteroaryl or heteroaryl fused to a phenyl ring
- Z is aryl, heteroaryl, or heteroaryl fused to a phenyl
- E and G are independently CH2, NR 5 , or O, or S or a bond:
- Y is cycloalkyl, cycloheteroalkyl, -C ⁇ C5-perfluoroalkyl, alkyl, alkenyl, alkynyl, hctcroalkyl, alkylaryl, or heteroaryl;
- J is aryl, heteroaryl, heteroaryl fused to a phenyl, cycloalkyl, cycloheteroalkyl, -C 1 -C5-perfl uoroalkyl, alkyl, alkenyl, or alkynyl;
- R 5 and R 6 are independently H, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, -C ⁇ -C4-perfluoroalkyl, alkyl, alkenyl, or alkynyl;
- R 7 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or 3-6 membered cycloheteroalkyl; or
- R 7 CH 2 -N-A- can form a non-aromatic 1,2-benzo-fused 7-10 membered heterocyclic ring optionally containing an additional heteroatom selected from O, S and N wherein said heterocyclic ring may be optionally fused to another benzene ring;
- L is -C(O , S(O) y , -NR 5 C(O)NR6-, -NR 5 C(O)O-, -0C(O)NR5-, -SC(Oh - C(O)S-, -NR5C(0)-, -C(0)NR 5 -, -SC(0)NR5, -NR 5 C(O)S-, -OC(0)0-; y is 1 or 2; and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.
- Preferred compounds of the invention are those wherein:
- A is aryl, heteroaryl or heteroaryl fused to a phenyl ring optionally substituted by one or more of R 1 , R 2 , R 3 and R 4 the same or different;
- Z is aryl, heteroaryl, or heteroaryl fused to a phenyl, optionally substituted by one or more of R 10 , R 11 , R 12 and R 13 the same or different;
- R 26 , R 27 , R 28 , R 29 , R 30 and R 31 are independently -H, -COR5, -F,-Br, -Cl, -I,
- E and G are independently CH2, NR 5 , or O, or S or a bond:
- Y is -C3-C6-cycloalkyl, -C3-C6-cycloheteroalkyl, -C ⁇ -C5-perfluoroalkyl, straight chain or branched -Ci-C ⁇ alkyl, straight or branched chain -C 2 -C6-alkenyl, or straight or branched chain C 2 -C6-alkynyl or heteroalkyl, alkylaryl, heteroaryl optionally substituted with R 20 , R 21 , R 22 > and R 23 ;
- J is aryl, heteroaryl, or heteroaryl fused to a phenyl; optionally substituted with R 14 , R 15 , R 16 > and Rl7 or -C 3 -C 6 -cycloalkyl, -C 3 -C6-cycloheteroalkyl, -C1-C5- perfJuoroalkyl, straight chain or branched -Cj- , alky], straight or branched chain - C2-C ⁇ -alkenyl, or straight or branched chain C 2 -C6-alkynyl;
- R 5 and R 6 are independently H, aryl, heteroaryl, -C3-C6-cycloalkyl, -C3-C6- cycloheteroalkyl, -C ⁇ -C4-perfluoroalkyl, or straight chain or branched -C1-C6 alkyl, - C2-C6-alkenyl, or -C 2 -C6-alkynyl, each optionally substituted with -OH, -COR 8 , - CN, -C(O)NR 8 OR 9 , -C 2 -C 6 -alkenyl, -C 2 -C 6 -alkynyl, -OR 8 , -C ⁇ -C 4 -perfluoroalkyl, - S(O) x R 8 , -OPO(OR 8 )OR9, -PO(OR 8 )R 9 , -OC(O)NR 8 R9, -COOR 8 ,
- R 7 is phenyl or naphthyl, optionally substituted by R 24 , R 25 , R 26 and R 27 or a 5 to 6 membered heteroaryl group optionally substituted by R 28 , R 29 , R 30 and R 31 ; or R 7 is C 3 -C 6 cycloalkyl or 3-6 membered cycloheteroalkyl; or R 7 CH 2 -N-A- (where R 7 is bonded to A) can form a non-aromatic 1,2-benzo- fused 7-10 membered heterocyclic ring optionally containing an additional heteroatom selected from O, S and N wherein said heterocyclic ring may be optionally fused to another benzene ring such as for example: or (fused): R 8 and R
- R 18 and R 32 are independently aryl, heteroaryl,-C3-C6-cycloalkyl, -C3-C6- cycloheteroalkyl, -C ⁇ -C 4 -perfluoroalkyl, or straight chain or branched -Ci-C ⁇ alkyl, - C -C6-alkenyl, or -C 2 -C6-alkynyl, each optionally substituted with -OH, -COR 8 , - CN, -C(O)NR 8 OR 9 , -C 2 -C 6 -alkenyl, -C 2 -C 6 -alkynyl, -OR 8 , -C ⁇ -C 4 -perfluoroalkyl, -S(O) x R 8 , -OPO(OR 8 )OR9, -PO(OR 8 )R 9 , -OC(O)NR 8 R9, -COOR 8 , -
- R 19 is aryl or heteroaryl, -C3-C7cycloalkyl or 3 to 6 membered cycloheteroalkyl, -C ⁇ -C 4 -perfluoroalkyl, straight chain or branched -C ⁇ -C6-alkyl, - C 2 -C6-alkenyl, or -C 2 -C6-alkynyl, each optionally substituted with hydroxy, alkoxy, aryloxy, -C ⁇ -C -perfluoroalkyl, amino, mono- and di-Ci-C ⁇ -alkylamino, carboxylic acid, carboalkoxy and carboaryloxy, nitro, cyano, carboxamido primary, mono- and di-C 1 -C6-alkylcarbamoyl;
- L is -C(O)-.
- S(O) y -NR 5 C(O)NR ⁇ -NR5C(O)0-, -OC(O)NR5-, -SC(0)-, - C(0)S-, -NR 5 C(O)-, -C(O)NR 5 -, -SC(O)NR5, -NR5C(O)S-, -OC(O)O-; y is 1 or 2; and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.
- both of the carbons of A adjacent to the carbon bearing the sulfonamido group have a substituent other than hydrogen.
- Examples of A are phenyl optionally substituted by C j -Cg straight or branched chain alkyl.
- Examples of Z are phenyl, e.g. where E ispara to the -SO2- group.
- E and G are independently selected from NH, O and S.
- E is O and G is NH.
- Y is C j -Cg straight chain alkyl, and more preferably C2-C3 straight chain alkyl.
- E and G are independently selected from CH2, NH, O and S and Y is -C ⁇ -C 4 -perfluoroalkyl, or straight chain or branched -C 1 -C 6 alkyl, -C 2 -C 6 -alkenyl, or C 2 -C 6 -alkynyl.
- E and G are independently selected from CH2, NH, O and S and Y is straight chain or branched -Ci-C ⁇ alkyl.
- G is CH2
- Y is - C 2 -C 5 -perfluoroalkyl, or straight chain or branched -Ci-Cg alkyl
- E and G are CH 2
- Y is straight chain or branched -Ci-C ⁇ alkyl, and more preferably Y is straight chain or branched -C 1 -C 5 alkyl.
- J is preferably heteroaryl fused to a phenyl and particularly preferred is where
- J is benzofuranyl, benzothienyl and quinolinyl. J may be indolyl. When R 14 and R 15 are on adjacent atoms of J, R 14 , R 15 and J may together preferably form a bicyclic oxygen containing aryl moiety such as benzodioxanyl or benzodioxlyl.
- Preferred compounds of the present invention include: Quinoline-2-carboxylic acid (2- ⁇ 4-[(2-hydroxycarbamoyl-6-methyl-phenyl)- methyl-sulfamoyl]-phenoxy ⁇ -ethyl)-amide
- Halogen means fluoro, chloro, bromo and iodo.
- Alkyl as used herein means a branched or straight chain radical having from 1 to 20 carbon atoms optionally substituted with one or more groups selected from halogen, cyano, nitro, hydroxy, sulfhydryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl, aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl, carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido, arylsulfonamido, aryl, heteroaryl, and more preferably from 1 to 6 carbon atoms also optionally substituted.
- alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl also optionally substituted as well as perfluoroalkyl.
- Alkenyl as used herein means a branched or straight chain radical having from 2 to 20 carbon atoms optionally substituted with one or more groups selected from halogen, cyano, nitro, hydroxy, sulfhydryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl, aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl, carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido, arylsulfonamido, aryl, heteroaryl, and more preferably from 2 to 6 carbon atoms, with the chain containing at least one carbon-carbon double bond.
- Alkenyl may be used synonymously with the term olefin and includes alkylidenes.
- Exemplary alkenyl groups include but are not limited to
- Alkynyl as used herein means a branched or straight chain radical having from 2 to 20 carbon atoms optionally substituted with one or more groups selected from halogen, cyano, nitro, hydroxy, sulfhydryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl, aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl, carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido, arylsulfonamido, aryl, heteroaryl, and more preferably from 3 to 10 carbon atoms, with the chain containing at least one carbon-carbon triple bond.
- Alkoxy as used herein means an alkyl-O- group in which the alkyl group is as previously described.
- exemplary alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
- Aryl as used herein refers to phenyl or naphthyl which may be optionally substituted as described above (e.g. R 1-4 , R 10-13 , R l4 -1 etc.,) such as with one to four substituents selected from the group of alkyl, halogen, cyano, nitro, hydroxy, sulfhydryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl, aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl, carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido, arylsulfonamido, aryl, or heteroaryl.
- Heteroaryl refers to a 5-6 membered heteroaromatic ring having from 1 to 3 heteroatoms independently selected from N, NH, O and S. Heteroaryl may be optionally substituted with substituents as described above (e.g.
- R 1 " 4 , R 10 " 13 , R 14 " 17 ) such as selected from the group halogen, cyano, nitro, hydroxy, sulfhydryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl, aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl, carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido, arylsulfonamido, aryl, and heteroaryl.
- Heteroaryl includes, but is not limited to pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole and oxazole.
- Cycloalkyl or saturated or unsaturated carbocyclic ring refers to a cyclic alkyl group having from 3 to 7 carbon atoms and may include from 1 to 2 double bonds. Cycloalkyl groups may be optionally substituted.
- Cycloheteroalkyl refers to 3 to 7 membered saturated or unsaturated heterocyclic ring having one to three heteroatoms independently selected from N, NH, O, and S and optionally having 1 or 2 double bonds. Cycloheteroalkyl groups may be optionally substituted with from one to three groups.
- heterocycloalkyl or heterocyclic ring includes, but is not limited to oxazolidine, thiazolidine, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetramethylene sulfone, dihydropyran, tetrahydropyran, piperidine, pyrrolidine, dioxane, morpholine, azepine and diazepine.
- heteroaryl fused to a phenyl includes, but is not limited to, benzoxazole, benzoisoxazole, indole, isoindole, benzothiophene, benzofuran, quinoline, quinazoline, quinoxaline, benzotriazole, benzimidazole, benzthiazole, benzopyrazole and isoquinoline. Substitutions may occur on one or both rings.
- Pharmaceutical acceptable salts are encompassed by the present invention and include, as appropriate, inorganic and organic salts.
- Exemplary acid salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate,
- Other compounds that are acids can also form salts with alkali metals or alkali earth metals, such as sodium, potassium, calcium, or magnesium, or with organic bases or basic quaternary ammonium salts.
- the compounds according to the invention can be in various stereoisomeric forms such as enantiomers or diastereomers.
- the invention includes optically pure forms of compounds of the present invention prepared in accordance with known methods.
- the following compounds (1-10) which may be used in preparing invention compounds are known and references are given hereinbelow.
- the invention compounds may be prepared using conventional techniques known to those skilled in the art of organic synthesis.
- this invention provides a process for preparing a compound of Formula I as defined above which comprises one of the following: a) reacting a compound of formula II: (II)
- the N,N-disubstituted sulfonamide ester may be hydrolyzed to the carboxylic acid and then subjected to a nucleophilic displacement of the fluoro substituent, or it can be treated directly with a suitable nucleophile and subsequently hydrolyzed to the acid.
- the acid may then be converted into the corresponding hydroxamic acid.
- Scheme II depicts the preparation of suitable nucleophiles (for when E and G are independently N, O, or S and L is -C(O)- or S(O)x) employed in the displacement of the aryl fluoride.
- nucleophiles for use in the displacement reaction can be prepared via the route in Scheme III.
- a suitable ester is condensed with a lactone to provide a ⁇ -ketolactone. This lactone is then ring opened with concomitant decarboxylation to provide the requisite nucleophile for use in the displacement reaction.
- the N,N-disubstituted sulfonamide ester may be hydrolyzed to the carboxylic acid and then subjected to a palladium catalyzed coupling to a suitable alkyl boron reagent (compound A, prepared via the route depicted in Scheme 5), or it can be treated directly with a suitable alkyl boron reagent and subsequently hydrolyzed to the acid.
- a suitable alkyl boron reagent compound A, prepared via the route depicted in Scheme 5
- the acid may then be converted into the corresponding hydroxamic acid.
- Compound A (where L is -C(O)-) may be prepared via the following route.
- a precursor carboxylic acid is converted to the Weinreb amide via formation of the acid chloride and subsequent displacement with methoxymethyl amine.
- the amide is then treated with a grignard reagent, the olefin of which is subsequently hydroborated with 9-BBN for use in the palladium coupling reaction.
- Scheme 5
- compounds of the present invention are particularly useful for the treatment of rheumatoid arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease and HIV infection.
- Compounds of this invention may be provided to a patient in need thereof.
- the pharmaceutical carrier may be solid or liquid and generally may be any pharmaceutically acceptable carrier.
- Formulation of drugs is discussed, for example, in Hoover, J.E., Remington 's Pharameutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 1975.
- Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
- the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain up to 99% of the active ingredient.
- Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
- Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
- the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic nn
- liquid carrier can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
- the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
- Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
- the compounds of this invention may be administered rectally in the form of a conventional suppository.
- the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
- the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
- the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
- the creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type.
- Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
- a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
- the dosage to be used in the treatment of a specific patient suffering from a disease or condition in which MMPs and TACE are involved must be subjectively determined by the attending physician.
- the variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient. Treatment will generally be initiated with small dosages less than the optimum dose of the ⁇
- the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules.
- the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
- the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing liquids.
- the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
- Example 3 The product of Example 3 (0.17 g, 0.33 mmol) was dissolved in DMF (5 ml).
- 1-hydroxybenzotriazole (HOBT) 0.1 g, 0.8 mmol
- l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride 0.1 g, 0.92 mmol
- hydroxy lamine hydrochloride 0.18 g, 2.64 mmol
- triethylamine (0.46 ml, 3.3 mmol
- Example 2 The product of Example 2 (0.442 g, 1.37 mmol) was coupled to N-(3- hydroxypropyl)-l-benzofuran-2-carboxamide (0.3 g, 1.37 mmol) using the procedure of Example 3 to provide 0.37 g (53% yield) of an off white powder.
- Electrospray Mass Spec m/z 523.2 (M+H) + .
- Example 5 The product of Example 5 (0.172 g, 0.33 mmol) was converted to the hydroxamic acid using the procedure of Example 4 to provide 0.073 g (41% yield) of a white solid.
- Electrospray Mass Spec 538.1 m/z (M+H) + .
- Example 2 The product of Example 2 (0.40 g, 1.24 mmol) was coupled to N-(4- hydroxybutyl)-l-benzofuran-2-carboxamide, prepared according to Example 17, (0.29 g, 1.24 mmol) using the procedure of Example 3 to provide 0.34 g (51% yield) of an off white powder.
- Example 7 The product of Example 7 (0.2 g, 0.37 mmol) was converted to the hydroxamic acid using the procedure of Example 4 to provide 0.063 g (31% yield) of a white solid.
- Electrospray Mass Spec 552.2 m/z (M+H) + .
- Example 9 Example 9
- Example 2 2-[(4- ⁇ 3-[(lH-Indole-2-carbonyl)-amino]-propoxy ⁇ -benzenesulfonyl)-methyl- amino]-3-methyl-benzoic acid
- the product of Example 2 (0.27 g, 0.83 mmol) was coupled to N-(3- hydroxypropyl)-lH-indole-2-carboxamide, prepared according to Example 18, (0.20 g, 0.91 mmol) using the procedure of Example 3 to provide 0.4 g (91% yield) of yellow solid powder.
- Example 9 The product of Example 9 (0.2 g, 0.38 mmol) was converted to the hydroxamic acid using the procedure of Example 4 to provide 0.112 g (55% yield) of a white solid.
- Example 2 The product of Example 2 (0.15 g, 0.846 mmol) was coupled to N-(2- hydroxyethyl)-l-benzothiophene-2-carboxamide, prepared according to Example 19,
- Example 11 The product of Example 11 (0.2 g, 0.38 mmol) was converted to the hydroxamic acid using the procedure of Example 4 to provide 0.048 g (25% yield) of a white solid.
- Example 2 The product of Example 2 (0.30 g, 0.92 mmol) was coupled to N-(3- hydroxypropyl)-l,3-benzodioxole-5-carboxamide, prepared according to Example 20, (0.205 g, 0.92 mmol) using the procedure of Example 3 to provide 0.23 g (49% yield) of yellow solid.
- Example 13 The product of Example 13 (0.2 g, 0.38 mmol) was converted to the hydroxamic acid using the procedure of Example 4 to provide 0.102 g (50% yield) of a white solid.
- Example 2 The product of Example 2 (0.30 g, 0.92 mmol) was coupled to N-(4- hydroxybutyl)-l,3-benzodioxole-5-carboxamide, prepared according to Example 21, (0.23 g, 0.96 mmol) using the procedure of Example 3 to provide 0.30 g (60% yield) of yellow solid.
- Example 15 The product of Example 15 (0.15 g, 0.28 mmol) was converted to the hydroxamic acid using the procedure of Example 4 to provide 0.092 g (40% yield) of a white solid.
- Example 2 The product of Example 2 (0.5 g, 1.58 mmol) was coupled to N-(3- hydroxypropyl)-l-benzothiophene-2-carboxamide (1.26 g, 5.37 mmol) using the procedure of Example 3 to provide 0.16 g (19% yield) of an off white solid. Electrospray Mass Spec: m/z 539.3 (M+H) + .
- Example 26 The product of Example 26 (0.16 g, 0.30 mmol) was converted to the hydroxamic acid using the procedure of Example 4 to provide 0.1 g (60% yield) as a pink foam. MP 100-105 °C. Electrospray Mass Spec: m/z 554.0 (M+H) + .
- Example 29 2-[Benzyl-(4-fluoro-benzenesulfonyl)-amino]-3,5-dimethyl-benzoic acid methyl ester To a solution of 1.00g (2.86 mmol) of the product of Example 28 in lOmL of
- Example 30 2-[[(4- ⁇ 2-[(Benzofuran-2-carbonyl)- amino]ethoxy ⁇ benzenesulfonyl]benzylamino]-3,5-dimethyl-benzoic acid
- Sodium hydride (0.240 g, 5.99 mmol, 60% dispersion in mineral oil) was added to DMF (8 ml) and cooled to 0 °C.
- Example 29 The product of Example 29 (0.383 g, 0.87 mmol) was then added in one portion and the reaction was allowed to stir overnight. The reaction was then quenched with water, extracted with EtOAc, washed with water, brine, dried over MgSO 4 , and concentrated in vacuo to provide an oil which was chromatographed using hexane to 2/1 hexane/EtOAc as eluant to provide the product as a mixture of esters which was used directly in the next reaction. The mixture of esters (233 mg) was dissolved in THF:MeOH:H 2 O
- the enzyme activity is measured by the rate of the color increase.
- the thiopeptide substrate is made up fresh as a 20 mM stock in 100% DMSO and the DTNB is dissolved in 100% DMSO as a 100 mM stock and stored in the dark at room temperature.
- Both the substrate and DTNB are diluted together to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCl 2 ) before use.
- substrate buffer 50 mM HEPES pH 7.5, 5 mM CaCl 2
- the stock of enzyme is diluted with assay buffer (50 mM HEPES, pH 7.5, 5 mM CaC- 2 , 0.02% Brij) to the desired final concentration.
- the assay buffer, enzyme, vehicle or inhibitor, and DTNB/substrate are added in this order to a 96 well plate (total reaction volume of 200 ⁇ l) and the increase in color is monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader and the increase in color over time is plotted as a linear line.
- a fluorescent peptide substrate is used.
- the peptide substrate contains a fluorescent group and a quenching group.
- MMP Upon cleavage of the substrate by an MMP, the fluorescence that is generated is quantitated on the fluorescence plate reader.
- the assay is run in HCBC assay buffer (50mM HEPES, pH 7.0, 5 mM Ca+ 2 , 0.02% Brij, 0.5% Cysteine), with human recombinant MMP-1, MMP-9, or MMP-13.
- the substrate is dissolved in methanol and stored frozen in 1 mM aliquots.
- substrate and enzymes are diluted in HCBC buffer to the desired concentrations.
- the slope of the line is calculated and represents the reaction rate.
- the linearity of the reaction rate is confirmed (r ⁇ >0.85).
- the mean (x ⁇ sem) of the control rate is calculated and compared for statistical significance (p ⁇ 0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships can be generated using multiple doses of drug and IC50 values with 95% CI are estimated using linear regression.
- each well receives a solution composed of 10 ⁇ L tumor necrosis factor-alpa converting enzyme (TACE; Immunex, final concentration l ⁇ g/mL), 70 ⁇ L Tris buffer, pH 7.4 containing 10% glycerol (final concentration 10 mM), and 10 ⁇ L of test compound solution in DMSO (final concentration l ⁇ M, DMSO concentration ⁇ 1%) and incubated for 10 minutes at room temperature.
- TACE tumor necrosis factor-alpa converting enzyme
- DMSO final concentration 100 ⁇ M
- the reaction is read (excitation 340 nm, emission 420 nm) for 10 min. and the increase in fluorescence over time is plotted as a linear line. The slope of the line is calculated and represents the reaction rate.
- the linearity of the reaction rate is confirmed (r 2 >0.85).
- the mean (x ⁇ sem) of the control rate is calculated and compared for statistical significance (p ⁇ 0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships can be generate using multiple doses of drug and IC 50 values with 95% CI are estimated using linear regression.
- Compounds of this invention are shown to inhibit the enzymes MMP-1, MMP-9, MMP- 13, and TACE and are therefore useful in the treatment of conditions resulting from overexpression or excess activation of MMPs and TACE.
- diseases are, for example, atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from atherosclerotic plaque rupture, restenosis, MMP- mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, angiogenesis, tumor metastasis, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, and periodontal disease.
- Compounds of the present invention are also believed to be useful for the treatment of age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization or corneal graft rejection.
- compounds of the present invention are believed to be useful for the treatment of graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, or HIV infection.
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AU743901B2 (en) * | 1996-10-16 | 2002-02-07 | Wyeth Holdings Corporation | Ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloprote inase and tace inhibitors |
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