WO2002034753A2 - Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors - Google Patents

Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors Download PDF

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Publication number
WO2002034753A2
WO2002034753A2 PCT/IB2001/001986 IB0101986W WO0234753A2 WO 2002034753 A2 WO2002034753 A2 WO 2002034753A2 IB 0101986 W IB0101986 W IB 0101986W WO 0234753 A2 WO0234753 A2 WO 0234753A2
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WIPO (PCT)
Prior art keywords
group
pyridin
alkyl
spiro
triaza
Prior art date
Application number
PCT/IB2001/001986
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English (en)
French (fr)
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WO2002034753A3 (en
Inventor
Brian Scott Bronk
Mark Carl Noe
Martin James Wythes
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Pfizer Products Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority to APAP/P/2001/002318A priority Critical patent/AP2001002318A0/en
Priority to EEP200300196A priority patent/EE200300196A/xx
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Priority to BR0114913-0A priority patent/BR0114913A/pt
Priority to JP2002537743A priority patent/JP2004518635A/ja
Priority to HU0301577A priority patent/HUP0301577A3/hu
Priority to EP01978721A priority patent/EP1332146A2/en
Priority to CA002425283A priority patent/CA2425283A1/en
Priority to PL01366201A priority patent/PL366201A1/xx
Priority to KR10-2003-7005753A priority patent/KR20040004412A/ko
Priority to IL15494801A priority patent/IL154948A0/xx
Priority to SK497-2003A priority patent/SK4972003A3/sk
Priority to EA200300306A priority patent/EA005762B1/ru
Priority to AU2002210813A priority patent/AU2002210813A1/en
Priority to MXPA03003735A priority patent/MXPA03003735A/es
Publication of WO2002034753A2 publication Critical patent/WO2002034753A2/en
Publication of WO2002034753A3 publication Critical patent/WO2002034753A3/en
Priority to BG107653A priority patent/BG107653A/bg
Priority to IS6762A priority patent/IS6762A/is
Priority to NO20031853A priority patent/NO20031853L/no
Priority to HR20030332A priority patent/HRP20030332A2/hr

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to 5-spiro-pyrimidi ⁇ e-2,4,6-trione metalloproteinase inhibitors and to pharmaceutical compositions and methods of treatment of inflammation, cancer and other disorders.
  • the compounds of the present invention are inhibitors of zinc metalloendopeptidases, especially those belonging to the class of matrix metalloproteinases (also called MMP or matrixin).
  • MMP matrix metalloproteinases
  • the MMP subfamily of enzymes currently contains seventeen members (MMP-1 , MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11 , MMP-12, MMP- 3, MMP-14, MMP-15, MMP-16, MMP- 7, MMP- 8, MMP-19, MMP-20).
  • MMP-1 MMP-1 , MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11 , MMP-12, MMP- 3, MMP-14, MMP-15, MMP-16, MMP- 7, MMP- 8, MMP-19, MMP-20.
  • MMP-13 an enzyme with potent activity at degrading type II collagen (the principal collagen in cartilage), has been demonstrated to be overexpressed in osteoarthritic cartilage (Mitchell, et al., J. Clin. Invest., 97, 761 (1996)).
  • Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are also overexpressed in osteoarthritic cartilage and inhibition of some or all of these MMP's is expected to slow or block the accelerated loss of cartilage typical of joint diseases such as osteoarthritis or rheumatoid arthritis.
  • MMP inhibitors are exemplified in European Patent Publication 606,046, published July 13, 1994.
  • Several pyrimidine-2,4,6-trione MMP inhibitors are referred to in PCT publication WO 98/58925, published December 30, 1998.
  • PCT publication WO 00/47565, published August 17, 2000 refers to certain aryl substituted pyrimidine-2,4,6-trione MMP inhibitors.
  • United States Non-provisional application 09/635156, filed August 9, 2000 (which claims priority to United States Provisional application 60/148547 filed August 12, 1999) refers to heteroaryl substituted pyrimidine-2,4,6-trione MMP inhibitors.
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R 1U , R ⁇ , R 1 and R 1J is independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, (CrC 4 )alkenyl, (C 1 -C 4 )alkynyl, (C 6 -C 10 )aryl, (CrC ⁇ heteroaryl, (C 3 -C 8 )cycloalkyl and (d-C ⁇ Jheterocyclyl; wherein each of said (C C )alkyl, (C 6 -C ⁇ 0 )aryl, (CrC 10 )heteroaryl, (C 3 -C 8 )cycloalkyl and (C C 10 )heterocyclyl may be optionally substituted on any of the ring carbon atoms capable of forming an additional
  • X is (C 5 -C ⁇ o)aryl or (C C ⁇ o)heteroaryl;
  • R 14 is hydrogen or (C ⁇ -C 4 )alkyl
  • Z is selected from the group consisting of (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C C 10 )heterocyclyl and (CrC ⁇ heteroaryl; wherein one or two carbon-carbon single bonds of said (C 3 -C 8 )cycloa!kyl or (C 1 -C 10 )heterocyclyl may optionally be replaced by carbon-carbon double bonds; wherein each of said X or Z may be independently optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents per ring independently selected from F, Cl, Br, CN, OH, (C 1 -C 4 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C C 4 )perfluoroalkoxy, (C 1 -C 4 )alkoxy and (C 3 -C 8 )cycloalkyloxy;
  • G is R 15 -(CR 16 R 17 ) P -; wherein G is a substituent on any ring carbon atom of Z capable of forming an additional bond and is oriented at a position other than alpha to the point of attachment of the Z ring to Y; p is an integer from 0 to 4;
  • R 15 is independently selected from the group consisting of halo, -CN, -N0 2 , OH, (C r C 4 )alkenyl, (C C 4 )alkynyl, (C 1 -C 4 )perfluoroalkyl, perfluoro(C C 4 )alkoxy, R 18 -, R 18 -0-, R 18 -(C
  • each of R and R is independently selected from hydrogen and (C C 4 )alkyl; or R 16 and R 17 may optionally be taken together with the carbon to which they are attached to form a 5 to 10-membered carbocyclic ring;
  • R 18 , R 19 , R 20 and R 21 are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C C 10 )heteroaryl and (C C 10 )heterocyclyl; wherein said (C 6 -C ⁇ 0 )aryl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )heteroaryl and (C-,- C 10 )heterocyclyl moieties may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents per ring independently selected from F, Cl, Br, CN, OH, (C C 4 )alkyl, (C ⁇ -C 4 )perfluoroalkyl, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 4 )
  • R 22 is selected from the group consisting of (C 1 -C )alkyl, (C 6 -C 10 )aryl, (C 3 - C 8 )cycloalkyl, (C r C ⁇ o)heteroaryl and (C r C ⁇ 0 )heterocyclyl; wherein said (C 6 -C 10 )aryl, (C 3 - C 8 )cycloalkyl, (C r C ⁇ 0 )heteroaryl and (C 1 -C 10 )heterocyclyl moieties may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents per ring independently selected from F, Cl, Br, CN, OH, (CrC 4 )alkyl, (C,- C 4 )perfluoroalkyl, (C 1 -C )perfluoroalkoxy, (C C 4 )alkoxy, amino, (C 1 -C 4
  • the present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I.
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maieate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, para-toluenesulfonate and pamoate [i.e., 1 ,1'-methylene-bis-(2-hydroxy-3- naphthoate)]salts.
  • the invention also relates to base addition salts of formula I.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water- soluble amine addition salts such as N-methylglucamine (meglumine) and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • a bond as used herein in the group Y, means that the groups X and Z are directly connected through a carbon-carbon bond so as to form pendent aryl rings such as diphenyl.
  • the dashed lines as used in each of the heterocyclic ring "A" of formulae a), b), c), g), h), i), k) and I) refer to optional double bonds.
  • the exact positions of the optional double bonds for each of the heterocyclic ring "A" of formulae a), b), c), g), h), i), k) and I) are as defined in the specification.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched moieties, or combinations thereof. Alkyl groups, wherever they occur, may be optionally substituted by a suitable substituent.
  • alkenyl as used herein, unless otherwise indicated, includes hydrocarbon radicals containing at least one olefin linkage and having straight, branched moieties, or combinations thereof.
  • alkynyl includes hydrocarbon radicals containing at least one carbon-carbon triple bond linkage and having straight, branched moieties or combinations thereof.
  • cycloalkyl includes a mono or bicyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.); optionally containing 1or 2 double bonds and optionally substituted by 1 to 3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C 1 -C 4 )alkoxy, (C 6
  • halo includes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one or more hydrogens, such as phe ⁇ yl or naphthyl, optionally substituted by 1 to 3 suitable substituents such as fluoro, chloro, cyano, nifro, trifluoromethyl, (CrC 6 )alkoxy, (C 6 -C 10 )aryloxy, (C 3 -C 8 )cycloalkyloxy, trifluoromethoxy, difluoromethoxy, or (C r C 6 )alkyl.
  • heteroaryl includes an organic radical derived from an aromatic heterocyclic compound by removal of one or more hydrogens, such as benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazoly), benzotbiopheny), benzoxazoiyl, chromanyl, cinnolinyi furazanyl, furopyridinyl, furyl, imidazolyl, i ⁇ daz ⁇ lyl, indolinyl, indolizinyl, indofyl, 3H- indolyl, isoindolyl, isoquinoiinyl, isothiazolyi, isoxazolyl, naphthyridinyl, oxadiazolyi, oxazolyl, phthalazinyl, pteridi ⁇ yl
  • heterocyclyl includes an organic radical derived from a non-aromatic heterocyclic compound by removal of one or more hydrogens, such as 3-azabicyc!o[3.1.0]hexa ⁇ yl, 3-azabicyclo[4.1.0]-heptanyl, azetidinyl, dihydrofuranyl, dihydropyra ⁇ yl, dihydrothienyl, dioxanyl, 1 ,3-dioxolanyI, 1,4-dithianyl, hexahydroazepinyl, hexahydropyrimidine, imidazolidiny), imidazolinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, pjperidinyl, 2H-pyranyl, 4H-pyra ⁇ yl, pyrazolidinyl, pyrazolinyl, pyrroli
  • piperidinyl can be piperidin-1-yl (N-attached) or piperidin-4- yl (C-attached).
  • the foregoing groups, as derived from the compounds listed above, can be optionally substituted where such is possible by a suitable substituent, such as oxo, F, Cl, Br, CN, OH, (C C 4 )alkyl, (C ⁇ -C 4 )perfluoroa.kyl (C C 4 )perfluoroa.koxy, (C C 4 )alkoxy, or (C 3 - C s )cycloalkyloxy.
  • a suitable substituent such as oxo, F, Cl, Br, CN, OH, (C C 4 )alkyl, (C ⁇ -C 4 )perfluoroa.kyl (C C 4 )perfluoroa.koxy, (C C 4 )alkoxy, or (C 3 - C s )cycloalkyloxy.
  • a suitable substituent is intended to mean a chemically and pharmaceutically acceptable functional group i.e., a moiety that does not negate the inhibitory activity of the inventive compounds.
  • suitable substituents may be routinely selected by those skilled in the art.
  • Illustrative examples of suitable substituents include, but are not limited to halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl or heteroaralkyl groups, aralkoxy or heteroaralkoxy groups, carboxy groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups dialkylamino carbonyl groups, arylcarbonyl groups, aryl
  • Some compounds of formula I contain chiral centers and therefore exist in different enantiomeric forms.
  • This invention relates to all optical isomers, enantiomers, diastereomers and stereoisomers of the compounds of formula I and mixtures thereof.
  • the compounds of the invention also exist in different tautomeric forms.
  • This invention relates to all tautomers of formula I.
  • Those skilled in the art are well aware that the pyrimidine-2,4,6-trione nucleus exists as a mixture of tautomers in solution.
  • the various ratios of the tautomers in solid and liquid form is dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a compound.
  • the heterocyclic ring "A" of the compounds of the formula I is selected from the formulae a) or b):
  • X is (C 6 -C 10 )aryl, preferably phenyl.
  • the heterocyclic ring "A” has the formulae a) or b), wherein X is (C 6 -C 10 )aryl, preferably phenyl.
  • the heterocyclic ring "A” has the formulae a) or b), wherein X is (C 6 -C 10 )aryl, preferably phenyl.
  • Y is selected from the group consisting of CH 2 [N(R 14 )]-, >NR 14 , -NR 14 (CH 2 ) n -, -S0 2 [N(R 14 )]- and -[N(R 14 )]-S0 2 -, wherein R 14 is hydrogen or methyl; and n is 1 or 2.
  • the heterocyclic ring "A” has the formulae a) or b), wherein X is (d-C ⁇ o)heteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pter
  • Y is a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - or -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • the heterocyclic ring "A” has the formulae a) or b), wherein X is (CrCioJheteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl,- furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyI, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, p
  • the heterocyclic ring "A” has the formulae a) or b), wherein X is (C C 10 )heteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteri
  • Y is selected from the group consisting of CH 2 [N(R 14 )]-, >NR 14 , -NR 14 (CH 2 ) n -, - S0 2 [N(R 14 )]- and -[N(R 14 )]-S0 2 -, wherein R 14 is hydrogen or methyl; and n is 1 or 2.
  • the heterocyclic ring "A” has the formula a), wherein X is (C ⁇ -C 10 )het-eroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridin
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • the heterocyclic ring "A” has the formula a), as defined in the aforesaid paragraph, wherein in the heterocyclic ring "A" the dashed line is a double bond.
  • the heterocyclic ring "A” has the formula b), wherein X is (d-CioJheteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyI, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridiny
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • the heterocyclic ring "A” has the formula b), as defined in the aforesaid paragraph, wherein in the heterocyclic ring "A" the dashed line is a double bond.
  • the heterocyclic ring "A” has the formula c):
  • X is (d-C ⁇ o)heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is selected from the group consisting of pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • the heterocyclic ring “A” has the formula c), wherein in the heterocyclic ring “A” the dashed line is a double bond, such that the heterocyclic ring “A” of formula c is selected from the group consisting of:
  • heterocyclic ring "A” has the formula d):
  • X is (d-C ⁇ o)heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur,
  • Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably
  • Y is oxygen
  • heterocyclic ring "A” has the formula e):
  • X is (C ⁇ -C 10 )heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • heterocyclic ring "A” has the formula f):
  • X is (d-C 10 )heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • heterocyclic ring "A” has the formula g):
  • X is (C 1 -C 10 )heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • the heterocyclic ring “A” has the formula g), as defined in the aforesaid paragraph, wherein in the heterocyclic ring “A” the dashed line is a double bond.
  • heterocyclic ring "A” has the formula h):
  • X is (C 1 -C 10 )heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • the heterocyclic ring “A” has the formula h), as defined in the aforesaid paragraph, wherein in the heterocyclic ring “A” the dashed line is a double bond.
  • the heterocyclic ring “A” has the formula i):
  • X is (d-C 10 )heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -0CH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • the heterocyclic ring “A” has the formula i), wherein in the heterocyclic ring “A” the dashed line is a double bond, such that the heterocyclic ring “A” of formula i) is selected from the group consisting of:
  • heterocyclic ring "A” has the formula selected from the group consisting of
  • X is (C ⁇ -C 10 )heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • heterocyclic ring "A” has the formula j):
  • X is (d-do)heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • heterocyclic ring "A” has the formula k):
  • X is (C 1 -C 10 )heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • the heterocyclic ring “A” has the formula k), as defined in the aforesaid paragraph, wherein in the heterocyclic ring “A” the dashed line is a double bond.
  • heterocyclic ring "A” has the formula I):
  • X is (CrC ⁇ o)heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • the heterocyclic ring “A” has the formula I), wherein in the heterocyclic ring “A” the dashed line is a double bond, such that the heterocyclic ring “A” of formula I is selected from the group consisting of:
  • heterocyclic ring "A” has the formula m):
  • X is (d-do)heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • heterocyclic ring "A” has the formula n):
  • X is (C C ⁇ 0 )heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • the heterocyclic ring "A" has the formula o):
  • X is (d-d heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.
  • Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • each of R 1 , R 2 , R 3 , R 4 , R 10 , R 11 , R 12 and R 13 is selected from the group consisting of hydrogen, (d-C 4 )alkyl, (d-C 4 )alkenyl, (d-djalkynyl, (C 6 -Ci 0 )aryl, (C 1 -C ⁇ 0 )heteroaryl, (C 3 -C 8 )cycloalkyl and (C C 10 )heterocyclyl; and wherein each of said (d-C 4 )alkyl, (C 6 -C ⁇ o)aryl, (C C 10 )heteroaryl, (C 3 -C 8 )cycloalkyl and (C r C 10 )heterocyclyl may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond with 1-3 substituents independently selected from halo, (C C )alkyi
  • a generic or sub-generic embodiment of each of the foregoing embodiments are those compounds wherein each of R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 is selected from the group consisting of hydrogen, (C C )alkyl, (C 6 -C ⁇ 0 )aryl, (d-C 10 )heteroaryl, and (C 3 -C 8 )cycloa!kyl.
  • a preferred generic or sub-generic embodiment is directed to those foregoing embodiments wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 is selected from hydrogen and (d-C 4 )alkyl, such as methyl.
  • each of R 5 , R 6 , R 7 and R 8 is selected from the group consisting of hydrogen, (d-C 4 )alkyl, (C ⁇ -d)alkenyl, (C C 4 )a
  • (C 3 -C 8 )cycloalkyl and (C 1 -C 1Q )heterocyclyl may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond with 1-3 substituents independently selected from halo, (d-C 4 )alkyl, (C C 4 )alkoxy, -CN, -OH and -NH 2 .
  • one or two of R 5 , R 6 , R 7 and R 8 is/are a group other than hydrogen.
  • R 9 is independently selected from hydrogen, (d-C 4 )alkyI, (C 6 -C 10 )ary
  • R 9 is independently selected from hydrogen and (C C 4 )alkyl, such as methyl.
  • Z is a (C 3 -C 8 )cycloalkyl or a (d- C 10 )heterocyclyl, selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, N-methyl-3-azetidinyl, piperazinyl, piperidinyl, 1 ,3-oxazolidin-4-on-5-yl, 1 ,3-oxazolidin-2,4-dion-5-yl, 4,5-dihydro-1 ,2-oxazolidin-3-on-4-yl, 1 ,3- thiazolidin-4-on-5-yl, 1 ,3-thiazolidin-2,4-dion-5-yl, 1 ,3-imidazolidin-4-on-5-yl, 1 ,3-imidazolidin-on-5-yl,
  • Z is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, N-methyl-3-azetidinyl, piperazinyl, piperidinyl, N-methylpiperidinyl and morpholinyl.
  • more preferably Z is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.
  • most preferably Z is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.
  • Z is a (C.-C ⁇ o)heteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H- indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyri
  • either X or Z is substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from F, Cl, Br, CN, OH, (C C 4 )alkyl, (C C 4 )perfluoroalkyl, (C C )perfluoroalkoxy, (C ⁇ -C 4 )alkoxy and (C 3 -C 8 )cycloalkyloxy.
  • both X and Z are substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from F, Cl, Br, CN, OH, (C C 4 )alkyl, (d-C ⁇ perfluoroalkyl, (d- C 4 )perfluoroalkoxy, (C 1 -C 4 )alkoxy and (C 3 -C 8 )cycloalkyloxy.
  • G is R 5 -(CR 16 R 17 ) P -; wherein p is 0; R 15 is selected from the group consisting of halo, -CN, and R 8 ; wherein said R 18 is selected from the group consisting hydrogen, (C ⁇ -C 4 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (d-dojheteroaryl and (d-dojheterocyclyl; wherein said (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (C C 10 )heteroaryl and (C C ⁇ o)heterocyclyl moieties may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents per ring independently selected from F, Cl, Br, CN, OH, (C C )alkyl, (C r C 4 )
  • (d-C 10 )heterocyclyl moieties may also optionally be substituted by oxo; wherein said (d-
  • G is R 15 -(CR 16 R 17 ) P -; wherein p is 1; R 15 is
  • each of R 16 or R 17 is independently hydrogen; and each of R 19 and R 20 is hydrogen or (C ⁇ -C 10 )heteroaryl, such as 2-oxazolyl, 2-pyrazolyl, or 3-pyrazolyl.
  • G is R 15 -(CR 16 R 7 ) P -; wherein p is 1 ; R 15 is
  • each of R 16 or R 17 is independently hydrogen; each of R 19 and R 20 is
  • R 23 is selected from the group consisting of hydrogen and (d- C 4 )alkyl.
  • G is R 15 -(CR 16 R 17 ) P -; wherein p is 1 ; R 15 is
  • each of R 16 and R 17 is independently hydrogen or (d-C 4 )alkyl; R 19 and R 21 are taken together with the nitrogen to which they are attached to form a 3 to 8 membered heterocyclic ring.
  • G is R 15 -(CR 16 R 17 ) P -; wherein p is 1 to 4, preferably 1 ; R 15 is selected from the group consisting of halo, -CN and R 18 ; each of R 16 and R 17 is independently hydrogen or (C C 4 )alkyl; said R 18 is selected from the group consisting of hydrogen, (C C 4 )alkyI, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (d-C 10 )heteroaryl and (C C ⁇ o)heterocyclyl; wherein said (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, (d-C 10 )heteroaryl and (d- C ⁇ o)heterocyclyl moieties may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents per ring independently selected from F, Cl,
  • G is R 15 -(CR 16 R 17 ) p wherein p is 1 to 4, preferably 1 ; R 15 is selected from the group consisting of R 18 ; each of R 16 and R 7 is independently hydrogen or (C C 4 )alkyl; wherein said R 18 is selected from the group consisting of hydrogen and (C r C 4 )alkyl.
  • G is R 15 -(CR 16 R 17 ) P -; wherein p is 0; and G is oriented at a position other than alpha to the point of attachment of the Z ring to Y.
  • G is R 5 -(CR 16 R 17 ) P -; wherein p is 0; and G is oriented at a position meta to the point of attachment of the Z ring to Y.
  • G is R 15 -(CR 16 R 7 ) P -; wherein p is 1 to 4, preferably 1 ; and G is oriented at a position other than alpha to the point of attachment of the Z ring to Y.
  • G is R 15 -(CR 16 R 17 ) P -; wherein p is 1 to 4, preferably 1 ; and G is oriented at a position meta to the point of attachment of the Z ring to Y.
  • R 11 , R 12 and R 13 is a group other than hydrogen.
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 is hydrogen.
  • either X or Z is not substituted by any optional substituents.
  • both X and Z are not substituted by any optional substituents.
  • G is R 15 -(CR 16 R 17 ) P -; wherein p is 0; R 15 is selected from the group consisting of halo, -CN and (C C ⁇ o)heteroaryl. More preferably, R 15 is bromo, fluoro, -CN or oxadiazolyl, preferably [1 ,3,4] oxadiazol-2-yl.
  • G is R 15 -(CR 16 R 17 ) P -; wherein p is 0 or 1 ; R 15 is R 18 ; each of R 16 and R 7 is hydrogen; and R 18 is independently hydrogen or (C C )alkyl; preferably methyl.
  • G is R 15 -(CR 16 R 17 ) P -; wherein p is 0 or 1 ; wherein G is oriented at a position para to the point of attachment of the Z ring to Y.
  • G is R 5 -(CR 16 R 17 ) P -; wherein p is 1 ;
  • R 19 is (C 1 -C 4 )alkyl, more preferably methyl, ethyl, or butyl; or (C 3 -C 8 )cycloalkyl, more preferably cyclobutyl; and R 21 is hydrogen.
  • G is R 15 -(CR 16 R 7 ) P -; wherein p is 1 ;
  • R 5 is (d-dojheteroaryl, such as 2-pyrazolyl; and wherein each of R 16 and R 17 is independently hydrogen.
  • heterocyclic ring "A” has the formula a) or b):
  • X is (d-C ⁇ o)heteroaryl selected from the group consisting of pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl; and Y is selected from the group consisting of a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - and -CH 2 0-; more preferably Y is oxygen, -OCH 2 - or -CH 2 0-; most preferably Y is oxygen.
  • X is (C,-C 10 )heteroaryl selected from the group consisting of pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl; most preferably wherein the pyridinyl together with the "A" ring and the group Y-Z-G has the formula:
  • Y is a bond, oxygen, sulfur, -CH 2 -, >S0 2 , -OCH 2 - or -CH 2 0-; preferably Y is oxygen, -OCH 2 - or -CH 2 0-; more preferably Y is oxygen.
  • Other preferred compounds of the invention include compounds of formula I, wherein the heterocyclic ring "A” has the formula a) or b), as defined above;
  • X is pyridinyl, most preferably wherein the pyridinyl together with the "A" ring and the group Y-Z-G has the formula a") or b") as defined above;
  • Y is oxygen;
  • Z is (C 6 -C 10 )aryl, preferably phenyl;
  • G is R 15 - (CR 16 R 17 ) P -; wherein p is 1;
  • R 15 is (d-C 10 )heteroaryl, such as 2-pyrazolyl; each of R 16 and R 17 is independently hydrogen or (d-C 4 )alkyl, such as methyl, preferably hydrogen; and wherein G is oriented at a position para to the point of attachment of the Z ring to Y.
  • Most preferred compounds of the invention include compounds of formula I, wherein the heterocyclic ring "A” has the formula a) or b), as defined above;
  • X is pyridinyl, most preferably wherein the pyridinyl together with the "A" ring and the group Y-Z-G has the formula a") or b") as defined above;
  • Y is oxygen;
  • Z is (C 6 -C 10 )aryl, preferably phenyl;
  • G is R 15 - (CR 16 R 17 ) P -; wherein p is 0;
  • R 15 is selected from the group consisting of hydrogen, -CN, halo and oxadiazolyl; and wherein G is oriented at a position para to the point of attachment of the Z ring to Y.
  • X is pyridinyl, most preferably wherein the pyridinyl together with the "A" ring and the group Y-Z-G has the formula a") or b") as defined above;
  • Y is oxygen;
  • Z is (C 6 -C 10 )aryl, preferably phenyl;
  • G is R 15 - (CR 6 R 7 ) P -; wherein p is 1 ;
  • R 19 is selected from the group consisting of (C C 4 )alkyl and (C 3 -C 8 )cycloalkyl, such as methyl, ethyl, propyl, butyl, or cyclobutyl;
  • R 21 is selected from the group consisting of hydrogen or (C C 4 )alky
  • Azetidine-1-carboxylic acid 4-[5-(2,7,9,11 -tetraoxo-1 ,8,10-triaza-spiro[5.5]undec-1-yl)- pyridin-2-y)oxy]-benzylamide; 1-[6-(4-Pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-1 ,8,10-triaza-spiro[5.5]undecane- 2,7,9,11-tetraone;
  • Azetidine-1-carboxylic acid 4-[5-(2,6,8,10-tetraoxo-1 ,3,7,9-tetraaza-spiro[4.5]dec-1-yl)- pyridin-2-yloxy]-benzylamide; 1-[6-(4-Pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-1 ,3,7,9-tetraaza-spiro[4.5]decane-
  • Azetidine-1-carboxylic acid 4-[5-(1, 1,3,6,8, 10-hexaoxo-1 ⁇ 6 -thia-2,4,7,9-tetraaza- spiro[4.5]dec-4-yl)-pyridin-2-yloxy]-benzylamide; 1,1-Dioxo-4-[6-(4-pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-1 ⁇ 6 -thia-2,4,7,9-tetraaza- spiro[4.5]decane-3,6,8,10-tetraone;
  • Azetidine-1-carboxylic acid 4-[5-(2,4,6,8,10-pentaoxo-1 ,3,7,9-tetraaza-spiro[4.5]dec-1- yl)-pyridin-2-yloxy]-benzylamide;
  • Azetidine-1-carboxylic acid 4-[5-(2,2,6,8,10-pentaoxo-2 ⁇ 6 -thia-1 ,7,9-triaza- spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-benzylamide; 2,2-Dioxo-1 -[6-(4-pyrazol-1 -ylmethyl-phenoxy)-pyridin-3-yl]-2 ⁇ 6 -thia-1 ,7,9-triaza- spiro[4.5]decane-6,8,10-trione;
  • Azetidine-1-carboxylic acid 4-[5-(6,8,10-trioxo-1 ,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin- 2-yloxy]-benzylamide;
  • Azetidine-1-carboxylic acid 4-[5-(2,6,8,10-tetraoxo-1 ,7,9-triaza-spiro[4.5Jdec-1-yl)- pyridin-2-yloxy]-benzylamide; and the pharmaceutically acceptable salts thereof.
  • Specific preferred compounds of formula I are selected from the group consisting of:
  • Cyclobutanecarboxylic acid 4-[5-(2,6,8,10-tetraoxo-1 ,7,9-triaza-spiro[4.5]dec-1-yl)- pyridin-2-yloxy]-benzylamide; 1 -[6-(4-Bromo-phenoxy)-pyridin-3-yI]-1 ,7,9-triaza-spiro[4.5]decane-2,6,8, 10-tetraone;
  • the present invention also relates to a pharmaceutical composition for the treatment of a condition selected from the group consisting of connective tissue disorders, inflammatory disorders, immunology/allergy disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system (CNS) disorders, liver/kidney diseases, reproductive health disorders, gastric disorders, skin disorders " and cancers and other diseases characterized by metalloproteinase activity in a mammal, including a human, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in such treatments and a pharmaceutically acceptable carrier.
  • a condition selected from the group consisting of connective tissue disorders, inflammatory disorders, immunology/allergy disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system (CNS) disorders, liver/kidney diseases, reproductive health disorders, gastric disorders, skin disorders " and cancers and other diseases characterized by metalloproteinase activity in a mammal, including a human, comprising an amount of a compound of formula
  • the present invention also relates to a pharmaceutical composition for the inhibition of matrix metalloproteinases or other metalloproteinases involved in matrix degradation, in a mammal, including a human, comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a method for treating a condition selected from the group consisting of connective tissue disorders, inflammatory disorders, immunology/allergy disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system (CNS) disorders, liver/kidney diseases, reproductive health disorders, gastric disorders, skin disorders and cancers and other diseases characterized by matrix metalloproteinase activity in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in treating such a condition.
  • a condition selected from the group consisting of connective tissue disorders, inflammatory disorders, immunology/allergy disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system (CNS) disorders, liver/kidney diseases, reproductive health disorders, gastric disorders, skin disorders and cancers and other diseases characterized by matrix metalloproteinase activity in a mammal, including a human, comprising administering to said mammal an
  • the present invention also relates to a method for the inhibition of matrix metalloproteinases or other metalloproteinases involved in matrix degradation, in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • inhibitors of formula I with differential metalloprotease activity preferably MMP-13 inhibitory activity.
  • One group of preferred inhibitors of formula I the inventors have been able to identify include those which selectively inhibit MMP-13 preferentially over MMP-1.
  • the compounds of the invention also possess selectivity over a related group of enzymes known as reprolysins, such as TACE and aggrecanase.
  • Another group of preferred inhibitors of formula I the inventors have been able to identify include those which selectively inhibit MMP-13 preferentially over MMP-1 and MMP-14.
  • Another group of preferred inhibitors of formula I the inventors have been able to identify include those which selectively inhibit MMP-13 preferentially over MMP-1 and 12.
  • Another group of preferred inhibitors of formula I the inventors have been able to identify include those which selectively inhibit MMP-13 preferentially over MMP-1 , 12 and 14.
  • Another group of preferred inhibitors of formula I the inventors have been able to identify include those which selectively inhibit MMP-13 preferentially over MMP-1 , 2, 3, 7, 9 and 14.
  • Most preferred compounds of the invention selectively inhibit MMP-13 preferentially over MMP-1 , 2, 3, 7, 9, 12 and 14 and mammalian reprolysins.
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • Connective tissue disorders refers to disorders such as degenerative cartilage loss following traumatic joint injury, osteoarthritis, osteoporosis, Paget's disease, loosening of artificial joint implants, periodontal disease and gingivitis.
  • Destruction of articular cartilage refers to connective tissue disorders resulting in articular cartilage destruction, preferably joint injury, reactive arthritis, acute pyrophosphate arthritis (pseudogout), psoriatic arthritis, or juvenile rheumatoid arthritis, more preferably osteoarthritis.
  • Inflammatory disorders refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease and cachexia.
  • Immunology/allergy disorders refers to disorders such as organ transplant toxicity, allergic reactions, allergic contact hypersensitivity, autoimmune disorders such as those disorders associated with granulomatous inflammation/tissue remodeling (such as asthma), immunosuppression and sarcoid.
  • autoimmune disorders such as those disorders associated with granulomatous inflammation/tissue remodeling (such as asthma), immunosuppression and sarcoid.
  • infectious diseases including those mediated by viruses, bacteria, fungi or mycobacterial infection, as used herein refers to disorders such as septic arthritis, AIDS, fever; Prion diseases, myasthenia gravis, Malaria, sepsis, hemodynamic shock and septic shock.
  • Respiratory diseases refers to disorders such as chronic obstructive pulmonary disease (including emphysema), acute respiratory distress syndrome, asthma, hyperoxic alveolar injury and idiopathic pulmonary fibrosis and other fibrotic lung diseases.
  • Cardiovascular diseases refers to disorders such as atherosclerosis including atherosclerotic plaque rupture; aortic aneurysm including abdominal aortic aneurysm and brain aortic aneurysm; congestive heart failure; myocardial and cerebral infarction; stroke; cerebral ischemia; coagulation and acute phase response; left ventricular dilation; post ischemic reperfusion injury; angiofibromas; hemangiomas; and restenosis.
  • Eye diseases refers to disorders such as aberrant angiogenesis, ocular angiogenesis, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, corneal graft rejection, corneal injury, neovascular glaucoma, corneal ulceration, corneal scarring, macular degeneration (including “Age Related Macular Degeneration (ARMD) including both wet and dry forms), proliferative vitreoretinopathy and retinopathy of prematurity.
  • ARMD Age Related Macular Degeneration
  • Methodabolic diseases refers to disorders such as diabetes (including non-insulin dependent diabetes mellitus, diabetic retinopathy, insulin resistance, diabetic ulceration).
  • Central Nervous System CNS disorders as used herein refers to disorders such as head trauma, spinal cord injury, Inflammatory diseases of the central nervous system, neuro- degenerative disorders (acute and chronic), Alzheimer's disease, demyelinating diseases of the nervous system, Huntington's disease, Parkinson's disease, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, migraine, depression and anorexia.
  • Liver/Kidney diseases refers to disorders such as nephrotic syndromes such as glomerulonephritis and glomerular disease of the kidney, proteinuria, cirrhosis of the liver and interstitial nephritis.
  • Reproductive Health disorders refers to disorders such as endometriosis, contraception (male/female), dysmenorrhea, dysfunctional uterine bleeding, premature rupture of fetal membranes and abortifactant.
  • Gastric disorders refers to disorders such as coionic anastomosis and gastric ulcers.
  • Skin disorders refers to disorders such as skin aging, pressure sores, psoriasis, eczema, dermatitis, radiation damage, tissue ulceration, decubital ulcers, epidermolysis bullosa, abnormal wound healing (topical and oral formulations), burns and scleritis.
  • Cancers refers to disorders such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostrate cancer, tumor invasion, tumor growth tumor metastasis, cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skin, cervix uteri, corpus endometrium, ovary, testis, bladder, kidney and other urinary tissues, eye brain and central nervous system, thyroid and other endocrine gland, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma and hematopoietic malignancies including leukemias and lymphomas including lymphocytic, granulocytic and monocytic.
  • pharynx lip, tongue, mouth, pharynx
  • esophagus stomach
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • compositions of the present invention prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 1 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • Isotopically- labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically-labelled reagent for a non-isotopically-labelled reagent.
  • This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the formula I.
  • This invention also encompasses methods of treating or preventing disorders that can be treated or prevented by the inhibition of matrix metalloproteinases or the inhibition of mammalian reprolysin comprising administering prodrugs of compounds of the formula I.
  • Compounds of formula I having free amino, amido, hydroxy, sulfonamide or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amido, amino, hydroxy or carboxylic acid groups of compounds of formula I.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4- hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters, which are covalentiy, bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain.
  • Prodrugs also include dimers of compounds of formula I.
  • the compounds of the invention are useful in treating a diverse array of diseases.
  • One of ordinary skill in the art will also appreciate that when using the compounds of the invention in the treatment of a specific disease that the compounds of the invention may be combined with various existing therapeutic agents used for that disease.
  • the compounds of the invention may be combined with agents such as TNF- inhibitors such as anti-TNF monoclonal antibodies (such as infliximab, D2E7 and CDP-870) and TNF receptor immunoglobulin molecules (such as etanercept), ICE inhibitors, MEKK1 inhibitors, COX-2 inhibitors such as celecoxib, rofecoxib, valdecoxib and etoricoxib; low dose methotrexate, lefunimide, steroids, glucosamines, chondrosamines/ sulfates, gabapentin, A-agonists, IL-1 process and release inhibitors, IL-1 receptor antagonists such as Kineret®, CCR-1 antagonists, hydroxychloroquine, d-penicilamine, auranofin or parenteral or oral gold.
  • TNF- inhibitors such as anti-TNF monoclonal antibodies (such as infliximab, D2E7 and CDP-870)
  • Suitable agents to be used in combination include standard non-steroidal anti-inflammatory agents (hereinafter NSAlD's) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib, valdecoxib, paracoxib, etoricoxib and rofecoxib, analgesics, steroids, glucosamines, chondrosamines/ sulfates, gabapentin, A-agonists, IL-1 process and release inhibitors, CCR-1 antagonists, LTD-4, L
  • NSAlD's standard non-steroidal anti-inflammatory agents
  • piroxicam
  • the compounds of the present invention may also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, paclitaxel, docetaxel and alkaloids, such as vincristine and antimetabolites such as methotrexate.
  • anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, paclitaxel, docetaxel and alkaloids, such as vincristine and antimetabolites such as methotrexate.
  • the compounds of the present invention may also be used in combination with cardiovascular agents such as calcium channel blockers (such as amlodipine and nifedipine), lipid lowering agents such as statins (such as lovastatin, atorvastatin, pravastatin and simvastatin), adrenergics such as doxazosin and terazosin; fibrates, beta-blockers, Ace inhibitors (such as captopril, lisinopril, fosinopril, enalapril and quinaprill), Angiotensin-2 receptor antagonists such as losartan and irbesartan; nitrates, CCB's, diuretics such as digitalis and platelet aggregation inhibitors.
  • cardiovascular agents such as calcium channel blockers (such as amlodipine and nifedipine), lipid lowering agents such as statins (such as lovastatin, atorvastatin, pravastatin and simva
  • the compounds of the present invention may also be used in combination with plaque rupture preventitive agents such as statins, zithromax, NSAIDs including aspirin, heparin, urarfarin, abciximab, TPA and platelet Inhibitors.
  • plaque rupture preventitive agents such as statins, zithromax, NSAIDs including aspirin, heparin, urarfarin, abciximab, TPA and platelet Inhibitors.
  • the compounds of the present invention may also be used in combination with stroke treatment agents such as NIF, NHEI's and CCRIR antagonists.
  • the compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as deprenyl, carbadopa, L-dopa, dopamine receptor agonists such as ropinirole, pergolide and pramipexole; MAOB inhibitors such as selegiline and rasagiline, catechol-O-methyltrasferase inhibitors such as tolcapone, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, NK-1 inhibitors, dopamine agonists and inhibitors of neuron-:.! nitric oxide synthase) and anti-Alzheimer's drugs such as do ⁇ epezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate,
  • CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as depreny
  • the compounds of the present invention may also be used in combination with osteoporosis agents such as roloxifene, droloxifene, iasofoxifene or fosomax and immunosuppressant agents such as FK-506 and rapamycin.
  • osteoporosis agents such as roloxifene, droloxifene, iasofoxifene or fosomax
  • immunosuppressant agents such as FK-506 and rapamycin.
  • the compounds of the present invention may also be used in combination with agents for the treatment of respiratory diseases such as PDE-IV inhibitors, steroidals such as fluticasone, triamcinolone, budesonide, budesonide and beclomethasone, anticholinergics such as ipratropium, sympathomimetics such as saimeterol, albuterol and Xopenex, decongestants such as fexofenadine, loratadine and cetirizine; leukotriene antagonists such as zafirlukast and motelukast; and mast cell stabilizers such as zileuton.
  • respiratory diseases such as PDE-IV inhibitors, steroidals such as fluticasone, triamcinolone, budesonide, budesonide and beclomethasone, anticholinergics such as ipratropium, sympathomimetics such as saimeterol, albuterol and Xopenex, decongestant
  • the compounds of the present invention may also be used in combination with agents for the treatment of skin disorders such as tretinoin, isotretinoin, steroids such as cortisone and mometasone, antibiotics such as tetracycline, antifungals such as clotrimazole, miconazole and fluconazole and PDE-IV inhibitors.
  • agents for the treatment of skin disorders such as tretinoin, isotretinoin, steroids such as cortisone and mometasone, antibiotics such as tetracycline, antifungals such as clotrimazole, miconazole and fluconazole and PDE-IV inhibitors.
  • the compounds of the present invention may also be used in combination with agents for the treatment of diabetes such as insulin, including human or humanized insulin and inhaled insulin, aldose reductase inhibitors, sorbitol dehydrogenase inhibitors, antidiabetic agents such as biguanides such as metformin; glitazones, glycosidase inhibitors such as acarbose, sulfonylureas such as glimepiride and glipizide; and thiazolidinediones such as pioglitazone, rosiglitazone and trogliazone.
  • Preferred combinations are useful for treating the side effects of diabetes such as retinopathy, nephropathy and neuropathy, preferably retinopathy.
  • Scheme 1 refers to the preparation of compounds of the formula I.
  • L 1 and L 2 are leaving groups such as alkoxy, preferably methoxy, ethoxy or benzyloxy, more preferably methoxy or ethoxy, with a urea of formula II (i.e., H 2 N-(CO)-NH 2 ) in the presence of a suitable base in a polar solvent.
  • Suitable bases include alkoxide bases, such as sodium methoxide, sodium ethoxide, or potassium terf-butoxide, preferably sodium ethoxide.
  • Suitable solvents include tetrahydrofuran, dimethylformamide, or alcohols (such as ethanol), preferably tetrahydrofuran or dimethylformamide.
  • the aforesaid reaction is conducted at a temperature of about 20°C to about 90°C, preferably about 50°C to about 80°C, for a time period of about 5 minutes to about 8 hours.
  • a compound of formulae llla-llll, respectively, can be prepared by reacting a compound of formulae IVa-IVI, respectively:
  • L 1 and L 2 are leaving groups such as alkoxy, preferably methoxy, ethoxy or benzyloxy, more preferably methoxy or ethoxy and wherein L 3 is a suitable leaving group, such as halo, para-tolylsulfonyloxy (OTs), or methylsulfonyloxy (OMs), preferably halo, such as bromo or iodo, with a suitable base in a polar solvent.
  • Suitable bases include tertiary amines, .such as triethylamine.
  • Other suitable bases include a strongly basic macro-reticular resin or gel type resin, such as Amberlyst 400 ® resin (hydroxide form).
  • Suitable solvents include alcoholic solvents, preferably ethanol.
  • the aforesaid reaction can be conducted at a temperature of about -10 °C to about 50 °C, preferably about 20 °C, for a period of about 6 to about 36 hours.
  • a compound of formulae lllm-llln, respectively, can be prepared by reacting a compound of formulae IVm-IVn, respectively:
  • L is a suitable leaving group, with a suitable base in a polar solvent according to methods analogous to the preparation of the compounds of formulae llla-llli in the foregoing paragraph.
  • Suitable leaving groups of the formula L 3 include halo, para-tolylsulfonyloxy (OTs), or methylsulfonyloxy (OMs).
  • OTs para-tolylsulfonyloxy
  • OMs methylsulfonyloxy
  • L 3 is halo, such as chloro.
  • the aforesaid reaction can be conducted at a temperature of about 0°C to about 50°C, preferably about 20 °C, for a period of about 1 hour to about 4 hours.
  • Suitable solvents include tetrahydrofuran, dimethylformamide and alcohol.
  • a compound of formulae IVa-IVi, respectively, can be prepared by reacting a compound of formula VI with a compound of general formula
  • each of L 3 and L 4 is a suitable leaving group, such as halo, para-tolylsulfonyloxy (OTs), or methylsulfonyloxy (OMs).
  • L 3 is halo, such as bromo, chloro or iodo.
  • L 4 is chloro or fluoro.
  • the aforementioned reaction may be conducted in the presence of a tertiary amine base, such as ⁇ /, ⁇ /-dimethylaniline or pyridine, in the presence of a suitable solvent, such as a hydrocarbon solvent (benzene or toluene), tetrahydrofuran or methylene chloride.
  • the aforementioned reaction is conducted at a temperature of about 20°C to about 90°C, preferably about 50°C to about 80°C, for a time period of about 30 minutes to about 6 hours.
  • the aforementioned reaction is conducted in an aromatic hydrocarbon solvent, such as benzene or toluene, in the absence of the aforementioned base.
  • aromatic hydrocarbon solvent such as benzene or toluene
  • a compound of formulae IVj-IVI, respectively, can be prepared by reacting a compound of formula VI with a compound of formula:
  • each of L 3 and L 4 is a suitable leaving group, such as halo, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs), according to the methods analogous to those described in the preparation of the compounds of formulae IVa-IVi in the foregoing paragraph.
  • L 3 is chloro, bromo, or iodo.
  • L 4 is chloro, bromo, or iodo.
  • the aforesaid reaction can be conducted at a temperature of about 0°C to about 50°C, preferably about 20°C, for a time period of about 30 minutes to about 12 hours.
  • each of L 3 and L 4 is a suitable leaving group, such as halo, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs), according to the methods analogous to those described in the preparation of the compounds of formulae IVa-IVi in the foregoing paragraph.
  • L 3 is halo, such as chloro.
  • L 4 is halo, such as chloro.
  • the aforesaid reaction can be conducted at a temperature of about 0°C to about 80°C, preferably about 0°C to about 40°C, for a time period of about 30 minutes to about 8 hours.
  • compounds of formulae IVd, IVe and IVf, respectively, can be prepared by reacting a compound of formula VI with a compound of formula
  • L 3 is preferably halo, most preferably chloro, bromo, or iodo.
  • the aforementioned reaction can be conducted in the presence of a tertiary amine base in a suitable solvent.
  • Suitable bases include ⁇ /,/V-dimethylaniline or pyridine.
  • Suitable solvents include hydrocarbon solvent (benzene or toluene), tetrahydrofuran, or methylene chloride, preferably aromatic hydrocarbon solvent, such as benzene or toluene.
  • the aforementioned reaction is conducted at a temperature of about 20°C to about 90°C, preferably about 50°C to about 80°C, for a time period of about 30 minutes to about 6 hours.
  • the aforementioned reaction is conducted in the absence of any aforementioned base.
  • compounds of formulae IVm and IVn, respectively, can be prepared by reacting a compound of formula VI with a compound of formula
  • L is preferably halo, most preferably chloro.
  • the aforementioned reaction can be conducted optionally in the presence of a tertiary amine base in a suitable solvent.
  • Suitable bases include ⁇ /,/V-dimethylaniline or pyridine.
  • Suitable solvents include a hydrocarbon solvent (benzene or toluene), tetrahydrofuran or methylene chloride, preferably aromatic hydrocarbon solvent, such as benzene or toluene.
  • the aforesaid reaction can be conducted at a temperature of about -10°C to about 50°C, preferably about 0°C to about 30°C, for a time period of about 30 minutes to about 12 hours.
  • the aforementioned reaction is conducted in the absence of any aforementioned base.
  • a compound of formula VI can be prepared by reacting a compound of formula H 2 N-
  • L 1 and L 2 are leaving groups, such as methoxy, ethoxy, or benzyloxy; preferably ethoxy; and L 5 is a leaving group, such as halo, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs); preferably halo; most preferably chloro or bromo.
  • OTs para-tolylsulfonyloxy
  • OMs methylsulfonyloxy
  • OMs methylsulfonyloxy
  • the aforesaid reaction can be performed either neat or in the presence of a suitable solvent, preferably neat, in the presence of a suitable base.
  • Suitable solvents include tetrahydrofuran or dimethylformamide.
  • Suitable bases include a weak tertiary amine base, preferably tertiary aniline bases, most preferably N,N-dimethylaniline.
  • the aforementioned reaction is conducted at a temperature of about 23°C to about 100°C, preferably about 50°C to about 90°C, for a time period of about 30 minutes to about 24 hours.
  • each of the compounds of formulae IVj-IVI may be isolated, but are preferably carried on to the next step without isolation.
  • the compound of formulae lllj-llll is preferably prepared in a one pot preparation from a compound of the formula VI.
  • the suitable solvent for the one-pot preparation is dimethylformamide, tetrahydrofuran, or alcohols, preferably alcohols, such as ethanol.
  • the one-pot preparation is conducted in the presence of an alkoxide base, preferably sodium methoxide or sodium ethoxide.
  • the aforesaid one pot preparation is conducted at a temperature of about 40°C to about 90°C, preferably about 60°C to about 80°C, for a time period of about 15 minutes to about 12 hours.
  • the compounds of formula H 2 N-X- Y-Z-G are commercially available or can be made by methods well known to those skilled in the art. Alternatively, the compounds of formula H 2 N-X- Y-Z-G can be prepared as described i ⁇ Scheme 3.
  • a compound of the formula VII can be made by methods well known in the art such as those described in PCT Patent Publication WO 98/58925 or reviewed in The Organic
  • Scheme 2 refers to the preparation of a compound of the formula I, wherein the heterocyclic ring "A" has the formula o, i.e., a compound of formula lo.
  • a compound of formula lo: lo can be prepared by reacting a compound of the formula lllo, wherein L 1 and L 2 are leaving groups, with a urea of formula II (i.e., H 2 N-(CO)-NH 2 ) in the presence of a suitable base in a polar solvent.
  • Suitable leaving groups include methoxy, ethoxy, or benzyloxy, preferably ethoxy.
  • Suitable bases include alkoxide bases, such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, preferably sodium ethoxide.
  • Suitable solvents include tetrahydrofuran, dimethylformamide, or alcohols (such as ethanol), preferably tetrahydrofuran or dimethylformamide. The aforesaid reaction is conducted at a temperature of about 20°C to about 90°C, preferably about 50°C to about 80°C, for a time period of about 5 minutes to about 8 hours.
  • a compound of formula lllo can be prepared by reacting a compound of formula IVo, wherein L 3 is a leaving group, with a suitable base in a polar solvent.
  • Suitable leaving groups include alkoxy (such as methoxy, ethoxy, or benzyloxy) or halo; preferably methoxy or ethoxy.
  • Suitable bases include alkoxide bases, preferably sodium methoxide or sodium ethoxide.
  • Suitable solvents include alcohols, preferably ethanol. The aforesaid reaction can be conducted at a temperature of about 0 °C to about 90 °C, preferably of about 60 °C to about 90 °C, for a period of about 1 hour to about 36 hours.
  • a compound of formula IVo can be prepared by reacting a compound of formula VI with the compound of formula Vo:
  • L 6 is a suitable leaving group, in a suitable solvent.
  • Suitable L 6 includes alkoxy or halo, such as chloro; preferably alkoxy; more preferably methoxy or ethoxy.
  • the aforesaid reaction may be conducted in the presence of a suitable tertiary amine base, such as triethylamine, ⁇ /, ⁇ /-dimethylaniline, or pyridine.
  • Suitable solvents include hydrocarbon solvents (benzene or toluene), tetrahydrofuran, or methylene chloride, preferably tetrahydrofuran.
  • the aforementioned reaction is conducted in tetrahydrofuran or dimethylformamide, in the presence of the aforementioned suitable tertiary amine base.
  • the aforesaid reaction may be conducted at a temperature of about 20°C to about 90°C, preferably about 50°C to about 80°C, for a time period of about 30 minutes to about 6 hours.
  • a compound of formula IVo may be isolated, but is preferably carried on to the next step without isolation.
  • a compound of formula lllo is preferably prepared in a one-pot preparation from a compound of the formula VI.
  • the suitable solvent for the one- pot preparation is dimethylformamide, tetrahydrofuran, or alcohols, preferably alcohol, such as ethanol.
  • the aforesaid one pot preparation is suitably conducted at a temperature of about O°C to about 70°C, preferably about 23°C to about 60°C, for a time period of about 30 minutes to about 24 hours.
  • a compound of formula VI can prepared by reacting a compound of formula H 2 N-X-Y-
  • Scheme 3 refers to the preparation of compounds of the formula H 2 N-X- Y-Z-G, which are intermediates useful in the preparation of compounds of formula I in Schemes 1 and 2.
  • compounds of formula H 2 N-X- Y-Z-G can be prepared by reacting a compound of formula VIII with a reducing agent, such as tin II chloride, in the presence of a suitable acid, such as hydrochloric acid, in a polar protic solvent.
  • Suitable solvents include an alcoholic solvent, water, or mixtures thereof, preferably a mixture of ethanol and water. The aforesaid reaction can be conducted at a temperature of about 40°C to about 100°C for a period of about 1 to about 12 hours.
  • the compounds of formula H 2 N-X- Y-Z-G can be prepared by reacting a compound of formula VIII with hydrogen gas, at a pressure between atmospheric pressure and 50 psi, in the presence of a catalyst and a polar solvent.
  • Suitable catalysts include a palladium or platinum catalyst, preferably Adams catalyst (i.e., platinum oxide), or palladium adsorbed on charcoal.
  • Suitable solvents include an alcoholic solvent, preferably methanol. The aforesaid reaction can be conducted at a temperature of about 20°C to about 50°C, preferably about 23°C, for a period of about 30 minutes to about 6 hours.
  • a compound of the formula VIII, wherein Y is oxygen, sulfur, -CH 2 S-, -CH 2 0-, >NR 14 , -CH 2 [N(R 14 )]- or -S0 2 [N(R 14 )]- can be prepared by reacting a compound of formula X, wherein the group L 7 is fluoro or chloro, with a compound of the formula: G-Z-Y-H (IX) wherein Y is oxygen, sulfur, -CH 2 S-, -CH 2 0-, >NR 14 , -CH 2 [N(R 14 )]- or -S0 2 [N(R 14 )]-, in the presence of a base in a polar aprotic solvent.
  • Suitable bases include an alkali metal hydride base; preferably sodium hydride.
  • Suitable solvents include dimethylformamide, tetrahydrofuran or 1 ,2-dimethoxyethane; preferably dimethylformamide. The aforesaid reaction can be conducted at a temperature of about 40°C to about 140°C, preferably about 80°C to about 120°C, for about 1 hour to about 24 hours.
  • the aforesaid compound of formula VIII wherein Y is oxygen, sulfur, -CH 2 S-, -CH 2 0-, >NR 14 , -CH 2 [N(R 14 )]- or -S0 2 [N(R 14 )]-, can be prepared in presence of an alkali metal hydroxide base, preferably potassium hydroxide, optionally in the presence of a phase transfer catalyst, such as a quaternary ammonium or phosphonium salt, preferably tetrabutyiammonium bromide, in an aromatic hydrocarbon solvent.
  • a phase transfer catalyst such as a quaternary ammonium or phosphonium salt, preferably tetrabutyiammonium bromide
  • the solvent is benzene or toluene.
  • the aforesaid reaction can be conducted at a temperature of about 0°C to about 120°C, preferably at about 23°C, for about 1 hour to about 12 hours.
  • the aforesaid compound of formula VIII wherein Y is oxygen, sulfur, -CH 2 S-, -CH 2 0-, >NR 14 , -CH 2 [N(R 14 )]- or -S0 2 [N(R 14 )]-, can be prepared under so called "Ulman coupling" conditions. Under such conditions, the aforesaid compound of formula VIII can be prepared by reacting a compound of formula X, wherein the group L 7 is bromo or chloro, with a compound of the formula:
  • G-Z-Y-H (IX) wherein Y is oxygen, sulfur, -CH 2 S-, -CH 2 0-, >NR 14 , -CH 2 [N(R 14 )]- or -S0 2 [N(R 14 )]-, in the presence of a base and a catalyst in a polar aprotic solvent.
  • Suitable bases include an alkali metal carbonate or hydroxide base, preferably potassium carbonate.
  • Suitable catalysts include a copper (0) catalyst, preferably finely powdered copper bronze.
  • Suitable solvents include dimethylformamide or 1-methyl-2-pyrrolidinone. The aforesaid reaction can be conducted at a temperature of about 80 °C to about 140 °C, for about 6 hours to about 24 hours.
  • the corresponding lower oxidation state for each compound of formula VIII, wherein the group Y is -CH 2 S0 2 - and -CH 2 SO- is a compound of formula VIII, wherein the group Y is -CH 2 S-.
  • the corresponding lower oxidation state for each compound of formula VIII, wherein the group Y is -S0 2 (CH 2 ) n - and -SO(CH 2 ) n - is a compound of formula VIII, wherein the group Y is -S-(CH 2 ) literal-.
  • Suitable oxidizing agents include a peroxy acid, preferably peracetic acid, or an organic peroxide, preferably m- chloroperoxybenzoic acid or ferf-butyl hydroperoxide.
  • Suitable solvents include methylene chloride or alcohol, such as ethanol. The aforesaid reaction can be conducted at a temperature of about -10°C to about 30°C, for about 1 hour to about 8 hours.
  • a compound of the formula VIII, wherein Y is -0(CH 2 ) n -, -S(CH 2 ) n - or -NR 14 (CH 2 ) n -, respectively, can be prepared by reacting a compound of the formula X, wherein the group L 7 is L 8 -(CH 2 ) n - and wherein the group L 8 is halo, such as chloro, bromo, iodo, mesyloxy (MsO), or tosyloxy (TsO), with a compound of formula:
  • Suitable bases include an alkali metal carbonate base, preferably potassium carbonate or cesium carbonate.
  • Suitable solvents include dimethylformamide or tetrahydrofuran. The aforesaid reaction can be conducted at a temperature of about 23°C to about 80°C, preferably about 20°C to about 50°C, for about 1 to about 24 hours.
  • Suitable catalysts include a palladium or nickel catalyst, preferably tetrakis triphenyl phosphine palludium (0) (Pd(PPh 3 ) ).
  • Suitable solvents include toluene, tetrahydrofuran, dimethylformamide, or dimethylsulfoxide.
  • the aforesaid reaction can be conducted at a temperature of about 23°C to about 110°C, for a period of about 1 hour to about 24 hours.
  • Such reactions can be facilitated by the presence of a copper salt, such as cuprous iodide or cuprous bromide.
  • a compound of the formula VIII, wherein Y is -C ⁇ C- can be prepared by reacting a compound of formula X, wherein L 7 is halo or triflate, preferably bromo or iodo, with a compound of the formula: G-Z-Y-H (IX) in the presence of a base, such as a trialkylamine base, preferably triethylamine and a palladium catalyst, preferably Pd(PPh 3 ) 4 in a solvent.
  • Suitable solvents include tetrahydrofuran or dimethylformamide.
  • the aforesaid reaction can be conducted at a temperature of about 23°C to about 60°C for a period of about 1 to about 24 hours.
  • a palladium catalyst is palladium adsorbed on charcoal.
  • Suitable solvents include methanol or ethyl acetate.
  • the aforesaid reaction can be conducted at a temperature of about 20°C to about 50°C, for about 1 hour to about 24 hours.
  • the compounds of the formula I which are basic in nature, are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1 ,1'-methylene-bis-(2-hydroxy-3- naphthoafe)] salts.
  • non-toxic acid addition salts i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid
  • Those compounds of the formula I which are also acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations.
  • such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I.
  • These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc.
  • These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • these salts may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields.
  • BIOLOGICAL ASSAYS The ability of the compounds of formula I or their pharmaceutically acceptable salts (hereinafter also referred to as the compounds of the present invention) to inhibit metalloproteinases or mammalian reprolysins and, consequently, demonstrate their effectiveness for treating diseases characterized by metalloproteinase activity is shown by the following in vitro and in vivo assay tests. MMP Assays
  • MMP-13 selective inhibitors can be identified by screening the inhibitors of the present invention through the MMP fluorescence assays described below and selecting those agents with MMP-13/MMP-X inhibition IC 50 ratios of 100 or greater and potency of less than 100 nM, where MMP-X refers to one or more other MMP's.
  • Non-selective collagenase inhibitors refer to agents which exhibit less than a 100 fold selectivity for the inhibition of MMP-13 enzyme activity over MMP-X enzyme activity or a potency of more than 100nM as defined by the IC 50 results from the MMP-13/MMP-X fluorescence assays described below.
  • the ability of collagenase inhibitors to inhibit collagenase activity is well known in the art.
  • MMP-1 Human Collagenase
  • Human recombinant collagenase is activated with trypsin.
  • the amount of trypsin is optimized for each lot of collagenase-1 but a typical reaction uses the following ratio: 5 ⁇ g trypsin per 100 ⁇ g of collagenase.
  • the trypsin and collagenase are incubated at room temperature for 10 minutes then a five fold excess (50 mg/10 mg trypsin) of soybean trypsin inhibitor is added.
  • Stock solutions (10 mM) of inhibitors are made up in dimethylsulfoxide and then diluted using the following scheme:
  • Collagenase-1 is diluted to 240 ng/ml and 25 ⁇ l is then added to appropriate wells of the microfluor plate. Final concentration of collagenase in the assay is 60 ng/ml.
  • Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH 2 ) is made as a 5 mM stock in dimethylsulfoxide and then diluted to 20 ⁇ M in assay buffer. The assay is initiated by the addition of 50 ⁇ l substrate per well of the microfluor plate to give a final concentration of 10 ⁇ M.
  • Fluorescence readings (360 nM excitation, 460 nm emission) are taken at time 0 and then at 20 minute intervals.
  • the assay is conducted at room temperature with a typical assay time of 3 hours Fluorescence versus time is then plotted for both the blank and collagenase containing samples (data from triplicate determinations is averaged).
  • a time point that provides a good signal (at least five fold over the blank) and that is on a linear part of the curve (usually around 120 minutes) is chosen to determine IC 50 values.
  • the zero time is used as a blank for each compound at each concentration and these values are subtracted from the 120 minute data.
  • Data is plotted as inhibitor concentration versus % control (inhibitor fluorescence divided by fluorescence of collagenase alone x 100). ICso's are determined from the concentration of inhibitor that gives a signal that is 50% of the control.
  • IC 50 S are reported to be less than 0.03 ⁇ M then the inhibitors are assayed at concentrations of 0.3 ⁇ M, 0.03 ⁇ M and 0.003 ⁇ M.
  • MMP-2 Human recombinant 72 kD gelatinase (MMP-2, gelatinase A) is activated for 16-18 hours with 1 mM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM stock in 0.2 N NaOH) at 4°C, rocking gently.
  • 10 mM dimethylsulfoxide stock solutions of inhibitors are diluted serially in assay buffer (50 mM TRIS, pH 7.5, 200 mM NaCI, 5 mM CaCI 2, 20 ⁇ M ZnCI 2 and 0.02% BRIJ-35 (voL/vol.)) using the following scheme: 10 mM — 120 ⁇ M > 12 ⁇ M > 1.2 ⁇ M > 0.12 ⁇ M
  • Activated enzyme is diluted to 100 ng/mL in assay buffer, 25 ⁇ L per well is added to appropriate wells of the microplate. Final enzyme concentration in the assay is 25 ng/mL (0.34 nM).
  • a five mM dimethylsulfoxide stock solution of substrate (Mca-Pro-Leu-Gly-Leu-Dpa- Ala-Arg-NH 2 ) is diluted in assay buffer to 20 ⁇ M.
  • the assay is initiated by addition of 50 ⁇ L of diluted substrate yielding a final assay concentration of 10 ⁇ M substrate.
  • fluorescence reading (320 excitation; 390 emission) is immediately taken and subsequent readings are taken every fifteen minutes at room temperature with a PerSeptive Biosystems CytoFluor Multi-Well Plate Reader with the gain at 90 units.
  • the average value of fluorescence of the enzyme and blank are plotted versus time.
  • MMP-3 Human recombinant stromelysin (MMP-3, stromelysin-1 ) is activated for 20-22 hours with 2 mM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM stock in 0.2 N NaOH) at 37°C.
  • 10 mM dimethylsulfoxide stock solutions of inhibitors are diluted serially in assay buffer (50 mM TRIS, pH 7.5, 150 mM NaCI, 10 mM CaCI 2 and 0.05% BRIJ-35 (vol./vol.)) using the following scheme: 10 mM — > 120 ⁇ M ⁇ 12 ⁇ M > 1.2 ⁇ M > 0.12 ⁇ M
  • Activated enzyme is diluted to 200 ng/mL in assay buffer, 25 ⁇ L per well is added to appropriate wells of the microplate. Final enzyme concentration in the assay is 50 ng/mL (0.875 nM).
  • a ten mM dimethylsulfoxide stock solution of substrate (Mca-Arg-Pro-Lys-Pro-Val- Glu-Nva-Trp-Arg-Lys(Dnp)-NH 2 ) is diluted in assay buffer to 6 ⁇ M.
  • the assay is initiated by addition of 50 ⁇ L of diluted substrate yielding a final assay concentration of 3 ⁇ M substrate.
  • fluorescence reading (320 excitation; 390 emission) is immediately taken and subsequent readings are taken every fifteen minutes at room temperature with a PerSeptive Biosystems CytoFluor Multi-Well Plate Reader with the gain at 90 units.
  • the average value of fluorescence of the enzyme and blank are plotted versus time. An early time point on the linear part of this curve is chosen for IC 50 determinations. The zero time point for each compound at each dilution is subtracted from the latter time point and the data then expressed as percent of enzyme control (inhibitor fluorescence divided by fluorescence of positive enzyme control x 100). Data is plotted as inhibitor concentration versus percent of enzyme control. IC 50 's are defined as the concentration of inhibitor that gives a signal that is 50% of the positive enzyme control.
  • MMP-9 Inhibition of Human 92 kD Gelatinase (MMP-9) Inhibition of 92 kD gelatinase (MMP-9) activity is assayed using the Mca-Pro-Leu-Gly-
  • Leu-Dpa-Ala-Arg-NH 2 substrate (10 ⁇ M) under similar conditions as described above for the inhibition of human collagenase (MMP-1).
  • Human recombinant 92 kD gelatinase (MMP-9, gelatinase B) is activated for 2 hours with 1mM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM stock in 0.2 N NaOH) at 37 C.
  • a five mM dimethylsulfoxide stock solution of substrate (Mca-Pro-Leu-Gly-Leu-Dpa- Ala-Arg-NH 2 ) is diluted in assay buffer to 20 ⁇ M.
  • the assay is initiated by addition of 50 ⁇ L of diluted substrate yielding a final assay concentration of 10 ⁇ M substrate.
  • a 0 time fluorescence reading (320 excitation; 390 emission) is immediately taken and subsequent readings are taken every fifteen minutes at room temperature with a PerSeptive Biosystems CytoFluor Multi-Well Plate Reader with the gain at 90 units.
  • the average value of fluorescence of the enzyme and blank are plotted versus time. An early time point on the linear part of this curve is chosen for IC 5 o determinations. The 0 time point for each compound at each dilution is subtracted from the latter time point and the data then expressed as percent of enzyme control (inhibitor fluorescence divided by fluorescence of positive enzyme control x 100). Data is plotted as inhibitor concentration versus percent of enzyme control. ICso's are defined as the concentration of inhibitor that gives a signal that is 50% of the positive enzyme control.
  • MMP-13 Human recombinant MMP-13 is activated with 2 mM APMA (p-aminophenyl mercuric acetate) for 1.5 hours, at 37°C and is diluted to 400 mg/ml in assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5 mM calcium chloride, 20 ⁇ M zinc chloride, 0.02% brij). Twenty-five microliters of diluted enzyme is added per well of a 96 well microfluor plate. The enzyme is then diluted in a 1:4 ratio in the assay by the addition of inhibitor and substrate to give a final concentration in the assay of 100 mg/ml.
  • assay buffer 50 mM Tris, pH 7.5, 200 mM sodium chloride, 5 mM calcium chloride, 20 ⁇ M zinc chloride, 0.02% brij.
  • Twenty-five microliters of diluted enzyme is added per well of a 96 well microfluor plate. The enzyme is then diluted in a
  • Positive controls consist of enzyme and substrate with no inhibitor and blanks consist of substrate only.
  • IC 50 's are determined as per inhibition of human collagenase (MMP-1 ). If ICso's are reported to be less than 0.03 ⁇ M, inhibitors are then assayed at final concentrations of 0.3 ⁇ M, 0.03 ⁇ M, 0.003 ⁇ M and 0.0003 ⁇ M.
  • Recombinant human proMMP-13 or proMMP-1 is activated according to the procedures outlined above.
  • the activated MMP-13 or MMP-1 is diluted to 0.6 ug/ml with buffer ( 50 mM Tris pH 7.5, 150 mM NaCI, 10 mM CaCI 2 , 1 uM ZnCI 2 , 0.05% Brij-35, 0.02% sodium azide).
  • buffer 50 mM Tris pH 7.5, 150 mM NaCI, 10 mM CaCI 2 , 1 uM ZnCI 2 , 0.05% Brij-35, 0.02% sodium azide.
  • Stock solutions of test compound (10mM) in dimethylsulfoxide are prepared. Dilutions of the test compounds in the Tris buffer, above, are made to 0.2, 2.0, 20, 200, 2000 and 20000 nM.
  • 100 ⁇ l of appropriate drug dilution and 100 ⁇ l of diluted enzyme are pipetted into wells of a 96 well plate containing collagen films labeled with 14 C-collagen.
  • the final enzyme concentration is 0.3 ⁇ g/ml while the final drug concentration is 0.1 , 1.0, 10, 100, 1000 nM.
  • Each drug concentration and control is analyzed in triplicate. Triplicate controls are also run for the conditions in which no enzyme is present and for enzyme in the absence of any compound.
  • the plates are incubated at 37°C for a time period such that around 30 - 50% of the available collagen is solubilized - determined by counting additional control wells at various time points. In most cases around 9 hours of incubation are required.
  • the supernatant from each well is removed and counted in a scintillation counter.
  • the background counts (determined by the counts in the wells with no enzyme) are subtracted from each sample and the % release calculated in relation to the wells with enzyme only and no inhibitor.
  • the triplicate values for each point are averaged and the data graphed as percent release versus drug concentration. IC 50 's are determined from the point at which 50% inhibition of release of radiolabeled collagen is obtained.
  • cartilage conditioned medium was analyzed for the identity of the active collagenases in cartilage conditioned medium. Assays were conducted as outlined above except that instead of using recombinant MMP-13 or recombinant MMP-1 , cartilage conditioned medium was the enzyme source.
  • Bovine nasal cartilage is a tissue that is very similar to articular cartilage, i.e. chondrocytes surrounded by a matrix that is primarily type II collagen and aggrecan. The tissue is used because it: (1 ) is very similar to articular cartilage, (2) is readily available, (3) is relatively homogeneous and (4) degrades with predictable kinetics after IL-1 stimulation.
  • Variation 1 Three plugs of bovine nasal cartilage (approximately 2 mm diameter x 1.5 mm long) are placed into each well of a 24 well tissue culture plate. One ml of serumless medium is then added to each well. Compounds are prepared as 10 mM stock solutions in DMSO and then diluted appropriately in serumless medium to final concentrations, ⁇ _£., 50, 500 and 5000 nM. Each concentration is assayed in triplicate. Human recombinant IL-1 ⁇ (5ng/mL) (IL-1 ) is added to triplicate control wells and to each well containing drug. Triplicate control welis are also set up in which neither drug nor IL- 1 are added.
  • the medium is removed and fresh medium containing IL-1 and the appropriate drug concentrations is added on days 6, 12, 18 and 24 or every 3 - 4 days if necessary.
  • the media removed at each time point is stored at -20°C for later analysis.
  • the medium is removed and stored. Aliquots (100 ⁇ l) from each well at each time point are pooled, digested with papain and then analyzed for hydroxyproline content. Background hydroxyproline (average of wells with no IL-1 and no drug) is subtracted from each data point and the average calculated for each triplicate. The data is then expressed as a percent of the IL-1 alone average value and plotted. The IC 50 is determined from this plot.
  • Variation 2 The experimental set-up is the same as outlined above in Variation 1 , until day 12.
  • the data is then expressed as a percent of the IL-1 alone average value and plotted.
  • the IC 50 is determined from this plot.
  • the time course of the experiment is shortened considerably.
  • the addition of trypsin for 48 hours after 12 days of IL-1 stimulation likely releases any type II collagen that has been damaged by collagenase activity but not yet released from the cartilage matrix.
  • trypsin treatment produces only low background levels of collagen degradation in the cartilage explants.
  • Human Monocyte Assay Human mononuclear cells were isolated from anti-coagulated human blood using a one- step Ficoll-hypaque separation technique. (2) The mononuclear cells were washed three times in Hanks balanced salt solution (HBSS) with divalent cations and resuspended to a density of 2 x 10 6 /ml in HBSS containing 1% BSA. Differential counts determined using the Abbott Cell Dyn 3500 analyzer indicated that monocytes ranged from 17 to 24% of the total cells in these preparations.
  • HBSS Hanks balanced salt solution
  • chondrocyte monolayers are washed two times in DMEM/ 1 % PSF/G and then allowed to incubate in fresh DMEM /1 % FBS overnight.
  • chondrocytes are washed once in DMEM/1 %PSF/G. The final wash is allowed to sit on the plates in the incubator while making dilutions.
  • Plates are labeled and only the interior 24 wells of the plate are used. On one of the plates, several columns are designated as IL-1 (no drug) and Control (no IL-1 , no drug). These control columns are periodically counted to monitor 35S-proteoglycan release. Control and IL-1 media are added to wells (450 ⁇ l) followed by compound (50 ⁇ l) so as to initiate the assay. Plates are incubated at 37°C, with a 5% C0 2 atmosphere. At 40-50 % release (when CPM from IL-1 media is 4-5 times control media) as assessed by liquid scintillation counting (LSC) of media samples, the assay is terminated (9- 12 hours).
  • LSC liquid scintillation counting
  • One group of preferred compounds possesses selective activity towards MMP-13 over MMP- 1.
  • Another preferred group of compounds possesses selective activity towards MMP-13 over MMP-1 , MMP-3 and MMP-7.
  • Another preferred group of compounds possesses selective activity towards MMP-13 over MMP-1 , MMP-3, MMP-7 and MMP-17.
  • Another preferred group of compounds possesses selective activity towards MMP-13 over MMP-1 , MMP-2, MMP-3, MMP-7, MMP-9 and MMP-14
  • Another preferred group of compounds possesses selective activity towards MMP-13 over MMP- 2 and MMP-14.
  • the compounds of the invention will be administered at dosages of about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg.
  • the active compound will be administered orally or parenterally.
  • some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the compounds of the present invention can be administered in a wide variety of different dosage forms, in general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelation and acacia.
  • disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelation and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • animals are advantageously contained in an animal feed or drinking water in a concentration of 5-5000 ppm, preferably 25 to 500 ppm.
  • a sterile injectable solution of the active ingredient is usually prepared.
  • Solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • the aqueous solutions should be suitably adjusted and buffered, preferably at a pH of greater than 8, if necessary and the liquid diluent first rendered isotonic.
  • These aqueous solutions are suitable intravenous injection purposes.
  • the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes.
  • the preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • compounds can be administered intramuscularly or subcutaneously at dosage levels of about 0.1 to 50 mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a single dose or up to 3 divided doses.
  • the active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • a suitable powder base such as lactose or starch.
  • direct application to the affected eye may be employed in the form of a formulation as eyedrops, aerosol, gels or ointments, or can be incorporated into collagen (such as poly-2-hydroxyethylmethacrylate and co-polymers thereof), or a hydrophilic polymer shield.
  • the materials can also be applied as a contact lens or via a local reservoir or as a subconjunctival formulation.
  • a sterile injectable solution of the active ingredient is usually prepared.
  • Solutions of a therapeutic compound of the present invention in an aqueous solution or suspension may be employed.
  • the aqueous solutions should be suitably adjusted and buffered, preferably at a pH between 5 and 8, if necessary and the liquid diluent first rendered isotonic.
  • Small amounts of polymers can be added to increase viscosity or for sustained release (such as cellulosic polymers, Dextran, polyethylene glycol, or alginic acid). These solutions are suitable for intraorbital injection purposes.
  • the preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • compounds can be administered intraorbitally at dosage levels of about 0.1 to 50 mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a single dose or up to 3 divided doses.
  • dosage forms intended for oral administration are also suitably formulated to provide controlled-, sustained- and/or delayed release of the active ingredient.
  • these would include delayed-release oral tablets, capsules and multiparticulates, as well as enteric-coated tablets and capsules which prevent release and adsorption of the active ingredient in the stomach of the patient and facilitate enteric delivery distal to the stomach, i.e., in the intestine.
  • Other typical oral dosage forms would include sustained-release oral tablets, capsules and multiparticulates which provide systemic delivery of the active ingredient in a controlled manner over a prolonged period of time, e.g., a 24-hour period.
  • a controlled-release oral dosage form may be prepared in the form of a fast-dissolving tablet, which would also preferably include highly soluble salt forms of the active ingredient.
  • Compounds of the formula I can be prepared by reacting the appropriate compound of formula HI with a urea of the formula II (i.e., H 2 N(CO)-NH 2 ) in the presence of a suitable base, such as an alkoxide base, preferably sodium ethoxide, in a polar solvent, such as an alcoholic solvent, preferably ethanol, at a temperature of 20°C to the boiling point of the solvent, preferably 80°C for 15 minutes to 3 hours.
  • a suitable base such as an alkoxide base, preferably sodium ethoxide
  • a polar solvent such as an alcoholic solvent, preferably ethanol
  • a compound of formula III can be prepared by reacting an appropriate compound of formula IV with a suitable base, such as a tertiary amine base or a polymer bound base, preferably Amberlyst-400 ® resin (hydroxide form), in a polar solvent, such as an alcoholic solvent, preferably ethanol, at a temperature of about 0°C to about 50°C, preferably about
  • a suitable base such as a tertiary amine base or a polymer bound base, preferably Amberlyst-400 ® resin (hydroxide form)
  • a polar solvent such as an alcoholic solvent, preferably ethanol
  • the compound of formula IV can be prepared by reacting the appropriate compound of the formula VI with a compound of the formula V, which has a general formula of L 3 -(A')-L 4 or L 3 -(A'), in an aprotic solvent, preferably and aromatic hydrocarbon solvent such as benzene or toluene, at a temperature of about 40°C and the boiling point of the solvent, preferably about 80°C, for a period of about 1 to about 6 hours.
  • an aprotic solvent preferably and aromatic hydrocarbon solvent such as benzene or toluene
  • the compound of formula VI can be prepared by reacting the appropriate compound of the formula NH 2 -X- Y-Z-G with a compound of the formula VII, which is a 2-halo malonate ester, preferably 2-bromodiethyl malonate, in the presence of a suitable base, such as a tertiary amine base, preferably /V, ⁇ /-dimethylaniline, at a temperature of about 20°C to about
  • a suitable base such as a tertiary amine base, preferably /V, ⁇ /-dimethylaniline
  • Amberlyst-400 (hydroxide form) resin 75 g was added and the mixture was stirred for 24 hours at 23 °C. The mixture was filtered and the resin was washed with 50 mL of methanol.
  • 1-r6-(4-vinyl-phenoxy.-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester A mixture of 1-[6-(4-bromo-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (5.8 g, 12.2 mmol), vinyltributyltin (3.9 mL, 12.3 mmol), tetrakistriphenylphosphine palladium (0) (0.60 g, 0.52 mmol) and 24 mL of toluene was heated to reflux for 1 hour.

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PCT/IB2001/001986 2000-10-26 2001-10-23 Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors WO2002034753A2 (en)

Priority Applications (18)

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SK497-2003A SK4972003A3 (en) 2000-10-26 2001-10-23 5-spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors
IL15494801A IL154948A0 (en) 2000-10-26 2001-10-23 Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors
EA200300306A EA005762B1 (ru) 2000-10-26 2001-10-23 Спиро-пиримидин-2,4,6-трионовые ингибиторы металлопротеиназы
EEP200300196A EE200300196A (et) 2000-10-26 2001-10-23 Spiropürimidiin-2,4,6-trioonmetalloproteinaasi inhibiitorid
HU0301577A HUP0301577A3 (en) 2000-10-26 2001-10-23 Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors, pharmaceutical compositions containing them and their use
EP01978721A EP1332146A2 (en) 2000-10-26 2001-10-23 Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors
CA002425283A CA2425283A1 (en) 2000-10-26 2001-10-23 Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors
PL01366201A PL366201A1 (en) 2000-10-26 2001-10-23 Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors
KR10-2003-7005753A KR20040004412A (ko) 2000-10-26 2001-10-23 스피로-피리미딘-2,4,6-트리온 메탈로프로테이나제 억제제
APAP/P/2001/002318A AP2001002318A0 (en) 2000-10-26 2001-10-23 Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors
JP2002537743A JP2004518635A (ja) 2000-10-26 2001-10-23 スピロ−ピリミジン−２，４，６−トリオンメタロプロテイナーゼ阻害剤
BR0114913-0A BR0114913A (pt) 2000-10-26 2001-10-23 Inibidores de metaloproteinase de espiro-pirimidina-2,4,6-triona
AU2002210813A AU2002210813A1 (en) 2000-10-26 2001-10-23 Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors
MXPA03003735A MXPA03003735A (es) 2000-10-26 2001-10-23 Inhibidores de espiropirimidin-2,4,6-triona metaloproteinasas.
BG107653A BG107653A (bg) 2000-10-26 2003-03-20 Спиро-пиримидин - 2,4,6-трионови инхибитори на металопротеиназa
IS6762A IS6762A (is) 2000-10-26 2003-03-27 Spíró-pýrimídín-2,4,6-tríón málmpróteinasa hindrar
NO20031853A NO20031853L (no) 2000-10-26 2003-04-24 Spiro-pyrimidin-2,4,6-trion metalloproteinaseinhibitorer
HR20030332A HRP20030332A2 (en) 2000-10-26 2003-04-28 Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors

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WO2003091252A1 (en) * 2002-04-25 2003-11-06 Bristol-Myers Squibb Company Spirobarbituric acid derivatives useful as inhibitors of matrix metalloproteases
WO2003091259A1 (en) * 2002-04-26 2003-11-06 Pfizer Products Inc. Triaryl-oxy-aryl-spiro-pyrimidine-2, 4, 6-trione metalloproteinase inhibitors
US6656932B2 (en) 2001-02-14 2003-12-02 Warner-Lambert Company Benzo thiadiazine matrix metalloproteinase inhibitors
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US6849637B2 (en) 2001-02-14 2005-02-01 Warner-Lambert Company Triazolo compounds as MMP inhibitors
US6849648B2 (en) 2001-10-12 2005-02-01 Warner-Lambert Company Phenylene alkyne matrix metalloproteinase inhibitors
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US6894057B2 (en) 2002-03-08 2005-05-17 Warner-Lambert Company Oxo-azabicyclic compounds
US6897223B2 (en) 2002-08-13 2005-05-24 Warner-Lambert Company Pyridine fused bicyclic metalloproteinase inhibitors
US6908917B2 (en) 2002-08-13 2005-06-21 Warner-Lambert Company Chromone derivatives as matrix metalloproteinase inhibitors
US6924276B2 (en) 2001-09-10 2005-08-02 Warner-Lambert Company Diacid-substituted heteroaryl derivatives as matrix metalloproteinase inhibitors
US6936616B2 (en) 2001-02-14 2005-08-30 Warner-Lambert Company Pyrimidine matrix metalloproteinase inhibitors
US6949651B2 (en) 2002-08-13 2005-09-27 Warner-Lambert Company Fused bicyclic metalloproteinase inhibitors
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US6962922B2 (en) 2001-10-12 2005-11-08 Warner-Lambert Company Llc Alkynylated quinazoline compounds
US6974822B2 (en) 2002-08-13 2005-12-13 Warner-Lambert Company Llc 3-isoquinolinone derivatives as matrix metalloproteinase inhibitors
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US6995151B2 (en) 2001-02-14 2006-02-07 Warner-Lambert Company Isophthalic acid derivatives as matrix metalloproteinase inhibitors
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US6849637B2 (en) 2001-02-14 2005-02-01 Warner-Lambert Company Triazolo compounds as MMP inhibitors
US7214712B2 (en) 2001-02-14 2007-05-08 Warner-Lambert Company Isophthalic acid derivatives as matrix metalloproteinase inhibitors
US7015237B2 (en) 2001-02-14 2006-03-21 Warner-Lambert Company Pyridine matrix metalloproteinase inhibitors
US6656932B2 (en) 2001-02-14 2003-12-02 Warner-Lambert Company Benzo thiadiazine matrix metalloproteinase inhibitors
US6995151B2 (en) 2001-02-14 2006-02-07 Warner-Lambert Company Isophthalic acid derivatives as matrix metalloproteinase inhibitors
US6936616B2 (en) 2001-02-14 2005-08-30 Warner-Lambert Company Pyrimidine matrix metalloproteinase inhibitors
US6881743B2 (en) 2001-02-14 2005-04-19 Warner-Lambert Company Pyridine matrix metalloproteinase inhibitors
US6924276B2 (en) 2001-09-10 2005-08-02 Warner-Lambert Company Diacid-substituted heteroaryl derivatives as matrix metalloproteinase inhibitors
US6849648B2 (en) 2001-10-12 2005-02-01 Warner-Lambert Company Phenylene alkyne matrix metalloproteinase inhibitors
US6962922B2 (en) 2001-10-12 2005-11-08 Warner-Lambert Company Llc Alkynylated quinazoline compounds
US6894057B2 (en) 2002-03-08 2005-05-17 Warner-Lambert Company Oxo-azabicyclic compounds
WO2003091252A1 (en) * 2002-04-25 2003-11-06 Bristol-Myers Squibb Company Spirobarbituric acid derivatives useful as inhibitors of matrix metalloproteases
WO2003091259A1 (en) * 2002-04-26 2003-11-06 Pfizer Products Inc. Triaryl-oxy-aryl-spiro-pyrimidine-2, 4, 6-trione metalloproteinase inhibitors
WO2003091258A1 (en) * 2002-04-26 2003-11-06 Pfizer Products Inc. N-substituted-heteroaryloxy-aryl-spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors
US6977261B2 (en) 2002-08-13 2005-12-20 Warner-Lambert Company Llc Azaisoquinoline derivatives as matrix metalloproteinase inhibitors
US7132424B2 (en) 2002-08-13 2006-11-07 Warner-Lambert Company Llc Monocyclic derivatives as matrix metalloproteinase inhibitors
US6908917B2 (en) 2002-08-13 2005-06-21 Warner-Lambert Company Chromone derivatives as matrix metalloproteinase inhibitors
US7179822B2 (en) 2002-08-13 2007-02-20 Warner-Lambert Company Hetero biaryl derivatives as matrix metalloproteinase inhibitors
US7160893B2 (en) 2002-08-13 2007-01-09 Warner-Lambert Company Pyrimidine-2,4-dione derivatives as matrix metalloproteinase inhibitors
US6949651B2 (en) 2002-08-13 2005-09-27 Warner-Lambert Company Fused bicyclic metalloproteinase inhibitors
US6897223B2 (en) 2002-08-13 2005-05-24 Warner-Lambert Company Pyridine fused bicyclic metalloproteinase inhibitors
US6828326B2 (en) 2002-08-13 2004-12-07 Warner-Lambert Company Pyrimidinone fused bicyclic metalloproteinase inhibitors
US6974822B2 (en) 2002-08-13 2005-12-13 Warner-Lambert Company Llc 3-isoquinolinone derivatives as matrix metalloproteinase inhibitors
US6869958B2 (en) 2002-08-13 2005-03-22 Warner-Lambert Company Fused tetrahydropyridine derivatives as matrix metalloproteinase inhibitors
WO2004014892A1 (en) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc Monocyclic derivatives as matrix metalloproteinase inhibitors
US7208490B2 (en) 2002-10-07 2007-04-24 Pharmacia & Upjohn Company Llc Tricyclic tetrahydroquinoline antibacterial agents
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EA200300306A1 (ru) 2003-08-28
CN1501937A (zh) 2004-06-02
EP1332146A2 (en) 2003-08-06
HUP0301577A2 (hu) 2003-11-28
AP2001002318A0 (en) 2001-12-31
SK4972003A3 (en) 2004-05-04
BR0114913A (pt) 2003-07-01
TNSN01149A1 (fr) 2005-11-10
ZA200302190B (en) 2004-04-28
IS6762A (is) 2003-03-27
CA2425283A1 (en) 2002-05-02
KR20040004412A (ko) 2004-01-13
AR035069A1 (es) 2004-04-14
ECSP034567A (es) 2003-06-25
MA26957A1 (fr) 2004-12-20
EA005762B1 (ru) 2005-06-30
HRP20030332A2 (en) 2003-06-30
NO20031853L (no) 2003-06-23
PL366201A1 (en) 2005-01-24
IL154948A0 (en) 2003-10-31
NO20031853D0 (no) 2003-04-24
OA12529A (en) 2006-06-02
EE200300196A (et) 2003-10-15
HN2001000244A (es) 2003-11-07
JP2004518635A (ja) 2004-06-24
SV2003000705A (es) 2003-01-13
WO2002034753A3 (en) 2002-08-15
GT200100213A (es) 2002-07-03
BG107653A (bg) 2003-12-31
MXPA03003735A (es) 2003-07-28
AU2002210813A1 (en) 2002-05-06
HUP0301577A3 (en) 2006-02-28
PE20020589A1 (es) 2002-07-06
PA8531401A1 (es) 2003-06-30
CZ20031083A3 (cs) 2004-03-17

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