+

WO2004024718A1 - Derives d'imidazolidinedione et leur utilisation en tant qu'inhibiteurs de metalloproteinase - Google Patents

Derives d'imidazolidinedione et leur utilisation en tant qu'inhibiteurs de metalloproteinase Download PDF

Info

Publication number
WO2004024718A1
WO2004024718A1 PCT/SE2003/001407 SE0301407W WO2004024718A1 WO 2004024718 A1 WO2004024718 A1 WO 2004024718A1 SE 0301407 W SE0301407 W SE 0301407W WO 2004024718 A1 WO2004024718 A1 WO 2004024718A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
formula
ring
methyl
compound
Prior art date
Application number
PCT/SE2003/001407
Other languages
English (en)
Inventor
David Chapman
Anders Eriksson
Anna Kristoffersson
Igor Shamovsky
Kristina Stenvall
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to AU2003258942A priority Critical patent/AU2003258942A1/en
Publication of WO2004024718A1 publication Critical patent/WO2004024718A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • Metalloproteinases are a superfamily of proteinases (enzymes) whose numbers in recent years have increased dramatically. Based on structural and functional considerations these enzymes have been classified into families and subfamilies as described in N.M. Hooper (1994) FEBS Letters 354-' 1-6.
  • metalloproteinases examples include the matrix metalloproteinases (MMPs) such as the collagenases (MMP1, MMP8, MMP13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloelastase (MMP12), enamelysin (MMP19), the MT-MMPs (MMP14, MMP15, MMP16, MMP17); the reprol sin or adamalysin or MDC family which includes the secretases and sheddases such as TNF converting enzymes (ADAM 10 and TACE); the astacin family which include enzymes such as procollagen processing proteinase (PCP); and other metalloproteinases such as aggrecanase, the endothelin converting enzyme family and the angiotensin converting enzyme family.
  • MMPs matrix metalloproteinases
  • Metalloproteinases are believed to be important in a plethora of physiological disease processes that involve tissue remodelling such as embryonic development, bone formation and uterine remodelling during menstruation. This is based on the ability of the metalloproteinases to cleave a broad range of matrix substrates such as collagen, proteoglycan and fibronectin. Metalloproteinases are also believed to be important in the processing, or secretion, of biological important cell mediators, such as tumour necrosis factor (TNF); and the post translational proteolysis processing, or shedding, of biologically important membrane proteins, such as the low affinity IgE receptor CD23 (for a more complete list see N. M. Hooper et al., (1997) Biochem J.
  • TNF tumour necrosis factor
  • Metalloproteinases have been associated with many diseases or conditions. Inhibition of the activity of one or more metalloproteinases may well be of benefit in these diseases or conditions, for example: various inflammatory and allergic diseases such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastro-intestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema, dermatitis); in tumour metastasis or invasion; in disease associated with uncontrolled degradation of the extracellular matrix such as osteoarthritis; in bone resorptive disease (such as osteoporosis and Paget's disease); in diseases associated with aberrant angiogenesis; the enhanced collagen remodelling associated with diabetes, periodontal disease (such as gingivitis), corneal ulceration, ulceration of the skin, post-operative conditions (such as colonic anastomosis) and dermal wound healing; dem
  • MMP12 also known as macrophage elastase or metalloelastase, was initially cloned in the mouse by Shapiro et al [1992, Journal of Biological Chemistry 267: 4664] and in man by the same group in 1995. MMP12 is preferentially expressed in activated macrophages, and has been shown to be secreted from alveolar macrophages from smokers [Shapiro et al, 1993, Journal of Biological Chemistry, 268: 23824] as well as in foam cells in atherosclerotic lesions [Matsumoto et al, 1998, Am J Pathol 153: 109].
  • a mouse model of COPD is based on challenge of mice with cigarette smoke for six months, two cigarettes a day six days a week. Wildtype mice developed pulmonary emphysema after this treatment. When MMP12 knock-out mice were tested in this model they developed no significant emphysema, strongly indicating that MMP12 is a key enzyme in the COPD pathogenesis.
  • MMPs such as MMP12 in COPD (emphysema and bronchitis) is discussed in Anderson and Shinagawa, 1999, Current Opinion in Anti-inflammatory and Immunomodulatory Investigational Drugs 1(1): 29-38.
  • MMP9 The expression of MMP9 is restricted normally to a few cell types, including trophoblasts, osteoclasts, neutrophils and macrophages. However, it's expression can be induced in these same cells and in other cell types by several mediators, including exposure of the cells to growth factors or cytokines. These are the same mediators often implicated in initiating an inflammatory response. As with other secreted MMPs, MMP9 is released as an inactive Pro-enzyme which is subsequently cleaved to form the enzymatically active enzyme. The proteases required for this activation in vivo are not known.
  • TIMP-1 tissue Inhibitor of Metalloproteinases -1
  • TIMP-1 binds to the C-terminal region of MMP9, leading to inhibition of the catalytic domain of MMP9.
  • the balance of induced expression of ProMMP9, cleavage of Pro- to active MMP9 and the presence of TIMP- 1 combine to determine the amount of catalytically active MMP9 which is present at a local site.
  • Proteolytically active MMP9 attacks substrates which include gelatin, elastin, and native Type IN and Type V collagens; it has no activity against native Type I collagen, proteoglycans or laminins.
  • substrates which include gelatin, elastin, and native Type IN and Type V collagens; it has no activity against native Type I collagen, proteoglycans or laminins.
  • MMP9 has been a growing body of data implicating roles for MMP9 in various physiological and pathological processes. Physiological roles include the invasion of embryonic trophoblasts through the uterine epithelium in the early stages of embryonic implantation; some role in the growth and development of bones; and migration of inflammatory cells from the vasculature into tissues.
  • MMP9 release measured using enzyme immunoassay, was significantly enhanced in fluids and in AM supernantants from untreated asthmatics compared with those from other populations [Am. J. Resp. Cell & Mol. Biol., Nov 1997, 17 (5):583-5911. Also, increased MMP9 expression has been observed in certain other pathological conditions, thereby implicating MMP9 in disease processes such as COPD, arthritis, tumour metastasis, Alzheimer's, Multiple Sclerosis, and plaque rupture in atherosclerosis leading to acute coronary conditions such as Myocardial Infarction.
  • R represents hydrogen, or a group selected from Cj-Cg alkyl and a saturated or unsaturated 3- to 10-membered ring system which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, carboxyl, -NR 2 R 3 , -CONR 4 R 5 , - alkyl, C ⁇ -C 6 alkoxy, Ci-C 6 alkylcarbonyl(oxy), -S(O) m C ⁇ -C6 alkyl where m is 0, 1 or 2, Cj-Cg alkyl sulphonylamino, Cj-Cg alkoxycarbonyl(amino), benzyloxy and a saturated or unsaturated 5- to 6- membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring in turn being optionally substituted with at least one substituent selected from halogen,
  • R , R , R and R each independently represent hydrogen or C ⁇ -C(, alkyl optionally substituted by at least one substituent selected from hydroxyl, halogen and Ci-Cg alkoxy;
  • 2 G represents a piperidine or a tetrahydropyridine ring
  • G represents a 5- or 6- membered aryl or heteroaryl monocyclic ring which may be optionally fused to a second ring to form a bicyclic ring system containing a total of 8- to
  • 10-ring atoms the monocyclic ring or fused bicyclic ring system being optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, nitro, -C6 alkyl (optionally substituted by one or more of cyano, halogen, hydroxyl and methoxy), C2-Cg alkenyl, C ⁇ -C alkoxy (optionally substituted by one or more halogen atoms), -S(O) n C ⁇ -C6 alkyl where n is 0, 1 or 2 (optionally substituted by one or more halogen atoms), Ci-C ⁇ alkylcarbonyl(amino), -Cg alkylcarbonyloxy, phenyl, benzyloxy and and and and and and and and
  • R and R each independently represent hydrogen or C ⁇ -C alkyl optionally substituted by at least one substituent selected from hydroxyl, halogen and Ci-C ⁇ alkoxy.
  • an alkyl or alkenyl substituent group or an alkyl moiety in a substituent group may be linear or branched.
  • a hydroxyalkyl substituent may contain one or more hydroxyl groups but preferably contains one or two hydroxyl groups.
  • R it should be understood that each of the saturated or unsaturated 3- to 10-membered ring system and the saturated or unsaturated 5- to 6-membered ring may have alicyclic or aromatic properties. An unsaturated ring system will be partially or fully unsaturated.
  • the second ring in the bicyclic ring system need not be aromatic and may contain one or more ring heteroatoms selected from nitrogen, oxygen and sulphur.
  • R represents hydrogen, or a group selected from -C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) and a saturated or unsaturated 3- to 10-membered ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur, each group being optionally substituted with at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g. chlorine, fluorine, bromine or
  • alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl
  • C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), Cj-Cg, preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), Cj-Cg, preferably C1-C4, alkylcarbonyl(oxy) (e.g.
  • alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or
  • saturated or unsaturated 3- to 10-membered ring systems that may be used, which may be monocyclic or polycyclic (e.g. bicyclic) in which the two or more rings are fused, include one or more (in any combination) of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, cyclopentenyl, cyclohexenyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, diazabicyclo[2.2.1]hept-2-yl, naphthyl, benzofuranyl, benzothienyl, benzodioxolyl, quinolinyl, 2,3-dihydrobenzofuranyl, tetrahydropyranyl, pyrazolyl, pyrazinyl, thiazolidinyl, indany
  • saturated or unsaturated 5- to 6-membered ring substituents in R include cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiomorpholinyl, pyrazolyl, pyrazinyl, pyridazinyl, thiazolidinyl, thienyl, isoxazolyl, pyrimidinyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl and pyridinyl.
  • Preferred rings include mo ⁇ holinyl, pyrimidinyl, phenyl, imidazolyl, piperidinyl, tetrahydropyranyl and triazolyl.
  • R Particular values for R include the following
  • R represents hydrogen, or a group selected from C1-C4 alkyl and a saturated or unsaturated 5- to 10-membered ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur, each group being optionally substituted with at least one substituent (e.g.
  • substituents independently selected from halogen, hydroxyl, cyano, carboxyl, -NR 2 R 3 , -CONR 4 R 5 , -C4 alkyl, C1-C4 alkoxy, -C4 alkylcarbonyl(oxy), -S(O) m C ⁇ -C 4 alkyl where m is 0, 1 or 2, -C4 alkylsulphonylamino, C1-C4 alkoxycarbonyl(amino), benzyloxy and a saturated or unsaturated 5- to 6- membered ring which may comprise at least one ring heteroatom (e.g.
  • substituent e.g. one, two or three substituents independently
  • R represents hydrogen or -C4 alkyl, particularly methyl.
  • alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl
  • substituent e.g. one, two or three substituents independently
  • hydroxyl e.g. halogen (e.g. chlorine, fluorine, bromine or iodine) and Cj-C ⁇ , preferably -C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy).
  • R , R , R and R each independently represent hydrogen or Cj-Cg, preferably C1-C4, alkyl, in particular methyl.
  • R , R and R each independently represent hydrogen or Cj-Cg, preferably C1-C4, alkyl, in particular methyl.
  • R , R , R and R each independently represent hydrogen.
  • 2 G represents piperidine or tetrahydropyridine such as 1 ,2,3,6-tetrahydropyridine of formula
  • G represents a 5- or 6- membered aryl or heteroaryl monocyclic ring which may be optionally fused to a second ring to form a bicyclic ring system containing a total of 8- to 10-ring atoms, the monocyclic ring or fused bicyclic ring system being optionally substituted with at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g.
  • Cj-Cg preferably -C4, alkoxy such as methoxy, ethoxy, n-propoxy or n-butoxy (optionally substituted by one or more, e.g. one, two or three, halogen atoms such as chlorine, fluorine, bromine or iodine, e.g. -OCF3), -S(O) n C ⁇ -C6, preferably C1-C4, alkyl where n is 0, 1 or 2 (optionally substituted by one or more, e.g. one, two or three, halogen atoms such as chlorine, fluorine, bromine or iodine) (e.g. methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl, ethylsulphonyl or -SCF3);
  • Ci-C ⁇ preferably C1-C4, alkylcarbonyl(amino) (e.g. methylcarbonyl(amino), ethylcarbonyl(amino), n-propylcarbonyl(amino), isopropylcarbonyl(amino), n-butylcarbonyl(amino), n-pentylcarbonyl(amino) or n-hexylcarbonyl(amino)), Cj-C ⁇ , preferably C1-C4, alkylcarbonyloxy (e.g.
  • a 5- or 6-membered heteroaryl ring will comprise at least one ring heteroatom (e.g. one, two or three ring heteroatoms independently) selected from nitrogen, oxygen and sulphur.
  • Examples of 5- or 6- membered aryl or heteroaryl monocyclic rings include phenyl, pyridinyl, thienyl, furanyl, pyrazinyl, pyrimidinyl, pyrrolyl and thiazolyl, for instance,
  • substituent(s) are located in the meta and/ 'or para positions, as illustrated in the examples below:
  • a preferred meta substituent is a C1-C3 alkyl group or -CH2CN.
  • a preferred para substituent is Br, CI, -CN, -CF3, -SCF3 or -OCF3.
  • the 5- or 6- membered aryl or heteroaryl monocyclic ring is fused to a second ring to form a bicyclic ring system containing a total of 8- to 10-ring atoms such as quinolinyl, isoquinolinyl, indolyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, naphthyl or dihydroindolyl.
  • a preferred bicyclic ring system is dihydrobenzofuranyl.
  • G represents a 5- or 6- membered aryl or heteroaryl monocyclic ring which may be optionally fused to a second ring to form a bicyclic ring system containing a total of 8- to 10-ring atoms, the monocyclic ring or fused bicyclic ring system being optionally substituted with one, two or three substituents independently selected from halogen, hydroxyl, cyano, nitro, C1-C4 alkyl (optionally substituted by one or more, e.g.
  • substituents independently selected from cyano, halogen, hydroxyl and methoxy
  • C2-C4 alkenyl C1-C4 alkoxy (optionally substituted by one or more, e.g. one, two or three, halogen atoms), -S(O) ⁇ C ⁇ -C4 alkyl where n is 0, 1 or 2 (optionally substituted by one or more, e.g. one, two or three, halogen atoms),
  • G represents a 6- membered aryl or heteroaryl monocyclic ring which may be optionally fused to a second ring to form a bicyclic ring system containing a total of 9- to 10-ring atoms, the monocyclic ring or fused bicyclic ring system being optionally substituted with one or two substituents independently selected from halogen, cyano and C1-C4 alkyl.
  • G represents phenyl, pyridinyl or dihydrobenzofuranyl, each of which is optionally substituted with one or two substituents independently selected from halogen (particularly chlorine), cyano and C1-C4 alkyl (particularly methyl).
  • G and G include the following:
  • R each independently represent hydrogen or C]-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by at least one substituent (e.g. one, two or three substituents independently) selected from hydroxyl, halogen (e.g. chlorine, fluorine, bromine or iodine) and Cj-C ⁇ , preferably -C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy).
  • substituent e.g. one, two or three substituents independently
  • R and R each independently represent hydrogen.
  • R represents -C4 alkyl
  • 2 G represents a piperidine or a tetrahydropyridine ring
  • G represents a 6- membered aryl or heteroaryl monocyclic ring which may be optionally fused to a second ring to form a bicyclic ring system containing a total of 9- to
  • 10-ring atoms the monocyclic ring or fused bicyclic ring system being optionally substituted with one or two substituents independently selected from halogen, cyano and
  • R 1 represents methyl
  • 2 G represents a piperidine or a tetrahydropyridine ring
  • G represents phenyl, pyridinyl or dihydrobenzofuranyl, each of which is optionally substituted with one or two substituents independently selected from chlorine, cyano and methyl.
  • Examples of compounds of the invention include:
  • the compounds according to the invention may contain one or more asymmetrically substituted carbon atoms.
  • the presence of one or more of these asymmetric centres (chiral centres) in compounds according to the invention can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof. Racemates may be separated into individual optically active forms using known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, pi 04- 107) including for example the formation of diastereomeric derivatives having convenient optically active auxiliary species followed by separation and then cleavage of the auxiliary species.
  • optically active centres exist in the compounds of the invention, we disclose all individual optically active forms and combinations of these as individual specific embodiments of the invention, as well as their corresponding racemates.
  • the compounds of the invention may be provided as pharmaceutically acceptable salts or solvates. These include acid addition salts such as hydrochloride, hydrobromide, citrate, tosylate and maleate salts and salts formed with phosphoric and sulphuric acid.
  • suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic a ine salt for example triethylamine.
  • Examples of solvates include hydrates.
  • the compounds of formula (I) have activity as pharmaceuticals.
  • the compounds of the invention are metalloproteinase inhibitors, in particular they are dual inhibitors of MMP 12 and MMP9 and may be used in the treatment of diseases or conditions mediated by MMP 12 and/or MMP9 such as asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis (such as rheumatoid arthritis and osteoarthritis), atherosclerosis and restenosis, cancer, invasion and metastasis, diseases involving tissue destruction, loosening of hip joint replacements, periodontal disease, fibrotic disease, infarction and heart disease, liver and renal fibrosis, endometriosis, diseases related to the weakening of the extracellular matrix, heart failure, aortic aneurysms, CNS related diseases such as Alzheimer's disease and Multiple Sclerosis (MS), and hematological disorders.
  • diseases or conditions mediated by MMP 12 and/or MMP9 such as asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis (
  • a compound is considered to be a dual inhibitor of MMP 12 and MMP9 if the potency of the compound (as measured by its IC50 value) is less than or equal to 100 nanomolar ( ⁇ 100 nm) for each of MMP12 and MMP9, or, if the ratio of the potencies (MMP9:MMP12) is less than or equal to 20 ( ⁇ 20).
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • the invention further provides a method of treating a disease or condition mediated by MMP 12 and/or MMP9 which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as hereinbefore defined.
  • the invention also provides a method of treating an obstructive airways disease (e.g. asthma or COPD) which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as hereinbefore defined.
  • an obstructive airways disease e.g. asthma or COPD
  • the daily dosage of the compound of formula (I)/salt/solvate (active ingredient) may be in the range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary.
  • unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
  • the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w, of active ingredient, and, from 1 to 99.95 %w, more preferably from 30 to 99.90 %w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal adminstration or by inhalation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more diseases or conditions referred to hereinabove such as "Symbicort" (trade mark) product.
  • the present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as defined above which comprises,
  • L represents a leaving group (e.g. a halogen atom such as chlorine) and R is as defined in formula (I); or
  • R , G and G are as defined in formula (I), with potassium cyanide and ammonium carbonate; and optionally after (a) or (b) forming a pharmaceutically acceptable salt or solvate.
  • reaction is conveniently carried in an organic solvent such as pyridine, dimethylformamide, tetrahydrofuran, acetonitrile or dichloromethane and optionally in the presence of a base such as triethylamine, ⁇ -methylmo ⁇ holine, pyridine or an alkali metal carbonate.
  • a base such as triethylamine, ⁇ -methylmo ⁇ holine, pyridine or an alkali metal carbonate.
  • the reaction will usually be carried out over about 1 to 24 hours at elevated temperature, for example, from ambient (20°C) to reflux temperature.
  • Compounds of formula (II) are either commercially available, are known in the literature (for example, from Wusttow et al, Synthesis, 1991, H, 993-995) or may be prepared using known techniques.
  • Compounds of formula (III) may be prepared as described by Mosher, J., J. Org. Chem., 2 233,, 11225577 ((11995588)),, oorr aalltteerrnnaattiivveellyy,, wwhheenn LL rreepprreessents chlorine, may be prepared by oxidative chlorination of* compounds of formula
  • R is as defined in formula (111), for example, as described by Griffith, O.W., J. Biol. Chem., 1983, 258 (3), 1591-1598.
  • reaction is conveniently carried out in the presence of a protic solvent such as ethanol and in a sealed vessel at about 40°C to 80°C for about 4-24 hours.
  • a protic solvent such as ethanol
  • G and G are as defined in formula (IN) with excess (e.g. 2-3 equivalents worth) strong base such as lithium diisopropylamide, lithium hexamethyldisilazane or butyl lithium in the presence of an organic solvent such as tetrahydrofuran, followed by reaction with a compound of formula wherein R represents an alkyl or aryl group and R is as defined in formula (IN), in a non-protic solvent.
  • excess (e.g. 2-3 equivalents worth) strong base such as lithium diisopropylamide, lithium hexamethyldisilazane or butyl lithium in the presence of an organic solvent such as tetrahydrofuran, followed by reaction with a compound of formula wherein R represents an alkyl or aryl group and R is as defined in formula (IN), in a non-protic solvent.
  • the starting materials were prepared as follows:
  • tert-Butyl 4- ⁇ r(trifluoromethyl)sulfonyl1oxyl-3.6-dihydropyridine-l(2H)-carboxylate A solution of tert-butyl 4-oxopiperidine-l-carboxylate (5.07 g, 25mmol) in THF (50 ml) was added drop wise to a solution of LDA (2M in THF, 15 ml, 30mmol) and THF (100 ml) over 25 mins at -78 °C.
  • the title compound was prepared by chiral separation of the racemic material using a
  • the starting material was prepared as follows: tert-Butyl 4-(4-cvano-3-methylphenyl)piperidine-l-carboxylate tert-Butyl 4-(4-cyano-3-methylphenyl)-3,6-dihydropyridine-l(2H)-carboxylate (171 mg, 0.57 mmol) was dissolved in EtOAc (10 ml), 10% Pd/C (10 mg) added and the mixture was hydrogenated at room temperature and 1 atm for 40 mins. The catalyst was filtered off and the solvent removed by rotary evaporation affording 171 mg (99%) of the title compound as a clear oil.
  • LC-MS (APCI) m/z 201 [M ⁇ + ].
  • Recombinant human MMP 12 catalytic domain may be expressed and purified as described by Parkar A.A. et al, (2000), Protein Expression and Purification, 20:152.
  • the purified enzyme can be used to monitor inhibitors of activity as follows: MMP 12 (50 ng/ml final concentration) is incubated for 60 minutes at room temperature with the synthetic substrate Mac-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH 2 in assay buffer (0.1M "Tris-HCl” (trade mark) buffer, pH 7.3 containing 0.1M NaCl, 20mM CaCl 2 , 0.020 mM ZnCl and 0.05% (w/v) "Brij 35" (trade mark) detergent) in the presence (5 concentrations) or absence of inhibitors.
  • assay buffer 0.1M "Tris-HCl” (trade mark) buffer, pH 7.3 containing 0.1M NaCl, 20mM CaCl 2 , 0.020 mM ZnCl and 0.0
  • Activity is determined by measuring the fluorescence at ⁇ ex 320nm and ⁇ em 405nm. Percent inhibition is calculated as follows: % Inhibition is equal to the [Fluorescence ⁇ inhibi t or - uo ⁇ es,ccnce back g round ] divided by the [Fluorescence m nM ⁇ inhibi t or- ⁇ ⁇ escence background ).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés représentés par la formule (I), dans laquelle R1, G1 et G2 sont tels que définis dans la description. L'invention concerne également des procédés de préparation de ces composés, des compositions pharmaceutiques les contenant, un procédé de préparation de ces compositions pharmaceutiques et leur utilisation en thérapie.
PCT/SE2003/001407 2002-09-11 2003-09-10 Derives d'imidazolidinedione et leur utilisation en tant qu'inhibiteurs de metalloproteinase WO2004024718A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003258942A AU2003258942A1 (en) 2002-09-11 2003-09-10 Imidazolidinedione-derivatives and their use as metalloproteinase inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0202693-8 2002-09-11
SE0202693A SE0202693D0 (sv) 2002-09-11 2002-09-11 Compounds

Publications (1)

Publication Number Publication Date
WO2004024718A1 true WO2004024718A1 (fr) 2004-03-25

Family

ID=20288963

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2003/001407 WO2004024718A1 (fr) 2002-09-11 2003-09-10 Derives d'imidazolidinedione et leur utilisation en tant qu'inhibiteurs de metalloproteinase

Country Status (3)

Country Link
AU (1) AU2003258942A1 (fr)
SE (1) SE0202693D0 (fr)
WO (1) WO2004024718A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006004533A1 (fr) * 2004-07-05 2006-01-12 Astrazeneca Ab Composes
WO2006065215A1 (fr) * 2004-12-17 2006-06-22 Astrazeneca Ab Nouveaux composes
WO2006065216A1 (fr) * 2004-12-17 2006-06-22 Astrazeneca Ab Derives d'hydantoine en tant qu'inhibiteurs de metalloproteinase
US7132434B2 (en) 2001-11-07 2006-11-07 Astrazeneca Ab Metalloproteinase inhibitors
WO2007106021A1 (fr) * 2006-03-16 2007-09-20 Astrazeneca Ab Procédé de synthèse de dérivés de chlorure de sulfonyle
US7354940B2 (en) 2002-08-27 2008-04-08 Astrazeneca Ab 2,5-dioxoimidazolidin-4-yl acetamines and analogues as inhibitors of metalloproteinase mmp12
JP2008513500A (ja) * 2004-09-21 2008-05-01 グラクソ グループ リミテッド 化学物質
US7368465B2 (en) 2001-03-15 2008-05-06 Astrazeneca Ab Metalloproteinase inhibitors
WO2009007747A3 (fr) * 2007-07-11 2009-03-05 Astrazeneca Ab Nouveaux composés
US7803793B2 (en) 2006-10-05 2010-09-28 Janssen Pharmaceutica Nv Heterocyclic derived metalloprotease inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1191024A1 (fr) * 2000-09-22 2002-03-27 Harald Tschesche Thiadiazines et leur utilisation comme inhibiteurs de métalloproteinases
WO2002074767A1 (fr) * 2001-03-15 2002-09-26 Astrazeneca Ab Inhibiteurs des metalloproteinases
WO2002074750A1 (fr) * 2001-03-15 2002-09-26 Astrazeneca Ab Inhibiteurs de metalloproteinase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1191024A1 (fr) * 2000-09-22 2002-03-27 Harald Tschesche Thiadiazines et leur utilisation comme inhibiteurs de métalloproteinases
WO2002074767A1 (fr) * 2001-03-15 2002-09-26 Astrazeneca Ab Inhibiteurs des metalloproteinases
WO2002074750A1 (fr) * 2001-03-15 2002-09-26 Astrazeneca Ab Inhibiteurs de metalloproteinase

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7625934B2 (en) 2001-03-15 2009-12-01 Astrazeneca Ab Metalloproteinase inhibitors
US7368465B2 (en) 2001-03-15 2008-05-06 Astrazeneca Ab Metalloproteinase inhibitors
US7132434B2 (en) 2001-11-07 2006-11-07 Astrazeneca Ab Metalloproteinase inhibitors
US7354940B2 (en) 2002-08-27 2008-04-08 Astrazeneca Ab 2,5-dioxoimidazolidin-4-yl acetamines and analogues as inhibitors of metalloproteinase mmp12
WO2006004533A1 (fr) * 2004-07-05 2006-01-12 Astrazeneca Ab Composes
JP2008505172A (ja) * 2004-07-05 2008-02-21 アストラゼネカ・アクチエボラーグ 化合物
JP2008513500A (ja) * 2004-09-21 2008-05-01 グラクソ グループ リミテッド 化学物質
RU2378269C2 (ru) * 2004-12-17 2010-01-10 Астразенека Аб Новые производные гидантоина в качестве ингибиторов металлопротеиназ
WO2006065216A1 (fr) * 2004-12-17 2006-06-22 Astrazeneca Ab Derives d'hydantoine en tant qu'inhibiteurs de metalloproteinase
RU2376301C2 (ru) * 2004-12-17 2009-12-20 Астразенека Аб Новые производные гидантоина в качестве ингибиторов металлопротеиназ
WO2006065215A1 (fr) * 2004-12-17 2006-06-22 Astrazeneca Ab Nouveaux composes
CN101080403B (zh) * 2004-12-17 2010-09-08 阿斯利康(瑞典)有限公司 作为金属蛋白酶抑制剂的新乙内酰脲衍生物
WO2007106021A1 (fr) * 2006-03-16 2007-09-20 Astrazeneca Ab Procédé de synthèse de dérivés de chlorure de sulfonyle
US7772403B2 (en) 2006-03-16 2010-08-10 Astrazeneca Ab Process to prepare sulfonyl chloride derivatives
US7803793B2 (en) 2006-10-05 2010-09-28 Janssen Pharmaceutica Nv Heterocyclic derived metalloprotease inhibitors
WO2009007747A3 (fr) * 2007-07-11 2009-03-05 Astrazeneca Ab Nouveaux composés

Also Published As

Publication number Publication date
AU2003258942A1 (en) 2004-04-30
SE0202693D0 (sv) 2002-09-11

Similar Documents

Publication Publication Date Title
US7662845B2 (en) 2,5-Dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase MMP12
JP5140058B2 (ja) メタロプロテイナーゼ阻害剤
US20040147573A1 (en) Metalloproteinase inhibitors
CA2569716C (fr) Derives de l'hydantoine pour le traitement des maladies respiratoires obstructives
US20100256166A1 (en) Novel Hydantoin Derivatives as Metalloproteinase Inhibitors
US20090299066A1 (en) Triazolone derivatives as mmp inhibitors for the treatment of asthma and copd
AU2002237626A1 (en) Metalloproteinase inhibitors
US20040110809A1 (en) Metalloproteinase inhibitors
WO2004024718A1 (fr) Derives d'imidazolidinedione et leur utilisation en tant qu'inhibiteurs de metalloproteinase
US7700604B2 (en) Hydantoin derivatives as metalloproteinase inhibitors
MXPA06014663A (es) Compuestos derivados de hdantoina.
WO2004024060A2 (fr) Composes
WO2005085232A1 (fr) Derives d'hydantoine destines a etre utilises en tant qu'inhibiteurs de tace et de l'aggrecanase
HK1099751B (en) Triazolone derivatives as mmp inhibitors for the treatment of asthma and copd
HK1091492B (en) Hydantoin derivatives as mmp inhibitors
HK1059932B (en) Metalloproteinase inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载