| Substituted azetidine compounds as cyclooxygenase-1-cyclooxygenase-2 inhibitors, and their preparation and use as medicaments -> Monitor Keywords |
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  Substituted azetidine compounds as cyclooxygenase-1-cyclooxygenase-2 inhibitors, and their preparation and use as medicamentsUSPTO Application #: 20070093469Title: Substituted azetidine compounds as cyclooxygenase-1-cyclooxygenase-2 inhibitors, and their preparation and use as medicaments Abstract: The present invention relates to substituted Azetidine compounds of general formula (I), methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans and animals. (end of abstract) Agent: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C. - Alexandria, VA, US Inventors: Rosa Cuberes Altisen, Jordi Frigola Constansa, Ines Alvares Mathieu USPTO Applicaton #: 20070093469 - Class: 514210170 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Four-membered And Includes At Least One Ring Nitrogen, Having -c(=x)-, Wherein X Is Chalcogen, Bonded Directly To The Four-membered Hetero Ring The Patent Description & Claims data below is from USPTO Patent Application 20070093469. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to substituted Azetidine compounds of general formula (I), methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans and animals. [0002] The metabolites of arachidonic acid, such as prostaglandins, lipoxygenases and thromboxane products are produced in a wide variety of tissues and play a key role in many physiological and pathophysiological processes, such as inflammation, pain and cancer. [0003] Prostaglandins, for example, are produced from cell membrane phospholipids via a cascade of enzymes, involving the conversion of arachidonic acid to a common prostaglandin precursor, PGH.sub.2, by the enzyme Cyclooxygenase. Today, two different subtypes of Cyclooxygenase are known, namely Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2). [0004] COX-1, which is not-inducible or modulated by glucocorticoids, is the constitutive cyclooxygenase isoform and is mainly responsible for the synthesis of cytoprotective prostaglandins in the gastrointestinal tract and the synthesis of thromboxane which triggers platelet aggregation in blood platelets. COX-2 is inducible and generally short lived except in the case of certain tumors where it is constitutively activated. COX-2 expression is stimulated in response to endotoxins, cytokines, hormones, growth factors and mitogens. [0005] Thus, the object of the present invention was to provide novel compounds that are particularly suitable as pharmacologically active substances in medicaments. Preferably these compounds should be suitable for inhibition of the Cyclooxygenase-1 and/or Cyclooxygenase-2 and for the prophylaxis and/or treatment of disorders related to these enzymes. [0006] It has surprisingly been found that the substituted compounds of general formula I given below, stereoisomers thereof, corresponding salts and corresponding solvates show inhibition of Cyclooxgenase-1 and Cyclooxygenase-2. [0007] Thus, in one of its aspects the present invention relates to substituted azetidine compounds of general formula I, wherein [0008] A represents a --C.dbd.O-moiety, a --CH.sub.2-moiety, a --CH.sub.2--C.dbd.O-moiety bonded to the azetidine ring via its carbonyl carbon atom, or a --O--C(.dbd.O)-moiety bonded to the azetidine ring via its carbonyl carbon atom, [0009] R.sup.1, R.sup.3, identical or different, represent a hydrogen atom or a linear or branched, saturated or unsaturated, optionally at least mono-substituted C.sub.1-4-aliphatic group, [0010] R.sup.2 represents a hydrogen atom, a hydroxyl group or a C.sub.1-3-alkoxy group, [0011] or R.sup.1 and R.sup.2 or R.sup.2 and R.sup.3 together form an --O--CH.sub.2--CH.sub.2-chain, which is optionally substituted with one or more methyl groups, [0012] R.sup.4 represents a hydrogen atom, an optionally at least mono-substituted aryl group, or a linear or branched, saturated or unsaturated aliphatic group, whereby said aliphatic group may be substituted by one or more substituents independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C.sub.1-4-alkoxy, branched or unbranched C.sub.1-4-perfluoroalkoxy and branched or unbranched C.sub.1-4-perfluoroalkyl, [0013] R.sup.5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, an --OR.sup.7-moiety, -an --NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an --NH--CO--R.sup.8-moiety, an --N(OH)--CO--NH.sub.2-moiety, an --O(CH.sub.2).sub.1-4ONO.sub.2-moiety, an optionally at least mono-substituted aryl group, or a carboxy-group, [0014] R.sup.6 represent a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, an --OR.sup.9-moiety, -an --NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an --NH--CO--R.sup.10-moiety, an --N(OH)--CO--NH.sub.2-moiety, an optionally at least mono-substituted aryl group, or a carboxy-group, [0015] R.sup.7, R.sup.8, R.sup.9, R.sup.10, independent from one another, represent a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, [0016] optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. [0017] It is highly preferred that for the substituted azetidine compounds of general formula I given above one or more of the following provisos (disclaimer) apply, namely [0018] that R.sup.1, R.sup.2 and R.sup.3 do not identically represent a hydrogen atom, and if A represents a --CH.sub.2-moiety, then at least two of the residues R.sup.1, R.sup.2 and R.sup.3 do not identically represent a hydrogen atom, [0019] that if A represents a --(C.dbd.O)-moiety, R.sup.4 represents a hydrogen atom and one of the residues R.sup.5 and R.sup.6 represents a hydrogen atom, then the other one of these residues R.sup.5 and R.sup.6 does not represent an --NH.sub.2-moiety, a --CONH.sub.2-moiety or a methyl group, which is substituted by an --NH.sub.2-moiety or an optionally substituted azaheterocycle, and [0020] that if A represents a --(C.dbd.O)-moiety, a --CH.sub.2--C.dbd.O-moiety bonded to the azetidine ring via its carbonyl atom, or a --O--C(.dbd.O)-moiety bonded to the azetidine ring via its carbonyl carbon atom and one of the residues R.sup.5 and R.sup.6 represents a hydrogen atom or a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, then the other one of these residues R.sup.5 and R.sup.6 does not represent an --NH.sub.2-- or -carboxy -moiety, [0021] If any of the afore mentioned substituents represents an aliphatic group, which is substituted by one or more, e.g. 1, 2, 3, 4 or 5, substituents, these substituents may, independent from one another, preferably be selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C.sub.1-4-alkoxy, branched or unbranched C.sub.1-4-perfluoroalkoxy, branched or unbranched C.sub.1-4-perfluoroalkyl, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy and CF.sub.3. [0022] Preferred linear or branched, saturated or unsaturated aliphatic groups, which may be substituted by one or more substituents, may preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, vinyl, ethinyl, propenyl, propinyl, butenyl and butinyl. [0023] If any of the afore mentioned substituents represents an aryl group, which is substituted by one or more, e.g. 1, 2, 3, 4 or 5, substituents, these substituents may, independent from one another, preferably be selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C.sub.1-4-alkyl, branched or unbranched C.sub.2-4-alkenyl, branched or unbranched C.sub.2-4-alkinyl, branched or unbranched C.sub.1-4-alkoxy, branched or unbranched C.sub.1-4-perfluoroalkoxy, branched or unbranched C.sub.1-4-perfluoroalkyl, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, n-propyl, iso-propyl, tert.-Butyl, n-Butyl, sec-Butyl, methoxy, ethoxy and CF.sub.3. [0024] Preferred aryl groups, which may optionally be at least mono-substituted, are phenyl and naphthyl. [0025] Preferred are compounds of general formula I given above, wherein R.sup.1 and R.sup.3, identical or different, represent a hydrogen atom or a linear or branched C.sub.1-4-alkyl group, preferably R.sup.1 and R.sup.3 are identical and represent an unsubstituted C.sub.1-4-alkyl group, more preferably R.sup.1 and R.sup.3 are identical and represent a C.sub.3-4 alkyl group, most preferably R.sup.1 and R.sup.3 are identical and represent an iso-propyl group or a tert.-Butyl group and R.sup.2, R.sup.4-R.sup.10 and A have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. [0026] Also preferred are compounds of general formula I given above, wherein R.sup.2 represents a hydrogen atom, a hydroxyl group or a methoxy group, and R.sup.1, R.sup.3-R.sup.10 and A have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. [0027] Furthermore, compounds of general formula I are preferred, in which R.sup.4 represents a hydrogen atom, an optionally at least mono-substituted phenyl group, or a linear or branched, saturated or unsaturated C.sub.1-6 aliphatic group, whereby said aliphatic group may be substituted with one or more substituents independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C.sub.1-4-alkoxy, branched or unbranched C.sub.1-4-perfluoroalkoxy and branched or unbranched C.sub.1-4-perfluoroalkyl, more preferably R.sup.4 a hydrogen atom, a methyl group or an unsubstituted phenyl group and R.sup.1-R.sup.3, R.sup.5-R.sup.10 and A have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. [0028] Preference is also given to compounds of general formula I given above, in which R.sup.5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched, saturated or unsaturated, optionally at least mono-substituted C.sub.1-6 aliphatic group, an --NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an --NH--CO--R.sup.8-moiety, an --N(OH)--CO--NH.sub.2-moiety, an --O(CH.sub.2).sub.4--ONO.sub.2-moiety, an optionally at least mono-substituted phenyl group, or a carboxy-group, preferably a hydrogen atom, a bromine atom, a hydroxyl group, an --NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an --NH--CO--R.sup.8-moiety, an --N(OH)--CO--NH.sub.2-moiety, --O(CH.sub.2).sub.4--ONO.sub.2-moiety, an unsubstituted phenyl group, or a carboxy-group, and R.sup.1-R.sup.4, R.sup.6-R.sup.10 and A have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. [0029] Also preferred are compounds of general formula I, in which R.sup.6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched, saturated or unsaturated, optionally at least mono-substituted C.sub.1-6 aliphatic group, an --NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an --NH--CO--R.sup.8-moiety, an --N(OH)--CO--NH.sub.2-moiety, an optionally at least mono-substituted phenyl group, or a carboxy-group, preferably a hydrogen atom, a hydroxyl group or a methyl group, and R.sup.1-R.sup.5, R.sup.7-R.sup.10 and A have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. [0030] Preferred are also compounds of general formula I given above, in which R.sup.7, R.sup.8, R.sup.9, R.sup.10, independent from one another, represent a linear or branched, saturated or unsaturated, optionally at least mono-substituted C.sub.1-6 aliphatic group, preferably a linear or branched C.sub.1-6 alkyl group, more preferably a methyl group or an ethyl group, and R.sup.1-R.sup.6 and A have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. [0031] Particularly preferred are substituted azetidine compounds of general formula I, wherein [0032] A represents a --C.dbd.O-moiety, a --CH.sub.2-moiety, a --CH.sub.2--C.dbd.O-moiety bonded to the azetidine ring via its carbonyl carbon atom, or a --O--C(.dbd.O)-moiety bonded to the azetidine ring via its carbonyl carbon atom, [0033] R.sup.1, R.sup.3 both represent an iso-propyl group or a tert.-butyl group, [0034] R.sup.2 represents a hydrogen atom, a hydroxyl group or a methoxy group, [0035] or R.sup.1 and R.sup.2 or R.sup.2 and R.sup.3 together form an --O--CH.sub.2--C(CH.sub.3).sub.2-chain, whereby the oxygen atom of said chain is bonded to the 4-position of the phenyl ring, [0036] R.sup.4 represents a hydrogen atom, a methyl group or an unsubstituted phenyl group, [0037] R.sup.5 represents a bromine atom, a hydroxyl group, -an --NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an --NH--CO--CF.sub.3-moiety, an --N(OH)--CO--NH.sub.2-moiety, an --O(CH.sub.2).sub.4ONO.sub.2-moiety, an unsubstituted phenyl group, or a carboxy-group, [0038] R.sup.6 represents hydrogen atom, a methyl group or a hydroxyl group, [0039] optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. [0040] Most particularly preferred are compounds of general formula I selected from the group consisting of [0041] [1] (3,5-di-tert-butyl-4-hydroxy-phenyly(3-hydroxy-azetidin-1-yl)-methanone; [0042] [2] (3,5-di-tert-butyl-phenyly)-(3-hydroxy-azetidin-1-yl)-methanone; [0043] [3] (3,5-di-tert-butyl4-hydroxy-phenyl)-(3-hydroxy-3-methyl-azetidin-1-yl- )-methanone; [0044] [4] (3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-2-methyl-azetidin-1-yl)-m- ethanone; [0045] [7] (3-Bromo-azetidin-1-yl)-(3,5-di-tert-butyl-4-hydroxy-phenyl)-methanone; [0046] [9] (3,5-di-tert-butyl-4-methoxy-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone; [0047] [10] (3-hydroxy-azetidin-1-yl)-(4-hydroxy-3,5-diisopropyl-phenyl)-methanone; [0048] [11] (3,5-di-tert-butyl-phenyl)-[3-(4-nitrooxy-butoxy)-azetidin-1-yl]-methanon- e; [0049] [12] (3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-2-phenyl-azetidin-1-yl)-m- ethanone; [0050] [13] (3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-3-phenyl-azetidin-1-yl)-m- ethanone; [0051] [14] (7-tert-butyl-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-(3-hydroxy-azetid- in-1-yl)-methanone; [0052] [15] [1-(3,5-di-tert-butyl-4-hydroxy-benzyl)-azetidin-3-yl]-N-hydroxy-urea; [0053] [16] N-[1-(3,5-di-tert-butyl-4-hydroxy-benzoyly (2S,3R)-2-methyl-azetidin-3-yl]-2,2,2-trifluoro-acetamide; [0054] [17] 1-(3,5-di-tert-butyl-4-hydroxy-benzyl)-azetidin-3-ol; [0055] [18] 2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-1-(3-hydroxy-azetidin-1-yl)-ethano- ne; [0056] [19] (3-hydroxy-azetidine-1-carboxylic acid)-3,5-di-tert-butyl-phenyl ester optionally in form of a corresponding salt or a corresponding solvate. [0057] In another aspect the present invention relates to a process for the preparation of the inventive substituted azetidine compounds of general formula I given above, according to which at least one compound of general formula II, wherein R.sup.1-R.sup.3 have the meaning given above, X represents a bond or an --(CH.sub.2)-moiety and R represents a carboxy group or an activated carbonyl group, is reacted with at least one compound of general formula III, optionally in the form of a corresponding salt, wherein R.sup.4-R.sup.6 have the meaning given above, to yield a compound of general formula I given above, wherein R.sup.1 to R.sup.6 have the meaning given above and A represents a --(C.dbd.O)-moiety or a --(CH.sub.2)--CO-moiety, which is optionally purified and/or optionally isolated, [0058] and optionally at least one compound of general formula I, wherein A represents a --(C.dbd.O)-moiety is reduced to yield at least one compound of general formula I, wherein R.sup.1-R.sup.6 have the meaning given above and A represents a --(CH.sub.2)-moiety, which is optionally purified and/or optionally isolated, [0059] or at least one compound of general formula IV, [0060] wherein R.sup.1-R.sup.3 have the meaning given above, is reacted with at least one compound of general formula III given above, to yield at least one compound of general formula I, wherein R.sup.1-R.sup.6 have the meaning given above and A represents an O--(C.dbd.O)-moiety, and said compound is optionally purified and/or optionally isolated. [0061] Compounds of general formula (II) may be prepared by conventional methods known to those skilled in the art. [0062] The reaction of compounds of general formula (II) and general formula (III) may also be carried out according to conventional methods well known to those skilled in the art. The compounds of general formula II may either be used in form of the free carboxylic acid, i.e. R represents a --COOH group, or in form of an activated carbonyl group. Suitable activating groups and methods for activation are well-known to those skilled in the art, e.g. activation with N,N-Dicyclohexylcarbodiimide or other coupling reagents. [0063] The reaction between compounds of of general formula II and compounds of general formula III is preferably carried out in a suitable reaction medium such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like. Reaction temperatures and reaction times may vary over a broad range. The temperature is preferably kept in the range of ambient temperature, i.e. approximately 25.degree. C. and the boiling point of the reaction medium. Suitable reaction times may vary over a broad range, i.e. from a few minutes to several hours. Continue reading... Full patent description for Substituted azetidine compounds as cyclooxygenase-1-cyclooxygenase-2 inhibitors, and their preparation and use as medicaments Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Substituted azetidine compounds as cyclooxygenase-1-cyclooxygenase-2 inhibitors, and their preparation and use as medicaments patent application. 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