WO2000007582A2 - Utilisation de derives de thiazolidinedione pour le traitement ou la prevention de cataractes - Google Patents

Utilisation de derives de thiazolidinedione pour le traitement ou la prevention de cataractes Download PDF

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Publication number
WO2000007582A2
WO2000007582A2 PCT/US1999/013810 US9913810W WO0007582A2 WO 2000007582 A2 WO2000007582 A2 WO 2000007582A2 US 9913810 W US9913810 W US 9913810W WO 0007582 A2 WO0007582 A2 WO 0007582A2
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group
cataracts
alkyl
substituted
pharmaceutically acceptable
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PCT/US1999/013810
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WO2000007582A3 (fr
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John Hardwick Johnson
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Warner-Lambert Company
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Priority to AU46949/99A priority Critical patent/AU4694999A/en
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Publication of WO2000007582A3 publication Critical patent/WO2000007582A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts

Definitions

  • the present invention relates to a method of using thiazolidinedione derivatives to treat or prevent cataracts.
  • Thiazolidinediones derivatives are known to be useful in the treatment of noninsulin dependent diabetes mellitus (NIDDM). Many thiazolidinedione derivatives and methods of making thiazolidinedione derivatives are known and have been disclosed in United States Patents 5,223,522, issued June 29, 1993;
  • Cataracts are characterized by a progressive, painless loss of vision due to opacity of the lens of the eye.
  • causes of cataracts include aging, exposure to x-rays, heat from infrared exposure, systemic disease, such as diabetes mellitus, uveitis or systemic medications, such as corticosteroids.
  • Treatment of cataracts presently includes prescription eyeglasses and surgery to remove the affected lens of the eye and replace it with an artificial lens. Thus, it would be useful to have a medicine that could be use to treat and/or prevent cataracts.
  • the present provides a method of treating or preventing cataracts, the method comprising administering to a patient having cataracts or at risk of developing cataracts a therapeutically effective amount of a compound of Formula I
  • R ⁇ and R ⁇ are the same or different and each represents a hydrogen atom or a C ⁇ -C5 alkyl group
  • R3 represents a hydrogen atom, a Cj-Cg aliphatic acyl group, an alicyclic acyl group, an aromatic acyl group, a heterocyclic acyl group, an araliphatic acyl group, a (Cj-Cg alkoxy)carbonyl group, or an aralkyloxycarbonyl group;
  • R4 and R ⁇ are the same or different and each represents a hydrogen atom, a Ci -C5 alkyl group or a C1-C5 alkoxy group, or R ⁇ and R ⁇ together represent a
  • R6 represents any one of the atoms or groups defined for R ⁇ and may be the same as or different from R 3 );
  • the present invention also provides a method of treating or preventing cataracts, the method comprising administering to a patient having cataracts or at risk of developing cataracts a therapeutically effective amount of a compound of Formula II
  • R ⁇ ⁇ is substituted or unsubstituted alkyl, alkoxy, cycloalkyl, phenylalkyl, phenyl, aromatic acyl group, a 5- or 6-membered heterocyclic group including 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or a group of the formula
  • Ri 3 and R14 are the same or different and each is lower alkyl or Ri 3 and
  • Ri 4 are combined to each other either directly or as interrupted by a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur to form a 5- or 6-membered ring; Ri 2 is a bond or a lower alkylene group; and wherein L ⁇ and L2 are the same or different and each is hydrogen or lower alkyl or L ⁇ and L2 are combined to form an alkylene group; or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method of treating or preventing cataracts, the method comprising administering to a patient having cataracts or at risk of developing cataracts a therapeutically effective amount of a compound of Formula III
  • Ri 5 and R ⁇ are independently hydrogen, lower alkyl containing
  • n 0 to 4 and the pharmaceutically acceptable salts thereof.
  • the present invention also provides a method of treating or preventing cataracts, the method comprising administering to a patient having cataracts or at risk of developing cataracts a therapeutically effective amount of a compound of Formula IV
  • Y is CH or N;
  • Z is hydrogen, (C ⁇ -C7)alkyl, (C3-C7)cycloalkyl, phenyl, naphthyl, pyridyl, furyl, thienyl, or phenyl mono- or disubstituted with the same or different groups which are (C ⁇ -C3)alkyl, trifluoromethyl, (C1 -C3)alkoxy, fluoro, chloro, or bromo;
  • Z1 is hydrogen or (C ⁇ -C3)alkyl
  • Ri 7 and Rjg are each independently hydrogen or methyl; and n is 1, 2, or 3; the pharmaceutically acceptable cationic salts thereof; and the pharmaceutically acceptable acid addition salts thereof when the compound contains a basic nitrogen.
  • the present invention also provides a method of treating or preventing cataracts, the method comprising administering to a patient having cataracts or at risk of developing cataracts a therapeutically effective amount of a compound of Formula V
  • a and B are each independently CH or N, with the proviso that when A or
  • B is N, the other is CH;
  • X] is S, SO, SO 2 , CH , CHOH, or CO; n is 0 or 1 ;
  • Y ⁇ is CHR20 or R21, with the proviso that when n is 1 and Yi is NR21 , X! is SO 2 or CO;
  • Rj9, R20, R-21 J and R22 are each independently hydrogen or methyl; and X2 and X3 are each independently hydrogen, methyl, trifluoromethyl, phenyl, benzyl, hydroxy, methoxy, phenoxy, benzyloxy, bromo, chloro, or fluoro; a pharmaceutically acceptable cationic salt thereof; or a pharmaceutically acceptable acid addition salt thereof when A or B is N.
  • the present invention also provides a method of treating or preventing cataracts, the method comprising administering to a patient having cataracts or at risk of developing cataracts a therapeutically effective amount of a compound of
  • R23 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or mono- or di-substituted phenyl wherein said substituents are independently alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen, or trifluoromethyl.
  • the present invention also provides a method of treating or preventing cataracts, the method comprising administering to a patient having cataracts or at risk of developing cataracts a therapeutically effective amount of a compound of Formula VII
  • A2 represents an alkyl group, a substituted or unsubstituted aryl group, or an aralkyl group wherein the alkylene or the aryl moiety may be substituted or unsubstituted;
  • A3 represents a benzene ring having in total up to 3 optional substituents;
  • R24 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group wherein the alkyl or the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group; or
  • A2 together with R24 represents substituted or unsubstituted C2-.3 polymethylene group, optional substituents for the polymethylene group being selected from alkyl or aryl or adjacent substituents together with the methylene carbon atoms to which they are attached form a substituted or unsubstituted phenylene group;
  • R25 and R26 each represent hydrogen, or R25 and R26 together represent a bond
  • the present invention also provides a method of treating or preventing cataracts, the method comprising administering to a patient having cataracts or at risk of developing cataracts a therapeutically effective amount of a compound of Formula VIII
  • R27 and R28 each independently represent an alkyl group, a substituted or unsubstituted aryl group, or an aralkyl group being substituted or unsubstituted in the aryl or alkyl moiety; or
  • R27 together with R28 represents a linking group, the linking group consisting of an optionally substituted methylene group and either a further optionally substituted methylene group or an O or S atom, optional substituents for the said methylene groups being selected from alkyl-, aryl, or aralkyl, or substituents of adjacent methylene groups together with the carbon atoms to which they are attached form a substituted or unsubstituted phenylene group;
  • R29 and R30 each represent hydrogen, or R29 and R30 together represent a bond
  • A4 represents a benzene ring having in total up to 3 optional substituents;
  • X5 represents O or S; and
  • n represents an integer in the range of from 2 to 6.
  • the present invention also provides a method of treating or preventing cataracts, the method comprising administering to a patient having cataracts or at risk of developing cataracts a therapeutically effective amount of a compound of Formula IX
  • A5 represents a substituted or unsubstituted aromatic heterocyclyl group
  • Ag represents a benzene ring having in total up to 5 substituents
  • X represents O, S, or NR32 wherein R32 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
  • Y2 represents O or S;
  • R31 represents a hydrogen, alkyl, aralkyl, or aryl group; and
  • n represents an integer in the range of from 2 to 6.
  • Suitable aromatic heterocyclyl groups include substituted or unsubstituted, single or fused ring aromatic heterocyclyl groups comprising up to 4 heteroatoms in each ring selected from oxygen, sulphur, or nitrogen.
  • Favored aromatic heterocyclyl groups include substituted or unsubstituted single ring aromatic heterocyclyl groups having 4 to 7 ring atoms, preferably 5 or 6 ring atoms.
  • the aromatic heterocyclyl group comprises 1 , 2, or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulphur, or nitrogen.
  • Suitable values for A5 when it represents a 5-membered aromatic heterocyclyl group include thiazolyl and oxazoyl, especially oxazoyl.
  • Suitable values for A5 when it represents a 6-membered aromatic heterocyclyl group include pyridyl or pyrimidinyl.
  • Suitable R31 represents an alkyl group, in particular a Ci .g alkyl group, for example a methyl group.
  • A5 represents a moiety of formula (a), (b), or (c): wherein:
  • R33 and R34 each independently represents a hydrogen atom, an alkyl group, or a substituted or unsubstituted aryl group or when R33 and R34 are each attached to adjacent carbon atoms, then R33 and R34 together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R33 and R34 together may be substituted or unsubstituted; and in the moiety of Formula (a), X7 represents oxygen or sulphur.
  • R33 and R34 together represent a moiety of
  • R35 and R3 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, or alkoxy.
  • the present invention also provides a method of treating or preventing cataracts, the method comprising administering to a patient having cataracts or at risk of developing cataracts a therapeutically effective amount of a compound of Formula X
  • A7 represents a substituted or unsubstituted aryl group
  • A represents a benzene ring having in total up to 5 substituents
  • X represents O, S, or NR39 wherein R39 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group
  • Y3 represents O or S;
  • R37 represents hydrogen
  • R3 represents hydrogen or an alkyl, aralkyl, or aryl group or R37 together with R38 represents a bond; and n represents an integer in the range of from 2 to 6.
  • Ri or R ⁇ represents an alkyl group
  • this may be a straight or branched chain alkyl group having from 1 to 5 carbon atoms and is preferably a primary or secondary alkyl group, for example the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl group.
  • R 3 , R6, or R ⁇ represents an aliphatic acyl group, this preferably has from 1 to 6 carbon atoms and may include one or more carbon-carbon double or triple bonds.
  • examples of such groups include the formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, and crotonyl groups.
  • R , R6, or R6 represents an alicyclic acyl group, it is preferably a cyclopentanecarbonyl, cyclohexanecarbonyl, or cycloheptanecarbonyl group.
  • R6, or R ⁇ represents an aromatic acyl group
  • the aromatic moiety thereof may optionally have one or more substituents (for example, nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl, or hydroxy substituents); examples of such aromatic acyl groups included the benzoyl, p-nitrobenzoyl, m-fiuorobenzoyl, o-chlorobenzoyl, p-aminobenzoyl, m-(dimethylamino)benzoyl, o-methoxybenzoyl, 3,4-dichlorobenzoyl, 3,5-di-t-butyl-4-hydroxybenzoyl, and 1-naphthoyl groups.
  • substituents for example, nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl, or hydroxy substituents
  • substituents for example, nitro, amino, alky
  • R , R6, or R ⁇ represents a heterocyclic acyl group
  • the heterocyclic moiety thereof preferably has one or more, preferably one, oxygen, sulfur, or nitrogen heteroatoms and has from 4 to 7 ring atoms
  • examples of such heterocyclic acyl groups include the 2-furoyl, 3-thenoyl, 3-pyridinecarbonyl (nicotinoyl), and 4-pyridinecarbonyl groups.
  • R 3 , R6, or R ⁇ represents an araliphatic acyl group
  • the aliphatic moiety thereof may optionally have one or more carbon-carbon double or triple bonds and the aryl moiety thereof may optionally have one or more substituents (for example, nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl, or hydroxy substituents);
  • substituents for example, nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl, or hydroxy substituents
  • examples of such araliphatic acyl groups include the phenylacetyl, p-chlorophenylacetyl, phenylpropionyl, and cinnamoyl groups.
  • R 3 , R6 5 or R6 represents a (Ci -C ⁇ alkoxy ⁇ arbonyl group, the alkyl
  • R3, R6, or R6 is therefore preferably a methoxycarbonyl or ethoxycarbonyl group.
  • R 3 , R° or R ⁇ represents an aralkyloxycarbonyl group
  • the aralkyl moiety thereof may be any one of those included within the araliphatic acyl group represented by R 3 , R6, 0 r R ⁇ , but is preferably a benzyloxycarbonyl group.
  • R ⁇ and R ⁇ represent alkyl groups, they may be the same or different and may be straight or branched chain alkyl groups. They preferably have from 1 to 5 carbon atoms and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and isopentyl groups.
  • R ⁇ and R ⁇ represent alkoxy groups, these may be the same or different and may be straight or branched chain groups, preferably having from
  • R ⁇ and R ⁇ may together represent a
  • C ⁇ -C6 aliphatic acyl group an aromatic acyl group, or a heterocyclic acyl group.
  • R5 are the same or different and each represents a hydrogen atom or a C1-C5 alkyl group; n is 1 or 2; and W represents the -CH2- or >CO group.
  • R 3 represents a hydrogen atom, a C1-C5 aliphatic acyl group, a benzoyl group, or a nicotinyl group.
  • R* and R ⁇ are the same or different and each represents a C1-C5 alkyl group
  • R ⁇ and R ⁇ are the same or different and each represents the hydrogen atom or the methyl group
  • R3 represents a hydrogen atom or a C ⁇ -C4 aliphatic acyl group.
  • W represents the -CH2- or >CO group
  • Y and Z both represent oxygen atoms
  • n is 1 or 2
  • Rl and R ⁇ are the same or different and each represents a C1 -C4 alkyl group
  • R2 and R ⁇ are the same or different and each represents the hydrogen atom or the methyl group
  • R3 represents a hydrogen atom or a C1 -C4 aliphatic acyl group.
  • Preferred compounds among the compounds of Formula 1 are those wherein:
  • Rl is a C1-C4 alkyl group, more preferably a methyl or isobutyl group, most preferably a methyl group;
  • R2 is a hydrogen atom or a C ⁇ -C4 alkyl group, preferably a hydrogen atom, or a methyl or isopropyl group, more preferably a hydrogen atom or a methyl group, most preferably a methyl group;
  • R3 is a hydrogen atom, a C1 -C4 aliphatic acyl group, an aromatic acyl group or a pyridinecarbonyl group, preferably a hydrogen atom, or an acetyl, butyryl, benzoyl, or nicotinyl group, more preferably a hydrogen atom or an acetyl, butyryl or benzoyl group, most preferably a hydrogen atom or an acetyl group;
  • R4 is a hydrogen atom, a C ⁇ -C4 alkyl group or a C ⁇ or C2 alkoxy group, preferably a methyl, isopropyl, t-butyl, or methoxy group, more preferably a methyl or t-butyl group, most preferably a methyl group;
  • R5 is a hydrogen atom, a C1 -C4 alkyl group or a C ⁇ or C2 alkoxy group, preferably a hydrogen atom, or a methyl or methoxy group, more preferably a hydrogen atom or a methyl group, and most preferably a methyl group;
  • n is 1 or 2, preferably 1 ;
  • Y is an oxygen atom;
  • Z is an oxygen atom or an imino group, most preferably an oxygen atom
  • the substituents may be any from 1 to 3 selected from nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl, or hydroxy, the aromatic acyl group may be benzoyl and naphthoyl.
  • the alkyl group R ⁇ 1 may be a straight chain or branched alkyl of 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl; the cycloalkyl group R ⁇ ⁇ may be a cycloalkyl group of 3 to 7 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl; and the phenylalkyl group R ⁇ ⁇ may be a phenylalkyl group of 7 to 11 carbon atoms such as benzyl and phenethyl.
  • heterocyclic group R ⁇ ⁇ may be mentioned 5- or 6-membered groups each including 1 or 2 hetero-atoms selected from among nitrogen, oxygen, and sulfur, such as pyridyl, thienyl, furyl, thiazolyl, etc.
  • the lower alkyls Ri 3 and R14 may each be a lower alkyl of 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, and n-butyl.
  • Ri 3 and R14 are combined to each other to form a 5- or 6-membered heterocyclic group as taken together with the adjacent N atom, ie, in the form of
  • this heterocyclic group may further include a heteroatom selected from among nitrogen, oxygen, and sulfur as exemplified by piperidino, morpholino, pyrrolidino, and piperazino.
  • the lower alkylene group R12 may contain 1 to
  • R12 when R12 is a bond, the atoms adjacent thereto on both sides are directly combined together.
  • the lower alkyls h ⁇ and L2 there may be mentioned lower alkyl groups of 1 to 3 carbon atoms, such as methyl and ethyl.
  • the alkylene group formed as L ⁇ and L2 are joined together is a group of the formula -(CH2) n - [where n is an integer of 2 to 6].
  • n is an integer of 2 to 6].
  • the cycloalkyl, phenylalkyl, phenyl, and heterocyclic groups mentioned above, as well as said heterocyclic group is a group of the formula -(CH2) n - [where n is an integer of 2 to 6].
  • substituents may be mentioned lower alkyls (eg, methyl, ethyl, etc.), lower alkoxy groups (eg, methoxy, ethoxy, etc.), halogens (eg, chlorine, bromine, etc.), and hydroxyl.
  • lower alkyls eg, methyl, ethyl, etc.
  • lower alkoxy groups eg, methoxy, ethoxy, etc.
  • halogens eg, chlorine, bromine, etc.
  • hydroxyl hydroxyl
  • the preferred compounds of Formula III are those wherein R ⁇ ⁇ and
  • Rjg are independently hydrogen, lower alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms, halogen, ethynyl, nitrile, trifluoromethyl, vinyl, or nitro; n is 1 or 2 and the pharmaceutically acceptable salts thereof.
  • -CH N- and Y is CH.
  • X is O or S and Y is N forming an oxazol-4-yl, oxazol-5-yl, thiazol-4-yl, or thiazol-5-yl group; most particularly a 2-[(2-thienyl), (2-furyl), phenyl, or substituted phenyl]-5-methyl- 4-oxazolyl group.
  • the preferred compounds in Formula V are: a) those wherein the dotted line represents no bond, A and B are each CH, Xi is CO, n is 0, R19 is hydrogen, Z is CH 2 CH or CHICH and X3 is hydrogen, particularly when X2 is hydrogen, 2-methoxy,
  • X2 is hydrogen or 4-chloro.
  • a preferred group of compounds is that of Formula VI wherein R23 is
  • (C1 -Cg)alkyl (C3-C7)cycloalkyl, phenyl, halophenyl, or (Cj-C6)alkylphenyl.
  • R23 is phenyl, methylphenyl, fluorophenyl, chlorophenyl, or cyclohexyl.
  • the term ''aryl includes phenyl and naphthyl, suitably phenyl, optionally substituted with up to 5, preferably up to 3, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxyearbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
  • halogen refers to fluorine, chlorine, bromine, and iodine; preferably chlorine.
  • alkyl and alkoxy relate to groups having straight or branched carbon chains, containing up to 12 carbon atoms.
  • Suitable alkyl groups are C]_i2 alkyl groups, especially Ci .g alkyl groups, eg, methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, or tert-butyl groups.
  • Suitable substituents for any alkyl group include those indicated above in relation to the term "aryl”.
  • Suitable substituents for any heterocyclyl group include up to 4 substituents selected from the group consisting of alkyl, alkoxy, aryl, and halogen or any 2 substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a benzene ring, and wherein the carbon atoms of the aryl group represented by the said
  • Pharmaceutically acceptable acid addition salts of the compounds of Formulas I through X include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like
  • nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like and gluconate, galacturonate, n-methyl glucamine (see, for example, Berge S.M. et al., "Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977;66:1-19).
  • the acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner or as above.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1-19).
  • the base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner or as above.
  • the free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in different configurations. The compounds can, therefore, form stereoisomers. Although these are all represented herein by a limited number of molecular formulas, the present invention includes the use of both the individual, isolated isomers and mixtures, including racemates, thereof.
  • thiazolidene part of the compound of Formulas I through X can exist in the form of tautomeric isomers. All of the tautomers are represented by Formulas I through X, and are intended to be a part of the present invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included.
  • Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsules, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mg according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds utilized in the pharmaceutical methods of this invention are administered along with a pharmaceutically acceptable carrier at the initial dosage of about 0.01 mg to about 30 mg per kilogram daily.
  • 0.01 mg to about 10 mg per kilogram is preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • the example set forth below is intended to illustrate a particular embodiment of the invention and is not intended to limit the scope of the specification, including the claims, in any manner.

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

Abstract

La présente invention concerne une méthode d'utilisation de dérivés de thiazolidinone pour traiter ou prévenir les cataractes.
PCT/US1999/013810 1998-08-06 1999-06-18 Utilisation de derives de thiazolidinedione pour le traitement ou la prevention de cataractes WO2000007582A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU46949/99A AU4694999A (en) 1998-08-06 1999-06-18 Use of thiazolidinedione derivatives for the treatment or prevention of cataracts

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US9551898P 1998-08-06 1998-08-06
US60/095,518 1998-08-06

Publications (2)

Publication Number Publication Date
WO2000007582A2 true WO2000007582A2 (fr) 2000-02-17
WO2000007582A3 WO2000007582A3 (fr) 2000-06-22

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AR (1) AR021749A1 (fr)
CO (1) CO5050324A1 (fr)
PE (1) PE20000946A1 (fr)
UY (1) UY25643A1 (fr)
WO (1) WO2000007582A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019131897A1 (fr) * 2017-12-28 2019-07-04 国立大学法人福井大学 Agent prophylactique et/ou agent thérapeutique contre la cataracte, composition médicinale pour prévenir et/ou traiter la cataracte, utilisation d'un activateur de ppar pour produire ces derniers, et collyre

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0139421B1 (fr) * 1983-08-30 1988-04-27 Sankyo Company Limited Dérivés de la thiazolidine, leur préparation et composition les contenant
EP0277836A1 (fr) * 1987-02-04 1988-08-10 Sankyo Company Limited Dérivés de la thiazolidinone leur préparation et leur application
EP0869126A1 (fr) * 1997-04-02 1998-10-07 Sankyo Company Limited Dérivés de dithiolane leur préparation et leur effet thérapeutique

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62234085A (ja) * 1985-12-18 1987-10-14 Sankyo Co Ltd チアゾリジン誘導体を有効成分とする糖尿病性合併症治療剤
CA2265656A1 (fr) * 1996-09-12 1998-03-19 Sankyo Company, Limited Potentialisateur d'activite de glutathione-reductase contenant de la troglitazone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0139421B1 (fr) * 1983-08-30 1988-04-27 Sankyo Company Limited Dérivés de la thiazolidine, leur préparation et composition les contenant
EP0277836A1 (fr) * 1987-02-04 1988-08-10 Sankyo Company Limited Dérivés de la thiazolidinone leur préparation et leur application
EP0869126A1 (fr) * 1997-04-02 1998-10-07 Sankyo Company Limited Dérivés de dithiolane leur préparation et leur effet thérapeutique

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Troglitazone, Noscal.RTM.." DRUGS OF THE FUTURE, (1995) 20/9 (974-976)., XP000853998 *
ARAKI, KAZUSI (1) ET AL: "Troglitazone suppresses diabetic nephropathy and cataract formation without decreasing plasma glucose and blood pressure in severely diabetic ZDF rats." DIABETES, (1999) VOL. 48, NO. SUPPL. 1, PP. A138. MEETING INFO.: 59TH SCIENTIFIC SESSIONS OF THE AMERICAN DIABETES ASSOCIATION SAN DIEGO, CALIFORNIA, USA JUNE 19-22, 1999 AMERICAN DIABETES ASSOCIATION.,May 1999 (1999-05), XP000856147 *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US HORIKOSHI, HIROYOSHI ET AL: "Pharmaceutical compositions containing thiazolidine derivatives for the treatment of diseases related to diabetes" XP002123769 & JP 62 234085 A (SANKYO CO., LTD., JAPAN) 14 October 1987 (1987-10-14) *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US YOKOYAMA, TOMIHISA ET AL: "Glutathione reductase activity potentiator containing troglitazone" XP002123768 & WO 98 10760 A (SANKYO CO., LTD., JAPAN;YOKOYAMA, TOMIHISA; FUJIWARA, TOSHIHIKO; HORIK) 19 March 1998 (1998-03-19) *
MADAR Z (REPRINT) ET AL: "EFFECT OF CS-045 ON CATARACT APPEARANCE IN SAND RAT MODEL FOR DIABETES TYPE-II" DIABETES, (MAY 1993) VOL. 42, SUPP. 1, PP. A198. ISSN: 0012-1797., XP000853997 *
YOKOYAMA, TOMIHISA ET AL: "Inhibition of galactose-induced cataractogenesis by troglitazone, a new antidiabetic drug with an antioxidant property, in rat lens culture" J. OCUL. PHARMACOL. THER. (1999), 15(1), 73-83, XP000853996 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019131897A1 (fr) * 2017-12-28 2019-07-04 国立大学法人福井大学 Agent prophylactique et/ou agent thérapeutique contre la cataracte, composition médicinale pour prévenir et/ou traiter la cataracte, utilisation d'un activateur de ppar pour produire ces derniers, et collyre
JPWO2019131897A1 (ja) * 2017-12-28 2020-12-10 国立大学法人福井大学 白内障の予防剤および／または治療剤、白内障の予防および／または治療のための医薬組成物、これらを製造するためのｐｐａｒ活性化剤の使用、ならびに点眼剤

Also Published As

Publication number Publication date
PE20000946A1 (es) 2000-10-18
AR021749A1 (es) 2002-08-07
WO2000007582A3 (fr) 2000-06-22
UY25643A1 (es) 1999-11-17
CO5050324A1 (es) 2001-06-27

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