WO1997018811A1 - Procede de traitement de dystrophie myotonique - Google Patents

Procede de traitement de dystrophie myotonique Download PDF

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Publication number
WO1997018811A1
WO1997018811A1 PCT/US1996/017633 US9617633W WO9718811A1 WO 1997018811 A1 WO1997018811 A1 WO 1997018811A1 US 9617633 W US9617633 W US 9617633W WO 9718811 A1 WO9718811 A1 WO 9718811A1
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group
myotonic dystrophy
compound
alkyl
administering
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PCT/US1996/017633
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English (en)
Inventor
Dean Lockwood
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Warner-Lambert Company
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Priority to AU76045/96A priority Critical patent/AU7604596A/en
Publication of WO1997018811A1 publication Critical patent/WO1997018811A1/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
    • A61K31/41—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
    • 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
    • A61K31/433—Thidiazoles

Definitions

  • the present invention provides a method of treating myotonic dystrophy.
  • Myotonic dystrophy is the most common form of muscular dystrophy. This disease affects about one person in 8,000 and is a multisystem autosomal-dominant disease, carried on Chromosome 19, that has a wide spectrum of symptoms. In general, the major symptoms of myotonic dystrophy arise from damage to skeletal, cardiac, and smooth muscles.
  • Specific symptoms include, but are not limited to, cataracts, muscle weakness (particularly in the face, forearms, and foot dorsiflexors) , myotonia, muscle wasting, respiratory distress, hypotonia, feeding difficulty, talipes, mental retardation, cardiac arrhythmias (such as heart block, conduction disturbance, and atrial tachyarrhythmias) and respiratory disturbances (such as respiratory failure, sleep apnea, and hypersomnia).
  • the genetic defect that underlies myotonic dystrophy has recently been shown to involve the expansion of CTG repeats in the 3 ' -untranslated region of a gene that codes for a serine kinase. This gene is located at ql3.3 on the long arm of Chromosome 19. It has also been noticed that persons having myotonic dystrophy exhibit insulin resistance. See, for example, Livingston, et al . , "Myotonic Dystrophy: Phenotype-Genotype and Insulin Resistence, " Diabetes Review, 1994 ; 2(1) : 29-42, which is hereby incorporated by reference.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom or a C- ⁇ - ⁇ alkyl group
  • R 3 represents a hydrogen atom, a C -C 8 aliphatic acyl group, an alicyclic acyl group, an aromatic acyl group, a heterocyclic acyl group, an araliphatic acyl group, a (C 1 -C 6 alkox )carbonyl group, or an aralkyl- oxycarbonyl group;
  • the compound of Formula I is 5- [ [4- [ (3 ,4-dihydro-6-hydroxy- 2,5,7, 8-tetramethyl-2H-l-benzopyran-2-yl)methoxy] - phenyl]methyl] -2, 4-thiazolidinedione.
  • Another embodiment provides a method of treating myotonic dystrophy, the method comprising administering to a patient having myotonic dystrophy a therapeutically effective amount of a compound of Formula II
  • R 11 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
  • R 13 and R 14 are the same or different and each is lower alkyl or R 13 and R 14 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; wherein R 12 means a bond or a lower alkylene group; and wherein L x and L 2 are the same or different and each is hydrogen or lower alkyl or L and L 2 are combined to form an alkylene group, or a pharmaceutically acceptable salt thereof .
  • R 15 and R 16 are independently hydrogen, lower alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms, halogen, ethynyl, nitrile, methylthio, trifluoromethyl, vinyl, nitro, or halogen substituted benzyloxy; n is 0 to 4 and the pharmaceutically acceptable salts thereof.
  • the present invention also provides a method of treating myotonic dystrophy, the method comprising administering to a patient having myotonic dystrophy a therapeutically effective amount of a compound of Formula IV
  • Y is CH or N
  • Z is hydrogen, (C 1 -C 7 ) alkyl, (C 3 -C 7 )cycloalkyl, phenyl, naphthyl, pyridyl, furyl, thienyl, or phenyl mono- or disubstituted with the same or different groups which are (C-
  • Z ⁇ is hydrogen or C- y -C ⁇ )alkyl;
  • R 17 and R 18 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 provides a method of treating myotonic dystrophy, the method comprising administering to a patient having myotonic dystrophy 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, S0 2 , CH 2 , CHOH, or CO; n is 0 or 1; - is CHR 20 or R 21 , with the proviso that when n is 1 and Y 1 is NR 21 , X 2 is S0 2 or CO;
  • R i 9 ' R 20 ' R 2 i' anc ⁇ R 22 are each independently hydrogen or methyl
  • X 2 and X 3 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 provides a method of treating myotonic dystrophy, the method comprising administering to a patient having myotonic dystrophy a therapeutically effective amount of a compound of Formula VI
  • the present invention provides a method of treating myotonic dystrophy, the method comprising administering to a patient having myotonic dystrophy a therapeutically effective amount of a compound of Formula VII
  • a 2 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
  • a 3 represents a benzene ring having in total up to
  • R 24 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
  • a 2 together with R 24 represents substituted or unsubstituted C 2-3 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;
  • R 25 and R 26 each represent hydrogen, or R 25 and R 6 together represent a bond
  • the present invention provides a method of treating myotonic dystrophy, the method comprising administering to a patient having myotonic dystrophy a therapeutically effective amount of a compound of Formula VIII
  • R 27 and R 28 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 R 27 together with R 28 represents a linking group, the linking group consisting of an optionally substituted methylene group and either a further optionally substituted methylene group or an 0 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;
  • R 29 and R 30 each represent hydrogen, or R 2g and R 30 together represent a bond;
  • a 4 represents a benzene ring having in total up to 3 optional substituents;
  • X 5 represents O or S; and n represents an integer in the range of from 2 to 6.
  • the present invention provides a method of treating myotonic dystrophy, the method comprising administering to a patient having myotonic dystrophy a therapeutically effective amount of a compound of Formula IX
  • a 5 represents a substituted or unsubstituted aromatic heterocyclyl group
  • a 6 represents a benzene ring having in total up to 5 substituents
  • X 6 represents O, S, or NR 32 wherein R 32 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;
  • Y 2 represents 0 or S
  • R 31 represents an alkyl, aralkyl, or aryl group
  • n represents an integer in the range of from 2 to 6.
  • the present invention provides a method of treating myotonic dystrophy, the method comprising administering to a patient having myotonic dystrophy a therapeutically effective amount of a compound of Formula X
  • a 7 represents a substituted or unsubstituted aryl group
  • a 8 represents a benzene ring having in total up to
  • X 8 represents 0, S, or NR 39 wherein R 39 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; Y 3 represents O or S;
  • R 37 represents hydrogen
  • R 38 represents hydrogen or an alkyl, aralkyl, or aryl group or R 37 together with R 38 represents a bond; and n represents an integer in the range of from 2 to 6.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, Y, and Z are as defined above
  • the alkyl group may be a straight or branched chain alkyl group having from 1 to
  • R 3 or R 6 represents an aliphatic acyl group
  • the aliphatic acyl group preferably has from 1 to
  • groups include the formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, acryloyi, methacryloyl, and crotonyl groups .
  • R 3 or R 6 represents an alicyclic acyl group, it is preferably a cyclopentanecarbonyl, cyclohexane- carbonyl, or cycloheptanecarbonyl group.
  • R 3 or R 6 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-fluorobenzoyl, 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
  • examples of such aromatic acyl groups included the benzoyl
  • R 3 or R 6 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 or R 6 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 or R 6 represents a (C ⁇ C g alkoxy)carbonyl group
  • the alkyl moiety thereof may be any one of those alkyl groups as defined for R 1 and R 2 , but is preferably a methyl or ethyl group, and the alkoxycarbonyl group represented by R 3 or R 6 is therefore preferably a methoxycarbonyl or ethoxycarbonyl group.
  • R 3 or R 6 represents an aralkyloxycarbonyl group
  • the aralkyl moiety thereof may be any one of those included within the araliphatic acyl group represented by R 3 or R 6 , but is preferably a benzyloxycarbonyl group .
  • R 4 and R 5 represent alkyl groups
  • the alkyl groups can be the same or different and can be straight or branched chain alkyl groups.
  • the alkyl groups 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 4 and R 5 represent alkoxy groups
  • the alkoxy groups can be the same or different and can be straight or branched chain groups, preferably having from 1 to 4 carbon atoms . Examples include the methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups.
  • R 4 and R 5 can together represent a C 1 -C 4 alkylenedioxy group, more preferably a methylenedioxy or ethylenedioxy group.
  • Preferred classes of compounds of Formula I are as follows :
  • R 3 represents a hydrogen atom, a C- ⁇ C g aliphatic acyl group, an aromatic acyl group, or a heterocyclic acyl group.
  • R 1 , R 2 , R 4 , and R 5 are the same or different and each represents a hydrogen atom or a C 1 -C 5 alkyl group; n is 1 or 2; and W represents the ⁇ CH 2 - or >C0 group.
  • R 3 represents a hydrogen atom, a aliphatic acyl group, a benzoyl group, or a nicotinyl group.
  • R 1 and R 4 are the same or different and each represents a C ⁇ Cs alkyl group
  • R 2 and R 5 are the same or different and each represents the hydrogen atom or the methyl group
  • R 3 represents a hydrogen atom or a C ⁇ -C, ! aliphatic acyl group.
  • W represents the -CH 2 - or >C0 group
  • Y and Z both represent oxygen atoms
  • n is 1 or 2
  • R 1 and R 4 are the same or different and each represents a C 1 -C 4 alkyl group
  • R 2 and R 5 are the same or different and each represents the hydrogen atom or the methyl group
  • R 3 represents a hydrogen atom or a C ⁇ - ⁇ aliphatic acyl group.
  • R 1 is a C- ⁇ C ⁇ j alkyl group, more preferably a methyl or isobutyl group, most preferably a methyl group;
  • R 2 is a hydrogen atom or a C ⁇ -C 4 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;
  • R 3 is a hydrogen atom, a C- j _-C 4 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;
  • R 4 is a hydrogen atom, a C - ⁇ alkyl group or a C ⁇ or C 2 alkoxy group, preferably a methyl, isopropyl, t-butyl, or methoxy group, more preferably a methyl or t-butyl group, most preferably a methyl group;
  • R 5 is a hydrogen atom, a C 1 -C 4 alkyl group or a C ⁇ or C 2 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 12 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 1;I may be a cycloalkyl group of 3 to 7 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl; and the phenylalkyl group R l 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.
  • R 1X is R 13
  • R 14 the lower alkyls R 13 and R 14 may each be a lower alkyl of 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, and n-butyl.
  • R 13 and R 14 are combined to each other to form a 5- or 6-membered heterocyclic group as taken together with the adjacent N atom, i.e., 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 R 12 may contain 1 to 3 carbon atoms and thus may be, for example, methylene, ethylene, or trimethylene.
  • the bond R 12 is equivalent to the symbol "-", ".”, or the like which is used in chemical structural formulas, and when R 12 represents such a bond, the compound of general Formula II is represented by the following general Formula 11(a)
  • R 12 when R 12 is a bond, the atoms adjacent thereto on both sides are directly combined together.
  • the lower alkyls L ⁇ and L 2 there may be mentioned lower alkyl groups of 1 to 3 carbon atoms, such as methyl and ethyl .
  • the alkylene group formed as L 2 and L 2 are joined together is a group of the formula -(CH 2 ) n - [where n is an integer of 2 to 6] .
  • substituents may be mentioned lower alkyls (e.g. , methyl, ethyl, etc. ), lower alkoxy groups (e.g., methoxy, ethoxy, etc. ), halogens (e.g., chlorine, bromine, etc.), and hydroxyl.
  • lower alkyls e.g. , methyl, ethyl, etc.
  • lower alkoxy groups e.g., methoxy, ethoxy, etc.
  • halogens e.g., chlorine, bromine, etc.
  • R 15 and R 16 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.
  • Preferred in Formula IV are compounds wherein the dotted line represents no bond, particularly wherein D is CO or CHOH. More preferred are compounds wherein
  • Y is CH.
  • X is 0 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.
  • X 2 is hydrogen or 4-chloro.
  • a preferred group of compounds is that of Formula VI wherein R 23 is (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, phenyl, halophenyl, or (C j ⁇ -Cg)alkylphenyl .
  • R 23 is phenyl, methylphenyl, fluorophenyl, chlorophenyl, or cyclohexyl .
  • aryl includes phenyl and naphthyl, substituted phenyl, optionally substituted with up to 5, preferably up to 3, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyi, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonyl alkyl, 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 1 , 12 alkyl groups, especially C- ⁇ g alkyl groups, e.g., 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 2 substituents may themselves be substituted or unsubstituted.
  • a most preferred compound of the present invention is :
  • Ciglitazone is also known as 5-[p-[(l- Methylcyclohexyl)methoxy]benzyl] -2,4-thiazolidinedione .
  • Pioglitazone is also known as 5- [p- [2- (5-Ethyl-2- pyridyl)ethoxy]benzyl] -2, 4-thiazolidinedione .
  • Darglitazone is also known as 5- [p- [3- (5-Methyl- 2-phenyl-4-oxazolyl)propionyl]benzyl] -2,4- thiazolidinedione.
  • Englitazone is also known as 5- [ [ (2R) -2-Benzyl-6- ⁇ hromanyl]methyl] -2, 4-thiazolidinedione .
  • BRL 49653 is also known as 5- [ (4- [2-Methyl- 2- (prindinylamino)ethoxy]phenyl)methyl] -2, 4- thiazolidinedione- (Z) -2-butenedioate (1:1) .
  • patient includes humans and other animals .
  • the compounds of Formulas I through X are capable of further forming both pharmaceutically acceptable acid addition and/or base salts . All of these forms are within the scope of the present invention.
  • 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.
  • 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, ' -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.
  • 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. Where stereospecific synthesis techniques are employed or optically active compounds are employed as starting materials in the preparation of the compounds, individual isomers may be prepared directly; on the other hand, if a mixture of isomers is prepared, the individual isomers may be obtained by conventional resolution techniques, or the mixture may be used as it is, without resolution.
  • 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 600 mg preferably 0.5 mg to 400 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 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 compounds of the present invention, and methods of making these compounds, are known and disclosed in U.S.

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Abstract

Cette invention concerne un procédé de traitement de dystrophie myotonique, lequel consiste à administrer à un patient une quantité suffisante pour être efficace sur le plan thérapeutique, d'un dérivé de thiazolidinedione ou d'un dérivé d'oxyde de 3H-1,2,3,5-oxathiadiazole-2.
PCT/US1996/017633 1995-11-17 1996-11-04 Procede de traitement de dystrophie myotonique WO1997018811A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU76045/96A AU7604596A (en) 1995-11-17 1996-11-04 A method of treating myotonic dystrophy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US737395P 1995-11-17 1995-11-17
US60/007,373 1995-11-20

Publications (1)

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WO1997018811A1 true WO1997018811A1 (fr) 1997-05-29

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PCT/US1996/017633 WO1997018811A1 (fr) 1995-11-17 1996-11-04 Procede de traitement de dystrophie myotonique

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AU (1) AU7604596A (fr)
WO (1) WO1997018811A1 (fr)
ZA (1) ZA969591B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055122A1 (fr) * 1997-06-05 1998-12-10 Smithkline Beecham Plc Composition renfermant de la 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione
WO2011121109A1 (fr) * 2010-04-02 2011-10-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions comprenant un activateur (metformine/troglitazone) d'ampk pour le traitement d'une dystrophie myotonique de type 1 (dm1)
US8546077B2 (en) 2007-09-11 2013-10-01 UNIVERSITé LAVAL Prostaglandin E2 modulation and uses thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4287200A (en) * 1978-08-04 1981-09-01 Takeda Chemical Industries, Ltd. Thiazolidine derivatives
US4572912A (en) * 1983-08-30 1986-02-25 Sankyo Company Limited Thiazolidine derivatives, their preparation and compositions containing them
US4897405A (en) * 1989-04-21 1990-01-30 American Home Products Corporation Novel naphthalenylalkyl-3H-1,2,3,5-oxathiadiazole 2-oxides useful as antihyperglycemic agents
US5120754A (en) * 1988-03-08 1992-06-09 Pfizer Inc. Thiazolidinedione hypoglycemic agents
US5132317A (en) * 1989-08-25 1992-07-21 Beecham Group P.L.C. Compounds

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
US4287200A (en) * 1978-08-04 1981-09-01 Takeda Chemical Industries, Ltd. Thiazolidine derivatives
US4572912A (en) * 1983-08-30 1986-02-25 Sankyo Company Limited Thiazolidine derivatives, their preparation and compositions containing them
US5120754A (en) * 1988-03-08 1992-06-09 Pfizer Inc. Thiazolidinedione hypoglycemic agents
US4897405A (en) * 1989-04-21 1990-01-30 American Home Products Corporation Novel naphthalenylalkyl-3H-1,2,3,5-oxathiadiazole 2-oxides useful as antihyperglycemic agents
US5132317A (en) * 1989-08-25 1992-07-21 Beecham Group P.L.C. Compounds

Non-Patent Citations (3)

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Title
DUBEY ET AL.: "Pioglitazone attenuates hypertension and inhibits growth of renal arteriolar smooth muscle in rats", AM. J. PHYSIOL., vol. 265, no. 4Pt2, 1993, pages R726 - R732, XP000616559 *
PERSHADSINGH ET AL.: "Thiazolidinediones inhibit PDGF-induced proliferation and promote differentiation of human aortic smooth muscle cells in culture", HYPERTENSION, vol. 26, no. 3, 19 September 1995 (1995-09-19) - 22 September 1995 (1995-09-22), pages 577, XP000616558 *
ZHANG ET AL.: "Effects of pioglitazone on calcium channels in vascular smooth muscle", HYPERTENSION, vol. 24, no. 2, 1994, pages 170 - 175, XP000616557 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055122A1 (fr) * 1997-06-05 1998-12-10 Smithkline Beecham Plc Composition renfermant de la 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione
EA002384B1 (ru) * 1997-06-05 2002-04-25 Смитклайн Бичам Плс Композиция, включающая 5-[4-[2-(n-метил-n-(2-пиридил)амино)этокси]бензил]тиазолидин-2,4-дион
US8546077B2 (en) 2007-09-11 2013-10-01 UNIVERSITé LAVAL Prostaglandin E2 modulation and uses thereof
WO2011121109A1 (fr) * 2010-04-02 2011-10-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions comprenant un activateur (metformine/troglitazone) d'ampk pour le traitement d'une dystrophie myotonique de type 1 (dm1)
US20130085169A1 (en) * 2010-04-02 2013-04-04 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and compositions comprising ampk activator (metformin/troglitazone) for the treatment of myotonic dystrophy type 1 (dm1)

Also Published As

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ZA969591B (en) 1997-06-02
AU7604596A (en) 1997-06-11

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