WO1997018811A1

WO1997018811A1 - A method of treating myotonic dystrophy

Info

Publication number: WO1997018811A1
Application number: PCT/US1996/017633
Authority: WO
Inventors: Dean Lockwood
Original assignee: Warner-Lambert Company
Priority date: 1995-11-17
Filing date: 1996-11-04
Publication date: 1997-05-29
Also published as: ZA969591B; AU7604596A

Abstract

This invention provides a method of treating myotonic dystrophy by administering to a patient a therapeutically effective amount of a thiazolidinedione derivative or a 3H-1,2,3,5-oxathiadiazole-2 oxide derivative.

Description

A METHOD OF TREATING MYOTONIC DYSTROPHY

FIELD OF THE INVENTION

The present invention provides a method of treating myotonic dystrophy.

BACKGROUND OF THE INVENTION

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.

Thus, it would be useful to have compounds which can be used to treat myotonic dystrophy.

SUMMARY OF THE INVENTION

The present invention provides a method of treating myotonic dystrophy comprising administering to a patient having myotonic dystrophy a therapeutically effective amount of a compound of Formula I

wherein R¹ and R² are the same or different and each represents a hydrogen atom or a C-^-^ alkyl group;

R³ represents a hydrogen atom, a C -C₈ aliphatic acyl group, an alicyclic acyl group, an aromatic acyl group, a heterocyclic acyl group, an araliphatic acyl group, a (C₁-C₆ alkox )carbonyl group, or an aralkyl- oxycarbonyl group;

R⁴ and R⁵ are the same or different and each represents a hydrogen atom, a C-^^ alkyl group or a C -^ alkoxy group, or R⁴ and R⁵ together represent a ^cι"^c ₄ alkylenedioxy group; n is 1, 2, or 3; represents the -CH₂-, CO, or CH-OR⁶ group (in which R⁶ represents any 1 of the atoms or groups defined for R³ and may be the same as or different from R³); and Y and Z are the same or different and each represents an oxygen atom or an imino (=NH) group; and pharmaceutically acceptable salts thereof.

In a preferred embodiment of the method, 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

L—C—Rrr-0— (' 7—CH; CH—C=0 R_n S ,NH ^{1 J}

C II

0 wherein R₁₁ 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

R₁₃

wherein R₁₃ and R₁₄ are the same or different and each is lower alkyl or R₁₃ and R₁₄ 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 R₁₂ means a bond or a lower alkylene group; and wherein L_x 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 .

Also provided is 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 III

wherein R₁₅ and R₁₆ 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

wherein the dotted line represents a bond or no bond;

V is -CH = CH-, -N = CH-, -CH = N- or S; D is CH₂, CHOH, CO, C = NOR₁₇ or CH = CH; X is S, 0, NR₁₈, -CH = N or -N = CH;

Y is CH or N;

Z is hydrogen, (C₁-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, (C -C_jjal oxy, fluoro, chloro, or bromo; Z_η is hydrogen or C-_y-C^)alkyl; R₁₇ and R₁₈ 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. In another embodiment, 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

wherein the dotted line represents a bond or no bond;

A and B are each independently CH or N, with the proviso that when A or B is N, the other is CH;

X_η is S, SO, S0₂, CH₂, CHOH, or CO; n is 0 or 1; - is CHR₂₀ or R₂₁, with the proviso that when n is 1 and Y₁ is NR₂₁, X₂ is S0₂ or CO;

Z₂ is CHR₂₂, CH₂CH₂, CH=CH, CH CH , OCH₂, SCH₂,

O SOCH₂, or S0₂CH₂; ^Ri₉' ^R ₂₀' ^R ₂i' ^anc^ ^R ₂₂ ^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.

In another embodiment, 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

or a pharmaceutically acceptable salt thereof, wherein R₂₃ is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, or mono- or disubstituted phenyl wherein said substituents are independently alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen, or trifluoromethyl. In another embodiment, 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

or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein: 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 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;

R₂₅ and R₂₆ each represent hydrogen, or R₂₅ and R ₆ together represent a bond;

X₄ represents O or S; and n represents an integer in the range of from 2 to 6. In another embodiment, 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

or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate therefor, wherein:

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 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;

R₂₉ and R₃₀ each represent hydrogen, or R_2g 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. In another embodiment, 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

or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein:

A₅ represents a substituted or unsubstituted aromatic heterocyclyl group;

A₆ represents a benzene ring having in total up to 5 substituents;

X₆ 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 0 or S; R₃₁ represents an alkyl, aralkyl, or aryl group; and n represents an integer in the range of from 2 to 6.

In another embodiment, 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

"7 ^•X^Λ _B8—

A₇ represents a substituted or unsubstituted aryl group;

A₈ represents a benzene ring having in total up to

5 substituents; X₈ represents 0, 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;

R₃₈ 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.

DETAILED DESCRIPTION OF THE INVENTION

Compounds used in the method of the present invention, which are 5- [4- (chromoanalkoxy)benzyl] thiazolidene derivatives, may be represented by the Formulas (la), (lb), and (Ic)

(in which R¹, R², R³ , R⁴ , R⁵, R⁶, n, Y, and Z are as defined above) and include pharmaceutically acceptable salts thereof . In the compounds of the invention, where R¹ or R² represents an alkyl group, the alkyl group 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. Where R³ or R⁶ represents an aliphatic acyl group, the aliphatic acyl group preferably has from 1 to

6 carbon atoms and can include one or more carbon- carbon double or triple bonds. Examples of such groups include the formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, acryloyi, methacryloyl, and crotonyl groups .

Where R³ or R⁶ represents an alicyclic acyl group, it is preferably a cyclopentanecarbonyl, cyclohexane- carbonyl, or cycloheptanecarbonyl group.

Where R³ or R⁶ 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.

Where R³ or R⁶ 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.

Where R³ or R⁶ 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); examples of such araliphatic acyl groups include the phenylacetyl, p-chlorophenylacetyl, phenylpropionyl, and cinnamoyl groups.

Where R³ or R⁶ represents a (C^C_g alkoxy)carbonyl group, the alkyl moiety thereof may be any one of those alkyl groups as defined for R¹ and R², but is preferably a methyl or ethyl group, and the alkoxycarbonyl group represented by R³ or R⁶ is therefore preferably a methoxycarbonyl or ethoxycarbonyl group.

Where R³ or R⁶ represents an aralkyloxycarbonyl group, the aralkyl moiety thereof may be any one of those included within the araliphatic acyl group represented by R³ or R⁶, but is preferably a benzyloxycarbonyl group .

Where R⁴ and R⁵ 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. Where R⁴ and R⁵ 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. Alternatively, R⁴ and R⁵ can together represent a C₁-C₄ alkylenedioxy group, more preferably a methylenedioxy or ethylenedioxy group.

Preferred classes of compounds of Formula I are as follows :

(1) Compounds in which R³ represents a hydrogen atom, a C-^C_g aliphatic acyl group, an aromatic acyl group, or a heterocyclic acyl group.

(2) Compounds in which Y represents an oxygen atom; R¹ and R² are the same or different and each represents a hydrogen atom or a C_j-C₈ alkyl group; R³ represents a hydrogen atom, a C-^-Cg aliphatic acyl group, an aromatic acyl group, or a pyridinecarbonyl group; and R⁴ and R⁵ are the same or different and each represents a hydrogen atom, a C-^Cg alkyl group, or a C_x or C₂ alkoxy group. (3) Compounds as defined in (2) above, in which:

R¹, R², R⁴, and 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 >C0 group.

(4) Compounds as defined in (3) above, in which R³ represents a hydrogen atom, a

aliphatic acyl group, a benzoyl group, or a nicotinyl group.

(5) Compounds as defined in (4) above, in which: R¹ and R⁴ are the same or different and each represents a C^Cs alkyl group; R² and R⁵ are the same or different and each represents the hydrogen atom or the methyl group; and R³ represents a hydrogen atom or a Cη-C,_! aliphatic acyl group.

(6) Compounds in which: W represents the -CH₂- or >C0 group; Y and Z both represent oxygen atoms; n is 1 or 2; R¹ and R⁴ are the same or different and each represents a C₁-C₄ alkyl group; R² and R⁵ are the same or different and each represents the hydrogen atom or the methyl group; and R³ represents a hydrogen atom or a C_}-^ aliphatic acyl group.

(7) Compounds as defined in (6) above, in which n is 1.

(8) Compounds as defined in (6) or (7) above, in which W represents the -CH₂- group.

Preferred compounds among the compounds of Formula I are those wherein: R¹ is a C-^C_^j alkyl group, more preferably a methyl or isobutyl group, most preferably a methyl group;

R² is a hydrogen atom or a Cη-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 C-_j_-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 -^ alkyl group or a C_λ 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_λ 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; and

W is a -CH₂- or >C=0 group, preferably a -CH₂- group.

Referring to the general Formula II, 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 R₁₂ 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. As examples of the 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. When R_1X is R₁₃

N N -

^R14 the lower alkyls R₁₃ 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. When R₁₃ and R₁₄ 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 R₁₂ may contain 1 to 3 carbon atoms and thus may be, for example, methylene, ethylene, or trimethylene. The bond R₁₂ is equivalent to the symbol "-", ".", or the like which is used in chemical structural formulas, and when R₁₂ represents such a bond, the compound of general Formula II is represented by the following general Formula 11(a)

Thus, when R₁₂ is a bond, the atoms adjacent thereto on both sides are directly combined together. As examples of the lower alkyls L_λ 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 L₂ and L₂ are joined together is a group of the formula -(CH₂)_n- [where n is an integer of 2 to 6] . The cycloalkyl, phenylalkyl, phenyl, and heterocyclic groups mentioned above, as well as said heterocyclic group

may have 1 to 3 substituents in optional positions on the respective rings . As examples of such 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. The case also falls within the scope of the general Formula II that an alkylenedioxy group of the formula -0-(CH₂)_m-0- [is an integer of 1 to 3], such as methylenedioxy, is attached to the two adjacent carbon atoms on the ring to form an additional ring. The preferred compounds of Formula III are those wherein R₁₅ and R₁₆ 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 = CH-, -CH = N-, or S and n is 2, particularly those compounds wherein X is O and Y is N, X is S and

Y is N, X is S and Y is CH or X is -CH = N- and

Y is CH. In the most preferred compounds 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. The preferred compounds in Formula V are: a) those wherein the dotted line represents no bond, A and B are each CH, X_λ is CO, n is 0, R₁₉ is hydrogen, Z₂ is CH₂CH₂ or CH=CH and X₃ is hydrogen, particularly when X₂ is hydrogen, 2-methoxy, 4-benzyloxy, or 4-phenyl; b) those wherein A and B are each CH, X_χ is S or S0₂, n is 0, R₁₉ is hydrogen, Z₂ is CH₂CH₂, and X₃ is hydrogen, particularly when

X₂ is hydrogen or 4-chloro. A preferred group of compounds is that of Formula VI wherein R₂₃ is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, phenyl, halophenyl, or (C_j^-Cg)alkylphenyl . Especially preferred within this group are the compounds where R₂₃ is phenyl, methylphenyl, fluorophenyl, chlorophenyl, or cyclohexyl .

When used herein with regard to Formulas VII through X, the term "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.

The term "halogen" refers to fluorine, chlorine, bromine, and iodine; preferably chlorine.

The terms "alkyl" and "alkoxy" relate to groups having straight or branched carbon chains, containing up to 12 carbon atoms.

Suitable alkyl groups are C₁,₁₂ 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 :

5- [ [4- [ (3, 4-dihydro-6-hydroxy-2, 5, 7 , 8-tetramethyl- 2H-l-benzopyran-2-yl)methoxy]phenyl]methyl] - 2, 4-thiazolidinedione. Other preferred compounds of the present method include ciglitazone, pioglitazone, darglitazone, englitazone, and BRL 49653.

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- σhromanyl]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) . The term "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. Also contemplated are 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 . Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of 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. 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. 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.

Furthermore, the 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.

For preparing pharmaceutical compositions from the compounds 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. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.

In tablets, 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. For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and 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. For parenteral injection 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 .

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such 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. In such 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. Also, 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, however, 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. Patents 5,223,522 issued June 29, 1993; 5,132,317 issued July 12, 1992; 5,120,754 issued June 9, 1992; 5,061,717 issued October 29, 1991; 4,897,405 issued January 30, 1990; 4,873,255 issued October 10, 1989; 4,687,777 issued August 18, 1987; 4,572,912, issued February 25, 1986; and 4,287,200, issued September 1, 1981. These issued patents are incorporated herein by reference.

Claims

1. 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 I

wherein R¹ and R² are the same or different and each represents a hydrogen atom or a C^ ^ alkyl group;

R³ represents a hydrogen atom, a C-^C_g aliphatic acyl group, an alicyclic acyl group, an aromatic acyl group, a heterocyclic acyl group, an araliphatic acyl group, a ( C₁ -C₆ alkoxy)carbonyl group, or an aralkyloxycarbonyl group;

R⁴ and R⁵ are the same or different and each represents a hydrogen atom, a Cη-^ alkyl group or a C- 'C_S alkoxy group, or R⁴ and R⁵ together represent a C₁-C₄ alkylenedioxy group; n is 1, 2, or 3;

W represents the -CH₂-, CO, or CH-OR⁶ group (in which R⁶ represents any one of the atoms or groups defined for R³ and may be the same as or different from R³) ; and

Y and Z are the same or different and each represents an oxygen atom or an imino (=NH) group; and pharmaceutically acceptable salts thereof .

2. A method of treating myotonic dystrophy, the method comprising administering to a patient having myotonic dystrophy a therapeutically effective amount of a compound of Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier.

3. The method of Claim 2 comprising administering to the patient a therapeutically effective amount of a compound of Formula wherein Y and Z are oxygen.

4. The method of Claim 2 comprising administering to the patient a therapeutically effective amount of a compound of Formula I wherein W is -CH₂- .

5. The method of Claim 2 comprising administering to the patient a therapeutically effective amount of a compound of Formula wherein n is 1.

6. The method of Claim 2 comprising administering to the patient a therapeutically effective amount of a compound of Formula I wherein R_η, R₂, R₄, and R₅ are lower alkyl and R₃ is H.

7. The method of Claim 2 comprising administering to the patient a therapeutically effective amount of a compound of Formula I wherein Z and Y are oxygen, n is 1, and W is -CH₂- .

8. The method of Claim 2 comprising administering to the patient a therapeutically effective amount of a compound of Formula I wherein the compound is 5- [ [4- [ (3,4-dihydro-6-hydroxy-2, 5,7,8- tetrameth l-2H-1-benzopyran-2-y1)methoxy]phenyl] methyl] -2, 4-thiazolidinedione.

9. 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

wherein R₂₁ 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

_^N—

^R14

wherein R₁₃ and R₁₄ are the same or different and each is lower alkyl or R₁₃ and R₁₄ 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 R₁₂ means a bond or a lower alkylene group; and wherein L₂ and L₂ are the same or different and each is hydrogen or lower alkyl or _x and L₂ are combined to form an alkylene group, or a pharmaceutically acceptable salt thereof.

10. A method of treating myotonic dystrophy, the method comprising administering to a patient having myotonic dystrophy a therapeutically effective amount of a compound according to Claim 9 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier.

11. The method of Claim 10 comprising administering to the patient a therapeutically effective amount of a compound of Formula II wherein the compound is pioglitazone.

12. The method of Claim 10 comprising administering to the patient a therapeutically effective amount of a compound of Formula II wherein the compound is ciglitazone.

13. 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 III

wherein R₁₅ and R₁₆ 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 .

14. 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

wherein the dotted line represents a bond or no bond;

Y is CH or N; Z is hydrogen, (C^C_?) alkyl,

(C₃-C₇)cycloalkyl, phenyl, naphthyl, pyridyl, furyl, thienyl, or phenyl mono- or disubstituted with the same or different groups which are (C₁-C₃)alkyl, trifluoromethyl, (C_α-C₃)alkoxy, fluoro, chloro, or bromo;

Z_η is hydrogen or (Ci-C-_j)alkyl; R₁₇ and R₁₈ 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.

15. 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

wherein the dotted line represents a bond or no bond; A and B are each independently CH or N, with the proviso that when A or B is N, the other is CH; _χ is S, SO, S0₂, CH₂, CHOH, or CO; n is 0 or 1;

Y_λ is CHR₂₀ or R₂₁, with the proviso that when n is 1 and Y is NR₂₁, X_λ is S0₂ or CO;

Z₂ is CHR₂₂, CH₂CH₂, CH=CH, CH CH , OCH₂, \ /

O SCH₂, SOCH₂ or S0₂CH₂;

R₁₉, R ₀/ R₂₁' ^and R₂₂ are each independently hydrogen or methyl; and

16. 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

or a pharmaceutically acceptable salt thereof, wherein R₂₃ is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, or mono- or disubstituted phenyl wherein said substituents are independently alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen, or trifluoromethyl.

17. 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

.—0—CO— VII

O or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein: 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; X represents 0 or S; and n represents an integer in the range of from 2 to 6.

18. 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

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 0 or S; and n represents an integer in the range of from 2 to 6.

19. 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

A₅ represents a substituted or unsubstituted aromatic heterocyclyl group;

A₆ represents a benzene ring having in total up to 5 substituents;

X₆ represents 0, 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 0 or S;

^R ₃i represents an alkyl, aralkyl, or aryl group; and n represents an integer in the range of from 2 to 6.

20. 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

A₇ represents a substituted or unsubstituted aryl group;

A₈ represents a benzene ring having in total up to 5 substituents;

X₈ 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 0 or S; R₃₇ represents hydrogen; R₃₈ 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.

21. A method of treating myotonic dystrophy, the method comprising administering to a patient having myotonic dystrophy a therapeutically effective amount of: [ (±) -5- [ (4- [2-Methyl-2- (pyridinylamino) - ethoxy]phenyl)methyl] -2, 4-thiazolidinedione- (Z) - 2-butenedioate; englitazone; or darglitazone.