SK16498A3 - A method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus - Google Patents

Abstract

This invention provides a method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus by administering to a patient a therapeutically effective amount of a thiazolidione derivative and/or a related compound.

Description

Drug for reducing the amount of exogenous insulin

Technical field

The invention relates to the manufacture of a medicament for exogenous insulin administered to non-insulin dependent diabetes mellitus of the compounds defined below.

to reduce the patient using an amount having certain

BACKGROUND OF THE INVENTION

Diabetes is one of the most widespread chronic diseases worldwide with significant personal and financial implications for patients and their families, as well as for society. There are various types of diabetes with clear ethology and pathogenesis. For example, diabetes mellitus is a carbohydrate metabolism disorder characterized by hyperglycemia and glycosuria and is due to insufficient insulin production or utilization.

Non-insulin-dependent type II diabetes. is a form, particularly in adults, proportionate to the need but mediated use and tissues.

diabetes mellitus diabetes mellitus, in which the disorder is glucose metabolism

CNIDDM). or occurring insulin formation in insulin in peripheral

Clear NIDDN is characterized by three major anomalies: insulin-mediated glucose degradation; worsening of food-stimulated insulin secretion; and hepatic overproduction of glucose.

Failure to treat with NIDDI (IC (blood glucose control)) may result in cardiovascular death or other complications of diabetes including retinopathy, nephropathy and peripheral neuropathy.

Treatment of NIDDNs to control blood glucose levels of patients suffering from NIDDM includes diet and exercise as well as the administration of sulfonylureas and biguanide therapeutics. Currently, compounds such as metformin and acarbose are also used to treat patients suffering from N1DDI1. However, in some patients suffering from NIDDM, hyperglycemia cannot be adequately controlled by diet and exercise, and / or by the use of such patients. patient. For example, reactions to insulin (hypoglycaemic) may occur as a result of faulty dosing of insulin, missed food, unplanned exercise or without obvious benefit. In addition, local and / or generalized allergic reactions and immunological resistance to insulin may occur.

of therapeutic compounds. administer exogenous insulin.

SUMMARY OF THE INVENTION

The invention relates to a method of reducing exogenous insulin administered to a patient having a non-insulin dependent diabetes mellltus. A partial reduction or total reduction of exogenous insulin administered to a patient having non-insulin-dependent diabetes mellltus may also be called insulin rescue as the need to use insulin to control serum glucose is eliminated. As shown below, in still ongoing clinical trials, 7 of the 17 human subjects were totally deprived of the need for exogenous insulin, a highly stimulating and unexpected discovery. whereas to the knowledge of the art, it has been concluded that a patient having NIDDM and requiring insulin suffers from insulin resistance and B-cell failure. B cells are cells in the pancreas in which they are formed. endogenous insulin.

See, for example, Saad 1 * 1.F., The American Journal of Medicine. 1991 90x229-235, which discusses the role of pancreatic B-cell wear in the progression of insulin resistance in NIDDM.

The invention provides a method of reducing the amount of exogenous

Insulin administered to a patient having a non-insulin dependent dlabetes mellltus comprising administering to said patient a therapeutically effective amount of a compound of Formula I.

2 — CH — C = Y ^Λ II

S> NH

T

From which

R and R _a are the same or different and each is H or _C-C alkyl;

R 5 represents a hydrogen atom. Cx-C _A aliphatic acyl group. an all-cyclic acyl group, an aromatic acyl group, a heterocyclic acyl group. araliphatic acyl, CCx-C ₍ alkoxy) carbonyl, or aralkoxycarbonyl:

R ₄ and R 5 have the same or different meanings and each represents a hydrogen atom, a C 1 -C 8 alkyl group. _Cx-C, alkoxy group, or R ₄ and R _s together are C x C. * Alkyléndioxyskuplnu:

represents 1, 2 or 3;

U is -CH ₂ -. -CO, or a group CH-OR a (wherein R _A is any of the atoms or groups defined for R 5 and may have the same or different meanings as R ₃ ); and

Y and Z have the same or different meanings and each represents an oxygen atom or an imocappline (= NH);

and pharmaceutically acceptable salts thereof.

In a preferred embodiment of the process, the compound of formula I is 5-C 4-C C 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2. 4-thiazolidinedione.

Another embodiment provides a method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus, the method comprising administering a therapeutically effective amount of a compound of Formula II to a patient having noninsulin-dependent diabetes mellitus.

IX in which

R 11 is substituted or unsubstituted alkyl, alkoxy, cycloalkyl, phenylalkyl, phenyl. an aromatic acyl group, a 5 or 6-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. or a group of formula ‘13

N-14 wherein R ₁₃ and R ₁₃ are lower alkyl, either directly or including nitrogen, of the 6-membered ring;

have the same or different meanings, and each or R 18 and R 16 are joined to each other through a heteroatom selected from oxygen and sulfur to form 5- or 2-

R 1a represents a bond or a lower alkylene group; and

L x and L _a have the same or different meanings and each represents hydrogen or lower alkyl, or χ χ and _{2 2} combine to form an alkylene group, or a pharmaceutically acceptable salt thereof.

The invention also provides a method of reducing the amount of exogenously administered insulin to a patient having a non-insulin-dependent dlabetes mellitus, the method comprising administering a therapeutically effective amount of a compound of Formula III to a patient having a non-insulin-dependent dlabetes mellituss

III

R 1 and R 2 independently represent hydrogen, lower alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen. ethynyl, nitrile, methylthio, trifluoromethyl. vinyl, nitro or halogen substituted benzyloxy;

n is 0 to 4;

and pharmaceutically acceptable salts thereof.

The invention also provides a method of reducing the amount of exogenous insulin administered to a patient having a noninsulin-dependent dlabetes mellitus. wherein the method comprises administering a therapeutically effective amount of a compound of Formula IV to a patient having a noninsulin-dependent dlabetes mellitus:

IV wherein the dotted line represents a bond or no bond;

V is -CH = CH-. N-CH. -CH = N- or S;

D is CH _and . CHOH, CO. C. ^The NOR ₁₇ or CH = CH;

X is SO NR _xe . -CH = N or -N = CH;

Y is CH or N, Z is hydrogen. <-A- C _x) alkyl, CC ₃ -C ₇₎ cycloalkyl, phenyl. naphthyl, pyridyl, furyl, thienyl or phenyl mono- or disubstituted with the same or different groups ₍ C ₁ -C ₃ ) alkyl. trifluoromethyl, ₍ C ₁ -C ₃ ) alkoxy, fluoro, chloro or bromo;

Z _x is hydrogen or ₍ C ₁ -C ₃ ) alkyl;

R R - R and _{x b} are independently hydrogen or methyl; and n is 1, 2 or 3;

and the pharmaceutically acceptable pharmaceutically acceptable addition compound thereof contains basic nitrogen.

cationic salts; and its acid salts, if any

According to another embodiment, the invention provides a method for the amount of exogenous insulin administered to a patient of mellitus, wherein the noninsulin-dependent dlabetes comprises administering therapeutically to a patient having mellitus t, having a method of effective amount of a compound with noninsullendependent dlabetes.

wherein the dotted line represents a bond or no bond;

A and B are each independently CH or N, provided that when A or B is N. then the other is CH;

X x is S, SO. SO, CH ₂ . CHOH or CO; n is 0 or 1;

Y x is CHR ₂₀ or CHR ₂₁ subject to. that if n is 1 and

Yx is NR ₂₁ . X _x is SO ₂ or CO;

Z ₂ is CHR ₂₂ . CH ₂ CH ₂ . CH = CH, CH - CH. OCH _a , SCH ₂ , SOCH ₂ or \ /

SO ₂ CH ₂ ;

Ri9. R a> R 21 and R 22 each independently represent hydrogen or methyl and

X ₂ and X ₃ each independently represent hydrogen, methyl, trifluoromethyl, phenyl. benzyl, hydroxy, inethoxy, phenoxy, benzyloxy, bromine, chlorine or fluorine;

a pharmaceutically acceptable cationic salt thereof; or a pharmaceutically acceptable acid addition salt thereof, when A or B is N.

According to another embodiment, the invention provides a method of reducing the amount of exogenous insulin administered to a patient having a noninsulin-dependent dlabetes mellltus. wherein the method comprises administering a therapeutically effective amount of a compound of Formula VI to a patient having an inellitus with a non-dependent dlabetes

or a pharmaceutically acceptable salt thereof, wherein

Ras is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, mono- or di-substituted phenyl, wherein said substituents independently represent alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen or trifluoromethyl .

According to another embodiment, the invention provides a method of reducing the amount of exogenous insulin administered to a patient having a noninsulin-dependent dlabetes mellltus, the method comprising administering a therapeutically effective amount of a compound of formula VII with

A 1 -O-CO-M- (CH ₂ ) - X f and ₃ + ch-9- _hh

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

_And A represents an alkyl group, a substituted or nesubstltuovanú aryl, or aralkyl, wherein the alkylene or the aryl moiety may be substituted or unsubstituted;

A ₃ represents a benzene ring having a total of up to 3 optional substituents;

R a - represents a hydrogen atom, an alkyl group. acyl. an aralkyl group in which the alkyl or aryl component may be substituted or unsubstituted or substituted or unsubstituted aryl; or A _and together with R _a - * represent a substituted or unsubstituted C _and -3 polymethylene group, wherein optional polymethylene group substituents are selected from alkyl or aryl. or adjacent substituents together with the carbon atoms of the methylene group to which they are attached form a substituted or unsubstituted phenylene group;

R a and R a _are each hydrogen, or R _a is R a. together form a bond with is O or S; and n is a number ranging from 2 to 6.

In another embodiment, the invention provides a method of reducing the amount of exogenous insulin administered to a patient having nonlnzullndependentný dlabetes mellitus, the method comprising administering a therapeutically effective amount of a compound of formula VIII to a patient having nonlnzullndependentný dlabetes mellitus * ^R 27 ^R 28

CO 2 N- (CH ₂ )

WHAT

-r

VIII, or a tautomeric form thereof, and / or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable solvate thereof, wherein R ab each independently represents an alkyl group. substituted or unsubstituted aryl, or aralkyl which is substituted or unsubstituted in the aryl or alkyl moiety;

R 27 together with R _aa denote a linking group wherein the linking group consists of an optionally substituted methylene group and either a further optionally substituted methylene group or an O or S atom, wherein optional substituents of said methylene groups are selected from the group consisting of alkylaryl 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 ₂ <? and R _3c each represents hydrogen. and R _a9 and R _N3 together form a bond;

represents a benzene ring having up to 3 optional substituents;

X _a is O or S; and n is a number ranging from 2 to 6.

According to another embodiment, the invention provides a method of reducing the amount of exogenous insulin administered to a patient having non-insulin dependent diabetes mellitus. wherein the method comprises administering a therapeutically effective amount of a compound of Formula IX to a patient having non-insulin dependent diabetes mellitus.

A5 ^X r < ^CH 2> ^ 310

IX or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof. where X

A _s represents a substituted or unsubstituted heterocyclic group;

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

X _A is O, S, or NR _35a , wherein R ₃₂ is hydrogen, alkyl. acylskuplnu. an aralkyl group in which the aryl component may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;

Y ₂ is O or S;

R 31 represents alkyl, aralkyl or aryl; and n is from 2 to 6.

means Clslo

According to another embodiment, the invention provides a method of reducing the amount of exogenous Insulin administered to a patient having a noninsulin-dependent dlabetes mellltus, the method comprising administering to a patient having a noninsulin-dependent dlabetes mellltus a therapeutically effective amount of a compound of Formula X.

Γ38Ο ^l 7 ^"x r ^<CB NH, or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable solvate thereof, wherein *

I represents a substituted or unsubstituted aryl group;

As is a benzene ring having up to 5 substituents in total;

X 5 is O, S or NR ₃₉ . wherein R ₃₉ represents a hydrogen atom, an alkyl group. acyl, aralkyl. wherein the aryl component may be substituted or unsubstituted. or a substituted or unsubstituted aryl group;

Y 3 is O or S;

R37 is hydrogen;

R 5 is hydrogen or alkyl. aralkyl. or aryl group or R 37 together with R ₃ q represents a bond; and n is Clslo ranging from 2 to 6.

Description of the figures in the attached drawing

Figure 1 is a graph showing mean blood glucose levels and mean total daily dose of exogenous insulin of patients during a period of administration of a compound of the invention to patients.

DETAILED DESCRIPTION OF THE INVENTION

Compounds suitable for the process of the invention which are derivatives of 5-C4-Cromoanalkoxy) benzyl] thiazolidene can be represented by formulas (C a). (Cb) and cic)

(Ia)

(Ib) (Ic)

C wherein R 1. R _a . Rs. · R *. Rs and R _Ä . n, Y and Z are as defined above) and include their pharmaceutically acceptable salts.

In the compounds of the invention. where R _x or R _a represents an alkyl group, the alkyl group may be a straight or branched chain alkyl group having 1 to 5 carbon atoms, and is preferably a primary or secondary alkyl group, for example methyl, ethyl, propyl, isopropyl. butyl, isobutyl, pentyl or isopentyl.

When R _a and R _a represents an aliphatic acyl group. preferably, the aliphatic acyl group has up to 1 to 6 carbon atoms and may include one or more double or triple carbon-carbon bonds. Examples of these groups include formyl, acetyl. propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl. acryloyl, methacryloyl and crotonyl.

When R ₃ or R _a represents an alicyclic acyl group, preferred is a cyclopentanecarbonyl, cyclohexanecarbonyl or cycloheptanecarbonyl group.

When R ₃ or R _a is aromatic acyl group. the aromatic component thereof may optionally have one or more substituents (for example, substituents such as nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl or hydroxy); examples of these aromatic acyl groups include benzoyl. P-nitrobenzoyl, m-fluorobenzoyl, o-chlorobenzoyl, p-aminobenzoyl. m (dlmetylamlno) benzoyl. o-methoxybenzoyl, 3,4-dichlorobenzoyl, 3,5-di-tert-butyl-4-hydroxybenzoyl and 1-naphthoyl groups.

Where R or R _a represents a heterocyclic acyl group. thus, the heterocyclic component thereof preferably has one oxygen, sulfur or nitrogen heteroatom and has 4 to 7 ring atoms; examples of such heterocyclic acyl groups include 2-furoyl, 3-tenoyl. 3-pyridinecarbonyl (nicotinoyl) and 4-pyridinecarbonyl groups.

Where R 5 or R ₄ is an araliphatic acyl group, the aliphatic component may optionally have one or more carbon-carbon double or triple bonds and the aryl component may optionally have one or more substituents (for example, substituents such as nitro, amino, alkylamino, dialkylamino, alkoxy, halo). (alkyl or hydroxy): examples of such araliphatic acyl groups include phenylacetyl. p-chlorophenylacetyl and phenylpropionyl and clnamoyl.

When R ₃ or R _a is C _A CCI-alkoxy) carbonyl group, the alkyl moiety may be any of the alkyl groups defined for R and R _a. but is preferably a methyl or ethyl group, and the alkoxycarbonyl group represented by R _p and R _f is then preferably methoxycarbonyl or ethoxycarbonyl.

When R _a and R _a is an aralkoxycarbonyl group, the aralkyl moiety may be any one of those included within the araliphatic acyl showing R ₃ and R @ _R, but is preferably a benzyloxycarbonyl group.

If Rq. and R _a means alkyl. the alkyl groups may be the same or different and may be straight or branched chain alkyl groups. These alkyl groups preferably have from 1 to 5 carbon atoms and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and isopentyl.

When R ^ and R _s is alkoxy, the alkoxy groups may be the same or different and may be straight or branched and preferably have from 1 to 4 carbon atoms. Examples thereof include methoxy, ethoxy. propoxy. isopropoxy and butoxy. Alternatively, R 6 and R 8 _may together represent C 1 -C 4 alkylenedioxy, preferably methylenedioxy or ethylenedioxy.

Preferred classes of compounds of formula I are the following: (1) Compounds in which R ₃ represents a hydrogen atom, a C 1 -C ₄ aliphatic acyl group. an aromatic acyl group or a heterocyclic acyl group;

Zl23 Compounds in which Y represents an oxygen atom; R and R ₂ are the same or different and each represents a hydrogen atom or a C _x -C alkyl; R _p is hydrogen. C - (^ acylskuplnu aliphatic, aromatic or acylskuplnu pyrldlnkarboriylovú group; and R ₄ and R _s are the same or different and each is H, C _p alkylskuplnu or C _x and C ₂ alkoxyskuplriu;

C3) a compound as defined in item C-2) wherein R _x, R _2, R and R are the same or different and each is H or C-C _in alkylskuplnu; n is 1 or 2; and U is -CH _and - or>CO;

4) The compounds as defined in the above 3) wherein R ₃ is H, C _s aliphatic acylskuplnu, benzoyl or a radical nikotlnylovú;

5) The compounds as defined in item (4) wherein: R _x and R ₂ are the same or different and each is a _C-C alkyl; R ₂ and R _s are the same or different and each is hydrogen or methyl; and _R is H or C _x -C »acylskuplnu aliphatic;

6) the compounds wherein: U is -CH ₂ - or>CO; Y and Z are both oxygen; n is 1 or 2; R _x and R ₂ are the same or different and each is a C x-Csalkylskuplnu; Ra and R = the same or different meanings and each represents a hydrogen atom or a methyl group; and _R is H or Ci-C ^ aliphatic acylskuplnu;

C7) Compounds as defined in (6) above wherein n is 1;

8) The compounds as defined in the above 6) and <7) wherein U is -CH ₂ -.

Preferred compounds of the compounds of formula I are those compounds. In which"

R 1 represents a C 1 -C ₄ alkyl group. more preferably methyl or isobutyl, most preferably methyl;

R 6 is hydrogen or C 1 -C ₄ alkyl. preferably a hydrogen atom. or methylcapher or isopropylcapher. more preferably a hydrogen atom or a methyl group. most preferably methylcap;

R ₃ is H, _Ci-C4 aliphatic acyl group. an aromatic acyl group or a pyrdinecarbonyl group, preferably a hydrogen atom or an acetyl group. butyryl. benzoyl or nicotinyl, more preferably hydrogen or acetyl. a butyryl or benzoyl group, most preferably a hydrogen atom or an acetyl group;

R ₄ is hydrogen. Ci-C ₄ alkyl or C _x and C "alkoxy group, preferably a group consisting of methyl, isopropyl, t-butyl or methoxy, more preferably methyl or tert-butyl, most preferably metylskuplnu;

R 5 represents a hydrogen atom. Ci-C ₄ alkyl or C _x and C "alkoxy group, preferably hydrogen or metylskuplnu or metoxyskuplnu. more preferably a hydrogen atom or a methyl group and most preferably a methyl group;

n is 1 or 2. more preferably 1;

Y represents an oxygen atom;

Z represents an oxygen atom or an immunocappline, most preferably an oxygen atom; and

U is -CH 2 - or> CO. preferably -CH 2 -.

As regards the general formula II. the substituents may be any of 1 to 3 selected from nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl or hydroxy; the aromatic group may be benzoyl or naphthoyl. The alkyl group R 11 may have a straight or branched chain of 1 to 10 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, i-pentyl. n-hexyl, n-heptyl. n-octyl, n-nonyl and n-decyl; the cycloalkyl group R 11 may be a cycloalkyl group having 3 to 7 carbon atoms such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl; the phenylalkyl group R &lt; _{1 &gt;} can be a phenylalkyl group having 7 to 11 carbon atoms such as benzyl and phenethyl. Examples of the heterocyclic group R _1X include 5- or 6-membered groups each containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, such as pyridyl, thienyl, furyl, thiazolyl, and the like. If Ri * means '13 '14

N-lower alkyl, R _{1 S,} and R ₁₄ may be lower alkyl of 1 to 4 carbon atoms, such as methyl, ethyl. n-propyl, i-propyl and n-butyl. When R 1 _S and R 4 are linked to each other to form a 5- or 6-membered heterocyclic group, i.e.

the heterocyclic group may further comprise a heteroatom selected from the group consisting of nitrogen. oxygen and sulfur, and examples include groups such as plperdino, morpholino, pyrrolinedino and plperazino. The lower alkylene group R _{x 2} may contain 1 to 3 carbon atoms and may, for example, be methylene. ethylene or trimethylene. The bond R ₁₂ is equivalent to a symbol or the like used in the chemical structural formulas and when R _X 2 represents such a bond.

the compound of formula II is represented by the following formula II Ca)

Thus, when R ₃₁ is a bond, the atoms adjacent to the bond on both sides are directly linked to each other. Examples of lower alkyls L ₁ and L ₂ include lower alkyl groups having 1 to 3 carbon atoms, such as methyl and ethyl. Alternatively, the group formed by linking Li and L _{3 together} is a group of formula -CCH _a ) _n - (where n is a number from 2 to 6). Cycloalkyl, phenylalkyl. the phenyl and heterocyclic groups mentioned above, as well as a group of said heterocykllcká ^l 13 y ₁₄ /

N - may have 1 to 3 substituents at optional positions on the respective rings. Examples of such substituents include lower alkyls (e.g., methyl, ethyl, etc.), lower alkoxy groups (e.g., methoxy, ethoxy, etc.). halogens (e.g., chlorine, bromine, etc.) and hydroxyl. Also included in formula II is an alkylenedioxy group of the formula -O- (CH ₃ ) _m -O (m is from 1 to 3), such as ethylenedioxy. which is attached to two adjacent carbon atoms in the ring to form another ring.

Preferred compounds of formula III are those wherein R 18 and R 16 independently represent hydrogen, lower alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, ethynyl, nitrile. trifluoromethyl, wooll or nitros is 1 or 2 and their pharmaceutically acceptable salts.

Preferred compounds of formula IV are those in which the dotted line does not indicate any bond and especially those. wherein D is CO or CHOH. More preferred are compounds wherein V is -CH = CH-. -CH = N- or Sa is 2, especially 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 O or Sa is N to form oxazol-4-yl, oxazol-5-yl, thiazol-4-yl or thiazol-5-yls (especially 2-CC2-thienyl), C2-furyl) , phenyl. or substituted phenyl] -5-methyl-4-oxazolyl.

Preferred compounds of formula V are:

a) those wherein the dotted line represents a bond, each A and B is CH, X is CO, n is 0, R _{t 9} is hydrogen, _and Z is CH ₂ CH ₂ or CH = CH and _X3 is hydrogen, particularly when X ₂ is hydrogen. 2-methoxy, 4-benzyloxy or 4-phenyls

(b) compounds. wherein each A and B is CH. X _x is S or SO ₂ . n is 0, R ₁₉ is hydrogen. Z ₂ is CH ₂ CH ₂ and X ₃ is hydrogen, especially when X ₂ is hydrogen or 4-chloro.

A preferred group of compounds of formula VI, a group of compounds wherein R ₂₃ represents a _CCI-C) alkyl, CC ₃ -C ₇₎ cycloalkyl, phenyl. halophenyl or _<R C C) alkyl phenyl. Within this group, compounds in which R ₂₃ is phenyl, methylphenyl are very preferred. phenyl. chlorophenyl or cyclohexyl.

With respect to formulas VII to X. the term aryl used herein includes phenyl and naphthyl, substituted phenyl optionally substituted with up to 5 groups, preferably up to 3, selected from the group consisting of halogen, alkyl, phenyl. alkoxy, haloalkyl. hydroxy. amino. nitro. carboxy. alkoxycarbonyl. alkoxycarbonylalkyl, alkylcarbonyloxy or alkylcarbonyl.

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

The term alkyl and alkoxy refers to groups having straight or branched chain carbon atoms containing up to 12 carbon atoms.

Suitable alkyl groups are C x-Cia-alkyl, especially C-C _A alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, isobutyl or tert-butyl.

Suitable substituents for any alkyl group include those listed above for the term aryl.

Suitable substituents for any heterocyclic group include up to 4 substituents selected from the group consisting of alkyl, alkoxy, aryl and halogen, or some two substituents on adjacent carbon atoms together with the carbon atoms to which they are attached to form an aryl group, preferably a benzene ring and carbon atoms of that aryl the groups represented by the two substituents may themselves be substituted or unsubstituted.

The most preferred compound of the invention is:

5-LL4-LC3. 4-Dihydro-N-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl-3,4-thiazolidinedione.

Other preferred compounds of the invention include ciglitazone, pioglitazone, darglitazone, englitazori and BRL 49653.

Ciglitazone is also known as 5-Cp-lCl-methylcyclohexyl) methoxy] benzyl] -2,4-thiazolidinedione.

Pioglitazone is also known as 5-lp-12- (5-ethyl-2-pyridyl) ethoxy] benzyl] -2. 4-thiazolidinedione.

Darglitazone is also known as 5-Ep-13- (5-ethyl-2-phenyl-4-oxazolyl) propionyl] benzyl] -2,4-thiazolidinedione.

Englitazone is also known as 5-CCC2R) -2-benzyl-6-chromanyl] methyl-2,4-thiazolidinedione.

BRL 49653 is also known as 5-lC4-C2-methyl-2- (pyridinylamino) ethoxy] phenylmethyl-2,4-thiazolidinedione (Z) -2-butanedioate (XII).

The term patient encompasses humans and other glandular glands. The term exogenous insulin means insulin that is administered to a patient from an external source as compared to endogenous insulin that is secreted by the patient's pancreas.

The sentence of reducing the amount of exogenous insulin administered to a patient having non-insulin dependent diabetes mellitus means that in a patient in need of blood sugar control using exogenous insulin, the amount of insulin required to maintain the desired blood sugar levels without administration of a compound of the invention is higher than the amount of insulin required. compounds of the invention. It is also understood that the term reduction also includes complete discontinuation of the administration of exogenous insulin to a patient.

Surprising and unexpected is. that in patients requiring exogenous insulin because of their blood glucose levels, which could not be controlled by diet and exercise and / or commonly used therapeutic agents, insulin could be completely discontinued and adequate blood glucose control was achieved by administering the compound of the present method. Thus, the present method provides a method of treating the most severe cases of noninsulin-dependent diabetes mellitus. that require exogenous insulin. In addition. the present invention allows complete exclusion of the administration of exogenous insulin to patients. who needed it until now.

In general, it is desirable to control blood glucose levels for laCno in patients having NIDDays in the range of about BO mg / dl to about 140 mg / dl. What is the normal range as defined by American

Diabetes Association. Ranges of from about 150 mg / dl to about 200 mg / dl are considered to be controlled. Generally, a person having diabetes mellltus is defined as having a glucose value of 140 mg / dl or greater.

In the present method, patients generally exhibit a fasting C-peptide level of 1.5 ng / ml or higher.

The compounds of formulas I to X are capable of forming pharmaceutically acceptable salts of both types, acid addition salts or basic salts. Both of these types are within the scope of the invention.

Pharmaceutically acceptable acid addition salts of compounds I to X include salts derived from nontoxic inorganic acids such as hydrochloric acid. nitrous, phosphorous. sulfur, brook, iodine. hydrofluoric. phosphorous and the like, as well as salts derived from non-toxic organic acids. such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedloic acids. aromatic acids, aliphatic and aromatic sulfonic acids. atrf. Thus, these salts include sulfate, pyrosulfate, hydrogen sulfate, sulfite, hydrogen sulfate, nitrate, phosphate, morphine phosphate. dihydrogen phosphate, metaphosphate, pyrophosphate. chloride, bromld. iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate. oxalate. malonate, succinate, suberate. sebacate. fumarate. mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate. phenylacetate. citrate, lactate, maleate, viticulture, methanesulfonate and the like. The amino acid salt form is also contemplated. such as arginate and the like; and forms such as glucorate, galacturonate. n-methylglucamine (see, e.g., Berge

S. 1 * 1, et al., Pharmaceutical Salts Journal of Pharmaceutical Science. , 1977; 66 «1-19).

These acid addition salts of the aforementioned basic compounds are prepared by contacting the free base compound with a sufficient amount of the desired acid to obtain a salt in a conventional manner. The free base compound can be regenerated by contacting the salt form with the base and isolating the free base in the usual manner or as described above. The free base compounds differ somewhat from their respective salts in certain physical properties, such as solubility in polar solvents, but otherwise for the purposes of the present invention these salts are equivalent to their respective free bases. ¹

Pharmaceutically acceptable base addition salts are prepared with metals or amines such as alkali and alkaline earth metals or organic amines. Examples of cationic metals include sodium. potassium. magnesium. calcium and the like. Examples of suitable amines are N, N'-dibenzylethylenediamine. chloroprocaine. choline. dletanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaline (see, e.g., Berge S. 1 * 1 et al., Pharmaceutical Salts Journal of Pharmaceutical Science. 1977; 66 pp. 1-19).

The base addition salts of said acidic compounds are prepared by contacting the free acid compound with a sufficient amount of the desired base to afford the salt in a conventional manner. The free acid compound can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner or as described above. The free acid compounds differ somewhat from their respective salts in some physical properties, such as solubility in polar solvents, but otherwise for the purposes of this invention, these salts are equivalent to their respective free acids.

Certain compounds of the invention may exist in unsolvated forms as well as solvated forms including hydrated forms. In general, these solvated forms. including hydrated forms, are equivalent to the solvated forms and are intended to be included within the scope of this invention.

Certain compounds of the invention have one or more chiral centers, and each center may exist in different configurations. Therefore, these compounds form stereoisomers. Although these compounds are illustrated herein by a limited number of molecular formulas, the present invention encompasses the use of both individual isolated isomers as well as mixtures thereof including racemates thereof. Where stereospecific synthesis methods are used, or optically active compounds are used as starting compounds in the preparation of these compounds. individual isomers are prepared directly; on the other hand, if an isomer mixture is prepared. the individual isomers may be obtained by conventional resolution techniques or may be used as such. without cleavage.

Furthermore, the azolidene component of compounds 1 to X may exist in the form of tautomeric isomers. All of these tautomeric forms represented by Formulas 1 to X are considered to be part of this invention.

Pharmaceutically acceptable carriers for the preparation of pharmaceutical compositions of the compounds of the invention may be solid or liquid. Solid forms of such formulations include powders, tablets, pills, capsules, cachets. suppositories and dispersible granules. The solid carrier may be one or more substances which may also act as diluents. odor and flavorings, binders, preservatives, disintegrants or encapsulating agents.

In powders, the carrier is a finely divided solid, admixed with the finely divided active ingredient.

In tablets, the active ingredient is admixed in suitable proportions with a carrier having the necessary binding properties and compressed to the desired shape and size.

These powders and tablets preferably contain from five to ten to about seventeen percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose. sodium carboxymethylcellulose, low melting wax. cocoa butter and the like. The term formulation is intended to include a processed active ingredient with an encapsulating agent, such as a carrier in the form of a capsule, in which the active ingredient, with or without other carriers, is surrounded by the carrier and is thus associated therewith. The same is true for wafers and lozenges. Tablets, powders, capsules and lozenges can be used as solid dosage forms suitable for oral use.

To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein by mixing. The molten homogeneous mixture is then poured into suitably shaped molds and allowed to cool to solidify.

Liquid form preparations include solutions, suspensions and emulsions, for example, aqueous solutions or solutions containing water and propylene glycol. For parenteral injection, the liquid preparations may be formulated in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, flavors, stabilizers and thickeners as desired.

Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water with a viscous material, such as natural or synthetic gums. resins, methylcellulose. sodium carboxymethylcellulose and other well known suspending agents.

Also included in the oral formulation are solid formulations intended shortly before use to convert from solid forms to liquid formulations. These preparations include solutions, suspensions and emulsions. These preparations may contain, in addition to the active ingredient, coloring agents, flavorings, odorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solvents and the like.

The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be in packaged form containing unitary amounts of the preparation, such as tablets, capsules in a container, and powders in vials or ampoules. The unit dosage form can be a capsule, tablet, cachet, or lozenge itself. or it may be an appropriate number of any of the in packaged form.

The amount of active ingredient in the dosage unit formulation may be varied or adjusted to 0.1 mg to 600 mg, preferably from 0.5 mg to 400 mg, depending on the particular application and potency of the active ingredient. The composition may also, if desired, contain other compatible therapeutic agents.

these benefits however is possible change in patient. seriousness of the condition. which has a flat compound. determination right benefit for opportunities experienced workers in the field.

Depending on the needs being treated and the particular condition used is in the art. Generally, treatment is initiated at less than optimal doses of the compound. Thereafter, the dosage is increased by small increments until an optimum effect is achieved under these circumstances. For convenience, and if desired, the total daily dosage may be divided and administered in portions throughout the day.

The compounds of the invention are disclosed in U.S. Pat. No. 5,132,317, issued Jul. 12, 1992; 5, 061, 717, issued 29 of the invention, and methods for their preparation are known, and U.S. Patent 5,223,522, issued June 29, 1993;

1992 No. 5,120,754, issued June 9, 1991; 4, 897, 405, issued

January 30, 1990; 4,673,255, issued October 10, 1989;

4, 687. 777, issued Aug. 18, 1987; 4,572, 912, issued May 25, 1992;

February 1988; and 4,287,200. issued September 1, 1981. These patents are incorporated herein by reference.

The examples below are intended to illustrate particular embodiments of the invention and do not limit the description or claims in any way.

I

DETAILED DESCRIPTION OF THE INVENTION

Example

Clinical study - study 5-C4 C4-CC3,4-dihydro-6-hydroxy-2, 5.7. 8-tetramethyl-2H-1-benzopyran-2-yl) inethoxy-3-phenyl] methyl] -2. 4-thiazolidinediamine with N1DDI1 patients requiring insulin

Study protocol

All patients participating in the study and meeting the selection criteria below received 400 mg of 5-Ľ 4 -L <3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl (methoxy) phenyl.] methyl] -2,4-tolzolidinedione daily C (as two 200 mg tablets), while initially maintaining their usual insulin therapy. Fasting glucose (FSG), hemoglobin A _1c CHbA _{X c} >, C-peptide and total insulin in serum were performed every two weeks. Patients used home answering machines to monitor blood glucose levels among clinic visitors and to decide on insulin dose adjustments when they visited the clinic.

Based on information from your home answering machine, insulin doses were adjusted according to data from the previous two weeks. At the first visit when controlled glucose levels were reached, the insulin dose was reduced by one-half of the original dose. On further visits to the clinic, if maintenance of glucose levels was still evident. the dose administered was halved. This decrease was performed until the exogenous insulin was stopped.

Selection of patients

Patients had to meet these criteria; 1) have a diagnosis of NIDDM according to National Diabetes Data Group criteria; 2) have a proven failure of sulfonylureas to control blood sugar levels; 3) have proven poor control based on glycosylated hemoglobin values above the normal range (i.e., an HbAic value greater than the upper limit of normal values); 4) have a C-peptide value greater than 1.5 ng / ml; 5) be over 18 years of age; and G) undergo concurrent insulin therapy for 6 months or less.

The study included 17 patients at a two-week interval at one center. In all patients, there was a 2-week baseline period during which their insulin doses were kept constant and glucose levels were monitored at home 2-3 times / day. This frequency of home glucose monitoring was maintained throughout the study and values were recorded in the home recorder. These values were evaluated during the study at 2-week intervals. The evaluators were instructed to reduce the insulin dose in those patients who appeared to improve glucose control at visits on glucose control or stabilized by monitoring glucose levels or at any time during the study if a reduction was necessary for safety reasons. Similarly, the evaluator could increase the insulin dose if glucose control appeared to be impaired. The data presented represent results after 8 weeks of the total of 12 weeks of the planned study, the last 4 weeks still ongoing.

Patient characteristics average age (range) average weight average HbAi _e average C-peptide average blood glucose average duration of diabetes (10 males. 7 females) 57 years (35-72)

104 kg (76-126)

11.8% (8.6-15.4)

2. 8 mg / ml (1.5-4.2) 205 mg / dl (101-363) 11 years (2-31) average insulin duration average insulin dose

The results

As mentioned above, this results from a 12-week study. For years (6 months to 15 years) units / day (C20-21), the summary is a preliminary basis of a favorable reduction in blood glucose levels in all patients with a reduction in their insulin dose or withdrawal. The mean dose reduction of insulin is 60 X with a range of 30 X to 100 X. Glucose levels were decreased by 10 X (20 mg / dl) over the range of 0 to 133 mg / dl for the whole group. (See Figure 1).

In a total of 7 patients, insulin was currently discontinued (8 weeks). There was no overall decrease in mean blood glucose levels in these patients as in the group. but their mean level was maintained at 160 mg / dl with a decrease in insulin from 42 units / day to 0. Three of these patients had a fasting blood glucose lower than 140 mg / dl. Four of these 7 patients were without insulin for one month, maintaining their glucose control. All seven patients are simultaneously maintained on 5-β-4-β (3,4-dihydro-6-hydroxy-2,5,5,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl) methyl) -2,4-thiazolidinedione.

In 10 patients who were still on insulin, there was a 45X (39 units) moderate decrease in their daily insulin dose, and their insulin requirements seem to continue to decrease. At the same time, their blood glucose control improved with an average reduction in blood glucose of 15% (36 mg / dl).

This group of subjects significantly reduced their total exogenous insulin requirements with improved glycemic control. Prior to this study, patients were treated in tertiary care to educate patients and actively manage glucose management. However, even with this method of treatment, glucose control was shown to be low based on a mean Hbi _{c of} 11.8. This value underlines the fact that patients treated with Insulin do not have proper glucose control despite this treatment.

All patients had reduced their insulin doses and 7 patients were able to stop their insulin completely. In this last group of 3/7 patients, fasting glucose was normal for diabetic controls. Because there is a potential risk of increased atherosclerosis when injecting large doses of exogenous Insulin. the possibility of reducing insulin use and improving glycemic control is important.

Claims (13)

Use of a compound of formula I (I) wherein R and _R are the same or different and each represents a hydrogen atom or a _C-C alkylskuplnu; R ₃ is H, C-C _and an aliphatic acyl group, an alicyclic acylskuplnu, aromatic acyl group, a heterocyclic acylskuplnu, araliphatic acyl group, (C1-C alkoxy and) karbonylskuplnu, or aralkoxycarbonyl; R ₄ and R _s are the same or different and each is a hydrogen atom, a C-C or C alkylskuplnu -C ₃ alkoxy, or R and _R together are C _x -C ₄ alkyléridioxyskuplnu; n is 1, 2 or 3; U is _a -CH -, CO, or CH-OR _A wherein R _a represents any of the atoms or groups defined for _R3 and may be the same or different with respect to R _3, and Y and Z have the same or different meanings and each represents an oxygen atom or an atom of 1 (NH); and pharmaceutically acceptable salts thereof for the manufacture of a medicament for reducing the amount of exogenous Insulin administered to a patient having a noninsulin dependent drug dlabetes mellltus. The use according to claim 1, wherein the compound of formula I is used in admixture with a pharmaceutically acceptable additive, diluent or carrier. Third Use according to Claim 2 where in compound with general formula Y and Z each represent an oxygen atom. 4th Use according to of claim 2. where in compound with general formula I U represents methylene. 5th Use according to Claim 2 where in compound with general formula I n represents number 1. 6th Use according to Claim 2 where in compound with general IR _x . R _fi . R <, and _R are each lower alkyl, e R 5 represents a hydrogen atom. Use according to claim 2, wherein in the compound of formula I, Z and Y are each oxygen, n is 1 and W is methylene. The use of claim 2, wherein the compound is 5-L14-LC3. 4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy3phenyl] methyl3-2. 4-thiazolidinedione. Use of a compound of formula II wherein R 11 represents substituted or unsubstituted alkyl, alkoxy, cycloalkyl. phenylalkyl. phenyl. an aromatic acyl group, a 5 or 6-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or a group of formula ^I 13 '14 N— where R _is a R ₄ are the same or different and each is lower alkyl, or R _X and R ₁₄ are joined together either directly or through an interrupted form hetertfatóm selected from nitrogen, oxygen, and sulfur to form a 5- or 6-membered ring; R 1a represents a bond or a lower alkylene group; and Li and La have the same or different meanings and each represents hydrogen or lower alkyl, or L _x and L _and are linked to form an alkylene group. or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reducing the amount of exogenous insulin administered to a patient having a noninsulin-dependent dlabetes mellltus. 10th Use according to Claim 9 wherein the compound is general formula I is used in the mixture with pharmaceutical acceptable additive , diluent or and the carrier. 11th Use according to Claim 10 wherein the compound s 'general formula II is ploglltazone. 12th Use according to Claim 10 wherein the compound s general formula II is clglitazone. (III) Use of a compound of formula 111 wherein R 18 and R 16 independently represent hydrogen, lower alkyl of 1 to 6 carbon atoms. alkoxy of 1 to 6 carbon atoms, halogen. ethinyl. nitrile, methylthio. trifluoromethyl, vinyl. nitro or halogen substituted benzyloxy group; n is 0 to 4; and a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reducing the amount of exogenous insulin administered to a patient having non-insulin dependent diabetes mellitus. Use of a compound of formula IV wherein (IV) the dotted line represents an optional bond; V is -CH = CH-. N-CH. -CH = N- or S; D is CH _and . CHOH. WHAT. C = NOR ₁₇ or CH = CH _: X is SO NR _i . -CH = N or -N = CH; Y is CH or N; Z is hydrogen, (C _x -C _y) alkyl. CC ₃ -C ₇ ) cycloalkyl, phenyl. naphthyl, pyridyl, furyl, thienyl or phenyl mono- or disubstituted with the same or different groups selected from the group consisting of (C 1 -C ₃ ) alkyl, trifluoromethyl, ₍ C ₁ -C ₃ ) alkoxy. fluorine, chlorine and bromine; Z is hydrogen or _{x <X} C _C3) alkyl; R _@ a and R 7 independently are hydrogen or methyl; and n is 1, 2 or 3; a pharmaceutically acceptable cationic salt thereof, and a pharmaceutically acceptable acid addition salt thereof, when the compound contains a basic nitrogen, for the manufacture of a medicament for reducing the amount of exogenous insulin administered to a patient having a noninsulin-induced dlabetes mellitus. 15th Use of a compound of formula V wherein the dotted line represents an optional bond; A and B are each independently CH or N, provided that when A or B is N, the other is CH; X _x is S, SO, SO _and . CH _a . CHOH or CO 2 is 0 or 1; Y x is C.HR _{2 O} or R _2X , provided that when n is 1 a Yx is NR ₂₁ . thus Χχ represents SO ₂ or CG; Z ₂ is CHR ₂₂ . CH ₂ CH ₂ , CH = CH. CH-CH, OCH ₂ . SCH ₂ . SOCH _and / / ABOUT SG ₂ CH ₂ ; R x ₉ . R ₂₀ , R ₂₁ and R ₂₂ each independently represent hydrogen or methyl and X ₂ and X ₃ each independently represent hydrogen. methyl, trifluoromethyl, phenyl. benzyl. hydroxy. methoxy, phenoxy, benzyloxy. bromine, chlorine or fluorine; a pharmaceutically acceptable cationic salt thereof; or a pharmaceutically acceptable acid addition salt thereof, when A or B is N, for the manufacture of a medicament for reducing the amount of exogenous insulin administered to a patient having a non-dependent dlabetes mellltus. 1G. Use of a compound of formula VI wherein R ₂₃ is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or mono- or di-substituted phenyl, wherein the substituents are independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 3 atoms carbon, halogen or trifluoromethyl; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for reducing the amount of exogenous insulin administered to a patient having a non-insulin dependent dlabetes mellltus. Use of a compound of formula VII Even-O-CO- C VII) where And _a is alkylskuplnu, substituted or nesubstltuovanú arylskuplnu. or aralkyl group. wherein the alkylene or aryl component may be substituted or unsubstituted; A _s represents a benzene ring optionally containing up to 3 substituents; R ₂₄ . represents a hydrogen atom, an alkyl group. acyl, aralkyl wherein the alkyl or aryl component may be substituted or unsubstituted, or substituted or unsubstituted aryl; or A ₂ and R ₂₄ together are a substituted or nesubstltuovanú C ₂ -s polymethylene group, wherein the optional groups independently a polymethylene group being selected from the group consisting of a alkylskuplnu arylskuplnu, or adjacent groups independently together with the methylene carbon atoms to which they are attached, form a substituted or phenylene nesubstltuovanú group; I _R2S and R2 ₌ and each represents hydrogen, or _R2S and _R2A together represent a bond; is a number ranging from 2 to 6; X ₄ is G or S; and or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof. for the manufacture of a medicament for reducing the amount of exogenous insulin administered to a patient having non-insulin dependent diabetes mellitus. Use of a compound of formula VIII wherein R "7 and R q ₂ are each independently an alkyl group. substituted or unsubstituted aryl, or aralkyl substituted or unsubstituted in the aryl or alkyl component; or R27 Rsb together represents a linker which consists of an optionally substituted methylene group and either another optionally substituted methylene group. or O or S. wherein the optional substituents of said methylene groups are selected from the group consisting of 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 a are each hydrogen, or R ₂₉ and R _a together form a bond; A ₄ represents a benzene ring optionally containing up to 3 substituents; X is O or S; a. ·. ι n is a number ranging from 2 to 6; or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for reducing the amount of exogenous insulin administered to a patient having non-insulin-dependent diabetes mellitus. Use of a compound of formula IX Up to ^X 6 ^{'<CH2> "i} £ 2 N ^CH 9 ¥' ^{J t} 1IB CIX5 sS About where A ₅ represents a substituted or unsubstituted aromatic heterocyclic group; represents a benzene ring having up to 5 substituents in total; Ώ _ώ means O, S or NR ₃₂ . wherein NR ₃₂ is hydrogen, alkyl, acyl. an aralkyl group wherein the aryl component may be substituted or unsubstituted, or substituted or unsubstituted aryl; _And Y is O or S; R ₃₁ represents an alkyl, aralkyl or aryl group; and n is an integer ranging from 2 to 6; or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for reducing the amount of exogenous insulin administered to a patient having non-insulin-dependent diabetes mellitus. 20. Use of a compound of formula X ^ 37 ^ 380 ^S -S About where A 2 - represents substituted or unsubstituted aryl scpery; A represents _a benzene ring having in total up to 5 substituents; X _a is O, S or NR ₃₉ wherein R ₃₉ is H, alkylskuplnu. acyl, aralkyl. wherein the aryl component may be substituted or unsubstituted, or substituted or unsubstituted aryl; Y ₃ is O or S; R ₃₇ is hydrogen; R _3B represents hydrogen or alkyl, aralkyl, or aryl; or R ₃₇ - together with R _3B represents a bond; and n is a number ranging from 2 to 6; or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof. for the manufacture of a medicament for reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellltus. Use of E (±) -5-E C 4 -C 12 -methyl-2- (pyridinylamino) ethoxy] phenyl] methyl] -2,4-thiazolidinedione (Z) -2-butenedioate, englltazone or darglltazone for the manufacture of drugs for reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellltus.