EP0851757A2 - A method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus - Google Patents

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

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Publication number
EP0851757A2
EP0851757A2 EP96926171A EP96926171A EP0851757A2 EP 0851757 A2 EP0851757 A2 EP 0851757A2 EP 96926171 A EP96926171 A EP 96926171A EP 96926171 A EP96926171 A EP 96926171A EP 0851757 A2 EP0851757 A2 EP 0851757A2
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EP
European Patent Office
Prior art keywords
group
patient
noninsulin
diabetes mellitus
compound
Prior art date
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Application number
EP96926171A
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German (de)
English (en)
French (fr)
Inventor
Randall W. Whitcomb
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the present invention provides a method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus .
  • Diabetes is one of the most prevalent chronic disorders worldwide with significant personal and financial costs for patients and their families, as well as for society. Different types of diabetes exist with distinct etiologies and pathogeneses .
  • diabetes mellitus is a disorder of carbohydrate metabolism, characterized by hyperglycemia and glycosuria and resulting from inadequate production or utilization of insulin.
  • Noninsulin-dependent diabetes mellitus or Type II diabetes, is a form of diabetes mellitus that occurs predominantly in adults in whom adequate production of insulin is available for use, yet a defect exists in insulin-mediated utilization and metabolism of glucose in peripheral tissues.
  • Overt NIDDM is characterized by three major metabolic abnormalities: resistance to insulin- mediated glucose disposal; impairment of nutrient- stimulated insulin secretion; and overproduction of glucose by the liver. Failure to treat NIDDM (i.e., control blood glucose levels) can result in mortality due to cardiovascular disease and in other diabetic complications including retinopathy, nephropathy, and peripheral neuropathy.
  • NIDDM blood glucose levels in patients having NIDDM
  • diet and exercise as well as the use of sulfonylurea and biguanide therapeutic compounds.
  • the compounds metformin and acarbose have recently been used ro treat patients having NIDDM.
  • hyperglycemia cannot be adequately controlled by diet and exercise and/or the use of such therapeutic compounds.
  • exogenous insulin must be administered to the patient.
  • the administration of insulin by injection to a patient in addition to being expensive and painful, can result in various conditions or complications that are detrimental to the patient. For example, an insulin reaction (hypoglycemia) can occur because of an error in insulin dosage, a missed meal, unplanned exercise or without apparent cause.
  • the present invention is a method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus.
  • a partial or total reduction of the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus can also be called "insulin rescue" as the patient is rescued from the need to use exogenous insulin to control serum glucose levels.
  • insulin rescue As described below, in ongoing clinical trials 7 out of 17 human patients given a compound of the present method were completely removed or rescued from the need for exogenous insulin, a very exciting and unexpected discovery, as it was thought by those skilled in the art that a patient having NIDDM and requiring insulin suffered from insulin resistance and B-cell failure.
  • B-cells are the cells in the pancreas that make endogenous insulin.
  • R- ⁇ and R 2 are the same or different and each represents a hydrogen atom or a C ⁇ -C ⁇ alkyl group
  • R- j represents a hydrogen atom, a C- ⁇ -Cg aliphatic acyl group, an alicyclic acyl group, an aromatic acyl group, a heterocyclic acyl group, an araliphatic acyl group, a (C- ⁇ -Cg alkoxy) carbonyl group, or an aralkyl- oxycarbonyl group;
  • R and R5 are the same or different and each represents a hydrogen atom, a C- ⁇ -Cg alkyl group or a c l _c 5 a l ° ⁇ y group, or R ⁇ and Rq together represent a C 1 -C 4 alkylenedioxy group; n is 1 , 2 , or 3 ; represents the -CH 2 *** , CO, or CH-ORg group (in which Rg represents any 1 of the ⁇ atoms or groups defined for R 3 and may be the same as or different from R3) ; and
  • 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 reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus, the method comprising administering to a patient having noninsulin-dependent diabetes mellitus a therapeutically effective amount of a compound of Formula II
  • R 1;L 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
  • R1 and R 14 are the same or different and each is lower alkyl or R 13 and R 14 are combined to each other either directly or as interrupted by a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur to form a 5- or 6-membered ring; wherein R 12 means a bond or a lower alkylene group; and wherein L- ⁇ and L 2 are the same or different and each is hydrogen or lower alkyl or L- j _ and L 2 are combined to form an alkylene group, or a pharmaceutically acceptable salt thereof.
  • R,r and R- ⁇ g 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.
  • Y is CH or N
  • Z is hydrogen, (C- ⁇ -Cy) alkyl, (C3-C7)cycloalkyl, phenyl, naphthyl, pyridyl, furyl, thienyl, or phenyl mono- or disubstituted with the same or different groups which are C ⁇ - ⁇ )alkyl, trifluoromethyl,
  • Z- ⁇ is hydrogen or C ⁇ 'C ⁇ )alkyl
  • R-L 7 and R- ⁇ Q are each independently hydrogen or methyl; and n is 1, 2, or 3; the pharmaceutically acceptable cationic salts thereof; and the pharmaceutically acceptable acid addition salts thereof when the compound contains a basic nitrogen.
  • the present invention provides a method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus, the method comprising administering to a patient having noninsulin-dependent diabetes mellitus a therapeutically effective amount of a compound of Formula V
  • a and B are each independently CH or N, with the proviso that when A or B is N, the other is CH;
  • X is S , SO , S0 2 , CH 2 , CHOH , or CO ;
  • n is 0 or 1 ;
  • R 1 9 ' R 20' R 2 1 ' an ⁇ ⁇ R 22 are eacn independently hydrogen or methyl; and X 2 and X 3 are each independently hydrogen, methyl, trifluoromethyl, phenyl, benzyl, hydroxy, methoxy, phenoxy, benzyloxy, bromo, chloro, or fluoro; a pharmaceutically acceptable cationic salt thereof; or a pharmaceutically acceptable acid addition salt thereof when A or B is N.
  • the present invention provides a method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus, the method comprising administering to a patient having noninsulin-dependent diabetes mellitus a therapeutically effective amount of a compound of Formula VI
  • R 23 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.
  • the present invention 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 VII
  • a 2 represents an alkyl group, a substituted or unsubstituted aryl group, or an aralkyl group wherein the alkylene or the aryl moiety may be substituted or unsubstituted;
  • a ⁇ represents a benzene ring having in total up to
  • R 24 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group wherein the alkyl, or the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group; or A 2 together with R 24 represents substituted or unsubstituted C 2 _ 3 polymethylene group, optional substituents for the polymethylene group being selected from alkyl or aryl or adjacent substituents together with the methylene carbon atoms to which they are attached form a substituted or unsubstituted phenylene group,* R 5 and R 2 each represent hydrogen, or R 2 ⁇ and R together represent a bond; X 4 represents O or S; and n represents an integer in the range of from 2 to 6.
  • the present invention provides a method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus. the method comprising administering to a patient having noninsulin-dependent diabetes mellitus a therapeutically effective amount of a compound of Formula VIII
  • R 7 and R 28 each independently represent an alkyl group, a substituted or unsubstituted aryl group, or an aralkyl group being substituted or unsubstituted in the aryl or alkyl moiety; or
  • R 27 together with R 28 represents a linking group, the linking group consisting of an optionally substituted methylene group and either a further optionally substituted methylene group or an 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;
  • R 29 and R 30 each represent hydrogen, or R 29 and R 3Q together represent a bond; 4 represents a benzene ring having in total up to 3 optional substituents;
  • X5 represents O or S; and
  • n represents an integer in the range of from 2 to 6.
  • the present invention provides a method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus, the method comprising administering to a patient having noninsulin-dependent diabetes mellitus a therapeutically effective amount of a compound of Formula IX
  • A5 represents a substituted or unsubstituted aromatic heterocyclyl group
  • Ag represents a benzene ring having in total up to 5 substituents
  • X represents O, S, or NR 3 wherein R represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group
  • Y 2 represents O or S;
  • R -L represents an alkyl, aralkyl, or aryl group; and n represents an integer in the range of from 2 to 6.
  • the present invention provides a method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus, the method comprising administering to a patient having noninsulin-dependent diabetes mellitus a therapeutically effective amount of a compound of Formula X
  • a 7 represents a substituted or unsubstituted aryl group
  • Ag represents a benzene ring having in total up to
  • Xg represents O, S, or NR 3g wherein R 3 g represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
  • Y 3 represents O or S
  • R 37 represents hydrogen;
  • R 38 represents hydrogen or an alkyl, aralkyl, or aryl group or R 37 together with R 3 g represents a bond; and
  • n represents an integer in the range of from 2 to 6.
  • Figure 1 shows a chart representing patients' mean blood glucose levels and mean total daily exogenous insulin over time with the administration of a compound of the present method.
  • R- ⁇ R 2 , R 3 , R 4 , R 5 , R , n, Y, and Z are as defined above
  • pharmaceutically acceptable salts thereof include pharmaceutically acceptable salts thereof.
  • R- ⁇ or R 2 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.
  • R 3 or R g 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 .
  • R 3 or Rg represents an alicyclic acyl group, it is preferably a cyclopentanecarbonyl, cyclohexane- carbonyl, or cycloheptanecarbonyl group.
  • R 3 or Rg represents an aromatic acyl group
  • the aromatic moiety thereof may optionally have one or more substituents (for example, nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl, or hydroxy substituents); examples of such aromatic acyl groups included the benzoyl, p-nitrobenzoyl, m-fluorobenzoyl, o-chlorobenzoyl, p-aminobenzoyl, m- (dimethylamino)benzoyl, o-methoxybenzoyl, 3, 4-dichlorobenzoyl, 3, 5-di-t-butyl-4-hydroxybenzoyl, and 1-naphthoyl groups.
  • substituents for example, nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl, or hydroxy substituents
  • examples of such aromatic acyl groups included the benzoyl,
  • R or R represents a heterocyclic acyl group
  • the heterocyclic moiety thereof preferably has one or more, preferably one, oxygen, sulfur, or nitrogen heteroatoms and has from 4 to 7 ring atoms
  • examples of such heterocyclic acyl groups include the 2-furoyl, 3-thenoyl, 3-pyridinecarbonyl (nicotinoyl) , and 4-pyridinecarbonyl groups.
  • R or R represents an araliphatic acyl group
  • the aliphatic moiety thereof may optionally have one or more carbon-carbon double or triple bonds and the aryl moiety thereof may optionally have one or more substituents (for example, nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl, or hydroxy substituents);
  • substituents for example, nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl, or hydroxy substituents
  • examples of such araliphatic acyl groups include the phenylacetyl, p-chlorophenylacetyl, phenylpropionyl, and cinnamoyl groups.
  • R 3 or Rg represents a (C- ⁇ -Cg alkoxy)carbonyl group
  • the alkyl moiety thereof may be any one of those alkyl groups as defined for R j _ and R 2 , but is preferably a methyl or ethyl group, and the alkoxycarbonyl group represented by R 3 or R g is therefore preferably a methoxycarbonyl or ethoxycarbonyl group.
  • R 3 or Rg represents an aralkyloxycarbonyl group
  • the aralkyl moiety thereof may be any one of those included within the araliphatic acyl group represented by R 3 or Rg, but is preferably a benzyloxycarbonyl group.
  • R 4 and R 5 represent alkyl groups
  • the alkyl groups can be the same or different and can be straight or branched chain alkyl groups .
  • the alkyl groups preferably have from 1 to 5 carbon atoms and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and isopentyl groups.
  • R 4 and R 5 represent alkoxy groups
  • the alkoxy groups can be the same or different and can be straight or branched chain groups, preferably having from 1 to 4 carbon atoms. Examples include the methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups.
  • R 4 and R ⁇ can together represent a C- ] _-C 4 alkylenedioxy group, more preferably a methylenedioxy or ethylenedioxy group.
  • Preferred classes of compounds of Formula I are as follows :
  • R 3 represents a hydrogen atom, a C- j ⁇ -C aliphatic acyl group, an aromatic acyl group, or a heterocyclic acyl group.
  • Y represents an oxygen atom
  • R- ⁇ and R 2 are the same or different and each represents a hydrogen atom or a C- ⁇ C ⁇ alkyl group
  • R 3 represents a hydrogen atom, a C -Cg aliphatic acyl group, an aromatic acyl group, or a pyridinecarbonyl group
  • 4 and R ⁇ are the same or different and each represents a hydrogen atom, a C - ⁇ -C ⁇ alkyl group, or a C- j _ or C 2 alkoxy group.
  • R- ] _, R 2 , R 4 , and R 5 are the same or different and each represents a hydrogen atom or a C- ⁇ -C ⁇ alkyl group; n is 1 or 2; and W represents the -CH 2 - or >CO group.
  • R 3 represents a hydrogen atom, a C- ⁇ -C ⁇ aliphatic acyl group, a benzoyl group, or a nicotinyl group.
  • R-L and R 4 are the same or different and each represents a C- ⁇ -C ⁇ alkyl group
  • R 2 and R 5 are the same or different and each represents the hydrogen atom or the methyl group
  • R 3 represents a hydrogen atom or a C ] _-C 4 aliphatic acyl group.
  • W represents the -CH - or >CO group
  • Y and Z both represent oxygen atoms
  • n is 1 or 2
  • R- ⁇ and R 4 are the same or different and each represents a C 1 ⁇ C 4 alkyl group
  • R 2 and R 5 are the same or different and each represents the hydrogen atom or the methyl group
  • R 3 represents a hydrogen atom or a C-L-C 4 aliphatic acyl group.
  • Preferred compounds among the compounds of Formula I are those wherein:
  • R _ is a C ⁇ -C 4 alkyl group, more preferably a methyl or isobutyl group, most preferably a methyl group;
  • R 2 is a hydrogen atom or a C- ⁇ -C 4 alkyl group, preferably a hydrogen atom, or a methyl or isopropyl group, more preferably a hydrogen atom or a methyl group, most preferably a methyl group;
  • R 3 is a hydrogen atom, a C- [ _-C 4 aliphatic acyl group, an aromatic acyl group or a pyridinecarbonyl group, preferably a hydrogen atom, or an acetyl, butyryl, benzoyl, or nicotinyl group, more preferably a hydrogen atom or an acetyl, butyryl or benzoyl group, most preferably a hydrogen atom or an acetyl group;
  • R 4 is a hydrogen atom, a C- ⁇ - ⁇ alkyl group or a C- ⁇ or C alkoxy group, preferably a methyl, isopropyl, t-butyl, or methoxy group, more
  • C-L or C 2 alkoxy group preferably a hydrogen atom, or a methyl or methoxy group, more preferably a hydrogen atom or a methyl group, and most preferably a methyl group;
  • n is 1 or 2, preferably 1;
  • Y is an oxygen atom
  • Z is an oxygen atom or an imino group, most preferably an oxygen atom
  • the substituents may be any from 1 to 3 selected from nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl, or hydroxy, the aromatic acyl group may be benzoyl and naphthoyl .
  • the alkyl group R- ⁇ may be a straight chain or branched alkyl of 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl; the cycloalkyl group R- ⁇ may be a cycloalkyl group of 3 to 7 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl; and the phenylalkyl group R- may be a phenylalkyl group of 7 to 11 carbon atoms such as benzyl and phenethyl.
  • heterocyclic group R ⁇ may be mentioned 5- or 6-membered groups each including 1 or 2 hetero-atoms selected from among nitrogen, oxygen, and sulfur, such as pyridyl, thienyl, furyl, thiazolyl, etc.
  • R 1:L is R 13
  • the lower alkyls R ⁇ and R 14 may each be a lower alkyl of 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, and n-butyl.
  • R 13 and R 14 are combined to each other to form a 5- or 6-membered heterocyclic group as taken together with the adjacent
  • N atom i.e., in the form of
  • this heterocyclic group may further include a heteroatom selected from among nitrogen, oxygen, and sulfur as exemplified by piperidino, morpholino, pyrrolidine and piperazine
  • the lower alkylene group R 12 may contain 1 to 3 carbon atoms and thus may be, for example, methylene, ethylene, or trimethylene.
  • the bond R ⁇ 2 is equivalent to the symbol "-", ".”, or the like which is used in chemical structural formulas, and when R ⁇ 2 represents such a bond, the compound of general Formula II is represented by the following general Formula 11(a)
  • R j _ is a bond
  • the atoms adjacent thereto on both sides are directly combined together.
  • the lower alkyls L- j _ and L 2 there may be mentioned lower alkyl groups of 1 to 3 carbon atoms, such as methyl and ethyl .
  • the alkylene group formed as L- j _ and L 2 are joined together is a group of the formula -(CH 2 ) n ⁇ [where n is an integer of 2 to 6].
  • substituents may be mentioned lower alkyls (e.g., methyl, ethyl, etc.), lower alkoxy groups (e.g., methoxy, ethoxy, etc.), halogens (e.g., chlorine, bromine, etc.), and hydroxyl .
  • lower alkyls e.g., methyl, ethyl, etc.
  • lower alkoxy groups e.g., methoxy, ethoxy, etc.
  • halogens e.g., chlorine, bromine, etc.
  • hydroxyl hydroxyl
  • the preferred compounds of Formula III are those wherein R- ⁇ and R 16 are independently hydrogen, lower alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms, halogen, ethynyl, nitrile, trifluoromethyl, vinyl, or nitro; n is 1 or 2 and the pharmaceutically acceptable salts thereof.
  • Preferred in Formula IV are compounds wherein the dotted line represents no bond, particularly wherein D is CO or CHOH. More preferred are compounds wherein
  • Y is CH.
  • X is O or S and Y is N forming an oxazol-4-yl, oxazol-5-yl, thiazol-4-yl, or thiazol-5-yl group; most particularly a 2- [ (2-thienyl) , (2-furyl), phenyl, or substituted phenyl] -5-methyl-4-oxazolyl group.
  • a preferred group of compounds is that of Formula VI wherein R 23 is (C ⁇ C )alkyl, (C 3 -C 7 )cycloalkyl, phenyl, halophenyl, or (C- ⁇ -Cg)alkylphenyl .
  • R 23 is phenyl, methylphenyl, fluorophenyl, chlorophenyl, or cyclohexyl.
  • aryl includes phenyl and naphthyl, substituted phenyl, optionally substituted with up to 5, preferably up to 3, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonyl alkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
  • halogen refers to fluorine, chlorine, bromine, and iodine; preferably chlorine.
  • alkyl and alkoxy relate to groups having straight or branched carbon chains, containing up to 12 carbon atoms .
  • Suitable alkyl groups are C- j __ ] _ alkyl groups, especially C- j __ alkyl groups, e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, or tert-butyl groups .
  • Suitable substituents for any alkyl group include those indicated above in relation to the term "aryl” .
  • Suitable substituents for any heterocyclyl group include up to 4 substituents selected from the group consisting of alkyl, alkoxy, aryl, and halogen or any 2 substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a benzene ring, and wherein the carbon atoms of the aryl group represented by the said 2 substituents may themselves be substituted or unsubstituted.
  • a most preferred compound of the present invention is:
  • ciglitazone 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] enzyl] -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- chromanyl]methyl] -2,4-thiazolidinedione.
  • BRL 49653 is also known as 5- [ (4- [2-Methyl- 2- (prindinylamino)ethoxy]phenyl)methyl] -2,4- thiazolidinedione- (Z) -2-bu enedioate (1:1) .
  • exogenous insulin means insulin which is administered to a patient from an external source as compared to endogenous insulin, which is insulin that is secreted by the pancreas of the patient.
  • reducing the amount of exogenous insulin administered to a patient having noninsulin- dependent diabetes mellitus means that in a patient requiring the control of blood sugar levels using exogenous insulin, the amount of insulin required to achieve the desired control of blood sugar levels in the absence of a compound of the present invention is more than the amount of insulin required when a compound of the present invention is administered to the patient. It is also intended that the term “reduction” include complete cessation of the administration of exogenous insulin to a patient. It is surprising and unexpected that patients requiring exogenous insulin because their blood glucose levels could not be adequately controlled by diet and exercise and/or any of the commonly used therapeutic substances could be completely removed from insulin and that adequate control of blood glucose could be achieved by the administration of a compound of the present method.
  • the present method provides a way of treating the most severe cases of noninsulin- dependent diabetes mellitus-those requiring exogenous insulin. Moreover, the present method provides for the complete cessation of exogenous insulin administration in those patients where insulin had heretobefore been required.
  • the range of about 150 mg/dL to about 200 mg/dL has been considered as providing adequate control.
  • a person having diabetes mellitus has been defined as a person having a fasting glucose of 140 mg/dL or higher.
  • the patients of the present method typically show a C-peptide level (fasting) that is 1.5 ng/mL or higher.
  • the compounds of Formulas I through X are capable of further forming both pharmaceutically acceptable acid addition and/or base salts . All of these forms are within the scope of the present invention.
  • Pharmaceutically acceptable acid addition salts of the compounds of Formulas I through X include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like and gluconate, galacturonate, n-methyl glucamine (see, for example, Berge S.M., et al. , "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1-19).
  • the acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner or as above.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines .
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are N,N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge S.M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1-19).
  • the base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner or as above.
  • the free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in different configurations. The compounds can, therefore, form stereoisomers . Although these are all represented herein by a limited number of molecular formulas, the present invention includes the use of both the individual, isolated isomers and mixtures, including racemates, thereof.
  • thiazolidene part of the compound of Formulas I through X can exist in the form of tautomeric isomers . All of the tautomers are represented by Formulas I through X, and are intended to be a part of the present invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules .
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • 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.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter, 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.
  • 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 .
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsules, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 600 mg preferably 0.5 mg to 400 mg according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents .
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art.
  • treatment is initiated with smaller dosages which are less than the optimum dose of the compound.
  • the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day, if desired.
  • the insulin dose was adjusted accordingly. At the first visit that glycemic control was achieved, the insulin dose was decreased to half the value at baseline. At subsequent visits to the clinic, if glycemic control was still evident, the current insulin dose was halved. This reduction continued until the patient no longer required exogenous insulin.
  • Patients were to: 1) have NIDDM as defined by the criteria of the National Diabetes Data Group; 2) have evidence of failure of blood sugar control on sulfonylureas; 3) have evidence of poor control as documented by a glycosylated hemoglobin above the normal range (i.e., HbA lc greater than the upper limit of normal); 4) have a C-peptide greater than 1.5 ng/mL; 5) be over 18 years of age; and 6) have concomitant therapy with insulin for 6 months or less.
  • this summary represents 8-week interim data from a 12-week study. Based upon a favorable decrease in blood glucose levels, all

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EP96926171A 1995-08-10 1996-07-29 A method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus Withdrawn EP0851757A2 (en)

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GB2335597A (en) * 1998-03-27 1999-09-29 Glaxo Group Ltd Stereoisomers of Troglitazone in the Treatment of Diabetes
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
EP1087963B1 (en) 1998-06-19 2004-08-25 Chiron Corporation Inhibitors of glycogen synthase kinase 3
FR2838968A1 (fr) * 2002-04-30 2003-10-31 Lipha Association d'insuline et d'un derive de thiazolidinedione et son utilisation pour traiter le diabete

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EP0749751A2 (en) 1995-06-20 1996-12-27 Takeda Chemical Industries, Ltd. Pharmaceutical composition for use in tteatment of diabetes

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JPS6051189A (ja) * 1983-08-30 1985-03-22 Sankyo Co Ltd チアゾリジン誘導体およびその製造法
US4873255A (en) * 1987-02-04 1989-10-10 Sankyo Company Limited Thiazolidinone derivatives, their preparation and their use
US5478852C1 (en) * 1993-09-15 2001-03-13 Sankyo Co Use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of impaired glucose tolerance in order to prevent or delay the onset of noninsulin-dependent diabetes mellitus

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DATABASE DIALOG F-D-C REPORTS 1 January 1900 (1900-01-01), "WARNER-LAMBERT'S ATORVASTATIN COMPARISON TO OTHER STATINS SHOWS HIGHER EFFICACY COMPANY SAYS: ANTI-DIABETIC***TROGLITAZONE*** NDA FILING BY DECEMBER 1996", XP000667296
H.TAKINO ET AL: "Increased Insulin Responsiveness after CS-045 Treatment in Diabetes Associated with Werner's Syndrome", DIABETES RESEARCH AND CLINICAL PRACTICE, vol. 24, no. 3, July 1994 (1994-07-01), pages 162 - 172, XP000667297
TANAKA ET AL: "Usefulness of CS-045 in NIDDM Patients under Treatment with Insulin", TONYOBYOU (DIABETES), vol. 37, no. 2, 1994, pages 139 (6), XP000667295

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CN1192683A (zh) 1998-09-09
NO980556L (no) 1998-02-09
CZ32998A3 (cs) 1998-10-14
HUP9802543A2 (hu) 1999-07-28
WO1997005875A2 (en) 1997-02-20
NZ313874A (en) 2000-09-29
BG102235A (en) 1998-09-30
CA2221241A1 (en) 1997-02-20
AU724989B2 (en) 2000-10-05
IL122191A0 (en) 1998-04-05
KR19990036290A (ko) 1999-05-25
AU6641196A (en) 1997-03-05
EA199800177A1 (ru) 1998-10-29

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